FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Liebman, MN Marincola, FM AF Liebman, Michael N. Marincola, Francesco M. TI Expanding the perspective of translational medicine: the value of observational data SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material ID CORONARY-HEART-DISEASE; HEALTH; WOMEN AB In 2003, the Journal of Translational Medicine was launched to foster the publication of high quality research in both "bench-to-bedside" as well as ex vivo human observation. In spite of the success of several large-scale observational studies, e.g. Framingham Heart Study, the opportunity to expand upon the ex vivo human observation has remained limited within the field of translational medicine. We believe that this presents a significant opportunity that merits consideration in both the planning and analysis of large scale observational studies and can contribute greatly to expanding our approaches in translational medicine C1 [Liebman, Michael N.] Strateg Med Inc, Kennett Sq, PA 19348 USA. [Marincola, Francesco M.] NIH, Bethesda, MD 20892 USA. RP Liebman, MN (reprint author), Strateg Med Inc, 231 Deepdale Dr, Kennett Sq, PA 19348 USA. EM m.liebman@strategicmedicine.com NR 7 TC 5 Z9 5 U1 0 U2 2 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 MAR 27 PY 2012 VL 10 AR 61 DI 10.1186/1479-5876-10-61 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 921RB UT WOS:000302493700001 PM 22452969 ER PT J AU Jamal, SM Strait, J Meirelles, O Ding, J Mehring, LD Sperry, B Saadi, A Singh, T Nayda, J Karikkineth, A Tarasov, K Orru, M Van der Harst, P Verweij, N Dei, M Cucca, F Schlessinger, D Lakatta, E AF Jamal, Sameer M. Strait, James Meirelles, Osorio Ding, Jun Mehring, Lindsay D. Sperry, Brett Saadi, Abdulghani Singh, Tania Nayda, John Karikkineth, Ajoy Tarasov, Kirill Orru, Marco Van der Harst, Pim Verweij, Niek Dei, Mariano Cucca, Francesco Schlessinger, David Lakatta, Edward TI EARLY REPOLARIZATION PATTERN: CLINICAL CORRELATES OF SPECIFIC ELECTROCARDIOGRAPHIC SUBTYPES AND GENOME WIDE ASSOCIATION STUDY OF A SARDINIAN POPULATION SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 61st Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) CY MAR 24-27, 2012 CL Chicago, IL SP Amer Coll Cardiol (ACC) C1 NIA, Baltimore, MD 21224 USA. Georgetown Univ, Washington Hosp Ctr, Washington, DC USA. RI Verweij, Niek/A-4499-2017 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 27 PY 2012 VL 59 IS 13 SU S BP E719 EP E719 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 919LB UT WOS:000302326700720 ER PT J AU Koh, KK Quon, M Choi, H AF Koh, Kwang K. Quon, Michael Choi, Hanul TI SIGNIFICANT DIFFERENTIAL EFFECTS OF OMEGA-3 FATTY ACIDS AND FENOFIBRATE IN PATIENTS WITH HYPERTRIGLYCERIDEMIA SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 61st Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) CY MAR 24-27, 2012 CL Chicago, IL SP Amer Coll Cardiol (ACC) C1 Gachon Univ, Gil Med Ctr, Inchon, South Korea. NIH, Bethesda, MD 20892 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 27 PY 2012 VL 59 IS 13 SU S BP E1694 EP E1694 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 919LB UT WOS:000302326701805 ER PT J AU Strait, JB Jamal, S Saadi, A Sperry, B Mehring, L Singh, T Nayda, J Tanaka, T David, M Canepa, M Moni, M Ferrucci, L Lakatta, E AF Strait, James B. Jamal, Sameer Saadi, Abdulghani Sperry, Brett Mehring, Lindsay Singh, Tania Nayda, John Tanaka, Toshiko David, Melissa Canepa, Marco Moni, Monika Ferrucci, Luigi Lakatta, Edward TI ECHOCARDIOGRAPHIC AND CLINICAL CORRELATES OF SPECIFIC EARLY REPOLARIZATION SUBTYPES ON ELECTROCARDIOGRAM SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 61st Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) CY MAR 24-27, 2012 CL Chicago, IL SP Amer Coll Cardiol (ACC) C1 NIA, Baltimore, MD 21224 USA. Georgetown Washington Hosp Ctr, Washington, DC 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 27 PY 2012 VL 59 IS 13 SU S BP E658 EP E658 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 919LB UT WOS:000302326700660 ER PT J AU Vargas, JD Chen, MY Arai, AE Mullikin, JC Bluemke, DA Biesecker, LG AF Vargas, Jose D. Chen, Marcus Y. Arai, Andrew E. Mullikin, James C. Bluemke, David A. Biesecker, Leslie G. TI RARE CODING GENETIC VARIANTS AND CORONARY ARTERY CALCIUM IN THE CLINSEQTM STUDY SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 61st Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) CY MAR 24-27, 2012 CL Chicago, IL SP Amer Coll Cardiol (ACC) C1 NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 27 PY 2012 VL 59 IS 13 SU S BP E1187 EP E1187 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 919LB UT WOS:000302326701298 ER PT J AU Horkay, F Basser, PJ Hecht, AM Geissler, E AF Horkay, Ferenc Basser, Peter J. Hecht, Anne-Marie Geissler, Erik TI Chondroitin Sulfate in Solution: Effects of Mono- and Divalent Salts SO MACROMOLECULES LA English DT Article ID HUMAN ARTICULAR-CARTILAGE; ANGLE NEUTRON-SCATTERING; AGE-RELATED-CHANGES; SPINAL-CORD-INJURY; POLYELECTROLYTE SOLUTIONS; POLY(VINYL ALCOHOL); LIGHT-SCATTERING; HYDROGELS; ABC; GLYCOSAMINOGLYCANS AB Chondroitin sulfate (CS) is a linear sulfated polysaccharide found in cartilage and other tissues in the body. Small-angle neutron scattering (SANS) and dynamic light scattering (DLS) measurements are made on semidilute CS solutions to determine ion-induced changes in the local order of the CS chains and in their dynamic properties. In salt-free CS solutions SANS detects the correlation peak due to local ordering between adjacent chains in which the characteristic interchain distance is d approximate to 57 angstrom. In both monovalent and divalent salts (NaCl and CaCl2) aligned linear regions are distinguishable, corresponding to distance scales ranging from the length of the monomer unit (8 angstrom) to about 1000 angstrom. With increasing calcium ion concentration, the scattering intensity increases. Even in the presence of 200 mM CaCl2, however, neither phase separation nor cross-linking occurs. DLS in the CS solutions reveals two characteristic relaxation modes, the fast mode corresponding to the thermal concentration fluctuations. The collective diffusion coefficient D decreases with increasing calcium ion concentration and exhibits a power law function of the single variable c/J, where c is the CS concentration and J is the ionic strength of the salt in the solution. This result implies that the effect of the sodium and calcium ions on the dynamic properties of CS solutions is fully accounted for by the ionic strength. C1 [Horkay, Ferenc; Basser, Peter J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Hecht, Anne-Marie; Geissler, Erik] Univ Grenoble 1, CNRS, UMR 5588, Lab Interdisciplinaire Phys, F-38402 St Martin Dheres, France. RP Horkay, F (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Tissue Biophys & Biomimet, Program Pediat Imaging & Tissue Sci, NIH, 13 South Dr, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov RI Basser, Peter/H-5477-2011 FU NICHD, NIH FX This research was supported by the Intramural Research Program of the NICHD, NIH. We acknowledge the support of the National Institute of Standards and Technology, U.S. Department of Commerce, in providing the neutron research facilities used in this work. This work utilized facilities supported in part by the National Science Foundation under Agreement DMR-0944772. We gratefully acknowledge the help and consultation of Dr. Boualem Hammouda (NIST) with the SANS experiment. NR 50 TC 11 Z9 11 U1 2 U2 27 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0024-9297 J9 MACROMOLECULES JI Macromolecules PD MAR 27 PY 2012 VL 45 IS 6 BP 2882 EP 2890 DI 10.1021/ma202693s PG 9 WC Polymer Science SC Polymer Science GA 914JT UT WOS:000301946600029 PM 23814316 ER PT J AU Levy, Y Thiebaut, R Gougeon, ML Molina, JM Weiss, L Girard, PM Venet, A Morlat, P Poirier, B Lascaux, AS Boucherie, C Sereni, D Rouzioux, C Viard, JP Lane, C Delfraissy, JF Sereti, I Chene, G AF Levy, Yves Thiebaut, Rodolphe Gougeon, Marie-Lise Molina, Jean-Michel Weiss, Laurence Girard, Pierre-Marie Venet, Alain Morlat, Philippe Poirier, Beatrice Lascaux, Anne-Sophie Boucherie, Celine Sereni, Daniel Rouzioux, Christine Viard, Jean-Paul Lane, Cliff Delfraissy, Jean-Francois Sereti, Irini Chene, Genevieve CA ILIADE Study Grp TI Effect of intermittent interleukin-2 therapy on CD4(+) T-cell counts following antiretroviral cessation in patients with HIV SO AIDS LA English DT Article DE antiretroviral therapy interruption; HIV; interleukin-2 ID RANDOMIZED CONTROLLED-TRIAL; IN-VIVO EXPANSION; INFECTED PATIENTS; TREATMENT INTERRUPTION; GENERAL-POPULATION; IL-2 THERAPY; SUPPRESSION; CELLS/MM(3); ACTIVATION; INDUCTION AB Background: Interleukin (IL)-2 therapy impacts T-cell homeostasis. Whether IL-2 expanded CD4(+) T cells may persist following viral rebound has not been fully investigated. Methods: Patients with CD4(+) T cells 500/mu l or more and HIV RNA less than 50 copies/ml were randomized to continue antiretroviral therapy (ART) either alone (n = 67) or combined with three IL-2 cycles (n = 81; 6 million units) twice daily for 5 days at weeks 0, 8, and 16 before stopping ART (week 24). Patients were followed up to 168 weeks. Results: At week 24, median CD4(+) T-cell counts were 1198 and 703 cells/mu l in the IL-2 and control groups, respectively (P<0.001). At week 72, 27% (IL-2 group) and 45% (control group; P = 0.03) of patients were in failure (defined as no interruption of ART at week 24, CD4 drop below 350 cells/ml or ART resumption). After week 24, a biphasic decline (before and after week 32) of CD4 was noted =106 and =7 cells/mu l per month in controls and = 234 and =17 in IL-2 group (all P < 0.0001). At week 96, IL-2-expanded CD4(+)CD25(+) T cells remained higher than in the control group (26 vs. 16%, P = 0.006). Conclusion: In IL-2-treated patients, CD4(+)CD25(+) T cells persisting despite viral replication allow a longer period of ART interruption. (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Levy, Yves; Lascaux, Anne-Sophie] Hop Henri Mondor, AP HP, Serv Immunol Clin, Grp Henri Mondor Albert Chenevier, F-94010 Creteil, France. [Levy, Yves] INSERM, Unite U955, F-75654 Paris 13, France. [Levy, Yves] Univ Paris Est, Fac Med, UMR S 955, Paris, France. [Thiebaut, Rodolphe; Morlat, Philippe; Boucherie, Celine; Chene, Genevieve] INSERM, U897, F-75654 Paris 13, France. [Thiebaut, Rodolphe; Chene, Genevieve] Univ Bordeaux Segalen, ISPED, Bordeaux, France. [Thiebaut, Rodolphe; Morlat, Philippe; Chene, Genevieve] CHU Bordeaux, Bordeaux, France. [Gougeon, Marie-Lise; Poirier, Beatrice] Inst Pasteur, Antiviral Immun Biotherapy & Vaccine Unit, Paris, France. [Molina, Jean-Michel; Sereni, Daniel] St Louis Hosp, AP HP, St Louis, France. [Weiss, Laurence] Hop Europeen Georges Pompidou, AP HP, Paris, France. [Girard, Pierre-Marie] St Antoine Hosp, AP HP, Paris, France. [Venet, Alain] INSERM, U1012, Le Kremlin Bicetre, France. [Rouzioux, Christine] Univ Paris 05, Hop Necker, AP HP, Paris, France. [Viard, Jean-Paul] Hop Hotel Dieu, AP HP, Paris, France. [Lane, Cliff; Sereti, Irini] NIH, Bethesda, MD USA. [Delfraissy, Jean-Francois] Hop Kremlin Bicetre, AP HP, Le Kremlin Bicetre, France. RP Levy, Y (reprint author), Hop Henri Mondor, AP HP, Serv Immunol Clin, Grp Henri Mondor Albert Chenevier, 51 Ave Marechal de Lattre de Tassigny, F-94010 Creteil, France. EM yves.levy@hmn.aphp.fr RI chene, genevieve/H-8665-2014 FU French National Agency for Research on AIDS and Viral Hepatitis (ANRS) [118]; NIAID/NIH [NIH 04-I-0018 trial] FX This study was supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS, Trial No. 118) and the Intramural Research Program of NIAID/NIH (NIH 04-I-0018 trial). NR 31 TC 10 Z9 11 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 27 PY 2012 VL 26 IS 6 BP 711 EP 720 DI 10.1097/QAD.0b013e3283519214 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 914UA UT WOS:000301976900007 PM 22301410 ER PT J AU DeRose, EF Perera, L Murray, MS Kunkel, TA London, RE AF DeRose, Eugene F. Perera, Lalith Murray, Michael S. Kunkel, Thomas A. London, Robert E. TI Solution Structure of the Dickerson DNA Dodecamer Containing a Single Ribonucleotide SO BIOCHEMISTRY LA English DT Article ID EXCHANGEABLE PROTON RESONANCES; CRYSTAL-STRUCTURE; B-DNA; DIPOLAR COUPLINGS; OKAZAKI FRAGMENT; TOPOISOMERASE-I; NMR STRUCTURE; A-DNA; RNA; DUPLEX AB Ribonucleotides are frequently incorporated into DNA during replication. They are recognized and processed by several cellular enzymes, and their continued presence in the yeast nuclear genome results in replicative stress and genome instability. Thus, it is important to understand the effects of isolated ribonucleotide incorporation on DNA structure. With this goal in mind, we describe the nuclear magnetic resonance structure of the self-complementary Dickerson dodecamer sequence [d(CGC)rGd(AATTCGCG)](2) containing two symmetrically positioned riboguanosines. The absence of an observable H-1-H-2 scalar coupling interaction indicates a C3'-endo conformation for the ribose. Longer-range structural perturbations resulting from the presence of the ribonucleotide are limited to the adjacent and transhelical nucleotides, while the global B-form DNA structure is maintained. Because crystallographic studies have indicated that isolated ribonucleotides promote global B -> A transitions, we also performed molecular modeling analyses to evaluate the structural consequences of higher ribonucleotide substitution levels. Increasing the ribonucleotide content increased the minor groove width toward values more similar to that of A-DNA, but even 50% ribonucleotide substitution did not fully convert the B-DNA to A-DNA. Comparing our structure with the structure of an RNase H2-bound DNA supports the conclusion that, as with other DNA protein complexes, the DNA conformation is strongly influenced by the interaction with the protein. C1 [DeRose, Eugene F.; Perera, Lalith; Murray, Michael S.; Kunkel, Thomas A.; London, Robert E.] NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Murray, Michael S.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, MR Lab Struct Biol 01, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov RI perera, Lalith/B-6879-2012 OI perera, Lalith/0000-0003-0823-1631 FU National Institute of Environmental Health Sciences (NIEHS) [Z01-ES050111, Z01 ES065070, HHSN273200700046U] FX This research was supported by Grant Z01-ES050111 to R.E.L. and Grant Z01 ES065070 to T.A.K., both in the Intramural Research Program of the National Institute of Environmental Health Sciences (NIEHS). E.F.D. is supported by the NIEHS under Delivery Order HHSN273200700046U. NR 53 TC 25 Z9 25 U1 1 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 27 PY 2012 VL 51 IS 12 BP 2407 EP 2416 DI 10.1021/bi201710q PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 914JQ UT WOS:000301946300005 PM 22390730 ER PT J AU Tsurupa, G Pechik, I Litvinov, RI Hantgan, RR Tjandra, N Weisel, JW Medved, L AF Tsurupa, Galina Pechik, Igor Litvinov, Rustem I. Hantgan, Roy R. Tjandra, Nico Weisel, John W. Medved, Leonid TI On the Mechanism of alpha C Polymer Formation in Fibrin SO BIOCHEMISTRY LA English DT Article ID AMINO-ACID-SEQUENCE; FIBRONECTIN-BINDING; BOVINE FIBRINOGEN; STRUCTURAL ORGANIZATION; ELECTRON-MICROSCOPY; DOMAIN FRAGMENT; CROSS-LINKING; FACTOR-XIIIA; SITES; CHAIN AB Our previous studies revealed that the fibrinogen alpha C-domains undergo conformational changes and adopt a physiologically active conformation upon their self-association into alpha C polymers in fibrin. In the present study, we analyzed the mechanism of alpha C polymer formation and tested our hypothesis that self-association of the alpha C-domains occurs through the interaction between their N-terminal subdomains and may include beta-hairpin swapping. Our binding experiments performed by size-exclusion chromatography and optical trap-based force spectroscopy revealed that the alpha C-domains self-associate exclusively through their N-terminal subdomains, while their C-terminal subdomains were found to interact with the alpha C-connectors that tether the alpha C-domains to the bulk of the molecule. This interaction should reinforce the structure of alpha C polymers and provide the proper orientation of their reactive residues for efficient cross-linking by factor XIIIa. Molecular modeling of self-association of the N-terminal subdomains confirmed that the hypothesized beta-hairpin swapping does not impose any steric hindrance. To "freeze" the conformation of the N-terminal subdomain and prevent the hypothesized beta-hairpin swapping, we introduced by site-directed mutagenesis an extra disulfide bond between two beta-hairpins of the bovine A alpha 406-483 fragment corresponding to this subdomain. The experiments performed by circular dichroism revealed that A alpha 406-483 mutant containing Lys429Cys/Thr463Cys mutations preserved its beta-sheet structure. However, in contrast to wild-type A alpha 406-483, this mutant had lower tendency for oligomerization, and its structure was not stabilized upon oligomerization, in agreement with the above hypothesis. On the basis of the results obtained and our previous findings, we propose a model of fibrin alpha C polymer structure and molecular mechanism of assembly. C1 [Tsurupa, Galina; Medved, Leonid] Univ Maryland, Ctr Vasc & Inflammatory Dis, Sch Med, Baltimore, MD 21201 USA. [Tsurupa, Galina; Medved, Leonid] Univ Maryland, Dept Biochem, Sch Med, Baltimore, MD 21201 USA. [Pechik, Igor] Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. [Litvinov, Rustem I.; Weisel, John W.] Univ Penn, Dept Cell & Dev Biol, Perelman Sch Med, Philadelphia, PA 19104 USA. [Hantgan, Roy R.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27157 USA. [Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Medved, L (reprint author), Univ Maryland, Ctr Vasc & Inflammatory Dis, Sch Med, Baltimore, MD 21201 USA. EM lmedved@som.umaryland.edu RI Litvinov, Rustem/E-5291-2011 OI Litvinov, Rustem/0000-0003-0643-1496 FU National Institutes of Health [HL056051, HL030954, HL090774]; National Heart Lung, and Blood Institute FX This work was supported by National Institutes of Health Grants HL056051 to L.M., HL030954 and HL090774 to J.W.W., and by the Intramural Research Program of the National Heart Lung, and Blood Institute to N.T. NR 54 TC 15 Z9 15 U1 0 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 27 PY 2012 VL 51 IS 12 BP 2526 EP 2538 DI 10.1021/bi2017848 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 914JQ UT WOS:000301946300017 PM 22397628 ER PT J AU Trabert, B Graubard, BI Erickson, RL McGlynn, KA AF Trabert, B. Graubard, B. I. Erickson, R. L. McGlynn, K. A. TI Childhood infections, orchitis and testicular germ cell tumours: a report from the STEED study and a meta-analysis of existing data SO BRITISH JOURNAL OF CANCER LA English DT Article DE testicular germ cell tumours; childhood infections; mumps; orchitis; case-control ID RISK-FACTORS; YOUNG MEN; CANCER; TESTIS; EPIDEMIOLOGY; ETIOLOGY AB BACKGROUND: Similarities between the age-specific incidence pattern of testicular germ cell tumours (TGCTs) and the age-specific incidence pattern of cancers of viral origin prompted us to evaluate the relationship between common infections occurring during childhood or young adult life and TGCT using existing data from the US Servicemen's Testicular Tumor Environmental and Endocrine Determinants (STEED) case-control study. METHODS: TGCT cases diagnosed between 2002 and 2005 (n = 767) were matched on age, race and serum draw date to at least one control (n = 929). RESULTS: None of the infections evaluated were associated with TGCT risk. Further, a meta-analysis of mumps and mumps orchitis or orchitis infection did not support an association with TGCT (mumps pooled odds ratio (OR): 1.03, 95% confidence interval (CI): 0.89-1.20; mumps orchitis or orchitis pooled OR: 1.80, 95% CI: 0.74-4.42). CONCLUSION: Based on our evaluation of childhood and early life infections and meta-analyses of mumps and mumps orchitis and/or orchitis, TGCT does not appear to be associated with common childhood infections. C1 [Trabert, B.; McGlynn, K. A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. [Graubard, B. I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. [Erickson, R. L.] Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. RP Trabert, B (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,Suite 550, Rockville, MD 20852 USA. EM trabertbl@mail.nih.gov RI Trabert, Britton/F-8051-2015 FU National Cancer Institute FX This work was supported by the Intramural Research Program of the National Cancer Institute. NR 21 TC 2 Z9 2 U1 0 U2 3 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 MAR 27 PY 2012 VL 106 IS 7 BP 1331 EP 1334 DI 10.1038/bjc.2012.45 PG 4 WC Oncology SC Oncology GA 916VG UT WOS:000302130700012 PM 22343618 ER PT J AU Fu, YP Kohaar, I Rothman, N Earl, J Figueroa, JD Ye, Y Malats, N Tang, W Liu, L Garcia-Closas, M Muchmore, B Chatterjee, N Tarway, M Kogevinas, M Porter-Gill, P Baris, D Mumy, A Albanes, D Purdue, MP Hutchinson, A Carrato, A Tardon, A Serra, C Garcia-Closas, R Lloreta, J Johnson, A Schwenn, M Karagas, MR Schned, A Diver, WR Gapstur, SM Thun, MJ Virtamo, J Chanock, SJ Fraumeni, JF Silverman, DT Wu, XF Real, FX Prokunina-Olsson, L AF Fu, Yi-Ping Kohaar, Indu Rothman, Nathaniel Earl, Julie Figueroa, Jonine D. Ye, Yuanqing Malats, Nuria Tang, Wei Liu, Luyang Garcia-Closas, Montserrat Muchmore, Brian Chatterjee, Nilanjan Tarway, McAnthony Kogevinas, Manolis Porter-Gill, Patricia Baris, Dalsu Mumy, Adam Albanes, Demetrius Purdue, Mark P. Hutchinson, Amy Carrato, Alfredo Tardon, Adonina Serra, Consol Garcia-Closas, Reina Lloreta, Josep Johnson, Alison Schwenn, Molly Karagas, Margaret R. Schned, Alan Diver, W. Ryan Gapstur, Susan M. Thun, Michael J. Virtamo, Jarmo Chanock, Stephen J. Fraumeni, Joseph F., Jr. Silverman, Debra T. Wu, Xifeng Real, Francisco X. Prokunina-Olsson, Ludmila TI Common genetic variants in the PSCA gene influence gene expression and bladder cancer risk SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID STEM-CELL ANTIGEN; GENOME-WIDE ASSOCIATION; CONFERS SUSCEPTIBILITY; PROSTATE-CANCER; IDENTIFICATION; ENHANCERS; SMOKING AB Genome-wide association studies have identified a SNP, rs2294008, on 8q24.3 within the prostate stem cell antigen (PSCA) gene, as a risk factor for bladder cancer. To fine-map this region, we imputed 642 SNPs within 100 Kb of rs2294008 in addition to 33 markers genotyped in one of the reported genome-wide association study in 8,652 subjects. A multivariable logistic regression model adjusted for rs2294008 revealed a unique signal, rs2978974 (r(2) = 0.02, D' = 0.19 with rs2294008). In the combined analysis of 5,393 cases and 7,324 controls, we detected a per-allele odds ratio (OR) = 1.11 [95% confidence interval (CI) = 1.06-1.17, P = 5.8 x 10(-5)] for rs2294008 and OR = 1.07 (95% CI = 1.02-1.13, P= 9.7 x 10(-3)) for rs2978974. The effect was stronger in carriers of both risk variants (OR = 1.24, 95% CI = 1.08-1.41, P = 1.8 x 10(-3)) and there was a significant multiplicative interaction (P = 0.035) between these two SNPs, which requires replication in future studies. The T risk allele of rs2294008 was associated with increased PSCA mRNA expression in two sets of bladder tumor samples (n = 36, P = 0.0007 and n = 34, P = 0.0054) and in normal bladder samples (n = 35, P = 0.0155), but rs2978974 was not associated with PSCA expression. SNP rs2978974 is located 10 Kb upstream of rs2294008, within an alternative untranslated first exon of PSCA. The non-risk allele G of rs2978974 showed strong interaction with nuclear proteins from five cell lines tested, implying a regulatory function. In conclusion, a joint effect of two PSCA SNPs, rs2294008 and rs2978974, suggests that both variants may be important for bladder cancer susceptibility, possibly through different mechanisms that influence the control of mRNA expression and interaction with regulatory factors. C1 [Rothman, Nathaniel; Figueroa, Jonine D.; Garcia-Closas, Montserrat; Chatterjee, Nilanjan; Baris, Dalsu; Albanes, Demetrius; Purdue, Mark P.; Fraumeni, Joseph F., Jr.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Fu, Yi-Ping; Kohaar, Indu; Tang, Wei; Liu, Luyang; Muchmore, Brian; Tarway, McAnthony; Porter-Gill, Patricia; Mumy, Adam; Chanock, Stephen J.; Prokunina-Olsson, Ludmila] NCI, Lab Translat Gen, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Earl, Julie; Real, Francisco X.] Ctr Nacl Invest Oncol, Epithelial Carcinogenesis Grp, Mol Pathol Programme, Madrid 28029, Spain. [Ye, Yuanqing] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Malats, Nuria] Spanish Natl Canc Res Ctr, Genet & Mol Epidemiol Grp, Madrid 28029, Spain. [Garcia-Closas, Montserrat] Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England. [Kogevinas, Manolis] Ctr Res Environm Epidemiol, Barcelona 08003, Spain. [Kogevinas, Manolis; Tardon, Adonina] Municipal Inst Med Res, Barcelona 08003, Spain. [Kogevinas, Manolis] Ctr Invest Biomed Red Epidemiol & Salud Publ, Barcelona 08003, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens 11521, Greece. [Hutchinson, Amy] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21702 USA. [Carrato, Alfredo] Ramon & Cajal Univ Hosp, Madrid 28034, Spain. [Tardon, Adonina] Univ Oviedo, Inst Univ Oncol, Oviedo 33003, Spain. [Serra, Consol; Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt Salut, Barcelona 08003, Spain. [Lloreta, Josep] Univ Pompeu Fabra, Hosp del Mar, Inst Municipa Invest Med, Barcelona 08003, Spain. [Garcia-Closas, Reina] Hosp Univ Canarias, Unidad Invest, San Cristobal la Laguna 38320, Spain. [Johnson, Alison] Vermont Canc Registry, Burlington, VT 05401 USA. [Schwenn, Molly] Maine Canc Registry, Augusta, ME 04333 USA. [Karagas, Margaret R.; Schned, Alan] Dartmouth Med Sch, Hanover, NH 03755 USA. [Diver, W. Ryan; Gapstur, Susan M.; Thun, Michael J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki 00271, Finland. RP Fraumeni, JF (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. EM fraumeni@nih.gov; prokuninal@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Tang, Wei/H-7103-2013; Serra, C/E-6879-2014; Garcia-Closas, Montserrat /F-3871-2015; Malats, Nuria/H-7041-2015; Purdue, Mark/C-9228-2016; Kogevinas, Manolis/C-3918-2017; Lloreta, J/I-2112-2014 OI Tang, Wei/0000-0002-7089-4391; Serra, C/0000-0001-8337-8356; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784; Purdue, Mark/0000-0003-1177-3108; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Lloreta, J/0000-0003-1644-9470 FU Information Management Services; Institut Municipal d'Investigacio Medica; Westat, Inc.; Marques de Valdecilla University Hospital; Hospital Ciudad de Coria; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; US Public Health Service from the National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004] FX We thank the following for their support of this project: Leslie Carroll, Jane Wang, Anne Taylor, and Kirk Snyder (Information Management Services); Gemma Castano-Vinyals, Fernando Fernandez, Maria Sala, and Montserrat Tora (Institut Municipal d'Investigacio Medica); Paul Hurwitz, Charles Lawrence, Anna McIntosh, and Robert Saal (Westat, Inc.); Marta Lopez-Brea and Fernando Rivera (Marques de Valdecilla University Hospital); and Angeles Panadero (Hospital Ciudad de Coria). This project has been funded in part by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. Additionally, this research was supported by US 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. 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. Additional funding information is provided in SI Materials and Methods. NR 40 TC 41 Z9 43 U1 2 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 27 PY 2012 VL 109 IS 13 BP 4974 EP 4979 DI 10.1073/pnas.1202189109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 917HT UT WOS:000302164200055 PM 22416122 ER PT J AU Chianini, F Fernandez-Borges, N Vidal, E Gibbard, L Pintadoe, B de Castro, J Priola, SA Hamilton, S Eaton, SL Finlayson, J Pang, Y Steele, P Reid, HW Dagleish, MP Castilla, J AF Chianini, Francesca Fernandez-Borges, Natalia Vidal, Enric Gibbard, Louise Pintadoe, Belen de Castro, Jorge Priola, Suzette A. Hamilton, Scott Eaton, Samantha L. Finlayson, Jeanie Pang, Yvonne Steele, Philip Reid, Hugh W. Dagleish, Mark P. Castilla, Joaquin TI Rabbits are not resistant to prion infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE in vitro replication; scrapie; transmissible spongiform encephalopathy ID MISFOLDING CYCLIC AMPLIFICATION; IN-VITRO; SPONGIFORM ENCEPHALOPATHY; SPECIES-BARRIER; PROTEIN; SCRAPIE; PROPAGATION; REPLICATION; TRANSMISSION; GENERATION AB The ability of prions to infect some species and not others is determined by the transmission barrier. This unexplained phenomenon has led to the belief that certain species were not susceptible to transmissible spongiform encephalopathies (TSEs) and therefore represented negligible risk to human health if consumed. Using the protein misfolding cyclic amplification (PMCA) technique, we were able to overcome the species barrier in rabbits, which have been classified as TSE resistant for four decades. Rabbit brain homogenate, either unseeded or seeded in vitro with disease-related prions obtained from different species, was subjected to serial rounds of PMCA. De novo rabbit prions produced in vitro from unseeded material were tested for infectivity in rabbits, with one of three intracerebrally challenged animals succumbing to disease at 766 d and displaying all of the characteristics of a TSE, thereby demonstrating that leporids are not resistant to prion infection. Material from the brain of the clinically affected rabbit containing abnormal prion protein resulted in a 100% attack rate after its inoculation in transgenic mice overexpressing rabbit PrP. Transmissibility to rabbits (>470 d) has been confirmed in 2 of 10 rabbits after intracerebral challenge. Despite rabbits no longer being able to be classified as resistant to TSEs, an outbreak of "mad rabbit disease" is unlikely. C1 [Fernandez-Borges, Natalia; Castilla, Joaquin] CIC BioGUNE, Derio 48160, Bizkaia, Spain. [Chianini, Francesca; Gibbard, Louise; Hamilton, Scott; Eaton, Samantha L.; Finlayson, Jeanie; Pang, Yvonne; Steele, Philip; Reid, Hugh W.; Dagleish, Mark P.] Moredun Res Inst, Edinburgh EH26 0PZ, Midlothian, Scotland. [Castilla, Joaquin] Basque Fdn Sci, IKERBASQUE, Bilbao 48011, Bizkaia, Spain. [Priola, Suzette A.] NIAID, Lab Persistent Viral Dis, NIH, Hamilton, MT 59840 USA. [Fernandez-Borges, Natalia; de Castro, Jorge; Castilla, Joaquin] Scripps Florida, Dept Infectol, Jupiter, FL 33458 USA. [Vidal, Enric] Univ Autonoma Barcelona, UAB IRTA, CReSA, E-08193 Barcelona, Spain. [Pintadoe, Belen] CNB, Madrid 28049, Spain. RP Castilla, J (reprint author), CIC BioGUNE, Derio 48160, Bizkaia, Spain. EM castilla@joaquincastilla.com RI Castilla, Joaquin/E-6952-2012; Fernandez-Borges, Natalia/H-1875-2012; Castilla, Joaquin/D-5261-2011; Chianini, Francesca/K-1451-2013; Pintado, Belen/N-3233-2014; OI Castilla, Joaquin/0000-0002-2216-1361; Chianini, Francesca/0000-0001-9962-446X; Pintado, Belen/0000-0002-8485-2520; Vidal, Enric/0000-0002-4965-3286 FU national grants from Spain [AGL2009-11553-C02-01, AGL2008-05296-C02]; Basque government [PI2010-18]; National Institutes of Health (NIH) [1R01NS060790-01A2]; NIH, National Institute of Allergy and Infectious Diseases [1-Z01-AI000752-12]; Scripps and the Moredun Research Institute FX The authors acknowledge the IKERBASQUE Foundation; support for vivarium and maintenance from CIC bioGUNE; Drs. Jean E. Jewel and Tomas Mayoral for the CWD and BSE brain tissue samples; Drs. Silvia Siso (AHVLA Lasswade), Ashwin Woodhoo (CIC bioGUNE), and Mike Fontaine (MRI) for useful discussion and advice; the Roslin Institute for use of equipment; and Moredun Bioservices for care and maintenance of animals. This work was financially supported by national grants from Spain (AGL2009-11553-C02-01 and AGL2008-05296-C02); Basque government Grant PI2010-18; National Institutes of Health (NIH) Grant 1R01NS060790-01A2; Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases 1-Z01-AI000752-12; and Etortek Research Programs 2011/2013, Scripps and the Moredun Research Institute. NR 24 TC 28 Z9 29 U1 4 U2 18 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 MAR 27 PY 2012 VL 109 IS 13 BP 5080 EP 5085 DI 10.1073/pnas.1120076109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 917HT UT WOS:000302164200074 PM 22416127 ER PT J AU Gladwin, MT Sachdev, V AF Gladwin, Mark T. Sachdev, Vandana TI Cardiovascular Abnormalities in Sickle Cell Disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review DE cell; disease; sickle ID PULMONARY ARTERIAL-HYPERTENSION; VENTRICULAR DIASTOLIC DYSFUNCTION; SYSTOLIC HEART-FAILURE; MYOCARDIAL-ISCHEMIA; EXERCISE CAPACITY; FREE HEMOGLOBIN; CARDIAC ABNORMALITIES; OXYGEN DESATURATION; TISSUE DOPPLER; ADULT PATIENTS AB Sickle cell disease is characterized by recurrent episodes of ischemia-reperfusion injury to multiple vital organ systems and a chronic hemolytic anemia, both contributing to progressive organ dysfunction. The introduction of treatments that induce protective fetal hemoglobin and reduce infectious complications has greatly prolonged survival. However, with increased longevity, cardiovascular complications are increasingly evident, with the notable development of a progressive proliferative systemic vasculopathy, pulmonary hypertension (PH), and left ventricular diastolic dysfunction. Pulmonary hypertension is reported in autopsy studies, and numerous clinical studies have shown that increased pulmonary pressures are an important risk marker for mortality in these patients. In epidemiological studies, the development of PH is associated with intravascular hemolysis, cutaneous leg ulceration, renal insufficiency, iron overload, and liver dysfunction. Chronic anemia in sickle cell disease results in cardiac chamber dilation and a compensatory increase in left ventricular mass. This is often accompanied by left ventricular diastolic dysfunction that has also been a strong independent predictor of mortality in patients with sickle cell disease. Both PH and diastolic dysfunction are associated with marked abnormalities in exercise capacity in these patients. Sudden death is an increasingly recognized problem, and further cardiac investigations are necessary to recognize and treat high-risk patients. (J Am Coll Cardiol 2012; 59: 1123-33) (C) 2012 by the American College of Cardiology Foundation C1 [Gladwin, Mark T.] Univ Pittsburgh, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Gladwin, Mark T.] Univ Pittsburgh, Vasc Med Inst, Pittsburgh, PA 15213 USA. [Sachdev, Vandana] NHLBI, Cardiovasc & Pulm, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), Univ Pittsburgh, Montefiore Hosp, 3459 5th Ave,NW 628, Pittsburgh, PA 15213 USA. EM gladwinmt@upmc.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services; NIH [R01HL098032, RO1HL096973, PO1HL103455]; Institute for Transfusion Medicine; Hemophilia Center of Western Pennsylvania FX This work was supported in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services. Dr. Gladwin receives research support from NIH grants R01HL098032, RO1HL096973, and PO1HL103455, the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania. Dr. Sachdev has reported that she has no relationships relevant to the contents of this paper to disclose. NR 104 TC 49 Z9 54 U1 3 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 27 PY 2012 VL 59 IS 13 BP 1123 EP 1133 DI 10.1016/j.jacc.2011.10.900 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 914LB UT WOS:000301950300002 PM 22440212 ER PT J AU McDermott, MM Liu, KA Tian, L Guralnik, JM Criqui, MH Liao, YH Ferrucci, L AF McDermott, Mary M. Liu, Kiang Tian, Lu Guralnik, Jack M. Criqui, Michael H. Liao, Yihua Ferrucci, Luigi TI Calf Muscle Characteristics, Strength Measures, and Mortality in Peripheral Arterial Disease A Longitudinal Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE intermittent claudication; mortality; physical functioning; prognosis ID LOWER-EXTREMITY ISCHEMIA; ANKLE BRACHIAL INDEX; SKELETAL-MUSCLE; FUNCTIONAL PERFORMANCE; PHYSICAL-ACTIVITY; CLAUDICATION; ASSOCIATIONS; IMPAIRMENT; PREVALENCE; SYMPTOMS AB Objectives This study analyzed whether lower calf muscle density and poorer upper and lower extremity strength are associated with higher mortality rates in men and women with peripheral arterial disease (PAD). Background Men and women with lower extremity PAD have lower calf muscle density and reduced lower extremity strength compared with individuals without PAD. Methods At baseline, participants underwent measurement of calf muscle density with computed tomography in addition to knee extension power and isometric knee extension, plantar flexion, and hand grip strength measures. Participants were followed up annually for up to 4 years. Results were adjusted for age, sex, race, body mass index, ankle-brachial index, smoking, physical activity, and comorbidities. Results Among 434 PAD participants, 103 (24%) died during a mean follow-up of 47.6 months. Lower calf muscle density was associated with higher all-cause mortality (lowest density tertile hazard ratio [HR]: 1.80 [95% confidence interval (CI): 1.07 to 3.03], second tertile HR: 0.91 (95% CI: 0.51 to 1.62); highest density tertile HR: 1.00; p trend = 0.020) and higher cardiovascular disease mortality (lowest density tertile HR: 2.39 [95% CI: 0.90 to 6.30], second tertile HR: 0.85 [95% CI: 0.27 to 2.71]; highest density tertile HR: 1.00; p trend = 0.047). Poorer plantar flexion strength (p trend = 0.004), lower baseline leg power (p trend = 0.046), and poorer handgrip (p trend = 0.005) were associated with higher all-cause mortality. Conclusions These data demonstrate that lower calf muscle density and weaker plantar flexion strength, knee extension power, and hand grip were associated with increased mortality in these participants with PAD, independently of the ankle-brachial index and other confounders. (J Am Coll Cardiol 2012; 59: 1159-67) (C) 2012 by the American College of Cardiology Foundation C1 [McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [McDermott, Mary M.; Liu, Kiang; Liao, Yihua] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Tian, Lu] Stanford Univ, Dept Hlth Res & Policy Biostat, Palo Alto, CA 94304 USA. [Guralnik, Jack M.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Baltimore, MD 21201 USA. [Criqui, Michael H.] Univ Calif San Diego, Div Prevent Med, San Diego, CA 92103 USA. [Ferrucci, Luigi] NIA, Intramural Res Program, Bethesda, MD 20892 USA. RP McDermott, MM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med, 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU National Heart, Lung, and Blood Institute [R01-HL58099, R01-HL64739, R01-HL071223, R01-HL076298, R01-HL083064]; National Center for Research Resources, National Institutes of Health [RR-00048]; National Institute on Aging, National Institutes of Health FX This study was supported by grants R01-HL58099, R01-HL64739, R01-HL071223, R01-HL076298, and R01-HL083064 from the National Heart, Lung, and Blood Institute and by grant RR-00048 from the National Center for Research Resources, National Institutes of Health. Supported in part by the Intramural Research Program, National Institute on Aging, National Institutes of Health. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Alan T. Hirsch, MD, served as Guest Editor for this paper. NR 24 TC 33 Z9 33 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 27 PY 2012 VL 59 IS 13 BP 1159 EP 1167 DI 10.1016/j.jacc.2011.12.019 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 914LB UT WOS:000301950300006 PM 22440216 ER PT J AU Belanger, JM Raviv, Y Viard, M Baxa, U Blumenthal, R AF Belanger, Julie M. Raviv, Yossef Viard, Mathias Baxa, Ulrich Blumenthal, Robert TI Orthogonal inactivation of influenza and the creation of detergent resistant viral aggregates: towards a novel vaccine strategy SO VIROLOGY JOURNAL LA English DT Article DE Influenza virus; Detergent; Detergent resistance; Hemagglutinin; Triton; Vaccine; Inactivation; Human immunodeficiency virus; HIV-1; Orthogonal ID STRUCTURAL INTEGRITY; VIRUS INACTIVATION; UVA IRRADIATION; PRESERVATION; PROTEINS; NUCLEOPROTEIN; MEMBRANES AB Background: It has been previously shown that enveloped viruses can be inactivated using aryl azides, such as 1-iodo- 5-azidonaphthalene (INA), plus UVA irradiation with preservation of surface epitopes in the inactivated virus preparations. Prolonged UVA irradiation in the presence of INA results in ROS-species formation, which in turn results in detergent resistant viral protein fractions. Results: Herein, we characterize the applicability of this technique to inactivate influenza. It is shown that influenza virus + INA (100 micromolar) + UVA irradiation for 30 minutes results in a significant (p < 0.05) increase in pelletablehemagglutinin after Triton X-100 treatment followed by ultracentrifugation. Additionally, characterization of the virus suspension by immunogold labeling in cryo-EM, and viral pellet characterization via immunoprecipitation with a neutralizing antibody, shows preservation of neutralization epitopes after this treatment. Conclusion: These orthogonally inactivated viral preparations with detergent resistant fractions are being explored as a novel route for safe, effective inactivated vaccines generated from a variety of enveloped viruses. C1 [Belanger, Julie M.; Blumenthal, Robert] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. [Raviv, Yossef; Viard, Mathias] NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA. [Baxa, Ulrich] NCI, Adv Technol Program, SAIC Frederick, Frederick, MD 21702 USA. [Belanger, Julie M.] Kings Coll, Dept Chem & Phys, Wilkes Barre, PA USA. RP Blumenthal, R (reprint author), NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. EM blumenthalr@mail.nih.govc RI Belanger, Julie/A-5734-2009 OI Belanger, Julie/0000-0002-7236-2778 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; NIAID FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Further funding was provided by a grant from the NIAID Intramural Biodefense Research Program. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 20 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 1743-422X J9 VIROL J JI Virol. J. PD MAR 26 PY 2012 VL 9 AR 72 DI 10.1186/1743-422X-9-72 PG 12 WC Virology SC Virology GA 950OH UT WOS:000304658100001 PM 22449007 ER PT J AU Bahta, M Lountos, GT Beverly, D Ulrich, RG Waugh, DS Burke, TR AF Bahta, Medhanit Lountos, George T. Beverly, Dyas Ulrich, Robert G. Waugh, David S. Burke, Terrence R., Jr. TI Nitrophenylphosphate substrate screening and oxime-based ligation for the development of nanomolar affinity inhibitors of the Yersinia pestis protein tyrosine phosphatase YopH SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Bahta, Medhanit; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Lountos, George T.; Waugh, David S.] NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Beverly, Dyas; Ulrich, Robert G.] USAMRIID, Lab Mol Immunol, Frederick, MD 21702 USA. EM bahtam@mail.nih.gov RI Lountos, George/B-3983-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 34-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503201692 ER PT J AU Barchi, JJ AF Barchi, Joseph J. TI Various nano-guises of the TF antigen for anticancer therapy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Barchi, Joseph J.] NCI, Frederick, MD 21701 USA. EM barchi@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 13-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475101083 ER PT J AU Basant, N Roth, B Habib, M Wang, XS AF Basant, Nikita Roth, Bryan Habib, Muhammad Wang, Xiang Simon TI Shape-based screening by hybrid query assisted with molecular docking to mine diverse and selective histone deacetylase (HD2) inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Basant, Nikita; Habib, Muhammad; Wang, Xiang Simon] Howard Univ, Coll Pharm, Dept Pharmaceut Sci, Washington, DC 20059 USA. [Roth, Bryan] Univ N Carolina, NIMH, Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. [Roth, Bryan] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. EM nikita_basant@yahoo.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 571-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475104730 ER PT J AU Battistel, MD Shangold, M Trinh, L Shiloach, J Freedberg, DI AF Battistel, Marcos D. Shangold, Michael Trinh, Loc Shiloach, Joseph Freedberg, Daron I. TI Hydrogen bonding, the foundations of helicity in a tetramer of alpha 2-8 sialic acid SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Battistel, Marcos D.; Shangold, Michael; Freedberg, Daron I.] US FDA, CBER, OVRR, Rockville, MD 20852 USA. [Trinh, Loc] NIH, SBDPI, Bethesda, MD 20892 USA. [Shiloach, Joseph] NIDDK, NIH, Bethesda, MD 20892 USA. EM battiste@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 131-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475101194 ER PT J AU Bolton, E AF Bolton, Evan TI New strategies to normalize chemical structure representations and weed-out impractical small molecules SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Bolton, Evan] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 54-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475103388 ER PT J AU Cheruku, P Plaza, A Keffer, JL Bewley, CA AF Cheruku, Pradeep Plaza, Alberto Keffer, Jessica L. Bewley, Carole A. TI Namalide, a natural cyclic peptide and its analogs as carboxypeptidase A inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Cheruku, Pradeep; Plaza, Alberto; Keffer, Jessica L.; Bewley, Carole A.] NIDDK, Dept Bioorgan Chem, NIH, Bethesda, MD 20878 USA. EM cherukup@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 110-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503201766 ER PT J AU Chung, HS Gopich, IV McHale, K Louis, JM Eaton, WA AF Chung, Hoi Sung Gopich, Irina V. McHale, Kevin Louis, John M. Eaton, William A. TI Measurement of average transition-path time for protein folding in single molecule FRET experiments SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Chung, Hoi Sung; Gopich, Irina V.; McHale, Kevin; Louis, John M.; Eaton, William A.] NIDDK, LCP, NIH, Bethesda, MD 20892 USA. EM chunghoi@niddk.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 56-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503203306 ER PT J AU Dogo-Isonagie, C Lam, S Acharya, P Kwong, P Bewley, C AF Dogo-Isonagie, Cajetan Lam, Son Acharya, Priyamvada Kwong, Peter Bewley, Carole TI Synthetic CCR5-derived peptides that inhibit HIV entry SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Dogo-Isonagie, Cajetan; Lam, Son; Bewley, Carole] NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. [Acharya, Priyamvada; Kwong, Peter] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. EM dogoisonagieci@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 405-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503202064 ER PT J AU Dogo-Isonagie, C Lam, SN Archaya, P Kwong, PD Bewley, CA AF Dogo-Isonagie, Cajetan Lam, Son N. Archaya, Priyamvada Kwong, Peter D. Bewley, Carole A. TI Insights into interactions of the GCPR CCR5 with the HIV viral envelope SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Dogo-Isonagie, Cajetan; Lam, Son N.; Bewley, Carole A.] NIDDK, NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. [Archaya, Priyamvada; Kwong, Peter D.] NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. EM dogoisonagieci@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 273-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503201923 ER PT J AU Dutta, AK Peterson, AW Zhao, HY He, HJ Zangmeister, R Schuck, P Tarlov, MJ AF Dutta, Amit K. Peterson, Alexander W. Zhao, Huaying He, Hua-Jun Zangmeister, Rebecca Schuck, Peter Tarlov, Michael J. TI Effect of lectin-glycoprotein binding strength on glycoanalysis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Dutta, Amit K.; Peterson, Alexander W.; He, Hua-Jun; Zangmeister, Rebecca; Tarlov, Michael J.] NIST, Div Biochem Sci, Mat Measurements Lab, Gaithersburg, MD 20899 USA. [Dutta, Amit K.; Zhao, Huaying; Schuck, Peter] NIBIB, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD USA. EM duttabapi2@gmail.com RI Zangmeister, Rebecca/D-6641-2017 OI Zangmeister, Rebecca/0000-0002-0540-6240 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 76-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475100615 ER PT J AU Gawrisch, K Gaede, HC Soubias, O Teague, WE Casas, R Dustman, JM AF Gawrisch, Klaus Gaede, Holly C. Soubias, Olivier Teague, Walter E., Jr. Casas, Rachel Dustman, John M. TI Influence of phospholipid chemical structure on lateral diffusion rates in fluid bilayers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Gawrisch, Klaus; Soubias, Olivier; Teague, Walter E., Jr.; Casas, Rachel; Dustman, John M.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Gaede, Holly C.] Texas A&M Univ, Dept Chem, College Stn, TX 77843 USA. EM gawrisch@helix.nih.gov RI Gaede, Holly/B-7392-2015 OI Gaede, Holly/0000-0003-4444-4394 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 88-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475103545 ER PT J AU Gildersleeve, J AF Gildersleeve, Jeffrey TI Personalizing cancer treatment with the aid of glycan array technology SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Gildersleeve, Jeffrey] NCI, Biol Chem Lab, Frederick, MD 21702 USA. EM gildersj@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 15-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475101085 ER PT J AU Hager, G AF Hager, Gordon TI How transcription factors bind to chromatin SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Hager, Gordon] NCI, Ctr Excellence Chromosome Biol, NIH, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 12-LIFE PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503201648 ER PT J AU Hakkinen, P AF Hakkinen, Pertti TI (US) National Library of Medicine's downloadable, online, and smartphone tools for first responders and others, Part 2: CHEMM (Chemical Hazards Emergency Medical Management) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Hakkinen, Pertti] NIH, Specialized Informat Serv, Natl Lib Med, Bethesda, MD 20892 USA. EM hakkinenp@mail.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 21-CHAS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475101702 ER PT J AU Horkay, F Basser, PJ Hecht, AM Geissler, E AF Horkay, Ferenc Basser, Peter J. Hecht, Anne-Marie Geissler, Erik TI Proteoglycan assemblies in cartilage SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Horkay, Ferenc; Basser, Peter J.] NICHD, NIH, Bethesda, MD 20892 USA. [Hecht, Anne-Marie; Geissler, Erik] Univ Grenoble 1, Spectrometrie Phys Lab, F-38402 St Martin Dheres, France. EM horkay@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 441-PMSE PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503204158 ER PT J AU Horkay, F Horkayne-Szakaly, I Dimitriadis, EK Silva, C Basser, PJ AF Horkay, Ferenc Horkayne-Szakaly, Iren Dimitriadis, Emilios K. Silva, Candida Basser, Peter J. TI Nanomechanical properties of cartilage SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Horkay, Ferenc; Horkayne-Szakaly, Iren; Silva, Candida; Basser, Peter J.] NICHD, NIH, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] NIBIB, NIH, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 457-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475100979 ER PT J AU Hou, SJ Sail, D Kovac, P AF Hou, Shu-jie Sail, Deepak Kovac, Pavol TI First chemical synthesis of the conjugation ready hexasaccharide antigen of Vibrio cholerae O:139 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Hou, Shu-jie; Sail, Deepak; Kovac, Pavol] NIDDK, LBC, Sect Carbohydrates, NIH, Bethesda, MD 20892 USA. EM saild@mail.nih.gov RI Kovac, Pavol/B-8813-2008 OI Kovac, Pavol/0000-0001-5044-3449 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 89-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475101154 ER PT J AU Jacobson, KA Stevens, RC Abagyan, R Deflorian, F Gao, ZG Gakh, AA Tosh, DK Kumar, TS Xu, F Katritch, V AF Jacobson, Kenneth A. Stevens, Raymond C. Abagyan, Ruben Deflorian, Francesca Gao, Zhan-Guo Gakh, Andrei A. Tosh, Dilip K. Kumar, T. S. Xu, Fei Katritch, Vsevolod TI Structure-based design of adenosine receptor ligands SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Jacobson, Kenneth A.; Deflorian, Francesca; Gao, Zhan-Guo; Gakh, Andrei A.; Tosh, Dilip K.; Kumar, T. S.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Abagyan, Ruben] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92063 USA. [Stevens, Raymond C.; Xu, Fei; Katritch, Vsevolod] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Stevens, Raymond C.; Xu, Fei; Katritch, Vsevolod] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; Katritch, Vsevolod/Q-8357-2016 OI Jacobson, Kenneth/0000-0001-8104-1493; NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 275-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503201925 ER PT J AU Jiang, ZP McGlinchey, RP Pfefferkorn, CM Yap, TL Lee, JC AF Jiang, Zhiping McGlinchey, Ryan P. Pfefferkorn, Candace M. Yap, Thai Leong Lee, Jennifer C. TI From unstructured to a-helical to b-sheet: Fluorescent studies of apolipoprotein c-III, a-synuclein, and the Pmel17 repeat domain SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Jiang, Zhiping; McGlinchey, Ryan P.; Pfefferkorn, Candace M.; Yap, Thai Leong; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 87-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503203337 ER PT J AU Keck, GE Poudel, YB Cummins, TJ Rudra, A Covel, JA Kedei, N Lewin, NE Blumberg, PM AF Keck, Gary E. Poudel, Yam B. Cummins, Thomas J. Rudra, Arnab Covel, Jonathan A. Kedei, Noemi Lewin, Nancy E. Blumberg, Peter M. TI Total synthesis and biological evaluation of bryostatin 7 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Keck, Gary E.; Poudel, Yam B.; Rudra, Arnab; Covel, Jonathan A.; Kedei, Noemi] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. [Kedei, Noemi; Lewin, Nancy E.; Blumberg, Peter M.] NCI, NIH, LCBG, Ctr Canc Res, Bethesda, MD 20892 USA. EM ypoudel@scripps.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 232-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503202449 ER PT J AU Kiselev, E Agama, K Pommier, Y Cushman, M AF Kiselev, Evgeny Agama, Keli Pommier, Yves Cushman, Mark TI Structure-activity relationship study of azaindenoisoquinoline topoisomerase I inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Kiselev, Evgeny; Cushman, Mark] Purdue Univ, Dept Med Chem & Mol Pharmacol, Sch Pharm, W Lafayette, IN 47906 USA. [Kiselev, Evgeny; Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47906 USA. [Agama, Keli; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM ekiselev@purdue.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 450-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503202106 ER PT J AU Klitzing, HA Lou, KY Zimmerberg, J Weber, PK Kraft, ML AF Klitzing, Haley A. Lou, Kaiyan Zimmerberg, Joshua Weber, Peter K. Kraft, Mary L. TI High-resolution secondary ion mass spectrometry reveals changes in long range sphingolipid organization with time SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Klitzing, Haley A.; Kraft, Mary L.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. [Lou, Kaiyan; Kraft, Mary L.] Univ Illinois, Dept Chem & Biomol Engn, Urbana, IL 61801 USA. [Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Weber, Peter K.] Lawrence Livermore Natl Lab, Glenn T Seaborg Inst, Livermore, CA 94551 USA. EM klitzin1@illinois.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 234-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475100521 ER PT J AU Kobayashi, H Mitsunaga, M Ogawa, M Choyke, PL AF Kobayashi, Hisataka Mitsunaga, Makoto Ogawa, Mikako Choyke, Peter L. TI Photo-immunotherapy: A super-controlled molecular target-specific cancer theranostics, evolving from the molecular imaging technology SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Kobayashi, Hisataka; Mitsunaga, Makoto; Ogawa, Mikako; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 36-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475100576 ER PT J AU Kosa, N Foley, T Burkart, M AF Kosa, Nicolas Foley, Timothy Burkart, Michael TI Fluorescent-based inhibitor screening for Sfp-type PPTases SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Kosa, Nicolas; Foley, Timothy; Burkart, Michael] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Foley, Timothy] NIH, Chem Genom Ctr, Rockville, MD 20850 USA. EM nkosa@ucsd.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 70-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475100403 ER PT J AU Kraft, ML Frisz, JF Klitzing, HA Lou, KY Hanafin, WP Wilson, RL Lizunov, V Carpenter, KJ Zimmerberg, J Weber, PK AF Kraft, Mary L. Frisz, Jessica F. Klitzing, Haley A. Lou, Kaiyan Hanafin, William P. Wilson, Robert L. Lizunov, Vladimir Carpenter, Kevin J. Zimmerberg, Joshua Weber, Peter K. TI High-resolution secondary ion mass spectrometry reveals the cholesterol and lipid distribution within the plasma membranes of fibroblast cells SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Kraft, Mary L.; Lou, Kaiyan; Hanafin, William P.] Univ Illinois, Dept Chem & Biomol Engn, Urbana, IL 61801 USA. [Kraft, Mary L.; Frisz, Jessica F.; Klitzing, Haley A.; Wilson, Robert L.] Univ Illinois, Dept Chem, Urbana, IL 61801 USA. [Carpenter, Kevin J.; Weber, Peter K.] Lawrence Livermore Natl Lab, Glenn T Seaborg Inst, Livermore, CA 94551 USA. [Lizunov, Vladimir; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM mlkraft@illinois.edu NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 198-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475103651 ER PT J AU Lee, J Dona, V Boshoff, HI Barry, CE AF Lee, Jinwoo Dona, Valentina Boshoff, Helena I. Barry, Clifton E. TI Synthesis and structure activity relationship of pyrazole derivatives as anti-tuberculosis agents SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Lee, Jinwoo; Dona, Valentina; Boshoff, Helena I.; Barry, Clifton E.] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. EM jinwoo.lee@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 150-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503201805 ER PT J AU Li, FY AF Li, Fuying TI Probes for narcotic receptor mediated phenomena: Conceputalization, synthesis and pharmacological evaluation of ring-expanded Phenylmorphans SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Li, Fuying] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Rockville, MD 20852 USA. EM lif4@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 129-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503201784 ER PT J AU Loesgen, S Shahzad-Ul-Hussan, S Bewley, CA AF Loesgen, Sandra Shahzad-Ul-Hussan, Syed Bewley, Carole A. TI HIV-1 Inhibitors from nature: Understanding and optimizing potent cyanobacterial carbohydrate-binding proteins SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Loesgen, Sandra; Bewley, Carole A.] NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. [Shahzad-Ul-Hussan, Syed] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. EM sandra.loesgen@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 28-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475101095 ER PT J AU Lusvarghi, S O'Keefe, BR Le Grice, SFJ AF Lusvarghi, Sabrina O'Keefe, Barry R. Le Grice, Stuart F. J. TI Metallomicrobicides: A smarter way to target HIV SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Lusvarghi, Sabrina; O'Keefe, Barry R.; Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM sabrinal@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 279-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475100526 ER PT J AU Michino, M Duan, LH Han, Y Donthamsetti, P Banala, A Newman, AH Javitch, JA Shi, L AF Michino, Mayako Duan, Lihua Han, Yang Donthamsetti, Prashant Banala, Ashwini Newman, Amy H. Javitch, Jonathan A. Shi, Lei TI Structural basis for dopamine D3 receptor subtype-selectivity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Michino, Mayako; Shi, Lei] Cornell Univ, Weill Cornell Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA. [Michino, Mayako; Shi, Lei] Cornell Univ, Weill Cornell Med Coll, HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsau, New York, NY 10021 USA. [Duan, Lihua; Han, Yang; Donthamsetti, Prashant; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Ctr Mol Recognit, New York, NY 10032 USA. [Duan, Lihua; Han, Yang; Donthamsetti, Prashant; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Duan, Lihua; Han, Yang; Donthamsetti, Prashant; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. [Banala, Ashwini; Newman, Amy H.] NIDA, Med Chem Sect, Intramural Res Program, Baltimore, MD 21224 USA. EM mam2134@med.cornell.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 359-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475104540 ER PT J AU Moore, NM AF Moore, Nicole M. TI Convergence of physical and life sciences perspectives in cancer research SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Moore, Nicole M.] NCI, Off Phys Sci Oncol, Bethesda, MD 20892 USA. EM moorenm@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 372-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503204617 ER PT J AU Munge, BS Coffey, AL Doucette, JM Somba, BK Malhotra, R Patel, V Gutkind, S Rusling, JF AF Munge, Bernard S. Coffey, Amy L. Doucette, Jaimee M. Somba, Brian K. Malhotra, Ruchika Patel, Vyomesh Gutkind, Silvio Rusling, James F. TI Nanostructured immunosensor for attomolar detection of cancer biomarkers using massively labeled superparamagnetic particles SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Munge, Bernard S.; Coffey, Amy L.; Doucette, Jaimee M.; Somba, Brian K.] Salve Regina Univ, Dept Chem, Newport, RI 02840 USA. [Malhotra, Ruchika; Rusling, James F.] Univ Connecticut, Dept Chem, Storrs, CT 06269 USA. [Patel, Vyomesh; Gutkind, Silvio] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM bernard.munge@salve.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 41-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475100174 ER PT J AU Namuswe, F Amann, BT Berg, JM AF Namuswe, Frances Amann, Barbara T. Berg, Jeremy M. TI Investigating the metal binding cooperativity between adjacent TRAF-like zinc finger domains SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Namuswe, Frances; Amann, Barbara T.] NIH, Mol Biol Lab, Bethesda, MD 20892 USA. [Berg, Jeremy M.] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15213 USA. EM namuswef@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 117-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475100445 ER PT J AU Nicklaus, MC Sitzmann, M AF Nicklaus, Marc C. Sitzmann, Markus TI Representing chemical information by URLs: The chemical identifier resolver as a general chemoinformatics tool SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Nicklaus, Marc C.; Sitzmann, Markus] NCI, NCI Frederick, NIH, Frederick, MD 21702 USA. EM mn1@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 109-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475103439 ER PT J AU North, H Scott, KR Stables, JP Wang, XS AF North, Henry Scott, Kenneth R. Stables, James P. Wang, Xiang S. TI Cheminfomatic modeling of enaminones anticonvulsants with dual set of animal activities SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [North, Henry; Scott, Kenneth R.; Wang, Xiang S.] Howard Univ, Coll Pharm, Dept Pharmaceut Sci CDRD, Washington, DC 20059 USA. [Stables, James P.] NINDS, Epilepsy Branch, Rockville, MD 20852 USA. EM henry.north@howard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 299-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475104483 ER PT J AU Okur, A Smith, DB Brooks, BR AF Okur, Asim Smith, Daniel B. Brooks, Bernard R. TI Evaluating the performance of reservoir replica exchange methods through transition state theory SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Okur, Asim; Brooks, Bernard R.] NHLBI, NIH, Bethesda, MD 20892 USA. [Smith, Daniel B.] Univ Pittsburgh, Dept Math, Pittsburgh, PA 15260 USA. EM okura@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 214-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475104401 ER PT J AU Olsen, MJ Clewett, C Iacoban, P Hubbard, M Cox, T Stables, JP AF Olsen, Mark J. Clewett, Cathy Iacoban, Paulina Hubbard, Matthew Cox, Thomas Stables, James P. TI Synthesis and anticonvulsant activity of 4-aryl-2-hydroxytetronimides SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Olsen, Mark J.; Iacoban, Paulina; Hubbard, Matthew; Cox, Thomas] Midwestern Univ, Dept Pharmaceut Sci, Glendale, AZ 85308 USA. [Clewett, Cathy] West Texas A&M Univ, Dept Math Chem & Phys, Canyon, TX 79015 USA. [Stables, James P.] NINDS, ASP Program, Rockville, MD 20852 USA. EM molsen@midwestern.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 28-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503201686 ER PT J AU Qian, WJ Park, JE Liu, F Lim, D Scharow, A Berg, T Yaffe, MB Lee, KS Burke, TR AF Qian, Wenjian Park, Jung-Eun Liu, Fa Lim, Dan Scharow, Andrej Berg, Thorsten Yaffe, Michael B. Lee, Kyung S. Burke, Terrence R., Jr. TI Structure-based development of biovailable polo-like kinase 1 (Plk1) polo-box domain-binding peptides SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Qian, Wenjian; Liu, Fa; Burke, Terrence R., Jr.] NCI, NIH, Biol Chem Lab, Frederick, MD 21702 USA. [Park, Jung-Eun; Lee, Kyung S.] NCI, NIH, Lab Metab, Bethesda, MD 20892 USA. [Lim, Dan; Yaffe, Michael B.] MIT, Dept Biol & Biol Engn, Ctr Canc Res, Cambridge, MA 02139 USA. [Scharow, Andrej; Berg, Thorsten] Univ Leipzig, Inst Organ Chem, D-04109 Leipzig, Germany. EM qianw2@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 343-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503202004 ER PT J AU Rogers, SA Patnaik, S Marugan, J Sidransky, E Inglese, J Austin, CP Schoenen, F Aube, J AF Rogers, Steven A. Patnaik, Samarjit Marugan, Juan Sidransky, Ellen Inglese, James Austin, Christopher P. Schoenen, Frank Aube, Jeffrey TI Synthesis and biological evaluation of small molecule activators of the N370S mutant form of glucocerebrosidase as a potential therapy for Gaucher disease SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Rogers, Steven A.; Schoenen, Frank; Aube, Jeffrey] Univ Kansas, Specialized Chem Ctr, Lawrence, KS 66044 USA. [Sidransky, Ellen] NIMH, Porter Neurosci Res Ctr, Mol Neurogenet Sect, Bethesda, MD 20892 USA. [Patnaik, Samarjit; Marugan, Juan; Inglese, James; Austin, Christopher P.] NIH, Ctr Translat Therapeut, Rockville, MD 20892 USA. EM sarogers@ku.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 455-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503202111 ER PT J AU Rosta, E Yang, W Hummer, G AF Rosta, Edina Yang, Wei Hummer, Gerhard TI On two-metal ion catalysis: Study in Ribonuclease H SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Rosta, Edina; Yang, Wei; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM rosta@helix.nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 537-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475104704 ER PT J AU Sitzmann, M Nicklaus, MC AF Sitzmann, Markus Nicklaus, Marc C. TI Accessing NCI/CADD web resources by InChI SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Sitzmann, Markus; Nicklaus, Marc C.] Natl Canc Inst Frederick, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. EM sitzmann@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 112-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475103442 ER PT J AU Stephenson, RM Bhirde, A Chen, XY Walker, ARH AF Stephenson, Rachel M. Bhirde, Ashwinkumar Chen, Xiaoyuan Walker, Angela R. Hight TI Dispersant-dependence of the resonance Raman spectra and excitation profiles for aqueous SWCNT solutions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Stephenson, Rachel M.; Walker, Angela R. Hight] NIST, Phys Measurement Lab, Gaithersburg, MD 20899 USA. [Bhirde, Ashwinkumar; Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. EM rachel.stephenson@nist.gov RI Hight Walker, Angela/C-3373-2009 OI Hight Walker, Angela/0000-0003-1385-0672 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 212-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475103664 ER PT J AU Tosh, DK Phan, K Deflorian, F Wei, Q Gao, ZG Jacobson, KA AF Tosh, Dilip K. Khai Phan Deflorian, Francesca Wei, Qiang Gao, Zhan-Guo Jacobson, Kenneth A. TI Discovery of truncated (N)-methanocarba nucleosides as A(1) adenosine receptor agonists SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Tosh, Dilip K.; Khai Phan; Deflorian, Francesca; Wei, Qiang; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. EM toshd@niddk.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 136-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503201791 ER PT J AU Uh, E Yang, XX Boshoff, HI Barry, CE AF Uh, Eugene Yang, Xinxin Boshoff, Helena I. Barry, Clifton E., III TI Aminopyrimidine kills Mycobacterium tuberculosis by inhibition of decaprenylphosphoryl-beta-d-ribose 2 '-epimerase SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Uh, Eugene; Yang, Xinxin; Boshoff, Helena I.; Barry, Clifton E., III] NIAID, NIH, Bethesda, MD 20892 USA. EM eugeneuh@gwmail.gwu.edu NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 393-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503202052 ER PT J AU Wang, YL AF Wang, Yanli TI Identifying druggable targets by mining open chemical biology data SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Wang, Yanli] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 84-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475103414 ER PT J AU Weibel, DB Renner, LD Eswaramoorthy, P Krishnamurthy, K AF Weibel, Douglas B. Renner, Lars D. Eswaramoorthy, Prahathees Krishnamurthy, Kumaran TI Bacterial membrane curvature controls the formation of cardiolipin microdomains SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Weibel, Douglas B.; Renner, Lars D.] Univ Wisconsin, Madison, WI 53706 USA. [Eswaramoorthy, Prahathees; Krishnamurthy, Kumaran] NCI, NIH, Bethesda, MD 20892 USA. EM weibel@biochem.wisc.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 84-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475103541 ER PT J AU Yancey, JA Biswas, P Vellore, NA Kucukkal, TG Collier, G Brooks, BR Stuart, SJ Latour, RA AF Yancey, Jeremy A. Biswas, Pradip Vellore, Nadeem A. Kucukkal, Tugba G. Collier, Galen Brooks, Bernard R. Stuart, Steven J. Latour, Robert A. TI Modeling multiphase systems with independent force fields controlling intra- and inter-phase interactions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Yancey, Jeremy A.; Vellore, Nadeem A.; Collier, Galen; Latour, Robert A.] Clemson Univ, Dept Bioengn, Clemson, SC 29634 USA. [Kucukkal, Tugba G.; Stuart, Steven J.] Clemson Univ, Dept Chem, Clemson, SC 29634 USA. [Biswas, Pradip] Tougaloo Coll, Dept Phys, Tougaloo, MS 39174 USA. [Brooks, Bernard R.] NIH, Lab Computat Biol, Bethesda, MD 20892 USA. EM jyancey@g.clemson.edu RI Vellore, Nadeem/C-5763-2011 OI Vellore, Nadeem/0000-0003-4853-1508 NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 121-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475104317 ER PT J AU Yong, KJ Baidoo, KE Milenic, DE Brechbiel, MW AF Yong, Kwon J. Baidoo, Kwamena E. Milenic, Diane E. Brechbiel, Martin W. TI Pb-212 radioimmunotherapy - observations along a lengthy long road forward SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Yong, Kwon J.; Baidoo, Kwamena E.; Milenic, Diane E.; Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 11-NUCL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503202124 ER PT J AU Yu, X Wang, QM Zhao, J Zhao, C Ma, BY Nussinov, R Zheng, J AF Yu, Xiang Wang, Qiuming Zhao, Jun Zhao, Chao Ma, Buyong Nussinov, Ruth Zheng, Jie TI Molecular structures of polymorphic amyloid-b oligomers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Yu, Xiang; Wang, Qiuming; Zhao, Jun; Zhao, Chao; Zheng, Jie] Univ Akron, Dept Chem & Biomol Engn, Akron, OH 44325 USA. [Ma, Buyong; Nussinov, Ruth] SAIC Frederick Inc, Natl Canc Inst Frederick, Ctr Canc, Res Nanobiol Program, Frederick, MD 21702 USA. EM yx13@zips.uakron.edu RI Wang, Qiuming/E-6254-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 38-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475104235 ER PT J AU Zhang, Y Louis, JM Sayer, JM Wang, YF Harrison, RW Weber, IT AF Zhang, Ying Louis, John M. Sayer, Jane M. Wang, Yuan-Fang Harrison, Robert W. Weber, Irene T. TI HIV-1 protease drug resistance mutant L76V exhibits decreased dimer stability and lower rate of autoprocessing via reduced internal hydrophobic contacts SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Zhang, Ying; Weber, Irene T.] Georgia State Univ, Dept Chem, Atlanta, GA 30303 USA. [Wang, Yuan-Fang; Harrison, Robert W.; Weber, Irene T.] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. [Harrison, Robert W.] Georgia State Univ, Dept Comp Sci, Atlanta, GA 30303 USA. [Louis, John M.; Sayer, Jane M.] Natl Inst Diabet & Digest & Kidney Dis, Chem Phys Lab, NIH, Atlanta, GA 30303 USA. EM yzhang20@student.gsu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 82-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475100414 ER PT J AU Zhao, Q Gong, R Kumar, S Prabakaran, P Gehlsen, K Dimitrov, DS AF Zhao, Qi Gong, Rui Kumar, Sandeep Prabakaran, Ponraj Gehlsen, Kurt Dimitrov, Dimiter S. TI Novel antibody CH2-domain based binders to nucleolin: Isolation, characterization and improvement of stability and aggregation SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Zhao, Qi; Gong, Rui; Prabakaran, Ponraj; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. [Kumar, Sandeep] Pfizer Inc, BioTherapeut Pharmaceut Sci, St Louis, MO 63017 USA. [Prabakaran, Ponraj] Sci Applicat Int Corp Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. [Gehlsen, Kurt] Res Corp Technol Inc, Tucson, AZ USA. EM dimiter.dimitrov@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 195-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475100730 ER PT J AU Zhao, XZ Maddali, K Smith, SJ Metifiot, M Hare, S Marchand, C Cherepanov, P Hughes, SH Pommier, Y Burke, TR AF Zhao, Xue Zhi Maddali, Kasthuraiah Smith, Steven J. Metifiot, Mathieu Hare, Stephen Marchand, Christophe Cherepanov, Peter Hughes, Stephen H. Pommier, Yves Burke, Terrence R., Jr. TI 6,7-Dihydroxy-1-oxoisoindoline-4-sulfonamide-containing HIV-1 integrase inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Zhao, Xue Zhi; Burke, Terrence R., Jr.] NCI, NIH, Biol Chem Lab, Frederick, MD 21702 USA. [Maddali, Kasthuraiah; Metifiot, Mathieu; Marchand, Christophe; Pommier, Yves] NCI, NIH, Mol Pharmacol Lab, Betheada, MD 20892 USA. [Smith, Steven J.; Hughes, Stephen H.] NCI, NIH, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Hare, Stephen; Cherepanov, Peter] Univ London Imperial Coll Sci Technol & Med, Div Infect Dis, London, England. EM zhaoxue@mail.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 171-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503201825 ER PT J AU Zheng, J Zhao, J Yu, X Jang, H Nussinov, R AF Zheng, Jie Zhao, Jun Yu, Xiang Jang, Hyunbum Nussinov, Ruth TI Amyloid ion channels: Selective or non-selective channel? SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 11th International Biorelated Polymer Symposium / 243rd National Spring Meeting of the American-Chemical-Society (ACS) CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc, Div Polymer Chem Inc, Amer Chem Soc C1 [Zheng, Jie; Zhao, Jun; Yu, Xiang] Univ Akron, Dept Chem & Biomol Engn, Akron, OH 44325 USA. [Jang, Hyunbum; Nussinov, Ruth] NCI, Ctr Canc Res Nanobiol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM zhengj@uakron.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 232-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219AH UT WOS:000324475100765 ER PT J AU Zhu, FQ Hummer, G AF Zhu, Fangqiang Hummer, Gerhard TI Water in ion channel gating SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 243rd National Spring Meeting of the American-Chemical-Society CY MAR 25-29, 2012 CL San Diego, CA SP Amer Chem Soc C1 [Zhu, Fangqiang; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2012 VL 243 MA 91-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 219JX UT WOS:000324503203341 ER PT J AU Chen, XH Peer, CJ Alfaro, R Tian, T Spencer, SD Figg, WD AF Chen, Xiaohong Peer, Cody J. Alfaro, Raul Tian, Tian Spencer, Shawn D. Figg, William D. TI Quantification of irinotecan, SN38, and SN38G in human and porcine plasma by ultra high-performance liquid chromatography-tandem mass spectrometry and its application to hepatic chemoembolization SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE Irinotecan; SN38; Camptothecin; Mass spectrometry; Ultra-high performance liquid chromatography ID ACTIVE METABOLITE SN-38; DRUG ELUTING BEADS; CAMPTOTHECIN DERIVATIVE IRINOTECAN; FLUORESCENCE DETECTION; LIVER METASTASES; 7-ETHYL-10-HYDROXYCAMPTOTHECIN SN-38; COLORECTAL-CANCER; MAJOR METABOLITES; CARBOXYLATE FORMS; LACTONE FORMS AB An analytical method was developed and validated for the quantitative determination of irinotecan, its active metabolite SN38, and glucuronidated SN38 (SN38-G) in both porcine and human plasma. Calibration curves were linear within the concentration range of 0.5-100 ng/mL for SN38 and SN38-G, and 5-1000 ng/mL for irinotecan. Sample pretreatment involved solid-phase extraction of 0.1 mL aliquots of plasma. Irinotecan, SN38, SN38-G, and the internal standards, irinotecan-d10, tolbutamide, and camptothecin, respectively, were separated on a Waters ACQUITY UPLC (TM) BEH RP18 column (2.1 mm x 50 mm, 1.7 mu m), using a mobile phase composed of methanol and 0.1% formic acid. Accuracy of quality control samples in human plasma ranged from 98.5 to 110.3%, 99.5 to 101.7% and 96.2 to 98.9% for irinotecan, SN38, and SN38-G, respectively. Precision of the three analytes in the same order ranged from 0.8 to 2.8%, 2.4 to 5.7%, and 2.4 to 2.8%. All three analytes proved stable in plasma through four freeze/thaw cycles, as well as through 6 h in whole blood at room temperature. The method was likewise validated in porcine plasma with comparable accuracies and precisions also within the generally acceptable range. The validated method was applied to both preclinical and clinical trials involving hepatic chemoembolization of irinotecan drug-eluting beads to study the pharmacokinetics of the three analytes. Published by Elsevier B.V. C1 [Figg, William D.] NCI, Clin Pharmacol Program, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Chen, Xiaohong; Spencer, Shawn D.] NCI, Clin Pharmacol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Alfaro, Raul] NIH, Pharm Sect, Ctr Clin, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, NIH, Ctr Canc Res, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, as well as the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. Some authors are affiliated with the SAIC Frederick, Inc., with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. NR 36 TC 13 Z9 13 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD MAR 25 PY 2012 VL 62 BP 140 EP 148 DI 10.1016/j.jpba.2012.01.008 PG 9 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 902IQ UT WOS:000301032200018 PM 22305081 ER PT J AU Swinburn, B Hall, KD AF Swinburn, Boyd Hall, Kevin D. TI Diet composition and obesity reply SO LANCET LA English DT Letter C1 [Hall, Kevin D.] NIDDK, NIH, Bethesda, MD 20892 USA. [Swinburn, Boyd] Deakin Univ, WHO Collaborating Ctr Obes Prevent, Melbourne, Vic, Australia. RP Hall, KD (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov NR 4 TC 1 Z9 1 U1 0 U2 6 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 MAR 24 PY 2012 VL 379 IS 9821 BP 1100 EP 1101 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 916VR UT WOS:000302131800025 ER PT J AU Archer, J Baillie, G Watson, SJ Kellam, P Rambaut, A Robertson, DL AF Archer, John Baillie, Greg Watson, Simon J. Kellam, Paul Rambaut, Andrew Robertson, David L. TI Analysis of high-depth sequence data for studying viral diversity: a comparison of next generation sequencing platforms using Segminator II SO BMC BIOINFORMATICS LA English DT Article ID HIV-1 DRUG-RESISTANCE; HIGH-THROUGHPUT; SNP DISCOVERY; VARIANTS; QUALITY; READS; BIOINFORMATICS; ALIGNMENT; MINORITY; ACCURACY AB Background: Next generation sequencing provides detailed insight into the variation present within viral populations, introducing the possibility of treatment strategies that are both reactive and predictive. Current software tools, however, need to be scaled up to accommodate for high-depth viral data sets, which are often temporally or spatially linked. In addition, due to the development of novel sequencing platforms and chemistries, each with implicit strengths and weaknesses, it will be helpful for researchers to be able to routinely compare and combine data sets from different platforms/chemistries. In particular, error associated with a specific sequencing process must be quantified so that true biological variation may be identified. Results: Segminator II was developed to allow for the efficient comparison of data sets derived from different sources. We demonstrate its usage by comparing large data sets from 12 influenza H1N1 samples sequenced on both the 454 Life Sciences and Illumina platforms, permitting quantification of platform error. For mismatches median error rates at 0.10 and 0.12%, respectively, suggested that both platforms performed similarly. For insertions and deletions median error rates within the 454 data (at 0.3 and 0.2%, respectively) were significantly higher than those within the Illumina data (0.004 and 0.006%, respectively). In agreement with previous observations these higher rates were strongly associated with homopolymeric stretches on the 454 platform. Outside of such regions both platforms had similar indel error profiles. Additionally, we apply our software to the identification of low frequency variants. Conclusion: We have demonstrated, using Segminator II, that it is possible to distinguish platform specific error from biological variation using data derived from two different platforms. We have used this approach to quantify the amount of error present within the 454 and Illumina platforms in relation to genomic location as well as location on the read. Given that next generation data is increasingly important in the analysis of drug-resistance and vaccine trials, this software will be useful to the pathogen research community. A zip file containing the source code and jar file is freely available for download from http://www.bioinf.manchester.ac.uk/segminator/. C1 [Archer, John; Robertson, David L.] Univ Manchester, Fac Life Sci, Manchester, Lancs, England. [Baillie, Greg; Watson, Simon J.; Kellam, Paul] Wellcome Trust Sanger Inst, Cambridge, England. [Kellam, Paul] UCL, Div Infect & Immun, UCL MRC Ctr Med Mol Virol, London, England. [Rambaut, Andrew] Univ Edinburgh, Inst Evolutionary Biol, Edinburgh, Midlothian, Scotland. [Rambaut, Andrew] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Archer, J (reprint author), Univ Manchester, Fac Life Sci, Manchester, Lancs, England. EM john.archer@manchester.ac.uk; david.robertson@manchester.ac.uk RI Baillie, Gregory/F-9478-2013; OI Baillie, Gregory/0000-0002-6130-250X; Archer, John/0000-0001-6212-0962; Rambaut, Andrew/0000-0003-4337-3707 FU BBSRC [BB/H012419/1] FX We wish to thank BBSRC for funding, project grant: BB/H012419/1. We also wish to thank Felix Feyertag, Bram Vrancken and Kenneth Henry for useful discussion. NR 38 TC 40 Z9 40 U1 2 U2 20 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 MAR 23 PY 2012 VL 13 AR 47 DI 10.1186/1471-2105-13-47 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 946JU UT WOS:000304348700001 PM 22443413 ER PT J AU Xiao, TS Tine, JPY AF Xiao, Tsan Sam Tine, Jenny P. -Y. TI NLRX1 Has a Tail to Tell SO IMMUNITY LA English DT Editorial Material ID OXYGEN SPECIES PRODUCTION; NF-KAPPA-B; MITOCHONDRIAL; INFECTION; PATHWAYS; MAVS AB In this issue of Immunity, Hong et al. (2012) report the first structural analysis of the C-terminal fragment of an NLR (nucleotide-binding domain [NBD] and leucine-rich repeat [LRR]-containing) protein, NLRX1. This fragment forms a hexamer and binds RNA. C1 [Xiao, Tsan Sam] NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Tine, Jenny P. -Y.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Ctr Translat Immunol, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Tine, Jenny P. -Y.] Inflammatory Dis Inst, Chapel Hill, NC 27599 USA. RP Xiao, TS (reprint author), NIAID, Struct Immunobiol Unit, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM xiaot@niaid.nih.gov; jenny_ting@med.unc.edu RI Xiao, Tsan/I-7616-2013; Xiao, Tsan/A-8590-2010 OI Xiao, Tsan/0000-0001-9688-475X; FU Intramural NIH HHS [ZIA AI000960-07]; NCI NIH HHS [R01 CA156330]; NIAID NIH HHS [U54 AI057157] NR 10 TC 5 Z9 5 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAR 23 PY 2012 VL 36 IS 3 BP 311 EP 312 DI 10.1016/j.immuni.2012.03.002 PG 2 WC Immunology SC Immunology GA 915ST UT WOS:000302048400001 PM 22444625 ER PT J AU Migueles, SA Connors, M AF Migueles, Stephen A. Connors, Mark TI Small Molecules and Big Killers: The Challenge of Eliminating the Latent HIV Reservoir SO IMMUNITY LA English DT Editorial Material ID INFECTION AB In this issue of Immunity, Shan et al. (2012) explore the elimination of cells latently infected with HIV and the potential implications for strategies to eradicate the virus from infected patients. C1 [Migueles, Stephen A.; Connors, Mark] NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Connors, M (reprint author), NIAID, HIV Specif Immun Sect, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mconnors@nih.gov NR 10 TC 6 Z9 6 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAR 23 PY 2012 VL 36 IS 3 BP 320 EP 321 DI 10.1016/j.immuni.2012.03.006 PG 2 WC Immunology SC Immunology GA 915ST UT WOS:000302048400005 PM 22444629 ER PT J AU Geng, H Sakato, M DeRocco, V Yamane, K Du, CW Erie, DA Hingorani, M Hsieh, P AF Geng, Hui Sakato, Miho DeRocco, Vanessa Yamane, Kazuhiko Du, Chunwei Erie, Dorothy A. Hingorani, Manju Hsieh, Peggy TI Biochemical Analysis of the Human Mismatch Repair Proteins hMutS alpha MSH2(G674A)-MSH6 and MSH2-MSH6(T1219D) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE MSH2-MSH6; NUCLEOTIDE-BINDING SITES; HUMAN NUCLEAR EXTRACTS; MUTL-ALPHA; DNA-REPAIR; DOMINANT MUTATIONS; MISPAIR-BINDING; ATR KINASE; COMPLEX; MSH2 AB The heterodimeric human MSH2-MSH6 protein initiates DNA mismatch repair (MMR) by recognizing mismatched bases that result from replication errors. Msh2(G674A) or Msh6(T1217D) mice that have mutations in or near the ATP binding site of MSH2 or ATP hydrolysis catalytic site of MSH6 develop cancer and have a reduced lifespan due to loss of the MMR pathway (Lin, D. P., Wang, Y., Scherer, S. J., Clark, A. B., Yang, K., Avdievich, E., Jin, B., Werling, U., Parris, T., Kurihara, N., Umar, A., Kucherlapati, R., Lipkin, M., Kunkel, T. A., and Edelmann, W. (2004) Cancer Res. 64, 517522; Yang, G., Scherer, S. J., Shell, S. S., Yang, K., Kim, M., Lipkin, M., Kucherlapati, R., Kolodner, R. D., and Edelmann, W. (2004) Cancer Cell 6, 139150). Mouse embryonic fibroblasts from these mice retain an apoptotic response to DNA damage. Mutant human MutS alpha proteins MSH2(G674A)-MSH6(wt) and MSH2(wt)-MSH6T(1219D) are profiled in a variety of functional assays and as expected fail to support MMR in vitro, although they retain mismatch recognition activity. Kinetic analyses of DNA binding and ATPase activities and examination of the excision step of MMR reveal that the two mutants differ in their underlying molecular defects. MSH2(wt)-MSH6(T1219D) fails to couple nucleotide binding and mismatch recognition, whereas MSH2(G674A)-MSH6(wt) has a partial defect in nucleotide binding. Nevertheless, both mutant proteins remain bound to the mismatch and fail to promote efficient excision thereby inhibiting MMR in vitro in a dominant manner. Implications of these findings for MMR and DNA damage signaling by MMR proteins are discussed. C1 [Geng, Hui; Yamane, Kazuhiko; Du, Chunwei; Hsieh, Peggy] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. [Sakato, Miho; Hingorani, Manju] Wesleyan Univ, Dept Mol Biol & Biochem, Middletown, CT 06459 USA. [DeRocco, Vanessa; Erie, Dorothy A.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Hsieh, P (reprint author), 9000 Rockville Pike,5 Mem Dr,MSC 0538,Bldg 5 Rm 3, Bethesda, MD 20892 USA. EM peggyh@intra.niddk.nih.gov FU National Institutes of Health of NIDDK [F31 GM087096, GM 079480]; State of Connecticut Department of Public Health [2011-0138] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of NIDDK (to H. G., C. D., K.Y., and P. H.) and Grants F31 GM087096 (to V. R.) and GM 079480 (to D. A. E.). This work was also supported by State of Connecticut Department of Public Health Grant 2011-0138 (to M.H.). NR 54 TC 11 Z9 11 U1 0 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2012 VL 287 IS 13 BP 9777 EP 9791 DI 10.1074/jbc.M111.316919 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 917IN UT WOS:000302167200011 PM 22277660 ER PT J AU Fujimoto, K Matsuura, K Hu-Wang, E Lu, R Shi, YB AF Fujimoto, Kenta Matsuura, Kazuo Hu-Wang, Eileen Lu, Rosemary Shi, Yun-Bo TI Thyroid Hormone Activates Protein Arginine Methyltransferase 1 Expression by Directly Inducing c-Myc Transcription during Xenopus Intestinal Stem Cell Development SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMPHIBIAN METAMORPHOSIS; POSTEMBRYONIC DEVELOPMENT; EPITHELIAL DEVELOPMENT; RECEPTOR SUPERFAMILY; GENE REPRESSION; TR-ALPHA; LAEVIS; BETA; RECRUITMENT; FROG AB Adult organ-specific stem cells are essential for organ homeostasis and tissue repair and regeneration. The formation of such stem cells during vertebrate development is poorly understood. Intestinal remodeling during thyroid hormone (T3)-dependent Xenopus metamorphosis resembles postembryonic intestinal maturation in mammals. During metamorphosis, the intestine is remodeled de novo via a yet unknown mechanism. Protein arginine methyltransferase 1 (PRMT1) is up-regulated in and required for adult intestinal stem cells during metamorphosis. PRMT1 up-regulation is the earliest known molecular event for the developing stem cells and is also conserved during zebrafish and mouse intestinal development. To analyze how PRMT1 is specifically up-regulated during the formation of the adult intestinal stem cells, wecloned the Xenopus PRMT1 promoter and characterized it in CaCo-2 cells, a human cell line with intestinal stem cell characteristics. Through a series deletion and mutational analyses, we showed that the stem cell-associated transcription factor c-Myc could bind to a conserved site in the first intron to activate the promoter. Furthermore, we demonstrated that during metamorphosis, both c-Myc and PRMT1 were highly up-regulated, specifically in the remodeling intestine but not the resorbing tail, and that c-Myc was induced by T3 prior to PRMT1 up-regulation. In addition, we showed that T3 directly activated the c-Myc gene during metamorphosis in the intestine via binding of the T3 receptor to the c-Myc promoter. These results suggest that T3 induces c-Myc transcription directly in the intestine, that c-Myc, in turn, activates PRMT1 expression, and that this is an important gene regulation cascade controlling intestinal stem cell development. C1 [Fujimoto, Kenta; Matsuura, Kazuo; Hu-Wang, Eileen; Lu, Rosemary; Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, PCRM,NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, PCRM,NIH, Bethesda, MD 20892 USA. EM Shi@helix.nih.gov FU NICHD, National Institutes of Health; Japan Society for the Promotion of Sciences (NIH) FX This work was supported, in whole or in part, by the NICHD, National Institutes of Health intramural research program. This work was also supported by a fellowship by the Japan Society for the Promotion of Sciences (NIH) (to K. F.). This work was also supported by a Fellowship for Japanese Biochemical and Behavioral Researchers at NIH from Japan Society for the Promotion of Science (to K. F.). NR 77 TC 10 Z9 12 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 MAR 23 PY 2012 VL 287 IS 13 BP 10039 EP 10050 DI 10.1074/jbc.M111.335661 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 917IN UT WOS:000302167200036 PM 22315222 ER PT J AU Arakaki, M Ishikawa, M Nakamura, T Iwamoto, T Yamada, A Fukumoto, E Saito, M Otsu, K Harada, H Yamada, Y Fukumoto, S AF Arakaki, Makiko Ishikawa, Masaki Nakamura, Takashi Iwamoto, Tsutomu Yamada, Aya Fukumoto, Emiko Saito, Masahiro Otsu, Keishi Harada, Hidemitsu Yamada, Yoshihiko Fukumoto, Satoshi TI Role of Epithelial-Stem Cell Interactions during Dental Cell Differentiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TOOTH MORPHOGENESIS; IN-VIVO; FACTOR EPIPROFIN; DEFINED FACTORS; NEURAL CREST; EXPRESSION; TEETH; PLURIPOTENT; INDUCTION; PULP AB Epithelial-mesenchymal interactions regulate the growth and morphogenesis of ectodermal organs such as teeth. Dental pulp stem cells (DPSCs) are a part of dental mesenchyme, derived from the cranial neural crest, and differentiate into dentin forming odontoblasts. However, the interactions between DPSCs and epithelium have not been clearly elucidated. In this study, we established a mouse dental pulp stem cell line (SP) comprised of enriched side population cells that displayed a multipotent capacity to differentiate into odontogenic, osteogenic, adipogenic, and neurogenic cells. We also analyzed the interactions between SP cells and cells from the rat dental epithelial SF2 line. When cultured with SF2 cells, SP cells differentiated into odontoblasts that expressed dentin sialophosphoprotein. This differentiation was regulated by BMP2 and BMP4, and inhibited by the BMP antagonist Noggin. We also found that mouse iPS cells cultured with mitomycin C-treated SF2-24 cells displayed an epithelial cell-like morphology. Those cells expressed the epithelial cell markers p63 and cytokeratin-14, and the ameloblast markers ameloblastin and enamelin, whereas they did not express the endodermal cell marker Gata6 or mesodermal cell marker brachyury. This is the first report of differentiation of iPS cells into ameloblasts via interactions with dental epithelium. Co-culturing with dental epithelial cells appears to induce stem cell differentiation that favors an odontogenic cell fate, which may be a useful approach for tooth bioengineering strategies. C1 [Arakaki, Makiko; Nakamura, Takashi; Iwamoto, Tsutomu; Yamada, Aya; Fukumoto, Emiko; Fukumoto, Satoshi] Tohoku Univ, Dept Oral Hlth & Dev Sci, Grad Sch Dent, Div Pediat Dent, Sendai, Miyagi 9808575, Japan. [Ishikawa, Masaki; Yamada, Yoshihiko] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Saito, Masahiro] Tokyo Univ Sci, Fac Ind Sci & Technol, Chiba 2788510, Japan. [Otsu, Keishi; Harada, Hidemitsu] Iwate Med Coll, Sch Dent, Dept Oral Anat 2, Morioka, Iwate 0208505, Japan. RP Fukumoto, S (reprint author), Tohoku Univ, Dept Oral Hlth & Dev Sci, Grad Sch Dent, Div Pediat Dent, Sendai, Miyagi 9808575, Japan. EM fukumoto@dent.tohoku.ac.jp RI Nakamura, Takashi/P-7796-2016 OI Nakamura, Takashi/0000-0001-9904-1037 FU NIDCR, National Institutes of Health; Ministry of Education, Science, and Culture of Japan [20679006, 21792054, 21792154]; NEXT program [LS010]; Takeda Science Foundation FX This work was supported, in whole or in part, by the Intramural Research Program of the NIDCR, National Institutes of Health (to Y. Y.). This work was also supported by Grants-in-aid 20679006 (to S. F.), 21792054 (to A. Y.), 21792154 (to E. F.) from the Ministry of Education, Science, and Culture of Japan, and the NEXT program (LS010, to S. F.), and by grants from the Takeda Science Foundation. NR 42 TC 37 Z9 40 U1 1 U2 18 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2012 VL 287 IS 13 BP 10590 EP 10601 DI 10.1074/jbc.M111.285874 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 917IN UT WOS:000302167200084 PM 22298769 ER PT J AU Fleming, JM Ginsburg, E Goldhar, AS Plant, J Vonderhaar, BK AF Fleming, Jodie M. Ginsburg, Erika Goldhar, Anita S. Plant, Joshua Vonderhaar, Barbara K. TI Progesterone Receptor Activates Msx2 Expression by Downregulating TNAP/Akp2 and Activating the Bmp Pathway in EpH4 Mouse Mammary Epithelial Cells SO PLOS ONE LA English DT Article ID BREAST-CANCER CELLS; HORMONE REPLACEMENT THERAPY; MESENCHYMAL TRANSITION; GLAND DEVELOPMENT; BONE METASTASIS; GENE-REGULATION; ESTROGEN; GROWTH; PROLIFERATION; ALK2 AB Previously we demonstrated that EpH4 mouse mammary epithelial cells induced the homeobox transcription factor Msx2 either when transfected with the progesterone receptor (PR) or when treated with Bmp2/4. Msx2 upregulation was unaffected by Wnt inhibitors s-FRP or Dkk1, but was inhibited by the Bmp antagonist Noggin. We therefore hypothesized that PR signaling to Msx2 acts through the Bmp receptor pathway. Herein, we confirm that transcripts for Alk2/ActR1A, a non-canonical BmpR Type I, are upregulated in mammary epithelial cells overexpressing PR (EpH4-PR). Increased phosphorylation of Smads 1,5, 8, known substrates for Alk2 and other BmpR Type I proteins, was observed as was their translocation to the nucleus in EpH4-PR cells. Analysis also showed that Tissue Non-Specific Alkaline Phosphatase (TNAP/Akp2) was also found to be downregulated in EpH4-PR cells. When an Akp2 promoter-reporter construct containing a 1/2PRE site was transfected into EpH4-PR cells, its expression was downregulated. Moreover, siRNA mediated knockdown of Akp2 increased both Alk2 and Msx2 expression. Collectively these data suggest that PR inhibition of Akp2 results in increased Alk2 activity, increased phosphorylation of Smads 1,5,8, and ultimately upregulation of Msx2. These studies imply that reactivation of the Akp2 gene could be helpful in downregulating aberrant Msx2 expression in PR+ breast cancers. C1 [Fleming, Jodie M.; Ginsburg, Erika; Goldhar, Anita S.; Plant, Joshua; Vonderhaar, Barbara K.] NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Fleming, Jodie M.] N Carolina Cent Univ, Dept Biol, Durham, NC USA. RP Fleming, JM (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM ginsbure@mail.nih.gov FU NCI NIH HHS [SC2 CA176585] NR 46 TC 1 Z9 1 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 22 PY 2012 VL 7 IS 3 AR e34058 DI 10.1371/journal.pone.0034058 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 940QX UT WOS:000303909200041 PM 22457812 ER PT J AU Nader, N Ng, SSM Wang, YH Abel, BS Chrousos, GP Kino, T AF Nader, Nancy Ng, Sinnie Sin Man Wang, Yonghong Abel, Brent S. Chrousos, George P. Kino, Tomoshige TI Liver X Receptors Regulate the Transcriptional Activity of the Glucocorticoid Receptor: Implications for the Carbohydrate Metabolism SO PLOS ONE LA English DT Article ID PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE; POTENTIAL CLINICAL-IMPLICATIONS; RESPONSE ELEMENTS; ESTROGEN-RECEPTOR; NUCLEAR RECEPTORS; LIPID-METABOLISM; ACCESSORY FACTOR; LXR-ALPHA; RAT-LIVER; EXPRESSION AB GLUCOCORTICOIDS are steroid hormones that strongly influence intermediary carbohydrate metabolism by increasing the transcription rate of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, and suppress the immune system through the glucocorticoid receptor (GR). The liver X receptors (LXRs), on the other hand, bind to cholesterol metabolites, heterodimerize with the retinoid X receptor (RXR), and regulate the cholesterol turnover, the hepatic glucose metabolism by decreasing the expression of G6Pase, and repress a set of inflammatory genes in immune cells. Since the actions of these receptors overlap with each other, we evaluated the crosstalk between the GR- and LXR-mediated signaling systems. Transient transfection-based reporter assays and gene silencing methods using siRNAs for LXRs showed that overexpression/ligand (GW3965) activation of LXRs/RXRs repressed GR- stimulated transactivation of certain glucocorticoid response element (GRE)-driven promoters in a gene-specific fashion. Activation of LXRs by GW3965 attenuated dexamethasone-stimulated elevation of circulating glucose in rats. It also suppressed dexamethasone-induced mRNA expression of hepatic glucose-6-phosphatase (G6Pase) in rats, mice and human hepatoma HepG2 cells, whereas endogenous, unliganded LXRs were required for dexamethasone-induced mRNA expression of phosphoenolpyruvate carboxylase. In microarray transcriptomic analysis of rat liver, GW3965 differentially regulated glucocorticoid-induced transcriptional activity of about 15% of endogenous glucocorticoid-responsive genes. To examine the mechanism through which activated LXRs attenuated GR transcriptional activity, we examined LXR alpha/RXR alpha binding to GREs. Endogenous LXR alpha/RXR alpha bound GREs and inhibited GR binding to these DNA sequences both in in vitro and in vivo chromatin immunoprecipitation assays, while their recombinant proteins did so on classic or G6Pase GREs in gel mobility shift assays. We propose that administration of LXR agonists may be beneficial in glucocorticoid treatment- or stress-associated dysmetabolic states by directly and gene-specifically attenuating the transcriptional activity of the GR on glucose and/or lipid metabolism. C1 [Nader, Nancy; Ng, Sinnie Sin Man; Abel, Brent S.; Kino, Tomoshige] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, Natl Inst Hlth, Bethesda, MD USA. [Ng, Sinnie Sin Man] Chinese Univ Hong Kong, Sch Biomed Sci, Fac Med, Shatin, Hong Kong, Peoples R China. [Ng, Sinnie Sin Man] Hong Kong Special Adm Reg, Hong Kong, Hong Kong, Peoples R China. [Wang, Yonghong] Natl Canc Inst, Adv Technol Ctr, Natl Inst Hlth, Gaithersburg, MD USA. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. RP Nader, N (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Mol Hormone Act, Program Reprod & Adult Endocrinol, Natl Inst Hlth, Bethesda, MD USA. EM nadernancy@hotmail.com FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This study was funded by the Intramural Research Program of the 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 56 TC 17 Z9 17 U1 0 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 22 PY 2012 VL 7 IS 3 AR e26751 DI 10.1371/journal.pone.0026751 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 940QX UT WOS:000303909200001 PM 22457708 ER PT J AU Kozak, CA AF Kozak, Christine A. TI Viewpoint on Emv2, the onlhy endogenous ecotropic murine leukemia virus of C57BL/6 mice SO RETROVIROLOGY LA English DT Editorial Material ID STRAINS; GENES AB Here I comment on the articles by Lee and colleagues (Retrovirology 2011, 8: 82) and Lee and Cho (Retrovirology 2012, 9: 23) dealing with an endogenous ecotropic mouse leukemia virus found in C57BL mice. C1 NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), NIAID, Mol Microbiol Lab, Bldg 4,Room 329,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. EM ckozak@niaid.nih.gov NR 13 TC 2 Z9 2 U1 0 U2 1 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 MAR 22 PY 2012 VL 9 AR 25 DI 10.1186/1742-4690-9-25 PG 2 WC Virology SC Virology GA 933RG UT WOS:000303379200001 PM 22439739 ER PT J AU Kochenderfer, JN Dudley, ME Feldman, SA Wilson, WH Spaner, DE Maric, I Stetler-Stevenson, M Phan, GQ Hughes, MS Sherry, RM Yang, JC Kammula, US Devillier, L Carpenter, R Nathan, DAN Morgan, RA Laurencot, C Rosenberg, SA AF Kochenderfer, James N. Dudley, Mark E. Feldman, Steven A. Wilson, Wyndham H. Spaner, David E. Maric, Irina Stetler-Stevenson, Maryalice Phan, Giao Q. Hughes, Marybeth S. Sherry, Richard M. Yang, James C. Kammula, Udai S. Devillier, Laura Carpenter, Robert Nathan, Debbie-Ann N. Morgan, Richard A. Laurencot, Carolyn Rosenberg, Steven A. TI B-cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; HIGH-DOSE INTERLEUKIN-2; NON-HODGKIN-LYMPHOMA; PHASE-I TRIAL; ANTITUMOR-ACTIVITY; ADOPTIVE IMMUNOTHERAPY; MONOCLONAL-ANTIBODY; CANCER-PATIENTS; ADVERSE EVENT AB We conducted a clinical trial to assess adoptive transfer of T cells genetically modified to express an anti-CD19 chimeric Ag receptor (CAR). Our clinical protocol consisted of chemotherapy followed by an infusion of anti-CD19-CAR-transduced T cells and a course of IL-2. Six of the 8 patients treated on our protocol obtained remissions of their advanced, progressive B-cell malignancies. Four of the 8 patients treated on the protocol had long-term depletion of normal polyclonal CD19(+) B-lineage cells. Cells containing the anti-CD19 CAR gene were detected in the blood of all patients. Four of the 8 treated patients had prominent elevations in serum levels of the inflammatory cytokines IFN gamma and TNF. The severity of acute toxicities experienced by the patients correlated with serum IFN gamma and TNF levels. The infused anti-CD19-CAR-transduced T cells were a possible source of these inflammatory cytokines because we demonstrated peripheral blood T cells that produced TNF and IFN gamma ex vivo in a CD19-specific manner after anti-CD19-CAR-transduced T-cell infusions. Anti-CD19-CAR-transduced T cells have great promise to improve the treatment of B-cell malignancies because of a potent ability to eradicate CD19(+) cells in vivo; however, reversible cytokine-associated toxicities occurred after CAR-transduced T-cell infusions. This trial was registered with ClinicalTrials.gov as NCT00924326. (Blood. 2012; 119(12): 2709-2720) C1 [Kochenderfer, James N.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. [Dudley, Mark E.; Feldman, Steven A.; Phan, Giao Q.; Hughes, Marybeth S.; Sherry, Richard M.; Yang, James C.; Kammula, Udai S.; Devillier, Laura; Nathan, Debbie-Ann N.; Morgan, Richard A.; Laurencot, Carolyn; Rosenberg, Steven A.] NCI, Surg Branch, Bethesda, MD 20892 USA. [Wilson, Wyndham H.] NCI, Metab Branch, Bethesda, MD 20892 USA. [Spaner, David E.] Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. [Maric, Irina] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice] NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Kochenderfer, JN (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, 10 Ctr Dr,CRC Rm 3-3330, Bethesda, MD 20892 USA. EM kochendj@mail.nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This work was supported by intramural funding of the Center for Cancer Research, National Cancer Institute, National Institutes of Health. NR 50 TC 474 Z9 495 U1 12 U2 70 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 MAR 22 PY 2012 VL 119 IS 12 BP 2709 EP 2720 DI 10.1182/blood-2011-10-384388 PG 12 WC Hematology SC Hematology GA 916RU UT WOS:000302121700007 PM 22160384 ER PT J AU Thomas, A Mailankody, S Korde, N Kristinsson, SY Turesson, I Landgren, O AF Thomas, Anish Mailankody, Sham Korde, Neha Kristinsson, Sigurdur Y. Turesson, Ingemar Landgren, Ola TI Second malignancies after multiple myeloma: from 1960s to 2010s SO BLOOD LA English DT Review ID ATOMIC-BOMB SURVIVORS; SEER CANCER REGISTRIES; PLASMA-CELL MYELOMA; UNDETERMINED SIGNIFICANCE; MYELODYSPLASTIC SYNDROME; MONOCLONAL GAMMOPATHY; HODGKINS-DISEASE; ACUTE-LEUKEMIA; UNITED-STATES; BREAST-CANCER AB Based on small numbers, recent reports from 3 randomized trials have consistently demonstrated more hematologic malignancies in patients treated with lenalidomide as maintenance (vs placebo). This fact has prompted concern and highlighted the association between multiple myeloma and second malignancies. Furthermore, an excess of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) after multiple myeloma has been known for over 4 decades. Most prior studies have been restricted because of small numbers of patients, inadequate follow-up, and limitations of ascertainment of second malignancies. Although the underlying biologic mechanisms of AML/MDS after multiple myeloma are unknown, treatment-related factors are presumed to be responsible. Recently, an excess risk of AML/MDS was found among 5652 patients with IgG/IgA (but not IgM) monoclonal gammopathy of undetermined significance, supporting a role for disease-related factors. Furthermore, there is evidence to suggest that polymorphisms in germline genes may contribute to a person's susceptibility to subsequent cancers, whereas the potential influence of environmental and behavioral factors remains poorly understood. This review discusses current knowledge regarding second malignancies after multiple myeloma and gives future directions for efforts designed to characterize underlying biologic mechanisms, with the goal to maximize survival and minimize the risk for second malignancies for individual patients. (Blood. 2012; 119(12): 2731-2737) C1 [Landgren, Ola] NCI, Multiple Myeloma Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. [Kristinsson, Sigurdur Y.] Karolinska Univ Hosp & Inst, Dept Med, Stockholm, Sweden. [Turesson, Ingemar] Skane Univ Hosp, Div Med, Malmo, Sweden. RP Landgren, O (reprint author), NCI, Multiple Myeloma Sect, Metab Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 13N240, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov RI Kristinsson, Sigurdur /M-2910-2015; OI Kristinsson, Sigurdur /0000-0002-4964-7476; Thomas, Anish/0000-0003-3293-3115 FU National Cancer Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute of the National Institutes of Health. NR 71 TC 50 Z9 52 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 MAR 22 PY 2012 VL 119 IS 12 BP 2731 EP 2737 DI 10.1182/blood-2011-12-381426 PG 7 WC Hematology SC Hematology GA 916RU UT WOS:000302121700009 PM 22310913 ER PT J AU Simhadri, VR Andersen, JF Calvo, E Choi, SC Coligan, JE Borrego, F AF Simhadri, Venkateswara R. Andersen, John F. Calvo, Eric Choi, Seung-Chul Coligan, John E. Borrego, Francisco TI Human CD300a binds to phosphatidylethanolamine and phosphatidylserine, and modulates the phagocytosis of dead cells SO BLOOD LA English DT Article ID RECEPTOR IRP60 CD300A; IMMUNOGLOBULIN-LIKE RECEPTORS; INHIBITORY RECEPTOR; APOPTOTIC CELLS; ANNEXIN-V; GENERAL FEATURE; NK CELLS; B-CELLS; CLEARANCE; IDENTIFICATION AB CD300a is an immunoreceptor tyrosine-based inhibitory motif (ITIM) containing molecule that belongs to the CD300 family of paired activating/inhibitory receptors. It has been shown that its ligation inhibits activation signals on cells of both myeloid and lymphoid lineages. The ligands for CD300a have not been identified. Here, we show that a CD300a-Ig fusion protein specifically binds to apoptotic cells that are evolutionary apart, such as human and insect cells, suggesting that the ligand has to be conserved. Using surface plasmon resonance, ultracentrifugation, ELISA, and reporter cell assays, we identified phosphatidylethanolamine (PE) and phosphatidylserine (PS), 2 phospholipids that translocate to the outer leaflet of the plasma membrane of dead cells, as the ligands for CD300a. Mutational and structural modeling studies identified residues that are involved in the binding of CD300a to PE and PS and that form a cavity where the hydrophilic heads of PE and PS, can penetrate. CD300a down-regulates the uptake of apoptotic cells by macrophages and its ectopic expression in CD300a-negative cell lines also decreased the engulfment of dead cells. Collectively, our results indicate that PE and PS are ligands for CD300a, and that this interaction plays an important role in regulating the removal of dead cells. (Blood. 2012; 119(12): 2799-2809) C1 [Simhadri, Venkateswara R.; Borrego, Francisco] US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. [Andersen, John F.; Calvo, Eric] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Choi, Seung-Chul; Coligan, John E.] NIAID, Receptor Cell Biol Sect, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. RP Borrego, F (reprint author), US FDA, Lab Mol & Dev Immunol, Div Monoclonal Antibodies, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Bdg 29B,Rm 3NN18,29 Lincoln Dr,HFD-123, Bethesda, MD 20892 USA. EM francisco.borrego@fda.hhs.gov OI Calvo, Eric/0000-0001-7880-2730 FU Food and Drug Administration; National Institute of Allergy and Infectious Diseases FX This work was funded by the intramural programs of the Food and Drug Administration and the National Institute of Allergy and Infectious Diseases. NR 50 TC 55 Z9 56 U1 0 U2 2 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 MAR 22 PY 2012 VL 119 IS 12 BP 2799 EP 2809 DI 10.1182/blood-2011-08-372425 PG 11 WC Hematology SC Hematology GA 916RU UT WOS:000302121700017 PM 22302738 ER PT J AU Kim, YC Bhairavabhotla, R Yoon, J Golding, A Thornton, AM Tran, DQ Shevach, EM AF Kim, Yong Chan Bhairavabhotla, Ravikiran Yoon, Jeongheon Golding, Amit Thornton, Angela M. Tran, Dat Q. Shevach, Ethan M. TI Oligodeoxynucleotides stabilize Helios-expressing Foxp3(+) human T regulatory cells during in vitro expansion SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; TGF-BETA; VIVO AB Foxp3(+) regulatory T cells (Tregs) maintain self-tolerance and adoptive therapy, and using Foxp3(+) Tregs has been proposed as treatment for autoimmune diseases. The clinical use of Tregs will require large numbers of cells and methods for in vitro expansion of Tregs are being developed. Foxp3(+) Tregs can be divided into 2 subpopulations based on expression of the transcription factor, Helios. Foxp3(+) Helios(+) Tregs (70%) are thymic-derived, whereas Foxp3(+) Helios(-) Tregs (30%) are induced in the periphery. Foxp3(+) Helios(+) Tregs differ from Foxp3(+) Helios(-) Tregs in terms of epigenetic changes at the Foxp3 locus, their capacity to produce effector cytokines, and their stability of Foxp3 expression on days to weeks of expansion in vitro. Addition of a 25 mer DNA oligonucleotide of random composition for a short period during the expansion of Foxp3(+) Tregs in vitro results in prolonged stabilization of the Foxp3(+)Helios(+) subpopulation and yields an optimal population for use in cellular biotherapy. (Blood. 2012; 119(12): 2810-2818) C1 [Kim, Yong Chan; Bhairavabhotla, Ravikiran; Golding, Amit; Thornton, Angela M.; Shevach, Ethan M.] NIAID, Labs Immunol, NIH, Bethesda, MD 20892 USA. [Tran, Dat Q.] Univ Texas Med Sch, Dept Pediat, Houston, TX USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 11N315, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov OI Golding, Amit/0000-0003-3659-6654 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID) FX This study was supported by funds from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID). NR 24 TC 54 Z9 54 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 MAR 22 PY 2012 VL 119 IS 12 BP 2810 EP 2818 DI 10.1182/blood-2011-09-377895 PG 9 WC Hematology SC Hematology GA 916RU UT WOS:000302121700018 PM 22294730 ER PT J AU Recher, M Burns, SO de la Fuente, MA Volpi, S Dahlberg, C Walter, JE Moffitt, K Mathew, D Honke, N Lang, PA Patrizi, L Falet, H Keszei, M Mizui, M Csizmadia, E Candotti, F Nadeau, K Bouma, G Delmonte, OM Frugoni, F Fomin, ABF Buchbinder, D Lundequist, EM Massaad, MJ Tsokos, GC Hartwig, J Manis, J Terhorst, C Geha, RS Snapper, S Lang, KS Malley, R Westerberg, L Thrasher, AJ Notarangelo, LD AF Recher, Mike Burns, Siobhan O. de la Fuente, Miguel A. Volpi, Stefano Dahlberg, Carin Walter, Jolan E. Moffitt, Kristin Mathew, Divij Honke, Nadine Lang, Philipp A. Patrizi, Laura Falet, Herve Keszei, Marton Mizui, Masayuki Csizmadia, Eva Candotti, Fabio Nadeau, Kari Bouma, Gerben Delmonte, Ottavia M. Frugoni, Francesco Fomin, Angela B. Ferraz Buchbinder, David Lundequist, Emma Maria Massaad, Michel J. Tsokos, George C. Hartwig, John Manis, John Terhorst, Cox Geha, Raif S. Snapper, Scott Lang, Karl S. Malley, Richard Westerberg, Lisa Thrasher, Adrian J. Notarangelo, Luigi D. TI B cell-intrinsic deficiency of the Wiskott-Aldrich syndrome protein (WASp) causes severe abnormalities of the peripheral B-cell compartment in mice SO BLOOD LA English DT Article ID SPLENIC MARGINAL ZONE; REGULATORY T-CELLS; DENDRITIC CELLS; SYNAPSE FORMATION; IMMUNE-RESPONSE; IN-VITRO; AUTOIMMUNITY; HOMEOSTASIS; ACTIVATION; EXPANSION AB Wiskott Aldrich syndrome (WAS) is caused by mutations in the WAS gene that encodes for a protein (WASp) involved in cytoskeleton organization in hematopoietic cells. Several distinctive abnormalities of T, B, and natural killer lymphocytes; dendritic cells; and phagocytes have been found in WASp-deficient patients and mice; however, the in vivo consequence of WASp deficiency within individual blood cell lineages has not been definitively evaluated. By conditional gene deletion we have generated mice with selective deficiency of WASp in the B-cell lineage (B/WcKO mice). We show that this is sufficient to cause a severe reduction of marginal zone B cells and inability to respond to type II T-independent Ags, thereby recapitulating phenotypic features of complete WASp deficiency. In addition, B/WcKO mice showed prominent signs of B-cell dysregulation, as indicated by an increase in serum IgM levels, expansion of germinal center B cells and plasma cells, and elevated autoantibody production. These findings are accompanied by hyperproliferation of WASp-deficient follicular and germinal center B cells in heterozygous B/WcKO mice in vivo and excessive differentiation of WASp-deficient B cells into class-switched plasmablasts in vitro, suggesting that WASp-dependent B cell-intrinsic mechanisms critically contribute to WAS-associated autoimmunity. (Blood. 2012;119(12):2819-2828) C1 [Recher, Mike; de la Fuente, Miguel A.; Volpi, Stefano; Walter, Jolan E.; Mathew, Divij; Patrizi, Laura; Delmonte, Ottavia M.; Frugoni, Francesco; Fomin, Angela B. Ferraz; Lundequist, Emma Maria; Massaad, Michel J.; Geha, Raif S.; Notarangelo, Luigi D.] Childrens Hosp, Div Immunol, Boston, MA 02115 USA. [Recher, Mike; de la Fuente, Miguel A.; Volpi, Stefano; Walter, Jolan E.; Mathew, Divij; Patrizi, Laura; Delmonte, Ottavia M.; Frugoni, Francesco; Fomin, Angela B. Ferraz; Lundequist, Emma Maria; Massaad, Michel J.; Geha, Raif S.; Notarangelo, Luigi D.] Manton Ctr Orphan Dis Res, Boston, MA USA. [Burns, Siobhan O.; Bouma, Gerben; Thrasher, Adrian J.] Inst Child Hlth, Ctr Immunodeficiency, Mol Immunol Unit, London, England. [Burns, Siobhan O.; Thrasher, Adrian J.] Great Ormond St Hosp Children Natl Hlth Serv Trus, London, England. [de la Fuente, Miguel A.] Univ Valladolid, Inst Biol & Genet Mol, E-47002 Valladolid, Spain. [Dahlberg, Carin; Westerberg, Lisa] Karolinska Inst, Dept Med, Translat Immunol Unit, Stockholm, Sweden. [Moffitt, Kristin; Malley, Richard] Childrens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Honke, Nadine; Lang, Philipp A.; Lang, Karl S.] Univ Dusseldorf, Dept Gastroenterol Hepatol & Infectiol, D-40225 Dusseldorf, Germany. [Falet, Herve; Hartwig, John] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Translat Med,Brigham & Womens Hosp, Boston, MA 02115 USA. [Keszei, Marton; Terhorst, Cox] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Immunol, Boston, MA 02215 USA. [Mizui, Masayuki; Tsokos, George C.] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Rheumatol, Boston, MA 02215 USA. [Csizmadia, Eva] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Transplantat Inst,Dept Med, Boston, MA 02215 USA. [Candotti, Fabio] NHGRI, Disorders Immun Sect, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. [Nadeau, Kari] Stanford Med Sch, Div Immunol & Allergy, Stanford, CA USA. [Nadeau, Kari] Lucile Packard Childrens Hosp, Stanford, CA USA. [Buchbinder, David] Univ Calif Irvine, Childrens Hosp Orange Cty, Div Pediat Hematol, Orange, CA USA. [Manis, John] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Snapper, Scott] Harvard Univ, Sch Med, Childrens Hosp Boston, Div Gastroenterol, Boston, MA USA. [Lang, Karl S.] Univ Essen Gesamthsch, Inst Immunol, Essen, Germany. RP Thrasher, AJ (reprint author), UCL Inst Child Hlth, Ctr Immunodeficiency, Mol Immunol Unit, 30 Guilford St, London WC1N 1EH, England. EM a.thrasher@ich.ucl.ac.uk; luigi.notarangelo@childrens.harvard.edu RI de la Fuente, Miiguel /C-7478-2013; Dahlberg, Carin/N-1625-2013; Keszei, Marton/F-3295-2014; Volpi, Stefano/O-3717-2014; Notarangelo, Luigi/F-9718-2016; Lang, Karl/R-2505-2016; OI Falet, Herve/0000-0003-0788-9204; de la Fuente, Miiguel /0000-0003-4619-8756; Dahlberg, Carin/0000-0002-8610-6302; Keszei, Marton/0000-0002-1158-2179; Volpi, Stefano/0000-0002-7129-868X; Notarangelo, Luigi/0000-0002-8335-0262; Bouma, Gerben/0000-0002-1465-9178; Westerberg, Lisa/0000-0003-2943-2192; Frugoni, Francesco/0000-0002-1769-8121 FU National Institutes of Health [2PO1HL059561-11-A1]; Manton Foundation; Swiss National Science Foundation (SNSF/SSMBS) [PASMP3-127678]; Karolinska Institutet; Swedish Research Foundation; FIS-ISCIII [PI10/02 511]; Consejeria de Educacion [VA244A11-2]; Wellcome Trust; Primary Immunodeficiency Association through the Academy of Medical Sciences FX This work was supported by the National Institutes of Health (grant 2PO1HL059561-11-A1, L.D.N.) and the Manton Foundation (L.D.N.); the Swiss National Science Foundation (SNSF/SSMBS; grant PASMP3-127678, M. R.); the Karolinska Institutet (L. W.); the Swedish Research Foundation (L. W.); FIS-ISCIII (grant PI10/02 511, M.A.d.l.F.); Consejeria de Educacion (M.A.d.l.F.; grant VA244A11-2, J.d.C.y.L.); the Wellcome Trust (A.J.T. and G. B.); and by a grant from the Primary Immunodeficiency Association through the Academy of Medical Sciences (S.O.B.). NR 48 TC 42 Z9 44 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 22 PY 2012 VL 119 IS 12 BP 2819 EP 2828 DI 10.1182/blood-2011-09-379412 PG 10 WC Hematology SC Hematology GA 916RU UT WOS:000302121700019 PM 22302739 ER PT J AU Enose-Akahata, Y Abrams, A Johnson, KR Maloney, EM Jacobson, S AF Enose-Akahata, Yoshimi Abrams, Anna Johnson, Kory R. Maloney, Elizabeth M. Jacobson, Steven TI Quantitative differences in HTLV-I antibody responses: classification and relative risk assessment for asymptomatic carriers and ATL and HAM/TSP patients from Jamaica SO BLOOD LA English DT Article ID VIRUS TYPE-I; T-CELL LEUKEMIA; MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; PROVIRAL DNA LOAD; PERIPHERAL-BLOOD; NATURAL-HISTORY; LEUKEMIA/LYMPHOMA; DISEASE; LYMPHOCYTES; INFECTION AB Adult T-cell leukemia (ATL) and human T-cell lymphotropic virus type I (HTLV-I)associated myelopathy/tropical spastic paraparesis (HAM/TSP) are known to be caused by HTLV-I infection. However, current methods used to determine HTLV-I infection do not differentiate between HTLV-I asymptomatic carriers (ACs) and ATL and HAM/TSP patients. Using the luciferase immunoprecipitation system, a highly sensitive, quantitative technology that can efficiently detect HTLV-I Ab responses, we examined Ab responses for HTLV-I in serum/plasma samples from 439 subjects in Jamaica, including HTLVI- seronegative donors, ACs, and ATL and HAM/TSP patients. The Ab responses of HTLV-I-infected subjects differed significantly from those of seronegative donors for all 3 immunodominant proteins, Gag, Env, and Tax. HAM/TSP patients had significantly higher Ab responses for Gag and Env compared with ACs, and Ab responses for all 3 Ags were higher in HAM/TSP patients than in ATL patients. Moreover, immunoreactivities for HTLV-I Ags as determined by the luciferase immunoprecipitation system could distinguish HAM/TSP patients from ACs at a true-positive rate of 85.42% and from ATL patients at a true-positive rate of 75.00%, and modeled in conjunction with subject information to distinguish HAM/TSP patients from ACs (odds ratio=14.12) and from ATL patients (odds ratio=7.00). The relative risk assessment resulting from these significant differences between Ab responses in HTLVI-infected groups may be a useful diagnostic tool in the future. (Blood. 2012; 119(12): 2829-2836) C1 [Enose-Akahata, Yoshimi; Abrams, Anna; Jacobson, Steven] NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Johnson, Kory R.] NINDS, Informat Technol & Bioinformat Program, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Maloney, Elizabeth M.] US FDA, Div Epidemiol 2, Off Surveillance & Epidemiol, Silver Spring, MD USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke, NIH FX This research was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, NIH. NR 46 TC 11 Z9 11 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 22 PY 2012 VL 119 IS 12 BP 2829 EP 2836 DI 10.1182/blood-2011-11-390807 PG 8 WC Hematology SC Hematology GA 916RU UT WOS:000302121700020 PM 22318200 ER PT J AU Greenblatt, S Li, L Slape, C Nguyen, B Novak, R Duffield, A Huso, D Desiderio, S Borowitz, MJ Aplan, P Small, D AF Greenblatt, Sarah Li, Li Slape, Christopher Bao Nguyen Novak, Rachel Duffield, Amy Huso, David Desiderio, Stephen Borowitz, Michael J. Aplan, Peter Small, Donald TI Knock-in of a FLT3/ITD mutation cooperates with a NUP98-HOXD13 fusion to generate acute myeloid leukemia in a mouse model SO BLOOD LA English DT Article ID INTERNAL TANDEM DUPLICATION; ACUTE MYELOGENOUS LEUKEMIA; WILD-TYPE ALLELE; HEMATOPOIETIC STEM-CELLS; BONE-MARROW; MYELODYSPLASTIC SYNDROME; EXPRESSION PATTERN; RECEPTOR GENE; HOX GENES; EX-VIVO AB Constitutive activation of FLT3 by internal tandem duplication (ITD) is one of the most common molecular alterations in acute myeloid leukemia (AML). FLT3/ITD mutations have also been observed in myelodysplastic syndrome patients both before and during progression to AML. Previous work has shown that insertion of an FLT3/ITD mutation into the murine Flt3 gene induces a myeloproliferative neoplasm, but not progression to acute leukemia, suggesting that additional cooperating events are required. We therefore combined the FLT3/ITD mutation with a model of myelodysplastic syndrome involving transgenic expression of the Nup98-HoxD13 (NHD13) fusion gene. Mice expressing both the FLT3/ITD and NHD13 transgene developed AML with 100% penetrance and short latency. These leukemias were driven by mutant FLT3 expression and were susceptible to treatment with FLT3 tyrosine kinase inhibitors. We also observed a spontaneous loss of the wild-type Flt3 allele in these AMLs, further modeling the loss of the heterozygosity phenomenon that is seen in human AML with FLT3-activating mutations. Because resistance to FLT3 inhibitors remains an important clinical issue, this model may help identify new molecular targets in collaborative signaling pathways. (Blood. 2012;119(12):2883-2894) C1 [Greenblatt, Sarah; Li, Li; Bao Nguyen; Small, Donald] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Slape, Christopher] Monash Univ, Cent Clin Sch, Melbourne, Vic 3004, Australia. [Novak, Rachel; Aplan, Peter] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Duffield, Amy; Borowitz, Michael J.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Huso, David] Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21205 USA. [Desiderio, Stephen] Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. [Small, Donald] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. RP Small, D (reprint author), Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, CRB Rm 251,1650 Orleans St, Baltimore, MD 21231 USA. EM donsmall@jhmi.edu RI Aplan, Peter/K-9064-2016; Slape, Christopher/H-8586-2016 OI Slape, Christopher/0000-0002-8407-3092 FU National Cancer Institute [CA90668, CA70970]; Leukemia & Lymphoma Society; Giant Food Pediatric Cancer Research Fund; National Institutes of Health, National Cancer Institute; Kyle Haydock Professorship FX This work was supported by the National Cancer Institute (CA90668, CA70970), Leukemia & Lymphoma Society, the Giant Food Pediatric Cancer Research Fund, and the Intramural Research Program of the National Institutes of Health, National Cancer Institute. D. S. is also supported by the Kyle Haydock Professorship. NR 47 TC 28 Z9 29 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 22 PY 2012 VL 119 IS 12 BP 2883 EP 2894 DI 10.1182/blood-2011-10-382283 PG 12 WC Hematology SC Hematology GA 916RU UT WOS:000302121700026 PM 22323452 ER PT J AU Zhang, Y Morgan, MJ Chen, K Choksi, S Liu, ZG AF Zhang, Yan Morgan, Michael J. Chen, Kun Choksi, Swati Liu, Zheng-gang TI Induction of autophagy is essential for monocyte-macrophage differentiation SO BLOOD LA English DT Article ID VITAMIN-D3 INDUCES AUTOPHAGY; MEDIATED CLEAVAGE; HUMAN MONOCYTES/MACROPHAGES; SELF-DIGESTION; T-LYMPHOCYTES; CELL-DEATH; C-ELEGANS; LIFE-SPAN; BECLIN 1; APOPTOSIS AB Monocytes are programmed to undergo apoptosis in the absence of stimulation. Stimuli that promote monocyte-macrophage differentiation not only cause cellular changes, but also prevent the default apoptosis of monocytes. In the present study, we demonstrate that autophagy is induced when monocytes are triggered to differentiate and that the induction of autophagy is pivotal for the survival and differentiation of monocytes. We also show that inhibition of autophagy results in apoptosis of cells that are engaged in differentiation. We found that the differentiation signal releases Beclin1 from Bcl-2 by activating JNK and blocks Atg5 cleavage, both of which are critical for the induction of autophagy. Preventing autophagy induction hampers differentiation and cytokine production; therefore, autophagy is an important transition from monocyte apoptosis to differentiation. (Blood. 2012;119(12):2895-2905) C1 [Zhang, Yan; Choksi, Swati; Liu, Zheng-gang] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Morgan, Michael J.] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO USA. [Chen, Kun] Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Jiangsu Diabet Res Ctr, Sch Life Sci, Nanjing 210008, Peoples R China. RP Liu, ZG (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bldg 37,Rm 1130,37 Convent Dr, Bethesda, MD 20892 USA. EM zgliu@helix.nih.gov FU Center for Cancer Research (NCI) FX This study was supported by the Intramural Research Program of The Center for Cancer Research (NCI). NR 50 TC 65 Z9 66 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 MAR 22 PY 2012 VL 119 IS 12 BP 2895 EP 2905 DI 10.1182/blood-2011-08-372383 PG 11 WC Hematology SC Hematology GA 916RU UT WOS:000302121700027 PM 22223827 ER PT J AU Hardy, NM Fellowes, V Rose, JJ Odom, J Pittaluga, S Steinberg, SM Blacklock-Schuver, B Avila, DN Memon, S Kurlander, RJ Khuu, HM Stetler-Stevenson, M Mena, E Dwyer, AJ Levine, BL June, CH Reshef, R Vonderheide, RH Gress, RE Fowler, DH Hakim, FT Bishop, MR AF Hardy, Nancy M. Fellowes, Vicki Rose, Jeremy J. Odom, Jeanne Pittaluga, Stefania Steinberg, Seth M. Blacklock-Schuver, Bazetta Avila, Daniele N. Memon, Sarfraz Kurlander, Roger J. Khuu, Hahn M. Stetler-Stevenson, Maryalice Mena, Esther Dwyer, Andrew J. Levine, Bruce L. June, Carl H. Reshef, Ran Vonderheide, Robert H. Gress, Ronald E. Fowler, Daniel H. Hakim, Frances T. Bishop, Michael R. TI Costimulated tumor-infiltrating lymphocytes are a feasible and safe alternative donor cell therapy for relapse after allogeneic stem cell transplantation SO BLOOD LA English DT Article ID I CLINICAL-TRIAL; T-CELLS; LEUKOCYTE INFUSIONS; PERSISTENCE; MALIGNANCY; REGRESSION; VIVO AB Donor lymphocyte infusion (DLI), a standard relapse treatment after allogeneic stem cell transplantation (AlloSCT), has limited efficacy and often triggers GVHD. We hypothesized that after AlloSCT tumor-infiltrating donor lymphocytes could be costimulated ex vivo to preferentially activate/expand antitumor effectors. We tested the feasibility and safety of costimulated, tumor-derived donor lymphocyte (TDL) infusion in a phase 1 trial. Tumor was resected from 8 patients with B-cell malignancy progression post-AlloSCT; tumor cell suspensions were costimulated with anti-CD3/anti-CD28 Ab-coated magnetic beads and cultured to generate TDL products for each patient. Costimulation yielded increased proportions of T-bet(+)FoxP3(-) type 1 effector donor T cells. A median of 2.04 x 10(7) TDL/kg was infused; TDLs were well tolerated, notably without GVHD. Two transient positron emission tomography (PET) responses and 2 mixed responses were observed in these refractory tumors. TDL are a feasible, tolerable, and novel donor cell therapy alternative for relapse after AlloSCT. This trial is registered at clinicaltrials.gov as no. NCT00445666. (Blood. 2012;119(12):2956-2959) C1 [Hardy, Nancy M.] NCI, Expt Transplantat & Immunol Branch, CCR, Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Pittaluga, Stefania; Stetler-Stevenson, Maryalice] NCI, CCR, Pathol Lab, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, CCR, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Kurlander, Roger J.] NCI, CCR, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Khuu, Hahn M.] NCI, CCR, Dept Transfus Med, CC, Bethesda, MD 20892 USA. [Mena, Esther] NCI, CCR, Mol Imaging Program, Bethesda, MD 20892 USA. [Dwyer, Andrew J.] NIH, Dept Radiol & Imagine Sci, CC, Bethesda, MD 20892 USA. [Levine, Bruce L.; June, Carl H.; Reshef, Ran; Vonderheide, Robert H.] Univ Penn, Dept Pathol & Lab Med, Abramson Canc Ctr, Perelman Sch Med, Philadelphia, PA 19104 USA. [Bishop, Michael R.] Med Coll Wisconsin, Div Hematol & Oncol, Ctr Clin Canc, Milwaukee, WI 53226 USA. RP Hardy, NM (reprint author), NCI, Expt Transplantat & Immunol Branch, CCR, Hatfield Clin Res Ctr, 10 Ctr Dr,Room 3E-3330, Bethesda, MD 20892 USA. EM hardyn@mail.nih.gov RI Levine, Bruce/D-1688-2009 FU Intramural National Cancer Institute, Center for Cancer Research (Bethesda, MD) FX This work was supported by the Intramural National Cancer Institute, Center for Cancer Research (Bethesda, MD). NR 18 TC 13 Z9 13 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAR 22 PY 2012 VL 119 IS 12 BP 2956 EP 2959 DI 10.1182/blood-2011-09-378398 PG 4 WC Hematology SC Hematology GA 916RU UT WOS:000302121700034 PM 22289893 ER PT J AU Molnar, Z Belgard, TG AF Molnar, Zoltan Belgard, T. Grant TI Transcriptional Profiling of Layers of the Primate Cerebral Cortex SO NEURON LA English DT Editorial Material ID HUMAN BRAIN; AREAS; RNA AB In this issue of Neuron, Bernard et al. (2012) report microarray-based transcriptional profiling of individually isolated layers from several cortical areas in adult Rhesus monkeys (Macaca mulatta). The resulting molecular signatures of neocortical organization are compared with human and mouse. C1 [Molnar, Zoltan; Belgard, T. Grant] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. [Belgard, T. Grant] Univ Oxford, MRC Funct Genom Unit, Oxford OX1 3QX, England. [Belgard, T. Grant] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Belgard, TG (reprint author), Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. EM zoltan.molnar@dpag.ox.ac.uk; grant@grantbelgard.com OI Molnar, Zoltan/0000-0002-6852-6004; Belgard, Tildon/0000-0002-6962-7894 FU Medical Research Council [G0900901] NR 15 TC 5 Z9 5 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 22 PY 2012 VL 73 IS 6 BP 1053 EP 1055 DI 10.1016/j.neuron.2012.03.007 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 915BU UT WOS:000301998700001 PM 22445331 ER PT J AU Johansen-Berg, H Baptista, CS Thomas, AG AF Johansen-Berg, Heidi Baptista, Cassandra Sampaio Thomas, Adam G. TI Human Structural Plasticity at Record Speed SO NEURON LA English DT Editorial Material AB How rapidly does learning shape our brains? A new study in this issue of Neuron by Sagi et al. (2012) that uses diffusion magnetic resonance imaging in both humans and rats suggests that just 2 hr of spatial learning is sufficient to change brain structure. C1 [Johansen-Berg, Heidi; Baptista, Cassandra Sampaio; Thomas, Adam G.] John Radcliffe Hosp, Oxford Ctr Funct MRI Brain, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England. [Thomas, Adam G.] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. RP Johansen-Berg, H (reprint author), John Radcliffe Hosp, Oxford Ctr Funct MRI Brain, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England. EM heidi@fmrib.ox.ac.uk OI , /0000-0002-7893-0289; Johansen-Berg, Heidi/0000-0002-4134-9730; Thomas, Adam/0000-0002-2850-1419 FU Intramural NIH HHS [Z99 MH999999]; Medical Research Council [G0700399]; Wellcome Trust [090955] NR 12 TC 25 Z9 25 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 22 PY 2012 VL 73 IS 6 BP 1058 EP 1060 DI 10.1016/j.neuron.2012.03.001 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 915BU UT WOS:000301998700003 PM 22445333 ER PT J AU Sharma, S Bhaumik, P Schmitz, W Venkatesan, R Hiltunen, JK Conzelmann, E Juffer, AH Wierenga, RK AF Sharma, Satyan Bhaumik, Prasenjit Schmitz, Werner Venkatesan, Rajaram Hiltunen, J. Kalervo Conzelmann, Ernst Juffer, Andre H. Wierenga, Rik K. TI The Enolization Chemistry of a Thioester-Dependent Racemase: The 1.4 angstrom Crystal Structure of a Reaction Intermediate Complex Characterized by Detailed QM/MM Calculations SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID METHYLACYL-COA RACEMASE; SERINE-PROTEASE CATALYSIS; BILE-ACID SYNTHESIS; MANDELATE RACEMASE; TRANSITION-STATE; MOLECULAR-DYNAMICS; CITRATE SYNTHASE; ENZYME CATALYSIS; ACTIVE-SITE; MYCOBACTERIUM-TUBERCULOSIS AB In the active site of the bacterial alpha-methylacyl-CoA racemase of Mycobacterium tuberculosis (MCR), the chirality of the 2-methyl branched C2-atom is interconverted between (S) and (R) isomers. Protein crystallographic data and quantum mechanics/molecular mechanics (QM/MM) computational approaches show that this interconversion is achieved via a planar enolate intermediate. The crystal structure, at 1.4 angstrom, visualizes the mode of binding of a reaction intermediate analogue, 2-methylacetoacetyl-CoA, in a well-defined planar enolate form. The computational studies confirm that in the conversion from (S) to (R), first a proton is abstracted by N delta 1 (His126), and subsequently the planar enolate form is reprotonated by O delta 2 (Asp156). The calculations also show that the negatively charged thioester oxygen of the enolate intermediate is stabilized by an oxyanion hole formed by N (Asp127), as well as by the side chain atoms of the catalytic residues, Asp 156 and His 126, both being protonated simultaneously, at the intermediate stage of the catalytic cycle. The computational analysis also reveals that the conversion of the (S)- to (R)- chirality is achieved by a movement of 1.7 angstrom of the chiral C2-carbon, with smaller shifts (approximately 1 angstrom) of the carbon atom of the 2-methyl group, the C3-atom of the fatty acid tail, and the C1-carbon and O1-oxygen atoms of the thioester moiety. C1 [Sharma, Satyan; Venkatesan, Rajaram; Hiltunen, J. Kalervo; Juffer, Andre H.; Wierenga, Rik K.] Univ Oulu, Bioctr Oulu, FI-90014 Oulu, Finland. [Sharma, Satyan; Venkatesan, Rajaram; Hiltunen, J. Kalervo; Juffer, Andre H.; Wierenga, Rik K.] Univ Oulu, Dept Biochem, FI-90014 Oulu, Finland. [Bhaumik, Prasenjit] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Schmitz, Werner; Conzelmann, Ernst] Univ Wurzburg, Theodor Boveri Inst Biowissensch, Biozentrum, D-97074 Wurzburg, Germany. RP Wierenga, RK (reprint author), Univ Oulu, Bioctr Oulu, POB 3000, FI-90014 Oulu, Finland. EM rik.wierenga@oulu.fi FU Academy of Finland; Sigrid Juselius Foundation FX We thank Paivi Pirilla for providing us with the 2-methylacetoacetyl-CoA. We thank the beamline scientists of ID 14-2 for excellent support. We thank CSC (Center of Scientific Computing) in Espoo (Finland) for providing computing power. This work was supported by grants from the Academy of Finland and the Sigrid Juselius Foundation. NR 76 TC 9 Z9 9 U1 2 U2 18 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 MAR 22 PY 2012 VL 116 IS 11 BP 3619 EP 3629 DI 10.1021/jp210185m PG 11 WC Chemistry, Physical SC Chemistry GA 912AV UT WOS:000301766700015 PM 22360758 ER PT J AU Narendra, DP Youle, RJ AF Narendra, Derek P. Youle, Richard J. TI NEURODEGENERATION Trouble in the cell's powerhouse SO NATURE LA English DT Editorial Material ID RECESSIVE SPASTIC ATAXIA; DYNAMIN-RELATED PROTEIN; DOMINANT OPTIC ATROPHY; CHARLEVOIX-SAGUENAY; MITOCHONDRIA; MUTATIONS; FISSION; ARSACS; OPA1 C1 [Narendra, Derek P.; Youle, Richard J.] Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Narendra, DP (reprint author), Natl Inst Neurol Disorders & Stroke, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 14 TC 10 Z9 10 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 MAR 22 PY 2012 VL 483 IS 7390 BP 418 EP 419 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 912CC UT WOS:000301771200033 PM 22398449 ER PT J AU Tsang, PS Cheuk, AT Chen, QR Song, YK Badgett, TC Wei, JS Khan, J AF Tsang, Patricia S. Cheuk, Adam T. Chen, Qing-Rong Song, Young K. Badgett, Thomas C. Wei, Jun S. Khan, Javed TI Synthetic Lethal Screen Identifies NF-kappa B as a Target for Combination Therapy with Topotecan for patients with Neuroblastoma SO BMC CANCER LA English DT Article ID CHILDRENS ONCOLOGY GROUP; GROUP PHASE-II; BONE-MARROW-TRANSPLANTATION; PROTEASOME INHIBITOR PS-341; HIGH-RISK NEUROBLASTOMA; CELL LUNG-CANCER; SOLID TUMORS; REFRACTORY NEUROBLASTOMA; TOPOISOMERASE-I; BORTEZOMIB AB Background: Despite aggressive multimodal treatments the overall survival of patients with high-risk neuroblastoma remains poor. The aim of this study was to identify novel combination chemotherapy to improve survival rate in patients with high-risk neuroblastoma. Methods: We took a synthetic lethal approach using a siRNA library targeting 418 apoptosis-related genes and identified genes and pathways whose inhibition synergized with topotecan. Microarray analyses of cells treated with topotecan were performed to identify if the same genes or pathways were altered by the drug. An inhibitor of this pathway was used in combination with topotecan to confirm synergism by in vitro and in vivo studies. Results: We found that there were nine genes whose suppression synergized with topotecan to enhance cell death, and the NF-kappa B signaling pathway was significantly enriched. Microarray analysis of cells treated with topotecan revealed a significant enrichment of NF-kappa B target genes among the differentially altered genes, suggesting that NF-kappa B pathway was activated in the treated cells. Combination of topotecan and known NF-kappa B inhibitors (NSC 676914 or bortezomib) significantly reduced cell growth and induced caspase 3 activity in vitro. Furthermore, in a neuroblastoma xenograft mouse model, combined treatment of topotecan and bortezomib significantly delayed tumor formation compared to single-drug treatments. Conclusions: Synthetic lethal screening provides a rational approach for selecting drugs for use in combination therapy and warrants clinical evaluation of the efficacy of the combination of topotecan and bortezomib or other NF-kappa B inhibitors in patients with high risk neuroblastoma. C1 [Tsang, Patricia S.; Cheuk, Adam T.; Chen, Qing-Rong; Song, Young K.; Badgett, Thomas C.; Wei, Jun S.; Khan, Javed] NCI, Oncogen Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Khan, J (reprint author), NCI, Oncogen Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We would like to thank Dr Paul Meltzer, Dr Natasha Caplen and Dr Scott Martin for providing the siRNA library and for useful discussions; and Dr David Azorsa for helpful technical advice. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 40 TC 6 Z9 7 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAR 21 PY 2012 VL 12 AR 101 DI 10.1186/1471-2407-12-101 PG 10 WC Oncology SC Oncology GA 951FC UT WOS:000304705200001 PM 22436457 ER PT J AU Ma, JL Zhang, L Brown, LM Li, JY Shen, L Pan, KF Liu, WD Hu, YR Han, ZX Crystal-Mansour, S Pee, D Blot, WJ Fraumeni, JF You, WC Gail, MH AF Ma, Jun-Ling Zhang, Lian Brown, Linda M. Li, Ji-You Shen, Lin Pan, Kai-Feng Liu, Wei-Dong Hu, Yuanreng Han, Zhong-Xiang Crystal-Mansour, Susan Pee, David Blot, William J. Fraumeni, Joseph F., Jr. You, Wei-Cheng Gail, Mitchell H. TI Fifteen-Year Effects of Helicobacter pylori, Garlic, and Vitamin Treatments on Gastric Cancer Incidence and Mortality SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENERAL-POPULATION; FACTORIAL TRIAL; SUPPLEMENTATION; LINXIAN; LESIONS; REDUCE; CHINA; RISK AB In the Shandong Intervention Trial, 2 weeks of antibiotic treatment for Helicobacter pylori reduced the prevalence of precancerous gastric lesions, whereas 7.3 years of oral supplementation with garlic extract and oil (garlic treatment) or vitamin C, vitamin E, and selenium (vitamin treatment) did not. Here we report 14.7-year follow-up for gastric cancer incidence and cause-specific mortality among 3365 randomly assigned subjects in this masked factorial placebo-controlled trial. Conditional logistic regression was used to estimate the odds of gastric cancer incidence, and the Cox proportional hazards model was used to estimate the relative hazard of cause-specific mortality. All statistical tests were two-sided. Gastric cancer was diagnosed in 3.0% of subjects who received H pylori treatment and in 4.6% of those who received placebo (odds ratio = 0.61, 95% confidence interval = 0.38 to 0.96, P = .032). Gastric cancer deaths occurred among 1.5% of subjects assigned H pylon treatment and among 2.1% of those assigned placebo (hazard ratio [HR] of death = 0.67, 95% CI = 0.36 to 1.28). Garlic and vitamin treatments were associated with non-statistically significant reductions in gastric cancer incidence and mortality. Vitamin treatment was associated with statistically significantly fewer deaths from gastric or esophageal cancer, a secondary endpoint (HR = 0.51, 95% CI = 0.30 to 0.87; P = .014). C1 [Fraumeni, Joseph F., Jr.; Gail, Mitchell H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ma, Jun-Ling; Zhang, Lian; Li, Ji-You; Shen, Lin; Pan, Kai-Feng; You, Wei-Cheng] Peking Univ, Key Lab Carcinogenesis & Translat Res, Minist Educ, Sch Oncol,Beijing Canc Hosp, Beijing 100142, Peoples R China. [Ma, Jun-Ling; Zhang, Lian; Li, Ji-You; Shen, Lin; Pan, Kai-Feng; You, Wei-Cheng] Beijing Inst Canc Res, Beijing, Peoples R China. [Hu, Yuanreng; Crystal-Mansour, Susan] Westat Corp, Rockville, MD USA. [Pee, David] Informat Management Serv Inc, Rockville, MD USA. [Brown, Linda M.] RTI Int, Rockville, MD USA. [Blot, William J.] Int Epidemiol Inst Ltd, Rockville, MD USA. [Blot, William J.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8032, Bethesda, MD 20892 USA. EM weichengyou@yahoo.com; gailm@mail.nih.gov FU National Institutes of Health, National Cancer Institute; National Cancer Institute [NO2-CP-71103, NO2-CP-21169]; National Basic Research Program of China [2004CB518702, 2010CB529303] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and in part by National Cancer Institute Contracts NO2-CP-71103 and NO2-CP-21169. National Cancer Institute contracts also supported work at Westat and at Information Management Services. Additional support was from the National Basic Research Program of China (973 program: 2004CB518702 and 2010CB529303). NR 10 TC 130 Z9 149 U1 2 U2 42 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAR 21 PY 2012 VL 104 IS 6 BP 488 EP 492 DI 10.1093/jnci/djs003 PG 5 WC Oncology SC Oncology GA 913PF UT WOS:000301889200012 PM 22271764 ER PT J AU Derbyshire, MK Lanczycki, CJ Bryant, SH Marchler-Bauer, A AF Derbyshire, Myra K. Lanczycki, Christopher J. Bryant, Stephen H. Marchler-Bauer, Aron TI Annotation of functional sites with the Conserved Domain Database SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID PROTEIN; SEQUENCES; CDD AB The overwhelming fraction of proteins whose sequences have been collected in comprehensive databases may never be assessed for function experimentally. Commonly, putative function is assigned based on similarity to experimentally characterized homologs, either on the level of the entire protein or for single evolutionarily conserved domains. The annotation of individual sites provides more detailed insights regarding the correspondence between sequence and function, as well as context for the interpretation of sequence variation and the outcomes of experiments. In general, site annotation has to be extracted from the published literature, and can often be transferred to closely related sequence neighbors. The National Center for Biotechnology Information's Conserved Domain Database (CDD) provides a system for curators to record functional (such as active sites or binding sites for cofactors) or characteristic sites (such as signature motifs), which are conserved across domain families, and for the transfer of that annotation to protein database sequences via high-confidence domain matches. Recently, CDD curators have begun to sort-site annotations into seven categories (active, polypeptide binding, nucleic acid binding, ion binding, chemical binding, post-translational modification and other) and here we present a first comparative analysis of sites obtained via domain model matches, juxtaposed with existing site annotation encountered in high-quality data sets. Site annotation derived from domain annotation has the potential to cover large fractions of protein sequences, and we observe that CDD-based site annotation complements existing site annotation in many cases, which may, in part, originate from CDD's curation practice of collecting sites conserved across diverse taxa and supported by evidence from multiple 3D structures. C1 [Derbyshire, Myra K.; Lanczycki, Christopher J.; Bryant, Stephen H.; Marchler-Bauer, Aron] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Marchler-Bauer, A (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38 A,Room 8N805,8600 Rockville Pike, Bethesda, MD 20894 USA. EM bauer@ncbi.nlm.nih.gov OI Marchler-Bauer, Aron/0000-0003-1516-0712 FU National Library of Medicine at the National Institutes of Health/DHHS FX This work was funded by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health/DHHS. Funding for open access charge: Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS. Comments, suggestions, and questions are welcome and should be directed to: info@ncbi.nlm.nih.gov. NR 13 TC 6 Z9 7 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD MAR 20 PY 2012 AR bar058 DI 10.1093/database/bar058 PG 6 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 954CB UT WOS:000304922200002 ER PT J AU Harte, RA Farrell, CM Loveland, JE Suner, MM Wilming, L Aken, B Barrell, D Frankish, A Wallin, C Searle, S Diekhans, M Harrow, J Pruitt, KD AF Harte, Rachel A. Farrell, Catherine M. Loveland, Jane E. Suner, Marie-Marthe Wilming, Laurens Aken, Bronwen Barrell, Daniel Frankish, Adam Wallin, Craig Searle, Steve Diekhans, Mark Harrow, Jennifer Pruitt, Kim D. TI Tracking and coordinating an international curation effort for the CCDS Project SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID MESSENGER-RNA DECAY; OPEN READING FRAMES; EXOME CAPTURE; TRANSLATION; INITIATION; SEQUENCE; GENOME; CONSERVATION; TRANSCRIPTS; PROKARYOTES AB The Consensus Coding Sequence (CCDS) collaboration involves curators at multiple centers with a goal of producing a conservative set of high quality, protein-coding region annotations for the human and mouse reference genome assemblies. The CCDS data set reflects a 'gold standard' definition of best supported protein annotations, and corresponding genes, which pass a standard series of quality assurance checks and are supported by manual curation. This data set supports use of genome annotation information by human and mouse researchers for effective experimental design, analysis and interpretation. The CCDS project consists of analysis of automated whole-genome annotation builds to identify identical CDS annotations, quality assurance testing and manual curation support. Identical CDS annotations are tracked with a CCDS identifier (ID) and any future change to the annotated CDS structure must be agreed upon by the collaborating members. CCDS curation guidelines were developed to address some aspects of curation in order to improve initial annotation consistency and to reduce time spent in discussing proposed annotation updates. Here, we present the current status of the CCDS database and details on our procedures to track and coordinate our efforts. We also present the relevant background and reasoning behind the curation standards that we have developed for CCDS database treatment of transcripts that are nonsense-mediated decay (NMD) candidates, for transcripts containing upstream open reading frames, for identifying the most likely translation start codons and for the annotation of readthrough transcripts. Examples are provided to illustrate the application of these guidelines. C1 [Farrell, Catherine M.; Wallin, Craig; Pruitt, Kim D.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Harte, Rachel A.; Diekhans, Mark] Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. [Loveland, Jane E.; Suner, Marie-Marthe; Wilming, Laurens; Aken, Bronwen; Barrell, Daniel; Frankish, Adam; Searle, Steve; Harrow, Jennifer] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. RP Pruitt, KD (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM Pruitt@ncbi.nlm.nih.gov OI Aken, Bronwen/0000-0002-3032-4095; Wilming, Laurens/0000-0002-4154-7358 FU National Institutes of Health, National Library of Medicine; National Human Genome Research Institute (NHGRI) [5U54 HG004555, 5U54HG00455-04]; Wellcome Trust Sanger Institute [0244-03]; Wellcome Trust [WT077198, WT062023] FX The work done at NCBI was supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. Work done at UCSC has been funded with Federal funds from the National Human Genome Research Institute (NHGRI) for the ENCODE project (prime award 5U54 HG004555, under subaward 0244-03 from the Wellcome Trust Sanger Institute). Work done at the Wellcome Trust Sanger Institute has been funded by the Wellcome Trust (grant number WT077198) for HAVANA and by the Wellcome Trust (grant number WT062023) and the National Human Genome Research Institute (grant number 5U54HG00455-04) for Ensembl. Funding for open access charge: the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 46 TC 18 Z9 18 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD MAR 20 PY 2012 AR bas008 DI 10.1093/database/bas008 PG 12 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 954BO UT WOS:000304920200006 ER PT J AU Hayamizu, TF de Coronado, S Fragoso, G Sioutos, N Kadin, JA Ringwald, M AF Hayamizu, Terry F. de Coronado, Sherri Fragoso, Gilberto Sioutos, Nicholas Kadin, James A. Ringwald, Martin TI The mouse-human anatomy ontology mapping project SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Article ID INFORMATION AB The overall objective of the Mouse-Human Anatomy Project (MHAP) was to facilitate the mapping and harmonization of anatomical terms used for mouse and human models by Mouse Genome Informatics (MGI) and the National Cancer Institute (NCI). The anatomy resources designated for this study were the Adult Mouse Anatomy (MA) ontology and the set of anatomy concepts contained in the NCI Thesaurus (NCIt). Several methods and software tools were identified and evaluated, then used to conduct an in-depth comparative analysis of the anatomy ontologies. Matches between mouse and human anatomy terms were determined and validated, resulting in a highly curated set of mappings between the two ontologies that has been used by other resources. These mappings will enable linking of data from mouse and human. As the anatomy ontologies have been expanded and refined, the mappings have been updated accordingly. Insights are presented into the overall process of comparing and mapping between ontologies, which may prove useful for further comparative analyses and ontology mapping efforts, especially those involving anatomy ontologies. Finally, issues concerning further development of the ontologies, updates to the mapping files, and possible additional applications and significance were considered. C1 [Hayamizu, Terry F.; Kadin, James A.; Ringwald, Martin] Jackson Lab, Bar Harbor, ME 04609 USA. [de Coronado, Sherri; Fragoso, Gilberto; Sioutos, Nicholas] NCI, Ctr Bioinformat, Rockville, MD 20852 USA. RP Hayamizu, TF (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM terry.hayamizu@jax.org; martin.ringwald@jax.org FU National Cancer Institute at the National Institute of Health, Cancer Biomedical Informatics Grid (caBIG(R)) [caBIG-VCDE-14-02-02]; National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD062499]; NIH [HD062499]; Vocabularies and Common Data Elements (VCDE) Workspace group FX National Cancer Institute at the National Institute of Health, Cancer Biomedical Informatics Grid (caBIG (R)) (project number caBIG-VCDE-14-02-02); and National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant number HD062499). Funding for open access charge: NIH (grant HD062499).; We thank Connie Coon and Frank Hartel for contributions to the NCIt; Olivier Bodenreider and Songmao Zhang for their work aligning the ontologies using lexical and structural similarity approaches; Elena Beisswanger and the OAEI for helpful suggestions with regards to updating the mappings; Chris Mungall for assistance in making the mappings available through the OBO Foundry and, with his colleagues, for work on the Uberon ontology; Brian Davis and the Vocabularies and Common Data Elements (VCDE) Workspace group for support and assistance with caBIG (R) tasks; and our MGI and NCI colleagues for their advice and support. NR 15 TC 5 Z9 5 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD MAR 20 PY 2012 AR bar066 DI 10.1093/database/bar066 PG 10 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 954CL UT WOS:000304923700005 ER PT J AU Aimola, P Carmignani, M Volpe, AR Di Benedetto, A Claudio, L Waalkes, MP van Bokhoven, A Tokar, EJ Claudio, PP AF Aimola, Pierpaolo Carmignani, Marco Volpe, Anna Rita Di Benedetto, Altomare Claudio, Luigi Waalkes, Michael P. van Bokhoven, Adrie Tokar, Erik J. Claudio, Pier Paolo TI Cadmium Induces p53-Dependent Apoptosis in Human Prostate Epithelial Cells SO PLOS ONE LA English DT Article ID INDUCED MALIGNANT-TRANSFORMATION; WISTAR CRL-(WI)BR RATS; DOSE-RESPONSE ANALYSIS; NOBLE NBL/CR RAT; INJECTION SITE; C-JUN; PROLIFERATIVE LESIONS; TUMOR SUPPRESSION; OXIDATIVE STRESS; CANCER CELLS AB Cadmium, a widespread toxic pollutant of occupational and environmental concern, is a known human carcinogen. The prostate is a potential target for cadmium carcinogenesis, although the underlying mechanisms are still unclear. Furthermore, cadmium may induce cell death by apoptosis in various cell types, and it has been hypothesized that a key factor in cadmium-induced malignant transformation is acquisition of apoptotic resistance. We investigated the in vitro effects produced by cadmium exposure in normal or tumor cells derived from human prostate epithelium, including RWPE-1 and its cadmium-transformed derivative CTPE, the primary adenocarcinoma 22Rv1 and CWR-R1 cells and LNCaP, PC-3 and DU145 metastatic cancer cell lines. Cells were treated for 24 hours with different concentrations of CdCl2 and apoptosis, cell cycle distribution and expression of tumor suppressor proteins were analyzed. Subsequently, cellular response to cadmium was evaluated after siRNA-mediated p53 silencing in wild type p53-expressing RWPE-1 and LNCaP cells, and after adenoviral p53 overexpression in p53-deficient DU145 and PC-3 cell lines. The cell lines exhibited different sensitivity to cadmium, and 24-hour exposure to different CdCl2 concentrations induced dose-and cell type-dependent apoptotic response and inhibition of cell proliferation that correlated with accumulation of functional p53 and overexpression of p21 in wild type p53-expressing cell lines. On the other hand, p53 silencing was able to suppress cadmium-induced apoptosis. Our results demonstrate that cadmium can induce p53-dependent apoptosis in human prostate epithelial cells and suggest p53 mutation as a possible contributing factor for the acquisition of apoptotic resistance in cadmium prostatic carcinogenesis. C1 [Aimola, Pierpaolo; Di Benedetto, Altomare; Claudio, Pier Paolo] Marshall Univ, Dept Biochem & Microbiol, Joan C Edwards Sch Med, Huntington, WV 25755 USA. [Aimola, Pierpaolo; Carmignani, Marco; Volpe, Anna Rita; Di Benedetto, Altomare] Univ Aquila, Dept Basic & Appl Biol, I-67100 Laquila, Italy. [Claudio, Luigi] Fdn Senatore Pascale, Dept Urol, Natl Canc Inst, Naples, Italy. [Waalkes, Michael P.; Tokar, Erik J.] Natl Inst Environm Hlth Sci, Natl Toxicol Program, Res Triangle Pk, NC USA. [van Bokhoven, Adrie] Univ Colorado Denver, Dept Pathol, Aurora, CO USA. [Claudio, Pier Paolo] Marshall Univ, Dept Surg, Joan C Edwards Sch Med, Huntington, WV USA. RP Aimola, P (reprint author), Marshall Univ, Dept Biochem & Microbiol, Joan C Edwards Sch Med, Huntington, WV 25755 USA. EM claudiop@marshall.edu OI Claudio, Pier Paolo/0000-0001-7790-1622 FU National Cancer Institute [CA131395, CA140024]; NIH [COBRE 5P20RR020180, WV-INBRE 5P20RR016477]; Cell Differentiation and Development Center (CDDC), Marshall University; NTP; NIEHS; Marshall University Biochemistry Department; Marshall University Microbiology & Surgery Department FX The present studies were supported in part by the awards number CA131395 and CA140024 from the National Cancer Institute, and in part by NIH-COBRE 5P20RR020180, WV-INBRE 5P20RR016477, and the Cell Differentiation and Development Center (CDDC), Marshall University (to PPC). These studies were also supported in part by the NTP and NIEHS. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institute of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; We gratefully acknowledge the Marshall University Biochemistry and Microbiology & Surgery Departments for their support. NR 53 TC 26 Z9 30 U1 3 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 MAR 20 PY 2012 VL 7 IS 3 AR e33647 DI 10.1371/journal.pone.0033647 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 939YB UT WOS:000303855700053 PM 22448262 ER PT J AU Ledwaba, L Tavel, JA Khabo, P Maja, P Qin, J Sangweni, P Liu, X Follmann, D Metcalf, JA Orsega, S Baseler, B Neaton, JD Lane, HC AF Ledwaba, Lotty Tavel, Jorge A. Khabo, Paul Maja, Patrick Qin, Jing Sangweni, Phumele Liu, Xiao Follmann, Dean Metcalf, Julia A. Orsega, Susan Baseler, Beth Neaton, James D. Lane, H. Clifford CA Project Phidisa Biomarkers Team TI Pre-ART Levels of Inflammation and Coagulation Markers Are Strong Predictors of Death in a South African Cohort with Advanced HIV Disease SO PLOS ONE LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS-INFECTION; HIV-1-INFECTED PATIENTS; COMBINATION THERAPY; DECLINING MORBIDITY; EARLY MORTALITY; 1ST YEAR; AIDS; ADULTS; ERA AB Background: Levels of high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and D-dimer predict mortality in HIV patients on antiretroviral therapy (ART) with relatively preserved CD4+ T cell counts. We hypothesized that elevated pre-ART levels of these markers among patients with advanced HIV would be associated with an increased risk of death following the initiation of ART. Methods: Pre-ART plasma from patients with advanced HIV in South Africa was used to measure hsCRP, IL-6 and D-dimer. Using a nested case-control study design, the biomarkers were measured for 187 deaths and two controls matched on age, sex, clinical site, follow-up time and CD4+ cell counts. Odds ratios were estimated using conditional logistic regression. In addition, for a random sample of 100 patients, biomarkers were measured at baseline and 6 months following randomization to determine whether ART altered their levels. Results: Median baseline biomarkers levels for cases and controls, respectively, were 11.25 vs. 3.6 mg/L for hsCRP, 1.41 vs. 0.98 mg/L for D-dimer, and 9.02 vs. 4.20 pg/mL for IL-6 (all p<0.0001). Adjusted odds ratios for the highest versus lowest quartile of baseline biomarker levels were 3.5 (95% CI: 1.9-6.7) for hsCRP, 2.6 (95% CI 1.4-4.9) for D-dimer, and 3.8 (95% CI: 1.87.8) for IL-6. These associations were stronger for deaths that occurred more proximal to the biomarker measurements. Levels of D-dimer and IL-6, but not hsCRP, were significantly lower at month 6 after commencing ART compared to baseline (p<0.0001). Conclusions: Among patients with advanced HIV disease, elevated pre-ART levels of hsCRP, IL-6 and D-dimer are strongly associated with early mortality after commencing ART. Elevated levels of inflammatory and coagulation biomarkers may identify patients who may benefit from aggressive clinical monitoring after commencing ART. Further investigation of strategies to reduce biomarkers of inflammation and coagulation in patients with advanced HIV disease is warranted. C1 [Ledwaba, Lotty; Khabo, Paul; Maja, Patrick; Sangweni, Phumele] Project Phidisa, Pretoria, South Africa. [Tavel, Jorge A.; Qin, Jing; Liu, Xiao; Follmann, Dean; Metcalf, Julia A.; Orsega, Susan; Lane, H. Clifford] NIH, Bethesda, MD 20892 USA. [Baseler, Beth] Frederick Inc, Sci Applicat Int Corp, Frederick, MD USA. [Neaton, James D.] Univ Minnesota, Minneapolis, MN USA. RP Ledwaba, L (reprint author), Project Phidisa, Pretoria, South Africa. EM lledwaba@phidisa.org FU South African National Defence Force; United States National Institutes of Health; United States Department of Defense; SAIC-Frederick, Inc.; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX Funding for the Phidisa Project, the Phidisa I and II studies, and this substudy were provided by the South African National Defence Force, the United States National Institutes of Health and the United States Department of Defense. SAIC-Frederick, Inc. helped fund the study through the employment of Beth Basseler and Xiao Liu who contributed to the study. 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. The funders had a role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 25 Z9 25 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 20 PY 2012 VL 7 IS 3 AR e24243 DI 10.1371/journal.pone.0024243 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 939YB UT WOS:000303855700001 PM 22448211 ER PT J AU Mirabelli, MC London, SJ Charles, LE Pompeii, LA Wagenknecht, LE AF Mirabelli, Maria C. London, Stephanie J. Charles, Luenda E. Pompeii, Lisa A. Wagenknecht, Lynne E. TI Occupation and three-year incidence of respiratory symptoms and lung function decline: the ARIC Study SO RESPIRATORY RESEARCH LA English DT Article DE ARIC study; epidemiology; occupation; respiratory tract disease ID OBSTRUCTIVE PULMONARY-DISEASE; ATHEROSCLEROSIS RISK; ONSET ASTHMA; POPULATION; EXPOSURE; ADULTS; STATEMENT; BURDEN; HEALTH AB Background: Specific occupations are associated with adverse respiratory health. Inhalation exposures encountered in these jobs may place workers at risk of new-onset respiratory disease. Methods: We analyzed data from 8,967 participants from the Atherosclerosis Risk in Communities (ARIC) study, a longitudinal cohort study. Participants included in this analysis were free of chronic cough and phlegm, wheezing, asthma, chronic bronchitis, emphysema, and other chronic lung conditions at the baseline examination, when they were aged 45-64 years. Using data collected in the baseline and first follow-up examination, we evaluated associations between occupation and the three-year incidence of cough, phlegm, wheezing, and airway obstruction and changes in forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) measured by spirometry. All associations were adjusted for age, cigarettes per day, race, smoking status, and study center. Results: During the approximately three-year follow-up, the percentage of participants developing chronic cough was 3%; chronic phlegm, 3%; wheezing, 3%; and airway obstruction, defined as FEV1 < lower limit of normal (LLN) and FEV1/FVC < LLN, 2%. The average annual declines in FEV1 and FVC were 56 mL and 66 mL, respectively, among men and 40 mL and 52 mL, respectively, among women. Relative to a referent category of managerial and administrative support occupations, elevated risks of new-onset chronic cough and chronic phlegm were observed for mechanics and repairers (chronic cough: RR: 1.81, 95% CI: 1.02, 3.21; chronic phlegm: RR: 2.10, 95% CI: 1.23, 3.57) and cleaning and building service workers (chronic cough: RR: 1.85, 95% CI: 1.01, 3.37; chronic phlegm: RR: 2.28, 95% CI: 1.27, 4.08). Despite the elevated risk of new-onset symptoms, employment in cleaning and building services was associated with attenuated lung function decline, particularly among men, who averaged annual declines in FEV1 and FVC of 14 mL and 23 mL, respectively, less than the declines observed in the referent population. Conclusions: Employment in mechanic and repair jobs and cleaning and building service occupations are associated with increased incidence of respiratory symptoms. Specific occupations affect the respiratory health of adults without pre-existing respiratory health symptoms and conditions, though long-term health consequences of inhalation exposures in these jobs remain largely unexplored. C1 [Mirabelli, Maria C.] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. [London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Charles, Luenda E.] NIOSH, Biostat & Epidemiol Branch, Hlth Effects Lab Div, Ctr Dis Control & Prevent,Dept Hlth & Human Serv, Morgantown, WV USA. [Pompeii, Lisa A.] Univ Texas Houston, Sch Publ Hlth, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Wagenknecht, Lynne E.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC USA. RP Mirabelli, MC (reprint author), Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. EM mmirabel@wakehealth.edu OI Mirabelli, Maria/0000-0002-3540-0085; London, Stephanie/0000-0003-4911-5290 FU Intramural NIH HHS; PHS HHS [HHSN268201100007C, HHSN268201100005C, HHSN268201100006C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C] NR 26 TC 7 Z9 7 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1465-993X J9 RESP RES JI Respir. Res. PD MAR 20 PY 2012 VL 13 AR 24 DI 10.1186/1465-9921-13-24 PG 9 WC Respiratory System SC Respiratory System GA 942PP UT WOS:000304058600001 PM 22433119 ER PT J AU Linard, C Tatem, AJ AF Linard, Catherine Tatem, Andrew J. TI Large-scale spatial population databases in infectious disease research SO INTERNATIONAL JOURNAL OF HEALTH GEOGRAPHICS LA English DT Review DE Human population; Global; Infectious diseases; Spatial demography; Health metrics ID PLASMODIUM-FALCIPARUM TRANSMISSION; TRANSMITTED HELMINTH INFECTIONS; HUMAN AFRICAN TRYPANOSOMIASIS; TICK-BORNE ENCEPHALITIS; SUB-SAHARAN AFRICA; MALARIA TRANSMISSION; GLOBAL DISTRIBUTION; AVIAN INFLUENZA; GREAT-BRITAIN; GEOSTATISTICAL PREDICTION AB Modelling studies on the spatial distribution and spread of infectious diseases are becoming increasingly detailed and sophisticated, with global risk mapping and epidemic modelling studies now popular. Yet, in deriving populations at risk of disease estimates, these spatial models must rely on existing global and regional datasets on population distribution, which are often based on outdated and coarse resolution data. Moreover, a variety of different methods have been used to model population distribution at large spatial scales. In this review we describe the main global gridded population datasets that are freely available for health researchers and compare their construction methods, and highlight the uncertainties inherent in these population datasets. We review their application in past studies on disease risk and dynamics, and discuss how the choice of dataset can affect results. Moreover, we highlight how the lack of contemporary, detailed and reliable data on human population distribution in low income countries is proving a barrier to obtaining accurate large-scale estimates of population at risk and constructing reliable models of disease spread, and suggest research directions required to further reduce these barriers. C1 [Linard, Catherine] Univ Libre Bruxelles, B-1050 Brussels, Belgium. [Linard, Catherine] Fonds Natl Rech Sci FRS FNRS, B-1000 Brussels, Belgium. [Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL 32610 USA. [Tatem, Andrew J.] NCI, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Linard, C (reprint author), Univ Libre Bruxelles, CP 160-12,Ave FD Roosevelt 50, B-1050 Brussels, Belgium. EM linard.catherine@gmail.com FU Wellcome Trust NR 141 TC 24 Z9 25 U1 3 U2 28 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-072X J9 INT J HEALTH GEOGR JI Int. J. Health Geogr. PD MAR 20 PY 2012 VL 11 AR 7 DI 10.1186/1476-072X-11-7 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 930QR UT WOS:000303154700001 PM 22433126 ER PT J AU Madonna, G Ullman, CD Gentilcore, G Palmieri, G Ascierto, PA AF Madonna, Gabriele Ullman, Claudio Dansky Gentilcore, Giusy Palmieri, Giuseppe Ascierto, Paolo Antonio TI NF-kappa B as potential target in the treatment of melanoma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review DE NF-kappa B; Melanoma; NBD peptide; Bortezomib; Curcumin ID NEMO-BINDING DOMAIN; STAGE-IV MELANOMA; MALIGNANT-MELANOMA; SIGNALING PATHWAY; PHASE-II; CELLS; KINASE; CURCUMIN; ACTIVATION; EXPRESSION AB The RAS/MAP kinase pathway has attracted attention because activating mutations of the BRAF serine/threonine kinase was described in over 50% of melanomas. Very recently, selective and potent BRAF inhibitors have been developed. Several other signal transduction pathways have been found to be constitutively active or mutated in other subsets of melanoma tumors that are potentially targetable with new agents. Among these, NF kappa B is another pathway that melanoma tumors use to achieve survival, proliferation and resistance to apoptosis. Inhibition of NF kappa B activation appears to be a very promising option for anti-cancer therapies. C1 [Madonna, Gabriele; Gentilcore, Giusy; Ascierto, Paolo Antonio] Ist Nazl Tumori Fdn, Unit Med Oncol & Innovat Therapy, Naples, Italy. [Ullman, Claudio Dansky] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Palmieri, Giuseppe] CNR, Inst Biomol Chem, Sassari, Italy. RP Ascierto, PA (reprint author), Ist Nazl Tumori Fdn, Unit Med Oncol & Innovat Therapy, Naples, Italy. EM paolo.ascierto@gmail.com NR 43 TC 49 Z9 52 U1 1 U2 7 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 MAR 20 PY 2012 VL 10 AR 53 DI 10.1186/1479-5876-10-53 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 931ZS UT WOS:000303258900002 PM 22433222 ER PT J AU Martinowich, K Cardinale, KM Schloesser, RJ Hsu, M Greig, NH Manji, HK AF Martinowich, Keri Cardinale, Kathleen M. Schloesser, Robert J. Hsu, Michael Greig, Nigel H. Manji, Husseini K. TI Acetylcholinesterase inhibition ameliorates deficits in motivational drive SO BEHAVIORAL AND BRAIN FUNCTIONS LA English DT Article DE Apathy; Motivation; Chronic stress; Cholinergic; FosB; c-fos; Nucleus accumbens; Basal forebrain ID ALZHEIMERS-DISEASE; NEUROPSYCHIATRIC SYMPTOMS; CHOLINERGIC HYPOTHESIS; BEHAVIORAL-RESPONSES; STRESS; APATHY; DEPRESSION; ANHEDONIA; REWARD; THERAPY AB Background: Apathy is frequently observed in numerous neurological disorders, including Alzheimer's and Parkinson's, as well as neuropsychiatric disorders including schizophrenia. Apathy is defined as a lack of motivation characterized by diminished goal-oriented behavior and self-initiated activity. This study evaluated a chronic restraint stress (CRS) protocol in modeling apathetic behavior, and determined whether administration of an anticholinesterase had utility in attenuating CRS-induced phenotypes. Methods: We assessed behavior as well as regional neuronal activity patterns using FosB immunohistochemistry after exposure to CRS for 6 h/d for a minimum of 21 d. Based on our FosB findings and recent clinical trials, we administered an anticholinesterase to evaluate attenuation of CRS-induced phenotypes. Results: CRS resulted in behaviors that reflect motivational loss and diminished emotional responsiveness. CRS-exposed mice showed differences in FosB accumulation, including changes in the cholinergic basal forebrain system. Facilitating cholinergic signaling ameliorated CRS-induced deficits in initiation and motivational drive and rescued immediate early gene activation in the medial septum and nucleus accumbens. Conclusions: Some CRS protocols may be useful for studying deficits in motivation and apathetic behavior. Amelioration of CRS-induced behaviors with an anticholinesterase supports a role for the cholinergic system in remediation of deficits in motivational drive. C1 [Martinowich, Keri; Cardinale, Kathleen M.; Schloesser, Robert J.; Hsu, Michael] NIMH, Mood & Anxiety Disorders Program MAP, NIH, Bethesda, MD 20892 USA. [Greig, Nigel H.] NIA, Lab Neurosci, Sect Drug Design & Dev, NIH, Bethesda, MD 20892 USA. [Martinowich, Keri] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Manji, Husseini K.] Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ 08560 USA. RP Martinowich, K (reprint author), NIMH, Mood & Anxiety Disorders Program MAP, NIH, 35 Convent Dr,Bldg 35,Room 1C-1012, Bethesda, MD 20892 USA. EM keri.martinowich@libd.org RI Martinowich, Keri/F-9841-2012; OI Martinowich, Keri/0000-0002-5237-0789 FU National Institute of Mental Health (NIMH); National Institute on Aging (NIA) FX Funding for this study was provided by the National Institute of Mental Health (NIMH) and the National Institute on Aging (NIA) Intramural Programs. NR 46 TC 2 Z9 2 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-9081 J9 BEHAV BRAIN FUNCT JI Behav. Brain Funct. PD MAR 20 PY 2012 VL 8 AR 15 DI 10.1186/1744-9081-8-15 PG 14 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 929HH UT WOS:000303051400001 PM 22433906 ER PT J AU Alfano, CM Ganz, PA Rowland, JH Hahn, EE AF Alfano, Catherine M. Ganz, Patricia A. Rowland, Julia H. Hahn, Erin E. TI Cancer Survivorship and Cancer Rehabilitation: Revitalizing the Link SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID CLINICAL ONCOLOGY PROGRAM; BREAST-CANCER; PHYSICAL-ACTIVITY; SURVIVAL; HEALTH; INSTITUTE; WOMEN C1 [Alfano, Catherine M.; Hahn, Erin E.] NCI, Off Canc Survivorship, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Sch Publ Hlth, Sch Med, Los Angeles, CA 90024 USA. [Ganz, Patricia A.; Hahn, Erin E.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Los Angeles, CA 90024 USA. RP Alfano, CM (reprint author), NCI, Off Canc Survivorship, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. OI Hahn, Erin E/0000-0002-8419-2331 NR 38 TC 43 Z9 43 U1 0 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 MAR 20 PY 2012 VL 30 IS 9 BP 904 EP 906 DI 10.1200/JCO.2011.37.1674 PG 3 WC Oncology SC Oncology GA 923OK UT WOS:000302628400007 PM 22355063 ER PT J AU Kleinerman, RA Yu, CL Little, MP Li, Y Abramson, D Seddon, J Tucker, MA AF Kleinerman, Ruth A. Yu, Chu-ling Little, Mark P. Li, Yi Abramson, David Seddon, Johanna Tucker, Margaret A. TI Variation of Second Cancer Risk by Family History of Retinoblastoma Among Long-Term Survivors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HEREDITARY RETINOBLASTOMA; RB1 MUTATIONS; FOLLOW-UP; RADIOTHERAPY; MORTALITY; SARCOMAS; GENE AB Purpose To evaluate the risk of second cancer (SC) in long-term survivors of retinoblastoma (Rb) according to classification of germline mutation, based on family history of Rb and laterality. Patients and Methods We assembled a cohort of 1,852 1-year survivors of Rb (bilateral, n = 1,036; unilateral, n = 816). SCs were ascertained by medical records and self-reports and confirmed by pathology reports. Classification of RB1 germline mutation, inherited or de novo, was inferred by laterality of Rb and positive family history of Rb. Standardized incidence ratios and cumulative incidence for all SCs combined and for soft tissue sarcomas, bone cancers, and melanoma were calculated. The influence of host-and therapy-related risk factors for SC was assessed by Poisson regression for bilateral survivors. Results We observed a relative risk (RR) of 1.37 (95% CI, 1.00 to 1.86) for SCs in bilateral survivors associated with a family history of Rb, adjusted for treatment, age, and length of follow-up. The risk for melanoma was significantly elevated for survivors with a family history of Rb (RR, 3.08; 95% CI, 1.23 to 7.16), but risks for bone or soft tissue sarcomas were not elevated. The cumulative incidence of SCs 50 years after diagnosis of bilateral Rb, with adjustment for competing risk of death, was significantly higher for survivors with a family history (47%; 95% CI, 35% to 59%) than survivors without a family history (38%; 95% CI, 32% to 44%; P = .004). Conclusion Rb survivors with bilateral disease and an inherited germline mutation are at slightly higher risk of an SC compared with those with a de novo germline mutation, in particular melanoma, perhaps because of shared genetic alterations. J Clin Oncol 30: 950-957. (C) 2012 by American Society of Clinical Oncology C1 [Kleinerman, Ruth A.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Li, Yi] Dana Farber Canc Inst, Boston, MA 02115 USA. [Seddon, Johanna] Tufts Univ New England Med Ctr, Boston, MA USA. [Abramson, David] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Kleinerman, RA (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, EPS 7044,6120 Execut Blvd, Rockville, MD 20852 USA. EM Kleinerr@mail.nih.gov RI Tucker, Margaret/B-4297-2015; OI Kleinerman, Ruth/0000-0001-7415-2478; Little, Mark/0000-0003-0980-7567 FU National Institutes of Health; National Cancer Institute FX Supported by the Intramural Research Program of the National Institutes of Health and the National Cancer Institute. NR 27 TC 31 Z9 32 U1 0 U2 1 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 MAR 20 PY 2012 VL 30 IS 9 BP 950 EP 957 DI 10.1200/JCO.2011.37.0239 PG 8 WC Oncology SC Oncology GA 923OK UT WOS:000302628400014 PM 22355046 ER PT J AU Szabo, A Zhou, HX AF Szabo, Attila Zhou, Huan-Xiang TI Role of Diffusion in the Kinetics of Reversible Enzyme-catalyzed Reactions SO BULLETIN OF THE KOREAN CHEMICAL SOCIETY LA English DT Article DE Diffusion-influenced reaction; Enzyme-catalyzed reaction; Michaelis-Menten kinetics ID DEPENDENT RATE COEFFICIENTS; MICHAELIS-MENTEN KINETICS; ASYMPTOTIC RELAXATION; SIMULATION; TRANSPORT; BINDING AB The accurate expression for the steady-state velocity of an irreversible enzyme-catalyzed reaction obtained by Shin and co-workers (J. Chem. Phys.. 2001, 115, 1455) is generalized to allow for the rebinding of the product. The amplitude of the power-law (t(-1/2)) relaxation of the free- and bound-enzyme concentrations to steady-state values is expressed in terms of the steady-state velocity and the intrinsic (chemical) rate constants. This result is conjectured to be exact, even though our expression for the steady-state velocity in terms of microscopic parameters is only approximate. C1 [Zhou, Huan-Xiang] Florida State Univ, Dept Phys, Tallahassee, FL 32306 USA. [Zhou, Huan-Xiang] Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. [Szabo, Attila] Natl Inst Digest & Kidney Dis, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Zhou, HX (reprint author), Florida State Univ, Dept Phys, Tallahassee, FL 32306 USA. EM hzhou@fsu.edu RI Szabo, Attila/H-3867-2012; Zhou, Huan-Xiang/M-5170-2016 OI Zhou, Huan-Xiang/0000-0001-9020-0302 FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases [GM58187]; NIH [GM58187] FX We thank Noam Agmon for his comments on the manuscript. This study was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases, and by grant GM58187 from the NIH. NR 15 TC 11 Z9 11 U1 5 U2 22 PU KOREAN CHEMICAL SOC PI SEOUL PA 635-4 YEOGSAM-DONG, KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 0253-2964 J9 B KOREAN CHEM SOC JI Bull. Korean Chem. Soc. PD MAR 20 PY 2012 VL 33 IS 3 BP 925 EP 928 DI 10.5012/bkcs.2012.33.3.925 PG 4 WC Chemistry, Multidisciplinary SC Chemistry GA 917RM UT WOS:000302196300028 PM 23418399 ER PT J AU Kim, W Lao, QZ Shin, YK Carlson, OD Lee, EK Gorospe, M Kulkarni, RN Egan, JM AF Kim, Wook Lao, Qizong Shin, Yu-Kyong Carlson, Olga D. Lee, Eun Kyung Gorospe, Myriam Kulkarni, Rohit N. Egan, Josephine M. TI Cannabinoids Induce Pancreatic beta-Cell Death by Directly Inhibiting Insulin Receptor Activation SO SCIENCE SIGNALING LA English DT Article ID FORKHEAD TRANSCRIPTION FACTOR; ENDOCANNABINOID SYSTEM; CB1 RECEPTOR; CYTOPLASMIC LOCALIZATION; DIABETES-MELLITUS; TYROSINE RESIDUES; CYCLE PROGRESSION; INDUCED APOPTOSIS; CANCER CELLS; LIPID RAFTS AB Cannabinoid 1 (CB1) receptors have been previously detected in pancreatic beta cells, where they attenuate insulin action. We now report that CB1 receptors form a heteromeric complex with insulin receptors and the heterotrimeric guanosine triphosphate-binding protein alpha subunit G alpha(i). G alpha(i) inhibited the kinase activity of the insulin receptor in beta cells by directly binding to the activation loop in the tyrosine kinase domain of the receptor. Consequently, phosphorylation of proapoptotic protein Bad was reduced and its apoptotic activity was stimulated, leading to beta-cell death. Pharmacological blockade or genetic deficiency of CB1 receptors enhanced insulin receptor signaling after injury, leading to reduced blood glucose concentrations and activation of Bad, which increased beta-cell survival. These findings provide direct evidence of physical and functional interactions between CB1 and insulin receptors and suggest a mechanism whereby peripherally acting CB1 receptor antagonists improve insulin action in insulin-sensitive tissues independent of the other metabolic effects of CB1 receptors. C1 [Kim, Wook; Lao, Qizong; Shin, Yu-Kyong; Carlson, Olga D.; Gorospe, Myriam; Egan, Josephine M.] NIA, NIH, Baltimore, MD 21224 USA. [Lee, Eun Kyung] Catholic Univ Korea, Coll Med, Dept Biochem, Seoul 137701, South Korea. [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Joslin Diabet Ctr, Dept Islet Cell Biol & Regenerat Med, Boston, MA 02215 USA. [Kulkarni, Rohit N.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. RP Egan, JM (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM eganj@grc.nia.nih.gov FU NIA/NIH; National Research Foundation of Korea (NRF); Korea government (MEST) [20110013116]; Catholic Medical Center Research Foundation; NIH [RO1 DK 67536, 68721] FX This work was supported by the Intramural Research Program of the NIA/NIH. E.K.L. is supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (20110013116) and the Catholic Medical Center Research Foundation. R.N.K. is supported by NIH RO1 DK 67536 and 68721. NR 57 TC 26 Z9 26 U1 1 U2 4 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 20 PY 2012 VL 5 IS 216 AR ra23 DI 10.1126/scisignal.2002519 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 916RQ UT WOS:000302121300003 PM 22434934 ER PT J AU Lu, JH Sun, PD AF Lu, Jinghua Sun, Peter D. TI The Structure of the TLR5-Flagellin Complex: A New Mode of Pathogen Detection, Conserved Receptor Dimerization for Signaling SO SCIENCE SIGNALING LA English DT Article ID TOLL-LIKE RECEPTORS; TLR4-MD-2 COMPLEX; CRYSTAL-STRUCTURE; RECOGNITION; FLAGELLIN AB Knowledge about how Toll-like receptors (TLRs) recognize pathogenic ligands is critical to understanding how these receptors are activated and to designing therapeutic compounds that target this family of receptors for inflammatory diseases. The crystal structure of TLR5 in complex with its bacterial ligand flagellin revealed that the ligand-binding mode for TLR5 is distinct from that of previously characterized TLRs. Nevertheless, like other TLRs, TLR5 forms a dimer in response to ligand binding. This work contributes to our current knowledge of TLR function and further demonstrates the ability of TLRs to couple versatile ligand recognition to a conserved receptor signaling mechanism. C1 [Lu, Jinghua; Sun, Peter D.] NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Sun, PD (reprint author), NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM psun@nih.gov NR 11 TC 7 Z9 7 U1 2 U2 12 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 20 PY 2012 VL 5 IS 216 AR pe11 DI 10.1126/scisignal.2002963 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 916RQ UT WOS:000302121300001 PM 22434932 ER PT J AU McAlister, GC Russell, JD Rumachik, NG Hebert, AS Syka, JEP Geer, LY Westphall, MS Pagliarini, DJ Coon, JJ AF McAlister, Graeme C. Russell, Jason D. Rumachik, Neil G. Hebert, Alexander S. Syka, John E. P. Geer, Lewis Y. Westphall, Michael S. Pagliarini, David J. Coon, Joshua J. TI Analysis of the Acidic Proteome with Negative Electron-Transfer Dissociation Mass Spectrometry SO ANALYTICAL CHEMISTRY LA English DT Article ID PHASE ION/ION REACTIONS; DETACHMENT DISSOCIATION; SEARCH ALGORITHM; PEPTIDES; ANIONS; CLEAVAGES; BACKBONE; HISTIDINE; IDENTIFICATIONS; FRAGMENTATIONS AB We describe the first implementation of negative electron-transfer dissociation (NETD) on a hybrid ion trap-orbitrap mass spectrometer and its application to high-throughput sequencing of peptide anions. NETD, coupled with high pH separations, negative electrospray ionization (ESI), and an NETD compatible version of OMSSA, is part of a complete workflow that includes the formation, interrogation, and sequencing of peptide anions. Together these interlocking pieces facilitated the identification of more than 2000 unique peptides from Saccharomyces cerevisiae representing the most comprehensive analysis of peptide anions by tandem mass spectrometry to date. The same S. cerevisiae samples were interrogated using traditional, positive modes of peptide LC-MS/MS analysis (e.g., acidic LC separations, positive ESI, and collision activated dissociation), and the resulting peptide identifications of the different workflows were compared. Due to a decreased flux of peptide anions and a tendency to produce lowly charged precursors, the NETD-based LC-MS/MS workflow was not as sensitive as the positive mode methods. However, the use of NETD readily permits access to underrepresented acidic portions of the proteome by identifying peptides that tend to have lower pI values. As such, NETD improves sequence coverage, filling out the acidic portions of proteins that are often overlooked by the other methods. C1 [McAlister, Graeme C.; Russell, Jason D.; Rumachik, Neil G.; Coon, Joshua J.] Univ Wisconsin, Dept Chem, Madison, WI 53706 USA. [Pagliarini, David J.] Univ Wisconsin, Dept Biochem, Madison, WI 53705 USA. [Hebert, Alexander S.; Coon, Joshua J.] Univ Wisconsin, Dept Biomol Chem, Madison, WI USA. [Westphall, Michael S.; Coon, Joshua J.] Univ Wisconsin, Genome Ctr Wisconsin, Madison, WI USA. [Geer, Lewis Y.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Syka, John E. P.] Thermo Fisher Sci, San Jose, CA USA. RP Coon, JJ (reprint author), Univ Wisconsin, Dept Chem, 1101 Univ Ave, Madison, WI 53706 USA. EM jcoon@chem.wisc.edu RI Geer, Lewis/H-2714-2014; OI Pagliarini, Dave/0000-0002-0001-0087 FU Thermo Fisher Scientific; National Institutes of Health [R01GM080148]; NIH, National Library of Medicine FX G.C.M. and J.D.R. contributed equally to this work. We thank AJ Bureta for figure design, Craig D. Wenger and Derek J. Bailey for assistance with data analysis, Jae C. Schwartz for helpful discussions, and Sarah Jacob for aid in manuscript preparation. We are grateful to Thermo Fisher Scientific and the National Institutes of Health (R01GM080148 to J.J.C.) for providing funding for this work. This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. NR 49 TC 21 Z9 21 U1 0 U2 40 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 EI 1520-6882 J9 ANAL CHEM JI Anal. Chem. PD MAR 20 PY 2012 VL 84 IS 6 BP 2875 EP 2882 DI 10.1021/ac203430u PG 8 WC Chemistry, Analytical SC Chemistry GA 910KB UT WOS:000301634500038 PM 22335612 ER PT J AU Waterfall, JJ Meltzer, PS AF Waterfall, Joshua J. Meltzer, Paul S. TI Targeting Epigenetic Misregulation in Synovial Sarcoma SO CANCER CELL LA English DT Editorial Material ID TUMORS AB Like many sarcomas, synovial sarcoma is driven by a characteristic oncogenic transcription factor fusion, SS18-SSX. In this issue of Cancer Cell, Su et al. elucidate the protein partners necessary for target gene misregulation and demonstrate a direct effect of histone deacetylase inhibitors on the SS18-SSX complex composition, expression misregulation, and apoptosis. C1 [Waterfall, Joshua J.; Meltzer, Paul S.] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Meltzer, PS (reprint author), NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM pmeltzer@mail.nih.gov NR 10 TC 4 Z9 4 U1 0 U2 2 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 MAR 20 PY 2012 VL 21 IS 3 BP 323 EP 324 DI 10.1016/j.ccr.2012.02.023 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 913YH UT WOS:000301912800004 PM 22439927 ER PT J AU Liu, ZH Thiele, CJ AF Liu, Zhihui Thiele, Carol J. TI ALK and MYCN: When Two Oncogenes Are Better than One SO CANCER CELL LA English DT Editorial Material ID NEUROBLASTOMA; EXPRESSION; GENES AB Mutations of ALK are frequently observed in MYCN-amplified neuroblastomas and correlate with poor clinical outcome, but how these oncogenes cooperate in neuroblastoma development remains unclear. In this issue of Cancer Cell, Zhu et al. describe a mechanism by which ALK and MYCN synergistically induce neuroblastoma in the zebrafish model system. C1 [Liu, Zhihui; Thiele, Carol J.] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Thiele, CJ (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ct47a@nih.gov FU Intramural NIH HHS [ZIA BC010788-04] NR 10 TC 2 Z9 3 U1 0 U2 2 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 MAR 20 PY 2012 VL 21 IS 3 BP 325 EP 326 DI 10.1016/j.ccr.2012.03.004 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 913YH UT WOS:000301912800005 PM 22439928 ER PT J AU Cai, Q Zakaria, HM Simone, A Sheng, ZH AF Cai, Qian Zakaria, Hesham Mostafa Simone, Anthony Sheng, Zu-Hang TI Spatial Parkin Translocation and Degradation of Damaged Mitochondria via Mitophagy in Live Cortical Neurons SO CURRENT BIOLOGY LA English DT Article ID NEURODEGENERATIVE DISEASES; OXIDATIVE STRESS; PINK1; TRANSPORT; DYNAMICS; DEPOLARIZATION; DEGENERATION; RECRUITMENT; DYSFUNCTION; DROSOPHILA AB Mitochondria are essential for neuronal survival and function. Proper degradation of aged and damaged mitochondria through mitophagy is a key cellular pathway for mitochondrial quality control. Recent studies have indicated that PINK1/Parkin-mediated pathways ensure mitochondrial integrity and function [1-8]. Trans location of Parkin to damaged mitochondria induces mitophagy in many nonneuronal cell types [9-16]. However, evidence showing Parkin translocation in primary neurons is controversial [9, 15, 17, 18], leaving unanswered questions as to how and where Parkin-mediated mitophagy occurs in neurons. Here, we report the unique process of dissipating mitochondrial Delta Psi(m)-induced and Parkin-mediated mitophagy in mature cortical neurons. Compared with nonneuronal cells, neuronal mitophagy is a much slower and compartmentally restricted process, coupled with reduced anterograde mitochondria! transport. Parkin-targeted mitochondria are accumulated in the somatodendritic regions where mature lysosomes are predominantly located. Time-lapse imaging shows dynamic formation and elimination of Parkin- and LC3-ring-like structures surrounding depolarized mitochondria through the autophagy-lysosomal pathway in the soma. Knocking down Parkin in neurons impairs the elimination of dysfunctional mitochondria. Thus, our study provides neuronal evidence for dynamic and spatial Parkin-mediated mitophagy, which will help us understand whether altered mitophagy contributes to pathogenesis of several major neurodegenerative diseases characterized by mitochondrial dysfunction and impaired transport. C1 [Cai, Qian; Zakaria, Hesham Mostafa; Simone, Anthony; Sheng, Zu-Hang] Natl Inst Neurol Disorders & Stroke, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Cai, Qian] Rutgers State Univ, Dept Cell Biol & Neurosci, Piscataway, NJ 08854 USA. [Zakaria, Hesham Mostafa] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20814 USA. RP Cai, Q (reprint author), Natl Inst Neurol Disorders & Stroke, Synapt Funct Sect, Porter Neurosci Res Ctr, NIH, Room 2B-215,35 Convent Dr, Bethesda, MD 20892 USA. EM cai@biology.rutgers.edu; shengz@ninds.nih.gov FU NINDS; NIH; Howard Hughes Medical Institute-NIH FX We thank R.J. Youle for helpful discussions; R.J. Youle, B. Lu, and M.J. LaVoie for Parkin DNA constructs; the members of the Sheng laboratory for technical assistance and helpful discussions; and S. Yang and D. Schoenberg for editing. This work was supported by the Intramural Research Program of NINDS, NIH (Z-H.S.), the NIH Pathway to Independence Award K99 (Q.C.), and Howard Hughes Medical Institute-NIH Research Scholars Program (H.M.Z.) NR 30 TC 100 Z9 101 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD MAR 20 PY 2012 VL 22 IS 6 BP 545 EP 552 DI 10.1016/j.cub.2012.02.005 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 913PW UT WOS:000301890900026 PM 22342752 ER PT J AU Wikstrom, M Hummer, G AF Wikstrom, Marten Hummer, Gerhard TI Stoichiometry of proton translocation by respiratory complex I and its mechanistic implications SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell respiration; proton pumping; conformational changes; phosphorylation potential ID NADH-QUINONE OXIDOREDUCTASE; MITOCHONDRIAL OXIDATIVE-PHOSPHORYLATION; CONSERVED CHARGED RESIDUES; ESCHERICHIA-COLI NDH-1; RAT-LIVER MITOCHONDRIA; MEMBRANE DOMAIN; ELECTRON-TRANSFER; SUBUNIT; UBIQUINONE; REDUCTASE AB Complex I (NADH-ubiquinone oxidoreductase) in the respiratory chain of mitochondria and several bacteria functions as a redox-driven proton pump that contributes to the generation of the protonmotive force across the inner mitochondrial or bacterial membrane and thus to the aerobic synthesis of ATP. The stoichiometry of proton translocation is thought to be 4 H+ per NADH oxidized (2 e(-)). Here we show that a H+/2 e(-) ratio of 3 appears more likely on the basis of the recently determined H+/ATP ratio of the mitochondrial F1Fo-ATP synthase of animal mitochondria and of a set of carefully determined ATP/2 e(-) ratios for different segments of the mitochondrial respiratory chain. This lower H+/2 e(-) ratio of 3 is independently supported by thermodynamic analyses of experiments with both mitochondria and submitochondrial particles. A reduced H+/2 e(-) stoichiometry of 3 has important mechanistic implications for this proton pump. In a rough mechanistic model, we suggest a concerted proton translocation mechanism in the three homologous and tightly packed antiporter-like subunits L, M, and N of the proton-translocating membrane domain of complex I. C1 [Wikstrom, Marten] Univ Helsinki, Helsinki Bioenerget Grp, Inst Biotechnol, FI-00014 Helsinki, Finland. [Hummer, Gerhard] NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. RP Wikstrom, M (reprint author), Univ Helsinki, Helsinki Bioenerget Grp, Inst Biotechnol, FI-00014 Helsinki, Finland. EM Marten.Wikstrom@Helsinki.Fi RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Sigrid Juselius Foundation; Biocentrum Helsinki; Academy of Finland FX G.H. is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. M. W. is supported by grants from the Sigrid Juselius Foundation, Biocentrum Helsinki, and the Academy of Finland. NR 41 TC 46 Z9 46 U1 1 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 MAR 20 PY 2012 VL 109 IS 12 BP 4431 EP 4436 DI 10.1073/pnas.1120949109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 911JH UT WOS:000301712600024 PM 22392981 ER PT J AU Hoadley, KA Xue, YT Ling, C Takata, M Wang, WD Keck, JL AF Hoadley, Kelly A. Xue, Yutong Ling, Chen Takata, Minoru Wang, Weidong Keck, James L. TI Defining the molecular interface that connects the Fanconi anemia protein FANCM to the Bloom syndrome dissolvasome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA recombination; X-ray crystallography ID HOLLIDAY JUNCTION DISSOLVASOME; MAINTAIN GENOME STABILITY; DAMAGE RESPONSE NETWORK; FOLD-CONTAINING PROTEIN; HOMOLOGOUS RECOMBINATION; ESSENTIAL COMPONENT; SYNDROME HELICASE; REPLICATION-FORK; RECQ HELICASES; DNA-REPAIR AB The RMI subcomplex (RMI1/RMI2) functions with the BLM helicase and topoisomerase IIIa in a complex called the "dissolvasome," which separates double-Holliday junction DNA structures that can arise during DNA repair. This activity suppresses potentially harmful sister chromatid exchange (SCE) events in wild-type cells but not in cells derived from Bloom syndrome patients with inactivating BLM mutations. The RMI subcomplex also associates with FANCM, a component of the Fanconi anemia (FA) core complex that is important for repair of stalled DNA replication forks. The RMI/FANCM interface appears to help coordinate dissolvasome and FA core complex activities, but its precise role remains poorly understood. Here, we define the structure of the RMI/FANCM interface and investigate its roles in coordinating cellular DNA-repair activities. The X-ray crystal structure of the RMI core complex bound to a well-conserved peptide from FANCM shows that FANCM binds to both RMI proteins through a hydrophobic "knobs-into-holes" packing arrangement. The RMI/FANCM interface is shown to be critical for interaction between the components of the dissolvasome and the FA core complex. FANCM variants that substitute alanine for key interface residues strongly destabilize the complex in solution and lead to increased SCE levels in cells that are similar to those observed in blm- or fancm-deficient cells. This study provides a molecular view of the RMI/FANCM complex and highlights a key interface utilized in coordinating the activities of two critical eukaryotic DNA-damage repair machines. C1 [Xue, Yutong; Ling, Chen; Wang, Weidong] NIA, Genet Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Hoadley, Kelly A.; Keck, James L.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Biomol Chem, Madison, WI 53706 USA. [Takata, Minoru] Kyoto Univ, Lab DNA Damage Signaling, Dept Late Effects Studies, Ctr Radiat Biol, Kyoto 6068501, Japan. RP Wang, WD (reprint author), NIA, Genet Lab, NIH, Biomed Res Ctr, 251 Bayview Blvd,10B113, Baltimore, MD 21224 USA. EM WangW@grc.nia.nih.gov; jlkeck@wisc.edu FU National Institutes of Health (NIH) [GM068061, GM07215]; National Institute on Aging [Z01 AG000657-08] FX We thank Advanced Photon Source staff (LS-CAT beamline) and Ken Satyshur for assistance with data collection and members of the Keck Lab for critical reading of this manuscript. We thank members of the Denu lab for their assistance with peptide purification and mass spectrometry. This work was funded by a grant from the National Institutes of Health (NIH) (GM068061, J.L.K.) and by the Intramural Research Program of the National Institute on Aging (Z01 AG000657-08, W. W.). K. A. H. was supported in part by an NIH training grant in Molecular Biosciences (GM07215). NR 30 TC 24 Z9 24 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 MAR 20 PY 2012 VL 109 IS 12 BP 4437 EP 4442 DI 10.1073/pnas.1117279109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 911JH UT WOS:000301712600025 PM 22392978 ER PT J AU Qiang, W Yau, WM Luo, YQ Mattson, MP Tycko, R AF Qiang, Wei Yau, Wai-Ming Luo, Yongquan Mattson, Mark P. Tycko, Robert TI Antiparallel beta-sheet architecture in Iowa-mutant beta-amyloid fibrils SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Alzheimer's disease; amyloid structure; solid state NMR ID SOLID-STATE NMR; NUCLEAR-MAGNETIC-RESONANCE; ROTATING SOLIDS; SUPRAMOLECULAR STRUCTURE; DISTANCE MEASUREMENTS; STRUCTURAL FEATURES; ELECTRON-MICROSCOPY; CHEMICAL-SHIFTS; POLAR ZIPPERS; PARALLEL AB Wild-type, full-length (40- and 42-residue) amyloid beta-peptide (A beta) fibrils have been shown by a variety of magnetic resonance techniques to contain cross-beta structures in which the beta-sheets have an in-register parallel supramolecular organization. In contrast, recent studies of fibrils formed in vitro by the Asp23-to-Asn mutant of 40-residue A beta (D23N-A beta(1-40)), which is associated with early onset neurodegeneration, indicate that D23N-A beta(1-40) fibrils can contain either parallel or antiparallel beta-sheets. We report a protocol for producing structurally pure antiparallel D23N-A beta(1-40) fibril samples and a series of solid state nuclear magnetic resonance and electron microscopy measurements that lead to a specific model for the antiparallel D23N-A beta(1-40) fibril structure. This model reveals how both parallel and antiparallel cross-beta structures can be constructed from similar peptide monomer conformations and stabilized by similar sets of interactions, primarily hydrophobic in nature. We find that antiparallel D23N-A beta(1-40) fibrils are thermodynamically metastable with respect to conversion to parallel structures, propagate less efficiently than parallel fibrils in seeded fibril growth, and therefore must nucleate more efficiently than parallel fibrils in order to be observable. Experiments in neuronal cell cultures indicate that both antiparallel and parallel D23N-A beta(1-40) fibrils are cytotoxic. Thus, our antiparallel D23N-A beta(1-40) fibril model represents a specific "toxic intermediate" in the aggregation process of a disease-associated A beta mutant. C1 [Qiang, Wei; Yau, Wai-Ming; Tycko, Robert] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Luo, Yongquan; Mattson, Mark P.] NIA, Neurosci Lab, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov RI Mattson, Mark/F-6038-2012; Qiang, Wei/I-1053-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Aging, within the National Institutes of Health FX This work was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute on Aging, within the National Institutes of Health. NR 51 TC 124 Z9 125 U1 5 U2 79 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 MAR 20 PY 2012 VL 109 IS 12 BP 4443 EP 4448 DI 10.1073/pnas.1111305109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 911JH UT WOS:000301712600026 PM 22403062 ER PT J AU Ma, XF Kovacs, M Conti, MA Wang, AB Zhang, YF Sellers, JR Adelstein, RS AF Ma, Xuefei Kovacs, Mihaly Conti, Mary Anne Wang, Aibing Zhang, Yingfan Sellers, James R. Adelstein, Robert S. TI Nonmuscle myosin II exerts tension but does not translocate actin in vertebrate cytokinesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cortical tension; myosin II kinetics; graded myosin knockdown; motor-impaired myosin; myosin-actin binding ID MYH9-RELATED DISEASE; FECHTNER-SYNDROME; FISSION YEAST; CELL-ADHESION; DYNAMICS; CONTRACTILE; MUTATIONS; MECHANISM; FURROW; INHIBITION AB During vertebrate cytokinesis it is thought that contractile ring constriction is driven by nonmuscle myosin II (NMII) translocation of antiparallel actin filaments. Here we report in situ, in vitro, and in vivo observations that challenge this hypothesis. Graded knockdown of NM II in cultured COS-7 cells reveals that the amount of NM II limits ring constriction. Restoration of the constriction rate with motor-impaired NM II mutants shows that the ability of NM II to translocate actin is not required for cytokinesis. Blebbistatin inhibition of cytokinesis indicates the importance of myosin strongly binding to actin and exerting tension during cytokinesis. This role is substantiated by transient kinetic experiments showing that the load-dependent mechanochemical properties of mutant NM II support efficient tension maintenance despite the inability to translocate actin. Under loaded conditions, mutant NM II exhibits a prolonged actin attachment in which a single mechanoenzymatic cycle spans most of the time of cytokinesis. This prolonged attachment promotes simultaneous binding of NM II heads to actin, thereby increasing tension and resisting expansion of the ring. The detachment of mutant NM II heads from actin is enhanced by assisting loads, which prevent mutant NM II from hampering furrow ingression during cytokinesis. In the 3D context of mouse hearts, mutant NM II-B R709C that cannot translocate actin filaments can rescue multinucleation in NM II-B ablated cardiomyocytes. We propose that the major roles of NM II in vertebrate cell cytokinesis are to bind and cross-link actin filaments and to exert tension on actin during contractile ring constriction. C1 [Ma, Xuefei; Conti, Mary Anne; Wang, Aibing; Zhang, Yingfan; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Kovacs, Mihaly] Eotvos Lorand Univ, Hungarian Acad Sci, Momentum Motor Enzymol Res Grp, Dept Biochem, H-1117 Budapest, Hungary. [Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Adelstein, RS (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. EM adelster@nhlbi.nih.gov RI Kovacs, Mihaly/A-6841-2011; OI Adelstein, Robert/0000-0002-8683-2144 FU Division of Intramural Research, National Heart, Lung, and Blood Institute; Norway Grant [NNF2-85613]; Hungarian Scientific Research Fund [K71915, NK81950]; Tarsadalmi Megujulas Operativ Program [4.2.1/B-09/1/KMR-2010-0003]; Hungarian Academy of Sciences [LP2011-006/2011] FX We thank Dr. Dennis E. Discher (University of Pennsylvania) for providing the plasmid NMHC II-B Y277F; and Dr. Edward Korn (Laboratory of Cell Biology, National Heart, Lung, and Blood Institute), Dr. Sachiyo Kawamoto, and members of the Laboratory of Molecular Cardiology for critical comments on the manuscript. We also thank Dr. Douglas Robinson (The Johns Hopkins University School of Medicine) for his expertise in the analysis of the dynamics of cytokinesis; Dr. Jianjun Bao for help with COS-7 experiments; Drs. Chengyu Liu and Yubin Du (National Heart, Lung, and Blood Institute Transgenic Core); and Drs. Christian A. Combs and Daniela Malide (National Heart, Lung, and Blood Institute Light Microscopy Core) for professional skills and advice. Antoine Smith and Dalton Saunders provided excellent technical assistance. This research was supported by the Division of Intramural Research, National Heart, Lung, and Blood Institute. M. K. is a Bolyai Fellow of the Hungarian Academy of Sciences and is funded by Norway Grant NNF2-85613, the Hungarian Scientific Research Fund (K71915 and NK81950), Tarsadalmi Megujulas Operativ Program Grant 4.2.1/B-09/1/KMR-2010-0003, and the "Momentum" Program of the Hungarian Academy of Sciences (LP2011-006/2011). NR 43 TC 52 Z9 52 U1 1 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 20 PY 2012 VL 109 IS 12 BP 4509 EP 4514 DI 10.1073/pnas.1116268109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 911JH UT WOS:000301712600037 PM 22393000 ER PT J AU Kumar, S Kellish, P Robinson, WE Wang, DY Appella, DH Arya, DP AF Kumar, Sunil Kellish, Patrick Robinson, W. Edward, Jr. Wang, Deyun Appella, Daniel H. Arya, Dev P. TI Click Dimers To Target HIV TAR RNA Conformation SO BIOCHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; NUCLEIC ACID INTERACTIONS; LONG TERMINAL REPEAT; DNA TRIPLE-HELIX; B-DNA; NEOMYCIN CONJUGATE; MAJOR GROOVE; RECOGNITION; BINDING; PROTEIN AB A series of neomycin dimers have been synthesized using "click chemistry" with varying functionality and length in the linker region to target the human immunodeficiency virus type 1 (HIV-1) TAR RNA region of the HIV virus. The TAR (Trans-Activation Responsive) RNA region, a 59 bp stem-loop structure located at the 5'-end of all nascent viral transcripts, interacts with its target, a key regulatory protein, Tat, and necessitates the replication of HIV-1. Neomycin, an aminosugar, has been shown to exhibit multiple binding sites on TAR RNA. This observation prompted us to design and synthesize a library of triazole-linked neomycin dimers using click chemistry. The binding between neomycin dimers and TAR RNA was characterized using spectroscopic techniques, including FID (fluorescent intercalator displacement), a FRET (fluorescence resonance energy transfer) competitive assay, circular dichroism (CD), and UV thermal denaturation. UV thermal denaturation studies demonstrate that binding of neomycin dimers increases the melting temperature (T-m) of the HIV TAR RNA up to 10 degrees C. Ethidium bromide displacement (FID) and a FRET competition assay revealed nanomolar binding affinity between neomycin dimers and HIV TAR RNA, while in case of neomycin, only weak binding was detected. More importantly, most of the dimers exhibited lower IC50 values toward HIV TAR RNA, when compared to the fluorescent Tat peptide, and show increased selectivity over mutant TAR RNA. Cytopathic effects investigated using MT-2 cells indicate a number of the dimers with high affinity toward TAR show promising anti-HIV activity. C1 [Kumar, Sunil; Kellish, Patrick; Arya, Dev P.] Clemson Univ, Dept Chem, Med Chem Lab, Clemson, SC 29634 USA. [Robinson, W. Edward, Jr.] Univ Calif Irvine, Dept Pathol & Lab Med, Irvine, CA 92697 USA. [Wang, Deyun; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Arya, DP (reprint author), Clemson Univ, Dept Chem, Med Chem Lab, Clemson, SC 29634 USA. EM dparya@clemson.edu RI perumal, murugiah/D-1565-2012 FU National Science Foundation [CHE/MCB-0134972]; National Institutes of Health [R15CA125724] FX We thank the National Science Foundation (CHE/MCB-0134972) and the National Institutes of Health (R15CA125724) for financial support. NR 67 TC 33 Z9 33 U1 4 U2 29 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 20 PY 2012 VL 51 IS 11 BP 2331 EP 2347 DI 10.1021/bi201657k PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 910KX UT WOS:000301636700017 PM 22339203 ER PT J AU Zhao, KJ Shi, YB AF Zhao, Keji Shi, Yun-Bo TI An anti-cancer Smurf SO CELL AND BIOSCIENCE LA English DT Article AB A novel, cancer-fighting function was recently discovered for Smad ubiquitination regulatory factor 2 (Smurf2). C1 [Zhao, Keji] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD 20892 USA. RP Zhao, KJ (reprint author), NHLBI, Syst Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov; shi@helix.nih.gov FU Intramural Research Program of NHLBI, NIH; NICHD, NIH FX The research in the authors' laboratories is supported by the Intramural Research Program of NHLBI (KZ) and NICHD (YBS), NIH. NR 5 TC 1 Z9 1 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD MAR 19 PY 2012 VL 2 AR 10 DI 10.1186/2045-3701-2-10 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 982RP UT WOS:000307063400001 PM 22429979 ER PT J AU Ried, T Gaiser, T AF Ried, Thomas Gaiser, Timo TI A recurrent fusion gene in high-grade endometrial stromal sarcoma: a new tool for diagnosis and therapy? SO GENOME MEDICINE LA English DT Editorial Material ID CANCER AB High-grade endometrial stromal sarcomas (ESSs) are an aggressive group of endometrial stromal tumors. A recent study described a recurrent chromosomal translocation (t(10;17)) occurring in ESS, which joins the gene 14-3-3 epsilon with either FAM22A or FAM22B. Expression of the resulting fusion gene leads to malignant transformation, and silencing of its expression reverses the malignant phenotype. Because the fusion can be readily detected in diagnostic samples using fluorescent in situ hybridization, this chromosomal aberration could be used to differentiate high-grade ESS from the low-grade, less aggressive form. Discovery of the new oncoprotein could also provide entry points for targeted therapies. C1 [Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Gaiser, Timo] Univ Med Mannheim, Dept Pathol, D-68167 Mannheim, Germany. RP Ried, T (reprint author), NCI, Genet Branch, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM riedt@mail.nih.gov; timo.gaiser@umm.de NR 11 TC 2 Z9 2 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD MAR 19 PY 2012 VL 4 AR 20 DI 10.1186/gm319 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 084VK UT WOS:000314567100001 PM 22429906 ER PT J AU Baas, DC Ho, L Tanck, MWT Fritsche, LG Merriam, JE Van het Slot, R Koeleman, BPC Gorgels, TGMF van Duijn, CM Uitterlinden, AG de Jong, PTVM Hofman, A ten Brink, JB Vingerling, JR Klaver, CCW Dean, M Weber, BHF Allikmets, R Hageman, GS Bergen, AAB AF Baas, Dominique C. Ho, Lintje Tanck, Michael W. T. Fritsche, Lars G. Merriam, Joanna E. Van het Slot, Ruben Koeleman, Bobby P. C. Gorgels, Theo G. M. F. van Duijn, Cornelia M. Uitterlinden, Andre G. de Jong, Paulus T. V. M. Hofman, Albert ten Brink, Jacoline B. Vingerling, Johannes R. Klaver, Caroline C. W. Dean, Michael Weber, Bernhard H. F. Allikmets, Rando Hageman, Gregory S. Bergen, Arthur A. B. TI Multicenter cohort association study of SLC2A1 single nucleotide polymorphisms and age-related macular degeneration SO MOLECULAR VISION LA English DT Article ID DEPENDENT DIABETES-MELLITUS; TRANSPORTER GLUT1 GENE; COMPLEMENT FACTOR-H; BLOOD-BRAIN-BARRIER; GLUCOSE-TRANSPORTER; HUMAN EYE; ENDOTHELIAL-CELLS; SERPING1 GENE; UNITED-STATES; SUSCEPTIBILITY AB Purpose: Age-related macular degeneration (AMD) is a major cause of blindness in older adults and has a genetically complex background. This study examines the potential association between single nucleotide polymorphisms (SNPs) in the glucose transporter 1 (SLC2A1) gene and AMD. SLC2A1 regulates the bioavailability of glucose in the retinal pigment epithelium (RPE), which might influence oxidative stress-mediated AMD pathology. Methods: Twenty-two SNPs spanning the SLC2A1 gene were genotyped in 375 cases and 199 controls from an initial discovery cohort (the Amsterdam-Rotterdam-Netherlands study). Replication testing was performed in The Rotterdam Study (the Netherlands) and study populations from Wurzburg (Germany), the Age Related Eye Disease Study (AREDS; United States), Columbia University (United States), and Iowa University (United States). Subsequently, a meta-analysis of SNP association was performed. Results: In the discovery cohort, significant genotypic association between three SNPs (rs3754219, rs4660687, and rs841853) and AMD was found. Replication in five large independent (Caucasian) cohorts (4,860 cases and 4,004 controls) did not yield consistent association results. The genotype frequencies for these SNPs were significantly different for the controls and/or cases among the six individual populations. Meta-analysis revealed significant heterogeneity of effect between the studies. Conclusions: No overall association between SLC2A1 SNPs and AMD was demonstrated. Since the genotype frequencies for the three SLC2A1 SNPs were significantly different for the controls and/or cases between the six cohorts, this study corroborates previous evidence that population dependent genetic risk heterogeneity in AMD exists. C1 [Baas, Dominique C.; Gorgels, Theo G. M. F.; de Jong, Paulus T. V. M.; ten Brink, Jacoline B.; Bergen, Arthur A. B.] NIN, Dept Clin & Mol Ophthalmogenet, Amsterdam, Netherlands. [Ho, Lintje; van Duijn, Cornelia M.; Uitterlinden, Andre G.; de Jong, Paulus T. V. M.; Hofman, Albert; Vingerling, Johannes R.; Klaver, Caroline C. W.] EMC, Dept Epidemiol, Rotterdam, Netherlands. [Ho, Lintje; Vingerling, Johannes R.; Klaver, Caroline C. W.] EMC, Dept Ophthalmol, Rotterdam, Netherlands. [Tanck, Michael W. T.] AMC, Dept Clin Epidemiol Biostat & Bioinformat, Amsterdam, Netherlands. [Fritsche, Lars G.; Weber, Bernhard H. F.] Univ Regensburg, Inst Human Genet, Regensburg, Germany. [Merriam, Joanna E.; Allikmets, Rando] Columbia Univ, Dept Ophthalmol Pathol & Cell Biol, New York, NY USA. [Van het Slot, Ruben; Koeleman, Bobby P. C.] UMC, Dept Med Genet, Res Sect, Utrecht, Netherlands. [de Jong, Paulus T. V. M.; Bergen, Arthur A. B.] AMC, Dept Ophthalmol, Amsterdam, Netherlands. [Uitterlinden, Andre G.] EMC, Dept Internal Med, Rotterdam, Netherlands. [Dean, Michael] NCI, Lab Expt Immunol, Canc & Inflammat Program, Frederick, MD 21701 USA. [Hageman, Gregory S.] Univ Iowa, Dept Ophthalmol & Visual Sci, Iowa City, IA 52242 USA. [Hageman, Gregory S.] Univ Calif Santa Barbara, Ctr Study Macular Degenerat, Santa Barbara, CA 93106 USA. [Bergen, Arthur A. B.] AMC, Dept Clin Genet, Amsterdam, Netherlands. RP Bergen, AAB (reprint author), Meibergdreef 47, NL-1105 BA Amsterdam, Netherlands. EM a.bergen@nin.knaw.nl RI Dean, Michael/G-8172-2012; Bergen, Arthur/J-3637-2013 OI Dean, Michael/0000-0003-2234-0631; FU Merck Sharpe and Dohme; Algemene Nederlandse Vereniging ter Voorkoming van Blindheid; Netherlands Macula Fund; LSBS; Netherlands Organization for Scientific Research (NWO) Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/NWO [050-060-810]; EMC and Erasmus University, Netherlands Organization for Health Research and Development (ZonMw); Ministries of Education, Culture and Science, and Health, Welfare and Sports; European Commission; Municipality of Rotterdam; National Cancer Institute, National Institutes of Health; National Eye Institute [EY13435, EY017404]; Macula Vision Research Foundation; Kaplen Foundation; Wigdeon Point Charitable Foundations; Research to Prevent Blindness; Department of Ophthalmology & Visual Sciences, University of Utah [NIHR24]; Research to Prevent Blindness, Inc. Baltimore, MD, USA FX This study was in part financed by an unrestricted research grant from Merck Sharpe and Dohme and by the Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, The Netherlands Macula Fund and LSBS (all to A.A.B). GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organization for Scientific Research (NWO) Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/NWO project nr. 050-060-810, the EMC and Erasmus University, Netherlands Organization for Health Research and Development (ZonMw), the Ministries of Education, Culture and Science, and Health, Welfare and Sports, the European Commission, and the Municipality of Rotterdam. The Franconian AMD study would like to thank Claudia N. Keilhauer (Department of Ophthalmology, University of Wurzburg, Germany) for recruiting individuals with AMD and the control subjects. Kerstin Meier (Institute of Human Genetics, University of Regensburg, Germany) for technical assistance. AREDS was supported (in part) by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The Columbia University study is supported in part by the grants from the National Eye Institute EY13435 and EY017404; the Macula Vision Research Foundation; Kaplen Foundation; Wigdeon Point Charitable Foundations and an unrestricted grant from Research to Prevent Blindness. G.S.H is supported by an unrestricted NIHR24 grant to the Department of Ophthalmology & Visual Sciences, University of Utah and a Senior Scientist Award (GSH) from Research to Prevent Blindness, Inc. Baltimore, MD, USA. The University of Iowa would like to thank Chris Pappas for technical assistance. NR 63 TC 3 Z9 3 U1 1 U2 6 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD MAR 17 PY 2012 VL 18 IS 72 BP 657 EP 674 PG 18 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 947JC UT WOS:000304425300001 PM 22509097 ER PT J AU Davey, G Bockarie, M Wanji, S Addiss, D Fuller, C Fox, L Mycoskie, M Gruin, M Tsegaye, A Ayele, FT Newport, M AF Davey, Gail Bockarie, Moses Wanji, Samuel Addiss, David Fuller, Claire Fox, LeAnne Mycoskie, Mike Gruin, Mark Tsegaye, Aster Ayele, Fasil Tekola Newport, Melanie TI Launch of the International Podoconiosis Initiative SO LANCET LA English DT Letter ID SOUTHERN ETHIOPIA C1 [Davey, Gail; Newport, Melanie] Univ Sussex, Brighton & Sussex Med Sch, Brighton BN1 9PS, E Sussex, England. [Bockarie, Moses] Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. [Wanji, Samuel] Res Fdn Trop Dis & Environm, Buea, Cameroon. [Addiss, David] Children Worms, Decatur, GA USA. [Fuller, Claire] Int Fdn Dermatol, London, England. [Fox, LeAnne] Ctr Dis Control & Prevent, Atlanta, GA USA. [Mycoskie, Mike] TOMS Shoes Inc, Santa Monica, CA USA. [Gruin, Mark] Int Orthodox Christian Char, Baltimore, MD USA. [Tsegaye, Aster] Univ Addis Ababa, Addis Ababa, Ethiopia. [Ayele, Fasil Tekola] NIH, Bethesda, MD 20892 USA. RP Davey, G (reprint author), Univ Sussex, Brighton & Sussex Med Sch, Brighton BN1 9PS, E Sussex, England. EM g.davey@bsms.ac.uk OI Davey, Gail/0000-0003-2796-7468 FU Medical Research Council [G1001337, MR/J008621/1] NR 5 TC 6 Z9 6 U1 1 U2 2 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 MAR 17 PY 2012 VL 379 IS 9820 BP 1004 EP 1004 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 911JE UT WOS:000301712300027 PM 22423883 ER PT J AU Thapar, A Collishaw, S Pine, DS Thapar, AK AF Thapar, Anita Collishaw, Stephan Pine, Daniel S. Thapar, Ajay K. TI Depression in adolescence SO LANCET LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIORAL THERAPY; SEROTONIN TRANSPORTER GENE; MIDDLE-INCOME COUNTRIES; RECENT LIFE EVENTS; MAJOR DEPRESSION; MATERNAL DEPRESSION; MENTAL-HEALTH; PSYCHIATRIC-DISORDERS; COMMUNITY SAMPLE AB Unipolar depressive disorder in adolescence is common worldwide but often unrecognised. The incidence, notably in girls, rises sharply after puberty and, by the end of adolescence, the 1 year prevalence rate exceeds 4%. The burden is highest in low-income and middle-income countries. Depression is associated with substantial present and future morbidity, and heightens suicide risk. The strongest risk factors for depression in adolescents are a family history of depression and exposure to psychosocial stress. Inherited risks, develop mental factors, sex hormones, and psychosocial adversity interact to increase risk through hormonal factors and associated perturbed neural pathways. Although many similarities between depression in adolescence and depression in adulthood exist, in adolescents the use of antidepressants is of concern and opinions about clinical management are divided. Effective treatments are available, but choices are dependent on depression severity and available resources. Prevention strategies targeted at high-risk groups are promising. C1 [Thapar, Anita; Collishaw, Stephan; Thapar, Ajay K.] Cardiff Univ, Sch Med, Dept Psychol Med & Neurol, Child & Adolescent Psychiat Sect, Cardiff CF14 4XN, S Glam, Wales. [Thapar, Anita; Collishaw, Stephan] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Cardiff CF14 4XN, S Glam, Wales. [Pine, Daniel S.] NIMH, Emot & Dev Branch, Intramural Res Program, Bethesda, MD 20892 USA. [Thapar, Ajay K.] Taff Riverside Practice, Cardiff, S Glam, Wales. RP Thapar, A (reprint author), Cardiff Univ, Sch Med, Dept Psychol Med & Neurol, Child & Adolescent Psychiat Sect, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. EM thapar@Cardiff.ac.uk OI Collishaw, Stephan/0000-0002-4296-820X; Thapar, Anita/0000-0002-3689-737X FU Sir Jules Thorn Charitable Trust; Waterloo Foundation FX The authors' research on depression is funded by the Sir Jules Thorn Charitable Trust. SC is supported by the Waterloo Foundation. We thank Sir Michael Rutter, Antonio Munoz, Robert Potter, Gemma Lewis, and Miriam Cooper for comments on an earlier draft, Robert Goodman for advice, and Peter MacSorley (medical student) for assistance with the literature search. NR 152 TC 207 Z9 220 U1 21 U2 145 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 MAR 17 PY 2012 VL 379 IS 9820 BP 1056 EP 1067 DI 10.1016/S0140-6736(11)60871-4 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 911JE UT WOS:000301712300034 PM 22305766 ER PT J AU Chawla, B Kumar, RR Tyagi, N Subramanian, G Srinivasan, N Park, MH Madhubala, R AF Chawla, Bhavna Kumar, Ravi Ranjan Tyagi, Nidhi Subramanian, Gowri Srinivasan, N. Park, Myung Hee Madhubala, Rentala TI A Unique Modification of the Eukaryotic Initiation Factor 5A Shows the Presence of the Complete Hypusine Pathway in Leishmania donovani SO PLOS ONE LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; AMINO-ACID-RESIDUES; DEOXYHYPUSINE HYDROXYLASE; CELL-GROWTH; 3-DIMENSIONAL STRUCTURES; CONTAINING PROTEIN; IDENTIFICATION; SYNTHASE; SPERMIDINE; PRECURSOR AB Deoxyhypusine hydroxylase (DOHH) catalyzes the final step in the post-translational synthesis of an unusual amino acid hypusine (N-(sic)-(4-amino-2-hydroxybutyl) lysine), which is present on only one cellular protein, eukaryotic initiation factor 5A (eIF5A). We present here the molecular and structural basis of the function of DOHH from the protozoan parasite, Leishmania donovani, which causes visceral leishmaniasis. The L. donovani DOHH gene is 981 bp and encodes a putative polypeptide of 326 amino acids. DOHH is a HEAT-repeat protein with eight tandem repeats of alpha-helical pairs. Four conserved histidine-glutamate sequences have been identified that may act as metal coordination sites. A similar to 42 kDa recombinant protein with a His-tag was obtained by heterologous expression of DOHH in Escherichia coli. Purified recombinant DOHH effectively catalyzed the hydroxylation of the intermediate, eIF5A-deoxyhypusine (eIF5A-Dhp), in vitro. L. donovani DOHH (LdDOHH) showed similar to 40.6% sequence identity with its human homolog. The alignment of L. donovani DOHH with the human homolog shows that there are two significant insertions in the former, corresponding to the alignment positions 159-162 (four amino acid residues) and 174-183 (ten amino acid residues) which are present in the variable loop connecting the N- and C-terminal halves of the protein, the latter being present near the substrate binding site. Deletion of the ten-amino-acid-long insertion decreased LdDOHH activity to 14% of the wild type recombinant LdDOHH. Metal chelators like ciclopirox olamine (CPX) and mimosine significantly inhibited the growth of L. donovani and DOHH activity in vitro. These inhibitors were more effective against the parasite enzyme than the human enzyme. This report, for the first time, confirms the presence of a complete hypusine pathway in a kinetoplastid unlike eubacteria and archaea. The structural differences between the L. donovani DOHH and the human homolog may be exploited for structure based design of selective inhibitors against the parasite. C1 [Chawla, Bhavna; Kumar, Ravi Ranjan; Subramanian, Gowri; Madhubala, Rentala] Jawaharlal Nehru Univ, Sch Life Sci, New Delhi 110067, India. [Tyagi, Nidhi; Srinivasan, N.] Indian Inst Sci, Mol Biophys Unit, Bangalore 560012, Karnataka, India. [Park, Myung Hee] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Chawla, B (reprint author), Jawaharlal Nehru Univ, Sch Life Sci, New Delhi 110067, India. EM madhubala@mail.jnu.ac.in OI madhubala, rentala/0000-0002-0034-399X; Tyagi, Nidhi/0000-0002-2065-9051 FU Council of Scientific and Industrial Research (CSIR), India; Department of Science and Technology (DST), India FX This work is supported by a grant from the Council of Scientific and Industrial Research (CSIR), India to Dr. Madhubala. Dr. Madhubala is a JC Bose Fellow supported by the Department of Science and Technology (DST), India. Dr. Chawla, Ravi Ranjan Kumar and Nidhi Tyagi are supported by CSIR, India. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 13 Z9 14 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 MAR 16 PY 2012 VL 7 IS 3 AR e33138 DI 10.1371/journal.pone.0033138 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 932RV UT WOS:000303309100024 PM 22438895 ER PT J AU Sun, C Fang, H Xie, T Auth, RD Patel, N Murray, PR Snoy, PJ Frucht, DM AF Sun, Chen Fang, Hui Xie, Tao Auth, Roger D. Patel, Nayana Murray, Patrick R. Snoy, Philip J. Frucht, David M. TI Anthrax Lethal Toxin Disrupts Intestinal Barrier Function and Causes Systemic Infections with Enteric Bacteria SO PLOS ONE LA English DT Article ID BACILLUS-ANTHRACIS; KAPPA-B; CELLS; ACTIVATION AB A variety of intestinal pathogens have virulence factors that target mitogen activated protein kinase (MAPK) signaling pathways, including Bacillus anthracis. Anthrax lethal toxin (LT) has specific proteolytic activity against the upstream regulators of MAPKs, the MAPK kinases (MKKs). Using a murine model of intoxication, we show that LT causes the dose-dependent disruption of intestinal epithelial integrity, characterized by mucosal erosion, ulceration, and bleeding. This pathology correlates with an LT-dependent blockade of intestinal crypt cell proliferation, accompanied by marked apoptosis in the villus tips. C57BL/6J mice treated with intravenous LT nearly uniformly develop systemic infections with commensal enteric organisms within 72 hours of administration. LT-dependent intestinal pathology depends upon its proteolytic activity and is partially attenuated by co-administration of broad spectrum antibiotics, indicating that it is both a cause and an effect of infection. These findings indicate that targeting of MAPK signaling pathways by anthrax LT compromises the structural integrity of the mucosal layer, serving to undermine the effectiveness of the intestinal barrier. Combined with the well-described immunosuppressive effects of LT, this disruption of the intestinal barrier provides a potential mechanism for host invasion via the enteric route, a common portal of entry during the natural infection cycle of Bacillus anthracis. C1 [Sun, Chen; Fang, Hui; Xie, Tao; Auth, Roger D.; Frucht, David M.] US FDA, Cell Biol Lab, Div Monoclonal Antibodies, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. [Patel, Nayana; Murray, Patrick R.] NIH, Dept Lab Med, Warren Magnusen Clin Ctr, Bethesda, MD 20892 USA. [Snoy, Philip J.] US FDA, Div Vet Serv, Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. RP Sun, C (reprint author), US FDA, Cell Biol Lab, Div Monoclonal Antibodies, Off Biotechnol Prod,Ctr Drug Evaluat & Res, Bethesda, MD 20014 USA. EM david.frucht@fda.hhs.gov FU United States government FX The United States government provided the funding to support this work. The information presented in this manuscript reflects the work of the authors and does not necessarily represent the policy of the United States Food and Drug Administration. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 9 Z9 9 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 MAR 16 PY 2012 VL 7 IS 3 AR e33583 DI 10.1371/journal.pone.0033583 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 932RV UT WOS:000303309100061 PM 22438953 ER PT J AU Pazgier, M Wei, G Ericksen, B Jung, G Wu, ZB de Leeuw, E Yuan, WR Szmacinski, H Lu, WY Lubkowski, J Lehrer, RI Lu, WY AF Pazgier, Marzena Wei, Gang Ericksen, Bryan Jung, Grace Wu, Zhibin de Leeuw, Erik Yuan, Weirong Szmacinski, Henryk Lu, Wei-Yue Lubkowski, Jacek Lehrer, Robert I. Lu, Wuyuan TI Sometimes It Takes Two to Tango CONTRIBUTIONS OF DIMERIZATION TO FUNCTIONS OF HUMAN alpha-DEFENSIN HNP1 PEPTIDE SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN ALPHA-DEFENSINS; PRECURSOR LIPID II; ANTIMICROBIAL PEPTIDES; INNATE IMMUNITY; PANETH CELLS; MECHANISM; DIMER; PROTEIN; BINDING; HD5 AB Human myeloid alpha-defensins called HNPs play multiple roles in innate host defense. The Trp-26 residue of HNP1 was previously shown to contribute importantly to its ability to kill S. aureus, inhibit anthrax lethal factor (LF), bind gp120 of HIV-1, dimerize, and undergo further self-association. To gain additional insights into the functional significance of dimerization, we compared wild type HNP1 to dimerization-impaired, N-methylated HNP1 monomers and to disulfide-tethered obligate HNP1 dimers. The structural effects of these modifications were confirmed by x-ray crystallographic analyses. Like the previously studied W26A mutation, N-methylation of Ile-20 dramatically reduced the ability of HNP1 to kill Staphylococcus aureus, inhibit LF, and bind gp120. Importantly, this modification had minimal effect on the ability of HNP1 to kill Escherichia coli. The W26A and MeIle-20 mutations impaired defensin activity synergistically. N-terminal covalent tethering rescued the ability of W26A-HNP1 to inhibit LF but failed to restore its defective killing of S. aureus. Surface plasmon resonance studies revealed that Trp-26 mediated the association of monomers and canonical dimers of HNP1 to immobilized HNP1, LF, and gp120, and also indicated a possible mode of tetramerization of HNP1 mediated by Ile-20 and Leu-25. This study demonstrates that dimerization contributes to some but not all of the many and varied activities of HNP1. C1 [Pazgier, Marzena; Lubkowski, Jacek] NCI, Macromol Assembly Struct & Cell Signaling Sect, NIH, Frederick, MD 21702 USA. [Pazgier, Marzena; Wei, Gang; Ericksen, Bryan; Wu, Zhibin; de Leeuw, Erik; Yuan, Weirong; Lu, Wuyuan] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Szmacinski, Henryk; Lu, Wuyuan] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Wei, Gang; Lu, Wei-Yue] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China. [Jung, Grace; Lehrer, Robert I.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. RP Lubkowski, J (reprint author), NCI, Macromol Assembly Struct & Cell Signaling Sect, NIH, Frederick, MD 21702 USA. EM lubkowsj@mail.nih.gov; wlu@ihv.umaryland.edu RI Lu, Wuyuan/B-2268-2010; Ericksen, Bryan/F-9047-2012; Lu, Weiyue/E-7938-2010 FU United States Department of Energy, Office of Science [W-31-109-Eng38]; United States Department of Energy, Office of Basic Energy Sciences [W-31-109-Eng38]; National Institutes of Health [AI072732, AI061482]; NCI, Center for Cancer Research; National Natural Science Foundation of China [30701060] FX We thank the X-ray Crystallography Core Facility of the University of Maryland at Baltimore for providing crystallographic equipment and resources. Use of the Advanced Photon Source was supported by the United States Department of Energy, Offices of Science and of Basic Energy Sciences, under Contract W-31-109-Eng38.; This work was supported, in whole or in part, by National Institutes of Health Grants AI072732 and AI061482 (to W. L.) and by the Intramural Research Program, NCI, Center for Cancer Research (to J. L.).; Supported by National Natural Science Foundation of China Grant 30701060. NR 52 TC 22 Z9 22 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 16 PY 2012 VL 287 IS 12 BP 8944 EP 8953 DI 10.1074/jbc.M111.332205 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 912KV UT WOS:000301797800025 PM 22270360 ER PT J AU Kasiviswanathan, R Gustafson, MA Copeland, WC Meyer, JN AF Kasiviswanathan, Rajesh Gustafson, Margaret A. Copeland, William C. Meyer, Joel N. TI Human Mitochondrial DNA Polymerase gamma Exhibits Potential for Bypass and Mutagenesis at UV-induced Cyclobutane Thymine Dimers SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ULTRAVIOLET-RADIATION EXPOSURE; MISMATCH-REPAIR ACTIVITY; NONMELANOMA SKIN-CANCER; ESCHERICHIA-COLI; NUCLEOTIDE INCORPORATION; MAMMALIAN MITOCHONDRIA; MALIGNANT-MELANOMA; OXIDATIVE STRESS; COMMON DELETION; LESION BYPASS AB Cyclobutane thymine dimers (T-T) comprise the majority of DNA damage caused by short wavelength ultraviolet radiation. These lesions generally block replicative DNA polymerases and are repaired by nucleotide excision repair or bypassed by translesion polymerases in the nucleus. Mitochondria lack nucleotide excision repair, and therefore, it is important to understand how the sole mitochondrial DNA polymerase, pol gamma, interacts with irreparable lesions such as T-T. We performed in vitro DNA polymerization assays to measure the kinetics of incorporation opposite the lesion and bypass of the lesion by pol gamma with a dimer-containing template. Exonuclease-deficient pol gamma bypassed thymine dimers with low relative efficiency; bypass was attenuated but still detectable when using exonuclease-proficient pol gamma. When bypass did occur, pol gamma misincorporated a guanine residue opposite the 3'-thymine of the dimer only 4-fold less efficiently than it incorporated an adenine. Surprisingly, the pol gamma exonuclease-proficient enzyme excised the incorrectly incorporated guanine at similar rates irrespective of the nature of the thymines in the template. In the presence of all four dNTPs, pol gamma extended the primer after incorporation of two adenines opposite the lesion with relatively higher efficiency compared with extension past either an adenine or a guanine incorporated opposite the 3'-thymine of the T-T. Our results suggest that T-T usually stalls mitochondrial DNA replication but also suggest a mechanism for the introduction of point mutations and deletions in the mitochondrial genomes of chronically UV-exposed cells. C1 [Gustafson, Margaret A.; Meyer, Joel N.] Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA. [Kasiviswanathan, Rajesh; Copeland, William C.] NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Meyer, JN (reprint author), Duke Univ, Nicholas Sch Environm, Durham, NC 27708 USA. EM joel.meyer@duke.edu RI Kasiviswanathan, Rajesh/D-2744-2012 FU National Institutes of Health [R21 NS065468, ES 065078] FX This work was supported, in whole or in part, by National Institutes of Health Grant R21 NS065468 (to J. N. M.) and ES 065078 (to W. C. C.). NR 59 TC 18 Z9 19 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 MAR 16 PY 2012 VL 287 IS 12 BP 9222 EP 9229 DI 10.1074/jbc.M111.306852 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 912KV UT WOS:000301797800050 PM 22194617 ER PT J AU Zhang, YH Li, ZG Sacks, DB Ames, JB AF Zhang, Yonghong Li, Zhigang Sacks, David B. Ames, James B. TI Structural Basis for Ca2+-induced Activation and Dimerization of Estrogen Receptor alpha by Calmodulin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TARGET RECOGNITION; BREAST-CANCER; TRANSCRIPTIONAL ACTIVITY; LIGHT-SCATTERING; CALCIUM-BINDING; NMR; COMPLEX; CHROMATOGRAPHY; CA2+/CALMODULIN; CONFORMATION AB The estrogen receptor alpha (ER-alpha) regulates expression of target genes implicated in development, metabolism, and breast cancer. Calcium-dependent regulation of ER-alpha is critical for activating gene expression and is controlled by calmodulin (CaM). Here, we present the NMR structures for the two lobes of CaM each bound to a localized region of ER-alpha (residues 287-305). A model of the complete CaM alpha ER-alpha complex was constructed by combining these two structures with additional data. The two lobes of CaM both compete for binding at the same site on ER-alpha (residues 292, 296, 299, 302, and 303), which explains why full-length CaM binds two molecules of ER-alpha in a 1:2 complex and stabilizes ER-alpha dimerization. Exposed glutamate residues in CaM (Glu(11), Glu(14), Glu(84), and Glu(87)) form salt bridges with key lysine residues in ER-alpha (Lys(299), Lys(302), and Lys(303)), which are likely to prevent ubiquitination at these sites and inhibit degradation of ER-alpha. Mutants of ER-alpha at the CaM-binding site (W292A and K299A) weaken binding to CaM, and I298E/K299D disrupts estrogen-induced transcription. CaM facilitates dimerization of ER-alpha in the absence of estrogen, and stimulation of ER-alpha by either Ca2+ and/or estrogen may serve to regulate transcription in a combinatorial fashion. C1 [Zhang, Yonghong; Ames, James B.] Univ Calif Davis, Dept Chem, Davis, CA 95616 USA. [Li, Zhigang; Sacks, David B.] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Ames, JB (reprint author), Univ Calif Davis, Dept Chem, 1 Shields Ave, Davis, CA 95616 USA. EM ames@chem.ucdavis.edu FU National Institutes of Health [EY012347, NS059969]; Intramural Research Program FX This work was supported, in whole or in part, by National Institutes of Health Grants EY012347 and NS059969 (to J. B. A.) and by the Intramural Research Program. NR 57 TC 15 Z9 15 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 MAR 16 PY 2012 VL 287 IS 12 BP 9336 EP 9344 DI 10.1074/jbc.M111.334797 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 912KV UT WOS:000301797800065 PM 22275375 ER PT J AU Chen, CY Samuel, TK Krause, M Dailey, HA Hamza, I AF Chen, Caiyong Samuel, Tamika K. Krause, Michael Dailey, Harry A. Hamza, Iqbal TI Heme Utilization in the Caenorhabditis elegans Hypodermal Cells Is Facilitated by Heme-responsive Gene-2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GLUTATHIONE-S-TRANSFERASE; BINDING PROTEIN; MOLECULAR CHARACTERIZATION; SACCHAROMYCES-CEREVISIAE; CADMIUM TOXICITY; CYTOCHROME-C; IRON UPTAKE; IDENTIFICATION; TRANSPORT; REDOX AB The roundworm Caenorhabditis elegans is a heme auxotroph that requires the coordinated actions of HRG-1 heme permeases to transport environmental heme into the intestine and HRG-3, a secreted protein, to deliver intestinal heme to other tissues including the embryo. Here we show that heme homeostasis in the extraintestinal hypodermal tissue was facilitated by the transmembrane protein HRG-2. Systemic heme deficiency up-regulated hrg-2 mRNA expression over 200-fold in the main body hypodermal syncytium, hyp 7. HRG-2 is a type I membrane protein that binds heme and localizes to the endoplasmic reticulum and apical plasma membrane. Cytochrome heme profiles are aberrant in HRG-2-deficient worms, a phenotype that was partially suppressed by heme supplementation. A heme-deficient yeast strain, ectopically expressing worm HRG-2, revealed significantly improved growth at submicromolar concentrations of exogenous heme. Taken together, our results implicate HRG-2 as a facilitator of heme utilization in the Caenorhabditis elegans hypodermis and provide a mechanism for the regulation of heme homeostasis in an extraintestinal tissue. C1 [Chen, Caiyong; Samuel, Tamika K.; Hamza, Iqbal] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [Chen, Caiyong; Samuel, Tamika K.; Hamza, Iqbal] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Krause, Michael] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Dailey, Harry A.] Univ Georgia, Dept Microbiol, Biomed & Hlth Sci Inst, Athens, GA 30602 USA. [Dailey, Harry A.] Univ Georgia, Dept Biochem & Mol Biol, Biomed & Hlth Sci Inst, Athens, GA 30602 USA. RP Hamza, I (reprint author), Univ Maryland, Dept Anim & Avian Sci, 2413 ANSC,Bldg 142, College Pk, MD 20742 USA. EM hamza@umd.edu OI Krause, Michael/0000-0001-6127-3940 FU National Institutes of Health (NIH) [R01DK74797]; NIH from NIDDK FX This work was supported, in whole or in part, by National Institutes of Health (NIH) Grant R01DK74797 (extramural funding) (to I. H.) and an NIH Intramural Research Program grant from the NIDDK (to M. K.). NR 59 TC 14 Z9 18 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 16 PY 2012 VL 287 IS 12 BP 9601 EP 9612 DI 10.1074/jbc.M111.307694 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 912KV UT WOS:000301797800091 PM 22303006 ER PT J AU Inagaki, S Ghirlando, R White, JF Gvozdenovic-Jeremic, J Northup, JK Grisshammer, R AF Inagaki, Sayaka Ghirlando, Rodolfo White, Jim F. Gvozdenovic-Jeremic, Jelena Northup, John K. Grisshammer, Reinhard TI Modulation of the Interaction between Neurotensin Receptor NTS1 and Gq Protein by Lipid SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE G-protein-coupled receptor; G protein; nanodisc; lipid; charge ID PHOSPHOLIPID-BILAYER NANODISCS; GTP-BINDING PROTEIN; COUPLED RECEPTORS; MONOMERIC RHODOPSIN; ANALYTICAL ULTRACENTRIFUGATION; FUNCTIONAL RECONSTITUTION; VISUAL TRANSDUCTION; MEMBRANE-PROTEINS; METARHODOPSIN-II; ROLES AB Membrane lipids have been implicated to influence the activity of G-protein-coupled receptors (GPCRs). Almost all of our knowledge on the role of lipids on GPCR and G protein function comes from work on the visual pigment rhodopsin and its G protein transducin, which reside in a highly specialized membrane environment. Thus, insight gained from rhodopsin signaling may not be simply translated to other nonvisual GPCRs. Here, we investigated the effect of lipid head group charges on the signal transduction properties of the class A GPCR neurotensin (NT) receptor 1 (NTS1) under defined experimental conditions, using self-assembled phospholipid nanodiscs prepared with the zwitter-ionic lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), the negatively charged 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG), or a POPC/POPG mixture. A combination of dynamic light scattering and sedimentation velocity showed that NTS1 was monomeric in POPC-, POPC/POPG-, and POPG-nanodiscs. Binding of the agonist NT to NTS1 occurred with similar affinities and was essentially unaffected by the phospholipid composition. In contrast, Gq protein coupling to NTS1 in various lipid nanodiscs was significantly different, and the apparent affinity of G alpha q and G beta(1)gamma(1) to activated NTS1 increased with increasing POPG content. NTS1-catalyzed GDP/GTP gamma S nucleotide exchange at G alpha q in the presence of G beta(1)gamma(1) and NT was crucially affected by the lipid type, with exchange rates higher by 1 or 2 orders of magnitude in POPC/POPG- and POPG-nanodiscs, respectively, compared to POPC-nanodiscs. Our data demonstrate that negatively charged lipids in the immediate vicinity of a nonvisual GPCR modulate the G-protein-coupling step. Published by Elsevier Ltd. C1 [Inagaki, Sayaka; White, Jim F.; Gvozdenovic-Jeremic, Jelena; Grisshammer, Reinhard] NINDS, Membrane Prot Struct Funct Unit, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Ghirlando, Rodolfo] NIDDKD, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Northup, John K.] Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, NIH, Dept Hlth & Human Serv, Rockville, MD 20850 USA. RP Grisshammer, R (reprint author), NINDS, Membrane Prot Struct Funct Unit, NIH, Dept Hlth & Human Serv, 5625 Fishers Lane,Room 4S12, Rockville, MD 20852 USA. EM rkgriss@helix.nih.gov RI Grisshammer, Reinhard/C-3089-2015 FU National Institutes of Health FX N-terminal protein sequence analysis was done at the Center for Biologics Evaluation and Research (Food and Drug Administration). DNA sequence analysis was performed by the National Institute of Neurological Disorders and Stroke (NINTDS) DNA Sequencing Facility. We thank Klaus Gawrisch and Walter Teague (National Institute on Alcohol Abuse and Alcoholism) for access to the NMR facility and for help and David Sibley (NINDS), Jurgen Wess (National Institute of Diabetes and Digestive and Kidney Diseases), Klaus Gawrisch (National Institute on Alcohol Abuse and Alcoholism), and Paul Randazzo (National Cancer Institute) for critical comments. This research was supported by the Intramural Research Program of the National Institutes of Health (S.I., J.F.W., J.J., R. Grisshammer: NINDS; R. Ghirlando: National Institute of Diabetes and Digestive and Kidney Diseases; J.K.N.: National Institute on Deafness and Other Communication Disorders). NR 99 TC 48 Z9 48 U1 2 U2 19 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 16 PY 2012 VL 417 IS 1-2 BP 95 EP 111 DI 10.1016/j.jmb.2012.01.023 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 910XW UT WOS:000301682900008 PM 22306739 ER PT J AU Stroncek, DF Berger, C Cheever, MA Childs, RW Dudley, ME Flynn, P Gattinoni, L Heath, JR Kalos, M Marincola, FM Miller, JS Mostoslavsky, G Powell, DJ Rao, M Restifo, NP Rosenberg, SA O'Shea, J Melief, CJM AF Stroncek, David F. Berger, Carolina Cheever, Martin A. Childs, Richard W. Dudley, Mark E. Flynn, Peter Gattinoni, Luca Heath, James R. Kalos, Michael Marincola, Francesco M. Miller, Jeffrey S. Mostoslavsky, Gustavo Powell, Daniel J., Jr. Rao, Mahendra Restifo, Nicholas P. Rosenberg, Steven A. O'Shea, John Melief, Cornelis J. M. TI New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID PLURIPOTENT STEM-CELLS; TUMOR-INFILTRATING LYMPHOCYTES; ENGINEERED T-CELLS; ADOPTIVE TRANSFER; METASTATIC MELANOMA; MEMORY; IMMUNOTHERAPY; REGRESSION; GENERATION; NUMBERS AB A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naive and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies. C1 [Stroncek, David F.; Marincola, Francesco M.] NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. [Berger, Carolina; Cheever, Martin A.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Cheever, Martin A.] Canc Immunotherapy Trials Network CITN, Seattle, WA USA. [Childs, Richard W.] NHLBI, NIH, Bethesda, MD 20892 USA. [Dudley, Mark E.; Gattinoni, Luca; Restifo, Nicholas P.; Rosenberg, Steven A.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Flynn, Peter] Fate Therapeut Inc, San Diego, CA USA. [Heath, James R.] CALTECH, Pasadena, CA 91125 USA. [Kalos, Michael; Powell, Daniel J., Jr.] Univ Penn, Philadelphia, PA 19104 USA. [Marincola, Francesco M.] Ctr Human Immunol, NIH, Bethesda, MD USA. [Miller, Jeffrey S.] Univ Minnesota, Minneapolis, MN USA. [Mostoslavsky, Gustavo] Boston Univ, Sch Med, Boston, MA 02118 USA. [Rao, Mahendra] Ctr Regenerat Med, NIH, Bethesda, MD USA. [O'Shea, John] NIAMSD, Bethesda, MD 20892 USA. [Melief, Cornelis J. M.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Melief, Cornelis J. M.] Immune Syst Activat, Leiden, Netherlands. RP Stroncek, DF (reprint author), NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov RI Gattinoni, Luca/A-2281-2008; Restifo, Nicholas/A-5713-2008; OI Gattinoni, Luca/0000-0003-2239-3282; Miller, Jeffrey S/0000-0002-0339-4944; Restifo, Nicholas P./0000-0003-4229-4580 NR 31 TC 24 Z9 25 U1 1 U2 16 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 MAR 15 PY 2012 VL 10 AR 48 DI 10.1186/1479-5876-10-48 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 949CP UT WOS:000304553800001 PM 22420641 ER PT J AU Castellano, JF Fletcher, BR Kelley-Bell, B Kim, DH Gallagher, M Rapp, PR AF Castellano, James F. Fletcher, Bonnie R. Kelley-Bell, Bennett Kim, David H. Gallagher, Michela Rapp, Peter R. TI Age-Related Memory Impairment Is Associated with Disrupted Multivariate Epigenetic Coordination in the Hippocampus SO PLOS ONE LA English DT Article ID SPATIAL-LEARNING IMPAIRMENT; GYRUS GRANULE NEURONS; LONG-TERM-MEMORY; SYNAPTIC PLASTICITY; TRANSCRIPTIONAL ACTIVATION; HISTONE ACETYLATION; RAT HIPPOCAMPUS; PHOSPHORYLATION; INHIBITORS; INDUCTION AB Mounting evidence linking epigenetic regulation to memory-related synaptic plasticity raises the possibility that altered chromatin modification dynamics might contribute to age-dependent cognitive decline. Here we show that the coordinated orchestration of both baseline and experience-dependent epigenetic regulation seen in the young adult hippocampus is lost in association with cognitive aging. Using a well-characterized rat model that reliably distinguishes aged individuals with significant memory impairment from others with normal memory, no single epigenetic mark or experience-dependent modification in the hippocampus uniquely predicted differences in the cognitive outcome of aging. The results instead point to a multivariate pattern in which modification-specific, bidirectional chromatin regulation is dependent on recent behavioral experience, chronological age, cognitive status, and hippocampal region. Whereas many epigenetic signatures were coupled with memory capacity among young adults and aged rats with preserved cognitive function, such associations were absent among aged rats with deficits in hippocampal memory. By comparison with the emphasis in current preclinical translational research on promoting chromatin modifications permissive for gene expression, our findings suggest that optimally successful hippocampal aging may hinge instead on enabling coordinated control across the epigenetic landscape. C1 [Castellano, James F.; Fletcher, Bonnie R.; Kelley-Bell, Bennett; Kim, David H.; Rapp, Peter R.] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. [Castellano, James F.] Mt Sinai Sch Med, Grad Program Neurosci, New York, NY USA. [Gallagher, Michela] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD USA. RP Castellano, JF (reprint author), NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. EM rappp@mail.nih.gov FU National Institute on Aging; National Institutes of Health [AG09973, AG032845] FX This research was supported in part by the Intramural Research Program of the National Institute on Aging, and by National Institutes of Health grants AG09973 (MG) and AG032845 (JFC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 25 Z9 26 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 MAR 15 PY 2012 VL 7 IS 3 AR e33249 DI 10.1371/journal.pone.0033249 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 932RU UT WOS:000303309000016 PM 22438904 ER PT J AU Furl, N Gallagher, S Averbeck, BB AF Furl, Nicholas Gallagher, Shannon Averbeck, Bruno B. TI A Selective Emotional Decision-Making Bias Elicited by Facial Expressions SO PLOS ONE LA English DT Article ID PREDICTION ERRORS; TEMPORAL PREDICTION; HUMAN STRIATUM; LEARNING-TASK; NEURAL BASIS; HUMAN BRAIN; OXYTOCIN; REWARD; METAANALYSIS; PERCEPTION AB Emotional and social information can sway otherwise rational decisions. For example, when participants decide between two faces that are probabilistically rewarded, they make biased choices that favor smiling relative to angry faces. This bias may arise because facial expressions evoke positive and negative emotional responses, which in turn may motivate social approach and avoidance. We tested a wide range of pictures that evoke emotions or convey social information, including animals, words, foods, a variety of scenes, and faces differing in trustworthiness or attractiveness, but we found only facial expressions biased decisions. Our results extend brain imaging and pharmacological findings, which suggest that a brain mechanism supporting social interaction may be involved. Facial expressions appear to exert special influence over this social interaction mechanism, one capable of biasing otherwise rational choices. These results illustrate that only specific types of emotional experiences can best sway our choices. C1 [Furl, Nicholas; Gallagher, Shannon; Averbeck, Bruno B.] NIMH, Unit Learning & Decis Making, Neuropsychol Lab, Bethesda, MD 20892 USA. RP Furl, N (reprint author), NIMH, Unit Learning & Decis Making, Neuropsychol Lab, Bethesda, MD 20892 USA. EM nick.furl@mrc-cbu.cam.ac.uk OI furl, nicholas/0000-0003-2488-1343 FU National Institutes of Health, National Institute of Mental Health FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 10 Z9 10 U1 0 U2 17 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 MAR 15 PY 2012 VL 7 IS 3 AR e33461 DI 10.1371/journal.pone.0033461 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 932RU UT WOS:000303309000027 PM 22438936 ER PT J AU Koch, BJ Ryan, JF Baxevanis, AD AF Koch, Bernard J. Ryan, Joseph F. Baxevanis, Andreas D. TI The Diversification of the LIM Superclass at the Base of the Metazoa Increased Subcellular Complexity and Promoted Multicellular Specialization SO PLOS ONE LA English DT Article ID CAENORHABDITIS-ELEGANS MUSCLE; FOCAL ADHESION PROTEIN; DOMAIN PROTEINS; ACTIN-BINDING; PLANAR POLARITY; HOMEOBOX GENES; CELL-ADHESION; ALPHA-ACTININ; F-ACTIN; GENOME AB Background: Throughout evolution, the LIM domain has been deployed in many different domain configurations, which has led to the formation of a large and distinct group of proteins. LIM proteins are involved in relaying stimuli received at the cell surface to the nucleus in order to regulate cell structure, motility, and division. Despite their fundamental roles in cellular processes and human disease, little is known about the evolution of the LIM superclass. Results: We have identified and characterized all known LIM domain-containing proteins in six metazoans and three non-metazoans. In addition, we performed a phylogenetic analysis on all LIM domains and, in the process, have identified a number of novel non-LIM domains and motifs in each of these proteins. Based on these results, we have formalized a classification system for LIM proteins, provided reasonable timing for class and family origin events; and identified lineage-specific loss events. Our analysis is the first detailed description of the full set of LIM proteins from the non-bilaterian species examined in this study. Conclusion: Six of the 14 LIM classes originated in the stem lineage of the Metazoa. The expansion of the LIM superclass at the base of the Metazoa undoubtedly contributed to the increase in subcellular complexity required for the transition from a unicellular to multicellular lifestyle and, as such, was a critically important event in the history of animal multicellularity. C1 [Koch, Bernard J.; Ryan, Joseph F.; Baxevanis, Andreas D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Koch, BJ (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM andy@nhgri.nih.gov FU National Human Genome Research Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. All authors work at the National Human Genome Research Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 109 TC 13 Z9 13 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 15 PY 2012 VL 7 IS 3 AR e33261 DI 10.1371/journal.pone.0033261 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 932RU UT WOS:000303309000018 PM 22438907 ER PT J AU Shivalkar, M Giniger, E AF Shivalkar, Madhuri Giniger, Edward TI Control of Dendritic Morphogenesis by Trio in Drosophila melanogaster SO PLOS ONE LA English DT Article ID ABL TYROSINE KINASE; SENSORY NEURONS; AXON GROWTH; RAC GTPASES; GEF TRIO; MECHANISMS; GUIDANCE; ABELSON; PROTEIN; DOMAIN AB Abl tyrosine kinase and its effectors among the Rho family of GTPases each act to control dendritic morphogenesis in Drosophila. It has not been established, however, which of the many GTPase regulators in the cell link these signaling molecules in the dendrite. In axons, the bifunctional guanine exchange factor, Trio, is an essential link between the Abl tyrosine kinase signaling pathway and Rho GTPases, particularly Rac, allowing these systems to act coordinately to control actin organization. In dendritic morphogenesis, however, Abl and Rac have contrary rather than reinforcing effects, raising the question of whether Trio is involved, and if so, whether it acts through Rac, Rho or both. We now find that Trio is expressed in sensory neurons of the Drosophila embryo and regulates their dendritic arborization. trio mutants display a reduction in dendritic branching and increase in average branch length, whereas over-expression of trio has the opposite effect. We further show that it is the Rac GEF domain of Trio, and not its Rho GEF domain that is primarily responsible for the dendritic function of Trio. Thus, Trio shapes the complexity of dendritic arbors and does so in a way that mimics the effects of its target, Rac. C1 [Shivalkar, Madhuri; Giniger, Edward] Natl Inst Neurol Disorders & Stroke, Axon Guidance & Neural Connect Unit, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. RP Shivalkar, M (reprint author), Natl Inst Neurol Disorders & Stroke, Axon Guidance & Neural Connect Unit, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. EM ginigere@ninds.nih.gov RI Giniger, Edward/C-1764-2015 OI Giniger, Edward/0000-0002-8340-6158 FU NINDS, NIH [Z01 NS003013] FX This work was supported by the Intramural Research Program of the NINDS, NIH (Z01 NS003013). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 6 Z9 6 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 MAR 15 PY 2012 VL 7 IS 3 AR e33737 DI 10.1371/journal.pone.0033737 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 932RU UT WOS:000303309000037 PM 22438988 ER PT J AU Strokappe, N Szynol, A Aasa-Chapman, M Gorlani, A Quigley, AF Hulsik, DL Chen, L Weiss, R de Haard, H Verrips, T AF Strokappe, Nika Szynol, Agnieszka Aasa-Chapman, Marlen Gorlani, Andrea Quigley, Anna Forsman Hulsik, David Lutje Chen, Lei Weiss, Robin de Haard, Hans Verrips, Theo TI Llama Antibody Fragments Recognizing Various Epitopes of the CD4bs Neutralize a Broad Range of HIV-1 Subtypes A, B and C SO PLOS ONE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODIES; GP120 ENVELOPE GLYCOPROTEIN; FUSION INHIBITOR T-20; BINDING-SITE; POTENT NEUTRALIZATION; CRYSTAL-STRUCTURE; ENV CLONES; PHAGE; VALIDATION AB Many of the neutralising antibodies, isolated to date, display limited activities against the globally most prevalent HIV-1 subtypes A and C. Therefore, those subtypes are considered to be an important target for antibody-based therapy. Variable domains of llama heavy chain antibodies (VHH) have some superior properties compared with classical antibodies. Therefore we describe the application of trimeric forms of envelope proteins (Env), derived from HIV-1 of subtype A and B/C, for a prolonged immunization of two llamas. A panel of VHH, which interfere with CD4 binding to HIV-1 Env were selected with use of panning. The results of binding and competition assays to various Env, including a variant with a stabilized CD4-binding state (gp120(Ds2)), cross-competition experiments, maturation analysis and neutralisation assays, enabled us to classify the selected VHH into three groups. The VHH of group I were efficient mainly against viruses of subtype A, C and B'/C. The VHH of group II resemble the broadly neutralising antibody (bnmAb) b12, neutralizing mainly subtype B and C viruses, however some had a broader neutralisation profile. A representative of the third group, 2E7, had an even higher neutralization breadth, neutralizing 21 out of the 26 tested strains belonging to the A, A/G, B, B/C and C subtypes. To evaluate the contribution of certain amino acids to the potency of the VHH a small set of the mutants were constructed. Surprisingly this yielded one mutant with slightly improved neutralisation potency against 92UG37.A9 (subtype A) and 96ZM651.02 (subtype C). These findings and the well-known stability of VHH indicate the potential application of these VHH as anti-HIV-1 microbicides. C1 [Strokappe, Nika; Szynol, Agnieszka; Gorlani, Andrea; de Haard, Hans; Verrips, Theo] Univ Utrecht, Dept Biol, Fac Sci, Utrecht, Netherlands. [Aasa-Chapman, Marlen; Quigley, Anna Forsman; Weiss, Robin] UCL, Div Infect & Immun, UCL MRC Ctr Med Mol Virol, London, England. [Hulsik, David Lutje] Univ Grenoble 1, EMBL, CNRS, Unit Virus Host Cell Interact UVHCI,UMI 3265, Grenoble, France. [Chen, Lei] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Strokappe, N (reprint author), Univ Utrecht, Dept Biol, Fac Sci, Utrecht, Netherlands. EM t.verrips@qvquality.com RI gorlani, andrea/C-5678-2014 FU Collaboration for AIDS Vaccine Discovery Grant [38637]; Bill & Melinda Gates Foundation; European Commission FX This study was funded in part by the Collaboration for AIDS Vaccine Discovery Grant number 38637 sponsored by the Bill & Melinda Gates Foundation (http://www.gatesfoundation.org/Pages/home.aspx); as well as the European Commission 6th Frame Work Programme as part of the European Microbicides Project (EMPRO; www.empro.org.uk) and the European Commission under the 7th Framework Programme as part of the Combined Highly Active Anti-Retroviral Microbicides (CHAARM; http://chaarm.eu/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 74 TC 22 Z9 25 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 15 PY 2012 VL 7 IS 3 AR e33298 DI 10.1371/journal.pone.0033298 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 932RU UT WOS:000303309000020 PM 22438910 ER PT J AU Jiao, GS Kim, S Moayeri, M Crown, D Thai, A Cregar-Hernandez, L McKasson, L Sankaran, B Lehrer, A Wong, T Johns, L Margosiak, SA Leppla, SH Johnson, AT AF Jiao, Guan-Sheng Kim, Seongjin Moayeri, Mahtab Crown, Devorah Thai, April Cregar-Hernandez, Lynne McKasson, Linda Sankaran, Banumathi Lehrer, Axel Wong, Teri Johns, Lisa Margosiak, Stephen A. Leppla, Stephen H. Johnson, Alan T. TI Antidotes to anthrax lethal factor intoxication. Part 3: Evaluation of core structures and further modifications to the C2-side chain SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Anthrax; Lethal factor; Inhibitor; In vitro ADME; X-ray crystallography ID INHALATIONAL ANTHRAX; KINASE-KINASE; INHIBITORS; TOXIN AB Four core structures capable of providing sub-nanomolar inhibitors of anthrax lethal factor (LF) were evaluated by comparing the potential for toxicity, physicochemical properties, in vitro ADME profiles, and relative efficacy in a rat lethal toxin (LT) model of LF intoxication. Poor efficacy in the rat LT model exhibited by the phenoxyacetic acid series (3) correlated with low rat microsome and plasma stability. Specific molecular interactions contributing to the high affinity of inhibitors with a secondary amine in the C2-side chain were revealed by X-ray crystallography. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Jiao, Guan-Sheng; Kim, Seongjin; Thai, April; Cregar-Hernandez, Lynne; McKasson, Linda; Lehrer, Axel; Wong, Teri; Johns, Lisa; Margosiak, Stephen A.; Johnson, Alan T.] PanThera Biopharma LLC, Aiea, HI 96701 USA. [Moayeri, Mahtab; Crown, Devorah; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. [Sankaran, Banumathi] Univ Calif Berkeley, Lawrence Berkeley Natl Lab, Adv Light Source, Berkeley, CA 94720 USA. RP Johnson, AT (reprint author), PanThera Biopharma LLC, Aiea, HI 96701 USA. EM ajohnson@pantherabio.com FU National Institutes of Health [R44 AI052587, U01 AI078067]; National Institute of Allergy and Infectious Diseases FX We thank the National Institutes of Health for their support of this work with Grants R44 AI052587 and U01 AI078067. The rat LT challenge studies were supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. The PK study was conducted by Covance Laboratories, Inc. (Madison, WI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID or the NIH. NR 20 TC 10 Z9 11 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAR 15 PY 2012 VL 22 IS 6 BP 2242 EP 2246 DI 10.1016/j.bmcl.2012.01.095 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 905PU UT WOS:000301285500023 PM 22342144 ER PT J AU Ghosh, AK Chapsal, BD Steffey, M Agniswamy, J Wang, YF Amano, M Weber, IT Mitsuya, H AF Ghosh, Arun K. Chapsal, Bruno D. Steffey, Melinda Agniswamy, Johnson Wang, Yuan-Fang Amano, Masayuki Weber, Irene T. Mitsuya, Hiroaki TI Substituent effects on P2-cyclopentyltetrahydrofuranyl urethanes: Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE HIV-1 protease inhibitors; P2 ligand; Drug resistance; Design and synthesis; X-ray crystal structure ID DRUG-RESISTANT MUTANTS; BIOLOGICAL EVALUATION; CRYSTAL-STRUCTURE; COMPLEXES; P2-LIGANDS; BACKBONE; TMC114 AB The design, synthesis, and biological evaluation of novel C3-substituted cyclopentyltetrahydrofuranyl (Cp-THF)-derived HIV-1 protease inhibitors are described. Various C3-functional groups on the Cp-THF ligand were investigated in order to maximize the ligand-binding site interactions in the flap region of the protease. Inhibitors 3c and 3d have displayed the most potent enzyme inhibitory and antiviral activity. Both inhibitors have maintained impressive activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 3c-bound HIV-1 protease revealed a number of important molecular insights into the ligand-binding site interactions. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Ghosh, Arun K.; Chapsal, Bruno D.; Steffey, Melinda] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Ghosh, Arun K.; Chapsal, Bruno D.; Steffey, Melinda] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Agniswamy, Johnson; Wang, Yuan-Fang; Weber, Irene T.] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. [Amano, Masayuki; Mitsuya, Hiroaki] Kumamoto Univ, Dept Hematol, Grad Sch Med & Pharmaceut Sci, Kumamoto 8608556, Japan. [Amano, Masayuki; Mitsuya, Hiroaki] Kumamoto Univ, Dept Infect Dis, Grad Sch Med & Pharmaceut Sci, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Ghosh, AK (reprint author), Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. EM akghosh@purdue.edu RI Ghartouchent, malek/B-9088-2012; Amano, Masayuki/N-7407-2016 OI Amano, Masayuki/0000-0003-0516-9502 FU National Institutes of Health [GM53386, GM62920]; Center for Cancer Research, National Cancer Institute, National Institutes of Health; Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho); Ministry of Health, Welfare, and Labor of Japan; Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases of Monbu-Kagakusho FX This research was supported by the National Institutes of Health (Grant GM53386 to A.K.G. and Grant GM62920 to I.T.W.). This work was also supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and in part by a Grant-in-Aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho), a Grant for Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan, and the Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo) of Monbu-Kagakusho. NR 20 TC 12 Z9 13 U1 0 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD MAR 15 PY 2012 VL 22 IS 6 BP 2308 EP 2311 DI 10.1016/j.bmcl.2012.01.061 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 905PU UT WOS:000301285500037 PM 22364812 ER PT J AU Schuit, E Stock, S Groenwold, RHH Maurel, K Combs, CA Garite, T Spong, CY Thom, EA Rouse, DJ Caritis, SN Saade, GR Zachary, JM Norman, JE Rode, L Klein, K Tabor, A Cetingoz, E Morrison, JC Magann, EF Briery, CM Serra, V Perales, A Meseguer, J Nassar, AH Lim, AC Moons, KGM Kwee, A Mol, BWJ AF Schuit, Ewoud Stock, Sarah Groenwold, Rolf H. H. Maurel, Kimberly Combs, C. Andrew Garite, Thomas Spong, Cathy Y. Thom, Elizabeth A. Rouse, Dwight J. Caritis, Steve N. Saade, George R. Zachary, Julia M. Norman, Jane E. Rode, Line Klein, Katharina Tabor, Ann Cetingoz, Elcin Morrison, John C. Magann, Everett F. Briery, Christian M. Serra, Vicente Perales, Alfredo Meseguer, Juan Nassar, Anwar H. Lim, Arianne C. Moons, Karel G. M. Kwee, Anneke Mol, Ben Willem J. TI Progestogens to prevent preterm birth in twin pregnancies: an individual participant data meta-analysis of randomized trials SO BMC PREGNANCY AND CHILDBIRTH LA English DT Article ID PATIENT DATA; 17-ALPHA-HYDROXYPROGESTERONE CAPROATE; DOUBLE-BLIND; PROGESTERONE; WOMEN; RISK AB Background: Preterm birth is the principal factor contributing to adverse outcomes in multiple pregnancies. Randomized controlled trials of progestogens to prevent preterm birth in twin pregnancies have shown no clear benefits. However, individual studies have not had sufficient power to evaluate potential benefits in women at particular high risk of early delivery (for example, women with a previous preterm birth or short cervix) or to determine adverse effects for rare outcomes such as intrauterine death. Methods/design: We propose an individual participant data meta-analysis of high quality randomized, double-blind, placebo-controlled trials of progestogen treatment in women with a twin pregnancy. The primary outcome will be adverse perinatal outcome (a composite measure of perinatal mortality and significant neonatal morbidity). Missing data will be imputed within each original study, before data of the individual studies are pooled. The effects of 17-hydroxyprogesterone caproate or vaginal progesterone treatment in women with twin pregnancies will be estimated by means of a random effects log-binomial model. Analyses will be adjusted for variables used in stratified randomization as appropriate. Pre-specified subgroup analysis will be performed to explore the effect of progestogen treatment in high-risk groups. Discussion: Combining individual patient data from different randomized trials has potential to provide valuable, clinically useful information regarding the benefits and potential harms of progestogens in women with twin pregnancy overall and in relevant subgroups. C1 [Schuit, Ewoud; Groenwold, Rolf H. H.; Moons, Karel G. M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Stock, Sarah; Norman, Jane E.] Univ Edinburgh, MC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland. [Maurel, Kimberly] CREQ, Obstetrix Med Grp, Fountain Valley, CA USA. [Combs, C. Andrew] Obstetrix Med Grp, San Jose, CA USA. [Garite, Thomas] CREQ, Obstetrix Med Grp, Steamboat Springs, CO USA. [Spong, Cathy Y.] NICHHD, Bethesda, MD 20892 USA. [Thom, Elizabeth A.; Zachary, Julia M.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Rouse, Dwight J.] Brown Univ, Dept Obstet & Gynecol, Providence, RI 02912 USA. [Caritis, Steve N.] Univ Pittsburgh, Magee Womens Hosp, Dept Obstet & Gynecol, Pittsburgh, PA 15213 USA. [Saade, George R.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX USA. [Rode, Line; Tabor, Ann] Rigshosp, Copenhagen Univ Hosp, Dept Fetal Med 4002, DK-2100 Copenhagen, Denmark. [Klein, Katharina] Med Univ Vienna, Dept Obstet & Feto Maternal, Vienna, Austria. [Cetingoz, Elcin] Zeynep Kamil Women & Children Dis Educ & Res Hosp, Dept Obstet & Gynecol, Istanbul, Turkey. [Morrison, John C.] Univ Mississippi, Med Ctr, Dept Obstet & Gynecol, Jackson, MS USA. [Magann, Everett F.] Univ Arkansas Med Sci, Dept Obstet & Gynecol, Little Rock, AR 72205 USA. [Briery, Christian M.] Willis Knighton Med Ctr, Dept Obstet & Gynecol, Shreveport, LA USA. [Serra, Vicente] Univ Valencia, Inst Valenciano Infertilidad, Maternal Fetal Med Unit, Valencia, Spain. [Perales, Alfredo] Univ Hosp La Fe, Dept Obstet & Gynecol, Valencia, Spain. [Meseguer, Juan] Hosp Univ Virgen de la Arrixaca, Dept Obstet & Ginecol, Murcia, Spain. [Nassar, Anwar H.] Amer Univ Beirut, Dept Obstet & Gynecol, Beirut, Lebanon. [Lim, Arianne C.; Mol, Ben Willem J.] Univ Amsterdam, Acad Med Ctr, Dept Obstet & Gynecol, NL-1105 AZ Amsterdam, Netherlands. [Kwee, Anneke] Univ Med Ctr Utrecht, Dept Obstet & Gynecol, Utrecht, Netherlands. RP Schuit, E (reprint author), Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. EM e.schuit@umcutrecht.nl RI Mol, Ben /I-4526-2012; OI Combs, C Andrew/0000-0002-5571-9579; caritis, steve/0000-0002-2169-0712 FU Medical Research Council [G1002033]; NICHD NIH HHS [U10 HD036801] NR 27 TC 8 Z9 8 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2393 J9 BMC PREGNANCY CHILDB JI BMC Pregnancy Childbirth PD MAR 15 PY 2012 VL 12 AR 13 DI 10.1186/1471-2393-12-13 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 919XH UT WOS:000302365000001 PM 22420582 ER PT J AU Kim, G Davidson, B Henning, R Wang, JB Yu, MS Annunziata, C Hetland, T Kohn, EC AF Kim, Geoffrey Davidson, Ben Henning, Ryan Wang, Junbai Yu, Minshu Annunziata, Christina Hetland, Thea Kohn, Elise C. TI Adhesion molecule protein signature in ovarian cancer effusions is prognostic of patient outcome SO CANCER LA English DT Article DE adhesion molecules; ascites; ovarian cancer; proteomics array ID E-CADHERIN EXPRESSION; CELL-CELL ADHESION; ADHERENS JUNCTIONS; PROTEOMIC ANALYSIS; MALIGNANT ASCITES; CARCINOMA CELLS; BETA-CATENIN; TUMOR-CELLS; PHASE-II; ANOIKIS AB BACKGROUND: Ovarian cancer cells in malignant effusions lack attachment to solid-phase matrix substrata and receive survival stimuli through cellcell and cellsoluble matrix molecule interactions. We hypothesized that adhesion-related survival and proliferation pathway signals can inform clinical outcomes and guide targeted therapeutics. METHODS: Lysed cell pellets from a blinded set of benign (n 20) and malignant (n 51) peritoneal and pleural ovarian cancer patient effusions were applied to reverse-phase protein arrays and examined using validated antibodies to adhesion-associated protein endpoints. Results were subjected to hierarchical clustering for signature development. Association between specimen type, protein expression, and clinicopathologic associations were analyzed using the Mann-Whitney U test. Survival outcomes were estimated using the Kaplan-Meier method with log-rank comparison. RESULTS: A cell adhesion protein signature obtained from unsupervised clustering distinguished malignant from benign effusions (P 6.18E-06). Protein subset analyses from malignant cases defined 3 cell adhesion protein clusters driven by E-cadherin, epithelial cell adhesion molecule, and N-cadherin, respectively. The components of the E-and N-cadherin clusters correlated with clinical outcome by Kaplan-Meier statistics. Univariate analysis indicated that FAK and phosphorylated AKT were associated with higher overall and progression-free survival (PFS) (P.03), and Akt, phosphorylated paxillin, and E-and N-cadherin were associated with improved PFS (P .05). If 4 or 5 of the index adhesion proteins were high, PFS was improved by multivariate analysis (P .01). CONCLUSIONS: This hypothesis-testing examination of tumor cell adhesion molecules and pathways yielded potential predictive biomarkers with which to triage patients to selected molecular therapeutics and may serve as a platform for biomarker-based stratification for clinical application. Cancer 2012; 118: 1543-53. Published 2011 by the American Cancer Society*. C1 [Kim, Geoffrey; Henning, Ryan; Yu, Minshu; Annunziata, Christina; Kohn, Elise C.] NCI, Mol Signaling Sect, Med Oncol Branch, Bethesda, MD 20892 USA. [Davidson, Ben; Wang, Junbai; Hetland, Thea] Oslo Univ Hosp, Norwegian Radium Hosp, Div Pathol, Oslo, Norway. [Hetland, Thea] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Gynecol Oncol, Oslo, Norway. [Davidson, Ben] Univ Oslo, Fac Med, Oslo, Norway. RP Kohn, EC (reprint author), 10 Ctr Dr,MSC 1906, Bethesda, MD 20892 USA. EM kohne@mail.nih.gov RI Wang, Junbai/B-2093-2008; Annunziata, Christina/L-3219-2016 OI Annunziata, Christina/0000-0003-2033-6532 FU Center for Cancer Research, National Cancer Institute; Norwegian Cancer Society; Inger and John Fredriksen Foundation for Ovarian Cancer Research FX This study was supported by the Intramural Program of the Center for Cancer Research, National Cancer Institute, and by a grant from the Norwegian Cancer Society and by the Inger and John Fredriksen Foundation for Ovarian Cancer Research. NR 51 TC 7 Z9 7 U1 0 U2 0 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 MAR 15 PY 2012 VL 118 IS 6 BP 1543 EP 1553 DI 10.1002/cncr.26449 PG 11 WC Oncology SC Oncology GA 901NE UT WOS:000300973000010 PM 22009736 ER PT J AU Brosh, RM AF Brosh, Robert M. TI Finding a needle in the haystack Recognition of DNA damage by collaboration between DNA repair proteins able to perform DNA charge transport SO CELL CYCLE LA English DT Editorial Material C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov NR 10 TC 0 Z9 0 U1 1 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 15 PY 2012 VL 11 IS 6 BP 1055 EP 1056 DI 10.4161/cc.11.6.19785 PG 2 WC Cell Biology SC Cell Biology GA 913DD UT WOS:000301851700004 PM 22377696 ER PT J AU Shizukuda, Y Tripodi, DJ Zalos, G Bolan, CD Yau, YY Leitman, SF Waclawiw, MA Rosing, DR AF Shizukuda, Yukitaka Tripodi, Dorothy J. Zalos, Gloria Bolan, Charles D. Yau, Yu-Ying Leitman, Susan F. Waclawiw, Myron A. Rosing, Douglas R. TI Incidence of Cardiac Arrhythmias in Asymptomatic Hereditary Hemochromatosis Subjects With C282Y Homozygosity SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID IRON OVERLOAD CARDIOMYOPATHY; FIBRILLATION; MANAGEMENT; EXERCISE; STRESS AB It is not well known whether systemic iron overload per se in hereditary hemochromatosis (HH) is associated with cardiac arrhythmias before other signs and symptoms of cardiovascular disease occur. In the present study, we examined the incidence of cardiac arrhythmia in cardiac asymptomatic subjects with HH (New York Heart Association functional class I) and compared it to that in age- and gender-matched normal volunteers. The 42 subjects with HH and the 19 normal control subjects were recruited through the National Heart, Lung, and Blood Institute-sponsored "Heart Study of Hemochromatosis." They completed 48-hour Holter electrocardiography ambulatory monitoring at the baseline evaluation. The subjects with HH were classified as newly diagnosed (group A) and chronically treated (group B) subjects. All subjects with HH had C282Y homozygosity, and the normal volunteers lacked any HFE gene mutations known to cause HH. Although statistically insignificant, the incidence of ventricular and supraventricular ectopy tended to be greater in the combined HH groups than in the controls. Supraventricular ectopy was more frequently noted in group B compared to in the controls (ectopy rate per hour 11.1 +/- 29.9 vs 1.5 +/- 3.5, p < 0.05, using the Kruskal-Wallis test). No examples of heart block, other than first-degree atrioventricular node block, were seen in any of the subjects. The incidence of cardiac arrhythmias was not significantly reduced after 6 months of intensive iron removal therapy in the group A subjects. No life-threatening arrhythmias were observed in our subjects with HH. In conclusion, our data suggest that the incidence of cardiac arrhythmias is, at most, marginally increased in asymptomatic subjects with HH. A larger clinical study is warranted to further clarify our observation. Published by Elsevier Inc. (Am J Cardiol 2012;109:856-860) C1 [Shizukuda, Yukitaka; Tripodi, Dorothy J.; Zalos, Gloria; Rosing, Douglas R.] NHLBI, Cardiopulm Branch, Bethesda, MD 20892 USA. [Waclawiw, Myron A.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Bolan, Charles D.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Yau, Yu-Ying; Leitman, Susan F.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. [Shizukuda, Yukitaka] Univ Cincinnati, Div Cardiovasc Med, Cincinnati, OH USA. [Shizukuda, Yukitaka] Cincinnati Vet Affairs Med Ctr, Cincinnati, OH USA. RP Shizukuda, Y (reprint author), NHLBI, Cardiopulm Branch, Bldg 10, Bethesda, MD 20892 USA. EM shizukya@uc.edu FU National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland FX This study was funded by intramural programs of the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. NR 19 TC 4 Z9 5 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAR 15 PY 2012 VL 109 IS 6 BP 856 EP 860 DI 10.1016/j.amjcard.2011.11.011 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 914QV UT WOS:000301967500013 PM 22196777 ER PT J AU Chandan, K van Iersel, MP Aladjem, MI Kohn, KW Luna, A AF Chandan, Kumar van Iersel, Martijn P. Aladjem, Mirit I. Kohn, Kurt W. Luna, Augustin TI PathVisio-Validator: a rule-based validation plugin for graphical pathway notations SO BIOINFORMATICS LA English DT Article ID BIOLOGICAL PATHWAYS; MARKUP LANGUAGE; EXCHANGE; FORMAT; MAPS AB Purpose: The PathVisio-Validator plugin aims to simplify the task of producing biological pathway diagrams that follow graphical standardized notations, such as Molecular Interaction Maps or the Systems Biology Graphical Notation. This plugin assists in the creation of pathway diagrams by ensuring correct usage of a notation, and thereby reducing ambiguity when diagrams are shared among biologists. Rulesets, needed in the validation process, can be generated for any graphical notation that a developer desires, using either Schematron or Groovy. The plugin also provides support for filtering validation results, validating on a subset of rules, and distinguishing errors and warnings. Availability: The PathVisio-Validator plugin works with versions of PathVisio 2.0.11 and later on Windows, Mac OS X and Linux. The plugin along with the instructions, example rulesets for Groovy and Schematron, and Java source code can be downloaded at http://pathvisio.org/wiki/PathVisioValidatorHelp. The software is developed under the open-source Apache 2.0 License and is freely available for both commercial and academic use. C1 [Chandan, Kumar] Keshav Mem Inst Technol, Hyderabad, Andhra Pradesh, India. [van Iersel, Martijn P.] BiGCaT Maastricht Univ, Dept Bioinformat, NL-6229 ER Maastricht, Netherlands. [Aladjem, Mirit I.; Kohn, Kurt W.; Luna, Augustin] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Luna, Augustin] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. RP Chandan, K (reprint author), Keshav Mem Inst Technol, Hyderabad, Andhra Pradesh, India. EM chandankmit@gmail.com; augustin@mail.nih.gov RI Aladjem, Mirit/G-2169-2010; van Iersel, Martijn/E-9105-2010 OI Aladjem, Mirit/0000-0002-1875-3110; van Iersel, Martijn/0000-0002-5877-4338 FU Google; National Institutes of Health, Center for Cancer Research, National Cancer Institute; Netherlands Consortium for Systems Biology (NCSB), Netherlands Genomics Initiative/Netherlands Organization for Scientific Research FX Funding: Google Summer of Code program, Intramural Research Program of the National Institutes of Health, Center for Cancer Research, National Cancer Institute; Netherlands Consortium for Systems Biology (NCSB), which is part of the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research, in part. NR 8 TC 3 Z9 3 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAR 15 PY 2012 VL 28 IS 6 BP 889 EP 890 DI 10.1093/bioinformatics/btr694 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 914SQ UT WOS:000301972900023 PM 22199389 ER PT J AU Stojmirovic, A Bliskovsky, A Yu, YK AF Stojmirovic, Aleksandar Bliskovsky, Alexander Yu, Yi-Kuo TI CytoSaddleSum: a functional enrichment analysis plugin for Cytoscape based on sum-of-weights scores SO BIOINFORMATICS LA English DT Article AB CytoSaddleSum provides Cytoscape users with access to the functionality of SaddleSum, a functional enrichment tool based on sum-of-weight scores. It operates by querying SaddleSum locally (using the standalone version) or remotely (through an HTTP request to a web server). The functional enrichment results are shown as a term relationship network, where nodes represent terms and edges show term relationships. Furthermore, query results are written as Cytoscape attributes allowing easy saving, retrieval and integration into network-based data analysis workflows. C1 [Stojmirovic, Aleksandar; Bliskovsky, Alexander; Yu, Yi-Kuo] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov OI Stojmirovic, Aleksandar/0000-0003-0957-6893 FU National Library of Medicine at National Institutes of Health FX Funding: Intramural Research Program of the National Library of Medicine at National Institutes of Health. NR 7 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAR 15 PY 2012 VL 28 IS 6 BP 893 EP 894 DI 10.1093/bioinformatics/bts041 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 914SQ UT WOS:000301972900025 PM 22345616 ER PT J AU Nandurdikar, RS Maciag, AE Cao, Z Keefer, LK Saavedra, JE AF Nandurdikar, Rahul S. Maciag, Anna E. Cao, Zhao Keefer, Larry K. Saavedra, Joseph E. TI Diazeniumdiolated carbamates: A novel class of nitric oxide donors SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Nitric oxide; Diazeniumdiolate prodrugs; Diazeniumdiolated carbamates; TOM protecting group; Intracellular nitric oxide ID NITROXYL; PRODRUG; HNO AB We report an indirect method for synthesis of previously inaccessible diazeniumdiolated carbamates. Synthesis involves use of previously reported triisopropylsilyloxymethylated isopropylamine diazeniumdiolate (TOM-ylated IPA/NO). These novel diazeniumdiolated carbamate prodrugs upon activation release nitric oxide (NO) similar to their secondary amine counterparts. They are also efficient sources of intracellular NO. These prodrugs may have potential applications as therapeutic NO-donors. (C) 2012 Elsevier Ltd. All rights C1 [Nandurdikar, Rahul S.; Keefer, Larry K.] NCI, Drug Design Sect, Biol Chem Lab, Frederick, MD 21702 USA. [Maciag, Anna E.; Cao, Zhao; Saavedra, Joseph E.] NCI, Basic Sci Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Nandurdikar, RS (reprint author), NCI, Drug Design Sect, Biol Chem Lab, Frederick, MD 21702 USA. EM nandurdikarr@mail.nih.gov; saavedjo@mail.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded with Federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E and by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We thank Dr. Sergey Tarasov and Ms. Marzena A. Dyba of the Biophysics Resource in the Structural Biophysics Laboratory, NCI-Frederick, for assistance with the high resolution mass spectrometry studies. NR 11 TC 10 Z9 10 U1 2 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAR 15 PY 2012 VL 20 IS 6 BP 2025 EP 2029 DI 10.1016/j.bmc.2012.01.046 PG 5 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 904MJ UT WOS:000301201100023 PM 22356735 ER PT J AU Ang, R Sebastian, S Ludwig, A Birnbaumer, L Tinker, A AF Ang, R. Sebastian, S. Ludwig, A. Birnbaumer, L. Tinker, A. TI Mice with conditional knockout of Galphai2 in the cardiac pacemaker system exhibit tachycardia with loss of HF power on HRV analysis SO CARDIOVASCULAR RESEARCH LA English DT Meeting Abstract CT 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology CY MAR 30-APR 01, 2012 CL London, ENGLAND SP European Soc Cardiol C1 [Ang, R.] UCL, Ctr Clin Pharmacol, London, England. [Sebastian, S.; Tinker, A.] Barts & London Queen Marys Sch Med & Dent, London, England. [Ludwig, A.] Univ Erlangen Nurnberg, Inst Expt & Clin Pharmacol & Toxicol, D-91054 Erlangen, Germany. [Birnbaumer, L.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 15 PY 2012 VL 93 SU 1 BP S20 EP S20 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 914TQ UT WOS:000301975800070 ER PT J AU Menazza, SM Canton, MC Di Lisa, FDL Schulz, RS AF Menazza, S. M. Canton, M. C. Di Lisa, F. D. L. Schulz, R. S. TI Oxidation of specific plasma proteins is directly correlated with oxidative derangement of myofibrillar proteins in pacing-induced failure of rabbit hearts SO CARDIOVASCULAR RESEARCH LA English DT Meeting Abstract CT 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology CY MAR 30-APR 01, 2012 CL London, ENGLAND SP European Soc Cardiol C1 [Menazza, S. M.] NHLBI, NIH, Bethesda, MD 20892 USA. [Canton, M. C.; Di Lisa, F. D. L.] Univ Padua, Dept Biomed Sci, Padua, Italy. [Schulz, R. S.] Univ Giessen, Inst Physiol, Giessen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 15 PY 2012 VL 93 SU 1 BP S85 EP S85 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 914TQ UT WOS:000301975800364 ER PT J AU Molica, F Burger, F Matter, CM Thomas, A Staub, C Zimmer, A Cravatt, B Pacher, P Steffens, S AF Molica, F. Burger, F. Matter, C. M. Thomas, A. Staub, C. Zimmer, A. Cravatt, B. Pacher, P. Steffens, S. TI CB1 cannabinoid receptor antagonism inhibits balloon-induced neointima formation in atherosclerotic mice SO CARDIOVASCULAR RESEARCH LA English DT Meeting Abstract CT 2nd Congress of the European-Society-of-Cardiology Council on Basic Cardiovascular Science - Frontiers in Cardiovascular Biology CY MAR 30-APR 01, 2012 CL London, ENGLAND SP European Soc Cardiol C1 [Molica, F.; Burger, F.; Steffens, S.] Univ Hosp Geneva, Geneva, Switzerland. [Matter, C. M.] Univ Zurich, Inst Physiol, Zurich, Switzerland. [Thomas, A.; Staub, C.] Univ Geneva, Fac Med, Inst Legal Med, Geneva, Switzerland. [Zimmer, A.] Univ Bonn, Inst Mol Psychiat, Bonn, Germany. [Cravatt, B.] Scripps Res Inst, La Jolla, CA 92037 USA. [Pacher, P.] NIH, Bethesda, MD 20892 USA. RI Zimmer, Andreas/B-8357-2009; Filippo, Molica/A-6315-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 15 PY 2012 VL 93 SU 1 BP S119 EP S119 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 914TQ UT WOS:000301975800511 ER PT J AU Kojima, H Muromoto, R Takahashi, M Takeuchi, S Takeda, Y Jetten, AM Matsuda, T AF Kojima, Hiroyuki Muromoto, Ryuta Takahashi, Miki Takeuchi, Shinji Takeda, Yukimasa Jetten, Anton M. Matsuda, Tadashi TI Inhibitory effects of azole-type fungicides on interleukin-17 gene expression via retinoic acid receptor-related orphan receptors alpha and gamma SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Fungicide; Interleukin 17; Mouse; Reporter gene assay; Retinoic acid receptor-related orphan receptor ID HAMSTER OVARY CELLS; ROR-GAMMA; T-CELLS; ANDROGEN RECEPTOR; NUCLEAR RECEPTORS; 200 PESTICIDES; DIFFERENTIATION; LIGAND; ESTROGEN; LINEAGE AB The retinoic acid receptor-related orphan receptors alpha and gamma (ROR alpha and ROR gamma), are key regulators of helper T (Th)17 cell differentiation, which is involved in the innate immune system and autoimmune disorders. However, it remains unclear whether environmental chemicals, including pesticides, have agonistic and/or antagonistic activity against ROR alpha/gamma. In this study, we investigated the ROR alpha/gamma activity of several azole-type fungicides, and the effects of these fungicides on the gene expression of interleukin (IL)-17, which mediates the function of Th17 cells. In the ROR-reporter gene assays, five azole-type fungicides (imibenconazole, trifiumizole, hexaconazole, tetraconazole and imazalil) suppressed ROR alpha- and/or ROR gamma-mediated transcriptional activity as did benzenesulphonamide T0901317, a ROR inverse agonist and a liver X receptor (LXR) agonist. In particular, imibenconazole, triflumizole and hexaconazole showed ROR gamma inverse agonistic activity at concentrations of 10(-6) M. However, unlike T0901317, these fungicides failed to show any LXR alpha/beta agonistic activity. Next, five azole-type fungicides, showing ROR inverse agonist activity, were tested on IL-17 mRNA expression in mouse T lymphoma EL4 cells treated with phorbol myristate acetate and ionomycin. The quantitative RT-PCR analysis revealed that these fungicides suppressed the expression of IL-17 mRNA without effecting ROR alpha and ROR gamma mRNA levels. In addition, the inhibitory effect of imibenconazole as well as that of T0901317 was absorbed in ROR alpha/gamma-knocked down EL4 cells. Taken together, these results suggest that some azole-type fungicides inhibit IL-17 production via ROR alpha/gamma. This also provides the first evidence that environmental chemicals can act as modulators of IL-17 expression in immune cells. (C) 2012 Elsevier Inc. All rights reserved. C1 [Kojima, Hiroyuki; Takeuchi, Shinji] Hokkaido Inst Publ Hlth, Kita Ku, Sapporo, Hokkaido 0600819, Japan. [Muromoto, Ryuta; Takahashi, Miki; Matsuda, Tadashi] Hokkaido Univ, Grad Sch Pharmaceut Sci, Kita Ku, Sapporo, Hokkaido 0600812, Japan. [Takeda, Yukimasa; Jetten, Anton M.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Kojima, H (reprint author), Hokkaido Inst Publ Hlth, Kita Ku, Kita 19,Nishi 12, Sapporo, Hokkaido 0600819, Japan. EM kojima@iph.pref.hokkaido.jp RI Matsuda, Tadashi/A-3835-2012; Muromoto, Ryuta/E-4203-2012; OI Jetten, Anton/0000-0003-0954-4445 FU Japan Society for the Promotion of Science (JSPS) [21590675] FX We would like to thank Dr. Kaoru Kobayashi (Faculty of Pharmaceutical Sciences, Chiba University, Japan) for providing the plasmids for LXR alpha/beta assays. This study was supported by Grant-in-Aid for Scientific Research (C) (21590675) from the Japan Society for the Promotion of Science (JSPS). NR 38 TC 15 Z9 17 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 15 PY 2012 VL 259 IS 3 BP 338 EP 345 DI 10.1016/j.taap.2012.01.011 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 913QP UT WOS:000301892800009 PM 22289359 ER PT J AU Yang, IV Tomfohr, J Singh, J Foss, CM Marshall, HE Que, LG McElvania-Tekippe, E Florence, S Sundy, JS Schwartz, DA AF Yang, Ivana V. Tomfohr, John Singh, Jaspal Foss, Catherine M. Marshall, Harvey E. Que, Loretta G. McElvania-Tekippe, Erin Florence, Sarita Sundy, John S. Schwartz, David A. TI The Clinical and Environmental Determinants of Airway Transcriptional Profiles in Allergic Asthma SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE environmental asthma; microarray; house dust mite; lipo-polysaccharide; atopy ID PLASMA ADRENOMEDULLIN; SUSCEPTIBILITY GENES; PERIPHERAL-BLOOD; DISEASE; C3; HYPERRESPONSIVENESS; 5-LIPOXYGENASE; INFLAMMATION; ASSOCIATION; INVOLVEMENT AB Rationale: Gene expression profiling of airway epithelial and inflammatory cells can be used to identify genes involved in environmental asthma. Methods: Airway epithelia and inflammatory cells were obtained via bronchial brush and bronchoalveolar lavage (BAL) from 39 subjects comprising three phenotypic groups (nonatopic nonasthmatic, atopic nonasthmatic, and atopic asthmatic) 4 hours after instillation of LPS, house dust mite antigen, and saline in three distinct subsegmental bronchi. RNA transcript levels were assessed using whole genome microarrays. Measurements and Main Results: Baseline (saline exposure) differences in gene expression were related to airflow obstruction in epithelial cells (C3, ALOX5AP, CCL18, and others), and to serum IgE (innate immune genes and focal adhesion pathway) and allergic-asthmatic phenotype (complement genes, histone deacetylases, and GATA1 transcription factor) in inflammatory cells. LPS stimulation resulted in pronounced transcriptional response across all subjects in both airway epithelia and BAL cells, with strong association to nuclear factor-kappa B and IFN-inducible genes as well as signatures of other transcription factors (NRF2, C/EBP, and E2F1) and histone proteins. No distinct transcriptional profile to LPS was observed in the asthma and atopy phenotype. Finally, although no consistent expression changes were observed across all subjects in response to house dust mite antigen stimulation, we observed subtle differences in gene expression (e.g., GATA1 and GATA2) in BAL cells related to the asthma and atopy phenotype. Conclusions: Our results indicate that among individuals with allergic asthma, transcriptional changes in airway epithelia and inflammatory cells are influenced by phenotype as well as environmental exposures. C1 [Yang, Ivana V.; Schwartz, David A.] Univ Colorado Denver, Dept Med, Aurora, CO 80045 USA. [Yang, Ivana V.; Schwartz, David A.] Natl Jewish Hlth, Ctr Genes Environm & Hlth, Denver, CO USA. [Yang, Ivana V.; Schwartz, David A.] Natl Jewish Hlth, Dept Med, Denver, CO USA. [Tomfohr, John] NHLBI, Lab Environm Lung Dis, Bethesda, MD 20892 USA. [Singh, Jaspal; Foss, Catherine M.; Marshall, Harvey E.; Que, Loretta G.; McElvania-Tekippe, Erin; Florence, Sarita; Sundy, John S.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Yang, IV (reprint author), Univ Colorado Denver, Dept Med, 12700 E 19th Ave,8611, Aurora, CO 80045 USA. EM ivana.yang@ucdenver.edu FU National Institute of Environmental Health Sciences [ES18181, ES011185, ES012496]; National Heart, Lung, and Blood Institute [HL082055]; National Center for Research Resources, Clinical Research Centers [M01-RR-30] FX Supported by the National Institute of Environmental Health Sciences (ES18181, ES011185, ES012496, and intramural funds); the National Heart, Lung, and Blood Institute (HL082055 and intramural funds); and the National Center for Research Resources, Clinical Research Centers Program (M01-RR-30). NR 29 TC 12 Z9 12 U1 0 U2 2 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 MAR 15 PY 2012 VL 185 IS 6 BP 620 EP 627 DI 10.1164/rccm.201108-1503OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 910WP UT WOS:000301674900008 PM 22246175 ER PT J AU Barkess, G Postnikov, Y Campos, CD Mishra, S Mohan, G Verma, S Bustin, M West, KL AF Barkess, Grainne Postnikov, Yuri Campos, Chrisanne D. Mishra, Shivam Mohan, Gokula Verma, Sakshi Bustin, Michael West, Katherine L. TI The chromatin-binding protein HMGN3 stimulates histone acetylation and transcription across the Glyt1 gene SO BIOCHEMICAL JOURNAL LA English DT Article DE acetylation; chromatin; elongation; epigenetics; HMGN; p300/CREB (cAMP-response-element-binding protein)-binding protein-associated factor (PCAF) ID POLYMERASE-II ELONGATION; IN-VIVO; CHROMOSOMAL-PROTEINS; DOWN-REGULATION; GENOME BROWSER; CODING REGIONS; EXPRESSION; NUCLEOSOMES; HMG-14; H3 AB HMGNs are nucleosome-binding proteins that alter the pattern of histone modifications and modulate the binding of linker histones to chromatin. The HMGN3 family member exists as two splice forms. HMGN3a which is full-length and HMGN3b which lacks the C-terminal RD (regulatory domain). In the present study, we have used the Glyt1 (glycine transporter 1) gene as a model system to investigate where HMGN proteins are bound across the locus in vivo. and to study how the two HMGN3 splice variants affect histone modifications and gene expression. We demonstrate that HMGN1, HMGN2, HMGN3a and HMGN3b are bound across the Glyt1 gene locus and surrounding regions, and are not enriched more highly at the promoter or putative enhancer. We conclude that the peaks of H3K4me3 (trimethylated Lys(4) of histone H3) and H3K9ac (acetylated Lys(9) of histone H3) at the active Glyt1a promoter do not play a major role in recruiting HMGN proteins. HMGN3a/b binding leads to increased H3K14 (Lys(14) of histone H3) acetylation and stimulates Glyt1a expression, but does not alter the levels of H3K4me3 or H3K9ac enrichment. Acetylation assays show that HMGN3a stimulates the ability of PCAF [p300/CREB (cAMP-response-element-binding protein)binding protein-associated factor] to acetylate nucleosomal H3 in vitro, whereas HMGN3b does not. We propose a model where HMGN3a/b-stimulated H3K14 acetylation across the bodies of large genes such as Glyt1 can lead to more efficient transcription elongation and increased mRNA production. C1 [Barkess, Grainne; Campos, Chrisanne D.; Mishra, Shivam; Mohan, Gokula; Verma, Sakshi; West, Katherine L.] Univ Glasgow, Coll Med Vet & Life Sci, Inst Canc Sci, Glasgow G11 6NT, Lanark, Scotland. [Postnikov, Yuri; Bustin, Michael] NCI, Lab Metab, CCR, NIH, Bethesda, MD 20892 USA. RP West, KL (reprint author), Univ Glasgow, Coll Med Vet & Life Sci, Inst Canc Sci, Glasgow G11 6NT, Lanark, Scotland. EM katherine.west@glasgow.ac.uk RI Bustin, Michael/G-6155-2015; OI Barkess, Grainne/0000-0003-1742-921X FU Biotechnology and Biological Sciences Research Council [BB/C006496/1]; University of Malaya, Kuala Lumpur, Malaysia; International Cancer Research [07-01271]; European Community Marie Curie International Reintegration [0066521]; National Cancer Institute; National Institutes of Health FX This work was supported by the Biotechnology and Biological Sciences Research Council [grant number BB/C006496/1]; the University of Malaya, Kuala Lumpur, Malaysia (Ph.D. funding to GM.); the Association for International Cancer Research [grant number 07-01271]; a European Community Marie Curie International Reintegration Grant [contract number 0066521]; and the Centre for Cancer Research intramural program of the National Cancer Institute and National Institutes of Health. NR 57 TC 7 Z9 8 U1 0 U2 6 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 MAR 15 PY 2012 VL 442 BP 495 EP 505 DI 10.1042/BJ20111502 PN 3 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 909JA UT WOS:000301559600004 PM 22150271 ER PT J AU Zanetti, KA Haznadar, M Welsh, JA Robles, AI Ryan, BM McClary, AC Bowman, ED Goodman, JE Bernig, T Chanock, SJ Harris, CC AF Zanetti, Krista A. Haznadar, Majda Welsh, Judith A. Robles, Ana I. Ryan, Brid M. McClary, Andrew C. Bowman, Elise D. Goodman, Julie E. Bernig, Toralf Chanock, Stephen J. Harris, Curtis C. TI 3 '-UTR and Functional Secretor Haplotypes in Mannose-Binding Lectin 2 Are Associated with Increased Colon Cancer Risk in African Americans SO CANCER RESEARCH LA English DT Article ID COLORECTAL-CANCER; GENETIC-VARIATION; COMPLEMENT ACTIVATION; PROTEIN LEVELS; POLYMORPHISMS; PATHWAY; DISEASE; POPULATION; VARIANTS; DATABASE AB Because chronic intestinal inflammation is a risk factor for colorectal cancer, we hypothesized that genetic variants of inflammatory mediators, such as mannose-binding lectin 2 (MBL2), are associated with colon cancer susceptibility. Here, we report the association of 24 AIBL2 single-nucleotide polyrnorphisms (SNP) and corresponding haplotypes with colon cancer risk in a case-control study. Four SNPs in the 3'-untranslated region (UTR) of the gene (rs10082466, rs2120132, rs2099902, and rs10450310) were associated with an increased risk of colon cancer in African Americans. ORs for homozygous variants versus wild-type ranged from 3.17 [95% confidence interval (CI), 1.57-6.40] to 4.51 (95% CI, 1.94-10.50), whereas the 3'-UTR region haplotype consisting of these four variants had an OR of 2.10 (95% CI, 1.42-3.12). The C allele of rs10082466 exhibited a binding affinity of miR-27a and this allele was associated with both lower MBL plasma levels and activity. We found that 5' secretor haplotypes known to correlate with moderate and low MBI, serum levels exhibited associations with increased risk of colon cancer in African Americans, specifically as driven by two haplotypes, LYPA and LYQC, relative to the referent HATA haplotype (LYPA: OR, 2.60; 95% CI, 1.33-5.08 and LYQC: OR, 2.28; 95% CI, 1.20-4.30). Similar associations were not observed in Caucasians. Together, our results support the hypothesis that genetic variations in MBL2 increase colon cancer susceptibility in African Americans, Cancer Res,. 72(6); 1467-77.(C) 2012 AACR C1 [Zanetti, Krista A.; Haznadar, Majda; Welsh, Judith A.; Robles, Ana I.; Ryan, Brid M.; McClary, Andrew C.; Bowman, Elise D.; Harris, Curtis C.] NCI, Lab Human Carcino genesis, Ctr Canc Res, Bethesda, MD 20892 USA. [Zanetti, Krista A.] Div Canc Control & Populat Sci, Host Susceptibil Factors Branch, Epidemiol & Genom Res Program, Rockville, MD USA. [McClary, Andrew C.] Howard Hughes Med Inst, Chevy Chase, MD USA. [Goodman, Julie E.] Gradient Corp, Cambridge, MA 02138 USA. [Bernig, Toralf; Chanock, Stephen J.] Natl Canc Inst, Lab Translat Gen, Div Canc Epidemiol & Genet, Gaithersburg, MD USA. RP Harris, CC (reprint author), NCI, Lab Human Carcino genesis, Ctr Canc Res, Bldg 37,Room 3068,37 Convent Dr,MSC 4258, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov FU NIH; Center for Cancer Research, National Cancer Institute; National Institute on Minority Health and Health Disparities; Cancer Prevention Fellowship Program; Division of Cancer Prevention, National Cancer Institute FX The work was supported by funding front the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute, and National Institute on Minority Health and Health Disparities and by funding from the Cancer Prevention Fellowship Program (2003-2007), Division of Cancer Prevention, National Cancer Institute to K.A. Zanetti. NR 34 TC 24 Z9 26 U1 0 U2 2 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 MAR 15 PY 2012 VL 72 IS 6 BP 1467 EP 1477 DI 10.1158/0008-5472.CAN-11-3073 PG 11 WC Oncology SC Oncology GA 910UC UT WOS:000301667300016 PM 22282660 ER PT J AU Bates, SE AF Bates, Susan E. TI Molecular Diagnostics: Are We There Yet? SO CLINICAL CANCER RESEARCH LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 MAR 15 PY 2012 VL 18 IS 6 BP 1514 EP 1514 DI 10.1158/1078-0432.CCR-11-2207 PG 1 WC Oncology SC Oncology GA 910VW UT WOS:000301672400006 PM 22422402 ER PT J AU Poste, G Carbone, DP Parkinson, DR Verweij, J Hewitt, SM Jessup, JM AF Poste, George Carbone, David P. Parkinson, David R. Verweij, Jaap Hewitt, Stephen M. Jessup, J. Milburn TI Leveling the Playing Field: Bringing Development of Biomarkers and Molecular Diagnostics up to the Standards for Drug Development SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; INTEGRATED GENOMIC ANALYSIS; LIKELIHOOD RATIOS; LUNG-CANCER; TRIAL; MUTATIONS; IMATINIB; PATHWAYS; SURVIVAL; THERAPY AB Molecular diagnostics are becoming increasingly important in clinical research to stratify or identify molecularly profiled patient cohorts for targeted therapies, to modify the dose of a therapeutic, and to assess early response to therapy or monitor patients. Molecular diagnostics can also be used to identify the pharmacogenetic risk of adverse drug reactions. The articles in this CCR Focus section on molecular diagnosis describe the development and use of markers to guide medical decisions regarding cancer patients. They define sources of preanalytic variability that need to be minimized, as well as the regulatory and financial challenges involved in developing diagnostics and integrating them into clinical practice. They also outline a National Cancer Institute program to assist diagnostic development. Molecular diagnostic clinical tests require rigor in their development and clinical validation, with sensitivity, specificity, and validity comparable to those required for the development of therapeutics. These diagnostics must be offered at a realistic cost that reflects both their clinical value and the costs associated with their development. When genome-sequencing technologies move into the clinic, they must be integrated with and traceable to current technology because they may identify more efficient and accurate approaches to drug development. In addition, regulators may define progressive drug approval for companion diagnostics that requires further evidence regarding efficacy and safety before full approval can be achieved. One way to accomplish this is to emphasize phase IV postmarketing, hypothesis-driven clinical trials with biological characterization that would permit an accurate definition of the association of low-prevalence gene alterations with toxicity or response in large cohorts. Clin Cancer Res; 18(6); 1515-23. (C)2012 AACR. C1 [Poste, George] Arizona State Univ, Complex Adapt Syst Initiat, Scottsdale, AZ USA. [Carbone, David P.] Vanderbilt Ingram Canc Ctr, Thorac Head & Neck Program, Nashville, TN USA. [Carbone, David P.] Vanderbilt Ingram Canc Ctr, Thorac Oncol Ctr, Nashville, TN USA. [Parkinson, David R.] Nodality Inc, San Francisco, CA USA. [Verweij, Jaap] Erasmus MC, Dept Med Oncol, Rotterdam, Netherlands. [Verweij, Jaap] Erasmus MC, Daniel den Hoed Canc Ctr, Rotterdam, Netherlands. [Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, Adv Technol Ctr, Gaithersburg, MD USA. [Jessup, J. Milburn] NCI, Canc Diag Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Jessup, JM (reprint author), NCI, Diagnost Evaluat Branch, Canc Diag Program, Div Canc Treatment & Diag, EPN 6040,6130 Execut Blvd, Rockville, MD 20892 USA. EM jessupj@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [U54 CA163069] NR 52 TC 27 Z9 28 U1 3 U2 7 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 MAR 15 PY 2012 VL 18 IS 6 BP 1515 EP 1523 DI 10.1158/1078-0432.CCR-11-2206 PG 9 WC Oncology SC Oncology GA 910VW UT WOS:000301672400007 PM 22422403 ER PT J AU Hewitt, SM Badve, SS True, LD AF Hewitt, Stephen M. Badve, Sunil S. True, Lawrence D. TI Impact of Preanalytic Factors on the Design and Application of Integral Biomarkers for Directing Patient Therapy SO CLINICAL CANCER RESEARCH LA English DT Article ID PARAFFIN-EMBEDDED TISSUES; SURGICAL PATHOLOGY; CLINICAL-TRIALS; BREAST-CANCER; CHALLENGES; PROTEOMICS; PLASMA; RECOMMENDATIONS; SECTIONS; ANTIGEN AB Molecular assays have been routinely applied to improve diagnosis for the last 25 years. Assays that guide therapy have a similar history; however, their evolution has lacked the focus on analytic integrity that is required for the molecularly targeted therapies of today. New molecularly targeted agents require assays of greater precision/quantitation to predict the likelihood of response, i.e., to identify patients whose tumors will respond, while at the same time excluding and protecting those patients whose tumors will not respond or in whom treatment will cause unacceptable toxicity. The handling of tissue has followed a fit-for-purpose approach focused on appropriateness for diagnostic needs, which is less rigorous than the demands of new molecular assays that interrogate DNA, RNA, and proteins in a quantitative, multiplex manner. There is a new appreciation of the importance and fragility of tissue specimens as the source of analytes to direct therapy. By applying a total test paradigm and defining and measuring sources of variability in specimens, we can develop a set of specifications that can be incorporated into the clinical-care environment to ensure that a specimen is appropriate for analysis and will return a true result. Clin Cancer Res; 18(6); 1524-30. (C)2012 AACR. C1 [Hewitt, Stephen M.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Badve, Sunil S.] Indiana Univ, Hlth Pathol Lab, Indianapolis, IN 46204 USA. [True, Lawrence D.] Univ Washington, Med Ctr, Dept Pathol, Seattle, WA 98195 USA. RP Hewitt, SM (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, MSC 4605, Bethesda, MD 20892 USA. EM hewitts@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU Intramural NIH HHS [Z99 CA999999] NR 29 TC 22 Z9 22 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 MAR 15 PY 2012 VL 18 IS 6 BP 1524 EP 1530 DI 10.1158/1078-0432.CCR-11-2204 PG 7 WC Oncology SC Oncology GA 910VW UT WOS:000301672400008 PM 22422404 ER PT J AU Williams, PM Lively, TG Jessup, JM Conley, BA AF Williams, P. Michael Lively, Tracy G. Jessup, J. Milburn Conley, Barbara A. TI Bridging the Gap: Moving Predictive and Prognostic Assays from Research to Clinical Use SO CLINICAL CANCER RESEARCH LA English DT Article ID GENOMIC REFERENCE MATERIALS; SURROGATE END-POINTS; AMERICAN-SOCIETY; DRUG DEVELOPMENT; BREAST-CANCER; TUMOR-MARKERS; MONOCLONAL-ANTIBODY; COLORECTAL-CANCER; METHOD VALIDATION; BIOMARKERS AB The development of clinically useful molecular diagnostics requires validation of clinical assay performance and achievement of clinical qualification in clinical trials. As discussed elsewhere in this Focus section on molecular diagnostics, validation of assay performance must be rigorous, especially when the assay will be used to guide treatment decisions. Here we review some of the problems associated with assay development, especially for academic investigators. These include lack of expertise and resources for analytical validation, lack of experience in designing projects for a specific clinical use, lack of specimens from appropriate patient groups, and lack of access to Clinical Laboratory Improvement Amendments-certified laboratories. In addition, financial support for assay validation has lagged behind financial support for marker discovery or drug development, even though the molecular diagnostic may be considered necessary for the successful use of the companion therapeutic. The National Cancer Institute supports a large number of clinical trials and a significant effort in drug development. In order to address some of these barriers for predictive and prognostic assays that will be used in clinical trials to select patients for a particular treatment, stratify patients into molecularly defined subgroups, or choose between treatments for molecularly defined tumors, the National Cancer Institute has begun a pilot program designed to lessen barriers to the development of validated prognostic and predictive assays. Clin Cancer Res; 18(6); 1531-9. (C)2012 AACR. C1 [Lively, Tracy G.; Jessup, J. Milburn; Conley, Barbara A.] NCI, Canc Diag Program, Div Canc Treatment & Diag, Rockville, MD 20892 USA. [Williams, P. Michael] Fairview Ctr, Mol Characterizat Clin Assay Dev Lab, Frederick, MD USA. RP Conley, BA (reprint author), NCI, Canc Diag Program, Div Canc Treatment & Diag, EPN 6038,6130 Execut Blvd, Rockville, MD 20892 USA. EM conleyba@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 54 TC 21 Z9 21 U1 0 U2 6 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 MAR 15 PY 2012 VL 18 IS 6 BP 1531 EP 1539 DI 10.1158/1078-0432.CCR-11-2203 PG 9 WC Oncology SC Oncology GA 910VW UT WOS:000301672400009 PM 22422405 ER PT J AU Schilsky, RL Doroshow, JH LeBlanc, M Conley, BA AF Schilsky, Richard L. Doroshow, James H. LeBlanc, Michael Conley, Barbara A. TI Development and Use of Integral Assays in Clinical Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID LUNG-CANCER; DRUG DEVELOPMENT; PREDICTIVE BIOMARKERS; METHOD VALIDATION; DESIGN; ISSUES AB Clinical trials that include integral biomarkers to determine eligibility, assign treatment, or assess outcome must employ robust assays to measure the molecular analyte of interest. The decision to develop a biomarker assay into a test suitable for use in humans should be driven by clinical need, that is, there should be a clear clinical purpose for undertaking the test development. Supporting in vitro or in vivo research on the ability of the marker to distinguish subgroups of patients with a given characteristic is necessary. The magnitude of the difference in treatment effect expected with use of the marker should be sufficient to support differential treatment prescription for marker-positive and -negative patients. Analytical and clinical validation of the marker assay should be completed before the clinical trial is initiated to ensure that the assay is stable enough for clinical use throughout the trial. Clinical use of the assay requires that it be performed in a Clinical Laboratory Improvement Amendments-accredited laboratory, and the need to apply for an Investigational Device Exemption from the U. S. Food and Drug Administration should be considered. In this article we elaborate on the steps required to get a biomarker assay ready for use as an integral component of a clinical trial and give an example of the use of an integral assay in a phase III trial. Clin Cancer Res; 18(6); 1540-6. (C)2012 AACR. C1 [Doroshow, James H.; Conley, Barbara A.] NCI, Div Canc Treatment & Diag, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Schilsky, Richard L.] Univ Chicago, Div Biol Sci, Hematol Oncol Sect, Chicago, IL 60637 USA. [Schilsky, Richard L.] Univ Chicago, Div Biol Sci, Ctr Comprehens Canc, Chicago, IL 60637 USA. [LeBlanc, Michael] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. RP Conley, BA (reprint author), NCI, Canc Diag Program, Div Canc Treatment & Diag, Dept Hlth & Human Serv, 6035A Execut Plaza N, Rockville, MD 20892 USA. EM conleyba@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [P01 CA053996] NR 19 TC 21 Z9 21 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 MAR 15 PY 2012 VL 18 IS 6 BP 1540 EP 1546 DI 10.1158/1078-0432.CCR-11-2202 PG 7 WC Oncology SC Oncology GA 910VW UT WOS:000301672400010 PM 22422406 ER PT J AU Meshinchi, S Hunger, SP Aplenc, R Adamson, PC Jessup, JM AF Meshinchi, Soheil Hunger, Stephen P. Aplenc, Richard Adamson, Peter C. Jessup, J. Milburn TI Lessons Learned from the Investigational Device Exemption Review of Children's Oncology Group Trial AAML1031 SO CLINICAL CANCER RESEARCH LA English DT Review ID ACUTE MYELOID-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; CANCER GROUP; SORAFENIB; COMPLICATIONS; REGRESSION; REMISSION; PATIENT; DISEASE AB The U.S. Food and Drug Administration is now exerting its regulatory authority over the use of molecular diagnostics and related assays for medical decision making in clinical trials, by performing pre-Investigational Device Exemption reviews in all phases of clinical trials. In this review, we assess the analytical performance of the assay for the diagnostic, and consider how that performance affects the diagnostic and the patient and their risks and benefits from treatment. We also discuss the process involved in the first review of a new Children's Oncology Group phase III trial in acute myelogenous leukemia. The lessons learned and recommendations for how to prepare for and incorporate this new level of regulatory review into the protocol development process are presented. Clin Cancer Res; 18(6); 1547-54. (C)2012 AACR. C1 [Jessup, J. Milburn] NCI, Canc Diag Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Meshinchi, Soheil] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98104 USA. [Hunger, Stephen P.] Childrens Hosp Colorado, Ctr Canc & Blood Disorders, Aurora, CO USA. [Hunger, Stephen P.] Univ Colorado, Sch Med, Dept Pediat, Aurora, CO USA. [Aplenc, Richard; Adamson, Peter C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Aplenc, Richard] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Jessup, J. Milburn] Childrens Oncol Grp, Arcadia, CA USA. RP Jessup, JM (reprint author), NCI, Diagnost Evaluat Branch, Canc Diag Program, Div Canc Treatment & Diag, EPN 6040,6130 Execut Blvd, Rockville, MD 20892 USA. EM jessupj@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [U10 CA098543] NR 22 TC 9 Z9 9 U1 0 U2 1 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 MAR 15 PY 2012 VL 18 IS 6 BP 1547 EP 1554 DI 10.1158/1078-0432.CCR-11-2205 PG 8 WC Oncology SC Oncology GA 910VW UT WOS:000301672400011 PM 22422407 ER PT J AU Chinnasamy, D Yu, ZY Kerkar, SP Zhang, L Morgan, RA Restifo, NP Rosenberg, SA AF Chinnasamy, Dhanalakshmi Yu, Zhiya Kerkar, Sid P. Zhang, Ling Morgan, Richard A. Restifo, Nicholas P. Rosenberg, Steven A. TI Local Delivery of Interleukin-12 Using T Cells Targeting VEGF Receptor-2 Eradicates Multiple Vascularized Tumors in Mice SO CLINICAL CANCER RESEARCH LA English DT Article ID MYELOID SUPPRESSOR-CELLS; METASTATIC MELANOMA; ANTITUMOR-ACTIVITY; CARCINOMA PATIENTS; IL-12 TRIGGERS; GENE-THERAPY; ANGIOGENESIS; GROWTH; EXPRESSION; GLIOBLASTOMA AB Purpose: We investigated the feasibility of delivering the proinflammatory cytokine interleukin (IL)-12 into tumor using T cells genetically engineered to express a chimeric antigen receptor (CAR) against the VEGF receptor-2 (VEGFR-2). Experimental Design: Two different strains of mice bearing five different established subcutaneous tumors were treated with syngeneic T cells cotransduced with an anti-VEGFR-2 CAR and a constitutively expressed single-chain murine IL-12 or an inducible IL-12 gene after host lymphodepletion. Tumor regression, survival of mice, and persistence of the transferred cells were evaluated. Results: Adoptive transfer of syngeneic T cells cotransduced with an anti-VEGFR-2 CAR and a constitutively expressing single-chain IL-12 resulted in the regression of five different established tumors of different histologies without the need for IL-2 administration. T cells transduced with either anti-VEGFR-2 CAR or single-chain IL-12 alone did not alter the tumor growth indicating that both of them had to be expressed in the same cell to mediate tumor regression. Anti-VEGFR-2 CAR and IL-12-cotransduced T cells infiltrated the tumors, expanded, and persisted for prolonged periods. The antitumor effect did not require the presence of host T and B cells but was dependent on host IL-12R-expressing cells. The anti-VEGFR-2 CAR changed the immunosuppressive tumor environment by altering/reducing both the systemic and the intratumoral CD11b(+)Gr1(+) myeloid suppressor cell subsets that expressed VEGFR-2. Conclusions: These results suggest that targeted delivery of IL-12 into the tumor environment with T cells redirected against VEGFR-2 is a promising approach for treating patients with a variety of solid tumor types. Clin Cancer Res; 18(6); 1672-83. (C)2012 AACR. C1 [Chinnasamy, Dhanalakshmi; Yu, Zhiya; Kerkar, Sid P.; Zhang, Ling; Morgan, Richard A.; Restifo, Nicholas P.; Rosenberg, Steven A.] NCI, Surg Branch, Clin Res Ctr, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, Clin Res Ctr, Bldg 10-CRC,Room 3-3940,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM SAR@mail.nih.gov RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU NIH; National Cancer Institute FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute. NR 50 TC 69 Z9 71 U1 2 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2012 VL 18 IS 6 BP 1672 EP 1683 DI 10.1158/1078-0432.CCR-11-3050 PG 12 WC Oncology SC Oncology GA 910VW UT WOS:000301672400024 PM 22291136 ER PT J AU Kummar, S Ji, JP Morgan, R Lenz, HJ Puhalla, SL Belani, CP Gandara, DR Allen, D Kiesel, B Beumer, JH Newman, EM Rubinstein, L Chen, A Zhang, YP Wang, LH Kinders, RJ Parchment, RE Tomaszewski, JE Doroshow, JH AF Kummar, Shivaani Ji, Jiuping Morgan, Robert Lenz, Heinz-Josef Puhalla, Shannon L. Belani, Chandra P. Gandara, David R. Allen, Deborah Kiesel, Brian Beumer, Jan H. Newman, Edward M. Rubinstein, Larry Chen, Alice Zhang, Yiping Wang, Lihua Kinders, Robert J. Parchment, Ralph E. Tomaszewski, Joseph E. Doroshow, James H. TI A Phase I Study of Veliparib in Combination with Metronomic Cyclophosphamide in Adults with Refractory Solid Tumors and Lymphomas SO CLINICAL CANCER RESEARCH LA English DT Article ID ADP-RIBOSE POLYMERASE; 0 CLINICAL-TRIAL; POLY(ADP-RIBOSE) POLYMERASE; ORAL CYCLOPHOSPHAMIDE; CANCER; INHIBITOR; CHEMOTHERAPY; GAMMA-H2AX; ABT-888; CELLS AB Purpose: Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Experimental Design: Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker gamma H2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Results: Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); gamma H2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. Conclusions: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA-positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma. Clin Cancer Res; 18(6); 1726-34. (C) 2012 AACR. C1 [Doroshow, James H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kummar, Shivaani; Rubinstein, Larry; Chen, Alice; Tomaszewski, Joseph E.; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Ji, Jiuping; Zhang, Yiping; Wang, Lihua; Kinders, Robert J.; Parchment, Ralph E.] NCI, Appl Dev Res Support Directorate, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21701 USA. [Morgan, Robert; Newman, Edward M.] City Hope Comprehens Canc Ctr, Duarte, CA USA. [Lenz, Heinz-Josef] USC Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Gandara, David R.] Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. [Puhalla, Shannon L.; Kiesel, Brian; Beumer, Jan H.] Univ Pittsburgh, Canc Inst, Mol Therapeut Drug Discovery Program, Pittsburgh, PA USA. [Beumer, Jan H.] Univ Pittsburgh, Sch Pharm, Pittsburgh, PA USA. [Belani, Chandra P.] Penn State Coll Med, Hershey, PA USA. RP Doroshow, JH (reprint author), NCI, Ctr Canc Res, NIH, Bldg 31,Room 3A44,31 Ctr Dr, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov OI Belani, Chandra/0000-0001-5049-5329; Beumer, Jan/0000-0002-8978-9401 FU NCI [U01-CA062505, U01-CA099168, P30-CA47904]; NIH [HHSN261200800001E]; Center for Cancer Research FX This work has been supported in whole or in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E and in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research. Additional support was provided by NCI, Cancer Therapy Evaluation Program cooperative agreements U01-CA062505 and U01-CA099168 and NCI grant P30-CA47904. NR 32 TC 85 Z9 86 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2012 VL 18 IS 6 BP 1726 EP 1734 DI 10.1158/1078-0432.CCR-11-2821 PG 9 WC Oncology SC Oncology GA 910VW UT WOS:000301672400029 PM 22307137 ER PT J AU Wacholder, S Yeager, M Liao, LM AF Wacholder, Sholom Yeager, Meredith Liao, Linda M. TI Invited Commentary: More Surprises From a Gene Desert SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE neoplasms; chromosomes; human; pair 8; diabetes mellitus; DNA; intergenic; genetic pleiotropy; mortality ID GENOME-WIDE ASSOCIATION; CHROMOSOME 8Q24; PROSTATE-CANCER; FALSE DISCOVERY; BLADDER-CANCER; RISK; LOCUS; EPIDEMIOLOGY; PROBABILITY; VARIANTS AB Pleiotropy across the 8q24 region is perhaps the most intriguing of the genome-wide association findings relating to cancer. This region of chromosome 8 is a gene desert, far from any recognized genes. Guarrera et al., whose work is reported in this issue (Am J Epidemiol. 2012;175(6):479-487), took an epidemiologic approach to learn more about the 8q24 region. They capitalized on their ascertainment of other endpoints in members of the cohort at the Turin site of the European Prospective Investigation Into Cancer and Nutrition to investigate multiple outcomes for additional pleiotropic effects in the 8q24 region. Alternative design options might involve genotyping of more variants, incorporation of more cases, or use of a single control group close to the size of the most common case group. Their analytic methods reflect the uncertainty of the underlying biology. The findings sharpen the scientific question about how variation in the 8q24 region affects pathogenesis. The genome-wide association effort is possible because of the economy of scale afforded by extremely dense genotyping. Strict adherence to the hypothesis-driven approach would ignore information that is obtainable at a trivial cost. The genome-wide association strategy tests whether agnostic data-mining methods can advance knowledge alongside or even in place of the standard hypothesis-driven approach, which is the conventional scientific method children learn in kindergarten and onward, even through graduate school and beyond. C1 [Wacholder, Sholom] Natl Canc Ctr, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD USA. [Liao, Linda M.] Natl Canc Inst, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD USA. [Yeager, Meredith] Natl Canc Inst, SAIC, Frederick, MD USA. RP Wacholder, S (reprint author), Natl Canc Inst, Natl Inst Hlth, Execut Plaza S,6120 Execut Blvd,Suite 5050,MSC 72, Rockville, MD 20852 USA. EM wacholds@mail.nih.gov RI perumal, murugiah/D-1565-2012; OI Liao, Linda/0000-0002-1923-5294 FU Intramural NIH HHS NR 29 TC 2 Z9 2 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 MAR 15 PY 2012 VL 175 IS 6 BP 488 EP 491 DI 10.1093/aje/kwr429 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 910XJ UT WOS:000301681600002 PM 22350582 ER PT J AU Dasharathy, SS Mumford, SL Pollack, AZ Perkins, NJ Mattison, DR Wactawski-Wende, J Schisterman, EF AF Dasharathy, Sonya S. Mumford, Sunni L. Pollack, Anna Z. Perkins, Neil J. Mattison, Donald R. Wactawski-Wende, Jean Schisterman, Enrique F. TI Menstrual Bleeding Patterns Among Regularly Menstruating Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE anovulation; bleeding patterns; menstrual blood loss; metrorrhagia; reproductive hormones ID MARGINAL STRUCTURAL MODELS; LATE-REPRODUCTIVE AGE; BREAST-CANCER; MENOPAUSAL TRANSITION; CYCLE CHARACTERISTICS; PHYSICAL-ACTIVITY; OVARIAN-CANCER; RISK; FERTILITY; IRREGULARITY AB Menstrual bleeding patterns are considered relevant indicators of reproductive health, though few studies have evaluated patterns among regularly menstruating premenopausal women. The authors evaluated self-reported bleeding patterns, incidence of spotting, and associations with reproductive hormones among 201 women in the BioCycle Study (2005-2007) with 2 consecutive cycles. Bleeding patterns were assessed by using daily questionnaires and pictograms. Marginal structural models were used to evaluate associations between endogenous hormone concentrations and subsequent total reported blood loss and bleeding length by weighted linear mixed-effects models and weighted parametric survival analysis models. Women bled for a median of 5 days (standard deviation: 1.5) during menstruation, with heavier bleeding during the first 3 days. Only 4.8% of women experienced midcycle bleeding. Increased levels of follicle-stimulating hormone (beta = 0.20, 95% confidence interval: 0.13, 0.27) and progesterone (beta = 0.06, 95% confidence interval: 0.03, 0.09) throughout the cycle were associated with heavier menstrual bleeding, and higher follicle-stimulating hormone levels were associated with longer menses. Bleeding duration and volume were reduced after anovulatory compared with ovulatory cycles (geometric mean blood loss: 29.6 vs. 47.2 mL; P = 0.07). Study findings suggest that detailed characterizations of bleeding patterns may provide more insight than previously thought as noninvasive markers for endocrine status in a given cycle. C1 [Dasharathy, Sonya S.; Mumford, Sunni L.; Pollack, Anna Z.; Perkins, Neil J.; Mattison, Donald R.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Wactawski-Wende, Jean] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. RP Schisterman, EF (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM schistee@mail.nih.gov RI Mattison, Donald/L-4661-2013; OI Mattison, Donald/0000-0001-5623-0874; Perkins, Neil/0000-0002-6802-4733; Pollack, Anna/0000-0002-4313-3298; Schisterman, Enrique/0000-0003-3757-641X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX This study 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 40 TC 19 Z9 22 U1 1 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 EI 1476-6256 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 15 PY 2012 VL 175 IS 6 BP 536 EP 545 DI 10.1093/aje/kwr356 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 910XJ UT WOS:000301681600008 PM 22350580 ER PT J AU Blackstone, C Murphy, CT AF Blackstone, Craig Murphy, Coleen T. TI Cell biology of disease and aging: a two-way street SO MOLECULAR BIOLOGY OF THE CELL LA English DT Editorial Material C1 [Blackstone, Craig] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Murphy, Coleen T.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Murphy, Coleen T.] Princeton Univ, Dept Mol Biol, Princeton, NJ 08544 USA. RP Blackstone, C (reprint author), Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov; ctmurphy@princeton.edu NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR 15 PY 2012 VL 23 IS 6 BP 975 EP 975 DI 10.1091/mbc.E11-12-0985 PG 1 WC Cell Biology SC Cell Biology GA 907XO UT WOS:000301453700011 ER PT J AU Cohen-Fix, O Shav-Tal, Y AF Cohen-Fix, Orna Shav-Tal, Yaron TI Nuclear biology: making sense of complex processes SO MOLECULAR BIOLOGY OF THE CELL LA English DT Editorial Material C1 [Cohen-Fix, Orna] NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. [Shav-Tal, Yaron] Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, IL-52900 Ramat Gan, Israel. [Shav-Tal, Yaron] Bar Ilan Univ, Inst Nanotechnol, IL-52900 Ramat Gan, Israel. RP Cohen-Fix, O (reprint author), NIDDK, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. EM ornacf@helix.nih.gov; Yaron.Shav-Tal@biu.ac.il NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR 15 PY 2012 VL 23 IS 6 BP 976 EP 976 DI 10.1091/mbc.E11-12-0981 PG 1 WC Cell Biology SC Cell Biology GA 907XO UT WOS:000301453700012 ER PT J AU Altan-Bonnet, N Steele-Mortimer, O AF Altan-Bonnet, Nihal Steele-Mortimer, Olivia TI Cell-pathogen interactions (viruses and bacteria) SO MOLECULAR BIOLOGY OF THE CELL LA English DT Editorial Material C1 [Altan-Bonnet, Nihal] Rutgers State Univ, Host Pathogen Dynam Grp, Dept Biol Sci, Newark, NJ 07102 USA. [Steele-Mortimer, Olivia] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Altan-Bonnet, N (reprint author), Rutgers State Univ, Host Pathogen Dynam Grp, Dept Biol Sci, Newark, NJ 07102 USA. EM nabonnet@andromeda.rutgers.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR 15 PY 2012 VL 23 IS 6 BP 978 EP 978 DI 10.1091/mbc.E11-12-0980 PG 1 WC Cell Biology SC Cell Biology GA 907XO UT WOS:000301453700014 ER PT J AU Reed, JL Scott, DE Bray, M AF Reed, Jennifer L. Scott, Dorothy E. Bray, Mike TI Eczema Vaccinatum SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID ATOPIC-DERMATITIS; SMALLPOX VACCINATION; SKIN INFLAMMATION; PROGRESSIVE VACCINIA; UNITED-STATES; MOUSE MODEL; VIRUS; DISEASE; COMPLICATIONS; CELLS AB Eczema vaccinatum (EV) is a complication of smallpox vaccination that can occur in persons with eczema/atopic dermatitis (AD), in which vaccinia virus disseminates to cause an extensive rash and systemic illness. Because persons with eczema are deferred from vaccination, only a single, accidentally transmitted case of EV has been described in the medical literature since military vaccination was resumed in the United States in 2002. To enhance understanding of EV, we review its history during the era of universal vaccination and discuss its relationship to complications in persons with other diseases or injuries of the skin. We then discuss current concepts of the pathophysiology of AD, noting how defective skin barrier function, epidermal hyperplasia, and abnormal immune responses favor the spread of poxviral infection, and identify a number of unanswered questions about EV. We conclude by considering how its occurrence might be minimized in the event of a return to universal vaccination. C1 [Reed, Jennifer L.; Scott, Dorothy E.] US FDA, Lab Plasma Derivat, Ctr Biol Evaluat & Res, Rockville, MD 20892 USA. [Bray, Mike] NIAID, Div Clin Res, NIH, Bethesda, MD 20892 USA. RP Reed, JL (reprint author), US FDA, Lab Plasma Derivat, Ctr Biol Evaluat & Res, 8800 Rockville Pike,HFM 345,NIH Bldg 29,Rm 302, Rockville, MD 20892 USA. EM jennifer.reed@fda.hhs.gov FU Food and Drug Administration, Center for Biologics Evaluation and Research FX This work is supported by the Food and Drug Administration, Center for Biologics Evaluation and Research operating funds. These findings and conclusions have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency determination or policy. NR 59 TC 17 Z9 17 U1 0 U2 2 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 MAR 15 PY 2012 VL 54 IS 6 BP 832 EP 840 DI 10.1093/cid/cir952 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 899CK UT WOS:000300790900017 PM 22291103 ER PT J AU Muller, JR Waldmann, TA Dubois, S AF Mueller, Juergen R. Waldmann, Thomas A. Dubois, Sigrid TI Selective Dependence of H2-M3-Restricted CD8 Responses on IL-15 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; MARROW-DERIVED CELLS; MEMORY T-CELLS; CUTTING EDGE; VIRUS; INTERLEUKIN-15; PROLIFERATION; IL-15R-ALPHA; MICE; NK AB We studied whether CD8 T cell responses that are mediated by unconventional MHC class Ib molecules are IL-15 dependent in mice. CD8(+) T cell responses to Listeria monocytogenes infection that are restricted by the MHC class Ib molecule H2-M3 decreased in the absence of IL-15, whereas other primary MHC class Ib- and MHC class Ia-restricted responses were IL-15 independent. This result was confirmed in MHC class Ia-deficient mice in which IL-15 deficiency also reduced H2-M3-restricted but not all CD8 T cell responses to L. monocytogenes. IL-15 deficiency did not affect proliferation or survival of responding H2-M3-restricted CD8(+) T cells, but IL-15 was necessary to detect H2-M3-restricted CD8(+) T cells in naive mice. This finding suggests that these CD8(+) T cells require IL-15 during development, but become IL-15 independent after activation. IL-15 was necessary for the survival of most class Ib-restricted CD8(+) T cells, starting at the mature thymocyte stage in naive mice, but does not affect a distinct CD44(low)/CD122(low) subpopulation. These data suggest that the nature of the selecting MHC class Ib molecule determines whether CD8(+) T cells acquire IL-15 dependence during thymic development. The Journal of Immunology, 2012, 188: 2575-2582. C1 [Mueller, Juergen R.; Waldmann, Thomas A.; Dubois, Sigrid] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Dubois, S (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10,Room 4B47,10 Ctr Dr, Bethesda, MD 20892 USA. EM duboiss@mail.nih.gov FU National Cancer Institute at the National Institutes of Health FX This work was supported by the intramural research program of the National Cancer Institute at the National Institutes of Health. NR 33 TC 1 Z9 1 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2012 VL 188 IS 6 BP 2575 EP 2582 DI 10.4049/jimmunol.1102393 PG 8 WC Immunology SC Immunology GA 903OD UT WOS:000301126000013 PM 22312130 ER PT J AU Horka, H Staudt, V Klein, M Taube, C Reuter, S Dehzad, N Andersen, JF Kopecky, J Schild, H Kotsyfakis, M Hoffmann, M Gerlitzki, B Stassen, M Bopp, T Schmitt, E AF Horka, Helena Staudt, Valerie Klein, Matthias Taube, Christian Reuter, Sebastian Dehzad, Nina Andersen, John F. Kopecky, Jan Schild, Hansjoerg Kotsyfakis, Michalis Hoffmann, Markus Gerlitzki, Bastian Stassen, Michael Bopp, Tobias Schmitt, Edgar TI The Tick Salivary Protein Sialostatin L Inhibits the Th9-Derived Production of the Asthma-Promoting Cytokine IL-9 and Is Effective in the Prevention of Experimental Asthma SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL-MEDIATED SUPPRESSION; CD4(+) T-CELLS; IXODES-SCAPULARIS; AIRWAY INFLAMMATION; EPITHELIAL-CELLS; TGF-BETA; INTERLEUKIN 9; EXPRESSION; ANTIBODY; DISEASE AB Ticks developed a multitude of different immune evasion strategies to obtain a blood meal. Sialostatin L is an immunosuppressive cysteine protease inhibitor present in the saliva of the hard tick Ixodes scapularis. In this study, we demonstrate that sialostatin L strongly inhibits the production of IL-9 by Th9 cells. Because we could show recently that Th9-derived IL-9 is essentially involved in the induction of asthma symptoms, sialostatin L was used for the treatment of experimental asthma. Application of sialostatin L in a model of experimental asthma almost completely abrogated airway hyperresponsiveness and eosinophilia. Our data suggest that sialostatin L can prevent experimental asthma, most likely by inhibiting the IL-9 production of Th9 cells. Thus, alternative to IL-9 neutralization sialostatin L provides the basis for the development of innovative therapeutic strategies to treat asthma. The Journal of Immunology, 2012, 188: 2669-2676. C1 [Staudt, Valerie; Klein, Matthias; Schild, Hansjoerg; Hoffmann, Markus; Gerlitzki, Bastian; Stassen, Michael; Bopp, Tobias; Schmitt, Edgar] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Immunol, D-55131 Mainz, Germany. [Horka, Helena; Kopecky, Jan; Kotsyfakis, Michalis] Univ S Bohemia, Inst Parasitol, Ctr Biol, Acad Sci Czech Republ, Ceske Budejovice 37005, Czech Republic. [Horka, Helena; Kopecky, Jan; Kotsyfakis, Michalis] Univ S Bohemia, Fac Sci, Ceske Budejovice 37005, Czech Republic. [Taube, Christian] Leiden Univ, Dept Pulmonol, Med Ctr, NL-2333 ZA Leiden, Netherlands. [Reuter, Sebastian; Dehzad, Nina] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Med Clin 3, D-55131 Mainz, Germany. [Andersen, John F.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Bopp, T (reprint author), Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Immunol, Bldg 708,Langenbeckstr 1, D-55131 Mainz, Germany. EM boppt@uni-mainz.de; eschmitt@uni-mainz.de RI Reuter, Sebastian/L-1804-2013; Langhansova, Helena /G-9292-2014; Kotsyfakis, Michail/G-9525-2014; Kopecky, Jan/G-9347-2014 OI Kotsyfakis, Michail/0000-0002-7526-1876; FU Deutsche Forschungsgemeinschaft [SFB TR52 TPA1, SCHM 1014/5-1]; DFG [Graduiertenkolleg 1043]; "Forschungszentrum Immunologie" of the University Medical Center; Asthma Core Facility; Johannes Gutenberg University Mainz; Grant Agency of the Czech Republic [P302/11/ J029]; Research Center of the Ministry of Education, Youth, and Sports of the Czech Republic [LC06009] FX This work was supported by Deutsche Forschungsgemeinschaft Grants SFB TR52 TPA1 (to M. Klein, T. B., and E. S.) and SCHM 1014/5-1 (to V. S., T. B., and E. S.); DFG-Graduiertenkolleg 1043: International Graduate School of Immunotherapy (to E. S. and T. B.); "Forschungszentrum Immunologie" of the University Medical Center (to E. S. and T. B.); the Asthma Core Facility (to C. T.); Johannes Gutenberg University Mainz; Grant Agency of the Czech Republic Bilateral Grant P302/11/ J029 (to H. H., M. Klein, and J.K.); and Research Center of the Ministry of Education, Youth, and Sports of the Czech Republic Grant LC06009 (to H. H. and J.K.). NR 42 TC 23 Z9 25 U1 1 U2 10 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2012 VL 188 IS 6 BP 2669 EP 2676 DI 10.4049/jimmunol.1100529 PG 8 WC Immunology SC Immunology GA 903OD UT WOS:000301126000022 PM 22327077 ER PT J AU Leelahavanichkul, A Bocharov, AV Kurlander, R Baranova, IN Vishnyakova, TG Souza, ACP Hu, XZ Doi, K Vaisman, B Amar, M Sviridov, D Chen, ZG Remaley, AT Csako, G Patterson, AP Yuen, PST Star, RA Eggerman, TL AF Leelahavanichkul, Asada Bocharov, Alexander V. Kurlander, Roger Baranova, Irina N. Vishnyakova, Tatyana G. Souza, Ana C. P. Hu, Xuzhen Doi, Kent Vaisman, Boris Amar, Marcelo Sviridov, Denis Chen, Zhigang Remaley, Alan T. Csako, Gyorgy Patterson, Amy P. Yuen, Peter S. T. Star, Robert A. Eggerman, Thomas L. TI Class B Scavenger Receptor Types I and II and CD36 Targeting Improves Sepsis Survival and Acute Outcomes in Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACUTE KIDNEY INJURY; ACUTE-RENAL-FAILURE; TOLL-LIKE RECEPTORS; APOLIPOPROTEIN-A-I; GLUCOCORTICOID PRODUCTION; INFLAMMATORY RESPONSES; BACTERIAL RECOGNITION; SIGNALING CASCADE; MIMETIC PEPTIDE; UNITED-STATES AB Class B scavenger receptors (SR-Bs), such as SR-BI/II or CD36, bind lipoproteins but also mediate bacterial recognition and phagocytosis. In evaluating whether blocking receptors can prevent intracellular bacterial proliferation, phagocyte cytotoxicity, and proinflammatory signaling in bacterial infection/sepsis, we found that SR-BI/II- or CD36-deficient phagocytes are characterized by a reduced intracellular bacterial survival and a lower cytokine response and were protected from bacterial cytotoxicity in the presence of antibiotics. Mice deficient in either SR-BI/II or CD36 are protected from antibiotic-treated cecal ligation and puncture (CLP)-induced sepsis, with greatly increased peritoneal granulocytic phagocyte survival (8-fold), a drastic diminution in peritoneal bacteria counts, and a 50-70% reduction in systemic inflammation (serum levels of IL-6, TNF-a, and IL-10) and organ damage relative to CLP in wild-type mice. The survival rate of CD36-deficient mice after CLP was 58% compared with 17% in control mice. When compensated for mineralocorticoid and glucocorticoid deficiency, SR-BI/II-deficient mice had nearly a 50% survival rate versus 5% in mineralo-/glucocorticoid-treated controls. Targeting SR-B receptors with L-37pA, a peptide that functions as an antagonist of SR-BI/II and CD36 receptors, also increased peritoneal granulocyte counts, as well as reduced peritoneal bacteria and bacterium-induced cytokine secretion. In the CLP mouse sepsis model, L-37pA improved survival from 6 to 27%, reduced multiple organ damage, and improved kidney function. These results demonstrate that the reduction of both SR-BI/II- and CD36-dependent bacterial invasion and inflammatory response in the presence of antibiotic treatment results in granulocyte survival and local bacterial containment, as well as reduces systemic inflammation and organ damage and improves animal survival during severe infections. The Journal of Immunology, 2012, 188: 2749-2758. C1 [Bocharov, Alexander V.; Kurlander, Roger; Baranova, Irina N.; Vishnyakova, Tatyana G.; Chen, Zhigang; Csako, Gyorgy; Patterson, Amy P.; Eggerman, Thomas L.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Leelahavanichkul, Asada; Souza, Ana C. P.; Hu, Xuzhen; Doi, Kent; Yuen, Peter S. T.; Star, Robert A.] NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. [Leelahavanichkul, Asada] Chulalongkorn Univ, Fac Med, Dept Microbiol, Bangkok 10330, Thailand. [Vaisman, Boris; Amar, Marcelo; Sviridov, Denis; Remaley, Alan T.] NHLBI, NIH, Bethesda, MD 20892 USA. [Patterson, Amy P.] NIH, Off Biotechnol Activ, Off Director, Bethesda, MD 20892 USA. [Eggerman, Thomas L.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Bocharov, AV (reprint author), NIH, Dept Lab Med, Ctr Clin, Bldg 9,Room 1N128,8800 Rockville Pike, Bethesda, MD 20892 USA. EM abocharov@cc.nih.gov RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 FU National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases; Clinical Center; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Diseases FX This work was supported by the National Institutes of Health Intramural Research Programs, including support from the National Institute of Diabetes and Digestive and Kidney Diseases; the Clinical Center; the National Heart, Lung, and Blood Institute; and the National Institute of Allergy and Infectious Diseases. NR 51 TC 21 Z9 22 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2012 VL 188 IS 6 BP 2749 EP 2758 DI 10.4049/jimmunol.1003445 PG 10 WC Immunology SC Immunology GA 903OD UT WOS:000301126000031 PM 22327076 ER PT J AU De Arras, L Yang, IV Lackford, B Riches, DWH Prekeris, R Freedman, JH Schwartz, DA Alper, S AF De Arras, Lesly Yang, Ivana V. Lackford, Brad Riches, David W. H. Prekeris, Rytis Freedman, Jonathan H. Schwartz, David A. Alper, Scott TI Spatiotemporal Inhibition of Innate Immunity Signaling by the Tbc1d23 RAB-GAP SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; NF-KAPPA-B; UNFOLDED PROTEIN RESPONSE; PATTERN-RECOGNITION RECEPTORS; ENDOPLASMIC-RETICULUM STRESS; XBP1 MESSENGER-RNA; IFN-BETA INDUCTION; TRANSCRIPTION FACTOR; ACTIVATION; MACROPHAGES AB We previously identified Tbc1d23 as a candidate novel regulator of innate immunity using comparative genomics RNA interference screens in Caenorhabditis elegans and mouse macrophages. Using Tbc1d23 knockout mice and macrophages engineered to overexpress Tbc1d23, we now show that Tbc1d23 is a general inhibitor of innate immunity signaling, strongly inhibiting multiple TLR and dectin-signaling pathways. Tbc1d23 likely acts downstream of the TLR-signaling adaptors MyD88 and Trif and upstream of the transcription factor XBP1. Importantly, like XBP1, Tbc1d23 affects the maintenance, but not the initiation, of inflammatory cytokine production induced by LPS. Tbc1d23 acts as a RAB-GAP to regulate innate immunity signaling. Thus, Tbc1d23 exerts its inhibitory effect on innate immunity signaling in a spatiotemporal fashion. The identification of a novel spatiotemporal regulator of innate immunity signaling validates the comparative genomics approach for innate immunity gene discovery. The Journal of Immunology, 2012, 188: 2905-2913. C1 [De Arras, Lesly; Riches, David W. H.; Alper, Scott] Natl Jewish Hlth, Integrated Dept Immunol, Denver, CO 80206 USA. [De Arras, Lesly; Riches, David W. H.; Alper, Scott] Univ Colorado, Denver, CO 80206 USA. [De Arras, Lesly; Yang, Ivana V.; Schwartz, David A.; Alper, Scott] Natl Jewish Hlth, Ctr Genes Environm & Hlth, Denver, CO 80206 USA. [Yang, Ivana V.; Riches, David W. H.; Schwartz, David A.] Univ Colorado, Dept Med, Aurora, CO 80045 USA. [Lackford, Brad] Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, Durham, NC 27709 USA. [Riches, David W. H.] Natl Jewish Hlth, Cell Biol Program, Dept Pediat, Denver, CO 80206 USA. [Prekeris, Rytis] Univ Colorado, Dept Cell & Dev Biol, Aurora, CO 80045 USA. [Freedman, Jonathan H.] Natl Inst Environm Hlth Sci, Lab Toxicol & Pharmacol, NIH, Durham, NC 27709 USA. RP Alper, S (reprint author), Natl Jewish Hlth, Integrated Dept Immunol, 1400 Jackson St, Denver, CO 80206 USA. EM alpers@njhealth.org FU National Institute of Environmental Health Sciences [R21ES019256, Z01ES102045, Z01ES101946]; National Heart Lung and Blood Institute FX This work was supported by R21ES019256 from the National Institute of Environmental Health Sciences and the Intramural Research Programs of the National Heart Lung and Blood Institute and the National Institute of Environmental Health Sciences (Z01ES102045 and Z01ES101946). NR 60 TC 7 Z9 7 U1 2 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 MAR 15 PY 2012 VL 188 IS 6 BP 2905 EP 2913 DI 10.4049/jimmunol.1102595 PG 9 WC Immunology SC Immunology GA 903OD UT WOS:000301126000046 PM 22312129 ER PT J AU Insel, TR Sahakian, BJ AF Insel, Thomas R. Sahakian, Barbara J. TI A plan for mental illness SO NATURE LA English DT Editorial Material ID HEALTH C1 [Insel, Thomas R.] NIMH, NIH, Bethesda, MD 20892 USA. [Sahakian, Barbara J.] Univ Cambridge, Dept Psychiat, Cambridge CB2 1TN, England. [Sahakian, Barbara J.] Univ Cambridge, MRC Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 1TN, England. RP Insel, TR (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. EM bjs1001@cam.ac.uk RI Nye, Jeffrey/G-6520-2012 OI Nye, Jeffrey/0000-0002-6056-281X NR 10 TC 37 Z9 38 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 15 PY 2012 VL 483 IS 7389 BP 269 EP 269 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 908HP UT WOS:000301481800023 PM 22422245 ER PT J AU Koralek, AC Jin, X Ii, JDL Costa, RM Carmena, JM AF Koralek, Aaron C. Jin, Xin Ii, John D. Long Costa, Rui M. Carmena, Jose M. TI Corticostriatal plasticity is necessary for learning intentional neuroprosthetic skills SO NATURE LA English DT Article ID COGNITIVE SKILL; PREFRONTAL CORTEX; STRIATAL NEURONS; MOTOR CORTEX; ACQUISITION; CONSOLIDATION; PERFORMANCE; CONTINGENCY; ACTIVATION; NETWORKS AB The ability to learn new skills and perfect them with practice applies not only to physical skills but also to abstract skills(1), like motor planning or neuroprosthetic actions. Although plasticity in corticostriatal circuits has been implicated in learning physical skills(2-4), it remains unclear if similar circuits or processes are required for abstract skill learning. Here we use a novel behavioural task in rodents to investigate the role of corticostriatal plasticity in abstract skill learning. Rodents learned to control the pitch of an auditory cursor to reach one of two targets by modulating activity in primary motor cortex irrespective of physical movement. Degradation of the relation between action and outcome, as well as sensory-specific devaluation and omission tests, demonstrate that these learned neuroprosthetic actions are intentional and goal-directed, rather than habitual. Striatal neurons change their activity with learning, with more neurons modulating their activity in relation to target-reaching as learning progresses. Concomitantly, strong relations between the activity of neurons in motor cortex and the striatum emerge. Specific deletion of striatal NMDA receptors impairs the development of this corticostriatal plasticity, and disrupts the ability to learn neuroprosthetic skills. These results suggest that corticostriatal plasticity is necessary for abstract skill learning, and that neuroprosthetic movements capitalize on the neural circuitry involved in natural motor learning. C1 [Jin, Xin; Costa, Rui M.] NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. [Koralek, Aaron C.; Ii, John D. Long; Carmena, Jose M.] Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. [Carmena, Jose M.] Univ Calif Berkeley, Dept Elect Engn & Comp Sci, Berkeley, CA 94720 USA. [Carmena, Jose M.] Univ Calif Berkeley, Program Cognit Sci, Berkeley, CA 94720 USA. [Carmena, Jose M.] Univ Calif Berkeley, UC Berkeley & UC San Francisco Joint Grad Grp Bio, Berkeley, CA 94720 USA. [Costa, Rui M.] Champalimaud Ctr Unknown, Champalimaud Neurosci Programme, P-1400038 Lisbon, Portugal. RP Costa, RM (reprint author), NIAAA, Lab Integrat Neurosci, NIH, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM ruicosta@fchampalimaud.org; carmena@eecs.berkeley.edu OI Koralek, Aaron/0000-0001-5205-0171; Costa, Rui/0000-0003-0495-8374 FU National Science Foundation [0954243]; Multiscale Systems Research Center; Defense Advanced Research Projects Agency [N66001-10-C-2008]; Division of Intramural Clinical and Basic Research of the National Institute on Alcohol Abuse and Alcoholism [239527]; European Research Council [STG 243393] FX We thank S. Venkatraman for the three-axis accelerometer, Y. Li for the RGS9L-Cre mice, K. Nakazawa for the NMDAR1-loxP mice, G. Luo for genotyping, M. Davis for advice on staining and G. Martins for performing immunohistochemistry. This work was supported by National Science Foundation CAREER Award 0954243, the Multiscale Systems Research Center and the Defense Advanced Research Projects Agency contract N66001-10-C-2008 to J. M. C., and the Division of Intramural Clinical and Basic Research of the National Institute on Alcohol Abuse and Alcoholism, Marie Curie International Reintegration Grant 239527 and European Research Council STG 243393 to R.M.C. NR 30 TC 112 Z9 113 U1 4 U2 38 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 15 PY 2012 VL 483 IS 7389 BP 331 EP 335 DI 10.1038/nature10845 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 908HP UT WOS:000301481800049 PM 22388818 ER PT J AU Kopald, BE Mirra, KM Egan, MF Weinberger, DR Goldberg, TE AF Kopald, Brandon E. Mirra, Kathryn M. Egan, Michael F. Weinberger, Daniel R. Goldberg, Terry E. TI Magnitude of Impact of Executive Functioning and IQ on Episodic Memory in Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Episodic memory; executive functioning; intelligence; memory; prefrontal cortex; schizophrenia ID 1ST-EPISODE PSYCHOSIS; HEALTHY CONTROLS; DEFICITS; RECOGNITION; METAANALYSIS; IMPAIRMENT; ACTIVATION; SIBLINGS AB Background: Research has implicated IQ and executive function (EF) as contributors to episodic memory impairments in schizophrenia. However, it has been difficult to quantitatively apportion the respective contributions of these factors. We conducted a series of analyses to objectively parse the associated variance and to determine to what extent episodic memory impairment in schizophrenia is independent of IQ and EF. Methods: Participants included 323 schizophrenia patients and 327 healthy controls from the National Insitute of Mental Health Sibling Study. Neurocognitive tests assessing IQ, EF, and episodic memory were administered. We examined group differences while controlling for IQ or EF in analyses of covariance, we used linear regression to quantify the amount of variance not explained by IQ or EF, and we matched control and patient subgroups on IQ or EF to determine if memory measures remained different. Results: Analyses of covariance revealed significant group differences between schizophrenia individuals and healthy control subjects across multiple episodic memory measures after controlling for IQ or EF. Furthermore, regressions with IQ and/or EF factors entered left more than 50% of variance in memory unaccounted. Follow-up true score variance analyses indicated that the majority of this variance was directly related to memory function. Matched subgroups also yielded subgroup differences on all memory measures. Conclusions: Findings across the multiple statistical strategies suggested that the mechanisms underlying the memory impairment in schizophrenia are fully attributable neither to IQ nor EF. Rather, they most likely reflect compromises in episodic memory processing itself and, by inference, the medial temporal system. C1 [Kopald, Brandon E.; Mirra, Kathryn M.; Goldberg, Terry E.] Hofstra N Shore Long Isl Jewish Sch Med, Feinstein Inst Med Res Psychiat Res, Manhasset, NY 11030 USA. [Egan, Michael F.; Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Goldberg, TE (reprint author), Hofstra N Shore Long Isl Jewish Sch Med, Feinstein Inst Med Res Psychiat Res, 350 Community Dr, Manhasset, NY 11030 USA. EM tgoldber@nshs.edu FU National Institutes of Health [P50 MH080173, HHSN-271-2009-00019C] FX This work was supported in part by National Institutes of Health Grants P50 MH080173 and HHSN-271-2009-00019C (BK, KM, TG). Dr. Goldberg has served as a consultant for Merck and GlaxoSmithKline and receives royalties for use of a cognitive test. Dr. Egan worked on this study while employed by the federal government; he is now an employee of Merck. Dr. Weinberger worked on this study while employed by the federal government. Drs. Kopald and Mirra report no biomedical financial interests or potential conflicts of interest. NR 27 TC 12 Z9 12 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 15 PY 2012 VL 71 IS 6 BP 545 EP 551 DI 10.1016/j.biopsych.2011.11.021 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 899BX UT WOS:000300789100015 PM 22265665 ER PT J AU Anticevic, A Van Snellenberg, JX Barch, DM AF Anticevic, Alan Van Snellenberg, Jared X. Barch, Deanna M. TI Neurobiology of Emotional Dysfunction in Schizophrenia: New Directions Revealed Through Meta-Analyses SO BIOLOGICAL PSYCHIATRY LA English DT Letter ID FACIAL EXPRESSION; EXPERIENCE C1 [Anticevic, Alan] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. [Anticevic, Alan] NIAAA, Ctr Translat Neurosci Alcoholism, New Haven, CT USA. [Anticevic, Alan] Connecticut Mental Hlth Ctr, Abraham Ribicoff Res Facil, New Haven, CT 06519 USA. [Van Snellenberg, Jared X.] New York State Psychiat Inst & Hosp, Div Cognit Neurosci, New York, NY 10032 USA. [Van Snellenberg, Jared X.] Columbia Univ, Dept Psychol, New York, NY 10027 USA. [Barch, Deanna M.] Washington Univ St Louis, Dept Psychol, St Louis, MO USA. [Barch, Deanna M.] Washington Univ St Louis, Dept Psychiat, St Louis, MO USA. [Barch, Deanna M.] Washington Univ St Louis, Dept Radiol, St Louis, MO USA. RP Anticevic, A (reprint author), Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. EM alan.anticevic@yale.edu RI Anticevic, Alan/E-7868-2010; Van Snellenberg, Jared/F-7889-2013; Barch, Deanna/G-8638-2013 OI Van Snellenberg, Jared/0000-0003-2442-2008; NR 17 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 15 PY 2012 VL 71 IS 6 BP E23 EP E24 DI 10.1016/j.biopsych.2011.10.039 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 899BX UT WOS:000300789100005 PM 22206874 ER PT J AU Swales, KE Moore, R Truss, NJ Tucker, A Warner, TD Negishi, M Bishop-Bailey, D AF Swales, Karen E. Moore, Rick Truss, Nicola J. Tucker, Arthur Warner, Timothy D. Negishi, Masahiko Bishop-Bailey, David TI Pregnane X receptor regulates drug metabolism and transport in the vasculature and protects from oxidative stress SO CARDIOVASCULAR RESEARCH LA English DT Article DE Pregnane X receptor; Nuclear receptors; Vascular endothelium; Vascular smooth muscle cells; Cytochrome P450 ID BLOOD-BRAIN-BARRIER; ENDOTHELIAL-CELL LINE; SMOOTH-MUSCLE-CELLS; P-GLYCOPROTEIN; UP-REGULATION; CYTOCHROME-P450 ENZYMES; HYPERPOLARIZING FACTOR; PLATELET-AGGREGATION; REDUCTASE INHIBITORS; NUCLEAR RECEPTORS AB Circulating endogenous, dietary, and foreign chemicals can contribute to vascular dysfunction. The mechanism by which the vasculature protects itself from these chemicals is unknown. This study investigates whether the pregnane X receptor (PXR), the major transcriptional regulator of hepatic drug metabolism and transport that responds to such xenobiotics, mediates vascular protection by co-ordinating a defence gene programme in the vasculature. PXR was detected in primary human and rat aortic endothelial and smooth muscle cells (SMC) and blood vessels including the human and rat aorta. Metabolic PXR target genes cytochrome P450 3A, 2B, 2C, and glutathione S-transferase mRNA and activity were induced by PXR ligands in rodent and human vascular cells and absent in the aortas from PXR-null mice stimulated in vivo or in rat aortic SMC expressing dominant-negative PXR. Activation of aortic PXR by classical agonists had several protective effects: increased xenobiotic metabolism demonstrated by bioactivation of the pro-drug clopidogrel, which reduced adenosine diphosphate-induced platelet aggregation; increased expression of multidrug resistance protein 1, mediating chemical efflux from the vasculature; and protection from reactive oxygen species-mediated cell death. PXR co-ordinately up-regulates drug metabolism, transport, and antioxidant genes to protect the vasculature from endogenous and exogenous insults, thus representing a novel gatekeeper for vascular defence. C1 [Swales, Karen E.] Univ Surrey, Fac Hlth & Med Sci, Guildford GU2 7XH, Surrey, England. [Moore, Rick; Negishi, Masahiko] NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Truss, Nicola J.; Tucker, Arthur; Warner, Timothy D.; Bishop-Bailey, David] Barts & London Queen Marys Sch Med & Dent, William Harvey Res Inst, London EC1M 6BQ, England. RP Swales, KE (reprint author), Univ Surrey, Fac Hlth & Med Sci, Guildford GU2 7XH, Surrey, England. EM k.swales@surrey.ac.uk RI Warner, Timothy/A-1980-2009 OI Warner, Timothy/0000-0003-3988-4408 FU Barts and the London Charitable Trust [427/438]; Wellcome Trust [074361/Z/04/Z]; European Community [LSHM-CT-2004-0050333]; British Heart Foundation [BS/02/002]; National Institutes of Health; National Institute of Environmental Health Sciences FX This work was supported by a Barts and the London Charitable Trust, research and advisory board non-clinical research fellowship (427/438) to K. E. S.; the Wellcome Trust (074361/Z/04/Z) to D.B.-B.; European Community FP6 funding (LSHM-CT-2004-0050333) to T. D. W.; the British Heart Foundation (BS/02/002) to D.B.-B.; and the Intramural Research Program of the National Institutes of Health and National Institute of Environmental Health Sciences to M.N. NR 49 TC 18 Z9 18 U1 2 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 15 PY 2012 VL 93 IS 4 BP 674 EP 681 DI 10.1093/cvr/cvr330 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 901TA UT WOS:000300988500018 PM 22166712 ER PT J AU Chattopadhyay, M Kodela, R Nath, N Dastagirzada, YM Velazquez-Martinez, CA Boring, D Kashfi, K AF Chattopadhyay, Mitali Kodela, Ravinder Nath, Niharika Dastagirzada, Yosef M. Velazquez-Martinez, Carlos A. Boring, Daniel Kashfi, Khosrow TI Hydrogen sulfide-releasing NSAIDs inhibit the growth of human cancer cells: A general property and evidence of a tissue type-independent effect SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Hydrogen sulfide; NSAIDs; Cancer prevention; COX-independent ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; OXIDE-DONATING ASPIRIN; NITRIC-OXIDE; COLON-CANCER; GASTROINTESTINAL-TRACT; POSITIONAL ISOMERISM; IN-VITRO; APOPTOSIS; PROLIFERATION; PHOSPHORYLATION AB Hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs (HS-NSAIDs) are an emerging novel class of compounds with significant anti-inflammatory properties. They consist of a traditional NSAID to which an H2S-releasing moiety is covalently attached. We examined the effects of four different HS-NSAIDs on the growth properties of eleven different human cancer cell lines of six different tissue origins. Human colon, breast, pancreatic, prostate, lung, and leukemia cancer cell lines were treated with HS-aspirin, -sulindac, -iburofen, -naproxen, and their traditional counterparts. HS-NSAIDs inhibited the growth of all cancer cell lines studied, with potencies of 28- to >3000-fold greater than that of their traditional counterparts. HS-aspirin (HS-ASA) was consistently the most potent. HS-NSAIDs inhibited cell proliferation, induced apoptosis, and caused G(0)/G(1) cell cycle block. Metabolism of HS-ASA by colon cells showed that the acetyl group of ASA was hydrolyzed rapidly, followed by hydrolysis of the ester bond linking the salicylate anion to the H2S releasing moiety, producing salicylic acid and ADT-OH from which H2S is released. In reconstitution studies, ASA and ADT-OH were individually less active than the intact HS-ASA towards cell growth inhibition. Additionally, the combination of these two components representing a fairly close approximation to the intact HS-ASA, was 95-fold less active than the intact HS-ASA for growth inhibition. Taken together, these results demonstrate that HS-NSAIDs have potential anti-growth activity against a wide variety of human cancer cells. (C) 2011 Elsevier Inc. All rights reserved. C1 [Chattopadhyay, Mitali; Kodela, Ravinder; Dastagirzada, Yosef M.; Kashfi, Khosrow] CUNY, Sch Med, Dept Physiol & Pharmacol, Sophie Davis Sch Biomed Educ, New York, NY 10031 USA. [Nath, Niharika] New York Inst Technol, Dept Life Sci, New York, NY 10023 USA. [Velazquez-Martinez, Carlos A.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. [Boring, Daniel] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Kashfi, K (reprint author), CUNY, Sch Med, Dept Physiol & Pharmacol, Sophie Davis Sch Biomed Educ, 138th St & Convent Ave, New York, NY 10031 USA. EM kashfi@med.cuny.edu FU National Cancer Institute through ThermoFisher [FBS-43312-26] FX Supported in part by the National Cancer Institute through a subcontract from ThermoFisher, contract # FBS-43312-26. NR 33 TC 45 Z9 47 U1 4 U2 36 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 MAR 15 PY 2012 VL 83 IS 6 BP 715 EP 722 DI 10.1016/j.bcp.2011.12.018 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898QP UT WOS:000300757200003 PM 22222427 ER PT J AU Chattopadhyay, M Kodela, R Nath, N Barsegian, A Boring, D Kashfi, K AF Chattopadhyay, Mitali Kodela, Ravinder Nath, Niharika Barsegian, Arpine Boring, Daniel Kashfi, Khosrow TI Hydrogen sulfide-releasing aspirin suppresses NF-kappa B signaling in estrogen receptor negative breast cancer cells in vitro and in vivo SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Hydrogen sulfide; Estrogen receptor negative breast cancer; NF-kappa B; Thioredoxin reductase; Chemoprevention ID DNA-BINDING ACTIVITY; THIOREDOXIN REDUCTASE; MYOCARDIAL-ISCHEMIA; GROWTH-INHIBITION; OXIDATIVE STRESS; ACTIVATION; EXPRESSION; APOPTOSIS; THERAPY; ACID AB Hormone-dependent estrogen receptor positive (ER+) breast cancers generally respond well to antiestrogen therapy. Unfortunately, hormone-independent estrogen receptor negative (ER) breast cancers are aggressive, respond poorly to current treatments and have a poor prognosis. New approaches and targets are needed for the prevention and treatment of ER breast cancer. The NF-kappa B signaling pathway is strongly implicated in ER tumor genesis, constituting a possible target for treatment. Hydrogen sulfide-releasing aspirin (HS-ASA), a novel and safer derivative of aspirin, has shown promise as an anti-cancer agent. We examined the growth inhibitory effect of HS-ASA via alterations in cell proliferation, cell cycle phase transitions, and apoptosis, using MDA-MB-231 cells as a model of triple negative breast cancer. Tumor xenografts in mice, representing human ER breast cancer, were evaluated for reduction in tumor size, followed by immunohistochemical analysis for proliferation, apoptosis and expression of NF-kappa B. HS-ASA suppressed the growth of MDA-MB-231 cells by induction of G(0)/G(1) arrest and apoptosis, down-regulation of NF-kappa B, reduction of thioredoxin reductase activity, and increased levels reactive oxygen species. Tumor xenografts in mice, were significantly reduced in volume and mass by HS-ASA treatment. The decrease in tumor mass was associated with inhibition of cell proliferation, induction of apoptosis and decrease in NF-kappa B levels in vivo. HS-ASA has anti-cancer potential against ER- breast cancer and merits further study. (C) 2011 Elsevier Inc. All rights reserved. C1 [Chattopadhyay, Mitali; Kodela, Ravinder; Barsegian, Arpine; Kashfi, Khosrow] CUNY, Sch Med, Dept Physiol & Pharmacol, Sophie Davis Sch Biomed Educ, New York, NY 10031 USA. [Nath, Niharika] New York Inst Technol, Dept Life Sci, New York, NY 10023 USA. [Boring, Daniel] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Kashfi, K (reprint author), CUNY, Sch Med, Dept Physiol & Pharmacol, Sophie Davis Sch Biomed Educ, 138th St & Convent Ave, New York, NY 10031 USA. EM kashfi@med.cuny.edu RI perumal, murugiah/D-1565-2012 FU National Cancer Institute through ThermoFisher [FBS-43312-26] FX Supported in part by the National Cancer Institute through a subcontract from ThermoFisher, contract # FBS-43312-26. NR 78 TC 32 Z9 33 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAR 15 PY 2012 VL 83 IS 6 BP 723 EP 732 DI 10.1016/j.bcp.2011.12.019 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898QP UT WOS:000300757200004 PM 22209867 ER PT J AU Chattopadhyay, M Kodela, R Nath, N Street, CR Velazquez-Martinez, CA Boring, D Kashfi, K AF Chattopadhyay, Mitali Kodela, Ravinder Nath, Niharika Street, Cherease R. Velazquez-Martinez, Carlos A. Boring, Daniel Kashfi, Khosrow TI Hydrogen sulfide-releasing aspirin modulates xenobiotic metabolizing enzymes in vitro and in vivo SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Xenobiotic metabolizing enzymes; GST; NOQ1; UGT; CYP 1A1; Hydrogen sulfide; NSAIDs ID GLUTATHIONE S-TRANSFERASES; ISCHEMIA-REPERFUSION INJURY; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SMOOTH-MUSCLE-CELLS; MYOCARDIAL-ISCHEMIA; CARNITINE PALMITOYLTRANSFERASE; UDP-GLUCURONOSYLTRANSFERASES; CANCER CHEMOPREVENTION; CHEMICAL CARCINOGENS; OXIDATIVE STRESS AB The balance between phase-I carcinogen-activating and phase-II detoxifying xenobiotic metabolizing enzymes is critical to determining an individual's risk for cancer. We evaluated the effect of Hydrogen sulfide-releasing aspirin (HS-ASA) on xenobiotic metabolizing enzymes in HT-29 human colon and Hepa 1c1c7 mouse liver adenocarcinoma cells and in Wistar rats. HS-ASA inhibited the growth of HT-29 and Hepa 1c1c7 cells, with an IC50 of 3.2 +/- 0.3 mu M and 4.2 +/- 0.4 mu M, respectively. The IC50 for ASA in both cell lines was greater than 5000 mu M at 24 h. In these cell lines, HS-ASA caused a dose-dependent increase in activity and expression of the phase-II enzymes glutathione S-transferase (GST) and NAD(P)H:quinoneoxireductase (NQO1). It also caused an increase in UDP-glucuronosyltransferase (UGT) expression. The levels of CYP 1A1 a phase-I enzyme was increased by HS-ASA in both cell lines. Pretreatment of cells with NaF, an esterase inhibitor, abrogated the HS-ASA-mediated increases in NQO1 enzyme activity. HS-ASA increased the protein levels of the transcription factor Nrf2, which is a regulator of the phase-II enzymes. In vivo, HS-ASA at 100 mg/kg/day had no effect on rat's weights; it induced a 3.4-fold and 1.4-fold increase in hepatic GST and NQ01 enzyme activities, respectively. GST and NQO1 protein levels were also increased. In contrast to that in cultured cells, CYP 1A1 protein levels were not altered in vivo. Therefore, HS-ASA induces phase-II enzymes, at least in part, through the action of H2S and by modulating Nrf2; these effects may be part of its mechanism of action against carcinogenesis. (C) 2011 Elsevier Inc. All rights reserved. C1 [Chattopadhyay, Mitali; Kodela, Ravinder; Street, Cherease R.; Kashfi, Khosrow] CUNY, Sch Med, Dept Physiol & Pharmacol, Sophie Davis Sch Biomed Educ, New York, NY 10031 USA. [Nath, Niharika] New York Inst Technol, Dept Life Sci, New York, NY 10023 USA. [Velazquez-Martinez, Carlos A.] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. [Boring, Daniel] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Kashfi, K (reprint author), CUNY, Sch Med, Dept Physiol & Pharmacol, Sophie Davis Sch Biomed Educ, 138th St & Convent Ave, New York, NY 10031 USA. EM kashfi@med.cuny.edu RI Ji, Haofeng/G-6206-2012 FU National Cancer Institute through ThermoFisher [FBS-43312-26] FX Supported in part by the National Cancer Institute through a subcontract from ThermoFisher, contract #FBS-43312-26. NR 61 TC 16 Z9 16 U1 3 U2 13 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 MAR 15 PY 2012 VL 83 IS 6 BP 733 EP 740 DI 10.1016/j.bcp.2011.12.020 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898QP UT WOS:000300757200005 PM 22209714 ER PT J AU Prendergast, A Linbo, TH Swarts, T Ungos, JM McGraw, HF Krispin, S Weinstein, BM Raible, DW AF Prendergast, Andrew Linbo, Tor H. Swarts, Tanya Ungos, Josette M. McGraw, Hillary F. Krispin, Shlomo Weinstein, Brant M. Raible, David W. TI The metalloproteinase inhibitor Reck is essential for zebrafish DRG development SO DEVELOPMENT LA English DT Article DE reck; Neural crest; Neurogenesis; Zebrafish ID CYSTEINE-RICH PROTEIN; KAZAL MOTIFS RECK; METASTASIS SUPPRESSOR RECK; DORSAL-ROOT GANGLIA; CELL LUNG-CANCER; IN-SITU HYBRIDIZATION; NEURAL-CREST; DOWN-REGULATION; PROGNOSTIC-SIGNIFICANCE; CLINICAL-SIGNIFICANCE AB The neural crest is a migratory, multipotent cell lineage that contributes to myriad tissues, including sensory neurons and glia of the dorsal root ganglia (DRG). To identify genes affecting cell fate specification in neural crest, we performed a forward genetic screen for mutations causing DRG deficiencies in zebrafish. This screen yielded a mutant lacking all DRG, which we named sensory deprived (sdp). We identified a total of four alleles of sdp, all of which possess lesions in the gene coding for reversion-inducing cysteine-rich protein containing Kazal motifs (Reck). Reck is an inhibitor of metalloproteinases previously shown to regulate cell motility. We found reck function to be both necessary for DRG formation and sufficient to rescue the sdp phenotype. reck is expressed in neural crest cells and is required in a cell-autonomous fashion for appropriate sensory neuron formation. In the absence of reck function, sensory neuron precursors fail to migrate to the position of the DRG, suggesting that this molecule is crucial for proper migration and differentiation. C1 [Prendergast, Andrew; Raible, David W.] Univ Washington, Grad Program Neurobiol & Behav, Seattle, WA 98195 USA. [Ungos, Josette M.; McGraw, Hillary F.; Raible, David W.] Univ Washington, Mol & Cellular Biol Grad Program, Seattle, WA 98195 USA. [Prendergast, Andrew; Linbo, Tor H.; Swarts, Tanya; Ungos, Josette M.; McGraw, Hillary F.; Raible, David W.] Univ Washington, Dept Biol Struct, Seattle, WA 98195 USA. [Krispin, Shlomo; Weinstein, Brant M.] NICHHD, Program Genom Differentiat, NIH, Bethesda, MD 20892 USA. RP Raible, DW (reprint author), Univ Washington, Grad Program Neurobiol & Behav, Seattle, WA 98195 USA. EM draible@u.washington.edu FU National Institute of General Medical Sciences [NRSA 2T32 GM007270]; National Institute of Neurological Disorders and Stroke [NS057220]; Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD001011] FX This investigation was supported in part by the National Institute of General Medical Sciences [NRSA 2T32 GM007270]; the National Institute of Neurological Disorders and Stroke [NS057220]; and the intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development [HD001011 to B. W.]. Deposited in PMC for release after 12 months. NR 69 TC 19 Z9 19 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 MAR 15 PY 2012 VL 139 IS 6 BP 1141 EP 1152 DI 10.1242/dev.072439 PG 12 WC Developmental Biology SC Developmental Biology GA 897HY UT WOS:000300640700011 PM 22296847 ER PT J AU Busser, BW Shokri, L Jaeger, SA Gisselbrecht, SS Singhania, A Berger, MF Zhou, B Bulyk, ML Michelson, AM AF Busser, Brian W. Shokri, Leila Jaeger, Savina A. Gisselbrecht, Stephen S. Singhania, Aditi Berger, Michael F. Zhou, Bo Bulyk, Martha L. Michelson, Alan M. TI Molecular mechanism underlying the regulatory specificity of a Drosophila homeodomain protein that specifies myoblast identity SO DEVELOPMENT LA English DT Article DE Homeodomain; Myoblast; Gene regulation ID TRANSCRIPTION FACTORS; SEQUENCE LOGOS; HOMEOBOX GENE; HOX PROTEINS; MUSCLE; DNA; MESODERM; DIVERSIFICATION; EXPRESSION; DIFFERENTIATION AB A subfamily of Drosophila homeodomain (HD) transcription factors (TFs) controls the identities of individual muscle founder cells (FCs). However, the molecular mechanisms by which these TFs generate unique FC genetic programs remain unknown. To investigate this problem, we first applied genome-wide mRNA expression profiling to identify genes that are activated or repressed by the muscle HD TFs Slouch (Slou) and Muscle segment homeobox (Msh). Next, we used protein-binding microarrays to define the sequences that are bound by Slou, Msh and other HD TFs that have mesodermal expression. These studies revealed that a large class of HDs, including Slou and Msh, predominantly recognize TAAT core sequences but that each HD also binds to unique sites that deviate from this canonical motif. To understand better the regulatory specificity of an individual FC identity HD, we evaluated the functions of atypical binding sites that are preferentially bound by Slou relative to other HDs within muscle enhancers that are either activated or repressed by this TF. These studies showed that Slou regulates the activities of particular myoblast enhancers through Slou-preferred sequences, whereas swapping these sequences for sites that are capable of binding to multiple HD family members does not support the normal regulatory functions of Slou. Moreover, atypical Slou-binding sites are overrepresented in putative enhancers associated with additional Slou-responsive FC genes. Collectively, these studies provide new insights into the roles of individual HD TFs in determining cellular identity, and suggest that the diversity of HD binding preferences can confer regulatory specificity. C1 [Shokri, Leila; Gisselbrecht, Stephen S.; Berger, Michael F.; Zhou, Bo; Bulyk, Martha L.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Bulyk, Martha L.] Harvard Univ, Sch Med, Harvard MIT Div Hlth Sci & Technol HST, Boston, MA 02115 USA. [Busser, Brian W.; Singhania, Aditi; Michelson, Alan M.] NHLBI, Lab Dev Syst Biol, Genet & Dev Biol Ctr, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Jaeger, Savina A.] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Bulyk, Martha L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bulyk, Martha L.] Harvard Univ, Comm Higher Degrees Biophys, Cambridge, MA 02138 USA. [Bulyk, Martha L.] Dana Farber Canc Inst, CCSB, Boston, MA 02115 USA. RP Bulyk, ML (reprint author), Brigham & Womens Hosp, Dept Med, Div Genet, 75 Francis St, Boston, MA 02115 USA. EM mlbulyk@receptor.med.harvard.edu; michelsonam@nhlbi.nih.gov OI Gisselbrecht, Stephen/0000-0001-8723-902X FU National Institutes of Health/National Institutes of General Medical Sciences (NIH/NIGMS) [U01 GM076603]; NIH/National Human Genome Research Institute (NHGRI) [R01 HG005287]; National Heart, Blood and Lung Institute (NHLBI) Division of Intramural Research; NIH [5 T32 GM007748-31]; NIH NRSA [1 F32 GM090645-01A1] FX This work was funded by National Institutes of Health/National Institutes of General Medical Sciences (NIH/NIGMS) [U01 GM076603 to M. L. B.], by NIH/National Human Genome Research Institute (NHGRI) [R01 HG005287 to M. L. B.], by the National Heart, Blood and Lung Institute (NHLBI) Division of Intramural Research (A. M. M.), by a NIH Training Grant [5 T32 GM007748-31 to L. S.], and by a NIH NRSA [1 F32 GM090645-01A1 to L. S.]. Deposited in PMC for immediate release. NR 64 TC 20 Z9 20 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 MAR 15 PY 2012 VL 139 IS 6 BP 1164 EP 1174 DI 10.1242/dev.077362 PG 11 WC Developmental Biology SC Developmental Biology GA 897HY UT WOS:000300640700013 PM 22296846 ER PT J AU Bagni, R Whitby, D AF Bagni, Rachel Whitby, Denise TI Age of Infection and Risk of Virally Associated Cancers: New Clues to an Old Puzzle SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID EPSTEIN-BARR-VIRUS; BURKITTS-LYMPHOMA; MALARIA; ANTIBODIES C1 [Whitby, Denise] NCI, Viral Oncol Sect, AIDS Vaccine Program, SAIC Frederick, Ft Detrick, MD 21702 USA. [Bagni, Rachel] NCI, Adv Technol Program, Ft Detrick, MD 21702 USA. RP Whitby, D (reprint author), NCI, Viral Oncol Sect, AIDS Vaccine Program, SAIC Frederick, 1050 Boyles St,Bldg 535,Rm 409,POB B, Ft Detrick, MD 21702 USA. EM whitbyd@mail.nih.gov FU NCI NIH HHS [N01CO12400] NR 10 TC 3 Z9 3 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 MAR 15 PY 2012 VL 205 IS 6 BP 873 EP 874 DI 10.1093/infdis/jir871 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 898FU UT WOS:000300724100003 PM 22301634 ER PT J AU Heegaard, NHH Schetter, AJ Welsh, JA Yoneda, M Bowman, ED Harris, CC AF Heegaard, Niels H. H. Schetter, Aaron J. Welsh, Judith A. Yoneda, Mitsuhiro Bowman, Elise D. Harris, Curtis C. TI Circulating micro-RNA expression profiles in early stage nonsmall cell lung cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE micro-RNA; lung cancer; early detection ID PREDICTS SURVIVAL; TRAIL RESISTANCE; BIOMARKERS; SERUM; PROGNOSIS; DIAGNOSIS; PCR; MICRORNA-223; SIGNATURE; PLATELETS AB Circulating micro-RNA (miR) profiles have been proposed as promising diagnostic and prognostic biomarkers for cancer, including lung cancer. We have developed methods to accurately and reproducibly measure micro-RNA levels in serum and plasma. Here, we study paired serum and plasma samples from 220 patients with early stage nonsmall cell lung cancer (NSCLC) and 220 matched controls. We use qRT-PCR to measure the circulating levels of 30 different miRs that have previously been reported to be differently expressed in lung cancer tissue. Duplicate RNA extractions were performed for 10% of all samples, and micro-RNA measurements were highly correlated among those duplicates. This demonstrates high reproducibility of our assay. The expressions of miR-146b, miR-221, let-7a, miR-155, miR-17-5p, miR-27a and miR-106a were significantly reduced in the serum of NSCLC cases, while miR-29c was significantly increased. No significant differences were observed in plasma of patients compared with controls. Overall, expression levels in serum did not correlate well with levels in plasma. In secondary analyses, reduced plasma expression of let-7b was modestly associated with worse cancer-specific mortality in all patients, and reduced serum expression of miR-223 was modestly associated with cancer-specific mortality in stage IA/B patients. MiR profiles also showed considerable differences comparing African American and European Americans. In summary, we found significant differences in miR expression when comparing cases and controls and find evidence that expression of let-7b is associated with prognosis in NSCLC. C1 [Heegaard, Niels H. H.; Schetter, Aaron J.; Welsh, Judith A.; Yoneda, Mitsuhiro; Bowman, Elise D.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Heegaard, Niels H. H.] Statens Serum Inst, Dept Clin Biochem & Immunol, DK-2300 Copenhagen, Denmark. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Room 3068,Bldg 37,37 Convent Dr, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov FU NIH; Statens Serum Institut FX Grant sponsors: NIH Intramural Program, Statens Serum Institut NR 38 TC 131 Z9 146 U1 5 U2 36 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 MAR 15 PY 2012 VL 130 IS 6 BP 1378 EP 1386 DI 10.1002/ijc.26153 PG 9 WC Oncology SC Oncology GA 878IV UT WOS:000299250700015 PM 21544802 ER PT J AU Kitahara, CM Platz, EA Park, Y Hollenbeck, AR Schatzkin, A de Gonzalez, AB AF Kitahara, Cari M. Platz, Elizabeth A. Park, Yikyung Hollenbeck, Albert R. Schatzkin, Arthur de Gonzalez, Amy Berrington TI Body fat distribution, weight change during adulthood, and thyroid cancer risk in the NIH-AARP Diet and Health Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE thyroid cancer; anthropometry; obesity; prospective study ID MASS INDEX; POOLED ANALYSIS; LARGE COHORT; ANTHROPOMETRIC FACTORS; WAIST CIRCUMFERENCE; NATIONAL-INSTITUTES; PHYSICAL-ACTIVITY; NEW-CALEDONIA; WOMEN; MEN AB Body mass index (BMI) has been positively associated with thyroid cancer risk in several studies, but the underlying mechanisms remain unclear. We examined the associations for waist and hip circumference and weight change during adulthood with thyroid cancer risk among 125,347 men and 72,363 women in the NIH-AARP Diet and Health Study who completed a second mailed questionnaire in 19961997. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated separately by sex and adjusted for race/ethnicity, education and smoking status. During follow-up (median = 10.1 years), 106 men and 105 women were diagnosed with a first primary thyroid cancer, as identified through linkage to state cancer registries. Having a large waist circumference (above the clinical cutpoint for normal: >102 cm in men and >88 cm in women) was associated with increased risk in both men (HR = 1.79, 95% CI: 1.212.63) and women (HR = 1.54, 95% CI: 1.052.26). Having both a large waist and BMI in the obese range (=30 kg/m2) approximately doubled the risk of thyroid cancer (HR in men = 2.13, 95% CI: 1.183.85; HR in women = 1.91, 95% CI: 1.313.25) compared to having a normal waist circumference/normal BMI (18.524.9 kg/m2). We also observed positive association for weight gain between ages 1835 in men (gained =10.0 kg vs. lost/gained <5 kg, HR = 1.49, 95% CI: 0.932.39, p-trend = 0.03), but the association was less pronounced in women. No clear association for weight gain in later life was observed. These results support a potential role for hormonal and metabolic parameters common to central adiposity in thyroid carcinogenesis. C1 [Kitahara, Cari M.] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Kitahara, Cari M.; Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Kitahara, CM (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. EM kitaharac@mail.nih.gov RI Kitahara, Cari/R-8267-2016; OI Park, Yikyung/0000-0002-6281-489X FU National Institutes of Health; National Cancer Institute FX Grant sponsors: Intramural Research Program of the National Institutes of Health and the National Cancer Institute NR 46 TC 19 Z9 20 U1 0 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 MAR 15 PY 2012 VL 130 IS 6 BP 1411 EP 1419 DI 10.1002/ijc.26161 PG 9 WC Oncology SC Oncology GA 878IV UT WOS:000299250700019 PM 21544808 ER PT J AU de Filippis, I de Lemos, APS Hostetler, JB Wollenberg, K Sacchi, CT Harrison, LH Bash, MC Prevots, DR AF de Filippis, Ivano de Lemos, Ana Paula S. Hostetler, Jessica B. Wollenberg, Kurt Sacchi, Claudio T. Harrison, Lee H. Bash, Margaret C. Prevots, D. Rebecca TI Molecular Epidemiology of Neisseria meningitidis Serogroup B in Brazil SO PLOS ONE LA English DT Article ID MENINGOCOCCAL DISEASE; FACTOR-H; VACCINE CANDIDATE; SAO-PAULO; PROTEIN; DIVERSITY; STRAINS; NADA; PORA; IDENTIFICATION AB Background: Neisseria meningitidis serogroup B has been predominant in Brazil, but no broadly effective vaccine is available to prevent endemic meningococcal disease. To understand genetic diversity among serogroup B strains in Brazil, we selected a nationally representative sample of clinical disease isolates from 2004, and a temporally representative sample for the state of Sao Paulo (1988-2006) for study (n = 372). Methods: We performed multi-locus sequence typing (MLST) and sequence analysis of five outer membrane protein (OMP) genes, including novel vaccine targets fHbp and nadA. Results: In 2004, strain B:4:P1.15,19 clonal complex ST-32/ET-5 (cc32) predominated throughout Brazil; regional variation in MLST sequence type (ST), fetA, and porB was significant but diversity was limited for nadA and fHbp. Between 1988 and 1996, the Sao Paulo isolates shifted from clonal complex ST-41/44/Lineage 3 (cc41/44) to cc32. OMP variation was associated with but not predicted by cc or ST. Overall, fHbp variant 1/subfamily B was present in 80% of isolates and showed little diversity. The majority of nadA were similar to reference allele 1. Conclusions: A predominant serogroup B lineage has circulated in Brazil for over a decade with significant regional and temporal diversity in ST, fetA, and porB, but not in nadA and fHbp. C1 [de Filippis, Ivano] Oswaldo Cruz Fdn FIOCRUZ, Natl Qual Control Inst INCQS, Rio De Janeiro, Brazil. [de Filippis, Ivano; Bash, Margaret C.] US FDA, Lab Bacterial Polysaccharides, CBER, Bethesda, MD 20014 USA. [de Filippis, Ivano; Prevots, D. Rebecca] NIAID, Epidemiol Unit, Lab Clin Infect Dis, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [de Lemos, Ana Paula S.] IAL, Dept Bacteriol, Sao Paulo, Brazil. [Hostetler, Jessica B.] JCVI, Rockville, MD USA. [Wollenberg, Kurt] NIAID, Off Cyberinfrastruct & Computat Biol OCICB, NIH, Bethesda, MD 20892 USA. [Sacchi, Claudio T.] Inst Adolfo Lutz Registro, Dept Immunol, Sao Paulo, Brazil. [Harrison, Lee H.] Univ Pittsburgh, Infect Dis Epidemiol Res Unit, Pittsburgh, PA USA. RP de Filippis, I (reprint author), Oswaldo Cruz Fdn FIOCRUZ, Natl Qual Control Inst INCQS, Rio De Janeiro, Brazil. EM rprevots@niaid.nih.gov FU Division of Intramural Research; Office of Global Research; National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH) [N01-AI30071]; Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA); NIAID [K24 AI52788]; Fogarty International Center, NIH [D43TW006592]; Fundacao de Amparo a Pesquisa (FAPESP) [07/00462-3]; Sanofi Pasteur; Novartis; Merck; Wyeth; GlaxoSmithKline FX This work was supported by the Division of Intramural Research, and the Office of Global Research, the National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH); the Center for Biologics Evaluation and Research (CBER), Food and Drug Administration (FDA); a career development award to Dr. Harrison, NIAID (K24 AI52788); a Fogarty International Center Global Infectious Diseases Research Training Program grant, NIH, to the University of Pittsburgh (D43TW006592); and by a grant from the Fundacao de Amparo a Pesquisa (FAPESP), to Sao Paulo, Brazil (07/00462-3). Microbial sequencing was supported through a contract to the J. Craig Venter Institute (N01-AI30071) from NIAID, NIH. Ivano de Filippis was a postdoctoral fellow at the NIH and FDA at the time this work was conducted. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Dr. Harrison receives research funding from Sanofi Pasteur; he has received consulting fees and speaking honoraria from Sanofi Pasteur, Novartis, Merck, Wyeth, and GlaxoSmithKline. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. None of the other authors have competing interests. NR 39 TC 14 Z9 14 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 MAR 14 PY 2012 VL 7 IS 3 AR e33016 DI 10.1371/journal.pone.0033016 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 931EO UT WOS:000303198600037 PM 22431994 ER PT J AU Yang, HT Ko, MSH AF Yang, Hsih-Te Ko, Minoru S. H. TI Stochastic Modeling for the Expression of a Gene Regulated by Competing Transcription Factors SO PLOS ONE LA English DT Article ID POSITIVE FEEDBACK; ESCHERICHIA-COLI; CELL FATE; NOISE; INDUCTION; MOLECULE; KINETICS; BINARY; SWITCH; LEVEL AB It is widely accepted that gene expression regulation is a stochastic event. The common approach for its computer simulation requires detailed information on the interactions of individual molecules, which is often not available for the analyses of biological experiments. As an alternative approach, we employed a more intuitive model to simulate the experimental result, the Markov-chain model, in which a gene is regulated by activators and repressors, which bind the same site in a mutually exclusive manner. Our stochastic simulation in the presence of both activators and repressors predicted a Hill-coefficient of the dose-response curve closer to the experimentally observed value than the calculated value based on the simple additive effects of activators alone and repressors alone. The simulation also reproduced the heterogeneity of gene expression levels among individual cells observed by Fluorescence Activated Cell Sorting analysis. Therefore, our approach may help to apply stochastic simulations to broader experimental data. C1 [Yang, Hsih-Te; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Yang, HT (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. EM ko.minoru1@gmail.com RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU National Institutes of Health (NIA) FX This work was supported entirely by the Intramural Program of the National Institutes of Health (NIA). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 2 Z9 2 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 MAR 14 PY 2012 VL 7 IS 3 AR e32376 DI 10.1371/journal.pone.0032376 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 931EO UT WOS:000303198600016 PM 22431973 ER PT J AU Tsukiyama, T Yamaguchi, TP AF Tsukiyama, Tadasuke Yamaguchi, Terry P. TI Mice lacking Wnt2b are viable and display a postnatal olfactory bulb phenotype SO NEUROSCIENCE LETTERS LA English DT Article DE Wnt; Embryogenesis; Brain; Redundancy; Olfactory bulb ID PROGENITOR CELLS; CEREBRAL-CORTEX; EXPRESSION; GENES; MOUSE; DIFFERENTIATION; IDENTIFICATION; INDUCTION; PROTEINS; EMBRYOS AB Wnts are secreted glycoproteins that play important roles in embryonic development. Wnt2b is transiently expressed in the primitive streak (PS) during gastrulation and in several organs during organogenesis. To determine the biological function of Wnt2b during mouse development, we established a conditional null allele of Wnt2b. Mice lacking Wnt2b were viable, fertile, and displayed a normal life span, however, the olfactory bulb in adult Wnt2b mutant mice was significantly reduced in length. Our results suggest that Wnt2b primarily plays a supportive role in gastrulation and organogenesis, functioning redundantly with canonical Wnts, such as Wnt2, in numerous tissues. (C) 2012 Elsevier Ireland Ltd. All rights reserved. C1 [Tsukiyama, Tadasuke] Hokkaido Univ, Dept Biochem, Grad Sch Med, Kita Ku, Sapporo, Hokkaido 0608638, Japan. [Tsukiyama, Tadasuke; Yamaguchi, Terry P.] NCI, Ctr Canc Res, Canc & Dev Biol Lab, Cell Signaling Vertebrate Dev Sect,NIH, Frederick, MD 21702 USA. RP Tsukiyama, T (reprint author), Hokkaido Univ, Dept Biochem, Grad Sch Med, Kita Ku, N15,W7, Sapporo, Hokkaido 0608638, Japan. EM tsukit@med.hokudai.ac.jp RI Tsukiyama, Tadasuke/D-7589-2012 FU NIH, National Cancer Institute, Center for Cancer Research [Z01 BC010345-08, Z01 BC010841-01]; JSPS at NIH [70216] FX We thank Kristin K. Bins for laboratory management, Cheri A. Rhoderick for administrative assistance and Dr. Sawamoto for comments on the manuscript. We also thank Serguei Kozlov and Jaime Greear for embryonic engineering and maintenance of mice. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research Z01 BC010345-08 and Z01 BC010841-01 (to T. P. Y.) and by a JSPS Research Fellowship for Japanese Biomedical and Behavioral Researchers at NIH 70216 (to T. T.). NR 28 TC 11 Z9 11 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 14 PY 2012 VL 512 IS 1 BP 48 EP 52 DI 10.1016/j.neulet.2012.01.062 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 921XX UT WOS:000302512500010 PM 22326927 ER PT J AU Zhu, JQ Choi, WS McCoy, JG Negri, A Zhu, JH Naini, S Li, JH Shen, M Huang, WW Bougie, D Rasmussen, M Aster, R Thomas, CJ Filizola, M Springer, TA Coller, BS AF Zhu, Jieqing Choi, Won-Seok McCoy, Joshua G. Negri, Ana Zhu, Jianghai Naini, Sarasija Li, Jihong Shen, Min Huang, Wenwei Bougie, Daniel Rasmussen, Mark Aster, Richard Thomas, Craig J. Filizola, Marta Springer, Timothy A. Coller, Barry S. TI Structure-Guided Design of a High-Affinity Platelet Integrin alpha(IIb)beta(3) Receptor Antagonist That Disrupts Mg2+ Binding to the MIDAS SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID EPTIFIBATIDE-INDUCED THROMBOCYTOPENIA; GLYCOPROTEIN IIB/IIIA ANTAGONISTS; ACUTE MYOCARDIAL-INFARCTION; GPIIB/IIIA ANTAGONISTS; CONFORMATIONAL-CHANGES; FIBRINOGEN BINDING; PRIMARY PCI; IIB-IIIA; RECOGNITION; ACTIVATION AB An integrin found on platelets, alpha(IIb)beta(3) mediates platelet aggregation, and alpha(IIb)beta(3) antagonists are effective antithrombotic agents in the clinic. Ligands bind to integrins in part by coordinating a magnesium ion (Mg2+) located in the beta subunit metal ion-dependent adhesion site (MIDAS). Drugs patterned on the integrin ligand sequence Arg-Gly-Asp have a basic moiety that binds the alpha(IIb) subunit and a carboxyl group that coordinates the MIDAS Mg2+ in the beta(3) subunits. They induce conformational changes in the beta(3) subunit that may have negative consequences such as exposing previously hidden epitopes and inducing the active conformation of the receptor. We recently reported an inhibitor of alpha(IIb)beta(3) (RUC-1) that binds exclusively to the alpha(IIb) subunit; here, we report the structure-based design and synthesis of RUC-2, a RUC-1 derivative with a similar to 100-fold higher affinity. RUC-2 does not induce major conformational changes in beta(3) as judged by monoclonal antibody binding, light scattering, gel chromatography, electron microscopy, and a receptor priming assay. X-ray crystallography of the RUC-2-alpha(IIb)beta(3) headpiece complex in 1 mM calcium ion (Ca2+)/5 mM Mg2+ at 2.6 angstrom revealed that RUC-2 binds to aIIb the way RUC-1 does, but in addition, it binds to the beta(3) MIDAS residue glutamic acid 220, thus displacing Mg2+ from the MIDAS. When the Mg2+ concentration was increased to 20 mM, however, Mg2+ was identified in the MIDAS and RUC-2 was absent. RUC-2's ability to inhibit ligand binding and platelet aggregation was diminished by increasing the Mg2+ concentration. Thus, RUC-2 inhibits ligand binding by a mechanism different from that of all other alpha(IIb)beta(3) antagonists and may offer advantages as a therapeutic agent. C1 [Choi, Won-Seok; Naini, Sarasija; Li, Jihong; Coller, Barry S.] Rockefeller Univ, Lab Blood & Vasc Biol, New York, NY 10065 USA. [Zhu, Jieqing; Zhu, Jianghai; Springer, Timothy A.] Harvard Univ, Sch Med, Childrens Hosp Boston, Immune Dis Inst, Boston, MA 02115 USA. [Zhu, Jieqing; Zhu, Jianghai; Springer, Timothy A.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Zhu, Jieqing; Bougie, Daniel; Rasmussen, Mark; Aster, Richard] Med Coll Wisconsin, BloodCtr Wisconsin, Milwaukee, WI 53201 USA. [McCoy, Joshua G.; Shen, Min; Huang, Wenwei; Thomas, Craig J.] NIH, NIH Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Negri, Ana; Filizola, Marta] Mt Sinai Sch Med, Dept Struct & Chem Biol, New York, NY 10029 USA. RP Coller, BS (reprint author), Rockefeller Univ, Lab Blood & Vasc Biol, New York, NY 10065 USA. EM collerb@rockefeller.edu FU National Heart, Lung, and Blood Institute [HL19278, HL13629, HL48675]; National Center for Research Resources, NIH [ULRR024143]; Molecular Libraries Initiative of the NIH Roadmap for Medical Research; National Human Genome Research Institute; Stony Brook University; National Research Foundation of Korea; Korean Government [NRF-2009-352-E00042]; NSF by Texas Advanced Computing Center [TG-MCB080109N] FX Funding: Supported, in part, by grants HL19278, HL13629, and HL48675 from the National Heart, Lung, and Blood Institute; Clinical and Translational Science Award grant ULRR024143 from the National Center for Research Resources, NIH; the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute; funds from Stony Brook University; and the National Research Foundation of Korea Grant funded by the Korean Government (NRF-2009-352-E00042). The computations were supported in part by the NSF through TeraGrid advanced computing resources provided by Texas Advanced Computing Center under grant TG-MCB080109N (principal investigator: M.F.). NR 54 TC 11 Z9 11 U1 2 U2 20 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 MAR 14 PY 2012 VL 4 IS 125 AR 125ra32 DI 10.1126/scitranslmed.3003576 PG 13 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 909BY UT WOS:000301538300007 PM 22422993 ER PT J AU Chan, T Back, TC Subleski, JJ Weiss, JM Ortaldo, JR Wiltrout, RH AF Chan, Tim Back, Timothy C. Subleski, Jeffrey J. Weiss, Jonathan M. Ortaldo, John R. Wiltrout, Robert H. TI Systemic IL-12 Administration Alters Hepatic Dendritic Cell Stimulation Capabilities SO PLOS ONE LA English DT Article ID CD8(+) T-CELLS; IN-VIVO; IMMUNE-RESPONSES; NK CELLS; ANTITUMOR IMMUNITY; ADAPTIVE IMMUNITY; NATURAL-KILLER; MOUSE-LIVER; GM-CSF; INTERLEUKIN-12 AB The liver is an immunologically unique organ containing tolerogenic dendritic cells (DC) that maintain an immunosuppressive microenvironment. Although systemic IL-12 administration can improve responses to tumors, the effects of IL-12-based treatments on DC, in particular hepatic DC, remain incompletely understood. In this study, we demonstrate systemic IL-12 administration induces a 2-3 fold increase in conventional, but not plasmacytoid, DC subsets in the liver. Following IL-12 administration, hepatic DC became more phenotypically and functionally mature, resembling the function of splenic DC, but differed as compared to their splenic counterparts in the production of IL-12 following co-stimulation with toll-like receptor (TLR) agonists. Hepatic DCs from IL-12 treated mice acquired enhanced T cell proliferative capabilities similar to levels observed using splenic DCs. Furthermore, IL-12 administration preferentially increased hepatic T cell activation and IFN gamma expression in the RENCA mouse model of renal cell carcinoma. Collectively, the data shows systemic IL-12 administration enables hepatic DCs to overcome at least some aspects of the inherently suppressive milieu of the hepatic environment that could have important implications for the design of IL-12-based immunotherapeutic strategies targeting hepatic malignancies and infections. C1 [Chan, Tim; Back, Timothy C.; Subleski, Jeffrey J.; Weiss, Jonathan M.; Ortaldo, John R.; Wiltrout, Robert H.] Natl Canc Inst, Natl Inst Hlth, Expt Immunol Lab, Canc & Inflammat Program,Ctr Canc Res, Frederick, MD 21702 USA. RP Wiltrout, RH (reprint author), Natl Canc Inst, Natl Inst Hlth, Expt Immunol Lab, Canc & Inflammat Program,Ctr Canc Res, Frederick, MD 21702 USA. EM wiltrour@mail.nih.gov FU National Cancer Institute, National Institutes of Health (NCI/NIH) FX This work was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health (NCI/NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 2 Z9 3 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 MAR 13 PY 2012 VL 7 IS 3 AR e33303 DI 10.1371/journal.pone.0033303 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 930IA UT WOS:000303129700049 PM 22428016 ER PT J AU Weinrich, M Nanda, H Worcester, DL Majkrzak, CF Maranville, BB Bezrukov, SM AF Weinrich, Michael Nanda, Hirsh Worcester, David L. Majkrzak, Charles F. Maranville, Brian B. Bezrukov, Sergey M. TI Halothane Changes the Domain Structure of a Binary Lipid Membrane SO LANGMUIR LA English DT Article ID X-RAY-SCATTERING; GENERAL-ANESTHESIA; GRAMICIDIN CHANNELS; MODEL MEMBRANE; PACKING STRESS; PHASE-DIAGRAM; HIGH-PRESSURE; BILAYERS; MIXTURES; ANGLE AB X-ray and neutron diffraction studies of a binary lipid membrane demonstrate that halothane at physiological concentrations produces a pronounced redistribution of lipids between domains of different lipid types identified by different lamellar d-spacings and isotope composition. In contrast, dichlorohexafluorocyclobutane (F6), a halogenated nonanesthetic, does not produce such significant effects. These findings demonstrate a specific effect of inhalational anesthetics on mixing phase equilibria of a lipid mixture. C1 [Weinrich, Michael] Eunice Kennedy Shriver Inst Child Hlth & Human De, Natl Ctr Med Rehabil Res, Bethesda, MD USA. [Bezrukov, Sergey M.] Eunice Kennedy Shriver Inst Child Hlth & Human De, Sect Mol Transport, Program Phys Biol, Bethesda, MD USA. [Nanda, Hirsh; Worcester, David L.; Majkrzak, Charles F.; Maranville, Brian B.] NIST, Ctr Neutron Res, Gaithersburg, MD 20899 USA. [Worcester, David L.] Univ Calif Irvine, Dept Physiol & Biophys, Irvine, CA 92717 USA. [Worcester, David L.] Univ Missouri, Div Biol, Columbia, MO USA. RP Weinrich, M (reprint author), Eunice Kennedy Shriver Inst Child Hlth & Human De, Natl Ctr Med Rehabil Res, Bethesda, MD USA. EM Mw287k@nih.gov FU NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development; U.S. National Institute of Health [GM86685] FX We thank Jens Lundbaek and Horia Petrache for fruitful discussions, and David Sandstrom for the generous use of his gas chromatograph. This study was supported by the NIH Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development. D.W. was supported by U.S. National Institute of Health Grant GM86685 (to Stephen H. White). The Center for Neutron Research provided facilities for neutron and X-ray diffraction. We thank Taner Yildirim and Jason Simmons for assistance with X-ray measurements. The identification of any commercial product or trade name does not imply any endorsement or recommendation by the National Institute of Standards and Technology. NR 47 TC 17 Z9 17 U1 2 U2 22 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD MAR 13 PY 2012 VL 28 IS 10 BP 4723 EP 4728 DI 10.1021/la204317k PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 907DD UT WOS:000301397100016 PM 22352350 ER PT J AU Finkel, T AF Finkel, Toren TI From Sulfenylation to Sulfhydration: What a Thiolate Needs to Tolerate SO SCIENCE SIGNALING LA English DT Article ID TYROSINE-PHOSPHATASE 1B; ENDOPLASMIC-RETICULUM STRESS; HYDROGEN-PEROXIDE; SIGNAL-TRANSDUCTION; OXIDATION; H2S; INACTIVATION; VASORELAXANT; GENERATION; CYSTEINE AB There is a growing appreciation that oxidants such as hydrogen peroxide (H2O2) and gasses such as nitric oxide (NO) and hydrogen sulfide (H2S) can act as modulators of various signaling pathways. Much of this signaling occurs through the modifications of specific, critical cysteine residues in target proteins. How such small diffusible molecules (H2O2, NO, H2S) can achieve the required specificity is incompletely understood. Now, new findings provide considerable insight into these and related questions. C1 NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10,CRC 5-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU NIH FX I am grateful to members of my laboratory for helpful suggestions and to I. Rovira for assistance with the manuscript. Funding: This work was supported by NIH Intramural funds. NR 28 TC 43 Z9 43 U1 0 U2 9 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 13 PY 2012 VL 5 IS 215 AR pe10 DI 10.1126/scisignal.2002943 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 907XG UT WOS:000301452300003 PM 22416275 ER PT J AU Techtmann, SM Ghirlando, R Kao, S Strebel, K Maynard, EL AF Techtmann, Stephen M. Ghirlando, Rodolfo Kao, Sandra Strebel, Klaus Maynard, Ernest L. TI Hydrodynamic and Functional Analysis of HIV-1 Vif Oligomerization SO BIOCHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; E3 UBIQUITIN LIGASE; PROTEIN SECONDARY STRUCTURE; DICHROISM SPECTROSCOPIC DATA; TYPE-1 VIF; CIRCULAR-DICHROISM; HUMAN APOBEC3G; SOCS-BOX; SEDIMENTATION-VELOCITY; VIRAL INFECTIVITY AB HIV-1 Vif is an accessory protein that induces the proteasomal degradation of the host restriction factor, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G). The N-terminal half of Vif binds to APOBEC3G, and the C-terminal half binds to subunits of a cullin 5-based ubiquitin ligase. This Vif-directed ubiquitin ligase induces the degradation of APOBEC3G (a cytidine deaminase) and thereby protects the viral genome from mutation. A conserved PPLP motif near the C-terminus of Vif is essential for Vif function and is also involved in Vif oligomerization. However, the mechanism and functional significance of Vif oligomerization is unclear. We employed analytical ultracentrifugation to examine the oligomeric properties of Vif in solution. Contrary to previous reports, we find that Vif oligomerization does not require the conserved PPLP motif Instead, our data suggest a more complex mechanism involving interactions among the HCCH motif, the BC box, and downstream residues in Vif Mutation of residues near the PPLP motif (S165 and V166) affected the oligomeric properties of Vif and weakened the ability of Vif to bind and induce the degradation of APOBEC3G. We propose that Vif oligomerization may represent a mechanism for regulating interactions with APOBEC3G. C1 [Techtmann, Stephen M.; Maynard, Ernest L.] Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Kao, Sandra; Strebel, Klaus] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Maynard, EL (reprint author), Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, Bethesda, MD 20814 USA. EM emaynard@usuhs.mil FU Edward Mallinckrodt Jr. Foundation; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Edward Mallinckrodt Jr. Foundation (E.L.M. and S.M.T.), the National Institutes of Health Intramural Research Programs of the National Institute of Allergy and Infectious Diseases (K.S. and S.K.), and the National Institute of Diabetes and Digestive and Kidney Diseases (R.G.). NR 69 TC 8 Z9 8 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 13 PY 2012 VL 51 IS 10 BP 2078 EP 2086 DI 10.1021/bi201738a PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 907DM UT WOS:000301398000006 PM 22369580 ER PT J AU Bambha, K Pierce, C Cox, C French, AL Tien, PC Sharp, GB Augenbraun, M Glesby, MJ Villacres, MC Plankey, M Strickler, HD Gange, SJ Peters, MG AF Bambha, Kiran Pierce, Christopher Cox, Christopher French, Audrey L. Tien, Phyllis C. Sharp, Gerald B. Augenbraun, Michael Glesby, Marshall J. Villacres, Maria C. Plankey, Michael Strickler, Howard D. Gange, Stephen J. Peters, Marion G. TI Assessing mortality in women with hepatitis C virus and HIV using indirect markers of fibrosis SO AIDS LA English DT Article DE fibrosis markers; hepatitis C virus; HIV; longitudinal study; mortality ID HUMAN-IMMUNODEFICIENCY-VIRUS; SIMPLE NONINVASIVE INDEX; LIVER FIBROSIS; ANTIRETROVIRAL THERAPY; COINFECTED PATIENTS; VIRAL-HEPATITIS; INFECTION; VARIABILITY; PROGRESSION; PREDICTION AB Objective: Co-infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality in HIV-infected individuals. However, predictors of mortality are poorly defined and most studies have focused predominantly on co-infection in men. We evaluated whether two indirect markers of hepatic fibrosis, aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 scores, were predictive of mortality in a well defined longitudinal cohort of HCV/HIV-co-infected women on HAART. Methods: HCV/HIV-co-infected women on antiretroviral therapy enrolled in Women's Interagency HIV Study (WIHS), a National Institutes of Health-funded prospective, multicenter, cohort study of women with and at risk for HIV infection were included. Using Cox regression analysis, associations between APRI and FIB-4 with all-cause mortality were assessed. Results: Four hundred and fifty HCV/HIV-co-infected women, of whom 191 women died, had a median follow-up of 6.6 years and 5739 WIHS visits. Compared with women with low APRI or FIB-4 levels, severe fibrosis was significantly associated with an increased risk of all-cause mortality {APRI: hazard ratio 2.78 [95% confidence interval (CI) 1.87, 4.12]; FIB-4: hazard ratio 2.58 (95% CI 1.68, 3.95)}. Crude death rates per 1000 patient-years increased with increasing liver fibrosis: 34.8 for mild, 51.3 for moderate and 167.9 for severe fibrosis as measured by FIB-4. Importantly, both APRI and FIB-4 increased during the 5 years prior to death for all women: the slope of increase was greater for women dying a liver-related death compared with nonliver-related death. Conclusion: Both APRI and FIB-4 are independently associated with all-cause mortality in HCV/HIV-co-infected women and may have clinical prognostic utility among women with HIV and HCV. (C) 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Peters, Marion G.] Univ Calif San Francisco, Div Gastroenterol, San Francisco, CA 94143 USA. [Pierce, Christopher; Cox, Christopher; Gange, Stephen J.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [French, Audrey L.] Stroger Hosp, CORE Ctr, Chicago, IL USA. [Sharp, Gerald B.] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Augenbraun, Michael] Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. [Glesby, Marshall J.] Weill Cornell Med Coll, New York, NY USA. [Villacres, Maria C.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Plankey, Michael] Georgetown Univ, Sch Med, Washington, DC USA. [Tien, Phyllis C.] Dept Vet Affairs Med Ctr, San Francisco, CA USA. [Strickler, Howard D.] Albert Einstein Coll Med, New York, NY USA. RP Peters, MG (reprint author), Univ Calif San Francisco, Div Gastroenterol, 513 Parnassus Ave,Box 0538,Room S-357, San Francisco, CA 94143 USA. EM marion.peters@ucsf.edu OI Gange, Stephen/0000-0001-7842-512X FU National Institute of Allergy and Infectious Diseases [UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, UO1-AI-42590]; National Institute of Child Health and Human Development [UO1-HD-32632]; National Cancer Institute; National Institute on Drug Abuse; National Institute on Deafness and Other Communication Disorders; NIAID [R21 A1088361, K23 66943] FX The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and by the National Institute of Child Health and Human Development (UO1-HD-32632). The study is co-funded by the National Cancer Institute, the National Institute on Drug Abuse and the National Institute on Deafness and Other Communication Disorders.; M.P. is supported by NIAID R21 A1088361. P.C.T. is supported by NIAID K23 66943 and this work is supported with resources and the use of facilities at the San Francisco CA Veterans Affairs Medical Center. NR 25 TC 24 Z9 24 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 13 PY 2012 VL 26 IS 5 BP 599 EP 607 DI 10.1097/QAD.0b013e32834fa121 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 906GN UT WOS:000301333000009 PM 22156972 ER PT J AU Uthman, O Mofenson, LM Nachega, JB AF Uthman, Olalekan Mofenson, Lynne M. Nachega, Jean B. TI Safety and effectiveness of efavirenz versus nevirapine-based regimens in resource-limited settings: evidence, clinical practice and modelling projections SO AIDS LA English DT Editorial Material DE efavirenz; effectiveness; modelling; nevirapine; safety; sub-Saharan Africa ID VIROLOGICAL OUTCOMES; HIV; METAANALYSIS; PREGNANCY; THERAPY; TRIAL C1 [Uthman, Olalekan] Keele Univ, Fac Hlth Sci, Dept Primary Care Sci, Keele, Staffs, England. [Uthman, Olalekan] Univ Ilorin, Dept Community Hlth & Epidemiol, Ilorin, Nigeria. [Mofenson, Lynne M.] Ctr Res Mothers & Children, NIH, Bethesda, MD USA. [Mofenson, Lynne M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Nachega, Jean B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Nachega, Jean B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Nachega, Jean B.] Univ Stellenbosch, Dept Med, Cape Town, South Africa. [Nachega, Jean B.] Univ Stellenbosch, Ctr Infect Dis, Cape Town, South Africa. RP Nachega, JB (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Global Dis Epidemiol & Control Program, 615N Wolfe St,Suite W5031, Baltimore, MD 21205 USA. EM jnachega@jhsph.edu OI Mofenson, Lynne/0000-0002-2818-9808; Uthman, Olalekan/0000-0002-8567-3081 FU PHS HHS [T84HA21652-01-00]; Wellcome Trust NR 15 TC 2 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 13 PY 2012 VL 26 IS 5 BP 639 EP 641 DI 10.1097/QAD.0b013e3283509a40 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 906GN UT WOS:000301333000014 PM 22398571 ER PT J AU Kuo, L Freed, EO AF Kuo, Lillian Freed, Eric O. TI ARRDC1 as a mediator of microvesicle budding SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID TRAFFICKING; MACHINERY; RECEPTOR; PROTEIN; COMPLEX C1 [Kuo, Lillian; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM efreed@nih.gov NR 13 TC 5 Z9 5 U1 1 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 MAR 13 PY 2012 VL 109 IS 11 BP 4025 EP 4026 DI 10.1073/pnas.1201441109 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 907OH UT WOS:000301426700010 PM 22378650 ER PT J AU Miao, YL Stein, P Jefferson, WN Padilla-Banks, E Williams, CJ AF Miao, Yi-Liang Stein, Paula Jefferson, Wendy N. Padilla-Banks, Elizabeth Williams, Carmen J. TI Calcium influx-mediated signaling is required for complete mouse egg activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CELL-CYCLE RESUMPTION; CA2+ OSCILLATIONS; FERTILIZATION; PROTEIN; SPERM; ENTRY; STIMULATION; POLYSPERMY; TRANSIENTS; RESPONSES AB Mammalian fertilization is accompanied by oscillations in egg cytoplasmic calcium (Ca2+) concentrations that are critical for completion of egg activation. These oscillations are initiated by Ca2+ release from inositol 1,4,5-trisphosphate (IP3)-sensitive intracellular stores. We tested the hypothesis that Ca2+ influx across the plasma membrane was a requisite component of egg activation signaling, and not simply a Ca2+ source for store repletion. Using intracytoplasmic sperm injection (ICSI) and standard in vitro fertilization (IVF), we found that Ca2+ influx was not required to initiate resumption of meiosis II. However, even if multiple oscillations in intracellular Ca2+ occurred, in the absence of Ca2+ influx, the fertilized eggs failed to emit the second polar body, resulting in formation of three pronuclei. Additional experiments using the Ca2+ chelator, BAPTA/AM, demonstrated that Ca2+ influx is sufficient to support polar body emission and pronucleus formation after only a single sperm-induced Ca2+ transient, whereas BAPTA/AM-treated ICSI or fertilized eggs cultured in Ca2+-free medium remained arrested in metaphase II. Inhibition of store-operated Ca2+ entry had no effect on ICSI-induced egg activation, so Ca2+ influx through alternative channels must participate in egg activation signaling. Ca2+ influx appears to be upstream of CaMKII gamma activity because eggs can be parthenogenetically activated with a constitutively active form of CaMKII gamma in the absence of extracellular Ca2+. These results suggest that Ca2+ influx at fertilization not only maintains Ca2+ oscillations by replenishing Ca2+ stores, but also activates critical signaling pathways upstream of CaMKII gamma that are required for second polar body emission. C1 [Miao, Yi-Liang; Jefferson, Wendy N.; Padilla-Banks, Elizabeth; Williams, Carmen J.] Natl Inst Environm Hlth Sci, Reprod Med Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Stein, Paula] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. RP Williams, CJ (reprint author), Natl Inst Environm Hlth Sci, Reprod Med Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. EM williamsc5@niehs.nih.gov RI Williams, Carmen/E-2170-2013 OI Williams, Carmen/0000-0001-6440-7086 FU National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES102985] FX We thank Jurrien Dean (National Institute of Diabetes and Digestive and Kidney Diseases) for the mZP2 antibody and Glaxo Smith Kline for the gift of Synta66; Jim Putney and Gary Bird (National Institute on Environmental Health Sciences) for critical reading of the manuscript and advice throughout this project; and Grace Kissling (National Institute on Environmental Health Sciences) for assistance with statistical analyses. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, Grant Z01-ES102985. NR 33 TC 50 Z9 50 U1 1 U2 16 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 MAR 13 PY 2012 VL 109 IS 11 BP 4169 EP 4174 DI 10.1073/pnas.1112333109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 907OH UT WOS:000301426700034 PM 22371584 ER PT J AU Baik, S Mbaziira, M Williams, M Ogwang, MD Kinyera, T Emmanuel, B Ziegler, JL Reynolds, SJ Mbulaiteye, SM AF Baik, Sonya Mbaziira, Mike Williams, Makeda Ogwang, Martin D. Kinyera, Tobias Emmanuel, Benjamin Ziegler, John L. Reynolds, Steven J. Mbulaiteye, Sam M. TI A case-control study of Burkitt lymphoma in East Africa: are local health facilities an appropriate source of representative controls? SO INFECTIOUS AGENTS AND CANCER LA English DT Article ID EPSTEIN-BARR-VIRUS; SICKLE-CELL TRAIT; MALARIA; CHILDREN; UGANDA; RISK; ANTIBODIES; DISEASE; GHANA AB Background: We investigated the feasibility and appropriateness of enrolling controls for Burkitt lymphoma (BL) from local health facilities in two regions in Uganda. Methods: BL case data were compiled from two local hospitals with capacity to diagnose and treat BL in Northwest and North-central regions of Uganda during 1997 to 2009. Local health facility data were compiled from children attending four representative local health facilities in the two regions over a two week period in May/June 2010. Age and sex patterns of BL cases and children at local facilities were compared and contrasted using frequency tables. Results: There were 999 BL cases diagnosed in the study area (92% of all BL cases treated at the hospitals): 64% were from North-central and 36% from North-west region. The mean age of BL cases was 7.0 years (standard deviation [SD] 3.0). Boys were younger than girls (6.6 years versus 7.2 years, P = 0.004) and cases from North-central region were younger than cases from North-west region (6.8 years versus 7.3 years, P = 0.014). There were 1012 children recorded at the four local health facilities: 91% at facilities in North-central region and 9% from facilities in North-west region. Daily attendance varied between 1 to 75 children per day. The mean age of children at health facilities was 2.2 years (SD 2.8); it did not differ by sex. Children at North-central region facilities were younger than children at North-west region facilities (1.8 years versus 6.6 years, P < 0.001). Conclusions: While many children attend local health facilities, confirming feasibility of obtaining controls, their mean age is much lower than BL cases. Health facilities may be suitable for obtaining young, but not older, controls. C1 [Baik, Sonya; Ziegler, John L.] UCSF, Global Hlth Sci, San Francisco, CA USA. [Mbaziira, Mike; Ogwang, Martin D.; Kinyera, Tobias] St Marys Hosp Lacor, EMBLEM Study Off, Gulu, Uganda. [Williams, Makeda] NCI, Ctr Global Hlth, Bethesda, MD 20892 USA. [Ogwang, Martin D.] St Marys Hosp Lacor, Dept Surg, Gulu, Uganda. [Emmanuel, Benjamin; Mbulaiteye, Sam M.] NCI, Infect & Immunoepidemiol Branch, Bethesda, MD 20892 USA. [Reynolds, Steven J.] NIAID, NIH, Div Intramural Res, Bethesda, MD 20892 USA. [Mbulaiteye, Sam M.] NCI, NIH, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet,Infect & Immunoepidemi, Rockville, MD 20852 USA. RP Mbulaiteye, SM (reprint author), NCI, Infect & Immunoepidemiol Branch, Bethesda, MD 20892 USA. EM mbulaits@mail.nih.gov FU Intramural Research Program, Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institute of Allergy and Infectious Diseases; National Institutes of Health; Department of Health and Human Services FX Funded by the Intramural Research Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services. We thank the staff of St. Mary's Hospital, Lacor, and Kuluva Hospital, as well the staff at the local health facilities for their cooperation with the study and advice. NR 28 TC 6 Z9 6 U1 2 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1750-9378 J9 INFECT AGENTS CANCER JI Infect. Agents Cancer PD MAR 13 PY 2012 VL 7 AR UNSP 5 DI 10.1186/1750-9378-7-5 PG 6 WC Oncology; Immunology SC Oncology; Immunology GA 241FS UT WOS:000326152400001 PM 22413839 ER PT J AU Crane, DD Scott, DP Bosio, CM AF Crane, Deborah D. Scott, Dana P. Bosio, Catharine M. TI Generation of a Convalescent Model of Virulent Francisella tularensis Infection for Assessment of Host Requirements for Survival of Tularemia SO PLOS ONE LA English DT Article ID LIVE VACCINE STRAIN; LISTERIA-MONOCYTOGENES INFECTION; INNATE IMMUNE-RESPONSE; KNOCK-OUT MICE; T-CELL SUBSETS; IFN-GAMMA; INTRACELLULAR BACTERIUM; AEROSOL INFECTION; DENDRITIC CELLS; RESPIRATORY-INFECTION AB Francisella tularensis is a facultative intracellular bacterium and the causative agent of tularemia. Development of novel vaccines and therapeutics for tularemia has been hampered by the lack of understanding of which immune components are required to survive infection. Defining these requirements for protection against virulent F. tularensis, such as strain SchuS4, has been difficult since experimentally infected animals typically die within 5 days after exposure to as few as 10 bacteria. Such a short mean time to death typically precludes development, and therefore assessment, of immune responses directed against virulent F. tularensis. To enable identification of the components of the immune system that are required for survival of virulent F. tularensis, we developed a convalescent model of tularemia in C57Bl/6 mice using low dose antibiotic therapy in which the host immune response is ultimately responsible for clearance of the bacterium. Using this model we demonstrate alpha bTCR(+) cells, gamma delta TCR+ cells, and B cells are necessary to survive primary SchuS4 infection. Analysis of mice deficient in specific soluble mediators shows that IL-12p40 and IL-12p35 are essential for survival of SchuS4 infection. We also show that IFN-gamma is required for survival of SchuS4 infection since mice lacking IFN-gamma R succumb to disease during the course of antibiotic therapy. Finally, we found that both CD4(+) and CD8(+) cells are the primary producers of IFN-gamma and that gamma delta TCR+ cells and NK cells make a minimal contribution toward production of this cytokine throughout infection. Together these data provide a novel model that identifies key cells and cytokines required for survival or exacerbation of infection with virulent F. tularensis and provides evidence that this model will be a useful tool for better understanding the dynamics of tularemia infection. C1 [Crane, Deborah D.; Bosio, Catharine M.] NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. [Scott, Dana P.] NIAID, Vet Pathol Sect, Rocky Mt Vet Branch, Rocky Mt Labs,NIH, Hamilton, MT USA. RP Crane, DD (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT USA. EM bosioc@niaid.nih.gov RI Bosio, Catharine/D-7456-2015 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 90 TC 19 Z9 19 U1 1 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 MAR 12 PY 2012 VL 7 IS 3 AR e33349 DI 10.1371/journal.pone.0033349 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 920DF UT WOS:000302381500130 PM 22428026 ER PT J AU Lim, S Bae, E Kim, HS Kim, TA Byun, K Kim, B Hong, S Im, JP Yun, C Lee, B Lee, B Park, SH Letterio, J Kim, SJ AF Lim, Seunghwan Bae, Eunjin Kim, Hae-Suk Kim, Tae-Aug Byun, Kyunghee Kim, Byungchul Hong, Suntaek Im, Jong Pil Yun, Chohee Lee, Bona Lee, Bonghee Park, Seok Hee Letterio, John Kim, Seong-Jin TI TRAF6 Mediates IL-1 beta/LPS-Induced Suppression of TGF-beta Signaling through Its Interaction with the Type III TGF-beta Receptor SO PLOS ONE LA English DT Article ID GROWTH-FACTOR-BETA; NF-KAPPA-B; TRANSCRIPTIONAL REGULATION; INDEPENDENT ACTIVATION; HEPATOMA-CELLS; CANCER; GENE; DIFFERENTIATION; POLYMORPHISMS; INFLAMMATION AB Transforming growth factor-beta 1 (TGF-beta 1) is an important anti-inflammatory cytokine that modulates and resolves inflammatory responses. Recent studies have demonstrated that inflammation enhances neoplastic risk and potentiates tumor progression. In the evolution of cancer, pro-inflammatory cytokines such as IL-1 beta must overcome the anti-inflammatory effects of TGF-beta to boost pro-inflammatory responses in epithelial cells. Here we show that IL-1 beta or Lipopolysaccharide (LPS) suppresses TGF-beta-induced anti-inflammatory signaling in a NF-kappa B-independent manner. TRAF6, a key molecule in IL-1 beta signaling, mediates this suppressive effect through interaction with the type III TGF-beta receptor (T beta RIII), which is TGF-beta-dependent and requires type I TGF-beta receptor (T beta RI) kinase activity. T beta RI phosphorylates T beta RIII at residue S829, which promotes the TRAF6/T beta RIII interaction and consequent sequestration of T beta RIII from the T beta RII/T beta RI complex. Our data indicate that IL-1 beta enhances the pro-inflammatory response by suppressing TGF-beta signaling through TRAF6-mediated sequestration of T beta RIII, which may be an important contributor to the early stages of tumor progression. C1 [Lim, Seunghwan; Kim, Hae-Suk; Im, Jong Pil; Yun, Chohee; Lee, Bona; Letterio, John; Kim, Seong-Jin] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Bae, Eunjin; Lee, Bona; Kim, Seong-Jin] CHA Univ, CHA Canc Inst, Seoul, South Korea. [Bae, Eunjin; Byun, Kyunghee; Hong, Suntaek; Lee, Bonghee; Kim, Seong-Jin] Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Songdo, Incheon, South Korea. [Kim, Tae-Aug] NCI, Lab Canc & Stem Cell Biol, Bethesda, MD 20892 USA. [Kim, Byungchul] Kangwon Natl Univ, Coll Nat Sci, Dept Biochem, Chunchon, South Korea. [Im, Jong Pil] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea. [Im, Jong Pil] Seoul Natl Univ, Coll Med, Liver Res Inst, Seoul, South Korea. [Park, Seok Hee] Sungkyunkwan Univ, Dept Mol Biol, Suwon, South Korea. RP Lim, S (reprint author), Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. EM kimsj@cha.ac.kr FU National Research Foundation of Korea [20090081756]; Korea Science and Engineering Foundation (KOSEF) [ROA-2007-000-20047-0] FX This work is supported in part by grants from National Research Foundation of Korea (Bio Technology Research & Development Program 20090081756 to S-JK, SH and SHP) and from Korea Science and Engineering Foundation (KOSEF) (ROA-2007-000-20047-0 to SHP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. NR 34 TC 5 Z9 5 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 MAR 12 PY 2012 VL 7 IS 3 AR e32705 DI 10.1371/journal.pone.0032705 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 920DF UT WOS:000302381500035 PM 22427868 ER PT J AU Simon-Sanchez, J Kilarski, LL Nalls, MA Martinez, M Schulte, C Holmans, P Gasser, T Hardy, J Singleton, AB Wood, NW Brice, A Heutink, P Williams, N Morris, HR AF Simon-Sanchez, Javier Kilarski, Laura L. Nalls, Michael A. Martinez, Maria Schulte, Claudia Holmans, Peter Gasser, Thomas Hardy, John Singleton, Andrew B. Wood, Nicholas W. Brice, Alexis Heutink, Peter Williams, Nigel Morris, Huw R. CA Int Parkinson's Dis Genomics Conso Wellcome Trust Case Control Consor TI Cooperative Genome-Wide Analysis Shows Increased Homozygosity in Early Onset Parkinson's Disease SO PLOS ONE LA English DT Article ID FAMILIAL AGGREGATION; ALZHEIMERS-DISEASE; EXTENDED TRACTS; NO EVIDENCE; ASSOCIATION; MUTATIONS; RUNS; METAANALYSIS; PINK1; LOCI AB Parkinson's disease (PD) occurs in both familial and sporadic forms, and both monogenic and complex genetic factors have been identified. Early onset PD (EOPD) is particularly associated with autosomal recessive (AR) mutations, and three genes, PARK2, PARK7 and PINK1, have been found to carry mutations leading to AR disease. Since mutations in these genes account for less than 10% of EOPD patients, we hypothesized that further recessive genetic factors are involved in this disorder, which may appear in extended runs of homozygosity. We carried out genome wide SNP genotyping to look for extended runs of homozygosity (ROHs) in 1,445 EOPD cases and 6,987 controls. Logistic regression analyses showed an increased level of genomic homozygosity in EOPD cases compared to controls. These differences are larger for ROH of 9 Mb and above, where there is a more than three-fold increase in the proportion of cases carrying a ROH. These differences are not explained by occult recessive mutations at existing loci. Controlling for genome wide homozygosity in logistic regression analyses increased the differences between cases and controls, indicating that in EOPD cases ROHs do not simply relate to genome wide measures of inbreeding. Homozygosity at a locus on chromosome 19p13.3 was identified as being more common in EOPD cases as compared to controls. Sequencing analysis of genes and predicted transcripts within this locus failed to identify a novel mutation causing EOPD in our cohort. There is an increased rate of genome wide homozygosity in EOPD, as measured by an increase in ROHs. These ROHs are a signature of inbreeding and do not necessarily harbour disease-causing genetic variants. Although there might be other regions of interest apart from chromosome 19p13.3, we lack the power to detect them with this analysis. C1 [Simon-Sanchez, Javier; Heutink, Peter] Vrije Univ Amsterdam, Sect Med Genom, Dept Clin Genet, Med Ctr, Amsterdam, Netherlands. [Kilarski, Laura L.; Holmans, Peter; Williams, Nigel; Morris, Huw R.; Wellcome Trust Case Control Consor] Cardiff Univ, Sch Med, MRC Ctr Neuropsychiat Genet & Genom, Cardiff, S Glam, Wales. [Nalls, Michael A.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Martinez, Maria] Fac Med Toulouse, INSERM, UMR 1043, F-31073 Toulouse, France. [Martinez, Maria] Univ Toulouse 3, F-31062 Toulouse, France. [Kilarski, Laura L.; Holmans, Peter; Williams, Nigel; Morris, Huw R.] Cardiff Univ, Sch Med, Dept Psychol Med & Neurol, Cardiff, S Glam, Wales. [Schulte, Claudia; Gasser, Thomas] German Ctr Neurodegenerat Dis, Hertie Inst Clin Brain Res, Dept Neurodegenerat Dis, Tubingen, Germany. [Schulte, Claudia; Gasser, Thomas] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany. [Hardy, John; Wood, Nicholas W.] UCL Inst Neurol, Dept Mol Neurosci, London, England. [Brice, Alexis] Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, Paris, France. [Brice, Alexis] INSERM, U975, Paris, France. [Brice, Alexis] CNRS, UMR 7225, Paris, France. RP Simon-Sanchez, J (reprint author), Vrije Univ Amsterdam, Sect Med Genom, Dept Clin Genet, Med Ctr, Amsterdam, Netherlands. EM williamsnm@cf.ac.uk; morrishr@cf.ac.uk RI Hardy, John/C-2451-2009; Morris, Huw/B-8527-2008; Singleton, Andrew/C-3010-2009; Traynor, Bryan/G-5690-2010; Holmans, Peter/F-4518-2015; Martinez, Maria/B-3111-2013; Wood, Nicholas/C-2505-2009; OI Morris, Huw/0000-0002-5473-3774; Holmans, Peter/0000-0003-0870-9412; Martinez, Maria/0000-0003-2180-4537; Wood, Nicholas/0000-0002-9500-3348; Schulte, Claudia/0000-0003-4006-1265; Kilarski, Laura/0000-0003-0645-3134 FU Medical Research Council UK [G0700943]; Parkinson's UK [8047, J-0804]; National Institute on Aging; Wellcome Trust/MRC [WT089698]; Department of Health NIHR Biomedical Research Centre; Wellcome Trust [085475/B/08/Z, 085475/Z/08/Z, 068545/Z/02]; Medical Research Council [G0000934]; Hersenstichting Nederland; Neuroscience Campus Amsterdam; Prinses Beatrix Fonds; Forschungszentrum fur Umwelt und Gesundheit (GSF); German Federal Ministry of Education, Science, Research and Technology; State of Bavaria; German National Genome Network (NGFNplus; German Ministry for Education and Research) [01GS08134]; German Ministry for Education and Research; German Federal Ministry of Education and Research (BMBF) NGFN [01GR0468]; ERA-Net NEURON [01GW0908]; Helmholtz Alliance Mental Health in an Ageing Society (HelMA) [HA-215]; Helmholtz Association FX This work was supported by the Medical Research Council UK (G0700943) and Parkinson's UK (Grant 8047 and J-0804). This work was supported in part by the Intramural Research Programs of the National Institute on Aging and the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services; project number Z01 AG000949-05. This work was supported in part by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium whose members are from the UCL/Institute of Neurology, the University of Sheffield and the MRC Protein Phosphorylation Unit at the University of Dundee. Additionally, part of the study was undertaken at UCLH/UCL using funding through a Department of Health NIHR Biomedical Research Centre. We used genome-wide association data generated by the Wellcome Trust Case-Control Consortium 2 (WTCCC2) from UK patients with Parkinson's disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. The WTCCC2 project was funded by the Wellcome Trust (085475/B/08/Z and 085475/Z/08/Z); the authors acknowledge use of the British 1958 Birth Cohort DNA collection funded by the Medical Research Council (G0000934) and the Wellcome Trust (068545/Z/02), and of the UK National Blood Service controls funded by the Wellcome Trust. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland (http://biowulf.nih.gov). The authors also want to thank the Hersenstichting Nederland (http://www.hersenstichting.nl), the Neuroscience Campus Amsterdam, and the Prinses Beatrix Fonds (http://www.prinsesbeatrixfonds.nl) for sponsoring this work. The KORA research platform (KORA: Cooperative Research in the Region of Augsburg; http://www.gsf.de/KORA) was initiated and financed by the Forschungszentrum fur Umwelt und Gesundheit (GSF), which is funded by the German Federal Ministry of Education, Science, Research and Technology and by the State of Bavaria. The study was additionally funded by the German National Genome Network (NGFNplus #01GS08134; German Ministry for Education and Research), and by the German Federal Ministry of Education and Research (BMBF) NGFN (01GR0468), and in the frame of ERA-Net NEURON (01GW0908). This work was also supported by the Helmholtz Alliance Mental Health in an Ageing Society (HelMA, HA-215) funded by the Initiative and Networking Fund of the Helmholtz Association. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 12 Z9 12 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 MAR 12 PY 2012 VL 7 IS 3 AR e28787 DI 10.1371/journal.pone.0028787 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 920DF UT WOS:000302381500001 PM 22427796 ER PT J AU Luo, JH Rossouw, J Tong, E Giovino, GA Lee, C Chen, C Ockene, JK Qi, LH Margolis, KL AF Luo, Juhua Rossouw, Jacques Tong, Elisa Giovino, Gary A. Lee, Cathy Chen, Chu Ockene, Judith K. Qi, Lihong Margolis, Karen L. TI Smoking Cessation, Weight Gain, and Risk of Type 2 Diabetes Mellitus Among Postmenopausal Women SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID METAANALYSIS; COHORT C1 [Luo, Juhua] W Virginia Univ, Dept Community Med, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. [Rossouw, Jacques] NHLBI, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Tong, Elisa] Univ Calif, Davis Med Ctr, Div Gen Internal Med, Sacramento, CA USA. [Giovino, Gary A.] SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Dept Community Hlth & Hlth Behav, Buffalo, NY 14260 USA. [Lee, Cathy] Univ Calif Los Angeles, David Geffen Sch Med, Dept Internal Med, Div Geriatr, Los Angeles, CA 90095 USA. [Lee, Cathy] Vet Affairs Greater Los Angeles Healthcare Syst, Ctr Geriatr Res Educ & Clin, Los Angeles, CA USA. [Chen, Chu] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Ockene, Judith K.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Qi, Lihong] Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Margolis, Karen L.] HealthPartners Res Fdn, Minneapolis, MN USA. RP Luo, JH (reprint author), W Virginia Univ, Dept Community Med, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. EM Jiluo@hsc.wvu.edu NR 9 TC 10 Z9 10 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 12 PY 2012 VL 172 IS 5 BP 438 EP 440 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 906XB UT WOS:000301381300017 PM 22412112 ER PT J AU Driver, JA Beiser, A Au, R Kreger, BE Splansky, GL Kurth, T Kiel, DP Lu, KP Seshadri, S Wolf, PA AF Driver, Jane A. Beiser, Alexa Au, Rhoda Kreger, Bernard E. Splansky, Greta Lee Kurth, Tobias Kiel, Douglas P. Lu, Kun Ping Seshadri, Sudha Wolf, Phillip A. TI Inverse association between cancer and Alzheimer's disease: results from the Framingham Heart Study SO BRITISH MEDICAL JOURNAL LA English DT Article ID PROLYL ISOMERASE PIN1; PARKINSONS-DISEASE; CELL-CYCLE; VASCULAR DEMENTIA; RISK; DIAGNOSIS; COHORT; CHEMOTHERAPY; HEALTH; AGE AB Objectives To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer's disease and to estimate the risk of incident cancer among participants with and without Alzheimer's disease. Design Community based prospective cohort study; nested age and sex matched case-control study. Setting Framingham Heart Study, USA. Participants 1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90). Main outcome measures Hazard ratios and 95% confidence intervals for the risks of Alzheimer's disease and cancer. Results Over a mean follow-up of 10 years, 221 cases of probable Alzheimer's disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer's disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer's disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer's disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer's disease (0.38) and any dementia (0.44). Conclusions Cancer survivors had a lower risk of Alzheimer's disease than those without cancer, and patients with Alzheimer's disease had a lower risk of incident cancer. The risk of Alzheimer's disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson's disease and suggests an inverse association between cancer and neurodegeneration. C1 [Driver, Jane A.] Ctr Geriatr Res Educ & Clin, Boston, MA 02130 USA. [Driver, Jane A.] Boston VA Med Ctr, Boston, MA 02130 USA. [Driver, Jane A.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Driver, Jane A.; Kurth, Tobias] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Beiser, Alexa; Au, Rhoda; Seshadri, Sudha; Wolf, Phillip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Beiser, Alexa] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Beiser, Alexa; Kreger, Bernard E.; Splansky, Greta Lee; Wolf, Phillip A.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Kreger, Bernard E.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Kurth, Tobias] INSERM, Neuroepidemiol U708, Bordeaux, France. [Kiel, Douglas P.; Lu, Kun Ping] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Med, Boston, MA 02215 USA. RP Driver, JA (reprint author), Ctr Geriatr Res Educ & Clin, Boston, MA 02130 USA. EM jdriver@partners.org RI Kurth, Tobias/A-9243-2012; OI Kurth, Tobias/0000-0001-7169-2620; Seshadri, Sudha/0000-0001-6135-2622; Au, Rhoda/0000-0001-7742-4491; Kiel, Douglas/0000-0001-8474-0310; Beiser, Alexa/0000-0001-8551-7778 FU Veterans' Administration; National Heart, Lung, and Blood Institute [N01-HC-25195]; National Institutes of Aging [AG16495, AG08122]; National Institute of Neurological Disorders and Stroke [NS17950] FX JAD was funded by a Veterans' Administration career development award. The Framingham Heart Study is supported by an National Heart, Lung, and Blood Institute contract (N01-HC-25195) and by grants from the National Institutes of Aging (AG16495 and AG08122) and National Institute of Neurological Disorders and Stroke (NS17950). The authors' work was independent of the funders. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. NR 52 TC 69 Z9 72 U1 2 U2 14 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BRIT MED J JI Br. Med. J. PD MAR 12 PY 2012 VL 344 AR e1442 DI 10.1136/bmj.e1442 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 913BO UT WOS:000301846500004 PM 22411920 ER PT J AU Huang, Y Ballinger, DG Dai, JY Peters, U Hinds, DA Cox, DR Beilharz, E Chlebowski, RT Rossouw, JE McTiernan, A Rohan, T Prentice, RL AF Huang, Ying Ballinger, Dennis G. Dai, James Y. Peters, Ulrike Hinds, David A. Cox, David R. Beilharz, Erica Chlebowski, Rowan T. Rossouw, Jacques E. McTiernan, Anne Rohan, Thomas Prentice, Ross L. TI Correction: Genetic variants in the MRPS30 region and postmenopausal breast cancer risk (vol 4, pg 19, 2012) SO GENOME MEDICINE LA English DT Correction C1 [Huang, Ying; Dai, James Y.; Peters, Ulrike; McTiernan, Anne; Prentice, Ross L.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Ballinger, Dennis G.; Hinds, David A.; Cox, David R.; Beilharz, Erica] Perlegen Sci Inc, Mountain View, CA 94043 USA. [Chlebowski, Rowan T.] Harbor UCLA Res & Educ Inst, Torrance, CA 90502 USA. [Rossouw, Jacques E.] NIH, Bethesda, MD 20892 USA. [Rohan, Thomas] Albert Einstein Coll Med, Bronx, NY 10461 USA. RP Prentice, RL (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,M3-A410,POB 19024, Seattle, WA 98109 USA. EM rprentic@fhcrc.org NR 2 TC 1 Z9 1 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-994X J9 GENOME MED JI Genome Med. PD MAR 12 PY 2012 VL 4 DI 10.1186/gm318 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 084VJ UT WOS:000314566900001 PM 22410340 ER PT J AU Salit, RB Fowler, DH Wilson, WH Dean, RM Pavletic, SZ Dunleavy, K Hakim, F Fry, TJ Steinberg, SM Hughes, TE Odom, J Bryant, K Gress, RE Bishop, MR AF Salit, Rachel B. Fowler, Daniel H. Wilson, Wyndham H. Dean, Robert M. Pavletic, Steven Z. Dunleavy, Kieron Hakim, Frances Fry, Terry J. Steinberg, Seth M. Hughes, Thomas E. Odom, Jeanne Bryant, Kelly Gress, Ronald E. Bishop, Michael R. TI Dose-Adjusted EPOCH-Rituximab Combined With Fludarabine Provides an Effective Bridge to Reduced-Intensity Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Lymphoid Malignancies SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NON-HODGKINS-LYMPHOMA; SALVAGE THERAPY; PHASE-II; CHEMOTHERAPY; REGIMEN; PRETRANSPLANT; CHIMERISM; DEPLETION; OUTCOMES; DISEASE AB Purpose There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R). Patients and Methods One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4(+) count <200/mu L) or progressive disease. Results Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3(+) (P<.001), CD4(+) (P<.001), and CD8(+) (P<.001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P<.001) and overall survival (98.5 v 16.2 months; P<.001). Conclusion DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies. J Clin Oncol 30: 830-836. (C) 2012 by American Society of Clinical Oncology C1 [Salit, Rachel B.; Fowler, Daniel H.; Wilson, Wyndham H.; Pavletic, Steven Z.; Dunleavy, Kieron; Hakim, Frances; Fry, Terry J.; Steinberg, Seth M.; Odom, Jeanne; Bryant, Kelly; Gress, Ronald E.; Bishop, Michael R.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Hughes, Thomas E.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Dean, Robert M.] Cleveland Clin Fdn, Taussig Canc Ctr, Cleveland, OH 44195 USA. RP Bishop, MR (reprint author), Med Coll Wisconsin, Ctr Clin Canc, 9200 W Wisconsin Ave, Milwaukee, WI 53226 USA. EM mbishop@mcw.edu FU Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD FX Supported by Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD. NR 35 TC 7 Z9 7 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 10 PY 2012 VL 30 IS 8 BP 830 EP 836 DI 10.1200/JCO.2011.37.0296 PG 7 WC Oncology SC Oncology GA 923NS UT WOS:000302626600018 PM 22312100 ER PT J AU David, A Das, SR Gibbs, JS Bennink, JR Yewdell, JW AF David, Alexandre Das, Suman R. Gibbs, James S. Bennink, Jack R. Yewdell, Jonathan W. TI Cysteinyl-tRNA Deacylation Can Be Uncoupled from Protein Synthesis SO PLOS ONE LA English DT Article ID RIBONUCLEIC-ACID SYNTHETASE; IN-VIVO; CELLS; RECOGNITION; TRANSLATION; INHIBITION; ABSENCE AB Aminoacyl-tRNA synthetases (ARSs) are critical components of protein translation, providing ribosomes with aminoacyl-tRNAs. In return, ribosomes release uncharged tRNAs as ARS substrates. Here, we show that tRNA deacylation can be uncoupled from protein synthesis in an amino acid specific manner. While tRNAs coupled to radiolabeled Met, Leu Lys, or Ser are stable in cells following translation inhibition with arsenite, radiolabeled Cys is released from tRNA at a high rate. We discuss possible translation independent functions for tRNA(Cys). C1 [David, Alexandre; Das, Suman R.; Gibbs, James S.; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP David, A (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI Das, Suman/C-8760-2009; David, Alexandre/B-2447-2013 OI David, Alexandre/0000-0003-3365-1339 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases FX This work was generously supported by the Division of Intramural Research, 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 20 TC 1 Z9 1 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 MAR 9 PY 2012 VL 7 IS 3 AR e33072 DI 10.1371/journal.pone.0033072 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 929KX UT WOS:000303062800042 PM 22427952 ER PT J AU Djamshidian, A O'Sullivan, SS Lees, A Averbeck, BB AF Djamshidian, Atbin O'Sullivan, Sean S. Lees, Andrew Averbeck, Bruno B. TI Effects of Dopamine on Sensitivity to Social Bias in Parkinson's Disease SO PLOS ONE LA English DT Article ID FACIAL EXPRESSION RECOGNITION; ANTERIOR CINGULATE CORTEX; IMPAIRED RECOGNITION; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; DECISION-MAKING; ANGRY FACES; SCHIZOPHRENIA; BEHAVIORS; OXYTOCIN AB Patients with Parkinson's disease (PD) sometimes develop impulsive compulsive behaviours (ICBs) due to their dopaminergic medication. We compared 26 impulsive and 27 non-impulsive patients with PD, both on and off medication, on a task that examined emotion bias in decision making. No group differences were detected, but patients on medication were less biased by emotions than patients off medication and the strongest effects were seen in patients with ICBs. PD patients with ICBs on medication also showed more learning from negative feedback and less from positive feedback, whereas off medication they showed the opposite effect. C1 [Djamshidian, Atbin; O'Sullivan, Sean S.; Lees, Andrew] UCL, Dept Mol Neurosci, London, England. [Averbeck, Bruno B.] UCL, Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London, England. [Djamshidian, Atbin; O'Sullivan, Sean S.; Lees, Andrew] UCL, Reta Lila Weston Inst Neurol Studies, London, England. [Averbeck, Bruno B.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Djamshidian, A (reprint author), UCL, Dept Mol Neurosci, London, England. EM bruno.averbeck@nih.gov RI Lees, Andrew/A-6605-2009; O'Sullivan, Sean/C-9333-2012; OI O'Sullivan, Sean/0000-0002-0583-7956; Djamshidian, Atbin/0000-0001-7174-6000 FU Reta Lila Howard Foundation; NIH; Wellcome Trust; PSP Association; Weston Trust FX This study was funded by the Reta Lila Howard Foundation, the Intramural research program of the NIH and the Wellcome Trust. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; SOS has received honoraria from Britannia Pharmaceuticals, AJL has received honoraria from Novartis, Teva, Meda, Boehringer Ingelheim, GSK, Ipsen, Lundbeck, Allergan, Orion; Grants: PSP Association, and the Weston Trust. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials, as detailed online in the guide for authors. NR 43 TC 2 Z9 2 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 9 PY 2012 VL 7 IS 3 AR e32889 DI 10.1371/journal.pone.0032889 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 929KX UT WOS:000303062800034 PM 22427905 ER PT J AU Gallo, A Tandon, M Alevizos, I Illei, GG AF Gallo, Alessia Tandon, Mayank Alevizos, Ilias Illei, Gabor G. TI The Majority of MicroRNAs Detectable in Serum and Saliva Is Concentrated in Exosomes SO PLOS ONE LA English DT Article ID CIRCULATING MICRORNAS; BIOMARKERS; MICROVESICLES; VESICLES; RELEASE; PLASMA; ROLES; CELL AB There is an increasing interest in using microRNAs (miRNA) as biomarkers in autoimmune diseases. They are easily accessible in many body fluids but it is controversial if they are circulating freely or are encapsulated in microvesicles, particularly exosomes. We investigated if the majority of miRNas in serum and saliva are free-circulating or concentrated in exosomes. Exosomes were isolated by ultracentrifugation from fresh and frozen human serum and saliva. The amount of selected miRNAs extracted from the exosomal pellet and the exosome-depleted serum and saliva was compared by quantitative RT-PCR. Some miRNAs tested are ubiquitously expressed, others were previously reported as biomarkers. We included miRNAs previously reported to be free circulating and some thought to be exosome specific. The purity of exosome fraction was confirmed by electronmicroscopy and western blot. The concentration of miRNAs was consistently higher in the exosome pellet compared to the exosome-depleted supernatant. We obtained the same results using an equal volume or equal amount of total RNA as input of the RT-qPCR. The concentration of miRNA in whole, unfractionated serum, was between the exosomal pellet and the exosome-depleted supernatant. Selected miRNAs, which were detectable in exosomes, were undetectable in whole serum and the exosome-depleted supernantant. Exosome isolation improves the sensitivity of miRNA amplification from human biologic fluids. Exosomal miRNA should be the starting point for early biomarker studies to reduce the probability of false negative results involving low abundance miRNAs that may be missed by using unfractionated serum or saliva. C1 [Gallo, Alessia; Tandon, Mayank; Alevizos, Ilias; Illei, Gabor G.] Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Gallo, A (reprint author), Natl Inst Dent & Craniofacial Res, Sjogrens Syndrome Clin, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD 20892 USA. EM illeig@mail.nih.gov FU National Institute of Dental and Craniofacial Research FX This research was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 14 TC 272 Z9 294 U1 10 U2 74 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 MAR 9 PY 2012 VL 7 IS 3 AR e30679 DI 10.1371/journal.pone.0030679 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 929KX UT WOS:000303062800002 PM 22427800 ER PT J AU Nayak, B Dias, FM Kumar, S Paldurai, A Collins, PL Samal, SK AF Nayak, Baibaswata Dias, Flavia Militino Kumar, Sachin Paldurai, Anandan Collins, Peter L. Samal, Siba K. TI Avian paramyxovirus serotypes 2-9 (APMV-2-9) vary in the ability to induce protective immunity in chickens against challenge with virulent Newcastle disease virus (APMV-1) SO VACCINE LA English DT Article DE Newcastle disease; NDV; Avian paramyxovirus; APMV; Vaccine; NDV challenge; Survival ID COMPLETE GENOME SEQUENCE; TURKEYS; STRAIN; RESISTANCE; YUCAIPA; NEURAMINIDASE; INFLUENZA; INFECTION; PROTEINS; POULTRY AB The avian paramyxoviruses (APMVs) belong to the genus Avulavirus of family Paramyxoviridae. The APMVs are classified into nine serotypes on the basis of hemagglutination inhibition (HI) and neuraminidase inhibition (NI) assays, although some serologic cross-reaction exists. Newcastle disease virus (NDV), which constitutes serotype 1 (APMV-1), is an important pathogen of poultry, but the pathogenic potential of the other APMV serotypes is poorly understood. Although antibodies to APMV -2 to -9 are prevalent in chickens, the effect of prior exposure to these serotypes on susceptibility to NDV infection and disease was not known. In the present study, chickens were immunized with APMV-2 to -9 by the oculo-nasal route and later were challenged by the same route with a highly virulent strain of NDV. Among APMV-2 to -9, only APMV-3 induced serum antibodies that cross-reacted significantly with NDV and had significant NDV-neutralizing activity in vitro. In mock-immunized chickens, challenge NDV replicated throughout the respiratory tract as well as in the brain, spleen, and enteric tract. In contrast, in APMV-3-immunized chickens, challenge NDV replication was restricted to the upper respiratory tract and trachea. Some of the other APMVs also induced partial restriction of challenge NDV replication: for example, challenge NOV was not detected in the brains of APMV-9-immunized chickens, and shedding from the respiratory tract was reduced in chickens immunized with APMV-8 and -9. All of the chickens immunized with APMV-3 survived the NDV challenge; with APMV-2, -7, -8, and -9 the percentage survival was 30%, 20%, 20%, and 52.5%, respectively; whereas none of the chickens immunized with APMV-4, -5, or -6 survived. These results show that prior infection of chickens with APMV-3 induced substantial protection against NDV challenge, whereas prior infection with APMV-2, -7, -8, and -9 can alter subsequent NOV infection. The induction of NDV-neutralizing antibodies was a marker for efficient protection, but partial protection also was observed in their absence. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Nayak, Baibaswata; Dias, Flavia Militino; Kumar, Sachin; Paldurai, Anandan; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016 FU NIAID [N01A060009]; NIAID-NIH FX We thank Daniel Rockemann for his excellent technical assistance and Lashae Green for proofreading the manuscript. "This research was supported by funding from NIAID contract no. N01A060009 (85% support) and NIAID-NIH Intramural Research Program (15% support). The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services; nor does the mention of trade names, commercial practices, or organizations imply endorsement by the U.S. Government." NR 35 TC 11 Z9 14 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAR 9 PY 2012 VL 30 IS 12 BP 2220 EP 2227 DI 10.1016/j.vaccine.2011.12.090 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 924AN UT WOS:000302662900032 PM 22222870 ER PT J AU Muenke, M AF Muenke, Maximilian TI 2011 William Allan Award Introduction: John M. Opitz SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Editorial Material ID MULTIPLE CONGENITAL ANOMALIES; DEVELOPMENTAL FIELD CONCEPT; MUTATIONS C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Muenke, M (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM mamuenke@mail.nih.gov NR 15 TC 0 Z9 0 U1 0 U2 0 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 MAR 9 PY 2012 VL 90 IS 3 BP 390 EP 391 DI 10.1016/j.ajhg.2012.01.011 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 911ZI UT WOS:000301762800003 PM 22405083 ER PT J AU Saxena, R Elbers, CC Guo, YR Peter, I Gaunt, TR Mega, JL Lanktree, MB Tare, A Castillo, BA Li, YR Johnson, T Bruinenberg, M Gilbert-Diamond, D Rajagopalan, R Voight, BF Balasubramanyam, A Barnard, J Bauer, F Baumert, J Bhangale, T Bohm, BO Braund, PS Burton, PR Chandrupatla, HR Clarke, R Cooper-DeHoff, RM Crook, ED Davey-Smith, G Day, IN de Boer, A de Groot, MCH Drenos, F Ferguson, J Fox, CS Furlong, CE Gibson, Q Gieger, C Gilhuijs-Pederson, LA Glessner, JT Goel, A Gong, Y Grant, SFA Grobbee, DE Hastie, C Humphries, SE Kim, CE Kivimaki, M Kleber, M Meisinger, C Kumari, M Langaee, TY Lawlor, DA Li, MY Lobmeyer, MT Maitland-van der Zee, AH Meijs, MFL Molony, CM Morrow, DA Murugesan, G Musani, SK Nelson, CP Newhouse, SJ O'Connell, JR Padmanabhan, S Palmen, J Patel, SR Pepine, CJ Pettinger, M Price, TS Rafelt, S Ranchalis, J Rasheed, A Rosenthal, E Ruczinski, I Shah, S Shen, HQ Silbernagel, G Smith, EN Spijkerman, AWM Stanton, A Steffes, MW Thorand, B Trip, M van der Harst, P van der A, DL van Iperen, EPA van Setten, J van Vliet-Ostaptchouk, JV Verweij, N Wolffenbuttel, BHR Young, T Zafarmand, MH Zmuda, JM Boehnke, M Altshuler, D McCarthy, M Kao, WHL Pankow, JS Cappola, TP Sever, P Poulter, N Caulfield, M Dominiczak, A Shields, DC Bhatt, DL Zhang, L Curtis, SP Danesh, J Casas, JP van der Schouw, YT Onland-Moret, NC Doevendans, PA Dorn, GW Farrall, M FitzGerald, GA Hamsten, A Hegele, R Hingorani, AD Hofker, MH Huggins, GS Illig, T Jarvik, GP Johnson, JA Klungel, OH Knowler, WC Koenig, W Marz, W Meigs, JB Melander, O Munroe, PB Mitchell, BD Bielinski, SJ Rader, DJ Reilly, MP Rich, SS Rotter, JI Saleheen, D Samani, NJ Schadt, EE Shuldiner, AR Silverstein, R Kottke-Marchant, K Talmud, PJ Watkins, H Asselbergs, FW de Bakker, PIW McCaffery, J Wijmenga, C Sabatine, MS Wilson, JG Reiner, A Bowden, DW Hakonarson, H Siscovick, DS Keating, BJ AF Saxena, Richa Elbers, Clara C. Guo, Yiran Peter, Inga Gaunt, Tom R. Mega, Jessica L. Lanktree, Matthew B. Tare, Archana Almoguera Castillo, Berta Li, Yun R. Johnson, Toby Bruinenberg, Marcel Gilbert-Diamond, Diane Rajagopalan, Ramakrishnan Voight, Benjamin F. Balasubramanyam, Ashok Barnard, John Bauer, Florianne Baumert, Jens Bhangale, Tushar Boehm, Bernhard O. Braund, Peter S. Burton, Paul R. Chandrupatla, Hareesh R. Clarke, Robert Cooper-DeHoff, Rhonda M. Crook, Errol D. Davey-Smith, George Day, Ian N. de Boer, Anthonius de Groot, Mark C. H. Drenos, Fotios Ferguson, Jane Fox, Caroline S. Furlong, Clement E. Gibson, Quince Gieger, Christian Gilhuijs-Pederson, Lisa A. Glessner, Joseph T. Goel, Anuj Gong, Yan Grant, Struan F. A. Grobbee, Diederick E. Hastie, Claire Humphries, Steve E. Kim, Cecilia E. Kivimaki, Mika Kleber, Marcus Meisinger, Christa Kumari, Meena Langaee, Taimour Y. Lawlor, Debbie A. Li, Mingyao Lobmeyer, Maximilian T. Maitland-van der Zee, Anke-Hilse Meijs, Matthijs F. L. Molony, Cliona M. Morrow, David A. Murugesan, Gurunathan Musani, Solomon K. Nelson, Christopher P. Newhouse, Stephen J. O'Connell, Jeffery R. Padmanabhan, Sandosh Palmen, Jutta Patel, Sanjey R. Pepine, Carl J. Pettinger, Mary Price, Thomas S. Rafelt, Suzanne Ranchalis, Jane Rasheed, Asif Rosenthal, Elisabeth Ruczinski, Ingo Shah, Sonia Shen, Haiqing Silbernagel, Guenther Smith, Erin N. Spijkerman, Annemieke W. M. Stanton, Alice Steffes, Michael W. Thorand, Barbara Trip, Mieke van der Harst, Pim van der A, Daphne L. van Iperen, Erik P. A. van Setten, Jessica van Vliet-Ostaptchouk, Jana V. Verweij, Niek Wolffenbuttel, Bruce H. R. Young, Taylor Zafarmand, M. Hadi Zmuda, Joseph M. Boehnke, Michael Altshuler, David McCarthy, Mark Kao, W. H. Linda Pankow, James S. Cappola, Thomas P. Sever, Peter Poulter, Neil Caulfield, Mark Dominiczak, Anna Shields, Denis C. Bhatt, Deepak L. Zhang, Li Curtis, Sean P. Danesh, John Casas, Juan P. van der Schouw, Yvonne T. Onland-Moret, N. Charlotte Doevendans, Pieter A. Dorn, Gerald W., II Farrall, Martin FitzGerald, Garret A. Hamsten, Anders Hegele, Robert Hingorani, Aroon D. Hofker, Marten H. Huggins, Gordon S. Illig, Thomas Jarvik, Gail P. Johnson, Julie A. Klungel, Olaf H. Knowler, William C. Koenig, Wolfgang Maerz, Winfried Meigs, James B. Melander, Olle Munroe, Patricia B. Mitchell, Braxton D. Bielinski, Susan J. Rader, Daniel J. Reilly, Muredach P. Rich, Stephen S. Rotter, Jerome I. Saleheen, Danish Samani, Nilesh J. Schadt, Eric E. Shuldiner, Alan R. Silverstein, Roy Kottke-Marchant, Kandice Talmud, Philippa J. Watkins, Hugh Asselbergs, Folkert W. de Bakker, Paul I. W. McCaffery, Jeanne Wijmenga, Cisca Sabatine, Marc S. Wilson, James G. Reiner, Alex Bowden, Donald W. Hakonarson, Hakon Siscovick, David S. Keating, Brendan J. CA Look AHEAD Res Grp Diagram Consortium ASCOT Investigators PROCARDIS TI Large-Scale Gene-Centric Meta-Analysis across 39 Studies Identifies Type 2 Diabetes Loci SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; INSULIN-RESISTANCE; COMMON VARIANTS; EUROPEAN AMERICANS; AFRICAN-AMERICANS; BLOOD-PRESSURE; RESOURCE CARE; RISK-FACTORS; SNP ARRAY AB To identify genetic factors contributing to type 2 diabetes (T2D), we performed large-scale meta-analyses by using a custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) with similar to 2000 candidate genes in 39 multiethnic population-based studies, case-control studies, and clinical trials totaling 17,418 cases and 70,298 controls. First, meta-analysis of 25 studies comprising 14,073 cases and 57,489 controls of European descent confirmed eight established T2D loci at genome-wide significance. In silico follow-up analysis of putative association signals found in independent genome-wide association studies (including 8,130 cases and 38,987 controls) performed by the DIAGRAM consortium identified a T2D locus at genome-wide significance (GATAD2A/CILP2/PBX4; p = 5.7 x 10(-9)) and two loci exceeding study-wide significance (SREBF1, and TH/INS; p < 2.4 x 10(-6)). Second, meta-analyses of 1,986 cases and 7,695 controls from eight African-American studies identified study-wide-significant (p = 2.4 x 10(-7)) variants in HMGA2 and replicated variants in TCF7L2 (p = 5.1 x 10(-15)). Third, conditional analysis revealed multiple known and novel independent signals within five T2D-associated genes in samples of European ancestry and within HMGA2 in African-American samples. Fourth, a multiethnic meta-analysis of all 39 studies identified T2D-associated variants in BCL2 (p = 2.1 x 10(-8)). 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[Silverstein, Roy] Case Western Reserve Univ, Dept Cell Biol, Lerner Res Inst,Dept Mol Med, Cleveland Clin Fdn,Cleveland Clin Lerner Coll Med, Cleveland, OH 44195 USA. [Kottke-Marchant, Kandice] Cleveland Clin, Pathol & Lab Med Inst, Cleveland, OH 44195 USA. [de Bakker, Paul I. W.] Harvard Univ, Sch Med, Div Genet, Brigham & Womens Hosp, Boston, MA 02115 USA. [McCaffery, Jeanne] Brown Univ, Miriam Hosp, Weight Control & Diabet Res Ctr, Providence, RI 02906 USA. [McCaffery, Jeanne] Brown Univ, Warren Alpert Sch Med, Providence, RI 02906 USA. [Bowden, Donald W.] Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC 27106 USA. [Hakonarson, Hakon; Keating, Brendan J.] Childrens Hosp, Div Human Genet, Abramson Res Ctr, Philadelphia, PA 19104 USA. [Hakonarson, Hakon; Keating, Brendan J.] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. [Siscovick, David S.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98101 USA. [Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98101 USA. RP Saxena, R (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. EM rsaxena@chgr.mgh.harvard.edu; keatingb@email.chop.edu RI Davey Smith, George/A-7407-2013; Price, Thomas/B-7372-2008; Thorand, Barbara/B-5349-2014; Jarvik, Gail/N-6476-2014; Gaunt, Tom/O-3918-2014; Onland-Moret, N. Charlotte/G-9185-2011; de Groot, Mark/A-9891-2012; Hegele, Robert/G-3301-2011; Bielinski, Suzette/A-2238-2009; Burton, Paul/H-7527-2016; Klungel, Olaf/I-9563-2016; Padmanabhan, Sandosh/S-3963-2016; Verweij, Niek/A-4499-2017; Guo, Yiran/H-4120-2011; Smith, Erin/E-5933-2011; Newhouse, Stephen/C-9330-2011; Ferguson, Jane/C-7154-2011; Wolffenbuttel, Bruce/A-8419-2011; Stanton, Alice/F-4697-2012; Grobbee, Diederick/C-7651-2014; Wijmenga, Cisca/D-2173-2009; Altshuler, David/A-4476-2009; de Bakker, Paul/B-8730-2009; Shah, Sonia/N-7547-2013; Meisinger, Christine/B-5358-2014 OI Lawlor, Debbie A/0000-0002-6793-2262; Pankow, James/0000-0001-7076-483X; Kleber, Marcus/0000-0003-0663-7275; Gieger, Christian/0000-0001-6986-9554; Wijmenga, Cisca/0000-0002-5635-1614; Patel, Sanjay/0000-0002-9142-5172; Kumari, Meena/0000-0001-9716-1035; Verweij, Niek/0000-0002-4303-7685; Meisinger, Christa/0000-0002-9026-6544; Watkins, Hugh/0000-0002-5287-9016; van Iperen, Erik/0000-0001-7107-3168; Mitchell, Braxton/0000-0003-4920-4744; Davey Smith, George/0000-0002-1407-8314; Lanktree, Matthew/0000-0002-5750-6286; Stanton, Alice/0000-0002-4961-165X; van Vliet-Ostaptchouk, Jana/0000-0002-7943-3153; Kivimaki, Mika/0000-0002-4699-5627; Talmud, Philippa/0000-0002-5560-1933; Johnson, Toby/0000-0002-5998-3270; Padmanabhan, Sandosh/0000-0003-3869-5808; Humphries, Stephen E/0000-0002-8221-6547; Price, Thomas/0000-0001-7356-2109; Thorand, Barbara/0000-0002-8416-6440; Jarvik, Gail/0000-0002-6710-8708; Gaunt, Tom/0000-0003-0924-3247; de Groot, Mark/0000-0002-5764-5788; Bielinski, Suzette/0000-0002-2905-5430; Guo, Yiran/0000-0002-6549-8589; Newhouse, Stephen/0000-0002-1843-9842; Ferguson, Jane/0000-0001-6896-1025; Wolffenbuttel, Bruce/0000-0001-9262-6921; Grobbee, Diederick/0000-0003-4472-4468; Altshuler, David/0000-0002-7250-4107; de Bakker, Paul/0000-0001-7735-7858; Shah, Sonia/0000-0001-5860-4526; FU National Heart, Lung, and Blood Institute; NIDDK NIH [DK089378]; Netherlands Organization for Scientific Research (NWO); Massachusetts Institute of Technology [N01-HC-65226] FX The CARe Consortium wishes 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. The following nine parent studies have contributed parent study data, ancillary study data, and DNA samples through the Broad Institute of Harvard University and the Massachusetts Institute of Technology (N01-HC-65226) to create this genotype/phenotype database for wide dissemination to the biomedical research community: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Cleveland Family Study (CFS), the Cooperative Study of Sickle Cell Disease (CSSCD), the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Framingham Heart Study (FHS), the Jackson Heart Study OHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). R.S. is partially supported by NIDDK NIH R21 (DK089378). C.C.E is supported by a Rubicon grant from the Netherlands Organization for Scientific Research (NWO). Additional acknowledgements for each cohort are listed in the Supplemental Data. Also see the Supplemental Data for conflict-of-interest disclosures for some of the authors. NR 80 TC 127 Z9 129 U1 1 U2 30 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 MAR 9 PY 2012 VL 90 IS 3 BP 410 EP 425 DI 10.1016/j.ajhg.2011.12.022 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 911ZI UT WOS:000301762800007 PM 22325160 ER PT J AU Kummar, S Chen, A Parchment, RE Kinders, RJ Ji, J Tomaszewski, JE Doroshow, JH AF Kummar, Shivaani Chen, Alice Parchment, Ralph E. Kinders, Robert J. Ji, Jay Tomaszewski, Joseph E. Doroshow, James H. TI Advances in using PARP inhibitors to treat cancer SO BMC MEDICINE LA English DT Review DE synthetic lethality; DNA repair; PARP clinical trials ID ADP-RIBOSE POLYMERASE; 0 CLINICAL-TRIAL; POLY(ADP-RIBOSE) POLYMERASE; SYNTHETIC LETHALITY; OVARIAN-CARCINOMA; BRCA2 MUTATIONS; EXCISION-REPAIR; BREAST-CANCER; MUTANT-CELLS; DNA AB The poly (ADP-ribose) polymerase (PARP) family of enzymes plays a critical role in the maintenance of DNA integrity as part of the base excision pathway of DNA repair. PARP1 is overexpressed in a variety of cancers, and its expression has been associated with overall prognosis in cancer, especially breast cancer. A series of new therapeutic agents that are potent inhibitors of the PARP1 and PARP2 isoforms have demonstrated important clinical activity in patients with breast or ovarian cancers that are caused by mutations in either the BRCA1 or 2 genes. Results from such studies may define a new therapeutic paradigm, wherein simultaneous loss of the capacity to repair DNA damage may have antitumor activity in itself, as well as enhance the antineoplastic potential of cytotoxic chemotherapeutic agents. C1 [Kummar, Shivaani; Chen, Alice; Tomaszewski, Joseph E.; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Parchment, Ralph E.; Kinders, Robert J.; Ji, Jay] NCI, Sci Applicat Int Corporat Frederick Inc, Appl Dev Res Directorate, Frederick, MD 21702 USA. [Doroshow, James H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Doroshow, JH (reprint author), NCI, Div Canc Treatment & Diag, Bldg 31,Room 3A-44,31 Ctr Dr, Bethesda, MD 20892 USA. EM doroshoj@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research; Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This project has been funded in whole or in part with federal funds from the National Cancer 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 NIH, National Cancer Institute, Center for Cancer Research and the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 33 TC 68 Z9 74 U1 5 U2 35 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD MAR 9 PY 2012 VL 10 AR 25 DI 10.1186/1741-7015-10-25 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 914JE UT WOS:000301944900001 PM 22401667 ER PT J AU de Castro, RO Zhang, J Groves, JR Barbu, EA Siraganian, RP AF de Castro, Rodrigo Orlandini Zhang, Juan Groves, Jacqueline R. Barbu, Emilia Alina Siraganian, Reuben P. TI Once Phosphorylated, Tyrosines in Carboxyl Terminus of Protein-tyrosine Kinase Syk Interact with Signaling Proteins, Including TULA-2, a Negative Regulator of Mast Cell Degranulation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FC-EPSILON-RI; AFFINITY IGE RECEPTOR; ACTIVATION LOOP TYROSINES; ADAPTER PROTEINS; ACTIN CYTOSKELETON; PHOSPHATASE; SLP-76; SHIP; IDENTIFICATION; SPECIFICITY AB Activation of the high affinity IgE-binding receptor (Fc epsilon RI) results in the tyrosine phosphorylation of two conserved tyrosines located close to the COOH terminus of the protein-tyrosine kinase Syk. Synthetic peptides representing the last 10 amino acids of the tail of Syk with these two tyrosines either nonphosphorylated or phosphorylated were used to precipitate proteins from mast cell lysates. Proteins specifically precipitated by the phosphorylated peptide were identified by mass spectrometry. These included the adaptor proteins SLP-76, Nck-1, Grb2, and Grb2-related adaptor downstream of Shc (GADS) and the protein phosphatases SHIP-1 and TULA-2 (also known as UBASH3B or STS-1). The presence of these in the precipitates was further confirmed by immunoblotting. Using the peptides as probes in far Western blots showed direct binding of the phosphorylated peptide to Nck-1 and SHIP-1. Immunoprecipitations suggested that there were complexes of these proteins associated with Syk especially after receptor activation; in these complexes are Nck, SHIP-1, SLP-76, Grb2, and TULA-2 (UBASH3B or STS-1). The decreased expression of TULA-2 by treatment of mast cells with siRNA increased the Fc epsilon RI-induced tyrosine phosphorylation of the activation loop tyrosines of Syk and the phosphorylation of phospholipase C-gamma 2. There was parallel enhancement of the receptor-induced degranulation and activation of nuclear factor for T cells or nuclear factor kappa B, indicating that TULA-2, like SHIP-1, functions as a negative regulator of Fc epsilon RI signaling in mast cells. Therefore, once phosphorylated, the terminal tyrosines of Syk bind complexes of proteins that are positive and negative regulators of signaling in mast cells. C1 [de Castro, Rodrigo Orlandini; Zhang, Juan; Groves, Jacqueline R.; Barbu, Emilia Alina; Siraganian, Reuben P.] NIDCR, Receptors & Signal Transduct Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Siraganian, RP (reprint author), NIDCR, Receptors & Signal Transduct Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. EM rs53x@nih.gov FU National Institutes of Health, NIDCR FX This work was supported, in whole or in part, by the National Institutes of Health National Institutes of Health Intramural Research Program, NIDCR. NR 59 TC 12 Z9 12 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 MAR 9 PY 2012 VL 287 IS 11 BP 8194 EP 8204 DI 10.1074/jbc.M111.326850 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 906MN UT WOS:000301349400035 PM 22267732 ER PT J AU Zhuang, M Wang, W De Feo, CJ Vassell, R Weiss, CD AF Zhuang, Min Wang, Wei De Feo, Christopher J. Vassell, Russell Weiss, Carol D. TI Trimeric, Coiled-coil Extension on Peptide Fusion Inhibitor of HIV-1 Influences Selection of Resistance Pathways SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; TERMINAL HEPTAD REPEAT; ENVELOPE GLYCOPROTEIN; SIV GP41; TRANSMEMBRANE GLYCOPROTEIN; CROSS-RESISTANCE; ATOMIC-STRUCTURE; MEMBRANE-FUSION; ENTRY INHIBITOR; CORE STRUCTURE AB Peptides corresponding to N- and C-terminal heptad repeat regions (HR1 and HR2, respectively) of viral fusion proteins can block infection of viruses in a dominant negative manner by interfering with refolding of the viral HR1 and HR2 to form a six-helix bundle (6HB) that drives fusion between viral and host cell membranes. The 6HB of the HIV gp41 (endogenous bundle) consists of an HR1 coiled-coil trimer with grooves lined by antiparallel HR2 helices. HR1 peptides form coiled-coil oligomers that may bind to gp41 HR2 as trimers to form a heterologous 6HB (inhibitor bundle) or to gp41 HR1 as monomers or dimers to form a heterologous coiled coil. To gain insights into mechanisms of Env entry and inhibition by HR1 peptides, we compared resistance to a peptide corresponding to 36 residues in gp41 HR1 (N36) and the same peptide with a coiled-coil trimerization domain fused to its N terminus (IZN36) that stabilizes the trimer and increases inhibitor potency (Eckert, D. M., and Kim, P. S. (2001) Proc. Nat. Acad. Sci. U. S. A. 98, 11187-11192). Whereas N36 selected two genetic pathways with equal probability, each defined by an early mutation in either HR1 or HR2, IZN36 preferentially selected the HR1 pathway. Both pathways conferred cross-resistance to both peptides. Each HR mutation enhanced the thermostability of the endogenous 6HB, potentially allowing the virus to simultaneously escape inhibitors targeting either gp41 HR1 or HR2. These findings inform inhibitor design and identify regions of plasticity in the highly conserved gp41 that modulate virus entry and escape from HR1 peptide inhibitors. C1 [Weiss, Carol D.] NIH, Off Vaccine Res & Review, Ctr Biol Evaluat & Res, US FDA, Bethesda, MD 20892 USA. [Zhuang, Min] Harbin Med Univ, Dept Microbiol, Harbin 150086, Heilongjiang, Peoples R China. RP Weiss, CD (reprint author), NIH, Off Vaccine Res & Review, Ctr Biol Evaluat & Res, US FDA, Bldg 29,Rm 532,29 Lincoln Dr, Bethesda, MD 20892 USA. EM carol.weiss@fda.hhs.gov RI Ghartouchent, malek/B-9088-2012; Weiss, Carol/F-6438-2011 OI Weiss, Carol/0000-0002-9965-1289 FU National Institutes of Health; United States Food and Drug Administration FX This work was supported in part by the National Institutes of Health Intramural AIDS Targeted Antiviral Program (to C. D. W.). This work was also supported in part by institutional funds from the United States Food and Drug Administration. NR 44 TC 8 Z9 8 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 9 PY 2012 VL 287 IS 11 BP 8297 EP 8309 DI 10.1074/jbc.M111.324483 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 906MN UT WOS:000301349400044 PM 22235115 ER PT J AU Deka, RK Brautigam, CA Goldberg, M Schuck, P Tomchick, DR Norgard, MV AF Deka, Ranjit K. Brautigam, Chad A. Goldberg, Martin Schuck, Peter Tomchick, Diana R. Norgard, Michael V. TI Structural, Bioinformatic, and In Vivo Analyses of Two Treponema pallidum Lipoproteins Reveal a Unique TRAP Transporter SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE TRAP transporter; syphilis; Treponema pallidum; TPR motif; protein interactions ID EXTRACYTOPLASMIC-SOLUTE-RECEPTOR; SUBSTRATE-BINDING PROTEIN; CRYSTAL-STRUCTURE; HAEMOPHILUS-INFLUENZAE; ACID-BINDING; RHODOBACTER-CAPSULATUS; MALTOSE TRANSPORTER; MAXIMUM-LIKELIHOOD; OUTER-MEMBRANE; WATER CHANNEL AB Treponema pallidum, the bacterial agent of syphilis, is predicted to encode one tripartite ATP-independent periplasmic transporter (TRAP-T). TRAP-Ts typically employ a periplasmic substrate-binding protein (SBP) to deliver the cognate ligand to the transmembrane symporter. Herein, we demonstrate that the genes encoding the putative TRAP-T components from T. pallidum, tp0957 (the SBP), and tp0958 (the symporter), are in an operon with an uncharacterized third gene, tp0956. We determined the crystal structure of recombinant Tp0956; the protein is trimeric and perforated by a pore. Part of Tp0956 forms an assembly similar to those of "tetratricopeptide repeat" (TPR) motifs. The crystal structure of recombinant Tp0957 was also determined; like the SBPs of other TRAP-Ts, there are two lobes separated by a cleft. In these other SBPs, the cleft binds a negatively charged ligand. However, the cleft of Tp0957 has a strikingly hydrophobic chemical composition, indicating that its ligand may be substantially different and likely hydrophobic. Analytical ultracentrifugation of the recombinant versions of Tp0956 and Tp0957 established that these proteins associate avidly. This unprecedented interaction was confirmed for the native molecules using in vivo cross-linking experiments. Finally, bioinforrnatic analyses suggested that this transporter exemplifies a new subfamily of TPATs (TPR-protein-associated TRAP-Ts) that require the action of a TPR-containing accessory protein for the periplasmic transport of a potentially hydrophobic ligand(s). (C) 2012 Elsevier Ltd. All rights reserved. C1 [Deka, Ranjit K.; Goldberg, Martin; Norgard, Michael V.] Univ Texas SW Med Ctr Dallas, Dept Microbiol, Dallas, TX 75390 USA. [Brautigam, Chad A.; Tomchick, Diana R.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. [Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Mol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Norgard, MV (reprint author), Univ Texas SW Med Ctr Dallas, Dept Microbiol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM Michael.Norgard@UTSouthwestern.edu OI Schuck, Peter/0000-0002-8859-6966; Tomchick, Diana/0000-0002-7529-4643 FU National Institutes of Health [AI056305]; Welch Foundation [I-0940]; National Institute of Biomedical Imaging and Bioengineering; U.S. Department of Energy, Office of Biological and Environmental Research [DE-AC02-06CH11357] FX We thank Dr. Zhiming Ouyang for technical assistance with the RT-PCR analyses, the scientists in the University of Texas Southwestern Protein Chemistry Core for protein sequence and mass analyses, and Dr. Lisa Kinch for helpful comments on the bioinformatics. This research was supported by a National Institutes of Health grant (AI056305) and a Welch Foundation grant (I-0940) to M.V.N. This work was also supported in part by the Intramural Research Program of the National Institute of Biomedical Imaging and Bioengineering (P.S.). Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center at the Advanced Photon Source. Argonne is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research, under contract DE-AC02-06CH11357. NR 71 TC 12 Z9 12 U1 0 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 9 PY 2012 VL 416 IS 5 BP 678 EP 696 DI 10.1016/j.jmb.2012.01.015 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 910XV UT WOS:000301682800007 PM 22306465 ER PT J AU Yuan, J Nguyen, CK Liu, XH Kanellopoulou, C Muljo, SA AF Yuan, Joan Nguyen, Cuong K. Liu, Xiuhuai Kanellopoulou, Chrysi Muljo, Stefan A. TI Lin28b Reprograms Adult Bone Marrow Hematopoietic Progenitors to Mediate Fetal-Like Lymphopoiesis SO SCIENCE LA English DT Article ID CD8(+) T-CELLS; STEM-CELLS; DEVELOPMENTAL SWITCH; MICRORNA BIOGENESIS; B-LYMPHOPOIESIS; NKT CELLS; EXPRESSION; LEVEL; MOUSE; MICE AB The immune system develops in waves during ontogeny; it is initially populated by cells generated from fetal hematopoietic stem cells (HSCs) and later by cells derived from adult HSCs. Remarkably, the genetic programs that control these two distinct stem cell fates remain poorly understood. We report that Lin28b is specifically expressed in mouse and human fetal liver and thymus, but not in adult bone marrow or thymus. We demonstrate that ectopic expression of Lin28 reprograms hematopoietic stem/progenitor cells (HSPCs) from adult bone marrow, which endows them with the ability to mediate multilineage reconstitution that resembles fetal lymphopoiesis, including increased development of B-1a, marginal zone B, gamma/delta (gamma delta) T cells, and natural killer T (NKT) cells. C1 [Yuan, Joan; Nguyen, Cuong K.; Liu, Xiuhuai; Kanellopoulou, Chrysi; Muljo, Stefan A.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Muljo, SA (reprint author), NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM stefan.muljo@nih.gov RI yuan, joan/A-8185-2013; Muljo, Stefan/F-5671-2015; Nguyen, Cuong/D-7567-2013 OI yuan, joan/0000-0001-9129-8356; Muljo, Stefan/0000-0003-1013-446X; Nguyen, Cuong/0000-0002-1741-669X FU NIAID, NIH FX We thank W. E. Paul for his generous support and advice throughout; T. Bender, J. Daniel, B. J. Fowlkes, R. Germain, M. Lenardo, W. E. Paul, and M. Schlissel for critical reading of this manuscript and constructive suggestions; K. Laky and B. J. Fowlkes for valuable advice and antibodies; NIH Tetramer Core Facility for reagents; M. Holt for NKT cell discussions; P. Burr for sequencing; J. Edwards and C. Eigsti for cell sorting; M. Foster for animal care; R. Zahr for technical support; and N. Bartonicek (EMBL-EBI, Hinxton, UK) for providing the RefSeq 3'UTR library for Sylamer analysis. We gratefully acknowledge the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http://biowulf.nih.gov) and NIAID Office of Cyber Infrastructure and Computational Biology High-Performance Computing cluster required for massively parallel sequencing analyses. The data reported in this paper are tabulated in the main text and in the Supporting Online Material. The RNA-Seq and NanoString data are available in the Gene Expression Omnibus (GEO) database (www.ncbi.nlm.nih.gov/geo) under the accession nos. GSE34854, GSE35081, and GSE35107. The materials and reagents used in the paper are available under a Materials Transfer Agreement. We apologize that we could not cite all the relevant references because of space limitations. The Integrative Immunobiology Unit is supported by the Intramural Research Program of the NIAID, NIH. The authors declare no competing financial interests. NR 52 TC 108 Z9 111 U1 1 U2 14 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 MAR 9 PY 2012 VL 335 IS 6073 BP 1195 EP 1200 DI 10.1126/science.1216557 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 904VB UT WOS:000301225100037 PM 22345399 ER PT J AU Mahat, DB Brennan-Laun, SE Fialcowitz-White, EJ Kishor, A Ross, CR Pozharskaya, T Rawn, JD Blackshear, PJ Hassel, BA Wilson, GM AF Mahat, Dig B. Brennan-Laun, Sarah E. Fialcowitz-White, Elizabeth J. Kishor, Aparna Ross, Christina R. Pozharskaya, Tatyana Rawn, J. David Blackshear, Perry J. Hassel, Bret A. Wilson, Gerald M. TI Coordinated Expression of Tristetraprolin Post-Transcriptionally Attenuates Mitogenic Induction of the Oncogenic Ser/Thr Kinase Pim-1 SO PLOS ONE LA English DT Article ID ACTIVATED PROTEIN-KINASE; MESSENGER-RNA DECAY; NECROSIS-FACTOR-ALPHA; AU-RICH ELEMENTS; ZINC-FINGER PROTEINS; BINDING PROTEIN; POSTTRANSLATIONAL MODIFICATION; DEPENDENT PHOSPHORYLATION; ELAV PROTEIN; C-MYC AB The serine/threonine kinase Pim-1 directs selected signaling events that promote cell growth and survival and is overexpressed in diverse human cancers. Pim-1 expression is tightly controlled through multiple mechanisms, including regulation of mRNA turnover. In several cultured cell models, mitogenic stimulation rapidly induced and stabilized PIM1 mRNA, however, vigorous destabilization 4-6 hours later helped restore basal expression levels. Acceleration of PIM1 mRNA turnover coincided with accumulation of tristetraprolin (TTP), an mRNA-destabilizing protein that targets transcripts containing AU-rich elements. TTP binds PIM1 mRNA in cells, and suppresses its expression by accelerating mRNA decay. Reporter mRNA decay assays localized the TTP-regulated mRNA decay element to a discrete AU-rich sequence in the distal 3'-untranslated region that binds TTP. These data suggest that coordinated stimulation of TTP and PIM1 expression limits the magnitude and duration of PIM1 mRNA accumulation by accelerating its degradation as TTP protein levels increase. Consistent with this model, PIM1 and TTP mRNA levels were well correlated across selected human tissue panels, and PIM1 mRNA was induced to significantly higher levels in mitogen-stimulated fibroblasts from TTP-deficient mice. Together, these data support a model whereby induction of TTP mediates a negative feedback circuit to limit expression of selected mitogen-activated genes. C1 [Mahat, Dig B.; Brennan-Laun, Sarah E.; Fialcowitz-White, Elizabeth J.; Kishor, Aparna; Ross, Christina R.; Pozharskaya, Tatyana; Wilson, Gerald M.] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Hassel, Bret A.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Hassel, Bret A.; Wilson, Gerald M.] Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Rawn, J. David] Towson Univ, Dept Chem, Baltimore, MD 21204 USA. [Blackshear, Perry J.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Mahat, DB (reprint author), Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. EM gwils001@umaryland.edu FU American Cancer Society [RSG-07-293-01-GMC]; National Institutes of Heatlh [CA102428]; VA Merit Review Award FX These studies were supported by American Cancer Society grant RSG-07-293-01-GMC and National Institutes of Heatlh grant CA102428 (to GMW) and by a VA Merit Review Award (to BAH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 80 TC 7 Z9 7 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 MAR 8 PY 2012 VL 7 IS 3 AR e33194 DI 10.1371/journal.pone.0033194 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 929KT UT WOS:000303062000036 PM 22413002 ER PT J AU Sundaresan, P Ravindran, RD Vashist, P Shanker, A Nitsch, D Talwar, B Maraini, G Camparini, M Nonyane, BAS Smeeth, L Chakravarthy, U Hejtmancik, JF Fletcher, AE AF Sundaresan, Periasamy Ravindran, Ravilla D. Vashist, Praveen Shanker, Ashwini Nitsch, Dorothea Talwar, Badrinath Maraini, Giovanni Camparini, Monica Nonyane, Bareng Aletta S. Smeeth, Liam Chakravarthy, Usha Hejtmancik, James F. Fletcher, Astrid E. TI EPHA2 Polymorphisms and Age-Related Cataract in India SO PLOS ONE LA English DT Article ID BEAVER DAM EYE; LENS OPACITIES; CORTICAL CATARACT; RISK-FACTORS; ASSOCIATION; POPULATION; DISEASES; NUCLEAR AB Objective: We investigated whether previously reported single nucleotide polymorphisms (SNPs) of EPHA2 in European studies are associated with cataract in India. Methods: We carried out a population-based genetic association study. We enumerated randomly sampled villages in two areas of north and south India to identify people aged 40 and over. Participants attended a clinical examination including lens photography and provided a blood sample for genotyping. Lens images were graded by the Lens Opacification Classification System (LOCS III). Cataract was defined as a LOCS III grade of nuclear >= 4, cortical >= 3, posterior sub-capsular (PSC) >= 2, or dense opacities or aphakia/pseudophakia in either eye. We genotyped SNPs rs3754334, rs7543472 and rs11260867 on genomic DNA extracted from peripheral blood leukocytes using TaqMan assays in an ABI 7900 real-time PCR. We used logistic regression with robust standard errors to examine the association between cataract and the EPHA2 SNPs, adjusting for age, sex and location. Results: 7418 participants had data on at least one of the SNPs investigated. Genotype frequencies of controls were in Hardy-Weinberg Equilibrium (p > 0.05). There was no association of rs3754334 with cataract or type of cataract. Minor allele homozygous genotypes of rs7543472 and rs11260867 compared to the major homozygote genotype were associated with cortical cataract, Odds ratio (OR) = 1.8, 95% Confidence Interval (CI) (1.1, 3.1) p = 0.03 and 2.9 (1.2, 7.1) p = 0.01 respectively, and with PSC cataract, OR = 1.5 (1.1, 2.2) p = 0.02 and 1.8 (0.9, 3.6) p = 0.07 respectively. There was no consistent association of SNPs with nuclear cataract or a combined variable of any type of cataract including operated cataract. Conclusions: Our results in the Indian population agree with previous studies of the association of EPHA2 variants with cortical cataracts. We report new findings for the association with PSC which is particularly prevalent in Indians. C1 [Sundaresan, Periasamy; Shanker, Ashwini] Aravind Eye Hosp, Dr G Venkataswamy Eye Res Inst, Dept Genet, Aravind Med Res Fdn, Madurai, Tamil Nadu, India. [Ravindran, Ravilla D.; Talwar, Badrinath] Aravind Eye Hosp, Pondicherry, India. [Vashist, Praveen] All India Inst Med Sci, Dr Rajendra Prasad Ctr Ophthalm Sci, New Delhi 110029, India. [Nitsch, Dorothea; Nonyane, Bareng Aletta S.; Smeeth, Liam; Fletcher, Astrid E.] London Sch Hyg & Trop Med, Fac Epidemiol & Populat Hlth, London WC1, England. [Maraini, Giovanni; Camparini, Monica] Univ Parma, Sez Oftalmol, Dipartimento Sci Otorino Odonto Oftalmol & Cerv F, I-43100 Parma, Italy. [Chakravarthy, Usha] Queens Univ Belfast, Ctr Vis & Vasc Sci, Sch Med Dent & Biomed Sci, Belfast BT7 1NN, Antrim, North Ireland. [Hejtmancik, James F.] NEI, Sect Ophthalm Mol Genet, Bethesda, MD 20892 USA. RP Sundaresan, P (reprint author), Aravind Eye Hosp, Dr G Venkataswamy Eye Res Inst, Dept Genet, Aravind Med Res Fdn, Madurai, Tamil Nadu, India. EM astrid.fletcher@lshtm.ac.uk OI Nonyane, Bareng/0000-0001-5633-7487 FU Wellcome Trust [098504, G082571, 073300] NR 18 TC 17 Z9 18 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 MAR 8 PY 2012 VL 7 IS 3 AR e33001 DI 10.1371/journal.pone.0033001 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 929KT UT WOS:000303062000026 PM 22412971 ER PT J AU Li, ZJ Huang, H Li, YY Jiang, X Chen, P Arnovitz, S Radmacher, MD Maharry, K Elkahloun, A Yang, XN He, CJ He, M Zhang, ZY Dohner, K Neilly, MB Price, C Lussier, YA Zhang, YM Larson, RA Le Beau, MM Caligiuri, MA Bullinger, L Valk, PJM Delwel, R Lowenberg, B Liu, PP Marcucci, G Bloomfield, CD Rowley, JD Chen, JJ AF Li, Zejuan Huang, Hao Li, Yuanyuan Jiang, Xi Chen, Ping Arnovitz, Stephen Radmacher, Michael D. Maharry, Kati Elkahloun, Abdel Yang, Xinan He, Chunjiang He, Miao Zhang, Zhiyu Dohner, Konstanze Neilly, Mary Beth Price, Colles Lussier, Yves A. Zhang, Yanming Larson, Richard A. Le Beau, Michelle M. Caligiuri, Michael A. Bullinger, Lars Valk, Peter J. M. Delwel, Ruud Lowenberg, Bob Liu, Paul P. Marcucci, Guido Bloomfield, Clara D. Rowley, Janet D. Chen, Jianjun TI Up-regulation of a HOXA-PBX3 homeobox-gene signature following down-regulation of miR-181 is associated with adverse prognosis in patients with cytogenetically abnormal AML SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MICRORNA EXPRESSION; TRANSCRIPTION FACTORS; CLASS PREDICTION; CEBPA MUTATIONS; HOX EXPRESSION; TARGETING HOX; GROUP-B; MLL; CANCER AB Increased expression levels of miR-181 family members have been shown to be associated with favorable outcome in patients with cytogenetically normal acute myeloid leukemia. Here we show that increased expression of miR-181a and miR-181b is also significantly (P < .05; Cox regression) associated with favorable overall survival in cytogenetically abnormal AML (CA-AML) patients. We further show that up-regulation of a gene signature composed of 4 potential miR-181 targets (including HOXA7, HOXA9, HOXA11, and PBX3), associated with down-regulation of miR-181 family members, is an independent predictor of adverse overall survival on multivariable testing in analysis of 183 CA-AML patients. The independent prognostic impact of this 4-homeobox-gene signature was confirmed in a validation set of 271 CA-AML patients. Furthermore, our in vitro and in vivo studies indicated that ectopic expression of miR-181b significantly promoted apoptosis and inhibited viability/proliferation of leukemic cells and delayed leukemogenesis; such effects could be reversed by forced expression of PBX3. Thus, the up-regulation of the 4 homeobox genes resulting from the down-regulation of miR-181 family members probably contribute to the poor prognosis of patients with nonfavorable CA-AML. Restoring expression of miR-181b and/or targeting the HOXA/PBX3 pathways may provide new strategies to improve survival substantially. (Blood. 2012;119(10):2314-2324) C1 [Li, Zejuan; Huang, Hao; Li, Yuanyuan; Jiang, Xi; Chen, Ping; Arnovitz, Stephen; He, Chunjiang; He, Miao; Neilly, Mary Beth; Price, Colles; Zhang, Yanming; Larson, Richard A.; Le Beau, Michelle M.; Rowley, Janet D.; Chen, Jianjun] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Radmacher, Michael D.; Maharry, Kati; Caligiuri, Michael A.; Marcucci, Guido; Bloomfield, Clara D.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Elkahloun, Abdel; Liu, Paul P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Yang, Xinan; Lussier, Yves A.] Univ Chicago, Dept Med, Ctr Biomed Informat, Med Genet Sect, Chicago, IL 60637 USA. [Zhang, Zhiyu] Univ Chicago, Tang Ctr Herbal Med Res, Chicago, IL 60637 USA. [Dohner, Konstanze; Bullinger, Lars] Univ Ulm, Dept Internal Med 3, D-7900 Ulm, Germany. [Valk, Peter J. M.; Delwel, Ruud; Lowenberg, Bob] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands. RP Chen, JJ (reprint author), Univ Chicago, Dept Med, Hematol Oncol Sect, 900 E 57th St,KCBD Rm 7134, Chicago, IL 60637 USA. EM jchen@medicine.bsd.uchicago.edu RI Liu, Paul/A-7976-2012; OI Liu, Paul/0000-0002-6779-025X; He, Chunjiang/0000-0002-4868-331X; Lussier, Yves/0000-0001-9854-1005; Larson, Richard/0000-0001-9168-3203 FU Leukemia & Lymphoma Society; CALGB [20801]; National Institutes of Health [CA127277, P01 CA40046, P30 CA014599]; American Cancer Society; Gabrielle's Angel Foundation for Cancer Research; Spastic Paralysis Foundation of the Illinois, Eastern Iowa Branch of Kiwanis International; Fidelity Foundation; U10 of the CALGB LCSC committee [U10 CA101140]; P50 of OSU Leukemia SPORE [P50CA140158]; Leukemia Clinical Research Foundation; National Human Genome Research Institute, National Institutes of Health; National Natural Science Foundation of China [60971099]; Deutsche Jose Carreras Leukamie Stiftung [R 06/41v]; Deutsche Forschungsgemeinschaft (Heisenberg-Stipendium) [BU 1339/3-1] FX This work was supported in part by the Leukemia & Lymphoma Society (Translational Research Grant, J.D.R. and J.C.), CALGB (pilot grant 20801, J.D.R. and J.C.), National Institutes of Health (R01 grant CA127277, J.C.), American Cancer Society (Research Scholar grant, J.C.), Leukemia & Lymphoma Society (Special Fellowship, Z.L.), Gabrielle's Angel Foundation for Cancer Research (J.C., Z.L., and H. H.), the Spastic Paralysis Foundation of the Illinois, Eastern Iowa Branch of Kiwanis International (J.D.R.), the Fidelity Foundation (J.D.R. and J.C.), the U10 of the CALGB LCSC committee (U10 CA101140, G.M.), the P50 of OSU Leukemia SPORE (P50CA140158 Project 2, C.D.B. and G.M.), Leukemia Clinical Research Foundation grant (C.D.B. and G.M), the Intramural Research Program of National Human Genome Research Institute, National Institutes of Health (A.E. and P.P.L.), the National Natural Science Foundation of China (60971099, X.Y.),the Deutsche Jose Carreras Leukamie Stiftung (grant R 06/41v, L.B.), the Deutsche Forschungsgemeinschaft (Heisenberg-Stipendium BU 1339/3-1, L.B), and National Institutes of Health (P01 CA40046, M.M.L.B.; and P30 CA014599, M.M.L.B.). NR 50 TC 75 Z9 84 U1 0 U2 9 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 MAR 8 PY 2012 VL 119 IS 10 BP 2314 EP 2324 DI 10.1182/blood-2011-10-386235 PG 11 WC Hematology SC Hematology GA 906OP UT WOS:000301356000022 PM 22251480 ER PT J AU Little, MP Rajaraman, P Curtis, RE Devesa, SS Inskip, PD Check, DP Linet, MS AF Little, M. P. Rajaraman, P. Curtis, R. E. Devesa, S. S. Inskip, P. D. Check, D. P. Linet, M. S. TI Mobile phone use and glioma risk: comparison of epidemiological study results with incidence trends in the United States SO BRITISH MEDICAL JOURNAL LA English DT Article ID CELLULAR-TELEPHONE USE; MALIGNANT BRAIN-TUMORS; CORDLESS PHONES; INCIDENCE RATES; DANISH COHORT; TIME TRENDS; CANCER; CLONALITY; RADIATION; DENMARK AB Objective In view of mobile phone exposure being classified as a possible human carcinogen by the International Agency for Research on Cancer (IARC), we determined the compatibility of two recent reports of glioma risk (forming the basis of the IARC's classification) with observed incidence trends in the United States. Design Comparison of observed rates with projected rates of glioma incidence for 1997-2008. We estimated projected rates by combining relative risks reported in the 2010 Interphone study and a 2011 Swedish study by Hardell and colleagues with rates adjusted for age, registry, and sex; data for mobile phone use; and various latency periods. Setting US population based data for glioma incidence in 1992-2008, from 12 registries in the Surveillance, Epidemiology, and End Results (SEER) programme (Atlanta, Detroit, Los Angeles, San Francisco, San Jose-Monterey, Seattle, rural Georgia, Connecticut, Hawaii, Iowa, New Mexico, and Utah). Participants Data for 24 813 non-Hispanic white people diagnosed with glioma at age 18 years or older. Results Age specific incidence rates of glioma remained generally constant in 1992-2008 (-0.02% change per year, 95% confidence interval -0.28% to 0.25%), a period coinciding with a substantial increase in mobile phone use from close to 0% to almost 100% of the US population. If phone use was associated with glioma risk, we expected glioma incidence rates to be higher than those observed, even with a latency period of 10 years and low relative risks (1.5). Based on relative risks of glioma by tumour latency and cumulative hours of phone use in the Swedish study, predicted rates should have been at least 40% higher than observed rates in 2008. However, predicted glioma rates based on the small proportion of highly exposed people in the Interphone study could be consistent with the observed data. Results remained valid if we used either non-regular users or low users of mobile phones as the baseline category, and if we constrained relative risks to be more than 1. Conclusions Raised risks of glioma with mobile phone use, as reported by one (Swedish) study forming the basis of the IARC's re-evaluation of mobile phone exposure, are not consistent with observed incidence trends in US population data, although the US data could be consistent with the modest excess risks in the Interphone study. C1 [Little, M. P.; Rajaraman, P.; Curtis, R. E.; Inskip, P. D.; Linet, M. S.] NCI, Radiat Epidemiol Branch, Rockville, MD 20852 USA. [Devesa, S. S.; Check, D. P.] NCI, Biostat Branch, Rockville, MD 20852 USA. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Rockville, MD 20852 USA. EM mark.little@nih.gov OI Little, Mark/0000-0003-0980-7567 FU National Institutes of Health; National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported by the Intramural Research Program of the National Institutes of Health, and the National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 40 TC 42 Z9 44 U1 2 U2 32 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD MAR 8 PY 2012 VL 344 AR e1147 DI 10.1136/bmj.e1147 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 908HL UT WOS:000301481400001 PM 22403263 ER PT J AU Andreani, A Granaiola, M Locatelli, A Morigi, R Rambaldi, M Varoli, L Calonghi, N Cappadone, C Farruggia, G Stefanelli, C Masotti, L Nguyen, TL Hamel, E Shoemaker, RH AF Andreani, Aldo Granaiola, Massimiliano Locatelli, Alessandra Morigi, Rita Rambaldi, Mirella Varoli, Lucilla Calonghi, Natalia Cappadone, Concettina Farruggia, Giovanna Stefanelli, Claudio Masotti, Lanfranco Nguyen, Tam L. Hamel, Ernest Shoemaker, Robert H. TI Substituted 3-(5-Imidazo[2,1-b]thiazolylmethylene)-2-indolinones and Analogues: Synthesis, Cytotoxic Activity, and Study of the Mechanism of Action SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POTENTIAL ANTITUMOR AGENTS; ANTIMITOTIC AGENTS; CANCER-CELLS; TUBULIN; GUANYLHYDRAZONES; DERIVATIVES; INHIBITORS; COLCHICINE; APOPTOSIS; GROWTH AB The synthesis of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones and analogues is reported. Their cytotoxic activity was evaluated according to protocols available at the National Cancer Institute (NCI), Bethesda, MD. The action of selected compounds was examined for potential inhibition of tubulin assembly in comparison with the potent colchicine site agent combretastatin A-4. The most potent compounds also strongly and selectively inhibited the phosphorylation of the oncoprotein kinase Akt in cancer cells. The effect of the most interesting compounds was examined on the growth of HT-29 colon cancer cells. These compounds caused the cells to arrest in the G2/M phase of the cell cycle, as would be expected for inhibitors of tubulin assembly. C1 [Andreani, Aldo; Granaiola, Massimiliano; Locatelli, Alessandra; Morigi, Rita; Rambaldi, Mirella; Varoli, Lucilla] Univ Bologna, Dipartimento Sci Farmaceut, I-40126 Bologna, Italy. [Calonghi, Natalia; Cappadone, Concettina; Farruggia, Giovanna; Stefanelli, Claudio; Masotti, Lanfranco] Univ Bologna, Dipartimento Biochim G Moruzzi, I-40126 Bologna, Italy. [Nguyen, Tam L.] NCI, Target Struct Based Drug Discovery Grp, SAIC Frederick Inc, Frederick, MD 21702 USA. [Hamel, Ernest; Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP Andreani, A (reprint author), Univ Bologna, Dipartimento Sci Farmaceut, Via Belmeloro 6, I-40126 Bologna, Italy. EM aldo.andreani@unibo.it FU University of Bologna, Italy (RFO); MIUR; National Cancer Institute, National Institutes of Health [N01-CO-12400]; Division of Cancer Treatment and Diagnosis of the National Cancer Institute FX This work was supported in part by a grant from the University of Bologna, Italy (RFO), and from MIUR (PRIN 2009). We are grateful to the National Cancer Institute (Bethesda, MD) for the anticancer tests. It has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the 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 42 TC 26 Z9 26 U1 0 U2 16 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 MAR 8 PY 2012 VL 55 IS 5 BP 2078 EP 2088 DI 10.1021/jm2012694 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 904CA UT WOS:000301170000025 PM 22283430 ER PT J AU Bao, XF Lu, SY Liow, JS Zoghbi, SS Jenko, KJ Clark, DT Gladding, RL Innis, RB Pike, VW AF Bao, Xiaofeng Lu, Shuiyu Liow, Jeih-San Zoghbi, Sami S. Jenko, Kimberly J. Clark, David T. Gladding, Robert L. Innis, Robert B. Pike, Victor W. TI Radiosynthesis and Evaluation of an F-18-Labeled Positron Emission Tomography (PET) Radioligand for Brain Histamine Subtype-3 Receptors Based on a Nonimidazole 2-Aminoethylbenzofuran Chemotype SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID H-3 RECEPTOR; IN-VIVO; RAT-BRAIN; FREE-FRACTION; H3 RECEPTOR; ANTAGONIST; BINDING; LIGAND; BIODISTRIBUTION; LOCALIZATION AB A known chemotype of H-3 receptor ligand was explored for development of a radioligand for imaging brain histamine subtype 3 (H-3) receptors in vivo with positron emission tomography (PET), namely nonimidazole 2-aminoethylbenzofurans, represented by the compound (R)-(2-(2-(2-methylpyrrolidin-1-yl)ethyl)benzofuran-5-yl)(4-fluorophenyl)-methanone (9). Compound 9 was labeled with fluorine-18 (t(1/2) = 109.7 min) in high specific activity by treating the prepared nitro analogue (12) with cyclotron-produced [F-18]-fluoride ion. [F-18]9 was studied with PET in mouse and in monkey after intravenous injection. [F-18]9 showed favorable properties as a candidate PET radioligand, including moderately high brain uptake with a high proportion of H-3 receptor-specific signal in the absence of radiodefluorination. The nitro compound 12 was found to have even higher H-3 receptor affinity, indicating the potential of this chemotype for the development of further promising PET ralioligands. C1 [Bao, Xiaofeng; Lu, Shuiyu; Liow, Jeih-San; Zoghbi, Sami S.; Jenko, Kimberly J.; Clark, David T.; Gladding, Robert L.; Innis, Robert B.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3 C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov RI Bao, Xiaofeng/K-5278-2013; OI Lu, Shuiyu/0000-0003-0310-4318 FU National Institutes of Health (NIMH) [HHSN-271-2008-00025-C] FX This study was supported by the Intramural Research Program of the National Institutes of Health (NIMH). We thank the NIH Clinical PET Department (Chief Dr. P. Herscovitch) for fluorine-18 production and PMOD Technologies for providing the image analysis software. Receptor binding assays were performed by the National Institute of Mental Health's Psychoactive Drug Screening Program, contract no. HHSN-271-2008-00025-C (NIMH PDSP). The NIMH PDSP is directed by Dr. Bryan L. Roth, MD Ph.D., at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda, MD, USA. We also thank Cheryl L. Morse (NIMH) for assistance in radiochemistry. NR 44 TC 15 Z9 15 U1 0 U2 13 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 MAR 8 PY 2012 VL 55 IS 5 BP 2406 EP 2415 DI 10.1021/jm201690h PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 904CA UT WOS:000301170000051 PM 22313227 ER PT J AU Savitz, J Nugent, AC Cannon, DM Carlson, PJ Davis, R Neumeister, A Rallis-Frutos, D Fromm, S Herscovitch, P Drevets, WC AF Savitz, Jonathan Nugent, Allison C. Cannon, Dara M. Carlson, Paul J. Davis, Rebecca Neumeister, Alexander Rallis-Frutos, Denise Fromm, Steve Herscovitch, Peter Drevets, Wayne C. TI Effects of arterial cannulation stress on regional cerebral blood flow in major depressive disorder SO SCIENTIFIC REPORTS LA English DT Article ID MEDIAL PREFRONTAL CORTEX; POSITRON-EMISSION-TOMOGRAPHY; ANTERIOR CINGULATE CORTEX; DEFAULT-MODE NETWORK; PAINFUL STIMULATION; HIPPOCAMPAL VOLUME; GLUCOSE-METABOLISM; BIPOLAR DISORDER; BRAIN ACTIVATION; CORTISOL-LEVELS AB Individuals with major depressive disorder (MDD) display abnormal neurophysiological responses to psychological stress but little is known about their neurophysiological responses to physiological stressors. Using [O-15]-H2O positron emission tomography we assessed whether the regional cerebral blood flow (rCBF) response to arterial cannulation differed between patients with MDD and healthy controls (HCs). Fifty-one MDDpatients and 62 HCs were scanned following arterial cannulation and 15MDDpatients and 17 HCs were scanned without arterial cannulation. A region-of-interest analysis showed that a significantly increased rCBF of the anterior cingulate cortex and right amygdala was associated with arterial cannulation in MDD. A whole brain analysis showed increased rCBF of the right post-central gyrus, left temporopolar cortex, and right amygdala during arterial cannulation in MDD patients. The rCBF in the right amygdala was significantly correlated with depression severity. Conceivably, the limbic response to invasive physical stress is greater in MDD subjects than in HCs. C1 [Savitz, Jonathan; Nugent, Allison C.; Davis, Rebecca; Rallis-Frutos, Denise; Fromm, Steve; Drevets, Wayne C.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Savitz, Jonathan; Drevets, Wayne C.] Laureate Inst Brain Res, Tulsa, OK USA. [Savitz, Jonathan] Tulsa Sch Community Med, Dept Med, Tulsa, OK USA. [Nugent, Allison C.] NIMH, Expt Therapeut Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Cannon, Dara M.] Natl Univ Ireland Galway, Clin Neuroimaging Lab, Galway, Ireland. [Carlson, Paul J.] Univ Utah, Salt Lake City VA, Salt Lake City, UT USA. [Carlson, Paul J.] Univ Utah, Dept Psychiat, Salt Lake City, UT USA. [Neumeister, Alexander] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Herscovitch, Peter] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Drevets, Wayne C.] Univ Oklahoma, Coll Med, Dept Psychiat, Tulsa, OK USA. RP Savitz, J (reprint author), NIMH, Sect Neuroimaging Mood & Anxiety Disorders, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. EM jonathansavitz@hotmail.com RI Savitz, Jonathan/C-3088-2009; Cannon, Dara/C-1323-2009; OI Savitz, Jonathan/0000-0001-8143-182X; Cannon, Dara/0000-0001-7378-3411; Nugent, Allison/0000-0003-2569-2480 NR 98 TC 2 Z9 2 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 8 PY 2012 VL 2 AR 308 DI 10.1038/srep00308 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 905TX UT WOS:000301299000002 PM 22403745 ER PT J AU Scally, A Dutheil, JY Hillier, LW Jordan, GE Goodhead, I Herrero, J Hobolth, A Lappalainen, T Mailund, T Marques-Bonet, T McCarthy, S Montgomery, SH Schwalie, PC Tang, YA Ward, MC Xue, YL Yngvadottir, B Alkan, C Andersen, LN Ayub, Q Ball, EV Beal, K Bradley, BJ Chen, Y Clee, CM Fitzgerald, S Graves, TA Gu, Y Heath, P Heger, A Karakoc, E Kolb-Kokocinski, A Laird, GK Lunter, G Meader, S Mort, M Mullikin, JC Munch, K O'Connor, TD Phillips, AD Prado-Martinez, J Rogers, AS Sajjadian, S Schmidt, D Shaw, K Simpson, JT Stenson, PD Turner, DJ Vigilant, L Vilella, AJ Whitener, W Zhu, BL Cooper, DN de Jong, P Dermitzakis, ET Eichler, EE Flicek, P Goldman, N Mundy, NI Ning, ZM Odom, DT Ponting, CP Quail, MA Ryder, OA Searle, SM Warren, WC Wilson, RK Schierup, MH Rogers, J Tyler-Smith, C Durbin, R AF Scally, Aylwyn Dutheil, Julien Y. Hillier, LaDeana W. Jordan, Gregory E. Goodhead, Ian Herrero, Javier Hobolth, Asger Lappalainen, Tuuli Mailund, Thomas Marques-Bonet, Tomas McCarthy, Shane Montgomery, Stephen H. Schwalie, Petra C. Tang, Y. Amy Ward, Michelle C. Xue, Yali Yngvadottir, Bryndis Alkan, Can Andersen, Lars N. Ayub, Qasim Ball, Edward V. Beal, Kathryn Bradley, Brenda J. Chen, Yuan Clee, Chris M. Fitzgerald, Stephen Graves, Tina A. Gu, Yong Heath, Paul Heger, Andreas Karakoc, Emre Kolb-Kokocinski, Anja Laird, Gavin K. Lunter, Gerton Meader, Stephen Mort, Matthew Mullikin, James C. Munch, Kasper O'Connor, Timothy D. Phillips, Andrew D. Prado-Martinez, Javier Rogers, Anthony S. Sajjadian, Saba Schmidt, Dominic Shaw, Katy Simpson, Jared T. Stenson, Peter D. Turner, Daniel J. Vigilant, Linda Vilella, Albert J. Whitener, Weldon Zhu, Baoli Cooper, David N. de Jong, Pieter Dermitzakis, Emmanouil T. Eichler, Evan E. Flicek, Paul Goldman, Nick Mundy, Nicholas I. Ning, Zemin Odom, Duncan T. Ponting, Chris P. Quail, Michael A. Ryder, Oliver A. Searle, Stephen M. Warren, Wesley C. Wilson, Richard K. Schierup, Mikkel H. Rogers, Jane Tyler-Smith, Chris Durbin, Richard TI Insights into hominid evolution from the gorilla genome sequence SO NATURE LA English DT Article ID COPY NUMBER; MUTATION; POPULATION; PRIMATES; HUMANS; CONSEQUENCES; CHIMPANZEES; PATTERNS; REVEALS; FAMILY AB Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution. C1 [Scally, Aylwyn; Goodhead, Ian; McCarthy, Shane; Tang, Y. Amy; Xue, Yali; Yngvadottir, Bryndis; Ayub, Qasim; Chen, Yuan; Clee, Chris M.; Gu, Yong; Heath, Paul; Kolb-Kokocinski, Anja; Laird, Gavin K.; Rogers, Anthony S.; Simpson, Jared T.; Turner, Daniel J.; Whitener, Weldon; Ning, Zemin; Odom, Duncan T.; Quail, Michael A.; Searle, Stephen M.; Rogers, Jane; Tyler-Smith, Chris; Durbin, Richard] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. [Dutheil, Julien Y.; Hobolth, Asger; Mailund, Thomas; Andersen, Lars N.; Munch, Kasper; Schierup, Mikkel H.] Aarhus Univ, Bioinformat Res Ctr, DK-8000 Aarhus C, Denmark. [Hillier, LaDeana W.; Marques-Bonet, Tomas; Alkan, Can; Karakoc, Emre; Sajjadian, Saba; Eichler, Evan E.] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA 98195 USA. [Jordan, Gregory E.; Herrero, Javier; Schwalie, Petra C.; Beal, Kathryn; Fitzgerald, Stephen; Vilella, Albert J.; Flicek, Paul; Goldman, Nick] European Bioinformat Inst, Hinxton CB10 1SD, England. [Lappalainen, Tuuli; Dermitzakis, Emmanouil T.] Univ Geneva, Sch Med, Dept Genet Med & Dev, CH-1211 Geneva 4, Switzerland. [Marques-Bonet, Tomas; Prado-Martinez, Javier] Inst Biol Evolut UPF CSIC, Barcelona 08003, Catalonia, Spain. [Marques-Bonet, Tomas] ICREA, Barcelona 08010, Spain. [Montgomery, Stephen H.; Bradley, Brenda J.; O'Connor, Timothy D.; Mundy, Nicholas I.] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England. [Ward, Michelle C.; Schmidt, Dominic; Odom, Duncan T.] Univ Cambridge, Dept Oncol, Hutchison MRC Res Ctr, Cambridge CB2 0XZ, England. [Ward, Michelle C.; Schmidt, Dominic; Odom, Duncan T.] Cambridge Res Inst, Canc Res UK, Li Ka Shing Ctr, Cambridge CB2 0RE, England. [Alkan, Can; Eichler, Evan E.] Univ Washington, Howard Hughes Med Inst, Seattle, WA USA. [Ball, Edward V.; Mort, Matthew; Phillips, Andrew D.; Shaw, Katy; Stenson, Peter D.; Cooper, David N.] Cardiff Univ, Inst Med Genet, Cardiff CF14 4XN, S Glam, Wales. [Bradley, Brenda J.] Yale Univ, Dept Anthropol, New Haven, CT 06511 USA. [Graves, Tina A.; Warren, Wesley C.; Wilson, Richard K.] Washington Univ, Sch Med, Genome Inst, St Louis, MO 63108 USA. [Heger, Andreas; Meader, Stephen; Ponting, Chris P.] Univ Oxford, Dept Physiol Anat & Genet, MRC Funct Genom Unit, Oxford OX1 3QX, England. [Lunter, Gerton] Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Mullikin, James C.] NHGRI, Comparat Genom Unit, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Vigilant, Linda] Max Planck Inst Evolutionary Anthropol, Primatol Dept, D-04103 Leipzig, Germany. [Zhu, Baoli; de Jong, Pieter] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. [Ryder, Oliver A.] San Diego Zoos Inst Conservat Res, Escondido, CA 92027 USA. RP Durbin, R (reprint author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Hinxton CB10 1SA, England. EM rd@sanger.ac.uk RI Alkan, Can/D-2982-2009; Munch, Kasper/A-1434-2010; Dermitzakis, Emmanouil/B-7687-2013; Ning, Zemin/D-2411-2013; Marques-Bonet, Tomas/I-4618-2014; Schierup, Mikkel/F-1675-2010; Cooper, David/H-4384-2011; Lunter, Gerton/H-4939-2016; Dutheil, Julien/K-5479-2016; OI Alkan, Can/0000-0002-5443-0706; Goodhead, Ian/0000-0002-3110-9442; Munch, Kasper/0000-0003-2880-6252; Marques-Bonet, Tomas/0000-0002-5597-3075; Schierup, Mikkel/0000-0002-5028-1790; Cooper, David/0000-0002-8943-8484; Dutheil, Julien/0000-0001-7753-4121; Odom, Duncan/0000-0001-6201-5599; Jordan, Gregory/0000-0002-7655-6000; Durbin, Richard/0000-0002-9130-1006; Prado-Martinez, Javier/0000-0001-5402-2721; Schwalie, Petra Catalina/0000-0002-6004-8095; Lappalainen, Tuuli/0000-0002-7746-8109; Mailund, Thomas/0000-0001-6206-9239; Vilella, Albert/0000-0002-2005-2516; Lunter, Gerton/0000-0002-3798-2058; Ayub, Qasim/0000-0003-3291-0917; Ning, Zemin/0000-0003-4359-776X; Herrero, Javier/0000-0001-7313-717X; Goldman, Nick/0000-0001-8486-2211; Flicek, Paul/0000-0002-3897-7955; Tang, Amy/0000-0003-0045-1234; Ponting, Chris/0000-0003-0202-7816; Hobolth, Asger/0000-0003-4056-1286; McCarthy, Shane/0000-0002-2715-4187; Heger, Andreas/0000-0001-7720-0447 FU Wellcome Trust [WT062023, WT089066, WT077192, WT077009, WT077198, 075491/Z/04]; EMBL; Gates Cambridge Trust; MRC; Lundbeck Foundation; Academy of Finlandand the Emil Aaltonen Foundation; Marie Curie fellowship; European Community [StG_20091118]; Spanish Ministry of Education [BES-2010-032251]; BBSRC; UK Medical Research Council; National Human Genome Research Institute, National Institutes of Health; Danish Council for Independent Research, Natural Sciences [09-062535]; Commonwealth Scholarship; Swiss National Science Foundation; Louis Jeantet Foundation; ERC; EMBO; Hutchinson Whampoa; NHGRI; BIOBASE GmbH; US National Science Foundation [DGE-0739133]; NHGRI [U54 HG003079]; NIH [HG002385] FX We thank H. Li and E. Birney for discussions, D. Zerbino, J. Stalker, L. Wilming, D. Rajan and H. Clawson for technical assistance, J. Ahringer for comments on the manuscript, K. Leus of the Center for Research and Conservation of the Royal Zoological Society of Antwerp for sample material from Mukisi, and the Marmoset Genome Analysis Consortium for permission to use the unpublished assembly of the marmoset genome. This research was supported in part by Wellcome Trust grants WT062023 (to J.H., K.B., S.F., A.J.V., P.F.), WT089066 (to R.D.), WT077192 (to R.D., S.M., A.K.-K., J.T.S., W.W.), WT077009 (to Y.X., B.Y., Q A., Y.C., C.T.-S.), WT077198 (to G.K.L.) and 075491/Z/04 (to G.L.); EMBL grants (to P.C.S., P.F.); scholarships from the Gates Cambridge Trust (to G.E.J. and T.D.O'C.); an MRC Special Fellowship in Biomedical Informatics (to A.S.); funding from the Lundbeck Foundation (to A.H.); the Academy of Finlandand the Emil Aaltonen Foundation (to T.L.); a Marie Curie fellowship (to T.M.-B.); the European Community's Seventh Framework Programme (FP7/2007-2013)/ERC Starting Grant (StG_20091118) (to T.M.-B.); an FPI grant from the Spanish Ministry of Education (BES-2010-032251) (to J.P.-M.); a BBSRC Doctoral Training Grant (to S.H.M.); grants from the UK Medical Research Council (to A.H., S.M., C.P.P.); the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (to J.C.M.); the Danish Council for Independent Research, Natural Sciences, grant no. 09-062535 (to K.M., M.H.S.); a Commonwealth Scholarship (to M.C.W.); the Swiss National Science Foundation, Louis Jeantet Foundation (to E.T.D.); an ERC Starting Grant and an EMBO Young Investigator Award, Hutchinson Whampoa (to D.T.O.); NHGRI support (to W.C.W.); support from BIOBASE GmbH (to E.V.B., P.D.S., M.M., A.D.P., K.S., D.N.C.); US National Science Foundation grant DGE-0739133 (to W.W.); NHGRI U54 HG003079 (to R.K.W.); NIH grant HG002385 (to E.E.E). E.E.E. is an investigator of the Howard Hughes Medical Institute. NR 51 TC 258 Z9 262 U1 13 U2 129 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 8 PY 2012 VL 483 IS 7388 BP 169 EP 175 DI 10.1038/nature10842 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 904DT UT WOS:000301174900029 PM 22398555 ER PT J AU Ngamskulrungroj, P Chang, Y Hansen, B Bugge, C Fischer, E Kwon-Chung, KJ AF Ngamskulrungroj, Popchai Chang, Yun Hansen, Bryan Bugge, Cliff Fischer, Elizabeth Kwon-Chung, Kyung J. TI Characterization of the Chromosome 4 Genes That Affect Fluconazole-Induced Disomy Formation in Cryptococcus neoformans SO PLOS ONE LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; AMINO-ACID SUBSTITUTIONS; AZOLE ANTIFUNGAL AGENTS; CANDIDA-ALBICANS; SACCHAROMYCES-CEREVISIAE; DRUG-RESISTANCE; RETROGRADE TRANSPORT; NUCLEAR-ENVELOPE; YEAST; IDENTIFICATION AB Heteroresistance in Cryptococcus neoformans is an intrinsic adaptive resistance to azoles and the heteroresistant phenotype is associated with disomic chromosomes. Two chromosome 1 (Chr1) genes, ERG11, the fluconazole target, and AFR1, a drug transporter, were reported as major factors in the emergence of Chr1 disomy. In the present study, we show Chr4 to be the second most frequently formed disomy at high concentrations of fluconazole (FLC) and characterize the importance of resident genes contributing to disomy formation. We deleted nine Chr4 genes presumed to have functions in ergosterol biosynthesis, membrane composition/integrity or drug transportation that could influence Chr4 disomy under FLC stress. Of these nine, disruption of three genes homologous to Sey1 (a GTPase), Glo3 and Gcs2 (the ADP-ribosylation factor GTPase activating proteins) significantly reduced the frequency of Chr4 disomy in heteroresistant clones. Furthermore, FLC resistant clones derived from sey1 Delta glo3 Delta did not show disomy of either Chr4 or Chr1 but instead had increased the copy number of the genes proximal to ERG11 locus on Chr1. Since the three genes are critical for the integrity of endoplasmic reticulum (ER) in Saccharomyces cerevisiae, we used Sec61 beta-GFP fusion as a marker to study the ER in the mutants. The cytoplasmic ER was found to be elongated in sey1D but without any discernable alteration in gcs2 Delta and glo3 Delta under fluorescence microscopy. The aberrant ER morphology of all three mutant strains, however, was discernable by transmission electron microscopy. A 3D reconstruction using Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) revealed considerably reduced reticulation in the ER of glo3 Delta and gcs2 Delta strains. In sey1 Delta, ER reticulation was barely detectable and cisternae were expanded extensively compared to the wild type strains. These data suggest that the genes required for maintenance of ER integrity are important for the formation of disomic chromosomes in C. neoformans under azole stress. C1 [Ngamskulrungroj, Popchai; Chang, Yun; Kwon-Chung, Kyung J.] NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Ngamskulrungroj, Popchai] Mahidol Univ, Dept Microbiol, Fac Med, Siriraj Hosp, Bangkok 10700, Thailand. [Hansen, Bryan; Fischer, Elizabeth] NIAID, Electron Microscopy Unit, Rocky Mt Labs, NIH, Hamilton, MT USA. [Bugge, Cliff] FEI Co, Hillsboro, OR USA. RP Ngamskulrungroj, P (reprint author), NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM june_kwon-chung@nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was primarily supported by funds from 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. No additional external funding was received for this study. NR 62 TC 11 Z9 11 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 MAR 7 PY 2012 VL 7 IS 3 AR e33022 DI 10.1371/journal.pone.0033022 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 929KK UT WOS:000303060800078 PM 22412978 ER PT J AU Thu, KL Vucic, EA Chari, R Zhang, W Lockwood, WW English, JC Fu, R Wang, P Feng, ZD MacAulay, CE Gazdar, AF Lam, S Lam, WL AF Thu, Kelsie L. Vucic, Emily A. Chari, Raj Zhang, Wei Lockwood, William W. English, John C. Fu, Rong Wang, Pei Feng, Ziding MacAulay, Calum E. Gazdar, Adi F. Lam, Stephen Lam, Wan L. TI Lung Adenocarcinoma of Never Smokers and Smokers Harbor Differential Regions of Genetic Alteration and Exhibit Different Levels of Genomic Instability SO PLOS ONE LA English DT Article ID SMALL-CELL; CHROMOSOMAL-ABERRATIONS; CANCER GENOME; COPY NUMBER; ARRAY CGH; NONSMOKERS; MUTATIONS; SIGNATURES; RESOLUTION; IMBALANCE AB Recent evidence suggests that the observed clinical distinctions between lung tumors in smokers and never smokers (NS) extend beyond specific gene mutations, such as EGFR, EML4-ALK, and KRAS, some of which have been translated into targeted therapies. However, the molecular alterations identified thus far cannot explain all of the clinical and biological disparities observed in lung tumors of NS and smokers. To this end, we performed an unbiased genome-wide, comparative study to identify novel genomic aberrations that differ between smokers and NS. High resolution whole genome DNA copy number profiling of 69 lung adenocarcinomas from smokers (n = 39) and NS (n = 30) revealed both global and regional disparities in the tumor genomes of these two groups. We found that NS lung tumors had a greater proportion of their genomes altered than those of smokers. Moreover, copy number gains on chromosomes 5q, 7p, and 16p occurred more frequently in NS. We validated our findings in two independently generated public datasets. Our findings provide a novel line of evidence distinguishing genetic differences between smoker and NS lung tumors, namely, that the extent of segmental genomic alterations is greater in NS tumors. Collectively, our findings provide evidence that these lung tumors are globally and genetically different, which implies they are likely driven by distinct molecular mechanisms. C1 [Thu, Kelsie L.; Vucic, Emily A.; Chari, Raj; Lockwood, William W.; MacAulay, Calum E.; Lam, Stephen; Lam, Wan L.] British Columbia Canc Res Ctr, Dept Integrat Oncol, Vancouver, BC V5Z 1L3, Canada. [Chari, Raj] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Zhang, Wei; Gazdar, Adi F.] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA. [Lockwood, William W.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [English, John C.] Vancouver Gen Hosp, Dept Pathol, Vancouver, BC V5Z 1M9, Canada. [Fu, Rong; Wang, Pei; Feng, Ziding] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Thu, KL (reprint author), British Columbia Canc Res Ctr, Dept Integrat Oncol, Vancouver, BC V5Z 1L3, Canada. EM kthu@bccrc.ca RI MacAulay, Calum/K-1795-2016; OI Vucic, Emily/0000-0002-2728-8708 FU Canadian Institutes for Health Research (CIHR) [MOP 86731, MOP 94867]; Canadian Cancer Society [CCS20485]; NCI Early Detection Research Network; Canary Foundation; Frederick Banting Canada Graduate Scholarship; Charles Best Canada Graduate Scholarship; Vanier Canada Graduate Scholarship; Banting Postdoctoral fellowship FX Funding provided by the Canadian Institutes for Health Research (CIHR; MOP 86731, MOP 94867), Canadian Cancer Society (CCS20485), NCI Early Detection Research Network, Canary Foundation, Frederick Banting and Charles Best Canada Graduate Scholarships [KLT, EAV and RC], Vanier Canada Graduate Scholarship [KLT], Banting Postdoctoral fellowship [RC], and CIHR Jean Francois St-Denis Fellowship in Cancer Research [WWL]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 23 Z9 26 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 MAR 7 PY 2012 VL 7 IS 3 AR e33003 DI 10.1371/journal.pone.0033003 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 929KK UT WOS:000303060800073 PM 22412972 ER PT J AU Ashrafian, H Czibik, G Bellahcene, M Aksentijevic, D Smith, AC Mitchell, SJ Dodd, MS Kirwan, J Byrne, JJ Ludwig, C Isackson, H Yavari, A Stottrup, NB Contractor, H Cahill, TJ Sahgal, N Ball, DR Birkler, RID Hargreaves, L Tennant, DA Land, J Lygate, CA Johannsen, M Kharbanda, RK Neubauer, S Redwood, C de Cabo, R Ahmet, I Talan, M Gunther, UL Robinson, AJ Viant, MR Pollard, PJ Tyler, DJ Watkins, H AF Ashrafian, Houman Czibik, Gabor Bellahcene, Mohamed Aksentijevic, Dunja Smith, Anthony C. Mitchell, Sarah J. Dodd, Michael S. Kirwan, Jennifer Byrne, Jonathan J. Ludwig, Christian Isackson, Henrik Yavari, Arash Stottrup, Nicolaj B. Contractor, Hussain Cahill, Thomas J. Sahgal, Natasha Ball, Daniel R. Birkler, Rune I. D. Hargreaves, Lain Tennant, Daniel A. Land, John Lygate, Craig A. Johannsen, Mogens Kharbanda, Rajesh K. Neubauer, Stefan Redwood, Charles de Cabo, Rafael Ahmet, Ismayil Talan, Mark Guenther, Ulrich L. Robinson, Alan J. Viant, Mark R. Pollard, Patrick J. Tyler, Damian J. Watkins, Hugh TI Fumarate Is Cardioprotective via Activation of the Nrf2 Antioxidant Pathway SO CELL METABOLISM LA English DT Article ID TRICARBOXYLIC-ACID-CYCLE; C-13 MAGNETIC-RESONANCE; IN-VIVO ASSESSMENT; HEME OXYGENASE-1; RAT-HEART; KEAP1-NRF2 PATHWAY; STRESS-RESPONSE; MYOCARDIAL-ISCHEMIA; REPERFUSION INJURY; EXPRESSION AB The citric acid cycle (CAC) metabolite fumarate has been proposed to be cardioprotective; however, its mechanisms of action remain to be determined. To augment cardiac fumarate levels and to assess fumarate's cardioprotective properties, we generated fumarate hydratase (Fh1) cardiac knockout (KO) mice. These fumarate-replete hearts were robustly protected from ischemia-reperfusion injury (I/R). To compensate for the loss of Fh1 activity, KO hearts maintain ATP levels in part by channeling amino acids into the CAC. In addition, by stabilizing the transcriptional regulator Nrf2, Fh1 KO hearts upregulate protective antioxidant response element genes. Supporting the importance of the latter mechanism, clinically relevant doses of dimethylfumarate upregulated Nrf2 and its target genes, hence protecting control hearts, but failed to similarly protect Nrf2-KO hearts in an in vivo model of myocardial infarction. We propose that clinically established fumarate derivatives activate the Nrf2 pathway and are readily testable cytoprotective agents. C1 [Ashrafian, Houman; Czibik, Gabor; Bellahcene, Mohamed; Aksentijevic, Dunja; Isackson, Henrik; Yavari, Arash; Contractor, Hussain; Cahill, Thomas J.; Lygate, Craig A.; Kharbanda, Rajesh K.; Neubauer, Stefan; Redwood, Charles; Watkins, Hugh] Univ Oxford, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Smith, Anthony C.; Robinson, Alan J.] Med Res Council Mitochondrial Biol Unit, Cambridge CB2 0XY, England. [Mitchell, Sarah J.] Univ Sydney, Royal N Shore Hosp, Kolling Inst Med Res, St Leonards, NSW 2065, Australia. [Mitchell, Sarah J.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Ahmet, Ismayil; Talan, Mark] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Dodd, Michael S.; Ball, Daniel R.; Tyler, Damian J.] Univ Oxford, Dept Physiol Anat & Genet, Cardiac Metab Res Grp, Oxford OX1 3QX, England. [Kirwan, Jennifer; Byrne, Jonathan J.; Viant, Mark R.] Univ Birmingham, Sch Biosci, Birmingham B15 2TT, W Midlands, England. [Ludwig, Christian; Tennant, Daniel A.; Guenther, Ulrich L.] Univ Birmingham, Sch Canc Sci, Birmingham B15 2TT, W Midlands, England. [Stottrup, Nicolaj B.; Birkler, Rune I. D.; Johannsen, Mogens] Aarhus Univ Hosp, Skejby Hosp, Dept Cardiol, Aarhus 8200 N, Denmark. [Stottrup, Nicolaj B.; Birkler, Rune I. D.; Johannsen, Mogens] Aarhus Univ Hosp, Sect Toxicol & Drug Anal, Dept Forens Med, Aarhus 8200 N, Denmark. [Hargreaves, Lain; Land, John; Pollard, Patrick J.] Natl Hosp Neurol, Neurometabol Unit, London WC1N 3BG, England. [Sahgal, Natasha; Watkins, Hugh] Univ Oxford, Nuffield Dept Med, Oxford OX3 7BN, England. RP Ashrafian, H (reprint author), Univ Oxford, Dept Cardiovasc Med, Oxford OX3 9DU, England. EM houman.ashrafian@cardiov.ox.ac.uk RI Pollard, Patrick/F-7516-2012; Ludwig, Christian/E-7679-2011; Johannsen, Mogens/E-5374-2011; Viant, Mark/B-6339-2009; de Cabo, Rafael/J-5230-2016; OI Kirwan, Jennifer/0000-0002-5423-1651; , rafael/0000-0003-2830-5693; Smith, Anthony/0000-0003-0141-0434; Watkins, Hugh/0000-0002-5287-9016; Tennant, Daniel/0000-0003-0499-2732; Kharbanda, Rajesh/0000-0002-5356-2395; Lygate, Craig/0000-0001-6079-0284; Pollard, Patrick/0000-0002-4459-4993; Ludwig, Christian/0000-0001-8901-6970; Tyler, Damian/0000-0002-0780-8905; Dodd, Michael/0000-0002-1217-4660; Johannsen, Mogens/0000-0002-2548-7025; Viant, Mark/0000-0001-5898-4119; de Cabo, Rafael/0000-0002-3354-2442; Yavari, Arash/0000-0002-0815-5088; Ashrafian, Houman/0000-0003-3988-378X FU Oxford British Heart Foundation Centre of Research Excellence; British Heart Foundation (BHF) [RG/02/010, RG/05/005]; Medical Research Council, UK; Medical Research Council; Oxford Instruments Molecular Biotools; GE Healthcare; Wellcome Trust [075491/Z/04]; Fondation Leducq [06CVD]; Lundbeck Foundation; National Health and Medical Research Council of Australia [1016439]; National Institute on Aging of the National Institutes of Health, USA; Beit Memorial Fellowship FX H.A. and H.W. are supported by the Oxford British Heart Foundation Centre of Research Excellence Award, and the the British Heart Foundation (BHF Grant RG/02/010). A.J.R. and A.C.S. are supported by the Medical Research Council, UK. D.A. and S.N. are supported by the British Heart Foundation Programme Grant RG/05/005. M.S.D., D.R.B., and D.J.T. are supported by research grants from the British Heart Foundation, the Medical Research Council, Oxford Instruments Molecular Biotools, and GE Healthcare. N.S.'s work is supported by the Core Award Grant 075491/Z/04 from the Wellcome Trust. N.B.S. is supported by the Fondation Leducq (06CVD) and the Lundbeck Foundation. P.J.P. is in receipt of a Beit Memorial Fellowship. S.J.M. is supported by a National Health and Medical Research Council of Australia CJ Martin Early Career Fellowship (1016439). The Thermo Scientific LTQ FT Ultra and Bruker NMR spectrometers used here were obtained through the Birmingham Science City Translational Medicine project, with support from Advantage West Midlands; the NMR spectrometer was further supported by the Wolfson Foundation. This study was also funded in part by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health, USA. We gratefully acknowledge and thank Dr. Reza Morovat, consultant clinical biochemist at the Oxford Radcliffe NHS Trust, Oxford; and Dawn Phillips-Boyer and Dawn Nines for their excellent animal care and assistance. NR 65 TC 71 Z9 73 U1 0 U2 18 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 MAR 7 PY 2012 VL 15 IS 3 BP 361 EP 371 DI 10.1016/j.cmet.2012.01.017 PG 11 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 911EZ UT WOS:000301701400016 PM 22405071 ER PT J AU Xue, L McNeil, BD Wu, XS Luo, FJ He, LM Wu, LG AF Xue, Lei McNeil, Benjamin D. Wu, Xin-Sheng Luo, Fujun He, Liming Wu, Ling-Gang TI A Membrane Pool Retrieved via Endocytosis Overshoot at Nerve Terminals: A Study of Its Retrieval Mechanism and Role SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SYNAPTIC VESICLE ENDOCYTOSIS; SLOW ENDOCYTOSIS; HIPPOCAMPAL SYNAPSES; CNS SYNAPSE; CALCIUM; EXOCYTOSIS; CALCINEURIN; DYNAMIN; CA2+; PITUITARY AB Endocytosis overshoot, which retrieves more membrane than vesicles just being exocytosed, occurs at nerve terminals and non-neuronal secretory cells. The mechanism that retrieves the overshoot membrane pool and the role of this pool remain largely unknown. We addressed this issue at the rat calyx of Held nerve terminal with capacitance measurements. We found that every calyx contained an overshoot pool similar to 1.8 times the readily releasable pool. Retrieval of this pool required large calcium influx, and was inhibited by blockers of calcium/calmodulin-activated calcineurin and dynamin, suggesting the involvement of calcineurin and dynamin in endocytosis overshoot. Depletion of the overshoot pool slowed down compensatory endocytosis, whereas recovery of the overshoot pool via exocytosis that deposited stranded vesicles to the plasma membrane led to recovery of compensatory endocytosis, suggesting that the overshoot pool enhances endocytosis efficiency. These results suggest that the overshoot pool exists at every nerve terminal, is of limited size arising from vesicles stranded at the plasma membrane, is retrieved via calcium/calmodulin/calcineurin and dynamin signaling pathway, and can enhance endocytosis efficiency. Potential mechanisms for how the endocytosis overshoot pool enhances endocytosis efficiency are discussed. C1 [Xue, Lei; McNeil, Benjamin D.; Wu, Xin-Sheng; Luo, Fujun; He, Liming; Wu, Ling-Gang] NINDS, Bethesda, MD 20892 USA. RP Wu, LG (reprint author), NINDS, 35 Convent Dr,Bldg 35,Rm 2B-1012, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov RI Luo, Fujun/I-1016-2013 FU National Institute of Neurological Disorders and Stroke FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program. NR 26 TC 9 Z9 9 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 7 PY 2012 VL 32 IS 10 BP 3398 EP 3404 DI 10.1523/JNEUROSCI.5943-11.2012 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 905SV UT WOS:000301295300015 PM 22399762 ER PT J AU Tokar, EJ Diwan, BA Waalkes, MP AF Tokar, Erik J. Diwan, Bhalchandra A. Waalkes, Michael P. TI Renal, hepatic, pulmonary and adrenal tumors induced by prenatal inorganic arsenic followed by dimethylarsinic acid in adulthood in CD1 mice SO TOXICOLOGY LETTERS LA English DT Article DE Arsenic; Mouse; Cancer; Kidney; Liver; Early; life; Lung; DMA ID EXPOSURE IN-UTERO; MALE F344 RATS; URINARY-BLADDER; POSTNATAL DIETHYLSTILBESTROL; CANCER-MORTALITY; DRINKING-WATER; CARCINOGENICITY; INDUCTION; LIVER; METABOLISM AB Inorganic arsenic, an early life carcinogen in humans and mice, can initiate lesions promotable by other agents in later life. The biomethylation product of arsenic, dimethylarsinic acid (DMA), is a multi-site tumor promoter. Thus, pregnant CD1 mice were given drinking water (0 ppm or 85 ppm arsenic) from gestation day 8 to 18 and after weaning male offspring received DMA (0 ppm or 200 ppm; drinking water) for up to 2 years. No renal tumors occurred in controls or DMA alone treated mice while gestational arsenic exposure plus later DMA induced a significant renal tumor incidence of 17% (primarily renal cell carcinoma). Arsenic plus DMA or arsenic alone also increased renal hyperplasia over control but DMA alone did not. Arsenic alone, DMA alone and arsenic plus DMA all induced urinary bladder hyperplasia (33-35%) versus control (2%). Compared to control (6%), arsenic alone tripled hepatocellular carcinoma (20%), and arsenic plus DMA doubled this rate again (43%), but DMA alone had no effect. DMA alone, arsenic alone, and arsenic plus DMA increased lung adenocarcinomas and adrenal adenomas versus control. Overall, DMA in adulthood promoted tumors/lesions initiated by prenatal arsenic in the kidney and liver, but acted independently in the urinary bladder, lung and adrenal. Published by Elsevier Ireland Ltd. C1 [Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Inorgan Toxicol Grp, Natl Toxicol Program, Branch Lab, Res Triangle Pk, NC 27709 USA. [Diwan, Bhalchandra A.] NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21701 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Toxicol Grp, Natl Toxicol Program, Branch Lab, 111 Alexander Dr,POB 12233,MD E0-07, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU NIEHS; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors wish to thank Drs. Bucher, Walker, Morgan and Person for critical evaluation of this manuscript and Dan Logsdon for expert technical assistance. This research was supported in part by the National Toxicology Program, NIEHS and by the Intramural Research program of the NIH, National Cancer Institute, Center for Cancer Research. This article may be the work product of an employee or group of employees of the NIEHS, National Institutes of Health (NIH), however, the statements contained herein do not necessarily represent the statements, opinions or conclusions of the NIEHS, NIH or the United States Government. This project was also supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 30 TC 17 Z9 17 U1 0 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD MAR 7 PY 2012 VL 209 IS 2 BP 179 EP 185 DI 10.1016/j.toxlet.2011.12.016 PG 7 WC Toxicology SC Toxicology GA 905MV UT WOS:000301277200011 PM 22230260 ER PT J AU Engel, J McDermott, MP Wiebe, S Langfitt, JT Stern, JM Dewar, S Sperling, MR Gardiner, I Erba, G Fried, I Jacobs, M Vinters, HV Mintzer, S Kieburtz, K AF Engel, Jerome, Jr. McDermott, Michael P. Wiebe, Samuel Langfitt, John T. Stern, John M. Dewar, Sandra Sperling, Michael R. Gardiner, Irenita Erba, Giuseppe Fried, Itzhak Jacobs, Margaret Vinters, Harry V. Mintzer, Scott Kieburtz, Karl CA Early Randomized Surgical Epilepsy TI Early Surgical Therapy for Drug-Resistant Temporal Lobe Epilepsy A Randomized Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID QUALITY-OF-LIFE; INTRACTABLE EPILEPSY; SURGERY; MULTICENTER; INVENTORY; LOBECTOMY; DIAGNOSIS; SEIZURES; OUTCOMES; LONG AB Context Despite reported success, surgery for pharmacoresistant seizures is often seen as a last resort. Patients are typically referred for surgery after 20 years of seizures, often too late to avoid significant disability and premature death. Objective We sought to determine whether surgery soon after failure of 2 antiepileptic drug (AED) trials is superior to continued medical management in controlling seizures and improving quality of life (QOL). Design, Setting, and Participants The Early Randomized Surgical Epilepsy Trial (ERSET) is a multicenter, controlled, parallel-group clinical trial performed at 16 US epilepsy surgery centers. The 38 participants (18 men and 20 women; aged >= 12 years) had mesial temporal lobe epilepsy (MTLE) and disabling seizues for no more than 2 consecutive years following adequate trials of 2 brand-name AEDs. Eligibility for anteromesial temporal resection (AMTR) was based on a standardized presurgical evaluation protocol. Participants were randomized to continued AED treatment or AMTR 2003-2007, and observed for 2 years. Planned enrollment was 200, but the trial was halted prematurely due to slow accrual. Intervention Receipt of continued AED treatment (n=23) or a standardized AMTR plus AED treatment (n=15). In the medical group, 7 participants underwent AMTR prior to the end of follow-up and 1 participant in the surgical group never received surgery. Main Outcome Measures The primary outcome variable was freedom from disabling seizures during year 2 of follow-up. Secondary outcome variables were health-related QOL (measured primarily by the 2-year change in the Quality of Life in Epilepsy 89 [QOLIE-89] overall T-score), cognitive function, and social adaptation. Results Zero of 23 participants in the medical group and 11 of 15 in the surgical group were seizure free during year 2 of follow-up (odds ratio=infinity; 95% CI, 11.8 to infinity; P<.001). In an intention-to-treat analysis, the mean improvement in QOLIE-89 overall T-score was higher in the surgical group than in the medical group but this difference was not statistically significant (12.6 vs 4.0 points; treatment effect=8.5; 95% CI, -1.0 to 18.1; P=.08). When data obtained after surgery from participants in the medical group were excluded, the effect of surgery on QOL was significant (12.8 vs 2.8 points; treatment effect=9.9; 95% CI, 2.2 to 17.7; P=.01). Memory decline (assessed using the Rey Auditory Verbal Learning Test) occurred in 4 participants (36%) after surgery, consistent with rates seen in the literature; but the sample was too small to permit definitive conclusions about treatment group differences in cognitive outcomes. Adverse events included a transient neurologic deficit attributed to a magnetic resonance imaging-identified postoperative stroke in a participant who had surgery and 3 cases of status epilepticus in the medical group. Conclusions Among patients with newly intractable disabling MTLE, resective surgery plus AED treatment resulted in a lower probability of seizures during year 2 of follow-up than continued AED treatment alone. Given the premature termination of the trial, the results should be interpreted with appropriate caution. C1 [Engel, Jerome, Jr.; Stern, John M.; Dewar, Sandra] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA. [McDermott, Michael P.] Univ Rochester, Dept Biostat & Computat Biol, Rochester, NY USA. [Wiebe, Samuel] Univ Calgary, Calgary, AB, Canada. [Wiebe, Samuel] Foothills Med Ctr, Div Neurol, Calgary, AB, Canada. [Langfitt, John T.; Erba, Giuseppe] Univ Rochester, Med Ctr, Dept Neurol, Rochester, NY 14642 USA. [Gardiner, Irenita; Kieburtz, Karl] Univ Rochester, Med Ctr, Ctr Human Expt Therapeut, Rochester, NY 14642 USA. [Fried, Itzhak; Mintzer, Scott] Thomas Jefferson Univ, Dept Neurol, Philadelphia, PA 19107 USA. [Sperling, Michael R.; Mintzer, Scott] Thomas Jefferson Univ, Jefferson Comprehens Epilepsy Ctr, Philadelphia, PA 19107 USA. [Fried, Itzhak] Ronald Reagan UCLA Med Ctr, Dept Neurosurg, Los Angeles, CA USA. [Vinters, Harry V.] Ronald Reagan UCLA Med Ctr, Dept Anat & Clin Pathol, Los Angeles, CA USA. [Jacobs, Margaret] Amer Epilepsy Soc, Hartford, CT USA. [Jacobs, Margaret] Natl Inst Neurol Disorders & Stroke, NIH, Rockville, MD USA. RP Engel, J (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, 710 Westwood Plaza, Los Angeles, CA 90095 USA. EM engel@ucla.edu RI French, Jacqueline/G-6795-2013; Lopez Rodriguez, Fernando/A-7557-2016 OI French, Jacqueline/0000-0003-2242-8027; Lopez Rodriguez, Fernando/0000-0002-0519-9624 FU National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke (NINDS); Medtronics; Valeant; Acorda; US Food and Drug Administration; Esai; Johnson Johnson; Novartis; Lippincott [WO2009/123734A1, WO2009/123735A1]; UCB Pharmaceuticals; Teva Pharmaceutical Industries; Smith and Nephew; Synosia; Impax Pharmaceuticals; Medivation; NeuroSearch Sweden AB; Boehringer-Ingelheim; Pfizer; Canadian Institutes of Health Research; International League Against Epilepsy; UCSF/Elekta; Northern Illinois University; University of Cincinnatti; NIH CSR (Center for Scientific Review); NINDS; Agency for Healthcare Research and Quality; UCB; Vertex; Sunovion; Eisai; Neuropace; SK Life Sciences; Neuronex; Epilepsia; National Institutes of Health [R21 NS37897, U01 NS42372] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Engel, Stern, Sperling, and Mintzer and Mss Gardiner and Jacobs report receipt of an institutional grant from the National Institutes of Health (NIH); and Drs McDermott, Langfitt, and Fried report receipt of an institutional grant from the National Institute of Neurological Disorders and Stroke (NINDS). Dr Engel reports receipt of consultancy fees from Medtronics, Valeant, Acorda, the US Food and Drug Administration, Best Doctors; receipt of fees to the institution for expert testimony; receipt of lecture/speakers bureau fees from Esai, Johnson & Johnson, Novartis, Lippincott; receipt of patent fees (WO2009/123734A1 and WO2009/123735A1); receipt of royalties from Wolters Kluwer, Wiley Blackwell, Elsevier, MedLink; and receipt of fees for travel accommodations/meeting expenses from UCB Pharmaceuticals. Dr McDermott reports receipt of fees to the institution for travel accommodations/meeting expenses for this study from NINDS, fees to the institution for consultancy from BoehringerIngelheim and Pfizer; receipt of consultancy fees from Teva Pharmaceutical Industries, Smith and Nephew, Synosia, Impax Pharmaceuticals; grant support or pending grant support to the institution from Medivation, NeuroSearch Sweden AB, Boehringer-Ingelheim, Pfizer. Dr Wiebe reports grant support from NINDS, fees for travel accommodations/meeting expenses from NINDS; employment with the University of Calgary; grant support or pending grant support from the Canadian Institutes of Health Research; fees for travel accommodations/meeting expenses from the International League Against Epilepsy. Dr Langfitt reports receipt of fees for travel accommodations/meeting expenses from NIH; consultancy fees from NINDS, UCSF/Elekta, Northern Illinois University, University of Cincinnatti, NIH CSR (Center for Scientific Review); grant support or pending grant support from NINDS and the Agency for Healthcare Research and Quality; fees to the institution for development of educational presentations from NIH. Dr Stern reports receipt of fees for travel accommodations/meeting expenses from NIH. Dr Sperling reports receipt of consultancy fees from UCB, Vertex, Sunovion; grant support or pending grant support from NIH, UCP, Vertex, Eisai, Sunovion, Medtronics, Neuropace, SK Life Sciences, Novartis, Neuronex; lecture/speakers bureau fees from UCB; other fees as associate editor from Epilepsia. Mss Gardiner and Dewar and Dr Erba report no disclosures.; This study was supported by the National Institutes of Health (grant numbers R21 NS37897 and U01 NS42372). NR 44 TC 225 Z9 228 U1 4 U2 40 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 MAR 7 PY 2012 VL 307 IS 9 BP 922 EP 930 DI 10.1001/jama.2012.220 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 904CU UT WOS:000301172100020 PM 22396514 ER PT J AU Lee, C Raffaghello, L Brandhorst, S Safdie, FM Bianchi, G Martin-Montalvo, A Pistoia, V Wei, M Hwang, S Merlino, A Emionite, L de Cabo, R Longo, VD AF Lee, Changhan Raffaghello, Lizzia Brandhorst, Sebastian Safdie, Fernando M. Bianchi, Giovanna Martin-Montalvo, Alejandro Pistoia, Vito Wei, Min Hwang, Saewon Merlino, Annalisa Emionite, Laura de Cabo, Rafael Longo, Valter D. TI Fasting Cycles Retard Growth of Tumors and Sensitize a Range of Cancer Cell Types to Chemotherapy SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID GENE SET ENRICHMENT; DIETARY RESTRICTION; LIFE-SPAN; CALORIC RESTRICTION; STRESS RESISTANCE; HUMANS; MODEL; YEAST; ACTIVATION; MECHANISMS AB Short-term starvation (or fasting) protects normal cells, mice, and potentially humans from the harmful side effects of a variety of chemotherapy drugs. Here, we show that treatment with starvation conditions sensitized yeast cells (Saccharomyces cerevisiae) expressing the oncogene-like RAS2(val19) to oxidative stress and 15 of 17 mammalian cancer cell lines to chemotherapeutic agents. Cycles of starvation were as effective as chemotherapeutic agents in delaying progression of different tumors and increased the effectiveness of these drugs against melanoma, glioma, and breast cancer cells. In mouse models of neuroblastoma, fasting cycles plus chemotherapy drugs-but not either treatment alone-resulted in long-term cancer-free survival. In 4T1 breast cancer cells, short-term starvation resulted in increased phosphorylation of the stress-sensitizing Akt and S6 kinases, increased oxidative stress, caspase-3 cleavage, DNA damage, and apoptosis. These studies suggest that multiple cycles of fasting promote differential stress sensitization in a wide range of tumors and could potentially replace or augment the efficacy of certain chemotherapy drugs in the treatment of various cancers. C1 [Lee, Changhan; Brandhorst, Sebastian; Safdie, Fernando M.; Wei, Min; Hwang, Saewon; Merlino, Annalisa; Longo, Valter D.] Univ So Calif, Dept Biol Sci, Andrus Gerontol Ctr, Los Angeles, CA 90089 USA. [Lee, Changhan; Brandhorst, Sebastian; Safdie, Fernando M.; Wei, Min; Hwang, Saewon; Merlino, Annalisa; Longo, Valter D.] Univ So Calif, Norris Canc Ctr, Los Angeles, CA 90089 USA. [Raffaghello, Lizzia; Bianchi, Giovanna; Pistoia, Vito] Giannina Gaslini Inst, Lab Oncol, I-16145 Genoa, Italy. [Brandhorst, Sebastian] Univ Duisburg Essen, Fac Biol, Ctr Med Biotechnol, D-45117 Essen, Germany. [Martin-Montalvo, Alejandro; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Emionite, Laura] Anim Res Facil Ist Tumori, I-16145 Genoa, Italy. RP Longo, VD (reprint author), Univ So Calif, Dept Biol Sci, Andrus Gerontol Ctr, 3715 McClintock Ave, Los Angeles, CA 90089 USA. EM vlongo@usc.edu RI perumal, murugiah/D-1565-2012; de Cabo, Rafael/J-5230-2016; Martin-Montalvo, Alejandro/C-2031-2017; OI Wei, Min/0000-0002-2649-9271; de Cabo, Rafael/0000-0002-3354-2442; Martin-Montalvo, Alejandro/0000-0002-3886-5355; Raffaghello, Lizzia/0000-0003-2357-0607; , rafael/0000-0003-2830-5693 FU NIH/National Institute on Aging [AG20642, AG025135, P01 AG034906]; Ted Bakewell (The Bakewell Foundation); V Foundation for Cancer Research; USC Norris Cancer Center; My First Associazione Italiana per la Ricerca sul Cancro; Fondazione Italiana Ricerca sul Cancro FX This study was funded in part by NIH/National Institute on Aging grants AG20642, AG025135, and P01 AG034906; Ted Bakewell (The Bakewell Foundation); the V Foundation for Cancer Research; and a USC Norris Cancer Center pilot grant to V.D.L. L.R. is a recipient of a My First Associazione Italiana per la Ricerca sul Cancro grant, and G.B. is a recipient of a Fondazione Italiana Ricerca sul Cancro fellowship. NR 34 TC 68 Z9 70 U1 4 U2 33 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 MAR 7 PY 2012 VL 4 IS 124 AR 124ra27 DI 10.1126/scitranslmed.3003293 PG 10 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 905UY UT WOS:000301302600003 PM 22323820 ER PT J AU Wayson, M Lee, C Sgouros, G Treves, ST Frey, E Bolch, WE AF Wayson, Michael Lee, Choonsik Sgouros, George Treves, S. Ted Frey, Eric Bolch, Wesley E. TI Internal photon and electron dosimetry of the newborn patient-a hybrid computational phantom study SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID ICRP REFERENCE NEWBORN; REFERENCE ADULT MALE; DOSE ASSESSMENT; NUCLEAR-MEDICINE; 1ST YEAR; MODELS; FAMILY; CHILDREN; MIRD; LIFE AB Estimates of radiation absorbed dose to organs of the nuclear medicine patient are a requirement for administered activity optimization and for stochastic risk assessment. Pediatric patients, and in particular the newborn child, represent that portion of the patient population where such optimization studies are most crucial owing to the enhanced tissue radiosensitivities and longer life expectancies of this patient subpopulation. In cases where whole-body CT imaging is not available, phantom-based calculations of radionuclide S values-absorbed dose to a target tissue per nuclear transformation in a source tissue-are required for dose and risk evaluation. In this study, a comprehensive model of electron and photon dosimetry of the reference newborn child is presented based on a high-resolution hybrid-voxel phantom from the University of Florida (UF) patient model series. Values of photon specific absorbed fraction (SAF) were assembled for both the reference male and female newborn using the radiation transport code MCNPX v2.6. Values of electron SAF were assembled in a unique and time-efficient manner whereby the collisional and radiative components of organ dose-for both self-and cross-dose terms-were computed separately. Dose to the newborn skeletal tissues were assessed via fluence-to-dose response functions reported for the first time in this study. Values of photon and electron SAFs were used to assemble a complete set of S values for some 16 radionuclides commonly associated with molecular imaging of the newborn. These values were then compared to those available in the OLINDA/EXM software. S value ratios for organ self-dose ranged from 0.46 to 1.42, while similar ratios for organ cross-dose varied from a low of 0.04 to a high of 3.49. These large discrepancies are due in large part to the simplistic organ modeling in the stylized newborn model used in the OLINDA/EXM software. A comprehensive model of internal dosimetry is presented in this study for the newborn nuclear medicine patient based upon the UF hybrid computational phantom. Photon dose response functions, photon and electron SAFs, and tables of radionuclide S values for the newborn child-both male and female-are given in a series of four electronic annexes available at stacks.iop.org/pmb/57/1433/mmedia. These values can be applied to optimization studies of image quality and stochastic risk for this most vulnerable class of pediatric patients. C1 [Wayson, Michael; Bolch, Wesley E.] Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA. [Lee, Choonsik] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sgouros, George; Frey, Eric] Johns Hopkins Med Inst, Dept Radiol, Baltimore, MD 21287 USA. [Treves, S. Ted] Childrens Hosp, Div Nucl Med, Boston, MA 02115 USA. RP Bolch, WE (reprint author), Univ Florida, J Crayton Pruitt Family Dept Biomed Engn, Gainesville, FL 32611 USA. EM mikew13@ufl.edu; wbolch@ufl.edu RI Lee, Choonsik/C-9023-2015 OI Lee, Choonsik/0000-0003-4289-9870 FU National Cancer Institute [R01 CA116743, R01 CA96441]; US Department of Energy [DE-FG07-06ID14773] FX This research was supported in part by grants R01 CA116743 and R01 CA96441 with the National Cancer Institute, and by grant DE-FG07-06ID14773 with the US Department of Energy. NR 31 TC 7 Z9 7 U1 0 U2 6 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD MAR 7 PY 2012 VL 57 IS 5 BP 1433 EP 1457 DI 10.1088/0031-9155/57/5/1433 PG 25 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 898XL UT WOS:000300775600024 PM 22354044 ER PT J AU Billig, EMW O'Meara, WP Riley, EM McKenzie, FE AF Billig, Erica M. W. O'Meara, Wendy P. Riley, Eleanor M. McKenzie, F. Ellis TI Developmental allometry and paediatric malaria SO MALARIA JOURNAL LA English DT Review DE Malaria; Age-dependent; Allometry; Severe malarial anaemia; Cerebral malaria; Paediatric malaria ID RED-BLOOD-CELL; PLASMODIUM-FALCIPARUM MALARIA; SPLENIC MARGINAL ZONE; AGE-RELATED-CHANGES; COMPLEMENT-REGULATORY PROTEINS; SUB-SAHARAN AFRICA; CEREBRAL MALARIA; TRANSMISSION INTENSITY; ANTIBODY-RESPONSES; HUMAN-ERYTHROCYTES AB WHO estimates that 80% of mortality due to malaria occurs among infants and young children. Though it has long been established that malaria disproportionately affects children under age five, our understanding of the underlying biological mechanisms for this distribution remains incomplete. Many studies use age as an indicator of exposure, but age may affect malaria burden independently of previous exposure. Not only does the severity of malaria infection change with age, but the clinical manifestation of disease does as well: younger children are more likely to suffer severe anaemia, while older children are more likely to develop cerebral malaria. Intensity of transmission and acquired immunity are important determinants of this age variation, but age differences remain consistent over varying transmission levels. Thus, age differences in clinical presentation may involve inherent age-related factors as well as still-undiscovered facets of acquired immunity, perhaps including the rates at which relevant aspects of immunity are acquired. The concept of "allometry" - the relative growth of a part in relation to that of an entire organism or to a standard - has not previously been applied in the context of malaria infection. However, because malaria affects a number of organs and cells, including the liver, red blood cells, white blood cells, and spleen, which may intrinsically develop at rates partly independent of each other and of a child's overall size, developmental allometry may influence the course and consequences of malaria infection. Here, scattered items of evidence have been collected from a variety of disciplines, aiming to suggest possible research paths for investigating exposure-independent age differences affecting clinical outcomes of malaria infection. C1 [Billig, Erica M. W.; McKenzie, F. Ellis] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [O'Meara, Wendy P.] Duke Univ, Sch Med, Durham, NC USA. [O'Meara, Wendy P.] Duke Global Hlth Inst, Durham, NC USA. [O'Meara, Wendy P.] Moi Univ, Eldoret, Kenya. [Riley, Eleanor M.] London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London WC1E 7HT, England. RP Billig, EMW (reprint author), NIH, Fogarty Int Ctr, Bldg 16, Bethesda, MD 20892 USA. EM erica.billig@nih.gov RI Riley, Eleanor/C-8960-2013 OI Riley, Eleanor/0000-0003-3447-3570 NR 132 TC 5 Z9 5 U1 1 U2 6 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 MAR 6 PY 2012 VL 11 AR 64 DI 10.1186/1475-2875-11-64 PG 13 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 931HD UT WOS:000303206100001 PM 22394452 ER PT J AU Lee, CW Bae, C Lee, J Ryu, JH Kim, HH Kohno, T Swartz, KJ Il Kim, J AF Lee, Chul Won Bae, Chanhyung Lee, Jaeho Ryu, Jae Ha Kim, Ha Hyung Kohno, Toshiyuki Swartz, Kenton J. Il Kim, Jae TI Solution Structure of Kurtoxin: A Gating Modifier Selective for Cav3 Voltage-Gated Ca2+ Channels SO BIOCHEMISTRY LA English DT Article ID DEPENDENT K+ CHANNEL; ALPHA-LIKE TOXIN; NUCLEAR-MAGNETIC-RESONANCE; POTATO CARBOXYPEPTIDASE INHIBITOR; 3-DIMENSIONAL SOLUTION STRUCTURE; ANDROCTONUS-AUSTRALIS HECTOR; RELAXATION MATRIX ANALYSIS; BUTHUS-MARTENSII KARSCH; OMEGA-GRAMMOTOXIN-SIA; CALCIUM-CHANNELS AB Kurtoxin is a 63-amino acid polypeptide isolated from the venom of the South African scorpion Parabuthus transvaalicus. It is the first and only peptide ligand known to interact with Cav3 (T-type) voltage-gated Ca2+ channels with high affinity and to modify the voltage-dependent gating of these channels. Here we describe the nuclear magnetic resonance (NMR) solution structure of kurtoxin determined using two- and three-dimensional NMR spectroscopy with dynamical simulated annealing calculations. The molecular structure of the toxin was highly similar to those of scorpion alpha-toxins and contained an alpha-helix, three beta-strands, and several turns stabilized by four disulfide bonds. This so-called "cysteine-stabilized alpha-helix and beta-sheet (CS alpha beta)" motif is found in a number of functionally varied small proteins. A detailed comparison of the backbone structure of kurtoxin with those of the scorpion a-toxins revealed that three regions [first long loop (Asp(8)-Ile(15)), beta-hairpin loop (Gly(39)-Leu(42)), and C-terminal segment (Arg(57)-Ala(63))] in kurtoxin significantly differ from the corresponding regions in scorpion alpha-toxins, suggesting that these regions may be important for interacting with Cav3 (T-type) Ca2+ channels. In addition, the surface profile of kurtoxin shows a larger and more focused electropositive patch along with a larger hydrophobic surface compared to those seen on scorpion alpha-toxins. These distinct surface properties of kurtoxin could explain its binding to Cav3 (T-type) voltage-gated Ca2+ channels. C1 [Lee, Chul Won; Bae, Chanhyung; Lee, Jaeho; Ryu, Jae Ha; Il Kim, Jae] Gwangju Inst Sci & Technol GIST, Dept Life Sci, Kwangju 500712, South Korea. [Lee, Chul Won] Chonnam Natl Univ, Dept Chem, Kwangju 500757, South Korea. [Kim, Ha Hyung] Chung Ang Univ, Coll Pharm, Seoul 156756, South Korea. [Kohno, Toshiyuki] Kitasato Univ, Dept Biochem, Sch Med, Kanagawa 2520374, Japan. [Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. RP Il Kim, J (reprint author), Gwangju Inst Sci & Technol GIST, Dept Life Sci, Kwangju 500712, South Korea. EM jikim@gist.ac.kr FU Next-Generation BioGreen 21 Program [PJ008158]; Rural Development Administration, Republic of Korea; National Research Foundation of Korea; Korean Government (MEST) [NRF-C1ABA001-2011-0018559]; Brain Research Center [M103KV010005-06K2201-00610]; BioImaging Research Center at the Gwangju Institute of Science and Technology; Basic Research Projects in High-tech Industrial Technology; Gwangju Institute of Science and Technology FX This research was supported by grants from the Next-Generation BioGreen 21 Program (PJ008158); the Rural Development Administration, Republic of Korea; a National Research Foundation of Korea grant funded by the Korean Government (MEST) (NRF-C1ABA001-2011-0018559); the Brain Research Center of the 21st Century Frontier Research Program (M103KV010005-06K2201-00610); and the BioImaging Research Center at the Gwangju Institute of Science and Technology and Basic Research Projects in High-tech Industrial Technology funded by the Gwangju Institute of Science and Technology in 2011. NR 112 TC 9 Z9 9 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 6 PY 2012 VL 51 IS 9 BP 1862 EP 1873 DI 10.1021/bi201633j PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 902EJ UT WOS:000301021100006 PM 22329781 ER PT J AU Durrett, R Gleeson, JP Lloyd, AL Mucha, PJ Shi, F Sivakoff, D Socolar, JES Varghese, C AF Durrett, Richard Gleeson, James P. Lloyd, Alun L. Mucha, Peter J. Shi, Feng Sivakoff, David Socolar, Joshua E. S. Varghese, Chris TI Graph fission in an evolving voter model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE coevolutionary network; quasi-stationary distribution; Wright-Fisher diffusion; approximate master equation ID SOCIAL NETWORKS; SIR DYNAMICS; COEVOLUTION; SEGREGATION; EVOLUTION; SYSTEMS AB We consider a simplified model of a social network in which individuals have one of two opinions (called 0 and 1) and their opinions and the network connections coevolve. Edges are picked at random. If the two connected individuals hold different opinions then, with probability 1 - alpha, one imitates the opinion of the other; otherwise (i.e., with probability alpha), the link between them is broken and one of them makes a new connection to an individual chosen at random (i) from those with the same opinion or (ii) from the network as a whole. The evolution of the system stops when there are no longer any discordant edges connecting individuals with different opinions. Letting rho be the fraction of voters holding the minority opinion after the evolution stops, we are interested in how rho depends on alpha and the initial fraction u of voters with opinion 1. In case (i), there is a critical value alpha(c) which does not depend on u, with rho approximate to u for alpha > alpha(c) and rho approximate to 0 for alpha < alpha(c). In case (ii), the transition point alpha(c)(u) depends on the initial density u. For a > alpha(c)(u), rho approximate to u, but for alpha < alpha(c)(u), we have rho(alpha,u) = rho(alpha, 1/2). Using simulations and approximate calculations, we explain why these two nearly identical models have such dramatically different phase transitions. C1 [Durrett, Richard; Sivakoff, David] Duke Univ, Dept Math, Durham, NC 27708 USA. [Gleeson, James P.] Univ Limerick, Dept Math & Stat, Math Applicat Consortium Sci Ind, Limerick, Ireland. [Lloyd, Alun L.] N Carolina State Univ, Dept Math, Raleigh, NC 27695 USA. [Lloyd, Alun L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Shi, Feng] Univ N Carolina, Dept Math, Chapel Hill, NC 27599 USA. [Socolar, Joshua E. S.; Varghese, Chris] Duke Univ, Dept Phys, Durham, NC 27708 USA. RP Durrett, R (reprint author), Duke Univ, Dept Math, Box 90320, Durham, NC 27708 USA. EM rtd@math.duke.edu RI Lloyd, Alun/H-4944-2012; Gleeson, James/G-1595-2014; OI Socolar, Joshua/0000-0003-0532-7099; Gleeson, James/0000-0003-3410-2817 FU National Science Foundation [DMS-1005470, DMS-0645369]; Science Foundation Ireland [06/IN.1/I366]; Mathematics Applications Consortium for Science and Industry [06/MI/005]; National Institutes of Health FX The authors thank Raissa D'Souza, Eric Kolaczyk, Tom Liggett, and Mason Porter for their many helpful suggestions. This work began during the 2010-2011 program on Complex Networks at the Statistical and Applied Mathematical Sciences Institute. This work was partially supported by National Science Foundation Grants DMS-1005470 (to R.D.) and DMS-0645369 (to P.J.M.), by Science Foundation Ireland Grants 06/IN.1/I366, and Mathematics Applications Consortium for Science and Industry 06/MI/005 (to J.P.G.), and by the Research and Policy for Infectious Disease Dynamics program at National Institutes of Health (A.L.L.). NR 49 TC 37 Z9 39 U1 1 U2 18 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 MAR 6 PY 2012 VL 109 IS 10 BP 3682 EP 3687 DI 10.1073/pnas.1200709109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903LJ UT WOS:000301117700023 PM 22355142 ER PT J AU Carvajal-Gonzalez, JM Gravotta, D Mattera, R Diaz, F Bay, AP Roman, AC Schreiner, RP Thuenauer, R Bonifacino, JS Rodriguez-Boulan, E AF Carvajal-Gonzalez, Jose Maria Gravotta, Diego Mattera, Rafael Diaz, Fernando Bay, Andres Perez Roman, Angel C. Schreiner, Ryan P. Thuenauer, Roland Bonifacino, Juan S. Rodriguez-Boulan, Enrique TI Basolateral sorting of the coxsackie and adenovirus receptor through interaction of a canonical YXX Phi motif with the clathrin adaptors AP-1A and AP-1B SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE trans-Golgi network; recycling endosomes; exocytosis; epithelial cells; protein sorting ID POLARIZED EPITHELIAL-CELLS; TRANS-GOLGI NETWORK; HIV-1 ENVELOPE GLYCOPROTEIN; CANINE KIDNEY-CELLS; MDCK CELLS; CYTOPLASMIC DOMAIN; TARGETING SIGNAL; LDL RECEPTOR; TYROSINE; TRAFFICKING AB The coxsackie and adenovirus receptor (CAR) plays key roles in epithelial barrier function at the tight junction, a localization guided in part by a tyrosine-based basolateral sorting signal, (318)YNQV(321). Sorting motifs of this type are known to route surface receptors into clathrin-mediated endocytosis through interaction with the medium subunit (mu 2) of the clathrin adaptor AP-2, but how they guide new and recycling membrane proteins basolaterally is unknown. Here, we show that YNQV functions as a canonical YXX Phi motif, with both Y318 and V321 required for the correct basolateral localization and biosynthetic sorting of CAR, and for interaction with a highly conserved pocket in the medium subunits (mu 1A and mu 1B) of the clathrin adaptors AP-1A and AP-1B. Knock-down experiments demonstrate that AP-1A plays a role in the biosynthetic sorting of CAR, complementary to the role of AP-1B in basolateral recycling of this receptor. Our study illustrates how two clathrin adaptors direct basolateral trafficking of a plasma membrane protein through interaction with a canonical YXX Phi motif. C1 [Mattera, Rafael; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Carvajal-Gonzalez, Jose Maria; Gravotta, Diego; Bay, Andres Perez; Schreiner, Ryan P.; Rodriguez-Boulan, Enrique] Weill Cornell Med Coll, Margaret Dyson Vis Res Inst, Dept Physiol & Biophys, Dept Cell & Dev Biol,Dept Ophthalmol, New York, NY 10065 USA. [Diaz, Fernando] Harvard Univ, Sch Med, Dept Microbiol & Immunobiol, Boston, MA 02115 USA. [Roman, Angel C.] CSIC, Inst Cajal, E-28002 Madrid, Spain. [Thuenauer, Roland] Ctr Adv Bioanal Linz GmbH, A-4020 Linz, Austria. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM juan@helix.nih.gov; boulan@med.cornell.edu OI Carvajal-Gonzalez, Jose Maria/0000-0001-6576-830X FU National Institutes of Health [EY08538, GM34107]; European Molecular Biology Organization; Dyson Foundation; Research to Prevent Blindness Foundation; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This work was supported by National Institutes of Health Grants EY08538 and GM34107 (to E.R.-B.); a European Molecular Biology Organization fellowship (to J.M.C.-G.); the Dyson Foundation and by the Research to Prevent Blindness Foundation; and by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R. M. and J.S.B.). NR 51 TC 43 Z9 43 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 6 PY 2012 VL 109 IS 10 BP 3820 EP 3825 DI 10.1073/pnas.1117949109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903LJ UT WOS:000301117700047 PM 22343291 ER PT J AU Diril, MK Ratnacaram, CK Padmakumar, VC Du, TH Wasser, M Coppola, V Tessarollo, L Kaldis, P AF Diril, M. Kasim Ratnacaram, Chandrahas Koumar Padmakumar, V. C. Du, Tiehua Wasser, Martin Coppola, Vincenzo Tessarollo, Lino Kaldis, Philipp TI Cyclin-dependent kinase 1 (Cdk1) is essential for cell division and suppression of DNA re-replication but not for liver regeneration SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; knockout mice; cell cycle regulation; polyploidy ID EMBRYONIC LETHALITY; EUKARYOTIC CELLS; PHASE; CANCER; MICE; TUMORIGENESIS; INHIBITION; MECHANISMS; TRANSITION; P27(KIP1) AB Cyclin-dependent kinase 1 (Cdk1) is an archetypical kinase and a central regulator that drives cells through G2 phase and mitosis. Knockouts of Cdk2, Cdk3, Cdk4, or Cdk6 have resulted in viable mice, but the in vivo functions of Cdk1 have not been fully explored in mammals. Here we have generated a conditional-knockout mouse model to study the functions of Cdk1 in vivo. Ablation of Cdk1 leads to arrest of embryonic development around the blastocyst stage. Interestingly, liver-specific deletion of Cdk1 is well tolerated, and liver regeneration after partial hepatectomy is not impaired, indicating that regeneration can be driven by cell growth without cell division. The loss of Cdk1 does not affect S phase progression but results in DNA re-replication because of an increase in Cdk2/cyclin A2 activity. Unlike other Cdks, loss of Cdk1 in the liver confers complete resistance against tumorigenesis induced by activated Ras and silencing of p53. C1 [Kaldis, Philipp] Natl Univ Singapore, Dept Biochem, Singapore 117597, Singapore. [Wasser, Martin] Natl Univ Singapore, Dept Biol Sci, Singapore 117597, Singapore. [Padmakumar, V. C.; Coppola, Vincenzo; Tessarollo, Lino] NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. EM kaldis@imcb.a-star.edu.sg RI Kaldis, Philipp/G-2714-2010; Coppola, Vincenzo/E-2917-2011; ASTAR, IMCB/E-2320-2012; OI Kaldis, Philipp/0000-0002-7247-7591; Coppola, Vincenzo/0000-0001-6163-1779; Wasser, Martin/0000-0002-8753-2346 FU Biomedical Research Council of the Agency for Science, Technology, and Research (A*STAR), Singapore FX We thank Eileen Southon and Susan Reid for help in generating the Cdk1FLOX/FLOX mice, and David Largaespada for transposase/transposon constructs. We appreciate that Jos Jonkers and Anton Berns provided the ROSA26-CreERT2 mice, Andy McMahon the Cre-Esr1 mice, Mark Lewandoski the beta-actin-Cre/Flpe mice, and T. Jake Liang the albumin-Cre mice. We thank Nancy Jenkins and Neal Copeland for advice, suggestions, reagents, and support. We are thankful to Cyril Berthet for reagents and discussion as well as to Steve Cohen and Neal Copeland for comments on the manuscript. We also thank Davor Solter and Barbara Knowles for technical advice; June Wang, Chloe Sim, and Vithya Anantaraja for animal care; Keith Rogers, Susan Rogers, and the technicians of the Pathology/Histotechnology Laboratory for superb analysis of mouse pathology; and the P. K. laboratory for support and discussions. This work was supported by the Biomedical Research Council of the Agency for Science, Technology, and Research (A*STAR), Singapore. NR 35 TC 71 Z9 71 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 6 PY 2012 VL 109 IS 10 BP 3826 EP 3831 DI 10.1073/pnas.1115201109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903LJ UT WOS:000301117700048 PM 22355113 ER PT J AU Zhang, M Mishra, S Sakthivel, R Rojas, M Ranjan, R Sullivan, WJ Fontoura, BMA Menard, R Dever, TE Nussenzweig, V AF Zhang, Min Mishra, Satish Sakthivel, Ramanavelan Rojas, Margarito Ranjan, Ravikant Sullivan, William J., Jr. Fontoura, Beatriz M. A. Menard, Robert Dever, Thomas E. Nussenzweig, Victor TI PK4, a eukaryotic initiation factor 2 alpha(eIF2 alpha) kinase, is essential for the development of the erythrocytic cycle of Plasmodium SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MAMMALIAN STRESS GRANULES; MALARIA PARASITES; TOXOPLASMA-GONDII; PROTEIN-KINASES; FALCIPARUM; PHOSPHORYLATION; FACTOR-2-ALPHA; LOCALIZATION; MUTAGENESIS; RESISTANCE AB In response to environmental stresses, the mammalian serine threonine kinases PERK, GCN2, HRI, and PKR phosphorylate the regulatory serine 51 of the eukaryotic translation initiation factor 2 alpha(eIF2 alpha) to inhibit global protein synthesis. Plasmodium, the protozoan that causes malaria, expresses three eIF2 alpha kinases: IK1, IK2, and PK4. Like GCN2, IK1 regulates stress response to amino acid starvation. IK2 inhibits development of malaria sporozoites present in the mosquito salivary glands. Here we show that the phosphorylation by PK4 of the regulatory serine 59 of Plasmodium eIF2 alpha is essential for the completion of the parasite's erythrocytic cycle that causes disease in humans. PK4 activity leads to the arrest of global protein synthesis in schizonts, where ontogeny of daughter merozoites takes place, and in gametocytes that infect Anopheles mosquitoes. The implication of these findings is that drugs that reduce PK4 activity should alleviate disease and inhibit malaria transmission. C1 [Zhang, Min; Mishra, Satish; Ranjan, Ravikant; Nussenzweig, Victor] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Sakthivel, Ramanavelan; Fontoura, Beatriz M. A.] Univ Texas SW Med Ctr Dallas, Dept Cell Biol, Dallas, TX 75390 USA. [Rojas, Margarito; Dever, Thomas E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Sullivan, William J., Jr.] Indiana Univ Sch Med, Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA. [Menard, Robert] Inst Pasteur, Unite Biol & Genet Paludisme, F-75015 Paris, France. RP Nussenzweig, V (reprint author), NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. EM victor.nussenzweig@nyumc.org RI Zhang, Min/G-4480-2011; Mishra, Satish/K-7473-2015; OI Zhang, Min/0000-0001-9794-4523; Mishra, Satish/0000-0002-8942-6416; Dever, Thomas/0000-0001-7120-9678 FU National Institutes of Health [AI084031, AI077502, R01 GM067159] FX This work was supported by National Institutes of Health Grants AI084031 and AI077502 (to W.J.S.); the Intramural Research Program of the National Institutes of Health (T.E.D.); and National Institutes of Health Grant R01 GM067159 (to B.M.A.F.). NR 38 TC 30 Z9 31 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 MAR 6 PY 2012 VL 109 IS 10 BP 3956 EP 3961 DI 10.1073/pnas.1121567109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903LJ UT WOS:000301117700070 PM 22355110 ER PT J AU Lu, HB Zou, QH Gu, H Raichle, ME Stein, EA Yang, YH AF Lu, Hanbing Zou, Qihong Gu, Hong Raichle, Marcus E. Stein, Elliot A. Yang, Yihong TI Rat brains also have a default mode network SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE functional MRI; resting state; intrinsic activity; connectivity; spontaneous fluctuation ID PREFRONTAL CORTICAL PROJECTIONS; INDEPENDENT COMPONENT ANALYSIS; PARIETAL ASSOCIATION CORTEX; RESTING-STATE CONNECTIVITY; FUNCTIONAL CONNECTIVITY; MACAQUE MONKEYS; AFFERENT CONNECTIONS; LONGITUDINAL COLUMNS; PERIAQUEDUCTAL GRAY; ORBITAL CORTEX AB The default mode network (DMN) in humans has been suggested to support a variety of cognitive functions and has been implicated in an array of neuropsychological disorders. However, its function (s) remains poorly understood. We show that rats possess a DMN that is broadly similar to the DMNs of nonhuman primates and humans. Our data suggest that, despite the distinct evolutionary paths between rodent and primate brain, a well-organized, intrinsically coherent DMN appears to be a fundamental feature in the mammalian brain whose primary functions might be to integrate multimodal sensory and affective information to guide behavior in anticipation of changing environmental contingencies. C1 [Raichle, Marcus E.] Washington Univ, Dept Radiol, St Louis, MO 63110 USA. [Raichle, Marcus E.] Washington Univ, Dept Neurol, St Louis, MO 63110 USA. [Raichle, Marcus E.] Washington Univ, Dept Anat & Neurobiol, St Louis, MO 63110 USA. [Raichle, Marcus E.] Washington Univ, Dept Biomed Engn, St Louis, MO 63110 USA. [Lu, Hanbing; Zou, Qihong; Gu, Hong; Stein, Elliot A.; Yang, Yihong] NIDA, Neuroimaging Res Branch, Intramural Res Programs, NIH, Baltimore, MD 21224 USA. [Zou, Qihong] Peking Univ, MRI Res Ctr, Beijing 100871, Peoples R China. [Zou, Qihong] Peking Univ, Beijing City Key Lab Med Phys & Engn, Beijing 100871, Peoples R China. RP Raichle, ME (reprint author), Washington Univ, Dept Radiol, St Louis, MO 63110 USA. EM marc@npg.wustl.edu; estein@intra.nida.nih.gov; yihongyang@intra.nida.nih.gov FU National Institute on Drug Abuse, National Institutes of Health; National Institute of Neurological Disorders and Stroke [NS06833]; China's National Strategic Basic Research Program ("973") [2012CB720700] FX We acknowledge the invaluable assistance of Joseph L. Price, Professor of Anatomy and Neurobiology, Washington University School of Medicine, who gave generously of his time in helping us interpret our imaging findings in the context of rat brain anatomy. This study is supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. M.E.R. is supported by Grant NS06833 from the National Institute of Neurological Disorders and Stroke. Q.Z. is supported by China's National Strategic Basic Research Program ("973") Grant 2012CB720700. NR 60 TC 140 Z9 144 U1 5 U2 30 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 MAR 6 PY 2012 VL 109 IS 10 BP 3979 EP 3984 DI 10.1073/pnas.1200506109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903LJ UT WOS:000301117700074 PM 22355129 ER PT J AU Kolbe, DL DeLoia, JA Porter-Gill, P Strange, M Petrykowska, HM Guirguis, A Krivak, TC Brody, LC Elnitski, L AF Kolbe, Diana L. DeLoia, Julie A. Porter-Gill, Patricia Strange, Mary Petrykowska, Hanna M. Guirguis, Alfred Krivak, Thomas C. Brody, Lawrence C. Elnitski, Laura TI Differential Analysis of Ovarian and Endometrial Cancers Identifies a Methylator Phenotype SO PLOS ONE LA English DT Article ID SEROUS CARCINOMA; GENE-EXPRESSION; LOW-GRADE; PATHWAYS; MODEL; MUTATIONS; TUMORS; CARCINOGENESIS; PROFILES; PATTERNS AB Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA. For comparison within the endometrioid subtype we added 6 primary uterine endometrioid tumors and 5 endometrioid metastases from uterus to ovary. Data was obtained from 27,578 CpG dinucleotides occurring in or near promoter regions of 14,495 genes. We identified 36 locations with significant increases or decreases in methylation in comparisons of serous tumors and normal fallopian tube samples. Moreover, unsupervised clustering techniques applied to all samples showed three major profiles comprising mostly normal samples, serous tumors, and endometrioid tumors including ovarian, uterine and metastatic origins. The clustering analysis identified 60 differentially methylated sites between the serous group and the normal group. An unrelated set of 25 serous tumors validated the reproducibility of the methylation patterns. In contrast, >1,000 genes were differentially methylated between endometrioid tumors and normal samples. This finding is consistent with a generalized regulatory disruption caused by a methylator phenotype. Through DNA methylation analyses we have identified genes with known roles in ovarian carcinoma etiology, whereas pathway analyses provided biological insight to the role of novel genes. Our finding of differences between serous and endometrioid ovarian tumors indicates that intervention strategies could be developed to specifically address subtypes of epithelial ovarian cancer. C1 [Kolbe, Diana L.; Petrykowska, Hanna M.; Elnitski, Laura] NHGRI, DIR GTB Genom Funct Anal Sect, NIH, Bethesda, MD 20892 USA. [Porter-Gill, Patricia; Brody, Lawrence C.] NHGRI, DIR GTB Mol Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. [DeLoia, Julie A.; Strange, Mary; Krivak, Thomas C.] Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. [DeLoia, Julie A.] George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC USA. [Guirguis, Alfred] Rush Univ, Dept Obstet & Gynecol, Chicago, IL 60612 USA. RP Kolbe, DL (reprint author), NHGRI, DIR GTB Genom Funct Anal Sect, NIH, Bethesda, MD 20892 USA. EM elnitski@mail.nih.gov OI Strange, Mary/0000-0003-3269-4185 FU National Human Genome Research Institute, National Institutes of Health; DoD GOC [04-124]; Magee Womens Research Institute FX Funding is provided by The Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (LE and LB), DoD GOC# 04-124 and Magee Womens Research Institute/Scaife Grant (TCK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 11 Z9 12 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 MAR 5 PY 2012 VL 7 IS 3 AR e32941 DI 10.1371/journal.pone.0032941 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 928WA UT WOS:000303017700123 PM 22403726 ER PT J AU Chamberlain, BT Batra, VK Beard, WA Kadina, AP Shock, DD Kashemirov, BA McKenna, CE Goodman, MF Wilson, SH AF Chamberlain, Brian T. Batra, Vinod K. Beard, William A. Kadina, Anastasia P. Shock, David D. Kashemirov, Boris A. McKenna, Charles E. Goodman, Myron F. Wilson, Samuel H. TI Stereospecific Formation of a Ternary Complex of (S)-alpha,beta-Fluoromethylene-dATP with DNA Pol beta SO CHEMBIOCHEM LA English DT Article DE enzymes; fluorine; inhibitors; nucleotides ID POLYMERASE-BETA; 5'-TRIPHOSPHATES; ANALOGS; FIDELITY; REPAIR C1 [Chamberlain, Brian T.; Kadina, Anastasia P.; Kashemirov, Boris A.; McKenna, Charles E.; Goodman, Myron F.] Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. [Chamberlain, Brian T.; Kadina, Anastasia P.; Kashemirov, Boris A.; McKenna, Charles E.; Goodman, Myron F.] Univ So Calif, Dept Biol, Los Angeles, CA 90089 USA. [Batra, Vinod K.; Beard, William A.; Shock, David D.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP McKenna, CE (reprint author), Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. EM mckenna@usc.edu; wilson5@niehs.nih.gov FU NIH [U19CA105010]; National Institutes of Health, National Institute of Environmental Health Sciences [Z01ES050158] FX This research was supported by NIH grant U19CA105010 and in part by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, project number Z01ES050158. We thank Inah Kang for assistance in preparing the manuscript. NR 18 TC 16 Z9 17 U1 0 U2 7 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD MAR 5 PY 2012 VL 13 IS 4 BP 528 EP 530 DI 10.1002/cbic.201100738 PG 3 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 900FI UT WOS:000300871600008 PM 22315190 ER PT J AU Shah, SS Diakite, SAS Traore, K Diakite, M Kwiatkowski, DP Rockett, KA Wellems, TE Fairhurst, RM AF Shah, Shivang S. Diakite, Seidina A. S. Traore, Karim Diakite, Mahamadou Kwiatkowski, Dominic P. Rockett, Kirk A. Wellems, Thomas E. Fairhurst, Rick M. TI A novel cytofluorometric assay for the detection and quantification of glucose-6-phosphate dehydrogenase deficiency SO SCIENTIFIC REPORTS LA English DT Article ID DEHYDROGENASE DEFICIENCY; LIPID-PEROXIDATION; HUMAN-ERYTHROCYTES; HYDROGEN-PEROXIDE; RED CELLS; G6PD; FLUORESCENCE; HEMOGLOBIN; HEME; LOCALIZATION AB Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymopathy that affects hundreds of millions of people worldwide, conferring increased risk of neonatal jaundice and oxidant-induced hemolytic anemia. Screening and diagnosis of G6PD deficiency is currently performed using genetic or biochemical assays, the former being cost ineffective in populations with significant allelic heterogeneity, and the latter being limited in ability to detect female heterozygotes. Cytochemical assays can obviate these shortcomings, but at the expense of added technical complexity and labor. We describe here a simple, novel cytofluorometric method that extends the classic methemoglobin reduction test, assessing G6PD deficiency at the level of an individual erythrocyte. In preliminary testing in Malian children, there was strong concordance between our method and established genetic and biochemical techniques. The assay is robust and economical, and could serve as a screening method as well as a research tool, especially for high-throughput applications such as flow cytometry. C1 [Shah, Shivang S.; Wellems, Thomas E.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Shah, Shivang S.; Kwiatkowski, Dominic P.; Rockett, Kirk A.] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Diakite, Seidina A. S.; Traore, Karim; Diakite, Mahamadou] Univ Bamako, Fac Med Pharm & Odontostomatol, Malaria Res & Training Ctr, Bamako, Mali. RP Fairhurst, RM (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM rfairhurst@niaid.nih.gov OI Kwiatkowski, Dominic/0000-0002-5023-0176 FU NIAID, NIH FX We thank all the children and their families who participated in this study, and Saibou Doumbia, Drissa Konate, Mory Doumbia, and Dick Sakai for their efforts in support of this work. This study was supported by the Intramural Research Program of the NIAID, NIH. NR 38 TC 18 Z9 18 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD MAR 5 PY 2012 VL 2 AR 299 DI 10.1038/srep00299 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 905TN UT WOS:000301297900001 PM 22393475 ER PT J AU Gopich, IV AF Gopich, Irina V. TI Likelihood functions for the analysis of single-molecule binned photon sequences SO CHEMICAL PHYSICS LA English DT Article DE Single molecule fluorescence spectroscopy; FRET; Hidden Markov models; Three-color FRET ID RESONANCE ENERGY-TRANSFER; HIDDEN MARKOV-MODELS; MODULATED POISSON-PROCESS; CONFORMATIONAL DYNAMICS; FRET; FLUORESCENCE; TRAJECTORIES; PROTEIN; KINETICS; SPECTROSCOPY AB We consider the analysis of a class of experiments in which the number of photons in consecutive time intervals is recorded. Sequence of photon counts or, alternatively, of FRET efficiencies can be studied using likelihood-based methods. For a kinetic model of the conformational dynamics and state-dependent Poisson photon statistics, the formalism to calculate the exact likelihood that this model describes such sequences of photons or FRET efficiencies is developed. Explicit analytic expressions for the likelihood function for a two-state kinetic model are provided. The important special case when conformational dynamics are so slow that at most a single transition occurs in a time bin is considered. By making a series of approximations, we eventually recover the likelihood function used in hidden Markov models. In this way, not only is insight gained into the range of validity of this procedure, but also an improved likelihood function can be obtained. Published by Elsevier B.V. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gopich, IV (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM irinag@niddk.nih.gov FU National Institutes of Health, NIDDK FX I thank A. Szabo for numerous extremely illuminating discussions, H. S. Chung for Fig. 1(a), and A. Berezhkovskii for helpful comments on the manuscript. This work was supported by the Intramural Research Program of the National Institutes of Health, NIDDK. NR 34 TC 4 Z9 4 U1 0 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0104 J9 CHEM PHYS JI Chem. Phys. PD MAR 2 PY 2012 VL 396 BP 53 EP 60 DI 10.1016/j.chemphys.2011.06.006 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 925NH UT WOS:000302767400008 PM 22711967 ER PT J AU Di Lieto, A Rantamaki, T Vesa, L Yanpallewar, S Antila, H Lindholm, J Rios, M Tessarollo, L Castren, E AF Di Lieto, Antonio Rantamaki, Tomi Vesa, Liisa Yanpallewar, Sudhirkumar Antila, Hanna Lindholm, Jesse Rios, Maribel Tessarollo, Lino Castren, Eero TI The Responsiveness of TrkB to BDNF and Antidepressant Drugs Is Differentially Regulated during Mouse Development SO PLOS ONE LA English DT Article ID NEUROTROPHIC FACTOR; HIPPOCAMPAL-NEURONS; TRUNCATED TRKB.T1; BRAIN; RECEPTOR; MICE; DEPRESSION; PLASTICITY; MODULATION; ACTIVATION AB Background: Previous studies suggest that the responsiveness of TrkB receptor to BDNF is developmentally regulated in rats. Antidepressant drugs (AD) have been shown to increase TrkB signalling in the adult rodent brain, and recent findings implicate a BDNF-independent mechanism behind this phenomenon. When administered during early postnatal life, ADs produce long-lasting biochemical and behavioural alterations that are observed in adult animals. Methodology: We have here examined the responsiveness of brain TrkB receptors to BDNF and ADs during early postnatal life of mouse, measured as autophosphorylation of TrkB (pTrkB). Principal Findings: We found that ADs fail to induce TrkB signalling before postnatal day 12 (P12) after which an adult response of TrkB to ADs was observed. Interestingly, there was a temporally inverse correlation between the appearance of the responsiveness of TrkB to systemic ADs and the marked developmental reduction of BDNF-induced TrkB in brain microslices ex vivo. Basal p-TrkB status in the brain of BDNF deficient mice was significantly reduced only during early postnatal period. Enhancing cAMP (cyclic adenosine monophosphate) signalling failed to facilitate TrkB responsiveness to BDNF. Reduced responsiveness of TrkB to BDNF was not produced by the developmental increase in the expression of dominant-negative truncated TrkB. T1 because this reduction was similarly observed in the brain microslices of trkB. T1(-/-) mice. Moreover, postnatal AD administration produced long-lasting behavioural alterations observable in adult mice, but the responses were different when mice were treated during the time when ADs did not (P4-9) or did (P16-21) activate TrkB. Conclusions: We have found that ADs induce the activation of TrkB only in mice older than 2 weeks and that responsiveness of brain microslices to BDNF is reduced during the same time period. Exposure to ADs before and after the age when ADs activate TrkB produces differential long-term behavioural responses in adult mice. C1 [Di Lieto, Antonio; Rantamaki, Tomi; Vesa, Liisa; Antila, Hanna; Lindholm, Jesse; Castren, Eero] Univ Helsinki, Neurosci Ctr, Sigrid Juselius Lab, Helsinki, Finland. [Yanpallewar, Sudhirkumar; Tessarollo, Lino] NCI, Neural Dev Sect, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21701 USA. [Rios, Maribel] Tufts Univ, Sch Med, Dept Neurosci, Boston, MA 02111 USA. RP Di Lieto, A (reprint author), Univ Helsinki, Neurosci Ctr, Sigrid Juselius Lab, Helsinki, Finland. EM eero.castren@helsinki.fi OI Antila, Hanna/0000-0001-8317-4564; Rantamaki, Tomi/0000-0002-0052-1434; Castren, Eero/0000-0002-1402-2791 FU Academy of Finland Center of Excellence; Helsinki Graduate Program in Biotechnology and Molecular Biology; Sigrid Juselius Foundation; United States National Institutes of Health, National Cancer Institute FX This study was financially supported by the Academy of Finland Center of Excellence Programme (E. C.), the Helsinki Graduate Program in Biotechnology and Molecular Biology (L. V.), the Sigrid Juselius Foundation (E. C.) and Intramural Research Program of the United States National Institutes of Health, National Cancer Institute (S.Y. and L. T.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 13 Z9 13 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 2 PY 2012 VL 7 IS 3 AR e32869 DI 10.1371/journal.pone.0032869 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 928TC UT WOS:000303006500035 PM 22396798 ER PT J AU Patrick, H Williams, GC AF Patrick, Heather Williams, Geoffrey C. TI Self-determination theory: its application to health behavior and complementarity with motivational interviewing SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; INTRINSIC MOTIVATION; MEDICATION ADHERENCE; SUPPORTING AUTONOMY; PHYSICAL-ACTIVITY; PROBLEM DRINKERS; DECISION-MAKING; AMERICAN-DREAM; WEIGHT CONTROL; INTERVENTION AB Mounting evidence implicates health behaviors (e.g., nutrition, physical activity, tobacco abstinence) in various health outcomes. As the science of behavior change has emerged, increasing emphasis has been placed on the use of theory in developing and testing interventions. Self-determination theory (SDT)-a theoretical perspective-and motivational interviewing (MI)-a set of clinical techniques-have both been used in health behavior intervention contexts. Although developed for somewhat different purposes and in relatively different domains, there is a good deal of conceptual overlap between SDT and MI. Accordingly, SDT may offer the theoretical backing that historically has been missing from MI, and MI may offer SDT some specific direction with respect to particular clinical techniques that have not been fully borne out within the confines of health related applications of SDT. Research is needed to empirically test the overlap and distinctions between SDT and MI and to determine the extent to which these two perspectives can be combined or co-exist as somewhat distinct approaches. C1 [Patrick, Heather] NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Williams, Geoffrey C.] Univ Rochester, Dept Med & Clin & Social Psychol, Rochester, NY 14607 USA. RP Patrick, H (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd, Rockville, MD 20852 USA. EM patrickha@mail.nih.gov NR 71 TC 50 Z9 51 U1 11 U2 54 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 MAR 2 PY 2012 VL 9 AR 18 DI 10.1186/1479-5868-9-18 PG 12 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 921MC UT WOS:000302480700001 PM 22385676 ER PT J AU Verstuyf, J Patrick, H Vansteenkiste, M Teixeira, PJ AF Verstuyf, Joke Patrick, Heather Vansteenkiste, Maarten Teixeira, Pedro J. TI Motivational dynamics of eating regulation: a self-determination theory perspective SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Review DE Eating Regulation; Eating Disorders; Self-Determination Theory; Motivation; Autonomous Regulation; Need Substitutes; Thin-Ideal ID PARENTAL PSYCHOLOGICAL CONTROL; WEIGHT-LOSS MAINTENANCE; INTRINSIC MOTIVATION; BODY-IMAGE; MALADAPTIVE PERFECTIONISM; DISORDER PATIENTS; BULIMIC SYMPTOMS; AUTONOMY SUPPORT; WOMEN; OBJECTIFICATION AB Within Western society, many people have difficulties adequately regulating their eating behaviors and weight. Although the literature on eating regulation is vast, little attention has been given to motivational dynamics involved in eating regulation. Grounded in Self-Determination Theory (SDT), the present contribution aims to provide a motivational perspective on eating regulation. The role of satisfaction and thwarting of the basic psychological needs for autonomy, competence, and relatedness is introduced as a mechanism to (a) explain the etiology of body image concerns and disordered eating and (b) understand the optimal regulation of ongoing eating behavior for healthy weight maintenance. An overview of empirical studies on these two research lines is provided. In a final section, the potential relevance and value of SDT in relation to prevailing theoretical models in the domain of eating regulation is discussed. Although research on SDT in the domain of eating regulation is still in its early stages and more research is clearly needed, this review suggests that the SDT represents a promising framework to more thoroughly study and understand the motivational processes involved in eating regulation and associated problems. C1 [Verstuyf, Joke; Vansteenkiste, Maarten] Univ Ghent, Dept Dev Personal & Social Psychol, B-9000 Ghent, Belgium. [Patrick, Heather] NCI, Rockville, MD 20852 USA. [Teixeira, Pedro J.] Univ Tecn Lisboa, Fac Human Kinet, P-1495688 Cruz Quebrada, Portugal. RP Verstuyf, J (reprint author), Univ Ghent, Dept Dev Personal & Social Psychol, H Dunantlaan 2, B-9000 Ghent, Belgium. EM Joke.Verstuyf@UGent.be RI Teixeira, Pedro/C-9817-2010 OI Teixeira, Pedro/0000-0001-7202-0527 FU Fund for Scientific Research-Flanders (FWO), Belgium FX We acknowledge Bart Soenens and Liesbet Boone for critically reading the manuscript and giving useful suggestions to improve the quality of the manuscript. We thank Richard Ryan for discussing theoretical statements and providing feedback on the figures attached to this manuscript. The first author, JV, is funded as a Research Assistant of the Fund for Scientific Research-Flanders (FWO), Belgium. NR 108 TC 31 Z9 31 U1 7 U2 62 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 MAR 2 PY 2012 VL 9 AR 21 DI 10.1186/1479-5868-9-21 PG 16 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 916FC UT WOS:000302083500001 PM 22385782 ER PT J AU Cheng, LZ Hansen, NF Zhao, L Du, YT Zou, CL Donovan, FX Chou, BK Zhou, GY Li, SJ Dowey, SN Ye, ZH Chandrasekharappa, SC Yang, HM Mullikin, JC Liu, PP AF Cheng, Linzhao Hansen, Nancy F. Zhao, Ling Du, Yutao Zou, Chunlin Donovan, Frank X. Chou, Bin-Kuan Zhou, Guangyu Li, Shijie Dowey, Sarah N. Ye, Zhaohui Chandrasekharappa, Settara C. Yang, Huanming Mullikin, James C. Liu, P. Paul CA NISC Comparative Sequencing Progra TI Low Incidence of DNA Sequence Variation in Human Induced Pluripotent Stem Cells Generated by Nonintegrating Plasmid Expression SO CELL STEM CELL LA English DT Article ID COPY NUMBER VARIATION; GENOME; MUTATIONS; ACCURATE; DERIVATION; SPECTRUM; CULTURE; GENES AB The utility of induced pluripotent stem cells (iPSCs) as models to study diseases and as sources for cell therapy depends on the integrity of their genomes. Despite recent publications of DNA sequence variations in the iPSCs, the true scope of such changes for the entire genome is not clear. Here we report the whole-genome sequencing of three human iPSC lines derived from two cell types of an adult donor by episomal vectors. The vector sequence was undetectable in the deeply sequenced iPSC lines. We identified 1,058-1,808 heterozygous single-nucleotide variants (SNVs), but no copy-number variants, in each iPSC line. Six to twelve of these SNVs were within coding regions in each iPSC line, but 50% of them are synonymous changes and the remaining are not selectively enriched for known genes associated with cancers. Our data thus suggest that episome-mediated reprogramming is not inherently mutagenic during integration-free iPSC induction. C1 [Cheng, Linzhao; Zou, Chunlin; Chou, Bin-Kuan; Dowey, Sarah N.; Ye, Zhaohui] Johns Hopkins Univ, Inst Cell Engn, Stem Cell Program, Baltimore, MD 21205 USA. [Cheng, Linzhao; Zou, Chunlin; Chou, Bin-Kuan; Dowey, Sarah N.; Ye, Zhaohui] Johns Hopkins Univ, Div Hematol, Baltimore, MD 21205 USA. [Hansen, Nancy F.; Mullikin, James C.] NHGRI, Comparat Genom Unit, NIH, Bethesda, MD 20892 USA. [Zhao, Ling; Liu, P. Paul] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. [Mullikin, James C.; NISC Comparative Sequencing Progra] NHGRI, NIH Intramural Sequencing Ctr NISC, NIH, Bethesda, MD 20892 USA. [Du, Yutao; Zhou, Guangyu; Li, Shijie; Yang, Huanming] Beijing Genom Inst BGI Shenzhen, Shenzhen 518000, Peoples R China. RP Cheng, LZ (reprint author), Johns Hopkins Univ, Inst Cell Engn, Stem Cell Program, Baltimore, MD 21205 USA. EM lcheng@welch.jhu.edu; pliu@mail.nih.gov RI perumal, murugiah/D-1565-2012; Liu, Paul/A-7976-2012; OI Liu, Paul/0000-0002-6779-025X; Ye, Zhaohui/0000-0001-5272-9168 FU Johns Hopkins University; NIH [RC2 HL101582, U01 HL099775, R01 HL073781]; NIH Center for Regenerative Medicine (NCRM); National Human Genome Research Institute at NIH FX We thank Raman Sood and Blake Carrington for PCR and Sanger sequencing for confirming mutations and Xianmin Zeng in The Buck Institute in California for providing DNA from neural progenitor cells derived from BC1 iPSCs. This study was supported in part by Johns Hopkins University and NIH grants (RC2 HL101582, U01 HL099775, and R01 HL073781), an award from the NIH Center for Regenerative Medicine (NCRM), and The Intramural Research Program of The National Human Genome Research Institute at NIH. NR 25 TC 107 Z9 113 U1 2 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1934-5909 J9 CELL STEM CELL JI Cell Stem Cell PD MAR 2 PY 2012 VL 10 IS 3 BP 337 EP 344 DI 10.1016/j.stem.2012.01.005 PG 8 WC Cell & Tissue Engineering; Cell Biology SC Cell Biology GA 908BX UT WOS:000301466500014 PM 22385660 ER PT J AU Bonzo, JA Ferry, CH Matsubara, T Kim, JH Gonzalez, FJ AF Bonzo, Jessica A. Ferry, Christina H. Matsubara, Tsutomu Kim, Jung-Hwan Gonzalez, Frank J. TI Suppression of Hepatocyte Proliferation by Hepatocyte Nuclear Factor 4 alpha in Adult Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BONE MORPHOGENETIC PROTEIN-7; HORMONE RECEPTOR SUPERFAMILY; HEPATOCELLULAR-CARCINOMA; LIVER-REGENERATION; TRANSCRIPTION FACTOR; GENE-EXPRESSION; PROSTATE-CANCER; MOUSE; HNF4-ALPHA; FIBROSIS AB Hepatocyte nuclear factor 4 alpha (HNF4 alpha) regulates genes involved in lipid and bile acid synthesis, gluconeogenesis, amino acid metabolism, and blood coagulation. In addition to its metabolic role, HNF4 alpha is critical for hepatocyte differentiation, and loss of HNF4 alpha is associated with hepatocellular carcinoma. The hepatocyte-specific Hnf4a knock-out mouse develops severe hepatomegaly and steatosis resulting in premature death, thereby limiting studies of the role of this transcription factor in the adult animal. In addition, gene compensation may complicate analysis of the phenotype of these mice. To overcome these issues, an acute Hnf4a knock-out mouse model was generated through use of the tamoxifen-inducible ErT2cre coupled to the serum albumin gene promoter. Microarray expression analysis revealed up-regulation of genes associated with proliferation and cell cycle control only in the acute liver-specific Hnf4 alpha-null mouse. BrdU and ki67 staining confirmed extensive hepatocyte proliferation in this model. Proliferation was associated with induction of the hepatomitogen Bmp7 as well as reduced basal apoptotic activity. The p53/p63 apoptosis effector gene Perp was further identified as a direct HNF4 alpha target gene. These data suggest that HNF4 alpha maintains hepatocyte differentiation in the adult healthy liver, and its loss may directly contribute to hepatocellular carcinoma development, thus indicating this factor as a possible liver tumor suppressor gene. C1 [Bonzo, Jessica A.; Ferry, Christina H.; Matsubara, Tsutomu; Kim, Jung-Hwan; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Rm 3106, Bethesda, MD 20892 USA. EM gonzalef@mail.nih.gov FU National Cancer Institute, National Institutes of Health (NIH); NIGMS, National Institutes of Health; National Institutes of Health Summer Internship Program FX This work was funded by the intramural research program at the National Cancer Institute, National Institutes of Health (NIH).; Supported by the Pharmacology Research Associate program through NIGMS, National Institutes of Health.; Supported by the National Institutes of Health Summer Internship Program. NR 58 TC 48 Z9 48 U1 0 U2 9 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 MAR 2 PY 2012 VL 287 IS 10 BP 7345 EP 7356 DI 10.1074/jbc.M111.334599 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 902SL UT WOS:000301060200036 PM 22241473 ER PT J AU Xu, X Hou, Y Yin, XY Bao, L Tang, AF Song, LT Li, FQ Tsang, S Wu, K Wu, HJ He, WM Zeng, L Xing, MJ Wu, RH Jiang, H Liu, X Cao, DD Guo, GW Hu, XD Gui, YT Li, ZS Xie, WY Sun, XJ Shi, M Cai, ZM Wang, B Zhong, MM Li, JX Lu, ZH Gu, N Zhang, XQ Goodman, L Bolund, L Wang, J Yang, HM Kristiansen, K Dean, M Li, YR Wang, J AF Xu, Xun Hou, Yong Yin, Xuyang Bao, Li Tang, Aifa Song, Luting Li, Fuqiang Tsang, Shirley Wu, Kui Wu, Hanjie He, Weiming Zeng, Liang Xing, Manjie Wu, Renhua Jiang, Hui Liu, Xiao Cao, Dandan Guo, Guangwu Hu, Xueda Gui, Yaoting Li, Zesong Xie, Wenyue Sun, Xiaojuan Shi, Min Cai, Zhiming Wang, Bin Zhong, Meiming Li, Jingxiang Lu, Zuhong Gu, Ning Zhang, Xiuqing Goodman, Laurie Bolund, Lars Wang, Jian Yang, Huanming Kristiansen, Karsten Dean, Michael Li, Yingrui Wang, Jun TI Single-Cell Exome Sequencing Reveals Single-Nucleotide Mutation Characteristics of a Kidney Tumor SO CELL LA English DT Article ID MULTIPLE DISPLACEMENT AMPLIFICATION; LUNG-CANCER; SULT1A1 POLYMORPHISM; LYSINE ACETYLATION; RENAL-CARCINOMA; HIF PATHWAY; GENOME; GENE; EXPRESSION; PROTEIN AB Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer and has very few mutations that are shared between different patients. To better understand the intratumoral genetics underlying mutations of ccRCC, we carried out single-cell exome sequencing on a ccRCC tumor and its adjacent kidney tissue. Our data indicate that this tumor was unlikely to have resulted from mutations in VHL and PBRM1. Quantitative population genetic analysis indicates that the tumor did not contain any significant clonal subpopulations and also showed that mutations that had different allele frequencies within the population also had different mutation spectrums. Analyses of these data allowed us to delineate a detailed intratumoral genetic landscape at a single-cell level. Our pilot study demonstrates that ccRCC may be more genetically complex than previously thought and provides information that can lead to new ways to investigate individual tumors, with the aim of developing more effective cellular targeted therapies. C1 [Xu, Xun; Hou, Yong; Yin, Xuyang; Bao, Li; Song, Luting; Li, Fuqiang; Wu, Kui; Wu, Hanjie; He, Weiming; Zeng, Liang; Xing, Manjie; Wu, Renhua; Jiang, Hui; Liu, Xiao; Cao, Dandan; Guo, Guangwu; Hu, Xueda; Wang, Bin; Zhong, Meiming; Li, Jingxiang; Zhang, Xiuqing; Goodman, Laurie; Bolund, Lars; Wang, Jian; Yang, Huanming; Kristiansen, Karsten; Dean, Michael; Li, Yingrui; Wang, Jun] BGI Shenzhen, Shenzhen 518083, Peoples R China. [Xu, Xun] BGI Amer, Cambridge, MA 02142 USA. [Hou, Yong; Lu, Zuhong; Gu, Ning] Southeast Univ, Sch Biol Sci & Med Engn, Nanjing 210096, Jiangsu, Peoples R China. [Hou, Yong; Lu, Zuhong; Gu, Ning] Southeast Univ, State Key Lab Bioelect, Nanjing 210096, Jiangsu, Peoples R China. [Tang, Aifa; Li, Zesong; Sun, Xiaojuan; Cai, Zhiming] Shenzhen Second Peoples Hosp, Dept Urol, Shenzhen 518035, Peoples R China. [Tang, Aifa; Li, Zesong; Sun, Xiaojuan; Cai, Zhiming] Shenzhen Univ, Inst Urogenital Dis, Shenzhen 518060, Peoples R China. [Tsang, Shirley] BioMatrix LLC, Rockville, MD 20849 USA. [Wu, Hanjie] S China Univ Technol, Sch Biosci & Biotechnol, Guangzhou 510641, Guangdong, Peoples R China. [Xie, Wenyue; Shi, Min; Cai, Zhiming] Peking Univ, Shenzhen PKU HKUST Med Ctr, Inst Urol,Shenzhen Hosp, Guangdong & Shenzhen Key Lab Male Reprod Med & Ge, Shenzhen 518036, Peoples R China. [Bolund, Lars] Univ Aarhus, Inst Human Genet, DK-8100 Aarhus, Denmark. [Kristiansen, Karsten; Wang, Jun] Univ Copenhagen, Dept Biol, DK-1165 Copenhagen, Denmark. [Wang, Jun] Univ Copenhagen, Novo Nordisk Fdn Ctr Basic Metab Res, DK-1165 Copenhagen, Denmark. [Dean, Michael] NCI, Canc & Inflammat Program, NIH, Frederick, MD 21701 USA. RP Wang, J (reprint author), BGI Shenzhen, Shenzhen 518083, Peoples R China. EM wangj@genomics.org.cn; deanm@mail.nih.gov; liyr@genomics.org.cn; wangj@genomics.org.cn RI Dean, Michael/G-8172-2012; Lu, Zuhong/A-5448-2013; Li, Yingrui/K-1064-2015; Kristiansen, Karsten/J-5148-2014; Wang, Jun/C-8434-2016; Wang, Jun/B-9503-2016; OI Dean, Michael/0000-0003-2234-0631; Kristiansen, Karsten/0000-0002-6024-0917; Wang, Jun/0000-0002-8540-8931; Goodman, Laurie/0000-0001-9724-5976; Wang, Jun/0000-0002-2113-5874; Wu, Hanjie/0000-0002-5451-4969; hou, yong/0000-0002-0420-0726 FU National Basic Research Program of China (973 program) [2011CB809202, 2011CB809203]; Chinese 863 program [2009AA022707, 2012AA02A201]; Shenzhen Municipal Government of China [ZYC201005250020A]; Key Laboratory Project, Shenzhen City [CX B200903 110066A, CXB201108250096A]; Shenzhen Key Laboratory of Gene Bank for National Life Science; Innovative Research Team of Guangdong; Guangdong Enterprise Key Laboratory of Human Disease Genomics; Shenzhen Key Laboratory, Shenzhen, China [CXB200903090055A, CXB201005250016A]; Danish Natural Science Research Council; Danish National Research Foundation; National Natural Science Foundation of China; Shenzhen Municipal Government; Local Government of Yantian District of Shenzhen; National Cancer Institute, National Institutes of Health, USA FX This work was supported by a National Basic Research Program of China (973 program numbers 2011CB809202 and 2011CB809203), the Chinese 863 program (numbers 2009AA022707 and 2012AA02A201), the Shenzhen Municipal Government of China (grant ZYC201005250020A), the Key Laboratory Project Supported by Shenzhen City (grants CX B200903 110066A and CXB201108250096A), and Shenzhen Key Laboratory of Gene Bank for National Life Science. This project was also supported by grants from the Innovative Research Team Project of Guangdong, the Guangdong Enterprise Key Laboratory of Human Disease Genomics, and the Promotion Program for Shenzhen Key Laboratory, Shenzhen, China (CXB200903090055A and CXB201005250016A). We also acknowledge the Ole Romer grant from the Danish Natural Science Research Council, the Danish National Research Foundation, the National Natural Science Foundation of China, and funds from the Shenzhen Municipal Government and the Local Government of Yantian District of Shenzhen. We also acknowledge support from the Intramural Research Program of the National Cancer Institute, National Institutes of Health, USA. NR 55 TC 259 Z9 281 U1 16 U2 134 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 2 PY 2012 VL 148 IS 5 BP 886 EP 895 DI 10.1016/j.cell.2012.02.025 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 901RR UT WOS:000300985000010 PM 22385958 ER PT J AU Kim, JY Liu, CY Zhang, FY Duan, X Wen, ZX Song, J Feighery, E Lu, B Rujescu, D St Clair, D Christian, K Callicott, JH Weinberger, DR Song, HJ Ming, GL AF Kim, Ju Young Liu, Cindy Y. Zhang, Fengyu Duan, Xin Wen, Zhexing Song, Juan Feighery, Emer Lu, Bai Rujescu, Dan St Clair, David Christian, Kimberly Callicott, Joseph H. Weinberger, Daniel R. Song, Hongjun Ming, Guo-Li TI Interplay between DISC1 and GABA Signaling Regulates Neurogenesis in Mice and Risk for Schizophrenia SO CELL LA English DT Article ID NEWLY GENERATED NEURONS; ADULT BRAIN; GENE-EXPRESSION; MOUSE HIPPOCAMPUS; DOWN-REGULATION; STRESS; INTEGRATION; MATURATION; KCC2; CELL AB How extrinsic stimuli and intrinsic factors interact to regulate continuous neurogenesis in the postnatal mammalian brain is unknown. Here we show that regulation of dendritic development of newborn neurons by Disrupted-in-Schizophrenia 1 (DISC1) during adult hippocampal neurogenesis requires neurotransmitter GABA-induced, NKCC1-dependent depolarization through a convergence onto the AKT-mTOR pathway. In contrast, DISC1 fails to modulate early-postnatal hippocampal neurogenesis when conversion of GABA-induced depolarization to hyperpolarization is accelerated. Extending the period of GABA-induced depolarization or maternal deprivation stress restores DISC1-dependent dendritic regulation through mTOR pathway during early-postnatal hippocampal neurogenesis. Furthermore, DISC1 and NKCC1 interact epistatically to affect risk for schizophrenia in two independent case control studies. Our study uncovers an interplay between intrinsic DISC1 and extrinsic GABA signaling, two schizophrenia susceptibility pathways, in controlling neurogenesis and suggests critical roles of developmental tempo and experience in manifesting the impact of susceptibility genes on neuronal development and risk for mental disorders. C1 [Kim, Ju Young; Liu, Cindy Y.; Duan, Xin; Wen, Zhexing; Song, Juan; Christian, Kimberly; Song, Hongjun; Ming, Guo-Li] Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA. [Kim, Ju Young; Liu, Cindy Y.; Wen, Zhexing; Song, Juan; Christian, Kimberly; Song, Hongjun; Ming, Guo-Li] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Zhang, Fengyu; Duan, Xin; Song, Hongjun; Ming, Guo-Li] Johns Hopkins Univ, Sch Med, Solomon Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Feighery, Emer; Lu, Bai; Callicott, Joseph H.; Weinberger, Daniel R.] NIMH, Gene Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Rujescu, Dan] Univ Munich, Dept Psychiat, D-80336 Munich, Germany. [St Clair, David] Univ Aberdeen, Royal Cornhill Hosp, Aberdeen AB25 2ZD, Scotland. [Weinberger, Daniel R.; Song, Hongjun] Lieber Inst Brain Dev, Baltimore, MD 21205 USA. RP Ming, GL (reprint author), Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA. EM gming1@jhmi.edu RI Ming, Guo-li/J-7880-2013; Wen, Zhexing/B-9313-2014; Callicott, Joseph/C-9102-2009 OI Callicott, Joseph/0000-0003-1298-3334 FU NIH [NS048271, HD069184, NS047344, MH087874]; MSCRF; NARSAD; IMHRO; NIMH FX We thank members of Ming and Song Laboratories for help and critical comments, L. Liu, Y. Cai, N. Powanpangkul, and Q. Hussaini for technical support, and A. Chiang and J. Wang for help with tissue processing. This work was supported by the NIH (NS048271 and HD069184), MSCRF, and NARSAD to G-l.M., by the NIH (NS047344 and MH087874) and IMHRO to H. S., by the NIMH intramural program to D. W., and by postdoctoral fellowships from MSCRF to J. Y. K., Z.W., J. S., and K. NR 51 TC 84 Z9 90 U1 1 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 2 PY 2012 VL 148 IS 5 BP 1051 EP 1064 DI 10.1016/j.cell.2011.12.037 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 901RR UT WOS:000300985000023 PM 22385968 ER PT J AU Hakim, O Misteli, T AF Hakim, Ofir Misteli, Tom TI SnapShot: Chromosome Confirmation Capture SO CELL LA English DT Editorial Material ID CONFORMATION CAPTURE; YEAST GENOME; ORGANIZATION; LOCI C1 [Hakim, Ofir; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Hakim, O (reprint author), NCI, NIH, Bethesda, MD 20892 USA. NR 20 TC 10 Z9 10 U1 4 U2 19 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 2 PY 2012 VL 148 IS 5 BP 1068 EP U245 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 901RR UT WOS:000300985000027 ER PT J AU Richard, SA Black, RE Checkley, W AF Richard, Stephanie A. Black, Robert E. Checkley, William TI Revisiting the Relationship of Weight and Height in Early Childhood SO ADVANCES IN NUTRITION LA English DT Article; Proceedings Paper CT Symposium on Building Convergence among Scientific, Programmatic, and Policy Communities - Working on Childhood Undernutrition in Developing Countries Given at the Annual Experimental Biology Meeting CY APR 11, 2011 CL Washington, DC ID HOUSEHOLD FOOD SECURITY; LINEAR GROWTH; RURAL BANGLADESH; PREGNANCY OUTCOMES; NUTRITIONAL-STATUS; PHYSICAL GROWTH; NATIONAL-CENTER; YOUNG-CHILDREN; UNDERNUTRITION; INTERVENTIONS AB Ponderal and linear growth of children has been widely studied; however, epidemiologic evidence of a relationship between the two is inconsistent. Child undernutrition in the form of low height for age and low weight for height continues to burden the developing world. A downward shift in the distribution of height for age in the first 2 y of life is commonly observed in many developing countries and is usually summarized as the percentage stunted (height for age Z-score <-2). Similar shifts are seen in weight for height; however, weight-for-height shifts are often less extreme, perhaps because weight for height is more tightly biologically controlled. Low height for age and low weight for height in childhood share some common factors, including food insecurity, infectious diseases, and inappropriate feeding practices. Reductions in weight for height, generally seen as a short-term response to inadequate dietary intake or utilization, are thought to precede decreases in height for age; however, given an adequate diet and no further insults, catch-up linear growth can occur. Serial instances of decreased weight for height, however, are thought to limit the degree of catch-up growth attained, contributing to linear growth retardation. Additional research is needed to identify the factors associated with recovery of linear growth after a child experiences decreased weight for height. Although the direct relationship between weight for height and height for age is likely limited, each of these measurements indicates important information about the general health of children and their risk of the development of illness or dying; therefore, eliminating the downward shift of height for age and weight for height in developing countries should be prioritized as a public policy. Adv. Nutr. 3: 250-254, 2012. C1 [Richard, Stephanie A.; Black, Robert E.; Checkley, William] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21218 USA. [Richard, Stephanie A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Checkley, W (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21218 USA. EM wcheckl1@jhmi.edu OI Black, Robert/0000-0001-9926-7984 NR 53 TC 10 Z9 10 U1 1 U2 12 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 MAR PY 2012 VL 3 IS 2 BP 250 EP 254 DI 10.3945/an.111.001099 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 066KO UT WOS:000313219900018 PM 22516736 ER PT J AU Broyles, LM Tate, JA Happ, MB AF Broyles, Lauren M. Tate, Judith A. Happ, Mary Beth TI USE OF AUGMENTATIVE AND ALTERNATIVE COMMUNICATION STRATEGIES BY FAMILY MEMBERS IN THE INTENSIVE CARE UNIT SO AMERICAN JOURNAL OF CRITICAL CARE LA English DT Article ID POSTTRAUMATIC-STRESS; VENTILATED PATIENTS; CRITICAL ILLNESS; DECISION-MAKING; HIGH-RISK; PATIENT; SYMPTOMS; LIFE; ICU; EXPERIENCES AB Background Little is known about communication between patients and their family members during critical illness and mechanical ventilation in the intensive care unit, including use of augmentative and alternative communication tools and strategies. Objectives To identify (1) which augmentative and alternative communication tools families use with nonspeaking intensive care patients and how they are used, and (2) what families and nurses say about communication of family members with nonspeaking intensive care patients. Methods A qualitative secondary analysis was conducted of existing data from a clinical trial testing interventions to improve communication between nurses and intensive care patients. Narrative study data (field notes, intervention logs, nurses' interviews) from 127 critically ill adults were reviewed for evidence of family involvement with augmentative and alternative communication tools. Qualitative content analysis was applied for thematic description of family members' and nurses' accounts of patient-family communication. Results Family involvement with augmentative and alternative communication tools was evident in 44% of the 93 patients who completed the parent study protocol. Spouses or significant others communicated with patients most often. Main themes describing patient-family communication included (1) families being unprepared and unaware, (2) families' perceptions of communication effectiveness, (3) nurses deferring to or guiding patient-family communication, (4) patients' communication characteristics, and (5) families' experience with and interest in augmentative and alternative communication tools. Conclusions Assessment by skilled bedside clinicians can reveal patients' communication potential and facilitate useful augmentative and alternative communication tools and strategies for patients and their families. (American Journal of Critical Care. 2012; 21(2): e21-e32) C1 [Broyles, Lauren M.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA 15206 USA. [Broyles, Lauren M.] Univ Pittsburgh, Div Gen Internal Med, Pittsburgh, PA 15260 USA. [Tate, Judith A.] Univ Pittsburgh, Dept Psychiat, NIMH, Pittsburgh, PA 15260 USA. [Happ, Mary Beth] Univ Pittsburgh, Dept Acute & Tertiary Care, UPMC Hlth Syst, Sch Nursing,Chair Nursing Sci, Pittsburgh, PA 15260 USA. RP Broyles, LM (reprint author), VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, 7180 Highland Dr,151C-H, Pittsburgh, PA 15206 USA. EM Lauren.Broyles@va.gov RI Tate, Judith/C-7447-2015 FU National Institute for Nursing Research [5K24- NR010244]; National Institute for Child Health and Human Development [5R01 HD043988]; US Department of Veterans Affairs [CDA 10-014] FX This study was supported by grants (M. Happ, principal investigator) from the National Institute for Nursing Research (5K24- NR010244) and the National Institute for Child Health and Human Development (5R01 HD043988). Dr Broyles is currently supported by a Career Development Award (CDA 10-014) from the US Department of Veterans Affairs. This material is the result of work supported with resources and the use of facilities at the VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania. Dr Tate is a National Institute of Mental Health postdoctoral research fellow in the clinical research training program in geriatric psychiatry at the University of Pittsburgh Department of Psychiatry (T32 MH19986, principal investigator, Reynolds). NR 61 TC 3 Z9 3 U1 2 U2 30 PU AMER ASSOC CRITICAL CARE NURSES PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1062-3264 J9 AM J CRIT CARE JI Am. J. Crit. Care PD MAR 1 PY 2012 VL 21 IS 2 BP E21 EP E32 DI 10.4037/ajcc2012752 PG 12 WC Critical Care Medicine; Nursing SC General & Internal Medicine; Nursing GA 031LC UT WOS:000310640300001 PM 22381993 ER PT J AU Baroni, M Mariani, T Elmo, A Spagnolo, E Cherubini, A Maggio, D Maggio, M Raadicchi, R Cepollaro, C Lauretani, F Bandinelli, S Conti, F Ferrucci, L Ruggiero, C AF Baroni, M. Mariani, T. Elmo, A. Spagnolo, E. Cherubini, A. Maggio, D. Maggio, M. Raadicchi, R. Cepollaro, C. Lauretani, F. Bandinelli, S. Conti, F. Ferrucci, L. Ruggiero, C. TI THE RELATIONSHIP BETWEEN LEG MUSCLE STRENGHT AND POWER AND PQCT BONE MINERAL PARAMETERS IN OLDER PERSONS LIVING IN THE COMMUNITY SO OSTEOPOROSIS INTERNATIONAL LA English DT Meeting Abstract CT IOF-ECCEO European Congress on Osteoporosis and Osteoarthritis / 2nd IOF-ESCEO Pre-Clinical Symposium CY MAR 21-24, 2012 CL Bordeaux, FRANCE SP Int Osteoporosis Fdn (IOF), European Soc Clin & Econom Aspects Osteoporosis & Osteoarthritis (ESCEO), Rottapharm, Madaus, Wisepress, Servier Int, Amgen, GlaxoSmithKline (GSK), MSD, B-Cube AG, BeamMed, Danone, Dfine Europe, D3A, Eli Lilly, Expanscience, GE Healthcare, Hologic, IDS, Medi, Medtron, Mindways, Nycomed, Optasia Med, Pfizer Inc C1 [Baroni, M.; Mariani, T.; Elmo, A.; Spagnolo, E.; Cherubini, A.; Maggio, D.; Raadicchi, R.; Ruggiero, C.] Univ Perugia, Institute Gerontol & Geriatr, Dept Clin & Expt Med, I-06100 Perugia, Italy. [Maggio, M.; Lauretani, F.] Univ Parma, Dept Internal Med & Biomed Sci, Sect Geriatr, I-43100 Parma, Italy. [Cepollaro, C.] Univ Florence, Dept Internal Med, Florence, Italy. [Bandinelli, S.] ASF, Geriatr Unit, Florence, Italy. [Ferrucci, L.] NIA, Clin Res Branch, ASTRA Unit, Baltimore, MD 21224 USA. [Conti, F.] Univ Roma La Sapienza, Dept Internal Med, Rome, Italy. NR 2 TC 0 Z9 0 U1 1 U2 3 PU SPRINGER LONDON LTD PI LONDON PA 236 GRAYS INN RD, 6TH FLOOR, LONDON WC1X 8HL, ENGLAND SN 0937-941X J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD MAR PY 2012 VL 23 SU 2 BP S367 EP S367 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 012TN UT WOS:000309259600624 ER PT J AU Okano, T Kelley, MW AF Okano, Takayuki Kelley, Matthew W. TI Stem Cell Therapy for the Inner Ear: Recent Advances and Future Directions SO TRENDS IN AMPLIFICATION LA English DT Article DE stem cell therapy; inner ear; hair cell; regeneration ID HEALTH INTERVIEW SURVEY; VESTIBULAR HAIR-CELLS; SUPPORTING CELLS; HEARING IMPAIRMENT; SENSORY EPITHELIA; NEUROTROPHIC FACTOR; MAMMALIAN COCHLEA; ACOUSTIC TRAUMA; MOUSE COCHLEA; MICE LACKING AB In vertebrates, perception of sound, motion, and balance is mediated through mechanosensory hair cells located within the inner ear. In mammals, hair cells are only generated during a short period of embryonic development. As a result, loss of hair cells as a consequence of injury, disease, or genetic mutation, leads to permanent sensory deficits. At present, cochlear implantation is the only option for profound hearing loss. However, outcomes are still variable and even the best implant cannot provide the acuity of a biological ear. The recent emergence of stem cell technology has the potential to open new approaches for hair cell regeneration. The goal of this review is to summarize the current state of inner ear stem cell research from a viewpoint of its clinical application for inner ear disorders to illustrate how complementary studies have the potential to promote and refine stem cell therapies for inner ear diseases. The review initially discusses our current understanding of the genetic pathways that regulate hair cell formation from inner ear progenitors during normal development. Subsequent sections discuss the possible use of endogenous inner ear stem cells to induce repair as well as the initial studies aimed at transplanting stem cells into the ear. C1 [Kelley, Matthew W.] Natl Inst Deafness & Other Commun Disorders, Lab Cochlear Dev, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Kelley, MW (reprint author), Natl Inst Deafness & Other Commun Disorders, Lab Cochlear Dev, NIH, Porter Neurosci Res Ctr, 35 Convent Dr, Bethesda, MD 20892 USA. EM Kelleymt@nidcd.nih.gov FU Intramural Program at the National Institute on Deafness and Other Communication Disorders (NIDCD) FX The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by funds from the Intramural Program at the National Institute on Deafness and Other Communication Disorders (NIDCD). NR 132 TC 22 Z9 23 U1 1 U2 24 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1084-7138 J9 TRENDS AMPLIF JI Trends Amplif. PD MAR PY 2012 VL 16 IS 1 BP 4 EP 18 DI 10.1177/1084713812440336 PG 15 GA 031ZX UT WOS:000310682600002 PM 22514095 ER PT J AU Srijanto, BR Cheney, CP Hedden, DL Gehl, AC Crilly, PB Huestis, MA Ferrell, TL AF Srijanto, Bernadeta R. Cheney, Christine P. Hedden, David L. Gehl, Anthony C. Crilly, Paul B. Huestis, Marilyn A. Ferrell, Thomas L. TI Piezoresistive Microcantilevers-Based Cocaine Biosensors SO SENSOR LETTERS LA English DT Article DE Cocaine Biosensors; Piezoresistive Microcantilevers; Oligonucleotide-Based Aptamers ID PERFORMANCE LIQUID-CHROMATOGRAPHY; CMOS CHEMICAL MICROSENSORS; WAVE IMMUNOASSAY SENSORS; PIEZOELECTRIC IMMUNOSENSOR; VAPOR DETECTION; HUMAN HAIR; METABOLITES; APTAMERS; ARRAY; CODEINE AB An aptamer-coated, piezoresistive, microcantilever-based biosensor has been fabricated and tested as presented here to measure the relative concentration of freebase cocaine in solution. Aptamers were used as the cocaine receptor due to their known high selectivity and affinity for the target molecules in buffered solutions. A Wheatstone bridge composed of four microcantilevers was utilized in converting the biological signal to an electrical signal. The approach here provides a prototype that will lead to a compact and low cost device that will be applicable for in-vivo applications. The performance of this sensor is demonstrated in an in-vitro experiment conducted by flowing a cocaine solution in distilled water over the microcantilever arrays. The response of the device had a limit of detection of 1 ng/ml, which is comparable to the conventional method of cocaine detection in the body performed using gas/liquid chromatography and mass spectrophotometry. C1 [Srijanto, Bernadeta R.] Univ Tennessee, Dept Elect Engn & Comp Sci, Knoxville, TN 37996 USA. [Cheney, Christine P.; Hedden, David L.; Gehl, Anthony C.; Ferrell, Thomas L.] Univ Tennessee, Dept Phys, Knoxville, TN 37996 USA. [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Crilly, Paul B.] US Coast Guard Acad, Dept Engn, Elect Engn Sect, New London, CT 06320 USA. RP Srijanto, BR (reprint author), Oak Ridge Natl Lab, Ctr Nanophase Mat Sci Div, Oak Ridge, TN 37831 USA. EM srijantobr@ornl.gov RI Srijanto, Bernadeta/D-4213-2016; OI Srijanto, Bernadeta/0000-0002-1188-1267; Gehl, Anthony/0000-0002-4841-403X FU National Institute on Alcohol Abuse and Alcoholism NIAAA [N01AA23012] FX This research was supported by the National Institute on Alcohol Abuse and Alcoholism NIAAA under Contract No. N01AA23012. NR 45 TC 9 Z9 9 U1 1 U2 28 PU AMER SCIENTIFIC PUBLISHERS PI VALENCIA PA 26650 THE OLD RD, STE 208, VALENCIA, CA 91381-0751 USA SN 1546-198X J9 SENSOR LETT JI Sens. Lett. PD MAR-APR PY 2012 VL 10 IS 3-4 BP 850 EP 855 DI 10.1166/sl.2012.2335 PG 6 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation; Physics, Applied SC Chemistry; Electrochemistry; Instruments & Instrumentation; Physics GA 009IE UT WOS:000309018700025 ER PT J AU Zhang, ZW Albert, PS Simons-Morton, B AF Zhang, Zhiwei Albert, Paul S. Simons-Morton, Bruce TI MARGINAL ANALYSIS OF LONGITUDINAL COUNT DATA IN LONG SEQUENCES: METHODS AND APPLICATIONS TO A DRIVING STUDY SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Correlation; generalized estimating equation; multiple outputation; overdispersion; random effect; separated blocks; within-cluster resampling ID ESTIMATING EQUATIONS; REGRESSION-MODEL; TIME-SERIES; BINARY DATA; JACKKNIFE; VARIANCE AB Most of the available methods for longitudinal data analysis are designed and validated for the situation where the number of subjects is large and the number of observations per subject is relatively small. Motivated by the Naturalistic Teenage Driving Study (NTDS), which represents the exact opposite situation, we examine standard and propose new methodology for marginal analysis of longitudinal count data in a small number of very long sequences. We consider standard methods based on generalized estimating equations, under working independence or an appropriate correlation structure, and find them unsatisfactory for dealing with time-dependent covariates when the counts are low. For this situation, we explore a within-cluster resampling (WCR) approach that involves repeated analyses of random subsamples with a final analysis that synthesizes results across subsamples. This leads to a novel WCR method which operates on separated blocks within subjects and which performs better than all of the previously considered methods. The methods are applied to the NTDS data and evaluated in simulation experiments mimicking the NTDS. C1 [Zhang, Zhiwei] US FDA, Div Biostat, Ctr Devices & Radiol Hlth, Silver Spring, MD 20993 USA. [Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Simons-Morton, Bruce] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Zhang, ZW (reprint author), US FDA, Div Biostat, Ctr Devices & Radiol Hlth, 10903 New Hampshire Ave, Silver Spring, MD 20993 USA. EM zhiwei.zhang@fda.hhs.gov; albertp@mail.nih.gov; mortonb@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported by the Intramural Research Program of the National Institutes of Health (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development. The computation was facilitated by the Biowulf cluster computer system made available by the Center for Information-Technology at the NIH. NR 24 TC 2 Z9 2 U1 2 U2 8 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD MAR PY 2012 VL 6 IS 1 BP 27 EP 54 DI 10.1214/11-AOAS507 PG 28 WC Statistics & Probability SC Mathematics GA 991QJ UT WOS:000307716000002 PM 27087885 ER PT J AU Klee, MM AF Klee, Maurice M. TI The Inventor Who Got More Than He Asked For SO IEEE PULSE LA English DT Editorial Material C1 [Klee, Maurice M.] Michigan State Univ, Coll Engn, E Lansing, MI 48824 USA. [Klee, Maurice M.] NIH, Bethesda, MD 20892 USA. EM mk@maurieklee.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 2154-2287 J9 IEEE PULSE JI IEEE Pulse PD MAR-APR PY 2012 VL 3 IS 2 BP 78 EP 78 DI 10.1109/MPUL.2012.2184459 PG 1 WC Engineering, Biomedical SC Engineering GA 992UY UT WOS:000307806600019 ER PT J AU Shukan, ET Boe, CY Hasenfus, AV Pieper, BA Snowdon, CT AF Shukan, Evan T. Boe, Carla Y. Hasenfus, Aimee V. Pieper, Bridget A. Snowdon, Charles T. TI Normal Hematologic and Serum Biochemical Values of Cotton-Top Tamarins (Saguinus oedipus) SO JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; MARROW-CHIMERIC PRIMATE; MONKEYS MACACA-MULATTA; NEW-WORLD PRIMATE; COLON-CANCER; CAPTIVE CHIMPANZEES; CLINICAL-CHEMISTRY; SOCIAL-ENVIRONMENT; PAN-TROGLODYTES; BLOOD-CHEMISTRY AB We obtained whole-blood hematologic and serum biochemical values from 38 captive-bred cotton-top tamarins (Saguinus oedipus). Data were analyzed to determine the effect of sex on blood parameters. Significant differences between either the means or medians of male and female tamarins were found for creatinine, hematocrit, hemoglobin, RBC count, and PCV. These results establish baseline hematologic and serum biochemical values and provide a useful resource not previously available in the peer-reviewed literature for the clinical care of cotton-top tamarins, a critically endangered New World primate, in a captive setting. C1 [Shukan, Evan T.] NINDS, NIH, Anim Hlth Care Sect, Bethesda, MD 20892 USA. [Boe, Carla Y.; Hasenfus, Aimee V.; Pieper, Bridget A.; Snowdon, Charles T.] Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. RP Shukan, ET (reprint author), NINDS, NIH, Anim Hlth Care Sect, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM shukanet@mail.nih.gov FU National Institute of Mental Health [MH029775, MH035215]; NIH, NINDS FX Support for this project and for the housing of these animals as part of other research protocols came from National Institute of Mental Health grants MH029775 and MH035215 and from the Dean of the College of Letters and Science. We also acknowledge Dr Sungyoung Auh (Office of the Clinical Director, NINDS, NIH) for her assistance with statistical analysis. This research was supported in part by the Intramural Research Program of the NIH, NINDS. NR 60 TC 2 Z9 2 U1 1 U2 4 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1559-6109 J9 J AM ASSOC LAB ANIM JI J. Amer. Assoc. Lab. Anim. Sci. PD MAR PY 2012 VL 51 IS 2 BP 150 EP 154 PG 5 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 978UV UT WOS:000306772200002 PM 22776113 ER PT J AU Kilimnik, G Jo, J Periwal, V Zielinski, MC Hara, M AF Kilimnik, German Jo, Junghyo Periwal, Vipul Zielinski, Mark C. Hara, Manami TI Quantification of islet size and architecture SO ISLETS LA English DT Article DE islet; islet size; islet architecture; pancreas; diabetes AB Human islets exhibit distinct islet architecture particularly in large islets that comprise of a relatively abundant fraction of alpha-cells intermingled with beta-cells, whereas mouse islets show largely similar architecture of a beta-cell core with alpha-cells in the periphery. In humans, islet architecture is islet-size dependent. Changes in endocrine cell mass preferentially occurred in large islets as demonstrated in our recent study on pathological changes of the pancreas in patients with type 2 diabetes. 1 The size dependency of human islets in morphological changes prompted us to develop a method to capture the representative islet distribution in the whole pancreas section combined with a semi-automated analysis to quantify changes in islet architecture. The computer-assisted quantification allows detailed examination of endocrine cell composition in individual islets and minimizes sampling bias. The standard immunohistochemistry based method is widely applicable to various specimens, which is particularly useful for large animal studies but is also applied to a large-scale analysis of the whole organ section from mice. In this article, we describe the method of image capture, parameters measured, data analysis and interpretation of the data. C1 [Kilimnik, German; Zielinski, Mark C.; Hara, Manami] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Jo, Junghyo; Periwal, Vipul] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. RP Hara, M (reprint author), Univ Chicago, Dept Med, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM mhara@midway.uchicago.edu RI Periwal, Vipul/I-1728-2012; Jo, Junghyo/D-4889-2011; OI Zielinski, Mark/0000-0002-6950-6689 FU US Public Health Service [DK-081527, DK-042086, DK-20595, DK-072473]; NIH, NIDDK FX The study is supported by US Public Health Service Grant DK-081527, DK-042086 and DK-20595 to the University of Chicago Diabetes Research and Training Center (Animal Models Core), DK-072473, and a gift from the Kovler Family Foundation (M.H.); and the intramural research program of the NIH, NIDDK (J.J. and V.P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 10 TC 21 Z9 21 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1938-2014 J9 ISLETS JI Islets PD MAR-APR PY 2012 VL 4 IS 2 BP 167 EP 172 DI 10.4161/isl.19256 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 961MY UT WOS:000305469800011 PM 22653677 ER PT J AU Uhlemann, AC Porcella, SF Trivedi, S Sullivan, SB Hafer, C Kennedy, AD Barbian, KD McCarthy, AJ Street, C Hirschberg, DL Lipkin, WI Lindsay, JA DeLeo, FR Lowy, FD AF Uhlemann, Anne-Catrin Porcella, Stephen F. Trivedi, Sheetal Sullivan, Sean B. Hafer, Cory Kennedy, Adam D. Barbian, Kent D. McCarthy, Alex J. Street, Craig Hirschberg, David L. Lipkin, W. Ian Lindsay, Jodi A. DeLeo, Frank R. Lowy, Franklin D. TI Identification of a Highly Transmissible Animal-Independent Staphylococcus aureus ST398 Clone with Distinct Genomic and Cell Adhesion Properties SO MBIO LA English DT Article ID METHICILLIN-RESISTANT; PIG FARMERS; MRSA CC398; HOST; HUMANS; SEQUENCE; STRAIN; COLONIZATION; ADAPTATION; POULTRY AB A methicillin-resistant Staphylococcus aureus (MRSA) clone known as ST398 has emerged as a major cause of acute infections in individuals who have close contact with livestock. More recently, the emergence of an animal-independent ST398 methicillin-sensitive S. aureus (MSSA) clone has been documented in several countries. However, the limited surveillance of MSSA has precluded an accurate assessment of the global spread of ST398 and its clinical relevance. Here we provide evidence that ST398 is a frequent source of MSSA infections in northern Manhattan and is readily transmitted between individuals in households. This contrasts with the limited transmissibility of livestock-associated ST398 (LA-ST398) MRSA strains between humans. Our whole-genome sequence analysis revealed that the chromosome of the human-associated ST398 MSSA clone is smaller than that of the LA-ST398 MRSA reference strain S0385, due mainly to fewer mobile genetic elements (MGEs). In contrast, human ST398 MSSA isolates harbored the prophage phi 3 and the human-specific immune evasion cluster (IEC) genes chp and scn. While most of the core genome was conserved between the human ST398 MSSA clone and S0385, these strains differed substantially in their repertoire and composition of intact adhesion genes. These genetic changes were associated with significantly enhanced adhesion of human ST398 MSSA isolates to human skin keratinocytes and keratin. We propose that the human ST398 MSSA clone can spread independent of animal contact using an optimized repertoire of MGEs and adhesion molecules adapted to transmission among humans. IMPORTANCE Staphylococcus aureus strains have generally been considered to be species specific. However, cross-species transfers of S. aureus clones, such as ST398 methicillin-resistant S. aureus (MRSA), from swine to humans have been reported. Recently, we observed the emergence of ST398 methicillin-susceptible S. aureus (MSSA) as a colonizing strain of humans in northern Manhattan. Here we report that ST398 is a frequent cause of MSSA infections in this urban setting. The ST398 MSSA clone was readily transmitted within households, independent of animal contact. We discovered that human ST398 MSSA genomes were smaller than that of the LA-ST398 strain S0385 due to fewer mobile genetic elements. Human and LA-ST398 strains also differed in their composition of adhesion genes and their ability to bind to human skin keratinocytes, providing a potential mechanism of S. aureus host adaptation. Our findings illustrate the importance of implementing molecular surveillance of MSSA given the evidence for the rapid and clinically undetected spread of ST398 MSSA. C1 [Uhlemann, Anne-Catrin; Trivedi, Sheetal; Sullivan, Sean B.; Hafer, Cory; Lowy, Franklin D.] Columbia Univ, Coll Phys & Surg, Div Infect Dis, Dept Med, New York, NY 10027 USA. [Porcella, Stephen F.; Barbian, Kent D.] NIAID, Genom Unit, Res Technol Sect, Rocky Mt Labs,NIH, Hamilton, MT USA. [Kennedy, Adam D.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. [McCarthy, Alex J.; Lindsay, Jodi A.] Univ London, Div Clin Sci, Ctr Infect, London, England. [Street, Craig; Hirschberg, David L.; Lipkin, W. Ian] Columbia Univ, Ctr Infect & Immun, Mailman Sch Publ Hlth, New York, NY USA. RP Uhlemann, AC (reprint author), Columbia Univ, Coll Phys & Surg, Div Infect Dis, Dept Med, New York, NY 10027 USA. EM au2110@columbia.edu RI Lindsay, Jodi/B-9565-2008; OI Lindsay, Jodi/0000-0002-5219-1625; DeLeo, Frank/0000-0003-3150-2516 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH; NIH [K08 AI090013, R01 AI077690, R01 AI077690-S1, AI057158]; Defense Threat Reduction Agency FX This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH, and by NIH funding to A.-C.U. (K08 AI090013), F.D.L. (R01 AI077690 and R01 AI077690-S1), and W.I.L. (AI057158) and the Defense Threat Reduction Agency. NR 40 TC 36 Z9 36 U1 2 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 2150-7511 J9 MBIO JI mBio PD MAR-APR PY 2012 VL 3 IS 2 AR e00027-12 DI 10.1128/mBio.00027-12 PG 9 WC Microbiology SC Microbiology GA 959FA UT WOS:000305297100005 ER PT J AU Myles, IA Datta, SK AF Myles, Ian A. Datta, Sandip K. TI Staphylococcus aureus: an introduction SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Editorial Material ID CHRONIC MUCOCUTANEOUS CANDIDIASIS; SOFT-TISSUE INFECTIONS; HYPER-IGE SYNDROME; PROTEIN-A; METHICILLIN-RESISTANCE; BACTERIAL-INFECTIONS; ATOPIC-DERMATITIS; ALPHA-HEMOLYSIN; CLUMPING FACTOR; ENTEROTOXIN-B C1 [Myles, Ian A.; Datta, Sandip K.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Datta, SK (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dattas@niaid.nih.gov OI Datta, Sandip/0000-0003-0243-7815 FU Intramural NIH HHS [ZIA AI001043-04] NR 71 TC 6 Z9 6 U1 0 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD MAR PY 2012 VL 34 IS 2 BP 181 EP 184 DI 10.1007/s00281-011-0301-9 PG 4 WC Immunology; Pathology SC Immunology; Pathology GA 958JR UT WOS:000305233300001 PM 22282052 ER PT J AU Otto, M AF Otto, Michael TI Molecular basis of Staphylococcus epidermidis infections SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE Staphylococcus epidermidis; Biofilm; Phenol-soluble modulins; Polysaccharide intercellular adhesin; Device-related infections; Hospital-associated infections ID POLYSACCHARIDE INTERCELLULAR ADHESIN; ACCUMULATION-ASSOCIATED PROTEIN; CATHETER-ASSOCIATED INFECTION; AUREUS NASAL COLONIZATION; HORIZONTAL GENE-TRANSFER; PHENOL-SOLUBLE MODULINS; SEQUENCE ELEMENT IS256; PEPTIDE-SENSING SYSTEM; WALL TEICHOIC-ACIDS; BIOFILM FORMATION AB Staphylococcus epidermidis is the most important member of the coagulase-negative staphylococci and one of the most abundant colonizers of human skin. While for a long time regarded as innocuous, it has been identified as the most frequent cause of device-related infections occurring in the hospital setting and is therefore now recognized as an important opportunistic pathogen. S. epidermidis produces a series of molecules that provide protection from host defenses. Specifically, many proteins and exopolymers, such as the exopolysaccharide PIA, contribute to biofilm formation and inhibit phagocytosis and the activity of human antimicrobial peptides. Furthermore, recent research has identified a family of pro-inflammatory peptides in S. epidermidis, the phenol-soluble modulins (PSMs), which have multiple functions in immune evasion and biofilm development, and may be cytolytic. However, in accordance with the relatively benign relationship that S. epidermidis has with its host, production of aggressive members of the PSM family is kept at a low level. Interestingly, in contrast to S. aureus with its large arsenal of toxins developed for causing infection in the human host, most if not all "virulence factors" of S. epidermidis appear to have original functions in the commensal lifestyle of this bacterium. C1 NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 138 TC 73 Z9 80 U1 1 U2 40 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD MAR PY 2012 VL 34 IS 2 BP 201 EP 214 DI 10.1007/s00281-011-0296-2 PG 14 WC Immunology; Pathology SC Immunology; Pathology GA 958JR UT WOS:000305233300003 PM 22095240 ER PT J AU Rigby, KM DeLeo, FR AF Rigby, Kevin M. DeLeo, Frank R. TI Neutrophils in innate host defense against Staphylococcus aureus infections SO SEMINARS IN IMMUNOPATHOLOGY LA English DT Review DE Staphylococcus aureus; MRSA; Neutrophil; Immune evasion ID PANTON-VALENTINE LEUKOCIDIN; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; PROGRAMMED CELL-DEATH; COMMUNITY-ACQUIRED PNEUMONIA; PHAGOCYTE NADPH OXIDASE; APOPTOSIS DIFFERENTIATION PROGRAM; CHRONIC GRANULOMATOUS-DISEASE; SUPEROXIDE ANION GENERATION; RESPIRATORY BURST OXIDASE; CATABOLIC MOBILE ELEMENT AB Staphylococcus aureus has been an important human pathogen throughout history and is currently a leading cause of bacterial infections worldwide. S. aureus has the unique ability to cause a continuum of diseases, ranging from minor skin infections to fatal necrotizing pneumonia. Moreover, the emergence of highly virulent, drug-resistant strains such as methicillin-resistant S. aureus in both healthcare and community settings is a major therapeutic concern. Neutrophils are the most prominent cellular component of the innate immune system and provide an essential primary defense against bacterial pathogens such as S. aureus. Neutrophils are rapidly recruited to sites of infection where they bind and ingest invading S. aureus, and this process triggers potent oxidative and non-oxidative antimicrobial killing mechanisms that serve to limit pathogen survival and dissemination. S. aureus has evolved numerous mechanisms to evade host defense strategies employed by neutrophils, including the ability to modulate normal neutrophil turnover, a process critical to the resolution of acute inflammation. Here we provide an overview of the role of neutrophils in host defense against bacterial pathogens and discuss strategies employed by S. aureus to circumvent neutrophil function. C1 [Rigby, Kevin M.; DeLeo, Frank R.] NIAID, Lab Human Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors are supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 299 TC 120 Z9 121 U1 2 U2 32 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2297 J9 SEMIN IMMUNOPATHOL JI Semin. Immunopathol. PD MAR PY 2012 VL 34 IS 2 BP 237 EP 259 DI 10.1007/s00281-011-0295-3 PG 23 WC Immunology; Pathology SC Immunology; Pathology GA 958JR UT WOS:000305233300005 PM 22080185 ER PT J AU Wei, LY Wu, JH Li, GQ Shi, N AF Wei, Linyi Wu, Jiuhong Li, Guanqun Shi, Ning TI Cis-enone Resorcylic Acid Lactones (RALs) as Irreversible Protein Kinase Inhibitors SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review DE Resorcylic acid lactones (RALs); irreversible protein kinase; MAPK kinases ID GROWTH-FACTOR RECEPTOR; SIGNALING PATHWAY; KAPPA-B; CASCADE; DESIGN; DRUG; TAK1; CANCER; POTENT; EGFR AB Resorcylic acid lactones (RALs) constitute a group of polyketide natural products with a large macrocyclic ring fused to resorcylic acid. Despite distinct core scaffold from all marketed kinase inhibitors, RALs bearing a cis-enone moiety have recently shown irreversible yet selective inhibition on a subset of kinases along the MAPK signaling pathway such as MEK, ERK and TAK1. The biochemical and structural studies have demonstrated that the cis-enone RALs can inhibit kinase activity by forming a covalent Michael adduct with an adequately positioned cysteine residue in the ATP binding pocket. This review discusses the mechanism of action, synthetic strategies, and structure-activity relationships (SARs) of cis-enone RALs. It is anticipated that design, synthesis and evaluation of cis-enone RALs analogs will diversify the chemical space of kinase inhibitors and facilitate the development of new leads for the treatment of various diseases such as cancer and inflammatory disorders. C1 [Wei, Linyi] NCI Frederick, Lab Synthet Chem, SAIC Frederick Inc, Frederick, MD 21702 USA. [Wu, Jiuhong; Shi, Ning] No 306 Hosp, Dept Pharm, Beijing 100101, Peoples R China. [Li, Guanqun] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. RP Wei, LY (reprint author), NCI Frederick, Lab Synthet Chem, SAIC Frederick Inc, Bldg 322,Rm 102, Frederick, MD 21702 USA. EM weil3@mail.nih.gov NR 54 TC 6 Z9 6 U1 0 U2 16 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAR PY 2012 VL 18 IS 9 BP 1186 EP 1198 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 950US UT WOS:000304676300003 PM 22316158 ER PT J AU Bienstock, RJ AF Bienstock, Rachelle J. TI Computational Drug Design Targeting Protein-Protein Interactions SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review DE Protein-protein interactions; fragment-based ligand design; protein-protein inhibitors; computational drug design; structure-based ligand design; protein-interface hot-spots ID SMALL-MOLECULE INHIBITORS; IMMUNODEFICIENCY-VIRUS TYPE-1; STRUCTURE-BASED DISCOVERY; REVERSE-TRANSCRIPTASE DIMER; P-ARYLTHIO CINNAMIDES; NITRIC-OXIDE SYNTHASE; DRUGGABLE HOT-SPOTS; NERVE GROWTH-FACTOR; CRYSTAL-STRUCTURE; WEB SERVER AB Novel discoveries in molecular disease pathways within the cell, combined with increasing information regarding protein binding partners has lead to a new approach in drug discovery. There is interest in designing drugs to modulate protein-protein interactions as opposed to solely targeting the catalytic active site within a single enzyme or protein. There are many challenges in this new approach to drug discovery, particularly since the protein-protein interface has a larger surface area, can comprise a discontinuous epitope, and is more amorphous and less well defined than the typical drug design target, a small contained enzyme-binding pocket. Computational methods to predict modes of protein-protein interaction, as well as protein interface hot spots, have garnered significant interest, in order to facilitate the development of drugs to successfully disrupt and inhibit protein-protein interactions. This review summarizes some current methods available for computational protein-protein docking, as well as tabulating some examples of the successful design of antagonists and small molecule inhibitors for protein-protein interactions. Several of these drugs are now beginning to appear in the clinic. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Bienstock, RJ (reprint author), NIEHS, POB 12233,MD F0-011, Res Triangle Pk, NC 27709 USA. EM biensto1@niehs.nih.gov NR 165 TC 33 Z9 33 U1 4 U2 60 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAR PY 2012 VL 18 IS 9 BP 1240 EP 1254 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 950US UT WOS:000304676300006 PM 22316151 ER PT J AU Nussinov, R Tsai, CJ AF Nussinov, Ruth Tsai, Chung-Jung TI The Different Ways through Which Specificity Works in Orthosteric and Allosteric Drugs SO CURRENT PHARMACEUTICAL DESIGN LA English DT Review DE Allostery; allosteric drug design; allosteric drug development; allosteric drug specificity; cellular network; pathways; affinity; concentration; dynamic landscape ID ENERGY LANDSCAPES; BINDING CASCADES; RECEPTORS; PROTEIN; PRINCIPLES; DISCOVERY; DESIGN; MODULATORS; RECOGNITION; ACTIVATION AB Currently, there are two types of drugs on the market: orthosteric, which bind at the active site; and allosteric, which bind elsewhere on the protein surface, and allosterically change the conformation of the protein binding site. In this perspective we argue that the different mechanisms through which the two drug types affect protein activity and their potential pitfalls call for different considerations in drug design. The key problem facing orthosteric drugs is side effects which can occur by drug binding to homologous proteins sharing a similar binding site. Hence, orthosteric drugs should have very high affinity to the target; this would allow a low dosage to selectively achieve the goal of target-only binding. By contrast, allosteric drugs work by shifting the free energy landscape. Their binding to the protein surface perturbs the protein surface atoms, and the perturbation propagates like waves, finally reaching the binding site. Effective drugs should have atoms in good contact with the 'right' protein atoms; that is, the contacts should elicit propagation waves optimally reaching the protein binding site target. While affinity is important, the design should consider the protein conformational ensemble and the preferred propagation states. We provide examples from functional in vivo scenarios for both types of cases, and suggest how high potency can be achieved in allosteric drug development. C1 [Nussinov, Ruth; Tsai, Chung-Jung] NCI Frederick, Ctr Canc Res Nanobiol Program, SAIC Frederick Inc, Basic Res Program, Ft Detrick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI Frederick, Ctr Canc Res Nanobiol Program, SAIC Frederick Inc, Basic Res Program, Bldg 469,Rm 151, Ft Detrick, MD 21702 USA. EM ruthnu@helix.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 58 TC 31 Z9 32 U1 0 U2 15 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1381-6128 J9 CURR PHARM DESIGN JI Curr. Pharm. Design PD MAR PY 2012 VL 18 IS 9 BP 1311 EP 1316 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 950US UT WOS:000304676300010 PM 22316155 ER PT J AU Hu, ZH Follmann, DA Qin, J AF Hu, Zonghui Follmann, Dean A. Qin, Jing TI Semiparametric Double Balancing Score Estimation for Incomplete Data With Ignorable Missingness SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Doubly robust; Nonparametric kernel regression; Propensity score ID PROPENSITY SCORE; KERNEL REGRESSION; MODELS; CONSISTENCY AB When estimating the marginal mean response with missing observations, a critical issue is robustness to model misspecification. In this article, we propose a semiparametric estimation method with extended double robustness that attains the optimal efficiency under less stringent requirement for model specifications than the doubly robust estimators. In this semiparametric estimation, covariate information is collapsed into a two-dimensional score S. with one dimension for (i) the pattern of missingness and the other for (ii) the pattern of response, both estimated from some working parametric models. The mean response E(Y) is then estimated by the sample mean of E(Y vertical bar S), which is estimated via nonparametric regression. The semiparametric estimator is consistent if either the "core" of (i) or the "core" of (ii) is captured by S, and attains the optimal efficiency if both are captured by S. As the "cores" can be obtained without correctly specifying the full parametric models for (i) or (ii), the proposed estimator can be more robust than other doubly robust estimators. As S contains the propensity score as one component, the proposed estimator avoids the use and the shortcomings of inverse propensity weighting. This semiparametric estimator is most appealing for high-dimensional covariates, where fully correct model specification is challenging and nonparametric estimation is not feasible due to the problem of dimensionality. Numerical performance is investigated by simulation studies. C1 [Hu, Zonghui; Follmann, Dean A.; Qin, Jing] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Hu, ZH (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM huzo@niaid.nih.gov; dfollmann@niaid.nih.gov; jqin@niaid.nih.gov NR 29 TC 2 Z9 2 U1 0 U2 3 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 EI 1537-274X J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD MAR PY 2012 VL 107 IS 497 BP 247 EP 257 DI 10.1080/01621459.2012.656009 PG 11 WC Statistics & Probability SC Mathematics GA 951QN UT WOS:000304735200020 ER PT J AU Hein, AM O'Banion, MK AF Hein, Amy M. O'Banion, M. Kerry TI Neuroinflammation and Cognitive Dysfunction in Chronic Disease and Aging SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Editorial Material ID ALZHEIMERS-DISEASE; AGED MICE; BRAIN; NEURODEGENERATION; MEMORY C1 [Hein, Amy M.; O'Banion, M. Kerry] Univ Rochester, Sch Med & Dent, Dept Neurobiol & Anat, Rochester, NY 14642 USA. [Hein, Amy M.] Natl Inst Neurol Disorders & Stroke, Amer Assoc Adv Sci, Amer Psychol Assoc Execut Branch, Washington, DC USA. RP O'Banion, MK (reprint author), Univ Rochester, Sch Med & Dent, Dept Neurobiol & Anat, 601 Elmwood Ave,Box 603, Rochester, NY 14642 USA. EM kerry_obanion@urmc.rochester.edu FU NIA NIH HHS [R01 AG03149]; NIAID NIH HHS [U19AI091036]; NIDA NIH HHS [R01DA026009]; NINDS NIH HHS [T32 NS051152] NR 24 TC 5 Z9 6 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD MAR PY 2012 VL 7 IS 1 SI SI BP 3 EP 6 DI 10.1007/s11481-011-9340-1 PG 4 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 943YM UT WOS:000304164000002 PM 22252623 ER PT J AU Hein, AM Zarcone, TJ Parfitt, DB Matousek, SB Carbonari, DM Olschowka, JA O'Banion, MK AF Hein, Amy M. Zarcone, Troy J. Parfitt, David B. Matousek, Sarah B. Carbonari, Dena M. Olschowka, John A. O'Banion, M. Kerry TI Behavioral, Structural and Molecular Changes following Long-term Hippocampal IL-1 beta Overexpression in Transgenic Mice SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE Interleukin-1 beta; Hippocampus; Neuroinflammation; Learning; Memory; Sickness behavior ID FOOD-MOTIVATED BEHAVIOR; INTERLEUKIN-1-BETA EXPRESSION; CHRONIC NEUROINFLAMMATION; COGNITIVE IMPAIRMENT; DORSAL-HIPPOCAMPUS; STROKE PATIENTS; BRAIN-INJURY; RATS; INFLAMMATION; DISEASE AB Chronic neuroinflammation is associated with many neurodegenerative and neurocognitive disorders, yet few animal models exist to study the behavioral effects of prolonged neuroinflammation. Therefore, we recently developed a transgenic mouse model harboring an interleukin-1 beta excisional activation transgene (IL-1 beta(XAT)). These mice display localized IL-1 beta overexpression and resultant neuroinflammation for up to 1 year following transgene induction. Initial behavioral studies demonstrated long-term memory deficits after 2 weeks of hippocampal IL-1 beta overexpression. In the present studies, we extend these behavioral studies both in scope and timing. We find long-term contextual but not auditory fear memory impairments following 3 months of IL-1 beta overexpression. On a battery of other behavioral tests, IL-1 beta overexpression in IL-1 beta(XAT) mice increased locomotor activity, especially in female mice, and had slight anxiolytic effects. No differences were found in operant conditioning or in basal or stress-induced CORT levels, despite profound hippocampal glial activation. Interestingly, the volume of discrete hippocampal cell layers was reduced after 6 but not 3 months of IL-1 beta overexpression. Therefore, this animal model provides a novel tool for examining the effects of chronic inflammation on discrete brain regions. C1 [O'Banion, M. Kerry] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Hein, Amy M.; Carbonari, Dena M.; Olschowka, John A.; O'Banion, M. Kerry] Univ Rochester, Sch Med & Dent, Dept Neurobiol & Anat, Rochester, NY 14642 USA. [Zarcone, Troy J.] NIAAA, Bethesda, MD 20892 USA. [Parfitt, David B.] SUNY Coll Geneseo, Geneseo, NY 14454 USA. [Matousek, Sarah B.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP O'Banion, MK (reprint author), Univ Rochester, Med Ctr, 601 Elmwood Ave,Box 603, Rochester, NY 14642 USA. EM Kerry_OBanion@urmc.rochester.edu RI Carbonari, Dena/H-3366-2011 OI Carbonari, Dena/0000-0003-0310-270X FU NIH [RO1 AG030149, P30 ES001247, T32 NS051152]; NINDS [NIH T32 NS051152] FX We would like to thank S. Kyrkanides and J. Miller for FIV packaging, M. Olschowka and J. Walter for animal colony management, and L. Trojancyzk for help with tissue processing. The present work was supported by NIH RO1 AG030149 andP30 ES001247. A. Hein was supported by an NINDS T32 training grant in neuroinflammation and glial cell biology (NIH T32 NS051152).; NIH RO1 AG030149, P30 ES001247, and T32 NS051152. NR 41 TC 12 Z9 13 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD MAR PY 2012 VL 7 IS 1 SI SI BP 145 EP 155 DI 10.1007/s11481-011-9294-3 PG 11 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 943YM UT WOS:000304164000011 PM 21748283 ER PT J AU Hu, XM Zhou, H Zhang, D Yang, SF Qian, L Wu, HM Chen, PS Wilson, B Gao, HM Lu, RB Hong, JS AF Hu, Xiaoming Zhou, Hui Zhang, Dan Yang, Sufen Qian, Li Wu, Hung-Ming Chen, Po-See Wilson, Belinda Gao, Hui-Ming Lu, Ru-band Hong, Jau-Shyong TI Clozapine Protects Dopaminergic Neurons from Inflammation-Induced Damage by Inhibiting Microglial Overactivation SO JOURNAL OF NEUROIMMUNE PHARMACOLOGY LA English DT Article DE Clozapine; Microglia; NADPH oxidase; Neurodegeneration; Neuroinflammation ID ATYPICAL ANTIPSYCHOTIC-DRUGS; NADPH OXIDASE ACTIVITY; NEURODEGENERATIVE DISEASES; PARKINSONS-DISEASE; PC12 CELLS; CHRONIC-SCHIZOPHRENICS; CLASS-III; IN-VITRO; ACTIVATION; NEUROTOXICITY AB Increasing evidence suggests a possible involvement of neuroinflammation in some psychiatric disorders, and also pharmacological reports indicate that anti-inflammatory effects are associated with therapeutic actions of psychoactive drugs, such as anti-depressants and antipsychotics. The purpose of this study was to explore whether clozapine, a widely used antipsychotic drugs, displays anti-inflammatory and neuroprotective effects. Using primary cortical and mesencephalic neuron-glia cultures, we found that clozapine was protective against inflammation-related neurodegeneration induced by lipopolysaccharide (LPS). Pretreatment of cortical or mesencephalic neuron-glia cultures with clozapine (0.1 or 1 mu M) for 24 h attenuated LPS-induced neurotoxicity. Clozapine also protected neurons against 1-methyl-4-phenylpyridinium(+) (MPP+)-induced neurotoxicity, but only in cultures containing microglia, indicating an indispensable role of microglia in clozapine-afforded neuroprotection. Further observation revealed attenuated LPS-induced microglial activation in primary neuron-glia cultures and in HAPI microglial cell line with clozapine pretreatment. Clozapine ameliorated the production of microglia-derived superoxide and intracellular reactive oxygen species (ROS), as well as the production of nitric oxide and TNF-alpha following LPS. In addition, the protective effect of clozapine was not observed in neuronglia cultures from mice lacking functional NADPH oxidase (PHOX), a key enzyme for superoxide production in immune cells. Further mechanistic studies demonstrated that clozapine pretreatment inhibited LPS-induced translocation of cytosolic subunit p47(phox) to the membrane in microglia, which was most likely through inhibiting the phosphoinositide 3-kinase (PI3K) pathway. Taken together, this study demonstrates that clozapine exerts neuroprotective effect via the attenuation of microglia activation through inhibition of PHOX-generated ROS production and suggests potential use of antipsychotic drugs for neuroprotection. C1 [Hu, Xiaoming; Zhou, Hui; Zhang, Dan; Yang, Sufen; Qian, Li; Wu, Hung-Ming; Chen, Po-See; Wilson, Belinda; Gao, Hui-Ming; Hong, Jau-Shyong] NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. [Wu, Hung-Ming; Lu, Ru-band] Natl Cheng Kung Univ, Inst Behav Med, Coll Med & Hosp, Tainan 70101, Taiwan. [Wu, Hung-Ming; Lu, Ru-band] Natl Cheng Kung Univ, Dept Psychiat, Coll Med & Hosp, Tainan 70101, Taiwan. [Hu, Xiaoming] Univ Pittsburgh, Dept Neurol, Sch Med, Pittsburgh, PA 15261 USA. [Hu, Xiaoming] Univ Pittsburgh, Pittsburgh Inst Neurodegenerat Dis, Sch Med, Pittsburgh, PA 15261 USA. RP Hong, JS (reprint author), NIEHS, Neuropharmacol Sect, Lab Toxicol & Pharmacol, NIH, MD F1-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM hong3@niehs.nih.gov FU National Institute of Environmental Health Sciences, National Institute of Health FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institute of Health. NR 58 TC 20 Z9 21 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1557-1890 J9 J NEUROIMMUNE PHARM JI J. Neuroimmune Pharm. PD MAR PY 2012 VL 7 IS 1 SI SI BP 187 EP 201 DI 10.1007/s11481-011-9309-0 PG 15 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 943YM UT WOS:000304164000015 PM 21870076 ER PT J AU Leoni, RF Paiva, FF Kang, BT Henning, EC Nascimento, GC Tannus, A de Araujo, DB Silva, AC AF Leoni, Renata F. Paiva, Fernando F. Kang, Byeong-Teck Henning, Erica C. Nascimento, George C. Tannus, Alberto de Araujo, Draulio B. Silva, Afonso C. TI Arterial Spin Labeling Measurements of Cerebral Perfusion Territories in Experimental Ischemic Stroke SO TRANSLATIONAL STROKE RESEARCH LA English DT Article DE Cerebral blood flow; Collateral flow; Magnetic resonance imaging; Vascular territory ID BRAIN-FEEDING ARTERIES; COLLATERAL CIRCULATION; BLOOD-FLOW; RAT; OCCLUSION; MRI; HYPERTENSION; WATER; ANGIOGRAPHY; INVERSION AB Collateral circulation, defined as the supplementary vascular network that maintains cerebral blood flow (CBF) when the main vessels fail, constitutes one important defense mechanism of the brain against ischemic stroke. In the present study, continuous arterial spin labeling (CASL) was used to quantify CBF and obtain perfusion territory maps of the major cerebral arteries in spontaneously hypertensive rats (SHRs) and their normotensive Wistar-Kyoto (WKY) controls. Results show that both WKY and SHR have complementary, yet significantly asymmetric perfusion territories. Right or left dominances were observed in territories of the anterior (ACA), middle and posterior cerebral arteries, and the thalamic artery. Magnetic resonance angiography showed that some of the asymmetries were correlated with variations of the ACA. The leptomeningeal circulation perfusing the outer layers of the cortex was observed as well. Significant and permanent changes in perfusion territories were obtained after temporary occlusion of the right middle cerebral artery in both SHR and WKY, regardless of their particular dominance. However, animals with right dominance presented a larger volume change of the left perfusion territory (23 +/- 9%) than animals with left dominance (7 +/- 5%, P<0.002). The data suggest that animals with contralesional dominance primarily safeguard local CBF values with small changes in contralesional perfusion territory, while animals with ipsilesional dominance show a reversal of dominance and a substantial increase in contralesional perfusion territory. These findings show the usefulness of CASL to probe the collateral circulation. C1 [Leoni, Renata F.; Paiva, Fernando F.; Kang, Byeong-Teck; Nascimento, George C.; Silva, Afonso C.] Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Leoni, Renata F.] Univ Sao Paulo, FFCLRP, Dept Fis, BR-14040901 Sao Paulo, Brazil. [Paiva, Fernando F.; Tannus, Alberto] Univ Sao Paulo, IFSC, Dept Fis & Informat, BR-13560970 Sao Paulo, Brazil. [Henning, Erica C.] Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD 20892 USA. [de Araujo, Draulio B.] Univ Fed Rio Grande Norte UFRN, Hosp Univ Onorio Lopes, Inst Cerebro, BR-59056045 Natal, RN, Brazil. RP Silva, AC (reprint author), Natl Inst Neurol Disorders & Stroke, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,MSC 1065,Bldg 10,Room B1D106, Bethesda, MD 20892 USA. EM SilvaA@ninds.nih.gov RI Araujo, Draulio/I-6038-2012; Sao Carlos Institute of Physics, IFSC/USP/M-2664-2016; Tannus, Alberto/B-9821-2012; OI Araujo, Draulio/0000-0002-6934-2485; Tannus, Alberto/0000-0002-1675-1971; Leoni, Renata/0000-0002-4568-0746; Paiva, Fernando/0000-0002-8989-9707 FU NIH, NINDS; FAPESP [2006/05706-5, 2003/13399-7, 2005/56663-1] FX The authors acknowledge the excellent technical assistance of Mrs. Xianfeng (Lisa) Zhang. This research was supported by the Intramural Research Program of the NIH, NINDS (Alan P. Koretsky, Scientific Director), and FAPESP (2006/05706-5, 2003/13399-7, 2005/56663-1). NR 38 TC 4 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1868-4483 J9 TRANSL STROKE RES JI Transl. Stroke Res. PD MAR PY 2012 VL 3 IS 1 SI SI BP 44 EP 55 DI 10.1007/s12975-011-0115-z PG 12 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 943YP UT WOS:000304164300007 PM 24323754 ER PT J AU Kummar, S AF Kummar, S. TI DEVELOPMENT OF MARKERS OF DNA REPAIR SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 10th International Symposium on Targeted Anticancer Therapies CY MAR 08-10, 2012 CL Amsterdam, NETHERLANDS C1 [Kummar, S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2012 VL 23 SU 1 BP 18 EP 18 PG 1 WC Oncology SC Oncology GA 940CH UT WOS:000303867100019 ER PT J AU Pommier, Y Das, BB Regairaz, M Zhang, Y AF Pommier, Y. Das, B. B. Regairaz, M. Zhang, Y. TI PARP INHIBITION AND EFFICACY OF TOPOISOMERASE I INHIBITORS SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 10th International Symposium on Targeted Anticancer Therapies CY MAR 08-10, 2012 CL Amsterdam, NETHERLANDS C1 [Pommier, Y.; Das, B. B.; Regairaz, M.; Zhang, Y.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2012 VL 23 SU 1 BP 19 EP 19 PG 1 WC Oncology SC Oncology GA 940CH UT WOS:000303867100022 ER PT J AU Seymour, L Ivy, SP Hilton, J Dancey, J Paller, C AF Seymour, L. Ivy, S. P. Hilton, J. Dancey, J. Paller, C. TI CLINICAL INTERACTIONS WITH COMBINATION OF NOVEL AGENTS SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 10th International Symposium on Targeted Anticancer Therapies CY MAR 08-10, 2012 CL Amsterdam, NETHERLANDS C1 [Seymour, L.; Hilton, J.; Dancey, J.] NCIC Clin Trials Grp, Kingston, ON, Canada. [Ivy, S. P.; Paller, C.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2012 VL 23 SU 1 BP 19 EP 19 PG 1 WC Oncology SC Oncology GA 940CH UT WOS:000303867100024 ER PT J AU Bates, SE AF Bates, S. E. TI EPIGENETIC TARGETS: ESTABLISHED AND IN THE PIPELINE SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 10th International Symposium on Targeted Anticancer Therapies CY MAR 08-10, 2012 CL Amsterdam, NETHERLANDS C1 [Bates, S. E.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2012 VL 23 SU 1 BP 23 EP 23 PG 1 WC Oncology SC Oncology GA 940CH UT WOS:000303867100039 ER PT J AU Avan, A Paolicchi, E Crea, F Funel, N Galvani, E Marquez, V Honeywell, R Danesi, R Peters, GJ Giovannetti, E AF Avan, A. Paolicchi, E. Crea, F. Funel, N. Galvani, E. Marquez, V. Honeywell, R. Danesi, R. Peters, G. J. Giovannetti, E. TI EZH2 AS A NOVEL THERAPEUTIC TARGET FOR TREATMENT OF PANCREATIC DUCTAL ADENOCARCINOMA SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 10th International Symposium on Targeted Anticancer Therapies CY MAR 08-10, 2012 CL Amsterdam, NETHERLANDS C1 [Avan, A.; Galvani, E.; Honeywell, R.; Peters, G. J.; Giovannetti, E.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Paolicchi, E.; Crea, F.; Funel, N.; Danesi, R.] Univ Pisa, Pisa, Italy. [Marquez, V.] NIH, Frederick, MD USA. RI Galvani, Elena/L-3133-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2012 VL 23 SU 1 BP 31 EP 32 PG 2 WC Oncology SC Oncology GA 940CH UT WOS:000303867100075 ER PT J AU Voortman, J Harada, T Chang, RP Killian, JK Suuriniemi, M Smith, WIJR Meltzer, PS Lucchi, M Giaccone, G AF Voortman, J. Harada, T. Chang, R. P. Killian, J. K. Suuriniemi, M. Smith, W. I. J. R. Meltzer, P. S. Lucchi, M. Giaccone, G. TI MUTATION ANALYSIS OF C-MET IN SMALL CELL LUNG CANCER AND NEUROENDOCRINE TUMORS SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 10th International Symposium on Targeted Anticancer Therapies CY MAR 08-10, 2012 CL Amsterdam, NETHERLANDS C1 [Voortman, J.] Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. [Harada, T.; Chang, R. P.; Killian, J. K.; Suuriniemi, M.; Meltzer, P. S.; Giaccone, G.] NCI, Bethesda, MD 20892 USA. [Smith, W. I. J. R.] Suburban Hosp, Bethesda, MD USA. [Lucchi, M.] Univ Pisa, Pisa, Italy. NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2012 VL 23 SU 1 BP 34 EP 34 PG 1 WC Oncology SC Oncology GA 940CH UT WOS:000303867100083 ER PT J AU Kagiya, GK Ogawa, R Hatashita, M Tanaka, Y Kouda, K Fukuda, S Mitchell, JB AF Kagiya, G. K. Ogawa, R. Hatashita, M. Tanaka, Y. Kouda, K. Fukuda, S. Mitchell, J. B. TI ENHANCEMENT OF HYPOXIC CELL KILLING BY THE NITROXIDE TEMPOL SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 10th International Symposium on Targeted Anticancer Therapies CY MAR 08-10, 2012 CL Amsterdam, NETHERLANDS C1 [Kagiya, G. K.] Kitasato Univ, Sagamihara, Kanagawa 228, Japan. [Ogawa, R.] Toyama Univ, Toyama 930, Japan. [Hatashita, M.; Tanaka, Y.] Wakasa Wan Energy Res Ctr, Tsuruga, Fukui, Japan. [Kouda, K.; Fukuda, S.] Natl Inst Radiol Sci, Chiba 260, Japan. [Mitchell, J. B.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2012 VL 23 SU 1 BP 36 EP 37 PG 2 WC Oncology SC Oncology GA 940CH UT WOS:000303867100092 ER PT J AU Menefee, M Bible, K Reidy-Lagunes, D Kane, M Allred, J Takebe, N Ehrlichman, C Shah, M AF Menefee, M. Bible, K. Reidy-Lagunes, D. Kane, M. Allred, J. Takebe, N. Ehrlichman, C. Shah, M. TI A PHASE II STUDY AT-101 IN PATIENTS WITH ADVANCED ADRENAL CORTICAL CARCINOMA (ACC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 10th International Symposium on Targeted Anticancer Therapies CY MAR 08-10, 2012 CL Amsterdam, NETHERLANDS C1 [Menefee, M.] Mayo Clin, Jacksonville, FL 32224 USA. [Bible, K.; Allred, J.; Ehrlichman, C.] Mayo Clin, Rochester, MN USA. [Reidy-Lagunes, D.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kane, M.] Univ Colorado, Denver, CO 80202 USA. [Takebe, N.] NCI, Rockville, MD USA. [Shah, M.] Ohio State Univ, Columbus, OH 43210 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD MAR PY 2012 VL 23 SU 1 BP 42 EP 42 PG 1 WC Oncology SC Oncology GA 940CH UT WOS:000303867100113 ER PT J AU Ogbureke, KUE Weinberger, PM Looney, SW Li, L Fisher, LW AF Ogbureke, Kalu U. E. Weinberger, Paul M. Looney, Stephen W. Li, Li Fisher, Larry W. TI Expressions of matrix metalloproteinase-9 (MMP-9), dentin sialophosphoprotein (DSPP), and osteopontin (OPN) at histologically negative surgical margins may predict recurrence of oral squamous cell carcinoma SO ONCOTARGET LA English DT Article DE Oral Cancer; DSPP; BSP; OPN; MMPs; Tumor-Free Margin ID LINKED GLYCOPROTEINS SIBLINGS; NECK-CANCER; MATRIX METALLOPROTEINASES; HEAD; PROTEINS; EIF4E; TRANSITION; MEMBERS; TONGUE; FAMILY AB Up to 50% of oral squamous cell carcinomas (OSCCs) recur following surgical resections with conventional "histologically-negative" margins. Three members of the SIBLING (Small Integrin Binding LIgand N-linked Gylcoprotein) family of proteins: dentin sialophophoprotein (DSPP); bone sialoprotein (BSP); and osteopontin OPN are upregulated in OSCCs. In this study, we aimed to correlate the expression of DSPP, OPN and BSP as well as three SIBLING-partners, matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-3 (MMP-3), and matrix metalloproteinase-9 (MMP-9), at histologically-negative margins of OSCCs with tumor recurrence. Immunohistochemical analyses of the SIBLINGs and MMP expressions at histologically-negative margins of OSCC was carried out in a retrospective study of 20 patients, and the results correlated with tumor recurrence. Each protein was dichotomized as "present" (>= 10% staining) or " absent" (< 10% staining). The Sensitivity, Specificity, Positive Predictive Value(PV+) and Negative Predictive Value (PV-) for recurrence was calculated for each protein, along with their overall diagnostic accuracy, calculated as: (number of true positives + number of true negatives)/number of patients. OSCC recurred in 9 of 20 patients (45%), a ratio not significantly different from the estimated population recurrence rate of 50% (p = 0.664). Among the SIBLINGs, DSPP and OPN showed the greatest Accuracy with DSPP being more Sensitive (89%) and OPN more Specific (64%). MMP-9 showed the greatest overall Accuracy (80%), slightly less Sensitivity (67%) and more Specificity (100%), than either DSPP or OPN. MMP-9 showed a superior positive PV than either DSPP or OPN. The negative PVs of OPN and MMP-9 were almost identical, and inferior to DSPP. We conclude that DSPP, OPN, or MMP-9 expressions at histologically-negative surgical margins predict OSCC recurrence, with MMP-9 being the preferred predictor. These proteins may identify patients who could benefit from more extensive resection, or from adjunct treatments such as radiotherapy. C1 [Ogbureke, Kalu U. E.; Looney, Stephen W.] Georgia Hlth Sci Univ, Coll Dent Med, Augusta, GA USA. [Ogbureke, Kalu U. E.; Weinberger, Paul M.] Georgia Hlth Sci Univ, Med Coll Georgia, Augusta, GA USA. [Ogbureke, Kalu U. E.; Looney, Stephen W.] Georgia Hlth Sci Univ, Coll Grad Studies, Augusta, GA USA. [Li, Li; Fisher, Larry W.] Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Ogbureke, KUE (reprint author), Georgia Hlth Sci Univ, Coll Dent Med, 1120 15th St, Augusta, GA USA. EM kogbureke@georgiahealth.edu RI Weinberger, Paul/B-7007-2008 OI Weinberger, Paul/0000-0002-5885-2631 FU National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH) [K23DE017791-01A1]; Division of Intramural Research, National Institute of Dental and Craniofacial Research of the National Institutes of Health FX Study was supported by Grant # K23DE017791-01A1 (KUEO) from the National Institute of Dental and Craniofacial Research (NIDCR), National Institutes of Health (NIH), and by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, of the Intramural Research Program of the National Institutes of Health (LL & LWF). NR 24 TC 18 Z9 18 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR PY 2012 VL 3 IS 3 BP 286 EP 298 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 941WD UT WOS:000303997100007 PM 22410369 ER PT J AU Yuan, HY Kopelovich, L Yin, YZ Lu, J Glazer, RI AF Yuan, Hongyan Kopelovich, Levy Yin, Yuzhi Lu, Jin Glazer, Robert I. TI Drug-Targeted Inhibition of Peroxisome Proliferator-Activated Receptor. Enhances the Chemopreventive Effect of Anti-Estrogen SO ONCOTARGET LA English DT Article DE PPAR gamma; ER alpha; fulvestrant; GW9662 ID PPAR-GAMMA; ESTROGEN-RECEPTOR; ADIPOCYTE DIFFERENTIATION; MAMMARY CARCINOGENESIS; LIGAND-BINDING; ANTAGONIST; CARCINOMA; AGONIST; CELLS; DELTA AB The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a key regulator of metabolism, proliferation, inflammation and differentiation, and upregulates tumor suppressor genes, such as PTEN, BRCA1 and PPAR gamma itself. Examination of mammary carcinogenesis in transgenic mice expressing the dominant-negative Pax8PPAR gamma fusion protein revealed that tumors were estrogen receptora (ER)-positive and sensitive to the ER antagonist, fulvestrant. Here we evaluated whether administration of an irreversible PPAR gamma inhibitor in vivo could similarly induce ER expression in otherwise ER-negative mammary tumors following induction of carcinogenesis, and sensitize them to the antitumor effects of fulvestrant. In addition, we wished to determine whether the effect of GW9662 was associated with a PPAR-selective gene expression profile. Mammary carcinogenesis was induced in wild-type FVB mice by treatment with medroxyprogesterone and dimethylbenz(a) anthracene (DMBA) that were subsequently maintained on a diet supplemented with 0.1% GW9662, and tumorigenesis and gene expression profiling of the resulting tumors were determined. Administration of GW9962 resulted in ER+ tumors that were highly sensitive to fulvestrant. Tumors from GW9662-treated animals exhibited reduced expression of a metabolic gene profile indicative of PPAR gamma inhibition, including PPAR gamma itself. Additionally, GW9662 upregulated the expression of several genes associated with the transcription, processing, splicing and translation of RNA. This study is the first to show that an irreversible PPAR gamma inhibitor can mimic a dominant-negative PPAR gamma transgene to elicit the development of ER-responsive tumors. These findings suggest that it may be possible to pharmacologically influence the responsiveness of tumors to anti-estrogen therapy. C1 [Yuan, Hongyan; Yin, Yuzhi; Lu, Jin; Glazer, Robert I.] Georgetown Univ, Sch Med, Dept Oncol, Washington, DC USA. [Yuan, Hongyan; Yin, Yuzhi; Lu, Jin; Glazer, Robert I.] Lombardi Comprehens Canc Ctr, Washington, DC USA. [Kopelovich, Levy] NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. [Yin, Yuzhi] NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. RP Glazer, RI (reprint author), Georgetown Univ, Sch Med, Dept Oncol, Washington, DC USA. EM glazerr@georgetown.edu FU National Cancer Institute, NIH [1NO1 CN43302-WA19, P30CA051008]; NIH FX This study was supported by contract 1NO1 CN43302-WA19 from the National Cancer Institute, NIH, and award P30CA051008 from the National Cancer Institute, NIH to the Lombardi Comprehensive Cancer Center (LCCC). This investigation was conducted using the Animal Research, Flow Cytometry, Genomics and Epigenomics, and Microscopy and Imaging Shared Resources of the LCCC, and by an animal facilities construction grant from the NIH. NR 36 TC 10 Z9 12 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1949-2553 J9 ONCOTARGET JI Oncotarget PD MAR PY 2012 VL 3 IS 3 BP 345 EP 356 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 941WD UT WOS:000303997100012 PM 22538444 ER PT J AU Miller, FG AF Miller, Franklin G. TI HOMAGE TO HENRY BEECHER (1904-1976) SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article ID BRAIN-DEATH; CLINICAL-RESEARCH; RANDOMIZED-TRIAL; POWERFUL PLACEBO; SURGERY; VERTEBROPLASTY; DEFINITIONS; FRACTURES; CRITERIA; SCIENCE AB The writings of Henry Beecher (1904-1976) have had an enormous influence on thinking and practice with respect to the ethics of medicine and clinical research. This essay examines the seminal contributions of Beecher as illustrated by four landmark articles concerning the ethics of clinical research, the placebo effect and placebo-controlled trials, the evaluation of invasive procedures, and "brain death" and vital organ transplantation. To appreciate Beecher's legacy, it is salutary to explicate the significance of his enduring contributions and to critically evaluate their limitations. C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov FU Clinical Center, NIH FX The opinions expressed are the views of the author and do not necessarily reflect the policy of the National Institutes of Health, the Public Health Service, or the U.S. Department of Health and Human Services.This research was supported by the Intramural Research Program of the Clinical Center, NIH. NR 51 TC 2 Z9 2 U1 0 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD SPR PY 2012 VL 55 IS 2 BP 218 EP 229 PG 12 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA 939UF UT WOS:000303843500006 PM 22643759 ER PT J AU Persson, EC Sewram, V Evans, AA London, WT Volkwyn, Y Shen, YJ Van Zyl, JA Chen, G Lin, WY Shephard, GS Taylor, PR Fan, JH Dawsey, SM Qiao, YL McGlynn, KA Abnet, CC AF Persson, E. Christina Sewram, Vikash Evans, Alison A. London, W. Thomas Volkwyn, Yvette Shen, Yen-Ju Van Zyl, Jacobus A. Chen, Gang Lin, Wenyao Shephard, Gordon S. Taylor, Philip R. Fan, Jin-Hu Dawsey, Sanford M. Qiao, You-Lin McGlynn, Katherine A. Abnet, Christian C. TI Fumonisin B-1 and risk of hepatocellular carcinoma in two Chinese cohorts SO FOOD AND CHEMICAL TOXICOLOGY LA English DT Article DE Fumonisin; Hepatocellular carcinoma; Cohort study; China; Epidemiology ID PRIMARY LIVER-CANCER; REPUBLIC-OF-CHINA; ESOPHAGEAL CANCER; HAIMEN-CITY; FOLLOW-UP; CORN; MYCOTOXINS; EXPOSURE; MORTALITY; HAIR AB Fumonisin B-1 (FB1), a mycotoxin that contaminates corn in certain climates, has been demonstrated to cause hepatocellular cancer (HCC) in animal models. Whether a relationship between FB1 and HCC exists in humans is not known. To examine the hypothesis, we conducted case-control studies nested within two large cohorts in China; the Haimen City Cohort and the General Population Study of the Nutritional Intervention Trials cohort in Linxian. In the Haimen City Cohort, nail FB1 levels were determined in 271 HCC cases and 280 controls. In the General Population Nutritional Intervention Trial, nail FB1 levels were determined in 72 HCC cases and 147 controls. In each population, odds ratios and 95% confidence intervals (95%CI) from logistic regression models estimated the association between measurable FB1 and HCC, adjusting for hepatitis B virus infection and other factors. A meta-analysis that included both populations was also conducted. The analysis revealed no statistically significant association between FB1 and HCC in either Haimen City (OR = 1.10, 95%CI = 0.64-1.89) or in Linxian (OR = 1.47, 95%CI = 0.70-3.07). Similarly, the pooled meta-analysis showed no statistically significant association between FB1 exposure and HCC (OR = 1.22, 95%CI = 0.79-1.89). These findings, although somewhat preliminary, do not support an associated between FB1 and HCC. Published by Elsevier Ltd. C1 [Persson, E. Christina; Taylor, Philip R.; Dawsey, Sanford M.; McGlynn, Katherine A.; Abnet, Christian C.] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Sewram, Vikash; Shen, Yen-Ju] MRC, Oncol Res Unit, Durban, South Africa. [Evans, Alison A.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [London, W. Thomas] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Volkwyn, Yvette; Shephard, Gordon S.] MRC, PROMEC Unit, Tygerberg, South Africa. [Van Zyl, Jacobus A.] MRC, Indigenous Knowledge Syst Res Unit, Cape Town, South Africa. [Chen, Gang] Hepatitis B Fdn, Doylestown, PA USA. [Lin, Wenyao] Haimen City Ctr Dis Control, Haimen City, Peoples R China. [Fan, Jin-Hu; Qiao, You-Lin] Chinese Acad Med Sci, Canc Inst Hosp, Beijing 100730, Peoples R China. RP Persson, EC (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Suite 550,Room 5008, Rockville, MD 20852 USA. EM christina.persson@nih.gov RI Evans, Alison/I-4970-2013; 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 Intramural NIH HHS [Z99 CA999999] NR 34 TC 6 Z9 6 U1 0 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-6915 EI 1873-6351 J9 FOOD CHEM TOXICOL JI Food Chem. Toxicol. PD MAR-APR PY 2012 VL 50 IS 3-4 BP 679 EP 683 DI 10.1016/j.fct.2011.11.029 PG 5 WC Food Science & Technology; Toxicology SC Food Science & Technology; Toxicology GA 932IR UT WOS:000303284600035 PM 22142693 ER PT J AU Chatterjee, D Chandran, B Berger, EA AF Chatterjee, Deboeeta Chandran, Bala Berger, Edward A. TI Selective killing of Kaposi's sarcoma-associated herpesvirus lytically infected cells with a recombinant immunotoxin targeting the viral gpK8.1A envelope glycoprotein SO MABS LA English DT Article DE targeted cytotoxic proteins; human herpesvirus-8; KSHV surface glycoprotein; KSHV lytic infection; multicentric Castleman disease; pseudomonas exotoxin A; ganciclovir; reciprocal drug potentiation ID MULTICENTRIC CASTLEMANS-DISEASE; HUMAN-IMMUNODEFICIENCY-VIRUS; PRIMARY EFFUSION LYMPHOMA; CD4-PSEUDOMONAS EXOTOXIN; CYTOTOXIC THERAPY; FUSION PROTEINS; DNA-SEQUENCES; HUMAN-HERPESVIRUS-8 REPLICATION; MONOCLONAL-ANTIBODY; HEPARAN-SULFATE AB Kaposi sarcoma-associated herpesvirus (KSHV, human herpesvirus 8) is etiologically associated with three neoplastic syndromes: Kaposi sarcoma and the uncommon HIV-associated B-cell lymphoproliferative disorders primary effusion lymphoma and multicentric Castleman disease. The incidence of the latter B-cell pathology has been increasing in spite of antiretroviral therapy; its association with lytic virus replication has prompted interest in therapeutic strategies aimed at this phase of the virus life cycle. We designed and expressed a recombinant immunotoxin (2014-PE38) targeting the gpK8.1A viral glycoprotein expressed on the surface of the virion and infected cells. We show that this immunotoxin selectively kills KSHV-infected cells in dose-dependent fashion, resulting in major reductions of infectious virus release. The immunotoxin and ganciclovir, an inhibitor of viral DNA replication, showed marked reciprocal potentiation of antiviral activities. These results suggest that the immunotoxin, alone or in combination, may represent a new approach to treat diseases associated with KSHV lytic replication. C1 [Chatterjee, Deboeeta; Berger, Edward A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Chandran, Bala] Rosalind Franklin Univ Med & Sci, Dept Microbiol & Immunol, Chicago, IL USA. RP Berger, EA (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM edward_berger@nih.gov FU NIH, NIAID FX We thank Jeffrey Vieira (University of Washington, Seattle WA) for donating the recombinant KSHV-infected stable cell lines as well as Joseph Newland and George Katsafanas (NIAID, NIH) for technical support as well as John Weldon, Tapan Bera and Ira Pastan (NCI, NIH) for providing control PE-based immunotoxins and technical advice. We are grateful to Bertrand Saunier and Yingyun Cai (NIAID, NIH) for sharing experimental insights. The excellent technical assistance of Virgilio Bundoc (NIAID, NIH) is acknowledged. This work was funded in part by the Intramural Program of the NIH, NIAID. NR 95 TC 6 Z9 6 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1942-0862 J9 MABS-AUSTIN JI mAbs PD MAR-APR PY 2012 VL 4 IS 2 BP 233 EP 242 DI 10.4161/mabs.4.2.19262 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 936MJ UT WOS:000303594200007 PM 22377676 ER PT J AU Chung, JH AF Chung, Jay H. TI Using PDE inhibitors to harness the benefits of calorie restriction: lessons from resveratrol SO AGING-US LA English DT Editorial Material ID ACTIVATED PROTEIN-KINASE; SIRT1 ACTIVATION; SKELETAL-MUSCLE; AMPK; EXERCISE; SIRTUINS C1 NHLBI, Lab Obes & Aging Res, Genet & Dev Biol Ctr, NIH, Bethesda, MD 20892 USA. RP Chung, JH (reprint author), NHLBI, Lab Obes & Aging Res, Genet & Dev Biol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM chungj@nhlbi.nih.gov NR 18 TC 14 Z9 14 U1 0 U2 2 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD MAR PY 2012 VL 4 IS 3 BP 144 EP 145 PG 2 WC Cell Biology SC Cell Biology GA 931SV UT WOS:000303240500001 PM 22388573 ER PT J AU Jirapongsananuruk, O Luangwedchakarn, V Niemela, JE Pacharn, P Visitsunthorn, N Thepthai, C Vichyanond, P Piboonpocanun, S Fleisher, TA AF Jirapongsananuruk, Orathai Luangwedchakarn, Voravich Niemela, Julie E. Pacharn, Punchama Visitsunthorn, Nualanong Thepthai, Charin Vichyanond, Pakit Piboonpocanun, Surapon Fleisher, Thomas A. TI Cryptococcal osteomyelitis hi a child with a novel compound mutation of the IL12RB1 gene SO ASIAN PACIFIC JOURNAL OF ALLERGY AND IMMUNOLOGY LA English DT Article DE Cryptococcal osteomyelitis; IL-12R beta 1 deficiency; Mycobacterial infection; recurrent Salmonella infection ID DEFICIENCY; MYCOBACTERIAL; FEATURES; IMMUNITY; PATIENT AB The IL-12p40/IL-12R beta 1 and IFN-gamma R1/IFN-gamma R2/STAT1 signaling pathways are important for clearing intracellular bacteria. Genetic defects within these pathways are associated with increased susceptibility to intracellular pathogens. Among these, IL-12R beta 1 deficiency is the most common defect and leads to infections with Salmonella and Mycobacterium spp. We report a child who presented with Cryptococcal osteomyelitis and history of disseminated Mycobacterial infection and recurrent Salmonella septicemia. Flow cytometry showed defective expression of IL-12R beta 1. Mutation analysis revealed a novel compound heterozygous mutation of IL12RB1, c.625C>T, p.Q209X was found in exon 7 on the paternal allele and c.710delC, p.P237HfsX5 was found in exon 8 on the maternal allele. As these mutations each result in a stop codon before the last spliceable exon, the transcripts likely underwent nonsense mediated decay, leading to a lack of IL12R beta 1 expression on the cell surface and eradicating signaling via the IL12 signaling pathway. (Asian Pac J Allergy Immunol 2012;30:79-82) C1 [Jirapongsananuruk, Orathai; Pacharn, Punchama; Visitsunthorn, Nualanong; Vichyanond, Pakit] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Pediat, Bangkok 10700, Thailand. [Luangwedchakarn, Voravich; Thepthai, Charin] Mahidol Univ, Siriraj Hosp, Fac Med, Dept Immunol, Bangkok 10700, Thailand. [Niemela, Julie E.; Fleisher, Thomas A.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Piboonpocanun, Surapon] Mahidol Univ, Inst Mol Biol & Genet, Nakhon Pathom, Thailand. RP Jirapongsananuruk, O (reprint author), Mahidol Univ, Siriraj Hosp, Fac Med, Dept Pediat, Bangkok 10700, Thailand. EM siojr@mahidol.ac.th NR 17 TC 6 Z9 6 U1 1 U2 3 PU ALLERGY IMMUNOL SOC THAILAND, PI BANGKOK PA MAHIDOL UNIV, DEPT MICROBIOL IMMUNOL, FACULTY TROPICAL MED, BANGKOK 10400, THAILAND SN 0125-877X J9 ASIAN PAC J ALLERGY JI Asian Pac. J. Allergy Immunol. PD MAR PY 2012 VL 30 IS 1 BP 79 EP 82 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA 928LU UT WOS:000302985100012 PM 22523911 ER PT J AU Malinovsky, Y Albert, PS Schisterman, EF AF Malinovsky, Yaakov Albert, Paul S. Schisterman, Enrique F. TI Pooling Designs for Outcomes under a Gaussian Random Effects Model SO BIOMETRICS LA English DT Article DE Covariance structure; Intraclass correlation coefficient; Pooling; Random effects model ID ROC CURVE ANALYSIS; POOLED ASSESSMENTS; REGRESSION-MODELS; DEFECTIVE MEMBERS; LARGE POPULATIONS; MESSENGER-RNA; BIOMARKERS; EFFICIENCY; WOMEN AB Due to the rising cost of laboratory assays, it has become increasingly common in epidemiological studies to pool biospecimens. This is particularly true in longitudinal studies, where the cost of performing multiple assays over time can be prohibitive. In this article, we consider the problem of estimating the parameters of a Gaussian random effects model when the repeated outcome is subject to pooling. We consider different pooling designs for the efficient maximum likelihood estimation of variance components, with particular attention to estimating the intraclass correlation coefficient. We evaluate the efficiencies of different pooling design strategies using analytic and simulation study results. We examine the robustness of the designs to skewed distributions and consider unbalanced designs. The design methodology is illustrated with a longitudinal study of premenopausal women focusing on assessing the reproducibility of F2-isoprostane, a biomarker of oxidative stress, over the menstrual cycle. C1 [Malinovsky, Yaakov; Albert, Paul S.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Malinovsky, Y (reprint author), Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21250 USA. EM yaakovm@umbc.edu OI Schisterman, Enrique/0000-0003-3757-641X FU American Chemistry Council; Eunice Kennedy Shriver National Institute of Child Health & Human Development FX The work was supported with funding from the American Chemistry Council and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health & Human Development. We thank Drs Zhiwei Zhang, Aijun Ye, and Sunni Mumford for helpful discussions. We also thank Sara Joslyn for editing the article. An associate editor and two referees made comments that resulted in significant improvements in the article. NR 23 TC 12 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2012 VL 68 IS 1 BP 45 EP 52 DI 10.1111/j.1541-0420.2011.01673.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 914BT UT WOS:000301924400006 PM 21981372 ER PT J AU Korn, EL AF Korn, Edward L. TI Discussion of the Paper of Ghosh, Taylor, and Sargent SO BIOMETRICS LA English DT Article ID END-POINTS; ASSESSING SURROGATES; MIXED MODELS; TRIAL C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Korn, EL (reprint author), NCI, Biometr Res Branch, Bethesda, MD 20892 USA. EM korne@ctep.nci.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2012 VL 68 IS 1 BP 236 EP 238 DI 10.1111/j.1541-0420.2011.01635.x PG 3 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 914BT UT WOS:000301924400031 PM 21668901 ER PT J AU Berger, VW Izmirlian, G Knoll, D AF Berger, Vance W. Izmirlian, Grant Knoll, Diana TI Discussion of the Paper of Ghosh, Taylor, and Sargent SO BIOMETRICS LA English DT Article ID SURROGATE END-POINTS; CLINICAL-TRIALS C1 [Berger, Vance W.; Izmirlian, Grant; Knoll, Diana] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM izmirlig@mail.nih.gov NR 9 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2012 VL 68 IS 1 BP 239 EP 241 DI 10.1111/j.1541-0420.2011.01636.x PG 3 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 914BT UT WOS:000301924400032 PM 21696380 ER PT J AU Baker, SG Sargent, DJ Buyse, M Burzykowski, T AF Baker, Stuart G. Sargent, Daniel J. Buyse, Marc Burzykowski, Tomasz TI Predicting Treatment Effect from Surrogate Endpoints and Historical Trials: An Extrapolation Involving Probabilities of a Binary Outcome or Survival to a Specific Time SO BIOMETRICS LA English DT Article DE Principal stratification; Randomized trials; Reproducibility ID ADVANCED COLORECTAL-CANCER; RANDOMIZED CLINICAL-TRIALS; VALIDATION; IDENTIFICATION; METAANALYSIS; BIOMARKERS; INFERENCE; CRITERIA; PROPOSAL AB Using multiple historical trials with surrogate and true endpoints, we consider various models to predict the effect of treatment on a true endpoint in a target trial in which only a surrogate endpoint is observed. This predicted result is computed using (1) a prediction model (mixture, linear, or principal stratification) estimated from historical trials and the surrogate endpoint of the target trial and (2) a random extrapolation error estimated from successively leaving out each trial among the historical trials. The method applies to either binary outcomes or survival to a particular time that is computed from censored survival data. We compute a 95% confidence interval for the predicted result and validate its coverage using simulation. To summarize the additional uncertainty from using a predicted instead of true result for the estimated treatment effect, we compute its multiplier of standard error. Software is available for download. C1 [Baker, Stuart G.] NCI, Bethesda, MD 20892 USA. [Sargent, Daniel J.] Mayo Clin, Rochester, MN 55905 USA. [Buyse, Marc] IDDI, B-1340 Louvain, Belgium. [Burzykowski, Tomasz] Hasselt Univ, B-3590 Diepenbeek, Belgium. RP Baker, SG (reprint author), NCI, EPN 3131,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. EM sb16i@nih.gov OI Sargent, Daniel/0000-0002-2684-4741 FU National Cancer Institute FX This work was supported by the National Cancer Institute. The authors are grateful to the MAGIC (Meta-Analysis Group in Cancer) and ACCENT (Adjuvant Colon Cancer Endpoints) collaborators, listed in Burzykowski et al. (2008), for providing the data. The authors thank the reviewers for helpful comments. NR 28 TC 11 Z9 11 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2012 VL 68 IS 1 BP 248 EP 257 DI 10.1111/j.1541-0420.2011.01646.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 914BT UT WOS:000301924400035 PM 21838732 ER PT J AU Caccavale, LJ Farhat, T Iannotti, RJ AF Caccavale, Laura J. Farhat, Tilda Iannotti, Ronald J. TI Social engagement in adolescence moderates the association between weight status and body image SO BODY IMAGE LA English DT Article DE Body image; Adolescents; Obesity; Social engagement ID RISK-FACTORS; MASS INDEX; FRIENDSHIP QUALITY; INVESTMENT SCALE; DISSATISFACTION; OBESITY; GIRLS; HEALTH; BEHAVIORS; CHILDREN AB This study examined whether the association between adolescent weight status and body image varies by social engagement. A nationally representative sample of 6909 students in grades 6-10 completed the 2006 HBSC survey. Separate linear regressions for boys and girls, controlling for age, race/ethnicity and socioeconomic status, were conducted with an interaction term (weight status x social engagement). Adolescents' overweight/obese status was related to body dissatisfaction. Social engagement moderated the relationship between weight status and body image for girls but not for boys. Overweight/obese boys had more body dissatisfaction compared to their normal/underweight peers, regardless of their social engagement. However, overweight/obese girls with more social engagement were more likely to have body satisfaction compared to overweight/obese girls with less social engagement. Encouraging adolescent girls to develop healthy relationships with peers may prevent them from developing body dissatisfaction. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Caccavale, Laura J.] Virginia Commonwealth Univ, Dept Psychol, Richmond, VA 23284 USA. [Farhat, Tilda; Iannotti, Ronald J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, NIH, Bethesda, MD USA. RP Caccavale, LJ (reprint author), Virginia Commonwealth Univ, Dept Psychol, 806 W Franklin St,POB 842018, Richmond, VA 23284 USA. EM caccavalelj@vcu.edu FU Intramural NIH HHS [Z99 HD999999]; NICHD NIH HHS [N01-HD-5-3401)] NR 46 TC 5 Z9 5 U1 2 U2 25 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1740-1445 J9 BODY IMAGE JI Body Image PD MAR PY 2012 VL 9 IS 2 BP 221 EP 226 DI 10.1016/j.bodyim.2012.01.001 PG 6 WC Psychology, Clinical; Psychiatry; Psychology, Multidisciplinary SC Psychology; Psychiatry GA 930YP UT WOS:000303181100005 PM 22325852 ER PT J AU Patel, SS AF Patel, Sejal S. TI Methods and Management: NIH Administrators, Federal Oversight, and the Framingham Heart Study SO BULLETIN OF THE HISTORY OF MEDICINE LA English DT Article DE National Institutes of Health; science administration; federal oversight; public administration; Framingham Heart Study; biostatistics; research methods; Wooldridge Review ID WORLD-WAR-II; UNITED-STATES; EPIDEMIOLOGY; DISEASE; RISK AB This article explores the 1965 controversy over the Framingham Heart Study in the midst of growing oversight into the management of science at the National Institutes of Health (NIH). It describes how, beginning in the early 1960s, federal overseers demanded that NIH administrators adopt particular management styles in administering programs and how these growing pressures led administrators to favor investigative pursuits that allowed for easy prospective accounting of program payoffs, especially those based on experimental methods designed to examine discrete interventions or outcomes of interest. In light of this changing managerial culture within the NIH, the Framingham study and other population laboratories-with their bases in observation and in open-ended study designs-became harder for NIH administrators to justify and defend. RP Patel, SS (reprint author), Natl Inst Hlth, Off Hist, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 OD999999] NR 31 TC 4 Z9 4 U1 0 U2 3 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0007-5140 J9 B HIST MED JI Bull. Hist. Med. PD SPR PY 2012 VL 86 IS 1 BP 94 EP 121 PG 28 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 930YC UT WOS:000303179700004 PM 22643985 ER PT J AU Sappol, M AF Sappol, Michael TI American Abyss: Savagery and Civilization in the Age of Industry SO BULLETIN OF THE HISTORY OF MEDICINE LA English DT Book Review C1 [Sappol, Michael] Natl Lib Med, Bethesda, MD 20894 USA. RP Sappol, M (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0007-5140 J9 B HIST MED JI Bull. Hist. Med. PD SPR PY 2012 VL 86 IS 1 BP 136 EP 138 PG 3 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 930YC UT WOS:000303179700013 ER PT J AU Enewold, L Zhou, J McGlynn, KA Devesa, SS Shriver, CD Potter, JF Zahm, SH Zhu, KM AF Enewold, Lindsey Zhou, Jing McGlynn, Katherine A. Devesa, Susan S. Shriver, Craig D. Potter, John F. Zahm, Shelia H. Zhu, Kangmin TI Racial Variation in Tumor Stage at Diagnosis Among Department of Defense Beneficiaries SO CANCER LA English DT Article DE Department of Defense health system; military; racial disparity; tumor state; equal health care access ID BREAST-CANCER MORTALITY; HEALTH-CARE-SYSTEM; AFRICAN-AMERICAN; UNITED-STATES; DISPARITIES; SURVIVAL; OUTCOMES; WHITE; RACE AB BACKGROUND: Tumor stage at diagnosis often varies by racial/ethnic group, possibly because of inequitable health care access. Within the Department of Defense (DoD) Military Health System, beneficiaries have equal health care access. The objective of this study was to determine whether tumor stage differed between whites and blacks with breast, cervical, colorectal, and prostate cancers, which have effective screening regimens, based on data from the DoD Automated Cancer Tumor Registry from 1990 to 2003. METHODS: Distributions of tumor stage (localized vs nonlocalized) between whites and blacks in the military were compared stratified by sex, active duty status, and age at diagnosis. Logistic regression was used to further adjust for age, marital status, year of diagnosis, geographic region, military service branch, and tumor grade. Distributions of tumor stage were then compared between the military and general populations. RESULTS: Racial differences in the distribution of stage were significant only among nonactive duty beneficiaries. After adjusting for covariates, earlier stages of breast cancer after age 49 years and prostate cancer after age 64 years were significantly more common among white than black nonactive duty beneficiaries (P < .05), although the absolute difference was minimal for prostate cancer. Racial differences in stage for cervical and colorectal cancers were not significant after adjustment. Compared with the general population, racial differences in the military were similar or were slightly attenuated. CONCLUSIONS: Racial disparities in stage at diagnosis were apparent in the DoD equal-access health care system among older nonactive duty beneficiaries. Socioeconomic status, supplemental insurance, cultural beliefs, and biologic factors may be related to these results. Cancer 2012;118:1397-403. (C) 2011 American Cancer Society. C1 [Enewold, Lindsey] Armed Forces Inst Pathol, US Mil Canc Inst, Walter Reed Army Med Ctr, Washington, DC 20306 USA. [McGlynn, Katherine A.; Devesa, Susan S.; Zahm, Shelia H.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Shriver, Craig D.] Walter Reed Army Med Ctr, Dept Surg, Div Surg Oncol, Washington, DC 20307 USA. [Potter, John F.; Zhu, Kangmin] Uniformed Serv Univ Hlth Sci, Dept Preventat Med & Biometr, Bethesda, MD USA. RP Enewold, L (reprint author), Armed Forces Inst Pathol, US Mil Canc Inst, Walter Reed Army Med Ctr, Bldg 54,Room N1512,6825 16th St NW, Washington, DC 20306 USA. EM lindsey.enewold@us.army.mil RI Zahm, Shelia/B-5025-2015 FU United States Military Cancer Institute; United States Military Cancer Institute through the Uniformed Services University of the Health Sciences; Henry M. Jackson Foundation for the Advancement of Military Medicine; Division of Cancer Epidemiology and Genetics, National Cancer Institute FX The authors thank the Armed Forces Institute of Pathology for providing the Automated Cancer Tumor Registry data, especially Ms. Annette Anderson for coordinating the process; Dr. Hongyu Wu of the US Marine Corp Institute for her help in computer programming; Dr. Larry Maxwell, Mr. William Mahr, and Ms. Anne Dimke of the United States Military Cancer Institute for their support and help; and Dr. Sally Bushhouse of the Minnesota Cancer Surveillance System for providing the useful Minnesota Patient and Tumor Resolution Algorithms document.; This research was supported by the United States Military Cancer Institute through the Uniformed Services University of the Health Sciences under the auspices of the Henry M. Jackson Foundation for the Advancement of Military Medicine and by the Division of Cancer Epidemiology and Genetics, National Cancer Institute. NR 30 TC 5 Z9 6 U1 1 U2 5 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 MAR 1 PY 2012 VL 118 IS 5 BP 1397 EP 1403 DI 10.1002/cncr.26208 PG 7 WC Oncology SC Oncology GA 897QD UT WOS:000300667800027 PM 21837685 ER PT J AU Cho, H Chung, J Kim, S Chay, D Hewitt, S Kim, J AF Cho, H. Chung, J. Kim, S. Chay, D. Hewitt, S. Kim, J. TI The expression of antiapoptotic protein API5 in cervical neoplasias SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Cho, H.; Kim, S.; Chay, D.; Kim, J.] Yonsei Univ, Coll Med, Seoul, South Korea. [Chung, J.; Hewitt, S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2012 VL 125 SU 1 MA 151 BP S64 EP S64 DI 10.1016/j.ygyno.2011.12.152 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 931NW UT WOS:000303227600151 ER PT J AU Cho, H Chung, J Kim, S Nam, E Kim, S Kim, S Chay, D Kim, Y Hewitt, S Kim, J AF Cho, H. Chung, J. Kim, S. Nam, E. Kim, S. Kim, S. Chay, D. Kim, Y. Hewitt, S. Kim, J. TI The expression of synaptonemal complex protein 3 (SCP3) and phospho-AKT in cervical neoplasias SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Cho, H.; Kim, S.; Nam, E.; Kim, S.; Kim, S.; Chay, D.; Kim, Y.; Kim, J.] Yonsei Univ, Coll Med, Seoul, South Korea. [Chung, J.; Hewitt, S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2012 VL 125 SU 1 MA 114 BP S49 EP S49 DI 10.1016/j.ygyno.2011.12.115 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 931NW UT WOS:000303227600116 ER PT J AU Kim, B Conway, C Kris, Y Hewitt, S Cho, H Kim, J AF Kim, B. Conway, C. Kris, Y. Hewitt, S. Cho, H. Kim, J. TI Influence of Nanog expression on prognosis of cervical cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Kim, B.; Conway, C.; Kris, Y.; Hewitt, S.] NCI, Bethesda, MD 20892 USA. [Cho, H.; Kim, J.] Yonsei Univ, Coll Med, Seoul, South Korea. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2012 VL 125 SU 1 MA 147 BP S62 EP S62 DI 10.1016/j.ygyno.2011.12.148 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 931NW UT WOS:000303227600147 ER PT J AU Pothuri, B Sparano, J Blank, S Curtin, J Chuang, E Hershman, D Tiersten, A Liebes, L Chen, A Muggia, F AF Pothuri, B. Sparano, J. Blank, S. Curtin, J. Chuang, E. Hershman, D. Tiersten, A. Liebes, L. Chen, A. Muggia, F. TI Phase I study of the PARP inhibitor ABT-888 (veliparib) and pegylated liposomal doxorubicin (PLD) in recurrent ovarian (ov) and breast (br) cancers SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Pothuri, B.; Blank, S.; Curtin, J.; Tiersten, A.; Liebes, L.; Muggia, F.] NYU, Sch Med, New York, NY USA. [Sparano, J.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Chuang, E.] New York Presbyterian Med Ctr, New York, NY USA. [Hershman, D.] Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. [Chen, A.] NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2012 VL 125 SU 1 MA 52 BP S22 EP S22 DI 10.1016/j.ygyno.2011.12.053 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 931NW UT WOS:000303227600053 ER PT J AU Wexler, P Gilbert, SG Thorp, N Faustman, E Breskin, DD AF Wexler, Philip Gilbert, Steven G. Thorp, Nick Faustman, Elaine Breskin, Donna D. TI The World Library of Toxicology, Chemical Safety, and Environmental Health (WLT) SO HUMAN & EXPERIMENTAL TOXICOLOGY LA English DT Article DE World Library of Toxicology; Global Toxicology Information; online toxicology information; wiki; IUTOX; NLM AB The World Library of Toxicology, Chemical Safety, and Environmental Health, commonly referred to as the World Library of Toxicology (WLT), is a multilingual online portal of links to key global resources, representing a host of individual countries and multilateral organizations. The Site is designed as a network of, and gateway to, toxicological information and activities from around the world. It is built on a Wiki platform by a roster of Country Correspondents, with the aim of efficiently exchanging information and stimulating collaboration among colleagues, and building capacity, with the ultimate objective of serving as a tool to help improve global public health. The. WLT was publicly launched on September 7, 2009, at the Seventh Congress of Toxicology in Developing Countries (CTDC-VII) in Sun City, South Africa. C1 [Wexler, Philip] US Natl Lib Med, Bethesda, MD 20894 USA. [Gilbert, Steven G.; Thorp, Nick] Inst Neurotoxicol & Neurol Disorders INND Toxiped, Seattle, WA USA. [Faustman, Elaine] Univ Washington, USA Dept Environm Hlth, Seattle, WA 98195 USA. [Breskin, Donna D.] IUTOX Headquarters, Int Union Toxicol, Reston, VA USA. RP Wexler, P (reprint author), US Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM wexlerp@mail.nih.gov OI Faustman, Elaine/0000-0002-3085-6403 NR 3 TC 2 Z9 2 U1 0 U2 0 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0960-3271 J9 HUM EXP TOXICOL JI Hum. Exp. Toxicol. PD MAR PY 2012 VL 31 IS 3 SI SI BP 207 EP 214 DI 10.1177/0960327110389500 PG 8 WC Toxicology SC Toxicology GA 928ZF UT WOS:000303030300002 PM 21071551 ER PT J AU Kim, HK Chanock, SJ AF Kim, Hye Kyung Chanock, Stephen J. TI Genome-wide association studies in melanoma: off to a good start SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article ID BASAL-CELL CARCINOMA; CUTANEOUS MELANOMA; SEQUENCE VARIANTS; BREAST-CANCER; IDENTIFIES 3; RISK; SUSCEPTIBILITY; LOCI; GENE; HERITABILITY C1 [Kim, Hye Kyung; Chanock, Stephen J.] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Kim, HK (reprint author), NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. EM chanocks@mail.nih.gov NR 20 TC 0 Z9 0 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD MAR PY 2012 VL 25 IS 2 DI 10.1111/j.1755-148X.2012.00981.x PG 4 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 897UK UT WOS:000300683200016 PM 22268896 ER PT J AU Walia, V Mu, EW Lin, JC Samuels, Y AF Walia, Vijay Mu, Euphemia W. Lin, Jimmy C. Samuels, Yardena TI Delving into somatic variation in sporadic melanoma SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Review DE melanoma; somatic mutation; sequencing ID KIT PROTEIN EXPRESSION; MALIGNANT-MELANOMA; ULTRAVIOLET-RADIATION; METASTATIC MELANOMA; HUMAN CANCER; MATRIX METALLOPROTEINASES; GENOMIC ANALYSES; RENAL-CARCINOMA; UVEAL MELANOMA; HUMAN BREAST AB Melanoma, the most aggressive form of skin cancer, has increased in incidence more rapidly than any other cancer. The completion of the human genome project and advancements in genomics technologies has allowed us to investigate genetic alterations of melanoma at a scale and depth that is unprecedented. Here, we survey the history of the different approaches taken to understand the genomics of melanoma from early candidate genes, to gene families, to genome-wide studies. The new era of whole-exome and whole-genome sequencing has paved the way for an in-depth understanding of melanoma biology, identification of new therapeutic targets, and development of novel personalized therapies for melanoma. C1 [Walia, Vijay; Samuels, Yardena] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. [Mu, Euphemia W.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Lin, Jimmy C.] Washington Univ, Sch Med, Dept Pathol & Immunol, Div Lab & Genom Med, St Louis, MO USA. RP Samuels, Y (reprint author), NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. EM samuelsy@mail.nih.gov RI Walia, Vijay/F-1647-2013 FU National Human Genome Research Institute, National Institutes of Health, USA FX We thank Mike Davies and Jared Gartner for insightful comments. This work was supported by the Intramural Research Programs of the National Human Genome Research Institute, National Institutes of Health, USA. NR 139 TC 22 Z9 22 U1 1 U2 7 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD MAR PY 2012 VL 25 IS 2 DI 10.1111/j.1755-148X.2012.00976.x PG 17 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 897UK UT WOS:000300683200009 PM 22260482 ER PT J AU Yang, XR Brown, K Landi, MT Ghiorzo, P Badenas, C Xu, M Hayward, NK Calista, D Landi, G Bruno, W Bianchi-Scarra, G Aguilera, P Puig, S Goldstein, AM Tucker, MA AF Yang, Xiaohong R. Brown, Kevin Landi, Maria T. Ghiorzo, Paola Badenas, Celia Xu, Mai Hayward, Nicholas K. Calista, Donato Landi, Giorgio Bruno, William Bianchi-Scarra, Giovanna Aguilera, Paula Puig, Susana Goldstein, Alisa M. Tucker, Margaret A. TI Duplication of CXC chemokine genes on chromosome 4q13 in a melanoma-prone family SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Article DE familial melanoma; germline copy number variations; disease susceptibility; CXC chemokines; chromosome 4q13 ID EXPRESSION; GROWTH; INTERLEUKIN-8; PROGRESSION; CELLS AB Copy number variations (CNVs) have been shown to contribute substantially to disease susceptibility in several inherited diseases including cancer. We conducted a genome-wide search for CNVs in blood-derived DNA from 79 individuals (62 melanoma patients and 17 spouse controls) of 30 high-risk melanoma-prone families without known segregating mutations using genome-wide comparative genomic hybridization (CGH) tiling arrays. We identified a duplicated region on chromosome 4q13 in germline DNA of all melanoma patients in a melanoma-prone family with three affected siblings. We confirmed the duplication using quantitative PCR and a custom-made CGH array design spanning the 4q13 region. The duplicated region contains 10 genes, most of which encode CXC chemokines. Among them, CXCL1 (melanoma growth-stimulating activity a) and IL8 (interleukin 8) have been shown to stimulate melanoma growth in vitro and in vivo. Our data suggest that the alteration of CXC chemokine genes may confer susceptibility to melanoma. C1 [Yang, Xiaohong R.; Brown, Kevin; Landi, Maria T.; Xu, Mai; Goldstein, Alisa M.; Tucker, Margaret A.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Ghiorzo, Paola; Bruno, William; Bianchi-Scarra, Giovanna] Univ Genoa, DOBIG, Dept Oncol Biol & Genet, Genoa, Italy. [Badenas, Celia] Hosp Clin Barcelona, Dept Biochem & Mol Genet, IDIBAPS, Barcelona, Spain. [Hayward, Nicholas K.] Queensland Inst Med Res, Oncogen Lab, Brisbane, Qld 4006, Australia. [Calista, Donato; Landi, Giorgio] Maurizio Bufalini Hosp, Cesena, Italy. [Bianchi-Scarra, Giovanna] San Martino Hosp, Lab Genet Rare Hereditary Canc, Genoa, Italy. [Aguilera, Paula; Puig, Susana] Hosp Clin Barcelona, Dept Dermatol, Melanoma Unit, IDIBAPS, Barcelona, Spain. [Puig, Susana] Inst Salud Carlos III, CIBER Enfermedades Raras, Barcelona, Spain. RP Yang, XR (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. EM royang@mail.nih.gov RI Bianchi Scarra, Giovanna/G-8933-2014; Tucker, Margaret/B-4297-2015; hayward, nicholas/C-1367-2015; Bruno, William/N-7477-2013; OI Bianchi Scarra, Giovanna/0000-0002-6127-1192; hayward, nicholas/0000-0003-4760-1033; Bruno, William/0000-0002-0337-0168; Badenas, Celia/0000-0002-0621-0477; Puig, Susana/0000-0003-1337-9745 FU NIH; NCI; DCEG; Fondo de Investigaciones Sanitarias, Spain [06/0265, 09/1393]; CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; AGAUR of Catalan Government, Spain [SGR 1337]; European Commission [LSHC-CT-2006-018702]; National Cancer Institute (NCI) of the US National Institute of Health (NIH) [CA83115]; Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III [Rio Hortega 10/00120]; Fondazione CARIGE; IMI and ACM; Italian Ministry of Health [DGRST.4/4235-P1.9.A.B]; National Health and Medical Research Council of Australia FX We are indebted to the participating families, whose generosity and cooperation have made this study possible. We thank Seq-Wright, Roche Nimblegen, and Biodiscovery for their molecular and informatic services. We also acknowledge the contributions to this work that were made by Virginia Pichler, Deborah Zametkin, Mary Fraser, and Barbara Rogers. This research was supported by the Intramural Research Program of the NIH, NCI, DCEG. The research at the Melanoma Unit in Barcelona is partially funded by Grants 06/0265 and 09/1393 from Fondo de Investigaciones Sanitarias, Spain; by the CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; by the AGAUR 2009 SGR 1337 of the Catalan Government, Spain; by the European Commission under the 6th Framework Programme, Contract nr: LSHC-CT-2006-018702 (GenoMEL); and by the National Cancer Institute (NCI) of the US National Institute of Health (NIH) (CA83115) and a personal grant to Paula Aguilera from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Rio Hortega 10/00120. Genoa team research has been supported by: Fondazione CARIGE 2010, IMI and ACM 2011, Italian Ministry of Health DGRST.4/4235-P1.9.A.B. NKH is supported by a Senior Principal Research Fellowship from the National Health and Medical Research Council of Australia. NR 16 TC 6 Z9 7 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD MAR PY 2012 VL 25 IS 2 DI 10.1111/j.1755-148X.2012.00969.x PG 6 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 897UK UT WOS:000300683200018 PM 22225770 ER PT J AU Venkova-Canova, T Saha, A Chattoraj, DK AF Venkova-Canova, Tatiana Saha, Anik Chattoraj, Dhruba K. TI A 29-mer site regulates transcription of the initiator gene as well as function of the replication origin of Vibrio cholerae chromosome II SO PLASMID LA English DT Article DE Vibrio cholerae; Secondary chromosome; Transcriptional autorepression; Operator site; Replication control; Hetero-handcuffing ID P1 PLASMID REPLICATION; ESCHERICHIA-COLI; DNA-REPLICATION; CELL-CYCLE; SEQUENCE; RCTB; INACTIVATION; SEGREGATION; METHYLATION; PROTEIN AB The region responsible for replication of Vibrio cholerae chromosome II (chrII) resembles those of plasmids that have repeated initiator binding sites (iterons) and an autorepressed initiator gene. ChrII has additional features: Its iterons require full methylation for initiator (RctB) binding, which makes them inactive for a part of the cell cycle when they are hemimethylated. RctB also binds to a second kind of site, called 39-mers, in a methylation independent manner. This binding is inhibitory to chrII replication. The site that RctB uses for autorepression has not been identified. Here we show that a 29-mer sequence, similar to the 39-mers, serves as that site, as we find that it binds RctB in vitro and suffices to repress the rctB promoter in vivo. The site is not subject to methylation and is likely to be active throughout the cell cycle. The 29-mer, like the 39-mers, could inhibit RctB-dependent mini-chrII replication in Escherichia coli, possibly by coupling with iterons via RctB bridges, as was seen in vitro. The 29-mer thus appears to play a dual role in regulating chrII replication: one independent of the cell cycle, the other dependent upon iteron methylation, hence responsive to the cell cycle. Published by Elsevier Inc. C1 [Venkova-Canova, Tatiana; Saha, Anik; Chattoraj, Dhruba K.] NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Venkova-Canova, T (reprint author), NCI, Lab Biochem & Mol Biol, NIH, 37 Convent Dr,Room 6044, Bethesda, MD 20892 USA. EM canovat@mail.nih.gov FU Center for Cancer Research, National Cancer Institute FX We thank Arnab Sarkar and Souvanik Adhya, for plasmid construction. We are grateful to Michael Yarmolinsky for a critical review of an earlier draft of this paper. This work was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute. NR 30 TC 9 Z9 9 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 0147-619X J9 PLASMID JI Plasmid PD MAR PY 2012 VL 67 IS 2 SI SI BP 102 EP 110 DI 10.1016/j.plasmid.2011.12.009 PG 9 WC Genetics & Heredity; Microbiology SC Genetics & Heredity; Microbiology GA 932RG UT WOS:000303307600006 PM 22248922 ER PT J AU Sawitzke, JA Youngren, B Thomason, LC Baker, T Sengupta, M Court, D Austin, S AF Sawitzke, James A. Youngren, Brenda Thomason, Lynn C. Baker, Teresa Sengupta, Manjistha Court, Donald Austin, Stuart TI The segregation of Escherichia coli minichromosomes constructed in vivo by recombineering SO PLASMID LA English DT Article DE Recombineering; Minichromosomes; oriC plasmids; Segregation; Localization ID HOMOLOGOUS RECOMBINATION; CHROMOSOME SEGREGATION; REPLICATION; ORIGIN; PLASMIDS; ABSENCE; SYSTEM AB Circularized regions of the chromosome containing the origin of replication, oriC, can be maintained as autonomous minichromosomes, oriC plasmids. We show that oriC plasmids containing precise, pre-determined segments of the chromosome can be generated by a simple in vivo recombineering technique. We generated two such plasmids carrying fluorescent markers. These were transferred to a recipient strain with a different fluorescent marker near the chromosomal copy of oriC. Thus the fates of the oriC plasmid and chromosomal origins could be followed independently in living cells by fluorescence microscopy. In contrast to a previous report, we show that there is a strong tendency of oriC plasmid copies to accumulate at the cell center as a single or double focus at the plane of cell division. This is not simply due to exclusion from the nucleoid space but rather appears to be a specific recognition and retention of the plasmid by some central-located cell site. Published by Elsevier Inc. C1 [Sawitzke, James A.; Youngren, Brenda; Baker, Teresa; Sengupta, Manjistha; Court, Donald; Austin, Stuart] NCI, Gene Regulat & Chromosome Biol Lab, CCR, Frederick, MD 21702 USA. [Thomason, Lynn C.] SAIC Frederick Inc, Gene Regulat & Chromosome Biol Lab, Basic Res Program, Frederick, MD USA. RP Austin, S (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, CCR, Frederick, MD 21702 USA. EM austin@ncifcrf.gov FU National Cancer Institute, National Institutes of Health [HHSN26120080001E]; NIH, National Cancer Institute, Center for Cancer Research FX The project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 19 TC 0 Z9 0 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 0147-619X J9 PLASMID JI Plasmid PD MAR PY 2012 VL 67 IS 2 SI SI BP 148 EP 154 DI 10.1016/j.plasmid.2012.01.002 PG 7 WC Genetics & Heredity; Microbiology SC Genetics & Heredity; Microbiology GA 932RG UT WOS:000303307600011 PM 22252137 ER PT J AU Shakeri, R Kamangar, F Nasrollahzadeh, D Nouraie, M Khademi, H Etemadi, A Islami, F Marjani, H Fahimi, S Sepehr, A Rahmati, A Abnet, CC Dawsey, SM Brennan, P Boffetta, P Malekzadeh, R Majdzadeh, R AF Shakeri, Ramin Kamangar, Farin Nasrollahzadeh, Dariush Nouraie, Mehdi Khademi, Hooman Etemadi, Arash Islami, Farhad Marjani, Hajiamin Fahimi, Saman Sepehr, Alireza Rahmati, Atieh Abnet, Christian C. Dawsey, Sanford M. Brennan, Paul Boffetta, Paolo Malekzadeh, Reza Majdzadeh, Reza TI Is Opium a Real Risk Factor for Esophageal Cancer or Just a Methodological Artifact? Hospital and Neighborhood Controls in Case-Control Studies SO PLOS ONE LA English DT Article ID POPULATION-CONTROLS; GOLESTAN COHORT; NORTHERN IRAN; ALCOHOL; SELECTION; QUESTION; TOBACCO; TRACT; AREA; DIET AB Background: Control selection is a major challenge in epidemiologic case-control studies. The aim of our study was to evaluate using hospital versus neighborhood control groups in studying risk factors of esophageal squamous cell carcinoma (ESCC). Methodology/Principal Findings: We compared the results of two different case-control studies of ESCC conducted in the same region by a single research group. Case definition and enrollment were the same in the two studies, but control selection differed. In the first study, we selected two age-and sex-matched controls from inpatient subjects in hospitals, while for the second we selected two age-and sex-matched controls from each subject's neighborhood of residence. We used the test of heterogeneity to compare the results of the two studies. We found no significant differences in exposure data for tobacco-related variables such as cigarette smoking, chewing Nass (a tobacco product) and hookah (water pipe) usage, but the frequency of opium usage was significantly different between hospital and neighborhood controls. Consequently, the inference drawn for the association between ESCC and tobacco use did not differ between the studies, but it did for opium use. In the study using neighborhood controls, opium use was associated with a significantly increased risk of ESCC (adjusted OR 1.77, 95% CI 1.17-2.68), while in the study using hospital controls, this was not the case (OR 1.09, 95% CI 0.63-1.87). Comparing the prevalence of opium consumption in the two control groups and a cohort enrolled from the same geographic area suggested that the neighborhood controls were more representative of the study base population for this exposure. Conclusions/Significance: Hospital and neighborhood controls did not lead us to the same conclusion for a major hypothesized risk factor for ESCC in this population. Our results show that control group selection is critical in drawing appropriate conclusions in observational studies. C1 [Shakeri, Ramin; Kamangar, Farin; Nasrollahzadeh, Dariush; Nouraie, Mehdi; Khademi, Hooman; Etemadi, Arash; Islami, Farhad; Marjani, Hajiamin; Fahimi, Saman; Sepehr, Alireza; Rahmati, Atieh; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. [Shakeri, Ramin; Kamangar, Farin; Etemadi, Arash; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Nasrollahzadeh, Dariush] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Nouraie, Mehdi] Howard Univ, Dept Internal Med, Washington, DC 20059 USA. [Nouraie, Mehdi] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Khademi, Hooman; Islami, Farhad; Brennan, Paul] Int Agcy Res Canc, F-69372 Lyon, France. [Fahimi, Saman] Univ Cambridge, Cambridge, England. [Sepehr, Alireza] Harvard Univ, Sch Med, Dept Pathol, BIDMC, Boston, MA 02115 USA. [Rahmati, Atieh] Univ Tehran Med Sci, Firoozgar Hosp, Gastrointestinal & Liver Dis Res Ctr, Tehran, Iran. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. [Majdzadeh, Reza] Univ Tehran Med Sci, Sch Publ Hlth, Dept Epidemiol & Biostat, Tehran, Iran. [Majdzadeh, Reza] Univ Tehran Med Sci, Knowledge Utilizat Res Ctr, Tehran, Iran. RP Shakeri, R (reprint author), Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. EM rezamajd@tums.ac.ir RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016; OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072; , Ramin/0000-0003-0487-3629; Malekzadeh, Reza/0000-0003-1043-3814 NR 23 TC 8 Z9 8 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 MAR 1 PY 2012 VL 7 IS 3 AR e32711 DI 10.1371/journal.pone.0032711 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 928SU UT WOS:000303005000036 PM 22396792 ER PT J AU Wagner, S Zensi, A Wien, SL Tschickardt, SE Maier, W Vogel, T Worek, F Pietrzik, CU Kreuter, J von Briesen, H AF Wagner, Sylvia Zensi, Anja Wien, Sascha L. Tschickardt, Sabrina E. Maier, Wladislaw Vogel, Tikva Worek, Franz Pietrzik, Claus U. Kreuter, Joerg von Briesen, Hagen TI Uptake Mechanism of ApoE-Modified Nanoparticles on Brain Capillary Endothelial Cells as a Blood-Brain Barrier Model SO PLOS ONE LA English DT Article ID RECEPTOR-RELATED PROTEIN; E-DERIVED PEPTIDE; 80-COATED POLYBUTYLCYANOACRYLATE NANOPARTICLES; PEGYLATED POLYCYANOACRYLATE NANOPARTICLES; POLY(BUTYL CYANOACRYLATE) NANOPARTICLES; APOLIPOPROTEIN-A-I; DRUG-DELIVERY; ELECTRICAL-RESISTANCE; DESOLVATION PROCESS; HSA-NANOPARTICLES AB Background: The blood-brain barrier (BBB) represents an insurmountable obstacle for most drugs thus obstructing an effective treatment of many brain diseases. One solution for overcoming this barrier is a transport by binding of these drugs to surface-modified nanoparticles. Especially apolipoprotein E (ApoE) appears to play a major role in the nanoparticle-mediated drug transport across the BBB. However, at present the underlying mechanism is incompletely understood. Methodology/Principal Findings: In this study, the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells was investigated to differentiate between active and passive uptake mechanism by flow cytometry and confocal laser scanning microscopy. Furthermore, different in vitro co-incubation experiments were performed with competing ligands of the respective receptor. Conclusions/Significance: This study confirms an active endocytotic uptake mechanism and shows the involvement of low density lipoprotein receptor family members, notably the low density lipoprotein receptor related protein, on the uptake of the ApoE-modified nanoparticles into the brain capillary endothelial cells. This knowledge of the uptake mechanism of ApoE-modified nanoparticles enables future developments to rationally create very specific and effective carriers to overcome the blood-brain barrier. C1 [Wagner, Sylvia; Wien, Sascha L.; von Briesen, Hagen] Fraunhofer Inst Biomed Engn, Dept Cell Biol & Appl Virol, St Ingbert, Germany. [Zensi, Anja; Kreuter, Joerg] Goethe Univ Frankfurt, Inst Pharmaceut Technol, Frankfurt, Germany. [Tschickardt, Sabrina E.; Maier, Wladislaw; Pietrzik, Claus U.] Johannes Gutenberg Univ Mainz, Univ Med Ctr, Inst Pathobiochem, Mainz, Germany. [Vogel, Tikva] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Vogel, Tikva] NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Worek, Franz] Bundeswehr Inst Pharmacol & Toxicol, Munich, Germany. RP Wagner, S (reprint author), Fraunhofer Inst Biomed Engn, Dept Cell Biol & Appl Virol, St Ingbert, Germany. EM hagen.briesen@ibmt.fraunhofer.de RI Fachbereich14, Dekanat/C-8553-2015; OI Worek, Franz/0000-0003-3531-3616 FU German Bundesministerium fur Bildung und Forschung (BMBF) [01EW1009, 01EW1010]; Deutsche Bundesamt fur Wehrtechnik und Beschaffung [U2.3 E/UR3G/5G031/5A802] FX This work was financially supported by the German Bundesministerium fur Bildung und Forschung (BMBF) (01EW1009, 01EW1010) and by the Deutsche Bundesamt fur Wehrtechnik und Beschaffung (U2.3 E/UR3G/5G031/5A802). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 60 Z9 61 U1 1 U2 26 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 1 PY 2012 VL 7 IS 3 AR e32568 DI 10.1371/journal.pone.0032568 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 928SU UT WOS:000303005000029 PM 22396775 ER PT J AU Kwintkiewicz, J Padilla-Banks, E Jefferson, WN Jacobs, IM Wade, PA Williams, CJ AF Kwintkiewicz, Jakub Padilla-Banks, Elizabeth Jefferson, Wendy N. Jacobs, Ilana M. Wade, Paul A. Williams, Carmen J. TI Metastasis-Associated Protein 3 (MTA3) Regulates G2/M Progression in Proliferating Mouse Granulosa Cells SO BIOLOGY OF REPRODUCTION LA English DT Article DE cell cycle; chromatin; cohesin; granulosa cells; NuRD complex; ovary ID CHROMATIN-REMODELING COMPLEX; HISTONE DEACETYLASE ACTIVITY; DNA-DAMAGE; MI-2/NURD COMPLEX; CYCLE PROGRESSION; OVARIAN-FOLLICLE; GENE-EXPRESSION; FACTOR CHD4; AURORA-B; COHESIN AB Metastasis-associated protein 3 (MTA3) is a constituent of the Mi-2/nucleosome remodeling and deacetylase (NuRD) protein complex that regulates gene expression by altering chromatin structure and can facilitate cohesin loading onto DNA. The biological function of MTA3 within the NuRD complex is unknown. Herein, we show that MTA3 was expressed highly in granulosa cell nuclei of all ovarian follicle stages and at lower levels in corpora lutea. We tested the hypothesis that MTA3-NuRD complex function is required for granulosa cell proliferation. In the ovary, MTA3 interacted with NuRD proteins CHD4 and HDAC1 and the core cohesin complex protein RAD21. In cultured mouse primary granulosa cells, depletion of endogenous MTA3 using RNA interference slowed cell proliferation; this effect was rescued by coexpression of exogenous MTA3. Slowing of cell proliferation correlated with a significant decrease in cyclin B1 and cyclin B2 expression. Granulosa cell populations lacking MTA3 contained a significantly higher percentage of cells in G2/M phase and a lower percentage in S phase compared with control cells. Furthermore, MTA3 depletion slowed entry into M phase as indicated by reduced phosphorylation of histone H3 at serine 10. These findings provide the first evidence to date that MTA3 interacts with NuRD and cohesin complex proteins in the ovary in vivo and regulates G2/M progression in proliferating granulosa cells. C1 [Kwintkiewicz, Jakub; Padilla-Banks, Elizabeth; Jefferson, Wendy N.; Jacobs, Ilana M.; Williams, Carmen J.] NIEHS, Reprod Med Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Wade, Paul A.] NIEHS, Eukaryot Transcript Regulat Grp, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Williams, CJ (reprint author), NIEHS, Reprod Med Grp, Lab Reprod & Dev Toxicol, NIH, POB 12233,MD E4-05, Res Triangle Pk, NC 27709 USA. EM williamsc5@niehs.nih.gov RI Williams, Carmen/E-2170-2013 OI Williams, Carmen/0000-0001-6440-7086 FU National Institute of Environmental Health Sciences, National Institutes of Health [Z01-ES102985, Z01-ES101965] FX Supported by grants Z01-ES102985, and Z01-ES101965 from the National Institute of Environmental Health Sciences, Intramural Research Program of the National Institutes of Health. NR 45 TC 3 Z9 3 U1 0 U2 4 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD MAR PY 2012 VL 86 IS 3 AR 64 DI 10.1095/biolreprod.111.096032 PG 8 WC Reproductive Biology SC Reproductive Biology GA 916SL UT WOS:000302123400004 PM 22075476 ER PT J AU Vyas, VV Esposito, D Sumpter, TL Broadt, TL Hartley, J Knapp, GC Cheng, W Jiang, MS Roach, JM Yang, XY Giardina, SL Mitra, G Yovandich, JL Creekmore, SP Waldmann, TA Zhu, JW AF Vyas, Vinay V. Esposito, Dominic Sumpter, Terry L. Broadt, Trevor L. Hartley, James Knapp, George C. Cheng, Wei Jiang, Man-Shiow Roach, John M. Yang, Xiaoyi Giardina, Steven L. Mitra, George Yovandich, Jason L. Creekmore, Stephen P. Waldmann, Thomas A. Zhu, Jianwei TI Clinical manufacturing of recombinant human interleukin 15. I. Production cell line development and protein expression in E. coli with stop codon optimization SO BIOTECHNOLOGY PROGRESS LA English DT Article DE interleukin 15; protein expression; stop codon; clinical manufacturing; E; coli ID CD8(+) T-CELLS; IN-VIVO; IL-15; READTHROUGH; TERMINATION; RECEPTOR; SIGNAL; PROLIFERATION; IMMUNOTHERAPY; SUPPRESSION AB Interleukin 15 (IL-15) has shown remarkable biological properties of promoting NK- and T-cell activation and proliferation, as well as enhancing antitumor immunity of CD8+ T cells in preclinical models. Here, we report the development of an E. coli cell line to express recombinant human Interleukin-15 (rhIL-15) for clinical manufacturing. Human IL-15 cDNA sequence was inserted into a pET28b plasmid and expressed in several E. coli BL21 strains. Through product quality comparisons among several E. coli strains, including E. coli BL21(DE3), BL21(DE3)pLysS, BLR(DE3)pLysS, and BL21-AI, E. coli BL21-AI was selected for clinical manufacturing. Expression optimization was carried out at shake flask and 20-L fermenter scales, and the product was expressed as inclusion bodies that were solubilized, refolded, and purified to yield active rhIL-15. Stop codons of the expression construct were further investigated after 1520% of the purified rhIL-15 showed an extraneous peak corresponding to an extra tryptophan residue based on peptide mapping and mass spectrometry analysis. It was determined that the presence of an extra tryptophan was due to a stop codon wobble effect, which could be eliminated by replacing TGA (opal) stop codon with TAA (ochre). As a novel strategy, a simple method of demonstrating lack of tRNA suppressors in the production host cells was developed to validate the cells in this study. The E. coli BL21-AI cells containing the rhIL-15 coding sequence with a triplet stop codon TAATAATGA were banked for further clinical manufacturing. (c) 2011 American Institute of Chemical Engineers Biotechnol. Prog., 2012 C1 [Vyas, Vinay V.; Sumpter, Terry L.; Broadt, Trevor L.; Knapp, George C.; Cheng, Wei; Jiang, Man-Shiow; Roach, John M.; Yang, Xiaoyi; Giardina, Steven L.; Mitra, George; Zhu, Jianwei] NCI, Biopharmaceut Dev Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Esposito, Dominic; Hartley, James; Yovandich, Jason L.; Creekmore, Stephen P.] NCI, Protein Express Lab, Adv Technol Program, SAIC Frederick, Frederick, MD 21702 USA. [Waldmann, Thomas A.] NCI, Ctr Canc Res, Metab Branch, Bethesda, MD 20892 USA. RP Zhu, JW (reprint author), NCI, Biopharmaceut Dev Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM zhujianwei@mail.nih.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400, HHSN261200800001E] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contracts N01-CO-12400 and #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 mentioning of trade names, commercial products, or organizations imply endorsement by the U.S. government. NR 32 TC 2 Z9 3 U1 4 U2 14 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 8756-7938 J9 BIOTECHNOL PROGR JI Biotechnol. Prog. PD MAR-APR PY 2012 VL 28 IS 2 BP 497 EP 507 DI 10.1002/btpr.746 PG 11 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 923GH UT WOS:000302607100024 PM 22162520 ER PT J AU Lisnyy, I Stahovskiy, E Kuchin, Y Klimchuk, L AF Lisnyy, Ivan Stahovskiy, Eduard Kuchin, Yuryy Klimchuk, Ludmila TI Postoperative pain and pge2 after preemptive analgesia with dexketoprofen. A randomized double blind placebo controlled study SO BRITISH JOURNAL OF ANAESTHESIA LA English DT Meeting Abstract CT 15th World-Federation-of-Societies-of-Anaesthesiologists (WFSA) World Congress of Anaesthesiologists CY MAR 25-30, 2012 CL Buenos Aires, ARGENTINA SP World Federat Soc Anaesthesiol (WFSA) C1 [Lisnyy, Ivan; Klimchuk, Ludmila] NCI, Dept Anesthesiol, Bethesda, MD 20892 USA. [Stahovskiy, Eduard] NCI, Oncourol Dept, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0007-0912 J9 BRIT J ANAESTH JI Br. J. Anaesth. PD MAR PY 2012 VL 108 SU 2 BP 401 EP 401 PG 1 WC Anesthesiology SC Anesthesiology GA 919CT UT WOS:000302299100675 ER PT J AU Mueller, SC Hardin, MG Korelitz, K Daniele, T Bemis, J Dozier, M Peloso, E Maheu, FS Pine, DS Ernst, M AF Mueller, Sven C. Hardin, Michael G. Korelitz, Katherine Daniele, Teresa Bemis, Jessica Dozier, Mary Peloso, Elizabeth Maheu, Francoise S. Pine, Daniel S. Ernst, Monique TI Incentive effect on inhibitory control in adolescents with early-life stress: An antisaccade study SO CHILD ABUSE & NEGLECT LA English DT Article DE Reward; Antisaccade; Cognitive control; Early adversity; Stress ID COGNITIVE CONTROL; EARLY DEPRIVATION; EYE-MOVEMENT; CHILDHOOD MALTREATMENT; DEPRESSED ADOLESCENTS; BRAIN-FUNCTION; SACCADE TASK; CHILDREN; HEALTHY; REWARD AB Objective: Early-life stress (ES) such as adoption, change of caregiver, or experience of emotional neglect may influence the way in which affected individuals respond to emotional stimuli of positive or negative valence. These modified responses may stem from a direct alteration of how emotional stimuli are coded, and/or the cognitive function implicated in emotion modulation, such as self-regulation or inhibition. These ES effects have been probed on tasks either targeting reward and inhibitory function. Findings revealed deficits in both reward processing and inhibitory control in ES youths. However, no work has yet examined whether incentives can improve automatic response or inhibitory control in ES youths. Method: To determine whether incentives would only improve self-regulated voluntary actions or generalize to automated motoric responses, participants were tested on a mixed eye movement task that included reflex-like prosaccades and voluntary controlled antisaccade eye movements. Seventeen adopted children (10 females, mean age 11.3 years) with a documented history of neglect and 29 typical healthy youths (16 females, mean age 11.9 years) performed the mixed prosaccade/antisaccade task during monetary incentive conditions or during no-incentive conditions. Results: Across both saccade types, ES adolescents responded more slowly than controls. As expected, control participants committed fewer errors on antisaccades during the monetary incentive condition relative to the no-incentive condition. By contrast, ES youths failed to show this incentive-related improvement on inhibitory control. No significant incentive effects were found with prepotent prosaccades trials in either group. Finally co-morbid psychopathology did not modulate the findings. Conclusions: These data suggest that youths with experience of early stress exhibit deficient modulation of inhibitory control by reward processes, in tandem with a reward-independent deficit in preparation for both automatic and controlled responses. These data may be relevant to interventions in ES youths. Published by Elsevier Ltd. C1 [Mueller, Sven C.; Korelitz, Katherine; Daniele, Teresa; Bemis, Jessica; Pine, Daniel S.; Ernst, Monique] NIMH, Sect Dev & Affect Neurosci, NIH, Bethesda, MD 20892 USA. [Mueller, Sven C.] Univ Ghent, Dept Expt Clin & Hlth Psychol, Ghent, Belgium. [Hardin, Michael G.] Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. [Dozier, Mary; Peloso, Elizabeth] Univ Delaware, Dept Psychol, Delaware, OH USA. [Maheu, Francoise S.] Univ Montreal, Dept Psychiat, Montreal, PQ H3C 3J7, Canada. [Maheu, Francoise S.] CHU Ste Justine, Res Ctr, Ste Justine, Canada. RP Mueller, SC (reprint author), Henri Dunantlaan 2, B-9000 Ghent, Belgium. EM Sven.Mueller@UGent.be FU Intramural NIH HHS [Z99 MH999999]; NIMH NIH HHS [R01 MH074374, R01 MH052135, R01 MH084135]; PHS HHS [NIMG 84135, NIMG 52135, NIMG 74374] NR 46 TC 12 Z9 12 U1 5 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2134 J9 CHILD ABUSE NEGLECT JI Child Abuse Negl. PD MAR PY 2012 VL 36 IS 3 BP 217 EP 225 DI 10.1016/j.chiabu.2011.10.010 PG 9 WC Family Studies; Psychology, Social; Social Work SC Family Studies; Psychology; Social Work GA 926IB UT WOS:000302823400003 PM 22425696 ER PT J AU Judd, LL AF Judd, Lewis L. TI DIMENSIONAL PARADIGM OF THE LONG-TERM COURSE OF UNIPOLAR MAJOR DEPRESSIVE DISORDER SO DEPRESSION AND ANXIETY LA English DT Article ID BRANCH COLLABORATIVE PROGRAM; WEEKLY SYMPTOMATIC STATUS; BIPOLAR-II DISORDERS; PSYCHOSOCIAL DISABILITY; NATURAL-HISTORY; FOLLOW-UP; RECOVERY; PSYCHOBIOLOGY C1 [Judd, Lewis L.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Judd, Lewis L.] NIMH, Bethesda, MD USA. RP Judd, LL (reprint author), Univ Calif San Diego, Dept Psychiat, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM ljudd@ucsd.edu NR 17 TC 5 Z9 5 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD MAR PY 2012 VL 29 IS 3 BP 167 EP 171 DI 10.1002/da.21934 PG 5 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 927JY UT WOS:000302904700001 PM 22511337 ER PT J AU Timpano, KR Rubenstein, LM Murphy, DL AF Timpano, Kiara R. Rubenstein, Liza M. Murphy, Dennis L. TI Phenomenological features and clinical impact of affective disorders in OCD: a focus on the bipolar disorder and ocd connection SO DEPRESSION AND ANXIETY LA English DT Article DE obsessive-compulsive disorder; comorbidity; bipolar disorder; depression; anxiety disorders ID OBSESSIVE-COMPULSIVE DISORDER; NATIONAL-COMORBIDITY-SURVEY; POSTTRAUMATIC-STRESS-DISORDER; DSM-III-R; MAJOR DEPRESSION; 12-MONTH PREVALENCE; SURVEY REPLICATION; GLOBAL ASSESSMENT; SCALE; RELIABILITY AB Background: Given the general population prevalence rates of obsessive compulsive disorder (OCD) and the affective disorders, one would expect the co-occurrence of these syndromes to be rare. Yet findings by our group and others have revealed extremely high rates of comorbidity in OCD with both depressive disorders (DD; 50%) and bipolar disorder (BPD; 10%). The current investigation sought to further clarify the role affective disorder comorbidity-particularly that with BPD-may play in the clinical expression of OCD. Method: A total of 605 individuals with OCD were evaluated with the Structured Clinical Interview for DSM-IV. The sample included three groups: BPD (bipolar I or II; N=79, 13.1%), DD (major depression or dysthymia; N=388, 64.1%), and NAD (no affective disorder comorbidity; N=138, 22.8%). Group-wise comparisons were conducted on comorbidity patterns, impairment measures, and clinical features of OCD. Results: Analyses revealed a graded severity pattern, with the BPD group as the most severe, followed by the DD group, and finally the NAD group. Severity was reflected by the total number of Axis I disorders (P<.01), the number of psychiatric hospitalizations (P<.001), impairment measures (Ps<.05), and OCD symptoms (P<.01). It is worth noting that the impairment and OCD symptom severity findings were not attributable to the higher level of nonmood disorder comorbidities in the BPD and DD groups. Conclusion: Those individuals with comorbid affective disorders, particularly BPD, represent a clinically severe group compared to those without such comorbidity. Clarifying the phenomenological features of OCD-affective disorder comorbidity has important etiological and treatment implications. Depression and Anxiety 29:226-233, 2012. (C) 2011 Wiley Periodicals Inc. C1 [Timpano, Kiara R.] Univ Miami, Dept Psychol, Coral Gables, FL 33146 USA. [Rubenstein, Liza M.; Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Timpano, KR (reprint author), Univ Miami, Dept Psychol, 5665 Ponce de Leon Blvd, Coral Gables, FL 33146 USA. EM kiaratimpano@gmail.com OI Timpano, Kiara/0000-0002-0665-8722 FU NIMH, NIH FX This research was supported by the Intramural Research Program of the NIMH, NIH. The authors thank F. J. McMahon for helpful discussions, as well as T. DeGuzman, B. L. Justement, and D. Kazuba for their contributions to this research. NR 50 TC 11 Z9 12 U1 2 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD MAR PY 2012 VL 29 IS 3 BP 226 EP 233 DI 10.1002/da.20908 PG 8 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 927JY UT WOS:000302904700009 PM 22109969 ER PT J AU Rouault, TA AF Rouault, Tracey A. TI Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease SO DISEASE MODELS & MECHANISMS LA English DT Editorial Material ID FE-S PROTEINS; CONGENITAL SIDEROBLASTIC ANEMIA; FRIEDREICHS-ATAXIA; SCAFFOLD PROTEIN; COMPLEX-I; LACTIC-ACIDOSIS; CAUSES MYOPATHY; DOMAIN PROTEIN; YEAST FRATAXIN; HOMEOSTASIS AB Iron-sulfur (Fe-S) clusters are ubiquitous cofactors composed of iron and inorganic sulfur. They are required for the function of proteins involved in a wide range of activities, including electron transport in respiratory chain complexes, regulatory sensing, photosynthesis and DNA repair. The proteins involved in the biogenesis of Fe-S clusters are evolutionarily conserved from bacteria to humans, and many insights into the process of Fe-S cluster biogenesis have come from studies of model organisms, including bacteria, fungi and plants. It is now clear that several rare and seemingly dissimilar human diseases are attributable to defects in the basic process of Fe-S cluster biogenesis. Although these diseases which include Friedreich's ataxia (FRDA), ISCU myopathy, a rare form of sideroblastic anemia, an encephalomyopathy caused by dysfunction of respiratory chain complex I and multiple mitochondrial dysfunctions syndrome - affect different tissues, a feature common to many of them is that mitochondrial iron overload develops as a secondary consequence of a defect in Fe-S cluster biogenesis. This Commentary outlines the basic steps of Fe-S cluster biogenesis as they have been defined in model organisms. In addition, it draws attention to refinements of the process that might be specific to the subcellular compartmentalization of Fe-S cluster biogenesis proteins in some eukaryotes, including mammals. Finally, it outlines several important unresolved questions in the field that, once addressed, should offer important clues into how mitochondrial iron homeostasis is regulated, and how dysfunction in Fe-S cluster biogenesis can contribute to disease. C1 NICHHD, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Bethesda, MD 20892 USA. EM Rouault@mail.nih.gov NR 83 TC 119 Z9 122 U1 4 U2 27 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 J9 DIS MODEL MECH JI Dis. Model. Mech. PD MAR PY 2012 VL 5 IS 2 BP 155 EP 164 DI 10.1242/dmm.009019 PG 10 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 927IA UT WOS:000302899700002 PM 22382365 ER PT J AU Trunova, S Giniger, E AF Trunova, Svetlana Giniger, Edward TI Absence of the Cdk5 activator p35 causes adult-onset neurodegeneration in the central brain of Drosophila SO DISEASE MODELS & MECHANISMS LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; ALZHEIMERS-DISEASE; NERVOUS-SYSTEM; IN-VIVO; AUTOPHAGY; PHOSPHORYLATION; DISRUPTION; NEURONS; DEATH; MELANOGASTER AB Altered function of Cdk5 kinase is associated with many forms of neurodegenerative disease in humans. We show here that inactivating the Drosophila Cdk5 ortholog, by mutation of its activating subunit, p35, causes adult-onset neurodegeneration in the fly. In the mutants, a vacuolar neuropathology is observed in a specific structure of the central brain, the 'mushroom body', which is the seat of olfactory learning and memory. Analysis of cellular phenotypes in the mutant brains reveals some phenotypes that resemble natural aging in control flies, including an increase in apoptotic and necrotic cell death, axonal fragmentation, and accumulation of autophagosomes packed with crystalline-like depositions. Other phenotypes are unique to the mutants, notably age-dependent swellings of the proximal axon of mushroom body neurons. Many of these phenotypes are also characteristic of mammalian neurodegenerative disease, suggesting a close relationship between the mechanisms of Cdk5-associated neurodegeneration in fly and human. Together, these results identify the cellular processes that are unleashed in the absence of Cdk5 to initiate the neurodegenerative program, and they provide a model that can be used to determine what part each process plays in the progression to ultimate degeneration. C1 [Trunova, Svetlana; Giniger, Edward] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. [Trunova, Svetlana; Giniger, Edward] NHGRI, NIH, Bethesda, MD 20892 USA. RP Giniger, E (reprint author), Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. EM ginigere@ninds.nih.gov RI Giniger, Edward/C-1764-2015 OI Giniger, Edward/0000-0002-8340-6158 FU NINDS, National Institutes of Health (NIH) [Z01 NS003106] FX This work was supported by the Basic Neuroscience Program of the Intramural Research Program, NINDS, National Institutes of Health (NIH) [Z01 NS003106]. NR 54 TC 10 Z9 12 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 1754-8403 J9 DIS MODEL MECH JI Dis. Model. Mech. PD MAR PY 2012 VL 5 IS 2 BP 210 EP 219 DI 10.1242/dmm.008847 PG 10 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 927IA UT WOS:000302899700007 PM 22228754 ER PT J AU Campa, D Kaaks, R Le Marchand, L Haiman, CA Travis, R Ziegler, RG Hunter, DJ Lindstrom, S Canzian, F AF Campa, D. Kaaks, R. Le Marchand, L. Haiman, C. A. Travis, R. Ziegler, R. G. Hunter, D. J. Lindstroem, S. Canzian, F. TI An Investigation of Interactions Between Genetic Variants and Established Risk Factors for Breast Cancer in the NCI Breast and Prostate Cancer Cohort Consortium (BPC3) SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 8th European Breast Cancer Conference (EBCC) CY MAR 21-24, 2012 CL Vienna, AUSTRIA SP European Canc Org (ECCO) C1 [Campa, D.; Kaaks, R.; Canzian, F.] German Canc Res Ctr, D-6900 Heidelberg, Germany. [Le Marchand, L.] Univ Hawaii, Canc Res Ctr, Honolulu, HI 96813 USA. [Haiman, C. A.] Univ So Calif, Los Angeles, CA USA. [Travis, R.] Univ Oxford, Canc Epidemiol Unit, Oxford, England. [Ziegler, R. G.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Hunter, D. J.; Lindstroem, S.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RI Campa, Daniele/K-1617-2016 OI Campa, Daniele/0000-0003-3220-9944 NR 0 TC 0 Z9 0 U1 0 U2 5 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 MAR PY 2012 VL 48 SU 1 BP S167 EP S168 PG 2 WC Oncology SC Oncology GA 926AV UT WOS:000302804600424 ER PT J AU Rowland, J AF Rowland, J. TI Cancer Survivorship: NCI research and insights into this new and growing area SO EUROPEAN JOURNAL OF CANCER LA English DT Meeting Abstract CT 8th European Breast Cancer Conference (EBCC) CY MAR 21-24, 2012 CL Vienna, AUSTRIA SP European Canc Org (ECCO) C1 [Rowland, J.] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD MAR PY 2012 VL 48 SU 1 BP S47 EP S47 PG 1 WC Oncology SC Oncology GA 926AV UT WOS:000302804600037 ER PT J AU Peters, JA Kenen, R Hoskins, LM Glenn, GM Kratz, C Greene, MH AF Peters, June A. Kenen, Regina Hoskins, Lindsey M. Glenn, Gladys M. Kratz, Christian Greene, Mark H. TI Close ties: an exploratory Colored Eco-Genetic Relationship Map (CEGRM) study of social connections of men in Familial Testicular Cancer (FTC) families SO HEREDITARY CANCER IN CLINICAL PRACTICE LA English DT Article ID GERM-CELL TUMORS; LONG-TERM SURVIVORS; QUALITY-OF-LIFE; HEREDITARY BREAST; BREAST/OVARIAN CANCER; MARITAL RELATIONSHIPS; HEALTH COMMUNICATION; RISK-FACTOR; YOUNG MEN; MICROLITHIASIS AB Background: Testicular cancer, while rare compared with other adult solid tumors, is the most common cancer in young men in northern Europe and North America. Risk factors include white race, positive family history, contralateral testicular cancer, cryptorchidism, infertility and testicular microlithiasis. As the genetic causes of familial clusters (Familial Testicular Cancer of FTC) are being sought, it is also important to understand the psycho-social experiences of members of FTC families. Methods: This is a cross-sectional examination via the Colored Eco-Genetic Relationship Map (CEGRM) of social connections reported by 49 men in FTC families participating in NCI research study 02-C-178. Results: The CEGRM was acceptable and feasible for use with men in FTC families, and valuable in understanding their social connections. These men have largely adjusted to the TC history in themselves and/or their relatives. They have considerable social and emotional support from family and friends, although there is wide variability in sources and types. Conclusions: The CEGRM focuses on men's social connections and close emotional bonds in FTC families. This action-oriented process of placing colored symbols on significant relationships uncovered previously under-appreciated emotions accompanying men's social exchanges. Most men in FTC families succeed in re-establishing a sense of normalcy in their lives and social connections, in the aftermath of a testicular cancer diagnosis. C1 [Peters, June A.; Hoskins, Lindsey M.; Glenn, Gladys M.; Kratz, Christian; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Rockville, MD 20852 USA. [Kenen, Regina] Coll New Jersey, Dept Sociol & Anthropol, Ewing, NJ USA. RP Peters, JA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, 6120 Execut Blvd, Rockville, MD 20852 USA. EM petersju@mail.nih.gov FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute within U.S. National Institutes of Health; Westat, Inc., Rockville, MD, USA [NO2-CP-11019-50, N02-CP-65504] FX This work was supported by the Division of Cancer Epidemiology and Genetics of the National Cancer Institute within the Intramural Research Programs of the U.S. National Institutes of Health, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD, USA. NR 72 TC 2 Z9 2 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1731-2302 J9 HERED CANCER CLIN PR JI Hered. Cancer Clin. Pract. PD MAR 1 PY 2012 VL 10 AR 2 DI 10.1186/1897-4287-10-2 PG 14 WC Oncology SC Oncology GA 926WO UT WOS:000302862800001 PM 22381132 ER PT J AU Sun, JX Horst, OV Bumgarner, R Lakely, B Somerman, MJ Zhang, H AF Sun, Jian-Xun Horst, Orapin V. Bumgarner, Roger Lakely, Bryce Somerman, Martha J. Zhang, Hai TI Laser capture microdissection enables cellular and molecular studies of tooth root development SO INTERNATIONAL JOURNAL OF ORAL SCIENCE LA English DT Article DE gene; laser capture microdissection; microarray; PCR; root ID EPITHELIAL-MESENCHYMAL INTERACTIONS; BONE MORPHOGENETIC PROTEINS; RICH AMELOGENIN PEPTIDE; RAT DENTAL FOLLICLE; STEM-CELLS; MACULAR DEGENERATION; GENE-EXPRESSION; FIBULIN-2 EXPRESSION; IN-VITRO; RNA AB Epithelial-mesenchymal interactions (EMIs) are critical for tooth development. Molecular mechanisms mediating these interactions in root formation is not well understood. Laser capture microdissection (LCM) and subsequent microarray analyses enable large scale in situ molecular and cellular studies of root formation but to date have been hindered by technical challenges of gaining intact histological sections of non-decalcified mineralized teeth or jaws with well-preserved RNA. Here, we describe a new method to overcome this obstacle that permits LCM of dental epithelia, adjacent mesenchyme, odontoblasts and cementoblasts from mouse incisors and molars during root development. Using this method, we obtained RNA samples of high quality and successfully performed microarray analyses. Robust differences in gene expression, as well as genes not previously associated with root formation, were identified. Comparison of gene expression data from microarray with real-time reverse transcriptase polymerase chain reaction (RT-PCR) supported our findings. These genes include known markers of dental epithelia, mesenchyme, cementoblasts and odontoblasts, as well as novel genes such as those in the fibulin family. In conclusion, our new approach in tissue preparation enables LCM collection of intact cells with well-preserved RNA allowing subsequent gene expression analyses using microarray and RT-PCR to define key regulators of tooth root development. International Journal of Oral Science (2012) 4, 7-13; doi:10.1038/ijos.2012.15; published online 16 March 2012 C1 [Sun, Jian-Xun] Sichuan Univ, State Key Lab Oral Dis, Chengdu 610064, Peoples R China. [Sun, Jian-Xun] Univ Washington, Dept Periodontol, Seattle, WA 98195 USA. [Horst, Orapin V.] Univ Calif San Francisco, Dept Prevent & Restorat Dent Sci, Div Endodont, San Francisco, CA 94143 USA. [Bumgarner, Roger] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Lakely, Bryce] Univ Washington, Dept Urol, Seattle, WA 98195 USA. [Somerman, Martha J.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Zhang, Hai] Univ Washington, Dept Restorat Dent, Seattle, WA 98195 USA. RP Zhang, H (reprint author), 1959 NE Pacific St,Box 357456, Seattle, WA 98195 USA. EM haizhang@u.washington.edu RI Bumgarner, Roger/K-3531-2015 OI Bumgarner, Roger/0000-0002-8168-6985 FU NIH [DE15109]; State Key Laboratory of Oral Diseases in Chengdu, China FX The authors would like to thank Dr Robert L Vessella and Dr Colm Morrissey in the Department of Urology, University of Washington for their technical support of LCM; Dr Theo Bammler, Dr Michael Coon and Dr Dick Beyer in the Department of Environmental and Occupational Health Sciences, University of Washington for their technical assistance in microarray analyses; Dr Brian Foster for his critical comments. This work is supported by NIH grant no. DE15109 to Dr Martha Somerman and a grant from the State Key Laboratory of Oral Diseases in Chengdu, China to Dr Hai Zhang. NR 59 TC 7 Z9 7 U1 0 U2 13 PU SICHUAN UNIV PI CHENGDU PA SICHUAN UNIV, CHENGDU, SICHUAN, 610064 00000, PEOPLES R CHINA SN 1674-2818 J9 INT J ORAL SCI JI Int. J. Oral Sci. PD MAR PY 2012 VL 4 IS 1 BP 7 EP 13 DI 10.1038/ijos.2012.15 PG 7 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 927RI UT WOS:000302927400002 PM 22422086 ER PT J AU Hong, SH Ren, L Mendoza, A Eleswarapu, A Khanna, C AF Hong, Sung-Hyeok Ren, Ling Mendoza, Arnulfo Eleswarapu, Ananth Khanna, Chand TI Apoptosis Resistance and PKC Signaling: Distinguishing Features of High and Low Metastatic Cells SO NEOPLASIA LA English DT Article ID BREAST-CANCER METASTASIS; TUMOR-CELLS; IN-VIVO; OSTEOSARCOMA PATIENTS; AKT ACTIVATION; EWINGS-SARCOMA; MAMMARY-TUMOR; LINKER EZRIN; MOUSE MODEL; REAL-TIME AB The complexity of the process of metastasis is widely recognized. We report herein on a recurrent feature of high compared to low metastatic cells that is linked to their ability to survive early after their arrival at secondary sites. Using novel fluorescent-based imaging strategies that assess tumor cell interaction with the lung microenvironment, we have determined that most high and low metastatic cells can be distinguished within 6 hours of their arrival in the lung and further that this difference is defined by the ability of highmetastatic cells to resist apoptosis at the secondary site. Despite the complexity of the metastatic cascade, the performance of cells during this critical window is highly defining of their metastatic proclivity. To explore mechanisms, we next evaluated biochemical pathways that may be linked to this survival phenotype in highly metastatic cells. Interestingly, we found no association between the Akt survival pathway and this metastatic phenotype. Of all pathways examined, only protein kinase C (PKC) activation was significantly linked to survival of highly metastatic cells. These data provide a conceptual understanding of a defining difference between high and low metastatic cells. The connection to PKC activation may provide a biologic rationale for the use of PKC inhibition in the prevention of metastatic progression. C1 [Hong, Sung-Hyeok; Ren, Ling; Mendoza, Arnulfo; Eleswarapu, Ananth; Khanna, Chand] NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Eleswarapu, Ananth] Howard Hughes Med Inst, NIH, Res Scholars Program, Bethesda, MD 20817 USA. RP Khanna, C (reprint author), NCI, Tumor & Metastasis Biol Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, 37 Convent Dr,Bldg 37,Room 2144, Bethesda, MD 20892 USA. EM khannac@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 authors declare no conflict of interest. NR 48 TC 7 Z9 8 U1 0 U2 4 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD MAR PY 2012 VL 14 IS 3 BP 249 EP + DI 10.1593/neo.111498 PG 13 WC Oncology SC Oncology GA 922HW UT WOS:000302539000008 PM 22496624 ER PT J AU Busser, BW Taher, L Kim, Y Tansey, T Bloom, MJ Ovcharenko, I Michelson, AM AF Busser, Brian W. Taher, Leila Kim, Yongsok Tansey, Terese Bloom, Molly J. Ovcharenko, Ivan Michelson, Alan M. TI A Machine Learning Approach for Identifying Novel Cell Type-Specific Transcriptional Regulators of Myogenesis SO PLOS GENETICS LA English DT Article ID COMMON ORGANIZATIONAL FEATURES; DROSOPHILA EMBRYONIC MESODERM; GENOME-WIDE DISCOVERY; GENE-EXPRESSION; MUSCLE PROGENITORS; DNA-BINDING; HEART ENHANCERS; HOMEOBOX GENE; HOX PROTEINS; TARGET GENES AB Transcriptional enhancers integrate the contributions of multiple classes of transcription factors (TFs) to orchestrate the myriad spatio-temporal gene expression programs that occur during development. A molecular understanding of enhancers with similar activities requires the identification of both their unique and their shared sequence features. To address this problem, we combined phylogenetic profiling with a DNA-based enhancer sequence classifier that analyzes the TF binding sites (TFBSs) governing the transcription of a co-expressed gene set. We first assembled a small number of enhancers that are active in Drosophila melanogaster muscle founder cells (FCs) and other mesodermal cell types. Using phylogenetic profiling, we increased the number of enhancers by incorporating orthologous but divergent sequences from other Drosophila species. Functional assays revealed that the diverged enhancer orthologs were active in largely similar patterns as their D. melanogaster counterparts, although there was extensive evolutionary shuffling of known TFBSs. We then built and trained a classifier using this enhancer set and identified additional related enhancers based on the presence or absence of known and putative TFBSs. Predicted FC enhancers were over-represented in proximity to known FC genes; and many of the TFBSs learned by the classifier were found to be critical for enhancer activity, including POU homeodomain, Myb, Ets, Forkhead, and T-box motifs. Empirical testing also revealed that the T-box TF encoded by org-1 is a previously uncharacterized regulator of muscle cell identity. Finally, we found extensive diversity in the composition of TFBSs within known FC enhancers, suggesting that motif combinatorics plays an essential role in the cellular specificity exhibited by such enhancers. In summary, machine learning combined with evolutionary sequence analysis is useful for recognizing novel TFBSs and for facilitating the identification of cognate TFs that coordinate cell type-specific developmental gene expression patterns. C1 [Busser, Brian W.; Kim, Yongsok; Tansey, Terese; Bloom, Molly J.; Michelson, Alan M.] NHLBI, Lab Dev Syst Biol, NIH, Bethesda, MD 20892 USA. [Taher, Leila; Ovcharenko, Ivan] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Busser, BW (reprint author), NHLBI, Lab Dev Syst Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM ovcharen@nih.gov; michelsonam@nhlbi.nih.gov FU NHLBI Division of Intramural Research; NIH, National Library of Medicine FX This work was funded by the NHLBI Division of Intramural Research (AMM) and the Intramural Research Program of the NIH, National Library of Medicine (IO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 124 TC 23 Z9 23 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2012 VL 8 IS 3 AR e1002531 DI 10.1371/journal.pgen.1002531 PG 21 WC Genetics & Heredity SC Genetics & Heredity GA 918MV UT WOS:000302254800012 PM 22412381 ER PT J AU Galanter, JM Fernandez-Lopez, JC Gignoux, CR Barnholtz-Sloan, J Fernandez-Rozadilla, C Via, M Hidalgo-Miranda, A Contreras, AV Figueroa, LU Raska, P Jimenez-Sanchez, G Zolezzi, IS Torres, M Ponte, CR Ruiz, Y Salas, A Nguyen, E Eng, C Borjas, L Zabala, W Barreto, G Gonzalez, FR Ibarra, A Taboada, P Porras, L Moreno, F Bigham, A Gutierrez, G Brutsaert, T Leon-Velarde, F Moore, LG Vargas, E Cruz, M Escobedo, J Rodriguez-Santana, J Rodriguez-Cintron, W Chapela, R Ford, JG Bustamante, C Seminara, D Shriver, M Ziv, E Burchard, EG Haile, R Parra, E Carracedo, A AF Galanter, Joshua Mark Carlos Fernandez-Lopez, Juan Gignoux, Christopher R. Barnholtz-Sloan, Jill Fernandez-Rozadilla, Ceres Via, Marc Hidalgo-Miranda, Alfredo Contreras, Alejandra V. Uribe Figueroa, Laura Raska, Paola Jimenez-Sanchez, Gerardo Silva Zolezzi, Irma Torres, Maria Ruiz Ponte, Clara Ruiz, Yarimar Salas, Antonio Nguyen, Elizabeth Eng, Celeste Borjas, Lisbeth Zabala, William Barreto, Guillermo Rondon Gonzalez, Fernando Ibarra, Adriana Taboada, Patricia Porras, Liliana Moreno, Fabian Bigham, Abigail Gutierrez, Gerardo Brutsaert, Tom Leon-Velarde, Fabiola Moore, Lorna G. Vargas, Enrique Cruz, Miguel Escobedo, Jorge Rodriguez-Santana, Jose Rodriguez-Cintron, William Chapela, Rocio Ford, Jean G. Bustamante, Carlos Seminara, Daniela Shriver, Mark Ziv, Elad Burchard, Esteban Gonzalez Haile, Robert Parra, Esteban Carracedo, Angel CA LACE Consortium TI Development of a Panel of Genome-Wide Ancestry Informative Markers to Study Admixture Throughout the Americas SO PLOS GENETICS LA English DT Article ID NUCLEOTIDE-POLYMORPHISM PANEL; POPULATION-STRUCTURE; AFRICAN-AMERICANS; HISPANIC/LATINO POPULATIONS; GENETIC RELATEDNESS; STARR COUNTY; MEXICO-CITY; ASSOCIATION; INFERENCE; LINKAGE AB Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four admixed populations by comparing ancestry estimates based on the AIMs panel to estimates based on genome-wide association study (GWAS) data. The panel provided balanced discriminatory power among the three ancestral populations and accurate estimates of individual ancestry proportions (R-2 > 0.9 for ancestral components with significant between-subject variance). Finally, we genotyped samples from 18 populations from Latin America using the AIMs panel and estimated variability in ancestry within and between these populations. This panel and its reference genotype information will be useful resources to explore population history of admixture in Latin America and to correct for the potential effects of population stratification in admixed samples in the region. C1 [Galanter, Joshua Mark; Gignoux, Christopher R.; Nguyen, Elizabeth; Eng, Celeste; Ziv, Elad; Burchard, Esteban Gonzalez] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Carlos Fernandez-Lopez, Juan; Hidalgo-Miranda, Alfredo; Contreras, Alejandra V.; Uribe Figueroa, Laura; Jimenez-Sanchez, Gerardo; Silva Zolezzi, Irma] Inst Nacl Med Genom, Mexico City, DF, Mexico. [Barnholtz-Sloan, Jill; Raska, Paola] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Fernandez-Rozadilla, Ceres; Torres, Maria; Ruiz Ponte, Clara; Ruiz, Yarimar; Salas, Antonio; Zabala, William; Taboada, Patricia; Porras, Liliana; Carracedo, Angel] Univ Santiago de Compostela, CIBERER, Fdn Publ Galega Med Xen SERGAS, Santiago De Compostela, Spain. [Via, Marc] Univ Barcelona, Barcelona, Spain. [Borjas, Lisbeth; Zabala, William] Univ Zulia, Maracaibo 4011, Venezuela. [Barreto, Guillermo] Univ Valle, Santiago De Cali, Colombia. [Rondon Gonzalez, Fernando] Univ Ind Santander, Bucaramanga, Colombia. [Ibarra, Adriana] Univ Antioquia, Medellin, Colombia. [Taboada, Patricia] Inst Invest Forenses, Sucre, Bolivia. [Porras, Liliana] Univ Tecnol Pereira, Pereira, Colombia. [Moreno, Fabian] Serv Med Legal Chile, Unidad Genet Forense, Santiago, Chile. [Bigham, Abigail] Univ Michigan, Ann Arbor, MI 48109 USA. [Gutierrez, Gerardo] Univ Colorado, Boulder, CO 80309 USA. [Brutsaert, Tom] Syracuse Univ, Syracuse, NY USA. [Leon-Velarde, Fabiola] Univ Peruana Cayetano Heredia, Lima, Peru. [Moore, Lorna G.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Vargas, Enrique] Univ Mayor de San Andres, La Paz, Bolivia. [Cruz, Miguel] Mexican Social Secur Inst IMSS, Ctr Med Nacl Siglo 21, Mexico City, DF, Mexico. [Escobedo, Jorge] Hosp Gen Reg 1, IMSS, Mexico City, DF, Mexico. [Rodriguez-Santana, Jose] Ctr Neumol Pediat, San Juan, PR USA. [Rodriguez-Cintron, William] VA Caribbean Hlth Syst, San Juan, PR USA. [Chapela, Rocio] INER, Mexico City, DF, Mexico. [Ford, Jean G.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Bustamante, Carlos] Stanford Univ, Stanford, CA 94305 USA. [Seminara, Daniela] NCI, Bethesda, MD 20892 USA. [Shriver, Mark] Penn State Univ, University Pk, PA 16802 USA. [Haile, Robert] Univ So Calif, Los Angeles, CA USA. [Parra, Esteban] Univ Toronto, Mississauga, ON L5L 1C6, Canada. RP Galanter, JM (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM joshua.galanter@ucsf.edu RI Hidalgo-Miranda, Alfredo/B-2123-2010; Ziv, Elad/L-5396-2014; Via, Marc/L-6511-2014; Fernandez, Juan Carlos/C-4976-2013; Salas, Antonio/E-3977-2012; Ruiz-Ponte, Clara/I-3849-2015; Contreras, Alejandra Virginia/E-7815-2013 OI Nguyen, Elizabeth/0000-0002-8070-6382; parra, esteban J/0000-0002-2057-8577; Hidalgo-Miranda, Alfredo/0000-0003-2315-3977; Carracedo, Angel/0000-0003-1085-8986; Via, Marc/0000-0002-9966-9921; Fernandez, Juan Carlos/0000-0003-3680-4193; Salas, Antonio/0000-0002-2336-702X; Ruiz-Ponte, Clara/0000-0002-2200-0162; Fernandez-Rozadilla, Ceres/0000-0001-7330-4804; Torres, Maria/0000-0002-2658-0133; Contreras, Alejandra Virginia/0000-0003-3653-5958 FU National Cancer Institute; National Cancer Institute, National Institutes of Health [HHSN261201000641P]; NIH [R01HL078885, K23HL004464, 5R01HL088133, R01HL079647, T32GM007546, 2KL2RR024130, T32GM007175]; American Asthma Foundation; Sandler Foundation; Canadian Institutes of Health Research; Banting and Best Diabetes Centre; Canada Foundation for Innovation; Ontario Innovation Trust; CONACYT [SALUD-2005-C02-14412, 2007-C01-71068]; Proyectos Estrategicos; Apoyo Financiero Fundacion IMSS; Fundacion Gonzalo Rio Arronte I, A.P. Mexico; FIS [PS09/02368]; Ralph Hewitt Fellowship FX This work was made possible by the Latin American Cancer Epidemiology (LACE) Consortium, which has been supported with travel/meeting grants from the National Cancer Institute and by Contract #HHSN261201000641P from the National Cancer Institute, National Institutes of Health. The GALA study was funded by the NIH (R01HL078885, K23HL004464, 5R01HL088133), the American Asthma Foundation, and the Sandler Foundation. The Mexico City type 2 diabetes study was funded in Canada by the Canadian Institutes of Health Research, the Banting and Best Diabetes Centre, the Canada Foundation for Innovation, and The Ontario Innovation Trust, and in Mexico by the following grants: CONACYT SALUD-2005-C02-14412 and 2007-C01-71068, Proyectos Estrategicos, Apoyo Financiero Fundacion IMSS, and Fundacion Gonzalo Rio Arronte I, A.P. Mexico. Samples in Latin America were collected and typed with funding support from FIS PS09/02368 (FEDER funding). Samples in Bolivia were collected with funding support from the National Institutes of Health (R01HL079647). JMG received support from the National Institutes of Health (T32GM007546, 2KL2RR024130) and the Ralph Hewitt Fellowship. EP is the recipient of a CIHR New Investigator Award. CRG was supported in part by NIH Training Grant T32GM007175. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 61 TC 70 Z9 75 U1 0 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2012 VL 8 IS 3 AR e1002554 DI 10.1371/journal.pgen.1002554 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 918MV UT WOS:000302254800030 PM 22412386 ER PT J AU Hill, NS Kadoya, R Chattoraj, DK Levin, PA AF Hill, Norbert S. Kadoya, Ryosuke Chattoraj, Dhruba K. Levin, Petra Anne TI Cell Size and the Initiation of DNA Replication in Bacteria SO PLOS GENETICS LA English DT Article ID ESCHERICHIA-COLI K-12; MEDIAL FTSZ RING; BACILLUS-SUBTILIS; CHROMOSOME-REPLICATION; DIVISION CYCLE; GROWTH-RATE; SALMONELLA-TYPHIMURIUM; PROTEIN DETERMINES; GENE; MUTANT AB In eukaryotes, DNA replication is coupled to the cell cycle through the actions of cyclin-dependent kinases and associated factors. In bacteria, the prevailing view, based primarily from work in Escherichia coli, is that growth-dependent accumulation of the highly conserved initiator, DnaA, triggers initiation. However, the timing of initiation is unchanged in Bacillus subtilis mutants that are,30% smaller than wild-type cells, indicating that achievement of a particular cell size is not obligatory for initiation. Prompted by this finding, we re-examined the link between cell size and initiation in both E. coli and B. subtilis. Although changes in DNA replication have been shown to alter both E. coli and B. subtilis cell size, the converse ( the effect of cell size on DNA replication) has not been explored. Here, we report that the mechanisms responsible for coordinating DNA replication with cell size vary between these two model organisms. In contrast to B. subtilis, small E. coli mutants delayed replication initiation until they achieved the size at which wild-type cells initiate. Modest increases in DnaA alleviated the delay, supporting the view that growth-dependent accumulation of DnaA is the trigger for replication initiation in E. coli. Significantly, although small E. coli and B. subtilis cells both maintained wild-type concentration of DnaA, only the E. coli mutants failed to initiate on time. Thus, rather than the concentration, the total amount of DnaA appears to be more important for initiation timing in E. coli. The difference in behavior of the two bacteria appears to lie in the mechanisms that control the activity of DnaA. C1 [Hill, Norbert S.; Levin, Petra Anne] Washington Univ, Dept Biol, St Louis, MO 63130 USA. [Kadoya, Ryosuke; Chattoraj, Dhruba K.] NCI, Lab Biochem & Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hill, NS (reprint author), Washington Univ, Dept Biol, Campus Box 1137, St Louis, MO 63130 USA. EM plevin@wustl.edu FU Public Health Services from NIH [GM64671]; CCR, NCI FX This work was supported by Public Health Services grant (GM64671) from the NIH to PAL and by Intramural Research Program, CCR, NCI, to RK and DKC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 70 TC 43 Z9 45 U1 1 U2 28 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2012 VL 8 IS 3 AR e1002549 DI 10.1371/journal.pgen.1002549 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 918MV UT WOS:000302254800025 PM 22396664 ER PT J AU Lill, CM Roehr, JT McQueen, MB Kavvoura, FK Bagade, S Schjeide, BMM Schjeide, LM Meissner, E Zauft, U Allen, NC Liu, T Schilling, M Anderson, KJ Beecham, G Berg, D Biernacka, JM Brice, A DeStefano, AL Do, CB Eriksson, N Factor, SA Farrer, MJ Foroud, T Gasser, T Hamza, T Hardy, JA Heutink, P Hill-Burns, EM Klein, C Latourelle, JC Maraganore, DM Martin, ER Martinez, M Myers, RH Nalls, MA Pankratz, N Payami, H Satake, W Scott, WK Sharma, M Singleton, AB Stefansson, K Toda, T Tung, JY Vance, J Wood, NW Zabetian, CP Young, P Tanzi, RE Khoury, MJ Zipp, F Lehrach, H Ioannidis, JPA Bertram, L AF Lill, Christina M. Roehr, Johannes T. McQueen, Matthew B. Kavvoura, Fotini K. Bagade, Sachin Schjeide, Brit-Maren M. Schjeide, Leif M. Meissner, Esther Zauft, Ute Allen, Nicole C. Liu, Tian Schilling, Marcel Anderson, Kari J. Beecham, Gary Berg, Daniela Biernacka, Joanna M. Brice, Alexis DeStefano, Anita L. Do, Chuong B. Eriksson, Nicholas Factor, Stewart A. Farrer, Matthew J. Foroud, Tatiana Gasser, Thomas Hamza, Taye Hardy, John A. Heutink, Peter Hill-Burns, Erin M. Klein, Christine Latourelle, Jeanne C. Maraganore, Demetrius M. Martin, Eden R. Martinez, Maria Myers, Richard H. Nalls, Michael A. Pankratz, Nathan Payami, Haydeh Satake, Wataru Scott, William K. Sharma, Manu Singleton, Andrew B. Stefansson, Kari Toda, Tatsushi Tung, Joyce Y. Vance, Jeffery Wood, Nick W. Zabetian, Cyrus P. Young, Peter Tanzi, Rudolph E. Khoury, Muin J. Zipp, Frauke Lehrach, Hans Ioannidis, John P. A. Bertram, Lars CA Genetic Epidemiology Parkinson's IPDGC Parkinson's Dis GWAS Consortium WTCCC2 TI Comprehensive Research Synopsis and Systematic Meta-Analyses in Parkinson's Disease Genetics: The PDGene Database SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; ALPHA-SYNUCLEIN; RISK-FACTORS; MUTATIONS; VARIANTS; SUSCEPTIBILITY; DATASETS; TRIALS; REGION; VPS35 C1 [Lill, Christina M.; Roehr, Johannes T.; Schjeide, Brit-Maren M.; Schjeide, Leif M.; Meissner, Esther; Zauft, Ute; Liu, Tian; Schilling, Marcel; Lehrach, Hans; Bertram, Lars] Max Planck Inst Mol Genet, Neuropsychiat Genet Grp, Dept Vertebrate Genom, D-14195 Berlin, Germany. [Lill, Christina M.; Bagade, Sachin; Allen, Nicole C.; Tanzi, Rudolph E.; Bertram, Lars] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Lill, Christina M.; Zipp, Frauke] Johannes Gutenberg Univ Mainz, Dept Neurol, Med Ctr, Mainz, Germany. [Lill, Christina M.; Young, Peter] Univ Hosp, Dept Neurol, Munster, Germany. [Roehr, Johannes T.; Schilling, Marcel] Free Univ Berlin, Dept Math & Comp Sci, Berlin, Germany. [McQueen, Matthew B.] Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. [Kavvoura, Fotini K.; Ioannidis, John P. A.] Univ Ioannina, Sch Med, Clin & Mol Epidemiol Unit, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Kavvoura, Fotini K.] Royal Berkshire Hosp, Ctr Diabet & Endocrinol, Reading RG1 5AN, Berks, England. [Kavvoura, Fotini K.] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Churchill Hosp, Oxford, England. [Liu, Tian] Max Planck Inst Human Dev, Berlin, Germany. [Anderson, Kari J.; Biernacka, Joanna M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Beecham, Gary; Martin, Eden R.; Scott, William K.; Vance, Jeffery] Univ Miami, Miller Sch Med, John P Hussman Inst Human Genom, Miami, FL 33136 USA. [Berg, Daniela; Gasser, Thomas; Sharma, Manu] Univ Tubingen, Dept Neurodegenerat Dis, Hertie Inst Clin Brain Res, Tubingen, Germany. [Berg, Daniela; Gasser, Thomas; Sharma, Manu] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany. [Brice, Alexis] INSERM, UMR S975, Paris, France. [Brice, Alexis] Univ Paris 06, Ctr Rech, Inst Cerveau & Moelle Epiniere, UMR S975, Paris, France. [Brice, Alexis] CNRS, UMR 7225, Paris, France. [Brice, Alexis] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, Paris, France. [DeStefano, Anita L.; Latourelle, Jeanne C.; Myers, Richard H.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [DeStefano, Anita L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Do, Chuong B.; Eriksson, Nicholas; Tung, Joyce Y.] 23andMe, Mountain View, CA USA. [Factor, Stewart A.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [Farrer, Matthew J.] Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. [Foroud, Tatiana; Pankratz, Nathan] Indiana Univ Sch Med, Indianapolis, IN USA. [Hamza, Taye; Hill-Burns, Erin M.; Payami, Haydeh] New York State Dept Hlth, Wadsworth Ctr, Albany, NY USA. [Hardy, John A.; Wood, Nick W.] UCL, Dept Mol Neurosci, UCL Inst Neurol, London, England. [Heutink, Peter] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Sect Med Genom, Amsterdam, Netherlands. [Klein, Christine] Univ Lubeck, Sect Clin & Mol Neurogenet, Dept Neurol, Lubeck, Germany. [Maraganore, Demetrius M.] NorthShore Univ Hlth Syst, Dept Neurol, Evanston, IL USA. [Martinez, Maria] Fac Med Toulouse, INSERM, UMR 1043, CPTP, F-31073 Toulouse, France. [Martinez, Maria] Univ Toulouse 3, F-31062 Toulouse, France. [Nalls, Michael A.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Satake, Wataru; Toda, Tatsushi] Kobe Univ, Grad Sch Med, Div Neurol Mol Brain Sci, Kobe, Hyogo 657, Japan. [Wood, Nick W.] UCL, UCL Genet Inst, London, England. [Stefansson, Kari] deCODE Genet, Reykjavik, Iceland. [Zabetian, Cyrus P.] Univ Washington, VA Puget Sound Hlth Care Syst, Seattle, WA USA. [Zabetian, Cyrus P.] Univ Washington, Dept Neurol, Seattle, WA USA. [Khoury, Muin J.] Ctr Dis Control & Prevent, Off Publ Hlth Genom, Atlanta, GA USA. [Ioannidis, John P. A.] Fdn Res & Technol Hellas, Biomed Res Inst, Ioannina, Greece. [Ioannidis, John P. A.] Tufts Univ, Sch Med, Ctr Genet Epidemiol & Modeling, Boston, MA 02111 USA. [Ioannidis, John P. A.] Tufts Univ, Sch Med, Tufts Clin & Translat Sci Inst, Boston, MA 02111 USA. [Ioannidis, John P. A.] Stanford Univ, Dept Med, Stanford Prevent Res Ctr, Sch Med, Stanford, CA 94305 USA. [Ioannidis, John P. A.] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Stanford, CA 94305 USA. RP Lill, CM (reprint author), Max Planck Inst Mol Genet, Neuropsychiat Genet Grp, Dept Vertebrate Genom, Ihnestr 73, D-14195 Berlin, Germany. EM lbertram@molgen.mpg.de RI Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; Traynor, Bryan/G-5690-2010; Schilling, Marcel/O-3169-2013; Zipp, Frauke/C-9968-2015; Lill, Christina/J-9449-2015; Bertram, Lars/K-3889-2015; Martinez, Maria/B-3111-2013; Wood, Nicholas/C-2505-2009; OI Zabetian, Cyrus/0000-0002-7739-4306; Schilling, Marcel/0000-0002-3453-7792; Zipp, Frauke/0000-0002-1231-1928; Lill, Christina/0000-0002-2805-1307; Bertram, Lars/0000-0002-0108-124X; Martinez, Maria/0000-0003-2180-4537; Wood, Nicholas/0000-0002-9500-3348; Latourelle, Jeanne/0000-0002-4218-9572; Myers, Richard/0000-0002-8365-2674; Burns, Gully/0000-0003-1493-865X FU Michael J. Fox Foundation for Parkinson's Disease (MJFF); Cure Alzheimer's Fund (CAF); National Alliance for Research on Schizophrenia and Depression (NARSAD); Prize4Life; EMD Serono; Deutscher Akademischer Austauschdienst (DAAD); Fidelity Biosciences Research Initiative (FBRI); German Ministry for Education and Research (BMBF); Tufts Clinical and Translational Science Institute (Tufts CTSI); National Institute of Health/National Center for Research Resources [UL1 RR025752]; Michael J. Fox Foundation; Edmond J. Safra Michael J. Fox Foundation Global Genetics Consortium Initiative; NIH [R01 NS 036960, R01CA141668, R01NS37167, 2R01 ES10751]; National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services [Z01 AG000949-02, Z01-ES101986]; U.S. Department of Defense [W81XWH-09-2-0128]; Volkswagen Foundation; Hermann and Lilly Schilling Foundation; Alnylam Pharmaceuticals; Medtronic; NorthShore University Health System; Cephalon; Merck-Serono; Novartis; Eisai; Mayo Clinic; deCODE FX The main funding for this study was provided by the Michael J. Fox Foundation for Parkinson's Disease (MJFF) with additional financial support by the Cure Alzheimer's Fund (CAF), the National Alliance for Research on Schizophrenia and Depression (NARSAD), Prize4Life, and EMD Serono (all to L Bertram). CM Lill was supported by a fellowship from the Deutscher Akademischer Austauschdienst (DAAD) and Fidelity Biosciences Research Initiative (FBRI). L Bertram is also supported by the German Ministry for Education and Research (BMBF). JPA Ioannidis was supported through the Tufts Clinical and Translational Science Institute (Tufts CTSI) under funding from the National Institute of Health/National Center for Research Resources (UL1 RR025752). Points of view or opinions in this paper are those of the authors and do not necessarily represent the official position or policies of the Tufts CTSI. M Sharma was supported by the Michael J. Fox Foundation. The NeuroGenetics Research Consortium GWAS [15] was funded by the Edmond J. Safra Michael J. Fox Foundation Global Genetics Consortium Initiative and NIH R01 NS 036960. The work of the International Parkinson's Disease Genomics Consortium (IPDGC) was supported in part by the Intramural Research Programs of the National Institute on Aging, National Institute of Neurological Disorders and Stroke, National Institute of Environmental Health Sciences, National Human Genome Research Institute, National Institutes of Health, Department of Health and Human Services: project numbers Z01 AG000949-02 and Z01-ES101986. In addition the work of the IPDGC was supported by the U.S. Department of Defense, award number W81XWH-09-2-0128. Portions of the work of the IPDGC utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov). T Foroud received funds from the National Institutes of Health (R01CA141668 and R01NS37167). C Klein is the recipient of a career development award from the Volkswagen Foundation and from the Hermann and Lilly Schilling Foundation. DM Maraganore acknowledges active funding support from the National Institutes of Health (2R01 ES10751), Alnylam Pharmaceuticals, Medtronic, and NorthShore University Health System. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; CB Do, N Eriksson, and JY Tung are employed by 23andMe and own stock options in the company. MJ Farrer and Mayo Foundation received royalties from H. Lundbeck A/S and Isis Pharmaceuticals. In addition, MJ Farrer has received an honorarium for a seminar at Genzyme. T Gasser has received consultancy fees from Cephalon and Merck-Serono, grants from Novartis, payments for lectures including service on speakers' bureaus from Boehringer Ingelheim, Merck-Serono, UCB, and Valean, and holds patents NGFN2 and KASPP. JA Hardy has received consulting fees or honoraria from Eisai and his institute has received consulting fees or honoraria from Merck-Serono. DM Maraganore has received extramural research funding support from the National Institutes of Health (2R01 ES10751), the Michael J. Fox Foundation (Linked Efforts to Accelerate Parkinson Solutions Award, Edmond J. Safra Global Genetics Consortia Award), and from Alnylam Pharmaceuticals and Medtronic (observational studies of Parkinson's disease). DM Maraganore has also received intramural research funding support from the Mayo Clinic and from NorthShore University Health System. DM Maraganore filed a provisional patent for a method to predict Parkinson's disease. This provisional patent is unlicensed. He also filed a provisional patent for a method to treat neurodegenerative disorders. That provisional patent has been licensed to Alnylam Pharmaceuticals and DM Maraganore has received royalty payments in total of less than $20,000. K Stefansson has received grants from deCODE. NR 34 TC 224 Z9 226 U1 7 U2 36 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2012 VL 8 IS 3 AR e1002548 DI 10.1371/journal.pgen.1002548 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 918MV UT WOS:000302254800024 PM 22438815 ER PT J AU Pattaro, C Kottgen, A Teumer, A Garnaas, M Boger, CA Fuchsberger, C Olden, M Chen, MH Tin, A Taliun, D Li, M Gao, XY Gorski, M Yang, Q Hundertmark, C Foster, MC O'Seaghdha, CM Glazer, N Isaacs, A Liu, CT Smith, AV O'Connell, JR Struchalin, M Tanaka, T Li, G Johnson, AD Gierman, HJ Feitosa, M Hwang, SJ Atkinson, EJ Lohman, K Cornelis, MC Johansson, A Tonjes, A Dehghan, A Chouraki, V Holliday, EG Sorice, R Kutalik, Z Lehtimaki, T Esko, T Deshmukh, H Ulivi, S Chu, AY Murgia, F Trompet, S Imboden, M Kollerits, B Pistis, G Harris, TB Launer, LJ Aspelund, T Eiriksdottir, G Mitchell, BD Boerwinkle, E Schmidt, H Cavalieri, M Rao, M Hu, FB Demirkan, A Oostra, BA de Andrade, M Turner, ST Ding, JZ Andrews, JS Freedman, BI Koenig, W Illig, T Doring, A Wichmann, HE Kolcic, I Zemunik, T Boban, M Minelli, C Wheeler, HE Igl, W Zaboli, G Wild, SH Wright, AF Campbell, H Ellinghaus, D Nothlings, U Jacobs, G Biffar, R Endlich, K Ernst, F Homuth, G Kroemer, HK Nauck, M Stracke, S Volker, U Volzke, H Kovacs, P Stumvoll, M Magi, R Hofman, A Uitterlinden, AG Rivadeneira, F Aulchenko, YS Polasek, O Hastie, N Vitart, V Helmer, C Wang, JJ Ruggiero, D Bergmann, S Kahonen, M Viikari, J Nikopensius, T Province, M Ketkar, S Colhoun, H Doney, A Robino, A Giulianini, F Kramer, BK Portas, L Ford, I Buckley, BM Adam, M Thun, GA Paulweber, B Haun, M Sala, C Metzger, M Mitchell, P Ciullo, M Kim, SK Vollenweider, P Raitakari, O Metspalu, A Palmer, C Gasparini, P Pirastu, M Jukema, JW Probst-Hensch, NM Kronenberg, F Toniolo, D Gudnason, V Shuldiner, AR Coresh, J Schmidt, R Ferrucci, L Siscovick, DS van Duijn, CM Borecki, I Kardia, SLR Liu, YM Curhan, GC Rudan, I Gyllensten, U Wilson, JF Franke, A Pramstaller, PP Rettig, R Prokopenko, I Witteman, JCM Hayward, C Ridker, P Parsa, A Bochud, M Heid, IM Goessling, W Chasman, DI Kao, WHL Fox, CS AF Pattaro, Cristian Koettgen, Anna Teumer, Alexander Garnaas, Maija Boeger, Carsten A. Fuchsberger, Christian Olden, Matthias Chen, Ming-Huei Tin, Adrienne Taliun, Daniel Li, Man Gao, Xiaoyi Gorski, Mathias Yang, Qiong Hundertmark, Claudia Foster, Meredith C. O'Seaghdha, Conall M. Glazer, Nicole Isaacs, Aaron Liu, Ching-Ti Smith, Albert V. O'Connell, Jeffrey R. Struchalin, Maksim Tanaka, Toshiko Li, Guo Johnson, Andrew D. Gierman, Hinco J. Feitosa, Mary Hwang, Shih-Jen Atkinson, Elizabeth J. Lohman, Kurt Cornelis, Marilyn C. Johansson, Asa Toenjes, Anke Dehghan, Abbas Chouraki, Vincent Holliday, Elizabeth G. Sorice, Rossella Kutalik, Zoltan Lehtimaeki, Terho Esko, Tonu Deshmukh, Harshal Ulivi, Sheila Chu, Audrey Y. Murgia, Federico Trompet, Stella Imboden, Medea Kollerits, Barbara Pistis, Giorgio Harris, Tamara B. Launer, Lenore J. Aspelund, Thor Eiriksdottir, Gudny Mitchell, Braxton D. Boerwinkle, Eric Schmidt, Helena Cavalieri, Margherita Rao, Madhumathi Hu, Frank B. Demirkan, Ayse Oostra, Ben A. de Andrade, Mariza Turner, Stephen T. Ding, Jingzhong Andrews, Jeanette S. Freedman, Barry I. Koenig, Wolfgang Illig, Thomas Doering, Angela Wichmann, H. -Erich Kolcic, Ivana Zemunik, Tatijana Boban, Mladen Minelli, Cosetta Wheeler, Heather E. Igl, Wilmar Zaboli, Ghazal Wild, Sarah H. Wright, Alan F. Campbell, Harry Ellinghaus, David Nothlings, Ute Jacobs, Gunnar Biffar, Reiner Endlich, Karlhans Ernst, Florian Homuth, Georg Kroemer, Heyo K. Nauck, Matthias Stracke, Sylvia Voelker, Uwe Voelzke, Henry Kovacs, Peter Stumvoll, Michael Magi, Reedik Hofman, Albert Uitterlinden, Andre G. Rivadeneira, Fernando Aulchenko, Yurii S. Polasek, Ozren Hastie, Nick Vitart, Veronique Helmer, Catherine Wang, Jie Jin Ruggiero, Daniela Bergmann, Sven Kaehoenen, Mika Viikari, Jorma Nikopensius, Tiit Province, Michael Ketkar, Shamika Colhoun, Helen Doney, Alex Robino, Antonietta Giulianini, Franco Kraemer, Bernhard K. Portas, Laura Ford, Ian Buckley, Brendan M. Adam, Martin Thun, Gian-Andri Paulweber, Bernhard Haun, Margot Sala, Cinzia Metzger, Marie Mitchell, Paul Ciullo, Marina Kim, Stuart K. Vollenweider, Peter Raitakari, Olli Metspalu, Andres Palmer, Colin Gasparini, Paolo Pirastu, Mario Jukema, J. Wouter Probst-Hensch, Nicole M. Kronenberg, Florian Toniolo, Daniela Gudnason, Vilmundur Shuldiner, Alan R. Coresh, Josef Schmidt, Reinhold Ferrucci, Luigi Siscovick, David S. van Duijn, Cornelia M. Borecki, Ingrid Kardia, Sharon L. R. Liu, Yongmei Curhan, Gary C. Rudan, Igor Gyllensten, Ulf Wilson, James F. Franke, Andre Pramstaller, Peter P. Rettig, Rainer Prokopenko, Inga Witteman, Jacqueline C. M. Hayward, Caroline Ridker, Paul Parsa, Afshin Bochud, Murielle Heid, Iris M. Goessling, Wolfram Chasman, Daniel I. Kao, W. H. Linda Fox, Caroline S. CA CARDIoGRAM Consortium ICBP Consortium CARe Consortium WTCCC2 TI Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function SO PLOS GENETICS LA English DT Article ID GLOMERULAR-FILTRATION-RATE; RISK POPULATION COHORTS; GENE-EXPRESSION; SERUM CREATININE; COLLABORATIVE METAANALYSIS; HIGHER ALBUMINURIA; DISEASE; ZEBRAFISH; ORGANIZATION; VARIANTS AB Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genomewide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. 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[Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Schmidt, Helena] Med Univ Graz, Austrian Stroke Prevent Study, Inst Mol Biol & Biochem, Graz, Austria. [Schmidt, Helena] Med Univ Graz, Dept Neurol, Graz, Austria. [Cavalieri, Margherita; Schmidt, Reinhold] Med Univ Graz, Austrian Stroke Prevent Study, Univ Clin Neurol, Dept Special Neurol, Graz, Austria. [Rao, Madhumathi] Tufts Univ, Sch Med, Tufts Med Ctr, Tufts Evidence Practice Ctr,Div Nephrol, Boston, MA 02111 USA. [Turner, Stephen T.] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA. [Ding, Jingzhong] Wake Forest Sch Med, Dept Internal Med Geriatr, Winston Salem, NC USA. [Andrews, Jeanette S.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Freedman, Barry I.] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA. [Koenig, Wolfgang] Univ Ulm Klinikum, Abt Innere 2, Ulm, Germany. [Illig, Thomas; Doering, Angela] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Wichmann, H. -Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Wichmann, H. -Erich] Klinikum Grosshadern, Neuherberg, Germany. [Kolcic, Ivana; Zemunik, Tatijana; Boban, Mladen] Univ Split, Sch Med, Croatian Ctr Global Hlth, Split, Croatia. [Wheeler, Heather E.; Kim, Stuart K.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Wheeler, Heather E.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Wild, Sarah H.; Campbell, Harry; Rudan, Igor; Wilson, James F.] Univ Edinburgh, Sch Med, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Wright, Alan F.; Hastie, Nick; Vitart, Veronique; Hayward, Caroline] Western Gen Hosp, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Ellinghaus, David; Nothlings, Ute; Jacobs, Gunnar; Franke, Andre] Univ Kiel, Inst Clin Mol Biol, Kiel, Germany. [Nothlings, Ute; Jacobs, Gunnar] Univ Hosp Schleswig Holstein, Popgen Biobank, Kiel, Germany. [Biffar, Reiner] Ernst Moritz Arndt Univ Greifswald, Clin Prosthodont Dent Gerostomatol & Mat Sci, Greifswald, Germany. [Endlich, Karlhans] Ernst Moritz Arndt Univ Greifswald, Inst Anat & Cell Biol, Greifswald, Germany. [Kroemer, Heyo K.] Ernst Moritz Arndt Univ Greifswald, Inst Pharmacol, Greifswald, Germany. [Nauck, Matthias] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, Greifswald, Germany. [Stracke, Sylvia] Ernst Moritz Arndt Univ Greifswald, Clin Internal Med A, Greifswald, Germany. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Greifswald, Germany. [Kovacs, Peter] Univ Leipzig, Dept Med, Leipzig, Germany. [Magi, Reedik; Prokopenko, Inga] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. [Magi, Reedik; Prokopenko, Inga] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. [Uitterlinden, Andre G.; Rivadeneira, Fernando] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Polasek, Ozren] Univ Split, Fac Med, Croatian Ctr Global Hlth, Split, Croatia. [Helmer, Catherine] Univ Bordeaux 2, INSERM U897, ISPED, F-33076 Bordeaux, France. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Ctr Vis Res, Sydney, NSW 2006, Australia. [Wang, Jie Jin] Univ Melbourne, CERA, Melbourne, Vic, Australia. [Kaehoenen, Mika] Univ Tampere, Dept Clin Physiol, FIN-33101 Tampere, Finland. [Viikari, Jorma] Univ Turku, Dept Med, Turku, Finland. [Robino, Antonietta; Gasparini, Paolo] Univ Trieste, IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Kraemer, Bernhard K.] Univ Med Ctr Mannheim, Dept Med 5, Mannheim, Germany. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Buckley, Brendan M.] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Paulweber, Bernhard] Paracelsus Med Univ, Dept Internal Med 1, Salzburg, Austria. [Metzger, Marie] Univ Paris 11, CESP Team 10, Inserm UMRS 1018, Villejuif, France. [Vollenweider, Peter] CHU Vaudois, Dept Internal Med, Lausanne, Switzerland. [Raitakari, Olli] Univ Turku, Turku Univ Hosp, Dept Clin Physiol, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland. [Palmer, Colin] Univ Dundee, Ninewells Hosp & Med Sch, Biomed Res Inst, Dundee DD1 9SY, Scotland. [Jukema, J. Wouter] ICIN, Utrecht, Netherlands. [Jukema, J. Wouter] Einthoven Lab Expt Vasc Med, Leiden, Netherlands. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Coresh, Josef; Kao, W. H. Linda] Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD USA. [Kardia, Sharon L. R.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, Greifswald, Germany. [Parsa, Afshin] Univ Maryland, Sch Med, Div Nephrol, Baltimore, MD 21201 USA. [Bochud, Murielle] Univ Lausanne, CH-1066 Epalinges, Switzerland. [Bochud, Murielle] CHU Vaudois, Univ Inst Social & Prevent Med, Epalinges, Switzerland. [Goessling, Wolfram] Brigham & Womens Hosp, Dept Internal Med, Div Genet, Boston, MA USA. [Goessling, Wolfram] Brigham & Womens Hosp, Dept Internal Med, Div Gastroenterol, Boston, MA USA. [Goessling, Wolfram] Harvard Univ, Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA USA. RP Pattaro, C (reprint author), Univ Lubeck, European Acad Bozen Bolzano EURAC, Inst Med Genet, Bolzano, Italy. EM wkao@jhsph.edu; foxca@nhlbi.nih.gov RI Colaus, PsyColaus/K-6607-2013; Aulchenko, Yurii/M-8270-2013; Yang, Qiong/G-5438-2014; Pramstaller, Peter/C-2357-2008; Johansson, Asa/G-5270-2011; EHRET, Georg/A-9532-2009; Wang, Jie Jin/P-1499-2014; Kronenberg, Florian/B-1736-2008; Mitchell, Paul/P-1498-2014; HELMER, Catherine/I-6581-2015; Gudnason, Vilmundur/K-6885-2015; Wilson, James F/A-5704-2009; Kottgen, Anna/D-2920-2012; Palmer, Colin/C-7053-2008; Aspelund, Thor/C-5983-2008; Rudan, Igor/I-1467-2012; Li, Guo/E-5613-2012; Fuchsberger, Christian/C-9646-2010; Ellinghaus, David/G-4467-2012; Cavalieri, Margherita/G-8053-2012; Nothlings, Ute/B-2713-2010; Endlich, Karlhans/G-5485-2013; Johnson, Andrew/G-6520-2013; Ulivi, Sheila/H-3700-2013; Polasek, Ozren/B-6002-2011; Rivadeneira, Fernando/O-5385-2015; Prokopenko, Inga/H-3241-2014; Smith, Albert/K-5150-2015; ruggiero, daniela/K-5638-2016; Study, GoDARTS/K-9448-2016; Bochud, Murielle/A-3981-2010; Hayward, Caroline/M-8818-2016; Franke, Andre/B-2151-2010; Boban, Mladen/E-2777-2017; Kolcic, Ivana/E-2713-2017; Feitosa, Mary/K-8044-2012 OI Aulchenko, Yurii/0000-0002-7899-1575; Johansson, Asa/0000-0002-2915-4498; EHRET, Georg/0000-0002-5730-0675; Wang, Jie Jin/0000-0001-9491-4898; Kronenberg, Florian/0000-0003-2229-1120; HELMER, Catherine/0000-0002-5169-7421; Gudnason, Vilmundur/0000-0001-5696-0084; Wilson, James F/0000-0001-5751-9178; Palmer, Colin/0000-0002-6415-6560; Aspelund, Thor/0000-0002-7998-5433; Rudan, Igor/0000-0001-6993-6884; Ulivi, Sheila/0000-0003-3606-835X; Goessling, Wolfram/0000-0001-9972-1569; Klein, Ronald/0000-0002-4428-6237; Colhoun, Helen/0000-0002-8345-3288; Mitchell, Braxton/0000-0003-4920-4744; Dehghan, Abbas/0000-0001-6403-016X; Magi, Reedik/0000-0002-2964-6011; Chouraki, Vincent/0000-0002-4698-1794; Fuchsberger, Christian/0000-0002-5918-8947; Esko, Tonu/0000-0003-1982-6569; Thun, Gian Andri/0000-0003-4436-3455; Wheeler, Heather/0000-0003-1365-9667; Polasek, Ozren/0000-0002-5765-1862; Rivadeneira, Fernando/0000-0001-9435-9441; Prokopenko, Inga/0000-0003-1624-7457; Smith, Albert/0000-0003-1942-5845; ruggiero, daniela/0000-0003-3898-7827; Bochud, Murielle/0000-0002-5727-0218; Hayward, Caroline/0000-0002-9405-9550; Franke, Andre/0000-0003-1530-5811; Kolcic, Ivana/0000-0001-7918-6052; Feitosa, Mary/0000-0002-0933-2410 FU NIH [N01-AG-1-2100, R01 AG18728, R01 HL088119, U01 GM074518-04, U01 HL072515-06, U01 HL084756, NIH K12RR023250, HHSN268200625226C, 5R01HL08770003, 5R01HL08821502, HHSN268200782096C, 5R01HL08770002]; NIA (the Icelandic Heart Association) [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; Althingi (the Icelandic Parliament); University of Maryland General Clinical Research Center [M01 RR 16500]; Baltimore Veterans Administration Medical Center Geriatrics Research and Education Clinical Center; Paul Beeson Physician Faculty Scholars in Aging Program; Austrian Science Fund (FWF) [P20545-P05, P13180]; The Medical University of Graz; National Human Genome Research Institute [U01HG004402]; German Research Foundation [KO3598/2-1]; NIH (National Institute on Aging); National Center for Research Resources [M01RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491, R01DK058845]; Netherlands Organization for Scientific Research (NWO; Pioneergrant); Erasmus Medical Center; Centre for Medical Systems Biology (CMSB); Netherlands Kidney Foundation; NHLBI; NIDDK [5R01DK07568102, 5R01DK06833603]; National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; Affymetrix for genotyping services [N02-HL-6-4278]; Department of Medicine at Boston University School of Medicine and Boston Medical Center; National Heart, Lung, and Blood Institute of the National Institutes of Health [R01 HL-87660]; National Institutes of Aging; Children's Hospital, Boston, US [1 R01 DK075787-01A1]; German National Genome Research Net NGFN2; NGFNplus [01GS0823, 01GS0834]; Munich Center of Health Sciences (MC Health); Else Kroner-Fresenius-Stiftung [P48/08//A11/08]; Regensburg University Medical Center, Germany; Helmholtz Zentrum Munchen, German Research Center for Environmental Health; German Federal Ministry of Education and Research; State of Bavaria; University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center; NHS/HPFS; National Institute of Dental and Craniofacial Research [U01DE018993, U01DE018903]; Gene Environment-Association Studies (GENEVA) under NIH Genes; Environment and Health Initiative (GEI); NIH GEI [U01HG04424, U01HG004438]; Johns Hopkins University Center for Inherited Disease Research; National Cancer Institute [P01CA087969, P01CA055075, CA 047988]; Medical Research Council UK; Ministry of Science, Education, and Sport of the Republic of Croatia [108-1080315-0302]; Ministry of Health and Department of Educational Assistance; University and Research of the Autonomous Province of Bolzano; South Tyrolean Sparkasse Foundation; European Union [LSHG-CT-2006-018947]; Swedish Natural Sciences Research Council; European Union through EUROSPAN [LSHG-CT-2006-018947]; Foundation for Strategic Research (SSF); Linneaus Centre for Bioinformatics (LCB); NHS [DK66574]; Chief Scientist Office of the Scottish Government; Royal Society; German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN); Ministry of Science, Commerce, and Transportation of the State of Schleswig-Holstein; DFG excellence cluster "Inflammation at Interfaces"; German Research Council [KFO-152]; IFB (Integrated Research and Treatment Center) AdiposityDiseases [K7-37]; European Community [FP7/2007-2013]; ENGAGE [HEALTH-F4-2007-201413]; European Commission under a Marie Curie Intra-European; Netherlands Organisation of Scientific Research NWO Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases [014-93-015, RIDE2]; Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) [050-060-810]; Erasmus University, Rotterdam; The 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, the European Commission (DG XII); Municipality of Rotterdam; German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015 G]; NWO [918-76-619]; 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; Donald W. Reynolds Foundation; Fondation Leducq; Amgen; National Foundation for Alzheimer's disease; Institut Pasteur de Lille; Centre National de Genotypage; Fondation pour la Recherche Medicale; Caisse Nationale Maladie des Travailleurs Salaries; MGEN; Institut de la Longevite; Agence Francaise de Securite Sanitaire des Produits de Sante; Aquitaine and Bourgogne Regional Councils; Fondation de France; Ministry of Research/INSERM "Cohortes et collections de donnees biologiques; Australian RADGAC; Australian National Health; Medical Research Council, Canberra Australia [974159, 211069, 991407, 457349]; Australian National Health and Medical Research Council [512423, 475604, 529912]; Wellcome Trust, UK; Wellcome Trust Case Control Consortium 2 [085475/B/08/Z, 085475/08/Z]; Australian National Health and Medical Research Council; GlaxoSmithKline; Faculty of Biology and Medicine of Lausanne; Swiss National Science Foundation [33CSCO-122661, 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099]; Swiss School of Public Health Plus (SSPH+); Academy of Finland [117797, 121584, 126925]; Social Insurance Institution of Finland; University Hospital Medical; University Hospitals; Finnish Foundation of Cardiovascular Research; EGCUT [201413 ENGAGE, 212111 BBMRI, 205419 ECOGENE, 245536 OPENGENE]; Estonian Government [SF0180142s08]; European Union through the European Regional Development; Centre of Excellence in Genomics; Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection; Chief Scientist Office; Scottish Health Informatics Programme (SHIP); Telethon; FVG region; Fondo Trieste; EU [Vasoplus-037254]; Italian Ministry of Universities [FIRB -RBIN064YAT]; Assessorato Ricerca Regione Campania; Ente Parco Nazionale del Cilento e Vallo di Diano; Fondazione Banco di Napoli; Compagnia di San Paolo, Torino, Italy; Cariplo Fundation, Milano, Italy; Italian Ministry of Health Progetto Finalizzato; AstraZeneca; Italian Ministry of Education, University, and Research (MIUR) [5571/DSPAR/2002]; FIRB [718/Ric/2005]; Bristol-Myers Squibb, USA; Federal Office for Forest, Environment, and Landscape; Federal Office of Public Health, the Federal Office of Roads and Transport; canton's government of Aargau; Basel-Stadt; Basel-Land; Geneva; Luzern; Ticino; Zurich; Swiss Lung League; canton's Lung League of Basel Stadt/Basel Landschaft; Kamillo Eisner Stiftung; Genomics of Lipid-associated Disorders - GOLD; Austrian Genome Research Programme GEN-AU; AFAR/EMF; Stanford Dean's postdoctoral fellowship; NHGRI; NIGMS FX The AGES study has been funded by NIH contract N01-AG-1-2100, the NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Amish study was supported by grants and contracts from the NIH including R01 AG18728 (Amish Longevity Study), R01 HL088119 (Amish Calcification Study), U01 GM074518-04 (PAPI Study), U01 HL072515-06 (HAPI Study), U01 HL084756 and NIH K12RR023250 (University of Maryland MCRDP), the University of Maryland General Clinical Research Center, grant M01 RR 16500, the Baltimore Veterans Administration Medical Center Geriatrics Research and Education Clinical Center, and the Paul Beeson Physician Faculty Scholars in Aging Program. The ASPS research reported in this article was funded by the Austrian Science Fund (FWF) grant number P20545-P05 and P13180. The Medical University of Graz supported the databank of the ASPS. The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number, a component of the National Institutes of Health and NIH Roadmap for Medical Research. A Kottgen and C Hundertmark were supported by the grant KO3598/2-1 (Emmy Noether Programme) of the German Research Foundation. The BLSA was supported in part by the Intramural Research Program of the NIH (National Institute on Aging). 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, and grant numbers U01 HL080295 and R01 HL087652 from the National Heart, Lung, and Blood Institute, 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 http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The ERF study was supported by grants from the Netherlands Organization for Scientific Research (NWO; Pioneergrant), Erasmus Medical Center, the Centre for Medical Systems Biology (CMSB), and the Netherlands Kidney Foundation. The Family Heart Study (FHS) work was supported in part by NIH grants 5R01HL08770003, 5R01HL08821502 (M Province) from the NHLBI and 5R01DK07568102, 5R01DK06833603 from the NIDDK (I Borecki). The Framingham Heart Study research reported in this paper was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No.; N01-HC-25195) and its contract with Affymetrix for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The GENOA research was partially supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health R01 HL-87660. The Health Aging and Body Composition Study (Health ABC) was funded by the National Institutes of Aging. This research was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The GWAS 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. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. For the KORA F3 and F4 studies, the genetic epidemiological work was funded by the NIH subcontract from the Children's Hospital, Boston, US, (HE Wichmann, IM Heid, prime grant 1 R01 DK075787-01A1), the German National Genome Research Net NGFN2 and NGFNplus (H.E.Wichmann 01GS0823; WK project A3, number 01GS0834), the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ, and by the Else Kroner-Fresenius-Stiftung (P48/08//A11/08; CA Boger, BK Kramer). The kidney parameter measurements in F3 were funded by the Else Kroner-Fresenius-Stiftung (CA Boger, BK Kramer) and the Regensburg University Medical Center, Germany; in F4 by the University of Ulm, Germany (W Koenig). Genome-wide genotyping costs in F3 and F4 was in part funded by the Else Kroner-Fresenius-Stiftung (CA Boger, BK Kramer). De novo genotyping in F3 and F4 was funded by the Else Kroner-Fresenius-Stiftung (CA Boger, BK Kramer). The KORA research platform and the MONICA Augsburg studies were initiated and financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, by the German Federal Ministry of Education and Research, and by the State of Bavaria. Genotyping was performed in the Genome Analysis Center (GAC) of the Helmholtz Zentrum Munchen. The LINUX platform for computation was funded by the University of Regensburg for the Department of Epidemiology and Preventive Medicine at the Regensburg University Medical Center. The NHS/HPFS type 2 diabetes GWAS (U01HG004399) is a component of a collaborative project that includes 13 other GWAS (U01HG004738, U01HG004422, U01HG004402, U01HG004729, U01HG004726, U01HG004735, U01HG004415, U01HG004436, U01HG004423, U01HG004728, RFAHG006033; National Institute of Dental and Craniofacial Research: U01DE018993, U01DE018903) funded as part of the Gene Environment-Association Studies (GENEVA) under the NIH Genes, Environment and Health Initiative (GEI). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GENEVA Coordinating Center (U01HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information.; Genotyping was performed at the Broad Institute of MIT and Harvard, with funding support from the NIH GEI (U01HG04424), and Johns Hopkins University Center for Inherited Disease Research, with support from the NIH GEI (U01HG004438) and the NIH contract "High-throughput genotyping for studying the genetic contributions to human disease'' (HHSN268200782096C). Additional funding for the current research was provided by the National Cancer Institute (P01CA087969, P01CA055075) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058845). We thank the staff and participants of the NHS and HPFS for their dedication and commitment. The Korcula study was supported through the grants from the Medical Research Council UK to H Campbell, AF Wright, and I Rudan and by Ministry of Science, Education, and Sport of the Republic of Croatia to I Rudan (number 108-1080315-0302). The MICROS study was supported by the Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano, the South Tyrolean Sparkasse Foundation, and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). The Northern Swedish Population Health Study was supported by grants from the Swedish Natural Sciences Research Council, the European Union through the EUROSPAN project (contract no. LSHG-CT-2006-018947), the Foundation for Strategic Research (SSF), and the Linneaus Centre for Bioinformatics (LCB). The NHS renal function and albuminuria work was supported by DK66574. Additional funding for the current research was provided by the National Cancer Institute (P01CA087969, P01CA055075) and the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK058845). ORCADES was supported by the Chief Scientist Office of the Scottish Government, the Royal Society and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). DNA extractions were performed at the Wellcome Trust Clinical Research Facility in Edinburgh. The popgen study was supported by the German Ministry of Education and Research (BMBF) through the National Genome Research Network (NGFN) and the Ministry of Science, Commerce, and Transportation of the State of Schleswig-Holstein. The project has also received infrastructure support through the DFG excellence cluster "Inflammation at Interfaces." The Sorbs study was funded by grants from the German Research Council KFO-152 (to M Stumvoll) and the IFB (Integrated Research and Treatment Center) AdiposityDiseases (K7-37 to M Stumvoll and A Tonjes). We also thank Dr. Knut Krohn (Microarray Core Facility of the Interdisciplinary Centre for Clinical Research, University of Leipzig, Germany) for providing the genotyping platform. The research of Inga Prokopenko is funded in part through the European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project, grant agreement HEALTH-F4-2007-201413. R Magi acknowledges financial support from the European Commission under a Marie Curie Intra-European Fellowship. For the Rotterdam Study-I and Rotterdam Study-II, the GWAS was funded by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Consortium for Healthy Aging (NCHA) project nr. 050-060-810.; The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare, and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The Erasmus Computing Grid, Rotterdam (The Netherlands) and the national German MediGRID and Services@MediGRID part of the German D-Grid were both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G, for access to their grid resources. A Dehghan is supported by NWO grant (vici, 918-76-619). The Study of Health in Pomerania (SHIP) is part of the Community Medicine Research net of the University of Greifswald, Germany, 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. The Vis study was supported through the grants from the Medical Research Council UK to H Campbell, AF Wright, and I Rudan; and Ministry of Science, Education, and Sport of the Republic of Croatia to I Rudan (number 108-1080315-0302) and the European Union framework program 6 EUROSPAN project (contract no. LSHG-CT-2006-018947). The WGHS is supported by HL 043851 and HL69757 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen. The 3 City Study was supported by the National Foundation for Alzheimer's disease and related disorders, the Institut Pasteur de Lille and the Centre National de Genotypage. The 3 City Study was performed as part of a collaboration between the Institut National de la Sante et de la Recherche Medicale (Inserm), the Victor Segalen Bordeaux II University and Sanofi-Synthelabo. The Fondation pour la Recherche Medicale funded the preparation and initiation of the study. The 3C Study was also funded by the Caisse Nationale Maladie des Travailleurs Salaries, Direction Generale de la Sante, MGEN, Institut de la Longevite, Agence Francaise de Securite Sanitaire des Produits de Sante, the Aquitaine and Bourgogne Regional Councils, Fondation de France and the joint French Ministry of Research/INSERM "Cohortes et collections de donnees biologiques'' programme. Lille Genopole received an unconditional grant from Eisai. The Blue Mountains Eye Study (BMES) has been supported by the Australian RADGAC grant (1992-94) and Australian National Health and Medical Research Council, Canberra Australia (Grant Nos: 974159, 211069, 991407, 457349). The GWAS studies of BMES population are supported by the Australian National Health and Medical Research Council (Grant Nos: 512423, 475604, 529912) and the Wellcome Trust, UK (2008), as part of Wellcome Trust Case Control Consortium 2 (A Viswanathan, P McGuffin, P Mitchell, F Topouzis, P Foster, grant numbers 085475/B/08/Z and 085475/08/Z).; EG Holliday and JJ Wang are funded by the Australian National Health and Medical Research Council Fellowship Schemes. The CoLaus study received financial contributions from GlaxoSmithKline, the Faculty of Biology and Medicine of Lausanne, and the Swiss National Science Foundation (33CSCO-122661). M Bochud is supported by the Swiss School of Public Health Plus (SSPH+). The Cardiovascular Risk in Young Finns study (YFS) is supported by the Academy of Finland (grant no. 117797, 121584, and 126925), the Social Insurance Institution of Finland, University Hospital Medical funds to Tampere and Turku University Hospitals, and the Finnish Foundation of Cardiovascular Research. The Emil Aaaltonen Foundation (T Lehtimaki). EGCUT received support from FP7 grants ((201413 ENGAGE, 212111 BBMRI, 205419 ECOGENE, 245536 OPENGENE) and 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. The research of the FamHS-II was conducted in part using data and resources from the NHLBI Family Heart Study supported in part by NIH grant 5R01HL08770002. For the GoDARTs study, the Wellcome Trust provides support for Wellcome Trust United Kingdom Type 2 Diabetes Case Control Collection and the informatics support is provided by the Chief Scientist Office, and the Wellcome Trust funded Scottish Health Informatics Programme (SHIP). The INGI-Carlantino and INGI-FVG studies were supported by grants from Telethon, FVG region, and Fondo Trieste. The INGI-Cilento study was supported by grants from the EU (Vasoplus-037254), the Italian Ministry of Universities (FIRB -RBIN064YAT), the Assessorato Ricerca Regione Campania, the Ente Parco Nazionale del Cilento e Vallo di Diano, and the Fondazione Banco di Napoli to M Ciullo. The INGI - Val Borbera Study was supported from Compagnia di San Paolo, Torino, Italy, the Cariplo Fundation, Milano, Italy, and Italian Ministry of Health Progetto Finalizzato 2007 and 2009. The JUPITER trial and the genotyping were supported by AstraZeneca. The Ogliastra Genetic Park (OGP) - Replication Study and OGP - Talana study were supported by grants from the Italian Ministry of Education, University, and Research (MIUR) no. 5571/DSPAR/2002 and (FIRB) D. M. no. 718/Ric/2005. The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial was supported by an investigator initiated grant from Bristol-Myers Squibb, USA. The study was conducted, analyzed, and reported independently of the company. The SAPALDIA study was supported by the Swiss National Science Foundation (grants no 33CSCO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099), the Federal Office for Forest, Environment, and Landscape, the Federal Office of Public Health, the Federal Office of Roads and Transport, the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Zurich, the Swiss Lung League, the canton's Lung League of Basel Stadt/Basel Landschaft, Geneva, Ticino, and Zurich. The SAPHIR-study was partially supported by a grant from the Kamillo Eisner Stiftung to B Paulweber and by grants from the "Genomics of Lipid-associated Disorders - GOLD'' of the "Austrian Genome Research Programme GEN-AU" to F Kronenberg. eQTL analysis: HJ Gierman received support from the AFAR/EMF postdoctoral fellowship and the Stanford Dean's postdoctoral fellowship. HE Wheeler and SK Kim were supported by grants from the NIA, NHGRI and NIGMS. NR 57 TC 76 Z9 76 U1 4 U2 23 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2012 VL 8 IS 3 AR e1002584 DI 10.1371/journal.pgen.1002584 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 918MV UT WOS:000302254800059 PM 22479191 ER PT J AU Qayyum, R Snively, BM Ziv, E Nalls, MA Liu, YM Tang, WH Yanek, LR Lange, L Evans, MK Ganesh, S Austin, MA Lettre, G Becker, DM Zonderman, AB Singleton, AB Harris, TB Mohler, ER Logsdon, BA Kooperberg, C Folsom, AR Wilson, JG Becker, LC Reiner, AP AF Qayyum, Rehan Snively, Beverly M. Ziv, Elad Nalls, Michael A. Liu, Yongmei Tang, Weihong Yanek, Lisa R. Lange, Leslie Evans, Michele K. Ganesh, Santhi Austin, Melissa A. Lettre, Guillaume Becker, Diane M. Zonderman, Alan B. Singleton, Andrew B. Harris, Tamara B. Mohler, Emile R. Logsdon, Benjamin A. Kooperberg, Charles Folsom, Aaron R. Wilson, James G. Becker, Lewis C. Reiner, Alexander P. TI A Meta-Analysis and Genome-Wide Association Study of Platelet Count and Mean Platelet Volume in African Americans SO PLOS GENETICS LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; CORONARY-ARTERY; GENE-EXPRESSION; CAPPING PROTEIN; POPULATION; ACTIVATION; DISEASE; TRAITS; RISK; DIFFERENTIATION AB Several genetic variants associated with platelet count and mean platelet volume (MPV) were recently reported in people of European ancestry. In this meta-analysis of 7 genome-wide association studies (GWAS) enrolling African Americans, our aim was to identify novel genetic variants associated with platelet count and MPV. For all cohorts, GWAS analysis was performed using additive models after adjusting for age, sex, and population stratification. For both platelet phenotypes, meta-analyses were conducted using inverse-variance weighted fixed-effect models. Platelet aggregation assays in whole blood were performed in the participants of the GeneSTAR cohort. Genetic variants in ten independent regions were associated with platelet count (N = 16,388) with p < 5 x 10(-8) of which 5 have not been associated with platelet count in previous GWAS. The novel genetic variants associated with platelet count were in the following regions (the most significant SNP, closest gene, and p-value): 6p22 (rs12526480, LRRC16A, p = 9.1 x 10(-9)), 7q11 (rs13236689, CD36, p = 2.8 x 10(-9)), 10q21 (rs7896518, JMJD1C, p = 2.3 x 10(-1)2), 11q13 (rs477895, BAD, p = 4.9 x 10(-8)), and 20q13 (rs151361, SLMO2, p = 9.4 x 10(-9)). Three of these loci (10q21, 11q13, and 20q13) were replicated in European Americans (N = 14,909) and one (11q13) in Hispanic Americans (N = 3,462). For MPV (N = 4,531), genetic variants in 3 regions were significant at p, 5610 28, two of which were also associated with platelet count. Previously reported regions that were also significant in this study were 6p21, 6q23, 7q22, 12q24, and 19p13 for platelet count and 7q22, 17q11, and 19p13 for MPV. The most significant SNP in 1 region was also associated with ADP-induced maximal platelet aggregation in whole blood (12q24). Thus through a meta-analysis of GWAS enrolling African Americans, we have identified 5 novel regions associated with platelet count of which 3 were replicated in other ethnic groups. In addition, we also found one region associated with platelet aggregation that may play a potential role in atherothrombosis. C1 [Qayyum, Rehan; Yanek, Lisa R.; Becker, Diane M.; Becker, Lewis C.] Johns Hopkins Sch Med, GeneSTAR Res Program, Div Gen Internal Med, Baltimore, MD USA. [Snively, Beverly M.] Wake Forest Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Ziv, Elad] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Nalls, Michael A.; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC USA. [Tang, Weihong; Folsom, Aaron R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Lange, Leslie] Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC USA. [Evans, Michele K.] NIA, Hlth Dispar Res Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. [Ganesh, Santhi] Univ Michigan Hlth Syst, Div Cardiol, Ann Arbor, MI USA. [Austin, Melissa A.; Reiner, Alexander P.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Logsdon, Benjamin A.; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Program Biostat & Biomath, Seattle, WA 98104 USA. [Lettre, Guillaume] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Zonderman, Alan B.] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Baltimore, MD 21224 USA. [Mohler, Emile R.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Med, Jackson, MS 39216 USA. RP Qayyum, R (reprint author), Johns Hopkins Sch Med, GeneSTAR Res Program, Div Gen Internal Med, Baltimore, MD USA. EM rqayyum@jhmi.edu RI Singleton, Andrew/C-3010-2009; Ziv, Elad/L-5396-2014; OI Qayyum, Rehan/0000-0003-3086-8014; Zonderman, Alan B/0000-0002-6523-4778 FU National Heart, Lung, and Blood Institute [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C, HHSN268200782096C, R01 HL71862-06, 1K23HL105897-01]; NIH Roadmap for Medical Research; NIH, National Institute on Aging; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; NIA [1R01AG032098-01A1]; National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI consortia [U01 HL72518]; National Heart, Lung, and Blood Institute (NHLBI) through the STAMPEED consortia [R01 HL087698-01]; National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; Fondation de l'Institut de Cardiologie de Montreal; ARRA [N000949304]; NHGRI Genomics and Randomized Trials Network (GARNET) [U01 HG005152]; NIH Genes, Environment, and Health Initiative [GEI] [U01 HG004424]; GARNET Collaborative Research Group; [UL1RR025005]; [N01-HC-48047]; [N01-HC-95095]; [N01-HC-48048]; [N01-HC-48049]; [N01-HC-48050]; [N01-HC-45204]; [N01-HC-45205]; [N01-HC-05187]; [N01-HC-45134]; [N01-HC-95100]; [N01-HC-95170]; [N01-HC-95171]; [N01-HC-95172] FX The ARIC, CARDIA, and JHS studies contributed data, ancillary study data, and DNA samples through the Broad Institute (N01-HC-65226) to create genotype/phenotype data base for wide dissemination to the biomedical research community. The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The Coronary Artery Risk in Young Adults (CARDIA) was supported by grants to University of Alabama at Birmingham (N01-HC-48047, N01-HC-95095), University of Minnesota (N01-HC-48048), Northwestern University (N01-HC-48049), Kaiser Foundation Research Institute (N01-HC-48050), Tufts-New England Medical Center (N01-HC-45204), Wake Forest University (N01-HC-45205), Harbor-UCLA Research and Education Institute (N01-HC-05187), and University of California Irvine (N01-HC-45134, N01-HC-95100). The Jackson Heart Study (JHS) was supported by grants to Jackson State University (N01-HC-95170), University of Mississippi (N01-HC-95171), and Tougaloo College (N01-HC-95172). The Healthy Aging in Neighborhoods of Diversity across the Life Span Study (HANDLS) was supported by the Intramural Research Program of the NIH, National Institute on Aging and the National Center on Minority Health and Health Disparities (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). The Health ABC study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. 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. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. The GeneSTAR study was supported by the National Heart, Lung, and Blood Institute (NHLBI) through the PROGENI (U01 HL72518) and STAMPEED (R01 HL087698-01) consortia. The Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services, through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Additional support for this work was provided by the Fondation de l'Institut de Cardiologie de Montreal (to GL), and by NIH R01 HL71862-06 (to APR) NIH 1K23HL105897-01 (to RQ) and ARRA N000949304 (to APR). Funding support for WHI-GARNET was provided through the NHGRI Genomics and Randomized Trials Network (GARNET) (Grant Number U01 HG005152). Assistance with phenotype harmonization and genotype cleaning, as well as with general study coordination, was provided by the GARNET Coordinating Center (U01 HG005157).; Funding support for genotyping, which was performed at the Broad Institute of MIT and Harvard, was provided by the NIH Genes, Environment, and Health Initiative [GEI] (U01 HG004424). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; The authors wish to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the involved research institutions, study investigators, field staff, and study participants of Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk in Young Adults (CARDIA), Jackson Heart Study (JHS), and Broad Institute in creating the Candidate-gene Association Resource for biomedical research (CARe;http://public.nhlbi.nih.gov/GeneticsGenomics/home/care.aspx). The authors also wish to thank the investigators, staff, and participants of GeneSTAR, Health ABC, Healthy Aging in Neighborhoods of Diversity across the Life Span Study (HANDLS), and Women Health Initiative (WHI) for their important contributions. A listing of WHI investigators can be found at http://www.whiscience.org/publications/WHI_investigators_shortlist. pdf. The authors also wish to acknowledge the support of the GARNET Collaborative Research Group. NR 65 TC 37 Z9 40 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2012 VL 8 IS 3 AR e1002491 DI 10.1371/journal.pgen.1002491 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 918MV UT WOS:000302254800002 PM 22423221 ER PT J AU Vattikuti, S Guo, J Chow, CC AF Vattikuti, Shashaank Guo, Juen Chow, Carson C. TI Heritability and Genetic Correlations Explained by Common SNPs for Metabolic Syndrome Traits SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BODY-MASS INDEX; PHENOTYPIC CORRELATIONS; FAMILIAL RESEMBLANCE; BLOOD-PRESSURE; HUMAN HEIGHT; LOCI; POPULATION; LIPIDS; IMPACT AB We used a bivariate (multivariate) linear mixed-effects model to estimate the narrow-sense heritability (h(2)) and heritability explained by the common SNPs (h(g)(2)) for several metabolic syndrome (MetS) traits and the genetic correlation between pairs of traits for the Atherosclerosis Risk in Communities (ARIC) genome-wide association study (GWAS) population. MetS traits included body-mass index (BMI), waist-to-hip ratio (WHR), systolic blood pressure (SBP), fasting glucose (GLU), fasting insulin (INS), fasting trigylcerides (TG), and fasting high-density lipoprotein (HDL). We found the percentage of h(2) accounted for by common SNPs to be 58% of h(2) for height, 41% for BMI, 46% for WHR, 30% for GLU, 39% for INS, 34% for TG, 25% for HDL, and 80% for SBP. We confirmed prior reports for height and BMI using the ARIC population and independently in the Framingham Heart Study (FHS) population. We demonstrated that the multivariate model supported large genetic correlations between BMI and WHR and between TG and HDL. We also showed that the genetic correlations between the MetS traits are directly proportional to the phenotypic correlations. C1 [Vattikuti, Shashaank; Guo, Juen; Chow, Carson C.] Natl Inst Diabet & Digest & Kidney Dis NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Vattikuti, S (reprint author), Natl Inst Diabet & Digest & Kidney Dis NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM carsonc@mail.nih.gov RI Chow, Carson/A-7970-2009 FU NIH/NIDDK; National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health [HHSN268200625226C]; National Institutes of Health and NIH Roadmap for Medical Research [UL1RR025005]; National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University [N01-HC-25195, N02-HL-64278] FX This work was supported by the Intramural Research Program of the NIH/NIDDK. 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, N01-HC-55022, R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. The authors thank the staff and participants of the ARIC study for their important contributions. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Funding for SHARe genotyping was provided by NHLBI Contract N02-HL-64278. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 76 Z9 77 U1 2 U2 17 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD MAR PY 2012 VL 8 IS 3 AR e1002637 DI 10.1371/journal.pgen.1002637 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 918MV UT WOS:000302254800093 PM 22479213 ER PT J AU Jefferson, WN Patisaul, HB Williams, CJ AF Jefferson, Wendy N. Patisaul, Heather B. Williams, Carmen J. TI Reproductive consequences of developmental phytoestrogen exposure SO REPRODUCTION LA English DT Review ID SEXUALLY DIMORPHIC NUCLEUS; SPRAGUE-DAWLEY RATS; SOY FORMULA MILK; NEONATAL EXPOSURE; FEMALE RATS; ISOFLAVONE PHYTOESTROGENS; UTERINE ADENOCARCINOMA; ENDOCRINE DISRUPTORS; ESTROGENIC ACTIVITY; ALPHA-FETOPROTEIN AB Phytoestrogens, estrogenic compounds derived from plants, are ubiquitous in human and animal diets. These chemicals are generally much less potent than estradiol but act via similar mechanisms. The most common source of phytoestrogen exposure to humans is soybean-derived foods that are rich in the isoflavones genistein and daidzein. These isoflavones are also found at relatively high levels in soy-based infant formulas. Phytoestrogens have been promoted as healthy alternatives to synthetic estrogens and are found in many dietary supplements. The aim of this review is to examine the evidence that phytoestrogen exposure, particularly in the developmentally sensitive periods of life, has consequences for future reproductive health. Reproduction (2012) 143 247-260 C1 [Jefferson, Wendy N.; Williams, Carmen J.] NIEHS, Reprod Med Grp, Reprod & Dev Toxicol Lab, NIH,DHHS, Res Triangle Pk, NC 27709 USA. [Patisaul, Heather B.] N Carolina State Univ, Dept Biol, Raleigh, NC 27695 USA. RP Williams, CJ (reprint author), NIEHS, Reprod Med Grp, Reprod & Dev Toxicol Lab, NIH,DHHS, POB 12233,MD E4-05, Res Triangle Pk, NC 27709 USA. EM williamsc5@niehs.nih.gov FU NIH, National Institutes of Environmental Health Sciences [Z01-ES102405, R01-ES016001] FX This work was supported by the Intramural Research Program of the NIH, National Institutes of Environmental Health Sciences (Z01-ES102405, C J Williams) and by the NIH, National Institutes of Environmental Health Sciences (R01-ES016001, H B Patisaul). NR 128 TC 48 Z9 48 U1 5 U2 42 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1470-1626 J9 REPRODUCTION JI Reproduction PD MAR PY 2012 VL 143 IS 3 BP 247 EP 260 DI 10.1530/REP-11-0369 PG 14 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 927PR UT WOS:000302920900002 PM 22223686 ER PT J AU Hill, MJ Levy, G Levens, ED AF Hill, Micah J. Levy, Gary Levens, Eric D. TI Does exogenous LH in ovarian stimulation improve assisted reproduction success? An appraisal of the literature SO REPRODUCTIVE BIOMEDICINE ONLINE LA English DT Review DE assisted reproductive technology; follicle-stimulating hormone; human chorionic gonadotrophin; human menopausal gonadotrophin; luteinizing hormone ID IN-VITRO FERTILIZATION; HUMAN LUTEINIZING-HORMONE; HUMAN CHORIONIC-GONADOTROPIN; HUMAN MENOPAUSAL GONADOTROPIN; RECOMBINANT HUMAN FSH; INTRACYTOPLASMIC SPERM INJECTION; HIGHLY PURIFIED HMG; RANDOMIZED CONTROLLED-TRIAL; GNRH-ANTAGONIST PROTOCOL; OVULATION INDUCTION AB A review of the scientific literature on the use of exogenous LH in assisted reproductive technology was performed by searching the MEDLINE, PubMed and Cochrane online databases. Scientific evidence was reviewed comparing recombinant FSH-only protocols to protocols supplemented with exogenous LH activity: human menopausal gonadotrophin (HMG), recombinant LH and mid-follicular human chorionic gonadotrophin (HCG). Studies were further compared based on pituitary suppression with gonadotrophin-releasing hormone (GnRH) antagonist and agonist protocols. Primary focus was given to randomized controlled trials and meta-analyses. Data from hypogonadotrophic hypogonadal patients demonstrated the importance of LH activity for success of assisted reproduction treatment. However, the majority of normogonadotrophic patients had adequate endogenous LH to successfully drive ovarian steroidogenesis and oocyte maturation. Exogenous LH supplementation was consistently associated with higher peak oestradiol concentrations. The use of HMG in long GnRH agonist cycles was associated with a 3-4% increase in live birth rate. There was insufficient evidence to make definitive conclusions on the need for exogenous LH activity in GnRH antagonist cycles or the benefit of recombinant LH and HCG protocols. Poor responders and patients 35 years of age and older may benefit from exogenous LH. (C) 2012, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. C1 [Hill, Micah J.; Levy, Gary; Levens, Eric D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. [Levens, Eric D.] Shady Grove Fertil Reprod Sci Ctr, Rockville, MD USA. RP Levens, ED (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. EM Eric.Levens@Integramed.com FU NICHD, NIH, Bethesda, MD, USA FX This work was supported in part by the Program in Reproductive and Adult Endocrinology, NICHD, NIH, Bethesda, MD, USA. The authors would like to thank Mary E Ryan, MLS, National Institutes of Health Library, Bethesda for her assistance in performing literature searches for this manuscript. NR 85 TC 13 Z9 18 U1 1 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1472-6483 J9 REPROD BIOMED ONLINE JI Reprod. Biomed. Online PD MAR PY 2012 VL 24 IS 3 BP 261 EP 271 DI 10.1016/j.rbmo.2011.12.005 PG 11 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 929FM UT WOS:000303046700003 PM 22285265 ER PT J AU Singh, AK Seavey, CN Horvath, KA Mohiuddin, MM AF Singh, Avneesh K. Seavey, Caleb N. Horvath, Keith A. Mohiuddin, Muhammad M. TI Ex-vivo expanded baboon CD4+CD25Hi Treg cells suppress baboon anti-pig T and B cell immune response SO XENOTRANSPLANTATION LA English DT Article DE rapamycin; T regulatory cells; Treg; xenograft ID REGULATORY CELLS; IN-VITRO; DENDRITIC CELLS; PERIPHERAL-BLOOD; EXPANSION; RAPAMYCIN; TRANSPLANTATION; INFLAMMATION; ACTIVATION; PHENOTYPE AB Background: CD4(+) CD25(+) FoxP3(+) regulatory T (Treg) cells play an important role in regulating immune responses. A very small number of Treg cells are present in peripheral blood and lymphoid organs, but due to their ability to suppress the immune response, they have a high potential for immunotherapy in clinics. Successful ex-vivo expansion of naturally occurring CD4(+) CD25(+) T cells has been achieved after TCR stimulation in the presence of T cell growth factors. In this study, we evaluated the role of these Treg cells in suppressing proliferative response of baboon T and B cells to pig xenoantigens. Methods: Naturally occurring baboon CD4(+) CD25(+) regulatory T cells (nTreg) were sorted from peripheral blood and expanded in the presence of either anti-CD3/CD28 beads or irradiated pig peripheral blood mononuclear cells with IL-2. Treg cells were also enriched directly from CD4(+) T cells cultured in the presence of rapamycin (0.1-10 nm). Mixed lymphocyte culture and polyclonal B cell stimulation with ex-vivo Treg cells were performed to assess the function of ex-vivo expanded Treg cells. Results: The nTreg cells were expanded to more than 200-fold in 4 weeks and retained all the nTreg cell phenotypic characteristics, including high levels of FoxP3 expression. 2-fold increase in enrichment of CD4(+) CD25(+) FoxP3(+) Treg cells from CD4(+) cells was observed with rapamycin compared to cultures without rapamycin. The ex-vivo expanded Treg cells obtained from both methods were able to suppress the baboon anti-porcine xenogeneic T and B cell immune response in-vitro efficiently (more than 90% suppression at 1 : 1 ratio of T regulatory cells: T effector cells), and their suppression potential was retained even at 1 : 256 ratio. However, freshly isolated nTreg cells had only 70% suppression at 1 : 1 ratio, and their suppressive ability was reduced to <= 50% at 1 : 16 ratio. Furthermore, we have found that ex-vivo expanded Treg can also suppress the proliferation of B cells after polyclonal stimulation. Forty to 50 percent reduction in B cell proliferation was observed when ex-vivo expanded Treg cells were added to the culture at a 1 : 1 ratio. The addition of CD4(+) CD25 (Neg) cells however induced vigorous proliferation. Conclusion: Ex-vivo expanded CD4(+) CD25(+) FoxP3(+) Treg cells can be used to efficiently suppress xenogeneic immune responses by inhibiting T and B cell proliferation. These ex-vivo expanded Treg cells may also be used with other immunosuppressive agents to overcome xenograft rejection in preclinical xenotransplantation models. C1 [Singh, Avneesh K.; Seavey, Caleb N.; Horvath, Keith A.; Mohiuddin, Muhammad M.] NHLBI, CSRP, NIH, Bethesda, MD 20892 USA. RP Mohiuddin, MM (reprint author), NHLBI, CSRP, NIH, Rm B1D47G,MSC 1550,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM mohiuddinm@mail.nih.gov RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X NR 26 TC 10 Z9 12 U1 1 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD MAR-APR PY 2012 VL 19 IS 2 BP 102 EP 111 DI 10.1111/j.1399-3089.2012.00697.x PG 10 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 925XT UT WOS:000302796400005 PM 22497512 ER PT J AU Rao, M AF Rao, Malla TI The International Centers of Excellence for Malaria Research Foreward SO ACTA TROPICA LA English DT Editorial Material C1 NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Rao, M (reprint author), NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. EM MRao@niaid.nih.gov NR 0 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X J9 ACTA TROP JI Acta Trop. PD MAR PY 2012 VL 121 IS 3 SI SI BP 157 EP 157 DI 10.1016/j.actatropica.2011.07.009 PG 1 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 924CN UT WOS:000302668500001 PM 21819955 ER PT J AU Ceesay, SJ Bojang, KA Nwakanma, D Conway, DJ Koita, OA Doumbia, SO Ndiaye, D Coulibaly, TF Diakite, M Traore, SF Coulibaly, M Ndiaye, JL Sarr, O Gaye, O Konate, L Sy, N Faye, B Faye, O Sogoba, N Jawara, M Dao, A Poudiougou, B Diawara, S Okebe, J Sangare, L Abubakar, I Sissako, A Diarra, A Keita, M Kandeh, B Long, CA Fairhurst, RM Duraisingh, M Perry, R Muskavitch, MAT Valim, C Volkman, SK Wirth, DF Krogstad, DJ AF Ceesay, Serign J. Bojang, Kalifa A. Nwakanma, Davis Conway, David J. Koita, Ousmane A. Doumbia, Seydou O. Ndiaye, Daouda Coulibaly, Tinzana F. Diakite, Mahamadou Traore, Sekou F. Coulibaly, Mamadou Ndiaye, Jean-Louis Sarr, Ousmane Gaye, Oumar Konate, Lassana Sy, Ngayo Faye, Babacar Faye, Ousmane Sogoba, Nafomon Jawara, Musa Dao, Adama Poudiougou, Belco Diawara, Sory Okebe, Joseph Sangare, Lansana Abubakar, Ismaela Sissako, Aliou Diarra, Ayouba Keita, Moussa Kandeh, Balla Long, Carole A. Fairhurst, Rick M. Duraisingh, Manoj Perry, Robert Muskavitch, Marc A. T. Valim, Clarissa Volkman, Sarah K. Wirth, Dyann F. Krogstad, Donald J. TI Sahel, savana, riverine and urban malaria in West Africa: Similar control policies with different outcomes SO ACTA TROPICA LA English DT Article DE Artemisinin Combination Therapies; Long-Lasting Insecticide Treated bed nets; Entomologic inoculation rate; Intermittent preventive treatment of malaria during pregnancy; Transmission intensity; Multiplicity of infection ID PLASMODIUM-FALCIPARUM; ERADICATION; ELIMINATION; TRANSMISSION; FEASIBILITY; PROSPECTS; KENYA AB The study sites for the West African ICEMR are in three countries (The Gambia, Senegal, Mali) and are located within 750 km of each other. In addition, the National Malaria Control Programmes of these countries have virtually identical policies: (1) Artemisinin Combination Therapies (ACTs) for the treatment of symptomatic Plasmodium falciparum infection, (2) Long-Lasting Insecticide-treated bed Nets (LLINs) to reduce the Entomololgic Inoculation Rate (EIR), and (3) sulfadoxine-pyrimethamine for the Intermittent Preventive Treatment of malaria during pregnancy (IPTp). However, the prevalence of P. falciparum malaria and the status of malaria control vary markedly across the four sites with differences in the duration of the transmission season (from 4-5 to 10-11 months), the intensity of transmission (with EIRs from unmeasurably low to 4-5 per person per month), multiplicity of infection (from a mean of 1.0 to means of 2-5) and the status of malaria control (from areas which have virtually no control to areas that are at the threshold of malaria elimination). The most important priority is the need to obtain comparable data on the population-based prevalence, incidence and transmission of malaria before new candidate interventions or combinations of interventions are introduced for malaria control. (C) 2011 Elsevier B.V. All rights reserved. C1 [Krogstad, Donald J.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Ceesay, Serign J.; Bojang, Kalifa A.; Nwakanma, Davis; Conway, David J.; Jawara, Musa; Okebe, Joseph; Abubakar, Ismaela] MRC Labs, Int Ctr Excellence Malaria Res ICEMR W Africa, Fajara, Gambia. [Conway, David J.] London Sch Hyg & Trop Med, London WC1, England. [Koita, Ousmane A.; Doumbia, Seydou O.; Coulibaly, Tinzana F.; Diakite, Mahamadou; Traore, Sekou F.; Coulibaly, Mamadou; Sogoba, Nafomon; Dao, Adama; Poudiougou, Belco; Diawara, Sory; Sangare, Lansana; Sissako, Aliou; Diarra, Ayouba; Keita, Moussa] Uniivers Bamako, Bamako, Mali. [Ndiaye, Daouda; Ndiaye, Jean-Louis; Sarr, Ousmane; Gaye, Oumar; Konate, Lassana; Sy, Ngayo; Faye, Babacar; Faye, Ousmane] Uniivers Cheikh Anta Diop, Dakar, Senegal. [Long, Carole A.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Duraisingh, Manoj; Valim, Clarissa; Volkman, Sarah K.; Wirth, Dyann F.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Muskavitch, Marc A. T.] Boston Coll, Chestnut Hill, MA 02167 USA. RP Krogstad, DJ (reprint author), Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. EM krogstad@tulane.edu OI Conway, David/0000-0002-8711-3037 FU National Institutes of Allergy and Infectious Diseases (NIAID) [U19 AI 089696] FX The studies described here have been supported by a cooperative agreement from the National Institutes of Allergy and Infectious Diseases (NIAID U19 AI 089696) for an international center of excellence in malaria research (ICEMR) award to a consortium involving the University of Bamako in Mali, the University Cheikh Anta Diop in Senegal, the Medical Research Council (MRC) Laboratories in The Gambia, Harvard School of Public Health, Boston College, London School of Hygiene and Tropical Medicine and the Tulane School of Public Health and Tropical Medicine. We thank our many colleagues for administrative and financial support (Abdoulie Barry, Ron Cail, Salif Camara, Rosie Chavez, Abou Alassane Diallo, Khady Toure Diop, Ramona Gonski, Shannon Joyce, Dembo Kanteh, Glen McGugan, Carmen Mejia, Papa Alioune Ndao, Seybatou Magatte Ndaw, Peter Noble, Malla Rao, Brenda Rodriguez, Mamkumbah Sanneh, Moussa Dien Sarr, IP Singh, Paula Strickland, Don Van Noy, Joan Vivestomas, Tonu Wali, James Clint Welty, Kijuana Yarls), advice and mentoring (Tumani Corrah, Abarahmane Dia, Amadou Diallo, Souleymanne Mboup, Saliou Ndiaye, Omar Ndir), information technology and computing support (Christopher Whalen, Brian Moyer), public health and malaria control partnerships (Moussa Thior, Mrs. Adam Jagne Sonko, Claude-Emile Rwagacondo), and for generous access to their personal expertise (Jennifer Anderson, Thomas P. Eisele, Ivo Foppa, Nicholas Manoukis, Meredith McMorrow, David Parker, Robert Perry, Margaret Pinder, Jon Eric Tongren, Sixte Zigirumugabe). NR 31 TC 8 Z9 8 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X J9 ACTA TROP JI Acta Trop. PD MAR PY 2012 VL 121 IS 3 SI SI BP 166 EP 174 DI 10.1016/j.actatropica.2011.11.005 PG 9 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 924CN UT WOS:000302668500003 PM 22119584 ER PT J AU Doumbia, SO Ndiaye, D Koita, OA Diakite, M Nwakanma, D Coulibaly, M Traore, SF Keating, J Milner, DA Ndiaye, JL Sene, PD Ahouidi, A Dieye, TN Gaye, O Okebe, J Ceesay, SJ Ngwa, A Oriero, EC Konate, L Sy, N Jawara, M Faye, O Keita, M Cisse, M Sogoba, N Poudiougou, B Diawara, S Sangare, L Coulibaly, T Seck, I Abubakar, I Gomis, J Mather, FJ Sissako, A Diarra, A Kandeh, B Whalen, C Moyer, B Nnedu, O Thiero, O Bei, AK Daniels, R Miura, K Long, CA Fairhurst, RM Duraisingh, M Muskavitch, MAT D'Alessandro, U Conway, DJ Volkman, SK Valim, C Wirth, DF Krogstad, DJ AF Doumbia, Seydou O. Ndiaye, Daouda Koita, Ousmane A. Diakite, Mahamadou Nwakanma, Davis Coulibaly, Mamadou Traore, Sekou F. Keating, Joseph Milner, Danny A., Jr. Ndiaye, Jean-Louis Sene, Papa Diogoye Ahouidi, Ambroise Dieye, Tandakha N. Gaye, Oumar Okebe, Joseph Ceesay, Serign J. Ngwa, Alfred Oriero, Eniyou C. Konate, Lassana Sy, Ngayo Jawara, Musa Faye, Ousmane Keita, Moussa Cisse, Moussa Sogoba, Nafomon Poudiougou, Belco Diawara, Sory Sangare, Lansana Coulibaly, Tinzana Seck, Ibrahima Abubakar, Ismaela Gomis, Jules Mather, Frances J. Sissako, Aliou Diarra, Ayouba Kandeh, Balla Whalen, Christopher Moyer, Brian Nnedu, Obinna Thiero, Oumar Bei, Amy K. Daniels, Rachel Miura, Kazutoyo Long, Carole A. Fairhurst, Rick M. Duraisingh, Manoj Muskavitch, Marc A. T. D'Alessandro, Umberto Conway, David J. Volkman, Sarah K. Valim, Clarissa Wirth, Dyann F. Krogstad, Donald J. TI Improving malaria control in West Africa: Interruption of transmission as a paradigm shift SO ACTA TROPICA LA English DT Article DE Malaria control; Paradigm shift; Plasmodium falciparum; Population-based data ID PLASMODIUM-FALCIPARUM MALARIA; SUB-SAHARAN AFRICA; ANOPHELES-GAMBIAE; P. FALCIPARUM; BURKINA-FASO; ERADICATION; EFFICACY; SAFETY; CYTOADHERENCE; ELIMINATION AB With the paradigm shift from the reduction of morbidity and mortality to the interruption of transmission, the focus of malaria control broadens from symptomatic infections in children <= 5 years of age to include asymptomatic infections in older children and adults. In addition, as control efforts intensify and the number of interventions increases, there will be decreases in prevalence, incidence and transmission with additional decreases in morbidity and mortality. Expected secondary consequences of these changes include upward shifts in the peak ages for infection (parasitemia) and disease, increases in the ages for acquisition of antiparasite humoral and cellular immune responses and increases in false-negative blood smears and rapid diagnostic tests. Strategies to monitor these changes must include: (1) studies of the entire population (that are not restricted to children <= 5 or <= 10 years of age), (2) study sites in both cities and rural areas (because of increasing urbanization across sub-Saharan Africa) and (3) innovative strategies for surveillance as the prevalence of infection decreases and the frequency of false-negative smears and rapid diagnostic tests increases. (C) 2011 Elsevier B.V. All rights reserved. C1 [Keating, Joseph; Mather, Frances J.; Nnedu, Obinna; Krogstad, Donald J.] Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Doumbia, Seydou O.; Koita, Ousmane A.; Diakite, Mahamadou; Coulibaly, Mamadou; Traore, Sekou F.; Keita, Moussa; Cisse, Moussa; Sogoba, Nafomon; Poudiougou, Belco; Diawara, Sory; Sangare, Lansana; Coulibaly, Tinzana; Sissako, Aliou; Diarra, Ayouba; Thiero, Oumar] Univ Bamako, Int Ctr Excellence Malaria Res W Africa, Bamako, Mali. [Ndiaye, Daouda; Ndiaye, Jean-Louis; Sene, Papa Diogoye; Ahouidi, Ambroise; Dieye, Tandakha N.; Gaye, Oumar; Konate, Lassana; Sy, Ngayo; Faye, Ousmane; Seck, Ibrahima; Gomis, Jules] Univ Cheikh Anta Diop, Dakar, Senegal. [Milner, Danny A., Jr.; Bei, Amy K.; Daniels, Rachel; Duraisingh, Manoj; Volkman, Sarah K.; Valim, Clarissa; Wirth, Dyann F.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Whalen, Christopher; Moyer, Brian] Res Data, Washington, DC USA. [Miura, Kazutoyo; Long, Carole A.; Fairhurst, Rick M.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Muskavitch, Marc A. T.] Boston Coll, Chestnut Hill, MA 02167 USA. [Conway, David J.] London Sch Hyg & Trop Med, London WC1, England. RP Krogstad, DJ (reprint author), Tulane Sch Publ Hlth & Trop Med, New Orleans, LA USA. EM krogstad@tulane.edu RI D'Alessandro, Umberto/D-3457-2015; OI D'Alessandro, Umberto/0000-0001-6341-5009; Conway, David/0000-0002-8711-3037 FU National Institutes of Allergy and Infectious Diseases (NIAID) [U19 AI 089696] FX The studies described and proposed here are supported by a cooperative agreement from the National Institutes of Allergy and Infectious Diseases (NIAID U19 AI 089696) for an International Center of Excellence in Malaria Research (ICEMR award) to a consortium involving the University of Bamako in Mali, the University Cheikh Anta Diop in Senegal, the Medical Research Council (MRC) Laboratories in The Gambia, Harvard School of Health; Boston College, London School of Hygiene and Tropical Medicine, the Laboratory of Malaria and Vector Research (NIAID) and the Tulane School of Public Health and Tropical Medicine. We thank our many colleagues for administrative and logistic support (Abdoulie Barry, Ron Cail, Salif Camara, Rosie Chavez, Abou Alassane Diallo, Khady Toure Diop, Ramona Gonski, Shannon Joyce, Dembo Kanteh, Denise Majnerick, Glen McGugan, Carmen Mejia, Papa Alioune Ndao, Seybatou Magatte Ndaw, Peter Noble, Malla Rao, Brenda Rodriguez, Mamkumbah Sanneh, Moussa Dieng Sarr, IP Singh, Paula Strickland, Don Van Noy, Joan Vivestomas, Tonu Wali, James Clint Welty, Kijuana Yarls), advice and mentoring (Tumani Corrah, Abdarahmane Dia, Amadou Diallo, Souleymanne Mboup, Saliou Nidaye, Omar Ndir), public health and malaria control partnerships (Moussa Thior, Mrs. Adam Jagne Sonko, Claude-Emile Rwagacondo) and for thoughtful discussions and access to their personal expertise (Jennifer Anderson, Thomas P. Eisele, Ivo Foppa, Nicholas Manoukis, Meredith McMorrow, David Parker, Robert Perry, Margaret Pinder, Jon Eric Tongren, Sixte Zigirumugabe). NR 47 TC 7 Z9 7 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X J9 ACTA TROP JI Acta Trop. PD MAR PY 2012 VL 121 IS 3 SI SI BP 175 EP 183 DI 10.1016/j.actatropica.2011.11.009 PG 9 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 924CN UT WOS:000302668500004 PM 22142790 ER PT J AU Cui, LW Yan, GY Sattabongkot, J Cao, YM Chen, B Chen, XG Fan, Q Fang, Q Jongwutiwes, S Parker, D Sirichaisinthop, J Kyaw, MP Su, XZ Yang, HL Yang, ZQ Wang, BM Xu, JW Zheng, B Zhong, DB Zhou, GF AF Cui, Liwang Yan, Guiyun Sattabongkot, Jetsumon Cao, Yaming Chen, Bin Chen, Xiaoguang Fan, Qi Fang, Qiang Jongwutiwes, Somchai Parker, Daniel Sirichaisinthop, Jeeraphat Kyaw, Myat Phone Su, Xin-zhuan Yang, Henglin Yang, Zhaoqing Wang, Baomin Xu, Jianwei Zheng, Bin Zhong, Daibin Zhou, Guofa TI Malaria in the Greater Mekong Subregion: Heterogeneity and complexity SO ACTA TROPICA LA English DT Article DE Malaria; The Greater Mekong Subregion; Epidemiology; Anopheles vectors; Drug resistance; Border malaria; Elimination ID PLASMODIUM-FALCIPARUM MALARIA; ANTIMALARIAL-DRUG RESISTANCE; ISOTHERMAL AMPLIFICATION LAMP; POLYMERASE-CHAIN-REACTION; ANOPHELES-DIRUS COMPLEX; CROSS-SECTIONAL SURVEY; IMPREGNATED BED NETS; SOUTHEAST-ASIA; MOLECULAR-IDENTIFICATION; ARTESUNATE-MEFLOQUINE AB The Greater Mekong Subregion (GMS), comprised of six countries including Cambodia, China's Yunnan Province, Lao PDR, Myanmar (Burma), Thailand and Vietnam, is one of the most threatening foci of malaria. Since the initiation of the WHO's Mekong Malaria Program a decade ago, malaria situation in the GMS has greatly improved, reflected in the continuous decline in annual malaria incidence and deaths. However, as many nations are moving towards malaria elimination, the GMS nations still face great challenges. Malaria epidemiology in this region exhibits enormous geographical heterogeneity with Myanmar and Cambodia remaining high-burden countries. Within each country, malaria distribution is also patchy, exemplified by 'border malaria' and 'forest malaria' with high transmission occurring along international borders and in forests or forest fringes, respectively. 'Border malaria' is extremely difficult to monitor, and frequent malaria introductions by migratory human populations constitute a major threat to neighboring, malaria-eliminating countries. Therefore, coordination between neighboring countries is essential for malaria elimination from the entire region. In addition to these operational difficulties, malaria control in the GMS also encounters several technological challenges. Contemporary malaria control measures rely heavily on effective chemotherapy and insecticide control of vector mosquitoes. However, the spread of multidrug resistance and potential emergence of artemisinin resistance in Plasmodium falciparum make resistance management a high priority in the GMS. This situation is further worsened by the circulation of counterfeit and substandard artemisinin-related drugs. In most endemic areas of the GMS, P. falciparum and Plasmodium vivax coexist, and in recent malaria control history, P. vivax has demonstrated remarkable resilience to control measures. Deployment of the only registered drug (primaquine) for the radical cure of vivax malaria is severely undermined due to high prevalence of glucose-6-phosphate dehydrogenase deficiency in target human populations. In the GMS, the dramatically different ecologies, diverse vector systems, and insecticide resistance render traditional mosquito control less efficient. Here we attempt to review the changing malaria epidemiology in the GMS, analyze the vector systems and patterns of malaria transmission, and identify the major challenges the malaria control community faces on its way to malaria elimination. (C) 2011 Elsevier B.V. All rights reserved. C1 [Cui, Liwang; Parker, Daniel] Penn State Univ, Dept Entomol, University Pk, PA 16801 USA. [Yan, Guiyun; Zhong, Daibin; Zhou, Guofa] Univ Calif Irvine, Program Publ Hlth, Irvine, CA 92697 USA. [Sattabongkot, Jetsumon] AFRIMS, Dept Entomol, Bangkok 10400, Thailand. [Cao, Yaming] China Med Univ, Coll Basic Med Sci, Dept Immunol, Shenyang, Peoples R China. [Cui, Liwang; Yan, Guiyun; Chen, Bin] Chongqing Normal Univ, Coll Life Sci, Chongqing 400047, Peoples R China. [Chen, Xiaoguang] So Med Univ, Sch Publ Hlth & Trop Med, Dept Etiobiol, Guangzhou 510515, Guangdong, Peoples R China. [Fan, Qi] Dalian Inst Biotechnol, Dalian 116024, Liaoning, Peoples R China. [Fang, Qiang] Bengbu Med Coll, Dept Microbiol & Parasitol, Bengbu 233030, Anhui, Peoples R China. [Jongwutiwes, Somchai] Chulalongkorn Univ, Fac Med, Dept Parasitol, Bangkok 10330, Thailand. [Sirichaisinthop, Jeeraphat] Vector Borne Dis Training Ctr, Sara Buri 18120, Thailand. [Kyaw, Myat Phone] Dept Med Res Lower Myanmar, Parasitol Res Div, Yangon 11191, Myanmar. [Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Yang, Henglin; Xu, Jianwei] Yunnan Inst Parasit Dis, Puer 665000, Yunnan, Peoples R China. [Yang, Zhaoqing] Kunming Med Univ, Dept Parasitol, Kunming 650031, Yunnan, Peoples R China. [Wang, Baomin] China Agr Univ, Coll Agron & Biotechnol, Beijing 100193, Peoples R China. [Zheng, Bin] Chinese Ctr Dis Control & Prevent, Natl Inst Parasit Dis, Shanghai 200025, Peoples R China. RP Cui, LW (reprint author), Penn State Univ, Dept Entomol, 501 ASI Bldg, University Pk, PA 16801 USA. EM luc2@psu.edu RI Parker, Daniel/B-5471-2013; OI Parker, Daniel/0000-0002-5352-7338; Su, Xinzhuan/0000-0003-3246-3248 FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) [U19 AI089672]; Division of Intramural Research, NIAID, NIH FX This work was supported by National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) (U19 AI089672) and partly by the Division of Intramural Research, NIAID, NIH. NR 144 TC 84 Z9 86 U1 4 U2 51 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X EI 1873-6254 J9 ACTA TROP JI Acta Trop. PD MAR PY 2012 VL 121 IS 3 SI SI BP 227 EP 239 DI 10.1016/j.actatropica.2011.02.016 PG 13 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 924CN UT WOS:000302668500011 PM 21382335 ER PT J AU Cui, LW Yan, GY Sattabongkot, J Chen, B Cao, YM Fan, Q Parker, D Sirichaisinthop, J Su, XZ Yang, HL Yang, ZQ Wang, BM Zhou, GF AF Cui, Liwang Yan, Guiyun Sattabongkot, Jetsumon Chen, Bin Cao, Yaming Fan, Qi Parker, Daniel Sirichaisinthop, Jeeraphat Su, Xin-zhuan Yang, Henglin Yang, Zhaoqing Wang, Baomin Zhou, Guofa TI Challenges and prospects for malaria elimination in the Greater Mekong Subregion SO ACTA TROPICA LA English DT Article DE Malaria; The Greater Mekong Subregion; Epidemiology; Vector systems; Drug resistance; Counterfeit drugs ID PLASMODIUM-FALCIPARUM MALARIA; ARTEMISININ-RESISTANT MALARIA; ARTESUNATE-MEFLOQUINE; SOUTHEAST-ASIA; CAMBODIA; BORDER; ANTIMALARIALS; DEPLOYMENT; THAILAND; EFFICACY AB Despite significant improvement in the malaria situation of the Greater Mekong Subregion (GMS), malaria control for the region continues to face a multitude of challenges. The extremely patchy malaria distribution, especially along international borders, makes disease surveillance and targeted control difficult. The vector systems are also diverse with dramatic differences in habitat ecology, biting behavior, and vectorial capacity, and there is a lack of effective transmission surveillance and control tools. Finally, in an era of heavy deployment of artemisinin-based combination therapies, the region acts as an epicenter of drug resistance, with the emergence of artemisinin resistant Plasmodium falciparum posing a threat to both regional and global malaria elimination campaigns. This problem is further exacerbated by the circulation of counterfeit and substandard artemisinin drugs. Accordingly, this Southeast Asian Malaria Research Center, consisting of a consortium of US and regional research institutions, has proposed four interlinked projects to address these most urgent problems in malaria control. The aims of these projects will help to substantially improve our understanding of malaria epidemiology, vector systems and their roles in malaria transmission, as well as the mechanisms of drug resistance in parasites. Through the training of next-generation scientists in malaria research, this program will help build up and strengthen regional research infrastructure and capacities, which are essential for sustained malaria control in this region. (C) 2011 Elsevier B.V. All rights reserved. C1 [Cui, Liwang; Parker, Daniel] Penn State Univ, Dept Entomol, University Pk, PA 16801 USA. [Yan, Guiyun; Zhou, Guofa] Univ Calif Irvine, Program Publ Hlth, Irvine, CA 92697 USA. [Sattabongkot, Jetsumon] AFRIMS, Dept Entomol, Bangkok 10400, Thailand. [Cui, Liwang; Yan, Guiyun; Chen, Bin] Chongqing Normal Univ, Coll Life Sci, Chongqing 400047, Peoples R China. [Cao, Yaming] China Med Univ, Dept Immunol, Coll Basic Med Sci, Shenyang, Peoples R China. [Fan, Qi] Dalian Inst Biotechnol, Dalian 116024, Liaoning Provin, Peoples R China. [Sirichaisinthop, Jeeraphat] Vector Borne Dis Training Ctr, Sara Buri 18120, Thailand. [Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. [Yang, Henglin] Yunnan Inst Parasit Dis, Puer 665000, Yunnan Province, Peoples R China. [Yang, Zhaoqing] Kunming Med Univ, Dept Parasitol, Kunming 650031, Yunnan, Peoples R China. [Wang, Baomin] China Agr Univ, Coll Agron Biotechnol, Beijing 100193, Peoples R China. RP Cui, LW (reprint author), Penn State Univ, Dept Entomol, 501 ASI Bldg, University Pk, PA 16801 USA. EM luc2@psu.edu RI Parker, Daniel/B-5471-2013; OI Parker, Daniel/0000-0002-5352-7338; Su, Xinzhuan/0000-0003-3246-3248 FU National Institute of Allergy and Infectious Diseases, NIH [U19 AI089672]; Division of Intramural Research, NIAID, NIH FX This work was supported by National Institute of Allergy and Infectious Diseases, NIH (U19 AI089672). X. Su is supported by the Division of Intramural Research, NIAID, NIH. NR 29 TC 24 Z9 25 U1 1 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X J9 ACTA TROP JI Acta Trop. PD MAR PY 2012 VL 121 IS 3 SI SI BP 240 EP 245 DI 10.1016/j.actatropica.2011.04.006 PG 6 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 924CN UT WOS:000302668500012 PM 21515238 ER PT J AU Herrera, S Quinones, ML Quintero, JP Corredor, V Fuller, DO Mateus, JC Calzada, JE Gutierrez, JB Llanos, A Soto, E Menendez, C Wu, YM Alonso, P Carrasquilla, G Galinski, M Beier, JC Arevalo-Herrera, M AF Herrera, Socrates Lucia Quinones, Martha Pablo Quintero, Juan Corredor, Vladimir Fuller, Douglas O. Cesar Mateus, Julio Calzada, Jose E. Gutierrez, Juan B. Llanos, Alejandro Soto, Edison Menendez, Clara Wu, Yimin Alonso, Pedro Carrasquilla, Gabriel Galinski, Mary Beier, John C. Arevalo-Herrera, Myriam TI Prospects for malaria elimination in non-Amazonian regions of Latin America SO ACTA TROPICA LA English DT Article DE Malaria; Plasmodium falciparum; Plasmodium vivax; Anopheles mosquitoes; Vector control; Epidemiology; Malaria elimination; Malaria pathogenesis; Non-Amazon regions; Latin America ID PLASMODIUM-VIVAX MALARIA; ASYMPTOMATIC MALARIA; VACCINE DEVELOPMENT; ANOPHELES-DARLINGI; COLOMBIAN PACIFIC; FALCIPARUM; RESISTANCE; AREA; TRANSMISSION; POPULATION AB Latin America contributes 1-1.2 million clinical malaria cases to the global malaria burden of about 300 million per year. In 21 malaria endemic countries, the population at risk in this region represents less than 10% of the total population exposed worldwide. Factors such as rapid deforestation, inadequate agricultural practices, climate change, political instability, and both increasing parasite drug resistance and vector resistance to insecticides contribute to malaria transmission. Recently, several malaria endemic countries have experienced a significant reduction in numbers of malaria cases. This is most likely due to actions taken by National Malaria Control Programs (NMCP) with the support from international funding agencies. We describe here the research strategies and activities to be undertaken by the Centro Latino Americano de Investigacion en Malaria (CLAIM), a new research center established for the non-Amazonian region of Latin America by the National Institute of Allergy and Infectious Diseases (NIAID). Throughout a network of countries in the region, initially including Colombia, Guatemala, Panama, and Peru. CLAIM will address major gaps in our understanding of changing malaria epidemiology, vector biology and control, and clinical malaria mainly due to Plasmodium vivax. In close partnership with NMCPs, CLAIM seeks to conduct research on how and why malaria is decreasing in many countries of the region as a basis for developing and implementing new strategies that will accelerate malaria elimination. (C) 2011 Elsevier B.V. All rights reserved. C1 [Herrera, Socrates; Pablo Quintero, Juan; Arevalo-Herrera, Myriam] Ctr Invest Cient Caucaseco, Cali 760042, Colombia. [Herrera, Socrates; Arevalo-Herrera, Myriam] Valle State Univ, Sch Hlth, Cali, Colombia. [Fuller, Douglas O.; Beier, John C.] Univ Miami, Coral Gables, FL 33124 USA. [Gutierrez, Juan B.] Ohio State Univ, Columbus, OH 43210 USA. [Llanos, Alejandro] Cayetano Heredia Univ, Lima, Peru. [Menendez, Clara; Alonso, Pedro] Univ Barcelona, Hosp Clin, Barcelona Ctr Int Hlth Res, E-08007 Barcelona, Spain. [Wu, Yimin] NIAD, Lab Malaria Immunol & Vaccinol, NIH, Bethesda, MD 20892 USA. [Galinski, Mary] Emory Univ Atlanta, Atlanta, GA USA. RP Herrera, S (reprint author), Ctr Invest Cient Caucaseco, Cali 760042, Colombia. EM sherrera@inmuno.org OI Gutierrez, Juan B./0000-0002-0627-5035 FU US National Institute of Allergy and Infectious Diseases (NIAID/NIH) [U19AI089702] FX This work has been supported by the US National Institute of Allergy and Infectious Diseases (NIAID/NIH) (Grant number U19AI089702). NR 71 TC 14 Z9 15 U1 0 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X J9 ACTA TROP JI Acta Trop. PD MAR PY 2012 VL 121 IS 3 SI SI BP 315 EP 323 DI 10.1016/j.actatropica.2011.06.018 PG 9 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 924CN UT WOS:000302668500020 PM 21781953 ER PT J AU Okamoto, J Sakuma, KL Yan, H Qiu, PY Palmer, PH Johnson, CA AF Okamoto, Janet Sakuma, Kari-Lyn Yan, He Qiu, Peiyuan Palmer, Paula H. Johnson, C. Anderson TI A Qualitative Exploration of Youth in the "New" China: Perspectives on Tobacco Use From Adolescents in Southwest China SO ASIA-PACIFIC JOURNAL OF PUBLIC HEALTH LA English DT Article DE smoking; China; adolescent ID SMOKING-BEHAVIOR; SCHOOL STUDENTS; ATTITUDES AB School-based prevention programs are not common in China and the attempts to modify successful Western prevention programs have largely shown little effect. Distinct cultural and social systems differences could explain why modified programs have been unsuccessful. Smoking behavior is examined from the perspective of Chinese adolescents as part of the development of a large intervention trial. A total of 16 focus groups with 128 participants were conducted in Chengdu in Sichuan province of China. Impressions of adolescent smokers were mixed, most seeing the behavior as common among boys. Smokers were seen as being overwhelmed and stressed. Girls' smoking was mostly seen as universally "bad" and reflecting poorly on a girl's character. However, a small portion of focus group participants suggested that female smoking was fashionable and trendy. With social norms changing rapidly in the "new" China, understanding what the new generation of Chinese youth thinks about smoking is critical in determining how to address and tailor prevention efforts. C1 [Okamoto, Janet] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Sakuma, Kari-Lyn] Penn State Univ, State Coll, PA USA. [Yan, He] Chengdu Municipal Ctr Dis Control & Prevent, Chengdu, Peoples R China. [Qiu, Peiyuan] Sichuan Univ, Chengdu 610064, Peoples R China. [Palmer, Paula H.; Johnson, C. Anderson] Claremont Grad Univ, Claremont, CA USA. RP Okamoto, J (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 4089B,MSC 7335, Bethesda, MD 20892 USA. EM okamotojm@mail.nih.gov OI Okamoto, Janet/0000-0002-3164-2183 FU Transdisciplinary Tobacco Use Research Center from the National Cancer Institute (NCI) [1 P50CA84735-01]; National Institute on Drug Abuse (NIDA); National Institute on Alcohol Abuse and Alcoholism (NIAAA) FX This research was supported by Transdisciplinary Tobacco Use Research Center funding (grant number 1 P50CA84735-01) from the National Cancer Institute (NCI), National Institute on Drug Abuse (NIDA), and National Institute on Alcohol Abuse and Alcoholism (NIAAA). NR 16 TC 1 Z9 1 U1 3 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1010-5395 J9 ASIA-PAC J PUBLIC HE JI Asia-Pac. J. Public Health PD MAR PY 2012 VL 24 IS 2 BP 296 EP 307 DI 10.1177/1010539510380735 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 923AJ UT WOS:000302590100007 PM 20829274 ER PT J AU Cho, YW Song, HJ Lee, JJ Lee, JH Lee, HJ Yi, SD Chang, HW Berl, MM Gaillard, WD Chang, Y AF Cho, Yong Won Song, Hui-Jin Lee, Jae Jun Lee, Joo Hwa Lee, Hui Joong Yi, Sang Doe Chang, Hyuk Won Berl, Madison M. Gaillard, William D. Chang, Yongmin TI Age-related differences in the brain areas outside the classical language areas among adults using category decision task SO BRAIN AND LANGUAGE LA English DT Article DE Language; fMRI; Laterality; Cognition ID MEDIAL TEMPORAL-LOBE; VERBAL FLUENCY TASK; PREFRONTAL CORTEX; WADA TEST; SUBCORTICAL FUNCTIONS; WORD GENERATION; WORKING-MEMORY; FRONTAL-CORTEX; FUNCTIONAL MRI; FMRI AB Older adults perform much like younger adults on language. This similar level of performance, however, may come about through different underlying brain processes. In the present study, we evaluated age-related differences in the brain areas outside the typical language areas among adults using a category decision task. Our results showed that similar activation patterns were found in classical language processing areas across the three age groups although regional lateralization indices in Broca's and Wernicke's areas decreased with age. The greatest differences, however, among the three groups were found primarily in the brain areas not associated with core language functioning including the hippocampus, middle frontal gyrus, ventromedial frontal cortex, medial superior parietal cortex and posterior cingulate cortex. Therefore, the non-classical language areas may exhibit an age-related difference between three age groups while the subjects show a similar activation pattern in the core, primary language processing during a semantic decision task. (C) 2012 Elsevier Inc. All rights reserved. C1 [Gaillard, William D.] George Washington Univ, Childrens Natl Med Ctr, Sch Med, Washington, DC 20010 USA. [Cho, Yong Won; Lee, Joo Hwa; Yi, Sang Doe] Keimyung Univ, Dongsan Med Ctr, Dept Neurol, Taegu, South Korea. [Lee, Hui Joong; Chang, Yongmin] Kyungpook Natl Univ & Hosp, Dept Med & Biol Engn, Taegu, South Korea. [Lee, Hui Joong; Chang, Yongmin] Kyungpook Natl Univ & Hosp, Dept Radiol, Taegu, South Korea. [Chang, Hyuk Won] Keimyung Univ, Dongsan Med Ctr, Dept Radiol, Taegu, South Korea. [Gaillard, William D.] NINDS, NIH, Bethesda, MD 20892 USA. [Chang, Yongmin] Kyungpook Natl Univ & Hosp, Dept Mol Med, Taegu, South Korea. RP Gaillard, WD (reprint author), George Washington Univ, Childrens Natl Med Ctr, Sch Med, 111 Michigan Ave, Washington, DC 20010 USA. EM wgaillar@cnmc.org; ychang@knu.ac.kr FU Ministry of Health Welfare [A092106]; Keimyung University Dongsan Medical Center in KOREA FX This work was supported by the Ministry of Health & Welfare (A092106) and a Research Promoting Grant from the Keimyung University Dongsan Medical Center in KOREA. NR 47 TC 1 Z9 1 U1 8 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD MAR PY 2012 VL 120 IS 3 BP 372 EP 380 DI 10.1016/j.bandl.2011.12.013 PG 9 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 911XX UT WOS:000301759100017 PM 22305968 ER PT J AU Stojilkovic, SS AF Stojilkovic, Stanko S. TI Molecular mechanisms of pituitary endocrine cell calcium handling SO CELL CALCIUM LA English DT Article DE Action potential; Calcium oscillations; cAMP; G protein-coupled receptors; IP3 receptor channels; Protein kinase A; Voltage-gated calcium channels ID THYROTROPIN-RELEASING-HORMONE; VOLTAGE-GATED CA2+; IDENTIFIED RAT CORTICOTROPHS; SECRETING ADENOMA CELLS; CYTOSOLIC-FREE CALCIUM; RECTIFYING K+ CURRENT; PROTEIN-KINASE-A; ANTERIOR-PITUITARY; ACTION-POTENTIALS; FROG MELANOTROPHS AB Endocrine pituitary cells express numerous voltage-gated Na+, Ca2+, K+, and Cl- channels and several ligand-gated channels, and they fire action potentials spontaneously. Depending on the cell type, this electrical activity can generate localized or global Ca2+ signals, the latter reaching the threshold for stimulus-secretion coupling. These cells also express numerous G-protein-coupled receptors, which can stimulate or silence electrical activity and Ca2+ influx through voltage-gated Ca2+ channels and hormone release. Receptors positively coupled to the adenylyl cyclase signaling pathway stimulate electrical activity with cAMP, which activates hyperpolarization-activated cyclic nucleotide-regulated channels directly, or by cAMP-dependent kinase-mediated phosphorylation of K+, Na+, Ca2+, and/or non-selective cation-conducting channels. Receptors that are negatively coupled to adenylyl cyclase signaling pathways inhibit spontaneous electrical activity and accompanied Ca2+ transients predominantly through the activation of inwardly rectifying K+ channels and the inhibition of voltage-gated Ca2+ channels. The Ca2+-mobilizing receptors activate inositol trisphosphate-gated Ca2+ channels in the endoplasmic reticulum, leading to Ca2+ release in an oscillatory or non-oscillatory manner, depending on the cell type. This Ca2+ release causes a cell type-specific modulation of electrical activity and intracellular Ca2+ handling. Published by Elsevier Ltd. C1 NICHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov FU NIH, NICHD FX SS is supported by an NIH grant from the Intramural Research Program of the NICHD, NIH. The author is thankful to Sir Michael J. Berridge for helpful discussions of calcium signaling in pituitary cells. NR 107 TC 12 Z9 12 U1 0 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD MAR-APR PY 2012 VL 51 IS 3-4 SI SI BP 212 EP 221 DI 10.1016/j.ceca.2011.11.003 PG 10 WC Cell Biology SC Cell Biology GA 920XV UT WOS:000302443500002 PM 22138111 ER PT J AU Wehby, GL Murray, JC Wilcox, A Lie, RT AF Wehby, George L. Murray, Jeffrey C. Wilcox, Allen Lie, Rolv T. TI Smoking and body weight: Evidence using genetic instruments SO ECONOMICS & HUMAN BIOLOGY LA English DT Article DE Smoking; Obesity; Body mass index; Genetic instrumental variables; Quantile regression; Mendelian randomization ID TRYPTOPHAN-HYDROXYLASE GENE; AMINOBUTYRIC-ACID RECEPTOR; NICOTINE DEPENDENCE; QUANTILE REGRESSION; ENVIRONMENTAL-INFLUENCES; MENDELIAN RANDOMIZATION; RISK-FACTOR; CIGARETTE-SMOKING; WEAK INSTRUMENTS; LUNG-CANCER AB Several studies have evaluated whether the high and rising obesity rates over the past three decades may be due to the declining smoking rates. There is mixed evidence across studies - some find negative smoking effects and positive cigarette cost effects on body weight, while others find opposite effects. This study applies a unique approach to identify the smoking effects on body weight and to evaluate the heterogeneity in these effects across the body mass index (BMI) distribution by utilizing genetic instruments for smoking. Using a data sample of 1057 mothers from Norway, the study finds heterogeneous effects of cigarette smoking on BMI - smoking increases BMI at low/moderate BMI levels and decreases BMI at high BMI levels. The study highlights the potential advantages and challenges of employing genetic instrumental variables to identify behavior effects including the importance of qualifying the instruments and the need for large samples. (C) 2011 Elsevier B.V. All rights reserved. C1 [Wehby, George L.] Univ Iowa, Dept Hlth Management & Policy, Coll Publ Hlth, Iowa City, IA 52242 USA. [Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Coll Med, Iowa City, IA 52242 USA. [Wilcox, Allen] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Lie, Rolv T.] Univ Bergen, Bergen, Norway. RP Wehby, GL (reprint author), Univ Iowa, Dept Hlth Management & Policy, Coll Publ Hlth, 200 Hawkins Dr,E205 GH, Iowa City, IA 52242 USA. EM george-wehby@uiowa.edu OI Wilcox, Allen/0000-0002-3376-1311 FU NIH/NIDCR [R03 DE018394, R01 DE20895]; NIH, National Institute of Environmental Health Sciences FX Data analysis was supported in part by NIH/NIDCR grants R03 DE018394 and R01 DE20895. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The authors thank research seminar participants and Robert Wallace at the University of Iowa and Shin-Yi Chou at Lehigh University for helpful comments. NR 86 TC 11 Z9 11 U1 4 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-677X EI 1873-6130 J9 ECON HUM BIOL JI Econ. Hum. Biol. PD MAR PY 2012 VL 10 IS 2 BP 113 EP 126 DI 10.1016/j.ehb.2011.09.002 PG 14 WC Economics; Public, Environmental & Occupational Health SC Business & Economics; Public, Environmental & Occupational Health GA 921ZI UT WOS:000302516200001 PM 22024417 ER PT J AU Metenou, S Kovacs, M Dembele, B Coulibaly, YI Klion, AD Nutman, TB AF Metenou, Simon Kovacs, Michael Dembele, Benoit Coulibaly, Yaya I. Klion, Amy D. Nutman, Thomas B. TI Interferon regulatory factor modulation underlies the bystander suppression of malaria antigen-driven IL-12 and IFN-gamma in filaria-malaria co-infection SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Cytokines; CXCR3 ligands; DCs; Interferon regulatory factors ID HUMAN DENDRITIC CELLS; PLASMODIUM-FALCIPARUM MALARIA; NF-KAPPA-B; IMMUNE-RESPONSES; LYMPHATIC FILARIASIS; GENE-EXPRESSION; HELMINTH INFECTIONS; BRUGIA-MALAYI; FACTOR-I; T-CELLS AB In areas where polyparasitism is highly prevalent, the impact of multiple parasites on the host response is underestimated. In particular, the presence of helminth infection coincident with malaria profoundly alters the production of malaria-specific IFN-?, IL-12p70, CXCL9, CXCL10 and CXCL11, cytokines/chemokines known to be critical in mediating malaria-specific immunity. In order to elucidate the mechanisms underlying the suppression of malaria-specific cytokines/chemokines, we assessed the expression of malaria-specific IL-12R beta 1, IL-12R beta 2 and interferon regulatory factor (IRF)-1 in blood obtained from 18 filaria-infected (Fil+) and 17 filaria-uninfected (Fil-) individuals in a filaria-malaria co-endemic region of Mali. We found that Fil+ individuals had significantly lower RNA expression of IRF-1 but not IL-12R beta 1 or IL-12R beta 2 in response to malaria antigen stimulation. We also measured the frequency of IL-12-producing DCs from these subjects and found that Fil+ subjects had lower frequencies of IL-12+ mDCs after malaria antigen stimulation than did the Fil- subjects. Modeling these data in vitro, we found that mDCs pre-exposed to live microfilariae not only produced significantly lower levels of CXCL-9, CXCL-10, IL-12p35, IL-12p40, IL-12p19 and CXCL-11 following stimulation with malaria antigen but also markedly downregulated the expression of IRF-1, IRF-2 and IRF-3 compared with microfilaria-unexposed mDCs. siRNA-inhibition of irf-1 in mDCs downregulated the production of IL-12p70 through repression of IL-12p35. Our data demonstrate that the modulation of IRFs seen in filarial (and presumably other tissue-invasive helminths) infection underlies the suppression of malaria-specific cytokines/chemokines that play a crucial role in immunity to malaria. C1 [Metenou, Simon; Kovacs, Michael; Klion, Amy D.; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. [Dembele, Benoit; Coulibaly, Yaya I.] Univ Bamako, Filariasis Unit, Fac Med Pharm & Dent, Bamako, Mali. RP Metenou, S (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD USA. EM metenous@niaid.nih.gov RI Metenou, Simon/C-1101-2013 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 49 TC 9 Z9 9 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD MAR PY 2012 VL 42 IS 3 BP 641 EP 650 DI 10.1002/eji.201141991 PG 10 WC Immunology SC Immunology GA 922IT UT WOS:000302541300012 PM 22213332 ER PT J AU Frick, KD Drye, LT Kempen, JH Dunn, JP Holland, GN Latkany, P Rao, NA Sen, HN Sugar, EA Thorne, JE Wang, RC Holbrook, JT AF Frick, Kevin D. Drye, Lea T. Kempen, John H. Dunn, James P. Holland, Gary N. Latkany, Paul Rao, Narsing A. Sen, H. Nida Sugar, Elizabeth A. Thorne, Jennifer E. Wang, Robert C. Holbrook, Janet T. CA Multictr Uveitis Steroid Treatment TI Associations among Visual Acuity and Vision- and Health-Related Quality of Life among Patients in the Multicenter Uveitis Steroid Treatment Trial SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID FUNCTION QUESTIONNAIRE; STATES; EQ-5D; INTERMEDIATE; POPULATION; IMPAIRMENT; VALIDITY; UTILITY; SCORES AB PURPOSE. To evaluate the associations between visual acuity and self-reported visual function; visual acuity and health-related quality of life (QoL) metrics; a summary measure of self-reported visual function and health-related QoL; and individual domains of self-reported visual function and health-related QoL in patients with uveitis. METHODS. Best-corrected visual acuity, vision-related functioning as assessed by the NEI VFQ-25, and health-related QoL as assessed by the SF-36 and EuroQoL EQ-5D questionnaires were obtained at enrollment in a clinical trial of uveitis treatments. Multivariate regression and Spearman correlations were used to evaluate associations between visual acuity, vision-related function, and health-related QoL. RESULTS. Among the 255 patients, median visual acuity in the better-seeing eyes was 20/25, the vision-related function score indicated impairment (median, 60), and health-related QoL scores were within the normal population range. Better visual acuity was predictive of higher visual function scores (P <= 0.001), a higher SF-36 physical component score, and a higher EQ-5D health utility score (P < 0.001). The vision-specific function score was predictive of all general health-related QoL (P < 0.001). The correlations between visual function score and general quality of life measures were moderate (p = 0.29-0.52). CONCLUSIONS. The vision-related function score correlated positively with visual acuity and moderately positively with general QoL measures. Cost-utility analyses relying on changes in generic healthy utility measures will be more likely to detect changes when there are clinically meaningful changes in vision-related function, rather than when there are only changes in visual acuity. (ClinicalTrials. gov number, NCT00132691.) (Invest Ophthalmol Vis Sci. 2012;53:1169-1176) DOI:10.1167/iovs.11-8259 C1 [Frick, Kevin D.] Johns Hopkins Univ, Dept Hlth Policy & Management, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. [Drye, Lea T.; Sugar, Elizabeth A.; Thorne, Jennifer E.; Holbrook, Janet T.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Ctr Clin Trials, Baltimore, MD USA. [Kempen, John H.] Univ Penn, Scheie Eye Inst, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Kempen, John H.] Univ Penn, Dept Oncol, Philadelphia, PA 19104 USA. [Dunn, James P.; Thorne, Jennifer E.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dept Ophthalmol, Baltimore, MD 21205 USA. [Holland, Gary N.] Univ Calif Los Angeles, David Geffen Sch Med, Jules Stein Eye Inst, Dept Ophthalmol, Los Angeles, CA 90095 USA. [Latkany, Paul] New York Eye & Ear Inst, Dept Ophthalmol, New York, NY USA. [Rao, Narsing A.] USC Sch Med, Doheny Eye Inst, Dept Ophthalmol, Los Angeles, CA USA. [Sen, H. Nida] NEI, NIH, Bethesda, MD 20892 USA. [Sugar, Elizabeth A.] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Sugar, Elizabeth A.] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Wang, Robert C.] Texas Retina Associates, Dallas, TX USA. RP Frick, KD (reprint author), 624 N Broadway,Room 606, Baltimore, MD 21205 USA. EM kfrick@jhsph.edu RI Taylor, Simon/C-1496-2008; OI Taylor, Simon/0000-0002-1228-881X; Drye, Lea/0000-0002-2964-1878 FU National Eye Institute [EYU10EY014655, EYU10EY014660, EY014656]; Research to Prevent Blindness (RPB); Paul and Evanina Mackall Foundation; RPB James S. Adams Special Scholar Award; RPB Sybil Harrington Special Scholar Award FX Supported by National Eye Institute Collaborative Grants EYU10EY014655, EYU10EY014660, and EY014656; Research to Prevent Blindness (RPB); and the Paul and Evanina Mackall Foundation. JHK was an RPB James S. Adams Special Scholar Award recipient during the time the study was conducted. JET is a recipient of the RPB Sybil Harrington Special Scholar Award. Bausch & Lomb provided support to the study in the form of donation of a limited number of fluocinolone acetonide implants for patients randomized to implant therapy who were uninsured or otherwise unable to pay for implants, but did not otherwise support the study. A representative of the National Eye Institute participated in the conduct of the study, including the study design and the collection, management, analysis, and interpretation of the data, as well as in the review and approval of the manuscript. NR 31 TC 23 Z9 24 U1 1 U2 12 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 MAR PY 2012 VL 53 IS 3 BP 1169 EP 1176 DI 10.1167/iovs.11-8259 PG 8 WC Ophthalmology SC Ophthalmology GA 925VT UT WOS:000302790700013 PM 22247489 ER PT J AU Naeem, MA Chavali, VRM Ali, S Iqbal, M Riazuddin, S Khan, SN Husnain, T Sieving, PA Ayyagari, R Riazuddin, S Hejtmancik, JF Riazuddin, SA AF Naeem, Muhammad Asif Chavali, Venkata R. M. Ali, Shahbaz Iqbal, Muhammad Riazuddin, Saima Khan, Shaheen N. Husnain, Tayyab Sieving, Paul A. Ayyagari, Radha Riazuddin, Sheikh Hejtmancik, J. Fielding Riazuddin, S. Amer TI GNAT1 Associated with Autosomal Recessive Congenital Stationary Night Blindness SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID DOMINANT RETINITIS-PIGMENTOSA; ALPHA-TRANSDUCIN GNAT1; RHODOPSIN MUTATION; NONSENSE MUTATION; MISSENSE MUTATION; G-PROTEIN; GENE; ROD; CATARACT; SUBUNIT AB PURPOSE. Congenital stationary night blindness is a nonprogressive retinal disorder manifesting as impaired night vision and is generally associated with other ocular symptoms, such as nystagmus, myopia, and strabismus. This study was conducted to further investigate the genetic basis of CSNB in a consanguineous Pakistani family. METHODS. A consanguineous family with multiple individuals manifesting cardinal symptoms of congenital stationary night blindness was ascertained. All family members underwent detailed ophthalmic examination, including fundus photographic examination and electroretinography. Blood samples were collected and genomic DNA was extracted. Exclusion and genome-wide linkage analyses were completed and two-point LOD scores were calculated. Bidirectional sequencing of GNAT1 was completed, and quantitative expression of Gnat1 transcript levels were investigated in ocular tissues at different postnatal intervals. RESULTS. The results of ophthalmic examinations were suggestive of early-onset stationary night blindness with no extraocular anomalies. The genome-wide scan localized the critical interval to chromosome 3, region p22.1-p14.3, with maximum two-point LOD scores of 3.09 at theta = 0, flanked by markers D3S3522 and D3S1289. Subsequently, a missense mutation in GNAT1, p. D129G, was identified, which segregated within the family, consistent wi