FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Garantziotis, S Li, ZW Potts, EN Kimata, K Zhuo, LS Morgan, DL Savani, RC Noble, PW Foster, WM Schwartz, DA Hollingsworth, JW AF Garantziotis, Stavros Li, Zhuowei Potts, Erin N. Kimata, Koji Zhuo, Lisheng Morgan, Daniel L. Savani, Rashmin C. Noble, Paul W. Foster, W. Michael Schwartz, David A. Hollingsworth, John W. TI Hyaluronan Mediates Ozone-induced Airway Hyperresponsiveness in Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INTER-ALPHA-INHIBITOR; INDUCED LUNG INJURY; HEAVY-CHAINS; MORTALITY; INFLAMMATION; HEALTH; CELLS; TSG-6; CD44; ACID AB Ozone is a common urban environmental air pollutant and significantly contributes to hospitalizations for respiratory illness. The mechanisms, which regulate ozone-induced broncho-constriction, remain poorly understood. Hyaluronan was recently shown to play a central role in the response to noninfectious lung injury. Therefore, we hypothesized that hyaluronan contributes to airway hyperreactivity (AHR) after exposure to ambient ozone. Using an established model of ozone-induced airways disease, we characterized the role of hyaluronan in airway hyperresponsiveness. The role of hyaluronan in response to ozone was determined by using therapeutic blockade, genetically modified animals, and direct challenge to hyaluronan. Ozone-exposed mice demonstrate enhanced AHR associated with elevated hyaluronan levels in the lavage fluid. Mice deficient in either CD44 (the major receptor for hyaluronan) or inter-alpha-trypsin inhibitor (molecule that facilitates hyaluronan binding) show similar elevations in hyaluronan but are protected from ozone-induced AHR. Mice pretreated with hyaluronan-binding peptide are protected from the development of ozone-induced AHR. Overexpression of hyaluronan enhances the airway response to ozone. Intratracheal instillation of endotoxin-free low molecular weight hyaluronan induces AHR dependent on CD44, whereas instillation of high molecular weight hyaluronan protects against ozone-induced AHR. In conclusion, we demonstrate that hyaluronan mediates ozone-induced AHR, which is dependent on the fragment size and both CD44 and inter-alpha-trypsin inhibitor. These data support the conclusion that pulmonary matrix can contribute to the development of airway hyperresponsiveness. C1 [Garantziotis, Stavros; Morgan, Daniel L.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Li, Zhuowei; Potts, Erin N.; Noble, Paul W.; Foster, W. Michael; Hollingsworth, John W.] Duke Univ, Med Ctr, Div Pulm Allergy & Crit Care Med, Durham, NC 27710 USA. [Kimata, Koji; Zhuo, Lisheng] Aichi Med Univ, Inst Mol Sci Med, Aichi 4801195, Japan. [Savani, Rashmin C.] Univ Texas SW Med Ctr Dallas, Div Pulm & Vasc Biol, Dallas, TX 75390 USA. [Savani, Rashmin C.] Univ Texas SW Med Ctr Dallas, Div Neonatal Perinatal Med, Dallas, TX 75390 USA. [Schwartz, David A.] Natl Jewish Med & Res Ctr, Div Pulm Med, Denver, CO 80206 USA. RP Hollingsworth, JW (reprint author), DUMC Box 103004, Durham, NC 27710 USA. EM holli017@mc.duke.edu RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU National Institutes of Health [ES11961]; NIEHS [ES16126]; NHLBI [HL91335, HL62472, HL73896] FX This work was supported, in whole or in part, by National Institutes of Health Grants ES11961 and ES16126 from the NIEHS, Grants HL91335, HL62472, and HL73896 from the NHLBI, and grants from the NIEHS (Intramural Research Program). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 32 TC 61 Z9 62 U1 0 U2 0 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 APR 24 PY 2009 VL 284 IS 17 BP 11309 EP 11317 DI 10.1074/jbc.M802400200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 437NP UT WOS:000265494500035 PM 19164299 ER PT J AU Hagen, N Van Veldhoven, PP Proia, RL Park, H Merrill, AH van Echten-Deckert, G AF Hagen, Nadine Van Veldhoven, Paul P. Proia, Richard L. Park, Hyejung Merrill, Alfred H., Jr. van Echten-Deckert, Gerhild TI Subcellular Origin of Sphingosine 1-Phosphate Is Essential for Its Toxic Effect in Lyase-deficient Neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROGRAMMED CELL-DEATH; CYCLIN D1; FUNCTIONAL-CHARACTERIZATION; SPHINGOLIPID METABOLISM; POSTMITOTIC NEURONS; MOLECULAR-CLONING; KINASE TYPE-2; SPHINGOSINE-1-PHOSPHATE; APOPTOSIS; PROTEIN AB Cerebellar granule cells from sphingosine 1-phosphate (S1P) lyase-deficient mice were used to study the toxicity of this potent sphingolipid metabolite in terminally differentiated postmitotic neurons. Based on earlier findings with the lyase-stable, semi-synthetic, cis-4-methylsphingosine phosphate, we hypothesized that accumulation of S1P above a certain threshold induces neuronal apoptosis. The present studies confirmed this conclusion and further revealed that for S1P to induce apoptosis in lyase-deficient neurons it must also be produced by sphingosine-kinase2 (SK2). These conclusions are based on the finding that incubation of lyase-deficient neurons with either sphingosine or S1P results in a similar elevation in cellular S1P; however, only S1P addition to the culture medium induces apoptosis. This was not due to S1P acting on the S1P receptor but to hydrolysis of S1P to sphingosine that was phosphorylated by the cells, as described before for cis-4-methylsphingosine. Although the cells produced S1P from both exogenously added sphingosine as well as sphingosine derived from exogenous S1P, the S1P from these two sources were not equivalent, because the former was primarily produced by SK1, whereas the latter was mainly formed by SK2 (as also was cis-4-methylsphingosine phosphate), based on studies in neurons lacking SK1 or SK2 activity. Thus, these investigations show that, due to the existence of at least two functionally distinct intracellular origins for S1P, exogenous S1P can be neurotoxic. In this model, S1P accumulated due to a defective lyase, however, this cause of toxicity might also be important in other cases, as illustrated by the neurotoxicity of cis-4-methylsphingosine phosphate. C1 [Hagen, Nadine; van Echten-Deckert, Gerhild] Univ Bonn, Kekule Inst, D-53121 Bonn, Germany. [Van Veldhoven, Paul P.] Katholieke Univ Leuven, Dept Mol Cell Biol, B-3000 Louvain, Belgium. [Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Park, Hyejung; Merrill, Alfred H., Jr.] Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. [Park, Hyejung; Merrill, Alfred H., Jr.] Georgia Inst Technol, Petit Inst Bioengn & Biosci, Atlanta, GA 30332 USA. RP van Echten-Deckert, G (reprint author), Univ Bonn, Kekule Inst, Gerhard Domagk Str 1, D-53121 Bonn, Germany. EM g.echten.deckert@uni-bonn.de RI Proia, Richard/A-7908-2012 FU National Institutes of Health, NIDDK Intramural Research Program; NIH [GM069338]; Deutsche Forschungsgemeinschaft [EC 118/2-2]; Fonds voor Wetenschappelijk Onderzoek-Vlaanderen [G.0405.02] FX This work was supported, in whole or in part, by National Institutes of Health, NIDDK Intramural Research Program (to R. L. P.). This work was also supported by NIH Grant GM069338 for the Sphingolipid Core of the Lipid MAPS Consortium (to A. H. M.) for the mass spectrometric analyses, the Deutsche Forschungsgemeinschaft (Grant EC 118/2-2 to G. v. E.-D.), and the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (Grant G.0405.02 to P. P. V. V.). NR 37 TC 38 Z9 38 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 APR 24 PY 2009 VL 284 IS 17 BP 11346 EP 11353 DI 10.1074/jbc.M807336200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 437NP UT WOS:000265494500039 PM 19251691 ER PT J AU Tian, P Bernstein, HD AF Tian, Pu Bernstein, Harris D. TI Identification of a Post-targeting Step Required for Efficient Cotranslational Translocation of Proteins across the Escherichia coli Inner Membrane SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SIGNAL-RECOGNITION PARTICLE; MALTOSE-BINDING PROTEIN; CYTOPLASMIC MEMBRANE; SEQUENCE RECOGNITION; MATURE SEQUENCE; SECY COMPLEX; EXPORT; PEPTIDE; SECRETION; PATHWAY AB Recent studies have shown that cytoplasmic proteins are exported efficiently in Escherichia coli only if they are attached to signal peptides that are recognized by the signal recognition particle and are thereby targeted to the SecYEG complex cotranslationally. The evidence suggests that the entry of these proteins into the secretory pathway at an early stage of translation is necessary to prevent them from folding into a translocation-incompetent conformation. We found, however, that several glycolytic enzymes attached to signal peptides that are recognized by the signal recognition particle were exported inefficiently. Based on previous studies of post-translational export, we hypothesized that the export block was due to the presence of basic residues at the extreme N terminus of each enzyme. Consistent with our hypothesis, we found that the introduction of negatively charged residues into this segment increased the efficiency of export. Export efficiency was sensitive to the number, position, and sequence context of charged residues. The importance of charge for efficient export was underscored by an in silico analysis that revealed a conserved negative charge bias at the N terminus of the mature region of bacterial presecretory proteins. Our results demonstrate that cotranslational targeting of a protein to the E. coli SecYEG complex does not ensure its export but that export also depends on a subsequent event (most likely the initiation of translocation) that involves sequences both within and just beyond the signal peptide. C1 [Tian, Pu; Bernstein, Harris D.] NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bldg 5,Rm 201, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov RI TIAN, PU/F-5739-2012 FU National Institutes of Health FX This work was supported, in whole or in part, by the National Institutes of Health. NR 44 TC 8 Z9 8 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 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 24 PY 2009 VL 284 IS 17 BP 11396 EP 11404 DI 10.1074/jbc.M900375200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 437NP UT WOS:000265494500044 PM 19211555 ER PT J AU Jana, SS Kim, KY Mao, J Kawamoto, S Sellers, JR Adelstein, RS AF Jana, Siddhartha S. Kim, Kye-Young Mao, Jian Kawamoto, Sachiyo Sellers, James R. Adelstein, Robert S. TI An Alternatively Spliced Isoform of Non-muscle Myosin II-C Is Not Regulated by Myosin Light Chain Phosphorylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SMOOTH-MUSCLE MYOSIN; ACTIN-BINDING LOOP; HEAVY-CHAIN; RHO-KINASE; MEROMYOSIN; CYTOKINESIS; EXPRESSION; LOCALIZATION; MECHANISM; BRAIN AB We report a novel isoform of non-muscle myosin II-C (NM II-C), NM II-C2, that is generated by alternative splicing of an exon, C2, encoding 41 amino acids in mice (33 in humans). The 41 amino acids are inserted into loop 2 of the NM II-C heavy chain within the actin binding region. Unlike most vertebrate non-muscle and smooth muscle myosin IIs, baculovirus-expressed mouse heavy meromyosin (HMM) II-C2 demonstrates no requirement for regulatory myosin light chain(MLC20) phosphorylation for maximum actin-activated MgATPase activity or maximum in vitro motility as measured by the sliding actin filament assay. In contrast, noninserted HMM II-C0 and another alternatively spliced isoform HMM II-C1, which contains 8 amino acids inserted into loop 1, are dependent on MLC20 phosphorylation for both actin-activated MgATPase activity and in vitro motility (Kim, K. Y., Kovacs, M., Kawamoto, S., Sellers, J. R., and Adelstein, R. S. (2005) J. Biol. Chem. 280, 22769-22775). HMM II-C1C2, which contains both the C1 and C2 inserts, does not require MLC20 phosphorylation for full activity similar to HMM II-C2. These constitutively active C2-inserted isoforms of NM II-C are expressed only in neuronal tissue. This is in contrast to NM II-C1 and NM II-C0, both of which are ubiquitously expressed. Full-lengthNMII-C2-GFP expressed in COS-7 cells localizes to filaments in interphase cells and to the cytokinetic ring in dividing cells. C1 [Jana, Siddhartha S.; Kim, Kye-Young; Mao, Jian; Kawamoto, Sachiyo; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Jana, Siddhartha S.] Indian Assoc Cultivat Sci, Dept Biol Chem, Kolkata 700032, India. RP Jana, SS (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. EM bcssj@iacs.res.in OI Adelstein, Robert/0000-0002-8683-2144 NR 38 TC 19 Z9 21 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD APR 24 PY 2009 VL 284 IS 17 BP 11563 EP 11571 DI 10.1074/jbc.M806574200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 437NP UT WOS:000265494500060 PM 19240025 ER PT J AU Yap, MN Bernstein, HD AF Yap, Mee-Ngan Bernstein, Harris D. TI The Plasticity of a Translation Arrest Motif Yields Insights into Nascent Polypeptide Recognition inside the Ribosome Tunnel SO MOLECULAR CELL LA English DT Article ID PEPTIDYL-TRANSFER-RNA; TNA OPERON EXPRESSION; ESCHERICHIA-COLI; EXIT TUNNEL; TRYPTOPHAN INDUCTION; MEMBRANE-PROTEINS; MESSENGER-RNA; A-SITE; SECM; TRANSLOCON AB The recognition of a C-terminal motif in E. coli SecM ((150)FXXXXWIXXXXGIRAGP(166)) inside the ribosome tunnel causes translation arrest, but the mechanism of recognition is unknown. Whereas single mutations in this motif impair recognition, we demonstrate that new arrest-inducing peptides can be created through remodeling of the SecM C terminus. We found that R163 is indispensable but that flanking residues that vary in number and position play an important secondary role in translation arrest. The observation that individual SecM variants showed a distinct pattern of crosslinking to ribosomal proteins suggests that each peptide adopts a unique conformation inside the tunnel. Based on the results, we propose that translation arrest occurs when the peptide conformation specified by flanking residues moves R163 into a precise intratunnel location. Our data indicate that translation arrest results from extensive communication between SecM and the tunnel and help to explain the striking diversity of arrest-inducing peptides found throughout nature. C1 [Yap, Mee-Ngan; Bernstein, Harris D.] NIDDKD, NIH, Genet & Biochem Branch, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDKD, NIH, Genet & Biochem Branch, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov FU NIDDK Intramural Research Program FX We thank John Atkins, Lauren Bakaletz, Alexander Mankin, Greg Phillips, Peter Schultz, Cathy Squires, and Michael Yarmolinsky for gifts of plasmids and strains and Will Prinz and Gigi Storz for critical reading of the manuscript. This work was supported by the NIDDK Intramural Research Program. NR 34 TC 57 Z9 58 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD APR 24 PY 2009 VL 34 IS 2 BP 201 EP 211 DI 10.1016/j.molcel.2009.04.002 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 437XX UT WOS:000265521300011 PM 19394297 ER PT J AU Wang, SS Purdue, MP Cerhan, JR Zheng, TZ Menashe, I Armstrong, BK Lan, Q Hartge, P Kricker, A Zhang, YW Morton, LM Vajdic, CM Holford, TR Severson, RK Grulich, A Leaderer, BP Davis, S Cozen, W Yeager, M Chanock, SJ Chatterjee, N Rothman, N AF Wang, Sophia S. Purdue, Mark P. Cerhan, James R. Zheng, Tongzhang Menashe, Idan Armstrong, Bruce K. Lan, Qing Hartge, Patricia Kricker, Anne Zhang, Yawei Morton, Lindsay M. Vajdic, Claire M. Holford, Theodore R. Severson, Richard K. Grulich, Andrew Leaderer, Brian P. Davis, Scott Cozen, Wendy Yeager, Meredith Chanock, Stephen J. Chatterjee, Nilanjan Rothman, Nathaniel TI Common Gene Variants in the Tumor Necrosis Factor (TNF) and TNF Receptor Superfamilies and NF-kappa B Transcription Factors and Non-Hodgkin Lymphoma Risk SO PLOS ONE LA English DT Article AB Background: A promoter polymorphism in the pro-inflammatory cytokine tumor necrosis factor (TNF) (TNF G-308A) is associated with increased non-Hodgkin lymphoma (NHL) risk. The protein product, TNF-alpha, activates the nuclear factor kappa beta (NF-kappa B) transcription factor, and is critical for inflammatory and apoptotic responses in cancer progression. We hypothesized that the TNF and NF-kappa B pathways are important for NHL and that gene variations across the pathways may alter NHL risk. Methodology/Principal Findings: We genotyped 500 tag single nucleotide polymorphisms (SNPs) from 48 candidate gene regions (defined as 20 kb 5', 10 kb 3') in the TNF and TNF receptor superfamilies and the NF-kappa B and related transcription factors, in 1946 NHL cases and 1808 controls pooled from three independent population-based case-control studies. We obtaineded a gene region-level summary of association by computing the minimum p-value ("minP test''). We used logistic regression to compute odds ratios and 95% confidence intervals for NHL and four major NHL subtypes in relation to SNP genotypes and haplotypes. For NHL, the tail strength statistic supported an overall relationship between the TNF/NF-kappa B pathway and NHL (p = 0.02). We confirmed the association between TNF/LTA on chromosome 6p21.3 with NHL and found the LTA rs2844484 SNP most significantly and specifically associated with the major subtype, diffuse large B-cell lymphoma (DLBCL) (p-trend = 0.001). We also implicated for the first time, variants in NFKBIL1 on chromosome 6p21.3, associated with NHL. Other gene regions identified as statistically significantly associated with NHL included FAS, IRF4, TNFSF13B, TANK, TNFSF7 and TNFRSF13C. Accordingly, the single most significant SNPs associated with NHL were FAS rs4934436 (p-trend = 0.0024), IRF4 rs12211228 (p-trend = 0.0026), TNFSF13B rs2582869 (p-trend = 0.0055), TANK rs1921310 (p-trend = 0.0025), TNFSF7 rs16994592 (p-trend = 0.0024), and TNFRSF13C rs6002551 (p-trend = 0.0074). All associations were consistent in each study with no apparent specificity for NHL subtype. Conclusions/Significance: Our results provide consistent evidence that variation in the TNF superfamily of genes and specifically within chromosome 6p21.3 impacts lymphomagenesis. Further characterization of these susceptibility loci and identification of functional variants are warranted. RP Wang, SS (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. EM wangso@mail.nih.gov RI Morton, Lindsay/B-5234-2015; Purdue, Mark/C-9228-2016 OI Morton, Lindsay/0000-0001-9767-2310; Purdue, Mark/0000-0003-1177-3108 FU Intramural NIH HHS; NCI NIH HHS [N02-PC-71105, N01 PC065064, N01 PC067008, N01 PC067009, N01 PC067010, N01-PC-67009, R01 CA062006] NR 51 TC 60 Z9 60 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 APR 24 PY 2009 VL 4 IS 4 AR e5360 DI 10.1371/journal.pone.0005360 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437VG UT WOS:000265514400022 PM 19390683 ER PT J AU Elsik, CG Tellam, RL Worley, KC Gibbs, RA Abatepaulo, ARR Abbey, CA Adelson, DL Aerts, J Ahola, V Alexander, L Alioto, T Almeida, IG Amadio, AF Anatriello, E Antonarakis, SE Anzola, JM Astashyn, A Bahadue, SM Baldwin, CL Barris, W Baxter, R Bell, SN Bennett, AK Bennett, GL Biase, FH Boldt, CR Bradley, DG Brinkman, FSL Brinkmeyer-Langford, CL Brown, WC Brownstein, MJ Buhay, C Caetano, AR Camara, F Carroll, JA Carvalho, WA Casey, T Cervelatti, EP Chack, J Chacko, E Chandrabose, MM Chapin, JE Chapple, CE Chen, HC Chen, L Cheng, Y Cheng, Z Childers, CP Chitko-McKown, CG Chiu, R Choi, JW Chrast, J Colley, AJ Connelley, T Cree, A Curry, S Dalrymple, B Diep Dao, M Davis, C de Oliveira, CJF de Miranda Santos, IKF de Campos, TA Deobald, H Devinoy, E Dickens, CM Ding, Y Dinh, HH De Donato, M Donohue, KE Donthu, R Dovc, P Dugan-Rocha, S Durbin, KJ Eberlein, A Edgar, RC Egan, A Eggen, A Eichler, EE Elhaik, E Ellis, SA Elnitski, L Ermolaeva, O Eyras, E Fitzsimmons, CJ Fowler, GR Franzin, AM Fritz, K Gabisi, RA Garcia, GR Garcia, JF Genini, S Gerlach, D German, JB Gilbert, JGR Gill, CA Gladney, CJ Glass, EJ Goodell, J Grant, JR Graur, D Greaser, ML Green, JA Green, RD Guan, L Guigo, R Hadsell, DL Hagen, DE Hakimov, HA Halgren, R Hamernik, DL Hamilton, C Harhay, GP Harrow, JL Hart, EA Hastings, N Havlak, P Henrichsen, CN Hernandez, J Hernandez, M Herzig, CTA Hiendleder, SG Hines, S Hitchens, ME Hlavina, W Hobbs, M Holder, M Holt, RA Hu, ZL Hume, J Iivanainen, A Ingham, A Iso-Touru, T Jamis, C Jann, O Jensen, K Jhangiani, SN Jiang, HY Johnson, AJ Jones, SJM Joshi, V Junier, T Kapetis, D Kappes, SM Kapustin, Y Keele, JW Kent, MP Kerr, T Khalil, SS Khatib, H Kiryutin, B Kitts, P Kokocinski, F Kolbehdari, D Kovar, CL Kriventseva, EV Kumar, CG Kumar, D Lahmers, KK Landrum, M Larkin, DM Lau, LPL Leach, R Lee, JCM Lee, S Lemay, DG Lewin, HA Lewis, LR Li, CX Lien, S Liu, GE Liu, YS Liu, Y Logan, KM Lopez, J Lozado, RJ Lutzow, YS Lynn, DJ MacNeil, MD Maglott, D Malinverni, R Maqbool, NJ Marques, E Marra, MA Martin, WF Martins, NF Maruyama, SR Matukumalli, LK Mazza, R McEwan, JC McKay, SD McLean, KL McWilliam, S Medrano, JF Memili, E Moen, C Molenaar, AL Moore, SS Moore, R More, DD Moreno, BT Morgan, MB Muntean, CT Muzny, DM Nandakumar, HP Nazareth, LV Nguyen, NB Nicholas, FW Nogueira, MFG Okwuonu, GO Olsaker, I Pant, SD Panzitta, F Pastor, RCP Patel, BM Payne, GM Plass, M Poli, MA Poslusny, N Pruitt, K Pu, LL Qin, X Rachagani, S Raison, JM Ranganathan, S Ratnakumar, A Razpet, A Reecy, J Reese, JT Ren, Y Reymond, A Riggs, PK Rijnkels, M Rincon, G Roberts, A Rodriguez-Osorio, N Rodriguez-Zas, SL Romero, NE Rosenwald, A Ruiz, SJ Sabo, A Salih, H Sando, L Santibanez, J Sapojnikov, V Schein, JE Schmutz, SM Schnabel, RD Schook, L Searle, SM Seo, SW Shen, YF Shen, LB Sherman, L Skow, LC Smith, T Snelling, WM Sodergren, E Solovyev, V Song, H Song, JZ Sonstegard, TS Southey, BR Souvorov, A Spurlock, D Steffen, D Stone, RT Stothard, P Sugimoto, Y Sweedler, JV Takasuga, A Tammen, I Taniguchi, M Taylor, JF Telugu, BPVL Ucla, C Urbanski, JM Utsunomiya, YT Van, CP Vattathil, S Verschoor, CP Waardenberg, AJ Walker, A Wang, ZQ Ward, R Warren, JT Waterman, RC Weikard, R Weinstock, GM Welsh, TH Wheeler, DA Wheeler, TT White, SN Whitside, MD Wilczek-Boney, K Williams, JL Williams, RL Wilming, LG Womack, J Wright, RA Wunderlich, KR Wyss, C Yang, MQ Yang, JQ Zdobnov, EM Zhang, JK Zhao, FQ Zhu, B AF Elsik, Christine G. Tellam, Ross L. Worley, Kim C. Gibbs, Richard A. Abatepaulo, Antonio R. R. Abbey, Colette A. Adelson, David L. Aerts, Jan Ahola, Virpi Alexander, Lee Alioto, Tyler Almeida, Iassudara G. Amadio, Ariel F. Anatriello, Elen Antonarakis, Stylianos E. Anzola, Juan M. Astashyn, Alex Bahadue, Suria M. Baldwin, Cynthia L. Barris, Wes Baxter, Rebecca Bell, Stephanie Nicole Bennett, Anna K. Bennett, Gary L. Biase, Fernando H. Boldt, Clayton R. Bradley, Daniel G. Brinkman, Fiona S. L. Brinkmeyer-Langford, Candice L. Brown, Wendy C. Brownstein, Michael J. Buhay, Christian Caetano, Alexandre R. Camara, Francisco Carroll, Jeffrey A. Carvalho, Wanessa A. Casey, Theresa Cervelatti, Elaine P. Chack, Joseph Chacko, Elsa Chandrabose, Mimi M. Chapin, Jennifer E. Chapple, Charles E. Chen, Hsiu-Chuan Chen, Lin Cheng, Ye Cheng, Ze Childers, Christopher P. Chitko-McKown, Carol G. Chiu, Readman Choi, Jungwoo Chrast, Jacqueline Colley, Adam J. Connelley, Tomothy Cree, Andy Curry, Stacey Dalrymple, Brian Diep Dao, Marvin Davis, Clay de Oliveira, Carlo J. F. de Miranda Santos, Isabel K. F. de Campos, Tatiana A. Deobald, Heather Devinoy, Eve Dickins, C. Michael Yan, Ding Dinh, Huyen H. De Donato, Marcos Donohue, Kaitlin E. Donthu, Ravikiran Dovc, Peter Dugan-Rocha, Shannon Durbin, K. James Eberlein, Annett Edgar, Robert C. Egan, Amy Eggen, Andre Eichler, Evan E. Elhaik, Eran Ellis, Shirley A. Elnitski, Laura Ermolaeva, Olga Eyras, Eduardo Fitzsimmons, Carolyn J. Fowler, Gerald R. Franzin, Alessandra M. Fritz, Krista Gabisi, Ramatu Ayiesha Garcia, Gustavo R. Garcia, Jose Fernando Genini, Sem Gerlach, Daniel German, J. Bruce Gilbert, James G. R. Gill, Clare A. Gladney, Cody J. Glass, Elizabeth J. Goodell, Jason Grant, Jason R. Graur, Dan Greaser, Marion L. Green, Jonathan A. Green, Ronnie D. Guan, Leluo Guigo, Roderic Hadsell, Darryl L. Hagen, Darren E. Hakimov, Hatam A. Halgren, Rob Hamernik, Debora L. Hamilton, Cerissa Harhay, Gregory P. Harrow, Jennifer L. Hart, Elizabeth A. Hastings, Nicola Havlak, Paul Henrichsen, Charlotte N. Hernandez, Judith Hernandez, Marta Herzig, Carolyn T. A. Hiendleder, Stefan G. Hines, Sandra Hitchens, Matthew Edward Hlavina, Wratko Hobbs, Matthew Holder, Michael Holt, Robert A. Hu, Zhi-Liang Hume, Jennifer Iivanainen, Antti Ingham, Aaron Iso-Touru, Terhi Jamis, Catherine Jann, Oliver Jensen, Kirsty Jhangiani, Shalini N. Jiang, Huaiyang Johnson, Angela Jolivet Jones, Steven J. M. Joshi, Vandita Junier, Thomas Kapetis, Dimos Kappes, Steve M. Kapustin, Yuri Keele, John W. Kent, Matthew P. Kerr, Tovah Khalil, Sari S. Khatib, Hasan Kiryutin, Boris Kitts, Paul Kokocinski, Felix Kolbehdari, Davood Kovar, Christie L. Kriventseva, Evgenia V. Kumar, Charu G. Kumar, Dinesh Lahmers, Kevin K. Landrum, Melissa Larkin, Denis M. Lau, Lilian P. L. Leach, Richard Lee, Justin C. M. Lee, Sandra Lemay, Danielle G. Lewin, Harris A. Lewis, Lora R. Li, Changxi Lien, Sigbjorn Liu, George E. Liu, Yih-shin Liu, Yue Logan, Krystin M. Lopez, John Lozado, Ryan J. Lutzow, Ylva Strandberg Lynn, David J. MacNeil, Michael D. Maglott, Donna Malinverni, Roberto Maqbool, Nauman J. Marques, Elisa Marra, Marco A. Martin, William F. Martins, Natalia F. Maruyama, Sandra R. Matukumalli, Lakshmi K. Mazza, Raffaele McEwan, John C. McKay, Stephanie D. McLean, Kim L. McWilliam, Sean Medrano, Juan F. Memili, Erdogan Moen, Charles Molenaar, Adrian J. Moore, Stephen S. Moore, Richard More, Daniela D. Moreno, Barbara T. Morgan, Margaret B. Muntean, Carl T. Muzny, Donna M. Nandakumar, Hari P. Nazareth, Lynne V. Nguyen, Ngoc Bich Nicholas, Frank W. Nogueira, Marcelo F. G. Okwuonu, Geoffrey O. Olsaker, Ingrid Pant, Sameer D. Panzitta, Francesca Pastor, Rosemeire C. P. Patel, Bella Mayurkumar Payne, Gemma M. Plass, Mireya Poli, Mario A. Poslusny, Nathan Pruitt, Kim Pu, Ling-Ling Qin, Xiang Rachagani, Satyanarayana Raison, Joy M. Ranganathan, Shoba Ratnakumar, Abhirami Razpet, Andrej Reecy, James Reese, Justin T. Ren, Yanru Reymond, Alexandre Riggs, Penny K. Rijnkels, Monique Rincon, Gonzalo Roberts, Andy Rodriguez-Osorio, Nelida Rodriguez-Zas, Sandra L. Romero, Natasha E. Rosenwald, Anne Ruiz, San Juana Sabo, Aniko Salih, Hanni Sando, Lillian Santibanez, Jireh Sapojnikov, Victor Schein, Jacqueline E. Schmutz, Sheila M. Schnabel, Robert D. Schook, Lawrence Searle, Stephen M. Seo, Seongwon Shen, Yufeng Shen, Libing Sherman, Laura Skow, Loren C. Smith, Timothy Snelling, Warren M. Sodergren, Erica Solovyev, Victor Song, Henry Song, Jiuzhou Sonstegard, Tad S. Southey, Bruce R. Souvorov, Alexandre Spurlock, Diane Steffen, David Stone, Roger T. Stothard, Paul Sugimoto, Yoshikazu Sweedler, Jonathan V. Takasuga, Akiko Tammen, Imke Taniguchi, Masaaki Taylor, Jeremy F. Telugu, Bhanu Prakash V. L. Ucla, Catherine Urbanski, Jennifer M. Utsunomiya, Yuri T. Van, Curtis P. Vattathil, Selina Verschoor, Chris P. Waardenberg, Ashley J. Walker, Angela Wang, Zhiquan Ward, Robert Warren, James T. Waterman, Richard C. Weikard, Rosemarie Weinstock, George M. Welsh, Thomas H., Jr. Wheeler, David A. Wheeler, Thomas T. White, Stephen N. Whiteside, Matthew D. Wilczek-Boney, Katarzyna Williams, John L. Williams, Rex Lee, Jr. Wilming, Laurens G. Womack, James Wright, Rita A. Wunderlich, Kris R. Wyss, Carine Yang, Mary Q. Yang, Jianqi Zdobnov, Evgeny M. Zhang, Jingkun Zhao, Feng-Qi Zhu, Bin CA Bovine Genome Sequencing & Analysis Consortium TI The Genome Sequence of Taurine Cattle: A Window to Ruminant Biology and Evolution SO SCIENCE LA English DT Article ID MAMMALIAN CHROMOSOME EVOLUTION; NEONATAL FC-RECEPTOR; GENE-EXPRESSION; BOVINE; ORGANIZATION; INTERFERON; FAMILY; ROLES; SINES; MAPS AB To understand the biology and evolution of ruminants, the cattle genome was sequenced to about sevenfold coverage. The cattle genome contains a minimum of 22,000 genes, with a core set of 14,345 orthologs shared among seven mammalian species of which 1217 are absent or undetected in noneutherian (marsupial or monotreme) genomes. Cattle-specific evolutionary breakpoint regions in chromosomes have a higher density of segmental duplications, enrichment of repetitive elements, and species-specific variations in genes associated with lactation and immune responsiveness. Genes involved in metabolism are generally highly conserved, although five metabolic genes are deleted or extensively diverged from their human orthologs. The cattle genome sequence thus provides a resource for understanding mammalian evolution and accelerating livestock genetic improvement for milk and meat production. C1 [Elsik, Christine G.] Georgetown Univ, Dept Biol, Washington, DC 20057 USA. [Tellam, Ross L.] CSIRO Livestock Ind, St Lucia, Qld 4067, Australia. 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Univ Sydney, Fac Vet Sci, Sydney, NSW 2006, Australia. Univ Lausanne, Ctr Integrative Genomics, CH-1015 Lausanne, Switzerland. Baylor Coll Med, Dept Pediat Nutr, USDA Agr Res Serv, Childrens Nutr Res Ctr, Houston, TX 77030 USA. Texas A&M Univ, Dept Vet Integrative Biosci, College Stn, TX 77843 USA. Univ Geneva Med Sch, Dept Genetic Med & Dev, CH-1211 Geneva, Switzerland. Swiss Inst Bioinformatics, CH-1211 Geneva, Switzerland. Imperial Coll, S Kensington Campus, Div Mol Biosci, London SW7 2AZ, England. Texas A&M Univ, Dept Vet Pathobiol, College Stn, TX 77843 USA. Natl Inst Hlth, Natl Lib Med, Natl Ctr Biotech Information, Bethesda, MD 20892 USA. Wellcome Trust Sanger Inst Hinxton, Informatics Dept, Cambridge CB10 1HH, England. Univ London, Royal Holloway Egham, Dept Comp Sci, Surrey TW20 0EX, England. Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. Johns Hopkins Univ Sch Med, McKusick Nathans Inst Genetic Med, Baltimore, MD 21205 USA. 45 Monterey Dr, Tiburon, CA 94920 USA. 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Univ Oriente, Inst Invest Biomed & Ciencias Aplicadas, Cumana 6101, Sucre, Venezuela. Univ Saskatchewan, Dept Anim & Poultry Sci, Saskatoon, SK S7N 5A8, Canada. INRA UR1196, Genomique Phys Lactation, F-78352 Jouy En Josas, France. Univ Ljubljana, Dept Anim Sci, SI-1230 Domzale, Slovenia. Res Inst Biol Farm Anim FBN, Res Unit Mol Biol, D-18196 Dummerstorf, Germany. Univ Wisconsin Madison, Dept Anim Sci, Madison, WI 53706 USA. Univ Guelph, Dept Mol & Cellular Biol, Guelph, ON N1G 2W1, Canada. EMBL Heidelberg, Cell Biol & Biophys, Heidelberg, Germany. ITACyL, Lab Mol Biol, E-47071 Valladolid, Spain. Univ Wisconsin, Dept Dairy Sci, Madison, WI 53706 USA. Monsanto Co, Ankeny, IA 50021 USA. Natl Bur Anim Genetic Res, Genes & Genetic Res Mol Anal Lab, Karnal 132001, Haryana, India. Agr & Agri-Food Canada, Lacombe Res Ctr, Lacombe, AL T4L 1W1, Canada. Univ Guelph, Biomed Sci, Guelph, ON N1G 2W6, Canada. Univ Cattolica Sacro Cuore, Zootechnics Inst, I-29100 Piacenza, Italy. Univ Calif Davis, Dept Anim Sci, Davis, CA 95616 USA. UNESP Sao Paulo State Univ, Dept Ciencias Biol, Fac Ciencias Letras, BR-19806900 Assis, SP, Brazil. Norwegian Sch Vet Sci, Dept Basic Sci & Aquatic Med, N-0033 Oslo, Norway. INTA, Inst Genetica Ewald Favret, RA-B1712WAA Buenos Aires, Argentina. Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117597, Singapore. Univ Antioquia, Grp CENTAURO, Medellin, Colombia. Univ Illinois, Dept Chem, Urbana, IL 61801 USA. Griffith Univ, Eskitis Inst Cell & Mol Therapies, Nathan, QLD 4111, Australia. Utah State Univ, Nutr & Food Sci, Logan, UT 84322 USA. USDA Agr Res Serv, Anim Dis Res Unit, Pullman, WA 99164 USA. Univ Iowa, Dept Pharm 2 344 BSB, Iowa City, IA 52242 USA. Univ Vermont, Dept Anim Sci 211 Terrill, Burlington, VT 05405 USA. RP Elsik, CG (reprint author), Georgetown Univ, Dept Biol, 406 Reiss,37th & O St NW, Washington, DC 20057 USA. EM ce75@georgetown.edu; ross.tellam@csiro.au; kworley@bcm.edu RI Maruyama, Sandra/G-1171-2012; Ingham, Aaron/C-1166-2008; Junier, Thomas/A-6748-2011; Eyras, Eduardo/A-1560-2010; MacNeil, Michael/A-6772-2009; Keele, John/A-5846-2009; Riggs, Penny/A-8192-2008; Ward, Robert/E-1250-2011; Zhu, Bin/E-4911-2010; Bradley, Daniel/A-3240-2012; Waardenberg, Ashley/D-2595-2012; Dalrymple, Brian/F-8721-2010; Nogueira, Marcelo/D-9801-2012; Holt, Robert/C-3303-2009; Antonarakis, Stylianos/N-8866-2014; Adelson, David/E-5506-2011; Schein, Jacquie/G-3674-2015; Camara Ferreira, Francisco/G-9841-2015; Hor, Charlotte/H-5908-2015; Tellam, Ross/H-2798-2013; Guigo, Roderic/D-1303-2010; Alioto, Tyler/K-7267-2015; Marra, Marco/B-5987-2008; Anatriello, Elen/N-1429-2015; de Miranda Santos, Isabel/D-5261-2016; Jones, Steven/C-3621-2009; Glass, Elizabeth/L-4612-2016; Gasull, Martina/A-6630-2013; de Miranda Santos, Isabel/B-7597-2012; Rodrigues Caetano, Alexandre/B-5227-2017; Elsik, Christine/C-4120-2017; Pant, Sameer/D-1448-2017; Seo, Seongwon/E-9687-2013; Greaser, Marion/C-6147-2012; Sweedler, Jonathan/A-9405-2009; Zdobnov, Evgeny/K-1133-2012; Kumar, Charu/A-1582-2013; Moore, Stephen/F-5285-2013; McWilliam, Sean/H-8978-2013; Garcia, Gustavo/E-5182-2013; Utsunomiya, Yuri Tani/K-5214-2013; Brinkman, Fiona/N-3195-2013; Tang, Macy/B-9798-2014; BIASE, FERNANDO/A-3994-2010; Franzin, Alessandra/D-4545-2013; Eyras, Eduardo/L-1053-2014; OI Riggs, Penny/0000-0003-3296-320X; Ward, Robert/0000-0002-6981-4040; Dalrymple, Brian/0000-0003-3891-5233; Antonarakis, Stylianos/0000-0001-8907-5823; Adelson, David/0000-0003-2404-5636; Camara Ferreira, Francisco/0000-0002-1971-5466; Hor, Charlotte/0000-0002-5361-2372; Tellam, Ross/0000-0003-2353-1640; Guigo, Roderic/0000-0002-5738-4477; Alioto, Tyler/0000-0002-2960-5420; Glass, Elizabeth/0000-0002-6183-0185; de Miranda Santos, Isabel/0000-0002-0438-4430; Rodrigues Caetano, Alexandre/0000-0002-3419-7337; Elsik, Christine/0000-0002-4248-7713; Pant, Sameer/0000-0002-0672-4478; Jensen, Kirsty/0000-0002-0005-6931; Wilming, Laurens/0000-0002-4154-7358; Rincon, Gonzalo/0000-0002-6149-9103; Gilbert, James/0000-0001-8079-3159; Ranganathan, Shoba/0000-0002-8290-813X; Greaser, Marion/0000-0002-6583-9566; Sweedler, Jonathan/0000-0003-3107-9922; Utsunomiya, Yuri Tani/0000-0002-6526-8337; Brinkman, Fiona/0000-0002-0584-4099; Eyras, Eduardo/0000-0003-0793-6218; Gerlach, Daniel/0000-0001-9338-3765; Schnabel, Robert/0000-0001-5018-7641; Casey, Theresa/0000-0002-8835-3550; White, Stephen N./0000-0001-9255-6054; Amadio, Ariel Fernando/0000-0002-1147-4485; Rodriguez-Osorio, Nelida/0000-0002-2235-979X; Schook, Lawrence/0000-0002-6580-8364; Van Tassell, Curtis/0000-0002-8416-2087; Gill, Clare/0000-0003-2640-1825; McEwan, John/0000-0003-4801-6207; Waardenberg, Ashley/0000-0002-9382-7490; Maqbool, Nauman/0000-0002-9404-3647; Bradley, Daniel G/0000-0001-7335-7092; Nicholas, Frank/0000-0002-9178-3965; Williams, John/0000-0001-5188-7957; plass, mireya/0000-0002-9891-2723; Maruyama, Sandra/0000-0001-6807-1452; Molenaar, Adrian J./0000-0001-7347-0714; Childers, Anna/0000-0002-0747-8539; Childers, Chris/0000-0002-1253-5550; Lahmers, Kevin/0000-0002-5290-3426; Solovyev, Victor/0000-0001-8885-493X FU National Human Genome Research Institute [U54 HG003273]; U.S. Department of Agriculture's Agricultural Research Service [59-0790-3-196]; Cooperative State Research, Education, and Extension Service National Research Initiative [2004-35216-14163]; the state of Texas; Genome British Columbia; Alberta Science and Research Authority; Commonwealth Scientific and Industrial Research Organization of Australia (CSIRO); Agritech Investments Ltd; Dairy Insight, Inc; AgResearch Ltd.; Research Council of Norway; Kleberg Foundation; National, Texas, and South Dakota Beef Check-off Funds FX Funded by the National Human Genome Research Institute (NHGRI U54 HG003273); the U.S. Department of Agriculture's Agricultural Research Service (USDA-ARS agreement no. 59-0790-3-196) and Cooperative State Research, Education, and Extension Service National Research Initiative (grant no. 2004-35216-14163); the state of Texas; Genome Canada through Genome British Columbia; the Alberta Science and Research Authority; the Commonwealth Scientific and Industrial Research Organization of Australia (CSIRO); Agritech Investments Ltd., Dairy Insight, Inc., and AgResearch Ltd., all of New Zealand; the Research Council of Norway; the Kleberg Foundation; and the National, Texas, and South Dakota Beef Check-off Funds. The master accession for this WGS sequencing project is AAFC03000000. The individual WGS sequences are AAFC03000001 to AAFC03131728, and the scaffold records are CM000177 to CM000206 (chromosomes) and DS490632 to DS495890 (unplaced scaffolds). NR 28 TC 512 Z9 637 U1 12 U2 157 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 APR 24 PY 2009 VL 324 IS 5926 BP 522 EP 528 DI 10.1126/science.1169588 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 436JU UT WOS:000265411200050 ER PT J AU Pise-Masison, CA Radonovich, M Dohoney, K Morris, JC O'Mahony, D Lee, MJ Trepel, J Waldmann, TA Janik, JE Brady, JN AF Pise-Masison, Cynthia A. Radonovich, Michael Dohoney, Kathleen Morris, John C. O'Mahony, Deirdre Lee, Min-Jung Trepel, Jane Waldmann, Thomas A. Janik, John E. Brady, John N. TI Gene expression profiling of ATL patients: compilation of disease-related genes and evidence for TCF4 involvement in BIRC5 gene expression and cell viability SO BLOOD LA English DT Article ID VIRUS TYPE-I; MONOCLONAL-ANTIBODY; T-CELLS; LEUKEMIA LYMPHOMA; COMPLETE RESPONSE; IL-2 RECEPTOR; BETA-CATENIN; HTLV-1 TAX; SURVIVIN; LEUKEMIA/LYMPHOMA AB Adult T-cell leukemia/lymphoma (ATL) is an aggressive and fatal disease. We have examined 32 patients with smoldering, chronic, lymphoma and acute leukemia using Affymetrix HG-U133A2.0 arrays. Using the BRB array program, we identified genes differentially expressed in leukemia cells compared with normal lymphocytes. Several unique genes were identified that were overexpressed in leukemic cells, including TNFSF11, RGS13, MAFb, CSPG2, C/EBP-alpha, and TCF4; 200 of the most highly overexpressed ATL genes were analyzed by the Pathway Studio, version 4.0 program. ATL leukemia cells were characterized by an increase in genes linked to "central" genes CDC2/cyclin B1, SYK/LYN, proliferating cell nuclear antigen, and BIRC5. Because of its potential therapeutic importance, we focused our studies on the regulation and function of BIRC5, whose expression was increased in 13 of 14 leukemia samples. TCF4 reporter assays and transfection of DN-TCF4 demonstrated that TCF4 regulates BIRC5 gene expression. Functionally, transfection of ATL cells with BIRC5 shRNA decreased BIRC5 expression and cell viability 80%. Clinical treatment of ATL patients with Zenapax or bortezomib decreased BIRC5 expression and cell viability. These experiments represent the first direct experimental evidence that BIRC5 plays an important role in ATL cell viability and provides important insight into ATL genesis and potential targeted therapies. (Blood. 2009;113:4016-4026) C1 [Pise-Masison, Cynthia A.; Radonovich, Michael; Dohoney, Kathleen; Brady, John N.] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Morris, John C.; O'Mahony, Deirdre; Waldmann, Thomas A.; Janik, John E.] NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. [Lee, Min-Jung; Trepel, Jane] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Brady, JN (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bradyj@mail.nih.gov FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 61 TC 37 Z9 37 U1 1 U2 2 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 APR 23 PY 2009 VL 113 IS 17 BP 4016 EP 4026 DI 10.1182/blood-2008-08-175901 PG 11 WC Hematology SC Hematology GA 436WO UT WOS:000265447000021 PM 19131553 ER PT J AU Newman, AH Grundt, P Cyriac, G Deschamps, JR Taylor, M Kumar, R Ho, D Luedtke, RR AF Newman, Amy Hauck Grundt, Peter Cyriac, George Deschamps, Jeffrey R. Taylor, Michelle Kumar, Rakesh Ho, David Luedtke, Robert R. TI N-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor Antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DOPAMINE D-3 RECEPTORS; PROTEIN-COUPLED RECEPTOR; POTENTIAL ANTIPSYCHOTIC AGENT; COCAINE-SEEKING BEHAVIOR; ABUSE THERAPEUTIC AGENTS; PARTIAL AGONIST; IN-VIVO; PHARMACOLOGICAL ACTIONS; INDUCED REINSTATEMENT; SELECTIVE LIGANDS AB In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl- and 2-OCH3-phenylpiperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R- and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compounds reported to date that show high affinity (K-i = 1 nM) for D3 and similar to 400-fold selectivity over the D2 receptor subtype. Several of these analogues showed exquisite selectivity for D3 receptors over >60 other receptors, further underscoring their value as in vivo research tools. These lead compounds also have appropriate physical characteristics for in vivo exploration and therefore will be useful in determining how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders. C1 [Newman, Amy Hauck; Grundt, Peter; Cyriac, George] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Taylor, Michelle; Kumar, Rakesh; Ho, David; Luedtke, Robert R.] Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Ft Worth, TX 76107 USA. [Deschamps, Jeffrey R.] USN, Res Lab, Washington, DC 20375 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov OI Deschamps, Jeffrey/0000-0001-5845-0010 FU NIDA-IRP; NIH [DA13584-03S1, DA13584-01]; NIDA Addiction Treatment Discovery Program [N01DA-1-8816]; NIDA [Y1-DA6002]; NIH Post Baccalaureate Intramural Research Training Award (IRTA) FX This work was supported by the NIDA-IRP, NIH Grants DA13584-03S1 and DA13584-01 (R.R.L.) and NIDA Addiction Treatment Discovery Program contract with SRI (Grant N01DA-1-8816). Crystallographic studies were supported by NIDA Contract Y1-DA6002. P.G. was supported by a NIH Postdoctoral Visiting Fellowship, and G.C. was supported by a NIH Post Baccalaureate Intramural Research Training Award (IRTA) fellowship. NR 62 TC 58 Z9 58 U1 1 U2 5 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 APR 23 PY 2009 VL 52 IS 8 BP 2559 EP 2570 DI 10.1021/jm900095y PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 434RV UT WOS:000265292700039 PM 19331412 ER PT J AU Li, QS Estes, JD Schlievert, PM Duan, LJ Brosnahan, AJ Southern, PJ Reilly, CS Peterson, ML Schultz-Darken, N Brunner, KG Nephew, KR Pambuccian, S Lifson, JD Carlis, JV Haase, AT AF Li, Qingsheng Estes, Jacob D. Schlievert, Patrick M. Duan, Lijie Brosnahan, Amanda J. Southern, Peter J. Reilly, Cavan S. Peterson, Marnie L. Schultz-Darken, Nancy Brunner, Kevin G. Nephew, Karla R. Pambuccian, Stefan Lifson, Jeffrey D. Carlis, John V. Haase, Ashley T. TI Glycerol monolaurate prevents mucosal SIV transmission SO NATURE LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CD4(+) T-CELLS; VAGINAL TRANSMISSION; EPITHELIAL-CELLS; INFECTION; HIV; CHEMOKINES; RESPONSES; IMMUNITY; INNATE AB Although there has been great progress in treating human immunodeficiency virus 1 (HIV-1) infection(1), preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission(2-4). Nonetheless, studies of vaginal transmission in the simian immunodeficiency virus (SIV)-rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry(5,6). Here we show in this SIV-macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3 alpha (also known as CCL20), plasmacytoid dendritic cells and CCR5(+) cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recruits CD4(+) T cells to fuel this obligate expansion. We then show that glycerol monolaurate-a widely used antimicrobial compound(7) with inhibitory activity against the production of MIP-3 alpha and other proinflammatory cytokines(8)-can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to blockHIV-1 mucosal transmission. C1 [Li, Qingsheng; Schlievert, Patrick M.; Duan, Lijie; Brosnahan, Amanda J.; Southern, Peter J.; Haase, Ashley T.] Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. [Estes, Jacob D.; Lifson, Jeffrey D.] NCI, AIDS & Canc Virus Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Reilly, Cavan S.] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Peterson, Marnie L.] Univ Minnesota, Coll Pharm, Dept Expt & Clin Pharmacol, Minneapolis, MN 55455 USA. [Schultz-Darken, Nancy; Brunner, Kevin G.; Nephew, Karla R.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. [Pambuccian, Stefan] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Carlis, John V.] Univ Minnesota, Inst Technol, Dept Comp Sci & Engn, Minneapolis, MN 55455 USA. RP Haase, AT (reprint author), Univ Minnesota, Dept Microbiol, MMC 196,420 Delaware St SE, Minneapolis, MN 55455 USA. EM haase001@umn.edu FU National Institute of Health (NIH) [R21 AI071976, P01 AI066314]; National Cancer Institute, NIH [N01-CO-12400, HHSN266200400088C]; National Center for Research Resources [P51 RR000167]; Research Facilities Improvement Program [RR15459-01, RR020141-01] FX We thank C. Miller and D. Lu at the California National Primate Research Center, for helpful discussion and virus stocks, J. Kemnitz at the Wisconsin National Primate Research Center, for discussion and administrative support, and C. O'Neill and T. Leonard for help with the manuscript and figures. This work was supported in part by National Institute of Health (NIH) grants R21 AI071976 and P01 AI066314 (A. T. H.), funds from the National Cancer Institute, NIH, under contracts N01-CO-12400 and HHSN266200400088C (J. D. L.), and grant number P51 RR000167 from the National Center for Research Resources, a component of the NIH, to the Wisconsin National Primate Research Center. This research was conducted in part at a facility constructed with support from Research Facilities Improvement Program grant numbers RR15459-01 and RR020141-01. This publication's contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCRR or NIH. NR 26 TC 333 Z9 342 U1 0 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD APR 23 PY 2009 VL 458 IS 7241 BP 1034 EP U113 DI 10.1038/nature07831 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 436KL UT WOS:000265412900044 PM 19262509 ER PT J AU Jones, RH Velazquez, EJ Michler, RE Sopko, G Oh, JK O'Connor, CM Hill, JA Menicanti, L Sadowski, Z Desvigne-Nickens, P Rouleau, JL Lee, KL AF Jones, Robert H. Velazquez, Eric J. Michler, Robert E. Sopko, George Oh, Jae K. O'Connor, Christopher M. Hill, James A. Menicanti, Lorenzo Sadowski, Zygmunt Desvigne-Nickens, Patrice Rouleau, Jean-Lucien Lee, Kerry L. CA STICH Hypothesis 2 Investigators TI Coronary Bypass Surgery with or without Surgical Ventricular Reconstruction SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID CONGESTIVE-HEART-FAILURE; ANTERIOR MYOCARDIAL-INFARCTION; CLINICAL-TRIALS; RESTORATION; THERAPY; CARVEDILOL; DISEASE AB Background Surgical ventricular reconstruction is a specific procedure designed to reduce left ventricular volume in patients with heart failure caused by coronary artery disease. We conducted a trial to address the question of whether surgical ventricular reconstruction added to coronary-artery bypass grafting (CABG) would decrease the rate of death or hospitalization for cardiac causes, as compared with CABG alone. Methods Between September 2002 and January 2006, a total of 1000 patients with an ejection fraction of 35% or less, coronary artery disease that was amenable to CABG, and dominant anterior left ventricular dysfunction that was amenable to surgical ventricular reconstruction were randomly assigned to undergo either CABG alone (499 patients) or CABG with surgical ventricular reconstruction (501 patients). The primary outcome was a composite of death from any cause and hospitalization for cardiac causes. The median follow-up was 48 months. Results Surgical ventricular reconstruction reduced the end-systolic volume index by 19%, as compared with a reduction of 6% with CABG alone. Cardiac symptoms and exercise tolerance improved from baseline to a similar degree in the two study groups. However, no significant difference was observed in the primary outcome, which occurred in 292 patients (59%) who were assigned to undergo CABG alone and in 289 patients (58%) who were assigned to undergo CABG with surgical ventricular reconstruction ( hazard ratio for the combined approach, 0.99; 95% confidence interval, 0.84 to 1.17; P = 0.90). Conclusions Adding surgical ventricular reconstruction to CABG reduced the left ventricular volume, as compared with CABG alone. However, this anatomical change was not associated with a greater improvement in symptoms or exercise tolerance or with a reduction in the rate of death or hospitalization for cardiac causes. (ClinicalTrials.gov number, NCT00023595.) C1 [Jones, Robert H.; Velazquez, Eric J.; O'Connor, Christopher M.; Lee, Kerry L.] Duke Univ, Med Ctr, Duke Clin Res Inst, Durham, NC 27710 USA. [Michler, Robert E.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. [Sopko, George; Desvigne-Nickens, Patrice] NHLBI, NIH, Bethesda, MD 20892 USA. [Oh, Jae K.] Mayo Clin, Rochester, MN USA. [Hill, James A.] Univ Florida, Coll Med, Gainesville, FL USA. [Menicanti, Lorenzo] San Donato Hosp, Milan, Italy. [Sadowski, Zygmunt] Natl Inst Cardiol, Warsaw, Poland. [Rouleau, Jean-Lucien] Univ Montreal, Inst Cardiol Montreal, Montreal, PQ, Canada. RP Jones, RH (reprint author), Duke Univ, Med Ctr, Duke Clin Res Inst, POB 2986, Durham, NC 27710 USA. EM jones060@mc.duke.edu RI Adlbrecht, Christopher/D-3971-2009; Crestanello, Juan/E-2930-2011 OI Adlbrecht, Christopher/0000-0003-3743-3881; FU National Heart, Lung, and Blood Institute [5U01-HL-69015, 5U01-HL-69013, 5U01-HL-69010] FX Supported by grants (5U01-HL-69015, 5U01-HL-69013, and 5U01-HL-69010) from the National Heart, Lung, and Blood Institute. NR 24 TC 282 Z9 300 U1 3 U2 21 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 23 PY 2009 VL 360 IS 17 BP 1705 EP 1717 DI 10.1056/NEJMoa0900559 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 435XY UT WOS:000265377800005 PM 19329820 ER PT J AU Ikram, MA Seshadri, S Bis, JC Fornage, M DeStefano, AL Aulchenko, YS Debette, S Lumley, T Folsom, AR van den Herik, EG Bos, MJ Beiser, A Cushman, M Launer, LJ Shahar, E Struchalin, M Du, YC Glazer, NL Rosamond, WD Rivadeneira, F Kelly-Hayes, M Lopez, OL Coresh, J Hofman, A DeCarli, C Heckbert, SR Koudstaal, PJ Yang, Q Smith, NL Kase, CS Rice, K Haritunians, T Roks, G de Kort, PLM Taylor, KD de Lau, LM Oostra, BA Uitterlinden, AG Rotter, JI Boerwinkle, E Psaty, BM Mosley, TH van Duijn, CM Breteler, MMB Longstreth, WT Wolf, PA AF Ikram, M. Arfan Seshadri, Sudha Bis, Joshua C. Fornage, Myriam DeStefano, Anita L. Aulchenko, Yurii S. Debette, Stephanie Lumley, Thomas Folsom, Aaron R. van den Herik, Evita G. Bos, Michiel J. Beiser, Alexa Cushman, Mary Launer, Lenore J. Shahar, Eyal Struchalin, Maksim Du, Yangchun Glazer, Nicole L. Rosamond, Wayne D. Rivadeneira, Fernando Kelly-Hayes, Margaret Lopez, Oscar L. Coresh, Josef Hofman, Albert DeCarli, Charles Heckbert, Susan R. Koudstaal, Peter J. Yang, Qiong Smith, Nicholas L. Kase, Carlos S. Rice, Kenneth Haritunians, Talin Roks, Gerwin de Kort, Paul L. M. Taylor, Kent D. de Lau, Lonneke M. Oostra, Ben A. Uitterlinden, Andre G. Rotter, Jerome I. Boerwinkle, Eric Psaty, Bruce M. Mosley, Thomas H. van Duijn, Cornelia M. Breteler, Monique M. B. Longstreth, W. T., Jr. Wolf, Philip A. TI Genomewide Association Studies of Stroke SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ISCHEMIC-STROKE; BLOOD-PRESSURE; WNK1 GENE; FOLLOW-UP; ATHEROSCLEROSIS RISK; WIDE ASSOCIATION; LIFETIME RISK; HEART-DISEASE; FRAMINGHAM; POPULATION AB Background The genes underlying the risk of stroke in the general population remain undetermined. Methods We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/- SD] age, 63 +/- 8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. Results Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P = 0.04) and 1.42 (95% CI, 1.06 to 1.91; P = 0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P = 0.03) and 1.19 (95% CI, 1.01 to 1.41; P = 0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. Conclusions A genetic locus on chromosome 12p13 is associated with an increased risk of stroke. C1 [Ikram, M. Arfan; Aulchenko, Yurii S.; Bos, Michiel J.; Struchalin, Maksim; Hofman, Albert; Oostra, Ben A.; Uitterlinden, Andre G.; van Duijn, Cornelia M.; Breteler, Monique M. B.] Erasmus MC Univ, Med Ctr, Dept Epidemiol, Rotterdam Study, Rotterdam, Netherlands. [van den Herik, Evita G.; Bos, Michiel J.; Koudstaal, Peter J.; de Lau, Lonneke M.] Erasmus MC Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands. [Struchalin, Maksim] Erasmus MC Univ, Med Ctr, Dept Forens Mol Biol, Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus MC Univ, Med Ctr, Dept Clin Chem, Rotterdam, Netherlands. [Roks, Gerwin; de Kort, Paul L. M.] St Elizabeth Hosp, Dept Neurol, Tilburg, Netherlands. [Roks, Gerwin; de Kort, Paul L. M.] TweeSteden Hosp, Dept Neurol, Tilburg, Netherlands. [Seshadri, Sudha; DeStefano, Anita L.; Debette, Stephanie; Beiser, Alexa; Du, Yangchun; Kelly-Hayes, Margaret; Kase, Carlos S.; Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Framingham Heart Study, Boston, MA 02118 USA. [DeStefano, Anita L.; Beiser, Alexa; Du, Yangchun; Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [DeCarli, Charles] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. [Bis, Joshua C.; Glazer, Nicole L.; Psaty, Bruce M.; Longstreth, W. T., Jr.] Univ Washington, Dept Med, Cardiovasc Hlth Study, Seattle, WA 98195 USA. [Lumley, Thomas; Rice, Kenneth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Heckbert, Susan R.; Smith, Nicholas L.; Psaty, Bruce M.; Longstreth, W. T., Jr.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Longstreth, W. T., Jr.] Univ Washington, Dept Neurol, Seattle, WA 98195 USA. [Heckbert, Susan R.; Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, Dept Vet Affairs Off, Res & Dev, Seattle, WA USA. [Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Grad Sch Biomed Sci, Houston, TX USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Brown Fdn Inst Mol Med, Atherosclerosis Risk Communities Study, Houston, TX USA. [Cushman, Mary] Univ Vermont, Dept Pathol & Med, Burlington, VT 05405 USA. [Lopez, Oscar L.] Univ Pittsburgh, Sch Med, Dept Neurol, Pittsburgh, PA 15261 USA. [Lopez, Oscar L.] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15261 USA. [Haritunians, Talin; Taylor, Kent D.; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Fornage, Myriam; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol, Minneapolis, MN 55455 USA. [Folsom, Aaron R.] Univ Minnesota, Community Hlth Sch Publ Hlth, Minneapolis, MN 55455 USA. [Shahar, Eyal] Univ Arizona, Div Epidemiol & Biostat, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA. [Rosamond, Wayne D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Coresh, Josef] Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Welch Ctr Prevent, Baltimore, MD USA. [Coresh, Josef] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Mosley, Thomas H.] Univ Mississippi, Med Ctr, Dept Geriatr Med, Jackson, MS USA. [Launer, Lenore J.] NIA, Intramural Res Program, Aging Gene Environm Susceptibil Reykjavik Study, Washington, DC USA. RP Seshadri, S (reprint author), Boston Univ, Sch Med, Dept Neurol, Framingham Heart Study, 72 E Concord St, Boston, MA 02118 USA. EM suseshad@bu.edu RI DeCarli, Charles/B-5541-2009; Rice, Kenneth/A-4150-2013; Aulchenko, Yurii/M-8270-2013; Yang, Qiong/G-5438-2014; Breteler, Monique /J-5058-2014; Rivadeneira, Fernando/O-5385-2015; OI Rice, Kenneth/0000-0001-5779-4495; Aulchenko, Yurii/0000-0002-7899-1575; Rivadeneira, Fernando/0000-0001-9435-9441; Ikram, Mohammad Arfan/0000-0003-0372-8585; Seshadri, Sudha/0000-0001-6135-2622; Beiser, Alexa/0000-0001-8551-7778 FU National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC55022, R01HL087641, R01HL59367, R01HL086694, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01HL080295, R01HL087652]; National Human Genome Research Institute [U01HG004402]; National Institutes of Health (NIH) [HHSN268200625226C]; NIH Roadmap for Medical Research [UL1RR025005]; National Institute of Neurological Disorders and Stroke (NINDS); National Center for Research Resources [M01RR00069]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Cardiovascular Health Study; grants from the National Heart, Lung, and Blood Institute [N01-HC-25195]; Affymetrix for genotyping services [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center for the use of the Linux Cluster for Genetic Analysis; NINDS [NS17950]; National Institute of Aging [AG08122, AG16495, AG033193]; Framingham Heart Study), the Netherlands Organization of Scientific Research [175.010.2005.011]; Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Ageing [050-060-810]; Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly; Ministry of Education, Culture, and Science; Ministry for Health, Welfare, and Sports; European Commission; Municipality of Rotterdam to the Rotterdam Study FX Supported by grants or contracts from the National Heart, Lung, and Blood Institute (N01-HC-55015, N01-HC-55016, N01HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC55022 R01HL087641, R01HL59367, and R01HL086694), the National Human Genome Research Institute (U01HG004402), and the National Institutes of Health (NIH) (HHSN268200625226C) and the NIH Roadmap for Medical Research (UL1RR025005) to the Atherosclerosis Risk in Communities study; grants from the National Heart, Lung, and Blood Institute (N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01-HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, U01HL080295, and R01HL087652), the National Institute of Neurological Disorders and Stroke (NINDS), the National Center for Research Resources (M01RR00069, to the Cedars-Sinai General Clinical Research Center Genotyping core), and the National Institute of Diabetes and Digestive and Kidney Diseases (DK063491, to the Southern California Diabetes Endocrinology Research Center) to the Cardiovascular Health Study; grants from the National Heart, Lung, and Blood Institute (N01-HC-25195) and its contract with Affymetrix for genotyping services (N02-HL-6-4278), the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center for the use of the Linux Cluster for Genetic Analysis; and by grants from the NINDS (NS17950) and the National Institute of Aging (AG08122, AG16495, and AG033193 to the Framingham Heart Study), the Netherlands Organization of Scientific Research (175.010.2005.011), the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Ageing (050-060-810), the Erasmus Medical Center and Erasmus University, Rotterdam, the Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare, and Sports, the European Commission, and the Municipality of Rotterdam to the Rotterdam Study. NR 39 TC 250 Z9 272 U1 0 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 23 PY 2009 VL 360 IS 17 BP 1718 EP 1728 DI 10.1056/NEJMoa0900094 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 435XY UT WOS:000265377800006 PM 19369658 ER PT J AU West, TG Hild, G Siththanandan, VB Webb, MR Corrie, JET Ferenczi, MA AF West, Timothy G. Hild, Gabor Siththanandan, Verl B. Webb, Martin R. Corrie, John E. T. Ferenczi, Michael A. TI Time Course and Strain Dependence of ADP Release during Contraction of Permeabilized Skeletal Muscle Fibers SO BIOPHYSICAL JOURNAL LA English DT Article ID RABBIT PSOAS MUSCLE; INORGANIC-PHOSPHATE; ADENOSINE 5'-TRIPHOSPHATE; ACTOMYOSIN SUBFRAGMENT-1; TEMPERATURE-DEPENDENCE; SHORTENING VELOCITY; FORCE DEVELOPMENT; ATP UTILIZATION; WORKING STROKE; CAGED-ATP AB A phosphorylated, single cysteine mutant of nucleoside diphosphate kinase, labeled with N-[2-(iodoacetamido)ethyl]-7-diethylaminocoumarin-3-carboxamide (P similar to NDPK-IDCC), was used as a fluorescence probe for time-resolved measurement of changes in [MgADP] during contraction of single permeabilized rabbit psoas fibers. The dephosphorylation of the phosphorylated protein by MgADP occurs within the lattice environment of permeabilized fibers with a second-order rate constant at 120 degrees C of 10(5) M(-1) s(-1). This dephosphorylation is accompanied by a change in coumarin fluorescence. We report the time course of P-NDPK-IDCC dephosphorylation during the period of active isometric force redevelopment after quick release of fiber strain at PCa(2+) of 4.5. After a rapid length decrease of 0.5% was applied to the fiber, the extra NDPK-IDCC produced during force recovery, above the value during the approximately steady state of isometric contraction, was 2.7 +/- 0.6 mu M and 4.7 +/- 1.5 mu M at 12 and 20 degrees C, respectively. The rates of P similar to NDPK-IDCC dephosphorylation during force recovery were 28 and 50 s(-1) at 12 and 20 degrees C, respectively. The time courses of isometric force and P similar to NDPK-IDCC dephosphorylation were simulated using a seven-state reaction scheme. Relative isometric force was modeled by changes in the occupancy of strongly bound A.M.ADP.P(i) and A.M.ADP states. A strain-sensitive A.M.ADP isomerization step was rate-limiting (3-6 s(-1)) in the cross-bridge turnover during isometric contraction. At 12 degrees C, the A.M.ADP.Pi and the pre- and postisomerization A.M.ADP states comprised 56%, 38%, and 7% of the isometric force-bearing AM states, respectively. At 20 degrees C, the force-bearing A.M.ADIP.P(i) state was a lower proportion of the total force-bearing states (37%), whereas the proportion of postisomerization A.M.ADP states was higher (19%). The simulations suggested that release of cross-bridge strain caused rapid depopulation of the preisomerization A.M.ADP state and transient accumulation of MgADP in the postisomerization A.M.ADP state. Hence, the strain-sensitive isomerization of A.M.ADP seems to explain the rate of change of P similar to NDPK-IDCC dephosphorylation during force recovery. The temperature-dependent isometric distribution of myosin states is consistent with the previous observation of a small decrease in amplitude of the P(i) transient during force recovery at 20 degrees C and the current observation of an increase in amplitude of the ADP-sensitive NDPK-IDCC transient. C1 [West, Timothy G.; Hild, Gabor; Ferenczi, Michael A.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Mol Med Sect, London, England. [Hild, Gabor] Univ Pecs, Dept Biophys, Pecs, Hungary. [Siththanandan, Verl B.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Webb, Martin R.; Corrie, John E. T.] Natl Inst Med Res, MRC, London NW7 1AA, England. RP West, TG (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, Mol Med Sect, London, England. EM t.west@imperial.ac.uk RI Ferenczi, Michael/F-9510-2015 OI Ferenczi, Michael/0000-0002-0349-331X FU Medical Research Council, UK FX We thank J. Hunter for producing the NDPK, and G. Reid (MRC National Institute for Medical Research, London, UK) for producing the NPE-caged ATP. We are grateful to R. Woledge and N. Curtin for their advice on the kinetic model and their comments on the manuscript. This work was supported by the Medical Research Council, UK. NR 38 TC 5 Z9 5 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD APR 22 PY 2009 VL 96 IS 8 BP 3281 EP 3294 DI 10.1016/j.bpj.2009.01.016 PG 14 WC Biophysics SC Biophysics GA 450BX UT WOS:000266377100030 PM 19383472 ER PT J AU Ardehali, MB Yao, J Adelman, K Fuda, NJ Petesch, SJ Webb, WW Lis, JT AF Ardehali, M. Behfar Yao, Jie Adelman, Karen Fuda, Nicholas J. Petesch, Steven J. Webb, Watt W. Lis, John T. TI Spt6 enhances the elongation rate of RNA polymerase II in vivo SO EMBO JOURNAL LA English DT Article DE elongation rate; hsp70; pol II; spt6; transcription elongation ID HEAT-SHOCK GENES; P-TEFB KINASE; TRANSCRIPTION ELONGATION; SACCHAROMYCES-CEREVISIAE; DROSOPHILA-MELANOGASTER; CHROMATIN-STRUCTURE; METHYLATION STATES; MOLECULAR EVIDENCE; HISTONE EVICTION; HSP70 GENE AB Several eukaryotic transcription factors have been shown to modulate the elongation rate of RNA polymerase II (Pol II) on naked or chromatin-reconstituted templates in vitro. However, none of the tested factors have been shown to directly affect the elongation rate of Pol II in vivo. We performed a directed RNAi knock-down (KD) screen targeting 141 candidate transcription factors and identified multiple factors, including Spt6, that alter the induced Hsp70 transcript levels in Drosophila S2 cells. Spt6 is known to interact with both nucleosome structure and Pol II, and it has properties consistent with having a role in elongation. Here, ChIP assays of the first wave of Pol II after heat shock in S2 cells show that KD of Spt6 reduces the rate of Pol II elongation. Also, fluorescence recovery after photobleaching assays of GFP-Pol II in salivary gland cells show that this Spt6-dependent effect on elongation rate persists during steady-state-induced transcription, reducing the elongation rate from similar to 1100 to 500 bp/min. Furthermore, RNAi depletion of Spt6 reveals its broad requirement during different stages of development. C1 [Ardehali, M. Behfar; Fuda, Nicholas J.; Petesch, Steven J.; Lis, John T.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. [Yao, Jie; Webb, Watt W.] Cornell Univ, Sch Appl & Engn Phys, Ithaca, NY 14853 USA. [Adelman, Karen] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Lis, JT (reprint author), Cornell Univ, Dept Mol Biol & Genet, 416 Biotechnol Bldg, Ithaca, NY 14853 USA. EM jtl10@cornell.edu RI Webb, Watt/B-5905-2011; Yao, Jie/E-2229-2017 OI Yao, Jie/0000-0002-7640-4840 FU National Institute of Health [GM25232]; NSF [CHE-0242328] FX We thank the members of the Lis Lab for helpful suggestions and critical reading of this manuscript, and Dr Richard Carthew for providing the pWIZ plasmid. We also thank Brooke LaFlamme for technical advice on dissection of pupal stage flies. This work was supported by the National Institute of Health Grant GM25232 to JTL. This work was also partly performed in the Developmental Resources for Biophysical Imaging Opto-electronics and was supported by an NSF grant CHE-0242328 to WWW and JTL. NR 63 TC 59 Z9 60 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD APR 22 PY 2009 VL 28 IS 8 BP 1067 EP 1077 DI 10.1038/emboj.2009.56 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 437HU UT WOS:000265478400010 PM 19279664 ER PT J AU Cohee, L Mills, LA Kagaayi, J Jacobs, I Galiwango, R Ludigo, J Ssekasanvu, J Reynolds, SJ AF Cohee, Lauren Mills, Lisa A. Kagaayi, Joseph Jacobs, Ilana Galiwango, Ronald Ludigo, James Ssekasanvu, Joseph Reynolds, Steven J. TI High retention and appropriate use of insecticide-treated nets distributed to HIV-affected households in Rakai, Uganda: results from interviews and home visits SO MALARIA JOURNAL LA English DT Article ID PROSPECTIVE COHORT; MALARIA; OWNERSHIP; SENEGAL; NIGERIA; ADULTS; ZAMBIA AB Background: Distribution of insecticide-treated nets (ITNs) has recently been incorporated into comprehensive care strategies for HIV-positive people in malaria-endemic areas. WHO now recommends free or low-cost distribution of ITNs to all persons in malaria-endemic areas, regardless of age, pregnancy and HIV status. Knowledge about and appropriate use of ITNs among HIV-positive ITN recipients and their household members has not been well characterized. Methods: 142 randomly selected adults were interviewed in July-August 2006 to assess knowledge, retention, and appropriate use of ITNs they had received through a PEPFAR-funded comprehensive HIV care programme in rural Uganda. Results: Among all participants, 102 (72%, CI: 65%-79%) reported they had no ITNs except those provided by the programme. Of 131 participants who stated they were given >= 1 ITN, 128 (98%, CI: 96%-100%) stated they still possessed at least one programme-provided ITN. Reported programme-ITN (pITN) use by participants was high: 119 participants (91%, CI: 86%-96%) reported having slept under pITN the night prior to the survey and 115 (88%, CI: 82%-94%) reported sleeping under pITN seven days per week. Being away from home and heat were the most common reasons given for not sleeping under an ITN. A sub-study of thirteen random home visits demonstrated concordance between participants' survey reports and actual use of ITNs in homes. Conclusion: There was excellent self-reported retention and appropriate use of ITNs distributed as a part of a community-based outpatient HIV care programme. Participants perceived ITNs as useful and were unlikely to have received ITNs from other sources. C1 [Cohee, Lauren; Mills, Lisa A.; Reynolds, Steven J.] Johns Hopkins Sch Med, Baltimore, MD USA. [Kagaayi, Joseph; Galiwango, Ronald; Ludigo, James; Ssekasanvu, Joseph] Rakai Hlth Sci Program, Kalisizo, Uganda. [Jacobs, Ilana] Univ Rochester, Sch Med, Rochester, NY USA. [Reynolds, Steven J.] NIAID, NIH, Bethesda, MD 20892 USA. RP Mills, LA (reprint author), Johns Hopkins Sch Med, 1830 E Monument St 401, Baltimore, MD USA. EM lcohee@jhmi.edu; lmills7@jhmi.edu; jkagayi@rhsp.org; Ilana_Jacobs@urmc.rochester.edu; rmgaliwango@rhsp.org; jludigo@yahoo.com; joesseka@yahoo.co.uk; sjr@jhmi.edu FU National Institutes of Health FX We thank the field teams of Rakai Health Sciences Program and the study participants, especially those whose homes were visited. Support for the study was provided by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 12 TC 6 Z9 6 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD APR 22 PY 2009 VL 8 AR 76 DI 10.1186/1475-2875-8-76 PG 6 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 449JQ UT WOS:000266327300001 PM 19383173 ER PT J AU Schloesser, RJ Manji, HK Martinowich, K AF Schloesser, Robert J. Manji, Husseini K. Martinowich, Keri TI Suppression of adult neurogenesis leads to an increased hypothalamo-pituitary-adrenal axis response SO NEUROREPORT LA English DT Article DE dentate gyrus; glucocorticoid; hippocampus; hypothalamo-pituitary-adrenal axis; neurogenesis; stress ID DENTATE GYRUS; GLUCOCORTICOID-RECEPTORS; DEPRESSIVE-ILLNESS; MATERNAL-BEHAVIOR; STRESS; HIPPOCAMPUS; RAT; ADRENOCORTICOTROPIN; PROLIFERATION; CORTISOL AB Stress and glucocorticoids are among the strongest inhibitors of adult hippocampal neurogenesis. Despite the known role of the hippocampus in negative feedback regulation of the hypothalamo-pituitary-adrenal axis, whether the loss of hippocampal neurogenesis affects this inhibition has not been examined. Here we tested whether suppression of adult neurogenesis affected the hypothalamo-pituitary-adrenal axis response. Our results show that suppression of neurogenesis leads to a potentiated hypothalamo-pituitary-adrenal axis response after an exposure to a mild stressor. This study suggests that suppressed neurogenesis regulates the hypothalamo-pituitary-adrenal axis response. NeuroReport 20:553-557 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Schloesser, Robert J.; Manji, Husseini K.] NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. EM manjih@mail.nih.gov RI Martinowich, Keri/F-9841-2012; OI Martinowich, Keri/0000-0002-5237-0789 FU National Institutes of Health; National Institute of Mental Health (Bethesda, Maryland, USA); National Institute of Mental Health FX This research was supported in whole by the National Institutes of Health, National Institute of Mental Health (Bethesda, Maryland, USA). Funding was provided by the National Institute of Mental Health. The authors thank Diane Venable for outstanding technical assistance. The authors declare no conflicts of interest. NR 19 TC 76 Z9 77 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD APR 22 PY 2009 VL 20 IS 6 BP 553 EP 557 DI 10.1097/WNR.0b013e3283293e59 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 438NV UT WOS:000265563200004 PM 19322118 ER PT J AU Ng, L Ma, M Curran, T Forrest, D AF Ng, Lily Ma, Michelle Curran, Tom Forrest, Douglas TI Developmental expression of thyroid hormone receptor beta(2) protein in cone photoreceptors in the mouse SO NEUROREPORT LA English DT Article DE colour visual system; cone photoreceptor; nuclear receptor; retina; thyroid hormone receptor beta 2 ID RETINAL DEVELOPMENT; OPSIN EXPRESSION; COLOR-VISION; RESISTANCE; PITUITARY; GRADIENT; PIGMENTS; BETA-2; GENES; ALPHA AB Thyroid hormone receptor beta 2 (TR beta 2) controls the patterning of cone opsin photopigments that mediate colour vision. We raised an antiserum against TR beta 2 to study cone photoreceptor development by western blot and immunostaining analyses. TR beta 2-positive cells first appeared between embryonic day 10 (E10) and E12. Numbers increased until near birth, correlating with generation of the cone population. At birth, signals decreased until postnatal day 10, then declined to very low levels in adulthood. TR beta 2-positive cells were initially dispersed but became aligned at the edge of the outer neuroblastic layer by E15. Postnatally, these cells migrated inwardly until postnatal day 10, then outwardly to the edge of the outer nuclear layer, the location of mature cones. TR beta 2 represents a functionally unique marker for cone development. NeuroReport 20:627-631 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Forrest, Douglas] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Curran, Tom] Childrens Hosp Penn, Joseph Stokes Jr Res Inst, Philadelphia, PA USA. RP Forrest, D (reprint author), NIDDK, Clin Endocrinol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM forrestd@niddk.nih.gov RI Curran, Tom/C-1164-2008; Curran, Tom/D-7515-2011 OI Curran, Tom/0000-0003-1444-7551; FU Hirschl Award; Intramural Programme at NIDDK FX This work was supported in part by Hirschl Award and the Intramural Programme at NIDDK. NR 25 TC 23 Z9 24 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD APR 22 PY 2009 VL 20 IS 6 BP 627 EP 631 DI 10.1097/WNR.0b013e32832a2c63 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 438NV UT WOS:000265563200018 PM 19282790 ER PT J AU Cornelis, MC Qi, L Zhang, CL Kraft, P Manson, J Cai, TX Hunter, DJ Hu, FB AF Cornelis, Marilyn C. Qi, Lu Zhang, Cuilin Kraft, Peter Manson, JoAnn Cai, Tianxi Hunter, David J. Hu, Frank B. TI Joint Effects of Common Genetic Variants on the Risk for Type 2 Diabetes in U. S. Men and Women of European Ancestry SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID GENOME-WIDE ASSOCIATION; PHYSICAL-ACTIVITY; GLUCOSE-INTOLERANCE; NURSES HEALTH; LIFE-STYLE; FAT MASS; MELLITUS; LOCI; METAANALYSIS; OBESITY AB Background: Genome-wide association studies have identified novel type 2 diabetes loci, each of which has a modest impact on risk. Objective: To examine the joint effects of several type 2 diabetes risk variants and their combination with conventional risk factors on type 2 diabetes risk in 2 prospective cohorts. Design: Nested case-control study. Setting: United States. Participants: 2809 patients with type 2 diabetes and 3501 healthy control participants of European ancestry from the Health Professionals Follow-up Study and Nurses' Health Study. Measurements: A genetic risk score (GRS) was calculated on the basis of 10 polymorphisms in 9 loci. Results: After adjustment for age and body mass index (BMI), the odds ratio for type 2 diabetes with each point of GRS, corresponding to 1 risk allele, was 1.19 ( 95% CI, 1.14 to 1.24) and 1.16 (CI, 1.12 to 1.20) for men and women, respectively. Persons with a BMI of 30 kg/m(2) or greater and a GRS in the highest quintile had an odds ratio of 14.06 (CI, 8.90 to 22.18) compared with persons with a BMI less than 25 kg/m(2) and a GRS in the lowest quintile after adjustment for age and sex. Persons with a positive family history of diabetes and a GRS in the highest quintile had an odds ratio of 9.20 (CI, 5.50 to 15.40) compared with persons without a family history of diabetes and with a GRS in the lowest quintile. The addition of the GRS to a model of conventional risk factors improved discrimination by 1% ( P < 0.001). Limitation: The study focused only on persons of European ancestry; whether GRS is associated with type 2 diabetes in other ethnic groups remains unknown. Conclusion: Although its discriminatory value is currently limited, a GRS that combines information from multiple genetic variants might be useful for identifying subgroups with a particularly high risk for type 2 diabetes. C1 [Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Hu, FB (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, Channing Lab, Bldg 2,665 Huntington Ave, Boston, MA 02115 USA. EM frank.hu@channing.harvard.edu FU National Institutes of Health [DK58845, CA87969]; Canadian Institutes of Health Research Fellowship; American Heart Association Scientist Development; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development FX By the National Institutes of Health (grants DK58845 and CA87969). Dr. Cornelis is a recipient of a Canadian Institutes of Health Research Fellowship. Dr. Qi is a recipient of the American Heart Association Scientist Development Award. Dr. Zhang is supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 46 TC 129 Z9 137 U1 0 U2 10 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD APR 21 PY 2009 VL 150 IS 8 BP 541 EP W98 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 437AD UT WOS:000265457000004 PM 19380854 ER PT J AU Sturm, A Cunningham, P Dean, M AF Sturm, Armin Cunningham, Phil Dean, Michael TI The ABC transporter gene family of Daphnia pulex SO BMC GENOMICS LA English DT Article ID ATP-BINDING CASSETTE; MULTIDRUG-RESISTANCE; DROSOPHILA-MELANOGASTER; P-GLYCOPROTEIN; CAENORHABDITIS-ELEGANS; DRUG-RESISTANCE; PROTEIN; EXPRESSION; CLONING; CHANNEL AB Background: The large gene superfamily of ABC (ATP-binding cassette) transporters encodes membrane proteins involved in trafficking processes across biological membranes and further essential cell biological functions. ABC transporters are evolutionary ancient and involved in the biochemical defence against toxicants. We report here a genome-wide survey of ABC proteins of Daphnia pulex, providing for the first time information on ABC proteins in crustacea, a primarily aquatic arthropod subphylum of high ecological and economical importance. Results: We identified 64 ABC proteins in the Daphnia genome, which possesses members of all current ABC subfamilies A to H. To unravel phylogenetic relationships, ABC proteins of Daphnia were compared to those from yeast, worm, fruit fly and human. A high conservation of Daphnia of ABC transporters was observed for proteins involved in fundamental cellular processes, including the mitochondrial half transporters of the ABCB subfamily, which function in iron metabolism and transport of Fe/S protein precursors, and the members of subfamilies ABCD, ABCE and ABCF, which have roles in very long chain fatty acid transport, initiation of gene transcription and protein translation, respectively. A number of Daphnia proteins showed one-to-one orthologous relationships to Drosophila ABC proteins including the sulfonyl urea receptor (SUR), the ecdysone transporter ET23, and the eye pigment precursor transporter scarlet. As the fruit fly, Daphnia lacked homologues to the TAP protein, which plays a role in antigene processing, and the cystic fibrosis transmembrane conductance regulator (CFTR), which functions as a chloride channel. Daphnia showed two proteins homologous to MDR (multidrug resistance) P-glycoproteins (ABCB subfamily) and six proteins homologous to MRPs (multidrug resistance-associated proteins) (ABCC subfamily). However, lineage specific gene duplications in the ABCB and ABCC subfamilies complicated the inference of function. A particularly high number of gene duplications were observed in the ABCG and ABCH subfamilies, which have 23 and 15 members, respectively. Conclusion: The in silico characterisation of ABC transporters in the Daphnia pulex genome revealed that the complement of ABC transporters is as complex in crustaceans as that other metazoans. Not surprisingly, among currently available genomes, Daphnia ABC transporters most closely resemble those of the fruit fly, another arthropod. C1 [Dean, Michael] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Sturm, Armin] Univ Stirling, Inst Aquaculture, Stirling FK9 4LA, Scotland. [Cunningham, Phil] Kings Coll London, Dept Biochem, London SE1 9NH, England. RP Dean, M (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM armin.sturm@stir.ac.uk; phil.cunningham@kcl.ac.uk; dean@ncifcrf.gov RI Dean, Michael/G-8172-2012; OI Dean, Michael/0000-0003-2234-0631; Sturm, Armin/0000-0003-2632-1999 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; METACyt Initiative of Indiana University FX The sequencing and portions of the analyses were performed at the DOE Joint Genome Institute under the auspices of the U.S. Department of Energy's Office of Science, Biological and Environmental Research Program, and by the University of California, Lawrence Livermore National Laboratory under Contract No. W-7405-Eng-48, Lawrence Berkeley National Laboratory under Contract No. DE-AC02-05CH11231, Los Alamos National Laboratory under Contract No. W-7405-ENG- 36 and in collaboration with the Daphnia Genomics Consortium (DGC) http://daphnia.cgb.indiana.edu. Supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Additional analyses were performed by wFleaBase, developed at the Genome Informatics Lab of Indiana University with support to Don Gilbert from the National Science Foundation and the National Institutes of Health. Coordination infrastructure for the DGC is provided by The Center for Genomics and Bioinformatics at Indiana University, which is supported in part by the METACyt Initiative of Indiana University, funded in part through a major grant from the Lilly Endowment, Inc. Our work benefits from, and contributes to the Daphnia Genomics Consortium. NR 72 TC 42 Z9 46 U1 1 U2 29 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD APR 21 PY 2009 VL 10 AR 170 DI 10.1186/1471-2164-10-170 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 455YR UT WOS:000266805400001 PM 19383151 ER PT J AU Soung, NK Park, JE Yu, LR Lee, KH Lee, JM Bang, JK Veenstra, TD Rhee, K Lee, KS AF Soung, Nak-Kyun Park, Jung-Eun Yu, Li-Rong Lee, Kyung H. Lee, Jung-Min Bang, Jeong K. Veenstra, Timothy D. Rhee, Kunsoo Lee, Kyung S. TI PIk1-Dependent and -Independent Roles of an ODF2 Splice Variant, hCenexin1, at the Centrosome of Somatic Cells SO DEVELOPMENTAL CELL LA English DT Article ID POLO-BOX DOMAIN; PRIMARY CILIUM FORMATION; DENSE FIBER PROTEINS; MICROTUBULE NUCLEATION; MOTHER CENTRIOLES; MITOTIC FUNCTIONS; PERICENTRIN; IDENTIFICATION; KINASE; PLK1 AB Outer dense fiber 2 (ODF2) was initially identified as a major component of the sperm tail cytoskeleton, and was later suggested to be localized to somatic centrosomes and required for the formation of primary cilia. Here we show that a splice variant of hODF2 called hCenexin1, but not hODF2 itself, efficiently localizes to somatic centrosomes via a variant-specific C-terminal extension and recruits PIk1 through a Cdc2-dependent phospho-S796 motif within the extension. This interaction and PIk1 activity were important for proper recruitment of pericentrin and gamma-tubulin, and, ultimately, for formation of normal bipolar spindles. Earlier in the cell cycle, hCenexin1, but again not hODF2, also contributed to centrosomal recruitment of ninein and primary cilia formation independent of PIk1 interaction. These findings provide a striking example of how a splice-generated C-terminal extension of a sperm tail-associating protein mediates unanticipated centrosomal events at distinct stages of the somatic cell cycle. C1 [Soung, Nak-Kyun; Park, Jung-Eun; Lee, Kyung H.; Lee, Kyung S.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Yu, Li-Rong] US FDA, Ctr Prote, Div Syst Toxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Lee, Jung-Min; Rhee, Kunsoo] Seoul Natl Univ, Sch Biol Sci, Seoul 151742, South Korea. [Bang, Jeong K.] Korea Basic Sci Inst, Pusan 609735, South Korea. [Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Ft Detrick, MD 21702 USA. RP Lee, KS (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM kyunglee@mail.nih.gov FU NCI intramural grants; Korea Basic Science Institute (KBSI) [N28079] FX We are grateful to Susan Garfield and Rachel H. Lee for critical reading of the manuscript. We also thank Brian Dynlacht, Raymond L. Erikson, Chou-Zen Giam, Sigrid Hoyer-Fender, Seung Ryul Kim, Ryoko Kuriyama, Seongju Lee, Jens Luders, Andreas Merdes, David O. Morgan, Yoshitaka Ono, Myung Hee Park, Laurence Pelletier, Helen Piwnica-Worms, Jerome B. Rattner, Jeffrey L. Salisbury, David J. Sharp, Mikiko Takahashi, and Michael B. Yaffe for reagents, Susan Garfield for technical assistance in microscopy, and Shoshana Segal and David J. Goldstein, Office of Science and Technology Partnerships, NCI for support for antibody production. This work was supported in part by NCI intramural grants (K.S.L. and T.D.V.) and Korea Basic Science Institute (KBSI) project N28079 (J.K.B.). The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 31 TC 42 Z9 42 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD APR 21 PY 2009 VL 16 IS 4 BP 539 EP 550 DI 10.1016/j.devcel.2009.02.004 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 437EX UT WOS:000265470400010 PM 19386263 ER PT J AU Kofinger, J Hummer, G Dellago, C AF Koefinger, Juergen Hummer, Gerhard Dellago, Christoph TI A one-dimensional dipole lattice model for water in narrow nanopores SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE chemical potential; lattice theory; liquid structure; Monte Carlo methods; nanoporous materials; water ID CARBON NANOTUBE MEMBRANES; PROTON CONDUCTION; MASS-TRANSPORT; ION-TRANSPORT; SIMULATIONS; PROTEINS; CHANNELS; BEHAVIOR AB We present a recently developed one-dimensional dipole lattice model that accurately captures the key properties of water in narrow nanopores. For this model, we derive three equivalent representations of the Hamiltonian that together yield a transparent physical picture of the energetics of the water chain and permit efficient computer simulations. In the charge representation, the Hamiltonian consists of nearest-neighbor interactions and Coulomb-like interactions of effective charges at the ends of dipole ordered segments. Approximations based on the charge picture shed light on the influence of the Coulomb-like interactions on the structure of nanopore water. We use Monte Carlo simulations to study the system behavior of the full Hamiltonian and its approximations as a function of chemical potential and system size and investigate the bimodal character of the density distribution occurring at small system sizes. C1 [Koefinger, Juergen; Dellago, Christoph] Univ Vienna, Fac Phys, A-1090 Vienna, Austria. [Hummer, Gerhard] NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kofinger, J (reprint author), Univ Vienna, Fac Phys, Boltzmanngasse 5, A-1090 Vienna, Austria. EM christoph.dellago@univie.ac.at RI Dellago, Christoph/E-1625-2011; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Intramural NIH HHS NR 32 TC 12 Z9 12 U1 0 U2 7 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD APR 21 PY 2009 VL 130 IS 15 AR 154110 DI 10.1063/1.3106223 PG 16 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 437KL UT WOS:000265486300013 PM 19388739 ER PT J AU Arsava, EM Rahman, R Rosand, J Lu, J Smith, EE Rost, NS Singhal, AB Lev, MH Furie, KL Koroshetz, WJ Sorensen, AG Ay, H AF Arsava, E. M. Rahman, R. Rosand, J. Lu, J. Smith, E. E. Rost, N. S. Singhal, A. B. Lev, M. H. Furie, K. L. Koroshetz, W. J. Sorensen, A. G. Ay, H. TI Severity of leukoaraiosis correlates with clinical outcome after ischemic stroke SO NEUROLOGY LA English DT Article ID WHITE-MATTER CHANGES; SCALE SCORE; MRI; AGE; LESIONS; BRAIN; CT; REHABILITATION; ENCEPHALOPATHY; CONNECTIVITY AB Background: Leukoaraiosis (LA) is closely associated with aging, a major determinant of clinical outcome after ischemic stroke. In this study we sought to identify whether LA, independent of advancing age, affects outcome after acute ischemic stroke. Methods: LA volume was quantified in 240 patients with ischemic stroke and MRI within 24 hours of symptom onset. We explored the relationship between LA volume at admission and clinical outcome at 6 months, as assessed by the modified Rankin Scale (mRS). An ordinal logistic regression model was developed to analyze the independent effect of LA volume on clinical outcome. Results: Bivariate analyses showed a significant correlation between LA volume and mRS at 6 months (r = 0.19, p = 0.003). Mean mRS was 1.7 +/- 1.8 among those in the lowest (<= 1.2 mL) and 2.5 +/- 1.9 in the highest (>9.9 mL) quartiles of LA volume (p = 0.01). The unfavorable prognostic effect of LA volume on clinical outcome was retained in the multivariable model (p = 0.002), which included age, gender, stroke risk factors (hypertension, diabetes mellitus, atrial fibrillation), previous history of brain infarction, admission plasma glucose level, admission NIH Stroke Scale score, IV rtPA treatment, and acute infarct volume on MRI as covariates. Conclusions: The volume of leukoaraiosis is a predictor of clinical outcome after ischemic stroke and this relationship persists after adjustment for important prognostic factors including age, initial stroke severity, and infarct volume. Neurology(R) 2009; 72: 1403-1410 C1 [Arsava, E. M.; Lu, J.; Lev, M. H.; Sorensen, A. G.; Ay, H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging,Dept Radiol, Boston, MA 02129 USA. [Rahman, R.; Rosand, J.; Smith, E. E.; Rost, N. S.; Singhal, A. B.; Furie, K. L.; Ay, H.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Stroke Serv,Dept Neurol, Boston, MA 02129 USA. [Rahman, R.; Rosand, J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02129 USA. [Rahman, R.; Rosand, J.; Rost, N. S.] MIT & Harvard, Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Koroshetz, W. J.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Ay, H (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, AA Martinos Ctr Biomed Imaging,Dept Radiol, 149 13th St,Room 2301, Boston, MA 02129 USA. EM hay@partners.org RI Arsava, Ethem Murat/I-9197-2013; OI Arsava, Ethem Murat/0000-0002-6527-4139; Smith, Eric/0000-0003-3956-1668 FU NIH [R01-NS059727, R01-NS051412, P50-NS051343, R01-HS011392, R01-NS038477] FX Supported by NIH grants R01-NS059727 (J.R.), R01-NS051412 and P50-NS051343 ( A. B. S.), P50-NS051343 ( M. H. L.), R01-HS011392 and P50-NS051343 ( K. L. F.), and R01-NS038477 ( A. G. S.). NR 39 TC 79 Z9 84 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 21 PY 2009 VL 72 IS 16 BP 1403 EP 1410 DI 10.1212/WNL.0b013e3181a18823 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 436DV UT WOS:000265393700007 PM 19380699 ER PT J AU Tao-Cheng, JH Dosemeci, A Gallant, PE Miller, S Galbraith, JA Winters, CA Azzam, R Reese, TS AF Tao-Cheng, J. -H. Dosemeci, A. Gallant, P. E. Miller, S. Galbraith, J. A. Winters, C. A. Azzam, R. Reese, T. S. TI RAPID TURNOVER OF SPINULES AT SYNAPTIC TERMINALS SO NEUROSCIENCE LA English DT Article DE hippocampal slice culture; acute brain slices; clathrin; vesicle recycling; electron microscopy ID RAT HIPPOCAMPAL SLICES; LONG-TERM POTENTIATION; PROTEIN-KINASE-II; POSTSYNAPTIC DENSITY; VESICLE ENDOCYTOSIS; DENTATE GYRUS; ACTIVE ZONE; MEMBRANE; DYNAMIN; INTERNALIZATION AB Spinules found in brain consist of small invaginations of plasma membranes which enclose membrane evaginations from adjacent cells. Here, we focus on the dynamic properties of the most common type, synaptic spinules, which reside in synaptic terminals. In order to test whether depolarization triggers synaptic spinule formation, hippocampal slice cultures (7-day-old rats, 10-14 days in culture) were exposed to high K(+) for 0.5-5 min, and examined by electron microscopy. Virtually no synaptic spinules were found in control slices representing a basal state, but numerous spinules appeared at both excitatory and inhibitory synapses after treatment with high K(+). Spinule formation peaked with similar to 1 min treatment at 37 degrees C, decreased with prolonged treatment, and disappeared after 1-2 min of washout in normal medium. The rate of disappearance of spinules was substantially slower at 4 degrees C. N-methyl-D-aspartic acid (NMDA) treatment also induced synaptic spinule formation, but to a lesser extent than high K(+) depolarization. In acute brain slices prepared from adult mice, synaptic spinules were abundant immediately after dissection at 4 degrees C, extremely rare in slices allowed to recover at 28 degrees C, but frequent after high K(+) depolarization. High pressure freezing of acute brain slices followed by freeze-substitution demonstrated that synaptic spinules are not induced by chemical fixation. These results indicate that spinules are absent in synapses at low levels of activity, but form and disappear quickly during sustained synaptic activity. The rapid turnover of synaptic spinules may represent an aspect of membrane retrieval during synaptic activity. Published by Elsevier Ltd on behalf of IBRO. C1 [Tao-Cheng, J. -H.; Azzam, R.] NINDS, EM Facil, NIH, Bethesda, MD 20892 USA. [Dosemeci, A.; Gallant, P. E.; Galbraith, J. A.; Winters, C. A.; Reese, T. S.] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Miller, S.] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. RP Tao-Cheng, JH (reprint author), NINDS, EM Facil, NIH, Bldg 49,Room 3A50, Bethesda, MD 20892 USA. EM chengs@ninds.nih.gov FU NIH; NINDS FX We thank Drs. M. W. Brightman and N. Otmakhov for helpful discussions and Virginia Crocker for assistance with the EM immunogold labeling. This research was supported by the intramural Research Program of the NIH, NINDS. NR 28 TC 14 Z9 15 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD APR 21 PY 2009 VL 160 IS 1 BP 42 EP 50 DI 10.1016/j.neuroscience.2009.02.031 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 435LG UT WOS:000265344800005 PM 19248820 ER PT J AU Moxley, JF Jewett, MC Antoniewicz, MR Villas-Boas, SG Alper, H Wheeler, RT Tong, L Hinnebusch, AG Ideker, T Nielsen, J Stephanopoulos, G AF Moxley, Joel F. Jewett, Michael C. Antoniewicz, Maciek R. Villas-Boas, Silas G. Alper, Hal Wheeler, Robert T. Tong, Lily Hinnebusch, Alan G. Ideker, Trey Nielsen, Jens Stephanopoulos, Gregory TI Linking high-resolution metabolic flux phenotypes and transcriptional regulation in yeast modulated by the global regulator Gcn4p SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE amino acid stress response; fluxomics; gcn4; systems biology ID SACCHAROMYCES-CEREVISIAE; REACTION NETWORKS; GENE-EXPRESSION; HIGH-THROUGHPUT; AMINO-ACIDS; DISTRIBUTIONS; STARVATION; PHENOMICS; RIBOSOME; PROTEIN AB Genome sequencing dramatically increased our ability to understand cellular response to perturbation. Integrating system-wide measurements such as gene expression with networks of protein protein interactions and transcription factor binding revealed critical insights into cellular behavior. However, the potential of systems biology approaches is limited by difficulties in integrating metabolic measurements across the functional levels of the cell despite their being most closely linked to cellular phenotype. To address this limitation, we developed a model-based approach to correlate mRNA and metabolic flux data that combines information from both interaction network models and flux determination models. We started by quantifying 5,764 mRNAs, 54 metabolites, and 83 experimental (13)C-based reaction fluxes in continuous cultures of yeast under stress in the absence or presence of global regulator Gcn4p. Although mRNA expression alone did not directly predict metabolic response, this correlation improved through incorporating a network-based model of amino acid biosynthesis (from r = 0.07 to 0.80 for mRNA-flux agreement). The model provides evidence of general biological principles: rewiring of metabolic flux (i.e., use of different reaction pathways) by transcriptional regulation and metabolite interaction density (i.e., level of pairwise metabolite-protein interactions) as a key biosynthetic control determinant. Furthermore, this model predicted flux rewiring in studies of follow-on transcriptional regulators that were experimentally validated with additional (13)C-based flux measurements. As a first step in linking metabolic control and genetic regulatory networks, this model underscores the importance of integrating diverse data types in large-scale cellular models. We anticipate that an integrated approach focusing on metabolic measurements will facilitate construction of more realistic models of cellular regulation for understanding diseases and constructing strains for industrial applications. C1 [Moxley, Joel F.; Antoniewicz, Maciek R.; Alper, Hal; Tong, Lily; Stephanopoulos, Gregory] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. [Wheeler, Robert T.; Ideker, Trey] Univ Calif San Diego, Dept Bioengn, San Diego, CA 92093 USA. [Hinnebusch, Alan G.] NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. [Alper, Hal] MIT, Whitehead Inst Biomed Res, Cambridge, MA 02139 USA. [Jewett, Michael C.; Villas-Boas, Silas G.; Nielsen, Jens] Tech Univ Denmark, Bioctr DTU, Ctr Microbial Biotechnol, DK-2800 Kongens Lyngby, Denmark. RP Stephanopoulos, G (reprint author), MIT, Dept Chem Engn, Cambridge, MA 02139 USA. EM gregstep@mit.edu RI Jewett, Michael/E-3506-2010; Antoniewicz, Maciek/D-4015-2009; Wheeler, Robert/B-9437-2013; OI Wheeler, Robert/0000-0003-3223-7021; Nielsen, Jens/0000-0002-9955-6003 FU National Institutes of Health [1R01 DK075850-01]; National Science Foundation International Research Fellowship Program; Singapore-Massachusetts Institute of Technology Alliance; National Center for Research Resources award [018627] FX We thank Ryan Kelley, Tong Ihn Lee, Scott McCuine, Chris Workman, Jose Aleman, Richard Young, and Gerald Fink for advice on experimental design and analysis. This work was supported by National Institutes of Health Grant 1R01 DK075850-01, the National Science Foundation International Research Fellowship Program, the Singapore-Massachusetts Institute of Technology Alliance, and National Center for Research Resources award 018627. NR 34 TC 88 Z9 91 U1 2 U2 14 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 APR 21 PY 2009 VL 106 IS 16 BP 6477 EP 6482 DI 10.1073/pnas.0811091106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437SI UT WOS:000265506800012 PM 19346491 ER PT J AU Redd, AD Dabitao, D Bream, JH Charvat, B Laeyendecker, O Kiwanuka, N Lutalo, T Kigozi, G Tobian, AAR Gamiel, J Neal, JD Oliver, AE Margolick, JB Sewankambo, N Reynolds, SJ Wawer, MJ Serwadda, D Gray, RH Quinn, TC AF Redd, Andrew D. Dabitao, Djeneba Bream, Jay H. Charvat, Blake Laeyendecker, Oliver Kiwanuka, Noah Lutalo, Tom Kigozi, Godfrey Tobian, Aaron A. R. Gamiel, Jordyn Neal, Jessica D. Oliver, Amy E. Margolick, Joseph B. Sewankambo, Nelson Reynolds, Steven J. Wawer, Maria J. Serwadda, David Gray, Ronald H. Quinn, Thomas C. TI Microbial translocation, the innate cytokine response, and HIV-1 disease progression in Africa SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HIV; microbial translocation ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL DEPLETION; IMMUNE ACTIVATION; TYPE-1 INFECTION; SIV INFECTION; UGANDA; RAKAI; AIDS; PATHOGENESIS; INDIVIDUALS AB Reports from the United States have demonstrated that elevated markers of microbial translocation from the gut may be found in chronic and advanced HIV-1 infection and are associated with an increase in immune activation. However, this phenomenon's role in HIV-1 disease in Africa is unknown. This study examined the longitudinal relationship between microbial translocation and circulating inflammatory cytokine responses in a cohort of people with varying rates of HIV-1 disease progression in Rakai, Uganda. Multiple markers for microbial translocation (lipopolysaccharide, endotoxin antibody, and sCD14) did not change significantly during HIV-1 disease progression. Moreover, circulating immunoreactive cytokine levels either decreased or remained virtually unchanged throughout disease progression. These data suggest that microbial translocation and its subsequent inflammatory immune response do not have a causal relationship with HIV-1 disease progression in Africa. C1 [Redd, Andrew D.; Laeyendecker, Oliver; Reynolds, Steven J.; Quinn, Thomas C.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Dabitao, Djeneba; Bream, Jay H.; Margolick, Joseph B.] Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Charvat, Blake; Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Univ, Dept Populat Family & Reprod Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Kiwanuka, Noah; Lutalo, Tom; Kigozi, Godfrey; Sewankambo, Nelson] Rakai Hlth Sci Program, Entebbe, Uganda. [Tobian, Aaron A. R.] Johns Hopkins Univ, Dept Pathol, Sch Med, Baltimore, MD 21287 USA. [Laeyendecker, Oliver; Gamiel, Jordyn; Neal, Jessica D.; Oliver, Amy E.; Quinn, Thomas C.] Johns Hopkins Univ, Dept Med, Sch Med, Baltimore, MD 21287 USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. RP Quinn, TC (reprint author), NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. EM tquinn@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; Redd, Andrew/D-1802-2010; OI Sewankambo, Nelson/0000-0001-9362-053X; Laeyendecker, Oliver/0000-0002-6429-4760 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, HIV Prevention Trials Network (HPTN), Office of AIDS Research, National Institutes of Health [U01AI068613]; Department of the Army (U.S. Army Medical Research and Material Command Cooperative Agreement) [DAMD17-98-2-8007]; National Institute of Allergy and Infectious Diseases [R01 A134826, R01 A134265]; National Institute of Child Health and Human Development [5P30HD06826]; World Bank STI Project, Uganda; Henry M. Jackson Foundation; Fogarty Foundation [5D43TW00010]; Bill and Melinda Gates Institute for Population and Reproductive Health FX This study was supported in part by funding from the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, HIV Prevention Trials Network (HPTN), and Office of AIDS Research, National Institutes of Health (Grant U01AI068613); Department of the Army (U.S. Army Medical Research and Material Command Cooperative Agreement DAMD17-98-2-8007); the National Institute of Allergy and Infectious Diseases (Grants R01 A134826 and R01 A134265); the National Institute of Child Health and Human Development (Grant 5P30HD06826); the World Bank STI Project, Uganda; the Henry M. Jackson Foundation; the Fogarty Foundation (Grant 5D43TW00010); and the Bill and Melinda Gates Institute for Population and Reproductive Health at Johns Hopkins University. We thank all of the participants of the Rakai cohort and the staff of the Rakai health science program. We also thank A. Asher, J. Brenchley, and D. Douek for assistance with technical training; A. Fauci for assistance with manuscript preparation; M. Chen and I. Boaz for sample identification; the Johns Hopkins Hospital Emergency Department for providing U. S. samples, and the Becton Dickinson Immune Function Laboratory at Johns Hopkins University. NR 28 TC 75 Z9 77 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 APR 21 PY 2009 VL 106 IS 16 BP 6718 EP 6723 DI 10.1073/pnas.0901983106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437SI UT WOS:000265506800054 PM 19357303 ER PT J AU Hurley, JH Ren, XF AF Hurley, James H. Ren, Xuefeng TI The circuitry of cargo flux in the ESCRT pathway SO JOURNAL OF CELL BIOLOGY LA English DT Editorial Material ID PROTEIN; COMPLEX; MODEL AB The endosomal sorting complex required for transport (ESCRT) complexes sort ubiquitinated membrane proteins into multivesicular bodies, which is a key step in the lysosomal degradation pathway. Shields et al. (Shields, S. B., A.J. Oestreich, S. Winistorfer, D. Nguyen, J.A. Payne, D.J. Katzmann, and R. Piper. 2009. J. Cell Biol. 185: 213-224) identify a new ubiquitin-binding site in ESCRT-I and provide evidence that the upstream ESCRT-I and -II complexes sort cargo in parallel rather than in series. C1 [Hurley, James H.; Ren, Xuefeng] NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov FU Intramural NIH HHS NR 14 TC 11 Z9 12 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD APR 20 PY 2009 VL 185 IS 2 BP 185 EP 187 DI 10.1083/jcb.200903013 PG 3 WC Cell Biology SC Cell Biology GA 439AR UT WOS:000265599200004 PM 19380875 ER PT J AU Galanis, E Jaeckle, KA Maurer, MJ Reid, JM Ames, MM Hardwick, JS Reilly, JF Loboda, A Nebozhyn, M Fantin, VR Richon, VM Scheithauer, B Giannini, C Flynn, PJ Moore, DF Zwiebel, J Buckner, JC AF Galanis, Evanthia Jaeckle, Kurt A. Maurer, Matthew J. Reid, Joel M. Ames, Matthew M. Hardwick, James S. Reilly, John F. Loboda, Andrey Nebozhyn, Michael Fantin, Valeria R. Richon, Victoria M. Scheithauer, Bernd Giannini, Caterina Flynn, Patrick J. Moore, Dennis F., Jr. Zwiebel, James Buckner, Jan C. TI Phase II Trial of Vorinostat in Recurrent Glioblastoma Multiforme: A North Central Cancer Treatment Group Study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SUBEROYLANILIDE HYDROXAMIC ACID; HISTONE DEACETYLASE INHIBITOR; IN-VITRO; GLIOMA; MICROARRAYS; EXPRESSION; RADIATION; GROWTH; CELLS; VIVO AB Purpose Vorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM). Patients and Methods Patients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period. Results A total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26% of patients and consisted mainly of fatigue (17%), dehydration (6%), and hypernatremia (5%); grade 3 or worse hematologic toxicity occurred in 26% of patients and consisted mainly of thrombocytopenia (22%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months. Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02). Conclusion Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted. J Clin Oncol 27: 2052-2058. (C) 2009 by American Society of Clinical Oncology C1 [Galanis, Evanthia] Mayo Clin, Rochester, MN 55905 USA. N Cent Canc Treatment Grp, Rochester, MN USA. NIH, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Wichita Community Clin Oncol Program, Wichita, KS USA. Merck, Whitehouse Stn, NJ USA. Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. Metro Minnesota Community Clin Oncol Program, St Louis Pk, MN USA. Mayo Clin, Dept Pathol, Div Med Oncol & Biostat, Rochester, MN USA. Mayo Clin, Dept Pathol, Div Oncol Res, Rochester, MN USA. RP Galanis, E (reprint author), Mayo Clin, Gonda 10-141,200 1st St SW, Rochester, MN 55905 USA. EM galanis.evanthia@mayo.edu FU North Central Cancer Treatment Group [U10 CA 25224, TRI 23XS026-T18]; Cancer Center [P30 CA 15083] FX Supported by North Central Cancer Treatment Group Grants NO. U10 CA 25224 and TRI 23XS026-T18 and Cancer Center Grant No. P30 CA 15083. NR 21 TC 163 Z9 164 U1 1 U2 8 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 APR 20 PY 2009 VL 27 IS 12 BP 2052 EP 2058 DI 10.1200/JCO.2008.19.0694 PG 7 WC Oncology SC Oncology GA 447MH UT WOS:000266194700022 PM 19307505 ER PT J AU Allegra, CJ Jessup, JM Somerfield, MR Hamilton, SR Hammond, EH Hayes, DF McAllister, PK Morton, RF Schilsky, RL AF Allegra, Carmen J. Jessup, J. Milburn Somerfield, Mark R. Hamilton, Stanley R. Hammond, Elizabeth H. Hayes, Daniel F. McAllister, Pamela K. Morton, Roscoe F. Schilsky, Richard L. TI American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS Gene Mutations in Patients With Metastatic Colorectal Carcinoma to Predict Response to Anti-Epidermal Growth Factor Receptor Monoclonal Antibody Therapy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CANCER PATIENTS; EGFR-FISH; CETUXIMAB; EXPRESSION; PANITUMUMAB; EFFICACY; PTEN AB Purpose An American Society of Clinical Oncology (ASCO) provisional clinical opinion (PCO), offers timely clinical direction to ASCO's oncologists following publication or presentation of potentially practice-changing data from major studies. This PCO addresses the utility of KRAS gene mutation testing in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody (MoAb) therapy with cetuximab or panitumumab (see Note). Clinical Context Recent results from phase II and III clinical trials demonstrate that patients with metastatic colorectal cancer benefit from therapy with monoclonal antibodies directed against the EGFR, when used either as monotherapy or combined with chemotherapy. Retrospective subset analyses of the data from these trials strongly suggest that patients who have KRAS mutations detected in codon 12 or 13 do not benefit from this therapy. Recent Data Five randomized controlled trials of cetuximab or panitumumab have evaluated outcomes for patients with metastatic colorectal carcinoma in relation to KRAS mutational status as no mutation detected (wild type) or abnormal (mutated). Another five single-arm studies have retrospectively evaluated tumor response according to KRAS status. Provisional Clinical Opinion Based on systematic reviews of the relevant literature, all patients with metastatic colorectal carcinoma who are candidates for anti-EGFR antibody therapy should have their tumor tested for KRAS mutations in a CLIA-accredited laboratory. If KRAS mutation in codon 12 or 13 is detected, then patients with metastatic colorectal carcinoma should not receive anti-EGFR antibody therapy as part of their treatment. NOTE. ASCO's provisional clinical opinions (PCOs) reflect expert consensus based on clinical evidence and literature available at the time they are written, and are intended to assist physicians in clinical decision-making and identify questions and settings for further research. Due to the rapid flow of scientific information in oncology, new evidence may have emerged since the time a PCO was submitted for publication. PCOs are not continually updated and may not reflect the most recent evidence. PCOs cannot account for individual variation among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It is the responsibility of the treating physician or other health care provider, relying on independent experience and knowledge of the patient, to determine the best course of treatment for the patient. Accordingly, adherence to any PCO is voluntary, with the ultimate determination regarding its application to be made by the physician in light of each patient's individual circumstances. ASCO PCOs describe the use of procedures and therapies in clinical practice and cannot be assumed to apply to the use of these interventions in the context of clinical trials. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of ASCO's PCOs, or for any errors or omissions. J Clin Oncol 27: 2091-2096. (C) 2009 by American Society of Clinical Oncology C1 Univ Florida, Dept Med, Div Hematol Oncol, Shands Canc Ctr, Gainesville, FL USA. NCI, Diagnost Evaluat Branch, Canc Diag Program, Div Canc Treatment & Diag,Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Div Pathol & Lab Med, Houston, TX 77030 USA. Univ Utah, Sch Med, Salt Lake City, UT USA. Univ Michigan, Med Ctr, Ann Arbor, MI USA. Univ Chicago, Pritzker Sch Med, Div Biol Sci, Chicago, IL 60637 USA. Med Oncol & Hematol Associates, Des Moines, IA USA. Amer Soc Clin Oncol, Canc Policy & Clin Affairs, Colorectal Canc Coalit, Alexandria, VA 22314 USA. RP Allegra, CJ (reprint author), Amer Soc Clin Oncol, Canc Policy & Clin Affairs, Colorectal Canc Coalit, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org NR 19 TC 692 Z9 720 U1 2 U2 32 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 APR 20 PY 2009 VL 27 IS 12 BP 2091 EP 2096 DI 10.1200/JCO.2009.21.9170 PG 6 WC Oncology SC Oncology GA 447MH UT WOS:000266194700027 PM 19188670 ER PT J AU Dodd, LE Korn, EL Freidlin, B Rubinstein, LV Mooney, MM Jaffe, CC Dancey, J AF Dodd, Lori E. Korn, Edward L. Freidlin, Boris Rubinstein, Lawrence V. Mooney, Margaret M. Jaffe, C. Carl Dancey, Janet TI Onsite Image Evaluations and Independent Image Blinded Reads: Close Cousins or Distant Relatives? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Dodd, Lori E.; Korn, Edward L.; Freidlin, Boris; Rubinstein, Lawrence V.; Mooney, Margaret M.] NCI, Bethesda, MD 20892 USA. [Jaffe, C. Carl] Boston Univ, Sch Med, Dept Radiol, Boston, MA 02118 USA. [Dancey, Janet] Ontario Inst Canc Res, Toronto, ON, Canada. RP Dodd, LE (reprint author), NCI, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 20 PY 2009 VL 27 IS 12 BP 2104 EP 2105 DI 10.1200/JCO.2008.21.4411 PG 3 WC Oncology SC Oncology GA 447MH UT WOS:000266194700033 ER PT J AU Caldwell, HK Young, WS AF Caldwell, Heather K. Young, W. Scott, III TI Persistence of reduced aggression in vasopressin 1b receptor knockout mice on a more "wild" background SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Avpr1b receptor; M.m. castaneus; Hippocampus ID MESSENGER RIBONUCLEIC-ACIDS; LATERAL SEPTAL VASOPRESSIN; SPECIES MUS-CASTANEUS; V1A RECEPTOR; RAT-BRAIN; LEUKEMIA VIRUSES; SYRIAN-HAMSTERS; SOCIAL-BEHAVIOR; V-1A RECEPTOR; ANTAGONIST AB It has been previously reported that vasopressin 1b receptor knockout (Avpr1b(-/-)) mice have reduced levels of aggressive behavior compared to wildtype littermates. However, as the background of the mice was always a mixture of 129/SvJ and C57BL/6, we wanted to determine if the phenotype persisted when our laboratory line was crossed with a wild-derived sub-species of house mice. To this end, we crossed our Avpr1b(-/-) mice with Mus musculus castaneus, one of the few sub-species that will breed with laboratory strains. Subsequent F(2) offspring were tested in a resident-intruder behavioral test to assess aggressive behavior. We found that even on this more "wild" background, Avpr1b(-/-) mice continued to demonstrate longer attack latencies and fewer attacks in a resident-intruder test than wildtype littermates. These findings are consistent with previous reports of reduced aggressive behavior in Avpr1b(-/-) mice and show that the deficit does persist on a different background strain. Further. these findings confirm the importance of the Avpr1b to normal displays of social forms of aggressive behavior. (C) 2009 Elsevier Inc. All rights reserved. C1 [Caldwell, Heather K.] Kent State Univ, Dept Biol Sci, Kent, OH 44242 USA. [Caldwell, Heather K.] Kent State Univ, Sch Biomed Sci, Kent, OH 44242 USA. [Young, W. Scott, III] NIMH, Sect Neural Gene Express, NIH, DHHS, Bethesda, MD 20892 USA. RP Caldwell, HK (reprint author), Kent State Univ, Dept Biol Sci, POB 5190,121 Cunningham, Kent, OH 44242 USA. EM hcaldwel@kent.edu RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 FU NIMH [Z01-MH-002498-20]; Division of Intramural Research, National Institute of Mental Health, National Institutes of Health, DHHS FX We thank Dr. Christine Kozak (NIAID) for providing us with the M. m. castaneus mice and the NIMH Animal Facility in Building 14 for their exceptional animal care. This research was supported, in part, by NIMH (Z01-MH-002498-20) from the Division of Intramural Research, National Institute of Mental Health, National Institutes of Health, DHHS. NR 37 TC 10 Z9 10 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD APR 20 PY 2009 VL 97 IS 1 BP 131 EP 134 DI 10.1016/j.physbeh.2009.02.006 PG 4 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 435NT UT WOS:000265351300020 PM 19419666 ER PT J AU Kino, T Manoli, I Kelkar, S Wang, YH Su, YA Chrousos, GP AF Kino, Tomoshige Manoli, Irini Kelkar, Sujata Wang, Yonghong Su, Yan A. Chrousos, George P. TI Glucocorticoid receptor (GR) beta has intrinsic, GR alpha-independent transcriptional activity SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE GR gene splicing variant; Gene expression; Nuclear translocation; RU 486 ID ISOFORMS AB The human glucocorticoid receptor (GR) gene produces C-terminal GR beta and GR alpha isoforms through alternative use of specific exons 9 beta and alpha, respectively. We explored the transcriptional activity of GR beta on endogenous genes by developing HeLa cells stably expressing EGFP-GR beta or EGFP. Microarray analyses revealed that GR beta had intrinsic gene-specific transcriptional activity, regulating mRNA expression of a large number of genes negatively or positively. Majority of GR beta-responsive genes was distinct from those modulated by GR alpha, while GR beta and GR alpha mutually modulated each other's transcriptional activity in a subpopulation of genes. We did not observe in HCT116 cells nuclear translocation of GR beta and activation of this receptor by RU 486, a synthetic steroid previously reported to bind GR beta and to induce nuclear translocation. Our results indicate that GR beta has intrinsic, GR alpha-independent, gene-specific transcriptional activity, in addition to its previously reported dominant negative effect on GR alpha-induced transactivation of GRE-driven promoters. Published by Elsevier Inc. C1 [Kino, Tomoshige; Kelkar, Sujata] CRC, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reproduct & Adult Endocrinol, Bethesda, MD 20892 USA. [Wang, Yonghong] NCI, Clin Mol Profiling Core, Adv Technol Ctr, Bethesda, MD 20892 USA. [Su, Yan A.] George Washington Univ, Dept Biochem & Mol Biol, Catherine Birch McCormick Genom Ctr, Sch Med & Hlth Sci, Washington, DC 20052 USA. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, GR-10679 Athens, Greece. RP Kino, T (reprint author), CRC, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reproduct & Adult Endocrinol, Bldg 10,Rm 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM kinot@mail.nih.gov OI Manoli, Irini/0000-0003-1543-2941 FU Intramural Research Program of NICHD [263MK611483]; NCCAR; NCI; NIH [NIH-NIDDK-06-925] FX This study was funded by the Intramural Research Program of NICHD, NCCAR and NCI, NIH. Y.A. Su was supported partially by the NIH research contract: NIH-NIDDK-06-925 from the NICHD Intramural Research Programs (263MK611483). We thank Drs. R.M. Evans, G.L. Hager and M. Okabe for providing the plasmids. NR 16 TC 73 Z9 78 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD APR 17 PY 2009 VL 381 IS 4 BP 671 EP 675 DI 10.1016/j.bbrc.2009.02.110 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 429OG UT WOS:000264929400042 PM 19248771 ER PT J AU Swanwick, CC Shapiro, ME Yi, ZH Chang, K Wenthold, RJ AF Swanwick, Catherine Croft Shapiro, Marietta E. Yi, Zhaohong Chang, Kai Wenthold, Robert J. TI NMDA receptors interact with flotillin-1 and-2, lipid raft-associated proteins SO FEBS LETTERS LA English DT Article DE Glutamate; Lipid raft; Hippocampus; Rat; Neuron ID MICRODOMAINS; SYNAPSES; SUBUNITS; PATHWAY; SPINES; FAMILY AB N-Methyl-D-aspartate receptors (NMDARs) mediate excitatory synaptic transmission in the brain. Here we demonstrate interactions between the NR2A and NR2B subunits of NMDARs with flotillin-1 (flot-1), a lipid raft-associated protein. When mapped, analogous regions in the far distal C-termini of NR2A and NR2B mediate binding to flot-1, and the prohibitin homology domain of flot-1 contains binding sites for NR2A and NR2B. Although NR2B can also directly bind to flot-2 via a separate region of its distal C-terminus, NMDARs were significantly more colocalized with flot-1 than flot-2 in cultured hippocampal neurons. Overall, this study defines a novel interaction between NMDARs and flotillins. C1 [Swanwick, Catherine Croft; Shapiro, Marietta E.; Yi, Zhaohong; Chang, Kai; Wenthold, Robert J.] Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Swanwick, CC (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bldg 50,Room 4146, Bethesda, MD 20892 USA. EM swanwickc@mail.nih.gov FU National Institute on Deafness and Other Communication Disorders (NIDCD); National Institute of General Medical Sciences (NIGMS) FX This research was funded by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders (NIDCD) and a Pharmacology Research Associate (PRAT) fellowship sponsored by the National Institute of General Medical Sciences (NIGMS). We thank Ya-Xian Wang for culturing the hippocampal neurons. NR 16 TC 18 Z9 22 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD APR 17 PY 2009 VL 583 IS 8 BP 1226 EP 1230 DI 10.1016/j.febslet.2009.03.017 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 438OT UT WOS:000265565700002 PM 19298817 ER PT J AU Hill, JA Hall, JA Sun, CM Cai, Q Ghyselinck, N Chambon, P Belkaid, Y Mathis, D Benoist, C AF Hill, Jonathan A. Hall, Jason A. Sun, Cheng-Ming Cai, Qj Ghyselinck, Norbert Chambon, Pierre Belkaid, Yasmine Mathis, Diane Benoist, Christophe TI Retinoic Acid Can Directly Promote TGF-beta-Mediated Foxp3(+) Treg Cell Conversion of Naive T Cells Response to Letter from Mucida et al. SO IMMUNITY LA English DT Letter ID INDUCTION; INHIBITION; EXPRESSION; RECEPTOR; PATHWAY C1 [Hill, Jonathan A.; Mathis, Diane; Benoist, Christophe] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Joslin Diabet Ctr,Sect Immunol & Immunog, Boston, MA 02215 USA. [Hall, Jason A.; Sun, Cheng-Ming; Belkaid, Yasmine] NIAID, NIH, Parasit Dis Lab, Mucosal Immun Unit, Bethesda, MD 20892 USA. [Hall, Jason A.] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. [Cai, Qj; Ghyselinck, Norbert; Chambon, Pierre] Univ Strasbourg 1, Inst Natl Sante & Rech Med, Ctr Natl Rech Sci, Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France. RP Benoist, C (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Joslin Diabet Ctr,Sect Immunol & Immunog, Boston, MA 02215 USA. EM cbdm@joslin.harvard.edu RI Cai, Qi/E-4357-2014; GHYSELINCK, Norbert/I-6999-2015 OI Cai, Qi/0000-0002-2598-542X; GHYSELINCK, Norbert/0000-0003-4042-6818 NR 8 TC 2 Z9 2 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 EI 1097-4180 J9 IMMUNITY JI Immunity PD APR 17 PY 2009 VL 30 IS 4 BP 472 EP 473 DI 10.1016/j.immuni.2009.03.012 PG 2 WC Immunology SC Immunology GA 435BT UT WOS:000265319000002 ER PT J AU Charles, N Watford, WT Ramos, HL Hellman, L Oettgen, HC Gomez, G Ryan, JJ O'Shea, JJ Rivera, J AF Charles, Nicolas Watford, Wendy T. Ramos, Haydee L. Hellman, Lars Oettgen, Hans C. Gomez, Gregorio Ryan, John J. O'Shea, John J. Rivera, Juan TI Lyn Kinase Controls Basophil GATA-3 Transcription Factor Expression and Induction of Th2 Cell Differentiation SO IMMUNITY LA English DT Article ID FC-EPSILON-RI; DEFICIENT MAST-CELLS; CYTOKINE PRODUCTION; NONRELEASER BASOPHILS; NEGATIVE REGULATION; AUTOIMMUNE-DISEASE; ALLERGIC RESPONSES; HISTAMINE-RELEASE; INTERFERON-GAMMA; GENETIC-EVIDENCE AB T helper 1 (Th1)-Th2 cell balance is key to host defense and its dysregulation has pathophysiological consequences. Basophils are important in Th2 cell differentiation. However, the factors controlling the onset and extent of basophil-mediated Th2 cell differentiation are unknown. Here, we demonstrate that Lyn kinase dampened basophil expression of the transcription factor GATA-3 and the initiation and extent of Th2 cell differentiation. Lyn-deficient mice had a marked basophilia, a constitutive Th2 cell skewing that was exacerbated upon in vivo challenge of basophils, produced antibodies to a normally inert antigen, and failed to appropriately respond to a Th1 cell-inducing pathogen. The Th2 cell skewing was dependent on basophils, immunoglobulin E, and interleukin-4, but was independent of mast cells. Our findings demonstrate that basophil-expressed Lyn kinase exerts regulatory control on Th2 cell differentiation and function. C1 [Charles, Nicolas; Rivera, Juan] NIAMS, NIH, Lab Immune Cell Signaling, Bethesda, MD 20892 USA. [Watford, Wendy T.; Ramos, Haydee L.; O'Shea, John J.] NIAMS, NIH, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Hellman, Lars] Uppsala Univ, Dept Cell & Mol Biol, SE-75124 Uppsala, Sweden. [Oettgen, Hans C.] Harvard Univ, Sch Med, Childrens Hosp, Dept Pediat,Div Immunol, Boston, MA 02115 USA. [Gomez, Gregorio; Ryan, John J.] Virginia Commonwealth Univ, Div Rheumatol Allergy & Immunol, Dept Internal Med, Richmond, VA 23284 USA. [Gomez, Gregorio; Ryan, John J.] Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. RP Rivera, J (reprint author), NIAMS, NIH, Lab Immune Cell Signaling, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov RI Charles, Nicolas/P-5430-2014 OI Charles, Nicolas/0000-0002-5416-5834 FU National Institutes of Health; Fondation pour la Recherche Medicale of France; MAID [R01-A1054471] FX This work was supported by the intramural research program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health. N.C. was supported in part by the Fondation pour la Recherche Medicale of France. H.C.O. is supported by MAID R01-A1054471. We thank D. Jankovic (NIAID) and J. Zhu (NIAID) for providing key reagents. We also thank the Laboratory Animal Care and Use Section, the Flow Cytometry Unit, and the Light Imaging Section of NIAMS for support of this work. We are grateful to H. Karasuyama (Tokyo Medical and Dental University) and R.L. Stevens (Harvard) for helpful discussions. The authors have no conflict of interest to declare. NR 41 TC 54 Z9 55 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD APR 17 PY 2009 VL 30 IS 4 BP 533 EP 543 DI 10.1016/j.immuni.2009.02.008 PG 11 WC Immunology SC Immunology GA 435BT UT WOS:000265319000010 PM 19362019 ER PT J AU Chung, Y Chang, SH Martinez, GJ Yang, XXO Nurieva, R Kang, HS Ma, L Watowich, SS Jetten, AM Tian, Q Dong, C AF Chung, Yeonseok Chang, Seon Hee Martinez, Gustavo J. Yang, Xuexian O. Nurieva, Roza Kang, Hong Soon Ma, Li Watowich, Stephanie S. Jetten, Anton M. Tian, Qiang Dong, Chen TI Critical Regulation of Early Th17 Cell Differentiation by Interleukin-1 Signaling SO IMMUNITY LA English DT Article ID ROR-GAMMA-T; ARYL-HYDROCARBON RECEPTOR; GROWTH-FACTOR-BETA; HYPER-IGE SYNDROME; TGF-BETA; AUTOIMMUNE MYOCARDITIS; HELPER-CELLS; T(H)17 CELLS; GENERATION; IL-21 AB T helper (Th) 17 cells have been recently discovered in both mouse and human. Here we show that interleukin-1 (IL-1) signaling on T cells is critically required for the early programming of Th17 cell lineage and Th17 cell-mediated autoimmunity. IL-1 receptor1 expression in T cells, which was induced by IL-6, was necessary for the induction of experimental autoimmune encephalomyelitis and for early Th17 cell differentiation in vivo. Moreover, IL-1 signaling in T cells was required in dendritic cell-mediated Th17 cell differentiation from naive or regulatory precursors and IL-1 synergized with IL-6 and IL-23 to regulate Th17 cell differentiation and maintain cytokine expression in effector Th17 cells. Importantly, IL-1 regulated the expression of the transcription factors IRF4 and ROR gamma t during Th17 cell differentiation; overexpression of these two factors resulted in IL-1-independent Th17 cell polarization. Our data thus indicate a critical role of IL-1 in Th17 cell differentiation and this pathway may serve as a unique target for Th17 cell-mediated immunopathology. C1 [Chung, Yeonseok; Chang, Seon Hee; Martinez, Gustavo J.; Yang, Xuexian O.; Nurieva, Roza; Watowich, Stephanie S.; Dong, Chen] Univ Texas Houston, MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. [Kang, Hong Soon; Jetten, Anton M.] Natl Inst Environm Sci, Cell Biol Sect, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Ma, Li; Tian, Qiang] Inst Syst Biol, Seattle, WA 98103 USA. RP Dong, C (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. EM cdong@mdanderson.org RI dong, chen /B-3181-2009; OI dong, chen /0000-0002-0084-9130; Jetten, Anton/0000-0003-0954-4445; Chung, Yeonseok/0000-0001-5780-4841; Watowich, Stephanie/0000-0003-1969-659X FU NIH; NIEHS; Leukemia and Lymphoma Society; MD Anderson Cancer Center; Gillson Longenbaugh Foundation; Schissler Foundation; American Heart Association; Cancer Research Institute; American Lung Association FX We thank A. Rudensky for Foxp3-GFP reporter mice, Z. He and K. Ramirez for helping cell sorting, and the entire Dong lab for their help. The work is supported by research grants from NIH (to C.D.), an Intramural Research Program of the NIEHS, NIH (to A.M.J.), Leukemia and Lymphoma Society (to C.D.), MD Anderson Cancer Center (to C.D. and S.S.W.), and the Gillson Longenbaugh Foundation (to S.S.W.). G.J.M. is a Schissler Foundation MD Anderson Cancer Center Fellow in cancer research. R.N. is a recipient of a Scientist Development Grant from the American Heart Association. C.D. is a Trust Fellow of the MD Anderson Cancer Center, a Cancer Research Institute Investigator, a Leukemia and Lymphoma Society Scholar, and an American Lung Association Career Investigator. NR 35 TC 501 Z9 528 U1 4 U2 45 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD APR 17 PY 2009 VL 30 IS 4 BP 576 EP 587 DI 10.1016/j.immuni.2009.02.007 PG 12 WC Immunology SC Immunology GA 435BT UT WOS:000265319000014 PM 19362022 ER PT J AU Thomas, JD Sloan, KB AF Thomas, Joshua D. Sloan, Kenneth B. TI Evaluation of alkyloxycarbonyloxymethyl (AOCOM) ethers as novel prodrugs of phenols for topical delivery: AOCOM prodrugs of acetaminophen SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE Prodrugs; Diffusion cell experiments; Roberts-Sloan equation; Lipid solubility; Water solubility; Topical delivery ID (ACYLOXY)ALKYL ALPHA-HALIDES; HAIRLESS MOUSE SKIN; PHYSICOCHEMICAL PROPERTIES; ENHANCED DELIVERY; IN-VITRO; PRODUCT DISTRIBUTION; HYDROLYSIS KINETICS; WATER SOLUBILITY; ESTER PRODRUGS; 5-FLUOROURACIL AB The maximum fluxes of a series of alkyloxycarbonyloxymethyl (AOCOM) ethers of acetaminophen (APAP) through hairless mouse skin from isopropyl myristate, IPM (J(MMIPM)) were measured. The J(MMIPM), solubilities in IPM (S(IPM)), water (S(AQ)) and pH 4.0 buffer (S(4.0)) and molecular weights MW were then fitted to the Roberts-Sloan (RS) equation: log J(M) = x + y log S(LIPID) + (1 - y) log S(AQ) - zMW. Only one of the prodrugs gave an improvement in the flux obtained by APAP itself. The general lack of improvement in flux seems to be due to the fact that there was no improvement in the S(AQ) values of the AOCOM derivatives compared to APAP. When the n = 5 members of the AOCOM series were added to the n = 66 database of J(MMIPM) to give n = 71 and fitted to the RS equation where S(LIPID) was S(IPM), the following coefficients were obtained: x = -0.562, y = 0.501, z = 0.00248, r(2) = 0.923. These results demonstrate the importance of improving S(AQ) for prodrugs to improve their solubilities in the skin and hence the flux of the parent drug. The RS equation, which is derived directly from Fick's law, explains this dependence of flux on SAQ. (C) 2008 Elsevier B.V. All rights reserved. C1 [Sloan, Kenneth B.] Univ Florida, Dept Med Chem, Gainesville, FL 32610 USA. [Thomas, Joshua D.] NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Sloan, KB (reprint author), Univ Florida, Dept Med Chem, POB 100485, Gainesville, FL 32610 USA. EM sloan@cop.ufl.edu NR 35 TC 6 Z9 6 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARM JI Int. J. Pharm. PD APR 17 PY 2009 VL 371 IS 1-2 BP 25 EP 32 DI 10.1016/j.ijpharm.2008.12.020 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 435RP UT WOS:000265361300004 PM 19136050 ER PT J AU Singh, S Manda, SM Sikder, D Birrer, MJ Rothermel, BA Garry, DJ Mammen, PPA AF Singh, Sarvjeet Manda, Shilpa M. Sikder, Devanjan Birrer, Michael J. Rothermel, Beverly A. Garry, Daniel J. Mammen, Pradeep P. A. TI Calcineurin Activates Cytoglobin Transcription in Hypoxic Myocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOMINANT-NEGATIVE MUTANT; HUMAN MYOGLOBIN PROMOTER; C-JUN; CARDIAC-HYPERTROPHY; OXIDATIVE STRESS; ANGIOTENSIN-II; IN-VITRO; OVEREXPRESSION PROTECTS; ADULT CARDIOMYOCYTES; REGULATORY ELEMENTS AB Cardiac hypertrophy develops in response to a variety of cardiovascular stresses and results in activation of numerous signaling cascades and proteins. In the present study, we demonstrate that cytoglobin is a stress-responsive hemoprotein in the hypoxia-induced hypertrophic myocardium and it is transcriptionally regulated by calcineurin-dependent transcription factors. The cytoglobin transcript level is abundantly expressed in the adult heart and in response to hypoxia cytoglobin expression is markedly up-regulated within the hypoxia-induced hypertrophic heart. To define the molecular mechanism resulting in the induction of cytoglobin, we undertook a transcriptional analysis of the 5' upstream regulatory region of the cytoglobin gene. Evolutionarily conserved binding elements for transcription factors HIF-1, AP-1, and NFAT are located within the upstream region of the cytoglobin gene. Transcriptional assays demonstrated that calcineurin activity modulates cytoglobin transcription. Increased calcineurin activity enhances the ability of NFAT and AP-1 to bind to the putative cytoglobin promoter, especially under hypoxic conditions. In addition, inhibition of calcineurin, NFAT, and/or AP-1 activities decreases endogenous cytoglobin transcript and protein levels. Thus, the regulation of cytoglobin transcription by calcineurin-dependent transcription factors suggests that cytoglobin may have a functional role in calcium-dependent events accompanying cardiac remodeling. C1 [Singh, Sarvjeet; Manda, Shilpa M.; Sikder, Devanjan; Rothermel, Beverly A.; Garry, Daniel J.; Mammen, Pradeep P. A.] Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA. [Garry, Daniel J.] Univ Texas SW Med Ctr Dallas, Dept Mol Biol, Dallas, TX 75390 USA. [Garry, Daniel J.; Mammen, Pradeep P. A.] Univ Texas SW Med Ctr Dallas, Donald W Reynolds Cardiovasc Clin Res Ctr, Dallas, TX 75390 USA. [Birrer, Michael J.] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. RP Mammen, PPA (reprint author), Univ Texas SW Med Ctr Dallas, Dept Internal Med, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM pradeep.mammen@utsouthwestern.edu RI singh, sarvjeet/F-1569-2015 FU National Institutes of Health [HL-63788, HL-076440]; American Heart Association-Texas; Donald W. Reynolds Clinical Cardiovascular Research Center; GlaxoSmithKline Research Foundation FX This study was supported, in whole or in part, by National Institutes of Health Grants HL-63788 (to D.J.G.) and HL-076440 (to P.P.A.M.). This study was also supported by grants from the American Heart Association-Texas Affiliate to (P.P.A.M.), the Donald W. Reynolds Clinical Cardiovascular Research Center (to D.J.G. and P.P.A.M.), and the GlaxoSmithKline Research Foundation (to P.P.A.M.). NR 78 TC 15 Z9 16 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 APR 17 PY 2009 VL 284 IS 16 BP 10409 EP 10421 DI 10.1074/jbc.M809572200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431ZZ UT WOS:000265104600015 PM 19203999 ER PT J AU Damek-Poprawa, M Diemer, T Lopes, VS Lillo, C Harper, DC Marks, MS Wu, Y Sparrow, JR Rachel, RA Williams, DS Boesze-Battaglia, K AF Damek-Poprawa, Monika Diemer, Tanja Lopes, Vanda S. Lillo, Concepcion Harper, Dawn C. Marks, Michael S. Wu, Yalin Sparrow, Janet R. Rachel, Rivka A. Williams, David S. Boesze-Battaglia, Kathleen TI Melanoregulin (MREG) Modulates Lysosome Function in Pigment Epithelial Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AGE-RELATED-CHANGES; COAT COLOR MUTATIONS; SUPPRESSOR GENE DSU; CATHEPSIN-D; DILUTE SUPPRESSOR; OUTER SEGMENTS; DEGRADATIVE FUNCTIONS; MACULAR DEGENERATION; RETINOID COMPONENT; STARGARDTS-DISEASE AB Melanoregulin (MREG), the product of the Mreg(dsu) gene, is a small highly charged protein, hypothesized to play a role in organelle biogenesis due to its effect on pigmentation in dilute, ashen, and leaden mutant mice. Here we provide evidence that MREG is required in lysosome-dependent phagosome degradation. In the Mreg(-/-) mouse, we show that loss of MREG function results in phagosome accumulation due to delayed degradation of engulfed material. Over time, the Mreg(-/-) mouse retinal pigment epithelial cells accumulate the lipofuscin component, A2E. MREG-deficient human and mouse retinal pigment epithelial cells exhibit diminished activity of the lysosomal hydrolase, cathepsin D, due to defective processing. Moreover, MREG localizes to small intracellular vesicles and associates with the endosomal phosphoinositide, phosphatidylinositol 3,5-biphosphate. Collectively, these studies suggest that MREG is required for lysosome maturation and support a role for MREG in intracellular trafficking. C1 [Damek-Poprawa, Monika; Boesze-Battaglia, Kathleen] Univ Penn, Dept Biochem, Sch Dent Med, Philadelphia, PA 19104 USA. [Diemer, Tanja; Lopes, Vanda S.; Williams, David S.] Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. [Diemer, Tanja; Lillo, Concepcion; Williams, David S.] Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. [Diemer, Tanja; Lillo, Concepcion; Williams, David S.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Wu, Yalin; Sparrow, Janet R.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Sparrow, Janet R.] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 USA. [Rachel, Rivka A.] NEI, NIH, Bethesda, MD 20892 USA. RP Boesze-Battaglia, K (reprint author), Univ Penn, Dept Biochem, Sch Dent Med, 240 S 40th St, Philadelphia, PA 19104 USA. EM battagli@biochem.dental.upenn.edu RI 2009, Secribsal/A-1266-2012; Lillo, Concepcion/A-6321-2009; OI Lillo, Concepcion/0000-0001-5814-9826; Marks, Michael/0000-0001-7435-7262 FU National Institutes of Health [EY-10420]; NEI [P30 EY001583, EY07042, EY-12951]; NEI, National Institutes of Health Core [P30 EY12598, EY00331] FX This work was supported, in whole or in part, by Public Health Service Grant EY-10420 from the National Institutes of Health, NEI and services were available through a Vision Core Grant (P30 EY001583) (to K. B.-B. and M. D.- P.), Public Health Service grant EY07042 from the NEI and services available through NEI, National Institutes of Health Core Grants (P30 EY12598 and EY00331) (to D. S. W.), Public Health Service Grant EY-12951 from the NEI (to J. R. S. and Y. W.), and Public Health Service Grant EY-15625 from the NEI (to M. S. M.). This work was also supported by an E. Matilda Ziegler Vision Award and University of Pennsylvania Research Foundation Award (KB- B). (to J. R. S. and Y. W.). NR 88 TC 19 Z9 19 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 APR 17 PY 2009 VL 284 IS 16 BP 10877 EP 10889 DI 10.1074/jbc.M808857200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431ZZ UT WOS:000265104600061 PM 19240024 ER PT J AU Kim, HS Siluk, D Wainer, IW AF Kim, Hee Seung Siluk, Danuta Wainer, Irving W. TI Quantitative determination of fenoterol and fenoterol derivatives in rat plasma using on-line immunoextraction and liquid chromatography/mass spectrometry SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 32nd International Symposium on High Performance Liquid Phase Separations and Related Techniques CY MAY 10-16, 2008 CL Baltimore, MD DE Fenoterol; Immunoextraction; Rat plasma; LC/MS ID PERFORMANCE IMMUNOAFFINITY CHROMATOGRAPHY; HUMAN SERUM-ALBUMIN; CARBAMAZEPINE BINDING; MASS-SPECTROMETRY; BETA(2)-AGONISTS; DERIVATIZATION; EXTRACTION; RESIDUES; URINE; BLOOD AB An on-line immunoextraction and liquid chromatography/mass spectrometry (LC/MS) method was developed and validated for the determination of R,R'-fenoterol, R,R'-methoxyfenoterol and R,S'-naphthylfenoterol in rat plasma. Sample preparation involved immunoextraction of analytes using an antibody raised against R.R'- and RS-aminofenoterol that was immobilized onto chromatographic support. LC was performed on a Waters hydrophilic interaction chromatography (HILIC) column (150 mm x 2.1 mm), using an isocratic mobile phase of methanol: ammonium acetate (10mM, pH 6.8) (90:10, v/v) at a flow rate of 0.2 ml/min. The MS was operated in the single ion monitoring mode (m/z 304.2 for R,R'-fenoterol, m/z 318.1 for R,R'-methoxyfenoterol, and m/z 339.2 for R,S'-naphthylfenoterol). Optimization of analytes desorption process from the immunoextraction column was performed by factorial analysis and the sample calibration curves were made with spiked rat plasma samples containing 0.5-100ng/ml of drugs. The cross-selectivity studies of the antibody were determined and the results suggested high selectivities toward R,R'-fenoterol, R,R'-methoxyfenoterol and RS-naphthylfenoterol. The accuracy of assay was more than 96% while intra-and inter-day precision of assay were less than 12.4%. Stability studies (2 h benchtop, freeze/thaw, and autosampler stability) were conducted and the analytes were stable through out studies. The validated method was used to determine the plasma concentration-time profiles of drugs after oral administration to rats of R,R'-fenoterol, R,R'-methoxyfenoterol and R,S'-naphthylfenoterol. Published by Elsevier B.V. C1 [Kim, Hee Seung; Siluk, Danuta; Wainer, Irving W.] NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Kim, HS (reprint author), NIA, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM kimhee@mail.nih.gov FU Intramural NIH HHS [Z01 AG000297-06] NR 24 TC 7 Z9 8 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD APR 17 PY 2009 VL 1216 IS 16 BP 3526 EP 3532 DI 10.1016/j.chroma.2008.08.046 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 434GD UT WOS:000265262300015 PM 18778830 ER PT J AU Wang, Y Xie, Y Bernier, M Wainer, IW AF Wang, Yan Xie, Yi Bernier, Michel Wainer, Irving W. TI Determination of free and protein-bound glutathione in HepG2 cells using capillary electrophoresis with laser-induced fluorescence detection SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 32nd International Symposium on High Performance Liquid Phase Separations and Related Techniques CY MAY 10-16, 2008 CL Baltimore, MD DE Glutathione; Pyrrolidine dithiocarbamate; 5-Iodoacetamidofluorescein; HepG2 cell; Capillary electrophoresis; Laser-induced fluorescence ID NF-KAPPA-B; OXIDATIVE STRESS; REDOX STATUS; THIOLS; SAMPLES; INJURY AB A rapid method using capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) was developed to determine free and protein-bound glutathione (GSH) in human HepG2 hepatocarcinoma cells. The samples were derivatized with 5-iodoacetamidofluorescein (5-IAF), and analyzed at 22 kV using sodium phosphate buffer (10 mM, pH 11.4) and an uncoated 58 cm x 75 mu m I.D. fused silica capillary. The analysis time was less than 10 min and N-acetylcysteine was used as internal standard. The derivatization conditions, such as reaction time. 5-IAF concentration, running buffer and cartridge temperature were optimized. Argon gas was used in the study to prevent the oxidization of GSH during sample preparation. The optimized method required only 30-40 nl sample per analysis and was fast and sensitive. The method was applied to the analyses of HepG2 cells treated with the small metal chelating agent, pyrrolidine dithiocarbamate (PDTC). The results demonstrate that the amount of protein-bound GSH. which reflects the amount of protein S-glutathionylation, increased in a time-dependent manner upon cell treatment with PDTC, reaching a maximum of over 50% increase 2 h post-PDTC. Published by Elsevier B.V. C1 [Wang, Yan; Xie, Yi; Bernier, Michel; Wainer, Irving W.] NIA, Clin Invest Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Wang, Y (reprint author), NIA, Clin Invest Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. EM wangy5@mail.nih.gov OI Bernier, Michel/0000-0002-5948-368X FU Intramural NIH HHS [Z01 AG000297-06] NR 16 TC 14 Z9 17 U1 1 U2 20 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD APR 17 PY 2009 VL 1216 IS 16 BP 3533 EP 3537 DI 10.1016/j.chroma.2008.06.027 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 434GD UT WOS:000265262300016 PM 18602637 ER PT J AU Liu, ZH Smith, CB AF Liu, Zhong-Hua Smith, Carolyn Beebe TI Dissociation of social and nonsocial anxiety in a mouse model of fragile X syndrome SO NEUROSCIENCE LETTERS LA English DT Article DE Fragile X syndrome; Anxiety; Social approach; Zero maze; Fmr1; FMRP ID FMR1 KNOCKOUT MOUSE; MENTAL-RETARDATION; MUTANT MOUSE; MICE; BEHAVIOR; MUTATION; DEFICITS; GLUCOSE; STRESS; FEAR AB Anxiety is a common symptom in fragile X patients. However, an anxiety-prone phenotype in mouse models of fragile X syndrome is not clear. In most studies of fmr1 knockout mice, decreased anxiety-like responses in exploratory-based models are found, but mice also exhibit abnormal social interactions. We hypothesize the coexistence of elevated social anxiety and reduced nonsocial anxiety in fmr1 knockout mice. In the present study, we applied an automated three-chambered social approach method and the elevated zero maze test to further investigate social interactions and general anxiety, respectively. Results indicate lower levels of both social approach behavior and response to social novelty in fmr1 knockout mice compared with wild-type littermates in the social interaction test. In the elevated zero maze,fmr1 knockout mice spent a greater percent time in open quadrants than wild-type mice, suggesting reduced nonsocial anxiety. These findings support the hypothesis that social and nonsocial anxiety can be dissociated and that in the fragile X mouse model, behavior consistent with hyper-social anxiety coexists with hypo-nonsocial anxiety. Published by Elsevier Ireland Ltd. C1 [Liu, Zhong-Hua; Smith, Carolyn Beebe] NIMH, Sect Neuroadaptat & Prot Metab, US Dept HHS, Bethesda, MD 20892 USA. RP Smith, CB (reprint author), NIMH, Sect Neuroadaptat & Prot Metab, US Dept HHS, Bldg 10 2D54,10 Ctr Dr, Bethesda, MD 20892 USA. EM beebe@mail.nih.gov FU Intramural Research Program of the National Institute of Mental Health; National Institutes of Health FX We wish to thank Zengyan Xia for overseeing the breeding colony and determining the genotypes of the mice. We also wish to thank Mei Qin for helpful discussions. The research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health. NR 33 TC 54 Z9 56 U1 0 U2 1 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 APR 17 PY 2009 VL 454 IS 1 BP 62 EP 66 DI 10.1016/j.neulet.2009.02.066 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 434LD UT WOS:000265275300013 PM 19429055 ER PT J AU Parker, SCJ Hansen, L Abaan, HO Tullius, TD Margulies, EH AF Parker, Stephen C. J. Hansen, Loren Abaan, Hatice Ozel Tullius, Thomas D. Margulies, Elliott H. TI Local DNA Topography Correlates with Functional Noncoding Regions of the Human Genome SO SCIENCE LA English DT Article ID REGULATORY SEQUENCES; MOUSE GENOME; CONSTRAINT; ELEMENTS; SITES; IDENTIFICATION; TRANSCRIPTION; RECOGNITION; 1-PERCENT AB The three-dimensional molecular structure of DNA, specifically the shape of the backbone and grooves of genomic DNA, can be dramatically affected by nucleotide changes, which can cause differences in protein-binding affinity and phenotype. We developed an algorithm to measure constraint on the basis of similarity of DNA topography among multiple species, using hydroxyl radical cleavage patterns to interrogate the solvent-accessible surface area of DNA. This algorithm found that 12% of bases in the human genome are evolutionarily constrained-double the number detected by nucleotide sequence-based algorithms. Topography-informed constrained regions correlated with functional noncoding elements, including enhancers, better than did regions identified solely on the basis of nucleotide sequence. These results support the idea that the molecular shape of DNA is under selection and can identify evolutionary history. C1 [Parker, Stephen C. J.; Hansen, Loren; Tullius, Thomas D.] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Hansen, Loren] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Abaan, Hatice Ozel; Margulies, Elliott H.] NIH, NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. [Tullius, Thomas D.] Boston Univ, Dept Chem, Boston, MA 02215 USA. RP Margulies, EH (reprint author), Boston Univ, Bioinformat Program, Boston, MA 02215 USA. EM tullius@bu.edu; elliott@nhgri.nih.gov RI Tullius, Thomas/A-9685-2008 OI Tullius, Thomas/0000-0003-4425-796X FU National Human Genome Research Institute (NHGRI), NIH [R01 HG003541]; Research Corporation for Science Advancement; Intramural Research Program of the NHGRI, NIH; National Academies Ford Foundation Dissertation Fellowship FX We thank E. D. Green and L. C. Brody for feedback on the manuscript, E. Bishop and D. Landsman for discussion, and G. K. McEwen for assistance with experimental steps. Funded by the National Human Genome Research Institute (NHGRI) of the NIH (grant R01 HG003541) to T.D.T. and by the Research Corporation for Science Advancement. E.H.M. was supported by the Intramural Research Program of the NHGRI, NIH. S.C.J.P. was supported by a National Academies Ford Foundation Dissertation Fellowship. NR 27 TC 120 Z9 124 U1 0 U2 9 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 APR 17 PY 2009 VL 324 IS 5925 BP 389 EP 392 DI 10.1126/science.1169050 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 433QT UT WOS:000265221600043 PM 19286520 ER PT J AU Derolf, AR Kristinsson, SY Andersson, TML Landgren, O Dickman, PW Bjorkholm, M AF Derolf, Asa Rangert Kristinsson, Sigurdur Yngvi Andersson, Therese M. -L. Landgren, Ola Dickman, Paul W. Bjorkholm, Magnus TI Improved patient survival for acute myeloid leukemia: a population-based study of 9729 patients diagnosed in Sweden between 1973 and 2005 SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; ACUTE NONLYMPHOCYTIC LEUKEMIA; ACUTE PROMYELOCYTIC LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; HEMATOLOGIC MALIGNANCIES; INTENSIVE CHEMOTHERAPY; CONSOLIDATION THERAPY; COMPLETE REMISSION; RELATIVE SURVIVAL AB We evaluated survival patterns for all registered acute myeloid leukemia (AML) patients diagnosed in Sweden in 1973 to 2005 (N = 9729; median age, 69 years). Patients were categorized into 6 age groups and 4 calendar periods (1973-1980, 1981-1988, 1989-1996, and 1997-2005). Relative survival ratios were computed as measures of patient survival. One-year survival improved over time in all age groups, whereas 5- and 10-year survival improved in all age groups, except for patients 80+ years. The 5-year relative survival ratios in the last calendar period were 0.65, 0.58, 0.36, 0.15, 0.05, and 0.01 for the age groups 0 to 18, 19 to 40, 41 to 60, 61 to 70, 71 to 80, and 80+ years, respectively. Intensified chemotherapy, a continuous improvement in supportive care, and allogeneic stem cell transplantation are probably the most important factors contributing to this finding. In contrast, there was no improvement in survival in AML patients with a prior diagnosis of a myelodysplastic syndrome during 1993 to 2005 (n = 219). In conclusion, AML survival has improved during the last decades. However, the majority of AML patients die of their disease and age remains an important predictor of prognosis. New effective agents with a more favorable toxicity profile are needed to improve survival, particularly in the elderly. (Blood. 2009; 113: 3666-3672) C1 [Derolf, Asa Rangert; Kristinsson, Sigurdur Yngvi; Landgren, Ola; Bjorkholm, Magnus] Karolinska Univ Hosp, Solna & Karolinska Inst, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. [Andersson, Therese M. -L.; Dickman, Paul W.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Landgren, Ola] NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Derolf, AR (reprint author), Karolinska Univ Hosp, Solna & Karolinska Inst, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. EM asa.derolf@karolinska.se RI Dickman, Paul/B-4572-2013; Kristinsson, Sigurdur /M-2910-2015; Andersson, Therese/E-7107-2016 OI Dickman, Paul/0000-0002-5788-3380; Kristinsson, Sigurdur /0000-0002-4964-7476; Andersson, Therese/0000-0001-8644-9041 FU Swedish Cancer Society; Stockholm County Council; Karolinska Institutet Foundations FX This work was supported by grants from the Swedish Cancer Society, Stockholm County Council, and the Karolinska Institutet Foundations. NR 51 TC 76 Z9 77 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 16 PY 2009 VL 113 IS 16 BP 3666 EP 3672 DI 10.1182/blood-2008-09-179341 PG 7 WC Hematology SC Hematology GA 436WD UT WOS:000265445900005 PM 19020306 ER PT J AU Longo, NS Lugar, PL Yavuz, S Zhang, W Krijger, PHL Russ, DE Jima, DD Dave, SS Grammer, AC Lipsky, PE AF Longo, Nancy S. Lugar, Patricia L. Yavuz, Sule Zhang, Wen Krijger, Peter H. L. Russ, Daniel E. Jima, Dereje D. Dave, Sandeep S. Grammer, Amrie C. Lipsky, Peter E. TI Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting SO BLOOD LA English DT Article ID INDUCED CYTIDINE DEAMINASE; MEMORY B-CELLS; CLASS-SWITCH RECOMBINATION; DNA-POLYMERASE-ETA; HEAVY-CHAIN REPERTOIRE; GERMINAL-CENTERS; CD40 LIGAND; IMMUNOGLOBULIN GENES; ANTIBODY DIVERSIFICATION; RGYW MOTIFS AB Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27(+) memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity. (Blood. 2009; 113: 3706-3715) C1 [Longo, Nancy S.; Lugar, Patricia L.; Yavuz, Sule; Zhang, Wen; Krijger, Peter H. L.; Grammer, Amrie C.; Lipsky, Peter E.] NIAMSD, Autoimmun Branch, Bethesda, MD 20892 USA. [Russ, Daniel E.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Jima, Dereje D.; Dave, Sandeep S.] Duke Univ, Duke Inst Genome Sci & Policy, Durham, NC USA. [Dave, Sandeep S.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Lipsky, PE (reprint author), NIAMSD, Autoimmun Branch, 9000 Rockville Pike,Bldg 10,Rm 6D47C, Bethesda, MD 20892 USA. EM peterlipsky@comcast.net OI Krijger, Peter/0000-0003-1702-348X; Russ, Daniel/0000-0003-4040-4416 FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; Doris Duke Charitable Foundation FX This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases intramural research program. S.S.D. was supported by the Doris Duke Charitable Foundation. NR 78 TC 32 Z9 32 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 APR 16 PY 2009 VL 113 IS 16 BP 3706 EP 3715 DI 10.1182/blood-2008-10-183632 PG 10 WC Hematology SC Hematology GA 436WD UT WOS:000265445900011 PM 19023113 ER PT J AU Fukumoto, R Andresen, V Bialuk, I Cecchinato, V Walser, JC Valeri, VW Nauroth, JM Gessain, A Nicot, C Franchini, G AF Fukumoto, Risaku Andresen, Vibeke Bialuk, Izabela Cecchinato, Valentina Walser, Jean-Claude Valeri, Valerio W. Nauroth, Julie M. Gessain, Antoine Nicot, Christophe Franchini, Genoveffa TI In vivo genetic mutations define predominant functions of the human T-cell leukemia/lymphoma virus p12(I) protein SO BLOOD LA English DT Article ID LEUKEMIA-VIRUS; TYPE-1 P12(I); HTLV-I; BOVINE PAPILLOMAVIRUS; NUCLEOTIDE-SEQUENCE; HAM/TSP PATIENTS; FRAME-II; ACTIVATION; EXPRESSION; INFECTION AB The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) ORF-I encodes a 99-amino acid hydrophobic membrane protein, p12(I), that affects receptors in different cellular compartments. We report here that proteolytic cleavage dictates different cellular localization and functions of p12(I). The removal of a noncanonical endoplasmic reticulum (ER) retention/retrieval signal within the amino terminus of p12(I) is necessary for trafficking to the Golgi apparatus and generation of a completely cleaved 8-kDa protein. The 8-kDa protein in turn traffics to the cell surface, is recruited to the immunologic synapse following T-cell receptor (TCR) ligation, and down-regulates TCR proximal signaling. The uncleaved 12-kDa form of p12(I) resides in the ER and interacts with the beta and gamma(c) chains of the interleukin-2 receptor (IL-2R), the heavy chain of the major histocompatibility complex (MHC) class I, as well as calreticulin and calnexin. Genetic analysis of ORF-I from ex vivo samples of HTLV-1-infected patients reveals predominant amino acid substitutions within ORF-I that affect proteolytic cleavage, suggesting that ER-associated functions of p12(I) may contribute to the survival and proliferation of the infected T cells in the host. (Blood. 2009; 113: 3726-3734) C1 [Fukumoto, Risaku; Andresen, Vibeke; Bialuk, Izabela; Cecchinato, Valentina; Valeri, Valerio W.; Nauroth, Julie M.; Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. [Walser, Jean-Claude] NIDDKD, Sect Genom Struct & Funct, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. [Gessain, Antoine] Inst Pasteur, Dept Virol, Unite Epidemiol & Physiopathol Virus Oncogenes, Paris, France. [Nicot, Christophe] Univ Kansas, Med Ctr, Dept Microbiol Mol Genet & Immunol, Kansas City, KS USA. RP Franchini, G (reprint author), Bldg 41,Rm D804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov FU National Institutes of Health (NIH); National Cancer Institute; Center for Cancer Research; Japan Society for the Promotion of Science (Tokyo, Japan) FX We thank Tom Misteli for helpful discussions; Robyn Washington Parks, Jonathan T. Magruder, Talisa A. Goss, Joanna Ostas, and Tad Guszcznski for assistance with some of the studies; Tatiana Karpova for helpful suggestions with the Zeiss 510 Meta microscope; and Steven Snodgrass and Ryan Kelly for editorial assistance.; This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. R. F. was supported in part by the Japan Society for the Promotion of Science (Tokyo, Japan). NR 32 TC 25 Z9 26 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 16 PY 2009 VL 113 IS 16 BP 3726 EP 3734 DI 10.1182/blood-2008-04-146928 PG 9 WC Hematology SC Hematology GA 436WD UT WOS:000265445900013 PM 18791162 ER PT J AU Weldon, JE Xiang, LM Chertov, O Margulies, I Kreitman, RJ FitzGerald, DJ Pastan, I AF Weldon, John E. Xiang, Laiman Chertov, Oleg Margulies, Inger Kreitman, Robert J. FitzGerald, David J. Pastan, Ira TI Aprotease-resistant immunotoxin against CD22 with greatly increased activity against CLL and diminished animal toxicity SO BLOOD LA English DT Article ID PSEUDOMONAS EXOTOXIN-A; HAIRY-CELL LEUKEMIA; GROWTH-FACTOR-ALPHA; PHASE-I TRIAL; RECOMBINANT IMMUNOTOXIN; ANTITUMOR-ACTIVITY; CATHEPSIN-S; DOMAIN-II; RFB4(DSFV)-PE38 BL22; ANTIGEN PRESENTATION AB Immunotoxins based on Pseudomonas exotoxin A (PE) are promising anticancer agents that combine a variable fragment (Fv) from an antibody to a tumor-associated antigen with a 38-kDa fragment of PE (PE38). The intoxication pathway of PE immunotoxins involves receptor-mediated internalization and trafficking through endosomes/lysosomes, during which the immunotoxin undergoes important proteolytic processing steps but must otherwise remain intact for eventual transport to the cytosol. We have investigated the proteolytic susceptibility of PE38 immunotoxins to lysosomal proteases and found that cleavage clusters within a limited segment of PE38. We subsequently generated mutants containing deletions in this region using HA22, an anti-CD22 Fv-PE38 immunotoxin currently undergoing clinical trials for B-cell malignancies. One mutant, HA22-LR, lacks all identified cleavage sites, is resistant to lysosomal degradation, and retains excellent biologic activity. HA22-LR killed chronic lymphocytic leukemia cells more potently and uniformly than HA22, suggesting that lysosomal protease digestion may limit immunotoxin efficacy unless the susceptible domain is eliminated. Remarkably, mice tolerated doses of HA22-LR at least 10-fold higher than lethal doses of HA22, and these higher doses exhibited markedly enhanced antitumor activity. We conclude that HA22-LR advances the therapeutic efficacy of HA22 by using an approach that may be applicable to other PE-based immunotoxins. (Blood. 2009; 113: 3792-3800) C1 [Weldon, John E.; Xiang, Laiman; Margulies, Inger; Kreitman, Robert J.; FitzGerald, David J.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Weldon, John E.] NIGMS, NIH, Bethesda, MD USA. [Chertov, Oleg] NCI, Sci Applicat Int Corp Frederick, Adv Technol Program, Prot Chem Lab, Frederick, MD USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, 37 Convent Dr,Rm 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov OI Weldon, John/0000-0002-6516-9064 FU National Cancer Institute, National Institutes of Health, Center for Cancer Research [N01-CO-12 400]; National Institute of General Medical Sciences FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, in part under a PRAT Fellowship (J.E.W.) by the National Institute of General Medical Sciences, and in part with federal funds from the National Cancer Institute, National Institutes of Health (contract N01-CO-12 400). NR 47 TC 79 Z9 79 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 16 PY 2009 VL 113 IS 16 BP 3792 EP 3800 DI 10.1182/blood-2008-08-173195 PG 9 WC Hematology SC Hematology GA 436WD UT WOS:000265445900020 PM 18988862 ER PT J AU Resch, AM Ogurtsov, AY Rogozin, IB Shabalina, SA Koonin, EV AF Resch, Alissa M. Ogurtsov, Aleksey Y. Rogozin, Igor B. Shabalina, Svetlana A. Koonin, Eugene V. TI Evolution of alternative and constitutive regions of mammalian 5 ' UTRs SO BMC GENOMICS LA English DT Article ID OPEN READING FRAMES; OPIOID-RECEPTOR GENE; MESSENGER-RNA; 5'-UNTRANSLATED REGION; TRANSLATIONAL REGULATION; TRANSCRIPTIONAL INITIATION; UNTRANSLATED REGION; SELECTION PRESSURE; SPLICED EXONS; UPSTREAM AUGS AB Background: Alternative splicing (AS) in protein-coding sequences has emerged as an important mechanism of regulation and diversification of animal gene function. By contrast, the extent and roles of alternative events including AS and alternative transcription initiation (ATI) within the 5'-untranslated regions (5'UTRs) of mammalian genes are not well characterized. Results: We evaluated the abundance, conservation and evolution of putative regulatory control elements, namely, upstream start codons (uAUGs) and open reading frames (uORFs), in the 5'UTRs of human and mouse genes impacted by alternative events. For genes with alternative 5'UTRs, the fraction of alternative sequences (those present in a subset of the transcripts) is much greater than that in the corresponding coding sequence, conceivably, because 5'UTRs are not bound by constraints on protein structure that limit AS in coding regions. Alternative regions of mammalian 5'UTRs evolve faster and are subject to a weaker purifying selection than constitutive portions. This relatively weak selection results in over-abundance of uAUGs and uORFs in the alternative regions of 5'UTRs compared to constitutive regions. Nevertheless, even in alternative regions, uORFs evolve under a stronger selection than the rest of the sequences, indicating that some of the uORFs are conserved regulatory elements; some of the non-conserved uORFs could be involved in species-specific regulation. Conclusion: The findings on the evolution and selection in alternative and constitutive regions presented here are consistent with the hypothesis that alternative events, namely, AS and ATI, in 5'UTRs of mammalian genes are likely to contribute to the regulation of translation. C1 [Resch, Alissa M.; Ogurtsov, Aleksey Y.; Rogozin, Igor B.; Shabalina, Svetlana A.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM resch@ncbi.nlm.nih.gov; ogurtsov@ncbi.nlm.nih.gov; rogozin@ncbi.nlm.nih.gov; shabalin@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov RI Shabalina, Svetlana/N-8939-2013 OI Shabalina, Svetlana/0000-0003-2272-7473 FU Intramural NIH HHS NR 72 TC 35 Z9 35 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD APR 16 PY 2009 VL 10 AR 162 DI 10.1186/1471-2164-10-162 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 441TU UT WOS:000265794200002 PM 19371439 ER PT J AU Lebiedowska, MK Wente, TM Dufour, M AF Lebiedowska, Maria K. Wente, Todd M. Dufour, Michelle TI The influence of foot position on body dynamics SO JOURNAL OF BIOMECHANICS LA English DT Article DE Body dynamics; Stiffness; Damping; Foot position; Toe landing ID LEG STIFFNESS; STRIDE FREQUENCY; WALKING SPEED; GAIT; CHILDREN; OPTIMIZATION; MECHANICS; MOVEMENTS; RESONANCE; PATTERNS AB During locomotion, the human body exhibits inherent dynamic properties such as mass (M). stiffness (K) and damping (B). During the gait cycle, foot contact with the ground progresses from the heel to the toe. Contact forces between the foot and ground are defined as ground reaction forces (GRF). It is unclear how body dynamics are affected by foot landing position. If the shape of GRF is indicative of body dynamics, Our understanding of gait patterns in normal and pathologic conditions may improve. The aims of this study were to determine:(1) whether foot landing position affects the inherent dynamics of the human body and (2) the extent to which the GRF curve reflects the response of inherent body dynamics to sudden loading. Eight non-disabled control volunteers performed a series of small jumps and landed on one leg with a fully extended knee in three foot landing positions: heel, mid-foot, and toe. They then walked at self-paced velocity over force plates. For each foot landing position, values of K, B and the dimensionless damping coefficient, xi, were calculated from the period of vertical body oscillations, T, and compared with an ANOVA test. In addition, the time between the two peaks of the vertical GRF, T(GRF), was compared with T We found that that K and B decreased and xi did not change (p < 0.01) between heel to toe-landing positions. T(GRF) was not different than T for the toe-landing position, which suggests that the dynamic body response has major impact on the shape of GRF. Published by Elsevier Ltd. C1 [Lebiedowska, Maria K.] NIH, Phys Disabil Branch, Dept Rehabil Med, Bethesda, MD 20892 USA. [Wente, Todd M.] Univ Arkansas Med Sci, Dept Orthoped Surg, Little Rock, AR 72205 USA. [Dufour, Michelle] Illinois Community Coll Board, Springfield, IL 62701 USA. RP Lebiedowska, MK (reprint author), NIH, Phys Disabil Branch, Dept Rehabil Med, BLDG 10 CRC RM 1-1469,10 Ctr Dr MSC 1604, Bethesda, MD 20892 USA. EM lebiedowskam@cc.nih.gov FU Intramural NIH HHS [NIH0011951440]; PHS HHS [NIH0011951440] NR 35 TC 12 Z9 14 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0021-9290 J9 J BIOMECH JI J. Biomech. PD APR 16 PY 2009 VL 42 IS 6 BP 762 EP 766 DI 10.1016/j.jbiomech.2008.12.021 PG 5 WC Biophysics; Engineering, Biomedical SC Biophysics; Engineering GA 436WS UT WOS:000265447400013 PM 19249785 ER PT J AU Trujillo-Orrego, N Pineda, DA Arango, CP Puerta, IC Lopera, F Aguirre-Acevedo, DC Hincapie-Henao, L Pineda-Alvarez, DE Arcos-Burgos, M Muenke, M AF Trujillo-Orrego, N. Pineda, D. A. Arango, C. P. Puerta, I. C. Lopera, F. Aguirre-Acevedo, D. C. Hincapie-Henao, L. Pineda-Alvarez, D. E. Arcos-Burgos, M. Muenke, M. TI ATTENTION DEFICIT HYPERACTIVITY BEHAVIORAL PHENOTYPE DIMENSIONS OF ADULTS FROM ANTIOQUIAN FAMILIES USING THE WENDER-UTAH SCALE-SPANISH VERSION SO REVISTA DE NEUROLOGIA LA Spanish DT Article DE ADHD; Adults; Attention disorder; Behavior; Factor analysis; Hyperactivity; Phenotype; Rating scales; Wender ID DEFICIT/HYPERACTIVITY DISORDER; RATING-SCALE; DIAGNOSTIC INTERVIEW; RETROSPECTIVE ASSESSMENT; PSYCHIATRIC COMORBIDITY; ADHD; CHILDREN; RELIABILITY; VALIDITY; POPULATION AB Introduction. The Wender-Utah Rating Scale (WURS) has been used for retrospective screening of attention deficit hyperactivity disorders(ADHD) symptoms and its comorbidities. Aim. To establish the ADHD behavioral phenotype dimensions of adults from 140 Antioquian families with genetic segregation for ADHD diagnosis, using the WURS-Spanish version. Subjects and methods. 392 adults from both genders, belonging to nuclear and multigenerational families with one or more ADHD affected members were selected. The Composite International Diagnostic Interview (CIDI) for mental disorder was administered to establish the gold standard diagnosis of ADHD through the long life. All participants fulfill the WURS. Exploratory and confirmatory factor analyses were done to determine the behavioral dimensions of the ADHD phenotype. Results. A factor structure of four dimensions was derived, measuring behavioral decontrol, hyperactivity,, inattention and anxiety, and which explained the 60% of the total variance. Conclusions. The behavioral adult ADHD phenotype in the Antioquian families was conformed by four dimensions, which could be used in heritability and linkage future studies. [REV NEUROL 2009; 48: 400-6] C1 [Trujillo-Orrego, N.; Pineda, D. A.; Lopera, F.; Aguirre-Acevedo, D. C.; Hincapie-Henao, L.; Pineda-Alvarez, D. E.; Arcos-Burgos, M.] Univ Antioquia, Grp Neurociencias Antioquia, Medellin 1226, Colombia. [Arango, C. P.; Puerta, I. C.; Aguirre-Acevedo, D. C.] Univ San Buenaventura, Grp Neuropsicol & Conducta, Medellin, Colombia. [Arcos-Burgos, M.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Pineda-Alvarez, D. E.; Muenke, M.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Trujillo-Orrego, N (reprint author), Univ Antioquia, Grp Neurociencias Antioquia, Calle 62 52-59,CO 057, Medellin 1226, Colombia. EM natalitra@hotmail.com OI Puerta Lopera, Isabel Cristina/0000-0002-3533-8015 NR 47 TC 5 Z9 5 U1 5 U2 5 PU REVISTA DE NEUROLOGIA PI BARCELONA PA C/O CESAR VIGUERA, EDITOR, APDO 94121, 08080 BARCELONA, SPAIN SN 0210-0010 J9 REV NEUROLOGIA JI Rev. Neurologia PD APR 16 PY 2009 VL 48 IS 8 BP 400 EP 406 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 436BC UT WOS:000265386600003 PM 19340779 ER PT J AU Redon, CE Dickey, JS Bonner, WM Sedelnikova, OA AF Redon, Christophe E. Dickey, Jennifer S. Bonner, William M. Sedelnikova, Olga A. TI gamma-H2AX as a biomarker of DNA damage induced by ionizing radiation in human peripheral blood lymphocytes and artificial skin SO ADVANCES IN SPACE RESEARCH LA English DT Article DE DNA damage; gamma-H2AX; Blood; Lymphocytes; Skin; gamma-Radiation ID DOUBLE-STRAND BREAKS; ATAXIA-TELANGIECTASIA; HISTONE H2AX; HUMAN-CELLS; IN-VIVO; FOCI; REPAIR; IRRADIATION; INDUCTION; EXPOSURE AB Ionizing radiation (IR) exposure is inevitable in our modern society and can lead to a variety of deleterious effects including cancer and birth defects. A reliable, reproducible and sensitive assessment of exposure to IR and the individual response to that exposure would provide much needed information for the optimal treatment of each donor examined. We have developed a diagnostic test for IR exposure based on detection of the phosphorylated form of variant histone H2AX (gamma-H2AX), which occurs specifically at sites of DNA double-strand breaks (DSBs). The cell responds to a nascent DSB through the phosphorylation of thousands of H2AX molecules flanking the damaged site. This highly amplified response can be visualized as a gamma-H2AX focus in the chromatin that can be detected in situ with the appropriate antibody. Here we assess the usability of gamma-H2AX focus formation as a possible biodosimeter for human exposure to IR using peripheral blood lymphocytes irradiated ex vivo and three-dimensional artificial models of human skin biopsies. In both systems, the tissues were exposed to 0.2-5 Gy, doses of IR that might be realistically encountered in various scenarios such as cancer radiotherapies or accidental exposure to radiation. Since the gamma-H2AX response is maximal 30 min after exposure and declines over a period of hours as the cells repair the damage, we examined the time limitations of the useful detectability of gamma-H2AX foci. We report that a linear response proportional to the initial radiation dose was obtained 48 and 24 h after exposure in blood samples and skin cells respectively. Thus, detection of gamma-H2AX formation to monitor DNA damage in minimally invasive blood and skin tests could be useful tools to determine radiation dose exposure and analyze its effects on humans. Published by Elsevier Ltd. on behalf of COSPAR. C1 [Redon, Christophe E.; Dickey, Jennifer S.; Bonner, William M.; Sedelnikova, Olga A.] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. RP Redon, CE (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. EM redonc@mail.nih.gov FU MAID; National Cancer Institute, Centcr for Cancer Research, NIH FX We thank Dr. Asako J. Nakamura, NCI, for critical reading of the manuscript. We thank Irina Kareva and Ksenla Gouliaeva for data entry and statistical analysis. This study was funded by the MAID Radiation/Nuclear Countermeasures Program and the Intramural Research Program of the National Cancer Institute, Centcr for Cancer Research, NIH. NR 32 TC 100 Z9 113 U1 3 U2 11 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0273-1177 J9 ADV SPACE RES JI Adv. Space Res. PD APR 15 PY 2009 VL 43 IS 8 BP 1171 EP 1178 DI 10.1016/j.asr.2008.10.011 PG 8 WC Astronomy & Astrophysics; Geosciences, Multidisciplinary; Meteorology & Atmospheric Sciences SC Astronomy & Astrophysics; Geology; Meteorology & Atmospheric Sciences GA 438OV UT WOS:000265565900001 PM 20046946 ER PT J AU Gonzales, JM Lowry, BA Brown, PB Beyl, CA Nyochemberg, L AF Gonzales, John M., Jr. Lowry, Brett A. Brown, Paul B. Beyl, Caula A. Nyochemberg, Leopold TI The effects of composting on the nutritional composition of fibrous bio-regenerative life support systems (BLSS) plant waste residues and its impact on the growth of Nile tilapia (Oreochromis niloticus) SO ADVANCES IN SPACE RESEARCH LA English DT Article ID PLEUROTUS-OSTREATUS; WHEAT-STRAW; FISH; DIETS; FEED; MEAL; DEGRADATION; RETENTION; LIGNIN; ROHU AB Utilization of bio-regenerative life support systems (BLSS) plant waste residues as a nutritional source by Nile tilapia (Oreochromis niloticus) has proven problematic as a result of high concentrations of fibrous compounds in the plant waste residues. Nutritional improvement of plant waste. residues by composting with the oyster mushroom (Pleurotus ostreatus), and the effects on growth and nutrient utilization of Nile tilapia fed such residues were evaluated. Five Nile tilapia (mean weight = 70.9 +/- 3.1 g) were stocked in triplicate aquaria and fed one of two experimental diets, cowpea (CP) and composted cowpea (CCP), twice daily for a period of 8 weeks. Composting of cowpea residue resulted in reduced concentrations of nitrogen-free extract, hemi-cellulose and trypsin inhibitor activity. though trypsin inhibitor activity remained high. Composting did not reduce crude fiber, lignin, or cellulose concentrations in the diet. No significant differences (P < 0.05) were observed in weight gain, specific growth rate, survival rate, daily consumption, and food conversion ratio between tilapia fed CP and CCP. These results suggest that P. ostreatus is not a suitable candidate for culture in conjunction with the culture of Nile tilapia. Additional work is needed to determine what, if any, benefit can be obtained from incorporating composted residue as feed for Nile tilapia. (C) 2009 COSPAR. Published by Elsevier Ltd. All rights reserved. C1 [Gonzales, John M., Jr.] NICHHD, NIH, Bethesda, MD 20892 USA. [Lowry, Brett A.; Brown, Paul B.] Purdue Univ, Dept Forestry & Nat Resources, W Lafayette, IN 47904 USA. [Beyl, Caula A.; Nyochemberg, Leopold] Alabama A&M Univ, Dept Plant & Soil Sci, Normal, AL 35762 USA. RP Gonzales, JM (reprint author), NICHHD, NIH, 6 Ctr Dr, Bethesda, MD 20892 USA. EM gonzaljo@mail.nih.gov FU NASA FX The authors thank Northern Tilapia Inc., for their donation of tilapia broodstock, Drs. Mitchell and Massa for their donation of cowpea residue and to Dr. Bharadwai for his editorial comments. This project was funded by the NASA ALS/NSCORT Program. NR 45 TC 1 Z9 2 U1 3 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0273-1177 J9 ADV SPACE RES JI Adv. Space Res. PD APR 15 PY 2009 VL 43 IS 8 BP 1243 EP 1249 DI 10.1016/j.asr.2009.01.026 PG 7 WC Astronomy & Astrophysics; Geosciences, Multidisciplinary; Meteorology & Atmospheric Sciences SC Astronomy & Astrophysics; Geology; Meteorology & Atmospheric Sciences GA 438OV UT WOS:000265565900011 ER PT J AU Gonzales, JM AF Gonzales, John M., Jr. TI Aquaculture in bio-regenerative life support systems (BLSS): Considerations SO ADVANCES IN SPACE RESEARCH LA English DT Article DE Bio-regenerative life support systems; Tilapia; Space habitation ID TILAPIA OREOCHROMIS-NILOTICUS; NILE TILAPIA; FLESH QUALITY; RAW SPIRULINA; SPAWNING PERFORMANCE; SUPPLEMENTARY FEED; TOTAL REPLACEMENT; REARING TILAPIA; SEWAGE-SLUDGE; TREATED FISH AB A significant amount of research has been invested into understanding the effects of including fish culture in bio-regenerative life support systems (BLSS) for long duration space habitation. While the benefits of fish culture as a sub-process for waste treatment and food production continue to be identified, other pressing issues arise that affect the overall equivalent system mass associated with fish culture ill a BLSS. This paper is meant to provide insight into several issues affecting fish culture in a BLSS that will require attention ill the Future if fish meant for consumption are to be cultured in a BLSS. (C) 2009 COSPAR. Published by Elsevier Ltd. All rights reserved. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Gonzales, JM (reprint author), NICHHD, NIH, 6 Ctr Dr, Bethesda, MD 20892 USA. EM gonzaljo@mail.nih.gov NR 100 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 0273-1177 J9 ADV SPACE RES JI Adv. Space Res. PD APR 15 PY 2009 VL 43 IS 8 BP 1250 EP 1255 DI 10.1016/j.asr.2009.01.034 PG 6 WC Astronomy & Astrophysics; Geosciences, Multidisciplinary; Meteorology & Atmospheric Sciences SC Astronomy & Astrophysics; Geology; Meteorology & Atmospheric Sciences GA 438OV UT WOS:000265565900012 ER PT J AU Houston, DK Ding, J Nicklas, BJ Harris, TB Lee, JS Nevitt, MC Rubin, SM Tylavsky, FA Kritchevsky, SB AF Houston, Denise K. Ding, Jingzhong Nicklas, Barbara J. Harris, Tamara B. Lee, Jung Sun Nevitt, Michael C. Rubin, Susan M. Tylavsky, Frances A. Kritchevsky, Stephen B. CA Hlth ABC Study TI Overweight and Obesity Over the Adult Life Course and Incident Mobility Limitation in Older Adults SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE aged; mobility limitation; obesity; overweight ID BODY-MASS INDEX; PHYSICAL PERFORMANCE; WEIGHT HISTORY; RISK-FACTORS; MIDDLE-AGE; NHANES-I; DISABILITY; HEALTH; WOMEN; ASSOCIATION AB Obesity in middle and old age predicts mobility limitation; however, the cumulative effect of overweight and/or obesity over the adult life course is unknown. The association between overweight and/or obesity in young, middle, and late adulthood and its cumulative effect on incident mobility limitation was examined among community-dwelling US adults aged 70-79 years at baseline (1997-1998) in the Health, Aging and Body Composition Study (n = 2,845). Body mass index was calculated by using recalled weight at ages 25 and 50 years and measured weight at ages 70-79 years. Mobility limitation (difficulty walking 1/4 mile (0.4 km) or climbing 10 steps) was assessed semiannually over 7 years of follow-up and was reported by 43.0% of men and 53.7% of women. Men and women who were overweight or obese at all 3 time points had an increased risk of mobility limitation (hazard ratio = 1.61, 95% confidence interval: 1.25, 2.06 and hazard ratio = 2.85, 95% confidence interval: 2.15, 3.78, respectively) compared with those who were normal weight throughout. Furthermore, there was a significant graded response (P < 0.0001) on risk of mobility limitation for the cumulative effect of obesity in men and overweight and/or obesity in women. Onset of overweight and obesity in earlier life contributes to an increased risk of mobility limitation in old age. C1 [Houston, Denise K.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Sect Gerontol & Geriatr Med,Dept Internal Med, Winston Salem, NC 27157 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Lee, Jung Sun] Univ Georgia, Dept Food & Nutr, Athens, GA 30602 USA. [Nevitt, Michael C.; Rubin, Susan M.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Tylavsky, Frances A.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. RP Houston, DK (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Sect Gerontol & Geriatr Med,Dept Internal Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM dhouston@wfubmc.edu FU National Institutes of Health [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; Wake Forest University Claude D. Pepper Older Americans Independence Center [P30-AG21332] FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health; National Institute on Aging, National Institutes of Health ( contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106); and the Wake Forest University Claude D. Pepper Older Americans Independence Center (grant P30-AG21332 to D. K. H.). NR 28 TC 45 Z9 45 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 15 PY 2009 VL 169 IS 8 BP 927 EP 936 DI 10.1093/aje/kwp007 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 425KH UT WOS:000264634900002 PM 19270048 ER PT J AU Prentice, RL Shaw, PA Bingham, SA Beresford, SAA Caan, B Neuhouser, ML Patterson, RE Stefanick, ML Satterfield, S Thomson, CA Snetselaar, L Thomas, A Tinker, LF AF Prentice, Ross L. Shaw, Pamela A. Bingham, Sheila A. Beresford, Shirley A. A. Caan, Bette Neuhouser, Marian L. Patterson, Ruth E. Stefanick, Marcia L. Satterfield, Suzanne Thomson, Cynthia A. Snetselaar, Linda Thomas, Asha Tinker, Lesley F. TI Biomarker-calibrated Energy and Protein Consumption and Increased Cancer Risk Among Postmenopausal Women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bias (epidemiology); biological markers; diet; energy intake; epidemiologic methods; neoplasms; nutrition assessment; proteins ID DIETARY MODIFICATION TRIAL; MEASUREMENT ERROR; FAT; PATTERN; REGRESSION; DISEASE AB The authors previously reported equations, derived from the Nutrient Biomarker Study within the Women's Health Initiative, that produce calibrated estimates of energy, protein, and percentage of energy from protein consumption from corresponding food frequency questionnaire estimates and data on other factors, such as body mass index, age, and ethnicity. Here, these equations were applied to yield calibrated consumption estimates for 21,711 women enrolled in the Women's Health Initiative dietary modification trial comparison group and 59,105 women enrolled in the observational study. These estimates were related prospectively to total and site-specific invasive cancer incidence (1993-2005). In combined cohort analyses that do not control for body mass, uncalibrated energy was not associated with total cancer incidence or site-specific cancer incidence for most sites, whereas biomarker-calibrated energy was positively associated with total cancer (hazard ratio = 1.18, 95% confidence interval: 1.10, 1.27, for 20% consumption increase), as well as with breast, colon, endometrial, and kidney cancer (respective hazard ratios of 1.24, 1.35, 1.83, and 1.47). Calibrated protein was weakly associated, and calibrated percentage of energy from protein was inversely associated, with total cancer. Calibrated energy and body mass index associations were highly interdependent. Implications for the interpretation of nutritional epidemiology studies are described. C1 [Prentice, Ross L.; Neuhouser, Marian L.; Patterson, Ruth E.; Tinker, Lesley F.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Shaw, Pamela A.] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Bingham, Sheila A.] Univ Cambridge, MRC, Dunn Human Nutr Unit, Cambridge, England. [Beresford, Shirley A. A.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Caan, Bette] Kaiser Permanente, Div Res, Oakland, CA USA. [Stefanick, Marcia L.] Stanford Univ, Sch Med, Stanford Ctr Res Dis Prevent, Palo Alto, CA 94304 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Thomson, Cynthia A.] Univ Arizona, Dept Nutr Sci, Tucson, AZ USA. [Snetselaar, Linda] Univ Iowa, Dept Community & Behav Hlth, Iowa City, IA USA. [Thomas, Asha] Medstat Res Inst, Washington, DC USA. [Thomas, Asha] Johns Hopkins Univ, Sinai Hosp, Baltimore, MD USA. RP Prentice, RL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,POB 19024, Seattle, WA 98109 USA. EM rprentic@fhcrc.org FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 3211819, 32122, 42107-26, 42129-32, 44221]; National Cancer Institute [CA53996] FX This work was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services ( contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 3211819, 32122, 42107-26, 42129-32, and 44221). Clinical Trials Registration: ClinicalTrials. gov identifier: NCT00000611. Dr. Prentice'sworkwas partially supported by grant CA53996 from the National Cancer Institute. NR 27 TC 46 Z9 46 U1 1 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 15 PY 2009 VL 169 IS 8 BP 977 EP 989 DI 10.1093/aje/kwp008 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 425KH UT WOS:000264634900008 PM 19258487 ER PT J AU Cook, RL Zhu, F Belnap, BH Weber, K Cook, JA Vlahov, D Wilson, TE Hessol, NA Plankey, M Howard, AA Cole, SR Sharp, GB Richardson, JL Cohen, MH AF Cook, Robert L. Zhu, Fang Belnap, Bea Herbeck Weber, Kathleen Cook, Judith A. Vlahov, David Wilson, Tracey E. Hessol, Nancy A. Plankey, Michael Howard, Andrea A. Cole, Stephen R. Sharp, Gerald B. Richardson, Jean L. Cohen, Mardge H. TI Longitudinal Trends in Hazardous Alcohol Consumption Among Women With Human Immunodeficiency Virus Infection, 1995-2006 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; HIV; longitudinal studies; women ID DRUG-USE BEHAVIORS; INTERAGENCY HIV; ANTIRETROVIRAL THERAPY; MEDICATION ADHERENCE; CARE PROVIDERS; UNITED-STATES; HEPATITIS-C; HIGH-RISK; DRINKING; COHORT AB Hazardous alcohol consumption among women with human immunodeficiency virus (HIV) infection is associated with several adverse health and behavioral outcomes, but the proportion of HIV-positive women who engage in hazardous drinking over time is unclear. The authors sought to determine rates of hazardous alcohol consumption among these women over time and to identify factors associated with this behavior. Subjects were 2,770 HIV-positive women recruited from 6 US cities who participated in semiannual follow-up visits in the Women's Interagency HIV Study from 1995 to 2006. Hazardous alcohol consumption was defined as exceeding daily (>= 4 drinks) or weekly (> 7 drinks) consumption recommendations. Over the 11-year follow-up period, 14%-24% of the women reported past-year hazardous drinking, with a slight decrease in hazardous drinking over time. Women were significantly more likely to report hazardous drinking if they were unemployed, were not high school graduates, had been enrolled in the original cohort (1994-1995), had a CD4 cell count of 200-500 cells/mL, were hepatitis C-seropositive, or had symptoms of depression. Approximately 1 in 5 of the women met criteria for hazardous drinking. Interventions to identify and address hazardous drinking among HIV-positive women are urgently needed. C1 [Cook, Robert L.] Univ Florida, Dept Epidemiol & Biostat, Coll Publ Hlth & Hlth Profess, Gainesville, FL 32607 USA. [Zhu, Fang; Belnap, Bea Herbeck] Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA USA. [Weber, Kathleen; Cohen, Mardge H.] Cook Cty Bur Hlth Serv, CORE Ctr, Chicago, IL USA. [Weber, Kathleen; Cohen, Mardge H.] Rush Univ, Rush Sch Med, Dept Internal Med, Chicago, IL 60612 USA. [Cook, Judith A.] Univ Illinois, Dept Psychiat, Coll Med Chicago, Chicago, IL 60612 USA. [Vlahov, David] New York Acad Med, New York, NY USA. [Wilson, Tracey E.] Suny Downstate Med Ctr, Dept Prevent Med & Community Hlth, Brooklyn, NY 11203 USA. [Hessol, Nancy A.] Univ Calif San Francisco, Sch Pharm, Dept Clin Pharm, San Francisco, CA 94143 USA. [Hessol, Nancy A.] Univ Calif San Francisco, Sch Pharm, Dept Med, San Francisco, CA 94143 USA. [Hessol, Nancy A.] Univ Calif San Francisco, Sch Med, Dept Clin Pharm, San Francisco, CA USA. [Hessol, Nancy A.] Univ Calif San Francisco, Sch Med, Dept Med, San Francisco, CA 94143 USA. [Plankey, Michael] Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. [Howard, Andrea A.] Albert Einstein Coll Med, Montefiore Med Ctr, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Cole, Stephen R.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Sharp, Gerald B.] NIAID, Bethesda, MD 20892 USA. [Richardson, Jean L.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. RP Cook, RL (reprint author), Univ Florida, Dept Epidemiol & Biostat, Coll Publ Hlth & Hlth Profess, POB 100231, Gainesville, FL 32607 USA. EM cookrl@phhp.ufl.edu RI Cook, Judith/B-9107-2013 FU The Women's Interagency HIV Study; 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 Center for Research Resources [UL1 RR024131] FX The Women's Interagency HIV Study (WIHS) is funded by the National Institute of Allergy and Infectious Diseases (grants UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993, and UO1-AI-42590) and the National Institute of Child Health and Human Development (grant UO1-HD-32632). The study is cofunded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (University of California, San Francisco - Clinical and Translational Science Institute grant UL1 RR024131). NR 33 TC 19 Z9 19 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 15 PY 2009 VL 169 IS 8 BP 1025 EP 1032 DI 10.1093/aje/kwp004 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 425KH UT WOS:000264634900013 PM 19270052 ER PT J AU Davis, DA Tebbs, IR Daniels, SI Stahl, SJ Kaufman, JD Wingfield, P Bowman, MJ Chmielewski, J Yarchoan, R AF Davis, David A. Tebbs, Irene R. Daniels, Sarah I. Stahl, Stephen J. Kaufman, Joshua D. Wingfield, Paul Bowman, Michael J. Chmielewski, Jean Yarchoan, Robert TI Analysis and characterization of dimerization inhibition of a multi-drug-resistant Human Immunodeficiency Virus Type 1 protease using a novel size-exclusion chromatographic approach SO BIOCHEMICAL JOURNAL LA English DT Article DE autoproteolysis; dimerization inhibitor; gel filtration; HIV-1 protease (PR); monomer; peptide ID HIV-1 PROTEASE; INTERFACE PEPTIDES; VIRAL INFECTIVITY; MUTATIONS; PRECURSOR; DIMER; LIPOPEPTIDES; REPLICATION; MECHANISM; SUBSTRATE AB Active-site inhibitors of HIV-1 PR (protease) block viral replication by preventing viral maturation. However, HIV-1 often develops resistance to active-site inhibitors through multiple Mutations in PR and therefore. recent efforts have focused on inhibiting PR dimerization as an alternative approach. Dimerization inhibitors have been identified using kinetic analysis, but additional characterization of the effect of these inhibitors on PR by physical methods has been difficult. In the present study, we identified a PR(MDR) (multi-drug-resistant HIV-1 PR) that was highly resistant to autoproteolysis. Using this PR and a novel size-exclusion chromatographic: approach that incorporated fluorescence and MS detection, we were able to demonstrate inhibition of dimerization using P27 (peptide 27), a peptide dimerization inhibitor of PR previously identified on the basis of kinetic analysis. Incubation of PR(MDR) with P27, or other dimerization inhibitors, led to a dose- and time-dependent formation of PR monomers based on the change in elution time by size exclusion and its similar elution time to engineered forms of monomeric PR, namely PR(T26A) and glutathionylated PR. In contrast. incubation of PR(MDR) with a potent active-site inhibitor did not change the elution time for the PR(MDR) dimer. The monomeric PR induced by P27 had fluorescent characteristics which were consistent with unfolded PR. Structure-activity studies identified the active regions of P27 and experiments were performed to examine the effect of other dimerization inhibitors oil PR. The present study is the first characterization of dimerization inhibition of PR(MDR), a prime target for these inhibitors, using a novel size-exclusion chromatographic approach. C1 [Davis, David A.; Tebbs, Irene R.; Daniels, Sarah I.; Yarchoan, Robert] NCI, HIV & AIDS Malignancy Branch, Retrovirol Dis Sect, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Stahl, Stephen J.; Kaufman, Joshua D.; Wingfield, Paul] NIAMSD, Prot Express Lab, NIH, Bethesda, MD 20892 USA. [Bowman, Michael J.; Chmielewski, Jean] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. RP Davis, DA (reprint author), NCI, HIV & AIDS Malignancy Branch, Retrovirol Dis Sect, Ctr Canc Res,NIH, Bldg 10,Room 6N106, Bethesda, MD 20892 USA. EM dadavis@helix.nih.gov FU Center for Cancer Research; Nationa Cancer Institute; National Institutes of Health FX This work was supported in part by the Intramural Research Program of the Center for Cancer Research, Nationa Cancer Institute, National Institutes of Health. NR 49 TC 8 Z9 9 U1 0 U2 1 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 APR 15 PY 2009 VL 419 BP 497 EP 506 DI 10.1042/BJ20082068 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 433IG UT WOS:000265196900026 PM 19149765 ER PT J AU Insel, T AF Insel, Thomas TI Reverse Translation: Moving from Bedside to Bench SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Insel, Thomas] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 5 BP 1S EP 2S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200006 ER PT J AU Wang, KH AF Wang, Kuan Hong TI Imaging the Development and Plasticity of Prefrontal Neuronal Circuits SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Wang, Kuan Hong] NIMH, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 2 BP 1S EP 1S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200004 ER PT J AU Boyce, CA AF Boyce, Cheryl Anne TI Workshop on NIMH Grant Opportunities for Early Stage Investigators: Priorities in Translational and Neurodevelopmental Research SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Boyce, Cheryl Anne] NIMH, NIH, DHHS, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 7 BP 2S EP 2S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200008 ER PT J AU Salvadore, G Nugent, AC Neumeister, A Cannon, DM Drevets, WC AF Salvadore, Giacomo Nugent, Allison C. Neumeister, Alexander Cannon, Dara M. Drevets, Wayne C. TI Prefrontal Cortical Gray Matter Decreased in Currently-Depressed but not Currently Remitted Subjects with Major Depressive Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Salvadore, Giacomo; Nugent, Allison C.; Drevets, Wayne C.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Neumeister, Alexander] Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. [Cannon, Dara M.] Natl Univ Ireland Galway, Dept Psychiat, Galway, Ireland. RI Cannon, Dara/C-1323-2009 OI Cannon, Dara/0000-0001-7378-3411 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 11 BP 4S EP 4S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200012 ER PT J AU Schulze, TG Detera-Wadleigh, SD Akula, N Gupta, A Kassem, L Steele, J Pearl, J Strohmaier, J Breuer, R Schwarz, M Propping, P Noethen, MM Cichon, S Schumacher, J Rietsche, M McMahon, FJ AF Schulze, Thomas G. Detera-Wadleigh, Sevilla D. Akula, Nirmala Gupta, Ajay Kassem, Layla Steele, Jo Pearl, Justin Strohmaier, Jana Breuer, Rene Schwarz, Markus Propping, Peter Noethen, Markus M. Cichon, Sven Schumacher, Johannes Rietsche, Marcella McMahon, Francis J. CA NIMH Genetics Initiative Bipolar D TI Two Variants in Ankyrin 3 (ANK3) are Independent Genetic Risk Factors for Bipolar Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Gupta, Ajay] NIMH, MAPGenet, NIH, Bethesda, MD 20892 USA. [Schulze, Thomas G.; Strohmaier, Jana; Breuer, Rene; Rietsche, Marcella] CIMH, Mannheim, Germany. [Schwarz, Markus] Psychiat Zentrum Nordbaden, Wiesloch, Germany. [Propping, Peter; Noethen, Markus M.; Cichon, Sven] Univ Bonn, D-5300 Bonn, Germany. RI Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Schumacher, Johannes/F-4970-2015 OI Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Schumacher, Johannes/0000-0001-9217-6457 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 20 BP 7S EP 8S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200021 ER PT J AU Sambataro, F Mattay, VS Safrin, M Laumann, T Blasi, G Callicott, JH Weinberger, DR AF Sambataro, Fabio Mattay, Venkata S. Safrin, Martin Laumann, Timothy Blasi, Giuseppe Callicott, Joseph H. Weinberger, Daniel R. TI Altered Default Mode Network Connectivity in Patients with Schizophrenia and their Unaffected Siblings SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Sambataro, Fabio; Mattay, Venkata S.; Safrin, Martin; Laumann, Timothy; Callicott, Joseph H.; Weinberger, Daniel R.] NIMH, GCAP, NIH, Bethesda, MD 20892 USA. [Blasi, Giuseppe] Univ Bari, Inst Psychiat, Bari, Italy. NR 0 TC 0 Z9 0 U1 0 U2 2 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 APR 15 PY 2009 VL 65 IS 8 MA 26 BP 9S EP 9S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200027 ER PT J AU Du, J Wei, YL Liu, LD Khairova, R Wang, Y Blumenthal, R Machado-Vieira, R Wang, YT Manji, H AF Du, Jing Wei, Yanling Liu, Lidong Khairova, Rushaniya Wang, Yun Blumenthal, Rayah Machado-Vieira, Rodrigo Wang, Yutian Manji, Husseini TI GSK-3 Kinase Modulates AMPA Receptor Trafficking via Kinesin Cargo System: Molecular Mechanism for Mood Stabilizer? SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Du, Jing; Wei, Yanling; Khairova, Rushaniya; Wang, Yun; Blumenthal, Rayah; Machado-Vieira, Rodrigo] NIMH, Bethesda, MD 20892 USA. [Liu, Lidong; Wang, Yutian] Univ British Columbia, Dept Med, Brain Res Ctr, Vancouver, BC, Canada. [Manji, Husseini] Johnson & Johnson Pharmaceut & Res Dev LLC, Raritan, NJ USA. RI Wang, Yu Tian/A-4729-2008; MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 52 BP 16S EP 16S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200047 ER PT J AU Drevets, WC AF Drevets, Wayne C. TI Neurophysiological Markers of Emotional Processing Biases in Major Depression Predict Responses to SSRI SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Drevets, Wayne C.] NIMH, NIH, DIRP, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 63 BP 19S EP 19S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200058 ER PT J AU Callicott, JH AF Callicott, Joseph H. TI Beyond Dopamine in the Prefrontal Cortex: Prefrontal Efficiency Reflecting Genetic Interactions of COMT with Glutamate and GABA SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Callicott, Joseph H.] NIMH, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 78 BP 24S EP 24S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200073 ER PT J AU Kiselycznyk, CL Qi, HS Chen, G Manji, HK Svenningsson, P AF Kiselycznyk, Carly L. Qi, Hongshi Chen, Guang Manji, Husseini K. Svenningsson, Per TI Phosphorylation of Key Sites on the AMPA GluR1 Subunit is not Necessary for the Antidepressant-Like Effect of NR2b Subunit Antagonists and Imipramine in the Mouse Forced Swim Test SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Kiselycznyk, Carly L.; Qi, Hongshi; Svenningsson, Per] Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden. [Kiselycznyk, Carly L.; Chen, Guang; Manji, Husseini K.] NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. RI Chen, Guang/A-2570-2017 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 100 BP 30S EP 31S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200095 ER PT J AU Feder, A Skipper, J Taboas, WR Buchholz, K Blair, JR Guise, K Rebani, Y Collins, K aan het Rot, M Brodman, D Moreno, GA Murrough, JW Fan, J Neumeister, A Charney, DS AF Feder, Adriana Skipper, Jamie Taboas, William R. Buchholz, Katherine Blair, James R. Guise, Kevin Rebani, Yasmina Collins, Kate aan het Rot, Marije Brodman, Douglas Moreno, Gerardo Acosta Murrough, James W. Fan, Jin Neumeister, Alexander Charney, Dennis S. TI Emotion-Processing and Neural Markers of Risk for Major Depression: A Tryptophan Depletion Study SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Feder, Adriana; Skipper, Jamie; Taboas, William R.; Buchholz, Katherine; Guise, Kevin; Rebani, Yasmina; Collins, Kate; aan het Rot, Marije; Brodman, Douglas; Moreno, Gerardo Acosta; Murrough, James W.; Fan, Jin; Charney, Dennis S.] Mt Sinai Sch Med, New York, NY USA. [Blair, James R.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Neumeister, Alexander] Yale Univ, New York, NY USA. RI Murrough, James/J-7129-2013 OI Murrough, James/0000-0001-6286-1242 NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 102 BP 31S EP 31S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200097 ER PT J AU Hamidi, AB Pearson, BL Malkesman, O Martinowich, K Hunsberger, J O'Donnell, K Schloesser, R Dold, G Manji, HK Chen, G AF Hamidi, Anahita B. Pearson, Brandon L. Malkesman, Oz Martinowich, Keri Hunsberger, Joshua O'Donnell, Kelly Schloesser, Robert Dold, George Manji, Husseini K. Chen, Guang TI Temporal Profiles of Imipramine and Ketamine in the Learned Helplessness Paradigm SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Hamidi, Anahita B.; Pearson, Brandon L.; Malkesman, Oz; Martinowich, Keri; Hunsberger, Joshua; O'Donnell, Kelly; Schloesser, Robert; Dold, George; Manji, Husseini K.; Chen, Guang] NIH, Mol Pathophysiol Lab, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 103 BP 31S EP 32S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200098 ER PT J AU Austin, DR Yuan, PX Hunsberger, JG Drevets, W Manji, HK Guitart-Navarro, X Chen, G AF Austin, Daniel R. Yuan, Peixiong Hunsberger, Joshua G. Drevets, Wayne Manji, Husseini K. Guitart-Navarro, Xavier Chen, Guang TI Chronic Mood Stabilizer Treatment Alters Protein Expression of Bipolar Risk Genes Implicated by Whole Genome-Wide Association Study SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Austin, Daniel R.; Yuan, Peixiong; Hunsberger, Joshua G.; Drevets, Wayne; Manji, Husseini K.; Guitart-Navarro, Xavier; Chen, Guang] NIH, Mol Pathophysiol Lab, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 105 BP 32S EP 32S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200100 ER PT J AU Tragon, T Malkesman, O Chen, G Manji, HK AF Tragon, Tyson Malkesman, Oz Chen, Guang Manji, Husseini K. TI The Role of GRIK2 and Neurodevelopment in Mediating SSRI-Induced Behavioral Outcomes SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Tragon, Tyson; Malkesman, Oz; Chen, Guang; Manji, Husseini K.] NIH, Mol Pathophysiol Lab, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 104 BP 32S EP 32S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200099 ER PT J AU Hunsberger, JG Austin, DR Guarnieri, DJ DiLeone, RJ Chen, G Manji, HK AF Hunsberger, Joshua G. Austin, Daniel R. Guarnieri, Douglas J. DiLeone, Ralph J. Chen, Guang Manji, Husseini K. TI Accessing Behavioral Effects of Mood-Stabilizer-Regulated miR-34a SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Hunsberger, Joshua G.; Austin, Daniel R.; Chen, Guang; Manji, Husseini K.] NIMH, LMP, Bethesda, MD USA. [Guarnieri, Douglas J.; DiLeone, Ralph J.] Yale Univ, New Haven, CT USA. RI Chen, Guang/A-2570-2017 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 108 BP 33S EP 33S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200103 ER PT J AU Mueller, S Mazzone, L Maheu, F Van Ryzin, C Merke, D Ernst, M AF Mueller, Sven Mazzone, Luigi Maheu, Francoise Van Ryzin, Carol Merke, Deborah Ernst, Monique TI Examining the Impact of Early Steroid Abnormalities on Emotional Memory: An fMRI Study of Adolescents with Congenital Adrenal Hyperplasia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Mueller, Sven; Ernst, Monique] NIMH, NIH, Bethesda, MD 20892 USA. [Mazzone, Luigi] Univ Catania, Div Child Neurol & Psychiat, Catania, Italy. [Maheu, Francoise] Univ Montreal, Montreal, PQ, Canada. [Van Ryzin, Carol; Merke, Deborah] NIH, Ctr Clin, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 107 BP 33S EP 33S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200102 ER PT J AU Chen, JS Papaleo, F Tian, QJ Glineburg, P Song, J Liu, GP Pickel, J Lipska, BK Weinberger, DR AF Chen, Jingshan Papaleo, Francesco Tian, Qingjun Glineburg, Paul Song, Jian Liu, Guangping Pickel, James Lipska, Barbara K. Weinberger, Daniel R. TI Development of Knock-in Mutant Mice Carrying Human Catechol-O-Methyltransferase Met Mutation Mimicking the Functional Val158Met Polymorphism SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Chen, Jingshan; Papaleo, Francesco; Tian, Qingjun; Glineburg, Paul; Song, Jian; Liu, Guangping; Lipska, Barbara K.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Pickel, James] NIMH, Genet Lab, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 137 BP 42S EP 42S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200132 ER PT J AU Wang, Y Du, J Yuan, PX Zhou, RL Li, Z Innis, R Navarro, XG Manji, H AF Wang, Yun Du, Jing Yuan, Peixiong Zhou, Rulun Li, Zheng Innis, Robert Navarro, Xavier Guitart Manji, Husseini TI Regulation of Synaptic Plasticity by Glucocorticoids during Chronic Stress SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Wang, Yun; Yuan, Peixiong; Zhou, Rulun; Navarro, Xavier Guitart] NIMH, Biomarker Lab, NIH, Bethesda, MD 20892 USA. [Du, Jing] NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Li, Zheng] NIMH, Unit Synapse Dev & Plast, NIH, Bethesda, MD 20892 USA. [Innis, Robert; Manji, Husseini] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 138 BP 42S EP 42S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200133 ER PT J AU Luo, Q Mitchell, D Cheng, X Mondillo, K Mccaffrey, D Holroyd, T Carver, F Coppola, R Blair, J AF Luo, Qian Mitchell, Derek Cheng, Xi Mondillo, Krystal Mccaffrey, Dan Holroyd, Tom Carver, Fred Coppola, Richard Blair, James TI Visual Awareness, Emotion and Gamma Band Synchronization SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Luo, Qian; Mitchell, Derek; Cheng, Xi; Mondillo, Krystal; Mccaffrey, Dan; Holroyd, Tom; Carver, Fred; Coppola, Richard; Blair, James] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 154 BP 47S EP 48S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200149 ER PT J AU Mueller, S Maheu, F Dozier, M Peloso, E Mandell, D Leibenluft, E Pine, D Ernst, M AF Mueller, Sven Maheu, Francoise Dozier, Mary Peloso, Elizabeth Mandell, Darcy Leibenluft, Ellen Pine, Daniel Ernst, Monique TI Early Life Stress due to Maltreatment in Childhood alters Inhibitory Motor Control: An fMRI Study SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Mueller, Sven; Mandell, Darcy; Leibenluft, Ellen; Pine, Daniel; Ernst, Monique] NIMH, NIH, Bethesda, MD 20892 USA. [Maheu, Francoise] Univ Montreal, Montreal, PQ, Canada. [Dozier, Mary; Peloso, Elizabeth] Univ Delaware, Newark, DE USA. NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 155 BP 48S EP 48S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200150 ER PT J AU Morita, Y Fink, EN Nakata, K Hyde, TM Weinberger, DR Kleinman, JE Lipska, BK AF Morita, Yukitaka Fink, Erin N. Nakata, Kenji Hyde, Thomas M. Weinberger, Daniel R. Kleinman, Joel E. Lipska, Barbara K. TI Characterization of Novel Splice Variants of Disrupted-in-Schizophrenia-1 (DISC1) in Mouse Brain SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Morita, Yukitaka; Fink, Erin N.; Nakata, Kenji; Hyde, Thomas M.; Weinberger, Daniel R.; Kleinman, Joel E.; Lipska, Barbara K.] NIMH, Clin Brain Disorders Branch, Div Intramural Res Programs, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 182 BP 56S EP 56S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200177 ER PT J AU Bevilacqua, L Zhou, ZF Yuan, QP Yamini, G Moore, E Virkkunen, M Goldman, D AF Bevilacqua, Laura Zhou, Zhifeng Yuan, Qiaoping Yamini, Goli Moore, Elisa Virkkunen, Matti Goldman, David TI Re-sequencing for Rare and Uncommon Genetic Variants that may Influence Behavioral Dyscontrol and Impulsivity SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Bevilacqua, Laura; Zhou, Zhifeng; Yuan, Qiaoping; Yamini, Goli; Moore, Elisa; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Virkkunen, Matti] Univ Helsinki, Dept Psychiat, SF-00180 Helsinki, Finland. 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 188 BP 57S EP 57S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200182 ER PT J AU Hodgkinson, CA Enoch, MA Yuan, QP Shen, PH Goldman, D AF Hodgkinson, Colin A. Enoch, Mary-Anne Yuan, Qiaoping Shen, Pei-Hong Goldman, David TI Novel Pathways are Implicated in the Modulation of Electrical Activity in the Brain by GWAS for Resting EEG Traits SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Hodgkinson, Colin A.; Enoch, Mary-Anne; Yuan, Qiaoping; Shen, Pei-Hong; Goldman, David] NIAAA, Neurogenet Lab, Rockville, MD 20852 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 189 BP 58S EP 58S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200183 ER PT J AU Schulze, TG Kassem, L Han, EH McMahon, FJ Karypis, G AF Schulze, Thomas G. Kassem, Layla Han, Eui-Hong McMahon, Francis J. Karypis, George TI Identifying Genotype-Phenotype Signatures in Genome-Wide Association Data Sets Using Market-Basket-Analysis SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Schulze, Thomas G.; Kassem, Layla; McMahon, Francis J.] NIMH, MAPGenet, NIH, Bethesda, MD 20892 USA. [Han, Eui-Hong; Karypis, George] Univ Minnesota, Dept Comp Sci & Engn, Minneapolis, MN USA. RI Schulze, Thomas/H-2157-2013 NR 0 TC 0 Z9 0 U1 0 U2 2 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 APR 15 PY 2009 VL 65 IS 8 MA 190 BP 58S EP 58S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200184 ER PT J AU Srivastava, V Buzas, B Momenan, R Enoch, MA Hommer, D Goldman, D AF Srivastava, Vibhuti Buzas, Beata Momenan, Reza Enoch, Mary-Anne Hommer, Daniel Goldman, David TI SOD2 Diplotype Predicts Reduction In Gray Matter Volume In Chronic Alcoholics SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Srivastava, Vibhuti; Enoch, Mary-Anne; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. [Buzas, Beata] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Momenan, Reza; Hommer, Daniel] NIMH, Lab Clin & Translat Studies, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 191 BP 58S EP 58S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200185 ER PT J AU Chen, J Lee, CT Worden, L Freed, WJ AF Chen, Jia Lee, Chun-Ting Worden, Lila Freed, William J. TI Cocaine Exposure during Neurogenesis Alters the Distribution of Glutamate and GABA Neurons in the Developing Cerebral Cortex SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Chen, Jia; Lee, Chun-Ting; Worden, Lila; Freed, William J.] NIDA, IRP, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 215 BP 66S EP 66S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200209 ER PT J AU Ng, P Sinaii, N Green-Golan, L Lescheck, E VanRyzin, C Schroth, E Pine, D Merke, D Ernst, M AF Ng, Pamela Sinaii, Ninet Green-Golan, Liza Lescheck, Ellen VanRyzin, Carol Schroth, Elizabeth Pine, Daniel Merke, Deborah Ernst, Monique TI Children with Prepubertal Hyperandrogenism due to Classic Congenital Adrenal Hyperplasia or Familial Male Precocious Puberty are at Risk for Pyschopathology SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Sinaii, Ninet] NIMH, NIH, Ctr Clin, Bethesda, MD 20892 USA. [Green-Golan, Liza; VanRyzin, Carol; Merke, Deborah] NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. [Lescheck, Ellen] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 221 BP 67S EP 68S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200215 ER PT J AU Schloesser, RJ Martinowich, K Husseini, M AF Schloesser, Robert J. Martinowich, Keri Husseini, Manji TI Suppression of Adult Neurogenesis Leads to Hyperactive HPA-Axis SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Schloesser, Robert J.; Martinowich, Keri; Husseini, Manji] NIMH, LMP, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 223 BP 68S EP 68S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200217 ER PT J AU Malkesman, O Tragon, T Reed, JC Pellecchia, M Chen, G Manji, HK AF Malkesman, Oz Tragon, Tyson Reed, John C. Pellecchia, Maurizio Chen, Guang Manji, Husseini K. TI Bid Inhibitors as Potential Novel Anti-Depressant Drugs SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Malkesman, Oz; Tragon, Tyson; Chen, Guang; Manji, Husseini K.] NIMH, NIH, Bethesda, MD 20892 USA. [Reed, John C.; Pellecchia, Maurizio] Burnham Inst Med Res, La Jolla, CA USA. RI Chen, Guang/A-2570-2017 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 244 BP 75S EP 75S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200238 ER PT J AU Yuan, PX Zhou, RL Wang, Y Guitart, X Chen, G Innis, R Manji, HK AF Yuan, Peixiong Zhou, Rulun Wang, Yun Guitart, Xavier Chen, Guang Innis, Robert Manji, Husseini K. TI Abnormalities in the MEK Signaling Pathway in Postmortem Brain of Mood Disorder Subjects SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Yuan, Peixiong; Zhou, Rulun; Wang, Yun; Guitart, Xavier] NIMH, Biomarker Lab, NIH, Bethesda, MD 20892 USA. [Chen, Guang] NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Innis, Robert; Manji, Husseini K.] NIMH, Mood & Anxiety Disorder Program, NIH, Bethesda, MD 20892 USA. RI Chen, Guang/A-2570-2017 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 258 BP 78S EP 79S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200252 ER PT J AU Zhou, RL Yuan, PX Hunsberger, J Wang, Y Elkahloun, A Jacobowitz, D Malkesman, O Damschroder-Williams, P Du, J Guitart-Navarro, X Manji, H Chen, G AF Zhou, Rulun Yuan, Peixiong Hunsberger, Joshua Wang, Yun Elkahloun, Abdel Jacobowitz, David Malkesman, Oz Damschroder-Williams, Patricia Du, Jing Guitart-Navarro, Xavier Manji, Husseini Chen, Guang TI Profiling of microRNAs in Rat Hippocampus after Behavioral Stress Suggests Novel Mechanisms in the Regulation of Neuroplasticity SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Zhou, Rulun; Yuan, Peixiong; Hunsberger, Joshua; Wang, Yun; Malkesman, Oz; Damschroder-Williams, Patricia; Du, Jing; Guitart-Navarro, Xavier; Manji, Husseini; Chen, Guang] NIMH, NIH, Bethesda, MD 20892 USA. [Elkahloun, Abdel] NHGRI, NIH, Bethesda, MD 20892 USA. [Jacobowitz, David] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. RI Chen, Guang/A-2570-2017 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 263 BP 80S EP 80S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200257 ER PT J AU Zarate, CA AF Zarate, Carlos Alberto TI Plasticity Based Therapeutics for the Treatment of Severe Mood Disorders SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Zarate, Carlos Alberto] NIMH, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 270 BP 82S EP 82S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200263 ER PT J AU Laje, G Alda, M Opgen-Rhein, C Mueller, DJ AF Laje, Gonzalo Alda, Martin Opgen-Rhein, Carolin Mueller, Daniel J. TI Psychopharmacogenetics: A New Era of Rational Treatment in Psychiatry? SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Laje, Gonzalo] NIMH, Bethesda, MD 20892 USA. [Alda, Martin] Dalhousie Univ, Halifax, NS, Canada. [Opgen-Rhein, Carolin] Charite Univ Med Berlin, D-13353 Berlin, Germany. [Mueller, Daniel J.] Univ Toronto, Dept Psychiat, CAMH, Toronto, ON, Canada. NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 273 BP 83S EP 83S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200266 ER PT J AU Hyde, T Cookson, M Vawter, M Jeromin, A AF Hyde, Thomas Cookson, Mark Vawter, Marquis Jeromin, Andreas TI Integrated Approaches to Molecular Human Brain Mapping SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Hyde, Thomas] NIMH, NIH, Chevy Chase, MD USA. [Cookson, Mark] NIA, Bethesda, MD 20892 USA. [Vawter, Marquis] Univ Calif Irvine, Irvine, CA USA. [Jeromin, Andreas] Allen Inst Brain Sci, Seattle, WA 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 275 BP 84S EP 84S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200268 ER PT J AU Cannon, DM Klaver, JM Peck, SA Carlson, PJ Luckenbaugh, D Ichise, M Drevets, WC AF Cannon, Dara M. Klaver, Jackie M. Peck, Summer A. Carlson, Paul J. Luckenbaugh, Dave Ichise, Masanori Drevets, Wayne C. TI Serotonin Transporter Binding in Panic Disorder: A [C-11]DASB PET Study SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Cannon, Dara M.] Natl Univ Ireland, Galway, Ireland. [Klaver, Jackie M.; Peck, Summer A.; Carlson, Paul J.; Luckenbaugh, Dave; Drevets, Wayne C.] NIMH, NIH, Bethesda, MD 20892 USA. [Ichise, Masanori] Columbia Univ, New York, NY USA. RI Cannon, Dara/C-1323-2009 OI Cannon, Dara/0000-0001-7378-3411 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 279 BP 85S EP 85S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200273 ER PT J AU Rich, B Holroyd, T Carver, F Fox, N Coppola, R Pine, D Leibenluft, E AF Rich, Brendan Holroyd, Tom Carver, Frederick Fox, Nathan Coppola, Richard Pine, Daniel Leibenluft, Ellen TI A Magnetoencephalography (MEG) Study of Irritability in Pediatric Bipolar Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Rich, Brendan] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. [Holroyd, Tom; Carver, Frederick; Coppola, Richard] NIMH, MEG Core Facil, Bethesda, MD 20892 USA. [Fox, Nathan] Univ Maryland, Child Dev Lab, College Pk, MD 20742 USA. [Pine, Daniel; Leibenluft, Ellen] NIH, Mood & Anxiety Program, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 284 BP 87S EP 87S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200278 ER PT J AU Furey, ML Drevets, WC AF Furey, Maura L. Drevets, Wayne C. TI Scopolamine Produces Rapid Antidepressant Effects in MDD: A Replication Study SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Furey, Maura L.; Drevets, Wayne C.] NIMH, Mood & Anxiety Disorders Program, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 288 BP 88S EP 88S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200282 ER PT J AU Leibenluft, E AF Leibenluft, Ellen TI Behavioral Endophenotypes in Bipolar Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Leibenluft, Ellen] NIMH, Mood & Anxiety Program, Intramural Res Program, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 312 BP 94S EP 94S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200300 ER PT J AU Machado-Vieira, R Du, J Pivovarova, N Chen, G Andrews, SB Manji, HK AF Machado-Vieira, Rodrigo Du, J. Pivovarova, N. Chen, G. Andrews, S. B. Manji, H. K. TI Altered Intracellular Calcium Dynamics in Bipolar Subjects: A Bcl-2 Gene SNP (rs956572) as a Risk Allele for Bipolar Disorder SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 NIMH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. RI Du, Jing/A-9023-2012; MACHADO-VIEIRA, RODRIGO/D-8293-2012; Chen, Guang/A-2570-2017 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 317 BP 95S EP 95S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200305 ER PT J AU Zarate, CA AF Zarate, Carlos Alberto TI Developing Calcium Channel Modulator Compounds for the Treatment of Bipolar Disorder: Problems and Potential Solutions SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Zarate, Carlos Alberto] NIMH, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 319 BP 96S EP 96S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200307 ER PT J AU Barr, CS AF Barr, Christina S. TI Genome-Wide Identification of Epigenetic Markers of Early Life Stress in Primate Brain SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Barr, Christina S.] NIAAA, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 324 BP 97S EP 97S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200312 ER PT J AU Goldman, D Yuan, QP Zhou, ZF Yamini, GL Suomi, S Barr, C AF Goldman, David Yuan, Qiaoping Zhou, Zhifeng Yamini, Goli Suomi, Steve Barr, Christina TI New Gene Targets for Gene X Stress Interaction Identified by Genome-Wide Transcriptome and Chromatin Analysis in a Macaque Maternal Separation Model SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Goldman, David; Yuan, Qiaoping; Zhou, Zhifeng; Yamini, Goli; Suomi, Steve; Barr, Christina] NIAAA, Neurogenet Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 325 BP 97S EP 98S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200313 ER PT J AU Cardinale, K Schloesser, R Manji, H Martinowich, K AF Cardinale, Kathleen Schloesser, Robert Manji, Husseini Martinowich, Keri TI New Behavioral Parameters Measured in Response to Chronic Restraint Stress SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Cardinale, Kathleen; Schloesser, Robert; Manji, Husseini; Martinowich, Keri] NIMH, Mol Pathophysiol Lab, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 364 BP 109S EP 109S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200353 ER PT J AU Enoch, MA Yuan, QP Hodgkinson, CA Ducci, F Shen, PH Virkkunen, M Roy, A Goldman, D AF Enoch, Mary-Anne Yuan, Qiaoping Hodgkinson, Colin A. Ducci, Francesca Shen, Pei-Hong Virkkunen, Matti Roy, Alec Goldman, David TI Genes Encoding 5-HT3 Receptors Influence Alcoholism Vulnerability in Two Independent Populations SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Enoch, Mary-Anne; Yuan, Qiaoping; Hodgkinson, Colin A.; Ducci, Francesca; Shen, Pei-Hong; Goldman, David] NIAAA, LNG, NIH, SF-00180 Bethesda, MD USA. [Virkkunen, Matti] Univ Helsinki, Dept Psychiat, Helsinki, Finland. [Roy, Alec] New Jersey VA Hlth Care Syst, Psychiat Serv, Dept VA Affairs, E Orange, NJ 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 377 BP 113S EP 113S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200366 ER PT J AU Gorodetsky, E Roy, A Goldman, D Enoch, MA AF Gorodetsky, Elena Roy, Alec Goldman, David Enoch, Mary-Anne TI Association of FKBP5, A Stress-Related Gene, with Drug Dependence in African American Men SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Gorodetsky, Elena] NIMH, MAP, NIH, Bethesda, MD 20892 USA. [Roy, Alec] Vet Affairs Med Ctr, Psychiat Serv, E Orange, NJ USA. [Goldman, David; Enoch, Mary-Anne] NIAAA, LNG, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 378 BP 113S EP 113S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200367 ER PT J AU Tinsley, RK Carlson, P Luckenbaugh, D Nugent, A Neumeister, A Geraci, M Herscovitch, P Drevets, W AF Tinsley, Ruth K. Carlson, Paul Luckenbaugh, David Nugent, Allison Neumeister, Alex Geraci, Marilla Herscovitch, Peter Drevets, Wayne TI Gender Differences among Healthy and Panic Disorder Subjects using Noradrenergic Challenge and FDG PET Imaging SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Tinsley, Ruth K.; Luckenbaugh, David; Nugent, Allison; Geraci, Marilla; Drevets, Wayne] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Carlson, Paul] Univ Utah, Dept Psychiat, Salt Lake City, UT USA. [Neumeister, Alex] Yale Univ, Sch Med, Clin Neurosci Div, West Haven, CT 06516 USA. [Herscovitch, Peter] NIH, PET Dept, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 401 BP 120S EP 121S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200390 ER PT J AU Rao, JS Rapoport, SI Kim, HW AF Rao, Jagadeesh S. Rapoport, Stanley I. Kim, Hyung-Wook TI Altered Pro- and Anti-Apoptotic Factors in Postmortem Brain from Bipolar Disorder Patients SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Rao, Jagadeesh S.; Rapoport, Stanley I.; Kim, Hyung-Wook] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RI Kim, Hyung-Wook/B-6308-2009; Rao, Jagadeesh/C-1250-2009 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 446 BP 135S EP 135S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200435 ER PT J AU Fowler, KA Schechter, JC Pine, DS Sinclair, S Blair, RJR AF Fowler, Katherine A. Schechter, Julia C. Pine, Daniel S. Sinclair, Stephen Blair, R. J. R. TI Adolescents with Conduct Disorder and Callous and Unemotional Traits Demonstrate Impaired Processing of Emotionally Salient Words SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Fowler, Katherine A.; Schechter, Julia C.; Pine, Daniel S.; Sinclair, Stephen; Blair, R. J. R.] NIMH, Mood & Anxiety Program, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 480 BP 146S EP 147S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200469 ER PT J AU Hardin, MG Koelitz, K Mueller, S Bradley, BP Mogg, K Pine, DS Ernst, M AF Hardin, Michael G. Koelitz, Katy Mueller, Sven Bradley, Brendan P. Mogg, Karin Pine, Daniel S. Ernst, Monique TI Emotion Related influence on Cognitive Control in Anxious Adolescents SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Hardin, Michael G.; Koelitz, Katy; Mueller, Sven; Pine, Daniel S.; Ernst, Monique] NIMH, Emot Dev & Affect Neurosci Branch, Bethesda, MD 20892 USA. [Bradley, Brendan P.; Mogg, Karin] Univ Southampton, Sch Psychol, Southampton, Hants, England. RI Bradley, Brendan/B-9724-2008 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 478 BP 146S EP 146S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200467 ER PT J AU Rabin, C Sharp, W Lenroot, R Pierson, R Clasen, L Rapoport, J Shaw, P AF Rabin, Cara Sharp, Wendy Lenroot, Rhoshel Pierson, Ron Clasen, Liv Rapoport, Judith Shaw, Philip TI Cerebellar Volume Reductions in Monozygotic Twins Discordant for Attention-Deficit/Hyperactivity Disorder (ADHD) SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Rabin, Cara; Sharp, Wendy; Lenroot, Rhoshel; Clasen, Liv; Rapoport, Judith; Shaw, Philip] NIH, Bethesda, MD 20892 USA. [Pierson, Ron] Univ Iowa, Sch Med, Dept Psychiat, Iowa City, IA 52242 USA. NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 479 BP 146S EP 146S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200468 ER PT J AU Britton, JC Holroyd, T Norcross, M Detloff, A Shiffrin, N Goldwin, M Carver, FW Coppola, R Leibenluft, E Ernst, M Fox, NA Pine, DS Bar-Haim, Y AF Britton, Jennifer C. Holroyd, Thomas Norcross, Maxine Detloff, Allison Shiffrin, Nina Goldwin, Michelle Carver, Frederick W. Coppola, Richard Leibenluft, Ellen Ernst, Monique Fox, Nathan A. Pine, Daniel S. Bar-Haim, Yair TI Ventral Prefrontal Cortical Synchronization Activity may Mediate Attentional Control during a Dot-Probe Task in Healthy Adolescents SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Britton, Jennifer C.; Norcross, Maxine; Detloff, Allison; Shiffrin, Nina; Goldwin, Michelle; Leibenluft, Ellen; Ernst, Monique; Pine, Daniel S.] NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. [Holroyd, Thomas; Carver, Frederick W.; Coppola, Richard] NIMH, Magnetoencephalog Core Facil, Bethesda, MD 20892 USA. [Fox, Nathan A.] Univ Maryland, College Pk, MD 20742 USA. [Bar-Haim, Yair] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. RI Britton, Jennifer/J-4501-2013 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 482 BP 147S EP 147S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200471 ER PT J AU Wolf, RC Vasic, N Sambataro, F Gron, G Landwehrmeyer, GB Orth, M AF Wolf, Robert C. Vasic, Nenad Sambataro, Fabio Groen, Georg Landwehrmeyer, G. Bernhard Orth, Michael TI Regional Brain Activation Changes in Presymptomatic Huntington's Disease During States of Intrinsic and Phasic Alertness SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Wolf, Robert C.; Vasic, Nenad; Groen, Georg] Univ Ulm, Dept Psychiat & Psychotherapy 3, Ulm, Germany. [Sambataro, Fabio] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Landwehrmeyer, G. Bernhard; Orth, Michael] Univ Ulm, Dept Neurol, D-7900 Ulm, Germany. 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 500 BP 153S EP 153S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200489 ER PT J AU Podell, JE Sambataro, F Murty, VP Emery, MR Das, S Goldberg, TE Weinberger, DR Mattay, VS AF Podell, Jamie E. Sambataro, Fabio Murty, Vishnu P. Emery, Matthew R. Das, Saumitra Goldberg, Terry E. Weinberger, Daniel R. Mattay, Venkata S. TI Neurophysiological Correlates of Age-Related Impairment in Working Memory Updating SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Podell, Jamie E.; Sambataro, Fabio; Murty, Vishnu P.; Emery, Matthew R.; Das, Saumitra; Goldberg, Terry E.; Weinberger, Daniel R.; Mattay, Venkata S.] NIMH, CBDB, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 502 BP 154S EP 154S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200491 ER PT J AU Stankevich, B Rasetti, R Sambataro, F Malone, C Kolachana, B Das, S Emery, M Tan, HY Straub, R Callicott, JH Mattay, VS Weinberger, DR AF Stankevich, B. Rasetti, R. Sambataro, F. Malone, C. Kolachana, B. Das, S. Emery, M. Tan, H. Y. Straub, R. Callicott, J. H. Mattay, V. S. Weinberger, D. R. TI CAMK2A Genetic Variation Modulates Prefrontal Cortical Function during Working Memory across Adulthood SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Stankevich, B.; Rasetti, R.; Sambataro, F.; Malone, C.; Kolachana, B.; Das, S.; Emery, M.; Tan, H. Y.; Straub, R.; Callicott, J. H.; Mattay, V. S.; Weinberger, D. R.] NIMH, CBDB, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 503 BP 154S EP 154S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200492 ER PT J AU DeRosse, P Xu, K Burdick, KE Lencz, T Goldman, D Malhotra, AK AF DeRosse, Pamela Xu, Ke Burdick, Katherine E. Lencz, Todd Goldman, David Malhotra, Anil K. TI Relationship between DRD2 and Harm Avoidance in Healthy Volunteers SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [DeRosse, Pamela; Burdick, Katherine E.; Lencz, Todd; Malhotra, Anil K.] N Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Dept Psychiat Res, Glen Oaks, NY USA. [Xu, Ke] NIAAA, Neurogenet Lab, Behesda, MD USA. [Goldman, David] NIAAA, Neurogenet Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 516 BP 158S EP 158S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200505 ER PT J AU Leibenluft, E AF Leibenluft, Ellen TI Bipolar Disorder: A Developmental Neuroscience Approach SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Leibenluft, Ellen] NIMH, MAP, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 527 BP 162S EP 162S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200516 ER PT J AU Rapoport, JL AF Rapoport, Judith L. TI Schizophrenia and Autism: Relationship Revisited SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Rapoport, Judith L.] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 APR 15 PY 2009 VL 65 IS 8 MA 526 BP 162S EP 162S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200515 ER PT J AU Wang, KH AF Wang, Kuan Hong TI Imaging the Development and Plasticity of Prefrontal Neuronal Circuits SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Wang, Kuan Hong] NIMH, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 541 BP 166S EP 166S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200528 ER PT J AU Schulze, TG Perlis, R Smoller, J Aida, M Rybakowski, J Kato, T Laje, G Schumacher, J Manchia, M Del Zompo, M Reif, A Leckband, S Kelsoe, JR Bauer, M McMahon, FJ AF Schulze, Thomas G. Perlis, Roy Smoller, Jordan Aida, Martin Rybakowski, Janusz Kato, Tadafumi Laje, Gonzalo Schumacher, Johannes Manchia, Mirko Del Zompo, Maria Reif, Andreas Leckband, Susan Kelsoe, John R. Bauer, Michael McMahon, Francis J. CA Japanese Collaborative Grp Genetic NIMH Bipolar Genetics Study BiGS Int Grp Study Lithium Treated Pati TI The International Consortium on Lithium Genetics (ConLiGen): A Resource for Genome-Wide Association Studies of Lithium Response SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Schulze, Thomas G.; Laje, Gonzalo; Schumacher, Johannes; McMahon, Francis J.] NIMH, NIH, MAP Genet, Bethesda, MD 20892 USA. [Perlis, Roy; Smoller, Jordan] Harvard Univ, Boston, MA 02115 USA. [Aida, Martin] Dalhousie Univ, Halifax, NS, Canada. [Rybakowski, Janusz] Univ Med Sci, Poznan, Poland. [Kato, Tadafumi] RIKEN, Brain Sci Inst, Lab Mol Dynam Mental Disorders, Saitama, Japan. [Manchia, Mirko; Del Zompo, Maria] Univ Cagliari, Bb Brodie Dept Neurosci, I-09124 Cagliari, Italy. [Reif, Andreas] Univ Wurzburg, Wurzburg, Germany. [Leckband, Susan] VA Healthcare Syst, San Diego, CA USA. [Kelsoe, John R.] Univ Calif San Diego, San Diego, CA 92103 USA. [Bauer, Michael] Tech Univ Dresden, Dresden, Germany. RI Schulze, Thomas/H-2157-2013 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 544 BP 167S EP 167S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200531 ER PT J AU Altemus, M Peterson, JC Wells, MT Jobe, JB Charlson, ME AF Altemus, Margaret Peterson, Janey C. Wells, Martin T. Jobe, Jared B. Charlson, Mary E. TI Positive Affect Intervention Attenuates Inflammation and AM Cortisol Rise in Angioplasty Patients SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Altemus, Margaret; Peterson, Janey C.; Charlson, Mary E.] Weill Med Coll, New York, NY USA. [Wells, Martin T.] Cornell Univ, Ithaca, NY USA. [Jobe, Jared B.] NHLBI, Clin Applicat & Prevent Branch, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 549 BP 169S EP 169S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200536 ER PT J AU Hyde, TM AF Hyde, Thomas M. TI The Cation Chloride Co-Transporters KCC2 and NKCC1 and Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Hyde, Thomas M.] NIMH, IRP, GCAP, Clin Brain Disorders Branch, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 559 BP 170S EP 171S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200540 ER PT J AU Niculescu, AB Le-Niculescu, H Patel, S Bhat, M Kuczenski, R Faraone, SV Tsuang, MT McMahon, F Schork, NJ Nurnberger, JI AF Niculescu, Alexander B. Le-Niculescu, Helen Patel, Sagar Bhat, Meghana Kuczenski, Ronald Faraone, Steven V. Tsuang, Ming T. McMahon, Francis Schork, Nicholas J. Nurnberger, John I. TI Convergent Functional Genomics of Genome-Wide Association Data for Bipolar Disorder: Comprehensive Identification of Candidate Genes, Pathways and Mechanisms SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Niculescu, Alexander B.; Le-Niculescu, Helen; Patel, Sagar; Bhat, Meghana; Nurnberger, John I.] Indiana Univ, Sch Med, Indianapolis, IN USA. [Kuczenski, Ronald; Tsuang, Ming T.] UCSD, La Jolla, CA USA. [Kuczenski, Ronald; Tsuang, Ming T.] SUNY Upstate Med Univ, Syracuse, NY USA. [McMahon, Francis] NIMH, Mood & Anxiety Disorders Branch, Bethesda, MD 20892 USA. [Schork, Nicholas J.] Scripps Res Inst, La Jolla, CA 92037 USA. RI Niculescu, Alexander/A-3328-2012 NR 0 TC 0 Z9 0 U1 0 U2 2 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 APR 15 PY 2009 VL 65 IS 8 MA 551 BP 170S EP 170S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200538 ER PT J AU Law, AJ AF Law, Amanda J. TI Identification of NFIV1, a Developmental Specific Splice Variant of NRG1 Type IV: Regulation by rs6994992, Effects on Neuronal Development and Implications for Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Law, Amanda J.] Univ Oxford, Oxford, England. [Law, Amanda J.] NIMH, NIH, CBDB, Bethesda, MD 20892 USA. RI Law, Amanda/G-6372-2012 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 560 BP 171S EP 171S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200541 ER PT J AU Lipska, BK AF Lipska, Barbara K. TI Characterization and Genetic Association of Novel Splice Variants of Disrupted-in-Schizophrenia-1 (DISC1) in Human Brain SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Lipska, Barbara K.] NIMH, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 561 BP 171S EP 171S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200542 ER PT J AU Weinberger, DR AF Weinberger, Daniel R. TI A Primate and Brain Specific Isoform of KCNH2 is an Etiologic and Pathophysiologic Component of Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Weinberger, Daniel R.] NIMH, NIH, Inramural Res Program, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 562 BP 171S EP 172S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200543 ER PT J AU Wess, J AF Wess, Jurgen TI Muscarinic Receptor Knockout Mice: Central Roles for the Receptors SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Wess, Jurgen] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 563 BP 172S EP 172S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200544 ER PT J AU Drevets, WC AF Drevets, Wayne C. TI fMRI-PET Studies of Dysregulation in the Neural Circuits Underlying Reward Processing in Depression SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Drevets, Wayne C.] NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 574 BP 175S EP 175S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200555 ER PT J AU Zorrilla, EP Cottone, P Sabino, V Bajo, M Steardo, L Rice, K Conti, B Roberto, M Koob, GF AF Zorrilla, Eric P. Cottone, Pietro Sabino, Valentina Bajo, Michal Steardo, Luca Rice, Kenner Conti, Bruno Roberto, Marisa Koob, George F. TI CRF1 System Involvement in the "Dark Side" of Compulsive Eating SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Zorrilla, Eric P.; Cottone, Pietro; Sabino, Valentina; Bajo, Michal; Roberto, Marisa; Koob, George F.] Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. [Cottone, Pietro; Steardo, Luca] Univ Roma La Sapienza, Dept Human Physiol & Pharmacol, Rome, Italy. [Rice, Kenner] Natl Inst Drug Abuse, Med Chem Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Conti, Bruno] Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA. RI koob, george/P-8791-2016 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 576 BP 176S EP 176S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200557 ER PT J AU Chuang, DM AF Chuang, De-Maw TI Glia as a Target of Mood Stabilizers SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Chuang, De-Maw] NIMH, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 593 BP 181S EP 181S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200574 ER PT J AU Khairova, R Wei, YL Machado-Vieira, R Du, J Manji, H AF Khairova, Rushaniya Wei, Yanling Machado-Vieira, Rodrigo Du, Jing Manji, Husseini TI Neuronal-Glia Crosstalk: The Role of TNF-Alpha in Regulation of Synaptogenesis in Hippocampal Neurons SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Khairova, Rushaniya; Wei, Yanling; Machado-Vieira, Rodrigo; Du, Jing; Manji, Husseini] NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. RI MACHADO-VIEIRA, RODRIGO/D-8293-2012 OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 592 BP 181S EP 181S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200573 ER PT J AU Geramita, MA Savostyanova, A van der Veen, J Rebsch, C Barnett, A Shen, J Weinberger, DR Marenco, S AF Geramita, M. A. Savostyanova, A. van der Veen, J. Rebsch, C. Barnett, A. Shen, J. Weinberger, D. R. Marenco, S. TI GABA/Creatine Levels in the Medial Prefrontal Cortex and Frontal White Matter of Patients with Schizophrenia: A Proton Magnetic Resonance Spectroscopy (H-1-MRS) Study SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Geramita, M. A.; Savostyanova, A.; van der Veen, J.; Rebsch, C.; Barnett, A.; Shen, J.; Weinberger, D. R.; Marenco, S.] NIMH, NIH, Bethesda, MD 20892 USA. RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 NR 0 TC 0 Z9 0 U1 1 U2 2 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 APR 15 PY 2009 VL 65 IS 8 SU S MA 608 BP 185S EP 186S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200588 ER PT J AU Wisner, KM Dickinson, D Gold, JM Elvevag, B Weinberger, DR AF Wisner, Krista M. Dickinson, Dwight Gold, James M. Elvevag, Brita Weinberger, Daniel R. TI A Closer Look at Siblings Discordant for Schizophrenia: The Differential Performance of Symptomatology and Gender Subgroups on Cognitive Phenotypes SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Wisner, Krista M.; Dickinson, Dwight; Elvevag, Brita; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Dickinson, Dwight; Gold, James M.] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 610 BP 186S EP 186S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200590 ER PT J AU Yoshimi, A Tan, HY Marenco, S Prust, MJ Apud, J Hyde, TM Weinberger, DR Callicott, JH AF Yoshimi, Asuka Tan, Hao Yang Marenco, Stefano Prust, Morgan J. Apud, Jose Hyde, Thomas M. Weinberger, Daniel R. Callicott, Joseph H. TI Neurodevelopment and Imaging Genetics: Are Early Onset Features of Schizophrenia Reflected in fMRI Measures of Prefrontal Efficiency? SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Yoshimi, Asuka; Tan, Hao Yang; Prust, Morgan J.; Callicott, Joseph H.] NIMH, Unit Dynam Imaging Genet, Bethesda, MD 20892 USA. RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 609 BP 186S EP 186S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200589 ER PT J AU Ianni, AM Eisenberg, DR Bronstein, JA Apud, JA Weinberger, DR Berman, KF AF Ianni, Angela M. Eisenberg, Daniel R. Bronstein, Joel A. Apud, Jose A. Weinberger, Daniel R. Berman, Karen F. TI Antipsychotic Medications Affect Regional Cerebral Blood Flow in Patients with Schizophrenia during Working Memory SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Ianni, Angela M.; Eisenberg, Daniel R.; Bronstein, Joel A.; Berman, Karen F.] NIMH, Sect Integrat Neuroimaging, CBDB, NIH, Bethesda, MD 20892 USA. [Apud, Jose A.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RI Eisenberg, Daniel/C-7432-2014; Eisenberg, Daniel/S-4342-2016 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 613 BP 187S EP 187S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200593 ER PT J AU Rebsch, C Zhang, Y Stern, AJ Geramita, M Barnett, AS Shen, J Weinberger, DR Marenco, S AF Rebsch, C. Zhang, Y. Stern, A. J. Geramita, M. Barnett, Alan S. Shen, J. Weinberger, D. R. Marenco, S. TI Glutamate Measures in Schizophrenia (SCZ) Using TE-averaged PRESS at 3T SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Rebsch, C.; Zhang, Y.; Stern, A. J.; Geramita, M.; Barnett, Alan S.; Shen, J.; Weinberger, D. R.; Marenco, S.] NIMH, CBDB, NIH, Bethesda, MD 20892 USA. RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 612 BP 187S EP 187S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200592 ER PT J AU Wolf, RC Vasic, N Sambataro, F Hose, A Frasch, K Spitzer, M Walter, H AF Wolf, Robert C. Vasic, Nenad Sambataro, Fabio Hoese, Annett Frasch, Karel Spitzer, Manfred Walter, Henrik TI Temporally Anticorrelated Brain Networks During Working Memory Performance Reveal Prefrontal and Hippocampal Dysconnectivity in Patients with Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Wolf, Robert C.; Vasic, Nenad; Spitzer, Manfred] Univ Ulm, Dept Psychiat & Psychotherapy 3, Ulm, Germany. [Sambataro, Fabio] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. [Hoese, Annett; Frasch, Karel] Univ Ulm, Dept Psychiat & Psychotherapy 2, Ulm, Germany. [Walter, Henrik] Univ Bonn, Dept Psychiat, Div Med Psychol, D-5300 Bonn, Germany. RI Walter, Henrik/O-2612-2013 NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 637 BP 194S EP 194S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200615 ER PT J AU Fink, EN Morita, Y Nakata, K Hyde, TM Weinberger, DR Kleinman, JE Lipska, BK AF Fink, Erin N. Morita, Yukitaka Nakata, Kenji Hyde, Thomas M. Weinberger, Daniel R. Kleinman, Joel E. Lipska, Barbara K. TI Novel Human Splice Variants of DISC1 Encode Truncated Proteins SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Fink, Erin N.; Morita, Yukitaka; Nakata, Kenji; Hyde, Thomas M.; Weinberger, Daniel R.; Kleinman, Joel E.; Lipska, Barbara K.] NIH, Clin Brain Disorders Branch, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 651 BP 198S EP 198S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200628 ER PT J AU Lent, I Chen, Q Dickinson, D Vakkalanka, R Kolachana, B Straub, R Mattay, V Callicott, J Weinberger, D Kempf, L AF Lent, Ian Chen, Qiang Dickinson, Dwight Vakkalanka, Radhakrishna Kolachana, Bhaskar Straub, Richard Mattay, Venkata Callicott, Joseph Weinberger, Daniel Kempf, Lucas TI Genetic Variation Within the PRODH2 Gene is Associated with Schizophrenia and Improved Cognitive Factors and Protective Striatal-Frontal Circuitry in Unaffected Siblings SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Lent, Ian; Chen, Qiang; Dickinson, Dwight; Vakkalanka, Radhakrishna; Kolachana, Bhaskar; Straub, Richard; Mattay, Venkata; Callicott, Joseph; Weinberger, Daniel; Kempf, Lucas] NIMH, Cognit & Psychosis Program, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 653 BP 198S EP 199S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200630 ER PT J AU Tost, H Lipska, BK Lemaitre, H Vakkalanka, RK Callicott, JH Mattay, VS Kleinman, JE Marenco, S Weinberger, DR AF Tost, Heike Lipska, Barbara K. Lemaitre, Herve Vakkalanka, Radhakrishna K. Callicott, Joseph H. Mattay, Venkata S. Kleinman, Joel E. Marenco, Stefano Weinberger, Daniel R. TI No Effect of a Common Allelic Variant in the Reelin Gene on Intermediate Phenotype Measures of Brain Structure, Function and Protein Expression SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Tost, Heike; Lipska, Barbara K.; Lemaitre, Herve; Vakkalanka, Radhakrishna K.; Callicott, Joseph H.; Mattay, Venkata S.; Kleinman, Joel E.; Marenco, Stefano; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RI Marenco, Stefano/A-2409-2008 OI Marenco, Stefano/0000-0002-2488-2365 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 652 BP 198S EP 198S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200629 ER PT J AU Ali, T Lipska, BK Ye, TZ Herman, MM Weinberger, DR Kleinman, JE Hyde, TM AF Ali, Towhid Lipska, Barbara K. Ye, Tianzhang Herman, Mary M. Weinberger, Daniel R. Kleinman, Joel E. Hyde, Thomas M. TI Alterations in GABA-Related Transcripts across Development in Human Postmortem Brain: Implications for Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Ali, Towhid; Lipska, Barbara K.; Ye, Tianzhang; Herman, Mary M.; Weinberger, Daniel R.; Kleinman, Joel E.; Hyde, Thomas M.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, GCAP,IRP,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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 654 BP 199S EP 199S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200631 ER PT J AU Ellis, JK Hyde, TM Lipska, BK Weinberger, DR Kleinman, JE AF Ellis, Justin K. Hyde, Thomas M. Lipska, Barbara K. Weinberger, Daniel R. Kleinman, Joel E. TI Expression of BDNF Transcripts in Postmortem Human Brain across the Lifespan SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Ellis, Justin K.; Hyde, Thomas M.; Lipska, Barbara K.; Weinberger, Daniel R.; Kleinman, Joel E.] NIMH, Sect Neuropathol, Clin Brain Disorders Branch, GCAP,IRP,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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 655 BP 199S EP 199S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200632 ER PT J AU Kempf, L Lent, I Chen, Q Zhang, FY Vakkalanka, R Lemaitre, H Straub, RE Mattay, VA Callicott, JH Weinberger, DR AF Kempf, Lucas Lent, Ian Chen, Qiang Zhang, Fengyu Vakkalanka, Radhakrishna Lemaitre, Herve Straub, Richard E. Mattay, Venkata A. Callicott, Joseph H. Weinberger, Daniel R. TI Proline Cycle Genes Associated with Risk and Protection for Schizophrenia and Brain Structure and Functional Phenotype SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Kempf, Lucas; Lent, Ian; Chen, Qiang; Zhang, Fengyu; Vakkalanka, Radhakrishna; Lemaitre, Herve; Straub, Richard E.; Mattay, Venkata A.; Callicott, Joseph H.; Weinberger, Daniel R.] NIMH, GCAP, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 657 BP 200S EP 200S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200634 ER PT J AU Bakalar, JL Greenstein, DK Clasen, L Tossell, J Miller, R Mattai, AA Rapoport, JL Gogtay, N AF Bakalar, Jennifer L. Greenstein, Deanna K. Clasen, Liv Tossell, Julia Miller, Rachel Mattai, Anand A. Rapoport, Judith L. Gogtay, Nitin TI Absence of Abnormal Cortical Asymmetry in Childhood Onset Schizophrenia: A Longitudinal Study SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Bakalar, Jennifer L.; Greenstein, Deanna K.; Clasen, Liv; Tossell, Julia; Miller, Rachel; Mattai, Anand A.; Rapoport, Judith L.; Gogtay, Nitin] NIMH, NIH, Child Psychiat Branch, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 682 BP 207S EP 208S PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200658 ER PT J AU Mattai, A Fung, L Bakalar, J Tossell, J Miller, R Rapoport, J Gogtay, N AF Mattai, Arland Fung, Lawrence Bakalar, Jennifer Tossell, Julia Miller, Rachel Rapoport, Judith Gogtay, Nitin TI Use of Lithium Carbonate in the Management of Clozapine-Induced Neutropenia in Childhood-Onset Schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Mattai, Arland; Fung, Lawrence; Bakalar, Jennifer; Tossell, Julia; Miller, Rachel; Rapoport, Judith; Gogtay, Nitin] NIMH, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 698 BP 212S EP 212S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200673 ER PT J AU Currier, D Galfalvy, H Huang, YY Oquendo, M Brent, D Zhou, ZF Yuan, QP Shen, PH Haghighi, F Hodgkinson, C Cooper, T Goldman, D Mann, JJ AF Currier, Dianne Galfalvy, Hanga Huang Yung-Yu Oquendo, Maria Brent, David Zhou, Zhifeng Yuan, Qiaoping Shen, Pei-Hong Haghighi, Fatemeh Hodgkinson, Colin Cooper, Tom Goldman, David Mann, J. John TI CRHR1 and Other CRH-Related Genes are Associated with Mood Disorders and CSF CRH SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Currier, Dianne; Galfalvy, Hanga; Huang Yung-Yu; Oquendo, Maria; Haghighi, Fatemeh; Cooper, Tom; Mann, J. John] Columbia Univ, New York, NY USA. [Brent, David] Western Psychiat Inst & Clin, Pittsburgh, NY USA. [Zhou, Zhifeng; Yuan, Qiaoping; Shen, Pei-Hong; Hodgkinson, Colin; Goldman, David] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RI Hodgkinson, Colin/F-9899-2010 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 738 BP 225S EP 225S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200712 ER PT J AU Galfalvy, H Currier, D Oquendo, MA Huang, YY Haghighi, F Hodgkinson, CA Goldman, D Brent, D Mann, J AF Galfalvy, Hanga Currier, Dianne Oquendo, Maria A. Huang, Yung-Yu Haghighi, Fatemeh Hodgkinson, Colin A. Goldman, David Brent, David Mann, John TI Adrenergic Genotype, Noradrenaline Metabolite (MHPG) CSF Levels and Suicide Attempts in Major Depression SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Galfalvy, Hanga; Currier, Dianne; Oquendo, Maria A.; Huang, Yung-Yu; Haghighi, Fatemeh; Mann, John] Columbia Univ, New York, NY USA. [Hodgkinson, Colin A.; Goldman, David] NIAAA, Rockville, MD 20852 USA. [Brent, David] Western Psychiat Inst & Clin, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 739 BP 225S EP 225S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200713 ER PT J AU Ayhan, Y Abazyan, B Nomura, J Ladenheim, B Krasnova, IN Cadet, JL Ross, CA Pletnikov, MV AF Ayhan, Yavuz Abazyan, Bagrat Nomura, Jun Ladenheim, Bruce Krasnova, Irina N. Cadet, Jean-Luc Ross, Christopher A. Pletnikov, Mikhail V. TI Expression of Mutant DISC1 Produces Sex- and Time-dependent Monoamine Alterations in Mice SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Ayhan, Yavuz; Abazyan, Bagrat; Nomura, Jun; Ross, Christopher A.; Pletnikov, Mikhail V.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Ladenheim, Bruce; Krasnova, Irina N.; Cadet, Jean-Luc] NIDA, Mol Neuropsychiat Branch, NIH, DHHS, Baltimore, MD USA. RI Nomura, Jun/C-2411-2011 NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 752 BP 229S EP 229S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200726 ER PT J AU Nguyen, VT Eskandari, F Duan, ZG Wright, E Cizza, G AF Nguyen, Vi T. Eskandari, Farideh Duan, Zhigang Wright, Elizabeth Cizza, Giovanni TI Premenopausal Women with Major Depressive Disorder (MDD) have Lower 24-hour Adiponectin Levels with Preserved Circadian Rhythm and Higher ACTH vs. Cortisol Correlation: Implications for Greater Metabolic and Cardiovascular Risk SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Nguyen, Vi T.; Cizza, Giovanni] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD USA. [Nguyen, Vi T.] Massachusetts Gen Hosp, Pediat Endocrine Unit, Boston, MA 02114 USA. [Eskandari, Farideh] NIMH, Sect Neuroendocrine Immunol & Behav, Integrat Neural Immune Program, NIH, Bethesda, MD 20892 USA. [Duan, Zhigang; Wright, Elizabeth] NIDDK, Off Director, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 APR 15 PY 2009 VL 65 IS 8 MA 753 BP 230S EP 230S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200727 ER PT J AU Duncko, R Rothen, S Dodge, J Merikangas, KR AF Duncko, Roman Rothen, Stephane Dodge, Jessica Merikangas, Kathleen R. TI Nociceptive Eyeblink Reflex Excitability in Affective Disorders Spectrum and Migraine SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Duncko, Roman; Rothen, Stephane; Dodge, Jessica; Merikangas, Kathleen R.] NIMH, Genet Epidemiol Res Branch, NIH, Bethesda, MD 20892 USA. RI Rothen, Stephane/E-8325-2014 OI Rothen, Stephane/0000-0003-3891-277X 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 763 BP 233S EP 233S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200737 ER PT J AU Peck, SA Drevets, WC Klaver, JM Hodgkinson, CA Buzas, B Goldman, D Cannon, DM AF Peck, Summer A. Drevets, Wayne C. Klaver, Jackie M. Hodgkinson, Colin A. Buzas, Beata Goldman, David Cannon, Dara M. TI Serotonin Transporter Levels and Serotonin Transporter Promoter Polymorphism SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Peck, Summer A.; Drevets, Wayne C.; Klaver, Jackie M.] NIMH, NIH, Bethesda, MD 20892 USA. [Hodgkinson, Colin A.; Buzas, Beata; Goldman, David] NIAAA, NIH, Bethesda, MD USA. [Cannon, Dara M.] Natl Univ Ireland, Galway, Ireland. RI Cannon, Dara/C-1323-2009 OI Cannon, Dara/0000-0001-7378-3411 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 764 BP 233S EP 233S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200738 ER PT J AU Hamilton, JP Chen, G Thomason, ME Gotlib, IH AF Hamilton, J. Paul Chen, Gang Thomason, Moriah E. Gotlib, Ian H. TI Discovering Neural Primacy in Depression: Granger Causality Analysis of Resting State BOLD Data SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Hamilton, J. Paul; Thomason, Moriah E.; Gotlib, Ian H.] Stanford Univ, Stanford, CA 94305 USA. [Chen, Gang] NIMH, Hlth & Human Serv, 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 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD APR 15 PY 2009 VL 65 IS 8 MA 768 BP 234S EP 234S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200742 ER PT J AU Cheng, X Sambataro, F Pizarro, R Weinberger, DR Mattay, VS AF Cheng, Xi Sambataro, Fabio Pizarro, Ricardo Weinberger, Daniel R. Mattay, Venkata S. TI The Use of Task Irrelevant Information in Mining fMRI Data SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Cheng, Xi; Sambataro, Fabio; Pizarro, Ricardo; Weinberger, Daniel R.; Mattay, Venkata S.] NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 APR 15 PY 2009 VL 65 IS 8 MA 795 BP 243S EP 243S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200768 ER PT J AU Diazgranados, N Khalife, S Luckenbaugh, DA Ibrahim, L Wheeler-Castillo, C Brutsche, N Manji, HK Zarate, CA AF Diazgranados, Nancy Khalife, Sami Luckenbaugh, David A. Ibrahim, Lobna Wheeler-Castillo, Cristina Brutsche, Nancy Manji, Husseini K. Zarate, Carlos A. TI Rapid Resolution of Suicidal Ideation after a Single Ketamine Infusion in Patients with Treatment-Resistant Major Depression SO BIOLOGICAL PSYCHIATRY LA English DT Meeting Abstract CT 64th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 14-16, 2009 CL Vancouver, CANADA SP Soc Biol Psychiat C1 [Diazgranados, Nancy; Khalife, Sami; Luckenbaugh, David A.; Ibrahim, Lobna; Wheeler-Castillo, Cristina; Brutsche, Nancy; Zarate, Carlos A.] NIMH, Expt Therapeut Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Manji, Husseini K.] Johnson & Johnson, CNS & Pain, Titusville, NJ USA. NR 0 TC 0 Z9 0 U1 0 U2 2 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 APR 15 PY 2009 VL 65 IS 8 MA 796 BP 243S EP 243S PG 1 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 432OS UT WOS:000265144200769 ER PT J AU Bjork, JM Momenan, R Hommer, DW AF Bjork, James M. Momenan, Reza Hommer, Daniel W. TI Delay Discounting Correlates with Proportional Lateral Frontal Cortex Volumes SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Brain; decision making; delay discounting; frontal cortex; gray matter; impulsivity; magnetic resonance imaging; MRI ID CIGARETTE-SMOKING; NEURAL SYSTEMS; REWARDS; IMPULSIVITY; ADDICTION AB Background: Functional neuroimaging experiments in healthy control subjects have shown that choosing between small and immediate rewards versus larger but deferred rewards in delay discounting (DD) tasks recruits mesofrontal and lateral frontal cortex. Might individual differences in frontocortical gray matter morphology be related to preference for immediate reward? Methods: We related DD in a laboratory decision-making task to proportional frontocortical gray matter (GM) volumes calculated from segmented magnetic resonance images in 29 healthy adults. Results: Dorsolateral and inferolateral frontal cortex GM volumes (corrected as a proportion of whole cerebral brain volume) each correlated inversely with preference for immediate gratification during decision making, as indexed by DD constant k. Conversely, neither proportional orbitofrontal or mesofrontal cortex GM volume nor cerebral brain volume (CBV) or total intracranial volume (ICV; a measure of maximal brain growth) significantly correlated with severity of DD. Conclusions: Severity of discounting of delayed rewards correlates with proportional lateral frontocortical GM morphology but not with whole brain measures. In light of evidence of frontocortical abnormalities in substance dependence and sociopathy, future studies can assess whether reduced frontocortical volume itself is a morphological marker or risk factor for inability to delay gratification in psychiatric disorders. C1 [Bjork, James M.] NIDA, DCNBR, Bethesda, MD 20892 USA. [Momenan, Reza; Hommer, Daniel W.] NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD USA. RP Bjork, JM (reprint author), NIDA, DCNBR, Execut Blvd,Room 3151, Bethesda, MD 20892 USA. EM jbjork@mail.nih.gov OI Bjork, James/0000-0003-0593-3291 FU National Institute on Alcohol Abuse and Alcoholism FX We thank Micahel Kerich and Khai Van for image processing and Dr. Suzanne Mitchell for her donation of the delay discounting task. NR 20 TC 42 Z9 44 U1 1 U2 6 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 APR 15 PY 2009 VL 65 IS 8 BP 710 EP 713 DI 10.1016/j.biopsych.2008.11.023 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 428OG UT WOS:000264857400012 PM 19121516 ER PT J AU Le Foll, B Chefer, SI Kimes, AS Shumway, D Stein, EA Mukhin, AG Goldberg, SR AF Le Foll, Bernard Chefer, Svetlana I. Kimes, Alane S. Shumway, Dean Stein, Elliot A. Mukhin, Alexey G. Goldberg, Steven R. TI Baseline Expression of alpha 4 beta 2*Nicotinic Acetylcholine Receptors Predicts Motivation to Self-administer Nicotine SO BIOLOGICAL PSYCHIATRY LA English DT Article DE In vivo binding; nicotine self-administration; nicotinic receptors; nonhuman primates; positron emission tomography ID SQUIRREL-MONKEYS; DOPAMINE; BEHAVIOR; PET AB Background: Marked interindividual differences invulnerability to nicotine dependence exist, but factors underlying such differences are not well understood. The midbrain alpha 4 beta 2* subtype of nicotinic acetylcholine receptors (nAChRs) has been implicated in mediation of the reinforcing effects of nicotine responsible for dependence. However, no study has been performed evaluating the impact of interindividual differences in midbrain nAChR levels on motivation to self-administer nicotine. Methods: Baseline levels of alpha 4 beta 2* nAChRs were measured using 2-[(18)F]fluoro-A-85380 (2-FA) and positron emission tomography (PET) in five squirrel monkeys. Motivation to self-administer nicotine (number of lever presses) was subsequently measured using a progressive-ratio (PR) schedule of reinforcement. Results: Greater motivation to self-administer nicotine was associated with lower levels of midbrain nAChRs. Conclusions: The results suggest that level of expression of nAChRs is a contributing factor in the development of nicotine dependence. Similarly, it has been previously shown that low levels of dopamine D(2) receptors (DRD2) are associated with a higher preference for psychostimulant use in humans and nonhuman primates. Together, results from these PET studies of dopaminergic and nicotinic cholinergic transmission suggest that an inverse relationship between the availability of receptors that mediate reinforcement and the motivation to take drugs exists across different neurotransmitter systems. C1 [Le Foll, Bernard] Univ Toronto, Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON M5S 2S1, Canada. [Le Foll, Bernard; Goldberg, Steven R.] Natl Inst Drug Abuse, Intramural Res Program, Preclin Pharmacol Sect, Baltimore, MD USA. [Chefer, Svetlana I.; Kimes, Alane S.; Shumway, Dean; Stein, Elliot A.; Mukhin, Alexey G.] Natl Inst Drug Abuse, Neuroimaging Res Branch, Intramural Res Program, Baltimore, MD USA. [Mukhin, Alexey G.] Duke Univ, Med Ctr, Ctr Nicotine & Smoking Cessat Res, Durham, NC USA. RP Le Foll, B (reprint author), Univ Toronto, Ctr Addict & Mental Hlth, Translat Addict Res Lab, 33 Russell St, Toronto, ON M5S 2S1, Canada. EM bernard_lefoll@camh.net RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU National Institute on Drug Abuse, National Institutes of Health U.S. Department of Health and Human Services (DHHS) FX This study was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health U.S. Department of Health and Human Services (DHHS). NR 13 TC 19 Z9 19 U1 1 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 APR 15 PY 2009 VL 65 IS 8 BP 714 EP 716 DI 10.1016/j.biopsych.2008.09.036 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 428OG UT WOS:000264857400013 PM 19095220 ER PT J AU McGregor, LM Spunt, SL Furman, WL Stewart, CF Schaiquevich, P Krailo, MD Speights, R Ivy, P Adamson, PC Blaney, SM AF McGregor, Lisa M. Spunt, Sheri L. Furman, Wayne L. Stewart, Clinton F. Schaiquevich, Paula Krailo, Mark D. Speights, RoseAnne Ivy, Percy Adamson, Peter C. Blaney, Susan M. TI Phase 1 Study of Oxaliplatin and Irinotecan in Pediatric Patients With Refractory Solid Tumors SO CANCER LA English DT Article DE child; adolescent; phase 1 clinical trial; oxaliplatin; irinotecan ID METASTATIC COLORECTAL-CANCER; CHILDRENS ONCOLOGY GROUP; DNA TOPOISOMERASE-I; LOW-DOSE IRINOTECAN; CELL-LINES; PLUS IRINOTECAN; FOLINIC ACID; COMBINATION; TRIAL; PHARMACOKINETICS AB BACKGROUND: For this report, the authors estimated the maximum tolerated dose (MTD) and investigated the toxicities of oxaliplatin combined with irinotecan in children with refractory solid tumors. METHODS: Oxaliplatin was administered on Days 1 and 8 in combination with irinotecan on Days 1 through 5 and Days 8 through 12 of a 21-day cycle. An oral cephalosporin was administered daily to ameliorate irinotecan-associated diarrhea. Pharmacokinetic studies of oxaliplatin and uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotyping were performed. RESULTS: Thirteen patients were enrolled. Dose-limiting diarrhea (n = 3), serum lipase elevation (n = 3), serum amylase elevation (n = 2), colitis, abdominal pain, and headache (n = 1 each) occurred at the first dose level (oxaliplatin at a dose of 60 mg/m(2); irinotecan at a dose of 20 mg/m(2)). Only 1 of 7 patients who received reduced doses of both agents (40 mg/m(2)/dose oxaliplatin; 15 mg/m(2)/dose irinotecan) experienced a dose-limiting toxicity (DLT): diarrhea. When the oxaliplatin dose was re-escalated (60 mg/m(2)) with irinotecan at a dose of 15 mg/m(2), 2 of 3 patients had a DLT (1 episode of diarrhea, I episode of hypokalemia). Myelosuppression was minimal. One patient had a complete response, and another patient had stable disease for 6 cycles of therapy. The median oxaliplatin area under the concentration versus time curve (AUC(O ->infinity),) was 5.9 mu g . hour/mL (range, 1.87-7.6 mu g . hour/mL). The frequency of the 6/6, 6/7, and 7/7 UGT1A1 promoter genotypes was 5 of 10, 4 of 10, and I of 10, respectively. CONCLUSIONS: The oxaliplatin MTD was 40 mg/m(2) per dose on Days I and 8 in combination with irinotecan 15 mg/m(2) per dose on Days 1-5 and Days 8-12. There was some evidence of antitumor activity; however, severe toxicity, both expected (diarrhea) and unexpected (elevation in pancreatic enzymes), was observed. Cancer 2009;115:1765-75. (C) 2009 American Cancer Society. C1 [McGregor, Lisa M.; Spunt, Sheri L.; Furman, Wayne L.; Speights, RoseAnne] St Jude Childrens Hosp, Dept Oncol, Memphis, TN 38105 USA. [McGregor, Lisa M.; Spunt, Sheri L.; Furman, Wayne L.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA. [Stewart, Clinton F.; Schaiquevich, Paula] St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. [Krailo, Mark D.] Childrens Oncol Grp Operat Ctr, Arcadia, CA USA. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, Rockville, MD USA. [Adamson, Peter C.] Childrens Hosp Philadelphia, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA. [Blaney, Susan M.] Baylor Coll Med, Texas Childrens Canc Ctr, Dept Pediat, Houston, TX USA. RP McGregor, LM (reprint author), St Jude Childrens Hosp, Dept Oncol, 332 N Lauderdale St,Mailstop 260, Memphis, TN 38105 USA. EM lisa.mcgregor@stjude.org FU NCI [CA97452, CA21765]; National Center for Research Resources [M01-RR-00,037] FX Supported by NCI grants CA97452 and CA21765 and by National Center for Research Resources grant M01-RR-00,037. NR 61 TC 8 Z9 8 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD APR 15 PY 2009 VL 115 IS 8 BP 1765 EP 1775 DI 10.1002/cncr.24175 PG 11 WC Oncology SC Oncology GA 429KG UT WOS:000264918700021 PM 19170226 ER PT J AU Liersch, T Grade, M Gaedcke, J Varma, S Difilippantonio, MJ Langer, C Hess, CF Becker, H Ried, T Ghadimi, BM AF Liersch, Torsten Grade, Marian Gaedcke, Jochen Varma, Sudhir Difilippantonio, Michael J. Langer, Claus Hess, Clemens F. Becker, Heinz Ried, Thomas Ghadimi, B. Michael TI Preoperative chemoradiotherapy in locally advanced rectal cancer: correlation of a gene expression-based response signature with recurrence SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID COLORECTAL-CANCER; COLON-CANCER; NEOADJUVANT RADIOCHEMOTHERAPY; OLIGONUCLEOTIDE ARRAYS; ENDOPLASMIC-RETICULUM; CDNA MICROARRAYS; PREDICTION; TUMOR; CARCINOMA; ADENOCARCINOMA AB Preoperative chemoradiotherapy is recommended for locally advanced rectal cancer (UICC stage II/III). We recently demonstrated that responsive and nonresponsive tumors showed differential expression levels of 54 genes. In this follow-up study, we investigated the relationship between this gene set and disease-free (DFS) and overall survival (OS). Pretherapeutic biopsies from 30 participants in the CAO/ARO/AIO-94 trial of the German Rectal Cancer Study Group were analyzed using gene expression microarrays. Statistical analysis was performed to identify differentially expressed genes between recurrent and nonrecurrent tumors and to correlate these changes with disease recurrence and outcome. After a median follow-up of 59 months, seven of eight patients with recurrent disease was a nonresponder, and one responsive tumor recurred. Response to chemoradiotherapy was significantly correlated with an improved DFS (log rank P = 0.028), whereas OS did not differ significantly (P = 0.11). Applying a class comparison analysis, we identified 20 genes that were differentially expressed between recurrent and nonrecurrent tumors (P < 0.001). Analyzing the first two principal components of the 54 genes previously identified to predict response, we observed that this response signature correlated with an increased risk of cancer recurrence. These data suggest that the genetic basis of local response also affects the genetic basis of tumor recurrence. Genes that are indicative of nonresponse to preoperative chemoradiotherapy might also be linked to an increased risk of tumor recurrence. (c) 2009 Elsevier Inc. All rights reserved. C1 [Liersch, Torsten; Grade, Marian; Gaedcke, Jochen; Langer, Claus; Becker, Heinz; Ghadimi, B. Michael] Univ Gottingen, Univ Med Ctr, Dept Gen & Visceral Surg, D-37075 Gottingen, Germany. [Grade, Marian; Difilippantonio, Michael J.; Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Varma, Sudhir] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Hess, Clemens F.] Univ Med Ctr, Dept Radiat Oncol & Radiotherapy, Gottingen, Germany. RP Ghadimi, BM (reprint author), Univ Gottingen, Univ Med Ctr, Dept Gen & Visceral Surg, Robert Koch Str 40, D-37075 Gottingen, Germany. EM mghadim@uni-goettingen.de RI Varma, Sudhir/N-8763-2014 OI Varma, Sudhir/0000-0002-4096-4782 FU U.S. National Institutes of Health National Cancer Institute; Deutsche Forschungsgemeinschaft [KFO 179]; Deutsche Krebshilfe FX This research was supported in part by the Intramural Research Program of the U.S. National Institutes of Health National Cancer Institute, the Deutsche Forschungsgemeinschaft (KFO 179), and the Deutsche Krebshilfe (M.G.).; The authors would like to thank Ms. Jessica Eggert for excellent technical assistance, Buddy Chen for help with the illustrations, and Joseph Cheng for IT support. We are grateful to the investigators of the CAO/ARO/AIO-94 and CAO/ARO/AIO-04 trials, in particular to Drs. Rolf Saner and Claus Rodel. NR 49 TC 13 Z9 14 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD APR 15 PY 2009 VL 190 IS 2 BP 57 EP 65 DI 10.1016/j.cancergencyto.2008.11.011 PG 9 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 441NF UT WOS:000265775200001 PM 19380020 ER PT J AU Erdag, G Meck, JM Meloni-Ehrig, A Matyakhina, L Donohue, T Srinivasan, R Mowrey, P Kelly, J Smith, A Childs, R AF Erdag, Gulsun Meck, Jeanne M. Meloni-Ehrig, Aurelia Matyakhina, Ludmila Donohue, Theresa Srinivasan, Ramaprasad Mowrey, Philip Kelly, JoAnn Smith, Aleah Childs, Richard TI Long-term persistence of nonpathogenic clonal chromosome abnormalities in donor hematopoietic cells after allogeneic stem cell transplantation SO CANCER GENETICS AND CYTOGENETICS LA English DT Article ID BONE-MARROW-TRANSPLANTATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; CHRONIC GRANULOCYTIC-LEUKEMIA; OF-THE-LITERATURE; POSITIVE LEUKEMIA; IMATINIB MESYLATE; APLASTIC-ANEMIA; NEGATIVE CELLS; 2ND NEOPLASMS AB We describe the cases of two unrelated patients who exhibited multiple chromosomal abnormalities in donor cells after allogeneic peripheral blood stem cell transplantation (PBSCT). The patients were diagnosed with chronic myeloid leukemia and chronic lymphocytic leukemia, respectively, and both underwent nonmyeloablative conditioning with cyclophosphamide and fludarabine followed by PBSCT from their HLA-matched opposite-sex siblings. Post-transplant bone marrow cytogenetics showed full engraftment, and the early post-transplant studies demonstrated only normal donor metaphases. Subsequent studies of both patients, however, revealed a population of metaphase cells with abnormal, but apparently balanced, donor karyotypes. Chromosome studies performed on peripheral blood cells collected from both donors after transplantation were normal. Both patients remained in clinical remission during follow-up of approximately 8 years in one cases, and 6 years in the other case, despite the persistence of the abnormal clones. Chromosomal abnormalities in residual recipient cells after bone marrow or PBSCT are not unusual. In contrast, only rare reports of chromosome abnormalities in donor cells exists, all of which have been associated with post-bone marrow transplant myelodysplastic syndrome or acute leukemias. The present cases demonstrate the rare phenomenon of persistent clonal nonpathogenic chromosome aberrations in cells of donor origin. (c) 2009 Elsevier Inc. All rights reserved. C1 [Meck, Jeanne M.; Meloni-Ehrig, Aurelia; Matyakhina, Ludmila; Mowrey, Philip; Kelly, JoAnn] Quest Diagnost Nichols Inst, Dept Cytogenet, Chantilly, VA 20151 USA. [Erdag, Gulsun] Georgetown Univ, Dept Pathol, Washington, DC 20007 USA. [Donohue, Theresa; Srinivasan, Ramaprasad; Smith, Aleah; Childs, Richard] NHLBI, NIH, Bethesda, MD 20892 USA. RP Meck, JM (reprint author), Quest Diagnost Nichols Inst, Dept Cytogenet, Chantilly, VA 20151 USA. EM Jenne.M.Meck@QuestDiagnostics.com FU Intramural NIH HHS [Z99 HL999999] NR 30 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0165-4608 J9 CANCER GENET CYTOGEN JI Cancer Genet. Cytogenet. PD APR 15 PY 2009 VL 190 IS 2 BP 125 EP 130 DI 10.1016/j.cancergencyto.2009.01.001 PG 6 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 441NF UT WOS:000265775200013 PM 19380032 ER PT J AU Safaeian, M Schiffman, M Gage, J Solomon, D Wheeler, CM Castle, PE AF Safaeian, Mahboobeh Schiffman, Mark Gage, Julia Solomon, Diane Wheeler, Cosette M. Castle, Philip E. TI Detection of Precancerous Cervical Lesions Is Differential by Human Papillomavirus Type SO CANCER RESEARCH LA English DT Article ID ATYPICAL SQUAMOUS-CELLS; ASCUS-LSIL TRIAGE; RANDOMIZED-TRIAL; UNDETERMINED SIGNIFICANCE; CYTOLOGY INTERPRETATIONS; CANCER; METAANALYSIS; MANAGEMENT; RISK; WOMEN AB Epidemiologic studies have reported the underrepresentation of cervical precancerous lesions caused by human papillomavirus (HPV) types 18 and 45 (tIPV18/45) compared with the proportion of cervical cancers attributed to these HPV types. We investigated the timing of diagnosis of histologic cervical intraepithelial neoplasia grade 3 or worse (CIN3+) using data from the atypical squamous cells of undetermined significance-low-grade squamous intraepithelial lesion triage study (ALTS). Of the 2,725 women who underwent enrollment colposcopy, 412 of 472 (87.3%) diagnosed with histologic CIN3+ over the 2-year duration of ALTS could be assigned to a HPV type or group of types and were included in this analysis. Eighty-four percent of HPV16-positive CIN3+ were diagnosed at enrollment, compared with 57% of HPV18/45-positive CIN3+, and 58% of CIN3 positive for other carcinogenic HPV types at enrollment. In contrast, only 8% of HPV16-positive CIN3+ were diagnosed at exit, whereas 31% were HPV18/45 positive and 22% were positive for other carcinogenic types at study exit (P < 0.001). These results indicate the underrepresentation of HPV18/45 in precancers, whereas HPV16-associated CIN3+ is diagnosed much earlier. Whether the underrepresentation of 18/45 may be due to occult pathology needs further investigation. [Cancer Res 2009;69(8):3262-6] C1 [Safaeian, Mahboobeh; Schiffman, Mark; Gage, Julia; Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Solomon, Diane] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Wheeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Sch Med, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Wheeler, Cosette M.] Univ New Mexico, Hlth Sci Ctr, Sch Med, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. RP Safaeian, M (reprint author), NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, 6120 Execut Blvd,Suite 550, Rockville, MD 20852 USA. EM safaeianm@mail.nih.gov FU National Cancer Institute; NIH; Department of Health and Human Services [CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, CN-55105] FX National Cancer Institute, NIH, Department of Health and Human Services contract nos. CN-55153. CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159, and CN-55105. Some of the equipment and supplies were donated or provided at reduced costs by Digene Corporation, Cytyc Corporation, Denvu, Roche Molecular Systems, and TriPath Imaging, Inc. NR 17 TC 37 Z9 40 U1 0 U2 3 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 APR 15 PY 2009 VL 69 IS 8 BP 3262 EP 3266 DI 10.1158/0008-5472.CAN-08-4192 PG 5 WC Oncology SC Oncology GA 435AF UT WOS:000265314900005 PM 19351830 ER PT J AU Iliopoulos, D Bimpaki, EI Nesterova, M Stratakis, CA AF Iliopoulos, Dimitrios Bimpaki, Eirini I. Nesterova, Maria Stratakis, Constantine A. TI MicroRNA Signature of Primary Pigmented Nodular Adrenocortical Disease: Clinical Correlations and Regulation of Wnt Signaling SO CANCER RESEARCH LA English DT Article ID CARNEY COMPLEX; EXPRESSION; TUMORS; HYPERPLASIAS; PATHWAYS; MUTATION; GENES AB MicroRNAs comprise a novel group of gene regulators implicated in the development of different types of cancer; however, their role in primary pigmented nodular adrenocortical disease (PPNAD) has not been investigated. PPNAD is a bilateral adrenal hyperplasia often associated with Carney complex, a multiple neoplasia syndrome; both disorders are caused by protein kinase A (PKA) regulatory subunit type 1A (PRKARIA)-inactivating mutations. We identified a 44-microRNA gene signature of PPNAD after comparing PPNAD with normal adrenal samples. Specifically, 33 microRNAs were up-regulated and 11 down-regulated in PPNAD relative to normal tissues. These results were validated by stem loop real-time PCR analysis. Comparison of microRNA microarray data with clinicopathologic variables revealed a negative correlation (r = -0.9499) between let-7b expression and cortisol levels in patients with PPNAD. Integration of microRNA microarray with serial analysis of gene expression data together with bioinformatic algorithm predictions revealed nine microRNA-gene target pairs with a potential role in adrenal pathogenesis. Using a PPNAD cell line, we showed that miR-449 was up-regulated and identified its direct target, WNT1-inducible signaling pathway protein 2 (WISP2); in addition, pharmacologic inhibition of PKA resulted in the up-regulation of miR-449 leading to the suppression of WISP2. Overall, we investigated, for the first time, the microRNA profile and its clinical significance in PPNAD; these data also suggest that PKA, via microRNA regulation, affects the Writ signaling pathway, which through expression and clinical studies is suspected to be a primary mediator of PRKAR1A-related tumorigenesis. [Cancer Res 2009;69(8):3278-82] C1 [Bimpaki, Eirini I.; Nesterova, Maria; Stratakis, Constantine A.] NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Iliopoulos, Dimitrios] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. RP Stratakis, CA (reprint author), NICHHD, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bldg 10,CRC East Labs,Room 1-3330,10 Ctr Dr,MSC11, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU NIH [Z01-HD-000642-04]; University of Crete, School of Medicine, Postgraduate Program FX NIH intramural project Z01-HD-000642-04 (C.A. Stratakis) and in part by the University of Crete, School of Medicine, Postgraduate Program (E.I. Bimpaki and C.A. Stratakis). NR 18 TC 52 Z9 53 U1 0 U2 1 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 APR 15 PY 2009 VL 69 IS 8 BP 3278 EP 3282 DI 10.1158/0008-5472.CAN-09-0155 PG 5 WC Oncology SC Oncology GA 435AF UT WOS:000265314900008 PM 19351815 ER PT J AU Cohen, J Chen, Z Lu, SL Yang, XP Arun, P Ehsanian, R Brown, MS Lu, H Yan, B Diallo, O Wang, XJ Van Waes, C AF Cohen, Jonah Chen, Zhong Lu, Shi-Long Yang, Xin Ping Arun, Pattatheyil Ehsanian, Reza Brown, Matthew S. Lu, Hai Yan, Bin Diallo, Oumou Wang, Xiao-Jing Van Waes, Carter TI Attenuated Transforming Growth Factor beta Signaling Promotes Nuclear Factor-kappa B Activation in Head and Neck Cancer SO CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; TUMOR-SUPPRESSOR GENE; PROTEIN ACCUMULATION; MALIGNANT PHENOTYPE; PROGENITOR CELLS; P53 GENE; EXPRESSION; RECEPTOR; METASTASIS; TRANSCRIPTION AB Although constitutively activated nuclear factor-kappa beta (NF-kappa B), attenuated transforming growth factor beta (TGF beta) signaling, and TP53 mutations frequently occur in human cancers, how these pathways interact and together contribute to malignancy remains uncertain. Here, we found an association between overexpression of NF-kappa B-related genes, reduced expression of TGF beta receptor (T beta R) subunits and downstream targets, and TP53 genotype in head and neck squamous cell carcinoma (HNSCC). In response to recombinant TGF beta 1, both growth inhibition and TGIF( target gene modulation were attenuated or absent in a panel of human HNSCC lines. However, in HNSCC cells that retained residual TGF beta signaling, TGF beta 1 inhibited both constitutive and tumor necrosis factor alpha-stimulated NF-kappa B activity. Furthermore, HNSCC lines overexpressing mutant (mt) TP53 and human tumor specimens with positive TP53 nuclear staining exhibited reduced T beta RII and knocking down mtTP53 induced T beta RII, increasing TGF beta downstream gene expression while inhibiting proinflammatory NF-kappa B target gene expression. Transfection of ectopic T beta RII directly restored TGF beta signaling while inhibiting inhibitor kappa B alpha degradation and suppressing serine-536 phosphorylation of NF-kappa B p65 and NF-kappa B transcriptional activation, linking these alterations. Finally, experiments with T beta RII conditional knockout mice show that abrogation of TGF beta signaling promotes the sustained induction of NF-kappa B and its proinflammatory target genes during HNSCC tumorigenesis and progression. Together, these findings elucidate a regulatory framework in which attenuated TGF beta signaling promotes NF-kappa B activation and squamous epithelial malignancy in the setting of altered TP53 status. [Cancer Res 2009;69(8):3415-24] C1 [Cohen, Jonah; Chen, Zhong; Yang, Xin Ping; Arun, Pattatheyil; Ehsanian, Reza; Brown, Matthew S.; Lu, Hai; Yan, Bin; Diallo, Oumou; Van Waes, Carter] Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, NIH, Bethesda, MD 20892 USA. [Cohen, Jonah; Ehsanian, Reza] Howard Hughes Med Inst, NIH, Res Scholars Program, Bethesda, MD 20892 USA. [Lu, Shi-Long; Wang, Xiao-Jing] Oregon Hlth & Sci Univ, Dept Otolaryngol, Portland, OR 97201 USA. RP Van Waes, C (reprint author), Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, NIH, Bldg 10,CRC Room 4-2732,10 Ctr Dr, Bethesda, MD 20892 USA. EM chenz@nidcd.nih.gov; vanwaesc@nidcd.nih.gov OI Cohen, Jonah/0000-0001-9630-0531 FU NIDCD [Z01-DC-00073-01, 74-01]; [DE15953]; [CA79998] FX NIDCD intramural projects Z01-DC-00073-01 and 74-01 (C. Van Waes) and grants DE15953 and CA79998 (X-J. Wang). NR 47 TC 22 Z9 22 U1 0 U2 3 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 APR 15 PY 2009 VL 69 IS 8 BP 3415 EP 3424 DI 10.1158/0008-5472.CAN-08-3704 PG 10 WC Oncology SC Oncology GA 435AF UT WOS:000265314900025 PM 19351843 ER PT J AU Hussain, M Rao, M Humphries, AE Hong, JA Liu, F Yang, MC Caragacianu, D Schrump, DS AF Hussain, Mustafa Rao, Mahadev Humphries, Ashley E. Hong, Julie A. Liu, Fang Yang, Maocheng Caragacianu, Diana Schrump, David S. TI Tobacco Smoke Induces Polycomb-Mediated Repression of Dickkopf-1 in Lung Cancer Cells SO CANCER RESEARCH LA English DT Article ID DNA METHYLATION; STEM-CELLS; CHROMATIN PATTERN; SIGNALING NETWORK; POOR-PROGNOSIS; GROWTH-FACTOR; WNT; EXPRESSION; GENES; PATHWAYS AB Limited information is available about epigenetic mechanisms by which cigarette smoke enhances the initiation and progression of lung cancer. To examine this issue, A549 and Calu-6 lung cancer cells were cultured in normal media with or without tobacco smoke condensate (TSC) under clinically relevant exposure conditions. Ten-day TSC exposure dramatically increased the tumorigenicity of lung cancer cells in nude mice. Microarray and quantitative reverse transcription-PCR (RT-PCR) experiments revealed that this phenomenon coincided with diminished expression of Dickkopf-1 (Dkk-1). Western blot, chromatin immunoprecipitation, methylation-specific PCR, and pyrosequencing experiments showed that repression of Dkk-1 coincided with decreased H4K16Ac, increased H3K27me3, and recruitment of SirT1, EZH2, SUZ12, and Bmi1 without DNA hypermethylation within the Dkk-1 promoter despite prolonged TSC exposures. Removal of TSC from culture media resulted in loss of promoter-associated polycomb repressor complexes and reexpression of Dkk-1. siRNA-mediated knockdown of EZH2 and SirT1 partially abrogated TSC-mediated inhibition of Dkk-1 expression. Western blot and quantitative RT-PCR array experiments showed that TSC exposure as well as knockdown of Dkk-1 activated Writ signaling and significantly up-regulated Wnt5a in lung cancer cells. Knockdown of Dkk-1 recapitulated the dramatic protumorigenic effects of TSC exposure in Calu-6 cells. Despite the transient nature of Dkk-1 repression following TSC exposure in vitro, Dkk-1 remained silenced in tumor xenografts derived from TSC-treated Calu-6 cells. Collectively, these data provide evidence that cigarette smoke directly engages polycomb machinery to activate a signaling network implicated in maintenance of cancer stem cells. [Cancer Res 2009;69(8):3570-8] C1 [Hussain, Mustafa; Rao, Mahadev; Humphries, Ashley E.; Hong, Julie A.; Liu, Fang; Yang, Maocheng; Caragacianu, Diana; Schrump, David S.] NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res, Room 4-3942,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM David_Schrump@nih.gov NR 49 TC 72 Z9 75 U1 1 U2 8 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 APR 15 PY 2009 VL 69 IS 8 BP 3570 EP 3578 DI 10.1158/0008-5472.CAN-08-2807 PG 9 WC Oncology SC Oncology GA 435AF UT WOS:000265314900043 PM 19351856 ER PT J AU Strunnikov, A AF Strunnikov, Alexander TI Cdc14p regulates condensin binding to rDNA SO CELL CYCLE LA English DT Editorial Material C1 NICHD NIH, LGRD, Bethesda, MD 20892 USA. RP Strunnikov, A (reprint author), NICHD NIH, LGRD, 18T Lib Dr, Bethesda, MD 20892 USA. EM strunnik@mail.nih.gov OI Strunnikov, Alexander/0000-0002-9058-2256 NR 1 TC 1 Z9 1 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD APR 15 PY 2009 VL 8 IS 8 BP 1114 EP 1114 PG 1 WC Cell Biology SC Cell Biology GA 438YZ UT WOS:000265594200008 PM 19305166 ER PT J AU Boulanger, CA Smith, GH AF Boulanger, Corinne A. Smith, Gilbert H. TI Reprogramming cell fates in the mammary microenvironment SO CELL CYCLE LA English DT Article DE niche; transplantation; stem cells; re-programming; mammary; development ID ESTROGEN-RECEPTOR-ALPHA; STEM-CELL; EPITHELIAL-CELLS; IN-VIVO; BRANCHING MORPHOGENESIS; GLAND DEVELOPMENT; DIFFERENTIATION; MULTIPOTENT; REPERTOIRE; EXPRESSION AB The capacity of any portion of the murine mammary gland to produce a complete functional mammary outgrowth upon transplantation to an epithelium-divested fat pad is unaffected by the age or reproductive history of the donor. Likewise, through serial transplantations, no loss of potency is detected when compared to similar transplantations of the youngest mammary tissue tested. This demonstrates that stem cell activity is maintained intact throughout the lifetime of the animal despite aging and the repeated expansion and depletion of the mammary epithelium through multiple rounds of pregnancy, lactation and involution. These facts support the contention that mammary stem cells reside in protected tissue locales (niches), where their reproductive potency remains essentially unchanged through life. Disruption of the tissue, to produce dispersed cells results in the desecration of the protection afforded by the "niche" and leads to a reduced capacity of dispersed epithelial cells (in terms of the number transplanted) to recapitulate complete functional mammary structures. Our studies demonstrate that during the reformation of mammary stem cell niches by dispersed epithelial cells in the context of the intact epithelium-free mammary stroma, non-mammary cells may be sequestered and reprogrammed to perform mammary epithelial cell functions including those ascribed to mammary stem/progenitor cells. C1 [Boulanger, Corinne A.; Smith, Gilbert H.] NCI, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), NIH, Bldg 37,Rm 1106,37 Convent Dr, Bethesda, MD 20892 USA. EM gs4d@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 36 TC 16 Z9 16 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD APR 15 PY 2009 VL 8 IS 8 BP 1127 EP 1132 PG 6 WC Cell Biology SC Cell Biology GA 438YZ UT WOS:000265594200011 PM 19282662 ER PT J AU Di Costanzo, A Festa, L Duverger, O Vivo, M Guerrini, L La Mantia, G Morasso, MI Calabro, V AF Di Costanzo, Antonella Festa, Luisa Duverger, Olivier Vivo, Maria Guerrini, Luisa La Mantia, Girolama Morasso, Maria I. Calabro, Viola TI Homeodomain protein Dlx3 induces phosphorylation-dependent p63 degradation SO CELL CYCLE LA English DT Article DE Dlx3; homeodomain protein; p53 homolog; keratinocyte differentiation; protein degradation; Raf1; protein phosphorylation ID HAY-WELLS-SYNDROME; HOMEOBOX GENE DLX3; CELL-SURVIVAL; P53 HOMOLOG; DIFFERENTIATION; MUTATIONS; DELTA-NP63-ALPHA; KERATINOCYTES; APOPTOSIS; KINASE AB The epidermis is a stratified epithelium which develops depending on the transcription factor p63, a member of the p53 family of transcription factors. p63 is strongly expressed in the innermost basal layer where highly proliferative epithelial cells reside. p63 functions as a molecular switch that initiates epithelial stratification or cell fate determination while regulating proliferation and differentiation of developmentally mature keratinocytes. p63 acts upstream of Dlx3 homeobox gene in a transcriptional regulatory pathway relevant to ectodermal dysplasia. Here we show that Dlx3 triggers p63 protein degradation by a proteasome-dependent pathway. Mutant Delta Np63 alpha in which Threonine397 and Serine383 were replaced with Alanine as well as C-terminal truncated versions of Delta Np63 alpha are resistant to Dlx3-mediated degradation. Transient expression of Dlx3 is associated with Raf1 phosphorylation. Dlx3 is unable to promote p63 degradation in Raf1 depleted MEF cells or upon pharmacological knockdown of Raf1. Our data support a previously unrecognized role for Dlx3 in posttranslational regulation of Delta Np63 alpha protein level, a mechanism that may contribute to reduce the abundance of Delta Np63 alpha during differentiation of stratified epithelia. C1 [Di Costanzo, Antonella; Festa, Luisa; Vivo, Maria; La Mantia, Girolama; Calabro, Viola] Univ Naples Federico 2, Dept Struct & Mol Biol, Naples, Italy. [Duverger, Olivier; Morasso, Maria I.] NIAMS, Dev Skin Biol Unit, NIH, Bethesda, MD USA. [Guerrini, Luisa] Univ Milan, Dept Biomol Sci & Biotechnol, Milan, Italy. RP Calabro, V (reprint author), Univ Naples Federico 2, Dept Biol Struct & Funzionole, Viale Cinzia,Monte S Angelo, I-80126 Naples, Italy. EM vcalabro@unino.it FU Telethon [GGP030326, GGP05056]; AIRC and MIUR FX We thank A. Pollice for helpful discussion and critical reading. G. Napolitano for technical support. A. Costanzo for providing the RafBxB plasmid. We are grateful to Catrin Pritchard who provided us with the Raf1 (-/-) mouse fibroblast cell line. This work was supported by Telethon GGP030326, AIRC and MIUR to G.L. M.L.G. was supported by Telethon GGP05056. NR 33 TC 32 Z9 32 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD APR 15 PY 2009 VL 8 IS 8 BP 1185 EP 1195 PG 11 WC Cell Biology SC Cell Biology GA 438YZ UT WOS:000265594200021 PM 19282665 ER PT J AU Dong, F Budhu, AS Wang, XW AF Dong, Fei Budhu, Anuradha S. Wang, Xin Wei TI Translating the Metastasis Paradigm from Scientific Theory to Clinical Oncology SO CLINICAL CANCER RESEARCH LA English DT Article ID HEPATOCELLULAR-CARCINOMA CELLS; BREAST-CANCER METASTASIS; TUMOR PROGRESSION; SIGNATURE; SURVIVAL; EPCAM; PREDICTION; SORAFENIB; ERLOTINIB; FEATURES AB Cancer metastasis contributes to significant morbidity and mortality. Patients with metastatic cancer, often considered incurable, are provided with either supportive care or aggressive management without curative intent. Despite decades of research toward unraveling cancer progression mechanisms, the current body of knowledge has not translated into effective antimetastasis therapies, but recent findings challenge the classic notion that metastases develop during the late stages of carcinogenesis. Here, we evaluate the scientific evidence in the context of the multistage metastasis model. The resolution of current controversies has implications on both the prognostic value of molecular technology and the future of targeted therapies for the clinical benefit of metastasis patients. C1 [Wang, Xin Wei] NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Wang, XW (reprint author), NCI, Liver Carcinogenesis Sect, Human Carcinogenesis Lab, Ctr Canc Res,NIH, Bldg 37,Room 3044A,37 Convent Dr, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute FX Intramural Research Program of the Center for Cancer Research, National Cancer Institute. NR 44 TC 13 Z9 13 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 APR 15 PY 2009 VL 15 IS 8 BP 2588 EP 2593 DI 10.1158/1078-0432.CCR-08-2356 PG 6 WC Oncology SC Oncology GA 435AC UT WOS:000265314600003 PM 19351761 ER PT J AU You, M Wang, DL Liu, PY Vikis, H James, M Lu, Y Wang, Y Wang, M Chen, QO Jia, DM Wen, WD Yang, P Sun, ZF Pinney, SM Zheng, W Shu, XO Long, J Gao, YT Xiang, YB Chow, WH Rothman, N Petersen, GM de Andrade, M Wu, YH Cunningham, JM Wiest, JS Fain, PR Schwartz, AG Girard, L Gazdar, A Gaba, C Rothschild, H Mandal, D Coons, T Lee, J Kupert, E Seminara, D Minna, J Bailey-Wilson, JE Amos, CI Anderson, MW AF You, Ming Wang, Daolong Liu, Pengyuan Vikis, Haris James, Michael Lu, Yan Wang, Yian Wang, Min Chen, Qiong Jia, Dongmei Wen, Weidong Yang, Ping Sun, Zhifu Pinney, Susan M. Zheng, Wei Shu, Xiao-Ou Long, Jirong Gao, Yu-Tang Xiang, Yong-Bing Chow, Wong-Ho Rothman, Nat Petersen, Gloria M. de Andrade, Mariza Wu, Yanhong Cunningham, Julie M. Wiest, Jonathan S. Fain, Pamela R. Schwartz, Ann G. Girard, Luc Gazdar, Adi Gaba, Colette Rothschild, Henry Mandal, Diptasri Coons, Teresa Lee, Juwon Kupert, Elena Seminara, Daniela Minna, John Bailey-Wilson, Joan E. Amos, Christopher I. Anderson, Marshall W. TI Fine Mapping of Chromosome 6q23-25 Region in Familial Lung Cancer Families Reveals RGS17 as a Likely Candidate Gene SO CLINICAL CANCER RESEARCH LA English DT Article ID MENDELIAN INHERITANCE; RISK; POLYMORPHISM; RGS17/RGSZ2; RECEPTORS; GROWTH; MAPS AB Purpose: We have previously mapped a major susceptibility locus influencing familial lung cancer risk to chromosome 6q23-25. However, the causal gene at this locus remains undetermined. In this study, we further refined this locus to identify a single candidate gene, by fine mapping using microsatellite markers and association studies using high-density single nucleotide polymorphisms (SNP). Experimental Design: Six multigenerational families with five or more affected members were chosen for fine-mapping the 6q linkage region using microsatellite markers. For association mapping, we genotyped 24 6q-linked cases and 72 unrelated noncancer controls from the Genetic Epidemiology of Lung Cancer Consortium resources using the Affymetrix 500K chipset. Significant associations were validated in two independent familial lung cancer populations: 226 familial lung cases and 313 controls from the Genetic Epidemiology of Lung Cancer Consortium, and 154 familial cases and 325 controls from Mayo Clinic. Each familial case was chosen from one high-risk lung cancer family that has three or more affected members. Results: A region-wide scan across 6q23-25 found significant association between lung cancer susceptibility and three single nucleotide polymorphisms in the first intron of the RGS17 gene. This association was further confirmed in two independent familial lung cancer populations. By quantitative real-time PCR analysis of matched tumor and normal human tissues, we found that RGS17 transcript accumulation is highly and consistently increased in sporadic lung cancers. Human lung tumor cell proliferation and tumorigenesis in nude mice are inhibited upon knockdown of RGS17 levels. Conclusion: RGS17 is a major candidate for the familial lung cancer susceptibility locus on chromosome 6q23-25. C1 [You, Ming] Washington Univ, Dept Surg, St Louis, MO 63110 USA. [Yang, Ping; Sun, Zhifu; Petersen, Gloria M.; de Andrade, Mariza; Wu, Yanhong; Cunningham, Julie M.] Mayo Clin, Rochester, MN USA. [Pinney, Susan M.; Lee, Juwon; Anderson, Marshall W.] Univ Cincinnati, Cincinnati, OH USA. [Zheng, Wei; Shu, Xiao-Ou; Long, Jirong] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Gao, Yu-Tang; Xiang, Yong-Bing] Shanghai Canc Inst, Shanghai, Peoples R China. [Chow, Wong-Ho; Rothman, Nat; Wiest, Jonathan S.; Seminara, Daniela] NCI, Bethesda, MD 20892 USA. [Bailey-Wilson, Joan E.] NHGRI, Bethesda, MD 20892 USA. [Fain, Pamela R.] Univ Colorado, Denver, CO 80202 USA. [Schwartz, Ann G.] Karmanos Canc Inst, Detroit, MI USA. [Girard, Luc; Gazdar, Adi; Minna, John] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Gaba, Colette] Univ Toledo, Coll Med, Toledo, OH 43606 USA. [Rothschild, Henry; Mandal, Diptasri] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Coons, Teresa] Saccomanno Res Inst, Grand Junction, CO USA. [Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP You, M (reprint author), Washington Univ, Dept Surg, 660 Euclid Ave,Box 8109, St Louis, MO 63110 USA. EM youm@wudosis.wustl.edu OI Bailey-Wilson, Joan/0000-0002-9153-2920; Sun, Zhifu/0000-0001-8461-7523 FU NIH [U01CA76293, R01CA058554, R01CA093643, R01CA099147, R01CA099187, R01ES012063, R01ES013340, R03CA77118, R01CA80127, P30ES06096, P50CA70907, N01HG65404, N01-PC35145, P30CA22453, R01CA63700, DE-FGB-95ER62060]; Mayo Clinic intramural research funds; Department of Defense VITAL; Intramural Research Programs of the National Cancer Institute; National Human Genome Research Institute; [P30CA 15083] FX We thank the Fernald Medical Monitoring Program for sharing their biospecimens and data with us. We are grateful to the lung cancer families who participated in this research, and for the high caliber service of Vanderbilt University Microarray Shared Resource, Washington University Genotyping Core, Mayo Clinic Genotyping Shared Resource (supported in part by P30CA 15083), and to Julie Clark, Qiong Chen, Shaw Levy, Mark Watson, and Jennifer Baker for their assistance in various aspects of this work. We also thank David Lam (University of Hong Kong) and William Gerald (Memorial Sloan Kettering Cancer Center) for microarray data on the normal lung tissue samples. NR 36 TC 42 Z9 45 U1 0 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 APR 15 PY 2009 VL 15 IS 8 BP 2666 EP 2674 DI 10.1158/1078-0432.CCR-08-2335 PG 9 WC Oncology SC Oncology GA 435AC UT WOS:000265314600012 PM 19351763 ER PT J AU Sparano, JA Moulder, S Kazi, A Coppola, D Negassa, A Vahdat, L Li, TH Pellegrino, C Fineberg, S Munster, P Malafa, M Lee, D Hoschander, S Hopkins, U Hershman, D Wright, JJ Kleer, C Merajver, S Sebti, SM AF Sparano, Joseph A. Moulder, Stacy Kazi, Aslamuzzaman Coppola, Domenico Negassa, Abdissa Vahdat, Linda Li, Tianhong Pellegrino, Christine Fineberg, Susan Munster, Pam Malafa, Mokenge Lee, David Hoschander, Shira Hopkins, Una Hershman, Dawn Wright, John J. Kleer, Celina Merajver, Sofia Sebti, Said M. TI Phase II Trial of Tipifarnib plus Neoadjuvant Doxorubicin-Cyclophosphamide in Patients with Clinical Stage IIB-IIIC Breast Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID FARNESYL TRANSFERASE INHIBITOR; PATHOLOGICAL COMPLETE REMISSION; BIPOLAR SPINDLE FORMATION; SURGICAL ADJUVANT BREAST; PROJECT PROTOCOL B-27; RAS TRANSGENIC MICE; FARNESYLTRANSFERASE INHIBITOR; PREOPERATIVE CHEMOTHERAPY; ESTROGEN-RECEPTOR; RANDOMIZED-TRIAL AB Purpose: Tipifarnib is a famesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether adding tipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified. Experimental Design: Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p)-signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib during the first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10% or less expected for AC alone to 25% for AC-tipifarnib (alpha = 0.05, beta = 0.10). Results: Eleven patients had a breast pCR (25%; 95% confidence interval, 13-40%). FTase enzyme activity decreased in all patients (median, 91%; range, 24-100%) and p-STAT3 expression decreased in 7 of 9 (77%) patients. Low tumor Ki-67 expression (below the median of 60%) at baseline was significantly associated with resistance to therapy (P = 0.01). Conclusion: Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation. C1 [Sparano, Joseph A.] Montefiore Med Ctr, Dept Oncol, Montefiore Einstein Canc Ctr, New York Canc Consortium,Weiler Div, Bronx, NY 10461 USA. [Moulder, Stacy; Munster, Pam] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Breast Oncol Program, Tampa, FL USA. [Kazi, Aslamuzzaman; Coppola, Domenico; Malafa, Mokenge; Sebti, Said M.] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Drug Discovery Program, Tampa, FL USA. [Vahdat, Linda] Weill Cornell Med Ctr, New York, NY USA. [Hershman, Dawn] Columbia Presbyterian Med Ctr, New York, NY 10032 USA. [Wright, John J.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Kleer, Celina; Merajver, Sofia] Univ Michigan, Ann Arbor, MI 48109 USA. RP Sparano, JA (reprint author), Montefiore Med Ctr, Dept Oncol, Montefiore Einstein Canc Ctr, New York Canc Consortium,Weiler Div, 2 South,Room 47-48,1825 Eastchester Rd, Bronx, NY 10461 USA. EM jsparano@montefiore.org FU U.S. Department of Health and Human Service [N01-CM-62204, R01CA98473] FX The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S. C. Section 1734 solely to indicate this fact. NR 46 TC 32 Z9 32 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 APR 15 PY 2009 VL 15 IS 8 BP 2942 EP 2948 DI 10.1158/1078-0432.CCR-08-2658 PG 7 WC Oncology SC Oncology GA 435AC UT WOS:000265314600043 PM 19351752 ER PT J AU Levy, MZ Bowman, NM Kawai, V Plotkin, JB Waller, LA Cabrera, L Steurer, F Seitz, AE Pinedo-Cancino, VV del Carpio, JGC Benzaquen, EC McKenzie, FE Maguire, JH Gilman, RH Bern, C AF Levy, Michael Z. Bowman, Natalie M. Kawai, Vivian Plotkin, Joshua B. Waller, Lance A. Cabrera, Lilia Steurer, Frank Seitz, Amy E. Pinedo-Cancino, Viviana V. Cornejo del Carpio, Juan Geny Cordova Benzaquen, Eleazar McKenzie, F. Ellis Maguire, James H. Gilman, Robert H. Bern, Caryn TI Spatial Patterns in Discordant Diagnostic Test Results for Chagas Disease: Links to Transmission Hotspots SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID TRYPANOSOMA-CRUZI INFECTION; CHILDREN AB Diagnosis of Chagas disease is hindered by discordance between screening and confirmatory test results for Trypanosoma cruzi infection. In periurban Arequipa, Peru, spatial analysis revealed that individuals with discordant test results are spatially clustered in hotspots of T. cruzi transmission, suggesting that discordant results likely represent true infections in this setting. C1 [Levy, Michael Z.; McKenzie, F. Ellis] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bowman, Natalie M.] Johns Hopkins Univ, Johns Hopkins Hosp, Baltimore, MD USA. [Gilman, Robert H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Levy, Michael Z.; Plotkin, Joshua B.] Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. [Waller, Lance A.] Emory Univ, Div Biol & Biomed Sci, Program Populat Biol Ecol & Evolut, Atlanta, GA 30322 USA. [Steurer, Frank; Seitz, Amy E.; Bern, Caryn] Ctr Dis Control & Prevent, Div Parasit Dis, Atlanta, GA USA. [Maguire, James H.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Bowman, Natalie M.; Kawai, Vivian; Cabrera, Lilia; Pinedo-Cancino, Viviana V.; Gilman, Robert H.] AB PRISMA, Lima, Peru. [Cornejo del Carpio, Juan Geny; Cordova Benzaquen, Eleazar] Direcc Reg Minist Salud, Arequipa, Peru. RP Levy, MZ (reprint author), 16 Ctr Dr, Bethesda, MD 20892 USA. EM mzlevy@sas.upenn.edu RI Plotkin, Joshua/E-6947-2013 FU NIAID NIH HHS [5P50AI074285-02, 5T35AI007646-03, K01 AI079162, K01 AI079162-02, K01AI079162, P50 AI074285, R01 AI047498, R01-AI047498, T35 AI007646, U19 AI033061, U19-AI-33061]; NIEHS NIH HHS [R01 ES015525, R01 ES015525-02, R01-ES015525] NR 12 TC 10 Z9 10 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD APR 15 PY 2009 VL 48 IS 8 BP 1104 EP 1106 DI 10.1086/597464 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 420RR UT WOS:000264307400012 PM 19278335 ER PT J AU Lei, H Liu, J Fukushige, T Fire, A Krause, M AF Lei, Haiyan Liu, Jun Fukushige, Tetsunari Fire, Andrew Krause, Michael TI Caudal-like PAL-1 directly activates the bodywall muscle module regulator hlh-1 in C. elegans to initiate the embryonic muscle gene regulatory network SO DEVELOPMENT LA English DT Article DE C. elegans; Myogenesis; Caudal; MyoD; Embryogenesis ID NEURAL CREST DERIVATIVES; CAENORHABDITIS-ELEGANS; ALPHA-ENHANCER; CELL FATE; PROTEIN; EXPRESSION; MYOD; EMBRYOGENESIS; TRANSCRIPTION; POP-1 AB Previous work in C. elegans has shown that posterior embryonic bodywall muscle lineages are regulated through a genetically defined transcriptional cascade that includes PAL-1/Caudal-mediated activation of muscle-specific transcription factors, including HLH-1/MRF and UNC-120/SRF, which together orchestrate specification and differentiation. Using chromatin immunoprecipitation (ChIP) in embryos, we now demonstrate direct binding of PAL-1 in vivo to an hlh-1 enhancer element. Through mutational analysis of the evolutionarily conserved sequences within this enhancer, we identify two cis-acting elements and their associated transacting factors (PAL-1 and HLH-1) that are crucial for the temporal-spatial expression of hlh-1 and proper myogenesis. Our data demonstrate that hlh-1 is indeed a direct target of PAL-1 in the posterior embryonic C. elegans muscle lineages, defining a novel in vivo binding site for this crucial developmental regulator. We find that the same enhancer element is also a target of HLH-1 positive auto regulation, underlying (at least in part) the sustained high levels of CeMyoD in bodywall muscle throughout development. Together, these results provide a molecular framework for the gene regulatory network activating the muscle module during embryogenesis. C1 [Lei, Haiyan; Fukushige, Tetsunari; Krause, Michael] NIDDK, NIH, Bethesda, MD 20892 USA. [Liu, Jun] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. [Fire, Andrew] Stanford Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Fire, Andrew] Stanford Sch Med, Dept Genet, Stanford, CA 94305 USA. RP Krause, M (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM mwkrause@helix.nih.gov OI Krause, Michael/0000-0001-6127-3940 FU NIH [R01-GM066953, R01GM37706] FX This work was supported by NIH grants R01-GM066953 to J. L. and R01GM37706 to A. F., and by the Intramural Research Program of the NIH, NIDDK. Deposited in PMC for release after 12 months. NR 32 TC 24 Z9 38 U1 0 U2 4 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 APR 15 PY 2009 VL 136 IS 8 BP 1241 EP 1249 DI 10.1242/dev.030668 PG 9 WC Developmental Biology SC Developmental Biology GA 422BQ UT WOS:000264402400003 PM 19261701 ER PT J AU Tzchori, I Day, TF Carolan, PJ Zhao, Y Wassif, CA Li, L Lewandoski, M Gorivodsky, M Love, PE Porter, FD Westphal, H Yang, Y AF Tzchori, Itai Day, Timothy F. Carolan, Peter J. Zhao, Yangu Wassif, Christopher A. Li, Liqi Lewandoski, Mark Gorivodsky, Marat Love, Paul E. Porter, Forbes D. Westphal, Heiner Yang, Yingzi TI LIM homeobox transcription factors integrate signaling events that control three-dimensional limb patterning and growth SO DEVELOPMENT LA English DT Article DE Ldb1; Lhx9; Lhx2; Limb development; Lmx1b; Signaling; Mouse ID APICAL ECTODERMAL RIDGE; NAIL-PATELLA SYNDROME; VERTEBRATE LIMB; SONIC-HEDGEHOG; FEEDBACK LOOP; HOMEODOMAIN PROTEINS; NOTCH LIGAND; MOUSE LIMB; CELL FATE; BUD AB Vertebrate limb development is controlled by three signaling centers that regulate limb patterning and growth along the proximodistal (PD), anteroposterior (AP) and dorsoventral (DV) limb axes. Coordination of limb development along these three axes is achieved by interactions and feedback loops involving the secreted signaling molecules that mediate the activities of these signaling centers. However, it is unknown how these signaling interactions are processed in the responding cells. We have found that distinct LIM homeodomain transcription factors, encoded by the LIM homeobox (LIM-HD) genes Lhx2, Lhx9 and Lmx1b integrate the signaling events that link limb patterning and outgrowth along all three axes. Simultaneous loss of Lhx2 and Lhx9 function resulted in patterning and growth defects along the AP and the PD limb axes. Similar, but more severe, phenotypes were observed when the activities of all three factors, Lmx1b, Lhx2 and Lhx9, were significantly reduced by removing their obligatory cofactor Ldb1. This reveals that the dorsal limb-specific factor Lmx1b can partially compensate for the function of Lhx2 and Lhx9 in regulating AP and PD limb patterning and outgrowth. We further showed that Lhx2 and Lhx9 can fully substitute for each other, and that Lmx1b is partially redundant, in controlling the production of output signals in mesenchymal cells in response to Fgf8 and Shh signaling. Our results indicate that several distinct LIM-HD transcription factors in conjunction with their Ldb1 co-factor serve as common central integrators of distinct signaling interactions and feedback loops to coordinate limb patterning and outgrowth along the PD, AP and DV axes after limb bud formation. C1 [Tzchori, Itai; Zhao, Yangu; Westphal, Heiner] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mammalian Genes & Dev, Sect Mammalian Mol Genet, Bethesda, MD 20892 USA. [Day, Timothy F.; Carolan, Peter J.; Gorivodsky, Marat; Yang, Yingzi] Natl Human Genome Res Inst, Genet Dis Res Branch, Sect Dev Genet, Bethesda, MD 20892 USA. [Wassif, Christopher A.; Porter, Forbes D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Heritable Disorders Branch, Sect Mol Dysmorphol, Bethesda, MD 20892 USA. [Li, Liqi; Love, Paul E.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mammalian Genes & Dev, Sect Cellular & Dev Biol, Bethesda, MD 20892 USA. [Lewandoski, Mark] NCI, Lab Canc & Dev Biol, NIH, Frederick, MD 21702 USA. RP Westphal, H (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Mammalian Genes & Dev, Sect Mammalian Mol Genet, Bethesda, MD 20892 USA. EM hw@mail.nih.gov; yingzi@mail.nih.gov OI Wassif, Christopher/0000-0002-2524-1420 FU NIH FX We thank members of the Yang and Westphal laboratories for stimulating discussion, and Julia Fekecs for help with figure preparation. Dr Gail Martin kindly provided the Spry4 probe. This work was supported by NIH intramural research programs of NHGRI, NICHD and NCI. Deposited in PMC for release after 12 months. NR 64 TC 36 Z9 36 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 0950-1991 J9 DEVELOPMENT JI Development PD APR 15 PY 2009 VL 136 IS 8 BP 1375 EP 1385 DI 10.1242/dev.026476 PG 11 WC Developmental Biology SC Developmental Biology GA 422BQ UT WOS:000264402400015 PM 19304889 ER PT J AU Huang, LW Pu, YB Hu, WY Birch, L Luccio-Camelo, D Yamaguchi, T Prins, GS AF Huang, Liwei Pu, Yongbing Hu, Wen Yang Birch, Lynn Luccio-Camelo, Douglas Yamaguchi, Terry Prins, Gail S. TI The role of Wnt5a in prostate gland development SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Prostate; Prostate gland; Prostate development; Wnt5a; Estradiol ID NEONATAL ESTROGEN EXPOSURE; ADULT-RAT PROSTATE; EPITHELIAL BRANCHING MORPHOGENESIS; ANDROGEN RECEPTOR EXPRESSION; GENE-EXPRESSION; MAMMARY-GLAND; BETA-CATENIN; RETINOIC ACID; LUNG MORPHOGENESIS; MOUSE PROSTATE AB The Wnt genes encode a large family of secreted glycoproteins that play important roles in controlling tissue patterning, cell fate and proliferation during development. Currently, little is known regarding the role(s) of Wnt genes during prostate gland development. The present study examines the role of the noncanonical Wnt5a during prostate gland development in rat and murine models. In the rat prostate, Wnt5a mRNA is expressed by distal mesenchyme during the budding stage and localizes to periductal mesenchymal cells with an increasing proximal-to-distal gradient during branching morphogenesis. Wnt5a protein is secreted and localizes to periductal stroma, extracellular matrix and epithelial cells in the distal ducts. While Wnt5a expression is high during active morphogenesis in all prostate lobes, ventral prostate (VP) expression declines rapidly following morphogenesis while dorsal (DP) and lateral lobe (LP) expression remains high into adulthood. Steroids modulate prostatic Wnt5a expression during early development with testosterone suppressing Wnt5a and neonatal estrogen increasing expression. In vivo and ex vivo analyses of developing mouse and rat prostates were used to assess the functional roles of Wnt5a. Wnt5a(-/-) murine prostates rescued by organ culture exhibit disturbances in bud position and directed outgrowth leading to large bulbous sacs in place of elongating ducts. In contrast, epithelial cell proliferation, ductal elongation and branchpoint formation are suppressed in newborn rat prostates Cultured with exogenous Wnt5a protein. While renal grafts of Wnt5a(-/-) murine prostates revealed that Wnt5a is not essential for cyto- and functional differentiation, a role in luminal cell polarity and lumenization of the ducts was indicated. Wnt5a suppresses prostatic Shh expression while Shh stimulates Wnt5a expression in a lobe-specific manner during early development indicating that Wnt5a participates in cross-talk with other members of the gene regulatory network that control prostate development. Although Wnt5a does not influence prostatic expression of other Wnt morphogens, it suppresses Wif-1 expression and can thus indirectly modulate Wnt signaling. In summary, the present finds demonstrate that Wnt5a is essential for normal prostate development where it regulates bud outgrowth, ductal elongation, branching, cell polarity and lumenization. These findings contribute to the growing body of knowledge on regulatory mechanisms involved in prostate gland development which are key to understanding abnormal growth processes associated with aging. (C) 2009 Elsevier Inc. All rights reserved. C1 [Huang, Liwei; Pu, Yongbing; Hu, Wen Yang; Birch, Lynn; Luccio-Camelo, Douglas; Prins, Gail S.] Univ Illinois, Dept Urol, Coll Med, Chicago, IL 60612 USA. [Yamaguchi, Terry] NCI, NIH, Bethesda, MD 20892 USA. RP Prins, GS (reprint author), Univ Illinois, Dept Urol, Coll Med, MC 955,820 S Wood St, Chicago, IL 60612 USA. EM gprins@uic.edu FU NIH [DK40890]; American Urologic Association Foundation FX The authors thank Dr. Yiming Zhu from the University of Chicago for generously providing the rat Wnt5a plasmid and Ms. Anna Vogelzang for data analysis of prostate morphogenesis in real-time. This work was supported from an NIH grant DK40890 to GSP and American Urologic Association Foundation Fellowship to LH. NR 61 TC 38 Z9 38 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD APR 15 PY 2009 VL 328 IS 2 BP 188 EP 199 DI 10.1016/j.ydbio.2009.01.003 PG 12 WC Developmental Biology SC Developmental Biology GA 433XM UT WOS:000265239100002 PM 19389372 ER PT J AU Holmes, G Rothschild, G Roy, UB Deng, CX Mansukhani, A Basilico, C AF Holmes, Greg Rothschild, Gerson Roy, Upal Basu Deng, Chu-Xia Mansukhani, Alka Basilico, Claudio TI Early onset of craniosynostosis in an Apert mouse model reveals critical features of this pathology SO DEVELOPMENTAL BIOLOGY LA English DT Article DE Fgfr2; Craniosynostosis; Apert syndrome; Osteoblast; Coronal suture; Calvaria; Mouse; Intramembranous ossification ID SAETHRE-CHOTZEN-SYNDROME; SYNDROME FGFR2(+/S252W) MOUSE; CRANIAL SUTURE FUSION; OF-FUNCTION MUTATION; OSTEOBLAST DIFFERENTIATION; SKULL VAULT; BONE-DEVELOPMENT; SIGNALING PATHWAYS; CORONAL SUTURE; CALVARIAL BONE AB Activating mutations of FGFRs1-3 cause craniosynostosis (CS), the premature fusion of cranial bones, in man and mouse. The mechanisms by which such mutations lead to CS have been variously ascribed to increased osteoblast proliferation, differentiation, and apoptosis, but it is not always clear how these disturbances relate to the process of suture fusion. We have reassessed coronal Suture fusion in an Apert Fgfr2 (S252W) Mouse model. We find that the critical event of CS is the early loss of basal sutural mesenchyme as the osteogenic fronts, expressing activated Fgfr2, unite to form a contiguous skeletogenic membrane. A mild increase in osteoprogenitor proliferation precedes but does not accompany this event, and apoptosis is insignificant. On the other hand, the more apical coronal suture initially forms appropriately but then undergoes fusion, albeit at a slower rate, accompanied by a significant decrease in osteoprogenitor proliferation, and increased osteoblast maturation. Apoptosis now accompanies fusion, but is restricted to bone fronts in contact with one another. We correlated these in vivo observations with the intrinsic effects of the activated Fgfr2 S252W mutation in primary osteoblasts in culture, which show an increased capacity for both proliferation and differentiation. Our studies suggest that the major determinant of Fgfr2-induced craniosynostosis is the failure to respond to signals that would halt the recruitment or the advancement of osteoprogenitor cells at the sites where sutures should normally form. (C) 2009 Elsevier Inc. All rights reserved. C1 [Holmes, Greg; Rothschild, Gerson; Roy, Upal Basu; Deng, Chu-Xia; Mansukhani, Alka; Basilico, Claudio] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. [Deng, Chu-Xia] NIDDKD, Genet Dev & Dis Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. RP Basilico, C (reprint author), NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. EM claudio.basilico@med.nyu.edu OI Mansukhani, Alka/0000-0003-1020-3242 FU NYU Langone Research Histology Core; PHS; NIAMS [AR051358] FX We thank Ron Deckelbaum for helpful discussions, Lisa Dailey for critical reading of the manuscript, and Gillian Morriss-Kay and Cynthia Loomis for plasmids. Technical assistance was provided by the NYU Langone Research Histology Core. This investigation was supported by PHS grant AR051358 from the NIAMS. NR 54 TC 48 Z9 50 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD APR 15 PY 2009 VL 328 IS 2 BP 273 EP 284 DI 10.1016/j.ydbio.2009.01.026 PG 12 WC Developmental Biology SC Developmental Biology GA 433XM UT WOS:000265239100009 PM 19389359 ER PT J AU Smith, ST Wickramasinghe, P Olson, A Loukinov, D Lin, L Deng, J Xiong, YP Rux, J Sachidanandam, R Sun, H Lobanenkov, V Zhou, JM AF Smith, Sheryl T. Wickramasinghe, Priyankara Olson, Andrew Loukinov, Dmitri Lin, Lan Deng, Joy Xiong, Yanping Rux, John Sachidanandam, Ravi Sun, Hao Lobanenkov, Victor Zhou, Jumin TI Genome wide ChIP-chip analyses reveal important roles for CTCF in Drosophila genome organization SO DEVELOPMENTAL BIOLOGY LA English DT Article DE dCTCF; CTCF; Insulator; Drosophila; Abd-B; Chromatin domain; ChIP-chip; Genome ID ENHANCER-BLOCKING ACTIVITY; DNA-BINDING PROTEIN; C-MYC GENE; BITHORAX COMPLEX; INSULATOR ELEMENTS; CHROMATIN; TRANSCRIPTION; REGION; MECHANISMS; POLYCOMB AB Insulators or chromatin boundary elements are defined by their ability to block transcriptional activation by an enhancer and to prevent the spread of active or silenced chromatin. Recent Studies have increasingly suggested that insulator proteins play a role in large-scale genome organization. To better understand insulator function on the global scale, we conducted a genome-wide analysis of the binding sites for the insulator protein CTCF in Drosophila by Chromatin Immunoprecipitation (ChIP) followed by a tiling-array analysis. The analysis revealed CTCF binding to many known domain boundaries within the Abd-B gene of the BX-C including previously characterized Fab-8 and MCP insulators, and the Fab-6 region. Based on this finding, we characterized the Fab-6 insulator element. in genome-wide analysis, we found that dCTCF-binding sites are often Situated between closely positioned gene promoters, consistent with the role of CTCF as an insulator protein. Importantly, CTCF tends to bind gene promoters just upstream of transcription start sites, in contrast to the predicted binding sites of the insulator protein Su(Hw). These findings suggest that CTCF plays more active roles in regulating gene activity and it functions differently from other insulator proteins in organizing the Drosophila genome. (C) 2009 Elsevier Inc. All rights reserved. C1 [Smith, Sheryl T.; Wickramasinghe, Priyankara; Lin, Lan; Deng, Joy; Xiong, Yanping; Rux, John; Sun, Hao; Zhou, Jumin] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. [Olson, Andrew] Dart Neurosci LLC, San Diego, CA 92121 USA. [Loukinov, Dmitri; Lobanenkov, Victor] NIAID, Rockville, MD 20852 USA. [Sachidanandam, Ravi] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA. [Smith, Sheryl T.] Arcadia Univ, Dept Biol, Glenside, PA 19038 USA. RP Zhou, JM (reprint author), Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. EM zhouj@wistar.org RI Sun, Hao/J-9964-2013; OI Sun, Hao/0000-0002-5547-9501; Lobanenkov, Victor/0000-0001-6665-3635 FU NIH [GM65391, NS33768]; NCI Cancer Center; NIH; NIAID FX We thank Dale Dorsett and Ramana Davuluri for insightful discussions during the analyses. This work is supported in part by NIH grants GM 65391, NS33768 to J. Zhou, NCI Cancer Center grant the Wistar Institute and NIH training grant to S. Smith, and in part by an Intramural Funding from NIAID to D. Loukinov and V. Lobanenkov. NR 54 TC 47 Z9 49 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD APR 15 PY 2009 VL 328 IS 2 BP 518 EP 528 DI 10.1016/j.ydbio.2008.12.039 PG 11 WC Developmental Biology SC Developmental Biology GA 433XM UT WOS:000265239100031 PM 19210964 ER PT J AU Hinnebusch, AG AF Hinnebusch, Alan G. TI Active destruction of defective ribosomes by a ubiquitin ligase involved in DNA repair SO GENES & DEVELOPMENT LA English DT Article DE Ubiquitin; ribosome; genotoxic stress; quality control; rRNA ID RNA QUALITY-CONTROL; SACCHAROMYCES-CEREVISIAE; PROMOTES REPLICATION; PRE-RIBOSOMES; DAMAGED DNA; YEAST; DEGRADATION; AMINOACYLATION; SURVEILLANCE; SYSTEM AB Progression of DNA replication forks through damaged DNA requires a ubiquitin ligase comprised of the cullin Rtt101, the RING finger protein Hrt1, and the adaptor protein Mms1. Rtt101 and Mms1 were implicated recently by Fujii and colleagues (pp. 963-974) in the degradation of catalytically inactive mutant 25S ribosomal RNAS (rRNAs) in mature 60S ribosomal subunits, a process that requires ubiquitin and is accompanied by ubiquitination of 60S components. It now seems likely that the same ubiquitin ligase is enlisted to deal with defective rRNA and damaged DNA. C1 NIH, Lab Gene Regulat & Dev, Eunice Kennedy Shriver NICHHD, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NIH, Lab Gene Regulat & Dev, Eunice Kennedy Shriver NICHHD, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov FU NIH FX This work was supported in part by the Intramural Research Program of the NIH. NR 28 TC 9 Z9 9 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD APR 15 PY 2009 VL 23 IS 8 BP 891 EP 895 DI 10.1101/gad.1800509 PG 5 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 436XR UT WOS:000265449900001 PM 19390082 ER PT J AU Miao, J Xiao, Z Kanamaluru, D Min, G Yau, PM Veenstra, TD Ellis, E Strom, S Suino-Powell, K Xu, HE Kemper, JK AF Miao, Ji Xiao, Zhen Kanamaluru, Deepthi Min, Gyesik Yau, Peter M. Veenstra, Timothy D. Ellis, Ewa Strom, Steve Suino-Powell, Kelly Xu, H. Eric Kemper, Jongsook Kim TI Bile acid signaling pathways increase stability of Small Heterodimer Partner (SHP) by inhibiting ubiquitin-proteasomal degradation SO GENES & DEVELOPMENT LA English DT Article DE ERK; FGF19; SHP; bile acids; proteasome; protein stability ID NUCLEAR RECEPTOR SHP; NEGATIVE FEEDBACK-REGULATION; CHOLESTEROL 7-ALPHA-HYDROXYLASE; GENE-EXPRESSION; MOLECULAR-BASIS; BIOSYNTHESIS; MECHANISMS; REPRESSION; PHOSPHORYLATION; METABOLISM AB Small Heterodimer Partner (SHP) inhibits activities of numerous transcription factors involved in diverse biological pathways. As an important metabolic regulator, SHP plays a key role in maintaining cholesterol and bile acid homeostasis by inhibiting cholesterol conversion to bile acids. While SHP gene induction by increased bile acids is well established, whether SHP activity is also modulated remains unknown. Here, we report surprising findings that SHP is a rapidly degraded protein via the ubiquitin-proteasomal pathway and that bile acids or bile acid-induced intestinal fibroblast growth factor 19 (FGF19) increases stability of hepatic SHP by inhibiting proteasomal degradation in an extracellular signal-regulated kinase (ERK)-dependent manner. SHP was ubiquitinated at Lys122 and Lys123, and mutation of these sites altered its stability and repression activity. Tandem mass spectrometry revealed that upon bile acid treatment, SHP was phosphorylated at Ser26, within an ERK motif in SHP, and mutation of this site dramatically abolished SHP stability. Surprisingly, SHP stability was abnormally elevated in ob/ob mice and diet-induced obese mice. These results demonstrate an important role for regulation of SHP stability in bile acid signaling in normal conditions, and that abnormal stabilization of SHP may be associated with metabolic disorders, including obesity and diabetes. C1 [Miao, Ji; Kanamaluru, Deepthi; Min, Gyesik; Kemper, Jongsook Kim] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. [Xiao, Zhen; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21712 USA. [Yau, Peter M.] Univ Illinois, Carver Biotechnol Ctr, Urbana, IL 61801 USA. [Ellis, Ewa; Strom, Steve] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA 15260 USA. [Suino-Powell, Kelly; Xu, H. Eric] Van Andel Res Inst, Lab Struct Sci, Grand Rapids, MI 49503 USA. RP Kemper, JK (reprint author), Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61801 USA. EM jongsook@uiuc.edu RI Ellis, Ewa/D-5370-2014 OI Ellis, Ewa/0000-0002-3057-5337 FU NIH [DK062777]; AHA [0756028Z]; National Cancer Institute; National Institutes of Health [N01-CO-12400]; [DK071662] FX We thank Drs. W. Gu, Z. Ronai, and R. Hey for kindly providing plasmids for this study. We thank the Liver Tissue Procurement and Distribution System of the National Institutes of Health (University of Pittsburgh, PA) for providing human primary hepatocytes. Special thanks to B. Kemper for critical comments on the manuscript. This study was supported by grants DK071662 to H. E. X. and NIH DK062777 and AHA 0756028Z to J.K.K. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 to T. D. V. 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 31 TC 64 Z9 64 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD APR 15 PY 2009 VL 23 IS 8 BP 986 EP 996 DI 10.1101/gad.1773909 PG 11 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 436XR UT WOS:000265449900011 PM 19390091 ER PT J AU Chio, A Schymick, JC Restagno, G Scholz, SW Lombardo, F Lai, SL Mora, G Fung, HC Britton, A Arepalli, S Gibbs, JR Nalls, M Berger, S Kwee, LC Oddone, EZ Ding, JH Crews, C Rafferty, I Washecka, N Hernandez, D Ferrucci, L Bandinelli, S Guralnik, J Macciardi, F Torri, F Lupoli, S Chanock, SJ Thomas, G Hunter, DJ Gieger, C Wichmann, HE Calvo, A Mutani, R Battistini, S Giannini, F Caponnetto, C Mancardi, GL La Bella, V Valentino, F Monsurro, MR Tedeschi, G Marinou, K Sabatelli, M Conte, A Mandrioli, J Sola, P Salvi, F Bartolomei, I Siciliano, G Carlesi, C Orrell, RW Talbot, K Simmons, Z Connor, J Pioro, EP Dunkley, T Stephan, DA Kasperaviciute, D Fisher, EM Jabonka, S Sendtner, M Beck, M Bruijn, L Rothstein, J Schmidt, S Singleton, A Hardy, J Traynor, BJ AF Chio, Adriano Schymick, Jennifer C. Restagno, Gabriella Scholz, Sonja W. Lombardo, Federica Lai, Shiao-Lin Mora, Gabriele Fung, Hon-Chung Britton, Angela Arepalli, Sampath Gibbs, J. Raphael Nalls, Michael Berger, Stephen Kwee, Lydia Coulter Oddone, Eugene Z. Ding, Jinhui Crews, Cynthia Rafferty, Ian Washecka, Nicole Hernandez, Dena Ferrucci, Luigi Bandinelli, Stefania Guralnik, Jack Macciardi, Fabio Torri, Federica Lupoli, Sara Chanock, Stephen J. Thomas, Gilles Hunter, David J. Gieger, Christian Wichmann, H. Erich Calvo, Andrea Mutani, Roberto Battistini, Stefania Giannini, Fabio Caponnetto, Claudia Mancardi, Giovanni Luigi La Bella, Vincenzo Valentino, Francesca Monsurro, Maria Rosaria Tedeschi, Gioacchino Marinou, Kalliopi Sabatelli, Mario Conte, Amelia Mandrioli, Jessica Sola, Patrizia Salvi, Fabrizio Bartolomei, Ilaria Siciliano, Gabriele Carlesi, Cecilia Orrell, Richard W. Talbot, Kevin Simmons, Zachary Connor, James Pioro, Erik P. Dunkley, Travis Stephan, Dietrich A. Kasperaviciute, Dalia Fisher, Elizabeth M. Jabonka, Sibylle Sendtner, Michael Beck, Marcus Bruijn, Lucie Rothstein, Jeffrey Schmidt, Silke Singleton, Andrew Hardy, John Traynor, Bryan J. TI A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis SO HUMAN MOLECULAR GENETICS LA English DT Article ID PROSTATE-CANCER; GENETICS; POPULATION; SUSCEPTIBILITY; DISEASE; ALS; MUTATIONS; VETERANS; GENES AB The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors. C1 [Scholz, Sonja W.; Lai, Shiao-Lin; Britton, Angela; Arepalli, Sampath; Nalls, Michael; Hernandez, Dena; Singleton, Andrew; Traynor, Bryan J.] NIA, Neurogenet Lab, NIH, Mol Genet Unit, Bethesda, MD 20892 USA. [Chio, Adriano; Calvo, Andrea; Mutani, Roberto] Univ Turin, Dept Neurosci, Turin, Italy. [Schymick, Jennifer C.; Talbot, Kevin] Univ Oxford, Dept Physiol Anat & Genet, Oxford, England. [Restagno, Gabriella; Lombardo, Federica] ASO OIRM S Anna, Mol Genet Unit, Dept Clin Pathol, Turin, Italy. [Lai, Shiao-Lin; Gibbs, J. Raphael; Hernandez, Dena; Hardy, John] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Lai, Shiao-Lin; Gibbs, J. Raphael; Hernandez, Dena; Hardy, John] Inst Neurol, Reta Lila Weston Inst Neurol Studies, London WC1N 3BG, England. [Lai, Shiao-Lin; Fung, Hon-Chung] Chang Gung Mem Hosp, Dept Neurol, Kaohsiung, Taiwan. [Mora, Gabriele; Marinou, Kalliopi] Salvatore Maugeri Fdn, Lissone, Italy. [Gibbs, J. Raphael; Ding, Jinhui] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Kwee, Lydia Coulter; Schmidt, Silke] Duke Univ, Med Ctr, Ctr Human Genet, Durham, NC USA. [Kwee, Lydia Coulter; Oddone, Eugene Z.; Schmidt, Silke] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Oddone, Eugene Z.] Durham VAMC, Epidemiol Res & Informat Ctr, Durham, NC USA. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Bandinelli, Stefania] Azienda Sanit Firenze, Geriatr Unit, Florence, Italy. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Macciardi, Fabio; Torri, Federica] Univ Milan, Dept Sci & Biomed Technol, Milan, Italy. [Lupoli, Sara] Ist Sci San Raffaele, INSPE, I-20132 Milan, Italy. [Chanock, Stephen J.; Thomas, Gilles; Hunter, David J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gieger, Christian; Wichmann, H. Erich] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [Gieger, Christian; Wichmann, H. Erich] Univ Munich, Inst Med Informat Biometry & Epidemiol, Munich, Germany. [Battistini, Stefania; Giannini, Fabio] Univ Siena, Dept Neurosci, Neurol Sect, I-53100 Siena, Italy. [Caponnetto, Claudia; Mancardi, Giovanni Luigi] Univ Genoa, Dept Neurosci Ophthalmol & Genet, Genoa, Italy. [La Bella, Vincenzo; Valentino, Francesca] Univ Palermo, Dept Clin Neurosci, Sicily, Italy. [Monsurro, Maria Rosaria; Tedeschi, Gioacchino] Univ Naples 2, Dept Neurol Sci, Caserta, Italy. [Sabatelli, Mario; Conte, Amelia] Catholic Univ, Neurol Inst, Rome, Italy. [Sabatelli, Mario; Conte, Amelia] ICOMM Assoc ALS Res, Rome, Italy. [Mandrioli, Jessica; Sola, Patrizia] S Agostino Estense Hosp, Dept Neurosci, Modena, Italy. [Mandrioli, Jessica; Sola, Patrizia] Univ Modena, I-41100 Modena, Italy. [Salvi, Fabrizio; Bartolomei, Ilaria] Bellaria Hosp, Dept Neurol, Ctr Diag & Cure Rare Dis, Bologna, Italy. [Siciliano, Gabriele; Carlesi, Cecilia] Univ Pisa, Dept Neurosci, Pisa, Italy. [Orrell, Richard W.] UCL, Univ Dept Clin Neurosci, Inst Neurol, London, England. [Simmons, Zachary] Penn State Coll Med, Dept Neurol, Hershey, PA USA. [Connor, James] Penn State Coll Med, Dept Neurosurg, Hershey, PA USA. [Pioro, Erik P.] Cleveland Clin, Dept Neurol, Cleveland, OH 44106 USA. [Dunkley, Travis; Stephan, Dietrich A.] Translat Genom Inst TGEN, Neurogenom Div, Phoenix, AZ USA. [Kasperaviciute, Dalia; Fisher, Elizabeth M.] UCL Inst Neurol, Dept Neurodegenerat Dis, London, England. [Jabonka, Sibylle; Sendtner, Michael; Beck, Marcus] Univ Wurzburg, Inst Clin Neurobiol, Wurzburg, Germany. [Bruijn, Lucie] ALS Assoc, Palm Harbor, FL USA. [Rothstein, Jeffrey] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. RP Traynor, BJ (reprint author), NIA, Neurogenet Lab, NIH, Mol Genet Unit, Bldg 35,Room 1A 1000,35 Convent Dr, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov RI Macciardi, Fabio/N-3768-2014; Calvo, Andrea/K-4141-2016; Siciliano, Gabriele/K-7259-2016; Valentino, Francesca/K-8959-2016; Sendtner, Michael/J-1542-2012; Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; Kasperaviciute, Dalia/D-1493-2009; Gibbs, J. Raphael/A-3984-2010; Talbot, Kevin /F-7361-2011; Traynor, Bryan/G-5690-2010; rothstein, jeffrey/C-9470-2013; Orrell, Richard/L-2123-2013; Battistini, Stefania/N-2596-2015; La Bella, Vincenzo/H-4532-2012; MANDRIOLI, JESSICA/K-7235-2016; mancardi, giovanni luigi/K-8656-2016; OI Macciardi, Fabio/0000-0003-0537-4266; Calvo, Andrea/0000-0002-5122-7243; Siciliano, Gabriele/0000-0002-6142-2384; Valentino, Francesca/0000-0002-7641-9938; Sendtner, Michael/0000-0002-4737-2974; Battistini, Stefania/0000-0003-2887-7624; MANDRIOLI, JESSICA/0000-0002-9244-9782; Sabatelli, Mario/0000-0001-6635-4985; mancardi, giovanni luigi/0000-0001-8427-118X; Chio, Adriano/0000-0001-9579-5341; Gieger, Christian/0000-0001-6986-9554; Scholz, Sonja/0000-0002-6623-0429 FU National Institute on Aging [Z01 AG000949-02]; National Institute of Neurological Disorders and Stroke; National Institute of Mental Health; ALS Association [1230]; Istituto Superiore di Sanita [2005-10]; German Federal Ministry of Education and Research (BMBF); German National Genome Research Network (NGFN); National Institutes of Health [ES013244]; ALS [500A]; DNA bank [478]; Department of Veterans Affairs Cooperative Studies Program (CSP) FX This work was supported by the Intramural Research Program of the National Institute on Aging (project Z01 AG000949-02), the National Institute of Neurological Disorders and Stroke, and the National Institute of Mental Health; the ALS Association; the Packard Center for ALS Research at Johns Hopkins; Istituto Superiore di Sanita (grant number 2005-10 to FL); PF A15 Regione Piemonte (to GR); and the Medical Research Council to EF and DK). The MONICA/KORA Augsburg studies were financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFN). The KORA research was supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. We gratefully acknowledge support for the GENEVA study ('Genes and Environmental Exposures in Veterans with ALS') from the National Institutes of Health (grant number ES013244) and the ALS Association (grant number 1230). The National Registry of Veterans with ALS (grant number CSP #500A) and its DNA bank (grant number CSP #478) were supported by the Department of Veterans Affairs Cooperative Studies Program (CSP). NR 37 TC 72 Z9 72 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD APR 15 PY 2009 VL 18 IS 8 BP 1524 EP 1532 DI 10.1093/hmg/ddp059 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 428ZE UT WOS:000264889800017 PM 19193627 ER PT J AU Pennuto, M Palazzolo, I Poletti, A AF Pennuto, Maria Palazzolo, Isabella Poletti, Angelo TI Post-translational modifications of expanded polyglutamine proteins: impact on neurotoxicity SO HUMAN MOLECULAR GENETICS LA English DT Review ID CREB-BINDING PROTEIN; HUNTINGTONS-DISEASE BRAIN; ANDROGEN RECEPTOR PROTEIN; SPINOCEREBELLAR ATAXIA TYPE-1; PALLIDOLUYSIAN ATROPHY DRPLA; BULBAR MUSCULAR-ATROPHY; MUTANT HUNTINGTIN; CELL-DEATH; TRANSGENIC MICE; MOUSE MODEL AB Polyglutamine diseases are a family of nine neurodegenerative disorders caused by expansion in different genes of a CAG triplet repeat stretch, which encodes an elongated polyglutamine tract. This polyglutamine tract is thought to confer a toxic gain of function to the bearing proteins, which leads to late onset and progressive loss of neurons in specific regions of the central nervous system. The mechanisms underlying specificity for neuronal vulnerability remain enigmatic. One explanation is that the polyglutamine tract is not the only determinant of neurodegeneration and that protein context and post-translational events may also be crucial for pathogenesis. Here, we review how post-translational modifications of the polyglutamine proteins contribute to modulate neurotoxicity. C1 [Pennuto, Maria] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Palazzolo, Isabella] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Palazzolo, Isabella; Poletti, Angelo] Univ Milan, Ctr Eccellenza Studio Malattie Neurodegenerat, Dipartimento Endocrinol Fisiopatol & Biol Applica, I-20133 Milan, Italy. [Palazzolo, Isabella; Poletti, Angelo] Univ Florence Roma Tor Vergata & Milano, Ctr InterUniv Malattie Neurodegenerat, Milan, Italy. RP Pennuto, M (reprint author), Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. EM pennutom@mail.med.upenn.edu RI Poletti, Angelo/A-9016-2011; OI Poletti, Angelo/0000-0002-8883-0468; Pennuto, Maria/0000-0001-8634-0767 FU NINDS intramural funding; Telethon-Italy [GFP04005, GGP06063, GGP07063)]; Kennedy's Disease Association; Muscular Dystrophy Association Development; Fondazlone Cariplo (Italy); Ministero del Lavoro, della Salute e delle Politiche Sociali (Italy) FX This work was supported by NINDS intramural funding and Telethon-Italy (GFP04005), Kennedy's Disease Association and Muscular Dystrophy Association Development grants to M. P. and Telethon-Italy grants (GGP06063 and GGP07063), Fondazlone Cariplo (Italy) and Ministero del Lavoro, della Salute e delle Politiche Sociali (Italy) to A. P. NR 98 TC 47 Z9 47 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD APR 15 PY 2009 VL 18 BP R40 EP R47 DI 10.1093/hmg/ddn412 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 421XM UT WOS:000264391600005 PM 19297400 ER PT J AU Van der Watt, PJ Maske, CP Hendricks, DT Parker, MI Denny, L Govender, D Birrer, MJ Leaner, VD AF Van der Watt, Pauline J. Maske, Christopher P. Hendricks, Denver T. Parker, M. Iqbal Denny, Lynette Govender, Dhirendra Birrer, Michael J. Leaner, Virna D. TI The Karyopherin proteins, Crm1 and Karyopherin beta 1, are overexpressed in cervical cancer and are critical for cancer cell survival and proliferation SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cervical cancer; nuclear transport proteins; Crm1; Karyopherin beta 1; Karyopherin alpha 2 ID HUMAN-PAPILLOMAVIRUS TYPE-16; MINOR CAPSID PROTEIN; NUCLEAR EXPORT; IMPORTIN-ALPHA; MESSENGER-RNA; LEPTOMYCIN-B; NUCLEOCYTOPLASMIC TRANSPORT; INTRAEPITHELIAL NEOPLASIA; EXPRESSION; P53 AB The Karyopherin proteins are involved in nucleo-cytoplasmic trafficking and are critical for protein anti RNA subcellular localization. Recent studies suggest they are important in nuclear envelope component assembly, mitosis and replication. Since these are all critical cellular functions, alterations in the expression of the Karyopherins may have an impact on the biology of cancer cells. In this study, we examined the expression of the Karyopherins, Crm1, Karyopherin beta 1 (Kpn beta 1) and Karyopherin alpha 2 (Kpn alpha 2), in cervical tissue and cell lines. The functional significance of these proteins to cancer cells was investigated using individual siRNAs to inhibit their expression. Microarrays, quantitative RT-PCR and immunofluorescence revealed significantly higher expression of Crm1, Kpn beta 1 and Kpn alpha 2 in cervical cancer compared to normal tissue. Expression levels were similarly elevated in cervical cancer cell lines compared to normal cells, and in transformed epithelial and fibroblast cells. Inhibition of Crm1. and Kpn beta 1 in cancer cells significantly reduced cell proliferation, while Kpn alpha 2 inhibition had no effect. Noncancer cells were unaffected by the inhibition or Crml and Kpn beta 1. The reduction in proliferation of cancer cells was associated with an increase in a subG1 population by cell cycle analysis and Caspase-3/7 assays revealed increased apoptosis. Crml and Kpn beta 1 siRNA-indticed apoptosis was accompanied by an increase in the levels of growth inhibitory proteins, p539 p27, p21 and p18. Our results demonstrate that Crm1, Kpn beta 1 and Kpn alpha 2 are overexpressed in cervical cancer and that inhibiting the expression of Crm1 and Kpn beta 1, not Kpn alpha 2, induces cancer cell death, making Crm1 and Kpn beta 1 promising candidates as both biomarkers and potential anticancer therapeutic targets, (C) 2008 Wiley-Liss, Inc, C1 [Van der Watt, Pauline J.; Hendricks, Denver T.; Parker, M. Iqbal; Leaner, Virna D.] Univ Cape Town, Fac Hlth Serv, Div Med Biochem, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Maske, Christopher P.; Govender, Dhirendra] Univ Cape Town, Div Anat Pathol, Fac Hlth Sci, ZA-7925 Cape Town, South Africa. [Denny, Lynette] Univ Cape Town, Dept Obstet & Gynaecol, Fac Hlth Sci, ZA-7925 Cape Town, South Africa. [Parker, M. Iqbal] ICGEB Cape Town Component, Cape Town, South Africa. [Birrer, Michael J.] NCI, Dept Cell & Canc Biol, NIH, Bethesda, MD 20892 USA. RP Leaner, VD (reprint author), Univ Cape Town, Fac Hlth Serv, Div Med Biochem, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. EM Virna.Leaner@uct.ac.za NR 47 TC 119 Z9 119 U1 0 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD APR 15 PY 2009 VL 124 IS 8 BP 1829 EP 1840 DI 10.1002/ijc.24146 PG 12 WC Oncology SC Oncology GA 422UH UT WOS:000264452700011 PM 19117056 ER PT J AU Koessler, T Azzato, EM Perkins, B Macinnis, RJ Greenberg, D Easton, DF Pharoah, PDP AF Koessler, Thibaud Azzato, Elizabeth M. Perkins, Barbara Macinnis, Robert J. Greenberg, David Easton, Douglas F. Pharoah, Paul D. P. TI Common germline variation in mismatch repair genes and survival after a diagnosis of colorectal cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE colorectal cancer; single nucleotide polymorphism; haplotype; survival ID GENOME-WIDE ASSOCIATION; COLON-CANCER; MICROSATELLITE INSTABILITY; RISK; POLYMORPHISMS; PROGNOSIS; VARIANTS; DISEASE; LOCUS; SCAN AB The mismatch repair (MMR) genes are involved in the maintenance or genomic integrity. Recently, we showed that common variants in these genes are unlikely to contribute significantly to colorectal cancer risk. The aim of this study was to investigate the role of common variants in (lie mismatch repair pathway as prognostic markers in colorectal cancer patients. We genotyped 2,060 patients for 68 SNPs in 7 mismatch repair genes (MLH1, MLH3, MSH2, MSH3, MSH6, PMS1 and PMS2), using a single nucleotide polymorphism (SNP) tagging approach. Genotypes at the tag SNPs and multi-SNP haplotypes were tested for association with overall survival (OS) and disease specific survival (DSS) using a Cox regression model. Eight SNPs and 10 haplotypes were significant at a nominal p < 0.05 in the univariate analyses. Stepwise analysis showed that haplolype effects were mainly due to associated SNPs carried by these haplotypes. After adjustment for sex, age at diagnosis and stage when using overall survival and stage only when using disease specific survival, prognostic values were unattenuated. The most significant SNP associated with disease specific survival after adjustment was rs863221, located in MSH3 MR: 0.59, 95% confidence interval (CI) 0.42-0.82, p-value: 0.001). In conclusion, we find some evidence that common variants in mismatch repair genes may contribute to survival of patients will) colorectal cancer. (C) 2008 Wiley-Liss, Inc. C1 [Koessler, Thibaud; Azzato, Elizabeth M.; Perkins, Barbara; Macinnis, Robert J.; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge, England. [Azzato, Elizabeth M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Macinnis, Robert J.] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Greenberg, David] Eastern Canc Registrat & Informat Ctr, Cambridge, England. [Easton, Douglas F.] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. RP Koessler, T (reprint author), Strangeways Res Lab, Cambridge CB1 8RN, England. EM Thibaud@srl.cam.ac.uk RI Azzato, Elizabeth/A-1902-2009; OI MacInnis, Robert/0000-0002-1627-5047 FU Cancer Research UK [10118, ] NR 23 TC 8 Z9 9 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD APR 15 PY 2009 VL 124 IS 8 BP 1887 EP 1891 DI 10.1002/ijc.24120 PG 5 WC Oncology SC Oncology GA 422UH UT WOS:000264452700017 PM 19115210 ER PT J AU Scheid, JF Mouquet, H Feldhahn, N Walker, BD Pereyra, F Cutrell, E Seaman, MS Mascola, JR Wyatt, RT Wardemann, H Nussenzweig, MC AF Scheid, Johannes F. Mouquet, Hugo Feldhahn, Niklas Walker, Bruce D. Pereyra, Florencia Cutrell, Emily Seaman, Michael S. Mascola, John R. Wyatt, Richard T. Wardemann, Hedda Nussenzweig, Michel C. TI A method for identification of HIV gp140 binding memory B cells in human blood SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE HIV; Memory B cells; gp140 ID MONOCLONAL-ANTIBODIES; FREQUENCIES AB Antibodies to HIV are potentially important reagents for basic and clinical studies. Historically, these reagents have been produced by random cloning of heavy and light chains in phage display libraries [Burton, D.R., Barbas, C.F. III, Persson, M.A.A., Koenig, S., Chanock, R.M., and Lerner, R.A., (1991), A large array of human monoclonal antibodies to type 1 immnodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals. Proc. Nail. Acad. Sci. U. S. A. 88, 10134-10137.] and electrofusion techniques [Buchacher, A., Predl, R., Tauer, C.. Purtscher, M., Gruber, G., Heider, R., Steindl, F., Trkola, A., Jungbauer, A., and Katinger, H., (1992), Human monoclonal antibodies against gp41 and gp120 as potential agent for passive immunization. Vaccines 92, 191-195]. Here we describe a method to identify and potentially enrich human memory B cells from HIV infected patients that show serum titers of neutralizing antibodies. When biotinylated gp140 is used to stain peripheral blood mononuclear cells it identifies a distinct population of gp140 binding B cells by flow cytometry. (C) 2008 Elsevier B.V. All rights reserved. C1 [Nussenzweig, Michel C.] Rockefeller Univ, HHMI, New York, NY 10065 USA. [Scheid, Johannes F.; Mouquet, Hugo; Feldhahn, Niklas; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Mascola, John R.; Wyatt, Richard T.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Walker, Bruce D.; Pereyra, Florencia; Cutrell, Emily] Mass Gen Hosp, Partners AIDS Rsearch Ctr, Charlestown, MA 02129 USA. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Wardemann, Hedda] Max Planck Inst Infect Biol, D-10117 Berlin, Germany. RP Nussenzweig, MC (reprint author), Rockefeller Univ, HHMI, 1230 York Ave, New York, NY 10065 USA. EM nussen@mail.rockefeller.edu RI Mouquet, Hugo/M-2750-2014 FU Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [R01 AI037526, R01 AI037526-15] NR 11 TC 94 Z9 99 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD APR 15 PY 2009 VL 343 IS 2 BP 65 EP 67 DI 10.1016/j.jim.2008.11.012 PG 3 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 444FE UT WOS:000265965300001 PM 19100741 ER PT J AU Tang, J Zhou, R Luger, D Zhu, W Silver, PB Grajewski, RS Su, SB Chan, CC Adorini, L Caspi, RR AF Tang, Jun Zhou, Ru Luger, Dror Zhu, Wei Silver, Phyllis B. Grajewski, Rafael S. Su, Shao-Bo Chan, Chi-Chao Adorini, Luciano Caspi, Rachel R. TI Calcitriol Suppresses Antiretinal Autoimmunity through Inhibitory Effects on the Th17 Effector Response SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD4(+) T-CELLS; ROR-GAMMA-T; D-RECEPTOR AGONIST; VITAMIN-D; 1,25-DIHYDROXYVITAMIN D-3; DENDRITIC CELLS; TRANSCRIPTIONAL REGULATION; ALLOGRAFT-REJECTION; IFN-GAMMA; DIFFERENTIATION AB Experimental autoimmune uveitis (EAU) serves as a model for human autoimmune uveitis and for cell-mediated autoimmunity in general. EAU induced in mice by immunization with the retinal Ag interphotoreceptor retinoid-binding protein in CFA is driven by the Th17 response. Oral calcitriol (1,25-dihydroxyvitamin D(3)) prevented as well as partly reversed disease and suppressed immunological responses. In vitro, calcitriol directly suppressed IL-17 induction in purified naive CD4(+) T cells without inhibiting Th17 lineage commitment, as reflected by unaltered ROR gamma t, STAT3, and FoxP3 expression. In contrast, in vivo treatment with calcitriol of mice challenged for EAU impaired commitment to the Th17 lineage, as judged by reduction of both ROR gamma t and IL-17 in CD4(+) T cells. Innate immune response parameters in draining lymph nodes of treated mice were suppressed, as was production of IL-1, IL-6, TNF-alpha, and IL-12/IL-23p40, but not IL-10, by explanted splenic dendritic cells (DC). Finally, supernatants of calcitriol-conditioned bone marrow-derived DC had reduced ability to support Th17 polarization of naive CD4(+) T cells in vitro and in vivo. Thus, calcitriol appears to suppress autoimmunity by inhibiting the Th17 response at several levels, including the ability of DC to support priming of Th17 cells, the ability of CD4(+) T cells to commit to the Th17 lineage, and the ability of committed Th17 T cells to produce IL-17. The Journal of Immunology, 2009, 182: 4624-4632. C1 [Tang, Jun; Zhou, Ru; Luger, Dror; Zhu, Wei; Silver, Phyllis B.; Grajewski, Rafael S.; Su, Shao-Bo; Chan, Chi-Chao; Caspi, Rachel R.] NEI, NIH, Immunol Lab, Bethesda, MD 20892 USA. [Adorini, Luciano] BioXell, Milan, Italy. RP Caspi, RR (reprint author), NEI, NIH, Immunol Lab, Bldg 10,Room 10N222,10 Ctr Dr, Bethesda, MD 20892 USA. EM rcaspi@helix.nih.gov OI Caspi, Rachel/0000-0002-7140-7671 FU Intramural NIH HHS [Z01 EY000184-25] NR 43 TC 135 Z9 138 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 15 PY 2009 VL 182 IS 8 BP 4624 EP 4632 DI 10.4049/jimmunol.0801543 PG 9 WC Immunology SC Immunology GA 430QX UT WOS:000265004700020 PM 19342637 ER PT J AU Burgers, WA Riou, C Mlotshwa, M Maenetje, P Rosa, DD Brenchley, J Mlisana, K Douek, DC Koup, R Roederer, M de Bruyn, G Karim, SA Williamson, C Gray, CM AF Burgers, Wendy A. Riou, Catherine Mlotshwa, Mandla Maenetje, Pholo Rosa, Debra de Assis Brenchley, Jason Mlisana, Koleka Douek, Daniel C. Koup, Richard Roederer, Mario de Bruyn, Guy Karim, Salim Abdool Williamson, Carolyn Gray, Clive M. CA CAPRISA 002 Acute Infection Study Team TI Association of HIV-Specific and Total CD8(+) T Memory Phenotypes in Subtype C HIV-1 Infection with Viral Set Point SO JOURNAL OF IMMUNOLOGY LA English DT Article ID VIRUS TYPE-1 INFECTION; CELL RESPONSES; IMMUNE ACTIVATION; DISEASE PROGRESSION; PD-1 EXPRESSION; VACCINE DEVELOPMENT; CD4(+); LYMPHOCYTES; EFFECTOR; LOAD AB Understanding early immunological events during HIV-1 infection that may set the course of disease progression is important for identifying correlates of viral control. This study explores the association of differentiation profiles of HIV-specific and total memory CD8(+) T cells with viral set point. A cohort of 47 HIV-1-infected individuals, with differing viral set points at 12 mo, were recruited during acute infection. We identified that the magnitude of IFN-gamma(+) T cell responses at 6 mo postinfection did not associate with viral set point at 12 mo. A subset of 16 individuals was further studied to characterize CD8' T cells for expression patterns of markers for memory differentiation, survival (CD127), senescence (CD57), and negative regulation (programmed death-1). We show that viral control and the predicted tempo of HIV disease progression in the first year of infection was associated with a synchronous differentiation of HIV-specific and total CD8(+) memory subpopulations. At 6-9 mo postinfection, those with low viral set points had a significantly higher proportion of early differentiated HIV-specific and total memory CD8' cells of a central memory (CD45RO(+)CD27(+)CCR7(+)) and intermediate memory (CD45RO(-)CD27(+)CCR7(-)) phenotype. Those with high viral set points possessed significantly larger frequencies of effector memory (CD45RO(+)CD27(-)CCR7(-)) cells. The proportions of memory subsets significantly correlated with CD38(+)CD8(+) T cells. Thus, it is likely that a high Ag burden resulting in generalized immune activation may drive differentiation of HIV-specific and total memory CD8(+) T cells. The Journal of Immunology, 2009, 182: 4751-4761. C1 [Burgers, Wendy A.; Williamson, Carolyn] Univ Cape Town, Fac Hlth Sci, Div Med Virol, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. [Riou, Catherine; Mlotshwa, Mandla; Maenetje, Pholo; Rosa, Debra de Assis; Gray, Clive M.] Natl Inst Communicable Dis, AIDS Res Unit, Johannesburg, South Africa. [Brenchley, Jason] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Mlisana, Koleka; Karim, Salim Abdool] Univ KwaZulu Natal, CAPRISA, Nelson R Mandela Sch Med, Durban, South Africa. [Douek, Daniel C.] NIAID, Human Immunol Sect, NIH, Bethesda, MD 20892 USA. [Koup, Richard] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Roederer, Mario] NIAID, Immunotechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [de Bruyn, Guy] Univ Witwatersrand, Perinatal HIV Res Unit, Johannesburg, South Africa. RP Gray, CM (reprint author), Natl Inst Communicable Dis, Private Bag X4, ZA-2131 Johannesburg, South Africa. EM cgray@nicd.ac.za OI , Carolyn/0000-0003-0125-1226; Mlisana, Koleka/0000-0002-8436-3268; Burgers, Wendy/0000-0003-3396-9398 FU National Institute of Allergy and Infectious Diseases; National Institutes of Health; U.S. Department of Health and Human Services [U19 A151794]; Canada-Africa Prevention Trials Network; Bill and Melinda Gales Comprehensive T Cell Vaccine Immune Monitoring Consortium; Columbia University-Southern Africa Fogarty AIDS International Training Fellowship. FX This work was funded by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, U.S. Department of Health and Human Services Grant U19 A151794: the Canada-Africa Prevention Trials Network; and the Bill and Melinda Gales Comprehensive T Cell Vaccine Immune Monitoring Consortium award. W.B. was supported by a Columbia University-Southern Africa Fogarty AIDS International Training Fellowship. NR 58 TC 49 Z9 49 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 15 PY 2009 VL 182 IS 8 BP 4751 EP 4761 DI 10.4049/jimmunol.0803801 PG 11 WC Immunology SC Immunology GA 430QX UT WOS:000265004700035 PM 19342652 ER PT J AU Kamala, T Nanda, NK AF Kamala, Tirumalai Nanda, Navreet K. TI Protective Response to Leishmania major in BALB/c Mice Requires Antigen Processing in the Absence of DM SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL RESPONSES; INVARIANT CHAIN; HLA-DR; CUTANEOUS LEISHMANIASIS; DENDRITIC CELLS; IN-VIVO; INFECTION; IMMUNODOMINANT; RESISTANCE; EXPRESSION AB Protection from the parasite Leishmania major is mediated by CD4 T cells. BALB/c mice are susceptible to L. major and show a nonprotective immunodominant CD4 T cell response to Leishmania homolog of activated receptor for c-kinase (LACK) 158-173. Host genes that underlie BALB/c susceptibility to L. major infections are poorly defined. DM, a nonclassical MHC class II molecule, due to its peptide editing properties has been shown to 1) edit the repertoire of peptides displayed by APC, and 2) focus the display of epitopes by APC to the immunodominant ones. We tested the hypothesis that deficiency of DM, by causing presentation of a different array of epitopes by infected APC than that presented by DM-sufficient APC, may change the course of L major infection in the susceptible BALB/c mice. We show herein that unlike their susceptible wild-type counterparts, BALB/c mice deficient in DM are protected from infections with L. major. Furthermore, DM-deficient mice fail to display the immunodominant LACK 158-173 on infected APC. In its place, infected DM(-/-) hosts show elicitation of CD4 T cells specific for newer epitopes not presented by wild-type L. major-infected APC. Protection of BALB/c DM(-/-) mice is dependent on IFN-gamma. DM is thus a host susceptibility gene in BALB/c mice, and Ag processing in the absence of DM results in elicitation of a protective T cell response against L. major infections. This report suggests a novel mechanism to trigger host resistance against pathogens. The Journal of Immunology, 2009, 182: 4882-4890. C1 [Kamala, Tirumalai; Nanda, Navreet K.] NIH, Cellular & Mol Immunol Lab, T Cell Tolerance & Memory Sect, Bethesda, MD 20892 USA. [Nanda, Navreet K.] Medstar Res Inst, Hyattsville, MD 20873 USA. [Nanda, Navreet K.] Georgetown Univ, Med Ctr, Dept Microbiol & Immunol, Washington, DC 20057 USA. RP Nanda, NK (reprint author), NIH, Cellular & Mol Immunol Lab, T Cell Tolerance & Memory Sect, Bldg 4, Bethesda, MD 20892 USA. EM navreetn2000@yahoo.com FU Department of Defense [W8 IXWH-04-0013]; Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX Supported in part by Department of Defense (award W8 IXWH-04-0013; to N.K.N.) and the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 39 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD APR 15 PY 2009 VL 182 IS 8 BP 4882 EP 4890 DI 10.4049/jimmunol.0803956 PG 9 WC Immunology SC Immunology GA 430QX UT WOS:000265004700050 PM 19342667 ER PT J AU Hoofnagle, JH Wahed, AS Brown, RS Howell, CD Belle, SH AF Hoofnagle, Jay H. Wahed, Abdus S. Brown, Robert S., Jr. Howell, Charles D. Belle, Steven H. CA Virahep-C Study Grp TI Early Changes in Hepatitis C Virus (HCV) Levels in Response to Peginterferon and Ribavirin Treatment in Patients with Chronic HCV Genotype 1 Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CAUCASIAN AMERICAN PATIENTS; DYNAMICS IN-VIVO; AFRICAN-AMERICAN; PEGYLATED INTERFERON-ALPHA-2B; COMBINATION THERAPY; GENE-EXPRESSION; VIRAL DYNAMICS; PLUS RIBAVIRIN; NONRESPONDERS; MANAGEMENT AB Early changes in hepatitis C virus (HCV) RNA levels were assessed in a large cohort of African American and white patients with chronic hepatitis C due to HCV genotype 1 who underwent therapy with peginterferon alfa-2a and ribavirin in the Study of Viral Resistance to Antiviral Therapy of Hepatitis C (Virahep-C). Analyses were restricted to 341 patients who completed the first 28 days of therapy without dose modification. HCV RNA levels decreased in virtually all patients, but the amount of the change varied markedly. The overall 28-day decrease in HCV RNA levels was at least as predictive of a sustained virological response as the first- or second-phase viral kinetics responses. Factors associated with a smaller decrease in the HCVRNA level between baseline and day 28 included African American race, higher initial HCV RNA level, more severe hepatic fibrosis, and higher body weight. African American patients with similar 28-day decreases in viral levels as white patients were still less likely to achieve a sustained virological response. These results suggest that racial differences in the response to antiviral therapy are due to greater unresponsiveness to intracellular actions of interferon in African American individuals and that standard doses of peginterferon and ribavirin may be suboptimal for patients with higher body weights. C1 [Hoofnagle, Jay H.] NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD 20817 USA. [Howell, Charles D.] Univ Maryland, Sch Med, Div Hepatol, Baltimore, MD 21201 USA. [Wahed, Abdus S.; Belle, Steven H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. [Wahed, Abdus S.; Belle, Steven H.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Brown, Robert S., Jr.] New York Presbyterian Med Ctr, Div Gastroenterol & Hepatol, New York, NY USA. RP Hoofnagle, JH (reprint author), NIDDK, Liver Dis Res Branch, Div Digest Dis & Nutr, NIH, Bldg 31,Rm 9A27, Bethesda, MD 20817 USA. EM hoofnaglej@extra.niddk.nih.gov OI Wahed, Abdus/0000-0001-6911-7221 FU Roche Laboratories [U01 DK60329, U01 DK60340, U01 DK60324, U01 DK60344, U01 DK60327, U01 DK60335, U01 DK60352, U01 DK60342, U01 DK60345, U01 DK60309, U01 DK60346, U01 DK60349, U01 DK60341] FX Financial support: This study was funded as a cooperative agreement by the National Institute of Diabetes and Digestive and Kidney Diseases with cosupport from the National Center on Minority Health and Health Disparities and the Intramural Research Program of the National Cancer Institute and with further support under a cooperative research and development agreement with Roche Laboratories (grants U01 DK60329, U01 DK60340, U01 DK60324, U01 DK60344, U01 DK60327, U01 DK60335, U01 DK60352, U01 DK60342, U01 DK60345, U01 DK60309, U01 DK60346, U01 DK60349, and U01 DK60341). Other support: National Center for Research Resources General Clinical Research Centers Program (grants M01 RR00645 [New York Presbyterian], M02 RR000079 [University of California, San Francisco], M01 RR16500 [University of Maryland], M01 RR000042 [University of Michigan], and M01 RR00046 [University of North Carolina]). NR 29 TC 33 Z9 37 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 15 PY 2009 VL 199 IS 8 BP 1112 EP 1120 DI 10.1086/597384 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 422EB UT WOS:000264409000005 PM 19284286 ER PT J AU Jiang, W Lederman, MM Hunt, P Sieg, SF Haley, K Rodriguez, B Landay, A Martin, J Sinclair, E Asher, AI Deeks, SG Douek, DC Brenchley, JM AF Jiang, Wei Lederman, Michael M. Hunt, Peter Sieg, Scott F. Haley, Kathryn Rodriguez, Benigno Landay, Alan Martin, Jeffrey Sinclair, Elizabeth Asher, Ava I. Deeks, Steven G. Douek, Daniel C. Brenchley, Jason M. TI Plasma Levels of Bacterial DNA Correlate with Immune Activation and the Magnitude of Immune Restoration in Persons with Antiretroviral-Treated HIV Infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID T-CELL-ACTIVATION; IMMUNODEFICIENCY-VIRUS TYPE-1; THYMIC FUNCTION; VIROLOGICAL FAILURE; CD4(+); THERAPY; DISEASE; DEPLETION; INDIVIDUALS; SUPPRESSION AB The significance of elevated plasma levels of bacterial lipopolysaccharide (LPS) in persons with chronic HIV infection remains undefined. We measured LPS levels by use of limulus lysate assay, and DNA sequences encoding bacterial ribosomal 16S RNA (16S rDNA) were assessed by quantitative polymerase chain reactions in plasma samples obtained from 242 donors. Plasma levels of 16S rDNA were significantly higher in human immunodeficiency virus (HIV)-infected subjects than in uninfected subjects, and they correlated with LPS levels. Higher levels of 16S rDNA were associated with higher levels of T cell activation and with lower levels of CD4 T cell restoration during antiretroviral therapy. Antiretroviral therapy reduces but does not fully normalize plasma levels of bacterial 16S rDNA, an index of microbial translocation from the gastrointestinal tract. High levels of 16SrDNA during therapy are strongly associated with reduced increases in the CD4(+) T lymphocyte count, irrespective of plasma HIV RNA levels. These findings are consistent with the importance of microbial translocation in immunodeficiency and T cell homeostasis in chronic HIV infection. C1 [Lederman, Michael M.] Case Western Reserve Univ, Ctr AIDS Res, Cleveland, OH 44106 USA. [Landay, Alan] Rush Med Sch, Chicago, IL USA. [Asher, Ava I.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Brenchley, Jason M.] NIAID, Immunopathogenesis Unit, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Hunt, Peter; Martin, Jeffrey; Sinclair, Elizabeth; Deeks, Steven G.] Univ San Francisco, San Francisco Gen Hosp, San Francisco, CA 94117 USA. RP Lederman, MM (reprint author), Case Western Reserve Univ, Ctr AIDS Res, Cleveland, OH 44106 USA. EM MXL6@case.edu RI Rodriguez, Benigno/C-3365-2009 OI Rodriguez, Benigno/0000-0001-9736-7957 FU Center for AIDS Research at Case Western Reserve University [AI 36219]; AIDS Clinical Trials Group [AI 25879, AI 38858]; National Institute of Allergy and Infectious Diseases [AI 076174]; National Institutes of Health [AI055273, AI44595]; Center for AIDS Prevention Studies [P30 MH62246]; University of California, San Francisco (UCSF) [P30 AI27763, P30 MH59037]; UCSF Clinical and Translational Science Institute [UL1 RR024131-01]; University Hospitals Case Medical Center, Cleveland, Ohio FX Financial support: Center for AIDS Research at Case Western Reserve University (grant AI 36219); AIDS Clinical Trials Group (grants AI 25879 and AI 38858); National Institute of Allergy and Infectious Diseases (grant AI 076174). This work was supported in part by the intramural program of the National Institute of Allergy and Infectious Diseases. The Study on the Consequences of the Protease Inhibitor Era (SCOPE) cohort is supported by the National Institutes of Health (grants AI055273 and AI44595), the Center for AIDS Prevention Studies (grant P30 MH62246), the University of California, San Francisco (UCSF) Center for AIDS Research (grants P30 AI27763 and P30 MH59037) and the UCSF Clinical and Translational Science Institute (grant UL1 RR024131-01). The funders of this study had no role in study design, data collection and analysis, preparation of the manuscript, or the decision to publish it. Reprints or correspondence: Dr. Michael M. Lederman, Center for AIDS Research, Case Western Reserve University and University Hospitals Case Medical Center, Cleveland, Ohio 44106 (MXL6@case.edu). NR 34 TC 321 Z9 327 U1 1 U2 16 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD APR 15 PY 2009 VL 199 IS 8 BP 1177 EP 1185 DI 10.1086/597476 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 422EB UT WOS:000264409000013 PM 19265479 ER PT J AU Shneider, NA Mentis, GZ Schustak, J O'Donovan, MJ AF Shneider, Neil A. Mentis, George Z. Schustak, Joshua O'Donovan, Michael J. TI Functionally Reduced Sensorimotor Connections Form with Normal Specificity Despite Abnormal Muscle Spindle Development: The Role of Spindle-Derived Neurotrophin 3 SO JOURNAL OF NEUROSCIENCE LA English DT Article ID RAT SPINAL-CORD; TRANSCRIPTION FACTOR EGR3; TERM SYNAPTIC DEPRESSION; SCIATIC-NERVE AXOTOMY; MOTOR-NEURONS; NEONATAL-RAT; SENSORY NEURONS; MESSENGER-RNAS; MICE LACKING; MOTONEURONS AB The mechanisms controlling the formation of synaptic connections between muscle spindle afferents and spinal motor neurons are believed to be regulated by factors originating from muscle spindles. Here, we find that the connections form with appropriate specificity in mice with abnormal spindle development caused by the conditional elimination of the neuregulin1 receptor ErbB2 from muscle precursors. However, despite a modest (similar to 30%) decrease in the number of afferent terminals on motor neuron somata, the amplitude of afferent-evoked synaptic potentials recorded in motor neurons was reduced by similar to 80%, suggesting that many of the connections that form are functionally silent. The selective elimination of neurotrophin 3 (NT3) from muscle spindles had no effect on the amplitude of afferent-evoked ventral root potentials until the second postnatal week, revealing a late role for spindle-derived NT3 in the functional maintenance of the connections. These findings indicate that spindle-derived factors regulate the strength of the connections but not their initial formation or their specificity. C1 [Shneider, Neil A.; Mentis, George Z.; Schustak, Joshua; O'Donovan, Michael J.] NINCDS, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. [Shneider, Neil A.] Columbia Univ, Dept Neurol, New York, NY 10032 USA. [Shneider, Neil A.] Columbia Univ, Ctr Motor Neuron Biol & Dis, New York, NY 10032 USA. RP O'Donovan, MJ (reprint author), NINCDS, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. EM odonovm@ninds.nih.gov RI o'donovan, michael/A-2357-2015; OI o'donovan, michael/0000-0003-2487-7547; Shneider, Neil/0000-0002-3223-7366 FU National Institute of Neurological Disorders and Stroke; Project ALS; New York State Department of Health Spinal Cord Injury [C018610] FX This work was supported by the intramural program of the National Institute of Neurological Disorders and Stroke. N.A.S. was also supported by Project ALS and by a New York State Department of Health Spinal Cord Injury research grant (Contract C018610). We thank Monica Mendelsohn and Barbara Han for expert technical assistance in the generation of the Egr3-IRES-Cre mouse line and Hua Tian for her invaluable technical assistance. Special thanks to Tom Jessell and Chris Henderson for their support and critical comments on this manuscript. NR 51 TC 27 Z9 28 U1 0 U2 1 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 APR 15 PY 2009 VL 29 IS 15 BP 4719 EP 4735 DI 10.1523/JNEUROSCI.5790-08.2009 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 433UT UT WOS:000265232000005 PM 19369542 ER PT J AU Syczewska, M Lebiedowska, MK Pandyan, AD AF Syczewska, Malgorzata Lebiedowska, Maria K. Pandyan, Anand D. TI Quantifying repeatability of the Wartenberg pendulum test parameters in children with spasticity SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Wartenberg's test; Spasticity; Repeatability ID CEREBRAL-PALSY AB The Wartenberg (pendulum) test is commonly used in a variety of studies involving healthy subjects, patients with CP, stroke patients, and other neurological conditions. There is some evidence that the Wartenberg test may be able to differentiate healthy people from patients with spasticity. The aim of the study was to explore the within-session repeatability of primary outcome measures, i.e. relaxation indices derived from the Wartenberg test when test was performed by single investigator. Patients were lying supine, thigh along the horizontal line. The lower legs were allowed to hang freely over the table edge, and the knee motion in response to leg drop from the horizontal position was measured using motion system VICON with external markers attached to each leg at greater trochanter, lateral knee epicondyle. and lateral malleolus. Data from four consecutive trials were collected at 1 min intervals. The set of relaxation indices and maximum velocity was calculated for each trial. Data of 21 children (42 limbs) who underwent the evaluation due to spasticity problem were analysed. The repeated measure ANOVA test, one way analysis of variance, coefficients of correlation and determination were used to determine the repeatability of the relaxation indices, the association between the indices in time, and influence of the spasticity origin on the variability. The results show that relaxation indices, did not differ between the trails in statistically significant way in our group of patients with spasticity, however they exhibited high within-session variability in the individual patients (16-90%). Therefore the variability of the relaxation indices may restrict the clinical usefulness of the indices to monitor the changes of spasticity over time. Further, our findings do not seem to conform to the earlier reports demonstrating a systematic, time-dependent, change in the relaxation indices when repeated measures were taken within a session. In conclusion, this study demonstrates that although the Wartenberg test is repeatable in groups of patients, it does not provide us with repeatable measures in individual patients, thus if it is to be used as a replacement for other clinical tests of spasticity further investigations are needed to explain the substantial variability of the indices. (C) 2009 Elsevier B.V. All rights reserved. C1 [Syczewska, Malgorzata] Childrens Mem Hlth Inst, Dept Paediat Rehabil, PL-04730 Warsaw, Poland. [Lebiedowska, Maria K.] NIH, Dept Rehabil Med, Funct & Appl Biomech Sect, Bethesda, MD 20892 USA. [Pandyan, Anand D.] Keele Univ, Sch Hlth & Rehabil, Keele, Staffs, England. RP Syczewska, M (reprint author), Childrens Mem Hlth Inst, Dept Paediat Rehabil, Al Dzieci Polskich 20, PL-04730 Warsaw, Poland. EM m.syczewska@czd.pl NR 17 TC 10 Z9 10 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD APR 15 PY 2009 VL 178 IS 2 BP 340 EP 344 DI 10.1016/j.jneumeth.2008.12.031 PG 5 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 425BG UT WOS:000264611400014 PM 19183563 ER PT J AU Punturieri, A Szabo, E Croxton, TL Shapiro, SD Dubinett, SM AF Punturieri, Antonello Szabo, Eva Croxton, Thomas L. Shapiro, Steven D. Dubinett, Steven M. TI Lung Cancer and Chronic Obstructive Pulmonary Disease: Needs and Opportunities for Integrated Research SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID AIR-FLOW OBSTRUCTION; NF-KAPPA-B; BRONCHIAL EPITHELIUM; INHALED CORTICOSTEROIDS; MESENCHYMAL TRANSITION; NEUTROPHIL ELASTASE; TUMOR PROGRESSION; GENE-EXPRESSION; RISK; SMOKING AB Lung cancer and chronic obstructive pulmonary disease (COPD) are leading causes of morbidity and mortality in the United States and worldwide. They share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by the incidence of these diseases in only a fraction of smokers. The presence of COPD increases the risk of lung cancer up to 4.5-fold. To investigate commonalities in disease mechanisms and perspectives for disease chemoprevention, the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI) held a workshop. The participants identified four research objectives: 1) clarify common epidemiological characteristics of lung cancer and COPD; 2) identify shared genetic and epigenetic risk factors; 3) identify and validate biomarkers, molecular signatures, and imaging-derived measurements of each disease; and 4) determine common and disparate pathogenetic mechanisms. These objectives should be reached via four research approaches: 1) identify, publicize, and enable the evaluation and analysis of existing datasets and repositories of biospecimens; 2) obtain phenotypic and outcome data and biospecimens from large studies of subjects with and/or at risk for COPD and lung cancer; 3) develop and use animal and other preclinical models to investigate pathogenetic links between the diseases; and 4) conduct early-phase clinical trials of potential chemopreventive agents. To foster much needed research interactions, two final recommendations were made by the participants: 1) incorporate baseline phenotyping and outcome measures for both diseases in future longitudinal studies of each disease and 2) expand collaborative efforts between the NCI and NHLBI. C1 [Punturieri, Antonello; Croxton, Thomas L.] NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. [Szabo, Eva] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Shapiro, Steven D.] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Dubinett, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. RP Punturieri, A (reprint author), NHLBI, Div Lung Dis, Rm 10146,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM punturieria@nhlbi.nih.gov NR 79 TC 94 Z9 105 U1 1 U2 8 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 APR 15 PY 2009 VL 101 IS 8 BP 554 EP 559 DI 10.1093/jnci/djp023 PG 6 WC Oncology SC Oncology GA 434KE UT WOS:000265272800007 PM 19351920 ER PT J AU Yu, CL Tucker, MA Abramson, DH Furukawa, K Seddon, JM Stovall, M Fraumeni, JF Kleinerman, RA AF Yu, Chu-Ling Tucker, Margaret A. Abramson, David H. Furukawa, Kyoji Seddon, Johanna M. Stovall, Marilyn Fraumeni, Joseph F., Jr. Kleinerman, Ruth A. TI Cause-Specific Mortality in Long-Term Survivors of Retinoblastoma SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CHILDHOOD-CANCER SURVIVOR; RADIATION-RELATED RISK; HEREDITARY RETINOBLASTOMA; NONOCULAR TUMORS; 5-YEAR SURVIVORS; HODGKINS-DISEASE; FOLLOW-UP; STROKE AB Subsequent malignant neoplasms are a major cause of premature death in survivors of hereditary retinoblastoma. Radiotherapy further increases the risk of death. Mortality information is limited among long-term survivors who were irradiated for hereditary retinoblastoma. We examined cause-specific mortality among 1854 retinoblastoma survivors who were diagnosed from January 1, 1914, through December 31, 1996, at two US institutions. Standardized mortality ratios (SMRs) were calculated by use of US mortality data to estimate expected numbers of deaths. The relative rates (RRs) of mortality due to subsequent malignant neoplasms associated with multiple risk factors were evaluated with Poisson regression models. Cumulative mortality from subsequent malignant neoplasms was calculated by treating other causes of death as competing risks. A total of 151 deaths due to subsequent malignant neoplasms occurred among 1092 hereditary retinoblastoma survivors (SMR = 35, 95% confidence interval [CI] = 30 to 41) compared with 12 deaths among 762 nonhereditary retinoblastoma survivors (SMR = 2.5, 95% CI = 1.3 to 4.4). In this extended follow-up of retinoblastoma survivors, we found no evidence of excess mortality from non-neoplastic causes compared with the general population. However, excess mortality from subsequent malignant neoplasms (particularly sarcomas, melanomas, and cancers of the brain and other parts of the nervous system) among hereditary retinoblastoma survivors extended beyond 40 years after retinoblastoma diagnosis. The additional 13 years of follow-up since our last mortality study revealed a previously unreported increased risk of death due to cancers of the corpus uteri (primarily sarcomas) and confirmed the previously reported elevated risk of death from lung cancer among hereditary retinoblastoma survivors. Among hereditary and nonhereditary retinoblastoma survivors, the relative rates of mortality from subsequent malignant neoplasm were higher in those who had been treated with radiotherapy than in those who had not. Cumulative mortality from subsequent malignant neoplasms at 50 years after retinoblastoma diagnosis was 25.5% (95% CI = 20.8% to 30.2%) for hereditary retinoblastoma survivors and 1.0% (95% CI = 0.2% to 1.8%) for nonhereditary retinoblastoma survivors. The temporal patterns of site-specific excess risks of subsequent malignant neoplasms in retinoblastoma survivors should inform screening programs designed for the early detection and treatment of subsequent malignant neoplasms. C1 [Yu, Chu-Ling] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20892 USA. [Abramson, David H.] Mem Sloan Kettering Canc Ctr, Ophthalm Oncol Serv, New York, NY 10021 USA. [Furukawa, Kyoji] Radiat Effects Res Fdn, Dept Stat, Hiroshima, Japan. [Seddon, Johanna M.] Tufts Univ New England Med Ctr, Ophthalm Epidemiol & Genet Serv, Boston, MA USA. [Stovall, Marilyn] Univ Texas MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. RP Yu, CL (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd MSC 7238, Rockville, MD 20892 USA. EM yuchu@mail.nih.gov RI Tucker, Margaret/B-4297-2015; OI Kleinerman, Ruth/0000-0001-7415-2478 FU Intramural NIH HHS NR 32 TC 51 Z9 52 U1 0 U2 2 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 APR 15 PY 2009 VL 101 IS 8 BP 581 EP 591 DI 10.1093/jnci/djp046 PG 11 WC Oncology SC Oncology GA 434KE UT WOS:000265272800010 PM 19351917 ER PT J AU Bok, K Prikhodko, VG Green, KY Sosnovtsev, SV AF Bok, Karin Prikhodko, Victor G. Green, Kim Y. Sosnovtsev, Stanislav V. TI Apoptosis in Murine Norovirus-Infected RAW264.7 Cells Is Associated with Downregulation of Survivin SO JOURNAL OF VIROLOGY LA English DT Article ID RABBIT HEMORRHAGIC-DISEASE; FELINE CALICIVIRUS; CULTURED-CELLS; VIRUS-INFECTION; CANCER; PROTEIN; CLEAVAGE; PATHWAY; DEATH; PATHOGENESIS AB Noroviruses (NVs) are recognized as a major cause of nonbacterial gastroenteritis in humans. Studies of the human NVs continue to be hampered by the inability to propagate them in any cell culture system. Until recently, most data concerning NV replication were derived from studies of feline calicivirus and rabbit hemorrhagic disease virus, which are cultivable members of the family Caliciviridae. From such studies, it was proposed that caliciviruses induce apoptosis to facilitate the dissemination of viral progeny in the host. The discovery that MNV type 1 (MNV-1) grows in RAW264.7 cells provided the first cell culture system for use in studying the role of apoptosis in NV infection. We first showed that MNV-1 replication triggered apoptosis in infected RAW264.7 cells and then demonstrated that cell death was associated with activation of caspase-9 and caspase-3 through the mitochondrial pathway. This process was dependent on virus replication, since inactivated virus failed to induce signs of apoptosis. In order to better understand the apoptotic process induced by MNV-1 infection of RAW264.7 cells, we investigated the expression profiles of MNV-1-infected versus mock-infected cells. Survivin, a member of the inhibitor of apoptosis protein family, was found to be significantly downregulated in an inverse relationship with the virus genome replication. This study showed that, unlike other viruses that upregulate survivin, MNV-1 is the first virus found to downregulate the levels of survivin. We observed that MNV-1 replication in RAW264.7 cells activated caspases, resulting in apoptosis through the mitochondrial pathway, possibly as a result of downregulation of survivin. C1 [Sosnovtsev, Stanislav V.] NIAID, Norovirus Gastroenteritis Unit, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Sosnovtsev, SV (reprint author), NIAID, Norovirus Gastroenteritis Unit, Infect Dis Lab, NIH, 50 S Dr,Bldg 50,Room 6316, Bethesda, MD 20892 USA. EM ss216m@nih.gov OI Prikhodko, Victor/0000-0001-6006-9454 FU National Institutes of Health; National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 54 TC 27 Z9 27 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR 15 PY 2009 VL 83 IS 8 BP 3647 EP 3656 DI 10.1128/JVI.02028-08 PG 10 WC Virology SC Virology GA 420ZI UT WOS:000264327300022 PM 19211757 ER PT J AU Qi, L Kash, JC Dugan, VG Wang, RX Jin, GZ Cunningham, RE Taubenberger, JK AF Qi, Li Kash, John C. Dugan, Vivien G. Wang, Ruixue Jin, Guozhong Cunningham, Robert E. Taubenberger, Jeffery K. TI Role of Sialic Acid Binding Specificity of the 1918 Influenza Virus Hemagglutinin Protein in Virulence and Pathogenesis for Mice SO JOURNAL OF VIROLOGY LA English DT Article ID A VIRUSES; PANDEMIC VIRUS; RECEPTOR SPECIFICITY; IMMUNE-RESPONSE; H5N1 INFLUENZA; HUMAN AIRWAY; HOST IMMUNE; GENES; PATHOGENICITY; EVOLUTION AB The 1918 influenza pandemic caused more than 40 million deaths and likely resulted from the introduction and adaptation of a novel avian-like virus. Influenza A virus hemagglutinins are important in host switching and virulence. Avian-adapted influenza virus hemagglutinins bind sialic acid receptors linked via alpha 2-3 glycosidic bonds, while human-adapted hemagglutinins bind alpha 2-6 receptors. Sequence analysis of 1918 isolates showed hemagglutinin genes with alpha 2-6 or mixed alpha 2-6/alpha 2-3 binding. To characterize the role of the sialic acid binding specificity of the 1918 hemagglutinin, we evaluated in mice chimeric influenza viruses expressing wild-type and mutant hemagglutinin genes from avian and 1918 strains with differing receptor specificities. Viruses expressing 1918 hemagglutinin possessing either alpha 2-6, alpha 2-3, or alpha 2-3/alpha 2-6 sialic acid specificity were fatal to mice, with similar pathology and cellular tropism. Changing alpha 2-3 to alpha 2-6 binding specificity did not increase the lethality of an avian-adapted hemagglutinin. Thus, the 1918 hemagglutinin contains murine virulence determinants independent of receptor binding specificity. C1 [Qi, Li; Kash, John C.; Dugan, Vivien G.; Wang, Ruixue; Jin, Guozhong; Taubenberger, Jeffery K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Cunningham, Robert E.] Armed Forces Inst Pathol, Dept Biophys, Rockville, MD 20850 USA. RP Taubenberger, JK (reprint author), NIAID, Infect Dis Lab, NIH, 33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU Intramural Research Program of the NIH; NIAID FX This work was supported by the Intramural Research Program of the NIH and the NIAID. NR 43 TC 36 Z9 40 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR 15 PY 2009 VL 83 IS 8 BP 3754 EP 3761 DI 10.1128/JVI.02596-08 PG 8 WC Virology SC Virology GA 420ZI UT WOS:000264327300031 PM 19211766 ER PT J AU Ambrose, Z Herman, BD Sheen, CW Zelina, S Moore, KL Tachedjian, G Nissley, DV Sluis-Cremer, N AF Ambrose, Zandrea Herman, Brian D. Sheen, Chih-Wei Zelina, Shannon Moore, Katie L. Tachedjian, Gilda Nissley, Dwight V. Sluis-Cremer, Nicolas TI The Human Immunodeficiency Virus Type 1 Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutation I132M Confers Hypersensitivity to Nucleoside Analogs SO JOURNAL OF VIROLOGY LA English DT Article ID IN-VITRO; HIV-1; HYPERSUSCEPTIBILITY; PURIFICATION; SUBSTITUTION; SENSITIVITY; MUTANT; SITE AB We previously identified a rare mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), I132M, which confers high-level resistance to the nonnucleoside RT inhibitors (NNRTIs) nevirapine and delavirdine. In this study, we have further characterized the role of this mutation in viral replication capacity and in resistance to other RT inhibitors. Surprisingly, our data show that I132M confers marked hypersusceptibility to the nucleoside analogs lamivudine (3TC) and tenofovir at both the virus and enzyme levels. Subunit-selective mutagenesis studies revealed that the mutation in the p51 subunit of RT was responsible for the increased sensitivity to the drugs, and transient kinetic analyses showed that this hypersusceptibility was due to I132M decreasing the enzyme's affinity for the natural dCTP substrate but increasing its affinity for 3TC-triphosphate. Furthermore, the replication capacity of HIV-1 containing I132M is severely impaired. This decrease in viral replication capacity could be partially or completely compensated for by the A62V or L214I mutation, respectively. Taken together, these results help to explain the infrequent selection of I132M in patients for whom NNRTI regimens are failing and furthermore demonstrate that a single mutation outside of the polymerase active site and inside of the p51 subunit of RT can significantly influence nucleotide selectivity. C1 [Ambrose, Zandrea; Herman, Brian D.; Sheen, Chih-Wei; Zelina, Shannon; Sluis-Cremer, Nicolas] Univ Pittsburgh, Div Infect Dis, Dept Med, Sch Med, Pittsburgh, PA 15261 USA. [Nissley, Dwight V.] SAIC Frederick, Basic Sci Program, Frederick, MD 21702 USA. [Nissley, Dwight V.] NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. [Moore, Katie L.; Tachedjian, Gilda] Macfarlane Burnet Inst Med Res & Publ Hlth, Mol Interact Grp, Ctr Virol, Melbourne, Vic 3004, Australia. [Tachedjian, Gilda] Monash Univ, Dept Microbiol, Melbourne, Vic 3168, Australia. RP Ambrose, Z (reprint author), Univ Pittsburgh, Div Infect Dis, Dept Med, Sch Med, 817B Scaife Hall,3550 Terrace St, Pittsburgh, PA 15261 USA. EM ambrosez@dom.pitt.edu OI Tachedjian, Gilda/0000-0002-7733-7037 FU National Institutes of Health [R01 GM068406, N01-CO-12400]; National Cancer Institute; NHMRC [543105, 381705, 433903] FX The research was supported by grant R01 GM068406 from the National Institutes of Health to N. S.- C. and by federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 ( D. V. N.). G. T. was supported by NHMRC senior research fellowship 543105, and the research was supported by NHMRC project grants 381705 and 433903. NR 28 TC 12 Z9 12 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD APR 15 PY 2009 VL 83 IS 8 BP 3826 EP 3833 DI 10.1128/JVI.01968-08 PG 8 WC Virology SC Virology GA 420ZI UT WOS:000264327300039 PM 19193782 ER PT J AU Horner, TJ Lai, WS Stumpo, DJ Blackshear, PJ AF Horner, Thierry J. Lai, Wi S. Stumpo, Deborah J. Blackshear, Perry J. TI Stimulation of Polo-Like Kinase 3 mRNA Decay by Tristetraprolin SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ZINC-FINGER PROTEINS; AU-RICH ELEMENTS; CELL-CYCLE ARREST; SERINE/THREONINE KINASE; MAMMALIAN-CELLS; INDUCIBLE KINASE; GENE-EXPRESSION; TNF-ALPHA; IDENTIFICATION; BINDING AB Polo-like protein kinase 3 (Plk3) has been proposed to regulate entry into S phase and promote apoptosis in response to oxidative stress. Its mRNA contains three AU-rich elements (AREs) in its 3' untranslated region (3'-UTR) that can contribute to the rapid degradation of labile transcripts. We investigated the possibility that tristetraprolin (TTP), a tandem CCCH zinc finger protein, could promote the decay of Plk3 transcripts. TTP is known to stimulate the deadenylation and decay of mRNAs possessing one or more copies of the consensus nonamer motif UUAUUUAUU. In stable mouse fibroblast cell lines derived from wild-type and TTP knockout littermates, the decay of Plk3 transcripts after serum stimulation was slowed in the absence of TTP. The specificity of TTP for promoting the degradation of Plk3 was demonstrated by the unaltered decay of Plk3 mRNA in cell lines deficient in the TTP family members ZFP36L1 and ZFP36L2. We also found that the AREs present in the Plk3 transcript were essential for both the binding of TTP to the 3'-UTR and promoting the destruction of target transcripts in cotransfection experiments. The regulation of Plk3 mRNA stability by TTP may influence the control of the cell cycle by this protein kinase. C1 [Horner, Thierry J.; Lai, Wi S.; Stumpo, Deborah J.; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] NIEHS, Clin Res Program, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), A2 05 NIEHS, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov FU National Institute of Environmental Health Sciences, NIH FX This research was supported by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH. NR 54 TC 24 Z9 25 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD APR 15 PY 2009 VL 29 IS 8 BP 1999 EP 2010 DI 10.1128/MCB.00982-08 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 424HS UT WOS:000264558400002 PM 19188452 ER PT J AU Kwon, HS Lee, HS Ji, Y Rubin, JS Tomarev, SI AF Kwon, Heung-Sun Lee, Hee-Sheung Ji, Yun Rubin, Jeffrey S. Tomarev, Stanislav I. TI Myocilin Is a Modulator of Wnt Signaling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID HUMAN TRABECULAR MESHWORK; OPEN-ANGLE GLAUCOMA; SEQUENCE TAG ANALYSIS; AQUEOUS-HUMOR; BETA-CATENIN; VERTEBRATE GASTRULATION; INTRAOCULAR-PRESSURE; MOLECULAR-CLONING; SPEMANN ORGANIZER; WNT/BETA-CATENIN AB It is well documented that mutations in the MYOCILIN gene may lead to juvenile- and adult-onset primary open-angle glaucoma. However, the functions of wild-type myocilin are still not well understood. To study the functions of human myocilin and its two proteolytic fragments, these proteins were expressed in HEK293 cells. Conditioned medium from myocilin-expressing cells, as well as purified myocilin, induced the formation of stress fibers in primary cultures of human trabecular meshwork or NIH 3T3 cells. Stress fiber-inducing activity of myocilin was blocked by antibodies against myocilin, as well as secreted inhibitors of Wnt signaling, secreted Frizzled-related protein 1 (sFRP1) or sFRP3, and beta-catenin small interfering RNA. Interaction of myocilin with sFRP1, sFRP3, and several Frizzled receptors was confirmed by immunoprecipitation experiments and by binding of myocilin to the surface of cells expressing cysteine-rich domains of different Frizzled and sFRPs. Treatment of NIH 3T3 cells with myocilin and its fragments induced intracellular redistribution of beta-catenin and its accumulation on the cellular membrane but did not induce nuclear accumulation of beta-catenin. Overexpression of myocilin in the eye angle tissues of transgenic mice stimulated accumulation of beta-catenin in these tissues. Myocilin and Wnt proteins may perform redundant functions in the mammalian eye, since myocilin modulates Wnt signaling by interacting with components of this signaling pathway. C1 [Kwon, Heung-Sun; Lee, Hee-Sheung; Tomarev, Stanislav I.] NEI, Mol & Dev Biol Lab, Mol Mech Glaucoma Sect, NIH, Bethesda, MD 20892 USA. [Ji, Yun; Rubin, Jeffrey S.] NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Tomarev, SI (reprint author), NEI, Mol & Dev Biol Lab, Mol Mech Glaucoma Sect, NIH, 5635 Fishers Lane,Rm 1122, Bethesda, MD 20892 USA. EM tomarevs@nei.nih.gov RI Ji, Yun/B-7245-2009 OI Ji, Yun/0000-0001-6340-7009 FU National Institutes of Health; National Eye Institute and National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Eye Institute and National Cancer Institute. NR 93 TC 38 Z9 45 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD APR 15 PY 2009 VL 29 IS 8 BP 2139 EP 2154 DI 10.1128/MCB.01274-08 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 424HS UT WOS:000264558400014 PM 19188438 ER PT J AU Hart, RG Pearce, LA Ravina, BM Yaltho, TC Marler, JR AF Hart, Robert G. Pearce, Lesly A. Ravina, Bernard M. Yaltho, Toby C. Marler, John R. TI Neuroprotection Trials in Parkinson's Disease: Systematic Review SO MOVEMENT DISORDERS LA English DT Review DE Parkinson's disease; neuroprotection; disease-modifying; clinical trial ID CLINICAL-TRIALS; DOUBLE-BLIND; RANDOMIZED-TRIALS; COENZYME Q(10); END-POINT; PROGRESSION; SELEGILINE; LEVODOPA; DISABILITY; FUTILITY AB Treatments to slow the progression are a major unmet need in Parkinson's disease. Detailed assessment of randomized trials testing putative neuroprotective drugs was undertaken to inform the design. reporting, and interpretation of future studies. This study is a systematic review of trials testing neuroprotective drugs. Data were extracted independently by two coauthors. Fifteen completed, published trials involving 4,087 participants tested 13 different drugs in 18 double-blind comparisons with placebo. Seven comparisons involving 2,000 subjects assessed MAO-B inhibitors. The primary outcome was change in the Unified Parkinson's Disease Rating Scale score in eight trials and time to need for dopaminergic therapy ill seven. Mean participant age was 62 years. 35% were women, the interval from diagnosis to entry averaged 11 months, and the number of participants averaged 272 (largest = 806). Follow-up averaged < 16 months in all but two trials. Detailed randomization methods and success of double-blinding were reported in 20% and 13%. respectively. Based on the investigations conclusions, six trials were interpreted as consistent with a neuroprotective effect, three as negative, and five as either confounded or not meeting criteria for futility. Neuroprotection trials have involved relatively uniform groups of participants early in the clinical disease course, with outcomes weighted heavily toward motor deterioration. Future trials should include participants with wider ranges of disease stages and assess broader neurological outcomes. (C) 2009 Movement Disorder Society C1 [Hart, Robert G.; Yaltho, Toby C.] Univ Texas Hlth Sci Ctr San Antonio, Dept Neurol, San Antonio, TX 78229 USA. [Ravina, Bernard M.] Univ Rochester, Sch Med, Dept Neurol, Rochester, NY USA. [Marler, John R.] NINDS, NIH, Bethesda, MD 20892 USA. RP Hart, RG (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Neurol, 7703 Floyd Curl Dr,MC 7883, San Antonio, TX 78229 USA. EM hartr@uthscsa.edu NR 42 TC 37 Z9 38 U1 0 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD APR 15 PY 2009 VL 24 IS 5 BP 647 EP 654 DI 10.1002/mds.22432 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 439KG UT WOS:000265625400002 PM 19117366 ER PT J AU Camargos, ST Dornas, LO Momeni, P Lees, A Hardy, J Singleton, A Cardoso, F AF Camargos, Sarah Teixeira Dornas, Leonardo Oliveira Momeni, Parastoo Lees, Andrew Hardy, John Singleton, Andrew Cardoso, Francisco TI Familial Parkinsonism and Early Onset Parkinson's Disease in a Brazilian Movement Disorders Clinic: Phenotypic Characterization and Frequency of SNCA, PRKN, PINK1, and LRRK2 Mutations SO MOVEMENT DISORDERS LA English DT Article DE LRRK2; PINK1; PRKN; SNCA; Brazil ID GENE; COMMUNITY; AGE AB The aim of the study was to evaluate the frequency and to perform phenotypic and genotypic characterization of familial Parkinsonism and early onset Parkinson's disease (EOPD) in a Brazilian movement disorder unit. We performed a standardized clinical assessment of patients followed by sequencing of PRKN, PINK1 in EOPD cases and SNCA. LRRK2 in familial Parkinsonism individuals. During the period of study (January through December, 2006), we examined 575 Consecutive patients of whom 226 (39.3%) met the diagnosis of Parkinsonism and idiopathic Parkinson's disease (IPD) was diagnosed in 202 of the latter. OF the IPD cases, 45 (22.3%) had EOPD. The age at onset in the EOPD cases (n = 45) was 34.8 +/- 5.4 years (mean +/- standard deviation). The age at onset in the familial late-onset PD patients (n = 8) was 52.3 +/- 12.2 years. In the early onset cases, we identified five known mutations in PRKN, two single heterozygous and three compound heterozygous (P153R, T240M, 255Adel. W54R, V3I); in addition, we identified one novel initiation in PINK1 (homozygous deletion of exon 7). In the familial cases (late onset) 1 patient had a novel LRRK2 variant, Q923H, but no SNCA Mutations were identified. We have demonstrated that EOPD accounts for a high frequency of IPD cases in our tertiary referral center. PRKN was the most commonly mutated gene, but we also identified a novel Mutation in PINK1 and a novel variant in LRRK2. (C) 2009 Movement Disorder Society C1 [Camargos, Sarah Teixeira; Dornas, Leonardo Oliveira; Cardoso, Francisco] Univ Fed Minas Gerais, Dept Internal Med, Neurol Serv, Movement Disorders Grp, Belo Horizonte, MG, Brazil. [Momeni, Parastoo] Texas Tech Univ, Hlth Sci Ctr, Dept Neurol, Lubbock, TX 79409 USA. [Lees, Andrew; Hardy, John] UCL, Reta Lila Weston Inst Neurol Studies, London, England. [Hardy, John] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cardoso, F (reprint author), Av Pasteur 89-1107, Belo Horizonte, MG, Brazil. EM cardosofe@terra.com.br RI Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; Lees, Andrew/A-6605-2009; Cardoso, Francisco/A-2285-2014; CAMARGOS, SARAH/O-4670-2014 OI Cardoso, Francisco/0000-0003-0808-0116; CAMARGOS, SARAH/0000-0001-9829-6783 FU NIH [AG000957-05] FX We thank the patients for taking part in this study. This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services. The NIH project number associated with this work is Z01 AG000957-05 NR 33 TC 25 Z9 27 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD APR 15 PY 2009 VL 24 IS 5 BP 662 EP 666 DI 10.1002/mds.22365 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 439KG UT WOS:000265625400004 PM 19205068 ER PT J AU Wu, CW Gu, H Lu, HB Stein, EA Chen, JH Yang, YH AF Wu, Changwei W. Gu, Hong Lu, Hanbing Stein, Elliot A. Chen, Jyh-Horng Yang, Yihong TI Mapping functional connectivity based on synchronized CMRO2 fluctuations during the resting state SO NEUROIMAGE LA English DT Article DE Functional connectivity; BOLD; Perfusion; CMRO2 ID CEREBRAL METABOLIC-RATE; VISUAL-CORTEX; BLOOD-FLOW; OXYGEN-CONSUMPTION; HUMAN BRAIN; RAT-BRAIN; MRI; BOLD; ARCHITECTURE; SIGNAL AB Synchronized low-frequency fluctuations in the resting state functional MRI (fMRI) signal have been suggested to be associated with functional connectivity in brain networks. However, the underlying mechanism of this connectivity is still poorly understood, with the synchronized fluctuations could either originate from hemodynamic oscillations or represent true neuronal signaling. To better interpret the resting signal, in the current work, we examined spontaneous fluctuations at the level of cerebral metabolic rate of oxygenation (CMRO2), an index reflecting regional oxygen consumption and metabolism, and thus less sensitive to vascular dynamics. The CMRO2 signal was obtained based on a biophysical model with data acquired from simultaneous blood oxygenation level dependent (BOLD) and perfusion signals. CMRO2-based functional connectivity maps were generated in three brain networks: visual, default-mode, and hippocampus. Experiments were performed on twelve healthy participants during 'resting state' and as a comparison, with a visual task. CMRO2 signals in each of the abovementioned brain networks showed significant correlations. Functional connectivity maps from the CMRO2 signal are, in general, similar to those from BOLD and perfusion. In addition, we demonstrated that the three parameters (M, alpha and beta) in the biophysical model for calculating CMRO2 have negligible effects on the determination of the CMRO2-based connectivity strength. This study provides evidence that the spontaneous fluctuations in fMRI at rest likely originate from dynamic changes of cerebral metabolism reflecting neuronal activity. Published by Elsevier Inc. C1 [Wu, Changwei W.; Gu, Hong; Lu, Hanbing; Stein, Elliot A.; Yang, Yihong] Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Chen, Jyh-Horng] Natl Taiwan Univ, Dept Elect Engn, Interdisciplinary MRI MRS Lab, Taipei 106, Taiwan. RP Yang, YH (reprint author), Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, 251 Bayview Blvd,Suite 200,Room 7A709, Baltimore, MD 21224 USA. EM jhchen@ntu.edu.tw; yihongyang@intra.nida.nih.gov FU National Institute on Drug Abuse (NIDA); National Institute of Health (NIH) FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse (NIDA), National Institute of Health (NIH). NR 35 TC 33 Z9 33 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD APR 15 PY 2009 VL 45 IS 3 BP 694 EP 701 DI 10.1016/j.neuroimage.2008.12.066 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 421SK UT WOS:000264378400007 PM 19280693 ER PT J AU Sa-Nunes, A AF Sa-Nunes, Anderson TI Honoring a friend: Brutality ends career of a young Brazilian scientist SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Letter C1 NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Sa-Nunes, A (reprint author), NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Bldg TB3,Room 2E-28, Rockville, MD 20852 USA. EM anunes@mail.nih.gov RI Sa-Nunes, Anderson/D-8667-2012 OI Sa-Nunes, Anderson/0000-0002-1859-4973 NR 2 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 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD APR 15 PY 2009 VL 20 IS 3 BP 222 EP 222 DI 10.1016/j.niox.2008.12.006 PG 1 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 425RG UT WOS:000264654200012 PM 19168142 ER PT J AU Hunsberger, S Albert, PS London, WB AF Hunsberger, Sally Albert, Paul S. London, Wendy B. TI A finite mixture survival model to characterize risk groups of neuroblastoma SO STATISTICS IN MEDICINE LA English DT Article DE parametric cure model; classification; Bayesian information criteria ID CURE MODELS; BAYESIAN-ANALYSIS; UNKNOWN NUMBER; N-MYC; COMPONENTS; CANCER; STAGE AB Neuroblastoma is a childhood cancer with patients experiencing heterogeneous survival outcomes despite aggressive treatment. Disease outcomes range from early death to spontaneous regression of the tumor followed by cure. Owing to this heterogeneity, it is of interest to identify patients with similar types of neuroblastoma so that specific types of treatment can be developed. Oncologists are especially interested in identifying patients who will be cured so that the minimum amount of a potentially toxic treatment can be given to this group of patients. We analyze a large cohort of neuroblastoma patients and develop a finite mixture model that uses covariates to predict the probability of being in a Cure group or other (one or more) risk groups. A prediction method is developed that uses the estimated probabilities to assign a patient to different risk groups. The robustness of the model and the prediction method is examined via Simulation by looking at misclassification rates under misspecified models. Published in 2009 by John Wiley & Sons, Ltd. C1 [Hunsberger, Sally; Albert, Paul S.] NCI, Biometr Res Branch, Rockville, MD 20852 USA. [London, Wendy B.] Univ Florida, COG, Gainesville, FL 32601 USA. RP Hunsberger, S (reprint author), NCI, Biometr Res Branch, 6130 Execut Blvd,Rm 8120, Rockville, MD 20852 USA. EM sallyh@ctep.nci.nih.gov FU Intramural NIH HHS [Z99 AI999999]; NCI NIH HHS [U10 CA098543] NR 28 TC 1 Z9 1 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD APR 15 PY 2009 VL 28 IS 8 BP 1301 EP 1314 DI 10.1002/sim.3543 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 425NW UT WOS:000264645400007 PM 19184977 ER PT J AU Gail, MH Graubard, B Williamson, DE Flegal, KM AF Gail, Mitchell H. Graubard, Barry Williamson, David E. Flegal, Katherine M. TI Comments on 'Choice of time scale and its effect on significance of predictors in longitudinal studies' SO STATISTICS IN MEDICINE LA English DT Letter C1 [Gail, Mitchell H.; Graubard, Barry] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Williamson, David E.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Williamson, David E.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Gail, MH (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RI Flegal, Katherine/A-4608-2013; OI Flegal, Katherine/0000-0002-0838-469X FU Intramural NIH HHS [Z01 CP010188-03] NR 4 TC 16 Z9 16 U1 1 U2 8 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD APR 15 PY 2009 VL 28 IS 8 BP 1315 EP 1317 DI 10.1002/sim.3473 PG 3 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 425NW UT WOS:000264645400008 PM 19288532 ER PT J AU Rai, G Thomas, CJ Leister, W Maloney, DJ AF Rai, Ganesha Thomas, Craig J. Leister, William Maloney, David J. TI Synthesis of oxadiazole-2-oxide analogues as potential antischistosomal agents SO TETRAHEDRON LETTERS LA English DT Article ID UNSYMMETRICALLY SUBSTITUTED FUROXANS; SCHISTOSOMA-MANSONI; SYSTEM; THIOREDOXIN; GLUTATHIONE; DERIVATIVES; INFECTION; LIBRARIES; RELEASE; DISEASE AB The synthesis of several 1,2,5-oxadiazole-2-oxide (Furoxan) analogues is described herein. These compounds were prepared in an effort to probe the SAR around the phenyl substituent and oxadiazole core for our studies toward thioredoxin-glutathione reductase (TGR) inhibition and antischistosomal activity. Published by Elsevier Ltd. C1 [Rai, Ganesha; Thomas, Craig J.; Leister, William; Maloney, David J.] NHGRI, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Maloney, DJ (reprint author), NHGRI, NIH, Chem Genom Ctr, 9800 Med Ctr Dr,Bldg B,Room 2055,MSC 3370, Bethesda, MD 20892 USA. EM maloneyd@mail.nih.gov FU National Institutes of Health Roadmap for Medical Research FX The authors thank Jeremy Smith and Paul Shinn for assistance with compound management. This research was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research. NR 24 TC 19 Z9 19 U1 1 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD APR 15 PY 2009 VL 50 IS 15 BP 1710 EP 1713 DI 10.1016/j.tetlet.2009.01.120 PG 4 WC Chemistry, Organic SC Chemistry GA 422LC UT WOS:000264428300015 PM 19802367 ER PT J AU Dalal, D Tandri, H Judge, DP Amat, N Macedo, R Jain, R Tichnell, C Daly, A James, C Russell, SD Abraham, T Bluemke, DA Calkins, H AF Dalal, Darshan Tandri, Harikrishna Judge, Daniel P. Amat, Nuria Macedo, Robson Jain, Rahul Tichnell, Crystal Daly, Amy James, Cynthia Russell, Stuart D. Abraham, Theodore Bluemke, David A. Calkins, Hugh TI Morphologic Variants of Familial Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy A Genetics-Magnetic Resonance Imaging Correlation Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiomyopathy; arrhythmia; magnetic resonance imaging; genetics; diagnosis ID TASK-FORCE CRITERIA; NAXOS-DISEASE; PLAKOPHILIN-2 MUTATIONS; CLINICAL PROFILE; ANIMAL-MODEL; WOOLLY HAIR; CARDIOMYOPATHY; DYSPLASIA; PLAKOGLOBIN; DELETION AB Objectives The purpose of this study was to determine the extent of left ventricular (LV) involvement in individuals predisposed to developing arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), and to investigate novel morphologic variants of ARVD/C. Background The discovery of desmosomal mutations associated with ARVD/C has led researchers to hypothesize equal right ventricular (RV) and LV affliction in the disease process. Methods Thirty-eight (age 30 +/- 17 years; 18 males) family members of 12 desmosomal mutation-carrying ARVD/C pro-bands underwent genotyping and cardiac magnetic resonance imaging (CMR). The CMR investigators were blinded to clinical and genetic data. Results Twenty-five individuals had mutations in PKP2, DSP, and/or DSG2 genes. RV abnormalities were associated with the presence of mutation(s) and with disease severity determined by criteria (minor = 1; major = 2) points for ARVD/C diagnosis. The only LV abnormality detected, the presence of intramyocardial fat, was present in 4 individuals. Each of these individuals was a mutation carrier, whereas 1 had no previously described ARVD/C-related abnormality. On detailed CMR, a focal "crinkling" of the RV outflow tract and subtricuspid regions ("accordion sign") was observed in 60% of the mutation carriers and none of the noncarriers (p < 0.001). The sign was present in 0%, 37%, 71%, and 75% of individuals who met 1, 2, 3, and 4+ criteria points, respectively (p < 0.01). Conclusions Despite a possible LV involvement in ARVD/C, the overall LV structure and function are well preserved. Independent LV involvement is of rare occurrence. The accordion sign is a promising tool for early diagnosis of ARVD/C. Its diagnostic utility should be confirmed in larger cohorts. (J Am Coll Cardiol 2009; 53: 1289-99) c 2009 by the American College of Cardiology Foundation C1 [Dalal, Darshan; Tandri, Harikrishna; Judge, Daniel P.; Amat, Nuria; Jain, Rahul; Tichnell, Crystal; Daly, Amy; James, Cynthia; Russell, Stuart D.; Abraham, Theodore; Calkins, Hugh] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Macedo, Robson] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Dalal, D (reprint author), 600 N Wolfe St,Carnegie 592, Baltimore, MD 21209 USA. EM ddalal1@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU Bogle Foundation; Campanella family; Wilmerding Endowments; Healing Hearts; Donald W. Reynolds Foundation; W.W. Smith Charitable Trust; GE Healthcare; National Heart, Lung, and Blood Institute [HL093350] FX From the *Division of Cardiology, Department of Medicine, and dagger Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; and Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bethesda, Maryland. The Johns Hopkins ARVD Program is supported by the Bogle Foundation, the Campanella family, the Wilmerding Endowments, and Healing Hearts; this work was also supported by grants from the Donald W. Reynolds Foundation; and the W.W. Smith Charitable Trust. Dr. Abraham has received honoraria and research support from GE Healthcare. Dr. Tandri is supported by a grant from the National Heart, Lung, and Blood Institute (HL093350). Drs. Dalal and Tandri contributed equally to this work. NR 39 TC 37 Z9 41 U1 0 U2 2 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 APR 14 PY 2009 VL 53 IS 15 BP 1289 EP 1299 DI 10.1016/j.jacc.2008.12.045 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 430TV UT WOS:000265012600006 PM 19358943 ER PT J AU Merkies, ISJ Bril, V Dalakas, MC Deng, C Donofrio, P Hanna, K Hartung, HP Hughes, RAC Latov, N van Doorn, PA AF Merkies, I. S. J. Bril, V. Dalakas, M. C. Deng, C. Donofrio, P. Hanna, K. Hartung, H. -P. Hughes, R. A. C. Latov, N. van Doorn, P. A. CA ICE Study Grp TI Health-related quality-of-life improvements in CIDP with immune globulin IV 10% The ICE Study SO NEUROLOGY LA English DT Article ID INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY; INTRAVENOUS IMMUNOGLOBULIN TREATMENT; RANDOMIZED CONTROLLED TRIAL; MEDIATED POLYNEUROPATHIES; DOUBLE-BLIND; PSYCHOMETRIC EVALUATION; PREDNISOLONE; SCALE AB Background: Chronic inflammatory demyelinating polyradiculoneuropathy trials have demonstrated the efficacy of IV immunoglobulin vs placebo. However, these trails have not addressed the long-term impact on health-related quality of life (HRQoL). Methods: One hundred seventeen patients in a randomized, double-blind, response-conditional crossover trial received immune globulin IV, 10% caprylate/chromatography purified (IGIV-C [Gamunex (R)]), or placebo every 3 weeks for up to 24 weeks in the first period (FP). Participants whose inflammatory neuropathy cause and treatment disability score did not improve by >= 1 point received alternate treatment in a 24-week crossover period (CP). In either period, participants who improved and completed treatment were eligible to be randomly reassigned to a blinded 24-week extension phase (EP). HRQoL analyses were conducted using the Short Form-36 (R) (SF-36) and the Rotterdam Handicap Scale (RHS). Results: In the FP, greater improvements in both SF-36 physical and mental component scores were observed with IGIV-C vs placebo, with a significant improvement in the physical component score (difference 4.4 points; 95% confidence interval [CI] 0.7-8.0). Improvements in all SF-36 domains favored IGIV-C vs placebo, with physical functioning, role-physical, social functioning, and mental health reaching significance. Participants receiving IGIV-C experienced a larger improvement in RHS vs those receiving placebo (difference 3.4 points; 95% CI 1.4-5.5; p = 0.001). In the CP, similar general trends were observed. In the EP, mean SF-36 improvements were generally improved or maintained in participants who continued IGIV-C therapy; however, worsening was observed in participants re-randomized to placebo. Conclusions: Long-term therapy with immune globulin IV, 10% caprylate/chromatography purified, improves and maintains health-related quality of life in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology (R) 2009; 72: 1337-1344 C1 [Merkies, I. S. J.] Spaarne Hosp Hoofddorp, NL-2134 TM Hoofddorp, Netherlands. [Merkies, I. S. J.; van Doorn, P. A.] Erasmus MC, Dept Neurol, Rotterdam, Netherlands. [Bril, V.] Univ Hlth Network, Toronto, ON, Canada. [Dalakas, M. C.] NIH, Neuromuscular Dis Sect, Bethesda, MD 20892 USA. [Donofrio, P.] Vanderbilt Univ, Dept Neurol, Nashville, TN USA. [Deng, C.; Hanna, K.] Talecris Biotherapeut Inc, Res Triangle Pk, NC USA. [Hartung, H. -P.] Univ Dusseldorf, Dept Neurol, D-4000 Dusseldorf, Germany. [Hughes, R. A. C.] Guys Hosp, Kings Coll London, Dept Clin Neurosci, London SE1 9RT, England. [Latov, N.] Cornell Univ, Peripheral Neuropathy Ctr, New York, NY 10021 USA. RP Merkies, ISJ (reprint author), Spaarne Hosp Hoofddorp, Spaarnepoort 1, NL-2134 TM Hoofddorp, Netherlands. EM imerkies@spaarneziekenhuis.nl RI riva, nilo/J-7187-2012; mancardi, giovanni luigi/K-8656-2016; OI riva, nilo/0000-0002-0513-9517; mancardi, giovanni luigi/0000-0001-8427-118X; Caress, James/0000-0002-5814-6083 FU Talecris Biotherapeutics, Center for Science and Education (Research Triangle Park, NC); ICE Study Steering Committee FX Funding for the study was provided by Talecris Biotherapeutics, Center for Science and Education (Research Triangle Park, NC). I. S. J. M., V. B., M. C. D., P. D., H.-P. H., R. A. C. H., N. L., and P. A. v. D. received honoraria for participation on the ICE Study Steering Committee. H.-P. H. has received honoraria from Talecris Biotherapeutics for speaking at scientific symposia and for serving on a steering committee. C. D. and K. H. are employees of Talecris Biotherapeutics. NR 20 TC 36 Z9 36 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 14 PY 2009 VL 72 IS 15 BP 1337 EP 1344 DI 10.1212/WNL.0b013e3181a0fd80 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 432AZ UT WOS:000265107200009 PM 19365055 ER PT J AU Kernan, WN Viscoli, CM DeMarco, D Mendes, B Shrauger, K Schindler, JL McVeety, JC Sicklick, A Moalli, D Greco, P Bravata, DM Eisen, S Resor, L Sena, K Story, D Brass, LM Furie, KL Gutmann, L Hinnau, E Gorman, M Lovejoy, AM Inzucchi, SE Young, LH Horwitz, RI AF Kernan, W. N. Viscoli, C. M. DeMarco, D. Mendes, B. Shrauger, K. Schindler, J. L. McVeety, J. C. Sicklick, A. Moalli, D. Greco, P. Bravata, D. M. Eisen, S. Resor, L. Sena, K. Story, D. Brass, L. M. Furie, K. L. Gutmann, L. Hinnau, E. Gorman, M. Lovejoy, A. M. Inzucchi, S. E. Young, L. H. Horwitz, R. I. CA IRIS Trial Investigators TI Boosting enrollment in neurology trials with Local Identification and Outreach Networks (LIONs) SO NEUROLOGY LA English DT Article ID CLINICAL-TRIAL; RECRUITMENT; STROKE AB Objective: Our purpose was to develop a geographically localized, multi-institution strategy for improving enrolment in a trial of secondary stroke prevention. Methods: We invited 11 Connecticut hospitals to participate in a project named the Local Identification and Outreach Network (LION). Each hospital provided the names of patients with stroke or TIA, identified from electronic admission or discharge logs, to researchers at a central coordinating center. After obtaining permission from personal physicians, researchers contacted each patient to describe the study, screen for eligibility, and set up a home visit for consent. Researchers traveled throughout the state to enroll and follow participants. Outside the LION, investigators identified trial participants using conventional recruitment strategies. We compared recruitment success for the LION and other sites using data from January 1, 2005, through June 30, 2007. Results: The average monthly randomization rate from the LION was 4.0 participants, compared with 0.46 at 104 other Insulin Resistance Intervention after Stroke (IRIS) sites. The LION randomized on average 1.52/1,000 beds/month, compared with 0.76/1,000 beds/month at other IRIS sites (p = 0.03). The average cost to randomize and follow one participant was $8,697 for the LION, compared with $7,198 for other sites. Conclusion: A geographically based network of institutions, served by a central coordinating center, randomized substantially more patients per month compared with sites outside of the network. The high enrollment rate was a result of surveillance at multiple institutions and greater productivity at each institution. Although the cost per patient was higher for the network, compared with nonnetwork sites, cost savings could result from more rapid completion of research. Neurology (R) 2009; 72: 1345-1351 C1 [Kernan, W. N.; Viscoli, C. M.; DeMarco, D.; Mendes, B.; Shrauger, K.; Hinnau, E.; Lovejoy, A. M.; Inzucchi, S. E.; Young, L. H.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA. [Schindler, J. L.; McVeety, J. C.; Story, D.; Brass, L. M.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA. [Sicklick, A.] Yale Univ, Sch Med, Dept Orthopaed & Rehabil, New Haven, CT 06510 USA. [Horwitz, R. I.] Stanford Univ, Sch Med, Dept Med, Palo Alto, CA 94304 USA. [Bravata, D. M.] Indiana Univ, Sch Med, Richard L Roudebush VAMC, Indianapolis, IN USA. [Gorman, M.] Univ Vermont, Dept Neurol, Burlington, VT USA. [Furie, K. L.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Moalli, D.] Lawrence Mem Hosp, Groton, CT USA. [Greco, P.] St Marys Hosp, Waterbury, CT USA. [Eisen, S.] Waterbury Hosp & Hlth Ctr, Waterbury, CT USA. [Resor, L.] Stamford Hosp, Stamford, CT USA. [Shrauger, K.] Bridgeport Hosp, Bridgeport, CT USA. [Gutmann, L.] NINDS, NIH, Bethesda, MD 20892 USA. RP Kernan, WN (reprint author), Suite 515,2 Church St S, New Haven, CT 06519 USA. EM walter.kernan@yale.edu RI Tanne, David/F-2560-2010; Spence, J. David/K-6396-2013 OI Tanne, David/0000-0002-6699-2220; Spence, J. David/0000-0001-7478-1098 FU National Institute of Neurological Disorders and Stroke [U01 NS044876]; Takeda Pharmaceuticals North America, Inc FX Supported by the National Institute of Neurological Disorders and Stroke (U01 NS044876) and by a grant from Takeda Pharmaceuticals North America, Inc. NR 8 TC 5 Z9 5 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD APR 14 PY 2009 VL 72 IS 15 BP 1345 EP 1351 DI 10.1212/WNL.0b013e3181a0fda3 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 432AZ UT WOS:000265107200010 PM 19365056 ER PT J AU O'Keefe, BR Vojdani, F Buffa, V Shattock, RJ Montefiori, DC Bakke, J Mirsalis, J d'Andrea, AL Hume, SD Bratcher, B Saucedo, CJ McMahon, JB Pogue, GP Palmer, KE AF O'Keefe, Barry R. Vojdani, Fakhrieh Buffa, Viviana Shattock, Robin J. Montefiori, David C. Bakke, James Mirsalis, Jon d'Andrea, Anna-Lisa Hume, Steven D. Bratcher, Barry Saucedo, Carrie J. McMahon, James B. Pogue, Gregory P. Palmer, Kenneth E. TI Scaleable manufacture of HIV-1 entry inhibitor griffithsin and validation of its safety and efficacy as a topical microbicide component SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE AIDS; lectin; plant; sexually transmitted; tobacco mosaic virus ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN CERVICAL TISSUE; ANTIVIRAL PROTEIN GRIFFITHSIN; CYANOVIRIN-N; VAGINAL TRANSMISSION; ENV CLONES; INFECTION; MACAQUES; PREVENTION; FUSION AB To prevent sexually transmitted HIV, the most desirable active ingredients of microbicides are antiretrovirals (ARVs) that directly target viral entry and avert infection at mucosal surfaces. However, most promising ARV entry inhibitors are biologicals, which are costly to manufacture and deliver to resource-poor areas where effective microbicides are urgently needed. Here, we report a manufacturing breakthrough for griffithsin (GRFT), one of the most potent HIV entry inhibitors. This red algal protein was produced in multigram quantities after extraction from Nicotiana benthamiana plants transduced with a tobacco mosaic virus vector expressing GRFT. Plant-produced GRFT (GRFT-P) was shown as active against HIV at picomolar concentrations, directly virucidal via binding to HIV envelope glycoproteins, and capable of blocking cell-to-cell HIV transmission. GRFT-P has broad-spectrum activity against HIV clades A, B, and C, with utility as a microbicide component for HIV prevention in established epidemics in sub-Saharan Africa, South Asia, China, and the industrialized West. Cognizant of the imperative that microbicides not induce epithelial damage or inflammatory responses, we also show that GRFT-P is nonirritating and noninflammatory in human cervical explants and in vivo in the rabbit vaginal irritation model. Moreover, GRFT-P is potently active in preventing infection of cervical explants by HIV-1 and has no mitogenic activity on cultured human lymphocytes. C1 [Vojdani, Fakhrieh; Pogue, Gregory P.; Palmer, Kenneth E.] Intrucept Biomed, Owensboro, KY 42301 USA. [O'Keefe, Barry R.; Saucedo, Carrie J.; McMahon, James B.] NCI, Mol Targets Dev Program, Frederick, MD 21702 USA. [Buffa, Viviana; Shattock, Robin J.] Univ London St Georges Hosp, Sch Med, London SW17 0RE, England. [Montefiori, David C.] Duke Univ, Sch Med, Dept Surg, Durham, NC 27708 USA. [Bakke, James; Mirsalis, Jon; d'Andrea, Anna-Lisa] SRI Int, Menlo Pk, CA 94025 USA. [Hume, Steven D.; Bratcher, Barry] Kentucky Bioproc, Owensboro, KY 42301 USA. [Saucedo, Carrie J.] SAIC Frederick, Frederick, MD 21702 USA. [Palmer, Kenneth E.] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. [Palmer, Kenneth E.] Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. RP Palmer, KE (reprint author), Intrucept Biomed, Owensboro, KY 42301 USA. EM kepalm02@gwise.louisville.edu RI D'Andrea, Annalisa/F-9836-2011; OI Palmer, Kenneth/0000-0002-2811-1111 FU National Institutes of Health (NIH) [AI076169, AI30034, N01-CO-12400]; National Institute of Allergy and Infectious Diseases [N01-AI-05417]; National Cancer Institute; Center for Cancer Research FX We thank Dr. Toshiyuki Mori for the GRFT expression plasmid; Roberta Gardella and Jennifer Wilson for assay support; and Andrew Marsh for editorial assistance. This work was supported by National Institutes of Health (NIH) Grants AI076169 (to K. E. P.) and AI30034 (to D. C. M.), National Institute of Allergy and Infectious Diseases Contract N01-AI-05417, and by federal funds from the National Cancer Institute, NIH (Contract N01-CO-12400). This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The content of this publication does not necessarily reflect the views or policies of the U. S. Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 31 TC 124 Z9 128 U1 2 U2 12 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 APR 14 PY 2009 VL 106 IS 15 BP 6099 EP 6104 DI 10.1073/pnas.0901506106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 433AB UT WOS:000265174600015 PM 19332801 ER PT J AU Davis, JS Epstein, ND AF Davis, Julien S. Epstein, Neal D. TI Mechanistic role of movement and strain sensitivity in muscle contraction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE enthalpy-entropy compensation; length step; non-Arrhenius; protein folding; tension generation ID RABBIT PSOAS MUSCLE; FREE-ENERGY TRANSDUCTION; HUXLEY-SIMMONS PHASE-2; CROSS-BRIDGE CYCLE; FORCE GENERATION; PHOSPHATE RELEASE; INORGANIC-PHOSPHATE; TENSION GENERATION; TEMPERATURE-JUMP; SKELETAL-MUSCLES AB Tension generation can be studied by applying step perturbations to contracting muscle fibers and subdividing the mechanical response into exponential phases. The de novo tension-generating isomerization is associated with one of these phases. Earlier work has shown that a temperature jump perturbs the equilibrium constant directly to increase tension. Here, we show that a length jump functions quite differently. Astep release (relative movement of thick and thin filaments) appears to release a steric constraint on an ensemble of noncompetent postphosphate release actomyosin cross-bridges, enabling them to generate tension, a concentration jump in effect. Structural studies [Taylor KA, et al. (1999) Tomographic 3D reconstruction of quick-frozen, Ca(2+)-activated contracting insect flight muscle. Cell 99: 421-431] that map to these kinetics indicate that both catalytic and lever arm domains of noncompetent myosin heads change angle on actin, whereas lever arm movement alone mediates the power stroke. Together, these kinetic and structural observations show a 13-nm overall interaction distance of myosin with actin, including a final 4-to 6-nm power stroke when the catalytic domain is fixed on actin. Raising fiber temperature with both perturbation techniques accelerates the forward, but slows the reverse rate constant of tension generation, kinetics akin to the unfolding/folding of small proteins. Decreasing strain, however, causes both forward and reverse rate constants to increase. Despite these changes in rate, the equilibrium constant is strain-insensitive. Activation enthalpy and entropy data show this invariance to be the result of enthalpy entropy compensation. Reaction amplitudes confirm a strain-invariant equilibrium constant and thus a strain-insensitive ratio of pretension-to tension-generating states as work is done. C1 [Davis, Julien S.; Epstein, Neal D.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Davis, JS (reprint author), NHLBI, Mol Cardiol Lab, NIH, 10 Ctr Dr,MSC 1760,Bldg 10,Room 8N212, Bethesda, MD 20892 USA. EM davisjs@mail.nih.gov FU National Heart, Lung, and Blood Institute; National Institutes of Health FX We thank Drs. Paul Blank, Banu Ozkan, and Steve Winitsky for discussions and comments on the manuscript and graphic artist Ethan Tyler for Fig. 5. This work was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 49 TC 15 Z9 15 U1 4 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 APR 14 PY 2009 VL 106 IS 15 BP 6140 EP 6145 DI 10.1073/pnas.0812487106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 433AB UT WOS:000265174600022 PM 19325123 ER PT J AU Zhang, F Tang, ZS Hou, X Lennartsson, J Li, Y Koch, AW Scotney, P Lee, C Arjunan, P Dong, LJ Kumar, A Rissanen, TT Wang, B Nagai, N Fons, P Fariss, R Zhang, YQ Wawrousek, E Tansey, G Raber, J Fong, GH Ding, H Greenberg, DA Becker, KG Herbert, JM Nash, A Yla-Herttuala, S Cao, YH Watts, RJ Li, XR AF Zhang, Fan Tang, Zhongshu Hou, Xu Lennartsson, Johan Li, Yang Koch, Alexander W. Scotney, Pierre Lee, Chunsik Arjunan, Pachiappan Dong, Lijin Kumar, Anil Rissanen, Tuomas T. Wang, Bin Nagai, Nobuo Fons, Pierre Fariss, Robert Zhang, Yongqing Wawrousek, Eric Tansey, Ginger Raber, James Fong, Guo-Hua Ding, Hao Greenberg, David A. Becker, Kevin G. Herbert, Jean-Marc Nash, Andrew Yla-Herttuala, Seppo Cao, Yihai Watts, Ryan J. Li, Xuri TI VEGF-B is dispensable for blood vessel growth but critical for their survival, and VEGF-B targeting inhibits pathological angiogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE apoptosis; vascular survival; ocular neovascularization ID HYPOXIC PULMONARY-HYPERTENSION; IN-VIVO; FAMILY-MEMBERS; MICE; GENE; PERMEABILITY; NEUROPILIN-1; LETHALITY; ISCHEMIA; LACKING AB VEGF-B, a homolog of VEGF discovered a long time ago, has not been considered an important target in antiangiogenic therapy. Instead, it has received little attention from the field. In this study, using different animal models and multiple types of vascular cells, we revealed that although VEGF-B is dispensable for blood vessel growth, it is critical for their survival. Importantly, the survival effect of VEGF-B is not only on vascular endothelial cells, but also on pericytes, smooth muscle cells, and vascular stem/progenitor cells. In vivo, VEGF-B targeting inhibited both choroidal and retinal neovascularization. Mechanistically, we found that the vascular survival effect of VEGF-B is achieved by regulating the expression of many vascular prosurvival genes via both NP-1 and VEGFR-1. Our work thus indicates that the function of VEGF-B in the vascular system is to act as a "survival,'' rather than an "angiogenic'' factor and that VEGF-B inhibition may offer new therapeutic opportunities to treat neovascular diseases. C1 [Zhang, Fan; Tang, Zhongshu; Hou, Xu; Li, Yang; Lee, Chunsik; Arjunan, Pachiappan; Dong, Lijin; Kumar, Anil; Fariss, Robert; Wawrousek, Eric; Tansey, Ginger; Raber, James; Li, Xuri] NEI, NIH, Bethesda, MD 20892 USA. [Lennartsson, Johan] Uppsala Univ, Ludwig Inst Canc Res, SE-75124 Uppsala, Sweden. [Koch, Alexander W.; Watts, Ryan J.] Genentech Inc, Prot Chem, Neurodegenerat Labs, San Francisco, CA 94080 USA. [Scotney, Pierre; Nash, Andrew] CSL Ltd, Parkville, Vic 3052, Australia. [Rissanen, Tuomas T.; Yla-Herttuala, Seppo] Univ Kuopio, Dept Biotechnol & Mol Med, FIN-70211 Kuopio, Finland. [Wang, Bin] Weifang Med Univ, Affiliated Hosp, Med Imaging Ctr, Dept Radiol, Weifang 261042, Peoples R China. [Nagai, Nobuo] Kinki Univ, Sch Med, Dept Physiol, Osaka 5898511, Japan. [Fons, Pierre; Herbert, Jean-Marc] Sanofi Aventis Rech, Cardiovasc Thrombosis Res Dept, F-31036 Toulouse, France. [Zhang, Yongqing; Becker, Kevin G.] NIA, TRIAD Technol Ctr, NIH, Baltimore, MD 21224 USA. [Fong, Guo-Hua] Univ Connecticut, Ctr Vasc Biol, Farmington, CT 06030 USA. [Ding, Hao] Univ Manitoba, Dept Biochem & Med Genet, Winnipeg, MB R3E 3P5, Canada. [Greenberg, David A.] Buck Inst Age Res, Novato, CA 94945 USA. [Cao, Yihai] Karolinska Inst, Dept Microbiol, S-17177 Stockholm, Sweden. RP Li, XR (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM lixur@nei.nih.gov RI Kumar, Anil/K-8504-2012; OI Becker, Kevin/0000-0002-6794-6656 FU National Institutes of Health; National Institute on Aging; National Eye Institute FX We thank Dr. Ken-ichi Hosoya at the Faculty of Pharmaceutical Sciences, University of Toyama, Japan, for kindly providing the rat retinal cell lines. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging and the National Eye Institute. NR 30 TC 124 Z9 128 U1 1 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 14 PY 2009 VL 106 IS 15 BP 6152 EP 6157 DI 10.1073/pnas.0813061106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 433AB UT WOS:000265174600024 PM 19369214 ER PT J AU Puxeddu, E Uhart, M Li, CC Ahmad, F Pacheco-Rodriguez, G Manganiello, VC Moss, J Vaughan, M AF Puxeddu, Ermanno Uhart, Marina Li, Chun-Chun Ahmad, Faiyaz Pacheco-Rodriguez, Gustavo Manganiello, Vincent C. Moss, Joel Vaughan, Martha TI Interaction of phosphodiesterase 3A with brefeldin A-inhibited guanine nucleotide-exchange proteins BIG1 and BIG2 and effect on ARF1 activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ADP-RIBOSYLATION FACTORS; KINASE-A; SIGNALING COMPLEXES; SEC7 DOMAIN; ACTIVATION; PHOSPHORYLATION; IDENTIFICATION; TRANSPORT; PKA AB ADP-ribosylation factors (ARFs) have crucial roles in vesicular trafficking. Brefeldin A-inhibited guanine nucleotide-exchange proteins (BIG) 1 and BIG2 catalyze the activation of class I ARFs by accelerating replacement of bound GDP with GTP. Several additional and differing actions of BIG1 and BIG2 have been described. These include the presence in BIG2 of 3 A kinase-anchoring protein (AKAP) domains, one of which is identical in BIG1. Proteins that contain AKAP sequences act as scaffolds for the assembly of PKA with other enzymes, substrates, and regulators in complexes that constitute molecular machines for the reception, transduction, and integration of signals from cAMP or other sources, which are initiated, propagated, and transmitted by chemical, electrical, or mechanical means. Specific depletion of HeLa cell PDE3A with small interfering RNA significantly decreased membrane-associated BIG1 and BIG2, which by confocal immunofluorescence microscopy were widely dispersed from an initial perinuclear Golgi concentration. Concurrently, activated ARF1-GTP was significantly decreased. Selective inhibition of PDE3A by 1-h incubation of cells with cilostamide similarly decreased membrane-associated BIG1. We suggest that decreasing PDE3A allowed cAMP to accumulate in microdomains where its enzymatic activity limited cAMP concentration. There, cAMP-activated PKA phosphorylated BIG1 and BIG2 (AKAPs for assembly of PKA, PDE3A, and other molecules), which decreased their GEP activity and thereby amounts of activated ARF1-GTP. Thus, PDE3A in these BIG1 and BIG2 AKAP complexes may contribute to the regulation of ARF function via limitation of cAMP effects with spatial and temporal specificity. C1 [Puxeddu, Ermanno; Uhart, Marina; Li, Chun-Chun; Ahmad, Faiyaz; Pacheco-Rodriguez, Gustavo; Manganiello, Vincent C.; Moss, Joel; Vaughan, Martha] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Vaughan, M (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM vaughanm@mail.nih.gov RI Puxeddu, Ermanno/K-8777-2016 OI Puxeddu, Ermanno/0000-0002-5486-7764 FU National Institutes of Health National Heart, Lung, and Blood Institute FX We thank Dr. Christian Combs and Dr. Daniela Malide (National Heart, Lung, and Blood Institute Confocal Microscopy Core Facility) for invaluable help. This work was supported by the Intramural Research Program of the National Institutes of Health National Heart, Lung, and Blood Institute. NR 32 TC 18 Z9 20 U1 1 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 APR 14 PY 2009 VL 106 IS 15 BP 6158 EP 6163 DI 10.1073/pnas.0901558106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 433AB UT WOS:000265174600025 PM 19332778 ER PT J AU Wang, Y DiGiovanna, JJ Stern, JB Hornyak, TJ Raffeld, M Khan, SG Oh, KS Hollander, MC Dennis, PA Kraemer, KH AF Wang, Yun DiGiovanna, John J. Stern, Jere B. Hornyak, Thomas J. Raffeld, Mark Khan, Sikandar G. Oh, Kyu-Seon Hollander, M. Christine Dennis, Philip A. Kraemer, Kenneth H. TI Evidence of ultraviolet type mutations in xeroderma pigmentosum melanomas SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA repair; ultraviolet radiation; PTEN; skin cancer; laser capture microdissection ID DNA-POLYMERASE-IOTA; CUTANEOUS MELANOMA; SKIN-CANCER; MALIGNANT-MELANOMA; PTEN/MMAC1 ALTERATIONS; PTEN EXPRESSION; HIGH-FREQUENCY; CELL LINES; P53 GENE; RADIATION AB To look for a direct role of ultraviolet radiation (UV) exposure in cutaneous melanoma induction, we studied xeroderma pigmentosum (XP) patients who have defective DNA repair resulting in a 1000-fold increase in melanoma risk. These XP melanomas have the same anatomic distribution as melanomas in the general population. We analyzed laser capture microdissection samples of skin melanomas from XP patients studied at the National Institutes of Health. The tumor suppressor gene PTEN was sequenced and analyzed for UV-induced mutations. Samples from 59 melanomas ( 47 melanomas in situ and 12 invasive melanomas) from 8 XP patients showed mutations in the PTEN tumor suppressor gene in 56% of the melanomas. Further, 91% of the melanomas with mutations had 1 to 4 UV type base substitution mutations ( occurring at adjacent pyrimidines) (P < 0.0001 compared to random mutations). We found a high frequency of amino-acid-altering mutations in the melanomas and demonstrated that these mutations impaired PTEN function; UV damage plays a direct role in induction of mutations and in inactivation of the PTEN gene in XP melanomas including in situ, the earliest stage of melanoma. This gene is known to be a key regulator of carcinogenesis and therefore these data provide solid mechanistic support for UV protection for prevention of melanoma. C1 [Wang, Yun; DiGiovanna, John J.; Khan, Sikandar G.; Oh, Kyu-Seon; Kraemer, Kenneth H.] NCI, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Stern, Jere B.; Raffeld, Mark] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Hornyak, Thomas J.] NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Dennis, Philip A.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [DiGiovanna, John J.] Brown Univ, Warren Alpert Med Sch, Dept Dermatol, Div Dermatopharmacol, Providence, RI 02912 USA. RP Kraemer, KH (reprint author), NCI, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM kraemerk@nih.gov FU Intramural NIH HHS NR 56 TC 43 Z9 44 U1 1 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 APR 14 PY 2009 VL 106 IS 15 BP 6279 EP 6284 DI 10.1073/pnas.0812401106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 433AB UT WOS:000265174600046 PM 19329485 ER PT J AU Thaler, C Koushik, SV Puhl, HL Blank, PS Vogel, SS AF Thaler, Christopher Koushik, Srinagesh V. Puhl, Henry L., III Blank, Paul S. Vogel, Steven S. TI Structural rearrangement of CaMKII alpha catalytic domains encodes activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anisotropy; calcium; FRET; switch; memory ID PROTEIN-KINASE-II; FLUORESCENT PROTEINS; ASSOCIATION DOMAIN; DENDRITIC SPINES; LIVING CELLS; TRANSLOCATION; NEURONS; FRET; PHOSPHORYLATION; OLIGOMERIZATION AB At its fundamental level, human memory is thought to occur at individual synaptic contact sites and manifest as persistent changes in synaptic efficacy. In digital electronics, the fundamental structure for implementing memory is the flip-flop switch, a circuit that can be triggered to flip between two stable states. Recently, crystals of Ca(2+)/calmodulin-dependent protein kinase II alpha (CaMKII alpha) catalytic domains, the enzymatic portion of a dodecameric holoenzyme involved in memory, were found to form dimers [Rosenberg OS, Deindl S, Sung RJ, Nairn AC, Kuriyan J (2005) Structure of the autoinhibited kinase domain of CaMKII and SAXS analysis of the holoenzyme. Cell 123:849-860]. Although the formation of dimers in the intact holoenzyme has not been established, several features of the crystal structure suggest that dimers could act as a synaptic switch. ATP-binding sites were occluded, and the T286 autophosphorylation site responsible for persistent kinase activation was buried. These features would act to stabilize an autoinhibited "paired''-enzyme state. Ca(2+)-calmodulin binding was postulated to trigger the formation of an active state with unpaired catalytic domains. This conformation would allow ATP access and expose T286, autophosphorylation of which would act to maintain the "unpaired'' conformation. We used fluorescence anisotropy and FRET imaging of Venus-tagged CaMKII alpha to test the hypothesis that neuronal CaMKII alpha can flip between two stable conformations in living cells. Our data support the existence of catalytic domain pairs, and glutamate receptor activation in neurons triggered an increase in anisotropy consistent with a structural transition from a paired to unpaired conformation. NEUROSCIENCE C1 [Thaler, Christopher; Koushik, Srinagesh V.; Puhl, Henry L., III; Vogel, Steven S.] NIAAA, Bethesda, MD 20892 USA. [Blank, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. RP Vogel, SS (reprint author), NIAAA, 5625 Fishers Lane, Bethesda, MD 20892 USA. EM stevevog@mail.nih.gov RI Vogel, Steven/A-3585-2012; OI Puhl, Henry/0000-0003-3095-7201 FU National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health FX We thank Drs. S. Ikeda, D. Lovinger, R. Costa, and R. Colbran for critically reading this manuscript and Drs. H. Chen and M. Davis for guidance. This work was supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 33 TC 35 Z9 35 U1 1 U2 8 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 APR 14 PY 2009 VL 106 IS 15 BP 6369 EP 6374 DI 10.1073/pnas.0901913106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 433AB UT WOS:000265174600061 PM 19339497 ER PT J AU Gautam, D Jeon, J Starost, MF Han, SJ Hamdan, FF Cui, YH Parlow, AF Gavrilova, O Szalayova, I Mezey, E Wess, J AF Gautam, Dinesh Jeon, Jongrye Starost, Matthew F. Han, Sung-Jun Hamdan, Fadi F. Cui, Yinghong Parlow, Albert F. Gavrilova, Oksana Szalayova, Ildiko Mezey, Eva Wess, Juergen TI Neuronal M-3 muscarinic acetylcholine receptors are essential for somatotroph proliferation and normal somatic growth SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anterior pituitary gland; dwarfism; knockout mice ID HORMONE-RELEASING-HORMONE; GHRH KNOCKOUT MOUSE; NERVOUS-SYSTEM; PITUITARY DEVELOPMENT; ANTERIOR-PITUITARY; TARGETED ABLATION; GENE-EXPRESSION; TRANSGENIC MICE; MOLECULAR-BASIS; SECRETION AB The molecular pathways that promote the proliferation and maintenance of pituitary somatotrophs and other cell types of the anterior pituitary gland are not well understood at present. However, such knowledge is likely to lead to the development of novel drugs useful for the treatment of various human growth disorders. Although muscarinic cholinergic pathways have been implicated in regulating somatotroph function, the physiological relevance of this effect and the localization and nature of the receptor subtypes involved in this activity remain unclear. We report the surprising observation that mutant mice that selectively lack the M-3 muscarinic acetylcholine receptor subtype in the brain (neurons and glial cells; Br-M3-KO mice) showed a dwarf phenotype associated with a pronounced hypoplasia of the anterior pituitary gland and a marked decrease in pituitary and serum growth hormone (GH) and prolactin. Remarkably, treatment of Br-M3-KO mice with CJC-1295, a synthetic GH-releasing hormone (GHRH) analog, rescued the growth deficit displayed by Br-M3-KO mice by restoring normal pituitary size and normal serum GH and IGF-1 levels. These findings, together with results from M-3 receptor/GHRH colocalization studies and hypothalamic hormone measurements, support a model in which central (hypothalamic) M-3 receptors are required for the proper function of hypothalamic GHRH neurons. Our data reveal an unexpected and critical role for central M-3 receptors in regulating longitudinal growth by promoting the proliferation of pituitary somatotroph cells. C1 [Gautam, Dinesh; Jeon, Jongrye; Han, Sung-Jun; Hamdan, Fadi F.; Cui, Yinghong; Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Starost, Matthew F.] NIH, Diagnost & Res Serv Branch, Off Director, Bethesda, MD 20892 USA. [Parlow, Albert F.] Harbor UCLA Med Ctr, Natl Hormone & Peptide Program, Torrance, CA 90509 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD 20892 USA. [Szalayova, Ildiko; Mezey, Eva] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov RI Han, Sung-Jun/B-9547-2012 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Dental and Craniofacial Research; National Institutes of Health FX We thank Drs. Karen Thibaudeau and Tom Ulich (ConjuChem, Montreal) for providing us with the CJC-1295 compound. This work was supported by the Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 43 TC 17 Z9 17 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 APR 14 PY 2009 VL 106 IS 15 BP 6398 EP 6403 DI 10.1073/pnas.0900977106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 433AB UT WOS:000265174600066 PM 19332789 ER PT J AU Wang, GJ Volkow, ND Fowler, JS AF Wang, Gene-Jack Volkow, Nora D. Fowler, Joanna S. TI Reply to Burgard: Gender differences in eating behaviors and obesity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Letter C1 [Wang, Gene-Jack; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Wang, Gene-Jack; Fowler, Joanna S.] NIAAA, Natl Inst Drug Abuse, Rockville, MD 20857 USA. [Volkow, Nora D.] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. RP Wang, GJ (reprint author), Brookhaven Natl Lab, Dept Med, 30 Bell Ave, Upton, NY 11973 USA. EM gjwang@bnl.gov NR 6 TC 2 Z9 2 U1 0 U2 1 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 APR 14 PY 2009 VL 106 IS 15 BP E37 EP E37 DI 10.1073/pnas.0901996106 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 433AB UT WOS:000265174600074 ER PT J AU Liu, Y Belkina, NV Shaw, S AF Liu, Yin Belkina, Natalya V. Shaw, Stephen TI HIV Infection of T Cells: Actin-in and Actin-out SO SCIENCE SIGNALING LA English DT Article ID ERM PROTEINS; VIRUS ENTRY; CYTOSKELETON; SYNAPSE; PHOSPHORYLATION; LYMPHOCYTES; RECEPTORS; MEMBRANE; SPREAD; CORTEX AB Three studies shed light on the decade-old observation that the actin cytoskeleton is hijacked to facilitate entry of HIV into its target cells. Polymerization of actin is required to assemble high concentrations of CD4 and CXCR4 at the plasma membrane, which promote viral binding and entry in both the simple model of infection by free virus and the more physiologically relevant route of infection through the virological synapse. Three types of actin-interacting proteins-filamin, ezrin/radixin/moesin (ERM), and cofilin-are now shown to play critical roles in this process. Filamin binds to both CD4 and CXCR4 in a manner promoted by signaling of the HIV gp120 glycoprotein. ERM proteins attach actin filaments to the membrane and may promote polymerization of actin. Early in the process of viral entry, cofilin is inactivated, which is proposed to facilitate the early assembly of actin filaments, but cofilin is reported to be activated soon thereafter to facilitate postentry events. This complex role of cofilin may help to reconcile the paradox that actin polymerization promotes initial binding and fusion steps but inhibits some subsequent early postentry events. C1 [Liu, Yin; Belkina, Natalya V.; Shaw, Stephen] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Shaw, S (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM sshaw@nih.gov FU Intramural NIH HHS NR 27 TC 27 Z9 28 U1 3 U2 10 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 APR 14 PY 2009 VL 2 IS 66 AR pe23 DI 10.1126/scisignal.266pe23 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 567VF UT WOS:000275474200002 PM 19366992 ER PT J AU Tilburt, JC Curlin, FA Kaptchuk, TJ Clarridge, B Bolcic-Jankovic, D Emanuel, EJ Miller, FG AF Tilburt, Jon C. Curlin, Farr A. Kaptchuk, Ted J. Clarridge, Brian Bolcic-Jankovic, Dragana Emanuel, Ezekiel J. Miller, Franklin G. TI Alternative Medicine Research in Clinical Practice A US National Survey SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID COMPLEMENTARY MEDICINE; GENERAL-PRACTITIONERS; PHYSICIANS; UK; OSTEOARTHRITIS; EDUCATION; THERAPY; KNEE AB Background: Little is known about whether federally funded complementary and alternative medicine (CAM) research is translating into clinical practice. We sought to describe the awareness of CAM clinical trials, the ability to interpret research results, the acceptance of research evidence, and the predictors of trial awareness among US clinicians. Methods: We conducted a cross-sectional mailed survey of 2400 practicing US acupuncturists, naturopaths, internists, and rheumatologists. Results: A total of 1561 clinicians (65%) responded. Of the respondents, 59% were aware of at least 1 major CAM clinical trial; only 23% were aware of both trials. A minority of acupuncturists (20%), naturopaths (25%), internists (17%), and rheumatologists (33%) were "very confident" in interpreting research results (P <.001). Fewer acupuncturists (17%) and naturopaths (24%) than internists (58%) and rheumatologists (74%) rated the results of randomized controlled trials as "very useful" (P <.001). Twice as many internists (53%) and rheumatologists (64%) rated patient preferences as "least important" compared with acupuncturists (27%) and naturopaths (31%) (P <.001). In multivariate analyses, for clinicians aware of at least 1 trial, male sex (odds ratio [OR], 1.30 [95% confidence interval {CI}, 1.05-1.62]), prior research experience (OR, 1.45 [95% CI, 1.13-1.86]), institutional or academic practice setting (ORs, 1.98 [95% CI, 1.01-3.91], and 1.23 [95% CI, 0.73-2.09], respectively), and rating randomized trials as "very useful" (OR, 1.46 [95% CI, 1.12-1.91]) (P <.001) for clinical decision making were positively associated with CAM trial awareness. Acupuncturists, naturopaths, and internists (ORs, 0.15 [95% CI, 0.10-0.23], 0.15 [95% CI, 0.09-0.24], and 0.18 [95% CI, 0.12-0.28], respectively) were all similarly less aware of CAM trial results compared with rheumatologists. Conclusion: For clinical research in CAM to achieve its social value, concerted efforts must be undertaken to train clinicians and improve the dissemination of research results. C1 [Tilburt, Jon C.] Mayo Clin, Div Gen Internal Med, Rochester, MN 55905 USA. [Tilburt, Jon C.] Mayo Clin, Program Professionalism & Bioeth, Rochester, MN 55905 USA. [Tilburt, Jon C.; Miller, Franklin G.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. [Curlin, Farr A.] Univ Chicago, Sect Internal Med, Chicago, IL 60637 USA. [Curlin, Farr A.] Univ Chicago, McClean Ctr Clin Med Eth, Chicago, IL 60637 USA. [Kaptchuk, Ted J.] Harvard Univ, Sch Med, Osher Res Ctr, Boston, MA USA. [Clarridge, Brian; Bolcic-Jankovic, Dragana] Univ Massachusetts, Survey Res Ctr, Boston, MA 02125 USA. RP Tilburt, JC (reprint author), Mayo Clin, Div Gen Internal Med, 200 1st St SW, Rochester, MN 55905 USA. EM tilburt.jon@mayo.edu FU National Center for Complementary and Alternative Medicine and the Department of Bioethics; National Institutes of Health; National Center for Complementary and Alternative Medicine [1 K23 AT002749] FX Funding for this research was provided by the National Center for Complementary and Alternative Medicine and the Department of Bioethics, National Institutes of Health. Dr Curlin is supported by grant 1 K23 AT002749 from the National Center for Complementary and Alternative Medicine. NR 32 TC 19 Z9 19 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD APR 13 PY 2009 VL 169 IS 7 BP 670 EP 677 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 432AK UT WOS:000265105700004 PM 19364996 ER PT J AU Gao, SK Fitzpatrick, AL Psaty, B Jiang, R Post, W Cutler, J Maciejewski, ML AF Gao, Sue K. Fitzpatrick, Annette L. Psaty, Bruce Jiang, Rui Post, Wendy Cutler, Jeffrey Maciejewski, Matthew L. TI Suboptimal Nutritional Intake for Hypertension Control in 4 Ethnic Groups SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID BLOOD-PRESSURE; DIETARY PATTERNS; MULTIETHNIC COHORT; CLINICAL-TRIAL; ATHEROSCLEROSIS; POTASSIUM; ADULTS AB Background: This study compared intake of specific nutrients based on the Dietary Approaches to Stop Hypertension (DASH) guidelines for hypertension management among multiethnic middle-aged and older adults. Methods: We conducted quantitative analysis using baseline data of a prospective cohort study of 5972 adults aged 45 to 84 years recruited between July 2000 and August 2002 who participated in the Multi-Ethnic Study of Atherosclerosis (MESA). Diet information was collected using a 120-item food frequency questionnaire. Bivariate and multivariate methods were used to evaluate associations between DASH-accordant intake of each nutrient (fat, saturated fat, cholesterol, protein, fiber, calcium, magnesium, and potassium) with ethnicity and hypertension status. Results: Lessthan 30% of MESA participants met any DASH nutrient target. DASH accordance was lowest in saturated fat intake and highest in cholesterol intake(5.3% and 29.5% of the participants, respectively). Multivariate analyses showed significant ethnic differences in DASH accordance in all nutrients but saturated fat. Compared with white participants, Chinese American participants had greater DASH accordance in cholesterol (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.13-1.67) and protein intake (2.32; 1.55-3.49) but less in total fat (0.47; 0.30-0.74), magnesium (0.58; 0.51-0.67), and potassium intake(0.40; 0.20-0.81); African Americans and Hispanics had greater DASH accordance in fiber intake (1.36; 1.13-1.62; and 2.23; 1.53-3.23, respectively) but less in calcium intake (0.44; 0.37-0.52; and 0.79; 0.68-0.91, respectively). Diagnosed and uncontrolled hypertension was associated with less DASH accordance in saturated fat(OR, 0.80; 95% CI, 0.70-0.91) and magnesium(0.80; 0.71-0.91). DASH accordance differed significantly with and without inclusion of dietary supplements in the analysis. Conclusions: There is significant variation in DASH goal attainment among different ethnic groups. Assessments of nutrient intake that exclude dietary supplements may be underestimating DASH accordance. C1 [Gao, Sue K.] Amgen Inc, Thousand Oaks, CA 91320 USA. [Gao, Sue K.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Fitzpatrick, Annette L.; Psaty, Bruce] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Jiang, Rui] Columbia Univ, Dept Med, New York, NY USA. [Post, Wendy] Johns Hopkins Univ, Div Cardiol, Baltimore, MD USA. [Cutler, Jeffrey] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Maciejewski, Matthew L.] Duke Univ, Med Ctr, Ctr Hlth Serv Res Primary Care, Durham VA Med Ctr, Durham, NC USA. [Maciejewski, Matthew L.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Gao, SK (reprint author), Amgen Inc, 1 Amgen Ctr Dr,MS28-3A, Thousand Oaks, CA 91320 USA. EM sgao@amgen.com FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95165, N01-HC-95169]; National Center for Complementary and Alternative Medicine [1 R21 AT002152-01] FX This research was supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute and grant 1 R21 AT002152-01 from the National Center for Complementary and Alternative Medicine. NR 16 TC 22 Z9 23 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD APR 13 PY 2009 VL 169 IS 7 BP 702 EP 707 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 432AK UT WOS:000265105700008 PM 19365000 ER PT J AU Kalogeropoulos, A Georgiopoulou, V Kritchevsky, SB Psaty, BM Smith, NL Newman, AB Rodondi, N Satterfield, S Bauer, DC Bibbins-Domingo, K Smith, AL Wilson, PWF Vasan, RS Harris, TB Butler, J AF Kalogeropoulos, Andreas Georgiopoulou, Vasiliki Kritchevsky, Stephen B. Psaty, Bruce M. Smith, Nicholas L. Newman, Anne B. Rodondi, Nicolas Satterfield, Suzanne Bauer, Douglas C. Bibbins-Domingo, Kirsten Smith, Andrew L. Wilson, Peter W. F. Vasan, Ramachandran S. Harris, Tamara B. Butler, Javed TI Epidemiology of Incident Heart Failure in a Contemporary Elderly Cohort The Health, Aging, and Body Composition Study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID RISK-FACTORS; SURVIVAL; POPULATION; PREVALENCE; PROGNOSIS; ASSOCIATION; COMMUNITY; TRENDS; ADULTS; DEATH AB Background: The race- and sex-specific epidemiology of incident heart failure (HF) among a contemporary elderly cohort are not well described. Methods: We studied 2934 participants without HF enrolled in the Health, Aging, and Body Composition Study (mean [SD] age, 73.6 [2.9] years; 47.9% men; 58.6% white; and 41.4% black) and assessed the incidence of HF, population-attributable risk (PAR) of independent risk factors for HF, and outcomes of incident HF. Results: During a median follow-up of 7.1 years, 258 participants (8.8%) developed HF (13.6 cases per 1000 person-years; 95% confidence interval, 12.1-15.4). Men and black participants were more likely to develop HF. No significant sex-based differences were observed in risk factors. Coronary heart disease (PAR, 23.9% for white participants and 29.5% for black participants) and uncontrolled blood pressure (PAR, 21.3% for white participants and 30.1% for black participants) carried the highest PAR in both races. Among black participants, 6 of 8 risk factors assessed (smoking, increased heart rate, coronary heart disease, left ventricular hypertrophy, uncontrolled blood pressure, and reduced glomerular filtration rate) had more than 5% higher PAR compared with that among white participants, leading to a higher overall proportion of HF attributable to modifiable risk factors in black participants vs white participants (67.8% vs 48.9%). Participants who developed HF had higher annual mortality (18.0% vs 2.7%). No racial difference in survival after HF was noted; however, rehospitalization rates were higher among black participants (62.1 vs 30.3 hospitalizations per 100 person-years, P <.001). Conclusions: Incident HF is common in older persons; a large proportion of HF risk is attributed to modifiable risk factors. Racial differences in risk factors for HF and in hospitalization rates after HF need to be considered in prevention and treatment efforts. C1 [Kalogeropoulos, Andreas; Georgiopoulou, Vasiliki; Smith, Nicholas L.; Wilson, Peter W. F.; Butler, Javed] Emory Univ, Dept Med, Atlanta, GA 30322 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.] VA Puget Sound Hlth Care Syst, Seattle VA Epidemiol Res & Informat Ctr, Seattle, WA USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Rodondi, Nicolas] Univ Lausanne, Dept Ambulatory Care & Community Med, Lausanne, Switzerland. [Satterfield, Suzanne] Univ Memphis, Dept Prevent Med, Memphis, TN 38152 USA. [Bauer, Douglas C.; Bibbins-Domingo, Kirsten] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Vasan, Ramachandran S.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Harris, Tamara B.] NIA, Geriatr Epidemiol Sect, NIH, Bethesda, MD 20892 USA. RP Butler, J (reprint author), Emory Univ, Emory Univ Hosp, Div Cardiol, 1365 Clifton Rd NE,Ste AT430, Atlanta, GA 30322 USA. EM javed.butler@emory.edu RI Kalogeropoulos, Andreas/A-9494-2009; Newman, Anne/C-6408-2013; OI Kalogeropoulos, Andreas/0000-0002-1284-429X; Newman, Anne/0000-0002-0106-1150; Ramachandran, Vasan/0000-0001-7357-5970 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institutes of Health FX This study was supported in part by the Intramural Research Program of the National Institute on Aging and by grants N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 from the National Institute on Aging, National Institutes of Health. NR 36 TC 78 Z9 82 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD APR 13 PY 2009 VL 169 IS 7 BP 708 EP 715 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 432AK UT WOS:000265105700010 PM 19365001 ER PT J AU Hosui, A Kimura, A Yamaji, D Zhu, BM Na, R Hennighausen, L AF Hosui, Atsushi Kimura, Akiko Yamaji, Daisuke Zhu, Bing-mei Na, Risu Hennighausen, Lothar TI Loss of STAT5 causes liver fibrosis and cancer development through increased TGF-beta and STAT3 activation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID GROWTH-FACTOR-I; HEPATOCELLULAR-CARCINOMA; CONSTITUTIVE ACTIVATION; MESENCHYMAL TRANSITION; LYMPHOID DEVELOPMENT; CELL-PROLIFERATION; COMPLEMENTARY-DNA; HEPATIC-FIBROSIS; MAMMARY-GLAND; T-CELLS AB The molecular mechanisms underlying the development of hepatocellular carcinoma are not fully understood. Liver-specific signal transducer and activator of transcription (STAT) 5A/B-null mice (STAT5-LKO) were treated with carbon tetrachloride (CCl(4)), and histological analyses revealed liver fibrosis and tumors. Transforming growth factor (TGF)-beta levels and STAT3 activity were elevated in liver tissue from STAT5-LKO mice upon CCl(4) treatment. To define the molecular link between STAT5 silencing and TGF-beta up-regulation, as well as STAT3 activation, we examined STAT5-null mouse embryonic fibroblasts and primary hepatocytes. These cells displayed elevated TGF-beta protein levels, whereas messenger RNA levels remained almost unchanged. Protease inhibitor studies revealed that STAT5 deficiency enhanced the stability of mature TGF-beta. Immunoprecipitation and immunohistochemistry analyses demonstrated that STAT5, through its N-terminal sequences, could bind to TGF-beta and that retroviral-mediated overexpression of STAT5 decreased TGF-beta levels. To confirm the in vivo significance of the N-terminal domain of STAT5, we treated mice that expressed STAT5 lacking the N terminus (STAT5-Delta N) with CCl(4). STAT5-Delta N mice developed CCl(4)-induced liver fibrosis but no tumors. In conclusion, loss of STAT5 results in elevated TGF-beta levels and enhanced growth hormone-induced STAT3 activity. We propose that a deregulated STAT5-TGF-beta-STAT3 network contributes to the development of chronic liver disease. C1 [Hosui, Atsushi; Kimura, Akiko; Yamaji, Daisuke; Zhu, Bing-mei; Na, Risu; Hennighausen, Lothar] NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Hosui, Atsushi] Osaka Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Suita, Osaka 5650871, Japan. RP Hennighausen, L (reprint author), NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. EM hosui@gh.med.osaka-u.ac.jp; lotharh@mail.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health FX This work was supported by the intramural program of the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health. NR 54 TC 59 Z9 63 U1 0 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD APR 13 PY 2009 VL 206 IS 4 BP 819 EP 831 DI 10.1084/jem.20080003 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 444VX UT WOS:000266009600010 PM 19332876 ER PT J AU Price, DA Asher, TE Wilson, NA Nason, MC Brenchley, JM Metzler, IS Venturi, V Gostick, E Chattopadhyay, PK Roederer, M Davenport, MP Watkins, DI Douek, DC AF Price, David A. Asher, Tedi E. Wilson, Nancy A. Nason, Martha C. Brenchley, Jason M. Metzler, Ian S. Venturi, Vanessa Gostick, Emma Chattopadhyay, Pratip K. Roederer, Mario Davenport, Miles P. Watkins, David I. Douek, Daniel C. TI Public clonotype usage identifies protective Gag-specific CD8(+) T cell responses in SIV infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MAJOR HISTOCOMPATIBILITY COMPLEX; STRUCTURALLY CONSTRAINED EPITOPE; CLASS-I MOLECULE; MHC-CLASS-I; CROSS-REACTIVITY; IMMUNE-RESPONSES; CTL ESCAPE; ANTIRETROVIRAL TREATMENT; LYMPHOCYTE RESPONSES AB Despite the pressing need for an AIDS vaccine, the determinants of protective immunity to HIV remain concealed within the complexity of adaptive immune responses. We dissected immunodominant virus-specific CD8(+) T cell populations in Mamu-A*01(+) rhesus macaques with primary SIV infection to elucidate the hallmarks of effective immunity at the level of individual constituent clonotypes, which were identified according to the expression of distinct T cell receptors (TCRs). The number of public clonotypes, defined as those that expressed identical TCR beta-chain amino acid sequences and recurred in multiple individuals, contained within the acute phase CD8(+) T cell population specific for the biologically constrained Gag CM9 (CTPYDINQM; residues 181-189) epitope correlated negatively with the virus load set point. This independent molecular signature of protection was confirmed in a prospective vaccine trial, in which clonotype engagement was governed by the nature of the antigen rather than the context of exposure and public clonotype usage was associated with enhanced recognition of epitope variants. Thus, the pattern of antigen-specific clonotype recruitment within a protective CD8(+) T cell population is a prognostic indicator of vaccine efficacy and biological outcome in an AIDS virus infection. C1 [Price, David A.; Asher, Tedi E.; Brenchley, Jason M.; Metzler, Ian S.; Chattopadhyay, Pratip K.; Roederer, Mario; Douek, Daniel C.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Nason, Martha C.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Brenchley, Jason M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Price, David A.; Gostick, Emma] Cardiff Univ, Sch Med, Dept Med Biochem & Immunol, Cardiff CF14 4XN, S Glam, Wales. [Wilson, Nancy A.; Watkins, David I.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53711 USA. [Venturi, Vanessa; Davenport, Miles P.] Univ New S Wales, Ctr Vasc Res, Sydney, NSW 2052, Australia. RP Price, DA (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dprice1@mail.nih.gov; ddouek@mail.nih.gov RI Chattopadhyay, Pratip/B-9227-2008; Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Chattopadhyay, Pratip/0000-0002-5457-9666 FU Intramural Research Program of the Vaccine Research Center; National Institute of Allergy and Infectious Diseases; National Institutes of Health; Australian Research Council; Medical Research Council (UK) FX This work was supported by the Intramural Research Program of the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and by the Australian Research Council. D. A. Price is a Medical Research Council (UK) Senior Clinical Fellow. M. P. Davenport is a Sylvia and Charles Viertel Senior Medical Research Fellow. NR 64 TC 89 Z9 90 U1 0 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD APR 13 PY 2009 VL 206 IS 4 BP 923 EP 936 DI 10.1084/jem.20081127 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 444VX UT WOS:000266009600017 PM 19349463 ER PT J AU Webster, JA Gibbs, JR Clarke, J Ray, M Zhang, WX Holmans, P Rohrer, K Zhao, A Marlowe, L Kaleem, M McCorquodale, DS Cuello, C Leung, D Bryden, L Nath, P Zismann, VL Joshipura, K Huentelman, MJ Hu-Lince, D Coon, KD Craig, DW Pearson, JV Heward, CB Reiman, EM Stephan, D Hardy, J Myers, AJ AF Webster, Jennifer A. Gibbs, J. Raphael Clarke, Jennifer Ray, Monika Zhang, Weixiong Holmans, Peter Rohrer, Kristen Zhao, Alice Marlowe, Lauren Kaleem, Mona McCorquodale, Donald S., III Cuello, Cindy Leung, Doris Bryden, Leslie Nath, Priti Zismann, Victoria L. Joshipura, Keta Huentelman, Matthew J. Hu-Lince, Diane Coon, Keith D. Craig, David W. Pearson, John V. Heward, Christopher B. Reiman, Eric M. Stephan, Dietrich Hardy, John Myers, Amanda J. CA NACC-Neuropathol Grp TI Genetic Control of Human Brain Transcript Expression in Alzheimer Disease SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; MULTILOCUS GENOTYPE DATA; RISK; ONSET; MAPT; INFERENCE; VARIANTS; PROTEINS; TISSUES; LOCI AB We recently surveyed the relationship between the human brain transcriptome and genome in a series of neuropathologically normal postmortem samples. We have now analyzed additional samples with a confirmed pathologic diagnosis of late-onset Alzheimer disease (LOAD; final n = 188 controls, 176 cases). Nine percent of the cortical transcripts that we analyzed had expression profiles correlated with their genotypes in the combined cohort, and approximately 5% of transcripts had SNP-transcript relationships that Could distinguish LOAD samples. Two of these transcripts have been previously implicated in LOAD candidate-gene SNP-expression screens. This study shows how the relationship between common inherited genetic variants and brain transcript expression can be used in the study of human brain disorders. We suggest that studying the transcriptome as a quantitative endo-phenotype has greater power for discovering risk SNPs influencing expression than the use of discrete diagnostic categories such as presence or absence of disease. C1 [McCorquodale, Donald S., III; Cuello, Cindy; Myers, Amanda J.] Univ Miami, Miller Sch Med, Div Neurosci, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. [Webster, Jennifer A.; Zismann, Victoria L.; Joshipura, Keta; Huentelman, Matthew J.; Hu-Lince, Diane; Coon, Keith D.; Craig, David W.; Pearson, John V.; Reiman, Eric M.; Stephan, Dietrich] Translat Genom Res Inst, Neurogenom Div, Phoenix, AZ 85004 USA. [Webster, Jennifer A.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Gibbs, J. Raphael; Rohrer, Kristen; Zhao, Alice; Marlowe, Lauren; Kaleem, Mona; Leung, Doris; Bryden, Leslie; Nath, Priti; Hardy, John] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Gibbs, J. Raphael; Hardy, John] UCL, Inst Neurol, Reta Lila Weston Inst, London WC1N 3BG, England. [Gibbs, J. Raphael; Hardy, John] UCL, Inst Neurol, Dept Mol Neurosci & Neurodegenerat Dis, London WC1N 3BG, England. [Clarke, Jennifer] Univ Miami, Miller Sch Med, Dept Epidemiol & Publ Hlth, Sch Med, Miami, FL 33133 USA. [Zhang, Weixiong] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Ray, Monika; Zhang, Weixiong] Washington Univ, Dept Comp Sci & Engn, St Louis, MO 63130 USA. [Holmans, Peter] Cardiff Univ, Dept Psychol Med, Biostat & Bioinformat Unit, Cardiff CF14 4XN, S Glam, Wales. [Coon, Keith D.] St Josephs Hosp, Div Thorac Oncol Res, Phoenix, AZ 85013 USA. [Heward, Christopher B.] Kronos Sci Lab, Phoenix, AZ 85016 USA. [Reiman, Eric M.; Stephan, Dietrich] Banner Alzheimers Inst, Phoenix, AZ 85006 USA. [Myers, Amanda J.] Johnnie B Byrd Sr Alzheimers Ctr & Res Inst, Tampa, FL 33613 USA. RP Myers, AJ (reprint author), Univ Miami, Miller Sch Med, Div Neurosci, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. EM amyers@med.miami.edu RI Hardy, John/C-2451-2009; Myers, Amanda/B-1796-2010; Gibbs, J. Raphael/A-3984-2010; Holmans, Peter/F-4518-2015; Pearson, John/F-2249-2011; Leung, Doris/R-5447-2016; OI Myers, Amanda/0000-0002-3100-9396; Holmans, Peter/0000-0003-0870-9412; Pearson, John/0000-0003-0904-4598; Leung, Doris/0000-0002-2558-7798; Clarke, Jennifer/0000-0002-2723-7249 FU Medical Research Council [G0701075]; NIA NIH HHS [P30 AG019610, U01 AG016976]; NINDS NIH HHS [R01 NS059873] NR 44 TC 136 Z9 138 U1 2 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD APR 10 PY 2009 VL 84 IS 4 BP 445 EP 458 DI 10.1016/j.ajhg.2009.03.011 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 433VB UT WOS:000265232800003 PM 19361613 ER PT J AU Tanaka, T Scheet, P Giusti, B Bandinelli, S Piras, MG Usala, G Lai, S Mulas, A Corsi, AM Vestrini, A Sofi, F Gori, AM Abbate, R Guralnik, J Singleton, A Abecasis, GR Schlessinger, D Uda, M Ferrucci, L AF Tanaka, Toshiko Scheet, Paul Giusti, Betti Bandinelli, Stelfania Piras, Maria Grazia Usala, Gianluca Lai, Sandra Mulas, Antonella Corsi, Anna Maria Vestrini, Anna Sofi, Francesco Gori, Anna Maria Abbate, Rosanna Guralnik, Jack Singleton, Andrew Abecasis, Goncalo R. Schlessinger, David Uda, Manuela Ferrucci, Luigi TI Genome-wide Association Study of Vitamin B6, Vitamin B12, Folate, and Homocysteine Blood Concentrations SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CORONARY-HEART-DISEASE; NEURAL-TUBE DEFECTS; ALKALINE-PHOSPHATASE GENE; ONE-CARBON METABOLISM; HELICOBACTER-PYLORI; CARDIOVASCULAR-DISEASE; VASCULAR-DISEASE; DNA METHYLATION; SYNAPTOTAGMIN-I; COMMON MUTATION AB The B vitamins are components of one-carbon metabolism (OCM) that contribute to DNA synthesis and methylation. Homocysteine, a by-product of OCM, has been associated with coronary heart disease, stroke and neurological disease. To investigate genetic factors that affect circulating vitamin B6, vitamin B12, folate and homocysteine, a genome-wide association analysis was conducted in the InCHIANTI (N = 1175), SardiNIA (N = 1115), and BLSA (N = 640) studies. The top loci were replicated in an independent sample of 687 participants in the Progetto Nutrizione study. Polymorphisms in the ALPL gene (rs4654748, p = 8.30 x 10(-18)) were associated with vitamin B6 and FUT2 (rs6022662, p = 2.83 x 10(-20)) with vitamin B12 serum levels. The association of MTHFR, a gene consistently associated with homocysteine, was confirmed in this meta-analysis. The ALPL gene likely influences the catabolism of vitamin B6 while FUT2 interferes with absorption of vitamin B12. These findings highlight mechanisms that affect vitamin B6, vitamin B12 and homocysteine serum levels. C1 [Tanaka, Toshiko] Medstar Res Inst, Baltimore, MD 21250 USA. [Tanaka, Toshiko; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21250 USA. [Scheet, Paul] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Giusti, Betti; Vestrini, Anna; Sofi, Francesco; Gori, Anna Maria; Abbate, Rosanna] Univ Florence, Dept Med & Surg Crit Care, I-50134 Florence, Italy. [Bandinelli, Stelfania] ASF, Geriatr Unit, I-50125 Florence, Italy. [Piras, Maria Grazia; Usala, Gianluca; Lai, Sandra; Mulas, Antonella; Uda, Manuela] CNR, Ist Neurogenet & Neurofarmacol, I-09042 Cagliari, Italy. [Corsi, Anna Maria] Tuscany Reg Hlth Agcy, I-50134 Florence, Italy. [Gori, Anna Maria] IRCCS, Fdn Don Carlo Gnocchi, Ctr S Maria Ulivi, I-50134 Florence, Italy. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Schlessinger, David] NIA, Gerontol Res Ctr, Baltimore, MD 21250 USA. RP Tanaka, T (reprint author), Medstar Res Inst, Baltimore, MD 21250 USA. EM tanakato@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Abecasis, Goncalo/B-7840-2010; Sofi, Francesco/J-3941-2016; Giusti, Betti/K-6978-2016; OI Sofi, Francesco/0000-0001-7113-7424; Giusti, Betti/0000-0002-8708-9444; Mulas, Antonella/0000-0002-6856-1483; Gori, annamaria.gori@unifi.it/0000-0001-6857-5861; piras, maria grazia/0000-0001-9004-0900; Abecasis, Goncalo/0000-0003-1509-1825 FU Italian Ministry of Health [ICS110.1/RF97.71]; U.S. National Institute on Aging [263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002]; National Institute on Aging, National Institutes of Health (NIH), Baltimore, Maryland; MedStar Research Institute; NIA [NO1-AG-1-2109]; Genopolis government FIRB [RBLA038RMA_008] FX The InCHIANTI study baseline (1998-2000) was supported as a "targeted project" (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the U.S. National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336); the InCHIANTI Follow-up 1 (2001-2003) was funded by the U.S. National Institute on Aging (Contracts: N.1-AG-1-1 and N.1-AG-1-2111); the InCHIANTI Follow-ups 2 and 3 studies (2004-2010) were financed by the U.S. National Institute on Aging(Contract: N01-AG-5-0002). BLSA and InCHIANTI were supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH), Baltimore, Maryland. A portion of that support was through a R&D contract with MedStar Research Institute. The SardiNIA team was supported by Contract NO1-AG-1-2109 from the NIA. The replication experiments were supported by a grant from Genopolis government FIRB project (RBLA038RMA_008). NR 48 TC 107 Z9 110 U1 2 U2 13 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 APR 10 PY 2009 VL 84 IS 4 BP 477 EP 482 DI 10.1016/j.ajhg.2009.02.011 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 433VB UT WOS:000265232800006 PM 19303062 ER PT J AU Horak, M Wenthold, RJ AF Horak, Martin Wenthold, Robert J. TI Different Roles of C-terminal Cassettes in the Trafficking of Full-length NR1 Subunits to the Cell Surface SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ER RETENTION SIGNAL; NMDA RECEPTOR SUBUNITS; D-ASPARTATE RECEPTORS; ENDOPLASMIC-RETICULUM; SPLICE VARIANTS; TRANSMEMBRANE PROTEINS; PHOSPHORYLATION; EXPRESSION; IDENTIFICATION; DELIVERY AB N-Methyl-D-aspartate (NMDA) receptors are glutamategated ion channels composed of NR1 and NR2 subunits. When expressed alone, the most prevalent NR1 splice variant and all NR2 subunits are retained in the endoplasmic reticulum (ER), whereas other NR1 splice variants reach the cell surface to varying degrees. Because similar trafficking patterns have been seen for single transmembrane domain chimeric proteins with appended C termini of NMDA receptor subunits, these chimeric proteins have been used as a model for studying the mechanisms underlying the ER retention and surface trafficking of NMDA receptors. Using this approach, an RRR motif in the C1 cassette has been identified as a major ER retention signal present in NR1 subunits, and the surface localization of other NR1 splice variants has been explained by the absence of the C1 cassette or by the presence of a PDZ/coatomer protein complex II-binding domain in the C2' cassette. However, when we tested these conclusions using full-length NR1 constructs, a more complex role of the C-terminal cassettes in the trafficking of NR1 subunits emerged. Our experiments showed that two independent ER retention motifs in the C1 cassette, KKK and RRR, are the signals mediating ER retention of the full-length NR1 subunits and that the C2 cassette has an additional inhibitory effect on the forward trafficking of NR1 subunits. On the other hand, C0 and C2' cassettes had an enhancing effect on the trafficking of NR1 subunits to the cell surface. Our observations identify the unique roles of C-terminal cassettes in the trafficking of full-length NR1 subunits. C1 [Horak, Martin; Wenthold, Robert J.] NIDCD, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Horak, M (reprint author), NIDCD, Neurochem Lab, NIH, Rm 4146,50 S Dr, Bethesda, MD 20892 USA. EM horakm@nidcd.nih.gov RI Horak, Martin/F-9819-2010; Horak, Martin/A-7297-2010 FU National Institutes of Health NIDCD Intramural Program FX This work was supported, in whole or in part, by the National Institutes of Health NIDCD Intramural Program. NR 29 TC 33 Z9 34 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 10 PY 2009 VL 284 IS 15 BP 9683 EP 9691 DI 10.1074/jbc.M807050200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429AJ UT WOS:000264892900008 PM 19188369 ER PT J AU Sakamoto, K Ito, Y Hatanaka, T Soni, PB Mori, T Sugimura, K AF Sakamoto, Kotaro Ito, Yuji Hatanaka, Takaaki Soni, Preeti Brijiral Mori, Toshiyuki Sugimura, Kazuhisa TI Discovery and Characterization of a Peptide Motif That Specifically Recognizes a Non-native Conformation of Human IgG Induced by Acidic pH Conditions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MONOCLONAL-ANTIBODIES; PHAGE DISPLAY; PROTEIN-A; AFFINITY PURIFICATION; SYNTHETIC LIGAND; IMMUNOGLOBULIN-G; LIBRARY; BINDING; DESIGN; REGION AB In therapeutic antibody preparation, acidic pH conditions are generally used for elution from Protein A affinity column of IgG or for its viral inactivation. Exposing IgG to low pH conditions induces conformational changes, leading to its functional damage or loss, although the mechanisms have not been fully elucidated. In this study using random peptide T7 phage display libraries, we isolated a unique and novel peptide motif that specifically recognized the non-native conformer ( acid conformer) of human IgG that was generated by the low pH treatment, but not the native conformer. We examined the generation conditions and biochemical properties of acid conformer using the peptide motif as an affinity ligand. The acid conformer was easily generated at acidic pH (25 degrees C). The peptides isolated here could contribute to the elucidation of the mechanisms of antibody dysfunction or aggregation during acid exposure as well as storage of human IgG. C1 [Sakamoto, Kotaro; Ito, Yuji; Hatanaka, Takaaki; Sugimura, Kazuhisa] Kagoshima Univ, Fac Engn, Kagoshima 8900065, Japan. [Mori, Toshiyuki] NCI, Mol Targets Dev Program, Ctr Canc Res, NIH, Ft Detrick, MD 21702 USA. [Ito, Yuji; Soni, Preeti Brijiral] Japan Sci & Technol Agcy, Innovat Satellite Miyazaki, Miyazaki 8800805, Japan. RP Ito, Y (reprint author), Kagoshima Univ, Fac Engn, Kagoshima 8900065, Japan. EM yito@be.kagoshima-u.ac.jp FU National Institutes of Health NCI Center for Cancer Research; Japan Science and Technology Agency. FX This work was supported, in whole or in part, by the National Institutes of Health NCI Center for Cancer Research ( Intramural Research Program). This work was also supported by funds from the Japan Science and Technology Agency. NR 22 TC 19 Z9 19 U1 1 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 APR 10 PY 2009 VL 284 IS 15 BP 9986 EP 9993 DI 10.1074/jbc.M807618200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429AJ UT WOS:000264892900041 PM 19233852 ER PT J AU Sarnovsky, R Rea, J Makowski, M Hertle, R Kelly, C Antignani, A Pastrana, DV FitzGerald, DJ AF Sarnovsky, Robert Rea, Jennifer Makowski, Matt Hertle, Ralf Kelly, Colleen Antignani, Antonella Pastrana, Diana V. FitzGerald, David J. TI Proteolytic Cleavage of a C-terminal Prosequence, Leading to Autoprocessing at the N Terminus, Activates Leucine Aminopeptidase from Pseudomonas aeruginosa SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPITHELIAL-CELLS; PHOSPHOLIPASE-C; IDENTIFICATION; RESISTANCE; ELASTASE; PROTEASE AB At high bacterial cell density the gene expression program of Pseudomonas aeruginosa is regulated by quorum sensing. Among the gene products highly up-regulated by this system is an exoprotease, leucine aminopeptidase (PA-LAP), which is co-expressed with several known virulence factors and secreted as a proenzyme. We undertook a study of its activation by expressing the full-length proform of PA-LAP recombinantly in Escherichia coli (here termed, rLAP55) and characterizing individual steps in its conversion to an active enzyme. Activation is initiated with the proteolytic removal of a C-terminal prosequence. Removal of similar to 20 amino acids is accomplished by Pseudomonas elastase, which is also positively regulated by quorum sensing. Activation is also mediated by other proteases that cleave rLAP55 near its C terminus. The importance of the C terminus was confirmed by showing that C-terminal deletions of 1-24 amino acids produce a fully active enzyme. The removal of C-terminal prosequences either by proteolysis or deletion leads to an unusual autoprocessing event at the N terminus. Autoprocessing is apparently an intramolecular event, requires the active site of LAP, and results in the removal of 12 N-terminal amino acids. Furthermore, a detailed analysis of the C-terminal prosequence suggests that the proenzyme state is dependent on the presence of a basic side chain contributed by the last amino acid, lysine 536. Our data support a model whereby full-length PA-LAP is activated in a two-step process; proteolytic cleavage at the C terminus is followed by an intramolecular autocatalytic removal of a 12-amino acid propeptide at the N terminus. C1 [FitzGerald, David J.] NCI, Mol Biol Lab, CCR, Natl Inst Hlth,HHS, Bethesda, MD 20892 USA. RP FitzGerald, DJ (reprint author), NCI, Mol Biol Lab, CCR, Natl Inst Hlth,HHS, 37 Convent Dr,Rm 5124, Bethesda, MD 20892 USA. EM djpf@helix.nih.gov FU National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health, Intramural Research Program, NCI, Center for Cancer Research. NR 22 TC 3 Z9 3 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 10 PY 2009 VL 284 IS 15 BP 10243 EP 10253 DI 10.1074/jbc.M808686200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 429AJ UT WOS:000264892900066 PM 19213733 ER PT J AU Dilts, DM Sandler, AB Cheng, SK Crites, JS Ferranti, LB Wu, AY Finnigan, S Friedman, S Mooney, M Abrams, J AF Dilts, David M. Sandler, Alan B. Cheng, Steven K. Crites, Joshua S. Ferranti, Lori B. Wu, Amy Y. Finnigan, Shanda Friedman, Steven Mooney, Margaret Abrams, Jeffrey TI Steps and Time to Process Clinical Trials at the Cancer Therapy Evaluation Program SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COOPERATIVE-ONCOLOGY-GROUP; INSTITUTE; BARRIERS; INDUSTRY AB Purpose To examine the processes and document the calendar time required for the National Cancer Institute's Cancer Therapy Evaluation Program (CTEP) and Central Institutional Review Board (CIRB) to evaluate and approve phase III clinical trials. Methods Process steps were documented by (1) interviewing CTEP and CIRB staff regarding the steps required to activate a trial from initial concept submission to trial activation by a cooperative group, (2) reviewing standard operating procedures, and (3) inspecting trial records and documents for selected trials to identify any additional steps. Calendar time was collected from initial concept submission to activation using retrospective data from the CTEP Protocol and Information Office. Results At least 296 distinct processes are required for phase III trial activation: at least 239 working steps, 52 major decision points, 20 processing loops, and 11 stopping points. Of the 195 trials activated during the January 1, 2000, to December 31, 2007, study period, a sample of 167 (85.6%) was used for gathering timing data. Median calendar days from initial formal concept submission to CTEP to trial activation by a cooperative group was 602 days (interquartile range, 454 to 861 days). This time has not significantly changed over the past 8 years. There is a high variation in the time required to activate a clinical trial. Conclusion Because of their complexity, the overall development time for phase III clinical trials is lengthy, process laden, and highly variable. To streamline the process, a solution must be sought that includes all parties involved in developing trials. J Clin Oncol 27: 1761-1766. (C) 2009 by American Society of Clinical Oncology C1 [Crites, Joshua S.] Ctr Management Res Healthcare, Nashville, TN 37235 USA. Vanderbilt Univ, Engn Management Program, Owen Grad Sch Management, Nashville, TN 37235 USA. Vanderbilt Univ, Sch Med, Nashville, TN 37235 USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Crites, JS (reprint author), Ctr Management Res Healthcare, VU Box 351518 Stn B, Nashville, TN 37235 USA. EM joshua.crites@vanderbilt.edu FU NCI NIH HHS [U10 CA021115, 3U10 CA21115-32] NR 14 TC 41 Z9 41 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 10 PY 2009 VL 27 IS 11 BP 1761 EP 1766 DI 10.1200/JCO.2008.19.9133 PG 6 WC Oncology SC Oncology GA 447ME UT WOS:000266194400008 PM 19255315 ER PT J AU Bertagnolli, MM Niedzwiecki, D Compton, CC Hahn, HP Hall, M Damas, B Jewell, SD Mayer, RJ Goldberg, RM Saltz, LB Warren, RS Redston, M AF Bertagnolli, Monica M. Niedzwiecki, Donna Compton, Carolyn C. Hahn, Hejin P. Hall, Margaret Damas, Beatrice Jewell, Scott D. Mayer, Robert J. Goldberg, Richard M. Saltz, Leonard B. Warren, Robert S. Redston, Mark TI Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COLORECTAL-CANCER; FRAMESHIFT MUTATIONS; MUTATOR PHENOTYPE; GENE; CELLS; MECHANISM; CPT-11; HMLH1; CARCINOGENESIS; CAMPTOTHECIN AB Purpose Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) - based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers. Patients and Methods Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono-and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Results Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117). Conclusion Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV. J Clin Oncol 27: 1814-1821. (C) 2009 by American Society of Clinical Oncology C1 [Bertagnolli, Monica M.] Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Duke Univ, Canc & Leukemia Grp Stat Ctr B, Med Ctr, Durham, NC 27706 USA. Univ N Carolina, Chapel Hill, NC USA. NCI, Bethesda, MD 20892 USA. Ohio State Univ, Columbus, OH 43210 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Bertagnolli, MM (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM mbertagnolli@partners.org RI Goldberg , Richard/M-1311-2013; OI Saltz, Leonard/0000-0001-8353-4670 FU NCI NIH HHS [CA31946, CA33601, U10 CA031946, U10 CA033601] NR 35 TC 201 Z9 208 U1 0 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 10 PY 2009 VL 27 IS 11 BP 1814 EP 1821 DI 10.1200/JCO.2008.18.2071 PG 8 WC Oncology SC Oncology GA 447ME UT WOS:000266194400016 PM 19273709 ER PT J AU Di Maio, M Chiodini, P Georgoulias, V Hatzidaki, D Takeda, K Wachters, FM Gebbia, V Smit, EF Morabito, A Gallo, C Perrone, F Gridelli, C AF Di Maio, Massimo Chiodini, Paolo Georgoulias, Vassilis Hatzidaki, Dora Takeda, Koji Wachters, Floris M. Gebbia, Vittorio Smit, Egbert F. Morabito, Alessandro Gallo, Ciro Perrone, Francesco Gridelli, Cesare TI Meta-Analysis of Single-Agent Chemotherapy Compared With Combination Chemotherapy As Second-Line Treatment of Advanced Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RANDOMIZED PHASE-II; PATIENT DATA METAANALYSIS; DOCETAXEL; TRIAL; IRINOTECAN; MULTICENTER; GEMCITABINE; CISPLATIN; TIME AB Purpose Doublet chemotherapy is more effective than single-agent as first-line treatment of advanced non-small-cell lung cancer (NSCLC). As second-line treatment, several randomized trials have been performed comparing single-agent with doublet chemotherapy, but each trial had an insufficient power to detect potentially relevant differences in survival. Methods We performed meta-analysis of individual patient data from randomized trials, both published and unpublished, comparing single-agent with doublet chemotherapy as second-line treatment of advanced NSCLC. Primary end point was overall survival (OS). All statistical analyses were stratified by trial. Results Eight eligible trials were identified. Data of two trials were not available, and data of six trials (847 patients) were collected. Median age was 61 years. Performance status was 0 or 1 in 90%; 80% of patients had received previous platin-based chemotherapy. OS was not significantly different between arms (P = .32). Median OS was 37.3 and 34.7 weeks in the doublet and single-agent arms, respectively. Hazard ratio (HR) was 0.92 (95% CI, 0.79 to 1.08). Response rate was 15.1% with doublet and 7.3% with single-agent (P = .0004). Median progression-free survival was 14 weeks for doublet and 11.7 weeks for single agent (P = .0009; HR, 0.79; 95% CI, 0.68 to 0.91). There was no significant heterogeneity among trials for the three efficacy outcomes. Patients treated with doublet chemotherapy had significantly more grade 3 to 4 hematologic (41% v 25%; P = .0001) and grade 3 to 4 nonhematologic toxicity (28% v 22%; P = .034). Conclusion Doublet chemotherapy as second-line treatment of advanced NSCLC significantly increases response rate and progression-free survival, but is more toxic and does not improve overall survival compared to single-agent. J Clin Oncol 27: 1836-1843. (C) 2009 by American Society of Clinical Oncology C1 [Gridelli, Cesare] SG Moscati Hosp, Div Med Oncol, I-83100 Avellino, Italy. Natl Canc Inst, Clin Trials Unit, Bethesda, MD 20892 USA. Univ Naples 2, Dept Med & Publ Hlth, Naples, Italy. N Giannettasio Hosp, Div Med Oncol, Rossano, Italy. Univ Palermo, I-90133 Palermo, Italy. Univ Gen Hosp, Dept Med Oncol, Iraklion, Crete, Greece. Osaka City Gen Hosp, Osaka, Japan. Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, NL-9713 AV Groningen, Netherlands. Vrije Univ Amsterdam, Dept Pulm Dis, Med Ctr, Amsterdam, Netherlands. RP Gridelli, C (reprint author), SG Moscati Hosp, Div Med Oncol, I-83100 Avellino, Italy. EM cgridelli@libero.it RI Chiodini, Paolo/E-7290-2014; Gridelli, Cesare/K-7909-2016; Di Maio, Massimo/K-9990-2016; OI Chiodini, Paolo/0000-0003-0139-2264; Di Maio, Massimo/0000-0001-8906-3785; Gebbia, Vittorio/0000-0001-8848-5951; Morabito, Alessandro/0000-0002-1319-9608 NR 20 TC 86 Z9 88 U1 1 U2 9 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD APR 10 PY 2009 VL 27 IS 11 BP 1836 EP 1843 DI 10.1200/JCO.2008.17.5844 PG 8 WC Oncology SC Oncology GA 447ME UT WOS:000266194400019 PM 19273711 ER PT J AU Imboden, H Patil, J Nussberger, J Nicoud, F Hess, B Ahmed, N Schaffner, T Wellner, M Muller, D Inagami, T Senbonmatsu, T Pavel, J Saavedra, JM AF Imboden, Hans Patil, Jaspal Nussberger, Juerg Nicoud, Francoise Hess, Benno Ahmed, Nermin Schaffner, Thomas Wellner, Maren Mueller, Dominik Inagami, Tadashi Senbonmatsu, Takaaki Pavel, Jaroslav Saavedra, Juan M. TI Endogenous angiotensinergic system in neurons of rat and human trigeminal ganglia SO REGULATORY PEPTIDES LA English DT Article DE Renin-angiotensin system; Tissue angiotensin; Neuronal angiotensin; HPLC-RIA; Sensory system; Pain ID SPONTANEOUSLY HYPERTENSIVE-RATS; MESSENGER-RNA; SUBSTANCE-P; PROPHYLACTIC TREATMENT; CONVERTING ENZYME; MOUSE-TISSUES; PINEAL-GLAND; RENIN; BRAIN; LOCALIZATION AB To clarify the role of Angiotensin II (Ang II) in the sensory system and especially in the trigeminal ganglia, we studied the expression of angiotensinogen (Ang-N)-, renin-, angiotensin converting enzyme (ACE)- and cathepsin D-mRNA, and the presence of Ang II and substance P in the rat and human trigeminal ganglia. The rat trigeminal ganglia expressed substantial amounts of Ang-N- and ACE mRNA as determined by quantitative real time PCR. Renin mRNA was untraceable in rat samples. Cathepsin D was detected in the rat trigeminal ganglia indicating the possibility of existence of pathways alternative to renin for Ang I formation. In situ hybridization in rat trigeminal ganglia revealed expression of Ang-N mRNA in the cytoplasm of numerous neurons. By using immunocytochemistry, a number of neurons and their processes in both the rat and human trigeminal ganglia were stained for Ang II. Post in situ hybridization immunocytochemistry reveals that in the rat trigeminal ganglia some, but not all Ang-N mRNA-positive neurons marked for Ang II. In some neurons Substance P was found colocalized with Ang II. Angiotensins from rat trigeminal ganglia were quantitated by radioimmunoassay with and without prior separation by high performance liquid chromatography. Immunoreactive angiotensin II (ir-Ang II) was consistently present and the sum of true Ang II (1-8) octapeptide and its specifically measured metabolites were found to account for it. Radioimmunological and immunocytochemical evidence of ir-Ang II in neuronal tissue is compatible with Ang II as a neurotransmitter. In conclusion, these results suggest that Ang II could be produced locally in the neurons of rat trigeminal ganglia. The localization and colocalization of neuronal Ang II with Substance P in the trigeminal ganglia neurons may be the basis for a participation and function of Ang II in the regulation of nociception and migraine pathology. (C) 2009 Elsevier B.V. All rights reserved. C1 [Imboden, Hans; Patil, Jaspal; Hess, Benno; Ahmed, Nermin] Univ Bern, Inst Cell Biol, CH-3012 Bern, Switzerland. [Schaffner, Thomas] Univ Bern, Inst Pathol, CH-3012 Bern, Switzerland. [Wellner, Maren; Mueller, Dominik] Max Delbruck Ctr Mol Med, Berlin, Germany. [Inagami, Tadashi; Senbonmatsu, Takaaki] Vanderbilt Dept Biochem, Nashville, TN USA. [Pavel, Jaroslav; Saavedra, Juan M.] NIMH, Pharmacol Sect, Bethesda, MD 20892 USA. [Nussberger, Juerg; Nicoud, Francoise] Univ Hosp, Dept Internal Med, Lausanne, Switzerland. RP Imboden, H (reprint author), Univ Bern, Inst Cell Biol, Baltzerstr 4, CH-3012 Bern, Switzerland. EM hans.imboden@izb.unibe.ch FU Berne University Research Foundation; Novartis Pharma Switzerland FX We are grateful to the Berne University Research Foundation and Novartis Pharma Switzerland for the financial support. We wish to thank Susanne Gygax, Andreas Gruber and Jana Czychi for technical assistance. NR 57 TC 17 Z9 17 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-0115 J9 REGUL PEPTIDES JI Regul. Pept. PD APR 10 PY 2009 VL 154 IS 1-3 BP 23 EP 31 DI 10.1016/j.regpep.2009.02.002 PG 9 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 437QU UT WOS:000265502800004 PM 19323983 ER PT J AU Akopyants, NS Kimblin, N Secundino, N Patrick, R Peters, N Lawyer, P Dobson, DE Beverley, SM Sacks, DL AF Akopyants, Natalia S. Kimblin, Nicola Secundino, Nagila Patrick, Rachel Peters, Nathan Lawyer, Phillip Dobson, Deborah E. Beverley, Stephen M. Sacks, David L. TI Demonstration of Genetic Exchange During Cyclical Development of Leishmania in the Sand Fly Vector SO SCIENCE LA English DT Article ID TRYPANOSOMA-BRUCEI; GENOMIC ORGANIZATION; DONOVANI COMPLEX; MAJOR FRIEDLIN; RECOMBINATION; TRANSMISSION; EXPRESSION; VIRULENCE; MARKER; CROSS AB Genetic exchange has not been shown to be a mechanism underlying the extensive diversity of Leishmania parasites. We report here evidence that the invertebrate stages of Leishmania are capable of having a sexual cycle consistent with a meiotic process like that described for African trypanosomes. Hybrid progeny were generated that bore full genomic complements from both parents, but kinetoplast DNA maxicircles from one parent. Mating occurred only in the sand fly vector, and hybrids were transmitted to the mammalian host by sand fly bite. Genetic exchange likely contributes to phenotypic diversity in natural populations, and analysis of hybrid progeny will be useful for positional cloning of the genes controlling traits such as virulence, tissue tropism, and drug resistance. C1 [Kimblin, Nicola; Secundino, Nagila; Patrick, Rachel; Peters, Nathan; Lawyer, Phillip; Sacks, David L.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Akopyants, Natalia S.; Dobson, Deborah E.; Beverley, Stephen M.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. RP Sacks, DL (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM dsacks@nih.gov OI Beverley, Stephen/0000-0001-5319-0811 FU Intramural Research Program of the NIH; National Institute of Allergy and Infectious Diseases (NIAID) [A1029646, A1020941] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (NIAID), and in part by NIAID grant support (S.M.B., D.E.D., and N.S.A. A1029646 and A1020941). We thank K. Owens for inventorying and shipping parasite strains; K. Beacht for mouse infection studies; and M. Grigg, L. Miller, and A. Sher for critical review of the manuscript. Maxicircle sequences have been submitted to GenBank and had been assigned accession numbers FJ349262 to FJ349263 (12S rRNA) and FJ349264 to FJ349265 (Divergent region). NR 26 TC 128 Z9 130 U1 1 U2 10 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 APR 10 PY 2009 VL 324 IS 5924 BP 265 EP 268 DI 10.1126/science.1169464 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 430WX UT WOS:000265024400050 PM 19359589 ER PT J AU Ali, MA Li, QX Fischer, ER Cohen, JI AF Ali, Mir A. Li, Qingxue Fischer, Elizabeth R. Cohen, Jeffrey I. TI The insulin degrading enzyme binding domain of varicella-zoster virus (VZV) glycoprotein E is important for cell-to-cell spread and VZV infectivity, while a glycoprotein I binding domain is essential for infection SO VIROLOGY LA English DT Article DE Glycoprotein E; Varicella-zoster virus; Herpes simplex virus; Glycoprotein I; Insulin degrading enzyme ID HERPES-SIMPLEX VIRUS-1; VIRAL REPLICATION; EXTRACELLULAR DOMAIN; POLIOVIRUS RECEPTOR; EPITHELIAL-CELLS; MAMMALIAN-CELLS; TERMINAL REGION; GENE-EXPRESSION; PROTEIN; COMPLEX AB Varicella-zoster virus (VZV) glycoprotein E (gE) interacts with glycoprotein I and with insulin degrading enzyme (IDE), which is a receptor for the virus. We found that a VZV gE deletion mutant could only be grown in cells expressing gE. Expression of VZV gE on the surface of cells did not interfere with VZV infection. HSV deleted for gE is impaired for cell-to-cell spread; VZV gE could not complement this activity in an HSV gE null mutant. VZV lacking the IDE binding domain of gE grew to peak titers nearly equivalent to parental virus: however, it was impaired for cell-to-cell spread and for infectivity with cell-free virus. VZV deleted for a region of gE that binds glycoprotein I could not replicate in cell culture unless grown in cells expressing gE. We conclude that the IDE binding domain is important for efficient cell-to-cell spread and infectivity of cell-free virus. (C) 2009 Published by Elsevier Inc. C1 [Ali, Mir A.; Li, Qingxue; Cohen, Jeffrey I.] NIH, Med Virol Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Fischer, Elizabeth R.] NIH, Res Technol Sect, Res Technol Branch, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Cohen, JI (reprint author), NIH, Med Virol Sect, Lab Clin Infect Dis, Bldg 10, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX This work was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases. We thank David johnson for HSV-1 F and HSV-1-gE beta, Bernard Roizrnan for plasmid Ac-CMV, Christine Tilarico for antibody to VZV thymidine kinase, Bagher Forghani for antibodies to VZV gE, and Yo Hoshino for assistance with artwork. NR 46 TC 16 Z9 16 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD APR 10 PY 2009 VL 386 IS 2 BP 270 EP 279 DI 10.1016/j.virol.2009.01.023 PG 10 WC Virology SC Virology GA 461YJ UT WOS:000267310200005 PM 19233447 ER PT J AU Resch, W Weisberg, AS Moss, B AF Resch, Wolfgang Weisberg, Andrea S. Moss, Bernard TI Expression of the highly conserved vaccinia virus E6 protein is required for virion morphogenesis SO VIROLOGY LA English DT Article DE Poxvirus replication; Poxvirus protein; Virion assembly; Conditional lethal mutant ID BACTERIAL ARTIFICIAL CHROMOSOME; FORM IMMATURE VIRIONS; COLI LAC REPRESSOR; ESCHERICHIA-COLI; MATURE VIRIONS; MAMMALIAN-CELLS; VIRAL MEMBRANES; DENSE VIROPLASM; A30L PROTEIN; GENE AB The vaccinia virus E6R gene (VACVWR062) is conserved in all members of the poxvirus family and encodes a protein associated with the mature virion. We confirmed this association and Provided evidence for an internal location. An inducible mutant that conditionally expresses E6 was constructed. In the absence of inducer, plaque formation and virus production were severely inhibited in several cell lines, whereas some replication Occurred in others. This difference could be due to variation in the stringency of repression, since we could not isolate a stable deletion mutant even in the More "permissive" cells. Under non-permissive conditions, viral late proteins were synthesized but processing of core proteins was inefficient, indicative of an assembly block. Transmission electron microscopy of sections of cells infected with the mutant in the absence of inducer revealed morphogenetic defects with crescents and empty immature virions adjacent to dense inclusions of viroplasm. Mature virions were infrequent and cores appeared to have lucent centers. Published by Elsevier Inc. C1 [Resch, Wolfgang; Weisberg, Andrea S.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 33 N Dr,MSC3210, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Intramural NIH HHS [Z01 AI000539-20] NR 40 TC 5 Z9 6 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 0042-6822 J9 VIROLOGY JI Virology PD APR 10 PY 2009 VL 386 IS 2 BP 478 EP 485 DI 10.1016/j.virol.2009.01.009 PG 8 WC Virology SC Virology GA 461YJ UT WOS:000267310200027 PM 19217136 ER PT J AU Pulsipher, MA Chitphakdithai, P Miller, JP Logan, BR King, RJ Rizzo, JD Leitman, SF Anderlini, P Haagenson, MD Kurian, S Klein, JP Horowitz, MM Confer, DL AF Pulsipher, Michael A. Chitphakdithai, Pintip Miller, John P. Logan, Brent R. King, Roberta J. Rizzo, J. Douglas Leitman, Susan F. Anderlini, Paolo Haagenson, Michael D. Kurian, Seira Klein, John P. Horowitz, Mary M. Confer, Dennis L. TI Adverse events among 2408 unrelated donors of peripheral blood stem cells: results of a prospective trial from the National Marrow Donor Program SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; BONE-MARROW; G-CSF; PROGENITOR CELLS; ALLOGENEIC TRANSPLANTATION; CONGENITAL NEUTROPENIA; SPONTANEOUS RUPTURE; HEALTHY DONORS; FOLLOW-UP; MOBILIZATION AB Limited data are available describing donor adverse events (AEs) associated with filgrastim mobilized peripheral blood stem cell (PBSC) collections in unrelated volunteers. We report results in 2408 unrelated PBSC donors prospectively evaluated by the National Marrow Donor Program (NMDP) between 1999 and 2004. Female donors had higher rates of AEs, requiring central line placement more often (17% vs 4%, P<.001), experiencing more apheresis-related AEs (20% vs 7%, P<.001), more bone pain (odds ratio [OR] = 1.49), and higher rates of grades II-IV and III-IV CALGB AEs (OR = 2.22 and 2.32). Obese donors experienced more bone pain (obese vs normal, OR = 1.73) and heavy donors had higher rates of CALGB toxicities (> 95 kg vs <70 kg, OR = 1.49). Six percent of donors experienced grade III-IV CALGB toxicities and 0.6% experienced toxicities that were considered serious and unexpected. Complete recovery is universal, however, and no late AEs attributable to donation have been identified. In conclusion, PBSC collection in unrelated donors is generally safe, but nearly all donors will experience bone pain, 1 in 4 will have significant headache, nausea, or citrate toxicity, and a small percentage will experience serious short-term adverse events. In addition, women and larger donors are at higher risk for donation-related AEs. (Blood. 2009; 113: 3604-3611) C1 [Pulsipher, Michael A.] Univ Utah, Sch Med, Primary Childrens Hosp, Salt Lake City, UT 84132 USA. [Chitphakdithai, Pintip; King, Roberta J.; Haagenson, Michael D.] CIBMTR, Minneapolis, MN USA. [Miller, John P.; Confer, Dennis L.] Natl Marrow Donor Program, Salt Lake City, UT USA. [Logan, Brent R.; Rizzo, J. Douglas; Klein, John P.; Horowitz, Mary M.] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Leitman, Susan F.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Anderlini, Paolo] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Kurian, Seira] Los Angeles Cty Dept Publ Hlth, Los Angeles, CA USA. RP Pulsipher, MA (reprint author), Univ Utah, Sch Med, Div Hematol Blood & Marrow Transplant, 30 N,1900 E,Room 5C402, Salt Lake City, UT 84132 USA. EM michael.pulsipher@hsc.utah.edu FU National Marrow Donor Program and the Health Resources and Services Administration [240-97-0036, 231-02-0007]; National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute [U24-CA76518]; Office of Naval Research; Health Resources and Services Administration (DHHS); AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen; Association of Medical Microbiology and Infectious Disease Canada; Astellas Pharma US; Baxter International; Bayer HealthCare Pharmaceuticals; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; Celgene; CellGenix; Centers for Disease Control and Prevention; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex; CytoTherm; DOR BioPharma; Dynal Biotech; Invitrogen Company; Enzon Pharmaceuticals; European Group for Blood and Marrow Transplantation; Gambro BCT; Gamida Cell; Genzyme; Histogenetics; HKS Medical Information Systems; Hospira; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery; Merck Company; Medical College of Wisconsin; MGI Pharma; Michigan Community Blood Centers; Millennium Pharmaceuticals; Miller Pharmacal Group; Milliman USA; Miltenyi Biotec; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics; Otsuka Pharmaceutical Development & Commercialization; Pall Life Sciences; PDL BioPharma; Pfizer; Pharmion; Saladax Biomedical; Schering Plough; Society for Healthcare Epidemiology of America; StemCyte; StemSoft Software; Sysmex; Teva Pharmaceutical Industries; Marrow Foundation; THERAKOS; Vidacare; Vion Pharmaceuticals; ViraCor Laboratories; ViroPharma; Wellpoint FX This project has been supported by funding from the National Marrow Donor Program and the Health Resources and Services Administration contract nos. 240-97-0036 and 231-02-0007 to the National Marrow Donor Program.; The CIBMTR is supported by Public Health Service Grant U24- CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute; Office of Naval Research; Health Resources and Services Administration (DHHS); and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen; anonymous donation to the Medical College of Wisconsin; Association of Medical Microbiology and Infectious Disease Canada; Astellas Pharma US; Baxter International; Bayer HealthCare Pharmaceuticals; BloodCenter of Wisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; Celgene; CellGenix; Centers for Disease Control and Prevention; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex; CytoTherm; DOR BioPharma; Dynal Biotech, an Invitrogen Company; Enzon Pharmaceuticals; European Group for Blood and Marrow Transplantation; Gambro BCT; Gamida Cell; Genzyme; Histogenetics; HKS Medical Information Systems; Hospira; Infectious Diseases Society of America; Kiadis Pharma; Kirin Brewery; Merck & Company; The Medical College of Wisconsin; MGI Pharma; Michigan Community Blood Centers; Millennium Pharmaceuticals; Miller Pharmacal Group; Milliman USA; Miltenyi Biotec; National Marrow Donor Program; Nature Publishing Group; New York Blood Center; Novartis Oncology; Oncology Nursing Society; Osiris Therapeutics; Otsuka Pharmaceutical Development & Commercialization; Pall Life Sciences; PDL BioPharma; Pfizer; Pharmion; Saladax Biomedical; Schering Plough; Society for Healthcare Epidemiology of America; StemCyte; StemSoft Software; Sysmex; Teva Pharmaceutical Industries; The Marrow Foundation; THERAKOS; Vidacare; Vion Pharmaceuticals; ViraCor Laboratories; ViroPharma; and Wellpoint.; The views expressed in this article do not reflect the official policy or position of the Health Resources and Services Administration, the National Marrow Donor Program, the National Institutes of Health, the Department of the Navy, the Department of Defense, or any other agency of the US government. NR 30 TC 97 Z9 98 U1 0 U2 2 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 APR 9 PY 2009 VL 113 IS 15 BP 3604 EP 3611 DI 10.1182/blood-2008-08-175323 PG 8 WC Hematology SC Hematology GA 431HN UT WOS:000265052300029 PM 19190248 ER PT J AU Imanguli, MM Swaim, WD League, SC Gress, RE Pavletic, SZ Hakim, FT AF Imanguli, Matin M. Swaim, William D. League, Stacy C. Gress, Ronald E. Pavletic, Steven Z. Hakim, Frances T. TI Increased T-bet(+) cytotoxic effectors and type I interferon-mediated processes in chronic graft-versus-host disease of the oral mucosa SO BLOOD LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; CONSENSUS DEVELOPMENT PROJECT; SYSTEMIC-LUPUS-ERYTHEMATOSUS; WORKING GROUP-REPORT; MEMORY T-CELLS; CHRONIC GVHD; AUTOIMMUNE-DISEASES; GENE-EXPRESSION; TRANSCRIPTION FACTOR; CLINICAL-TRIALS AB Although chronic graft-versus-host disease (cGVHD) is a major long-term complication of allogeneic hematopoietic stem cell transplantation, little is known of its pathogenesis. We have systematically examined oral mucosa among cGVHD patients and determined that the clinical severity of oral cGVHD was correlated with apoptotic epithelial cells, often found adjacent to infiltrating effector-memory T cells expressing markers of cytotoxicity and type I cytokine polarization. Accumulation of T-bet(+) T-cell effectors was associated with both increased proliferation and the expression of the type I chemokine receptor CXCR3. Concurrently, in both infiltrating cells and keratinocytes, we observed increased expression of the CXCR3 ligand MIG (CXCL9) and interleukin-15 (IL-15), type I interferon (IFN)-inducible factors that support the migration, type I differentiation, and expansion of alloreactive effectors. In severely affected mucosa, we observed high levels of MxA, a protein specifically induced by type I IFN, and signal transducer and activator of transcription 1 (STAT1) phosphorylation, a critical step in the IFN-signaling pathway, along with increased numbers of plasmacytoid dendritic cells. These data challenge the current paradigm of cGVHD as a type II cytokine-driven disorder and support the model that oral cGVHD results from type I IFN-driven immigration, proliferation, and differentiation of T-bet(+) type I T effectors. The clinical trials are registered at http://www.clinicaltrials.gov as NCT00331968. (Blood. 2009; 113: 3620-3630) C1 [Imanguli, Matin M.; League, Stacy C.; Gress, Ronald E.; Pavletic, Steven Z.; Hakim, Frances T.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Swaim, William D.] NIDCR, Mol Physiol & Therapeut Branch, Bethesda, MD USA. RP Hakim, FT (reprint author), NCI, Expt Transplantat & Immunol Branch, 10 Ctr Dr,12C216, Bethesda, MD 20892 USA. EM hakimf@mail.nih.gov FU National Cancer Institute (Bethesda, MD) FX We thank all the members of the chronic GVHD protocol team for their help in data collection related to this study, and in particular Drs David Kleiner, Sandra Mitchell, Jean-Pierre Guadagnini, and Jane Atkinson, Ms Daniele Avila, and Mr Mike Krumlauf. We thank Dr Yu-Waye Chu for the paper revision and helpful suggestions. Finally, we are grateful to all the patients who volunteered for this study.; This study received funding from the National Cancer Institute (Bethesda, MD). NR 51 TC 60 Z9 61 U1 0 U2 3 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 APR 9 PY 2009 VL 113 IS 15 BP 3620 EP 3630 DI 10.1182/blood-2008-07-168351 PG 11 WC Hematology SC Hematology GA 431HN UT WOS:000265052300031 PM 19168793 ER PT J AU Rivas, FM Stables, JP Murphree, L Edwankar, RV Edwankar, CR Huang, S Jain, HD Zhou, H Majumder, S Sankar, S Roth, BL Ramerstorfer, J Furtmuller, R Sieghart, W Cook, JA AF Rivas, Felix M. Stables, James P. Murphree, Lauren Edwankar, Rahul V. Edwankar, Chitra R. Huang, Shengming Jain, Hiteshkumar D. Zhou, Hao Majumder, Samarpan Sankar, Subramanian Roth, Bryan L. Ramerstorfer, Joachim Furtmueller, Roman Sieghart, Werner Cook, James A. TI Antiseizure Activity of Novel gamma-Aminobutyric Acid (A) Receptor Subtype-Selective Benzodiazepine Analogues in Mice and Rat Models SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID GABA(A) RECEPTORS; LIGANDS; SITE; METABOLISM; DIAZEPAM; SL651498; AGONISTS; BINDING AB The anti seizure activity of benzodiazepines (BDZs) 1-5 in mice and rats as animal models is described. These BDZs have selective efficacy for alpha 2 beta 3 gamma 2 and alpha 3 beta 3 gamma 2 GABA(A)-receptors. Significant anticonvulsant activity with little or no motor impairment and therapeutic indexes (TI) of 2.8-44 (mice, ip) were observed for compounds 2-4 in the subcutaneous metrazole seizure (scMET) test. In rats, orally (po) the TI was >5 to 105. These compounds represent novel leads in the search for anticonvulsants devoid of sedative, ataxic, and amnestic side effects. C1 [Rivas, Felix M.; Edwankar, Rahul V.; Edwankar, Chitra R.; Huang, Shengming; Jain, Hiteshkumar D.; Zhou, Hao; Cook, James A.] Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. [Stables, James P.; Murphree, Lauren] NINDS, Anticonvulsant Screening Program, Rockville, MD 20852 USA. [Majumder, Samarpan; Roth, Bryan L.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. [Sankar, Subramanian] CWRU Med Sch, Dept Biochem, Cleveland, OH 44106 USA. [Ramerstorfer, Joachim; Furtmueller, Roman; Sieghart, Werner] Med Univ Vienna, Ctr Brain Res, A-1090 Vienna, Austria. RP Cook, JA (reprint author), Univ Wisconsin, Dept Chem & Biochem, Milwaukee, WI 53211 USA. EM capncook@uwm.edu RI Roth, Bryan/F-3928-2010; Sieghart, Werner/A-4877-2013 OI Sieghart, Werner/0000-0002-0443-0302 FU NIMH [MH-46851]; Lynde and Harry Bradley Foundation; NIH FX We thank the NIMH for support of this work (MH-46851), and the Lynde and Harry Bradley Foundation. F.M.R. is grateful to the NIH for a Postdoctoral Fellowship. NR 33 TC 27 Z9 28 U1 1 U2 1 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 APR 9 PY 2009 VL 52 IS 7 BP 1795 EP 1798 DI 10.1021/jm801652d PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 428GK UT WOS:000264835800002 PM 19275170 ER PT J AU Cho, SJ Jensen, NH Kurome, T Kadari, S Manzano, ML Malberg, JE Caldarone, B Roth, BL Kozikowski, AP AF Cho, Sung Jin Jensen, Niels H. Kurome, Toru Kadari, Sudhakar Manzano, Michael L. Malberg, Jessica E. Caldarone, Barbara Roth, Bryan L. Kozikowski, Alan P. TI Selective 5-Hydroxytryptamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine: Identification of Drugs with Antidepressant-Like Action SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SEROTONIN 5-HT2C RECEPTOR; PROTEIN-COUPLED RECEPTOR; CRYSTAL-STRUCTURE; WAY-163909; DISCOVERY; AGENTS; HALLUCINOGENS; ANTAGONISTS; DISORDER; OXIDASE AB We report here the design, synthesis, and pharmacological properties of a series of compounds related to tranylcypromine (9), which itself was discovered as a lead compound in a high-throughput screening campaign. Starting from 9, which shows modest activity as a 5-HT(2C) agonist, a series of 1-aminomethyl-2-phenylcyclopropanes was investigated as 5-HT(2C) agonists through iterative structural modifications. Key pharmacophore feature of this new class of ligands is a 2-aminomethyl-trans-cyclopropyl side chain attached to a substituted benzene ring. Among the tested compounds, several were potent and efficacious 5-HT(2C) receptor agonists with selectivity over both 5-HT(2A) and 5-HT(2B) receptors in functional assays. The most promising compound is 37, with 120- and 14-fold selectivity over 5-HT(2A) and 5-HT(2B), respectively (EC(50) = 585, 65, and 4.8 nM at the 2A, 2B, and 2C subtypes, respectively). In animal studies, compound 37 (10-60 mg/kg) decreased immobility time in the mouse forced swim test. C1 [Jensen, Niels H.; Roth, Bryan L.] Univ N Carolina, Sch Med, Dept Pharmacol,Div Med Chem & Nat Prod, Comprehens Canc Ctr,Ctr Neurobiol, Chapel Hill, NC 27599 USA. [Jensen, Niels H.; Roth, Bryan L.] Univ N Carolina, Sch Med, NIMH Psychoact Drug Screening Program, Chapel Hill, NC 27599 USA. [Manzano, Michael L.; Malberg, Jessica E.; Caldarone, Barbara] Psychogenics Inc, Tarrytown, NY 10591 USA. [Cho, Sung Jin; Kurome, Toru; Kadari, Sudhakar; Kozikowski, Alan P.] Univ Illinois, Drug Discovery Program, Dept Med Chem & Pharmacognosy, Coll Pharm M C781, Chicago, IL 60612 USA. RP Roth, BL (reprint author), Univ N Carolina, Sch Med, Dept Pharmacol,Div Med Chem & Nat Prod, Comprehens Canc Ctr,Ctr Neurobiol, CB 7365, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu; kozikowa@uic.edu RI Roth, Bryan/F-3928-2010; Malberg, Jessica/J-9588-2014 OI Malberg, Jessica/0000-0002-4031-2629 FU NIH [R01 DA022317]; Korean Government [KRF-2007-357-C00071]; [R01 MH61887]; [N01MH80032]; [U19MH82441] FX This work was supported in part by NIH grant(R01 DA022317, grantee Alan P. Kozikowski), (R01 MH61887, N01MH80032, and U19MH82441, grantee Bryan L. Roth) and NIDA fellowship (2006-2007). This work was supported by the Korea Research Foundation Grant funded by the Korean Government (KRF-2007-357-C00071). We thank Dr. Rong He for help with the preparative of the manuscript and Dr. Arsen Gaysin for help with generating the data reported. S. J. Cho expresses appreciation to Dr. Suresh Tipparaju, Dr. Annamaria Lilienkampf, Dr. Sophie Gaudrel-Grosay, and Dr. Ki Duk Park for helpful discussions. NR 55 TC 22 Z9 22 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD APR 9 PY 2009 VL 52 IS 7 BP 1885 EP 1902 DI 10.1021/jm801354e PG 18 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 428GK UT WOS:000264835800011 PM 19284718 ER PT J AU Kim, Y de Castro, S Gao, ZG Ijzerman, AP Jacobson, KA AF Kim, Yoonkyung de Castro, Sonia Gao, Zhan-Guo Ijzerman, Adriaan P. Jacobson, Kenneth A. TI Novel 2- and 4-Substituted 1H-Imidazo[4,5-c]quinolin-4-amine Derivatives as Allosteric Modulators of the A(3) Adenosine Receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID AGONISTS; BINDING; PHARMACOLOGY; ENHANCEMENT; RADIOLIGAND; TARGET; SERIES AB 4-Arylamino and 2-cycloalkyl (including amino substitution) modifications were made in a series of 1H-imidazo[4,5-c]quinolin-4-amine derivatives as allosteric modulators of the human A3 adenosine receptor (AR). In addition to allosteric modulation of the maximum functional efficacy (in [S-35]GTP gamma S G protein binding assay) of the A(3)AR agonist C1-IB-MECA (15), some analogues also weakly inhibited equilibrium radioligand binding at ARs. 4-(3,5-Dichlorophenylamino) (6) or 2-(1-adamantyl) (20) substitution produced allosteric enhancement (twice the maximal agonist efficacy), with minimal inhibition of orthosteric AR binding. 2-(4-Tetrahydropyranyl) substitution abolished allosteric enhancement but preserved inhibition of orthosteric binding. Introduction of nitrogen in the six-membered ring at the 2 position, to improve aqueous solubility and provide a derivatization site, greatly reduced the allosteric enhancement. 2-(4-(Benzoylamino)cyclohexyl) analogues 23 and 24 were weak negative A3AR modulators. Thus, consistent with previous findings, the allosteric and orthosteric inhibitory A3AR effects in imidazoquinolines are structurally separable, suggesting the possible design of additional derivatives with enhanced positive or negative allosteric A3AR activity and improved selectivity in comparison to inhibition of orthosteric binding. C1 [Kim, Yoonkyung; de Castro, Sonia; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Ijzerman, Adriaan P.] Leiden Univ, Leiden Amsterdam Ctr Drug Res, Div Med Chem, NL-2300 RA Leiden, Netherlands. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI de castro, sonia/E-7303-2012; Jacobson, Kenneth/A-1530-2009; OI de castro, sonia/0000-0002-3838-6856; Jacobson, Kenneth/0000-0001-8104-1493; IJzerman, Ad/0000-0002-1182-2259 FU NIH; National Institute of Diabetes and Digestive and Kidney Diseases; European Union [QLK3-CT-2001-51963]; Ministerio de Educacion y Ciencia (Spain); Can-Fite Biopharma FX This research was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases, and by the European Union (Grant QLK3-CT-2001-51963). We thank Dr. Aniko Goblyos for preparation of compound 27, Dr. John Lloyd for collecting MS data, and Dr. Herman Yeh and Wesley White for the helpful advice on the NMR experiments. S.d.C. thanks Ministerio de Educacion y Ciencia (Spain) for financial support. Y.K. thanks the Can-Fite Biopharma for financial support. NR 28 TC 23 Z9 23 U1 3 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD APR 9 PY 2009 VL 52 IS 7 BP 2098 EP 2108 DI 10.1021/jm801659w PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 428GK UT WOS:000264835800031 PM 19284749 ER PT J AU Hanania, NA Sockrider, M Giraldo, L Valdez, R Flores, E Reibman, J DiMango, E Rogers, L Cammarata, C Carapetyan, K Sormillon, J Simpson, E Williams, L Sundy, J Dudek, G Newton, R Dugdale, A Teague, WG Fitzpatrick, A Khatri, S Patel, R Peabody, J Hunter, E Whitlock, D Smith, L Moy, J Naureckas, E Olopade, CS Hixon, J Brees, A Rivera, G Sietsema, S Zagaja, V Busk, M Williams, C Puntenney, P Busk, N Leone, F Hayes-Hampton, M Summer, WR Meyaski, G Wenzel, S Katial, R Lopez, L Lima, J Blake, K Santos, A Vega, K Lambiase, L Langford, T Schaeffer, D Lang, J Mcrae, M Karpel, J Cohen, R Ramdeo, R Irvin, CG Dixon, AE Kaminsky, DA Colletti, R Burns, SM Bourassa, LM Lang, SE Griffes, LV Pratt, R Nakos, KB Girard, KJ Mastronarde, J Mccoy, K Parsons, J Drake, J Compton, R Raterman, L Cosmar, D Gerald, LB Bailey, WC Erwin, S Kelley, A Laken, D Wanner, A Lockey, R Mendes, E McCullough, S Fimbel, B Grandstaff, M Blumenthal, MN Brottman, G Hagen, J Decker, A Lascewski, D Kelleher, S Bachman, K Quintard, C Sherry, C Salzman, G Pyszczynski, D Haney, P Castro, M Bacharier, L Sumino, K Scheipeter, ME Tarsi, J Wasserman, S Ramsdell, J Vitin, J Tucker, T Anthonisen, N Wise, R Holbrook, J Brown, E Amend-Libercci, D Barry, K Daniel, M Lears, A Leatherman, G Levine, C Masih, R Modak, S Nowakowski, D Prusakowski, N Shade, D Shiflett, C Sugar, E Richter, J Anthonisen, N Lancet, E Santos, A Taggart, V Edelman, N Wise, R Holbrook, J Hanania, N Williams, L Teague, G Smith, L Busk, M Leone, F Karpel, J Summer, W Blumenthal, M Lima, J Katial, R Irvin, C Reibman, J Dozor, A Mastronarde, J Castro, M Gerald, L Salzman, G Wanner, A Wasserman, S Lazarus, S Calhoun, W Kahrilas, P McWilliams, B Rogatko, A Sorkness, C Lancet, E Vento, R Edelman, N Rappaport, S Pezza, G Taggart, V Weinmann, G Snider, G Anthonisen, N Castro, M Fish, J Ingbar, D Jenkinson, S Mannino, D Perlstadt, H Rosenwasser, L Samet, J Schraufnagel, D Smith, J Smith, L Standiford, T Wanner, A Weaver, T AF Hanania, N. A. Sockrider, M. Giraldo, L. Valdez, R. Flores, E. Reibman, J. DiMango, E. Rogers, L. Cammarata, C. Carapetyan, K. Sormillon, J. Simpson, E. Williams, L. Sundy, J. Dudek, G. Newton, R. Dugdale, A. Teague, W. G. Fitzpatrick, A. Khatri, S. Patel, R. Peabody, J. Hunter, E. Whitlock, D. Smith, L. Moy, J. Naureckas, E. Olopade, C. S. Hixon, J. Brees, A. Rivera, G. Sietsema, S. Zagaja, V. Busk, M. Williams, C. Puntenney, P. Busk, N. Leone, F. Hayes-Hampton, M. Summer, W. R. Meyaski, G. Wenzel, S. Katial, R. Lopez, L. Lima, J. Blake, K. Santos, A. Vega, K. Lambiase, L. Langford, T. Schaeffer, D. Lang, J. McRae, M. Karpel, J. Cohen, R. Ramdeo, R. Irvin, C. G. Dixon, A. E. Kaminsky, D. A. Colletti, R. Burns, S. M. Bourassa, L. M. Lang, S. E. Griffes, L. V. Pratt, R. Nakos, K. B. Girard, K. J. Mastronarde, J. McCoy, K. Parsons, J. Drake, J. Compton, R. Raterman, L. Cosmar, D. Gerald, L. B. Bailey, W. C. Erwin, S. Kelley, A. Laken, D. Wanner, A. Lockey, R. Mendes, E. McCullough, S. Fimbel, B. Grandstaff, M. Blumenthal, M. N. Brottman, G. Hagen, J. Decker, A. Lascewski, D. Kelleher, S. Bachman, K. Quintard, C. Sherry, C. Salzman, G. Pyszczynski, D. Haney, P. Castro, M. Bacharier, L. Sumino, K. Scheipeter, M. E. Tarsi, J. Wasserman, S. Ramsdell, J. Vitin, J. Tucker, T. Anthonisen, N. Wise, R. Holbrook, J. Brown, E. Amend-Libercci, D. Barry, K. Daniel, M. Lears, A. Leatherman, G. Levine, C. Masih, R. Modak, S. Nowakowski, D. Prusakowski, N. Shade, D. Shiflett, C. Sugar, E. Richter, J. Anthonisen, N. Lancet, E. Santos, A. Taggart, V. Edelman, N. Wise, R. Holbrook, J. Hanania, N. Williams, L. Teague, G. Smith, L. Busk, M. Leone, F. Karpel, J. Summer, W. Blumenthal, M. Lima, J. Katial, R. Irvin, C. Reibman, J. Dozor, A. Mastronarde, J. Castro, M. Gerald, L. Salzman, G. Wanner, A. Wasserman, S. Lazarus, S. Calhoun, W. Kahrilas, P. McWilliams, B. Rogatko, A. Sorkness, C. Lancet, E. Vento, R. Edelman, N. Rappaport, S. Pezza, G. Taggart, V. Weinmann, G. Snider, G. Anthonisen, N. Castro, M. Fish, J. Ingbar, D. Jenkinson, S. Mannino, D. Perlstadt, H. Rosenwasser, L. Samet, J. Schraufnagel, D. Smith, J. Smith, L. Standiford, T. Wanner, A. Weaver, T. CA Amer Lung Assoc Asthma Clinical Re TI Efficacy of Esomeprazole for Treatment of Poorly Controlled Asthma. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GASTROESOPHAGEAL-REFLUX DISEASE; QUALITY-OF-LIFE; ESOPHAGEAL ACID PERFUSION; ADULT ASTHMATICS; PREVALENCE; SYMPTOMS; QUESTIONNAIRE; THERAPY; METHACHOLINE; VALIDATION AB Background: Gastroesophageal reflux is common among patients with asthma but often causes mild or no symptoms. It is not known whether treatment of gastroesophageal reflux with proton-pump inhibitors in patients who have poorly controlled asthma without symptoms of gastroesophageal reflux can substantially improve asthma control. Methods: In a parallel-group, double-blind trial, we randomly assigned 412 participants with inadequately controlled asthma, despite treatment with inhaled corticosteroids, and with minimal or no symptoms of gastroesophageal reflux to receive either 40 mg of esomeprazole twice a day or matching placebo. Participants were followed for 24 weeks with the use of daily asthma diaries, spirometry performed once every 4 weeks, and questionnaires that asked about asthma symptoms. We used ambulatory pH monitoring to ascertain the presence or absence of gastroesophageal reflux in the participants. The primary outcome was the rate of episodes of poor asthma control, as assessed on the basis of entries in asthma diaries. Results: Episodes of poor asthma control occurred with similar frequency in the placebo and esomeprazole groups (2.3 and 2.5 events per person-year, respectively; P=0.66). There was no treatment effect with respect to individual components of the episodes of poor asthma control or with respect to secondary outcomes, including pulmonary function, airway reactivity, asthma control, symptom scores, nocturnal awakening, or quality of life. The presence of gastroesophageal reflux, which was documented by pH monitoring in 40% of participants with minimal or no symptoms, did not identify a subgroup of patients that benefited from treatment with proton-pump inhibitors. There were fewer serious adverse events among patients receiving esomeprazole than among those receiving placebo (11 vs. 17). Conclusions: Despite a high prevalence of asymptomatic gastroesophageal reflux among patients with poorly controlled asthma, treatment with proton-pump inhibitors does not improve asthma control. Asymptomatic gastroesophageal reflux is not a likely cause of poorly controlled asthma. (ClinicalTrials.gov number, NCT00069823.) N Engl J Med 2009;360:1487-99. C1 [Sockrider, M.; Giraldo, L.; Valdez, R.; Flores, E.; Hanania, N.] Baylor Coll Med, Houston, TX 77030 USA. [Reibman, J.; DiMango, E.; Rogers, L.; Cammarata, C.; Carapetyan, K.; Sormillon, J.; Simpson, E.] Columbia Univ, New York Univ Consortium, New York, NY USA. [Williams, L.; Sundy, J.; Dudek, G.; Newton, R.; Dugdale, A.] Duke Univ, Med Ctr, Durham, NC USA. [Teague, W. G.; Fitzpatrick, A.; Khatri, S.; Patel, R.; Peabody, J.; Hunter, E.; Whitlock, D.] Emory Univ, Sch Med, Atlanta, GA USA. [Smith, L.; Moy, J.; Naureckas, E.; Olopade, C. S.; Hixon, J.; Brees, A.; Rivera, G.; Sietsema, S.; Zagaja, V.] Illinois Consortium, Chicago, IL USA. [Busk, M.; Williams, C.; Puntenney, P.; Busk, N.] Indiana Univ, Asthma Clin Res Ctr, Indianapolis, IN 46204 USA. [Leone, F.; Hayes-Hampton, M.] Univ Penn, Philadelphia, PA 19104 USA. [Summer, W. R.; Meyaski, G.] Louisiana State Univ, Hlth Sci Ctr, Ernest N Morial Asthma Allergy & Resp Dis Ctr, New Orleans, LA USA. [Wenzel, S.; Katial, R.; Lopez, L.] Natl Jewish Med & Res Ctr, Denver, CO USA. [Lima, J.; Blake, K.; Santos, A.; Vega, K.; Lambiase, L.; Langford, T.; Schaeffer, D.; Lang, J.; McRae, M.] Univ Florida Consortium, Nemours Childrens Clin, Jacksonville, FL USA. [Karpel, J.; Cohen, R.; Ramdeo, R.] N Shore Long Isl Jewish Hlth Syst, New Hyde Pk, NY USA. [Irvin, C. G.; Dixon, A. E.; Kaminsky, D. A.; Colletti, R.; Burns, S. M.; Bourassa, L. M.; Lang, S. E.; Griffes, L. V.; Pratt, R.; Nakos, K. B.; Girard, K. J.] No New England Consortium, Colchester, VT USA. [Mastronarde, J.; McCoy, K.; Parsons, J.; Drake, J.; Compton, R.; Raterman, L.; Cosmar, D.] Nationwide Childrens Hosp, Ohio State Univ Med Ctr, Columbus, OH USA. [Gerald, L. B.; Bailey, W. C.; Erwin, S.; Kelley, A.; Laken, D.] Univ Alabama Birmingham, Birmingham, AL USA. [Lockey, R.; McCullough, S.] Univ S Florida, Tampa, FL USA. [Wanner, A.; Mendes, E.] Univ Miami, Miami, FL USA. [Brottman, G.; Hagen, J.; Decker, A.; Lascewski, D.; Kelleher, S.; Bachman, K.; Quintard, C.; Sherry, C.; Blumenthal, M.] Univ Minnesota, Minneapolis, MN USA. [Salzman, G.; Pyszczynski, D.; Haney, P.] Univ Missouri, Sch Med, Kansas City, MO USA. [Castro, M.; Bacharier, L.; Sumino, K.; Scheipeter, M. E.; Tarsi, J.] Washington Univ, St Louis Asthma Clin Res Ctr, St Louis, MO 63130 USA. [Wasserman, S.; Ramsdell, J.; Vitin, J.; Tucker, T.] Univ Calif San Diego, San Diego, CA 92103 USA. [Anthonisen, N.] Resp Hosp, Winnipeg, MB, Canada. [Wise, R.; Holbrook, J.; Brown, E.; Amend-Libercci, D.; Barry, K.; Daniel, M.; Lears, A.; Leatherman, G.; Levine, C.; Masih, R.; Modak, S.; Nowakowski, D.; Prusakowski, N.; Shade, D.; Shiflett, C.; Sugar, E.] Johns Hopkins Univ, Ctr Clin Trials, Data Coordinating Ctr, Baltimore, MD USA. [Richter, J.] Temple Univ, Sch Med, Esophageal PH Probe Qual Control Ctr, Philadelphia, PA 19122 USA. [Lancet, E.; Edelman, N.; Vento, R.; Rappaport, S.; Pezza, G.] Amer Lung Assoc, Project Off, New York, NY 10019 USA. [Taggart, V.; Weinmann, G.] NHLBI, Project Off, Bethesda, MD 20892 USA. RP Hanania, NA (reprint author), Baylor Coll Med, Houston, TX 77030 USA. RI Parsons, Jonathan/E-3824-2011; OI Wise, Robert/0000-0002-8353-2349 FU National Heart, Lung, and Blood Institute [5U01HL072968]; American Lung Association FX Supported by grants from the National Heart, Lung, and Blood Institute (5U01HL072968) and the American Lung Association. The study drug and placebo were supplied by AstraZeneca. NR 44 TC 168 Z9 170 U1 1 U2 10 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 9 PY 2009 VL 360 IS 15 BP 1487 EP 1499 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 430GL UT WOS:000264976800005 ER PT J AU Rider, LG Atkinson, JC AF Rider, Lisa G. Atkinson, Jane C. TI Gingival and Periungual Vasculopathyof Juvenile Dermatomyositis. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Rider, Lisa G.; Atkinson, Jane C.] NIH, Bethesda, MD 20892 USA. RP Rider, LG (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM riderl@mail.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 9 PY 2009 VL 360 IS 15 BP 1540 EP 1540 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 430GL UT WOS:000264976800011 ER PT J AU Celi, FS AF Celi, Francesco S. TI Brown Adipose Tissue -- When It Pays to Be Inefficient. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID ENERGY-EXPENDITURE; FAT; ACTIVATION C1 NIDDK, Clin Endocrinol Branch, Bethesda, MD 20892 USA. RP Celi, FS (reprint author), NIDDK, Clin Endocrinol Branch, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 DK047057-01] NR 12 TC 61 Z9 65 U1 0 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 9 PY 2009 VL 360 IS 15 BP 1553 EP 1556 DI 10.1056/NEJMe0900466 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 430GL UT WOS:000264976800015 PM 19357412 ER PT J AU Tita, ATN Landon, MB Spong, CY AF Tita, Alan T. N. Landon, Mark B. Spong, Catherine Y. TI Timing of Elective Repeat Cesarean Delivery at Term Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID RISK C1 [Tita, Alan T. N.] Univ Alabama, Birmingham, AL 35249 USA. [Landon, Mark B.] Ohio State Univ, Columbus, OH 43210 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver NICHHD, Bethesda, MD 20892 USA. RP Tita, ATN (reprint author), Univ Alabama, Birmingham, AL 35249 USA. EM alan.tita@obgyn.uab.edu NR 3 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 9 PY 2009 VL 360 IS 15 BP 1570 EP 1571 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 430GL UT WOS:000264976800019 ER PT J AU Rivkees, SA Mattison, DR AF Rivkees, Scott A. Mattison, Donald R. TI Ending Propylthiouracil-Induced Liver Failure in Children. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID GRAVES-DISEASE C1 [Rivkees, Scott A.] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Mattison, Donald R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Rivkees, SA (reprint author), Yale Univ, Sch Med, 333 Cedar St, New Haven, CT 06520 USA. EM scott.rivkees@yale.edu RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 5 TC 46 Z9 47 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 9 PY 2009 VL 360 IS 15 BP 1574 EP 1575 DI 10.1056/NEJMc0809750 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 430GL UT WOS:000264976800026 PM 19357418 ER PT J AU de Cabo, R Navas, P AF de Cabo, Rafael Navas, Placido TI "AcCoA"lade for Energy and Life Span SO CELL METABOLISM LA English DT Editorial Material ID PHOSPHOENOLPYRUVATE CARBOXYKINASE; GLUCONEOGENESIS; ACETYLATION; METABOLISM; MOUSE; LIVER AB Faced with changing food availability, organisms adapt metabolism to survive. In a recent issue of Cell, Lin et al. (2009) described the acetylation of an extranuclear enzyme being regulated by acetyl-CoA. This finding connects nutrient availability, energy status, and survival. C1 [de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Navas, Placido] Univ Pablo Olavide CSIC, Ctr Andaluz Biol Desarrollo, E-41013 Seville, Spain. [Navas, Placido] ISCIII, Ctr Biomed Res Rare Dis CIBERER, E-41013 Seville, Spain. RP de Cabo, R (reprint author), NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. EM decabora@mail.nih.gov; pnavas@upo.es OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Intramural Research Program of the National Institute on Aging FX This work is supported by the Intramural Research Program of the National Institute on Aging. NR 11 TC 2 Z9 2 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD APR 8 PY 2009 VL 9 IS 4 BP 305 EP 306 DI 10.1016/j.cmet.2009.03.009 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 430YN UT WOS:000265028600002 PM 19356710 ER PT J AU Purushotham, A Schug, TT Xu, Q Surapureddi, S Guo, XM Li, XL AF Purushotham, Aparna Schug, Thaddeus T. Xu, Qing Surapureddi, Sailesh Guo, Xiumei Li, Xiaoling TI Hepatocyte-Specific Deletion of SIRT1 Alters Fatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation SO CELL METABOLISM LA English DT Article ID PROLIFERATOR-ACTIVATED-RECEPTOR; INSULIN-RESISTANCE; COACTIVATOR PGC-1; LIPID-METABOLISM; CELL-SURVIVAL; TRANSCRIPTION FACTORS; PROTEIN DEACETYLASES; CALORIE RESTRICTION; ADIPOSE-TISSUE; LIVER-DISEASE AB Hepatic metabolic derangements are key components in the development of fatty liver, insulin resistance, and atherosclerosis. SIRT1, a NAD(+)-dependent protein deacetylase, is an important regulator of energy homeostasis in response to nutrient availability. Here we demonstrate that hepatic SIRT1 regulates lipid homeostasis by positively regulating peroxisome proliferators-activated receptor alpha (PPAR alpha), a nuclear receptor that mediates the adaptive response to fasting and starvation. Hepatocyte-specific deletion of SIRT1 impairs PPAR alpha signaling and decreases fatty acid beta-oxidation, whereas overexpression of SIRT1 induces the expression of PPAR alpha targets. SIRT1 interacts with PPAR alpha and is required to activate PPARa coactivator PGC-1 alpha. When challenged with a high-fat diet, liver-specific SIRT1 knockout mice develop hepatic steatosis, hepatic inflammation, and endoplasmic reticulum stress. Taken together, our data indicate that SIRT1 plays a vital role in the regulation of hepatic lipid homeostasis and that pharmacological activation of SIRT1 may be important for the prevention of obesity-associated metabolic diseases. C1 [Purushotham, Aparna; Schug, Thaddeus T.; Xu, Qing; Guo, Xiumei; Li, Xiaoling] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Surapureddi, Sailesh] NIEHS, Pharmacol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Li, XL (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM lix3@niehs.nih.gov FU NIEHS Laboratory of Experimental Pathology; Intramural Research Program of the NIH; National Institute of Environmental Health Sciences [Z01 ES102205] FX We thank Drs. Anton Jetten, Paul Wade, and John Cidlowski for critical reading of the manuscript and Dr. Frederic Alt at Harvard Medical School for providing the SIRT1 axon 4 floxed allele. We also thank the NIEHS microarray facility for performing the microarray experiments and Jennifer Collins for analyzing the microarray data; the NIEHS Laboratory of Experimental Pathology for histological staining and serum hormone ELISA; and the NIEHS viral core facility for lentiviruses. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences to X.L. (Z01 ES102205). NR 64 TC 430 Z9 455 U1 10 U2 35 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 APR 8 PY 2009 VL 9 IS 4 BP 327 EP 338 DI 10.1016/j.cmet.2009.02.006 PG 12 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 430YN UT WOS:000265028600006 PM 19356714 ER PT J AU Gottlieb, S Rey, RA Malozowski, S AF Gottlieb, Silvia Rey, Rodolfo A. Malozowski, Saul TI Klinefelter Syndrome and Cryptorchidism SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Gottlieb, Silvia; Rey, Rodolfo A.] Hosp Ninos Dr Ricardo Gutierrez, Ctr Invest Endocrinol, Buenos Aires, DF, Argentina. [Malozowski, Saul] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Gottlieb, S (reprint author), Hosp Ninos Dr Ricardo Gutierrez, Ctr Invest Endocrinol, Buenos Aires, DF, Argentina. EM sm87j@nih.gov NR 3 TC 4 Z9 5 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD APR 8 PY 2009 VL 301 IS 14 BP 1436 EP 1437 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 429MN UT WOS:000264924900020 PM 19351939 ER PT J AU O'Connor, CM Whellan, DJ Lee, KL Keteyian, SJ Cooper, LS Ellis, SJ Leifer, ES Kraus, WE Kitzman, DW Blumenthal, JA Rendall, DS Miller, NH Fleg, JL Schulman, KA McKelvie, RS Zannad, F Pina, IL AF O'Connor, Christopher M. Whellan, David J. Lee, Kerry L. Keteyian, Steven J. Cooper, Lawton S. Ellis, Stephen J. Leifer, Eric S. Kraus, William E. Kitzman, Dalane W. Blumenthal, James A. Rendall, David S. Miller, Nancy Houston Fleg, Jerome L. Schulman, Kevin A. McKelvie, Robert S. Zannad, Faiez Pina, Ileana L. CA HF-ACTION Investigators TI Efficacy and Safety of Exercise Training in Patients With Chronic Heart Failure HF-ACTION Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article; Proceedings Paper CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc ID CARDIAC-RESYNCHRONIZATION; INVESTIGATING OUTCOMES; CLINICAL-TRIALS; MORBIDITY; MORTALITY; DIAGNOSIS; MANAGEMENT; CAPTOPRIL; CAPACITY; THERAPY AB Context Guidelines recommend that exercise training be considered for medically stable outpatients with heart failure. Previous studies have not had adequate statistical power to measure the effects of exercise training on clinical outcomes. Objective To test the efficacy and safety of exercise training among patients with heart failure. Design, Setting, and Patients Multicenter, randomized controlled trial of 2331 medically stable outpatients with heart failure and reduced ejection fraction. Participants in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) were randomized from April 2003 through February 2007 at 82 centers within the United States, Canada, and France; median follow-up was 30 months. Interventions Usual care plus aerobic exercise training, consisting of 36 supervised sessions followed by home-based training, or usual care alone. Main Outcome Measures Composite primary end point of all-cause mortality or hospitalization and prespecified secondary end points of all-cause mortality, cardiovascular mortality or cardiovascular hospitalization, and cardiovascular mortality or heart failure hospitalization. Results The median age was 59 years, 28% were women, and 37% had New York Heart Association class III or IV symptoms. Heart failure etiology was ischemic in 51%, and median left ventricular ejection fraction was 25%. Exercise adherence decreased from a median of 95 minutes per week during months 4 through 6 of follow-up to 74 minutes per week during months 10 through 12. A total of 759 patients (65%) in the exercise training group died or were hospitalized compared with 796 patients (68%) in the usual care group (hazard ratio [HR], 0.93 [95% confidence interval {CI}, 0.84-1.02]; P=.13). There were nonsignificant reductions in the exercise training group for mortality (189 patients [16%] in the exercise training group vs 198 patients [17%] in the usual care group; HR, 0.96 [95% CI, 0.79-1.17]; P=.70), cardiovascular mortality or cardiovascular hospitalization (632 [55%] in the exercise training group vs 677 [58%] in the usual care group; HR, 0.92 [95% CI, 0.83-1.03]; P=.14), and cardiovascular mortality or heart failure hospitalization (344 [30%] in the exercise training group vs 393 [34%] in the usual care group; HR, 0.87 [95% CI, 0.75-1.00]; P=.06). In prespecified supplementary analyses adjusting for highly prognostic baseline characteristics, the HRs were 0.89 (95% CI, 0.81-0.99; P=.03) for all-cause mortality or hospitalization, 0.91 (95% CI, 0.82-1.01; P=.09) for cardiovascular mortality or cardiovascular hospitalization, and 0.85 (95% CI, 0.74-0.99; P=.03) for cardiovascular mortality or heart failure hospitalization. Other adverse events were similar between the groups. Conclusions In the protocol-specified primary analysis, exercise training resulted in nonsignificant reductions in the primary end point of all-cause mortality or hospitalization and in key secondary clinical end points. After adjustment for highly prognostic predictors of the primary end point, exercise training was associated with modest significant reductions for both all-cause mortality or hospitalization and cardiovascular mortality or heart failure hospitalization. Trial Registration clinicaltrials.gov Identifier: NCT00047437 C1 [O'Connor, Christopher M.; Whellan, David J.; Lee, Kerry L.; Ellis, Stephen J.; Rendall, David S.; Schulman, Kevin A.] Duke Clin Res Inst, Durham, NC USA. [O'Connor, Christopher M.; Kraus, William E.; Schulman, Kevin A.] Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. [Lee, Kerry L.] Duke Univ, Sch Med, Dept Biostat & Bioinformat, Durham, NC 27706 USA. [Blumenthal, James A.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. [Whellan, David J.] Thomas Jefferson Univ, Jefferson Med Coll, Dept Med, Philadelphia, PA 19107 USA. [Keteyian, Steven J.] Henry Ford Hosp, Div Cardiovasc Med, Detroit, MI 48202 USA. [Cooper, Lawton S.; Leifer, Eric S.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Dis, Bethesda, MD 20892 USA. [Kitzman, Dalane W.] Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC 27109 USA. [Miller, Nancy Houston] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [McKelvie, Robert S.] Hamilton Hlth Sci, Hamilton, ON, Canada. [Zannad, Faiez] Univ Henri Poincare, Ctr Hosp Univ, INSERM, Ctr Invest Clin, Nancy, France. [Pina, Ileana L.] Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. RP O'Connor, CM (reprint author), Duke Clin Res Inst, POB 17969, Durham, NC USA. EM oconn002@mc.duke.edu RI Ventura, Hector/A-7691-2011; OI Kraus, William E/0000-0003-1930-9684 FU NHLBI NIH HHS [5U01HL064264, 5U01HL063747, 5U01HL064250, 5U01HL064257, 5U01HL064265, 5U01HL066461, 5U01HL066482, 5U01HL066491, 5U01HL066494, 5U01HL066497, 5U01HL066501, 5U01HL068973, 5U01HL068980, U01 HL063747, U01 HL063747-06S1, U01 HL064250, U01 HL064250-06, U01 HL064257, U01 HL064257-01A2, U01 HL064264, U01 HL064264-05, U01 HL064265, U01 HL064265-04, U01 HL066461, U01 HL066461-06S1, U01 HL066482, U01 HL066482-04, U01 HL066491, U01 HL066491-06, U01 HL066494, U01 HL066494-04, U01 HL066497, U01 HL066497-04, U01 HL066501, U01 HL066501-06, U01 HL068973, U01 HL068973-06, U01 HL068980, U01 HL068980-05]; NIA NIH HHS [R01 AG018915, R37 AG018915] NR 28 TC 598 Z9 623 U1 1 U2 51 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD APR 8 PY 2009 VL 301 IS 14 BP 1439 EP 1450 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 429MN UT WOS:000264924900024 PM 19351941 ER PT J AU Flynn, KE Pina, IL Whellan, DJ Lin, L Blumenthal, JA Ellis, SJ Fine, LJ Howlett, JG Keteyian, SJ Kitzman, DW Kraus, WE Miller, NH Schulman, KA Spertus, JA O'Connor, CM Weinfurt, KP AF Flynn, Kathryn E. Pina, Ileana L. Whellan, David J. Lin, Li Blumenthal, James A. Ellis, Stephen J. Fine, Lawrence J. Howlett, Jonathan G. Keteyian, Steven J. Kitzman, Dalane W. Kraus, William E. Miller, Nancy Houston Schulman, Kevin A. Spertus, John A. O'Connor, Christopher M. Weinfurt, Kevin P. TI Effects of Exercise Training on Health Status in Patients With Chronic Heart Failure HF-ACTION Randomized Controlled Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article; Proceedings Paper CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc ID QUALITY-OF-LIFE; CARDIAC RESYNCHRONIZATION; ELDERLY-PATIENTS; PREDICTORS; CAPACITY; OUTCOMES; MIRACLE AB Context Findings from previous studies of the effects of exercise training on patient-reported health status have been inconsistent. Objective To test the effects of exercise training on health status among patients with heart failure. Design, Setting, and Patients Multicenter, randomized controlled trial among 2331 medically stable outpatients with heart failure with left ventricular ejection fraction of 35% or less. Patients were randomized from April 2003 through February 2007. Interventions Usual care plus aerobic exercise training (n = 1172), consisting of 36 supervised sessions followed by home-based training, vs usual care alone (n = 1159). Randomization was stratified by heart failure etiology, which was a covariate in all models. Main Outcome Measures Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary scale and key subscales at baseline, every 3 months for 12 months, and annually thereafter for up to 4 years. The KCCQ is scored from 0 to 100 with higher scores corresponding to better health status. Treatment group effects were estimated using linear mixed models according to the intention-to-treat principle. Results Median follow-up was 2.5 years. At 3 months, usual care plus exercise training led to greater improvement in the KCCQ overall summary score (mean, 5.21; 95% confidence interval, 4.42 to 6.00) compared with usual care alone (3.28; 95% confidence interval, 2.48 to 4.09). The additional 1.93-point increase (95% confidence interval, 0.84 to 3.01) in the exercise training group was statistically significant (P < .001). After 3 months, there were no further significant changes in KCCQ score for either group (P = .85 for the difference between slopes), resulting in a sustained, greater improvement overall for the exercise group (P < .001). Results were similar on the KCCQ subscales, and no subgroup interactions were detected. Conclusions Exercise training conferred modest but statistically significant improvements in self-reported health status compared with usual care without training. Improvements occurred early and persisted over time. Trial Registration clinicaltrials.gov Identifier: NCT00047437. C1 [Flynn, Kathryn E.] Duke Univ, Sch Med, Duke Clin Res Inst, Ctr Clin & Genet Econ, Durham, NC 27715 USA. [Flynn, Kathryn E.; Blumenthal, James A.; Weinfurt, Kevin P.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC 27715 USA. [Kraus, William E.; Schulman, Kevin A.; O'Connor, Christopher M.] Duke Univ, Sch Med, Dept Med, Durham, NC 27715 USA. [Pina, Ileana L.] Case Western Reserve Univ, Sch Med, Dept Med, Cleveland, OH 44106 USA. [Whellan, David J.] Thomas Jefferson Univ, Jefferson Med Coll, Dept Med, Philadelphia, PA 19107 USA. [Fine, Lawrence J.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Miller, Nancy Houston] Stanford Univ, Dept Med, Stanford, CA 94305 USA. [Howlett, Jonathan G.] Dalhousie Univ, Queen Elizabeth Hlth Sci Ctr 2, Halifax, NS, Canada. [Keteyian, Steven J.] Henry Ford Hosp, Div Cardiovasc Med, Detroit, MI 48202 USA. [Kitzman, Dalane W.] Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC 27109 USA. [Spertus, John A.] St Lukes Hlth Syst, Mid Amer Heart Inst, Kansas City, MO USA. [Spertus, John A.] Univ Missouri Kansas City, Kansas City, MO USA. RP Flynn, KE (reprint author), Duke Univ, Sch Med, Duke Clin Res Inst, Ctr Clin & Genet Econ, POB 17969, Durham, NC 27715 USA. EM kathryn.flynn@duke.edu RI Flynn, Kathryn/M-5346-2013; OI Flynn, Kathryn/0000-0002-4427-3583; Kraus, William E/0000-0003-1930-9684 FU NHLBI NIH HHS [5U01HL063747, 5U01HL064250, 5U01HL064257, 5U01HL064264, 5U01HL064265, 5U01HL066461, 5U01HL066482, 5U01HL066491, 5U01HL066494, 5U01HL066497, 5U01HL066501, 5U01HL068973, 5U01HL068980, U01 HL063747, U01 HL063747-06S1, U01 HL064250, U01 HL064250-06, U01 HL064257, U01 HL064257-01A2, U01 HL064264, U01 HL064264-05, U01 HL064265, U01 HL064265-04, U01 HL066461, U01 HL066461-06S1, U01 HL066482, U01 HL066482-04, U01 HL066491, U01 HL066491-06, U01 HL066494, U01 HL066494-04, U01 HL066497, U01 HL066497-04, U01 HL066501, U01 HL066501-06, U01 HL068973, U01 HL068973-06, U01 HL068980, U01 HL068980-05]; NIA NIH HHS [R01 AG018915, R37 AG018915] NR 25 TC 262 Z9 274 U1 1 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD APR 8 PY 2009 VL 301 IS 14 BP 1451 EP 1459 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 429MN UT WOS:000264924900025 PM 19351942 ER PT J AU Virador, VM Davidson, B Czechowicz, J Mai, A Kassis, J Kohn, EC AF Virador, Victoria M. Davidson, Ben Czechowicz, Josephine Mai, Alisha Kassis, Jareer Kohn, Elise C. TI The Anti-Apoptotic Activity of BAG3 Is Restricted by Caspases and the Proteasome SO PLOS ONE LA English DT Article AB Background: Caspase-mediated cleavage and proteasomal degradation of ubiquitinated proteins are two independent mechanisms for the regulation of protein stability and cellular function. We previously reported BAG3 overexpression protected ubiquitinated clients, such as AKT, from proteasomal degradation and conferred cytoprotection against heat shock. We hypothesized that the BAG3 protein is regulated by proteolysis. Methodology/Principal Findings: Staurosporine (STS) was used as a tool to test for caspase involvement in BAG3 degradation. MDA435 and HeLa human cancer cell lines exposed to STS underwent apoptosis with a concomitant time and dose-dependent loss of BAG3, suggesting the survival role of BAG3 was subject to STS regulation. zVAD-fmk or caspase 3 and 9 inhibitors provided a strong but incomplete protection of both cells and BAG3 protein. Two putative caspase cleavage sites were tested: K (E) under barV (D) under bar (BAG3(E345A/D347A)) within the proline-rich center of BAG3 (PXXP) and the C-terminal L (E) under barA (D) under bar site (BAG3(E516A/D518A)). PXXP deletion mutant and BAG3(E345A/D347A), or BAG3(E516A/D518A) respectively slowed or stalled STS-mediated BAG3 loss. BAG3, ubiquitinated under basal growth conditions, underwent augmented ubiquitination upon STS treatment, while there was no increase in ubiquitination of the BAG3(E516A/D518A) caspase-resistant mutant. Caspase and proteasome inhibition resulted in partial and independent protection of BAG3 whereas inhibitors of both blocked BAG3 degradation. STS-induced apoptosis was increased when BAG3 was silenced, and retention of BAG3 was associated with cytoprotection. Conclusions/Significance: BAG3 is tightly controlled by selective degradation during STS exposure. Loss of BAG3 under STS injury required sequential caspase cleavage followed by polyubiquitination and proteasomal degradation. The need for dual regulation of BAG3 in apoptosis suggests a key role for BAG3 in cancer cell resistance to apoptosis. RP Virador, VM (reprint author), NCI, Mol Signaling Sect, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM vvirador@helix.nih.gov FU Intramural NIH HHS NR 37 TC 12 Z9 14 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 APR 8 PY 2009 VL 4 IS 4 AR e5136 DI 10.1371/journal.pone.0005136 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437RX UT WOS:000265505700023 PM 19352495 ER PT J AU Fine, HA AF Fine, Howard A. TI Glioma Stem Cells: Not All Created Equal SO CANCER CELL LA English DT Editorial Material ID TUMOR-INITIATING CELLS; TGF-BETA; BRAIN AB A growing body of evidence suggests that only a small subpopulation of malignant glioma cells have true tumorigenic potential. A study by Penuelas et al. in this issue of Cancer Cell demonstrates that TGF-beta can stimulate self-renewal and inhibit differentiation in a proportion of these glioma-initiating cells. C1 NCI, Ctr Canc Res, Neurooncol Branch, NINDS,NIH, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), NCI, Ctr Canc Res, Neurooncol Branch, NINDS,NIH, Bethesda, MD 20892 USA. EM hfine@mail.nih.gov NR 9 TC 15 Z9 16 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 APR 7 PY 2009 VL 15 IS 4 BP 247 EP 249 DI 10.1016/j.ccr.2009.03.010 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 432DR UT WOS:000265114200003 PM 19345322 ER PT J AU Xu, KX Shimelis, H Linn, DE Jiang, RC Yang, X Sun, F Guo, ZY Chen, HG Li, W Chen, HG Kong, XT Melamed, J Fang, SY Xiao, Z Veenstra, TD Qiu, Y AF Xu, Kexin Shimelis, Hermela Linn, Douglas E. Jiang, Richeng Yang, Xi Sun, Feng Guo, Zhiyong Chen, Hege Li, Wei Chen, Hegang Kong, Xiangtian Melamed, Jonathan Fang, Shengyun Xiao, Zhen Veenstra, Timothy D. Qiu, Yun TI Regulation of Androgen Receptor Transcriptional Activity and Specificity by RNF6-induced Ubiquitination SO CANCER CELL LA English DT Article ID RECURRENT PROSTATE-CANCER; CONJUGATING ENZYMES E2S; POLYUBIQUITIN CHAINS; TYROSINE PHOSPHORYLATION; DNA-REPAIR; PROTEIN; GENE; LIGASE; RING; DEGRADATION AB The androgen receptor (AR) plays a critical role in prostate cancer. We have identified a ubiquitin E3 ligase, RNF6, as an AR-associated protein in a proteomic screen. RNF6 induces AR ubiquitination and promotes AR transcriptional activity. Specific knockdown of RNF6 or mutation of RNF6-induced ubiquitination acceptor sites on AR selectively alters expression of a subset of AR target genes and diminishes recruitment of AR and its coactivators to androgen-responsive elements present in the regulatory region of these genes. Furthermore, RNF6 is overexpressed in hormone-refractory human prostate cancer tissues and required for prostate cancer cell growth under androgen-depleted conditions. Our data suggest that RNF6-induced ubiquitination may regulate AR transcriptional activity and specificity through modulating cofactor recruitment. C1 [Xu, Kexin; Shimelis, Hermela; Linn, Douglas E.; Jiang, Richeng; Yang, Xi; Sun, Feng; Guo, Zhiyong; Chen, Hege; Li, Wei; Qiu, Yun] Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. [Xu, Kexin; Shimelis, Hermela; Linn, Douglas E.; Jiang, Richeng; Yang, Xi; Sun, Feng; Guo, Zhiyong; Chen, Hege; Li, Wei; Qiu, Yun] Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Chen, Hegang] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Kong, Xiangtian; Melamed, Jonathan] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Fang, Shengyun] Univ Maryland, Inst Biotechnol, Ctr Med Biotechnol, Baltimore, MD 21201 USA. [Xiao, Zhen; Veenstra, Timothy D.] SAIC Frederick Inc, NCI, Lab Prote & Analyt Technol, Frederick, MD 21702 USA. RP Qiu, Y (reprint author), Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. EM yqiu@som.umaryland.edu RI Fang, Shengyun/H-3802-2011; OI Shimelis, Hermela/0000-0003-1284-8909; Melamed, Jonathan/0000-0003-2844-7990 FU NIH [CA106504, N01-CO-12400]; US Department of Defense (DOD) [W81XWH-06-10199, W81XWH-08-1-0126]; NCI [U01-CA86772]; DOD Predoctoral Fellowship [W81XWH-06-1-0005, W81XWH08-1-0068] FX We would like to thank B. Guan and C. Bieberich for their assistance with ubiquitination assays. This work was supported in part by NIH grant CA106504 and US Department of Defense (DOD) grants W81XWH-06-10199 and W81XWH-08-1-0126 to Y.O., NIH grant NCI U01-CA86772 to J.M., NIH contract N01-CO-12400 to T.D.V., DOD Predoctoral Fellowship W81XWH-06-1-0005 to KX, and DOD Predoctoral Fellowship W81XWH08-1-0068 to D.E.L. NR 54 TC 87 Z9 93 U1 0 U2 9 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 APR 7 PY 2009 VL 15 IS 4 BP 270 EP 282 DI 10.1016/j.ccr.2009.02.021 PG 13 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 432DR UT WOS:000265114200007 PM 19345326 ER PT J AU Preis, SR Hwang, SJ Coady, S Pencina, MJ D'Agostino, RB Savage, PJ Levy, D Fox, CS AF Preis, Sarah Rosner Hwang, Shih-Jen Coady, Sean Pencina, Michael J. D'Agostino, Ralph B., Sr. Savage, Peter J. Levy, Daniel Fox, Caroline S. TI Trends in All-Cause and Cardiovascular Disease Mortality Among Women and Men With and Without Diabetes Mellitus in the Framingham Heart Study, 1950 to 2005 SO CIRCULATION LA English DT Article DE diabetes mellitus; mortality; men; trends; women ID POPULATION; PREVALENCE; GLUCOSE; ADULTS; DECLINE; BURDEN; HEALTH AB Background-Despite population declines in all-cause mortality, women with diabetes mellitus may have experienced an increase in mortality rates compared with men. Methods and Results-We examined change in all-cause, cardiovascular, and non-cardiovascular disease mortality rates among Framingham Heart Study participants who attended examinations during an "earlier" ( 1950 to 1975; n = 930 deaths) and a "later" (1976 to 2001; n = 773 deaths) time period. Diabetes mellitus was defined as casual glucose >= 200 mg/dL, fasting plasma glucose >= 126 mg/dL, or treatment. Among women, the hazard ratios (HRs) for all-cause mortality in the later versus the earlier time period were 0.59 (95% confidence interval, 0.50 to 0.70; P < 0.0001) for those without diabetes mellitus and 0.48 ( 95% confidence interval, 0.32 to 0.71; P = 0.002) for those with diabetes mellitus. Similar results were observed in men. Among women and men, the HR of cardiovascular disease mortality declined among those with and without diabetes mellitus. Non-cardiovascular disease mortality declined among women without diabetes mellitus (HR, 0.76; P = 0.01), whereas no change was observed among women with diabetes mellitus or among men with or without diabetes mellitus. Individuals with versus those without diabetes mellitus were at increased risk of all-cause mortality in the earlier (HR, 2.44; P < 0.0001) and later (HR, 1.95; P < 0.0001) time periods. Conclusions-Reductions in all-cause mortality among women and men with diabetes mellitus have occurred over time. However, mortality rates among individuals with diabetes mellitus remain approximate to 2-fold higher compared with individuals without diabetes mellitus. (Circulation. 2009; 119: 1728-1735.) C1 [Preis, Sarah Rosner; Hwang, Shih-Jen; Levy, Daniel; Fox, Caroline S.] NHLBIs Framingham Heart Study, Framingham, MA 01702 USA. [Preis, Sarah Rosner; Hwang, Shih-Jen; Coady, Sean; Savage, Peter J.; Levy, Daniel; Fox, Caroline S.] NHLBI, NIH, Bethesda, MD 20892 USA. [Pencina, Michael J.; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol & Metab, Boston, MA 02115 USA. [Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. RP Fox, CS (reprint author), NHLBIs Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Preis, Sarah/0000-0002-9360-4166 FU National Heart, Lung, and Blood Institute [N01-HC-25195] FX This work was supported by the National Heart, Lung, and Blood Institute ( NIH contract N01-HC-25195). NR 22 TC 227 Z9 237 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD APR 7 PY 2009 VL 119 IS 13 BP 1728 EP U65 DI 10.1161/CIRCULATIONAHA.108.829176 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 429OA UT WOS:000264928800007 PM 19307472 ER PT J AU Percus, JK Percus, OE Di Mascio, M AF Percus, Jerrome K. Percus, Ora E. Di Mascio, Michele TI The amplitudes of viral blips in HIV-1 infected patients treated with antiretroviral therapy are power-law distributed SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Poisson; Kinetics; Reservoirs; HAART; Viral load ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4(+) T-CELLS; COMBINATION THERAPY; LATENT RESERVOIR; DRUG-RESISTANCE; IN-VIVO; HIV-1 INFECTION; RNA LEVELS; REPLICATION; DECAY AB We previously reported that in patients treated with highly active antiretroviral therapy (HAART) who achieve viral load (VL) suppression, low fluctuations of viral load over the threshold of detection (viral blips) more than 4 weeks apart occur at random, with a frequency that does not change with longer times of observation. The etiology of viral blips is currently unknown, but viral blip frequency inversely correlates with the decay of the latent reservoir, whose stability has been proposed as the major hurdle to HIV eradication. We show here that the distribution of viral blip amplitudes observed in a group of 272 patients successfully treated with highly active antiretroviral therapy appears to be power-law distributed. Such a distribution can be theoretically generated by randomly sampling the arrival of asynchronous and overlapping elementary pulses of viremia, with asymptotic exponential decay of kinetics, thus suggesting that the low fluctuations of viremia observed in patients during HAART treatment is, in part, a discrete phenomenon consistent with random activation of latently infected cells or release of virus and infected cells into the blood compartment from unknown sites of active viral replication. Published by Elsevier Ltd. C1 [Di Mascio, Michele] NIAID, NIH, Bethesda, MD 20892 USA. [Percus, Jerrome K.; Percus, Ora E.] New York Univ, Courant Inst, New York, NY 10012 USA. [Percus, Jerrome K.] New York Univ, Dept Phys, New York, NY 10003 USA. RP Di Mascio, M (reprint author), NIAID, NIH, Bethesda, MD 20892 USA. EM MDiMascio@niaid.nih.gov NR 36 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD APR 7 PY 2009 VL 257 IS 3 BP 454 EP 459 DI 10.1016/j.jtbi.2008.12.034 PG 6 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 422TC UT WOS:000264449600011 PM 19171155 ER PT J AU Li, G Arora, NC Xie, H Ning, H Lu, W Low, D Citrin, D Kaushal, A Zach, L Camphausen, K Miller, RW AF Li, Guang Arora, Naveen C. Xie, Huchen Ning, Holly Lu, Wei Low, Daniel Citrin, Deborah Kaushal, Aradhana Zach, Leor Camphausen, Kevin Miller, Robert W. TI Quantitative prediction of respiratory tidal volume based on the external torso volume change: a potential volumetric surrogate SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID 4-DIMENSIONAL COMPUTED-TOMOGRAPHY; LUNG-TUMOR MOTION; RADIATION-THERAPY; RADIOTHERAPY; CT; TRACKING; SURFACE; SYSTEM; RECONSTRUCTION; QUALITY AB An external respiratory surrogate that not only highly correlates with but also quantitatively predicts internal tidal volume should be useful in guiding four-dimensional computed tomography (4DCT), as well as 4D radiation therapy (4DRT). A volumetric surrogate should have advantages over external fiducial point(s) for monitoring respiration-induced motion of the torso, which deforms in synchronization with a patient-specific breathing pattern. This study establishes a linear relationship between the external torso volume change (TVC) and lung air volume change (AVC) by validating a proposed volume conservation hypothesis (TVC = AVC) throughout the respiratory cycle using 4DCT and spirometry. Fourteen patients' torso 4DCT images and corresponding spirometric tidal volumes were acquired to examine this hypothesis. The 4DCT images were acquired using dual surrogates in cine mode and amplitude-based binning in 12 respiratory stages, minimizing residual motion artifacts. Torso and lung volumes were calculated using threshold-based segmentation algorithms and volume changes were calculated relative to the full-exhalation stage. The TVC and AVC, as functions of respiratory stages, were compared, showing a high correlation (r = 0.992 +/- 0.005, p < 0.0001) as well as a linear relationship (slope = 1.027 +/- 0.061, R(2) = 0.980) without phase shift. The AVC was also compared to the spirometric tidal volumes, showing a similar linearity (slope = 1.030 +/- 0.092, R(2) = 0.947). In contrast, the thoracic and abdominal heights measured from 4DCT showed relatively low correlation (0.28 +/- 0.44 and 0.82 +/- 0.30, respectively) and location-dependent phase shifts. This novel approach establishes the foundation for developing an external volumetric respiratory surrogate. C1 [Li, Guang; Arora, Naveen C.; Xie, Huchen; Ning, Holly; Citrin, Deborah; Kaushal, Aradhana; Zach, Leor; Camphausen, Kevin; Miller, Robert W.] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lu, Wei; Low, Daniel] Washington Univ, Sch Med, Dept Radiat Oncol, St Louis, MO 63110 USA. RP Li, G (reprint author), NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. EM ligeorge@mail.nih.gov OI Li, Guang/0000-0002-9022-2883 NR 37 TC 10 Z9 10 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD APR 7 PY 2009 VL 54 IS 7 BP 1963 EP 1978 DI 10.1088/0031-9155/54/7/007 PG 16 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 420LY UT WOS:000264292500007 PM 19265201 ER PT J AU Stewart-Jones, G Wadle, A Hombach, A Shenderov, E Held, G Fischer, E Kleber, S Stenner-Liewen, F Bauer, S McMichael, A Knuth, A Abken, H Hombach, AA Cerundolo, V Jones, EY Renner, C AF Stewart-Jones, Guillaume Wadle, Andreas Hombach, Anja Shenderov, Eugene Held, Gerhard Fischer, Eliane Kleber, Sascha Stenner-Liewen, Frank Bauer, Stefan McMichael, Andrew Knuth, Alexander Abken, Hinrich Hombach, Andreas A. Cerundolo, Vincenzo Jones, E. Yvonne Renner, Christoph TI Rational development of high-affinity T-cell receptor-like antibodies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antibody engineering; crystallography; tumor immunology ID COMPLEX CLASS-I; MOLECULAR-GRAPHICS; PHAGE DISPLAY; ANTIGEN; MHC; SPECIFICITY; RECOGNITION; PEPTIDE; PROTEIN; TCRS AB T-cell interaction with a target cell is a key event in the adaptive immune response and primarily driven by T-cell receptor (TCR) recognition of peptide-MHC (pMHC) complexes. TCR avidity for a given pMHC is determined by number of MHC molecules, availability of coreceptors, and TCR affinity for MHC or peptide, respectively, with peptide recognition being the most important factor to confer target specificity. Here we present high-resolution crystal structures of 2 Fab antibodies in complex with the immunodominant NY-ESO-1(157-165) peptide analogue (SLLMWITQV) presented by HLA-A*0201 and compare them with a TCR recognizing the same pMHC. Binding to the central methionine-tryptophan peptide motif and orientation of binding were almost identical for Fabs and TCR. As the MW "peg'' dominates the contacts between Fab and peptide, we estimated the contributions of individual amino acids between the Fab and peptide to provide the rational basis for a peptide-focused second-generation, high-affinity antibody library. The final Fab candidate achieved better peptide binding by 2 light-chain mutations, giving a 20-fold affinity improvement to 2-4 nM, exceeding the affinity of the TCR by 1,000-fold. The high-affinity Fab when grafted as recombinant TCR on T cells conferred specific killing of HLA-A*0201/NY-ESO-1(157-165) target cells. In summary, we prove that affinity maturation of antibodies mimicking a TCR is possible and provide a strategy for engineering high-affinity antibodies that can be used in targeting specific pMHC complexes for diagnostic and therapeutic purposes. C1 [Stewart-Jones, Guillaume; Jones, E. Yvonne] Univ Oxford, Wellcome Trust Ctr Human Genet, Div Struct Biol, Oxford OX3 7BN, England. [Stewart-Jones, Guillaume; Shenderov, Eugene; McMichael, Andrew; Cerundolo, Vincenzo] Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DS, England. [Wadle, Andreas; Fischer, Eliane; Kleber, Sascha; Stenner-Liewen, Frank; Bauer, Stefan; Knuth, Alexander; Renner, Christoph] Univ Zurich Hosp, Dept Oncol, CH-8091 Zurich, Switzerland. [Hombach, Anja; Abken, Hinrich; Hombach, Andreas A.] Univ Cologne, Ctr Mol Med, D-50924 Cologne, Germany. [Hombach, Anja; Abken, Hinrich; Hombach, Andreas A.] Univ Cologne, Innere Med Klin, D-50924 Cologne, Germany. [Shenderov, Eugene] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Held, Gerhard] Univ Saarland, Sch Med, Dept Med 1, D-66421 Homburg, Germany. RP Jones, EY (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Div Struct Biol, Oxford OX3 7BN, England. EM yvonne@strubi.ox.ac.uk; christoph.renner@usz.ch RI Stewart-Jones, Guillaume/E-7013-2013; Fischer, Eliane/M-2590-2013; Jones, Yvonne/J-2293-2016; OI Fischer, Eliane/0000-0002-3399-3737; Jones, Yvonne/0000-0002-3834-1893; Cerundolo, Vincenzo/0000-0003-0040-3793 FU Medical Research Council; European Commission [LSHG-CT-2006-031220]; Wilhelm-Sander Stiftung; Cancer Research Institute; Cancer Research U. K. [C399/A2291]; Rhodes scholarship; National Institute of Allergy and Infectious Diseases, Division of Intramural Research, National Institutes of Health, Department of Health and Human Services FX We thank staff at the European Synchrotron Radiation Facility and the European Molecular Biology Laboratory outstation (Grenoble, France) for assistance with data collection. We thank Immanuel Luescher and Philippe Guillaume (Ludwig Institute for Cancer Research, Lausanne, Switzerland) for providing pMHC complexes. We thank Natko Nuber, Petra Schuberth, and Manuela Bienemann for construct generation and help with the T-cell assays. We acknowledge the Medical Research Council funded Oxford Protein Production Facility and the European Commission Integrated Program (SPINE2; LSHG-CT-2006-031220) for crystallization facilities. This work was supported in part by grants from the Wilhelm-Sander Stiftung, the Cancer Research Institute, Cancer Research U. K. (C399/A2291), and the Medical Research Council. This work was conducted as part of the Atlantic Philanthropies/Ludwig Institute for Cancer Research Clinical Discovery Program. E.Y.J. is a Cancer Research U. K. Principal Research Fellow. E. S. was supported by a Rhodes scholarship and by the National Institute of Allergy and Infectious Diseases, Division of Intramural Research, National Institutes of Health, Department of Health and Human Services. NR 31 TC 37 Z9 37 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 7 PY 2009 VL 106 IS 14 BP 5784 EP 5788 DI 10.1073/pnas.0901425106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 430CX UT WOS:000264967500060 PM 19307587 ER PT J AU Mathas, S Kreher, S Meaburn, KJ Johrens, K Lamprecht, B Assaf, C Sterry, W Kadin, ME Daibata, M Joos, S Hummel, M Stein, H Janz, M Anagnostopoulos, I Schrock, E Misteli, T Dorken, B AF Mathas, Stephan Kreher, Stephan Meaburn, Karen J. Joehrens, Korinna Lamprecht, Bjoern Assaf, Chalid Sterry, Wolfram Kadin, Marshall E. Daibata, Masanori Joos, Stefan Hummel, Michael Stein, Harald Janz, Martin Anagnostopoulos, Ioannis Schrock, Evelin Misteli, Tom Doerken, Bernd TI Gene deregulation and spatial genome reorganization near breakpoints prior to formation of translocations in anaplastic large cell lymphoma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer genetics; signal transduction; nuclear architecture; lymphomatoid papulosis ID TRANSCRIPTION FACTOR E2A; DOUBLE-STRAND BREAKS; NF-KAPPA-B; HODGKIN LYMPHOMA; CHROMOSOMAL TRANSLOCATIONS; CLASSICAL HODGKIN; DEFICIENCY LEADS; CSF-1 RECEPTOR; C-JUN; EXPRESSION AB Although the identification and characterization of translocations have rapidly increased, little is known about the mechanisms of how translocations occur in vivo. We used anaplastic large cell lymphoma (ALCL) with and without the characteristic t(2;5)(p23;q35) translocation to study the mechanisms of formation of translocations and of ALCL transformation. We report deregulation of several genes located near the ALCL translocation breakpoint, regardless of whether the tumor contains the t(2; 5). The affected genes include the oncogenic transcription factor Fra2 (located on 2p23), the HLH protein Id2 (2p25), and the oncogenic tyrosine kinase CSF1-receptor (5q33.1). Their up-regulation promotes cell survival and repression of T cell-specific gene expression programs that are characteristic for ALCL. The deregulated genes are in spatial proximity within the nuclear space of t(2;5)-negative ALCL cells, facilitating their translocation on induction of double-strand breaks. These data suggest that deregulation of breakpoint-proximal genes occurs before the formation of translocations, and that aberrant transcriptional activity of genomic regions is linked to their propensity to undergo chromosomal translocations. Also, our data demonstrate that deregulation of breakpoint-proximal genes has a key role in ALCL. C1 [Mathas, Stephan; Kreher, Stephan; Lamprecht, Bjoern; Janz, Martin; Doerken, Bernd] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. [Mathas, Stephan; Kreher, Stephan; Lamprecht, Bjoern; Janz, Martin; Doerken, Bernd] Med Univ Berlin, Charite, D-13353 Berlin, Germany. [Meaburn, Karen J.] NCI, NIH, Bethesda, MD 20892 USA. [Joehrens, Korinna; Hummel, Michael; Stein, Harald; Anagnostopoulos, Ioannis] Med Univ Berlin, Charite, Inst Pathol, D-12200 Berlin, Germany. [Assaf, Chalid; Sterry, Wolfram] Med Univ Berlin, Skin Canc Ctr Charite, Dept Dermatol Allergy & Venerol, D-10117 Berlin, Germany. [Kadin, Marshall E.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Kadin, Marshall E.] Boston Univ, Dept Dermatol, Providence, RI 02908 USA. [Kadin, Marshall E.] Roger Williams Med Ctr, Providence, RI 02908 USA. [Daibata, Masanori] Kochi Med Sch, Dept Hematol, Kochi 7838505, Japan. [Joos, Stefan] German Canc Res Ctr, D-69120 Heidelberg, Germany. [Schrock, Evelin] Tech Univ Dresden, Inst Clin Genet, D-01307 Dresden, Germany. RP Mathas, S (reprint author), Max Delbruck Ctr Mol Med, Robert Rossle Str 10, D-13125 Berlin, Germany. EM stephan.mathas@charite.de RI Mathas, Stephan/I-5589-2015; OI Meaburn, Karen/0000-0002-1327-5957 FU Deutsche Forschungsgemeinschaft; Wilhelm Sander-Stiftung; Berliner Krebsgesellschaft; National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This manuscript is dedicated to our friend and coworker Andreas Lietz, who died during the work on the project. We thank Franziska Hummel (Berlin), Simone Kressmann (Berlin), Brigitte Wollert-Wulf (Berlin), Constanze Cieluch (Berlin), Arleta Frensel (Dresden), and Petra Freitag (Dresden) for outstanding technical assistance, Peter Rahn (Berlin) for cell sorting, and Christin Wolfram (Berlin) for helpful discussion. The Fra2-JunB single-chain construct was kindly provided by Latifa Bakiri (Institut Pasteur, Paris). This work was supported in part by grants from the Deutsche Forschungsgemeinschaft, the Wilhelm Sander-Stiftung, the Berliner Krebsgesellschaft, and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 42 TC 48 Z9 51 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 APR 7 PY 2009 VL 106 IS 14 BP 5831 EP 5836 DI 10.1073/pnas.0900912106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 430CX UT WOS:000264967500068 PM 19321746 ER PT J AU Li, M Diep, BA Villaruz, AE Braughton, KR Jiang, XF Deleo, FR Chambers, HF Lu, Y Otto, M AF Li, Min Diep, Binh An Villaruz, Amer E. Braughton, Kevin R. Jiang, Xiaofei DeLeo, Frank R. Chambers, Henry F. Lu, Yuan Otto, Michael TI Evolution of virulence in epidemic community-associated methicillin-resistant Staphylococcus aureus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; PNEUMONIA; USA300; GENE; MRSA; EMERGENCE; PEPTIDES; CLONE; AGR; DETERMINANTS AB Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has recently emerged worldwide. The United States, in particular, is experiencing a serious epidemic of CA-MRSA that is almost entirely caused by an extraordinarily infectious strain named USA300. However, the molecular determinants underlying the pathogenic success of CA-MRSA are mostly unknown. To gain insight into the evolution of the exceptional potential of USA300 to cause disease, we compared the phylogeny and virulence of USA300 with that of closely related MRSA clones. We discovered that the sublineage from which USA300 evolved is characterized by a phenotype of high virulence that is clearly distinct from other MRSA strains. Namely, USA300 and its progenitor, USA500, had high virulence in animal infection models and the capacity to evade innate host defense mechanisms. Furthermore, our results indicate that increased virulence in the USA300/USA500 sublineage is attributable to differential expression of core genome-encoded virulence determinants, such as phenol-soluble modulins and alpha-toxin. Notably, the fact that the virulence phenotype of USA300 was already established in its progenitor indicates that acquisition of mobile genetic elements has played a limited role in the evolution of USA300 virulence and points to a possibly different role of those elements. Thus, our results highlight the importance of differential gene expression in the evolution of USA300 virulence. This finding calls for a profound revision of our notion about CA-MRSA pathogenesis at the molecular level and has important implications for design of therapeutics directed against CA-MRSA. C1 [Li, Min; Jiang, Xiaofei; Lu, Yuan] Fudan Univ, Shanghai Med Coll, Huashan Hosp, Dept Lab Med, Shanghai 200040, Peoples R China. [Diep, Binh An; Chambers, Henry F.] Univ Calif San Francisco, Dept Med, Div Infect Dis, San Francisco, CA 94110 USA. [Li, Min; Villaruz, Amer E.; Braughton, Kevin R.; DeLeo, Frank R.; Otto, Michael] NIAID, NIH, Bethesda, MD 20892 USA. RP Lu, Y (reprint author), Fudan Univ, Shanghai Med Coll, Huashan Hosp, Dept Lab Med, 12 Cent Urumqi Rd, Shanghai 200040, Peoples R China. EM yuanlu@hsh.stn.sh.cn; motto@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516; Otto, Michael/0000-0002-2222-4115 FU National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health; Shanghai Medical Key Discipline; Microbial Pathogenesis and Host Defense Postdoctoral Fellowship [5T32AI060537-02]; U. S. Public Health Service Grant [NIAID R01 AI070289] FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (M. O., F. R. D.); a grant from the Shanghai Medical Key Discipline (to M. L. and Y. L.); Microbial Pathogenesis and Host Defense Postdoctoral Fellowship 5T32AI060537-02 (to B. A. D.); and U. S. Public Health Service Grant NIAID R01 AI070289 (to H. F. C.). NR 42 TC 212 Z9 222 U1 4 U2 25 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD APR 7 PY 2009 VL 106 IS 14 BP 5883 EP 5888 DI 10.1073/pnas.0900743106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 430CX UT WOS:000264967500077 PM 19293374 ER PT J AU Sakata, K Woo, NH Martinowich, K Greene, JS Schloesser, RJ Shen, LY Lu, B AF Sakata, Kazuko Woo, Newton H. Martinowich, Keri Greene, Joshua S. Schloesser, Robert J. Shen, Liya Lu, Bai TI Critical role of promoter IV-driven BDNF transcription in GABAergic transmission and synaptic plasticity in the prefrontal cortex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE activity-dependent; GABAergic interneuron; knockout mice; parvalbumin; cortical inhibition ID RAT VISUAL-CORTEX; NEUROTROPHIC FACTOR; MESSENGER-RNA; DEVELOPMENTAL EXPRESSION; MULTIPLE PROMOTERS; IN-VIVO; BRAIN; INHIBITION; INTERNEURONS; HIPPOCAMPUS AB Transcription of Bdnf is controlled by multiple promoters, which drive expression of multiple transcripts encoding for the same protein. Promoter IV contributes significantly to activity-dependent brain-derived neurotrophic factor (BDNF) transcription. We have generated promoter IV mutant mice (BDNF-KIV)by inserting a GFP-STOP cassette within the Bdnf exon IV locus. This genetic manipulation results in disruption of promoter IV-mediated Bdnf expression. BDNF-KIV animals exhibited significant deficits in GABAergic interneurons in the prefrontal cortex (PFC), particularly those expressing parvalbumin, a subtype implicated in executive function and schizophrenia. Moreover, disruption of promoter IV-driven Bdnf transcription impaired inhibitory but not excitatory synaptic transmission recorded from layer V pyramidal neurons in the PFC. The attenuation of GABAergic inputs resulted in an aberrant appearance of spike-timing-dependent synaptic potentiation (STDP) in PFC slices derived from BDNF-KIV, but not wild-type littermates. These results demonstrate the importance of promoter IV-dependent Bdnf transcription in GABAergic function and reveal an unexpected regulation of STDP in the PFC by BDNF. C1 [Sakata, Kazuko; Woo, Newton H.; Lu, Bai] NICHHD, Sect Neural Dev & Plast, NIH, Bethesda, MD 20892 USA. [Martinowich, Keri; Schloesser, Robert J.] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Martinowich, Keri; Greene, Joshua S.; Lu, Bai] NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Shen, Liya] NCI, NIH, Bethesda, MD 20892 USA. RP Lu, B (reprint author), NICHHD, Sect Neural Dev & Plast, NIH, 35 Lincoln Dr, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Lu, Bai/A-4018-2012; Martinowich, Keri/F-9841-2012; OI Martinowich, Keri/0000-0002-5237-0789 FU National Institute of Child Health and Human Development; National Institute of Mental Health; Japan Society for the Promotion of Science; Alberta Heritage Foundation for Medical Research; Natural Sciences and Engineering Research Council; Canadian Institutes of Health Research FX We thank K. Nakazawa, K. Christian, P. Ernfors, and A. Morozov for thoughtful comments; D. Abebe, V. Senetorov, and S. Speransky for technical support; Q. Sun for assistance in immunohistochemistry; and P. Ernfors and S. Linnarsson for providing the genomic construct. This work is supported by the Intramural Research Programs of the National Institute of Child Health and Human Development and the National Institute of Mental Health. K. S. is supported in part by the Japan Society for the Promotion of Science, and N. H. W. is supported by fellowships from the Alberta Heritage Foundation for Medical Research, the Natural Sciences and Engineering Research Council, and the Canadian Institutes of Health Research. NR 29 TC 81 Z9 83 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 APR 7 PY 2009 VL 106 IS 14 BP 5942 EP 5947 DI 10.1073/pnas.0811431106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 430CX UT WOS:000264967500087 PM 19293383 ER PT J AU McNally, JG AF McNally, James G. TI Transcription, chromatin condensation, and gene migration SO JOURNAL OF CELL BIOLOGY LA English DT Editorial Material ID LIVING CELLS; IN-VIVO; ORGANIZATION; CHROMOSOMES; ACTIVATION; EXPRESSION; PROMOTER AB The binding of fluorescently tagged proteins to tandem DNA arrays has been instrumental in understanding nuclear organization and function. Through the use of more natural tandem DNA arrays, Hu et al. ( Hu, Y., I. Kireev, M. Plutz, N. Ashourian, and A. S. Belmont. 2009. J. Cell Biol. 185: 87-100) gain new insights into chromatin organization and dynamics, and into the association of splicing factors with active genes. C1 NCI, NIH, Bethesda, MD 20892 USA. RP McNally, JG (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mcnallyj@exchange.nih.gov NR 17 TC 2 Z9 2 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD APR 6 PY 2009 VL 185 IS 1 BP 7 EP 9 DI 10.1083/jcb.200903056 PG 3 WC Cell Biology SC Cell Biology GA 436KO UT WOS:000265413200003 PM 19349577 ER PT J AU Boon, K Bailey, NW Yang, J Steel, MP Groshong, S Kervitsky, D Brown, KK Schwarz, MI Schwartz, DA AF Boon, Kathy Bailey, Nathaniel W. Yang, Jun Steel, Mark P. Groshong, Steve Kervitsky, Dolly Brown, Kevin K. Schwarz, Marvin I. Schwartz, David A. TI Molecular Phenotypes Distinguish Patients with Relatively Stable from Progressive Idiopathic Pulmonary Fibrosis (IPF) SO PLOS ONE LA English DT Article AB Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic interstitial lung disease that is unresponsive to current therapy and often leads to death. However, the rate of disease progression differs among patients. We hypothesized that comparing the gene expression profiles between patients with stable disease and those in which the disease progressed rapidly will lead to biomarker discovery and contribute to the understanding of disease pathogenesis. Methodology and Principal Findings: To begin to address this hypothesis, we applied Serial Analysis of Gene Expression (SAGE) to generate lung expression profiles from diagnostic surgical lung biopsies in 6 individuals with relatively stable (or slowly progressive) IPF and 6 individuals with progressive IPF (based on changes in DLCO and FVC over 12 months). Our results indicate that this comprehensive lung IPF SAGE transcriptome is distinct from normal lung tissue and other chronic lung diseases. To identify candidate markers of disease progression, we compared the IPF SAGE profiles in stable and progressive disease, and identified a set of 102 transcripts that were at least 5-fold up regulated and a set of 89 transcripts that were at least 5-fold down regulated in the progressive group (P-value <= 0.05). The over expressed genes included surfactant protein A1, two members of the MAPK-EGR-1-HSP70 pathway that regulate cigarette-smoke induced inflammation, and Plunc (palate, lung and nasal epithelium associated), a gene not previously implicated in IPF. Interestingly, 26 of the up regulated genes are also increased in lung adenocarcinomas and have low or no expression in normal lung tissue. More importantly, we defined a SAGE molecular expression signature of 134 transcripts that sufficiently distinguished relatively stable from progressive IPF. Conclusions: These findings indicate that molecular signatures from lung parenchyma at the time of diagnosis could prove helpful in predicting the likelihood of disease progression or possibly understanding the biological activity of IPF. C1 NHLBI, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Duke Univ, Med Ctr, Durham, NC 27706 USA. Natl Jewish Hlth, Denver, CO USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. RP Boon, K (reprint author), NHLBI, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. EM Kathy.Boon@gmail.com FU National Heart, Lung, and Blood Institute; National Institute of Environmental Health Sciences FX This research was supported by the intramural research programs at the National Heart, Lung, and Blood Institute, and the National Institute of Environmental Health Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of manuscript. NR 55 TC 82 Z9 83 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 APR 6 PY 2009 VL 4 IS 4 AR e5134 DI 10.1371/journal.pone.0005134 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437RS UT WOS:000265505200007 PM 19347046 ER PT J AU Giliberto, L Borghi, R Piccini, A Mangerini, R Sorbi, S Cirmena, G Garuti, A Ghetti, B Tagliavini, F Mughal, MR Mattson, MP Zhu, XW Wang, XL Guglielmotto, M Tamagno, E Tabatona, M AF Giliberto, Luca Borghi, Roberta Piccini, Alessandra Mangerini, Rosa Sorbi, Sandro Cirmena, Gabriella Garuti, Anna Ghetti, Bernardino Tagliavini, Fabrizio Mughal, Mohamed R. Mattson, Mark P. Zhu, Xiongwei Wang, Xinglong Guglielmotto, Michela Tamagno, Elena Tabatona, Massimo TI Mutant Presenilin 1 Increases the Expression and Activity of BACE1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMYLOID PRECURSOR PROTEIN; GAMMA-SECRETASE ACTIVITY; ALZHEIMERS-DISEASE PATHOGENESIS; NF-KAPPA-B; BETA-SECRETASE; OXIDATIVE STRESS; A-BETA; TRANSCRIPTIONAL REGULATION; INTRACELLULAR DOMAINS; TERMINAL FRAGMENT AB Mutations of the presenilin 1 (PS1) gene are the most common cause of early onset familial Alzheimer disease (FAD). PS1 mutations alter the activity of the gamma-secretase on the beta-amyloid precursor protein (APP), leading to selective overproduction of beta-amyloid (A beta) 42 peptides, the species that forms oligomers that may exert toxic effects on neurons. Here we show that PS1 mutations, expressed both transiently and stably, in non-neuronal and neuronal cell lines increase the expression and the activity of the beta-secretase (BACE1), the rate-limiting step of A beta production. Also, BACE1 expression and activity are elevated in brains of PS1 mutant knock-in mice compared with wild type littermates as well as in cerebral cortex of FAD cases bearing various PS1 mutations compared with in sporadic AD cases and controls. The up-regulation of BACE1 by PS1 mutations requires the gamma-secretase cleavage of APP and is proportional to the amount of secreted A beta 42. A beta 42, and not AICD (APP intracellular domain), is indeed the APP derivative that mediates the overexpression of BACE1. The effect of PS1 mutations on BACE1 may contribute to determine the wide clinical and pathological phenotype of early onset FAD. C1 [Giliberto, Luca; Borghi, Roberta; Tabatona, Massimo] Univ Genoa, Dept Neurosci Ophthalmol & Genet, I-16132 Genoa, Italy. [Cirmena, Gabriella; Garuti, Anna] Univ Genoa, Dept Internal Med & Med Specialties, I-16132 Genoa, Italy. [Piccini, Alessandra] Natl Inst Canc Res, Dept Cell Biol, I-16132 Genoa, Italy. [Mangerini, Rosa] Univ Genoa, Dept Oncol Biol & Genet, I-16132 Genoa, Italy. [Mangerini, Rosa] Natl Canc Inst, I-16132 Genoa, Italy. [Sorbi, Sandro] Univ Florence, Dept Neurol & Psychiat Sci, I-50134 Florence, Italy. [Ghetti, Bernardino] Indiana Univ, Sch Med, Indiana Alzheimer Dis Ctr, Dept Pathol & Lab Med, Indianapolis, IN 46202 USA. [Tagliavini, Fabrizio] Ist Nazl Neurol Carlo Besta, Div Neuropathol & Neurol, I-20133 Milan, Italy. [Mughal, Mohamed R.; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Zhu, Xiongwei; Wang, Xinglong] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Guglielmotto, Michela; Tamagno, Elena] Univ Turin, Dept Expt Med & Oncol, I-10125 Turin, Italy. RP Tabatona, M (reprint author), Univ Genoa, Dept Neurosci Ophthalmol & Genet, Via De Toni 5, I-16132 Genoa, Italy. EM mtabaton@neurologia.unige.it RI Zhu, Xiongwei/A-9629-2009; , /C-1310-2010; Mattson, Mark/F-6038-2012; OI Wang, Xinglong/0000-0001-8657-0159; sorbi, sandro/0000-0002-0380-6670 FU Minister of Health, Italy; Telethon Foundation [GGP06009]; CARISA Foundation; Intramural Research Program of the NIA, National Institutes of Health; National Institutes of Health Public Health Service [AG10133]; National Institutes of Health [AG024028] FX This work was supported by the Minister of Health (to M. T.), Italy and Telethon Foundation Grant GGP06009 (to M. T.), CARISA Foundation (to M. T.), by the Intramural Research Program of the NIA, National Institutes of Health (to M. P. M.), National Institutes of Health Public Health Service Grant AG10133(to B. G.), and National Institutes of Health Grant AG024028 (to X. Z.). NR 65 TC 33 Z9 33 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 3 PY 2009 VL 284 IS 14 BP 9027 EP 9038 DI 10.1074/jbc.M805685200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 425WS UT WOS:000264669100005 PM 19196715 ER PT J AU Beauchamp, E Bulut, G Abaan, O Chen, K Merchant, A Matsui, W Endo, Y Rubin, JS Toretsky, J Uren, A AF Beauchamp, Elspeth Bulut, Gulay Abaan, Ogan Chen, Kevin Merchant, Akil Matsui, William Endo, Yoshimi Rubin, Jeffrey S. Toretsky, Jeffrey Ueren, Aykut TI GLI1 Is a Direct Transcriptional Target of EWS-FLI1 Oncoprotein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PRIMITIVE NEUROECTODERMAL TUMORS; HEDGEHOG SIGNALING PATHWAY; EWINGS-SARCOMA; PANCREATIC-CANCER; HUMAN HOMOLOG; IN-VITRO; GENE; MUTATIONS; ACTIVATION; EXPRESSION AB Ewing sarcoma family of tumors (ESFT) is an undifferentiated neoplasm of the bone and soft tissue. ESFT is characterized by a specific chromosomal translocation occurring between chromosome 22 and (in most cases) chromosome 11, which generates an aberrant transcription factor, EWS-FLI1. The function of EWS-FLI1 is essential for the maintenance of ESFT cell survival and tumorigenesis. The Hedgehog pathway is activated in several cancers. Oncogenic potential of the Hedgehog pathway is mediated by increasing the activity of the GLI family of transcription factors. Recent evidence suggests that EWS-FLI1 increases expression of GLI1 by an unknown mechanism. Our data from chromatin immunoprecipitation and promoter reporter studies indicated GLI1 as a direct transcriptional target of EWS-FLI1. Expression of EWS-FLI1 in non-ESFT cells increased GLI1 expression and GLI-dependent transcription. We also detected high levels of GLI1 protein in ESFT cell lines. Pharmacological inhibition of GLI1 protein function decreased proliferation and soft agar colony formation of ESFT cells. Our results establish GLI1 as a direct transcriptional target of EWS-FLI1 and suggest a potential role for GLI1 in ESFT tumorigenesis. C1 [Beauchamp, Elspeth; Bulut, Gulay; Abaan, Ogan; Chen, Kevin; Toretsky, Jeffrey; Ueren, Aykut] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Merchant, Akil; Matsui, William] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Endo, Yoshimi; Rubin, Jeffrey S.] NCI, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Uren, A (reprint author), 3970 Reservoir Rd NW,NRB,Rm E312, Washington, DC 20057 USA. EM au26@georgetown.edu RI Matsui, William/C-3383-2009; BULUT, GULAY/J-3180-2012; OI Matsui, William/0000-0002-3088-0964 FU National Institutes of Health [CA88004, CA10841]; Children's Cancer Foundation of Baltimore, MD; Intramural Research Program of the NCI, National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grants CA88004 (to J.T.) and CA10841 (to A.U.). This work was also supported by a grant from the Children's Cancer Foundation of Baltimore, MD, and the Intramural Research Program of the NCI, National Institutes of Health. NR 42 TC 77 Z9 82 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 APR 3 PY 2009 VL 284 IS 14 BP 9074 EP 9082 DI 10.1074/jbc.M806233200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 425WS UT WOS:000264669100010 PM 19189974 ER PT J AU Crawford, J Grujic, O Bruic, E Czjzek, M Grigg, ME Boulanger, MJ AF Crawford, Joanna Grujic, Ognjen Bruic, Ekaterina Czjzek, Mirjam Grigg, Michael E. Boulanger, Martin J. TI Structural Characterization of the Bradyzoite Surface Antigen (BSR4) from Toxoplasma gondii, a Unique Addition to the Surface Antigen Glycoprotein 1-related Superfamily SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID X-RAY SOLUTION; MACROMOLECULAR STRUCTURES; SOLUTION SCATTERING; CRYSTAL-STRUCTURE; SRS SUPERFAMILY; DATA-COLLECTION; PROTEINS; ENCEPHALITIS; DIFFRACTION; ASSEMBLIES AB Toxoplasma gondii is an obligate intracellular protozoan parasite that infects nearly one-third of the human population. The success of T. gondii is based on its complex life cycle; a lytic tachyzoite form disseminates infection, whereas an encysted bradyzoite form establishes a latent, chronic infection. Persistence and transmissibility is central to the survival of the parasite and is, in part, mediated by a family of antigenically distinct surface antigen glycoprotein (SAG)-related sequences (SRS) adhesins that play a dual role in host cell attachment and host immune evasion. More than 160 members of the SRS family have been identified with only the tachyzoite-expressed SAG1 structurally characterized. Here we report the first structural description of the bradyzoite adhesin BSR4 using x-ray crystallography and small angle x-ray scattering. The 1.90-angstrom crystal structure of BSR4 reveals an architecture comprised of tandem beta sandwich domains organized in a head to tail fashion with the N-terminal domain responsible for dimer formation. A restructured topology in BSR4 results in a ligand-binding site that is significantly reorganized in both structure and chemistry relative to SAG1, consistent with BSR4 binding a distinct physiological ligand. The small angle x-ray scattering solution structure of BSR4 highlights a potentially important structural role for the interdomain polymorphic linker that imparts significant flexibility that may promote structural adaptation during ligand binding. This study reveals an unexpected level of structural diversity within the SRS superfamily and provides important insight into the role of these virulence factors. C1 [Crawford, Joanna; Grujic, Ognjen; Bruic, Ekaterina; Boulanger, Martin J.] Univ Victoria, Dept Biochem & Microbiol, Victoria, BC V8W 3P6, Canada. [Czjzek, Mirjam] Univ Paris 06, CNRS, Stn Biol Roscoff, UMR7139, F-29682 Roscoff, France. [Grigg, Michael E.] NIAID, Mol Parasitol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Boulanger, MJ (reprint author), Univ Victoria, Dept Biochem & Microbiol, POB 3055 STN CSC, Victoria, BC V8W 3P6, Canada. EM mboulang@uvic.ca RI Crawford, Joanna /F-9135-2013 OI Crawford, Joanna /0000-0003-0786-6889 FU Canadian Institutes for Health Research; Intramural Research Program of the NIAID, National Institutes of Health FX This work was supported by a research grant from the Canadian Institutes for Health Research (to M.J.B.) and by the Intramural Research Program of the NIAID, National Institutes of Health (to M.E.G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 44 TC 17 Z9 19 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 APR 3 PY 2009 VL 284 IS 14 BP 9192 EP 9198 DI 10.1074/jbc.M808714200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 425WS UT WOS:000264669100025 PM 19155215 ER PT J AU Muftuoglu, M de Souza-Pinto, NC Dogan, A Aamann, M Stevnsner, T Rybanska, I Kirkali, G Dizdaroglu, M Bohr, VA AF Muftuoglu, Meltem de Souza-Pinto, Nadja C. Dogan, Arin Aamann, Maria Stevnsner, Tinna Rybanska, Ivana Kirkali, Gueldal Dizdaroglu, Miral Bohr, Vilhelm A. TI Cockayne Syndrome Group B Protein Stimulates Repair of Formamidopyrimidines by NEIL1 DNA Glycosylase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OXIDATIVELY DAMAGED DNA; BASE EXCISION-REPAIR; RNA-POLYMERASE-II; TRANSCRIPTION-COUPLED REPAIR; GENE-PRODUCT; CSB PROTEIN; SUBSTRATE-SPECIFICITY; XERODERMA-PIGMENTOSUM; HELICASE DOMAIN; OXIDIZED BASES AB Cockayne syndrome (CS) is a premature aging condition characterized by sensitivity to UV radiation. However, this phenotype does not explain the progressive neurodegeneration in CS patients. It could be due to the hypersensitivity of CSB-deficient cells to oxidative stress. So far most studies on the role of CSB in repair of oxidatively induced DNA lesions have focused on 7,8-dihydro-8-oxoguanine. This study examines the role of CSB in the repair of formamidopyrimidines 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyGua) and 4,6-diamino-5-formamidopyrimidine (FapyAde), which are substrates for endonuclease VIII-like (NEIL1) DNA glycosylase. Results presented here show that csb(-/-) mice have a higher level of endogenous FapyAde and FapyGua in DNA from brain and kidney than wild type mice as well as higher levels of endogenous FapyAde in genomic DNA and mtDNA from liver. In addition, CSB stimulates NEIL1 incision activity in vitro, and CSB and NEIL1 co-immunoprecipitate and co-localize in HeLa cells. When CSB and NEIL1 are depleted from HeLa cells by short hairpin RNA knockdown, repair of induced FapyGua is strongly inhibited. These results suggest that CSB plays a role in repair of formamidopyrimidines, possibly by interacting with and stimulating NEIL1, and that accumulation of such modifications may have a causal role in the pathogenesis of CS. C1 [Muftuoglu, Meltem; de Souza-Pinto, Nadja C.; Dogan, Arin; Aamann, Maria; Rybanska, Ivana; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Stevnsner, Tinna] Aarhus Univ, Dept Mol Biol, Danish Aging Res Ctr, DK-8000 Aarhus, Denmark. [Stevnsner, Tinna] Aarhus Univ, Danish Ctr Mol Gerontol, DK-8000 Aarhus, Denmark. [Kirkali, Gueldal; Dizdaroglu, Miral] NIST, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. [Dogan, Arin; Kirkali, Gueldal] Dokuz Eylul Univ, Fac Med, Dept Biochem, TR-35340 Izmir, Turkey. [Muftuoglu, Meltem] Univ Copenhagen, Ctr Healthy Ageing, DK-2200 Copenhagen, Denmark. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, Intramural Res Program, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov RI Souza-Pinto, Nadja/C-3462-2013; 3, INCT/H-4497-2013; Redoxoma, Inct/H-9962-2013; Dogan, Arin/L-6443-2015 OI Souza-Pinto, Nadja/0000-0003-4206-964X; Dogan, Arin/0000-0002-5362-5501 FU National Institutes of Health; National Institute on Aging; National Institute of Standards and Technology FX This work was supported, in whole or in part, by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, and National Institute of Standards and Technology. NR 55 TC 59 Z9 61 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD APR 3 PY 2009 VL 284 IS 14 BP 9270 EP 9279 DI 10.1074/jbc.M807006200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 425WS UT WOS:000264669100033 PM 19179336 ER PT J AU Cichocki, F Hanson, RJ Lenvik, T Pitt, M McCullar, V Li, H Anderson, SK Miller, JS AF Cichocki, Frank Hanson, Rebecca J. Lenvik, Todd Pitt, Michelle McCullar, Valarie Li, Hongchuan Anderson, Stephen K. Miller, Jeffrey S. TI The transcription factor c-Myc enhances KIR gene transcription through direct binding to an upstream distal promoter element SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; IG-LIKE RECEPTORS; INHIBITORY RECEPTORS; NK CELLS; PERIPHERAL-BLOOD; DNA METHYLATION; DROSOPHILA-MYC; SELF-MHC; IDENTIFICATION; INTERLEUKIN-15 AB The killer cell immunoglobulin-like receptor (KIR) repertoire of natural killer (NK) cells determines their ability to detect infected or transformed target cells. Although epigenetic mechanisms play a role in KIR gene expression, work in the mouse suggests that other regulatory elements may be involved at specific stages of NK-cell development. Here we report the effects of the transcription factor c-Myc on KIR expression. c-Myc directly binds to, and promotes transcription from, a distal element identified upstream of most KIR genes. Binding of endogenous c-Myc to the distal promoter element is significantly enhanced upon interleukin-15 (IL-15) stimulation in peripheral blood NK cells and correlates with an increase in KIR transcription. In addition, the overexpression of c-Myc during NK-cell development promotes transcription from the distal promoter element and contributes to the overall transcription of multiple KIR genes. Our data demonstrate the significance of the 5' promoter element upstream of the conventional KIR promoter region and support a model whereby IL-15 stimulates c-Myc binding at the distal KIR promoter during NK-cell development to promote KIR transcription. This finding provides a direct link between NK-cell activation signals and KIR expression required for acquisition of effector function during NK-cell education. (Blood. 2009; 113:3245-3253) C1 [Miller, Jeffrey S.] Univ Minnesota, Ctr Canc, MMC 806, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA. [Li, Hongchuan; Anderson, Stephen K.] NCI, Expt Immunol Lab, SAIC, Frederick, MD 21701 USA. RP Miller, JS (reprint author), Univ Minnesota, Ctr Canc, MMC 806, Div Hematol Oncol & Transplantat, Harvard St,E River Rd, Minneapolis, MN 55455 USA. EM mille011@umn.edu RI Anderson, Stephen/B-1727-2012; OI Anderson, Stephen/0000-0002-7856-4266; Miller, Jeffrey S/0000-0002-0339-4944 FU National Institutes of Health [P01-CA-111412, R01-HL-55417]; National Cancer Institute (NCI) [N01-CO-12400]; Intramural Research Program of the NIH, NCI, Center for Cancer Research FX This work was supported in part by National Institutes of Health (NIH) grants P01-CA-111412 and R01-HL-55417 (J. S. M.), in part with federal funds from the National Cancer Institute (NCI), NIH under contract N01-CO-12400 (S. K. A.), and in part by the Intramural Research Program of the NIH, NCI, Center for Cancer Research (S. K. A.). NR 46 TC 24 Z9 24 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD APR 2 PY 2009 VL 113 IS 14 BP 3245 EP 3253 DI 10.1182/blood-2008-07-166389 PG 9 WC Hematology SC Hematology GA 428LH UT WOS:000264848900018 PM 18987359 ER PT J AU Resch, W Zaslavsky, L Kiryutin, B Rozanov, M Bao, YM Tatusova, TA AF Resch, Wolfgang Zaslavsky, Leonid Kiryutin, Boris Rozanov, Michael Bao, Yiming Tatusova, Tatiana A. TI Virus variation resources at the National Center for Biotechnology Information: dengue virus SO BMC MICROBIOLOGY LA English DT Article ID HEMORRHAGIC-FEVER; PATHOGENESIS AB Background: There is an increasing number of complete and incomplete virus genome sequences available in public databases. This large body of sequence data harbors information about epidemiology, phylogeny, and virulence. Several specialized databases, such as the NCBI Influenza Virus Resource or the Los Alamos HIV database, offer sophisticated query interfaces along with integrated exploratory data analysis tools for individual virus species to facilitate extracting this information. Thus far, there has not been a comprehensive database for dengue virus, a significant public health threat. Results: We have created an integrated web resource for dengue virus. The technology developed for the NCBI Influenza Virus Resource has been extended to process non-segmented dengue virus genomes. In order to allow efficient processing of the dengue genome, which is large in comparison with individual influenza segments, we developed an offline pre-alignment procedure which generates a multiple sequence alignment of all dengue sequences. The pre-calculated alignment is then used to rapidly create alignments of sequence subsets in response to user queries. This improvement in technology will also facilitate the incorporation of additional virus species in the future. The set of virus-specific databases at NCBI, which will be referred to as Virus Variation Resources (VVR), allow users to build complex queries against virus-specific databases and then apply exploratory data analysis tools to the results. The metadata is automatically collected where possible, and extended with data extracted from the literature. Conclusion: The NCBI Dengue Virus Resource integrates dengue sequence information with relevant metadata (sample collection time and location, disease severity, serotype, sequenced genome region) and facilitates retrieval and preliminary analysis of dengue sequences using integrated web analysis and visualization tools. C1 [Resch, Wolfgang; Zaslavsky, Leonid; Kiryutin, Boris; Rozanov, Michael; Bao, Yiming; Tatusova, Tatiana A.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Rozanov, Michael] Leiden Univ, Med Ctr, Ctr Infect Dis, Dept Med Microbiol, NL-2300 RC Leiden, Netherlands. RP Tatusova, TA (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM wresch@ncbi.nlm.nih.gov; zaslavsk@ncbi.nlm.nih.gov; kiryutin@ncbi.nlm.nih.gov; m.rozanov@lumc.nl; bao@ncbi.nlm.nih.gov; tatiana@ncbi.nlm.nih.gov FU NIH; National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. We thank Dr. D. Lipman (NCBI), Dr. J. Ostell (NCBI), Dr. J. Rodney Brister (NCBI), Dr. S. Ciufo (NCBI), Dr. S. Watowich (UTMB), Dr. M Schreiber (NITD), Dr. E. Holmes (Pennsylvania State University), Dr. M. Miller (NIH Fogarty International Center), and the participants of the "Discovery and Evaluation of Therapeutics against Dengue" workshop for helpful discussions. P. Bolotov (NCBI), M. Kimelman (NCBI), and S. Zhdanov (NCBI) contributed to the setup of the database backend and daily scan of new sequence records. NR 16 TC 21 Z9 21 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD APR 2 PY 2009 VL 9 AR 65 DI 10.1186/1471-2180-9-65 PG 7 WC Microbiology SC Microbiology GA 442NL UT WOS:000265847800001 PM 19341451 ER PT J AU Jeong, H Then, F Melia, TJ Mazzulli, JR Cui, L Savas, JN Voisine, C Paganetti, P Tanese, N Hart, AC Yamamoto, A Krainc, D AF Jeong, Hyunkyung Then, Florian Melia, Thomas J., Jr. Mazzulli, Joseph R. Cui, Libin Savas, Jeffrey N. Voisine, Cindy Paganetti, Paolo Tanese, Naoko Hart, Anne C. Yamamoto, Ai Krainc, Dimitri TI Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation SO CELL LA English DT Article ID INCLUSION-BODY FORMATION; KNOCK-IN MOUSE; CAENORHABDITIS-ELEGANS; NEURODEGENERATIVE DISEASES; TRANSCRIPTIONAL REPRESSION; POLYGLUTAMINE EXPANSIONS; CELLULAR TOXICITY; SENSORY NEURON; DYSFUNCTION; PROTEIN AB Huntington's disease (HD) is an incurable neurodegenerative disease caused by neuronal accumulation of the mutant protein huntingtin. Improving clearance of the mutant protein is expected to prevent cellular dysfunction and neurodegeneration in HD. We report here that such clearance can be achieved by posttranslational modification of the mutant Huntingtin (Htt) by acetylation at lysine residue 444 (K444). Increased acetylation at K444 facilitates trafficking of mutant Htt into autophagosomes, significantly improves clearance of the mutant protein by macroautophagy, and reverses the toxic effects of mutant huntingtin in primary striatal and cortical neurons and in a transgenic C. elegans model of HD. In contrast, mutant Htt that is rendered resistant to acetylation dramatically accumulates and leads to neurodegeneration in cultured neurons and in mouse brain. These studies identify acetylation as a mechanism for removing accumulated protein in HD, and more broadly for actively targeting proteins for degradation by autophagy. C1 [Jeong, Hyunkyung; Then, Florian; Mazzulli, Joseph R.; Cui, Libin; Krainc, Dimitri] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat,Dept Neurol, Charlestown, MA 02129 USA. [Voisine, Cindy; Hart, Anne C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat,Ctr Canc Res, Charlestown, MA 02129 USA. [Melia, Thomas J., Jr.] Yale Univ, Dept Cell Biol, New Haven, CT 06519 USA. [Savas, Jeffrey N.; Tanese, Naoko] New York Univ, Sch Med, Dept Microbiol, New York, NY 10016 USA. [Savas, Jeffrey N.] New York Univ, Sch Med, NYU & NIH Grad Partnership Program Struct Biol, New York, NY 10016 USA. [Paganetti, Paolo] Novartis Pharma AG, NIBR Basel, Neurosci Dis, CH-4002 Basel, Switzerland. [Yamamoto, Ai] Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. RP Krainc, D (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, MassGen Inst Neurodegenerat,Dept Neurol, Charlestown, MA 02129 USA. EM krainc@helix.mgh.harvard.edu RI Yamamoto, Ai/D-1100-2011; OI Tanese, Naoko/0000-0002-1946-3211 FU DFG; [R01NS050352]; [R01 NS051303]; [R01 NS050199] FX We are grateful to Drs. K. Kegel, M. DiFiglia, C. D. Allis, A. Basu, H. Park, and A.B. Young and members of the Krainc laboratory for helpful suggestions and comments on the manuscript. We also thank Drs. D. Sarracino, B. Krastins, J. Kowalak, S. Markey, and A. Makusky for help with mass spectrometry; B. Hyman, W. Stoothoff, and C. Lill for help with live-cell imaging; E. Regulier for help with lentiviral transductions; A. Weiss and A. Roscic for help with HN10 cells; H. Ischiropoulos for use of HPLC system; N. Mizushima for Atg5-deficient cells; A. Kazantsev for CBP and CBP Delta Q constructs; Y. Yoshimori for GFP-LC3; G.A. Fitzgerald for p300 and P/CAF; P.W. Faber for osm::Htt564-150Q; and the New York Structural Biology Center for the EM facilities. This work was supported by R01NS050352 and R01 NS051303 (to D.K.) and R01 NS050199 (to A.Y.). F.T. is a fellow of the DFG. Author contributions: H.J. and F.T. contributed equally to this work. NR 48 TC 196 Z9 201 U1 5 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD APR 2 PY 2009 VL 137 IS 1 BP 60 EP 72 DI 10.1016/j.cell.2009.03.018 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 427XV UT WOS:000264813300014 PM 19345187 ER PT J AU Scheid, JF Mouquet, H Feldhahn, N Seaman, MS Velinzon, K Pietzsch, J Ott, RG Anthony, RM Zebroski, H Hurley, A Phogat, A Chakrabarti, B Li, YX Connors, M Pereyra, F Walker, BD Wardemann, H Ho, D Wyatt, RT Mascola, JR Ravetch, JV Nussenzweig, MC AF Scheid, Johannes F. Mouquet, Hugo Feldhahn, Niklas Seaman, Michael S. Velinzon, Klara Pietzsch, John Ott, Rene G. Anthony, Robert M. Zebroski, Henry Hurley, Arlene Phogat, Adhuna Chakrabarti, Bimal Li, Yuxing Connors, Mark Pereyra, Florencia Walker, Bruce D. Wardemann, Hedda Ho, David Wyatt, Richard T. Mascola, John R. Ravetch, Jeffrey V. Nussenzweig, Michel C. TI Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals SO NATURE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODIES; TYPE-1 GP120; PASSIVE TRANSFER; BINDING-SITE; EPITOPE; GLYCOPROTEIN; GP41; PRECURSORS; GENERATION AB Antibodies to conserved epitopes on the human immunodeficiency virus (HIV) surface protein gp140 can protect against infection in non-human primates, and some infected individuals show high titres of broadly neutralizing immunoglobulin (Ig)G antibodies in their serum. However, little is known about the specificity and activity of these antibodies(1-3). To characterize the memory antibody responses to HIV, we cloned 502 antibodies from HIV envelope-binding memory B cells from six HIV-infected patients with broadly neutralizing antibodies and low to intermediate viral loads. We show that in these patients, the B-cell memory response to gp140 is composed of up to 50 independent clones expressing high affinity neutralizing antibodies to the gp120 variable loops, the CD4-binding site, the co-receptor-binding site, and to a new neutralizing epitope that is in the same region of gp120 as the CD4-binding site. Thus, the IgG memory B-cell compartment in the selected group of patients with broad serum neutralizing activity to HIV is comprised of multiple clonal responses with neutralizing activity directed against several epitopes on gp120. C1 [Scheid, Johannes F.; Mouquet, Hugo; Feldhahn, Niklas; Velinzon, Klara; Pietzsch, John; Nussenzweig, Michel C.] Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. [Ott, Rene G.; Anthony, Robert M.; Ravetch, Jeffrey V.] Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10065 USA. [Zebroski, Henry] Rockefeller Univ, Prote Resource Ctr, New York, NY 10065 USA. [Hurley, Arlene] Rockefeller Univ, Rockefeller Univ Hosp, New York, NY 10065 USA. [Nussenzweig, Michel C.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA. [Scheid, Johannes F.] Charite Univ Med Berlin, D-10117 Berlin, Germany. [Seaman, Michael S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Pietzsch, John] Free Univ Berlin, Inst Chem & Biochem, D-14195 Berlin, Germany. [Phogat, Adhuna; Chakrabarti, Bimal; Li, Yuxing; Wyatt, Richard T.; Mascola, John R.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Connors, Mark] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Pereyra, Florencia; Walker, Bruce D.] Mass Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. [Wardemann, Hedda] Max Planck Inst Infect Biol, D-10117 Berlin, Germany. [Pereyra, Florencia; Walker, Bruce D.] Harvard Univ, Sch Med, Charlestown, MA 02129 USA. [Ho, David] Aaron Diamond AIDS Res Ctr, New York, NY 10065 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10065 USA. EM nussen@mail.rockefeller.edu RI Mouquet, Hugo/M-2750-2014 FU Rockefeller University; International Aids Vaccine Initiative; Bill and Melinda Gates Foundation; Intramural Research Program of the Vaccine Research Center; Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health; Deutscher Akademischer Austauschdienst; Fondation Recherche Medicale FX We thank D. Wycuff, E. Lybarger and B. Dey for supplying gp120 proteins for mapping studies, K. McKee for serum adsorption studies and N. Doria- Rose for her work with patient material from patients 4 and 6. This research was supported by the Rockefeller University, the International Aids Vaccine Initiative, the Bill and Melinda Gates Foundation, the Intramural Research Program of the Vaccine Research Center ( R. T. W., J. R. M.), and the Division of Intramural Research ( M. C.), National Institute of Allergy and Infectious Diseases, National Institutes of Health. J. F. S. was supported by the Deutscher Akademischer Austauschdienst, H. M. was supported by the Fondation Recherche Medicale. M. C. N. is a Howard Hughes Medical Institute investigator. NR 29 TC 474 Z9 485 U1 2 U2 50 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD APR 2 PY 2009 VL 458 IS 7238 BP 636 EP 640 DI 10.1038/nature07930 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 427RK UT WOS:000264796200042 PM 19287373 ER PT J AU Zhou, ZF Zhu, GS Hariri, AR Enoch, MA Scott, D Sinha, R Virkkunen, M Mash, DC Lipsky, RH Hu, XZ Hodgkinson, CA Xu, K Buzas, B Yuan, QP Shen, PH Ferrell, RE Manuck, SB Brown, SM Hauger, RL Stohler, CS Zubieta, JK Goldman, D AF Zhou, Zhifeng Zhu, Guanshan Hariri, Ahmad R. Enoch, Mary-Anne Scott, David Sinha, Rajita Virkkunen, Matti Mash, Deborah C. Lipsky, Robert H. Hu, Xian-Zhang Hodgkinson, Colin A. Xu, Ke Buzas, Beata Yuan, Qiaoping Shen, Pei-Hong Ferrell, Robert E. Manuck, Stephen B. Brown, Sarah M. Hauger, Richard L. Stohler, Christian S. Zubieta, Jon-Kar Goldman, David TI Is there an association between NPY and neuroticism? Reply SO NATURE LA English DT Letter ID GENETIC-VARIATION; GENOTYPE; AMYGDALA; POLYMORPHISM C1 [Zhou, Zhifeng; Zhu, Guanshan; Enoch, Mary-Anne; Lipsky, Robert H.; Hu, Xian-Zhang; Hodgkinson, Colin A.; Xu, Ke; Buzas, Beata; Yuan, Qiaoping; Shen, Pei-Hong; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Hariri, Ahmad R.; Ferrell, Robert E.; Manuck, Stephen B.; Brown, Sarah M.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15261 USA. [Hariri, Ahmad R.; Ferrell, Robert E.; Manuck, Stephen B.; Brown, Sarah M.] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15261 USA. [Hariri, Ahmad R.; Ferrell, Robert E.; Manuck, Stephen B.; Brown, Sarah M.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15261 USA. [Scott, David; Zubieta, Jon-Kar] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI 48109 USA. [Scott, David; Zubieta, Jon-Kar] Univ Michigan, Sch Med, Dept Radiol, Ann Arbor, MI 48109 USA. [Sinha, Rajita] Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06510 USA. [Virkkunen, Matti] Univ Helsinki, Dept Psychiat, Helsinki 00014, Finland. [Mash, Deborah C.] Univ Miami, Sch Med, Dept Neurol, Miami, FL 33124 USA. [Hauger, Richard L.] San Diego VA Healthcare Syst, Dept Psychiat, San Diego, CA 92161 USA. [Hauger, Richard L.] Univ Calif San Diego, San Diego, CA 92161 USA. [Stohler, Christian S.] Univ Maryland, Sch Dent, Baltimore, MD 21201 USA. RP Zhou, ZF (reprint author), NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM davidgoldman@mail.nih.gov RI Goldman, David/F-9772-2010; Hariri, Ahmad/D-5761-2011 OI Goldman, David/0000-0002-1724-5405; NR 9 TC 0 Z9 0 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD APR 2 PY 2009 VL 458 IS 7238 BP E7 EP E7 DI 10.1038/nature07928 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 427RK UT WOS:000264796200050 ER PT J AU Schiffman, M Wacholder, S AF Schiffman, Mark Wacholder, Sholom TI From India to the World - A Better Way to Prevent Cervical Cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HUMAN-PAPILLOMAVIRUS DNA; TRIAL; TESTS C1 [Schiffman, Mark; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 13 TC 31 Z9 32 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD APR 2 PY 2009 VL 360 IS 14 BP 1453 EP 1455 DI 10.1056/NEJMe0901167 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 427AL UT WOS:000264751800013 PM 19339726 ER PT J AU Shen, HCJ Adem, A Ylaya, K Wilson, A He, M Lorang, D Hewitt, SM Pechhold, K Harlan, DM Lubensky, IA Schmidt, LS Linehan, WM Libutti, SK AF Shen, H. -C. Jennifer Adem, Asha Ylaya, Kris Wilson, Arianne He, Mei Lorang, Dominique Hewitt, Stephen M. Pechhold, Klaus Harlan, David M. Lubensky, Irina A. Schmidt, Laura S. Linehan, W. Marston Libutti, Steven K. TI Deciphering von Hippel-Lindau (VHL/Vhl)-Associated Pancreatic Manifestations by Inactivating Vhl in Specific Pancreatic Cell Populations SO PLOS ONE LA English DT Article AB The von Hippel-Lindau (VHL) syndrome is a pleomorphic familial disease characterized by the development of highly vascularized tumors, such as hemangioblastomas of the central nervous system, pheochromocytomas, renal cell carcinomas, cysts and neuroendocrine tumors of the pancreas. Up to 75% of VHL patients are affected by VHL-associated pancreatic lesions; however, very few reports in the published literature have described the cellular origins and biological roles of VHL in the pancreas. Since homozygous loss of Vhl in mice resulted in embryonic lethality, this study aimed to characterize the functional significance of VHL in the pancreas by conditionally inactivating Vhl utilizing the Cre/LoxP system. Specifically, Vhl was inactivated in different pancreatic cell populations distinguished by their roles during embryonic organ development and their endocrine lineage commitment. With Cre recombinase expression directed by a glucagon promoter in a-cells or an insulin promoter in beta-cells, we showed that deletion of Vhl is dispensable for normal functions of the endocrine pancreas. In addition, deficiency of VHL protein (pVHL) in terminally differentiated alpha-cells or beta-cells is insufficient to induce pancreatic neuroendocrine tumorigenesis. Most significantly, we presented the first mouse model of VHL-associated pancreatic disease in mice lacking pVHL utilizing Pdx1-Cre transgenic mice to inactivate Vhl in pancreatic progenitor cells. The highly vascularized microcystic adenomas and hyperplastic islets that developed in Pdx1-Cre; Vhl f/f homozygous mice exhibited clinical features similar to VHL patients. Establishment of three different, cell-specific Vhl knockouts in the pancreas have allowed us to provide evidence suggesting that VHL is functionally important for postnatal ductal and exocrine pancreas, and that VHL-associated pancreatic lesions are likely to originate from progenitor cells, not mature endocrine cells. The novel model systems reported here will provide the basis for further functional and genetic studies to define molecular mechanisms involved in VHL-associated pancreatic diseases. C1 [Shen, H. -C. Jennifer; Adem, Asha; Wilson, Arianne; He, Mei; Lorang, Dominique; Libutti, Steven K.] NCI, Surg Branch, Tumor Angiogenesis Sect, Bethesda, MD 20892 USA. [Ylaya, Kris; Hewitt, Stephen M.] NCI, Lab Pathol, Tissue Array Res Program, Bethesda, MD USA. [Pechhold, Klaus; Harlan, David M.] NIDDKD, Diabetes Branch, Bethesda, MD USA. [Lubensky, Irina A.] NCI, Div Canc Treatment & Diagnosis, Rockville, MD USA. [Schmidt, Laura S.; Linehan, W. Marston] NCI, Urol Oncol Branch, Bethesda, MD USA. [Schmidt, Laura S.] NCI, Sci Applicat Int Corp SAIC Frederick Inc, Frederick, MD USA. RP Shen, HCJ (reprint author), NCI, Surg Branch, Tumor Angiogenesis Sect, Bldg 10, Bethesda, MD 20892 USA. EM Steven_Libutti@nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), [HHSN261200800001E] FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Cancer Institute (NCI), and with federal funds from the NIH-NCI, under contract HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 21 Z9 21 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 2 PY 2009 VL 4 IS 4 AR e4897 DI 10.1371/journal.pone.0004897 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437PZ UT WOS:000265500700001 PM 19340311 ER PT J AU Raman, B Meier, DC Evju, JK Semancik, S AF Raman, Baranidharan Meier, Douglas C. Evju, Jon K. Semancik, Steve TI Designing and optimizing microsensor arrays for recognizing chemical hazards in complex environments SO SENSORS AND ACTUATORS B-CHEMICAL LA English DT Article DE Microsensor arrays; Metal oxide sensors; Toxic industrial chemicals; Statistical analysis; Material evaluation; Selection and optimization ID MASS-SPECTROMETRY; WARFARE AGENTS; PATTERN-RECOGNITION; SENSOR ARRAYS; CHROMATOGRAPHY; FUTURE AB A generic approach to designing microsensor arrays for complex chemical sensing tasks is described and demonstrated for the problem of recognizing chemical hazards at sublethal concentrations, under varying ambient conditions, and in the presence of interfering chemicals. We present statistical methods to systematically assess the analytical information obtained from the conductometric responses of chemiresistive elements at different operating temperatures, test their reproducibility, and determine an optimal set of material compositions to be incorporated within an array for individual species recognition. These advances are critical to the production of pre-programmed microsensors for non-invasive trace analyte detection relevant to homeland security, medical diagnostics, and other applications. (C) 2008 Elsevier B.V. All rights reserved. C1 [Raman, Baranidharan; Meier, Douglas C.; Evju, Jon K.; Semancik, Steve] Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. [Raman, Baranidharan] NICHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Semancik, S (reprint author), Natl Inst Stand & Technol, Chem Sci & Technol Lab, 100 Bur Dr MS8362, Gaithersburg, MD 20899 USA. EM steves@nist.gov FU U.S. Department of Homeland Security, Science and Technology Directorate; NIH(NIBIB)-NIST FX We acknowledge partial financial support of this project by the U.S. Department of Homeland Security, Science and Technology Directorate. BR was supported by a NIH(NIBIB)-NIST joint Postdoctoral Associateship Award administered through the National Research Council. We thank Kurt Benkstein, Mike Carrier, Steve Fick, Jim Melvin, Wyatt Miller, Chip Montgomery, Casey Mungle, Jim Yost, Blaine Young, and Li Zhang for their valuable contributions to this project. We are grateful to Mark Stopfer for helpful comments on an earlier version of this manuscript. NR 33 TC 41 Z9 41 U1 1 U2 8 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0925-4005 J9 SENSOR ACTUAT B-CHEM JI Sens. Actuator B-Chem. PD APR 2 PY 2009 VL 137 IS 2 BP 617 EP 629 DI 10.1016/j.snb.2008.11.053 PG 13 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA 435EI UT WOS:000265326100036 ER PT J AU Hayward, AR AF Hayward, Anthony R. TI Commentary: Making Clinical Research a Robust Career Path SO ACADEMIC MEDICINE LA English DT Editorial Material AB This commentary relates to three articles in this issue of Academic Medicine, which address the vision of the National Institutes of Health (NIH) for clinical and translational research. Those articles encompass the first successful Clinical and Translational Science Award applicants' stated aims for their programs, the success of a Harvard training program, and the case for exposing medical students to research experiences. The positive recommendations each makes are timely and give the author an opportunity to draw attention to related NIH education and outreach programs. Meeting the NIH's mission "to extend healthy life and reduce the burdens of illness and disability" will need a coordinated approach to ensure that health care workers are aware of the importance of research-and that clinical researchers see a secure, research-related career structure in academic health centers. C1 NIH, NCRR, Div Clin Res Resources, Bethesda, MD 20892 USA. RP Hayward, AR (reprint author), NIH, NCRR, Div Clin Res Resources, Bldg 10, Bethesda, MD 20892 USA. EM haywarda@mail.nih.gov NR 4 TC 2 Z9 2 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD APR PY 2009 VL 84 IS 4 BP 409 EP 410 PG 2 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 466IQ UT WOS:000267655200005 PM 19318765 ER PT J AU Merikangas, KR Li, JJ Stipelman, B Yu, K Fucito, L Swendsen, J Zhang, H AF Merikangas, Kathleen R. Li, Julan Julia Stipelman, Brooke Yu, Kelly Fucito, Lisa Swendsen, Joel Zhang, Heping TI The familial aggregation of cannabis use disorders SO ADDICTION LA English DT Article DE Anxiety disorder; assortative mating; cannabis; comorbidity; family study; gene-environment interaction; mood disorder; substance use disorder ID SUBSTANCE USE DISORDERS; MARIJUANA USE; DRUG-USE; ALCOHOL DEPENDENCE; DIAGNOSTIC-CRITERIA; PSYCHIATRIC-DISORDERS; EPIDEMIOLOGIC SURVEY; ANXIETY DISORDERS; COMMUNITY SAMPLE; YOUNG ADULTHOOD AB The aim of this paper is to examine the familial aggregation of cannabis use disorders and other psychiatric conditions among first-degree relatives and spouses of probands with a cannabis use disorder. Controlled family study methods. Out-patient psychiatric clinics and the local community (same geographic area). Two hundred and sixty-two probands with a life-time history of cannabis use disorder, alcohol dependence, anxiety disorders or no history of any disorder, and their first-degree relatives and spouses. Cannabis use disorders and other DSM-III-R disorders in the relatives and spouses using the Schedule for Affective Disorders and Schizophrenia. Results reveal an elevated risk of life-time history of cannabis use disorders among siblings [odds ratio (OR: 3.6), adult offspring (OR): 6.9], and spouses (OR: 4.4) of probands with cannabis use disorders. There is a latent familial factor underlying cannabis use disorders that was shared partially with alcohol abuse/dependence. Comorbid mood and anxiety disorders aggregated independently from cannabis use disorders in families. Equal elevation in the magnitude of the association among the first-degree adult relatives and spouses of probands with a cannabis use disorder suggests the probable contribution of both environmental and genetic factors. These findings support a family-based approach to drug abuse intervention and the importance of future research concerning environmental mediators of familial transmission of drug abuse. C1 [Merikangas, Kathleen R.; Stipelman, Brooke; Yu, Kelly; Fucito, Lisa] NIMH, Sect Dev Genet Epidemiol, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20814 USA. [Li, Julan Julia; Zhang, Heping] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Swendsen, Joel] Univ Bordeaux, Natl Ctr Sci Res, CNRS 5231, Bordeaux, France. RP Merikangas, KR (reprint author), NIMH, Sect Dev Genet Epidemiol, Intramural Res Program, NIH,Dept Hlth & Human Serv, 35 Convent Dr,MSC 3720, Bethesda, MD 20814 USA. EM kathleen.merikangas@nih.gov FU National Institutes of Health [AA12044, DA017713, DA016750, DA12468]; [AA07080]; [DA09055]; [MH36197]; [MH0049] FX This work was supported in part by grants AA07080, DA09055, MH36197 and MH0049 (Dr Merikangas) and grants AA12044, DA017713, DA016750 and DA12468 (Dr Zhang and Mrs Li) from the National Institutes of Health. The views and opinions expressed in this report are those of the authors and should not be construed to represent the views of any of the sponsoring organizations, agencies or the US Government. NR 73 TC 15 Z9 15 U1 2 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD APR PY 2009 VL 104 IS 4 BP 622 EP 629 DI 10.1111/j.1360-0443.2008.02468.x PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 420RC UT WOS:000264305900016 PM 19335660 ER PT J AU Mannelli, P Patkar, AA Peindl, K Gorelick, DA Wu, LT Gottheil, E AF Mannelli, Paolo Patkar, Ashwin A. Peindl, Kathi Gorelick, David A. Wu, Li-Tzy Gottheil, Edward TI Very low dose naltrexone addition in opioid detoxification: a randomized, controlled trial SO ADDICTION BIOLOGY LA English DT Article DE Community treatment programs; craving; opioid agonist; antagonist interaction; opioid antagonist; opioid dependence; opioid withdrawal ID INPATIENT OPIATE DETOXIFICATION; DOUBLE-BLIND; FOLLOW-UP; WITHDRAWAL; DEPENDENCE; CLONIDINE; BUPRENORPHINE; ADDICTION; ANALGESIA; NALOXONE AB Although current treatments for opioid detoxification are not always effective, medical detoxification remains a required step before long-term interventions. The use of opioid antagonist medications to improve detoxification has produced inconsistent results. Very low dose naltrexone (VLNTX) was recently found to reduce opioid tolerance and dependence in animal and clinical studies. We decided to evaluate safety and efficacy of VLNTX adjunct to methadone in reducing withdrawal during detoxification. In a multi-center, double-blind, randomized study at community treatment programs, where most detoxifications are performed, 174 opioid-dependent subjects received NTX 0.125 mg, 0.250 mg or placebo daily for 6 days, together with methadone in tapering doses. VLNTX-treated individuals reported attenuated withdrawal symptoms [F = 7.24 (2,170); P = 0.001] and reduced craving [F = 3.73 (2,107); P = 0.03]. Treatment effects were more pronounced at discharge and were not accompanied by a significantly higher retention rate. There were no group differences in use of adjuvant medications and no treatment-related adverse events. Further studies should explore the use of VLNTX, combined with full and partial opioid agonist medications, in detoxification and long-term treatment of opioid dependence. C1 [Mannelli, Paolo; Patkar, Ashwin A.; Peindl, Kathi; Wu, Li-Tzy] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27705 USA. [Gorelick, David A.] Natl Inst Drug Abuse, Intramural Res Program, Bethesda, MD 20892 USA. [Gottheil, Edward] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. RP Mannelli, P (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, 2218 Elder St,Suite 123, Durham, NC 27705 USA. EM paolo.mannelli@duke.edu FU National Institute on Drug Abuse [DA15469]; Intramural Research Program; NIH, National Institute on Drug Abuse; American Psychiatric Association FX This research was supported by grant DA15469 from the National Institute on Drug Abuse to P. Mannelli. Dr. Gorelick is supported by the Intramural Research Program, NIH, National Institute on Drug Abuse. The authors wish to thank Stephen P. Weinstein for helping with recruitment, Michelle Kay Anderberg for recruitment and data collection, and Neena Ajwani for recruitment, data collection and manuscript editing. They also thank the personnel at Freedom House, Chapel Hill, NC and Kensington Hospital, Philadelphia, PA and all the individuals who participated in the clinical trial. Portions of this study were presented at the 160th annual meeting of the American Psychiatric Association, San Diego, CA, 19-24 May 2007. NR 49 TC 14 Z9 14 U1 6 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD APR PY 2009 VL 14 IS 2 BP 204 EP 213 DI 10.1111/j.1369-1600.2008.00119.x PG 10 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 415BE UT WOS:000263908500009 PM 18715283 ER PT J AU Jimenez-Hidalgo, M Santos-Ocana, C Padilla, S Villalba, JM Lopez-Lluch, G Martin-Montalvo, A Minor, RK Sinclair, DA de Cabo, R Navas, P AF Jimenez-Hidalgo, Maria Santos-Ocana, Carlos Padilla, Sergio Villalba, Jose M. Lopez-Lluch, Guillermo Martin-Montalvo, Alejandro Minor, Robin K. Sinclair, David A. de Cabo, Rafael Navas, Placido TI NQR1 controls lifespan by regulating the promotion of respiratory metabolism in yeast SO AGING CELL LA English DT Article DE chronological lifespan; coenzyme Q; coenzyme Q reductase; dietary restriction; NQR1; Plasma membrane; replicative lifespan ID CALORIE RESTRICTION EXTENDS; MEMBRANE ELECTRON-TRANSPORT; LIVER PLASMA-MEMBRANE; COENZYME-Q REDUCTASE; SACCHAROMYCES-CEREVISIAE; UP-REGULATION; OXIDATIVE STRESS; REDOX SYSTEM; CELLS; EXTENSION AB The activity and expression of plasma membrane NADH coenzyme Q reductase is increased by calorie restriction (CR) in rodents. Although this effect is well-established and is necessary for CR's ability to delay aging, the mechanism is unknown. Here we show that the Saccharomyces cerevisiae homolog, NADH-Coenzyme Q reductase 1 (NQR1), resides at the plasma membrane and when overexpressed extends both replicative and chronological lifespan. We show that NQR1 extends replicative lifespan in a SIR2-dependent manner by shifting cells towards respiratory metabolism. Chronological lifespan extension, in contrast, occurs via an SIR2-independent decrease in ethanol production. We conclude that NQR1 is a key mediator of lifespan extension by CR through its effects on yeast metabolism and discuss how these findings could suggest a function for this protein in lifespan extension in mammals. C1 [Jimenez-Hidalgo, Maria; Santos-Ocana, Carlos; Padilla, Sergio; Lopez-Lluch, Guillermo; Martin-Montalvo, Alejandro; Navas, Placido] Univ Pablo Olavide, CSIC, Ctr Andaluz Biol Desarrollo, E-41013 Seville, Spain. [Jimenez-Hidalgo, Maria; Santos-Ocana, Carlos; Padilla, Sergio; Lopez-Lluch, Guillermo; Martin-Montalvo, Alejandro; Navas, Placido] ISCIII, Ctr Biomed Res Rare Dis CIBERER, E-41013 Seville, Spain. [Villalba, Jose M.] Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, Cordoba 14014, Spain. [Sinclair, David A.] Harvard Univ, Sch Med, Dept Pathol, Paul F Glenn Labs Biol Mechanism Aging, Boston, MA 02115 USA. [Minor, Robin K.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP Navas, P (reprint author), Univ Pablo Olavide, CSIC, Ctr Andaluz Biol Desarrollo, E-41013 Seville, Spain. EM decabora@grc.nia.nih.gov; pnavas@upo.es RI de Cabo, Rafael/E-7996-2010; Lopez-Lluch, Guillermo/N-4742-2014; Martin-Montalvo, Alejandro/C-2031-2017; OI de Cabo, Rafael/0000-0002-3354-2442; Lopez-Lluch, Guillermo/0000-0001-9830-8502; Martin-Montalvo, Alejandro/0000-0002-3886-5355; Santos Ocana, Carlos/0000-0002-2379-796X; Sinclair, David/0000-0002-9936-436X; , rafael/0000-0003-2830-5693 FU Spanish Ministerio de Ciencia y Tecnologia [BFU2005-03017/BMC]; Universidad Pablo de Olavide [APP2E04053]; Intramural Research Program of the National Institute on Aging; National Institutes of Health FX The work was supported by the Spanish Ministerio de Ciencia y Tecnologia, Grant BFU2005-03017/BMC, by APP2E04053 Grant of the Universidad Pablo de Olavide, and in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 43 TC 21 Z9 22 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1474-9718 EI 1474-9726 J9 AGING CELL JI Aging Cell PD APR PY 2009 VL 8 IS 2 BP 140 EP 151 DI 10.1111/j.1474-9726.2009.00461.x PG 12 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 424ZQ UT WOS:000264607200006 PM 19239415 ER PT J AU Guralnik, JM Butterworth, S Patel, K Mishra, G Kuh, D AF Guralnik, Jack M. Butterworth, Suzanne Patel, Kushang Mishra, Gita Kuh, Diana TI Reduced midlife physical functioning among never married and childless men: evidence from the 1946 British Birth Cohort Study SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Aging; disability; marital status; parental status; physical function ID MARITAL-STATUS; GRIP STRENGTH; HEALTH-STATUS; MORTALITY; WOMEN; DISABILITY; AGE; POPULATION; PREDICTOR; LONGEVITY AB Background and aims: Marital and parental role characteristics are important factors in both men and women's health. Most studies to date have either focused on disease specific outcomes or summary measures of self-reported health rather than using functional tests of performance. The goal of this study is to investigate the extent to which marital and parental role characteristics are associated with midlife physical function. Methods: A prospective birth cohort study was carried out with reference to births that took place in England, Scotland, and Wales during one week in March of 1946. Regular assessment of 1353 men and 1411 women were made from six weeks after birth throughout childhood and adulthood. Handgrip strength, timed chair rising, and standing balance tests at age 53 years were used to calculate an aggregate physical performance score that ranged from 0 (poorest score) to 2.81. Results: The mean physical performance score was 1.42 (SD 0.42) for men and 1.30 (SD 0.37) for women. By age 53 years, 11% of men and 8% of women had married but remained childless; 6% of men and 4% of women had never married. Never married (X 1.15; 95% CI 1.06, 1.24) and childless married men ((x) over bar 1.36; 95% CI 1.30, 1.42) had significantly poorer physical performance scores than married men with children ((x) over bar 1.46; 95% CI 1.43, 1.48). These relationships remained after adjustment for adult social class and employment status, own educational attainment and body mass index at 53 years (beta=-0.18, 95% CI -0.27, -0.09 for never married and beta=-0.09, 95% CI -0.16, -0.03 for childless married, compared with married men with children). Of those men who had never married, 28% reported they were not working due to long-term health problems compared to 5% in both childless married men and married men with children. There were no marked differences in functional outcomes among women. Conclusions: In this representative middle-aged population, unmarried and childless men faced greater risk of poor midlife physical function, even after adjustment for confounders. These findings suggest that for men, marriage and parenthood protect against functional decline in midlife. Alternatively, physical performance may be a marker of poorer health in earlier life, which affects the chance of marriage and parenthood. (Aging Clin Exp Res 2009; 21: 174-181) (C) 2009, Editrice Kurtis C1 [Guralnik, Jack M.; Patel, Kushang] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Butterworth, Suzanne; Mishra, Gita; Kuh, Diana] Royal Free & Univ Coll Med Sch, MRC Unit Lifelong Hlth & Ageing, MRC Natl Survey Hlth & Dev, London WC1E 6BT, England. RP Guralnik, JM (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Room 3C-309, Bethesda, MD 20892 USA. EM jg48s@nih.gov FU NIH FX Supported in part by the Intramural Research Program, National Institute on Aging, NIH. NR 31 TC 9 Z9 9 U1 0 U2 12 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD APR PY 2009 VL 21 IS 2 BP 174 EP 181 PG 8 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 451GX UT WOS:000266459800011 PM 19448390 ER PT J AU Semba, RD Ferrucci, L Sun, K Beck, J Dalal, M Varadhan, R Walston, J Guralnik, JM Fried, LP AF Semba, Richard D. Ferrucci, Luigi Sun, Kai Beck, Justine Dalal, Mansi Varadhan, Ravi Walston, Jeremy Guralnik, Jack M. Fried, Linda P. TI Advanced glycation end products and their circulating receptors predict cardiovascular disease mortality in older community-dwelling women SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Advanced glycation end products; aging; atherosclerosis; cardiovascular disease; mortality ID SOLUBLE RECEPTOR; SERUM-LEVELS; RISK-FACTOR; DIABETES-MELLITUS; ENDOTHELIAL-CELLS; OXIDATIVE STRESS; HEART-FAILURE; ENDPRODUCTS; GLYCOTOXINS; EXPRESSION AB Aims: To characterize the relationship between advanced glycation end products (AGES) and circulating receptors for AGES (RAGE) with cardiovascular disease mortality. Methods: The relationships between serum AGES, total RAGE (sRAGE), and endogenous secretory RAGE (esRAGE), and mortality were characterized in 559 community-dwelling women, double dagger 65 years, in Baltimore, Maryland. Results: During 4.5 years of follow-up, 123 (22%) women died, of whom 54 died with cardiovascular disease. The measure of serum AGES was carboxymethyl-lysine (CML), a dominant AGE. Serum CML predicted cardiovascular disease mortality (Hazards Ratio [HR] for highest vs lower three quartiles, 1.94, 95% Confidence Interval [CI] 1.08-3.48, p=0.026), after adjusting for age, race, body mass index, and renal insufficiency. Serum sRAGE (ng/mL) and esRAGE (ng/mL) predicted cardiovascular disease mortality (HR per 1 Standard Deviation [SD] 1.27, 95% CI 0.98-1.65, p=0.07; HR 1.28, 95% CI 1.02-1.63, p=0.03), after adjusting for the same covariates. Among non-diabetic women, serum CML, sRAGE, and esRAGE, respectively, predicted cardiovascular disease mortality (HR for highest vs lower three quartiles, 2.29, 95% CI 1.21-4.34, p=0.01; HR per 1 SD, 1.24, 95% CI 0.92-1.65, p=0.16; HR per 1 SD 1.45, 95% CI 1.08-1.93, p=0.01), after adjusting for the same covariates. Conclusions: High circulating AGES and RAGE predict cardiovascular disease mortality among older community-dwelling women. AGEs are a potential target for interventions, as serum AGEs can be lowered by change in dietary pattern and pharmacological treatment. (Aging Clin Exp Res 2009; 21: 182-190) (C) 2009, Editrice Kurtis C1 [Semba, Richard D.; Sun, Kai; Beck, Justine; Dalal, Mansi; Varadhan, Ravi; Walston, Jeremy; Fried, Linda P.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. [Ferrucci, Luigi] NIA, Cli Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, 550 N Broadway,Suite 700, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu FU National Institute on Aging [RO1 AG027012, R01 AG029148]; NIH-NCRR; OPD-GCRC [RR00722]; NIA [NO1-AG12112]; Johns Hopkins Older Americans' Independence Center FX This work was supported by National Institute on Aging Grant RO1 AG027012. R01 AG029148, NIH-NCRR. OPD-GCRC grant RR00722, and NIA Contract NO1-AG12112, the Johns Hopkins Older Americans' Independence Center, and the Intramural Research Program, National Institute on Aging, NIH. NR 44 TC 45 Z9 45 U1 1 U2 6 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD APR PY 2009 VL 21 IS 2 BP 182 EP 190 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 451GX UT WOS:000266459800012 PM 19448391 ER PT J AU Chang, M Phillips, C Coppin, AK van der Linden, M Ferrucci, L Fried, L Guralnik, JM AF Chang, Milan Phillips, Caroline Coppin, Antonia K. van der Linden, Michiel Ferrucci, Luigi Fried, Linda Guralnik, Jack M. TI An association between incident disability and depressive symptoms over 3 years of follow-up among older women: The Women's Health and Aging Study SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article CT 57th Annual Meeting of the Gerontological-Society-of-America CY NOV 19-23, 2004 CL Washington, DC SP Gerontol Soc Amer DE Depressive symptoms; disability; older women ID LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE BATTERY; LATE-LIFE DEPRESSION; SUBSEQUENT DISABILITY; RISK-FACTORS; ADULTS; IMPAIRMENT; DEPENDENCE; DISORDERS AB Background and aims: To examine the impact of new disability on the incidence of depressive symptoms, with 3-year biannual data from The Woman's Health and Aging Study. Methods: Subjects (n=671) were selected if they were independent at baseline in 5 basic activities of daily living (ADLs) and were not depressed [scored <14 on the Geriatric Depression Scale (GDS; range 0 to 30)]. During the follow-ups, worsening of ADL disability (needed help on an increased number of ADLs) and onset of depressive symptoms (GDS score >= 14) were defined. For each pair of consecutive interviews in which depressive symptoms were not present in the first interview in the pair, we assessed incidence of worsening disability and depressive symptoms in the second interview of the pair. We also summarized the incidence of depressive symptoms 6 months later among the people who did not develop depressive symptoms at the time they reported a new disability. Results: Compared with those not developing disability, after adjusting for demographic characteristics, number of diseases, and ADL difficulty level at the moment of onset of the disability, the odds ratio (OR) for developing depressive symptoms at disability onset was 2.2 (95% Confidence Interval (CI) 1.1-4.3). For those developing new disability without depressive symptoms, the adjusted OR for developing depressive symptoms 6 months later was 1.7 (CI 0.6-4.8). Conclusion: Onset of new disability in basic ADLs had a significant impact on the development of depressive symptoms at the moment of onset. Our results demonstrate that clinicians should carefully evaluate depressive symptoms in patients with new onset of disability. (Aging Clin Exp Res 2009; 21: 191-197) (C) 2009, Editrice Kurtis C1 [Chang, Milan] Landspitali Univ Hosp, Geriatr Res Ctr, Reykjavik, Iceland. [Phillips, Caroline; Coppin, Antonia K.; van der Linden, Michiel; Ferrucci, Luigi; Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Fried, Linda] Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. [Fried, Linda] Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. [Fried, Linda] Johns Hopkins Ctr Aging & Hlth, Baltimore, MD USA. RP Chang, M (reprint author), Landspital Hosp, Gerontol Res Inst, IS-101 Reykjavik, Iceland. EM changmi@landspitali.is FU Intramural NIH HHS; NIA NIH HHS [N01 AG012112, N01-AG-1-2112] NR 21 TC 12 Z9 13 U1 0 U2 1 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD APR PY 2009 VL 21 IS 2 BP 191 EP 197 PG 7 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 451GX UT WOS:000266459800013 PM 19448392 ER PT J AU Wu, JJ Quijano, C Chen, E Liu, HJ Cao, L Fergusson, MM Rovira, II Gutkind, S Daniels, MP Komatsu, M Finkel, T AF Wu, J. Julie Quijano, Celia Chen, Edmund Liu, Hongjun Cao, Liu Fergusson, Maria M. Rovira, Ilsa I. Gutkind, Sarah Daniels, Mathew P. Komatsu, Masaaki Finkel, Toren TI Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy SO AGING-US LA English DT Article DE aging; mitochondria; oxidative stress; autophagy; Atg7 ID BETA-CELL MASS; LIFE-SPAN EXTENSION; SKELETAL-MUSCLE; C-ELEGANS; HEMODYNAMIC STRESS; INSULIN-SECRETION; MICE; DISEASE AB Impaired or deficient autophagy is believed to cause or contribute to aging, as well as a number of age-related pathologies. The exact mechanism through which alterations in autophagy induce these various pathologies is not well understood. Here we describe the creation of two in vivo mouse models that allow for the characterization of the alteration in mitochondrial function and the contribution of the corresponding oxidative stress following deletion of Atg7. Using these models we demonstrate that isolated mitochondria obtained from Atg7(-/-) skeletal muscle exhibit a significant defect in mitochondrial respiration. We further show that cells derived from Atg7(-/-) mice have an altered metabolic profile characterized by decreased resting mitochondrial oxygen consumption and a compensatory increase in basal glycolytic rates. Atg7(-/-) cells also exhibit evidence for increased steady state levels of reactive oxygen species. The observed mitochondrial dysfunction and oxidative stress is also evident in a mouse model where Atg7 is deleted within the pancreatic beta cell. In this model, the simple administration of an antioxidant can significantly ameliorate the physiological impairment in glucose-stimulated insulin secretion. Taken together, these results demonstrate the potential role of mitochondrial dysfunction and oxidative stress in autophagy related pathology. C1 [Wu, J. Julie; Quijano, Celia; Chen, Edmund; Liu, Hongjun; Cao, Liu; Fergusson, Maria M.; Rovira, Ilsa I.; Gutkind, Sarah; Finkel, Toren] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Daniels, Mathew P.] NHLBI, Elect Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. [Komatsu, Masaaki] Tokyo Metropolitan Inst Med Sci, Lab Frontier Sci, Tokyo 113, Japan. RP Finkel, T (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10-CRC 5-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU NIGMS; Ellison Medical Foundation; NIH FX We are grateful to Patricia S. Connelly and Amie L. Batson for assistance with electron microscopy, to Oksana Gavrilova for help with islet isolation, to Sushil Rane for advice on pancreatic analysis, to Michael Sack for help with quantification of mitochondrial number, and to Teng Lu for technical assistance. J.J.W. was supported by a NIGMS Pharmacology Research Associate (PRAT) Program fellowship and the work done in laboratory of T. F. is supported by The Ellison Medical Foundation and the NIH Intramural Program. NR 34 TC 140 Z9 143 U1 0 U2 8 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 APR PY 2009 VL 1 IS 4 BP 425 EP 437 PG 13 WC Cell Biology SC Cell Biology GA 579UN UT WOS:000276401100010 PM 20157526 ER PT J AU Sendagire, H Easterbrook, PJ Nankya, I Arts, E Thomas, D Reynolds, SJ AF Sendagire, Hakim Easterbrook, Philippa J. Nankya, Immaculate Arts, Eric Thomas, David Reynolds, Steven J. TI The Challenge of HIV-1 Antiretroviral Resistance in Africa in the Era of HAART SO AIDS REVIEWS LA English DT Review DE Antiretroviral therapy; ART; Resistance; Africa; Subtypes; Phenotypic; Genotypic ID SINGLE-DOSE NEVIRAPINE; C REVERSE-TRANSCRIPTASE; IMMUNODEFICIENCY-VIRUS TYPE-1; POL GENE DIVERSITY; DRUG-RESISTANCE; SUBTYPE-C; PREGNANT-WOMEN; COTE-DIVOIRE; SOUTH-AFRICA; UGANDAN WOMEN AB Antiretroviral therapy programs in Africa are currently providing treatment for almost two million people. The long-term success of large scale antiretroviral therapy programs in sub-Saharan Africa remains uncertain because of the limited information currently available on rates of virologic failure and selection for drug-resistant variants in the different HIV subtypes. This article provides a comprehensive review of the published literature on the prevalence of primary and secondary HIV drug resistance with different subtypes and in various settings across sub-Saharan Africa. (AIDS Rev. 2009;11:59-70) C1 [Sendagire, Hakim] Makerere Univ, Infect Dis Inst, Dept Microbiol, Kampala, Uganda. [Sendagire, Hakim] Makerere Univ, Dept Microbiol, Kampala, Uganda. [Easterbrook, Philippa J.] Guys Hosp, Dept HIV GU Med, Sch Med, Kings Coll London, London WC2R 2LS, England. [Easterbrook, Philippa J.] Kings Coll Hosp London, Dept HIV GU Med, Sch Med, Kings Coll London, London WC2R 2LS, England. [Easterbrook, Philippa J.] St Thomas Hosp, Dept HIV GU Med, Sch Med, Kings Coll London, London WC2R 2LS, England. [Nankya, Immaculate; Arts, Eric] Joint Clin Res Ctr, Kampala, Uganda. [Nankya, Immaculate; Arts, Eric] Case Western Reserve Univ, Dept Med, Div Infect Dis, Cleveland, OH 44106 USA. [Thomas, David; Reynolds, Steven J.] Johns Hopkins Univ, Div Infect Dis, Dept Med, Baltimore, MD USA. [Reynolds, Steven J.] NIAID, NIH, Bethesda, MD 20892 USA. RP Sendagire, H (reprint author), Makerere Univ, Infect Dis Inst, Dept Microbiol, POB 22418, Kampala, Uganda. EM hsendagire@idi.co.ug FU Sewankambo Scholarship fund FX We are grateful to the people who have contributed to this manuscript, Prof. Keith McAdam, Former Director of IDI; Dr. Yukari Manabe laboratory technical adviser IDI, all the visiting professors to IDI who have read through and guided this manuscript; Allan Ronald, Department of Medical Microbiology, University of Manitoba, Canada, W. Michael Scheld School of Medicine, University of Virginia, USA, Paul Bohjanen Department of Microbiology and department of Medicine, University of Minnesota, USA, Andrew Stergachis of the University of Washington, and Wally Schlech of Victoria General Hospital, Halifax, Canada. Hakim Sendagire is receiving research support from the Sewankambo Scholarship fund at the IDI. NR 63 TC 7 Z9 7 U1 0 U2 3 PU PERMANYER PUBL PI BARCELONA PA MALLORCA, 310, BARCELONA, 00000, SPAIN SN 1139-6121 J9 AIDS REV JI Aids Rev. PD APR-JUN PY 2009 VL 11 IS 2 BP 59 EP 70 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 466HB UT WOS:000267651100001 PM 19529746 ER PT J AU Moore, MD Hu, WS AF Moore, Michael D. Hu, Wei-Shau TI HIV-1 RNA Dimerization: It Takes Two to Tango SO AIDS REVIEWS LA English DT Review DE HIV-1; Genome; RNA; Dimerization; Recombination; Maturation ID IMMUNODEFICIENCY-VIRUS TYPE-1; MURINE LEUKEMIA-VIRUS; DIMER INITIATION COMPLEX; ACID-CHAPERONE ACTIVITY; NMR SOLUTION STRUCTURE; SPLICE DONOR SITE; VIRAL GENOMIC RNA; STEM-LOOP B; NUCLEOCAPSID PROTEIN; IN-VITRO AB Each viral particle of HIV-1, the infectious agent of AIDS, contains two copies of the full-length viral genomic RNA. Encapsidating two copies of genomic RNA is one of the characteristics of the retrovirus family. The two RNA molecules are both positive-sense and often identical; furthermore, each RNA encodes the full complement of genetic information required for viral replication. The two strands of RNA are intricately entwined within the core of the mature infectious virus as a ribonuclear complex with the viral proteins, including nucleocapsid. Multiple steps in the biogenesis of the genomic full-length RNA are involved in achieving this location and dimeric state. The viral sequences and proteins involved in the process of RNA dimerization, both for the initial interstrand contact and subsequent steps that result in the condensed, stable conformation of the genomic RNA, are outlined in this review. In addition, the impact of the dimeric state of HIV-1 viral RNA is discussed with respect to its importance in efficient viral replication and, consequently, the potential development of antiviral strategies designed to disrupt the formation of dimeric RNA. (AIDS Rev. 2009;11:91-102) C1 [Moore, Michael D.; Hu, Wei-Shau] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Hu, WS (reprint author), NCI, HIV Drug Resistance Program, Bldg 535 Room 336,1050 Boyles St, Frederick, MD 21702 USA. EM whu@ncifcrf.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Anne Arthur for editorial help, Drs. Alan Rein, Rebecca A. Russell and Vinay K. Pathak for input and reading of this manuscript. The authors are supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 111 TC 48 Z9 50 U1 0 U2 11 PU PERMANYER PUBL PI BARCELONA PA MALLORCA, 310, BARCELONA, 00000, SPAIN SN 1139-6121 J9 AIDS REV JI Aids Rev. PD APR-JUN PY 2009 VL 11 IS 2 BP 91 EP 102 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 466HB UT WOS:000267651100004 PM 19529749 ER PT J AU Wu, H Romieu, I Sienra-Monge, JJ Li, H del Rio-Navarro, BE London, SJ AF Wu, H. Romieu, I. Sienra-Monge, J. -J. Li, H. del Rio-Navarro, B. E. London, S. J. TI Genetic variation in ORM1-like 3 (ORMDL3) and gasdermin-like (GSDML) and childhood asthma SO ALLERGY LA English DT Article DE allergy; asthma; genetic predisposition to disease; meta-analysis; single nucleotide polymorphism ID CASE-PARENT TRIADS; BRONCHIAL HYPERRESPONSIVENESS; LINKAGE ANALYSIS; ASSOCIATION; EXPRESSION; CHILDREN; OZONE; FAMILY; MICE AB A genome-wide association study identified ORM1-like 3 (orosomucoid 1-like 3, ORMDL3) as an asthma candidate gene. Single nucleotide polymorphisms (SNPs) in the region including ORMDL3 on chromosome 17q21 were related to childhood asthma risk and ORMDL3 expression levels in Europeans. We examined whether polymorphisms in ORMDL3 and the adjacent gasdermin-like (GSDML) gene associated with asthma in the genome-wide association study are related to childhood asthma and atopy in a Mexico City population. We genotyped rs4378650 in ORMDL3 and rs7216389 in GSDML in 615 nuclear families consisting of asthmatic children aged 4-17 years and their parents. Atopy was determined by skin prick tests to 25 aeroallergens. Individuals carrying the C allele of rs4378650 or the T allele of rs7216389 had increased risk of asthma [relative risk (RR) = 1.73, 95% confidence interval (CI) 1.19-2.53, P = 0.003 for one or two copies of rs4378650 C, and RR = 1.64, 95% CI 1.12-2.38, P = 0.009 for one or two copies of rs7216389 T). Linkage disequilibrium between the two SNPs was high (r(2) = 0.92). Neither of the SNPs was associated with the degree of atopy. A meta-analysis of five published studies on rs7216389 in nine populations gave an odds ratio for asthma of 1.44 (95% CI, 1.35-1.54, P < 0.00001). Our results and the meta-analysis provide evidence to confirm the finding from a recent genome-wide association study that polymorphisms in ORMDL3 and the adjacent GSDML may contribute to childhood asthma. C1 [Wu, H.; Li, H.; London, S. J.] NIEHS, Lab Resp Biol, Div Intramural Res, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Romieu, I.] Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Sienra-Monge, J. -J.; del Rio-Navarro, B. E.] Hosp Infantil Mexico Dr Federico Gomez, Mexico City, DF, Mexico. [London, S. J.] NIEHS, Epidemiol Branch, Div Intramural Res, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP London, SJ (reprint author), NIEHS, Lab Resp Biol, Div Intramural Res, NIH,Dept Hlth & Human Serv, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. OI London, Stephanie/0000-0003-4911-5290 FU Division of Intramural Research, National Institute of Environmental Health Sciences [Z01 ES49019]; National Institutes of Health, Department of Health and Human Services, USA; National Council of Science and Technology [26206-M] FX We thank the children and parents who participated in this study; Stephan Chanock, MD, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, for determination of short tandem repeats for parentage testing; Grace Chiu, PhD (Westat, Research Triangle Park, NC) for data management and analysis; Susan Baker, Sarah Lein, and Sheri McReynolds (Coda Research Inc, Research Triangle Park, NC) for specimen handling; and Dulce Ramirez for participation in the fieldwork. NR 29 TC 69 Z9 77 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-4538 J9 ALLERGY JI Allergy PD APR PY 2009 VL 64 IS 4 BP 629 EP 635 DI 10.1111/j.1398-9995.2008.01912.x PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 418QF UT WOS:000264162600016 PM 19133921 ER PT J AU Becker, MC Wang, TH Wisniewski, L Wolski, K Libby, P Luscher, TF Borer, JS Mascette, AM Husni, ME Solomon, DH Graham, DY Yeomans, ND Krum, H Ruschitzka, F Lincoff, AM Nissen, SE AF Becker, Matthew C. Wang, Thomas H. Wisniewski, Lisa Wolski, Kathy Libby, Peter Luescher, Thomas F. Borer, Jeffrey S. Mascette, Alice M. Husni, M. Elaine Solomon, Daniel H. Graham, David Y. Yeomans, Neville D. Krum, Henry Ruschitzka, Frank Lincoff, A. Michael Nissen, Steven E. CA Precision Investigators TI Rationale, design, and governance of Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION), a cardiovascular end point trial of nonsteroidal antiinflammatory agents in patients with arthritis SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; SELECTIVE CYCLOOXYGENASE-2 INHIBITORS; UPPER GASTROINTESTINAL TOXICITY; POPULATION-BASED COHORT; RHEUMATOID-ARTHRITIS; CYCLO-OXYGENASE-2 INHIBITORS; RISK; DRUGS; ROFECOXIB; PREVENTION AB Background Pain management in patients with osteoarthritis or rheumatoid arthritis often requires long-term use of nonsteroidal antiinflammatory drugs (NSAIDs). However, the relative cardiovascular safety of these therapies remains uncertain. Methods The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial will evaluate the cardiovascular safety of celecoxib, ibuprofen, and naproxen. Approximately 20,000 patients with symptomatic osteoarthritis or rheumatoid arthritis at high risk for, or with, established cardiovascular disease will be randomized in this double-blind, triple dummy, multinational, multicenter study. The primary end point is the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The trial will continue until 762 primary events occur with at least 18 months follow-up. Noninferiority of any of the regimens will require a 97.5% upper Cl of the hazard ratio (HR) <= 1.33 and point estimate <= 1.12 for both intent-to-treat (ITT) and modified ITT populations. Conclusion PRECISION, the first study of patients with high cardiovascular risk chronically treated with a cyclooxygenase-2 selective inhibitor or nonselective NSAID, will define the relative cardiovascular safety profile of celecoxib, ibuprofen, and naproxen and provide data to help guide NSAID use for pain management for this population. (Am Heart J 2009; 157:606-12.) C1 [Becker, Matthew C.; Wang, Thomas H.; Wisniewski, Lisa; Wolski, Kathy; Lincoff, A. Michael; Nissen, Steven E.] Cleveland Clin Fdn, Dept Cardiol, Cleveland, OH 44195 USA. [Libby, Peter] Brigham & Womens Hosp, Dept Med, Div Cardiovasc, Boston, MA 02115 USA. [Luescher, Thomas F.; Ruschitzka, Frank] Univ Zurich Hosp, Dept Cardiol, CH-8091 Zurich, Switzerland. [Borer, Jeffrey S.] SUNY Hlth Sci Ctr, Div Cardiovasc Med, New York, NY USA. [Mascette, Alice M.] NHLBI, Bethesda, MD 20892 USA. [Husni, M. Elaine] Cleveland Clin Fdn, Orthoped & Rheumatol Inst, Cleveland, OH 44195 USA. [Solomon, Daniel H.] Brigham & Womens Hosp, Dept Rheumatol, Boston, MA 02115 USA. [Graham, David Y.] Baylor Coll Med, Dept Gastroenterol, Houston, TX 77030 USA. [Yeomans, Neville D.] Univ Western Sydney, Dean Med Unit, Sydney, NSW, Australia. [Krum, Henry] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. RP Nissen, SE (reprint author), Cleveland Clin, Dept Cardiovasc, F15,9500 Euclid Ave, Cleveland, OH 44195 USA. EM nissens@ccf.org NR 31 TC 59 Z9 63 U1 2 U2 6 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD APR PY 2009 VL 157 IS 4 BP 606 EP 612 DI 10.1016/j.ahj.2008.12.014 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 432CC UT WOS:000265110100003 PM 19332185 ER PT J AU Moore, SC AF Moore, Steven C. TI Waist versus weight-which matters more for mortality? SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID OBESITY; DEATHS; ADIPOSITY; MEN C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Moore, SC (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM moorest@mail.nih.gov RI Moore, Steven/D-8760-2016 OI Moore, Steven/0000-0002-8169-1661 FU Intramural NIH HHS NR 11 TC 21 Z9 21 U1 0 U2 0 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD APR 1 PY 2009 VL 89 IS 4 BP 1003 EP 1004 DI 10.3945/ajcn.2009.27598 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 420WF UT WOS:000264319200003 PM 19244373 ER PT J AU Chung, M Balk, EM Ip, S Raman, G Yu, WW Trikalinos, TA Lichtenstein, AH Yetley, EA Lau, J AF Chung, Mei Balk, Ethan M. Ip, Stanley Raman, Gowri Yu, Winifred W. Trikalinos, Thomas A. Lichtenstein, Alice H. Yetley, Elizabeth A. Lau, Joseph TI Reporting of systematic reviews of micronutrients and health: a critical appraisal SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Review ID RANDOMIZED CONTROLLED-TRIALS; VITAMIN-A SUPPLEMENTATION; CORTICOSTEROID-INDUCED OSTEOPOROSIS; PREGNANCY-INDUCED HYPERTENSION; IODINE DEFICIENCY DISORDERS; FOLIC-ACID SUPPLEMENTATION; BLOOD-PRESSURE RESPONSE; EVIDENCE-BASED MEDICINE; PROPOSED COCHRANE DIET; CORONARY-HEART-DISEASE AB Background: The quality of nutrition-related systematic reviews (SRs) is an unstudied but important factor affecting their usefulness. Objectives: The objectives were to evaluate the reporting quality of published SRs and to identify areas of improvement. Design: Descriptive and exploratory analyses of the reporting quality (7 nutrition items and 28 SR reporting items) of all English-language SRs published through July 2007 linking micronutrients and health outcomes in humans were conducted. Factors that may be associated with reporting quality were also evaluated. Results: We identified 141 eligible SRs of 21 micronutrients. Ninety SRs that included only interventional studies met a higher proportion of our reporting criteria (median: 62%; interquartile range: 51%, 72%) than did 31 SRs with only observational studies (median: 53%; interquartile range: 47%, 60%) or 20 SRs with both study designs (median: 47%; interquartile range: 39%, 52%) (P < 0.001). SRs published after consensus reporting standards (since 2003) met a higher proportion of the reporting criteria than did earlier SRs (median: 59% compared with 50%; P = 0.01); however, the reporting of nutrition variables remained unchanged (median: 38% compared with 33%; P = 0.7). The least-reported nutrition criteria were baseline nutrient exposures (28%) and effects of measurement errors from nutrition exposures (24%). Only 58 SRs (41%) used quality scales or checklists to assess the methodologic quality of the primary studies included. Conclusions: The reporting quality of SRs has improved 3 y after publication of SR reporting standards, but the reporting of nutrition variables has not. Improved adherence to consensus methods and reporting standards should improve the utility of nutrition SRs. Am J Clin Nutr 2009; 89:1099-113. C1 [Chung, Mei; Balk, Ethan M.; Ip, Stanley; Raman, Gowri; Trikalinos, Thomas A.; Lichtenstein, Alice H.; Lau, Joseph] Tufts Med Ctr, Tufts Evidence Based Practice Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA 02111 USA. [Chung, Mei; Yu, Winifred W.; Lichtenstein, Alice H.; Lau, Joseph] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Yu, Winifred W.; Lichtenstein, Alice H.] Tufts Univ, Jean Mayer US Dept Agr Human Nutr Res Ctr Aging, Cardiovasc Nutr Lab, Boston, MA 02111 USA. [Yetley, Elizabeth A.] NIH, Off Dietary Supplements, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lau, J (reprint author), Tufts Med Ctr, Tufts Evidence Based Practice Ctr, Inst Clin Res & Hlth Policy Studies, Box 63,800 Washington St, Boston, MA 02111 USA. EM jlau1@tuftsmedicalcenter.org FU NHLBI NIH HHS [T32 HL069772]; PHS HHS [290-02-0022] NR 185 TC 13 Z9 13 U1 1 U2 7 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD APR 1 PY 2009 VL 89 IS 4 BP 1099 EP 1113 DI 10.3945/ajcn.2008.26821 PG 15 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 420WF UT WOS:000264319200017 PM 19244363 ER PT J AU Lieffers, JR Mourtzakis, M Hall, KD McCargar, LJ Prado, CMM Baracos, VE AF Lieffers, Jessica R. Mourtzakis, Marina Hall, Kevin D. McCargar, Linda J. Prado, Carla M. M. Baracos, Vickie E. TI A viscerally driven cachexia syndrome in patients with advanced colorectal cancer: contributions of organ and tumor mass to whole-body energy demands SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID METASTATIC LIVER-TUMORS; ACUTE-PHASE RESPONSE; PANCREATIC-CANCER; WEIGHT-LOSS; NONSURGICAL MANAGEMENT; SKELETAL-MUSCLE; ADIPOSE-TISSUE; EXPENDITURE; FAT; CHEMOTHERAPY AB Background: Cancer cachexia-associated weight loss is poorly understood; energetically demanding tissues (eg, organ and tumor mass) and resting energy expenditure (REE) are reported to increase with advanced cancer. Objective: The objective was to quantify the potential contribution of increasing masses of energetically demanding tissues to REE with colorectal cancer cachexia progression. Design: A longitudinal computed tomography (CT) image review was performed to quantify organ size (liver, including metastases, and spleen) and peripheral tissues (skeletal muscle and adipose tissue) during colorectal cancer cachexia progression (n = 34). Body composition was prospectively evaluated by CT and dual-energy X-ray absorptiometry, and REE was determined by indirect calorimetry in advanced colorectal cancer patients (n 18). Results: Eleven months from death, the liver (2.3 +/- 0.7 kg) and spleen (0.32 +/- 0.2 kg) were larger than reference values. One month from death, liver weight increased to 3.0 +/- 1.5 kg (P 0.010), spleen showed a trend to increase (P = 0.077), and concurrent losses of muscle (4.2 kg) and fat (3.5 kg) (P < 0.05) were observed. The estimated percentage of fat-free mass (FFM) occupied by the liver increased from 4.5% to 7.0% (P < 0.001). The most rapid loss of peripheral tissues and liver and metastases gain occurred within 3 mo of death. A positive linear relation existed between liver mass and measured whole-body REE (r(2) = 0.35, P 0.010); because liver accounted for a larger percentage of FFM, measured REE center dot kg FFM(-1) center dot d(-1) increased (r(2) = 0.35, P = 0.010). Conclusions: Increases in mass and in the proportion of high metabolic rate tissues, including liver and tumor, represented a cumulative incremental REE of approximate to 17,700 kcal during the last 3 mo of life and may contribute substantially to cachexia-associated weight loss. Am J Clin Nutr 2009;89:1173-9. C1 [Baracos, Vickie E.] Univ Alberta, Div Palliat Care Med, Dept Oncol, Edmonton, AB T6G 1Z2, Canada. [Lieffers, Jessica R.; McCargar, Linda J.; Prado, Carla M. M.; Baracos, Vickie E.] Univ Alberta, Dept Agr Food & Nutr Sci, Edmonton, AB T6G 1Z2, Canada. [Hall, Kevin D.] NIDDK, Lab Biol Modelling, NIH, Bethesda, MD USA. RP Baracos, VE (reprint author), Univ Alberta, Div Palliat Care Med, Dept Oncol, 11560 Univ Ave, Edmonton, AB T6G 1Z2, Canada. EM vickie.baracos@ualberta.ca RI Hall, Kevin/F-2383-2010; OI Baracos, Vickie/0000-0002-9609-1001 FU NIH; NIDDK; Canadian Institutes for Heath Research Canada Graduate Scholarship Masters Award; Alberta Cancer Board Graduate Studentship; Canadian Institute of Health Research; Canadian Institutes of Health Research; Natural Sciences and Engineering Research Council of Canada; Alberta Cancer Board; Alberta Cancer Foundation FX Supported in part by the Intramural Research Program of the NIH, NIDDK; the Canadian Institutes for Heath Research Canada Graduate Scholarship Masters Award (to JRL); the Alberta Cancer Board Graduate Studentship from Alberta Cancer Board and Alberta Cancer Foundation, Edmonton, Canada (to JRL and CMMP); the Translational Research Training in Cancer fellowship from the Canadian Institute of Health Research (to MM and CMMP); and grants from the Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, Alberta Cancer Board, and Alberta Cancer Foundation. NR 35 TC 88 Z9 90 U1 1 U2 7 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD APR 1 PY 2009 VL 89 IS 4 BP 1173 EP 1179 DI 10.3945/ajcn.2008.27273 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 420WF UT WOS:000264319200025 PM 19244378 ER PT J AU Flegal, KM Graubard, BI AF Flegal, Katherine M. Graubard, Barry I. TI Estimates of excess deaths associated with body mass index and other anthropometric variables SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID CARDIOVASCULAR-DISEASE RISK; BIOELECTRICAL-IMPEDANCE ANALYSIS; WAIST-HIP RATIO; ABDOMINAL OBESITY; FOLLOW-UP; ALL-CAUSE; MORTALITY; OVERWEIGHT; WOMEN; CIRCUMFERENCE AB Background: Estimates of excess mortality associated with body mass index (BMI; in kg/m(2)) have been calculated for the US population. Objective: The objective of this article is to compare the excess mortality associated with BMI levels to the excess mortality associated with other anthropometric variables. Design: For the 1988-1994 Third National Health and Nutrition Examination Survey, estimates of excess deaths were calculated for standard BMI levels and for comparable levels of percentage body fat, waist circumference, hip and arm circumferences, waist-hip ratio, the sum of 4 skinfold thicknesses, and waist-stature ratio. The outcome measure is the percentage of deaths in the full sample in excess of those predicted for the reference category. Results: For the level equivalent to BMI < 18.5, estimates of excess deaths ranged from 0.3% for waist-hip ratio to 2.4% for percentage body fat. All except waist circumference, waist-hip ratio, and waiststature ratio were significantly greater than zero (P < 0.05). For the level equivalent to BMI 25 to > 30, the percentage of excess deaths was 0.1% for percentage body fat and negative for all other variables; estimates were significantly below zero only for circumferences and waist-stature ratio. For the level equivalent to BMI >= 30, estimates ranged from-1.7% for waist circumference to 1.5% for percentage of fat; none were significantly different from zero. Estimates for allcause mortality, obesity-related causes of death, and other causes of death showed no statistically significant or systematic differences between BMI and other variables. Conclusion: In this population-based study, attributable fractions of deaths were similar across measures. Am J Clin Nutr 2009; 89: 1213-9. C1 [Flegal, Katherine M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Graubard, Barry I.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 4201, Hyattsville, MD 20782 USA. EM kflegal@cdc.gov RI Flegal, Katherine/A-4608-2013; OI Flegal, Katherine/0000-0002-0838-469X FU Centers for Disease Control and Prevention; National Cancer Institute FX The findings and conclusions in this report are those of the authors and not necessarily those of the Centers for Disease Control and Prevention and the National Cancer Institute. NR 32 TC 57 Z9 61 U1 0 U2 4 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD APR 1 PY 2009 VL 89 IS 4 BP 1213 EP 1219 DI 10.3945/ajcn.2008.26698 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 420WF UT WOS:000264319200030 PM 19190072 ER PT J AU Shah, MH Varker, KA Collamore, M Zwiebel, JA Coit, D Kelsen, D Chung, KY AF Shah, Manisha H. Varker, Kimberley A. Collamore, Minden Zwiebel, James A. Coit, Daniel Kelsen, David Chung, Ki Y. TI G3139 (Genasense) in Patients With Advanced Merkel Cell Carcinoma SO AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS LA English DT Article DE Bcl-2 antisense therapy; G3139; Merkel cell carcinoma; phase II trial ID BCL-2 ANTISENSE OLIGONUCLEOTIDE; PHASE-I TRIAL; OBLIMERSEN SODIUM; MALIGNANT-MELANOMA; SINGLE INSTITUTION; IMATINIB MESYLATE; SOLID TUMORS; SKIN; CANCER; CHEMOTHERAPY AB Objectives: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine malignancy of the skin. Preclinical studies have identified up-regulation of the critical antiapoptosis gene bcl-2 in MCC. We conducted a multicenter phase 11 trial of the novel bcl-2 antisense agent (G3139, Genasense) in patients with advanced MCC. Methods: Twelve patients (9 men, 3 women) with histologically confirmed metastatic or regionally recurrent MCC were enrolled. Ten patients (83%) had received prior chemotherapy. Eight patients (67%) had Karnofsky performance status of 90 to 100. Patients received continuous IV infusion of G3139 (7 mg/kg/d) via central venous access in an outpatient setting for 14 days, followed by a 7-day rest period. Response was assessed at 6-week intervals. Patients were allowed to continue therapy until unacceptable toxicity or disease progression. Results: No objective responses were observed. The best response was stable disease in 3 patients and progressive disease in 9 patients. A median of 4 doses per patient (total 46 doses) was administered. Dose delays and/or reductions were required in 6 patients. One patient developed grade 4 lymphopenia. One patient developed grade 3 renal failure characterized by grade 3-elevated creatinine and grade 4 hyperkalemia. Other grade 3 events included cytopenia (n = 5), aspartate aminotransferase/alanine aminotranferease elevation (n = 3), hypophosphatemia (n = 2), and pain (n = 1). The most frequent grade I to 2 toxicities were elevated creatinine, ALT elevation, hypokalemia, lymphopenia, and fatigue. Conclusions: Bcl-2 antisense therapy (G3139) was well tolerated among patients with advanced MCC. Although probable antitumor activity was documented in I patient, no objective responses per Response Evaluation Criteria in Solid Tumors criteria were observed. C1 [Shah, Manisha H.; Varker, Kimberley A.; Collamore, Minden] Ohio State Univ, Ctr Comprehens Canc, Div Hematol & Oncol, Columbus, OH 43210 USA. [Zwiebel, James A.] NCI, CTEP, Bethesda, MD 20892 USA. [Coit, Daniel] Mem Sloan Kettering Canc Ctr, Dept Surg, Gastr & Mixed Tumor Serv, New York, NY 10021 USA. [Kelsen, David; Chung, Ki Y.] Mem Sloan Kettering Canc Ctr, Dept Med, Gastrointestinal Oncol Serv, New York, NY 10021 USA. RP Shah, MH (reprint author), Ohio State Univ, Ctr Comprehens Canc, Div Hematol & Oncol, A438 Starling Loving Hall,320 W 10th Ave, Columbus, OH 43210 USA. EM Manisha.Shah@osumc.edu FU National Institutes of Health [CA63185] FX Supported by National Institutes of Health Grant CA63185. NR 37 TC 14 Z9 14 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3732 J9 AM J CLIN ONCOL-CANC JI Am. J. Clin. Oncol.-Cancer Clin. Trials PD APR PY 2009 VL 32 IS 2 BP 174 EP 179 DI 10.1097/COC.0b013e31817eebf8 PG 6 WC Oncology SC Oncology GA 431JF UT WOS:000265056900013 PM 19307957 ER PT J AU Basso, O Wilcox, AJ AF Basso, Olga Wilcox, Allen J. TI Intersecting Birth Weight-specific Mortality Curves: Solving the Riddle SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE birth weight; confounding factors (epidemiology); infant mortality; smoking ID PERINATAL-MORTALITY; GESTATIONAL-AGE; INFANT; SMOKING; INCREASE AB Small babies from a population with higher infant mortality often have better survival than small babies from a lower-risk population. This phenomenon can in principle be explained entirely by the presence of unmeasured confounding factors that increase mortality and decrease birth weight. Using a previously developed model for birth weight-specific mortality, the authors demonstrate specifically how strong unmeasured confounders can cause mortality curves stratified by known risk factors to intersect. In this model, the addition of a simple exposure (one that reduces birth weight and independently increases mortality) will produce the familiar reversal of risk among small babies. Furthermore, the model explicitly shows how the mix of high- and low-risk babies within a given stratum of birth weight produces lower mortality for high-risk babies at low birth weights. If unmeasured confounders are, in fact, responsible for the intersection of weight-specific mortality curves, then they must also (by virtue of being confounders) contribute to the strength of the observed gradient of mortality by birth weight. It follows that the true gradient of mortality with birth weight would be weaker than what is observed, if indeed there is any true gradient at all. C1 [Basso, Olga] Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Basso, O (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, Mail Drop A3-05,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM bassoo2@niehs.nih.gov RI Basso, Olga/E-5384-2010; OI Basso, Olga/0000-0001-9298-4921; Wilcox, Allen/0000-0002-3376-1311 FU Intramural NIH HHS [Z01 ES044003-30]; NIEHS NIH HHS [Z01 ES044003] NR 21 TC 26 Z9 26 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2009 VL 169 IS 7 BP 787 EP 797 DI 10.1093/aje/kwp024 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 421VX UT WOS:000264387500001 PM 19240224 ER PT J AU Parker, JD Klebanoff, MA AF Parker, Jennifer D. Klebanoff, Mark A. TI Invited Commentary: Crossing Curves-025EFIt's Time to Focus on Gestational Age-specific Mortality SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE birth weight; directed graph; gestational age; infant mortality ID DIRECTED ACYCLIC GRAPHS; BIRTH-WEIGHT; PERINATAL-MORTALITY; INFANT-MORTALITY; PRETERM; STANDARDIZATION; SMOKING; CURVES; FOLATE; FETAL AB For decades, epidemiologists have observed that, among lower birth weight infants, higher risk infants have lower mortality rates than do lower risk infants. However, among higher birth weight infants, the pattern reverses, leading to a riddle of crossing birth weight-specific mortality curves. The riddle has been considered from different perspectives, including relative z scores, directed acyclic graphs, and, most recently, simulated mathematical models of underlying causal factors that produce the observed curves; similarly paradoxical gestational age-specific mortality curves uncross when calculations include all fetuses-at-risk rather than just infants delivered at a particular gestational age. However, researchers have generally focused on birth weight rather than gestational age, likely because birth weight is accurately measured and, if one assumes that birth weight is an intermediate variable between the underlying causal factors and mortality, is easier to model. Within the framework of existing analytical approaches, adding the complexity of a direct relation between gestational age and mortality, and possibly more complex relations among the casual factors, may be difficult. Nevertheless, duration of pregnancy seems a better proxy for the true construct of interest, whether the baby is mature enough to survive, so shifting attention to understanding the riddle of gestational age-specific mortality is encouraged. C1 [Parker, Jennifer D.] Ctr Dis Control & Prevent, Dept Hlth & Human Serv, Natl Ctr Hlth Stat, Off Anal & Epidemiol, Hyattsville, MD 20782 USA. [Klebanoff, Mark A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. RP Parker, JD (reprint author), Ctr Dis Control & Prevent, Dept Hlth & Human Serv, Natl Ctr Hlth Stat, Off Anal & Epidemiol, 3311 Toledo Rd, Hyattsville, MD 20782 USA. EM jdparker@cdc.gov FU Intramural NIH HHS NR 26 TC 6 Z9 6 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2009 VL 169 IS 7 BP 798 EP 801 DI 10.1093/aje/kwp025 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 421VX UT WOS:000264387500002 PM 19240223 ER PT J AU Loucks, EB Lynch, JW Pilote, L Fuhrer, R Almeida, ND Richard, H Agha, G Murabito, JM Benjamin, EJ AF Loucks, Eric B. Lynch, John W. Pilote, Louise Fuhrer, Rebecca Almeida, Nisha D. Richard, Hugues Agha, Golareh Murabito, Joanne M. Benjamin, Emelia J. TI Life-Course Socioeconomic Position and Incidence of Coronary Heart Disease SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; coronary disease; myocardial ischemia; social class; socioeconomic factors ID CAUSE-SPECIFIC MORTALITY; CARDIOVASCULAR-DISEASE; RISK-FACTORS; CHILDHOOD; ASSOCIATION; ADULTHOOD; CIRCUMSTANCES; INEQUALITIES; DISADVANTAGE; HEALTH AB Cumulative exposure to socioeconomic disadvantage across the life course may be inversely associated with coronary heart disease (CHD); the mechanisms are not fully clear. An objective of this study was to determine whether cumulative life-course socioeconomic position (SEP) is associated with CHD incidence in a well-characterized US cohort that had directly assessed childhood and adulthood measures of SEP and prospectively measured CHD incidence. Furthermore, analyses aimed to evaluate whether adjustment for CHD risk factors reduces the association between cumulative life-course SEP and CHD. The authors examined 1,835 subjects who participated in the Framingham Heart Study Offspring Cohort from 1971 through 2003 (mean age, 35.0 years; 52.4% women). Childhood SEP was measured as father's education; adulthood SEP was assessed as own education and occupation. CHD incidence included myocardial infarction, coronary insufficiency, and coronary death. Cox proportional hazards analyses indicated that cumulative SEP was associated with incident CHD after adjustment for age and sex (hazard ratio = 1.82, 95% confidence interval: 1.17, 2.85 for low vs. high cumulative SEP score). Adjustment for CHD risk factors reduced that magnitude of association (hazard ratio = 1.29, 95% confidence interval: 0.78, 2.13). These findings underscore the potential importance of CHD prevention and treatment efforts for those whose backgrounds include low SEP throughout life. C1 [Loucks, Eric B.] McGill Univ, Douglas Mental Hlth Inst, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ H4H 1R3, Canada. [Loucks, Eric B.; Almeida, Nisha D.] McGill Univ, Douglas Mental Hlth Inst, Dept Psychiat, Montreal, PQ H4H 1R3, Canada. [Lynch, John W.] Univ S Australia, Sch Hlth Sci, Adelaide, SA 5001, Australia. [Pilote, Louise; Richard, Hugues] McGill Univ, Dept Med, Montreal, PQ H4H 1R3, Canada. [Murabito, Joanne M.; Benjamin, Emelia J.] Boston Univ, Framingham, MA USA. [Murabito, Joanne M.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Murabito, Joanne M.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Murabito, Joanne M.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Prevent Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Cardiol, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. RP Loucks, EB (reprint author), McGill Univ, Douglas Mental Hlth Inst, Dept Epidemiol Biostat & Occupat Hlth, 6875 LaSalle Blvd, Montreal, PQ H4H 1R3, Canada. EM eric.loucks@mcgill.ca RI Lynch, John/A-4797-2008; Loucks, Eric/I-1272-2014; OI Lynch, John/0000-0003-2781-7902; Loucks, Eric/0000-0002-9962-0386; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [R01 HL076784-01, HL 064753, HL 076784, N01 HC 25195, N01HC25195, R01 HL064753, R01 HL064753-01, R01 HL064753-02, R01 HL064753-03, R01 HL064753-04, R01 HL076784, R01 HL076784-02, R01 HL076784-03, R01 HL076784-04, R01 HL076784-05]; NIA NIH HHS [AG 028321, R01 AG028321, R01 AG028321-01, R01 AG028321-02, R01 AG028321-03, R01 AG028321-04, R01 AG028321-05] NR 32 TC 59 Z9 60 U1 1 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2009 VL 169 IS 7 BP 829 EP 836 DI 10.1093/aje/kwn403 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 421VX UT WOS:000264387500005 PM 19179358 ER PT J AU Lynch, E Liu, K Wei, GS Spring, B Kiefe, C Greenland, P AF Lynch, Elizabeth Liu, Kiang Wei, Gina S. Spring, Bonnie Kiefe, Catarina Greenland, Philip TI The Relation Between Body Size Perception and Change in Body Mass Index Over 13 Years SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body image; body mass index; health status disparities; obesity; psychology; weight gain ID YOUNG-ADULTS; IMAGE DISSATISFACTION; SOCIOECONOMIC-STATUS; LOSE WEIGHT; BLACK-WOMEN; OBESITY; CARDIA; OVERWEIGHT; RISK; MEN AB The authors assessed associations of body size perception and weight change over 13 years in black men and women and white men and women from the Coronary Artery Risk Development in Young Adults (CARDIA) Study (1992-2005). The perceptions of self and ideal body size were measured by using the Stunkard 9-figure scale at the year 7 examination (1992-1993). Figures were classified into underweight, normal weight, overweight, and obese. Self-ideal discrepancy yielded 4 body size satisfaction categories. Body mass index (BMI) (measured at years 7, 10, 15, and 20) was the dependent variable in gender-specific adjusted multiple regression models stratified by year 7 BMI. Obese women who perceived themselves as obese lost 0.09 BMI units annually, while those who perceived themselves as normal weight gained 0.31 units annually (P = 0.0005); obese women who considered their body size much too large had less annual weight gain than did those who considered their body size a bit too large (0.21 vs. 0.38 BMI units; P = 0.009). Obese women with overweight ideal body size gained less weight annually than did those with normal weight ideal body size (0.12 vs. 0.27 BMI units; P = 0.04). Results for men showed fewer and weaker associations. When obese women perceive themselves as obese and feel that their body size is too large, they gain less weight over time. C1 [Lynch, Elizabeth] Rush Univ, Dept Prevent Med, Med Ctr, Chicago, IL 60612 USA. [Liu, Kiang; Spring, Bonnie; Greenland, Philip] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Wei, Gina S.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Kiefe, Catarina] Univ Alabama, Div Prevent Med, Birmingham, AL USA. RP Lynch, E (reprint author), Rush Univ, Dept Prevent Med, Med Ctr, 1700 W Van Buren,Suite 470, Chicago, IL 60612 USA. EM elizabeth_lynch@rush.edu FU National Heart, Lung, and Blood Institute [N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050]; National Institutes of Health FX Conflict of interest: none declared. NR 26 TC 40 Z9 41 U1 3 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2009 VL 169 IS 7 BP 857 EP 866 DI 10.1093/aje/kwn412 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 421VX UT WOS:000264387500008 PM 19221119 ER PT J AU Hermansen, SW Leitzmann, MF Schatzkin, A AF Hermansen, Sigurd W. Leitzmann, Michael F. Schatzkin, Arthur TI The Impact on National Death Index Ascertainment of Limiting Submissions to Social Security Administration Death Master File Matches in Epidemiologic Studies of Mortality SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE data collection; epidemiologic methods; information science; mortality; vital statistics ID DATABASES; LINKAGE; COHORT; HEALTH AB Although many epidemiologists use the National Death Index (NDI) as the "gold standard" for ascertainment of US mortality, high search costs per year and per subject for large cohorts warrant consideration of less costly alternatives. In this study, for 1995-2001 deaths, the authors compared matches of a random sample of 11,968 National Institutes of Health (NIH)-AARP Diet and Health Study subjects to the Social Security Administration's Death Master File (DMF) and commercial list updates (CLU) with matches of those subjects to the NDI. They examined how varying the lower limits of estimated DMF match probabilities (m scores of 0.60, 0.20, and 0.05) altered the benefits and costs of mortality ascertainment. Observed DMF/CLU ascertainment of NDI-identified decedents increased from 89.8% to 95.1% as m decreased from 0.60 (stringent) to 0.20 (less stringent) and increased further to 96.4% as m decreased to 0.05 (least stringent). At these same cutpoints, the false-match probability increased from 0.4% of the sample to 0.6% and then 2.3%. Limiting NDI cause-of-death searches to subjects found in DMF searches using less stringent match criteria, further supplemented by CLU vital status updates, improves vital status assessment while increasing substantially the cost-effectiveness of ascertaining mortality in large prospective cohort studies. C1 [Hermansen, Sigurd W.] WESTAT Corp, Rockville, MD 20850 USA. [Leitzmann, Michael F.; Schatzkin, Arthur] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Leitzmann, Michael F.] Univ Regensburg, Inst Epidemiol & Prevent Med, Regensburg, Germany. RP Schatzkin, A (reprint author), NCI, Div Canc Epidemiol & Genet, Execut Plaza S 3040,6120 Execut Blvd, Rockville, MD 20852 USA. EM schatzka@mail.nih.gov FU Intramural Research Program of the National Institutes of Health (Division of Cancer Epidemiology and Genetics, National Cancer Institute) FX Conflict of interest: none declared. NR 17 TC 21 Z9 21 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD APR 1 PY 2009 VL 169 IS 7 BP 901 EP 908 DI 10.1093/aje/kwn404 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 421VX UT WOS:000264387500013 PM 19251755 ER PT J AU Mistry, PK Weinreb, NJ Brady, RO Grabowski, GA AF Mistry, Pramod K. Weinreb, Neal J. Brady, Roscoe O. Grabowski, Gregory A. TI Gaucher disease: Resetting the clinical and scientific agenda SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material ID PULMONARY-HYPERTENSION; REPLACEMENT THERAPY; CANCER; INTERVENTION; DIAGNOSIS; PHENOTYPE; MARKERS; TYPE-1 C1 [Mistry, Pramod K.] Yale Univ, Sch Med, Sect Pediat Hepatol & Gastroenterol, Dept Pediat & Med, New Haven, CT 06562 USA. [Weinreb, Neal J.] Univ Res Fdn Lysosomal Storage Disorders, Coral Springs, FL USA. [Brady, Roscoe O.] NINDS, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. [Grabowski, Gregory A.] Cincinnati Childrens Hosp, Med Ctr, Div Human Genet, Cincinnati, OH USA. [Grabowski, Gregory A.] Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA. RP Mistry, PK (reprint author), Yale Univ, Sch Med, Sect Pediat Hepatol & Gastroenterol, Dept Pediat & Med, 333 Cedar St, New Haven, CT 06562 USA. EM pramod.mistry@yale.edu FU NIDDK NIH HHS [K24 DK066306-01A2, R01 DK036729-15, K24 DK066306, R01 DK036729, DK 36729, DK 066306] NR 30 TC 5 Z9 8 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD APR PY 2009 VL 84 IS 4 BP 205 EP 207 DI 10.1002/ajh.21384 PG 3 WC Hematology SC Hematology GA 429CG UT WOS:000264897800003 PM 19296473 ER PT J AU Hoerger, T Witterborn, J Segel, J Burrows, NR Eggers, P Pavkov, M Jordan, R Schoolwerth, AC Willams, D AF Hoerger, Thomas Witterborn, John Segel, Joel Burrows, Nilka Rios Eggers, Paul Pavkov, Meda Jordan, Regina Schoolwerth, Anton C. Willams, Desmond CA CDC CKD Initiat TI THE COST-EFFECTIVENESS OF SCREENING FOR MICROALBUMINURIA: A SIMULATION MODEL FOR CHRONIC KIDNEY DISEASE SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Meeting Abstract CT Spring Clinical Meeting of the National-Kidney-Foundation CY MAR 25-29, 2009 CL Nashville, TN SP Natl Kidney Fdn C1 [Hoerger, Thomas; Witterborn, John; Segel, Joel] RTI Int, Res Triangle Pk, NC USA. [Burrows, Nilka Rios; Pavkov, Meda; Jordan, Regina; Willams, Desmond] Ctr Dis Control & Prevent, Atlanta, GA USA. [Eggers, Paul] NIDDK, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD APR PY 2009 VL 53 IS 4 MA 79 BP A42 EP A42 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 425JI UT WOS:000264632400104 ER PT J AU Meilleur, KG Littleton-Kearney, MT AF Meilleur, Katherine G. Littleton-Kearney, Marguerite T. TI Interventions to Improve Patient Education Regarding Multifactorial Genetic Conditions: A Systematic Review SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Review DE genetic counseling; patient education; multifactorial; interventions ID RANDOMIZED CONTROLLED-TRIAL; BREAST-CANCER SUSCEPTIBILITY; INFORMED DECISION-MAKING; PROSTATE-CANCER; COMPUTER-PROGRAM; OVARIAN-CANCER; INFORMATION; BRCA1/2; AID; KNOWLEDGE AB The careful education of patients with complex genetic disease is essential. However, healthcare providers often have limited time to spend providing thorough genetic education. Furthermore, the number of healthcare professionals possessing strong genetics training may be inadequate to meet increasing patient demands. Due to such constraints, several interventions have been investigated over the past decade to identify potential resources for the facilitation of this specific type of patient education. This systematic literature review of these interventions for patient education attempts to elucidate the answer to the question: is there sufficient evidence for best practice for delivering genetic information to patients with multifactorial conditions? The various interventions (CD-ROM, group counseling, video/decision aid, and miscellaneous) were analyzed in terms of quality criteria and achievement of specific outcomes and were rated according to the Stetler model for evidence-based practice. Seven main outcomes were evaluated: (1) objective and subjective knowledge assessment, (2) psychological measures (general anxiety, depression, stress, cancer worry), (3) satisfaction/effectiveness of intervention, (4) time spent in counseling (time spent on basic genetic information vs. specific concerns), (5) decision-making/intent to undergo genetic testing, (6) treatment choice and value of that choice, and, finally (7) risk perception. Overall, the computer interventions resulted in more significant findings that were beneficial than any other category followed by the video category, although the group and miscellaneous categories did not measure all of the outcomes reported by the other two categories. Nevertheless, while these groups had neutral or negative findings in some of the outcomes, the computer intervention group showed significant improvement in genetics knowledge, psychological measures, satisfaction/effectiveness, time spent with counselor, and decision/intent to undergo testing. Published 2009 Wiley-Liss, Inc.(dagger) C1 [Meilleur, Katherine G.] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Meilleur, Katherine G.; Littleton-Kearney, Marguerite T.] Johns Hopkins Univ, Sch Nursing, Bethesda, MD USA. RP Meilleur, KG (reprint author), Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, 10 Ctr Dr,Bldg 10,Rm 5s-219,MSC 1671, Bethesda, MD 20892 USA. EM meilleurk@mail.nih.gov FU Intramural NIH HHS [Z99 NS999999]; NINR NIH HHS [R01 NR005339, R01 NR005339-09] NR 24 TC 16 Z9 16 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD APR PY 2009 VL 149A IS 4 BP 819 EP 830 DI 10.1002/ajmg.a.32723 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 430IN UT WOS:000264982900051 PM 19291763 ER PT J AU Courcoutsakis, NA Prassopoulos, PK Patronas, NJ AF Courcoutsakis, N. A. Prassopoulos, P. K. Patronas, N. J. TI Aggressive Leptomeningeal Hemangioblastomatosis of the Central Nervous System in a Patient with von Hippel-Lindau Disease SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article AB Hemangioblastomas of the central nervous system are the most common tumors seen in patients with von Hippel-Lindau (VHL) disease. A very rare case of diffuse leptomeningeal hemangioblastomatosis obliterating large areas of the subarachnoid space, both intracranial and within the spinal canal, which developed during a relatively short period, in a patient with VHL disease is presented. C1 [Courcoutsakis, N. A.; Prassopoulos, P. K.] Democritus Univ Thrace, Univ Hosp Alexandroupolis, Dept Radiol & Med Imaging, Alexandroupolis 68100, Greece. [Courcoutsakis, N. A.; Patronas, N. J.] NIH, Dept Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Courcoutsakis, NA (reprint author), Democritus Univ Thrace, Univ Hosp Alexandroupolis, Dept Radiol & Med Imaging, Alexandroupolis 68100, Greece. EM ncourcou@med.duth.gr NR 10 TC 5 Z9 6 U1 0 U2 3 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD APR PY 2009 VL 30 IS 4 BP 758 EP 760 DI 10.3174/ajnr.A1360 PG 3 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 438VL UT WOS:000265583700020 PM 19039053 ER PT J AU Holston, AM Qian, C Yu, KF Epstein, FH Karumanchi, A Levine, RJ AF Holston, Alexander M. Qian, Cong Yu, Kai F. Epstein, Franklin H. Karumanchi, Ananth Levine, Richard J. TI Circulating angiogenic factors in gestational proteinuria without hypertension SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE angiogenic factor; gestational proteinuria; placental growth factor; preeclampsia; soluble endoglin; soluble fms-like tyrosine kinase 1 ID ENDOTHELIAL GROWTH-FACTOR; HEALTHY NULLIPAROUS WOMEN; SOLUBLE ENDOGLIN; NORMAL-PREGNANCY; RISK-FACTORS; PREECLAMPSIA; RAT; KIDNEY; TRIAL; GLOMERULONEPHRITIS AB OBJECTIVE: Our goal was to determine whether obstetric outcomes and serum angiogenic factors are altered in women with gestational proteinuria without hypertension. STUDY DESIGN: We performed a nested case-control study of 108 women with gestational proteinuria and compared them with 1564 randomly selected women with normotension without proteinuria during pregnancy (control subjects) and with 319 women who experienced preeclampsia. RESULTS: Women with gestational proteinuria had greater body-mass index and higher blood pressure at study enrollment. Adverse obstetric outcomes were infrequent. Levels of free placental growth factor were lower than control levels beginning early in gestation. Compared with gestational-age matched control subjects, free placental growth factor was reduced beginning 6-8 weeks before proteinuria. Although soluble fms-like tyrosine kinase 1 and soluble endoglin concentrations were elevated 1-2 weeks before proteinuria, these elevations were modest and transient. After the onset of proteinuria, angiogenic factor levels generally did not differ significantly from control levels. CONCLUSION: Gestational proteinuria in healthy nulliparous women appears to be a mild variant of preeclampsia. C1 [Holston, Alexander M.; Yu, Kai F.; Levine, Richard J.] NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Holston, Alexander M.] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. [Qian, Cong] Allied Technol Grp, Rockville, MD USA. [Epstein, Franklin H.; Karumanchi, Ananth] Beth Israel Deaconess Med Ctr, Dept Med, Boston, MA 02215 USA. [Karumanchi, Ananth] Beth Israel Deaconess Med Ctr, Dept Obstet & Gynecol, Boston, MA 02215 USA. [Karumanchi, Ananth] Harvard Univ, Sch Med, Boston, MA USA. RP Levine, RJ (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM LevineRJ@mail.nih.gov FU National Institutes of Health [DK065997, HL079594]; US Navy; National Institute of Child Health and Human Development [N01-HD-1-3121, N01-HD-1-3126, N01-HD-3154, N01-HD-5-3246]; National Heart, Lung, and Blood Institute FX This study was supported by funds and salary from the intramural research program of the National Institutes of Health and by salary from the US Navy; by the National Institute of Child Health and Human Development under contracts N01-HD-1-3121 through 3126, N01-HD-3154, and N01-HD-5-3246, with cofunding from the National Heart, Lung, and Blood Institute (Calcium for Preeclampsia Prevention trial database and specimen repository); and by National Institutes of Health Grants DK065997 and HL079594 (S. A. K., an investigator of the Howard Hughes Medical Institute). NR 32 TC 9 Z9 11 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD APR PY 2009 VL 200 IS 4 AR 392.e1 DI 10.1016/j.ajog.2008.10.033 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 422BX UT WOS:000264403100015 PM 19168169 ER PT J AU Nares, S Moutsopoulos, NM Angelov, N Rangel, ZG Munson, PJ Sinha, N Wahl, SM AF Nares, Salvador Moutsopoulos, Niki M. Angelov, Nikola Rangel, Zoila G. Munson, Peter J. Sinha, Neha Wahl, Sharon M. TI Rapid Myeloid Cell Transcriptional and Proteomic Responses to Periodontopathogenic Porphyromonas gingivalis SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; KAPPA-B-ZETA; T-CELLS; PERIODONTAL-DISEASE; SIGNALING PATHWAYS; DENDRITIC CELLS; TH17 CELLS; RHEUMATOID-ARTHRITIS; IMMUNE-RESPONSES; GENE-EXPRESSION AB Long-lived monocytes, macrophages, and dendritic cells (DCs) are Toll-like receptor-expressing, antigen-presenting cells derived from a common myeloid lineage that play key roles in innate and adaptive immune responses. Based on immunohistochemical and molecular analyses of inflamed tissues from patients with chronic destructive periodontal disease, these cells, found in the inflammatory infiltrate, may drive the progressive periodontal pathogenesis. To investigate early transcriptional signatures and subsequent proteomic responses to the periodontal pathogen, Porphyromonas gingivalis, donor-matched human blood monocytes, differentiated DCs, and macrophages were exposed to P. gingivalis lipopolysaccharide (LPS) and gene expression levels were measured by oligonucleotide microarrays. In addition to striking differences in constitutive transcriptional profiles between these myeloid populations, we identify a P. gingivalis LPS-inducible convergent, transcriptional core response of more than 400 annotated genes/ESTs among these populations, reflected by a shared, but quantitatively distinct, proteomic response. Nonetheless, clear differences emerged between the monocytes, DCs, and macrophages. The finding that long-lived myeloid inflammatory cells, particularly DCs, rapidly and aggressively respond to P. gingivalis LPS by generating chemokines, proteases, and cytokines capable of driving T-helper cell lineage polarization without evidence of corresponding immunosuppressive path-ways highlights their prominent role in host defense and progressive tissue pathogenesis. The shared, unique, and/or complementary transcriptional and proteomic profiles may frame the context of the host response to P. gingivalis, contributing to the destructive nature of periodontal inflammation. (Am J Pathol 2009,174:1400-1414; DOI: 10.2353/ajpath.2009.080677) C1 [Nares, Salvador; Moutsopoulos, Niki M.; Angelov, Nikola; Sinha, Neha; Wahl, Sharon M.] NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Rangel, Zoila G.; Munson, Peter J.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD USA. [Nares, Salvador] Univ N Carolina, Dept Periodontol, Chapel Hill, NC USA. [Angelov, Nikola] Loma Linda Univ, Dept Periodont, Loma Linda, CA 92350 USA. RP Wahl, SM (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bldg 30,Rm 320,30 Convent Dr,MSC 4352, Bethesda, MD 20892 USA. EM smwahl@dir.nidcr.nih.gov FU Division of Intramural Research; National Institute of Dental and Craniofacial Research; Center for Information Technology; National Institutes of Health FX Supported by the Division of Intramural Research, National Institute of Dental and Craniofacial Research, and the Center for Information Technology, National Institutes of Health. NR 64 TC 19 Z9 19 U1 0 U2 1 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD APR PY 2009 VL 174 IS 4 BP 1400 EP 1414 DI 10.2353/ajpath.2009.080677 PG 15 WC Pathology SC Pathology GA 425SQ UT WOS:000264657800026 PM 19264901 ER PT J AU Chen, M Feng, HZ Gupta, D Kelleher, J Dickerson, KE Wang, J Hunt, D Jou, W Gavrilova, O Jin, JP Weinstein, LS AF Chen, Min Feng, Han-Zhong Gupta, Divakar Kelleher, James Dickerson, Kathryn E. Wang, Jie Hunt, Desmond Jou, William Gavrilova, Oksana Jin, Jian-Ping Weinstein, Lee S. TI G(s)alpha deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE G protein; atrophy ID ACTIVATED PROTEIN-KINASE; TRANSCRIPTIONAL COACTIVATOR; VENTROMEDIAL HYPOTHALAMUS; PERIPHERAL-TISSUES; KNOCKOUT MICE; PGC-1-ALPHA; RECEPTOR; TRANSPORT; BETA; SLOW AB Chen M, Feng HZ, Gupta D, Kelleher J, Dickerson KE, Wang J, Hunt D, Jou W, Gavrilova O, Jin JP, Weinstein LS. G(s)alpha deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency. Am J Physiol Cell Physiol 296: C930-C940, 2009. First published January 21, 2009; doi:10.1152/ajpcell.00443.2008.-The ubiquitously expressed G protein alpha-subunit G(s)alpha is required for receptor-stimulated intracellular cAMP responses and is an important regulator of energy and glucose metabolism. We have generated skeletal muscle-specific G(s)alpha-knockout (KO) mice (MGsKO) by mating G(s)alpha-floxed mice with muscle creatine kinase-cre transgenic mice. MGsKO mice had normal body weight and composition, and their serum glucose, insulin, free fatty acid, and triglyceride levels were similar to that of controls. However, MGsKO mice were glucose intolerant despite the fact that insulin sensitivity and glucose-stimulated insulin secretion were normal, suggesting an insulin-independent mechanism. Isolated muscles from MGsKO mice had increased basal glucose uptake and normal responses to a stimulator of AMP-activated protein kinase (AMPK), which indicates that AMPK and its downstream pathways are intact. Compared with control mice, MGsKO mice had reduced muscle mass with decreased cross-sectional area and force production. In addition, adult MGsKO mice showed an increased proportion of type I (slow-twitch, oxidative) fibers based on kinetic properties and myosin heavy chain isoforms, despite the fact that these muscles had reduced expression of peroxisome proliferator-activated receptor coactivator protein-1 alpha (PGC-1 alpha) and reduced mitochondrial content and oxidative capacity. Therefore G(s)alpha deficiency led to fast-to-slow fiber-type switching, which appeared to be dissociated from the expected change in oxidative capacity. MGsKO mice are a valuable model for future studies of the role of G(s)alpha signaling pathways in skeletal muscle adaptation and their effects on whole body metabolism. C1 [Chen, Min] NIDDK, Metab Dis Branch, Signal Transduct Sect, NIH, Bethesda, MD 20892 USA. [Jou, William; Gavrilova, Oksana] NIDDK, Mouse Metab Core Lab, NIH, Bethesda, MD 20892 USA. [Feng, Han-Zhong; Jin, Jian-Ping] Evanston NW Healthcare, Sect Mol Cardiol, Evanston, IL USA. [Feng, Han-Zhong; Jin, Jian-Ping] Northwestern Univ, Feinberg Sch Med, Evanston, IL USA. [Hunt, Desmond] NIDDK, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Chen, M (reprint author), NIDDK, Metab Dis Branch, Signal Transduct Sect, NIH, Bldg 10 Rm 8C101, Bethesda, MD 20892 USA. EM minc@intra.niddk.nih.gov FU Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH); U.S. Department of Health and Human Services; NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases Extramural Research Grant [AR-048816] FX This work was supported by the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), U.S. Department of Health and Human Services, and by NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases Extramural Research Grant AR-048816 ( to J.-P. Jin). NR 53 TC 20 Z9 21 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD APR PY 2009 VL 296 IS 4 BP C930 EP C940 DI 10.1152/ajpcell.00443.2008 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 427AX UT WOS:000264753200029 PM 19158402 ER PT J AU Labinskyy, N Mukhopadhyay, P Toth, J Szalai, G Veres, M Losonczy, G Pinto, JT Pacher, P Ballabh, P Podlutsky, A Austad, SN Csiszar, A Ungvari, Z AF Labinskyy, Nazar Mukhopadhyay, Partha Toth, Janos Szalai, Gabor Veres, Monika Losonczy, Gyorgy Pinto, John T. Pacher, Pal Ballabh, Praveen Podlutsky, Andrej Austad, Steven N. Csiszar, Anna Ungvari, Zoltan TI Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE senescence; comparative biology; vascular disease; atherosclerosis ID HYDROGEN-PEROXIDE PRODUCTION; MITOCHONDRIAL SUPEROXIDE-PRODUCTION; FREE-RADICAL PRODUCTION; LONGEST-LIVING RODENT; NAKED MOLE-RAT; H2O2 PRODUCTION; LIFE-SPAN; ENDOTHELIAL DYSFUNCTION; HEART-MITOCHONDRIA; CORONARY-ARTERIES AB Labinskyy N, Mukhopadhyay P, Toth J, Szalai G, Veres M, Losonczy G, Pinto JT, Pacher P, Ballabh P, Podlutsky A, Austad SN, Csiszar A, Ungvari Z. Longevity is associated with increased vascular resistance to high glucose-induced oxidative stress and inflammatory gene expression in Peromyscus leucopus. Am J Physiol Heart Circ Physiol 296: H946-H956, 2009. First published January 30, 2009; doi:10.1152/ajpheart.00693.2008.-Vascular aging is characterized by increased oxidative stress and proinflammatory phenotypic alterations. Metabolic stress, such as hyperglycemia in diabetes, is known to increase the production of ROS and promote inflammatory gene expression, accelerating vascular aging. The oxidative stress hypothesis of aging predicts that vascular cells of long-lived species exhibit lower steady-state production of ROS and/or superior resistance to the prooxidant effects of metabolic stress. We tested this hypothesis using two taxonomically related rodents, the white-footed mouse (Peromyscus leucopus) and the house mouse (Mus musculus), which show a more than twofold difference in maximum lifespan potential (8.2 and 3.5 yr, respectively). We compared interspecies differences in steady-state and high glucose (HG; 30 mmol/l)-induced production of O-2(center dot-) and H2O2, endothelial function, mitochondrial ROS generation, and inflammatory gene expression in cultured aortic segments. In P. leucopus aortas, steady- state endothelial O-2(center dot-) and H2O2 production and ROS generation by mitochondria were less than in M. musculus vessels. Furthermore, vessels of P. leucopus were more resistant to the prooxidant effects of HG. Primary fibroblasts from P. leucopus also exhibited less steady- state and HG-induced ROS production than M. musculus cells. In M. musculus arteries, HG elicited significant up-regulation of inflammatory markers (TNF-alpha, IL-6, ICAM-1, VCAM, and monocyte chemoattractant protein-1). In contrast, the proinflammatory effects of HG were blunted in P. leucopus vessels. Thus, increased life span potential in P. leucopus is associated with decreased cellular ROS generation and increased resistance to prooxidant and proinflammatory effects of metabolic stress, which accord with predictions of the oxidative stress hypothesis of aging. C1 [Labinskyy, Nazar; Toth, Janos; Csiszar, Anna; Ungvari, Zoltan] New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. [Mukhopadhyay, Partha; Pacher, Pal] NIAAA, Lab Physiol Studies, Sect Oxidat Stress Tissue Injury, Bethesda, MD USA. [Szalai, Gabor; Veres, Monika] Univ S Carolina, Dept Biol Sci, Columbia, SC 29208 USA. [Szalai, Gabor; Veres, Monika] Univ S Carolina, Peromyscus Stock Ctr, Columbia, SC 29208 USA. [Losonczy, Gyorgy; Ungvari, Zoltan] Semmelweis Univ, Dept Pulm, H-1085 Budapest, Hungary. [Pinto, John T.] New York Med Coll, Dept Biochem, Valhalla, NY 10595 USA. [Ballabh, Praveen] New York Med Coll, Dept Cell Biol & Anat, Valhalla, NY 10595 USA. [Ballabh, Praveen] New York Med Coll, Dept Pediat, Valhalla, NY 10595 USA. [Podlutsky, Andrej; Austad, Steven N.] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78229 USA. RP Ungvari, Z (reprint author), New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. EM anna_csiszar@nymc.edu; zoltan_ungvari@nymc.edu RI MUKHOPADHYAY, PARTHA/G-3890-2010; Pacher, Pal/B-6378-2008; Podlutsky, Andrej/F-5421-2015 OI MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Pacher, Pal/0000-0001-7036-8108; FU American Heart Association [0430108N, 0435140N]; American Diabetes Association; American Federation for Aging Research; National Institutes of Health ( NIH) [HL-077256, HL-43023]; Philip Morris U. S. A. Incorporated; Philip Morris International; Hungarian Scientific Research Fund [OTKA-K68758]; Intramural Research Program of NIH; Children's Hospital Foundation FX This work was supported by American Heart Association Grants 0430108N ( to Z. Ungvari) and 0435140N ( to A. Csiszar), the American Diabetes Association ( to Z. Ungvari), the American Federation for Aging Research ( to A. Csiszar), National Institutes of Health ( NIH) Grants HL-077256 and HL-43023 ( to Z. Ungvari), Philip Morris U. S. A. Incorporated and Philip Morris International ( to Z. Ungvari), Hungarian Scientific Research Fund OTKA-K68758 ( to G. Losonczy), the Intramural Research Program of NIH ( to P. Pacher), and the Children's Hospital Foundation ( to P. Ballabh). NR 63 TC 31 Z9 31 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD APR PY 2009 VL 296 IS 4 BP H946 EP H956 DI 10.1152/ajpheart.00693.2008 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 439WP UT WOS:000265658600008 PM 19181967 ER PT J AU Fedorova, LV Raju, V El-Okdi, N Shidyak, A Kennedy, DJ Vetteth, S Giovannucci, DR Bagrov, AY Fedorova, OV Shapiro, JI Malhotra, D AF Fedorova, Larisa V. Raju, Vanamala El-Okdi, Nasser Shidyak, Amjad Kennedy, David J. Vetteth, Sandeep Giovannucci, David R. Bagrov, Alexei Y. Fedorova, Olga V. Shapiro, Joseph I. Malhotra, Deepak TI The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE cardiotonic steroid hormone; ouabain; Na(+)-K(+)-ATPase; transcription factor Snail ID EXPERIMENTAL UREMIC CARDIOMYOPATHY; UNILATERAL URETERAL OBSTRUCTION; OUABAIN-LIKE IMMUNOREACTIVITY; EXOGENOUS CARDIAC-GLYCOSIDES; OXYGEN SPECIES MEDIATE; CELL-CELL CONTACTS; SODIUM-PUMP; ENDOGENOUS OUABAIN; NA/K-ATPASE; MYOFIBROBLAST TRANSITION AB Fedorova LV, Raju V, El-Okdi N, Shidyak A, Kennedy DJ, Vetteth S, Giovannucci DR, Bagrov AY, Fedorova OV, Shapiro JI, Malhotra D. The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition. Am J Physiol Renal Physiol 296: F922-F934, 2009. First published January 28, 2009; doi:10.1152/ajprenal.90605.2008.-We recently demonstrated that the cardiotonic steroid marinobufagenin (MBG) induced fibrosis in rat hearts through direct stimulation of collagen I secretion by cardiac fibroblasts. This stimulation was also responsible for the cardiac fibrosis seen in experimental renal failure. In this study, the effect of MBG on the development of renal fibrosis in rats was investigated. Four weeks of MBG infusion triggered mild periglomerular and peritubular fibrosis in the cortex and the appearance of fibrotic scars in the corticomedullary junction of the kidney. MBG also significantly increased the protein levels and nuclear localization of the transcription factor Snail in the tubular epithelia. It is known that activation of Snail is associated with epithelial-tomesenchymal transition (EMT) during renal fibrosis. To examine whether MBG alone can trigger EMT, we used the porcine proximal tubular cell line LLC-PK1. MBG (100 nM) caused LLC-PK1 cells grown to confluence to acquire a fibroblast-like shape and have an invasive motility. The expressions of the mesenchymal proteins collagen I, fibronectin, and vimentin were increased twofold. However, the total level of E-cadherin remained unchanged. These alterations in LLC-PK1 cells in the presence of MBG were accompanied by elevated expression and nuclear translocation of Snail. During the time course of EMT, MBG did not have measurable inhibitory effects on the ion pumping activity of its natural ligand, Na(+)-K(+)-ATPase. Our data suggest that the MBG may be an important factor in inducing EMT and, through this mechanism, elevated levels of MBG in chronic renal failure may play a role in the progressive fibrosis. C1 [Fedorova, Larisa V.; Raju, Vanamala; El-Okdi, Nasser; Shidyak, Amjad; Kennedy, David J.; Vetteth, Sandeep; Shapiro, Joseph I.; Malhotra, Deepak] Univ Toledo, Coll Med, Dept Med, Div Nephrol, Toledo, OH 43614 USA. [Giovannucci, David R.] Univ Toledo, Coll Med, Dept Neurosci, Toledo, OH 43614 USA. [Bagrov, Alexei Y.; Fedorova, Olga V.] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Malhotra, D (reprint author), Univ Toledo, Coll Med, Dept Med, Div Nephrol, 3000 Arlington Ave, Toledo, OH 43614 USA. EM Deepak.Malhotra@utoledo.edu FU Intramural NIH HHS; NHLBI NIH HHS [HL-67963] NR 96 TC 28 Z9 28 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD APR PY 2009 VL 296 IS 4 BP F922 EP F934 DI 10.1152/ajprenal.90605.2008 PG 13 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 422AO UT WOS:000264399600029 PM 19176701 ER PT J AU Allison, DB Newcomer, JW Dunn, AL Blumenthal, JA Fabricatore, AN Daumit, GL Cope, MB Riley, WT Vreeland, B Hibbeln, JR Alpert, JE AF Allison, David B. Newcomer, John W. Dunn, Andrea L. Blumenthal, James A. Fabricatore, Anthony N. Daumit, Gail L. Cope, Mark B. Riley, William T. Vreeland, Betty Hibbeln, Joseph R. Alpert, Jonathan E. TI Obesity Among Those with Mental Disorders A National Institute of Mental Health Meeting Report SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID INDUCED WEIGHT-GAIN; BODY-MASS INDEX; RANDOMIZED CONTROLLED-TRIAL; CATIE SCHIZOPHRENIA TRIAL; LIFE-STYLE INTERVENTION; LONG-TERM; SCHIZOAFFECTIVE DISORDER; ATYPICAL ANTIPSYCHOTICS; BARIATRIC SURGERY; MAINTENANCE TREATMENT AB The National Institute of Mental Health convened a meeting in October 2005 to review the literature on obesity, nutrition, and physical activity among those with mental disorders. The findings of this meeting and subsequent update of the literature review are Summarized here. Levels of obesity are higher in those With schizophrenia and depression, as is mortality from obesity-related conditions such as coronary heart disease. Medication side effects, particularly the metabolic side effects of antipsychotic medications, contribute to the high levels of obesity in those with schizophrenia, but increased obesity and visceral adiposity have been found in some but not all samples of drug-naive patients as well. Many of the weight-management strategies used in the general population may be applicable to those with mental disorders, but little is known about the effects of these strategies on this patient population or how these strategies may need to be adapted for the unique needs of those with mental disorders. The minimal research on weight-management programs for those with mental disorders indicates that meaningful changes in dietary intake and physical activity are possible. Physical activity is an important component of an), weight-management program, particularly for those with depression, for which a substantial body of research indicates both mental and physical health benefits. Obesity among those with mental disorders has not received adequate research attention, and empirically-based interventions to address the increasing prevalence of obesity and risk of cardiovascular and metabolic diseases in this population are lacking. C1 [Riley, William T.] NIMH, Bethesda, MD 20892 USA. [Allison, David B.; Cope, Mark B.] Univ Alabama, Birmingham, AL USA. [Newcomer, John W.] Washington Univ, Sch Med, St Louis, MO USA. [Dunn, Andrea L.] Klein Buendel Inc, Golden, CO USA. [Blumenthal, James A.] Duke Univ, Durham, NC USA. [Fabricatore, Anthony N.] Univ Penn, Philadelphia, PA 19104 USA. [Daumit, Gail L.] Johns Hopkins Univ, Baltimore, MD USA. [Hibbeln, Joseph R.] NIAAA, Bethesda, MD USA. [Vreeland, Betty] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [Alpert, Jonathan E.] Harvard Univ, Sch Med, Boston, MA USA. RP Riley, WT (reprint author), NIMH, 6001 Execut Blvd,MSC 9621, Bethesda, MD 20892 USA. EM wiriley@mail.nih.gov OI Alpert, Jonathan/0000-0002-4332-908X; Allison, David/0000-0003-3566-9399 NR 97 TC 161 Z9 163 U1 8 U2 24 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2009 VL 36 IS 4 BP 341 EP 350 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 422DP UT WOS:000264407700011 PM 19285199 ER PT J AU McKinnon, RA Orleans, T Kumanyika, SK Haire-Joshu, D Krebs-Smith, SM Finkelstein, EA Brownell, KD Thompson, JW Ballard-Barbash, R AF McKinnon, Robin A. Orleans, Tracy Kumanyika, Shiriki K. Haire-Joshu, Debra Krebs-Smith, Susan M. Finkelstein, Eric A. Brownell, Kelly D. Thompson, Joseph W. Ballard-Barbash, Rachel TI Considerations for an Obesity Policy Research Agenda SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID PREVENTION RESEARCH; CHILDHOOD OBESITY; PHYSICAL-ACTIVITY; PUBLIC-HEALTH; UNITED-STATES; FOOD; AMERICANS; ACCESS; COSTS AB The rise in obesity levels in the U.S. in the past several decades has been dramatic, with serious implications for public health and the economy. Experiences in tobacco control and other public health initiatives have shown that public policy may be a powerful tool to effect structural change to alter population-level behavior. In 2007, the National Cancer Institute convened a meeting to discuss priorities for a research agenda to inform obesity policy. Issues considered were how to define obesity policy research, key challenges and key partners in formulating and implementing an obesity policy research agenda, criteria by which to set research priorities, and specific research needs and questions. Themes that emerged were: (1) the embryonic nature of obesity policy research, (2) the need to study "natural experiments" resulting from policy-based efforts to address the obesity epidemic, (3) the importance of research focused beyond individual-level behavior change, (4) the need for economic research across several relevant policy areas, and (5) the overall urgency of taking action in the policy arena. Moving forward, timely evaluation of natural experiments is of especially high priority. A variety of policies intended to promote healthy weight in children and adults are being implemented in communities and at the state and national levels. Although some of these policies are supported by the findings of intervention research, additional research is needed to evaluate the implementation and quantify the impact of new policies designed to address obesity. C1 [McKinnon, Robin A.; Krebs-Smith, Susan M.; Ballard-Barbash, Rachel] NCI, Bethesda, MD 20892 USA. [Orleans, Tracy] Robert Wood Johnson Fdn, Princeton, NJ 08540 USA. [Kumanyika, Shiriki K.] Univ Penn, Philadelphia, PA 19104 USA. [Haire-Joshu, Debra] Washington Univ, St Louis, MO USA. [Finkelstein, Eric A.] RTI Int, Res Triangle Pk, Res Triangle Pk, NC 27709 USA. [Brownell, Kelly D.] Yale Univ, New Haven, CT USA. [Thompson, Joseph W.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. RP McKinnon, RA (reprint author), NCI, 130 Execut Blvd,EPN 4028, Bethesda, MD 20892 USA. EM mckinnonr@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 45 TC 39 Z9 39 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2009 VL 36 IS 4 BP 351 EP 357 DI 10.1016/j.amepre.2008.11.017 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 422DP UT WOS:000264407700012 PM 19211215 ER PT J AU McKinnon, RA Reedy, J Handy, SL Rodgers, AB AF McKinnon, Robin A. Reedy, Jill Handy, Susan L. Rodgers, Anne Brown TI Measuring the Food and Physical Activity Environments Shaping the Research Agenda Introduction SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material C1 [McKinnon, Robin A.; Reedy, Jill] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20982 USA. [Handy, Susan L.] Univ Calif Davis, Dept Environm Sci & Policy, Davis, CA 95616 USA. [Rodgers, Anne Brown] Natl Canc Inst Consultant, Bethesda, MD USA. RP McKinnon, RA (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4028,MSC 7344, Bethesda, MD 20982 USA. EM mckinnonr@mail.nih.gov NR 17 TC 49 Z9 50 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2009 VL 36 IS 4 BP S81 EP S85 DI 10.1016/j.amepre.2009.01.003 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 422DR UT WOS:000264407900001 PM 19285213 ER PT J AU McKinnon, RA Reedy, J Morrissette, MA Lytle, LA Yaroch, AL AF McKinnon, Robin A. Reedy, Jill Morrissette, Meredith A. Lytle, Leslie A. Yaroch, Amy L. TI Measures of the Food Environment A Compilation of the Literature, 1990-2007 SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID BODY-MASS INDEX; LOW-FAT MILK; GROCERY STORE ENVIRONMENT; SCHOOL-HEALTH POLICIES; PURCHASE FRESH FRUIT; VEGETABLE CONSUMPTION; MIDDLE-SCHOOL; NEIGHBORHOOD CHARACTERISTICS; NUTRITION ENVIRONMENT; SECONDARY-SCHOOLS AB Background: Valid and reliable measures are required to assess any effect of the food environment on individual dietary behavior, and form the foundation of research that may inform obesity-related policy. Although many methods of measuring the food environment exist, this area of research is still relatively new and there has been no systematic attempt to gather these measures, to compare and contrast them, or to report on their psychometric properties. Evidence acquisition: A structured literature search was conducted to identify peer-reviewed articles published between January 1990 and August 2007 that measured the community-level food environment. These articles were categorized into the following environments: food stores, restaurants, schools, and worksites. The measurement strategies in these studies were categorized as instruments (checklists, market baskets, inventories, or interviews/questionnaires) or methodologies (geographic, sales, menu, or nutrient analyses). Evidence synthesis: A total of 137 articles were identified that included measures of the food environment. synthesis: Researchers focused on assessing the accessibility, availability, affordability, and quality of the food environment. The most frequently used measure overall was some form of geographic analysis. Eighteen of the 137 articles (13.1%) tested for any psychometric properties, including inter-rater reliability, test-retest reliability, and/or validity. Conclusions: A greater focus on testing for reliability and validity of measures of the food environment may increase rigor in research in this area. Robust measures of the food environment may strengthen research on the effects of the community-level food environment on individual dietary behavior, assist in the development and evaluation of interventions, and inform policymaking targeted at reducing the prevalence of obesity and improving diet. C1 [McKinnon, Robin A.; Reedy, Jill; Yaroch, Amy L.] NCI, Bethesda, MD 20892 USA. [Morrissette, Meredith A.] NHLBI, Bethesda, MD 20892 USA. [Lytle, Leslie A.] Univ Minnesota, Dept Epidemiol & Community Hlth, Minneapolis, MN USA. RP McKinnon, RA (reprint author), NCI, 6130 Execut Blvd EPN 4028,MSC 7344, Bethesda, MD 20892 USA. EM mckinnonr@mail.nih.gov NR 161 TC 126 Z9 129 U1 9 U2 51 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2009 VL 36 IS 4 BP S124 EP S133 DI 10.1016/j.amepre.2009.01.012 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 422DR UT WOS:000264407900005 PM 19285203 ER PT J AU Story, M Giles-Corti, B Yaroch, AL Cummins, S Frank, LD Huang, TTK Lewis, LB AF Story, Mary Giles-Corti, Billie Yaroch, Amy Lazarus Cummins, Steven Frank, Lawrence Douglas Huang, Terry T-K Lewis, LaVonna Blair TI Work Group IV: Future Directions for Measures of the Food and Physical Activity Environments SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HEALTH; POLICY AB Much progress has been made in the past 5 to 10 years in measuring and understanding the impact of the food and physical activity environments on behavioral outcomes. Nevertheless, this research is in its infancy. A work group was convened to identify current evidence gaps and barriers in food and physical activity environments and policy research measures, and develop recommendations to guide future directions for measurement and methodologic research efforts. A nominal group process was used to determine six priority areas for food and physical activity environments and policy measures to move the field forward by 2015, including: (1) identify relevant factors in the food and physical activity environments to measure, including those most amenable to change; (2) improve understanding of mechanisms for relationships between the environment and physical activity, diet, and obesity; (3) develop simplified measures that are sensitive to change, valid for different Population groups and settings, and responsive to changing trends; (4) evaluate natural experiments to improve understanding of food and physical activity environments and their impact on behaviors and weight; (5) establish surveillance systems to predict and track change over time; and (6) develop standards for adopting effective health-promoting changes to the food and physical activity environments. The recommendations emanating from the work group highlight actions required to advance policy relevant research related to food and physical activity environments. C1 [Story, Mary] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN 55454 USA. [Giles-Corti, Billie] Univ Western Australia, Sch Populat Hlth, Crawley, WA, Australia. [Yaroch, Amy Lazarus] NCI, NIH, Bethesda, MD 20892 USA. [Cummins, Steven] Univ London, Dept Geog, London, England. [Frank, Lawrence Douglas] Univ British Columbia, Sch Community & Reg Planning, Vancouver, BC V5Z 1M9, Canada. [Huang, Terry T-K] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Lewis, LaVonna Blair] Univ So Calif, Sch Policy Planning & Dev, Los Angeles, CA USA. RP Story, M (reprint author), Univ Minnesota, Sch Publ Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM Story001@umn.edu RI Cummins, Steven/C-1230-2009 OI Cummins, Steven/0000-0002-3957-4357 FU Department of Health [PDA/03/07/014] NR 19 TC 40 Z9 40 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD APR PY 2009 VL 36 IS 4 BP S182 EP S188 DI 10.1016/j.amepre.2009.01.008 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 422DR UT WOS:000264407900014 PM 19285212 ER PT J AU Andreeva, VA Unger, JB Yaroch, AL Cockburn, MG Baezconde-Garbanati, L Reynolds, KD AF Andreeva, Valentina A. Unger, Jennifer B. Yaroch, Amy L. Cockburn, Myles G. Baezconde-Garbanati, Lourdes Reynolds, Kim D. TI Acculturation and Sun-Safe Behaviors Among US Latinos: Findings From the 2005 Health Information National Trends Survey SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID MEXICAN-AMERICAN ADULTS; SKIN-CANCER AWARENESS; UNITED-STATES; PROTECTION BEHAVIORS; CUTANEOUS MELANOMA; PRIMARY PREVENTION; PHYSICAL-ACTIVITY; RISK BEHAVIORS; SUNSCREEN USE; HISPANICS AB Objectives. We examined the relationship between acculturation and sun safety among US Latinos. Methods. We used linear regression models to analyze data from 496 Latino respondents to the 2005 Health Information National Trends Survey. Using sunscreen, seeking shade, and wearing protective clothing were the primary outcomes and were assessed by frequency scales. Acculturation was assessed with a composite index. Results. In bivariate models, acculturation was negatively associated with use of shade and protective clothing and positively associated with sunscreen use (all, P <.004). In adjusted models, acculturation was negatively associated with seeking shade and wearing protective clothing across gender and region of residence (all, P <.05). Conclusions. Our results demonstrated both adverse and beneficial effects of acculturation on Latinos' risk behaviors relating to skin cancer. Education about sun safety is needed for all Latinos and should be tailored to different levels of acculturation. Initiatives for Latinos who are not yet acculturated could focus on reinforcing existing sun-safe behaviors and presenting new ones, such as use of sunscreen; initiatives for highly acculturated Latinos might require more resources because the objective is behavior modification. (Am J Public Health. 2009;99:734-741. doi:10.2105/AJPH.2007.122796) C1 [Andreeva, Valentina A.; Unger, Jennifer B.; Cockburn, Myles G.; Baezconde-Garbanati, Lourdes; Reynolds, Kim D.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Yaroch, Amy L.] NCI, Hlth Promot & Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Andreeva, VA (reprint author), Univ So Calif, Keck Sch Med, Inst Prevent Res, 1000 S Fremont Ave,Unit 8,Suite 4108, Alhambra, CA 91803 USA. EM andreeva@usc.edu OI Unger, Jennifer/0000-0001-9064-6603 FU Centers for Disease Control and Prevention [U55/CCU921930-02]; National Institute of Environmental Health Sciences [5P30 ES07048]; National Cancer Institute [R01CA121052, CA100285]; Southern California Cancer Information Services Partnership Program of the National Cancer Institute [2P30 CA014089]; National Institute of Environmental Health Services [ES07048]; Patient Education and Community Outreach Center; Norris Comprehensive Cancer Center; University of Southern California FX M.G. Cockburn was supported in part by the Centers for Disease Control and Prevention (grant U55/CCU921930-02), the National Institute of Environmental Health Sciences (grant 5P30 ES07048), and the National Cancer Institute (grant R01CA121052). L. Baezconde-Garbanati was supported by the Southern California Cancer Information Services Partnership Program of the National Cancer Institute (grant 2P30 CA014089) and the National Institute of Environmental Health Services (grant ES07048), Patient Education and Community Outreach Center, Norris Comprehensive Cancer Center, Department of Preventive Medicine, University of Southern California, Los Angeles. K. D. Reynolds was supported by die National Cancer Institute (grant CA100285). NR 77 TC 34 Z9 34 U1 4 U2 7 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD APR PY 2009 VL 99 IS 4 BP 734 EP 741 DI 10.2105/AJPH.2007.122796 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 423RA UT WOS:000264512200027 PM 19150918 ER PT J AU Bray, M AF Bray, Mike TI Keeping an Eye on Poxviruses SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Editorial Material ID MONKEYPOX VIRUS; INFECTION; CONGO C1 NIAID, Integrated Res Facil, NIH, Ft Detrick, MD 21702 USA. RP Bray, M (reprint author), NIAID, Integrated Res Facil, NIH, 1437 Porter St, Ft Detrick, MD 21702 USA. EM mbray@niaid.nih.gov NR 10 TC 4 Z9 4 U1 0 U2 4 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD APR PY 2009 VL 80 IS 4 BP 499 EP 500 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 432CK UT WOS:000265110900001 PM 19346364 ER PT J AU Msamanga, GI Taha, TE Young, AM Brown, ER Hoffman, IF Read, JS Mudenda, V Goldenberg, RL Sharma, U Sinkala, M Fawzi, WW AF Msamanga, Gernard I. Taha, Taha E. Young, Alicia M. Brown, Elizabeth R. Hoffman, Irving F. Read, Jennifer S. Mudenda, Victor Goldenberg, Robert L. Sharma, Usha Sinkala, Moses Fawzi, Wafaie W. TI Placental Malaria and Mother-to-Child Transmission of Human Immunodeficiency Virus-1 SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID PLASMODIUM-FALCIPARUM MALARIA; SUB-SAHARAN AFRICA; HIV TRANSMISSION; PERINATAL TRANSMISSION; PROSPECTIVE COHORT; PREGNANT-WOMEN; DUAL INFECTION; WESTERN KENYA; MATERNAL HIV; RISK-FACTORS AB There are few studies of the association between placental malaria (PM) and mother-to-child transmission (MTCT) of human immunodeficiency virus-1 (HIV-1), and the results of published studies are inconsistent. To determine the association between PM and MTCT of HIV-1, we performed a secondary analysis of data from a clinical trial of antibiotics to reduce chorioamnionitis. Data regarding 1,662 HIV-1-infected women with live born singleton and first-born twin infants with information regarding PM and infant HIV-1 infection status at birth were analyzed. At the time of the study, women did not have access to antiretroviral drugs for treatment of acquired immunodeficiency syndrome but had received nevirapine prophylaxis to reduce the risk of MTCT of HIV-1. Placental malaria was not associated with the infant HIV-1. infection status at birth (P = 0.67). Adjustment for maternal plasma viral load and CD4+ cell count did not change these results (odds ratio = 1.06, 95% confidence interval = 0.51-2.20, P = 0.87). Placental malaria was more likely to be related to HIV-1 infection at birth among women with low viral load at baseline (P for interaction = 0.08). In conclusion, PM was not associated with infant HIV-1 infection status at birth. The interaction of maternal plasma viral load, PM, and MTCT of HIV-1 warrants further studies. C1 [Msamanga, Gernard I.] Muhimbili Univ Hlth & Allied Sci, Dept Community Hlth, Dar Es Salaam, Tanzania. [Taha, Taha E.] Johns Hopkins Univ, Bloomberg Sch Hyg & Publ Hlth, Baltimore, MD 21205 USA. [Young, Alicia M.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98109 USA. [Brown, Elizabeth R.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Hoffman, Irving F.] Univ N Carolina, Div Infect Dis, Chapel Hill, NC 27599 USA. [Read, Jennifer S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. [Mudenda, Victor] Univ Teaching Hosp, Dept Pathol, Lusaka, Zambia. [Goldenberg, Robert L.] Drexel Univ, Coll Med, Dept Obstet & Gynecol, Philadelphia, PA 19102 USA. [Sharma, Usha] NIAID, Prevent Sci Program, Div Aids, Bethesda, MD 20892 USA. [Sinkala, Moses] Directorate Hlth, Lusaka Urban Dist Hlth Management Team, Fairview Lusaka, Zambia. [Fawzi, Wafaie W.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Msamanga, GI (reprint author), Muhimbili Univ Hlth & Allied Sci, Dept Community Hlth, UN Rd,POB 65001, Dar Es Salaam, Tanzania. EM gmsamanga@muhas.ac.tz; ttaha@jhsph.edu; alicia@scharp.org; ebrown@scharp.org; hoffmani@med.unc.edu; jennifer_read@nih.gov; mudenda2003@yahoo.co.uk; rgoldenb@drexelmed.edu; usharma@niaid.nih.gov; moses@cidrcz.org; mina@hsph.harvard.edu RI Brown, Elizabeth/A-8984-2008 FU HIV Network for Prevention Trials (HIVNET); National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health; Department of Health and Human Services [N01-AI-35173]; Family Health International [N01-AI-45200]; Fred Hutchinson Cancer Research Center; Johns Hopkins University [N01-AI-35173-117/412]; MAID; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; National Institute of Mental Health; U.S. Department of Health and Human Services; Harvard University [U01-AI-48006, U01-AI-48005]; University of Alabama at Birmingham [U01-AI-47972] FX support:This study was supported by the HIV Network for Prevention Trials (HIVNET) and sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, and the Department of Health and Human Services through contract #N01-AI-35173 with Family Health International; contract #N01-AI-45200 with Fred Hutchinson Cancer Research Center; and subcontract #N01-AI-35173-117/412 with Johns Hopkins University. This work was also sponsored by the MAID, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute on Drug Abuse, the National Institute of Mental Health, and the Office of AIDS Research at the National Institutes of Health, the U.S. Department of Health and Human Services, Harvard University (U01-AI-48006), Johns Hopkins University (U01-AI-48005), and the University of Alabama at Birmingham (U01-AI-47972). Nevirapine (Viramune; Boehringer Ingelheim GmbH, Ingelheim, Germany) was provided by Boehringer Ingelheim Pharmaceuticals, Incorporated. NR 37 TC 13 Z9 13 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 EI 1476-1645 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD APR PY 2009 VL 80 IS 4 BP 508 EP 515 PG 8 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 432CK UT WOS:000265110900004 PM 19346367 ER PT J AU King, AA Shrestha, S Harvill, ET Bjornstad, ON AF King, Aaron A. Shrestha, Sourya Harvill, Eric T. Bjornstad, Ottar N. TI Evolution of Acute Infections and the Invasion-Persistence Trade-Off SO AMERICAN NATURALIST LA English DT Article DE acute infection; trade-off; evolution of infectious disease; pathogen evolution; dose response; Bordetella ID CRITICAL COMMUNITY SIZE; PARASITE VIRULENCE; BORDETELLA; MEASLES; MODELS; TIME; COEVOLUTION; COINFECTION; EPIDEMICS; SELECTION AB We seek to understand the conditions favoring the evolution of acute, highly transmissible infections. Most work on the life-history evolution of pathogens has focused on the transmission-virulence trade-off. Here we focus on a distinct trade-off that operates, even among avirulent pathogens, between a pathogen's speed of invasion and its ability to persist in a finite host population. Other authors have shown how this invasion-persistence trade-off can lead to intermediate pathogen attack rates but have done so only by imposing trade-offs between the pathogen's transmissibility and the duration of the infectious period. Here we delve deeper, by linking a model of within-host pathogen dynamics-in which pathogen life-history parameters figure directly-to an epidemiological model at the population level. We find that a key determinant of the evolutionary trajectory is the shape of the dose-response curve that relates within-host pathogen load to between-host transmission. In particular, under the usual assumption of proportionality we find that pathogens tend to evolve to the edge of their own extinction. Under more realistic assumptions, a critical host population size exists, above which highly acute pathogens are buffered from extinction. Our study is motivated by the emergence of acuteness in two human pathogens, Bordetella pertussis and Bordetella parapertussis, which independently evolved from an ancestor, Bordetella bronchiseptica, characterized by chronic (nonacute) infection of wildlife. In contrast to the plethora of models that predict evolution of more aggressive pathogens in larger or denser populations, the invasion-persistence trade-off also operates for frequency-dependent pathogens. C1 [King, Aaron A.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [King, Aaron A.] Univ Michigan, Dept Math, Ann Arbor, MI 48109 USA. [King, Aaron A.; Bjornstad, Ottar N.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Shrestha, Sourya] Univ Michigan, Appl & Interdisciplinary Math Program, Ann Arbor, MI 48109 USA. [Harvill, Eric T.] Penn State Univ, Dept Vet Sci, University Pk, PA 16803 USA. [Bjornstad, Ottar N.] Penn State Univ, Dept Entomol, University Pk, PA 16803 USA. [Bjornstad, Ottar N.] Penn State Univ, Dept Biol, University Pk, PA 16803 USA. RP King, AA (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM kingaa@umich.edu RI Bjornstad, Ottar/I-4518-2012; King, Aaron/B-8092-2012; OI King, Aaron/0000-0001-6159-3207; Shrestha, Sourya/0000-0002-6106-6834 FU Department of Ecology and Evolutionary Biology of the University of Michigan; Fogarty International Center; National Institutes of Health [AI 053075, GM083113]; Science and Technology Directorate, Department of Homeland Security FX We thank R. Antia and an anonymous reviewer for useful comments on the manuscript. The work was supported by the Department of Ecology and Evolutionary Biology of the University of Michigan ( to A. A. K.), grants from the Fogarty International Center ( to O. N. B.) and National Institutes of Health ( grants AI 053075 and GM083113 to E. T. H.), the Research and Policy for Infectious Disease Dynamics ( RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 32 TC 23 Z9 23 U1 0 U2 14 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0003-0147 J9 AM NAT JI Am. Nat. PD APR PY 2009 VL 173 IS 4 BP 446 EP 455 DI 10.1086/597217 PG 10 WC Ecology; Evolutionary Biology SC Environmental Sciences & Ecology; Evolutionary Biology GA 415MG UT WOS:000263937300005 PM 19231966 ER PT J AU Shakleya, DM Huestis, MA AF Shakleya, Diaa M. Huestis, Marilyn A. TI Simultaneous quantification of nicotine, opioids, cocaine, and metabolites in human fetal postmortem brain by liquid chromatography tandem mass spectrometry SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article; Proceedings Paper CT 15th Biennial Conference on Applied Surface Analysis CY SEP 08-10, 2008 CL Soest, GERMANY SP Inst Technol Wissenstransfer TWS, Univ Appl Sci S Westphalia, Deutsch Vakuum Gesell, Deutsch Phys Gesell, Fachverband Mikrosonden, Osterreich Gesell Mikrochem & Analy Chem, GOCh, Deutsch Arbeitskreis Angewandte Spekroskop, DASp GDCh-Fachgruppe Analy Chem, European Microbeam Anal Soc, EMAS, SCADEG Sekt Strukturelle & Chem Dunnsch & Grenzflachenanaly Kgl, Niederland Chem Vereinig, Schweizer Arbeits Gemeinsch Oberflach & Grenzflach SAOG, Deutsch Verband Mat Forsch & Pruf DVM, Verein Deutsch Eisenhuttenleute VDEh DE LCMSMS; Brain; Fetal; Cocaine; Opiate; Nicotine ID SOLID-PHASE EXTRACTION; UMBILICAL-CORD TISSUE; LIFE-STYLE; 2-ETHYLIDENE-1,5-DIMETHYL-3,3-DIPHENYLPYRROLIDINE EDDP; INFANT DEVELOPMENT; AMNIOTIC-FLUID; HUMAN MECONIUM; EXPOSURE; METHAMPHETAMINE; AMPHETAMINE AB A validated method for simultaneous LCMSMS quantification of nicotine, cocaine, 6-acetylmorphine (6AM), codeine, and metabolites in 100 mg fetal human brain was developed and validated. After homogenization and solid-phase extraction, analytes were resolved on a Hydro-RP analytical column with gradient elution. Empirically determined linearity was from 5-5,000 pg/mg for cocaine and benzoylecgonine (BE), 25-5,000 pg/mg for cotinine, ecgonine methyl ester (EME) and 6AM, 50-5000 pg/mg for trans-3-hydroxycotinine (OH-cotinine) and codeine, and 250-5,000 pg/mg for nicotine. Potential endogenous and exogenous interferences were resolved. Intra- and inter-assay analytical recoveries were a parts per thousand yen92%, intra- and inter-day and total assay imprecision were a parts per thousand currency sign14% RSD and extraction efficiencies were a parts per thousand yen67.2% with a parts per thousand currency sign83% matrix effect. Method applicability was demonstrated with a postmortem fetal brain containing 40 pg/mg cotinine, 65 pg/mg OH-cotinine, 13 pg/mg cocaine, 34 pg/mg EME, and 525 pg/mg BE. This validated method is useful for determination of nicotine, opioid, and cocaine biomarkers in brain. C1 [Shakleya, Diaa M.; Huestis, Marilyn A.] NIDA, Intramural Res Program, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, Biomed Res Ctr, 251 Bayview Blvd Suite 5A721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [ZIA DA000412-13, ZIA DA000413-13] NR 42 TC 20 Z9 21 U1 0 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD APR PY 2009 VL 393 IS 8 BP 1957 EP 1965 DI 10.1007/s00216-009-2661-8 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 426HF UT WOS:000264697900018 PM 19229524 ER PT J AU Gray, TR Shakleya, DM Huestis, MA AF Gray, Teresa R. Shakleya, Diaa M. Huestis, Marilyn A. TI A liquid chromatography tandem mass spectrometry method for the simultaneous quantification of 20 drugs of abuse and metabolites in human meconium SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article; Proceedings Paper CT 15th Biennial Conference on Applied Surface Analysis CY SEP 08-10, 2008 CL Soest, GERMANY SP Inst Technol Wissenstransfer TWS, Univ Appl Sci S Westphalia, Deutsch Vakuum Gesell, Deutsch Phys Gesell, Fachverband Mikrosonden, Osterreich Gesell Mikrochem & Analy Chem, GOCh, Deutsch Arbeitskreis Angewandte Spekroskop, DASp GDCh-Fachgruppe Analy Chem, European Microbeam Anal Soc, EMAS, SCADEG Sekt Strukturelle & Chem Dunnsch & Grenzflachenanaly Kgl, Niederland Chem Vereinig, Schweizer Arbeits Gemeinsch Oberflach & Grenzflach SAOG, Deutsch Verband Mat Forsch & Pruf DVM, Verein Deutsch Eisenhuttenleute VDEh DE Meconium; Drugs of abuse; Prenatal drug exposure; Liquid chromatography tandem mass spectrometry ID NEONATAL ABSTINENCE SYNDROME; LC-MS-MS; BUPRENORPHINE USE; LIFE-STYLE; GC-MS; METHADONE; PREGNANCY; VALIDATION; COCAINE; METHAMPHETAMINE AB A method for the simultaneous quantification of 20 cocaine, amphetamine, opiate, and nicotine analytes in meconium, the first neonatal feces, by liquid chromatography tandem mass spectrometry was developed and validated. Specimen preparation included methanol homogenization and solid phase extraction. Two injections were required to achieve sufficient sensitivity and linear dynamic range. Linearity ranged from 0.5-25 up to 500 ng/g (250 ng/g p-hydroxymethamphetamine), and correlation coefficients were > 0.996. Imprecision was < 10.0% CV, analytical recovery 85.5-123.1%, and extraction efficiencies > 46.7% at three concentrations across the linear range. Despite significant matrix effects of -305.7-40.7%, effects were similar for native and deuterated analytes. No carryover, endogenous or exogenous interferences were observed, with analyte stability at room temperature, 4 A degrees C, and -20 A degrees C and on the autosampler > 70%, except for 6-acetylmorphine, hydrocodone, oxycodone, and morphine. Method applicability was demonstrated by analyzing meconium from drug-exposed neonates. C1 [Gray, Teresa R.; Shakleya, Diaa M.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [ZIA DA000433-11] NR 49 TC 37 Z9 37 U1 0 U2 9 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD APR PY 2009 VL 393 IS 8 BP 1977 EP 1990 DI 10.1007/s00216-009-2680-5 PG 14 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 426HF UT WOS:000264697900020 PM 19241063 ER PT J AU Horowitz, PE Gild, WM AF Horowitz, Peter E. Gild, William M. TI Conventional Neuromuscular Monitoring versus Acceleromyography: It's Not the Monitor but the Anesthetist SO ANESTHESIOLOGY LA English DT Letter ID POSTANESTHESIA CARE-UNIT; QUANTITATIVE ASSESSMENT; BLOCK; CISATRACURIUM; ANTAGONISM; ROCURONIUM; COUNT C1 [Horowitz, Peter E.] Natl Inst Hlth Clin Ctr, Bethesda, MD USA. RP Horowitz, PE (reprint author), Natl Inst Hlth Clin Ctr, Bethesda, MD USA. EM horowitzpe@mail.nih.gov NR 12 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD APR PY 2009 VL 110 IS 4 BP 948 EP 949 PG 2 WC Anesthesiology SC Anesthesiology GA 424TX UT WOS:000264592300041 PM 19307875 ER PT J AU Wijman, CAC Mlynash, M Caulfield, AF Hsia, AW Eyngorn, I Bammer, R Fischbein, N Albers, GW Moseley, M AF Wijman, Christine A. C. Mlynash, Michael Caulfield, Anna Finley Hsia, Amie W. Eyngorn, Irina Bammer, Roland Fischbein, Nancy Albers, Gregory W. Moseley, Michael TI Prognostic Value of Brain Diffusion-Weighted Imaging after Cardiac Arrest SO ANNALS OF NEUROLOGY LA English DT Article ID CORTICAL LAMINAR NECROSIS; COMATOSE SURVIVORS; ISCHEMIC ENCEPHALOPATHY; METABOLIC RECOVERY; WHITE-MATTER; MRI; HYPOTHERMIA; RESUSCITATION; COEFFICIENT; PREDICTION AB Objective: Outcome prediction is challenging in comatose postcardiac arrest survivors. We assessed the Feasibility and prognostic utility of brain diffusion-weighted magnetic resonance imaging, (DWI) during the First week. Methods: Consecutive comatose postcardiac arrest patients were prospectively enrolled, AWI data of patients who met pre-defined specific prognostic criteria were used to determine distinguishing apparent diffusion coefficient (ADC) thresholds. Group I criteria were death at 6 months and absent motor response or absent pupillary reflexes or bilateral absent cortical responses at 72 hours or vegetative at I month. Group 2 criterion was survival at 6 months with a Glasgow Outcome Scale score of 4 or 5 (group 2A) or 3 (group 2B). The percentage of voxels below different ADC thresholds was calculated at 50 X 10(-6) mm(2)/sec intervals. Results: Overall, 86% of patients underwent DWI. Fifty-one patients with 62 brain DWIs were included. Forty patients met the specific prognostic criteria. The percentage of brain volume with in ADC value less than 650 to 700 X 10(-6) mm(2)/sec best differentiated between Group I and Groups 2A and 2B combined (p < 0.001), whereas the 400 to 450 X 10(-6) mm(2)/sec threshold best differentiated between Groups 2A and 2B (p = 0.003). The ideal time window for prognostication using DWI was between 49 arid 108 hours after the arrest. When comparing DWI in this time window with the 72-hour neurological examination, DWI improved the sensitivity for predicting Poor outcome by 38% while maintaining 100% specificity (p 0.021). Interpretation: Quantitative DWI in comatose postcardiac arrest Survivors holds promise as a prognostic adjunct. Ann Neurol 2009;65:394-402 C1 [Wijman, Christine A. C.; Mlynash, Michael; Caulfield, Anna Finley; Hsia, Amie W.; Eyngorn, Irina; Albers, Gregory W.] Stanford Univ, Dept Neurol & Neurol Sci, Stanford Stroke Ctr, Palo Alto, CA 94304 USA. [Hsia, Amie W.] NINDS, Stroke Branch, Bethesda, MD 20892 USA. [Bammer, Roland; Moseley, Michael] Stanford Univ, Lucas Magnet Resonance Spect & Imaging Ctr, Palo Alto, CA 94304 USA. [Bammer, Roland; Fischbein, Nancy; Moseley, Michael] Stanford Univ, Dept Radiol, Palo Alto, CA 94304 USA. RP Wijman, CAC (reprint author), Stanford Univ, Dept Neurol & Neurol Sci, Stanford Stroke Ctr, 701 Welch Rd,B325, Palo Alto, CA 94304 USA. EM cwijman@stanford.edu FU American Heart Association [0430275N]; Katherine McCormick Fund for Women; NIH [2R01EB002711]; NIBIB [R01NS34866] FX This work was supported by the American Heart Association (National Scientist Development Award 0430275N, C.A.C.W.), the Katherine McCormick Fund for Women (A.W.H.), the NIH (2R01EB002711, NIBIB R.B.; R01NS34866, NINDS M.M.). NR 22 TC 117 Z9 121 U1 2 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD APR PY 2009 VL 65 IS 4 BP 394 EP 402 DI 10.1002/ana.21632 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 439VT UT WOS:000265656200008 PM 19399889 ER PT J AU Stafstrom, CE Ockuly, JC Murphree, L Valley, MT Roopra, A Sutula, TP AF Stafstrom, Carl E. Ockuly, Jeffrey C. Murphree, Lauren Valley, Matthew T. Roopra, Avtar Sutula, Thomas P. TI Anticonvulsant and Antiepileptic Actions of 2-Deoxy-D-Glucose in Epilepsy Models SO ANNALS OF NEUROLOGY LA English DT Article ID RAT HIPPOCAMPAL SLICE; KETOGENIC DIET; ENERGY-METABOLISM; IN-VITRO; ELECTROGRAPHIC SEIZURES; BETA-HYDROXYBUTYRATE; GLUCOSE-UTILIZATION; SYNAPTIC FUNCTION; NEURAL ACTIVITY; KETONE-BODIES AB Objective: Conventional anticonvulsants reduce neuronal excitability through effects on ion channels and synaptic function. Anticonvulsant mechanisms of the ketogenic diet remain incompletely understood. Because carbohydrates are restricted in patients on the ketogenic diet, we evaluated the effects of limiting carbohydrate availability by reducing glycolysis using the glycolyric inhibitor 2-deoxy-D-glucose (2DG) in experimental models of seizures and epilepsy. Methods: Acute anticonvulsant actions of 2DG were assessed in vitro in rat hippocampal slices perfused with 7.5mM [K(+)](o), 4-aminopyridine, or bicuculline, and in vivo against seizures evoked by 6Hz stimulation in mice, audiogenic stimulation in Fring's mice, and maximal electroshock and subcutaneous pentylenetetrazol (Metrazol) in rats. Chronic antiepileptic effects of 2DG were evaluated in rats kindled from olfactory bulb or perforant path. Results: 2DG (10mM) reduced interictal epileptiform bursts induced by 7.5mM [K(+)](o), 4-aminopyridine, and bicuculline, and electrographic seizures induced by high [K(+)](o), in CA3 of hippocampus. 2DG reduced seizures evoked by 6Hz stimulation in mice (effective dose [ED]50 = 79.7mg/kg) and audiogenic stimulation in Fring's mice (ED50 = 206.4mg/kg). 2DG exerted chronic antiepileptic action by increasing afterdischarge thresholds in perforant path (but not olfactory bulb) kindling and caused a twofold slowing in progression of kindled seizures at both stimulation sites. 2DG did not protect against maximal electroshock or Metrazol seizures. Interpretation: The glycolytic inhibitor 2DG exerts acute anticonvulsant and chronic antiepileptic actions, and has a novel pattern of effectiveness in preclinical screening models. These results identify metabolic regulation as a potential therapeutic target for seizure suppression and modification of epileptogenesis. Ann Neurol 2009;65:435-448 C1 [Stafstrom, Carl E.; Ockuly, Jeffrey C.; Valley, Matthew T.; Roopra, Avtar; Sutula, Thomas P.] Univ Wisconsin, Dept Neurol, Madison, WI 53792 USA. [Stafstrom, Carl E.] Univ Wisconsin, Dept Pediat, Madison, WI 53792 USA. [Murphree, Lauren] NINDS, Antiepilept Screening Program, NIH, Bethesda, MD 20892 USA. [Sutula, Thomas P.] Univ Wisconsin, Dept Anat, Madison, WI 53792 USA. RP Stafstrom, CE (reprint author), Univ Wisconsin, Dept Neurol, H6-574,600 Highland Ave, Madison, WI 53792 USA. EM stafstrom@neurology.wisc.edu FU NIH [NINDS RO1-25020]; Wisconsin Alumni Research Foundation; Charlie Foundation; National Institute of Neurological Disorders and Stroke Antiepileptic Screening Program FX This work was Supported by the NIH (NINDS RO1-25020, T.P.S.), Wisconsin Alumni Research Foundation, The Charlie Foundation (C.E.S.), and the National Institute of Neurological Disorders and Stroke Antiepileptic Screening Program. NR 55 TC 53 Z9 57 U1 4 U2 16 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD APR PY 2009 VL 65 IS 4 BP 435 EP 447 DI 10.1002/ana.21603 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 439VT UT WOS:000265656200012 PM 19399874 ER PT J AU Park, D Stewart, PA Coble, JB AF Park, Donguk Stewart, Patrica A. Coble, Joseph B. TI Determinants of Exposure to Metalworking Fluid Aerosols: A Literature Review and Analysis of Reported Measurements SO ANNALS OF OCCUPATIONAL HYGIENE LA English DT Article DE enclosure; grinding operation; machining operation; mass median diameters (MMDs); metalworking aerosol fraction; metalworking fluids (MWFs) ID SMALL MACHINE SHOPS; AUTOMOBILE MANUFACTURING-INDUSTRY; MIST GENERATION; OIL MIST; OCCUPATIONAL-EXPOSURE; GRINDING OPERATIONS; MORTALITY; CANCER; WORKERS; AUTOWORKERS AB An extensive literature review of published metalworking fluid (MWF) aerosol measurement data was conducted to identify the major determinants that may affect exposure to aerosol fractions (total or inhalable, thoracic and respirable) and mass median diameters (MMDs). The identification of determinants was conducted through published studies and analysis of published measurement levels. For the latter, weighted arithmetic means (WAMs) by number of measurements were calculated and compared using analysis of variance and t-tests. The literature review found that the major factors affecting aerosol exposure levels were, primarily, decade, type of industry, operation and fluid and engineering control measures. Our analysis of total aerosol levels found a significant decline in measured levels from an average of 5.36 mg m(-3) prior to the 1970s and 2.52 mg m(-3) in the 1970s to 1.21 mg m(-3) in the 1980s, 0.50 mg m(-3) in the 1990s and 0.55 mg m(-3) in the 2000s. Significant declines from the 1990s to the 2000s also were found in thoracic fraction levels (0.48 versus 0.40 mg m(-3)), but not for the respirable fraction. The WAMs for the auto (1.47 mg m(-3)) and auto parts manufacturing industry (1.83 mg m(-3)) were significantly higher than that for small-job machine shops (0.68 mg m(-3)). In addition, a significant difference in the thoracic WAM was found between the automotive industry (0.46 mg m(-3)) and small-job machine shops (0.32 mg m(-3)). Operation type, in particular, grinding, was a significant factor affecting the total aerosol fraction [grinding operations (1.75 mg m(-3)) versus other machining (0.95 mg m(-3))], but the levels associated with these operations were not statistically different for either the thoracic or the respirable fractions. Across all decades, the total aerosol fraction for straight oils (1.49 mg m(-3)) was higher than for other fluid types (soluble = 1.08 mg m(-3), synthetic = 0.52 mg m(-3) and semisynthetic = 0.50 mg m(-3)). Fluid type was also found to be partly associated with differences in the respirable fraction level. We found that the total aerosols were measured by a variety of sampling media, devices and analytical methods. This diversity of approaches makes interpretation of the study results difficult. In conclusion, both the literature review and the measurement data analyzed found that decade and type of industry, operation and fluid were important determinants of total aerosol exposure. Industry type and fluid type were associated with differences in exposure to the thoracic and respirable fraction levels, respectively. C1 [Park, Donguk; Coble, Joseph B.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Park, Donguk] Korea Natl Open Univ, Dept Environm Hlth, Seoul 110791, South Korea. [Stewart, Patrica A.] Stewart Exposure Assessments LLC, Arlington, VA 22207 USA. RP Park, D (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS Room 8005, Rockville, MD 20852 USA. EM pdw545@knou.ac.kr FU National Cancer Institute; National Institutes of Health; Department of Health and Human Services FX Intramural funds from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 60 TC 18 Z9 18 U1 1 U2 12 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0003-4878 J9 ANN OCCUP HYG JI Ann. Occup. Hyg. PD APR PY 2009 VL 53 IS 3 BP 271 EP 288 DI 10.1093/annhyg/mep005 PG 18 WC Public, Environmental & Occupational Health; Toxicology SC Public, Environmental & Occupational Health; Toxicology GA 428YV UT WOS:000264888900008 PM 19329796 ER PT J AU Li, T Christos, PJ Sparano, JA Hershman, DL Hoschander, S O'Brien, K Wright, JJ Vahdat, LT AF Li, T. Christos, P. J. Sparano, J. A. Hershman, D. L. Hoschander, S. O'Brien, K. Wright, J. J. Vahdat, L. T. TI Phase II trial of the farnesyltransferase inhibitor tipifarnib plus fulvestrant in hormone receptor-positive metastatic breast cancer: New York Cancer Consortium Trial P6205 SO ANNALS OF ONCOLOGY LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 01-05, 2007 CL Chicago, IL SP Amer Soc Clin Oncol DE farnesyltransferase inhibitor; fulvestrant; metastatic breast cancer; postmenopausal; selective estrogen receptor downregulator; tipifarnib ID 2 MULTICENTER TRIALS; FARNESYL TRANSFERASE INHIBITOR; POSTMENOPAUSAL WOMEN; ENDOCRINE THERAPY; AROMATASE INHIBITORS; ACQUIRED-RESISTANCE; 2ND-LINE TREATMENT; RANDOMIZED-TRIAL; SOLID TUMORS; DOUBLE-BLIND AB Background: Fulvestrant produces a clinical benefit rate (CBR) of similar to 45% in tamoxifen-resistant, hormone receptor (HR)-positive metastatic breast cancer (MBC) and 32% in aromatase inhibitor (AI)-resistant disease. The farnesyltransferase inhibitor tipifarnib inhibits Ras signaling and has preclinical and clinical activity in endocrine therapy-resistant disease. The objective of this study was to determine the efficacy and safety of tipifarnib-fulvestrant combination in HR-positive MBC. Patients and methods: Postmenopausal women with no prior chemotherapy for metastatic disease received i.m. fulvestrant 250 mg on day 1 plus oral tipifarnib 300 mg twice daily on days 1-21 every 28 days. The primary end point was CBR. Results: The CBR was 51.6% [95% confidence interval (CI) 34.0% to 69.2%] in 31 eligible patients and 47.6% (95% CI 26.3% to 69.0%) in 21 patients with AI-resistant disease. A futility analysis indicated that it was unlikely to achieve the prespecified 70% CBR. Tipifarnib dose modification was required in 8 of 33 treated patients (24%). Conclusions: The target CBR of 70% for the tipifarnib-fulvestrant combination in HR-positive MBC was set too high and was not achieved. The 48% CBR in AI-resistant disease compares favorably with the 32% CBR observed with fulvestrant alone in prior studies and merit further clinical and translational evaluation. C1 [Li, T.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Oncol, Montefiore Einstein Canc Ctr, Bronx, NY 10461 USA. [Christos, P. J.; O'Brien, K.] Weill Cornell Med Coll, Weill Cornell Med Ctr, New York, NY USA. [Hershman, D. L.; Vahdat, L. T.] Columbia Presbyterian Med Coll, New York, NY USA. [Wright, J. J.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Li, T (reprint author), Montefiore Med Ctr, Albert Einstein Coll Med, Dept Oncol, Montefiore Einstein Canc Ctr, 1825 Eastchester Rd,2 South,Room 55, Bronx, NY 10461 USA. EM tli@montefiore.org OI O'Brien, Katie/0000-0002-1931-1349 FU NCI NIH HHS [N01-CM-62204] NR 30 TC 20 Z9 20 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD APR PY 2009 VL 20 IS 4 BP 642 EP 647 DI 10.1093/annonc/mdn689 PG 6 WC Oncology SC Oncology GA 425PN UT WOS:000264649700007 PM 19153124 ER PT J AU Huang, T Sun, LG Wang, YH Zhu, RB AF Huang, Tao Sun, Liguang Wang, Yuhong Zhu, Renbin TI Penguin occupation in the Vestfold Hills SO ANTARCTIC SCIENCE LA English DT Article DE climate change; East Antarctica; Holocene deglaciation; (14)C dating; ornithogenic sediments ID CAL KYR BP; ANTARCTIC PENINSULA; EAST ANTARCTICA; LATE-HOLOCENE; CLIMATE-CHANGE; ROSS SEA; ICE-CORE; LAKE; BAY; CALIBRATION AB During CHINARE-22 (December 2005-March 2006), we investigated six penguin colonies in the Vestfold Hills, East Antarctica, and collected several penguin ornithogenic sediment cores, samples of fresh guano and modem penguin bone and feather. We selected seven penguin bones and feathers and six sediments from the longest sediment core and performed AMS (14)C dating. The results indicate that penguins occupied the Vestfold Hills as early as 8500 calibrated years before present (cal. yr BP), following local deglaciation and the formation of the ice free area. This is the first report on the Holocene history of penguins in the Vestfold Hills. As in other areas of Antarctica, penguins occupied this area as soon as local ice retreated and the ice free area formed, and they are very sensitive to climatic and environmental changes. This work provides the foundation for understanding the history of penguins occupation in Vestfold Hills, East Antarctica. C1 [Huang, Tao; Sun, Liguang; Wang, Yuhong; Zhu, Renbin] Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Peoples R China. [Wang, Yuhong] NIH, Bethesda, MD 20892 USA. RP Sun, LG (reprint author), Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Peoples R China. EM slg@ustc.edu.cn RI Huang, Tao/B-5915-2009 FU National Natural Science Foundation of China [40730107]; Australia Antarctic Division Science Project [AAD2873] FX We would like to thank the Chinese Polar Administration, Chinese Polar Research Center, all the CHINARE22 team mates in Zhong Shan Station and all the members in Davis Station for their vigorous support and assistance. This study was funded by the National Natural Science Foundation of China (No. 40730107), the IPY 2007-2008 China Programme and was supported by the Australia Antarctic Division Science Project (AAD2873). We especially thank two anonymous reviewers for their critical comments and careful corrections on the manuscript. NR 33 TC 11 Z9 12 U1 1 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-1020 J9 ANTARCT SCI JI Antarct. Sci. PD APR PY 2009 VL 21 IS 2 BP 131 EP 134 DI 10.1017/S095410200800165X PG 4 WC Environmental Sciences; Geography, Physical; Geosciences, Multidisciplinary SC Environmental Sciences & Ecology; Physical Geography; Geology GA 425QM UT WOS:000264652200005 ER PT J AU Moriyama, B Elinoff, J Danner, RL Gea-Banacloche, J Pennick, G Rinaldi, MG Walsh, TJ AF Moriyama, Brad Elinoff, Jason Danner, Robert L. Gea-Banacloche, Juan Pennick, Gennethel Rinaldi, Michael G. Walsh, Thomas J. TI Accelerated Metabolism of Voriconazole and Its Partial Reversal by Cimetidine SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID CONTINUOUS VENOVENOUS HEMODIAFILTRATION; HUMAN HEPATOCYTES; CYP3A4 INDUCTION; DRUG; PHARMACOKINETICS; TRANSPORTERS; INFLAMMATION; DISPOSITION; EXPRESSION; RECEPTOR AB We report a case of accelerated metabolism of voriconazole during therapy for invasive pulmonary aspergillosis, resulting in subtherapeutic levels. Target voriconazole levels were restored with high dosages of voriconazole (up to 40 mg/kg of body weight/day) and the addition of cimetidine as a cytochrome P450 enzyme inhibitor. C1 [Gea-Banacloche, Juan; Walsh, Thomas J.] NCI, Bethesda, MD 20892 USA. [Moriyama, Brad] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Elinoff, Jason; Danner, Robert L.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Pennick, Gennethel; Rinaldi, Michael G.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. RP Walsh, TJ (reprint author), NCI, CRC 1-5750,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov FU National Institutes of Health FX This work was supported in part by the intramural research program of the National Institutes of Health. NR 19 TC 15 Z9 16 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD APR PY 2009 VL 53 IS 4 BP 1712 EP 1714 DI 10.1128/AAC.01221-08 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 421JU UT WOS:000264356000069 PM 19171800 ER PT J AU Sastalla, I Chim, K Cheung, GYC Pomerantsev, AP Leppla, SH AF Sastalla, Inka Chim, Kannie Cheung, Gordon Y. C. Pomerantsev, Andrei P. Leppla, Stephen H. TI Codon-Optimized Fluorescent Proteins Designed for Expression in Low-GC Gram-Positive Bacteria SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID GENE-EXPRESSION; BACILLUS-ANTHRACIS; STAPHYLOCOCCUS-AUREUS; UNSTABLE VARIANTS; ESCHERICHIA-COLI; MAMMALIAN-CELLS; TOXIN; SUBTILIS; TRANSCRIPTION; VIRULENCE AB Fluorescent proteins have wide applications in biology. However, not all of these proteins are properly expressed in bacteria, especially if the codon usage and genomic GC content of the host organism are not ideal for high expression. In this study, we analyzed the DNA sequences of multiple fluorescent protein genes with respect to codons and GC content and compared them to a low-GC gram-positive bacterium, Bacillus anthracis. We found high discrepancies for cyan fluorescent protein (CFP), yellow fluorescent protein (YFP), and the photoactivatable green fluorescent protein (PAGFP), but not GFP, with regard to GC content and codon usage. Concomitantly, when the proteins were expressed in B. anthracis, CFP- and YFP-derived fluorescence was undetectable microscopically, a phenomenon caused not by lack of gene transcription or degradation of the proteins but by lack of protein expression. To improve expression in bacteria with low genomic GC contents, we synthesized a codon-optimized gfp and constructed optimized photoactivatable pagfp, cfp, and yfp, which were in contrast to nonoptimized genes highly expressed in B. anthracis and in another low-GC gram-positive bacterium, Staphylococcus aureus. Using optimized GFP as a reporter, we were able to monitor the activity of the protective antigen promoter of B. anthracis and confirm its dependence on bicarbonate and regulators present on virulence plasmid pXO1. C1 [Sastalla, Inka; Chim, Kannie; Cheung, Gordon Y. C.; Pomerantsev, Andrei P.; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. RP Leppla, SH (reprint author), NIAID, Lab Bacterial Dis, NIH, Bldg 33, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov RI Cheung, Yiu Chong /K-3565-2012 FU National Institute of Allergy and Infectious Diseases, NIH FX We thank Jennifer Chua for assistance with characterization of the PAGFP. NR 51 TC 31 Z9 31 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD APR 1 PY 2009 VL 75 IS 7 BP 2099 EP 2110 DI 10.1128/AEM.02066-08 PG 12 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 424EX UT WOS:000264549400035 PM 19181829 ER PT J AU Liu, J Joshi, D Sempos, CT AF Liu, Jian Joshi, Divya Sempos, Christopher T. TI Non-high-density-lipoprotein cholesterol and cardiovascular risk factors among adolescents with and without impaired fasting glucose SO APPLIED PHYSIOLOGY NUTRITION AND METABOLISM-PHYSIOLOGIE APPLIQUEE NUTRITION ET METABOLISME LA English DT Article DE non-HDL; impaired fasting glucose; adolescents; metabolic risk factors; NHANES ID NUTRITION EXAMINATION SURVEY; CORONARY-HEART-DISEASE; TREATMENT-PANEL-III; NON-HDL CHOLESTEROL; METABOLIC SYNDROME; NATIONAL-HEALTH; US ADOLESCENTS; PREDICTOR; CHILDREN; OBESITY AB To evaluate how non-high-density-lipoprotein (non-HDL) is associated with impaired fasting glucose (IFG) and clustered metabolic risk (MR) factors among adolescents, we pooled 2764 adolescents, aged 12-19 years, from the National Health and Nutrition Examination Survey from 3 time periods (1999-2000, 2001-2002, and 2003-2004) who were free of diabetes and had fasted overnight for this analysis. IFG was defined as 100 <= glucose <= 125 mg(.)dL(-1). Age- and sex-specific cut-offs were used for 4 MR factors: higher levels of triglycerides, waist circumference, blood pressure, and lower levels of HDL. Clustered MR was defined as having any 2 of the 4 factors. Overall, approximately 11% of adolescents had IFG. The mean level of non-HDL cholesterol was much higher in those with IFG than in those without IFG, with adjustment for certain confounding variables (121.4 vs. 110.1 mg(.)dL(-1); p < 0.05). This difference could still be observed in adolescents with one or more clustered MR factors. However, there were no statistical differences in low-density-lipoprotein (LDL) level. Compared with those who were without IFG and not at high levels of non-HDL - after adjustment for age, sex, race, current smoking, and body mass index - the odds of having clustered MR factors were 1.08 (95% CI, 0.65-1.82) for those with IFG and low non-HDL cholesterol, 3.55 (2.29-5.48) for those without IFG but with high non-HDL cholesterol, and 10.10 (3.67-27.80) for those with both IFG and high non-HDL cholesterol. Moreover, those with IFG and at increased risk of obesity were more likely to have higher levels of non- HDL cholesterol (odds ratio (95% CI): 4.41 (2.28-8.50)), compared with those without IFG and not at increased risk of obesity. In summary, prediabetic adolescents with IFG and high levels of non-HDL cholesterol are more likely to have clustered MR factors. Thus, the levels of non-HDL cholesterol may be an important indicator in monitoring cardiovascular disease risk among adolescents with IFG. C1 [Liu, Jian; Joshi, Divya] Brock Univ, Dept Community Hlth Sci, St Catharines, ON L2S 3A1, Canada. [Sempos, Christopher T.] NIH, Bethesda, MD 20892 USA. RP Liu, J (reprint author), Brock Univ, Dept Community Hlth Sci, St Catharines, ON L2S 3A1, Canada. EM jliu@brocku.ca NR 29 TC 6 Z9 7 U1 0 U2 2 PU NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS PI OTTAWA PA BUILDING M 55, OTTAWA, ON K1A 0R6, CANADA SN 1715-5312 J9 APPL PHYSIOL NUTR ME JI Appl. Physiol. Nutr. Metab. PD APR PY 2009 VL 34 IS 2 BP 136 EP 142 DI 10.1139/H08-149 PG 7 WC Nutrition & Dietetics; Physiology; Sport Sciences SC Nutrition & Dietetics; Physiology; Sport Sciences GA 439CL UT WOS:000265604700006 PM 19370043 ER PT J AU Wilcox, E McGrath, C Blokhin, AV Gussio, R Hamel, E AF Wilcox, Elizabeth McGrath, Connor Blokhin, Andrei V. Gussio, Rick Hamel, Ernest TI Evidence for a distinct ligand binding site on tubulin discovered through inhibition by GDP of paclitaxel-induced tubulin assembly in the absence of exogenous GTP SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE Tubulin; GDP; Paclitaxel; Nucleotide binding sites; ATP; Microtubule-associated proteins ID MICROTUBULE-ASSOCIATED PROTEINS; AMINO-ACID-SEQUENCE; BETA-TUBULIN; NUCLEOTIDE-BINDING; ALPHA-TUBULIN; GUANINE-NUCLEOTIDES; STABILIZING AGENTS; CRYSTAL-STRUCTURE; PURIFIED TUBULIN; PORCINE BRAIN AB GDP inhibits paclitaxel-induced tubulin assembly without GTP when the tubulin bears GDP in the exchangeable site (E-site). initially, we thought inhibition was mediated through the E-site, since small amounts of GTP or Mg(2+), which favors GTP binding to the E-site, reduced inhibition by GDP. We thought trace GTP released from the nonexchangeable site (N-site) by tubulin denaturation was required for polymer nucleation, but microtubule length was unaffected by GDP. Further, enhancing polymer nucleation reduced inhibition by GDP. Other mechanisms involving the E-site were eliminated experimentally. Upon finding that ATP weakly inhibited paclitaxel-induced assembly, we concluded that another ligand binding site was responsible for these inhibitory effects, and we found that GDP was not binding at the taxoid, colchicine, or vinca sites. There may therefore be a lower affinity site on tubulin to which GDP can bind distinct from the E- and N-sites, possibly on alpha-tubulin, based on molecular modeling Studies. Published by Elsevier Inc. C1 [Wilcox, Elizabeth; Blokhin, Andrei V.; Hamel, Ernest] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [McGrath, Connor] NCI, Target Struct Based Drug Discovery Group, SAIC Frederick, Frederick, MD 21702 USA. [Gussio, Rick] NCI, Informat Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Hamel, E (reprint author), NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. EM hamele@mail.nih.gov FU National Cancer Institute [N01-CO-12400] FX The authors thank Dr. Dan Sackett for invaluable advice for the treatment of tubulin with subtilisin. This work was supported in part by National Cancer Institute contract number N01-CO-12400. NR 46 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD APR 1 PY 2009 VL 484 IS 1 BP 55 EP 62 DI 10.1016/j.abb.2008.12.022 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 429NP UT WOS:000264927700008 PM 19161972 ER PT J AU Bradford, PT Goldstein, AM McMaster, ML Tucker, MA AF Bradford, Porcia T. Goldstein, Alisa M. McMaster, Mary L. Tucker, Margaret A. TI Acral Lentiginous Melanoma Incidence and Survival Patterns in the United States, 1986-2005 SO ARCHIVES OF DERMATOLOGY LA English DT Article ID AMERICAN-JOINT-COMMITTEE; MALIGNANT-MELANOMA; CUTANEOUS MELANOMA; STAGING SYSTEM; PROGNOSIS; FEATURES; 21ST-CENTURY; POPULATION; VALIDATION; GENDER AB Objective: To examine incidence and survival patterns of acral lentiginous melanoma (ALM) in the United States. Design: Population-based registry study. Weused the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute to evaluate data from 17 population-based cancer registries from 1986 to 2005. Participants: A total 1413 subjects with histologically confirmed cases of ALM. Main Outcome Measure: Incidence and survival patterns of patients with ALM. Results: The age-adjusted incidence rate of ALM overall was 1.8 per million person-years. The proportion of ALMamong all melanoma subtypes was greatest in blacks (36%). Acral lentiginous melanoma had 5-and 10-year melanoma-specific survival rates of 80.3% and 67.5%, respectively, which were less than those for all cutaneous malignant melanomas overall (91.3% and 87.5%, respectively; P <.001). The ALM 5-and 10-year melanomaspecific survival rates were highest in non-Hispanic whites (82.6% and 69.4%), intermediate in blacks (77.2% and 71.5%), and lowest in Hispanic whites (72.8% and 57.3%) and Asian/Pacific Islanders (70.2% and 54.1%). Acral lentiginous melanoma thickness and stage correlated with survival according to sex and in the different racial groups. Conclusions: Population-based data showed that ALM is a rare melanoma subtype, although its proportion among all melanomas is higher in people of color. It is associated with a worse prognosis than cutaneous malignant melanoma overall. Hispanic whites and Asian/Pacific Islanders have worse survival rates than other groups, and factors such as increased tumor thickness and more advanced stage at presentation are the most likely explanations. C1 [Bradford, Porcia T.; Goldstein, Alisa M.; McMaster, Mary L.; Tucker, Margaret A.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Bradford, PT (reprint author), NCI, Genet Epidemiol Branch, DCEG, NIH, 6120 Execut Blvd,Room 7005, Rockville, MD 20852 USA. EM bradfordp@mail.nih.gov RI Tucker, Margaret/B-4297-2015 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Division of Cancer Epidemiology and Genetics FX Funding/Support: This study was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 38 TC 104 Z9 113 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD APR PY 2009 VL 145 IS 4 BP 427 EP 434 PG 8 WC Dermatology SC Dermatology GA 436JT UT WOS:000265411100007 PM 19380664 ER PT J AU Wendland, JR Moya, PR Timpano, KR Anavitarte, AP Kruse, MR Wheaton, MG Ren-Patterson, RF Murphy, DL AF Wendland, Jens R. Moya, Pablo R. Timpano, Kiara R. Anavitarte, Adriana P. Kruse, Matthew R. Wheaton, Michael G. Ren-Patterson, Renee F. Murphy, Dennis L. TI A Haplotype Containing Quantitative Trait Loci for SLC1A1 Gene Expression and Its Association With Obsessive-Compulsive Disorder SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID COMORBID TOURETTES-SYNDROME; OCD COLLABORATIVE GENETICS; TRANSPORTER GENE; TRANSGENIC MODEL; LINKAGE ANALYSIS; VARIANTS; SLC6A4; INDIVIDUALS; DIMENSIONS; FAMILIES AB Context: Recent evidence from linkage analyses and follow-up candidate gene studies supports the involvement of SLC1A1, which encodes the neuronal glutamate transporter, in the development of obsessive-compulsive disorder (OCD). Objectives: To determine the role of genetic variation of SLC1A1 in OCD in a large case-control study and to better understand how SLC1A1 variation affects functionality. Design: A case-control study. Setting: Publicly accessible SLC1A1 expression and genotype data. Patients: Three hundred twenty-five OCD probands and 662 ethnically and sex-matched controls. Interventions: Probands were assessed with the Structured Clinical Interview for DSM-IV, the Yale-Brown Obsessive Compulsive Scale, and the Saving Inventory Revised. Six single-nucleotide polymorphisms (SNPs) were genotyped. Multiple testing corrections for single-marker and haplotype analyses were performed by permutation. Results: Gene expression of SLC1A1 is heritable in lymphoblastoid cell lines. We identified 3 SNPs in or near SLC1A1 that correlated with gene expression levels, 1 of which had previously been associated with OCD. Two of these SNPs also predicted expression levels in human brain tissue, and 1 SNP was further functional in reporter gene studies. Two haplotypes at 3 SNPs, rs3087879, rs301430, and rs7858819, were significantly associated with OCD after multiple-testing correction and contained 2 SNPs associated with expression levels. In addition, another SNP correlating with SLC1A1 gene expression, rs3933331, was associated with an OCD-hoarding subphenotype as assessed by 2 independent, validated scales. Conclusions: Our case-control data corroborate previous smaller family-based studies that indicated that SLC1A1 is a susceptibility locus for OCD. The expression and genotype database-mining approach we used provides a potentially useful complementary approach to strengthen future candidate gene studies in neuropsychiatric and other disorders. C1 [Wendland, Jens R.; Moya, Pablo R.; Anavitarte, Adriana P.; Kruse, Matthew R.; Wheaton, Michael G.; Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Ren-Patterson, Renee F.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Timpano, Kiara R.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. RP Wendland, JR (reprint author), NHGRI, Med Genet Branch, NIH, 35 Convent Dr,Bldg 35,Porter Bldg,Room 1B209, Bethesda, MD 20892 USA. EM wendlandj@mail.nih.gov RI Wendland, Jens/A-1809-2012; Timpano, Kiara/C-8760-2012; OI Timpano, Kiara/0000-0002-0665-8722; Wheaton, Michael/0000-0002-7465-7879 FU Intramural Research Program of the National Institute of Mental Health, National Institutes of Health; NARSAD 2007 Young Investigator Award; National Institute of Mental Health Division of Intramural Research Programs Julius Axelrod Memorial Fellowship Training Award FX This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, and by a NARSAD 2007 Young Investigator Award and a National Institute of Mental Health Division of Intramural Research Programs Julius Axelrod Memorial Fellowship Training Award to Dr Wendland. NR 49 TC 63 Z9 66 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD APR PY 2009 VL 66 IS 4 BP 408 EP 416 PG 9 WC Psychiatry SC Psychiatry GA 429ML UT WOS:000264924400007 PM 19349310 ER PT J AU Hong, LE Gu, H Yang, Y Ross, TJ Salmeron, BJ Buchholz, B Thaker, GK Stein, EA AF Hong, L. Elliot Gu, Hong Yang, Yihong Ross, Thomas J. Salmeron, Betty Jo Buchholz, Brittany Thaker, Gunvant K. Stein, Elliot A. TI Association of Nicotine Addiction and Nicotine's Actions With Separate Cingulate Cortex Functional Circuits SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID HUMAN ANTERIOR CINGULATE; RESTING HUMAN BRAIN; RHESUS-MONKEY; DEFAULT MODE; SMOKING INITIATION; CEREBRAL-CORTEX; DRUG-ADDICTION; BLOOD-FLOW; CONNECTIVITY; DEPENDENCE AB Context: Understanding the mechanisms underlying nicotine addiction to develop more effective treatment is a public health priority. Research consistently shows that nicotine transiently improves multiple cognitive functions. However, using nicotine replacement to treat nicotine addiction yields generally inconsistent results. Although this dichotomy is well known, the reasons are unclear. Imaging studies showed that nicotine challenges almost always involve the cingulate cortex, suggesting that this locus may be a key region associated with nicotine addiction and its treatment. Objective: To identify cingulate functional circuits that are associated with the severity of nicotine addiction and study how nicotine affects them by means of region-specific resting-state functional magnetic resonance imaging. Design: Double-blind, placebo-controlled study. Setting: Outpatient clinics. Participants: Nineteen healthy smokers. Intervention: Single-dose (21- or 35-mg) nicotine patch. Main Outcome Measures: Correlation of nicotine addiction severity and cingulate resting-state functional connectivity, and effects of short-term nicotine administration on connectivity strength. Results: Clearly separated pathways that correlated with nicotine addiction vs nicotine's action were found. The severity of nicotine addiction was associated with the strength of dorsal anterior cingulate cortex (dACC) striatal circuits, which were not modified by nicotine patch administration. In contrast, short-term nicotine administration enhanced cingulate-neocortical functional connectivity patterns, which may play a role in nicotine's cognition-enhancing properties. Conclusions: Resting-state dACC-striatum functional connectivity may serve as a circuit-level biomarker for nicotine addiction, and the development of new therapeutic agents aiming to enhance the dACC-striatum functional pathways may be effective for nicotine addiction treatment. C1 [Hong, L. Elliot; Buchholz, Brittany; Thaker, Gunvant K.] Univ Maryland, Dept Psychiat, Maryland Psychiat Res Ctr, Sch Med, Baltimore, MD 21228 USA. [Gu, Hong; Yang, Yihong; Ross, Thomas J.; Salmeron, Betty Jo; Stein, Elliot A.] Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, Baltimore, MD USA. RP Hong, LE (reprint author), Univ Maryland, Dept Psychiat, Maryland Psychiat Res Ctr, Sch Med, POB 21247, Baltimore, MD 21228 USA. EM ehong@mprc.umaryland.edu RI Ross, Thomas/B-7469-2008; Salmeron, Betty Jo/M-1793-2016 OI Ross, Thomas/0000-0002-7745-3572; Salmeron, Betty Jo/0000-0003-1699-9333 FU National Institutes of Health [MH70644, 79172, 49826, 77852, 68580, N01-DA-5-9909]; National Institute on Drug Abuse Intramural Research Program; Neurophysiology Core of the University of Maryland General Clinical Research Center [M01-RR16500]; Maryland Cigarette Restitution Fund Program-Other Tobacco-Related Diseases Research FX This study was supported by National Institutes of Health grants MH70644, 79172, 49826, 77852, 68580, and N01-DA-5-9909; the National Institute on Drug Abuse Intramural Research Program; Neurophysiology Core of the University of Maryland General Clinical Research Center (M01-RR16500); and the Maryland Cigarette Restitution Fund Program-Other Tobacco-Related Diseases Research Grant. NR 62 TC 116 Z9 123 U1 0 U2 17 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD APR PY 2009 VL 66 IS 4 BP 431 EP 441 PG 11 WC Psychiatry SC Psychiatry GA 429ML UT WOS:000264924400010 PM 19349313 ER PT J AU Oh, U Blevins, G Griffith, C Richert, N Maric, D Lee, CR McFarland, H Jacobson, S AF Oh, Unsong Blevins, Gregg Griffith, Caitlin Richert, Nancy Maric, Dragan Lee, C. Richard McFarland, Henry Jacobson, Steven TI Regulatory T Cells Are Reduced During Anti-CD25 Antibody Treatment of Multiple Sclerosis SO ARCHIVES OF NEUROLOGY LA English DT Article ID HUMAN PERIPHERAL-BLOOD; X-LINKED SYNDROME; IMMUNE DYSREGULATION; SUPPRESSIVE FUNCTION; PROTEOLIPID PROTEIN; FOXP3 EXPRESSION; DACLIZUMAB; POLYENDOCRINOPATHY; PROLIFERATION; ENTEROPATHY AB Objective: Maintenance therapy with anti-CD25 antibody has emerged as a potentially useful treatment for multiple sclerosis (MS). Constitutive CD25 expression on CD4(+) CD25(+) regulatory T cells (T(reg)) suggests that anti-CD25 antibody treatment may potentially target a subset of T cells that exhibit immune suppressive properties. We examined changes to CD4(+) CD25(+) T(reg) in patients with MS receiving maintenance anti-CD25 monoclonal antibody treatment to determine the effect of treatment on T(reg) and, consequently, on immunological tolerance. Design: Peripheral blood and cerebrospinal fluid samples obtained from a before-and-after trial of anti-CD25 antibody monotherapy were examined to compare baseline and treatment differences in CD4(+) CD25(+) T(reg). Subjects: A total of 15 subjects with MS. One subject was withdrawn owing to an adverse effect. Results: Sustained reduction of the frequency of CD4(+) CD25(+) T(reg) was observed during treatment. Anti-CD25 antibody treatment led to evidence of impaired in vivo T(reg) proliferation and impaired ex vivo T(reg) suppression. Inflammatory MS activity was substantially reduced with treatment despite reduction of circulating T(reg), and there was no correlation between changes in the frequency of T(reg) and changes in brain inflammatory activity. However, new-onset inflammatory disease, notably dermatitis, was also observed in a number of subjects during treatment. Conclusion: The reduction in T(reg) did not negatively affect maintenance of central nervous system tolerance during anti-CD25 antibody treatment. The incidence of new-onset inflammatory disease outside of the central nervous system in a subset of patients, however, warrants further studies to examine the possibility of compartmental differences in the capacity to maintain tolerance in the setting of reduced CD4(+) CD25(+) T(reg). C1 [Oh, Unsong; Richert, Nancy; McFarland, Henry; Jacobson, Steven] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. [Maric, Dragan] NINDS, FACS Facil, NIH, Bethesda, MD 20892 USA. [Lee, C. Richard] NCI, Pathol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Blevins, Gregg] Univ Alberta Med & Dent, Edmonton, AB, Canada. [Griffith, Caitlin] Grove City Coll, Grove City, PA USA. RP Jacobson, S (reprint author), 10 Ctr Dr,Bldg 10,Room 5C103, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Neurological Disorders and Stroke. FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 38 TC 66 Z9 66 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD APR PY 2009 VL 66 IS 4 BP 471 EP 479 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 431ZX UT WOS:000265104400008 PM 19364932 ER PT J AU Bielekova, B Howard, T Packer, AN Richert, N Blevins, G Ohayon, J Waldmann, TA McFarland, HF Martin, R AF Bielekova, Bibiana Howard, Thomas Packer, Amy N. Richert, Nancy Blevins, Gregg Ohayon, Joan Waldmann, Thomas A. McFarland, Henry F. Martin, Roland TI Effect of Anti-CD25 Antibody Daclizumab in the Inhibition of Inflammation and Stabilization of Disease Progression in Multiple Sclerosis SO ARCHIVES OF NEUROLOGY LA English DT Article ID NATURAL-KILLER-CELLS; INTERFERON-BETA; THERAPY; BRAIN; NK AB Background: Several questions arise concerning the use of the anti-CD25 antibody daclizumab to treat multiple sclerosis (MS). Objectives: To answer the following 3 questions related to the efficacy of daclizumab therapy in patients with MS: Is the therapeutic effect of daclizumab dependent on combination with interferon beta? Is a higher dosage of daclizumab more efficacious in patients with persistent disease activity? Can biomarkers predict full vs partial therapeutic response to daclizumab? Design: An open-label baseline vs treatment phase II clinical trial of daclizumab in patients having MS with inadequate response to interferon beta. Three months of interferon beta treatment at baseline were followed by 5.5 months of interferon beta-daclizumab combination therapy. If patients experienced more than 75% reduction of contrast-enhancing lesions (CELs) on brain magnetic resonance imaging at month 5.5 compared with baseline, daclizumab was continued as monotherapy for 10 months. Otherwise, the dosage of daclizumab was doubled. Setting: Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. Patients: Fifteen patients with MS receiving standard preparations of interferon beta who experienced more than 1 MS exacerbation or whose clinical disability increased in the preceding 12 months and who had at least 2 CELs on baseline brain magnetic resonance images. Intervention: Daclizumab ( 1 mg/kg) as an intravenous infusion every 4 weeks in combination with interferon beta ( months 0-5.5) and as monotherapy ( months 6.5-15.5). Main Outcome Measures: The primary outcome was the reduction of CELs among interferon beta monotherapy, interferon beta-daclizumab combination therapy, and daclizumab monotherapy. The secondary outcomes included immunologic biomarkers and changes in clinical disability. Results: Overall, 5 of 15 patients (33%) experienced adverse effects of therapy. Two patients developed systemic adverse effects, and daclizumab therapy was discontinued. Although daclizumab monotherapy was efficacious in 9 of 13 patients with MS, interferon beta-daclizumab combination therapy was necessary to stabilize disease activity in the other 4 patients. Daclizumab therapy led to 72% inhibition of new CELs and significant improvement in clinical disability. Pilot biomarkers ( increase in CD56(bright) natural killer cells and decrease in CD8(+) T cells) were identified that can differentiate between full and partial daclizumab responders. Conclusions: Daclizumab monotherapy is effective in most patients who experienced persistent MS disease activity with interferon beta therapy. Interferon beta-daclizumab combination therapy or higher dosages of daclizumab may be necessary to achieve optimal therapeutic response in all patients. Biomarkers may identify patients with suboptimal response to daclizumab monotherapy. Administration among a large patient sample during a longer period is needed to fully define the safety and long-term efficacy of daclizumab as treatment for high-inflammatory MS. C1 [Bielekova, Bibiana; Howard, Thomas; Packer, Amy N.; Richert, Nancy; Blevins, Gregg; Ohayon, Joan; McFarland, Henry F.] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Waldmann, Thomas A.] NCI, Metab Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Blevins, Gregg] Univ Alberta, Div Neurol, Edmonton, AB, Canada. [Martin, Roland] Univ Clin Eppendorf, Inst Neuroimmunol & Clin Multiple Sclerosis Res, Ctr Mol Neurobiol Hamburg, Hamburg, Germany. RP Bielekova, B (reprint author), Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Natl Inst Hlth, Bldg 10,Room 5C103,10 Ctr Dr,MSC 1400, Bethesda, MD 20892 USA. EM Bibi.Bielekova@nih.gov FU Research Program of the National Institute of Neurological Disorders and Stroke; National Institutes of Health FX Drs Bielekova, Waldmann, McFarland, and Martin are coinventors on National Institutes of Health patents related to the use of daclizumab in MS and as such received royalty payments. Funding/ Support: This study was supported by the tramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 17 TC 116 Z9 118 U1 2 U2 9 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD APR PY 2009 VL 66 IS 4 BP 483 EP 489 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 431ZX UT WOS:000265104400009 PM 19364933 ER PT J AU Yeh, S Li, Z Forooghian, F Hwang, FS Cunningham, MA Pantanelli, S Lew, JC Wroblewski, KK Vitale, S Nussenblatt, RB AF Yeh, Steven Li, Zhuqing Forooghian, Farzin Hwang, Frank S. Cunningham, Matthew A. Pantanelli, Seth Lew, Julie C. Wroblewski, Keith K. Vitale, Susan Nussenblatt, Robert B. TI CD4(+)Foxp3(+) T-Regulatory Cells in Noninfectious Uveitis SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; RHEUMATOID-ARTHRITIS; MULTIPLE-SCLEROSIS; PERIPHERAL-BLOOD; SYNOVIAL-FLUID; ACTIVE UVEITIS; IN-VIVO; FOXP3; EXPRESSION; DISEASE AB Objective: To evaluate CD4(+)Foxp3(+) (forkhead box P3) T-regulatory cell populations in patients with uveitis and to determine if T-regulatory cell populations are associated with disease features. Methods: Patients with uveitis were evaluated for CD4(+)Foxp3(+) T-regulatory cells by flow cytometry. Systemic and ocular diagnoses, disease activity, and the presence of cystoid macular edema were reviewed. Percentages of CD4(+)Foxp3(+) lymphocytes were compared for patients with inactive vs active disease, systemic vs ocular diagnoses, and the presence or absence of cystoid macular edema. Real-time polymerase chain reaction testing was performed on 2 patients with extremely low CD4(+)Foxp3(+) cell populations to assess Foxp3 mRNA. Results: A total of 20 patients with intermediate uveitis, posterior uveitis, and panuveitis were evaluated. The mean age was 40.6 years and the mean visual acuity was 20/57. Percentages of CD4(+)Foxp3(+) cells were lower in patients with active compared with inactive uveitis (P <.05). No differences in T-regulatory cells were observed between the other subgroups. Two patients with recalcitrant uveitis who demonstrated less than 1% CD4(+)Foxp3(+) lymphocytes showed extremely low or absent Foxp3 mRNA. Conclusion: T-regulatory cells are reduced in patients with active compared with inactive disease. Severe depletion of CD4(+)Foxp3(+) T cells and Foxp3 mRNA in 2 patients with severe uveitis suggests that loss of the T-regulatory cells of uveitis may be a salient feature in certain patients. C1 [Yeh, Steven; Li, Zhuqing; Forooghian, Farzin; Hwang, Frank S.; Cunningham, Matthew A.; Pantanelli, Seth; Lew, Julie C.; Wroblewski, Keith K.; Nussenblatt, Robert B.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Forooghian, Farzin; Vitale, Susan] NEI, Dept Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Wroblewski, Keith K.] Walter Reed Army Med Ctr, Dept Ophthalmol, Washington, DC 20307 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,10N-112, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov FU Intramural Research Program of the National Eye Institute; National Institutes of Health; Heed Ophthalmic Foundation FX This study was supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health, and the Heed Ophthalmic Foundation (Dr Yeh). NR 33 TC 25 Z9 27 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD APR PY 2009 VL 127 IS 4 BP 407 EP 413 PG 7 WC Ophthalmology SC Ophthalmology GA 431ZN UT WOS:000265103400007 PM 19365016 ER PT J AU Jaffe, CC AF Jaffe, C. Carl TI Pathology and Imaging in Biomarker Development SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article; Proceedings Paper CT College-of-American-Pathologists Futurescape of Pathology Conference CY JUN 07-08, 2008 CL Rosemont, IL SP Coll Amer Pathologists C1 NCI, Canc Imaging Program, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Jaffe, CC (reprint author), NCI, Canc Imaging Program, Natl Inst Hlth, 6130 Exec Blvd EPN,Exec Plz N 3007, Bethesda, MD 20892 USA. EM jaffec1@mail.nih.gov NR 0 TC 4 Z9 4 U1 0 U2 0 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD APR PY 2009 VL 133 IS 4 BP 547 EP 549 PG 3 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 429NB UT WOS:000264926300014 PM 19391648 ER PT J AU Jiang, Y Wang, YL Kuang, Y Wang, BN Li, WY Gong, TX Jiang, ZH Yang, D Li, MY AF Jiang, Yan Wang, Yueling Kuang, Yu Wang, Baoning Li, Wanyi Gong, Tianxiang Jiang, Zhonghua Yang, De Li, Mingyuan TI Expression of mouse beta-defensin-3 in MDCK cells and its anti-influenza-virus activity SO ARCHIVES OF VIROLOGY LA English DT Article ID BETA-DEFENSINS; H5N1 INFECTION; MODEL; PATHOGENESIS; PEPTIDES; MICE AB Influenza (flu) pandemics have presented a threat to human health in the past century. Because of outbreaks of avian flu in humans in some developing countries in recent years, humans are more eager to find a way to control flu. Mammalian beta-defensins (beta-defensins) are associated primarily with mucosal and skin innate immunity. Previous studies have demonstrated antimicrobial properties of a variety of defensin peptides. We have identified the presence of mouse beta-defensin 1, 2, and 3 genes (Mbd-1, 2, and 3) in trachea and lung tissues by RT-PCR before and after infection with influenza virus. We constructed a eukaryotic expression plasmid containing Mbd-3, pcDNA 3.1(+)/MBD-3, and the plasmid was introduced into Madin-Darby canine kidney (MDCK) cells by transfection. The expression of Mbd-3 in MDCK cells was verified by immunofluorescence test, RT-PCR, and Western blot. The pcDNA 3.1(+)/MBD-3 plasmid was injected into mice to observe its effect against influenza A virus (IAV) in vivo. Mouse beta-defensin genes could be expressed in trachea and lung tissues before IAV infection, but expression of Mbd-2 and Mbd-3 was increased significantly after IAV infection. The survival rate of mice with MBD-3 against IAV challenge was 71.43%, and MDCK cells with MBD-3 could clearly inhibit IAV replication. The results demonstrated that mouse beta-defensins possess anti-influenza virus activity, suggesting that mouse beta-defensins might be used as agents to prevent and treat influenza. C1 [Jiang, Yan; Wang, Yueling; Kuang, Yu; Wang, Baoning; Li, Wanyi; Gong, Tianxiang; Jiang, Zhonghua; Li, Mingyuan] Sichuan Univ, W China Sch Preclin & Forens Med, Dept Microbiol, Chengdu 610041, Peoples R China. [Yang, De] NCI, Frederick Canc Res & Dev Ctr, Basic Res Program, SAIC Frederick & Lab Mol Immunoregulat,NIH, Frederick, MD 21702 USA. [Li, Mingyuan] Sichuan Univ, State Key Lab Oral Dis, Chengdu 610041, Sichuan, Peoples R China. RP Li, MY (reprint author), Sichuan Univ, W China Sch Preclin & Forens Med, Dept Microbiol, Chengdu 610041, Peoples R China. EM zxllmyus@yahoo.com FU Natural Science Foundation of China [30671964] FX This work was supported by grant 30671964 from Natural Science Foundation of China. We thank Dr. Min Wu for helpful discussion of this work and revising the manuscript. NR 26 TC 13 Z9 17 U1 1 U2 8 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PD APR PY 2009 VL 154 IS 4 BP 639 EP 647 DI 10.1007/s00705-009-0352-6 PG 9 WC Virology SC Virology GA 428SY UT WOS:000264871500012 PM 19301094 ER PT J AU Scharner, D Rossig, L Carmona, G Chavakis, E Urbich, C Fischer, A Kang, TB Wallach, D Chiang, YJ Deribe, YL Dikic, I Zeiher, AM Dimmeler, S AF Scharner, Doerte Roessig, Lothar Carmona, Guillaume Chavakis, Emmanouil Urbich, Carmen Fischer, Ariane Kang, Tae-Bong Wallach, David Chiang, Yungping Jeffrey Deribe, Yonathan Lissanu Dikic, Ivan Zeiher, Andreas M. Dimmeler, Stefanie TI Caspase-8 Is Involved in Neovascularization-Promoting Progenitor Cell Functions SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE progenitor cells; homing; integrin; angiogenesis; cell therapy ID ACUTE MYOCARDIAL-INFARCTION; ENDOTHELIAL-CELLS; LYMPHOCYTE-ACTIVATION; DIFFERENTIATION; TRANSPLANTATION; APOPTOSIS; DEATH; PROLIFERATION; ANGIOGENESIS; RECRUITMENT AB Objective-Endothelial progenitor cells (EPCs) comprise a heterogeneous population of cells, which improve therapeutic neovascularization after ischemia. The neovascularization-promoting potential of progenitor cells depends on survival and retention of the infused cells to the tissue. Caspases mediate apoptosis but are also involved in other critical biological processes. Therefore, we aimed to address the role of caspases in proangiogenic cells. Methods and Results-The caspase-8 inhibitor zIETD abrogated the ex vivo formation of EPCs, inhibited EPC adhesion and migration, and reduced their capacity to improve neovascularization in vivo. Consistently, cells isolated from caspase-8-deficient mice exhibited a reduced capacity for enhancing neovascularization when transplanted into mice after hindlimb ischemia. Because inhibition of Caspase-8 reduced the adhesion and homing functions of EPCs, we further determined the surface expression of integrins and receptors involved in cell recruitment to ischemic tissues. Pharmacological inhibition of caspase-8 and genetic depletion of caspase-8 reduced the expression of the fibronectin receptor subunits alpha 5 and beta 1 and the SDF-1 receptor CXCR4. Moreover, we identified the E3 ubiquitin ligase Cbl-b, which negatively regulates integrin and receptor-mediated signaling, as a potential Caspase-8 substrate. Conclusion-In summary, our data demonstrate a novel apoptosis-unrelated role of caspase-8 in proangiogenic cells. (Arterioscler Thromb Vasc Biol. 2009; 29: 571-578.) C1 [Scharner, Doerte; Roessig, Lothar; Carmona, Guillaume; Chavakis, Emmanouil; Urbich, Carmen; Fischer, Ariane; Zeiher, Andreas M.; Dimmeler, Stefanie] Goethe Univ Frankfurt, Dept Internal Med 3, D-60590 Frankfurt, Germany. [Kang, Tae-Bong; Wallach, David] Weizmann Inst Sci, IL-76100 Rehovot, Israel. [Chiang, Yungping Jeffrey] NCI, NIH, Bethesda, MD 20892 USA. RP Dimmeler, S (reprint author), Goethe Univ Frankfurt, Dept Internal Med 3, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. EM dimmeler@em.uni-frankfurt.de RI Dikic, Ivan/O-4650-2015 OI Dikic, Ivan/0000-0001-8156-9511 FU Deutsche Forschungsgemeinschaft FX This work was supported by the Deutsche Forschungsgemeinschaft (TR-SFB project B2 to S. D. and E. C. and project B5 to C. U.). NR 48 TC 14 Z9 15 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD APR PY 2009 VL 29 IS 4 BP 571 EP U268 DI 10.1161/ATVBAHA.108.182006 PG 16 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 421EQ UT WOS:000264342600023 PM 19122169 ER PT J AU Ball, R Shadomy, SV Meyer, A Huber, BT Leffell, MS Zachary, A Belotto, M Hilton, E Bryant-Genevier, M Schriefer, ME Miller, FW Braun, MM AF Ball, Robert Shadomy, Sean V. Meyer, Abbie Huber, Brigitte T. Leffell, Mary S. Zachary, Andrea Belotto, Michael Hilton, Eileen Bryant-Genevier, Marthe Schriefer, Martin E. Miller, Frederick W. Braun, M. Miles TI HLA Type and Immune Response to Borrelia burgdorferi Outer Surface Protein A in People in Whom Arthritis Developed After Lyme Disease Vaccination SO ARTHRITIS AND RHEUMATISM LA English DT Article ID T-CELL EPITOPE; ASSOCIATION; THERAPY; MIMICRY; HLA-DR4 AB Objective. To investigate whether persons with treatment-resistant Lyme arthritis-associated HLA alleles might develop arthritis as a result of an autoimmune reaction triggered by Borrelia burgdorferi outer surface protein A (OspA), the Lyme disease vaccine antigen. Methods. Persons in whom inflammatory arthritis had developed after Lyme disease vaccine (cases) were compared with 3 control groups: 1) inflammatory arthritis but not Lyme disease vaccine (arthritis controls), 2) Lyme disease vaccine but not inflammatory arthritis (vaccine controls), and 3) neither Lyme disease vaccine nor inflammatory arthritis (normal controls). HLA-DRB1 allele typing, Western blotting for Lyme antigen, and T cell reactivity testing were performed. Results. Twenty-seven cases were matched with 1.62 controls (54 in each control group). Odds ratios (ORs) for the presence of 1. or 2 treatment-resistant Lyme arthritis alleles were 0.8 (95% confidence interval [95% CI] 10.3-2.1), 1.6 (95% CI 0.5-4.4), and 1.75 (95% CI 0.6-5.3) in cases versus arthritis controls, vaccine controls, and normal controls, respectively. There were no significant differences in the frequency of DRB1 alleles. T cell response to OspA was similar between cases and vaccine controls, as measured using the stimulation index (OR 1.6 [95% CI 0.5-5.1]) or change in uptake of tritiated thymidine (counts per minute) (OR 0.7 [95% CI 0.2-2.3]), but cases were less likely to have IgG antibodies to OspA (OR 0.3 [95% CI 0.1-0.8]). Cases were sampled closer to the time of vaccination (median 3.59 years versus 5.48 years), and fewer cases had received 3 doses of vaccine (37% versus 93%). Conclusion. Treatment-resistant Lyme arthritis alleles were not found more commonly in persons who developed arthritis after Lyme disease vaccination, and immune responses to OspA were not significantly more common in arthritis cases. These results suggest that Lyme disease vaccine is not a major factor in the development of arthritis in these cases. C1 [Ball, Robert; Shadomy, Sean V.; Bryant-Genevier, Marthe; Braun, M. Miles] US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. [Meyer, Abbie; Huber, Brigitte T.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Leffell, Mary S.; Zachary, Andrea] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Belotto, Michael; Hilton, Eileen] Biomed Res Alliance New York, Great Neck, NY USA. [Schriefer, Martin E.] Ctr Dis Control & Prevent, Ft Collins, CO USA. [Miller, Frederick W.] Natl Inst Environm Hlth Sci, NIH, Bethesda, MD USA. RP Ball, R (reprint author), 1401 Rockville Pike,I HFM-222, Rockville, MD 20852 USA. EM Robert.Ball@fda.hhs.gov OI Miller, Frederick/0000-0003-2831-9593 FU US Department of Health; Human Services National Vaccine Program Office; National Institute of Environmental Health Sciences, NIH FX Supported by the US Department of Health and Human Services National Vaccine Program Office, the international program of the National Institute of Environmental Health Sciences, NIH, and the FDA. Dr. Shadomy is recipient of a fellowship from the US Department of Health and Human Services National Vaccine Program Office. NR 29 TC 19 Z9 19 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD APR PY 2009 VL 60 IS 4 BP 1179 EP 1186 DI 10.1002/art.24418 PG 8 WC Rheumatology SC Rheumatology GA 432RW UT WOS:000265152800033 PM 19333928 ER PT J AU Shukla, SJ Nguyen, DT MacArthur, R Simeonov, A Frazee, WJ Hallis, TM Marks, BD Singh, U Eliason, HC Printen, J Austin, CP Inglese, J Auld, DS AF Shukla, Sunita J. Nguyen, Dac-Trung MacArthur, Ryan Simeonov, Anton Frazee, William J. Hallis, Tina M. Marks, Bryan D. Singh, Upinder Eliason, Hildegard C. Printen, John Austin, Christopher P. Inglese, James Auld, Douglas S. TI Identification of Pregnane X Receptor Ligands Using Time-Resolved Fluorescence Resonance Energy Transfer and Quantitative High-Throughput Screening SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Article ID CONSTITUTIVE ANDROSTANE RECEPTOR; ORPHAN NUCLEAR RECEPTOR; DRUG-INTERACTIONS; STATISTICAL PARAMETER; PRIMARY CULTURES; ASSAYS; METABOLISM; PXR; CAR; INDUCTION AB The human pregnane X nuclear receptor (PXR) is a xenobiotic-regulated receptor that is activated by a range of diverse chemicals, including antibiotics, antifungals, glucocorticoids, and herbal extracts. PXR has been characterized as an important receptor in the metabolism of xenobiotics due to induction of cytochrome P450 isozymes and activation by a large number of prescribed medications. Developing methodologies that can efficiently detect PXR ligands will be clinically beneficial to avoid potential drug-drug interactions. To facilitate the identification of PXR ligands, a time-resolved fluorescence resonance energy transfer (TR-FRET) assay was miniaturized to a 1,536-well microtiter plate format to employ quantitative high-throughput screening (qHTS). The optimized 1,536-well TR-FRET assay showed Z'-factors of >= 0.5. Seven- to 15-point concentration-response curves (CRCs) were generated for 8,280 compounds using both terbium and fluorescein emission data, resulting in the generation of 241,664 data points. The qHTS method allowed us to retrospectively examine single concentration screening datasets to assess the sensitivity and selectivity of the PXR assay at different compound screening concentrations. Furthermore, nonspecific assay artifacts such as concentration-based quenching of the terbium signal and compound fluorescence were identified through the examination of CRCs for specific emission channels. The CRC information was also used to define chemotypes associated with PXR ligands. This study demonstrates the feasibility of profiling thousands of compounds against PXR using the TR-FRET assay in a high-throughput format. C1 [Shukla, Sunita J.; Nguyen, Dac-Trung; MacArthur, Ryan; Simeonov, Anton; Austin, Christopher P.; Inglese, James; Auld, Douglas S.] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Frazee, William J.; Hallis, Tina M.; Marks, Bryan D.; Singh, Upinder; Eliason, Hildegard C.; Printen, John] Invitrogen Discovery Assays & Serv, Madison, WI USA. RP Auld, DS (reprint author), NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. EM dauld@mail.nih.gov OI Nguyen, Dac-Trung/0000-0003-2591-9948 FU NIH; National Human Genome Research Institute FX This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The authors wish to acknowledge Paul Shinn and Adam Yasgar for compound management, Ajit Jadhav for informatics support, Richard Jones for instrument set up and support, Jeremy Smith and William Leister for quality control measurements of compounds, and Cynthia Wadsworth and Kaitie VanDenHeuvel-Kramer for excellent assay, product, and technical support. NR 42 TC 30 Z9 33 U1 0 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD APR PY 2009 VL 7 IS 2 BP 143 EP 169 DI 10.1089/adt.2009.193 PG 27 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 458KR UT WOS:000267018700004 PM 19505231 ER PT J AU Blum, A Shamburek, R AF Blum, A. Shamburek, R. TI The pleiotropic effects of statins on endothelial function, vascular inflammation, immunomodulation and thrombogenesis SO ATHEROSCLEROSIS LA English DT Review DE Endothelial function; Inflammation; Stein cells and statins ID COA REDUCTASE INHIBITORS; CORONARY-ARTERY DISEASE; PRIMARY PREVENTION; THERAPY; ATORVASTATIN; PRAVASTATIN; METAANALYSIS; RESTENOSIS; TRIALS; PLAQUE AB Statins have been demonstrated to significantly affect the prognosis and outcome of patients with risk factors to atherosclerosis (in primary and secondary prevention trials). Several clinical and recently basic studies have suggested an extra-beneficial effect of the statins in the prevention of atherosclerosis and coronary artery disease. These Studies showed that statins may affect the cardiovascular system beyond their effect on the lipid profile, and it was suggested that they affect the immunological system and vascular inflammation. Many of the beneficial pleiotropic effects of statins occur as a result of modulated endothelial function and reduced inflammatory processes. Attempting to understand these properties of statins is an exciting field of research that will also improve our understanding of vascular biology in health and disease, and thus enable the better use of this drug class in clinical practice. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Blum, A.] Technion Israel Inst Technol, Dept Med, Fac Med, Baruch Padeh Poria Med Ctr, IL-15208 Lower Galilee, Israel. [Shamburek, R.] NHLBI, Translat Branch, NIH, Bethesda, MD 20892 USA. RP Blum, A (reprint author), Technion Israel Inst Technol, Dept Med, Fac Med, Baruch Padeh Poria Med Ctr, IL-15208 Lower Galilee, Israel. EM navablum@hotmail.com NR 24 TC 134 Z9 151 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD APR PY 2009 VL 203 IS 2 BP 325 EP 330 DI 10.1016/j.atherosclerosis.2008.08.022 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 437CW UT WOS:000265464800001 PM 18834985 ER PT J AU Murabito, JM Keyes, MJ Guo, CY Keaney, JF Vasan, RS D'Agostino, RB Benjamin, EJ AF Murabito, Joanne M. Keyes, Michelle J. Guo, Chao-Yu Keaney, John F., Jr. Vasan, Ramachandran S. D'Agostino, Ralph B., Sr. Benjamin, Emelia J. TI Cross-sectional relations of multiple inflammatory biomarkers to peripheral arterial disease: The Framingham Offspring Study SO ATHEROSCLEROSIS LA English DT Article DE Peripheral arterial disease; Ankle-brachial index; Interleukin-6; Tumor necrosis factor receptor 2 ID C-REACTIVE-PROTEIN; NECROSIS-FACTOR-ALPHA; ANKLE-BRACHIAL INDEX; EDINBURGH ARTERY; RISK-FACTORS; CARDIOVASCULAR EVENTS; ADHESION MOLECULES; HEMOSTATIC FACTORS; INCIDENT CORONARY; RECEPTOR-II AB Background: Emerging evidence suggests that different inflammatory biomarkers operate through distinct biologic mechanisms. We hypothesized that the relation to peripheral arterial disease (PAD) varies for individual markers. Methods: In a community-based sample we measured 12 biomarkers including plasma CD40 ligand, fibrinogen, lipoprotein-associated phospholipase-A2 mass and activity, osteoprotegerin, P-selectin, and tumor necrosis factor receptor 2 (TNFR2); and serum C-reactive protein, intracellular adhesion molecule-1, interleukin-6, monocyte chemoattractant protein-1, and myeloperoxidase in Framingham Offspring Study participants (n = 2800, 53% women, mean age 61 years). We examined the cross-sectional relation of the biomarker panel to PAD using (I) a global test of significance to determine whether at least one of 12 biomarkers was related to PAD using the TEST statement in the LOGISTIC procedure in SAS and (2) stepwise multivariable logistic regression with forward selection of markers with separate models for (1) ankle-brachial index (ABI) category (<0.9, 0.9-1.0, >1.0) and (2) presence of clinical PAD (intermittent claudication or lower extremity revascularization). Results: The group of inflammatory biomarkers were significantly related to both ABI and clinical PAD (p = 0.01 and p = 0.02, respectively, multi-marker adjusted global significance test). Multivariable forward elimination regression retained interleukin-6 and TNFR2 as significantly associated with PAD. For one standard deviation change in interleukin-6 and TNFR2 concentrations, there was a 1.21 (p = 0.005) and 1.19 (in = 0.009) increased odds of a change in ABI level respectively. Similar results were observed for clinical PAD. Conclusion: Interleukin-6 and TNFR2 were significantly associated with PAD independent of established risk factors and each other, suggesting that each marker represents a distinct biologic pathway. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Murabito, Joanne M.; Keyes, Michelle J.; Vasan, Ramachandran S.; D'Agostino, Ralph B., Sr.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Cardiol, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. [Keyes, Michelle J.; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Stat & Consulting Unit, Boston, MA 02118 USA. [Guo, Chao-Yu] Childrens Hosp, Boston, MA 02115 USA. [Guo, Chao-Yu] Harvard Univ, Sch Med, Boston, MA USA. [Keaney, John F., Jr.] Univ Massachusetts, Sch Med, Worcester, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Epidemiol Sect, Boston, MA USA. RP Murabito, JM (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM murabito@bu.edu OI Murabito, Joanne/0000-0002-0192-7516; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NIH/NHLBI [N01-HC-25195]; NIH [RO1 HL064753, HL076784, AG028321] FX The Framingham Heart Study is supported by NIH/NHLBI contract N01-HC-25195. Additional funding for this work supported by NIH grants RO1 HL064753, HL076784, AG028321 (EJ.B.): HL 080124, HL 077477, HL71039, K24 HL 4334 (R.S.V.); tumor necrosis factor-alpha concentrations measured via American Diabetes Association Career Development Award and NCRR GCRC M01-RR-01066 James B. Meigs, MD, MPH. Lipoprotein-associated phospholipase-A2 Lp-PLA2 activity measurements were provided by GlaxoSmithKline at no cost to the FHS. NR 34 TC 36 Z9 37 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD APR PY 2009 VL 203 IS 2 BP 509 EP 514 DI 10.1016/j.atherosclerosis.2008.06.031 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 437CW UT WOS:000265464800028 PM 18701106 ER PT J AU Zuliani, G Volpato, S Galvani, M Ble, A Bandinelli, S Corsi, AM Lauretani, F Maggio, M Guralnik, JM Fellin, R Ferrucci, L AF Zuliani, Giovanni Volpato, Stefano Galvani, Matteo Ble, Alessandro Bandinelli, Stefania Corsi, Anna Maria Lauretani, Fulvio Maggio, Marcello Guralnik, Jack M. Fellin, Renato Ferrucci, Luigi TI Elevated C-reactive protein levels and metabolic syndrome in the elderly: The role of central obesity Data from the InChianti study SO ATHEROSCLEROSIS LA English DT Article DE Metabolic syndrome; C-reactive protein; Systemic inflammation; Waist circumference; Elderly ID ADIPOSE-TISSUE ACCUMULATION; CARDIOVASCULAR RISK-FACTORS; INNATE IMMUNE-SYSTEM; INSULIN-RESISTANCE; ANTHROPOMETRIC MEASUREMENTS; WAIST CIRCUMFERENCE; DISEASE; INFLAMMATION; ASSOCIATION; AGE AB Metabolic syndrome (MS) and "low grade" systemic inflammation (LGSI) are very common findings in the older population. Although MS and LGSI have been associated in adults, it is not known what is the real contribution of MS, and its single components, to LGSI in older persons, due to the potential confounding effect of comorbidity and aging. We investigated the relationship between increased C-reactive protein (CRP) plasma levels, a marker of LGSI, and MS in 1044 older (>= 65 years) community dwelling Italian individuals enrolled the InChianti study. Metabolic syndrome was defined by the NCEP-ATP III-AHA/NHLBI criteria. High sensitivity CRP (hs.CRP) levels were measured by enzyme-linked immunosorbent assay, and defined as high when >3 mg/L. The overall prevalence of MS was 31%. The prevalence of high hs.CRP was 54.5% in subjects with, and 41.3% in those without MS (p < 0.001). MS was associated with high hs.CRP levels after adjustment for age, gender, and comorbidity (OR: 1.93, 95% CI: 1.46-2.55). Compared to subjects with MS and no LGSI, individuals with MS and LGSI were characterized by higher waist circumference, BMI, and HOMA score. Multivariate logistic regression analysis confirmed the association between waist circumference and high hs.CRP levels in subjects with MS (waist circumference III vs. I tertile OR: 2.60, 95% CI: 1.79-3.77) independent of age, gender, and important confounding variables including comorbidity. Additional analyses, conducted with and without dichotomization of hs.CRP levels, confirmed the central role of waist circumference in the LGSI phenomenon, independent of gender and diagnosis of MS. We conclude that in older individuals, MS is associated with LGSI, but the association is mainly supported by a strong independent correlation between waist circumference and high hs.CRP levels. In the absence of this specific MS component, it seems that the contribution of MS to LGSI would be modest at best. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Zuliani, Giovanni; Volpato, Stefano; Galvani, Matteo; Fellin, Renato] Univ Ferrara, Sect Internal Med Gerontol & Geriatr, Dept Clin & Expt Med, I-44100 Ferrara, Italy. [Bandinelli, Stefania; Ferrucci, Luigi] ASF Geriatr Rehabil, Florence, Italy. [Corsi, Anna Maria; Lauretani, Fulvio] IOT, Tuscany Reg Hlth Agcy, Ferrara, Italy. [Corsi, Anna Maria] Univ Florence, Dept Med & Surg Crit Care, Ctr Study Mol Level Chron Degenerat & Neoplast Di, I-50121 Florence, Italy. [Maggio, Marcello] Univ Parma, Sect Geriatr, Dept Internal Med & Biomed Sci, I-43100 Parma, Italy. [Ble, Alessandro; Guralnik, Jack M.; Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. RP Zuliani, G (reprint author), Univ Ferrara, Sect Internal Med Gerontol & Geriatr, Dept Clin & Expt Med, Via Savonarola 9, I-44100 Ferrara, Italy. EM gzuliani@hotmail.com RI VOLPATO, STEFANO/H-2977-2014; Lauretani, Fulvio/K-5115-2016 OI VOLPATO, STEFANO/0000-0003-4335-6034; Zuliani, Giovanni/0000-0003-0969-3184; Lauretani, Fulvio/0000-0002-5287-9972 FU NIA NIH HHS [N01 AG050002, N01 AG916413, Z01 AG000015-50] NR 45 TC 29 Z9 33 U1 2 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD APR PY 2009 VL 203 IS 2 BP 626 EP 632 DI 10.1016/j.atherosclerosis.2008.07.038 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 437CW UT WOS:000265464800048 PM 18845301 ER PT J AU Berry, CA Hoffler, GW Jernigan, CA Kerwin, JP Mohler, SR AF Berry, Charles A. Hoffler, G. Wyckliffe Jernigan, Clarence A. Kerwin, Joseph P. Mohler, Stanley R. TI History of Space Medicine: The Formative Years at NASA SO AVIATION SPACE AND ENVIRONMENTAL MEDICINE LA English DT Article DE spaceflight; history AB Almost nothing was known about the effects of spaceflight on human physiology when, in May of 1961, President John F. Kennedy committed the United States to land a man on the Moon and return him safely to Earth within the decade. There were more questions than answers regarding the effects of acceleration, vibration, cabin pressure, CO(2) Concentration, and microgravity. There were known external threats to life, Such as solar and ultraviolet radiation, meteorites, and extreme temperatures as well as issues for which the physicians and scientists could not even formulate the questions. And there was no time for controlled experiments with the required numbers of animal or human subjects. Of necessity, risks were evaluated and mitigated or accepted based on minimal data. This article Summarizes presentations originally giver) as a panel at the 79(th) Annual Scientific Meeting of the Aerospace Medical Association in Boston in 2008. In it, five pioneers in space medicine at NASA looked back on the development of their field. The authors related personal anecdotes, discussed the roles of various people and presented examples of contributions to emerging U.S. initiatives for human spaceflight. Topics included the development of quarantine facilities for returning Apollo astronauts, the struggles between operational medicine and research personnel, and observations from the first U.S. medical officer to experience weightlessness on orbit. Brief biographies of the authors are appended to document their participation in these historic events. C1 [Berry, Charles A.] UTMB, Galveston, TX USA. [Berry, Charles A.; Kerwin, Joseph P.] Lyndon B Johnson Space Ctr, Houston, TX USA. [Berry, Charles A.] NASA Headquarters, Washington, DC USA. [Hoffler, G. Wyckliffe] Virginia Commonwealth Univ Med Coll Virginia, Richmond, VA USA. [Hoffler, G. Wyckliffe] Med Coll Georgia, Augusta, GA 30912 USA. [Hoffler, G. Wyckliffe] Ohio State Univ, Columbus, OH 43210 USA. [Hoffler, G. Wyckliffe; Jernigan, Clarence A.] NASA, Manned Spacecraft Ctr, Washington, DC USA. [Jernigan, Clarence A.] Galveston Cty Community Hlth Serv, Galveston Cty, TX USA. [Mohler, Stanley R.] NIH, Ctr Aging Res, Bethesda, MD 20892 USA. [Mohler, Stanley R.] FAA Headquarters, Civil Aviat Med Res Inst, Washington, DC USA. [Mohler, Stanley R.] FAA Headquarters, Aeromed Applicat Div, Washington, DC USA. [Mohler, Stanley R.] Wright State Univ, Aerosp Med Residency Program, Dayton, OH 45435 USA. FU Space Medicine Association FX This panel was sponsored by the Space Medicine Association, a constituent organization of the AsMA. This summary was edited by E. A. Bopp. The Space Medicine Association intends this to be the first of an annual series of panels on Space Medicine History. NR 0 TC 3 Z9 4 U1 1 U2 7 PU AEROSPACE MEDICAL ASSOC PI ALEXANDRIA PA 320 S HENRY ST, ALEXANDRIA, VA 22314-3579 USA SN 0095-6562 J9 AVIAT SPACE ENVIR MD JI Aviat. Space Environ. Med. PD APR PY 2009 VL 80 IS 4 BP 345 EP 352 DI 10.3357/ASEM.2463.2009 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Sport Sciences SC Public, Environmental & Occupational Health; General & Internal Medicine; Sport Sciences GA 427LL UT WOS:000264780700001 PM 19378903 ER PT J AU Dhonnchadha, BAN Fox, RG Stutz, SJ Rice, KC Cunningham, KA AF Dhonnchadha, B. A. Nic Fox, R. G. Stutz, S. J. Rice, K. C. Cunningham, K. A. TI Blockade of the Serotonin 5-HT2A Receptor Suppresses Cue-Evoked Reinstatement of Cocaine-Seeking Behavior in a Rat Self-Administration Model SO BEHAVIORAL NEUROSCIENCE LA English DT Review DE cocaine self-administration; cue-induced reinstatement; extinction; M100907; 5-HT2AR antagonist ID MEDIAL PREFRONTAL CORTEX; DISCRIMINATIVE STIMULUS PROPERTIES; INDUCED LOCOMOTOR-ACTIVITY; EXTRACELLULAR DOPAMINE LEVELS; DRUG-ASSOCIATED STIMULI; TIME-DEPENDENT CHANGES; NUCLEUS-ACCUMBENS; INDIVIDUAL-DIFFERENCES; BASOLATERAL AMYGDALA; FOOD RESTRICTION AB The serotonin 5-HT2A receptor (5-HT2AR) may play a role in reinstatement of drug-seeking. This study investigated the ability of a selective 5-HT2AR antagonist to suppress reinstatement evoked by exposure to cues conditioned to cocaine self-administration. Cocaine self-administration (0.75 mg/kg/0.1 mL/6 s infusion; FR 4) was trained in naive, free-fed rats to allow interpretation of results independent from changes related to food deprivation stress. Pretreatment with the selective 5-HT2AR antagonist M100907 (volinanserin) failed to reduce rates of operant responding for cocaine infusions. On the other hand, M100907 (0.001-0.8 mg/kg ip) significantly suppressed the cue-induced reinstatement of cocaine-seeking behavior following extinction; effective M100907 doses did not alter operant responding for cues previously associated with sucrose self-administration. Importantly, a greater magnitude of active lever presses on the initial extinction session (high extinction responders) predicted the maximal susceptibility to M100907-induced suppression of cue-evoked reinstatement. The findings indicate that blockade of the 5-HT2AR attenuates the incentive-motivational effects of cocaine-paired cues, particularly in high extinction responders, and suggests that M100907 may afford a therapeutic advance in suppression of cue-evoked craving and/or relapse. C1 [Dhonnchadha, B. A. Nic; Fox, R. G.; Stutz, S. J.; Cunningham, K. A.] Univ Texas Med Branch, Addict Res Ctr, Dept Pharmacol & Toxicol, Galveston, TX 77550 USA. [Rice, K. C.] NIDA, Chem Biol Res Branch, Drug Design & Synth Sect, Intramural Res Program,NIH, Bethesda, MD 20892 USA. RP Cunningham, KA (reprint author), Univ Texas Med Branch, Addict Res Ctr, Dept Pharmacol & Toxicol, Galveston, TX 77550 USA. EM kcunning@utmb.edu RI Cunningham, Kathryn/O-2718-2013 FU National Institute on Drug Abuse [DA 00260, DA 06511, DA 020087]; National Institute of Diabetes, Digestive and Kidney Diseases FX The work in this study was supported by grants from the National Institute on Drug Abuse; DA 00260, DA 06511, and DA 020087. This work was also partially supported by the intramural research program of the National Institute on Drug Abuse and the National Institute of Diabetes, Digestive and Kidney Diseases. NR 133 TC 49 Z9 49 U1 1 U2 3 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD APR PY 2009 VL 123 IS 2 BP 382 EP 396 DI 10.1037/a0014592 PG 15 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 424KO UT WOS:000264565800016 ER PT J AU Braulke, T Bonifacino, JS AF Braulke, Thomas Bonifacino, Juan S. TI Sorting of lysosomal proteins SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Review DE Lysosomal protein; Posttranslational modification; GlcNac-1-phosphotransferase; Mannose 6-phosphate; Adaptor protein complex ID MANNOSE 6-PHOSPHATE RECEPTOR; TRANS-GOLGI NETWORK; FACTOR-II RECEPTOR; CLATHRIN-COATED VESICLES; CASEIN KINASE-II; FORMYLGLYCINE-GENERATING ENZYME; EFFICIENT RETROGRADE TRANSPORT; ALPHA-N-ACETYLGLUCOSAMINIDASE; DOMAIN-CONTAINING PROTEIN; ADP-RIBOSYLATION FACTORS AB Lysosomes are composed of soluble and transmembrane proteins that are targeted to lysosomes in a signal-dependent manner. The majority of soluble acid hydrolases are modified with mannose 6-phosphate (M6P) residues, allowing their recognition by M6P receptors in the Golgi complex and ensuing transport to the endosomal/lysosomal system. Other soluble enzymes and non-enzymatic proteins are transported to lysosomes in an M6P-independent manner mediated by alternative receptors such as the lysosomal integral membrane protein LIMP-2 or sortilin. Sorting of cargo receptors and lysosomal transmembrane proteins requires sorting signals present in their cytosolic domains. These signals include dileucine-based motifs, DXXLL or [DE]XXXL[LI], and tyrosine-based motifs, YXXempty set, which interact with components of clathrin coats such as GGAs or adaptor protein complexes. In addition, phosphorylation and lipid modifications regulate signal recognition and trafficking of lysosomal membrane proteins. The complex interaction of both luminal and cytosolic signals with recognition proteins guarantees the specific and directed transport of proteins to lysosomes. (C) 2008 Elsevier B.V. All rights reserved. C1 [Braulke, Thomas] Univ Hamburg, Univ Med Ctr Hamburg Eppendorf, Dept Biochem, D-20246 Hamburg, Germany. [Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, Natl Inst Hlth, Bethesda, MD USA. RP Braulke, T (reprint author), Univ Hamburg, Univ Med Ctr Hamburg Eppendorf, Dept Biochem, Childrens Hosp Res Campus,Martinistr 52, D-20246 Hamburg, Germany. EM braulke@uke.uni-hamburg.de OI Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural Program of NICHD, NIH FX Work in the Braulke lab is supported by grants of Deutsche Forschungsgemeinschaft. Work in the Bonifacino lab is funded by the Intramural Program of NICHD, NIH. NR 195 TC 285 Z9 288 U1 3 U2 32 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD APR PY 2009 VL 1793 IS 4 BP 605 EP 614 DI 10.1016/j.bbamcr.2008.10.016 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 435UW UT WOS:000265369800002 PM 19046998 ER PT J AU Kaluz, S Kaluzova, M Liao, SY Lerman, M Stanbridge, EJ AF Kaluz, Stefan Kaluzova, Milota Liao, Shu-Yuan Lerman, Michael Stanbridge, Eric J. TI Transcriptional control of the tumor- and hypoxia-marker carbonic anhydrase 9: A one transcription factor (HIF-1) show? SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Review DE Carbonic anhydrase IX; Transcriptional regulation; Hypoxia; Hypoxia-inducible factor ID CARBONIC-ANHYDRASE-IX; RENAL-CELL CARCINOMA; INDUCIBLE FACTOR-I; GENE-EXPRESSION; CANCER-CELLS; DIAGNOSTIC BIOMARKER; CERVICAL CARCINOMAS; ENDOGENOUS MARKER; SUPPRESSOR GENE; DOWN-REGULATION AB Transcriptional activation by hypoxia is mediated by the hypoxia-inducible factor (HIF) via binding to the hypoxia-responsive element (HRE). Hypoxia in solid tumors associates with poorer outcome of the disease and reliable cellular markers of tumor hypoxia would represent a valuable diagnostic marker and a potential therapeutic target. In this category, carbonic anhydrase IX (CAIX) is one of the most promising candidates. Here, we summarize the knowledge about transcriptional regulation of CA9. The HRE is the central regulatory element in the CA9 promoter, whereas other elements are limited to lesser roles of amplification of signals received at the HRE. The analysis of known mechanisms of activation of C49 reveals the prominent role of the HIF-1 pathway. Experimental paradigms with uncoupled HIF-1 alpha stability and transcriptional activity (pericellular hypoxia, proteasomal inhibitor) provide evidence that CA9 expression monitors transcriptional activity of HIF-1, rather than the abundance of HIF-1 alpha. Furthermore, these paradigms could provide a corollary to some of the apparently discordant cases (CAIX+, HIF-1 alpha-) or (CAIX-, HIF-1 alpha+) observed in vivo. In conclusion, the existing data support the notion that CA9, due to the unique structure of its promoter, is one of the most sensitive endogenous sensors of HIF-1 activity. (C) 2009 Elsevier B.V. All rights reserved. C1 [Kaluz, Stefan; Kaluzova, Milota; Stanbridge, Eric J.] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA. [Liao, Shu-Yuan] Univ Calif Irvine, Dept Epidemiol, Sch Med, Irvine, CA 92697 USA. [Lerman, Michael] NCI, Immunobiol Lab, Frederick, MD 21701 USA. RP Kaluz, S (reprint author), Emory Univ, Winship Canc Inst, Dept Neurosurg, 1701 Uppergate Dr, Atlanta, GA 30322 USA. EM skaluz@emory.edu FU NIH [R01 CA104214] FX This work was supported by NIH grant R01 CA104214 (EJS). NR 84 TC 95 Z9 96 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD APR PY 2009 VL 1795 IS 2 BP 162 EP 172 DI 10.1016/j.bbcan.2009.01.001 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA 435UV UT WOS:000265369700009 PM 19344680 ER PT J AU Matsumoto, K Okajo, A Nagata, K DeGraff, WG Nyui, M Ueno, M Nakanishi, I Ozawa, T Mitchell, JB Krishna, MC Yamamoto, H Endo, K Anzai, K AF Matsumoto, Ken-ichiro Okajo, Aya Nagata, Katsura DeGraff, William G. Nyui, Minako Ueno, Megumi Nakanishi, Ikuo Ozawa, Toshihiko Mitchell, James B. Krishna, Murali C. Yamamoto, Haruhiko Endo, Kazutoyo Anzai, Kazunori TI Detection of Free Radical Reactions in an Aqueous Sample Induced by Low Linear-Energy-Transfer Irradiation SO BIOLOGICAL & PHARMACEUTICAL BULLETIN LA English DT Article DE low linear-energy-transfer irradiation; free radical reaction; nitroxyl radical; glutathione; reactive oxygen species ID RAT-LIVER; NONINVASIVE ANALYSIS; CONTRAST AGENTS; SPIN LABELS; SPECTROSCOPY; MICROSOMES; METABOLISM AB Quantitative detection of free radical reactions induced by low linear-energy-transfer (LET) irradiation in an aqueous solution was attempted using nitroxyl radicals. The stability and reactivity of reaction mixtures containing a nitroxyl radical and a hydrogen donor, i.e., glutathione (GSH), nicotinamide adenine dinucleotide (NADH), or nicotinamide adenine dinucleotide phosphate (NADPH), were tested. X-band electron paramagnetic resonance (EPR) measurements of several reaction mixtures were performed to find a suitable preparation to quantitatively detect free radical reactions produced by low LET irradiation. The EPR signal intensity of nitroxyl radicals was decreased by low LET irradiation when a hydrogen donor coexisted in the reaction mixture. The combination of 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (4-hydroxy-TEMPO, known as TEMPOL) and GSH was most preferable among other preparations tested in this paper, because of the sensitivity and irreversible reaction. The extent of the free radical reaction, i.e., formation of reactive oxygen species, in the reaction mixture depended on the radiation energy when an identical dose was given. C1 [Matsumoto, Ken-ichiro; Nagata, Katsura; Nyui, Minako; Ueno, Megumi; Nakanishi, Ikuo; Ozawa, Toshihiko; Anzai, Kazunori] Natl Inst Radiol Sci, Radiat Modifier Res Team, Heavy Ion Radiobiol Res Grp, Res Ctr Charged Particle Therapy, Chiba 2638555, Japan. [Okajo, Aya; Endo, Kazutoyo] Showa Pharmaceut Univ, Dept Phys Chem, Tokyo 1948543, Japan. [Nagata, Katsura; Yamamoto, Haruhiko] Kanagawa Univ, Fac Sci, Dept Appl Sci, Kanagawa 2591293, Japan. [DeGraff, William G.; Mitchell, James B.; Krishna, Murali C.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ozawa, Toshihiko] Yokohama Coll Pharm, Dept Anal Pharmacol, Kanagawa 2450066, Japan. RP Matsumoto, K (reprint author), Natl Inst Radiol Sci, Radiat Modifier Res Team, Heavy Ion Radiobiol Res Grp, Res Ctr Charged Particle Therapy, Chiba 2638555, Japan. EM matsumok@nirs.go.jp RI Anzai, Kazunori/C-8577-2009; Nakanishi, Ikuo/E-4430-2012 OI Nakanishi, Ikuo/0000-0001-9204-0664 NR 15 TC 8 Z9 8 U1 0 U2 2 PU PHARMACEUTICAL SOC JAPAN PI TOKYO PA 2-12-15 SHIBUYA, SHIBUYA-KU, TOKYO, 150-0002, JAPAN SN 0918-6158 J9 BIOL PHARM BULL JI Biol. Pharm. Bull. PD APR PY 2009 VL 32 IS 4 BP 542 EP 547 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 425CW UT WOS:000264615600003 PM 19336881 ER PT J AU Matsumoto, K AF Matsumoto, Ken-ichiro TI Utility Decay Rates of T-1-Weighted Magnetic Resonance Imaging Contrast Based on Redox-Sensitive Paramagnetic Nitroxyl Contrast Agents SO BIOLOGICAL & PHARMACEUTICAL BULLETIN LA English DT Article DE nitroxyl contrast agent; redox mapping; T-1-weighted contrast; magnetic resonance imaging; tissue redox status; tumor imaging ID FLOW MONITORING BFM; X-BAND EPR; SPIN LABELS; SUBCELLULAR-FRACTIONS; TUMOR; LIVER; REDUCTION; OXYGEN; METABOLISM; SPECTROSCOPY AB The availability and applicability of the combination of paramagnetic nitroxyl contrast agent and T-1-weighted gradient echo (GE)-based dynamic magnetic resonance imaging (MRI) measurement for redox imaging are described. The time courses of T-1-weighted GE MRI signal intensities according to first-order paramagnetic loss of a nitroxyl contrast agent were simulated for several experimental conditions. The apparent decay rate calculated based on decreasing T-1-weighted MRI contrast (k(MRI))can show an approximate value of the original decay rate (k(true)) discretionarily given for simulation with suitable experimental parameters. The difference between k(MRI) and k(true) can be sufficiently small under T-1-weighted spoiled gradient echo (SPGR) scan conditions (repetition time=75 ms, echo time=3 ms, and flip angle=45 degrees), with a conventional redox-sensitive nitroxyl contrast agent, such as 4-hydroxy-2,2,6,6,-tetramethylpiperidine-N-oxyl (TEMPOL) and/or 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-N-oxyl (carbamoyl-PROXYL), and with i.v. doses of below 1.5 mu mol/g b.w. for mice. The results of this simulation suggest that the k(MRI) of nitroxyl contrast agents can be the primary index of redox status under biological conditions. C1 [Matsumoto, Ken-ichiro] Natl Inst Radiol Sci, Radiat Modifier Team, Heavy Ion Radiobiol Res Grp, Res Ctr Charged Particle Therapy,Inage Ku, Chiba 2638555, Japan. [Matsumoto, Ken-ichiro] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Matsumoto, K (reprint author), Natl Inst Radiol Sci, Radiat Modifier Team, Heavy Ion Radiobiol Res Grp, Res Ctr Charged Particle Therapy,Inage Ku, 4-9-1 Anagawa, Chiba 2638555, Japan. EM matsumok@nirs.go.jp NR 36 TC 5 Z9 5 U1 0 U2 0 PU PHARMACEUTICAL SOC JAPAN PI TOKYO PA 2-12-15 SHIBUYA, SHIBUYA-KU, TOKYO, 150-0002, JAPAN SN 0918-6158 J9 BIOL PHARM BULL JI Biol. Pharm. Bull. PD APR PY 2009 VL 32 IS 4 BP 711 EP 716 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 425CW UT WOS:000264615600032 PM 19336910 ER PT J AU Mann, JJ Arango, VA Avenevoli, S Brent, DA Champagne, FA Clayton, P Currier, D Dougherty, DM Haghighi, F Hodge, SE Kleinman, J Lehner, T McMahon, F Moscicki, EK Oquendo, MA Pandey, GN Pearson, J Stanley, B Terwilliger, J Wenzel, A AF Mann, J. John Arango, Victoria A. Avenevoli, Shelli Brent, David A. Champagne, Frances A. Clayton, Paula Currier, Dianne Dougherty, Donald M. Haghighi, Fatemah Hodge, Susan E. Kleinman, Joel Lehner, Thomas McMahon, Francis Moscicki, Eve K. Oquendo, Maria A. Pandey, Ganshayarn N. Pearson, Jane Stanley, Barbara Terwilliger, Joseph Wenzel, Amy TI Candidate Endophenotypes for Genetic Studies of Suicidal Behavior SO BIOLOGICAL PSYCHIATRY LA English DT Review DE Endophenotype; genetics; suicide ID CATECHOL-O-METHYLTRANSFERASE; POSITRON-EMISSION-TOMOGRAPHY; MAJOR DEPRESSIVE DISORDER; TYROSINE KINASE-B; OXIDASE-A GENE; BIPOLAR DISORDER; POSTMORTEM BRAIN; PERSONALITY-DISORDERS; SEROTONIN TRANSPORTER; CEREBROSPINAL-FLUID AB Twin, adoption, and family studies have established the heritability of suicide attempts and suicide. Identifying specific suicide diathesis-related genes has proven more difficult. As with psychiatric disorders in general, methodological difficulties include complexity of the phenotype for suicidal behavior and distinguishing suicide diathesis-related genes from genes associated with mood disorders and other suicide-associated psychiatric illness. Adopting an endophenotype approach involving identification of genes associated with heritable intermediate phenotypes, including biological and/or behavioral markers more proximal to genes, is an approach being used for other psychiatric disorders. Therefore, a workshop convened by the American Foundation for Suicide Prevention, the Department of Psychiatry at Columbia University, and the National Institute of Mental Health sought to identify potential target endophenotypes for genetic studies of suicidal behavior. The most promising endophenotypes were trait aggression/impulsivity, early-onset major depression, neurocognitive function, and cortisol social stress response. Other candidate endophenotypes requiring further investigation include serotonergic neurotransmission, second messenger systems, and borderline personality disorder traits. C1 [Mann, J. John; Arango, Victoria A.; Champagne, Frances A.; Currier, Dianne; Haghighi, Fatemah; Hodge, Susan E.; Oquendo, Maria A.; Stanley, Barbara; Terwilliger, Joseph] Columbia Univ, Dept Psychiat, New York, NY 10032 USA. [Avenevoli, Shelli; Kleinman, Joel; Lehner, Thomas; McMahon, Francis; Moscicki, Eve K.; Pearson, Jane] NIMH, NIH, Bethesda, MD 20892 USA. [Brent, David A.] Western Psychiat Inst & Clin, New York, NY USA. [Clayton, Paula] Amer Fdn Suicide Prevent, New York, NY USA. [Dougherty, Donald M.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Pandey, Ganshayarn N.] Univ Illinois, Dept Psychiat, Chicago, IL 60612 USA. [Wenzel, Amy] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA. RP Mann, JJ (reprint author), Columbia Univ, New York State Psychiat Inst, Dept Mol Imaging & Neuropathol, 1051 Riverside Dr,Box 42, New York, NY 10032 USA. EM jjm@columbia.edu RI Stanley, Barbara/J-8736-2013; Arango, Victoria/K-9377-2015; OI Arango, Victoria/0000-0001-8811-400X; Currier, Dianne/0000-0002-6614-271X; McMahon, Francis/0000-0002-9469-305X FU Intramural NIH HHS [Z01 MH002903-02]; NIMH NIH HHS [R01 MH048514, R01 MH084995] NR 100 TC 157 Z9 161 U1 4 U2 16 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 APR 1 PY 2009 VL 65 IS 7 BP 556 EP 563 DI 10.1016/j.biopsych.2008.11.021 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 420SN UT WOS:000264309600003 PM 19201395 ER PT J AU Colvin, GA Berz, D Ramanathan, M Winer, ES Fast, L Elfenbein, GJ Quesenberry, PJ AF Colvin, Gerald A. Berz, David Ramanathan, Muthalagu Winer, Eric S. Fast, Loren Elfenbein, Gerald J. Quesenberry, Peter J. TI Nonengraftment Haploidentical Cellular Immunotherapy for Refractory Malignancies: Tumor Responses without Chimerism SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Haploidentical; Immunotherapy; Bone marrow transplantation; Radiation ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; ALLOGENEIC LYMPHOID-CELLS; HEMATOPOIETIC STEM-CELLS; MURINE MARROW; T-CELLS; HISTOCOMPATIBILITY ANTIGENS; HEMATOLOGIC MALIGNANCIES; ADOPTIVE IMMUNOTHERAPY; LEUKOCYTE INFUSIONS AB Allogeneic bone marrow transplantation relies on immunosuppression, which controls graft-versus-host disease (GVHD) and allows engraftment at the expense of diminished graft versus-tumor (GVT) activity. Advances in hematologic transplantation have prompted the development of effective, less-toxic regimens that attempt to balance GVH and GVT immunoreactions. We analyzed the safety and efficacy of haploidentical transplantation in a Phase I/II nonimmunosuppressive, nonmyeloablative setting. A total of 41 patients with relapsed refractory cancer received 100 cGy of total body irradiation (TBI), along with an infusion of 1 x 10(6) to 2 x 10(8) CD3(+) cells/kg; 29 patients received the highest dose. A postinfusional cellular graft rejection syndrome resembling engraftment syndrome was noted at the 2 highest CD3' infusion cohorts. There were 26 patients with hematologic malignancies with 14 responses, 9 of which were major. Two of 6 patients with lymphoma remained free of disease at 76 months and 82 months, respectively; there were 5 durable complete responses and 4 partial responses in 13 patients with acute myelogenous leukemia (AML). All responses occurred outside of donor chimerism. TBI at 100 cGy followed by HLA-haploidentical immunotherapy is a biologically active therapy for patients with refractory AML and lymphoma. Possible mechanisms contributing to its effectiveness include initial GVT kill, breaking of host tolerance to tumor through cross-reactive alloreactive responses, persistent nondetectable microchimerism, or some combination of these. C1 [Colvin, Gerald A.; Berz, David; Winer, Eric S.; Fast, Loren; Quesenberry, Peter J.] Rhode Isl Hosp, Div Hematol Oncol, Dept Med, Providence, RI 02903 USA. [Ramanathan, Muthalagu] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Elfenbein, Gerald J.] Boston Univ, Div Hematol Oncol, Dept Med, Boston, MA USA. RP Colvin, GA (reprint author), Rhode Isl Hosp, Div Hematol Oncol, Dept Med, George 3,593 Eddy St, Providence, RI 02903 USA. EM gcolvin@lifespan.org FU National Institutes of Health (NIH) [P20 RR 018757-02]; NIDDK [K08DK6498-01, DK0618585] FX This work was supported by National Institutes of Health (NIH) Grants P20 RR 018757-02, NIDDK K08DK6498-01, and DK0618585, and by the NIH loan repayment program. Additional funding was provided by patient donations and the Rhode Island Foundation. The authors thank Mary Falvey, Deborah Morgan, Linda Colvin, Patricia Karwan, and the BMT nursing team. They also thank Drs Jila Khorsand, Mehrdad Abedi, Kathy Radie-Keane, Lawrence Lum, Sheila Pascual, Samuel Chung, Diane Paggioli, Basma Ali, and Nicola Kouttab for their help with data analysis, chart review, and patient care. NR 50 TC 34 Z9 36 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD APR PY 2009 VL 15 IS 4 BP 421 EP 431 DI 10.1016/j.bbmt.2008.12.503 PG 11 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 425DA UT WOS:000264616000004 PM 19285629 ER PT J AU Kokkinaki, M Lee, TL He, ZP Jiang, JJ Golestaneh, N Hofmann, MC Chan, WY Dym, M AF Kokkinaki, Maria Lee, Tin-Lap He, Zuping Jiang, Jiji Golestaneh, Nady Hofmann, Marie-Claude Chan, Wai-Yee Dym, Martin TI The Molecular Signature of Spermatogonial Stem/Progenitor Cells in the 6-Day-Old Mouse Testis SO BIOLOGY OF REPRODUCTION LA English DT Article DE CSF1; CSF1R; GDNF; GFRA1; gene expression; microarray; mouse testis; spermatogonial stem/progenitor cells; testis ID COLONY-STIMULATING FACTOR; GERMLINE STEM-CELLS; SELF-RENEWAL; NEUROTROPHIC FACTOR; UNDIFFERENTIATED SPERMATOGONIA; SIGNALING PATHWAYS; BEARING RECEPTORS; A SPERMATOGONIA; IMMATURE MOUSE; GROWTH-FACTOR AB To characterize the molecular phenotype of spermatogonial stem cells (SSCs), we examined genes that are differentially expressed in the stem/progenitor spermatogonia compared to nonstem spermatogonia. We isolated type A spermatogonia (stem and nonstem type A) from 6-day-old mice using sedimentation velocity at unit gravity and further selected the stem/progenitor cell subpopulation by magnetic activated cell sorting with an antibody to GDNF-receptor-alpha-1 (GFRA1). It has been previously shown that GFRA1 is expressed in SSCs and is required for their stemness. The purity of the isolated cells was approximately 95% to 99% as indicated by immunocytochemistry using anti-GFRA1. Comparison of GFRA1-positive and GFRA1-negative spermatogonia by microarray analysis revealed 99 known genes and 12 uncharacterized transcripts that are overexpressed in the former cell population with a >2-fold change. Interestingly, the highest level of overexpression was observed for Csf1r, encoding the receptor for macrophage colony-stimulating factor (M-CSF, official symbol CSF1), which has a well-established role in the regulation of myeloid progenitor cells. Analysis of our microarray data with a bioinformatics software program (Ingenuity Systems) revealed the potential role of various signaling pathways in stem/progenitor spermatogonia and suggested a common pathway for GFRA1 and CSF1R that may lead to their proliferation. Further investigation to test this hypothesis has shown that CSF1 promotes cell proliferation in primary cultures of the isolated type A spermatogonia and in the spermatogonial-derived stem cell line C18-4. Semiquantitative RT-PCR and immunohistochemistry confirmed the previously mentioned microarray data. Collectively, this study provides novel molecular signatures for stem/progenitor spermatogonia and demonstrates a role for CSF1/CSF1R signaling in regulating their proliferation. C1 [Kokkinaki, Maria; He, Zuping; Jiang, Jiji; Golestaneh, Nady; Chan, Wai-Yee; Dym, Martin] Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Washington, DC 20057 USA. [Lee, Tin-Lap; Chan, Wai-Yee] NICHHD, NIH, Bethesda, MD 20892 USA. [Hofmann, Marie-Claude] Univ Illinois, Dept Vet Biosci, Urbana, IL 61801 USA. RP Dym, M (reprint author), Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, 3900 Reservoir Rd NW, Washington, DC 20057 USA. EM dymm@georgetown.edu RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU National Institutes of Health (NIH) [HD033728, HD012345]; 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 (to W.-Y.C.) and NIH grants HD033728 (to M. D.) and HD012345 to M.-C.H.). NR 53 TC 34 Z9 45 U1 1 U2 3 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 APR PY 2009 VL 80 IS 4 BP 707 EP 717 DI 10.1095/biolreprod.108.073809 PG 11 WC Reproductive Biology SC Reproductive Biology GA 422OG UT WOS:000264437000012 PM 19109221 ER PT J AU Chen, R Khormaee, S Eccleston, ME Slater, NKH AF Chen, Rongjun Khormaee, Sariah Eccleston, Mark E. Slater, Nigel K. H. TI The role of hydrophobic amino acid grafts in the enhancement of membrane-disruptive activity of pH-responsive pseudo-peptides SO BIOMATERIALS LA English DT Article DE pH-responsive polymer; Pseudo-peptide; Hydrophobic amino acid; Haemolysis; Cytotoxicity; Drug delivery ID NONVIRAL GENE DELIVERY; INTRACELLULAR DELIVERY; PHOSPHOLIPID-VESICLES; SYNTHETIC-POLYMERS; CELL-MEMBRANES; SIDE-CHAINS; IN-VIVO; POLYELECTROLYTE; VECTORS; SYSTEMS AB pH-responsive polymers have been synthesised by grafting L-Valine (PV-75), L-leucine (PL-75) and L-phenylalanine (PP-75) onto the pendant carboxylic acid moieties of a pseudo-peptide, poly(L-lysine isophthalamide), at a stoichiometric degree of substitution of 75 mol%. The effect of such modification on the pH-, concentration- and time-dependent cell membrane-disruptive activity of the grafted polymers has been investigated using a haemolysis model. At 0.025 mg mL(-1), the grafted polymers were almost non-haemolytic at pH 7.4, but mediated considerable membrane lysis after 60 min in the pH range characteristic of early endosomes, which ranked in the order: PP-75 > PL-75 > PV-75 > poly(L-lysine isophthalamide). PP-75 was 35-fold more lytic on a molar basis than the membrane-lytic peptide melittin. With increasing concentration, the grafted polymers showed an increased ability to lyse cell membranes and caused noticeable membrane disruption at physiological pH. The mechanism of the polymer-mediated membrane destabilisation has been investigated. The in-vitro cytotoxicity of the grafted polymers has been assessed using a propidium iodide fluorescence assay. it has been demonstrated by confocal microscopy that the grafted polymers can induce a significant release of endocytosed materials into the cytoplasm of HeLa cells, which is a feature critical for drug delivery applications. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Chen, Rongjun; Khormaee, Sariah; Slater, Nigel K. H.] Univ Cambridge, Dept Chem Engn & Biotechnol, Cambridge CB2 3RA, England. [Khormaee, Sariah] NINDS, Surg & Mol Neurooncol Unit, NIH, Bethesda, MD 20892 USA. [Eccleston, Mark E.] Vivamer Ltd, Cambridge CB3 0FD, England. RP Slater, NKH (reprint author), Univ Cambridge, Dept Chem Engn & Biotechnol, Pembroke St, Cambridge CB2 3RA, England. EM nkhs2@cam.ac.uk OI Chen, Rongjun/0000-0002-8133-5472 FU Gates Cambridge Trust; Universities UK; Intramural Research Program of the National Institute of Neurological Disorders and Stroke; National Institutes of Health; Marshall Aid Commemoration Commission FX Rongjun Chen wishes to thank the Gates Cambridge Trust and the Universities UK organisations for the financial support that enabled this work to be carried out. Sariah Khormaee acknowledges the support of the Intramural Research Program of the National Institute of Neurological Disorders and Stroke, National Institutes of Health and the Marshall Aid Commemoration Commission. NR 50 TC 59 Z9 59 U1 4 U2 26 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD APR PY 2009 VL 30 IS 10 BP 1954 EP 1961 DI 10.1016/j.biomaterials.2008.12.036 PG 8 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 418JZ UT WOS:000264145800011 PM 19138797 ER PT J AU Proschan, MA AF Proschan, Michael A. TI Sample size re-estimation in clinical trials SO BIOMETRICAL JOURNAL LA English DT Article CT International Conference on Statistics and Life Science CY MAR 10-13, 2008 CL Munich, GERMANY SP Int Biomet Soc, European Network DE Adaptive clinical trials; Combination functions; Conditional error functions; Sample size re-estimation; Two-stage methods ID I ERROR RATE; VARIANCE; DESIGNS; POWER AB Adaptive clinical trials are becoming very popular because of their flexibility in allowing mid-stream changes of sample size, endpoints, populations, etc. At the same time, they have been regarded with mistrust because they can produce bizarre results in very extreme settings. Understanding the advantages and disadvantages of these rapidly developing methods is a must. This paper reviews flexible methods for sample size re-estimation when the outcome is continuous. C1 NIAID, Bethesda, MD 20892 USA. RP Proschan, MA (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ProschaM@mail.nih.gov NR 24 TC 38 Z9 38 U1 1 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0323-3847 J9 BIOMETRICAL J JI Biom. J. PD APR PY 2009 VL 51 IS 2 BP 348 EP 357 DI 10.1002/bimj.200800266 PG 10 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 442UW UT WOS:000265867100009 PM 19358221 ER PT J AU Romagnoli, R Baraldi, PG Carrion, MD Cruz-Lopez, O Cara, CL Balzarini, J Hamel, E Canella, A Fabbri, E Gambari, R Basso, G Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Carrion, Maria Dora Cruz-Lopez, Olga Cara, Carlota Lopez Balzarini, Jan Hamel, Ernest Canella, Alessandro Fabbri, Enrica Gambari, Roberto Basso, Giuseppe Viola, Giampietro TI Hybrid alpha-bromoacryloylamido chalcones. Design, synthesis and biological evaluation SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID PROGRAMMED CELL-DEATH; ANTIMITOTIC AGENTS; CYTOTOXIC AGENTS; APOPTOSIS; MITOCHONDRIA; DERIVATIVES; DIFFERENTIATION; DISTAMYCIN; GENERATION; REDUCTION AB Research into the anti-tumor properties of chalcones has received significant attention over the last few years Two novel large series of alpha-bromoacryloylamido chalcones 1a-m and 2a-k containing a pair of Michael acceptors in their structures, corresponding to the alpha-bromoacryloyl moiety and the alpha,beta-unsaturated ketone system of the chalcone framework, were synthesized and evaluated for antiproliferative activity against five cancer cell lines. Such hybrid derivatives demonstrated significantly increased anti-tumor activity compared with the corresponding amino chalcones. The most promising lead molecules were 1k, 1m and 2j, which had the highest activity toward the five cell lines. Flow cytometry with K562 cells showed that the most active compounds resulted in a large proportion of the cells entering in the apoptotic sub-G0-G1 peak. Moreover, compound 1k induced apoptosis through the mitochondrial pathway and activated caspase-3. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Carrion, Maria Dora; Cruz-Lopez, Olga; Cara, Carlota Lopez] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Balzarini, Jan] Rega Inst, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. [Hamel, Ernest] NCI, NIH, Div Canc Treatment & Diag, Toxicol & Pharmacol Branch,Dev Therapeut Program, Frederick, MD 21702 USA. [Canella, Alessandro; Fabbri, Enrica; Gambari, Roberto] Univ Ferrara, Dipartmento Biochim & Biol Mol, I-44100 Ferrara, Italy. [Basso, Giuseppe; Viola, Giampietro] Univ Padua, Lab Oncoematol, Dipartimento Pediat, I-35131 Padua, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. EM rmr@unife.it; baraldi@unife.it RI Viola, Giampietro/I-4095-2012; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Gambari, Roberto/F-9555-2015; Carrion, M. Dora/G-8638-2015; Romagnoli, Romeo/G-9887-2015; Fabbri, Enrica/O-8059-2015; Baraldi, Pier Giovanni/B-7933-2017; Cruz-Lopez, Olga /F-3060-2017 OI Viola, Giampietro/0000-0001-9329-165X; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; BASSO, GIUSEPPE/0000-0002-2634-9302; Gambari, Roberto/0000-0001-9205-6033; Carrion, M. Dora/0000-0002-6794-3949; Fabbri, Enrica/0000-0002-9836-8262; FU GOA [05/19]; AIRC FX Financial support was provided by GOA (Krediet No. 05/19) of the K. U. Leuven. The technical assistance of Mrs. Lizette van Berckelaer was gratefully acknowledged. R. G. and C. L. C. are funded by AIRC and University of Granada, respectively. NR 36 TC 33 Z9 33 U1 0 U2 6 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 APR 1 PY 2009 VL 19 IS 7 BP 2022 EP 2028 DI 10.1016/j.bmcl.2009.02.038 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 418SS UT WOS:000264169700039 PM 19250822 ER PT J AU Sharov, AA AF Sharov, Alexei A. TI Role of Utility and Inference in the Evolution of Functional Information SO BIOSEMIOTICS LA English DT Article DE Biosemiotics; Pragmatism; Umwelt; Semantic closure; Self-organization; Inference; Evolution AB Functional information means an encoded network of functions in living organisms from molecular signaling pathways to an organism's behavior. It is represented by two components: code and an interpretation system, which together form a self-sustaining semantic closure. Semantic closure allows some freedom between components because small variations of the code are still interpretable. The interpretation system consists of inference rules that control the correspondence between the code and the function (phenotype) and determines the shape of the fitness landscape. The utility factor operates at multiple time scales: short-term selection drives evolution towards higher survival and reproduction rate within a given fitness landscape, and long-term selection favors those fitness landscapes that support adaptability and lead to evolutionary expansion of certain lineages. Inference rules make short-term selection possible by shaping the fitness landscape and defining possible directions of evolution, but they are under control of the long-term selection of lineages. Communication normally occurs within a set of agents with compatible interpretation systems, which I call communication system. Functional information cannot be directly transferred between communication systems with incompatible inference rules. Each biological species is a genetic communication system that carries unique functional information together with inference rules that determine evolutionary directions and constraints. This view of the relation between utility and inference can resolve the conflict between realism/positivism and pragmatism. Realism overemphasizes the role of inference in evolution of human knowledge because it assumes that logic is embedded in reality. Pragmatism substitutes usefulness for truth and therefore ignores the advantage of inference. The proposed concept of evolutionary pragmatism rejects the idea that logic is embedded in reality; instead, inference rules are constructed within each communication system to represent reality, and they evolve towards higher adaptability on a long time scale. C1 NIA, Genet Lab, Baltimore, MD 21224 USA. RP Sharov, AA (reprint author), NIA, Genet Lab, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sharoval@mail.nih.gov FU National Institute on Aging, NIH FX I thank Alexey Voinov (University of Vermont, Burlington, VT) and Olga Brazhnik (National Institute of Health, Bethesda, MD) for discussion of the manuscript. This work was supported by the Intramural Research Program of the National Institute on Aging, NIH. NR 25 TC 6 Z9 8 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1875-1342 J9 BIOSEMIOTICS-NETH JI Biosemiotics PD APR PY 2009 VL 2 IS 1 BP 101 EP 115 DI 10.1007/s12304-008-9032-2 PG 15 WC Humanities, Multidisciplinary; History & Philosophy Of Science SC Arts & Humanities - Other Topics; History & Philosophy of Science GA V17QX UT WOS:000207952800008 PM 20160960 ER PT J AU Dobbin, KK AF Dobbin, Kevin K. TI A method for constructing a confidence bound for the actual error rate of a prediction rule in high dimensions SO BIOSTATISTICS LA English DT Article DE Accuracy; Confidence interval; Error rate; Prediction ID DNA MICROARRAY DATA; GENE-EXPRESSION DATA; CLASSIFICATION; INTERVALS; VALIDATION; CANCER AB Constructing a confidence interval for the actual, conditional error rate of a prediction rule from multivariate data is problematic because this error rate is not a population parameter in the traditional sense-025EFit is a functional of the training set. When the training set changes, so does this "parameter." A valid method for constructing confidence intervals for the actual error rate had been previously developed by McLachlan. However, McLachlan's method cannot be applied in many cancer research settings because it requires the number of samples to be much larger than the number of dimensions (n >> p), and it assumes that no dimension-reducing feature selection step is performed. Here, an alternative to McLachlan's method is presented that can be applied when p >> n, with an additional adjustment in the presence of feature selection. Coverage probabilities of the new method are shown to be nominal or conservative over a wide range of scenarios. The new method is relatively simple to implement and not computationally burdensome. C1 NCI, Rockville, MD 20892 USA. RP Dobbin, KK (reprint author), NCI, 6130 Execut Blvd,EPN Room 8124, Rockville, MD 20892 USA. EM dobbinke@mail.nih.gov NR 26 TC 5 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 J9 BIOSTATISTICS JI Biostatistics PD APR PY 2009 VL 10 IS 2 BP 282 EP 296 DI 10.1093/biostatistics/kxn035 PG 15 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 413ZX UT WOS:000263834800007 PM 19039030 ER PT J AU Molloy, AM Brody, LC Mills, JL Scott, JM Kirke, PN AF Molloy, Anne M. Brody, Lawrence C. Mills, James L. Scott, John M. Kirke, Peadar N. TI The Search for Genetic Polymorphisms in the Homocysteine/Folate Pathway That Contribute to the Etiology of Human Neural Tube Defects SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Review DE MTHFR; folic acid; vitamin B-12; homocysteine; candidate genes ID GENOME-WIDE ASSOCIATION; REDUCED FOLATE CARRIER; THERMOLABILE METHYLENETETRAHYDROFOLATE REDUCTASE; GLUTAMATE CARBOXYPEPTIDASE-II; PERICONCEPTIONAL VITAMIN SUPPLEMENTATION; CYSTATHIONINE BETA-SYNTHASE; SPINA-BIFIDA; RISK-FACTOR; 5,10-METHYLENETETRAHYDROFOLATE REDUCTASE; FOLIC-ACID AB In this paper, we trace the history of current research into the genetic and biochemical mechanisms that underlie folate-preventable neural tube defects (NTDs). The inspired suggestion by Smithells that common vitamins might prevent NTDs ignited a decade of biochemical investigations-first exploring the nutritional and metabolic factors related to NTDs, then onto the hunt for NTD genes. Although NTDs were known to have a strong genetic component, the concept of common genetic variance being linked to disease risk was relatively novel in 1995, when the first folate-related polymorphism associated with NTDs was discovered. The realization that more genes must be involved started a rush to find polymorphic needles in genetic haystacks. Early efforts entailed the intellectually challenging and time-consuming task of identifying and analyzing candidate single nucleotide polymorphisms (SNPs) in folate pathway genes. Luckily, human genome research has developed rapidly, and the search for the genetic factors that contribute to the etiology of human NTDs has evolved to mirror the increased level of knowledge and data available on the human genome. Large-scale candidate gene analysis and genome-wide association studies are now readily available. With the technical hurdles removed, the remaining challenge is to gather a sample large enough to uncover the polymorphisms that contribute to NTD risk. In some respects the real work is beginning. Although moving forward is exciting, it is humbling that the most important result-prevention of NTDs by maternal folic acid supplementation-was achieved years ago, the direct result of Smithells' groundbreaking studies. Birth Defects Research (Part A) 85:285-294, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Molloy, Anne M.; Scott, John M.] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin 2, Ireland. [Brody, Lawrence C.] NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bethesda, MD USA. [Mills, James L.] Eunice Kennedy Shriver NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Kirke, Peadar N.] Hlth Res Board, Child Hlth Epidemiol Unit, Dublin, Ireland. RP Molloy, AM (reprint author), Trinity Coll Dublin, Sch Biochem & Immunol, Dublin 2, Ireland. EM amolloy@tcd.ie OI Molloy, Anne/0000-0002-1688-9049 FU Health Research Board, Ireland; Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Human Genome Research Institute; National Institutes of Health, Bethesda, Maryland FX This study was supported by the Health Research Board, Ireland, and the intramural research programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. NR 128 TC 40 Z9 44 U1 1 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD APR PY 2009 VL 85 IS 4 BP 285 EP 294 DI 10.1002/bdra.20566 PG 10 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 440BW UT WOS:000265674200007 PM 19235830 ER PT J AU Tripp, DA Nickel, JC Ross, S Mullins, C Stechyson, N AF Tripp, Dean A. Nickel, J. Curtis Ross, Stephanie Mullins, Chris Stechyson, Natalie TI Prevalence, symptom impact and predictors of chronic prostatitis-like symptoms in Canadian males aged 16-19 years SO BJU INTERNATIONAL LA English DT Article DE prostatitis; adolescent; catastrophizing; quality of life ID PELVIC PAIN SYNDROME; QUALITY-OF-LIFE; PRIMARY-CARE; MEN; VALIDATION; COHORT; INDEX AB To estimate the prevalence and examine the extent that pain, urinary symptoms, depression and pain catastrophizing predict the quality of life (QoL) in Canadian male adolescents, as the prevalence and impact of chronic prostatitis (CP)-like symptoms in adolescents is unknown. Participants completed the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), the Patient Health Questionnaire-depression screen (PHQ-D), and the Pain Catastrophizing Scale (PCS). CP-like case identification was based on NIH-CPSI report of pain/discomfort in perineum and/or with ejaculation and NIH-CPSI total pain score (0-20) of >= 4 (mild) and >= 8 (moderate-severe). The point prevalence was estimated and regressions used to examine predictors of diminished QoL gathered from the NIH-CPSI. The prevalence of at least mild CP-like symptoms in 264 Canadian adolescents aged 16-19 years (mean age 17.5, sd 1.1) was 8.3%, with 3% reporting moderate-severe CP-like symptoms. Pain, urinary symptoms, depression and catastrophizing were correlated with diminished QoL. Additionally, catastrophizing predicted diminished QoL when the variance of pain, urinary symptoms and depression were simultaneously considered in the analysis. Similar to that reported by older cohorts, these data provide the first point-prevalence estimate of CP-like symptoms in adolescents. These findings suggest increased vigilance to a potential diagnosis of adolescent CP syndrome and indicate that psychological features (i.e. catastrophizing) are significant in diminished QoL. Adolescent male chronic pelvic pain is an important and understudied area for future investigations. C1 [Tripp, Dean A.; Ross, Stephanie; Stechyson, Natalie] Queens Univ, Dept Psychol, Kingston, ON K7L 3N6, Canada. [Tripp, Dean A.] Queens Univ, Dept Anaesthesiol, Kingston, ON K7L 3N6, Canada. [Tripp, Dean A.; Nickel, J. Curtis] Queens Univ, Dept Urol, Kingston, ON K7L 3N6, Canada. [Mullins, Chris] NIDDK, NIH, Bethesda, MD USA. RP Tripp, DA (reprint author), Queens Univ, Dept Psychol, Humphrey Hall, Kingston, ON K7L 3N6, Canada. EM dean.tripp@queensu.ca FU NIH/NIDDK CPCRN [DK065174] FX This study was funded by NIH/NIDDK CPCRN Grant DK065174. NR 20 TC 16 Z9 19 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-4096 J9 BJU INT JI BJU Int. PD APR PY 2009 VL 103 IS 8 BP 1080 EP 1084 DI 10.1111/j.1464-410X.2008.08157.x PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 425AJ UT WOS:000264609100014 PM 19007369 ER PT J AU Li, WJ Kornak, J Harris, T Keyak, J Li, CX Lu, Y Cheng, XG Lang, T AF Li, Wenjun Kornak, John Harris, Tamara Keyak, Joyce Li, Caixia Lu, Ying Cheng, Xiaoguang Lang, Thomas TI Identify fracture-critical regions inside the proximal femur using statistical parametric mapping SO BONE LA English DT Article DE Osteoporosis; Proximal femur; QCT; Image registration; Statistical parametric mapping ID QUANTITATIVE COMPUTED-TOMOGRAPHY; OSTEOPOROSIS-RELATED FRACTURES; HIP FRACTURE; POSTMENOPAUSAL WOMEN; FEMORAL-NECK; PARATHYROID-HORMONE; RISK-ASSESSMENT; BONE STRENGTH; UNITED-STATES; REGISTRATION AB We identified regions inside the proximal femur that are most strongly associated with hip fracture. Bone densitometry based on such fracture-critical regions showed improved power in discriminating fracture patients from controls. Introduction: Hip fractures typically occur in lateral falls, with focal mechanical failure of the sub-volumes of tissue in which the applied stress exceeds the strength. In this Study, we describe a new methodology to identify proximal femoral tissue elements with highest association with hip fracture. We hypothesize that bone mineral density (BMD) measured in such sub-volumes discriminates hip fracture risk better than BMD in standard anatomic regions such as the femoral neck and trochanter. Materials and methods: We employed inter-subject registration to transform hip QCT images of 37 patients with hip fractures and 38 age-matched controls into a voxel-based statistical atlas. Within voxels, we performed t-tests between the two groups to identify the regions which differed most. We then randomly divided the 75 scans into a training set and a test set. From the training set, we derived a fracture-driven region of interest (ROI) based on association with fracture. In the test set, we measured BMD in this ROI to determine fracture discrimination efficacy using ROC analysis. Additionally, we compared the BMD distribution differences between the 29 patients with neck fractures and the 8 patients with trochanteric fractures. Results: By evaluating fracture discrimination power based on ROC analysis, the fracture-driven ROI had an AUC (area under curve) of 0.92, while anatomic ROIs (including the entire proximal femur, the femoral neck, trochanter and their cortical and trabecular compartments) had AUC values between 0.78 and 0.87. We also observed that the neck fracture patients had lower BMD (p=0.014) in a small region near the femoral neck and the femoral head, and patients with trochanteric fractures had lower BMD in trochanteric regions such as in the internal calcar septum (p=0.006). Conclusions: We have identified the sub-volumes of proximal femoral tissue which have the strongest association with hip fracture. The power to predict fracture can be improved, by focusing on BMD measurements in the fracture-critical regions, rather than in standard ROIs. (C) 2008 Elsevier Inc. All rights reserved. C1 [Li, Wenjun; Kornak, John; Li, Caixia; Lu, Ying; Lang, Thomas] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. [Kornak, John; Lu, Ying] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Keyak, Joyce] Univ Calif Irvine, Dept Orthopaed Surg, Irvine, CA 92697 USA. [Cheng, Xiaoguang] Bejing Ji Shui Tan Hosp, Dept Radiol, Beijing, Peoples R China. RP Li, WJ (reprint author), Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. EM wenjun.li@radiology.ucsf.edu RI Lang, Thomas/B-2685-2012 OI Lang, Thomas/0000-0002-3720-8038 FU NASA [NNJ04HF78G]; NIH [NIH-R42-AR45713]; Eli Lilly FX This study was supported by NASA Grant NNJ04HF78G and NIH grant NIH-R42-AR45713. Acquisition of patients was supported by a grant from Eli Lilly. NR 28 TC 33 Z9 33 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD APR PY 2009 VL 44 IS 4 BP 596 EP 602 DI 10.1016/j.bone.2008.12.008 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 425CK UT WOS:000264614400012 PM 19130910 ER PT J AU Gupta, S Scanderbeg, DJ Kamrava, M Yashar, CM AF Gupta, Sonia Scanderbeg, Daniel J. Kamrava, Mitch Yashar, Catheryn M. TI Unexpected toxicity in a patient treated with 3D conformal accelerated partial breast radiotherapy SO BRACHYTHERAPY LA English DT Article DE Breast cancer; Breast-conserving therapy; Radiation therapy; Accelerated partial breast irradiation; 3D conformal radiation therapy; External beam radiation therapy ID IRRADIATION; CANCER; BRACHYTHERAPY; TRIAL AB INTRODUCTION: With the publication of several trials demonstrating equivalence between partial breast irradiation and whole breast irradiation, the popularity of partial breast radiation has increased. Methods of delivery include interstitial brachytherapy, intracavitary brachytherapy, and 3D conformal irradiation, although the least amount of data exists on 3D conformal. Despite the relative paucity of data on 3D conformal, it is the most common method delivered oil the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39 trial. To date, minimal toxicities and good cosmetic results have been associated with accelerated partial breast irradiation. METHODS AND MATERIAL: In this case study, we present a 64-year-old female patient, diagnosed with Grade I tubular carcinoma, who developed both expected and unexpected toxicities after 3D conformal accelerated partial breast irradiation. DISCUSSION/RESULTS/CONCLUSION: Along with chest wall pain, she developed hyperpigmentation of the skin as well as fibrosis of the skin, pectoralis minor, and pectoralis major. The fibrosis she developed limited her comfortable range of motion in the ipsilateral arm. She also developed symptomatic fractures of the fourth and fifth ribs in the anterior axillary line. Upon fusing the treatment-planning CT with a diagnostic CT, it was evident that the rib fractures fell within the 100% isodose line of the 3D conformal plan. (C) 2009 Published by Elsevier Inc on behalf of American Brachytherapy Society. C1 [Gupta, Sonia; Scanderbeg, Daniel J.; Yashar, Catheryn M.] Univ Calif San Diego, Dept Radiat Oncol, La Jolla, CA 92093 USA. [Gupta, Sonia] George Washington Univ, Dept Radiat Oncol, Washington, DC USA. [Kamrava, Mitch] NCI, Bethesda, MD 20892 USA. RP Yashar, CM (reprint author), Univ Calif San Diego, Dept Radiat Oncol, 3855 Hlth Sci Dr, La Jolla, CA 92093 USA. EM cyashar@ucsd.edu NR 7 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1538-4721 J9 BRACHYTHERAPY JI Brachytherapy PD APR-JUN PY 2009 VL 8 IS 2 BP 207 EP 209 DI 10.1016/j.brachy.2008.12.005 PG 3 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 448OT UT WOS:000266272600008 PM 19230788 ER PT J AU Blair, RJR AF Blair, R. J. R. TI Too much of a good thing: increased grey matter in boys with conduct problems and callous-unemotional traits SO BRAIN LA English DT Editorial Material ID VENTROMEDIAL PREFRONTAL CORTEX; ORBITOFRONTAL CORTEX; PSYCHOPATHY C1 NIMH, Mood & Anxiety Program, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Blair, RJR (reprint author), NIMH, Mood & Anxiety Program, US Dept HHS, NIH, Bethesda, MD 20892 USA. EM jamesblair@mail.nih.gov NR 7 TC 5 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD APR PY 2009 VL 132 BP 831 EP 832 DI 10.1093/brain/awp051 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 434IY UT WOS:000265269600008 PM 19293238 ER PT J AU Schmidt, J Dalakas, MC AF Schmidt, Jens Dalakas, Marinos C. TI Inflammation interrelates to APP in sIBM: IL-1 induces accumulation of -amyloid SO BRAIN LA English DT Letter ID INCLUSION-BODY MYOSITIS; SKELETAL-MUSCLE; BETA; PATHOGENESIS; IBM C1 [Schmidt, Jens] Univ Gottingen, Dept Neurol, D-37073 Gottingen, Germany. [Schmidt, Jens] Univ Gottingen, Dept Expt & Clin Neuroimmunol, D-37073 Gottingen, Germany. [Schmidt, Jens; Dalakas, Marinos C.] NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. [Dalakas, Marinos C.] Thomas Jefferson Univ, Neuromuscular Div, Philadelphia, PA 19107 USA. RP Schmidt, J (reprint author), Univ Gottingen, Dept Neurol, Waldweg 33, D-37073 Gottingen, Germany. EM j.schmidt@gmx.org; marinos.dalakas@jefferson.edu RI Schmidt, Jens/B-5791-2013 NR 15 TC 2 Z9 2 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD APR PY 2009 VL 132 AR e107 DI 10.1093/brain/awn164 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 434IY UT WOS:000265269600006 ER PT J AU Siebner, HR Bergmann, TO Bestmann, S Massimini, M Johansen-Berg, H Mochizuki, H Bohning, DE Boorman, ED Groppa, S Miniussi, C Pascual-Leone, A Huber, R Taylor, PCJ Ilmoniemi, RJ De Gennaro, L Strafella, AP Kahkonen, S Kloppel, S Frisoni, GB George, MS Hallett, M Brandt, SA Rushworth, MF Ziemann, U Rothwell, JC Ward, N Cohen, LG Baudewig, J Paus, T Ugawa, Y Rossini, PM AF Siebner, Hartwig R. Bergmann, Til O. Bestmann, Sven Massimini, Marcello Johansen-Berg, Heidi Mochizuki, Hitoshi Bohning, Daryl E. Boorman, Erie D. Groppa, Sergiu Miniussi, Carlo Pascual-Leone, Alvaro Huber, Reto Taylor, Paul C. J. Ilmoniemi, Risto J. De Gennaro, Luigi Strafella, Antonio P. Kahkonen, Seppo Kloppel, Stefan Frisoni, Giovanni B. George, Mark S. Hallett, Mark Brandt, Stephan A. Rushworth, Matthew F. Ziemann, Ulf Rothwell, John C. Ward, Nick Cohen, Leonardo G. Baudewig, Jurgen Paus, Tomas Ugawa, Yoshikazu Rossini, Paolo M. TI Consensus paper: Combining transcranial stimulation with neuroimaging SO BRAIN STIMULATION LA English DT Review DE transcranial magnetic stimulation; TMS; neuroimaging; multimodal brain mapping; EEG; fMRI; MRI; PET; NIRS; MEG ID PRIMARY MOTOR CORTEX; POSITRON-EMISSION-TOMOGRAPHY; CONCURRENT TMS-FMRI; CEREBRAL-BLOOD-FLOW; DORSAL PREMOTOR CORTEX; HEMOGLOBIN-CONCENTRATION CHANGES; CORTICAL OSCILLATORY ACTIVITIES; NEAR-INFRARED SPECTROSCOPY; STRIATAL DOPAMINE RELEASE; THETA-BURST STIMULATION AB In the last decade, combined transcranial magnetic stimulation (TMS)-neuroimaging studies have greatly stimulated research in the field of TMS and neuroimaging. Here, we review how TMS can be combined with various neuroimaging techniques to investigate human brain function. When applied during neuroimaging (online approach), TMS can be used to test how focal cortex stimulation acutely modifies the activity and connectivity in the stimulated neuronal circuits. TMS and neuroimaging can also be separated in time (offline approach). A conditioning session of repetitive TMS (rTMS) may be used to induce rapid reorganization in functional brain networks. The temporospatial patterns of TMS-induced reorganization can be subsequently mapped by using neuroimaging methods. Alternatively, neuroimaging may be performed first to localize brain areas that are involved in a given task. The temporospatial information obtained by neuroimaging can be used to define the optimal site and time point of stimulation in a subsequent experiment in which TMS is used to probe the functional contribution of the stimulated area. to a specific task. In this review, we first address some general methodologic issues that need to be taken into account when using TMS in the context of neuroimaging. We then discuss the use of specific brain mapping techniques in conjunction with TMS. We emphasize that the various neuroimaging techniques offer complementary information and have different methodologic strengths and weaknesses. (C) 2009 Elsevier Inc. All rights reserved. C1 [Siebner, Hartwig R.] Copenhagen Univ Hosp, Danish Res Ctr Magnet Resonance, DK-2650 Hvidovre, Denmark. [Siebner, Hartwig R.; Bergmann, Til O.; Groppa, Sergiu] Univ Kiel, Dept Neurol, D-2300 Kiel, Germany. [Bestmann, Sven; Rothwell, John C.; Ward, Nick] Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. [Bestmann, Sven; Ward, Nick] UCL, Inst Neurol, Wellcome Trust Ctr Neuroimaging, London, England. [Massimini, Marcello] Univ Milan, Fac Med, Dept Clin Sci, I-20122 Milan, Italy. [Johansen-Berg, Heidi; Boorman, Erie D.] Univ Oxford, Ctr Funct Magnet Resonance Imaging Brain, Oxford, England. [Johansen-Berg, Heidi] Univ Oxford, Dept Clin Neurol, Oxford, England. [Mochizuki, Hitoshi; Ugawa, Yoshikazu] Fukushima Med Univ, Sch Med, Dept Neurol, Fukushima, Japan. [Bohning, Daryl E.; George, Mark S.] Med Univ S Carolina, Ctr Adv Imaging Res, Charleston, SC 29425 USA. [Bohning, Daryl E.] Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. [Miniussi, Carlo; De Gennaro, Luigi] IRCCS S Giovanni di Dio Fatebenefratelli, Brescia, Italy. [Miniussi, Carlo] Univ Brescia, Natl Inst Neurosci, Dept Biomed Sci & Biotechnol, Brescia, Italy. [Pascual-Leone, Alvaro] Beth Israel Deaconess Med Ctr, Berenson Allen Ctr Noninvas Brain Stimulat, Dept Neurol, Boston, MA 02215 USA. [Huber, Reto] Univ Childrens Hosp, Zurich, Switzerland. [Pascual-Leone, Alvaro] Harvard Univ, Sch Med, Boston, MA USA. [Taylor, Paul C. J.] Birkbeck Coll, Sch Psychol, London, England. [Ilmoniemi, Risto J.; Kahkonen, Seppo] Univ Helsinki, Cent Hosp, BioMag Lab, Helsinki, Finland. [Ilmoniemi, Risto J.] Helsinki Univ Technol, Dept Biomed Engn & Computat Sci, Helsinki, Finland. [De Gennaro, Luigi] Univ Roma La Sapienza, Dept Psychol, Rome, Italy. [Strafella, Antonio P.] Univ Toronto, Div Neurol, Toronto Western Hosp, Movement Disorders Ctr, Toronto, ON M5S 1A1, Canada. [Kahkonen, Seppo] Univ Helsinki, Cent Hosp, Pain Clin, Helsinki, Finland. [Kloppel, Stefan] Univ Clin Freiburg, Dept Psychiat & Psychotherapy, Freiburg, Germany. [Frisoni, Giovanni B.] Natl Ctr Alzheimers & Mental Dis, Brescia, Italy. [George, Mark S.] Med Univ S Carolina, Brain Stimulat Lab, Charleston, SC 29425 USA. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Brandt, Stephan A.] Charite Univ Med Berlin, Berlin NeuroImaging Ctr, Dept Neurol, Berlin, Germany. [Rushworth, Matthew F.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Ziemann, Ulf] Univ Frankfurt, Dept Neurol, D-6000 Frankfurt, Germany. [Cohen, Leonardo G.] NINDS, Human Cort Physiol & Stroke Neurorehabilitat Sect, NIH, Bethesda, MD 20892 USA. [Baudewig, Jurgen] Univ Gottingen, Fac Med, MR Res Neurol & Psychiat, Gottingen, Germany. [Paus, Tomas] Univ Nottingham, Brain & Body Ctr, Nottingham NG7 2RD, England. [Paus, Tomas] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada. [Rossini, Paolo M.] Casa Cura S Raffaele Cassino & IRCCS S Raffaele P, Rome, Italy. [Rossini, Paolo M.] Hosp Fatebenefratelli, Dept Neurosci, AFaR, Rome, Italy. [Rossini, Paolo M.] Neurol Clin, Rome, Italy. RP Siebner, HR (reprint author), Copenhagen Univ Hosp, Danish Res Ctr Magnet Resonance, Kettegaards Alle 30, DK-2650 Hvidovre, Denmark. EM hartwig.siebner@drcmr.dk RI Baudewig, Juergen/F-4468-2010; Bergmann, Til/F-9453-2010; Miniussi, Carlo/E-7602-2010; Ilmoniemi, Risto/E-9704-2012; Rossini, Paolo /D-4994-2013; Groppa, Sergiu/G-4606-2014; De Gennaro, Luigi/L-8711-2015; Siebner, Hartwig/G-4052-2016; Frisoni, Giovanni B/K-1360-2016; OI Johansen-Berg, Heidi/0000-0002-4134-9730; Massimini, Marcello/0000-0003-2271-957X; Bergmann, Til/0000-0002-2282-6618; Miniussi, Carlo/0000-0002-5436-4745; Ilmoniemi, Risto/0000-0002-3340-2618; Rossini, Paolo /0000-0003-2665-534X; De Gennaro, Luigi/0000-0003-3613-6631; Frisoni, Giovanni B/0000-0002-6419-1753; Rothwell, John/0000-0003-1367-6467 FU Biotechnology and Biological Sciences Research Council [BB/F02424X/1]; Medical Research Council [G0802146]; Wellcome Trust [078204] NR 151 TC 130 Z9 132 U1 4 U2 37 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X J9 BRAIN STIMUL JI Brain Stimul. PD APR PY 2009 VL 2 IS 2 BP 58 EP 80 DI 10.1016/j.brs.2008.11.002 PG 23 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 445RD UT WOS:000266068300002 PM 20633405 ER PT J AU Quartarone, A Classen, J Morgante, F Rosenkranz, K Hallett, M AF Quartarone, Angelo Classen, Joseph Morgante, Francesca Rosenkranz, Karin Hallett, Mark TI Consensus paper: Use of transcranial magnetic stimulation to probe motor cortex plasticity in dystonia and levodopa-induced dyskinesia SO BRAIN STIMULATION LA English DT Article DE dystonia; levodopa-induced dyskinesia; Parkinson's disease; plasticity; musicians; TMS ID PAIRED ASSOCIATIVE STIMULATION; LONG-TERM POTENTIATION; FOCAL HAND DYSTONIA; STRIATAL SYNAPTIC PLASTICITY; PARKINSONS-DISEASE; CORTICAL PLASTICITY; WRITERS CRAMP; SOMATOSENSORY CORTEX; PALLIDAL STIMULATION; DEPENDENT PLASTICITY AB Plasticity includes the ability of the nervous system to optimize neuronal activity at a cellular and system level according to the needs imposed by the environment. Neuroplasticity phenomena within sensorimotor cortex are crucial to enhance function to increase skillfulness. Such plasticity may be termed "adaptive" to indicate its ecologically beneficial role. In professional musicians, enhanced adaptive plasticity is associated with one of the highest level of motor skill a human being can achieve and the amount of these changes is even dependent on the age at which instrumental playing was started. In addition, adaptive neuroplastic changes occur when nervous system try to repair itself thus compensating dysfunctions. However, when these adaptive phenomena are pushed to an extreme, they can produce a maladaptive sensorimotor reorganization that interferes with motor performance rather than improving it. The model we discuss here is focal hand dystonia I which an intrinsic abnormality of neural plasticity, in some predisposed individuals, may lead to abnormal sensorimotor integration and to the appearance of a characteristic movement disorder. Deficient homeostatic control might be an important mechanism triggering this maladaptive reorganization, and future behavioral studies are needed to confirm this hypothesis. In the second part of this consensus paper, we will critically discuss as a second model, the hypothesis that levodopa-induced dyskinesia correlate with an aberrant form of plasticity in the human primary motor cortex, possibly because of abnormal oscillations within the basal ganglia loop. Disorders of cortical plasticity have not in the past been considered as possible causes of human clinical states. The recognition that this can occur, together with a speculative mechanism, generates an important and provocative hypothesis for future research at the clinical-scientific inter-face. (C) 2009 Elsevier Inc. All rights reserved. C1 [Quartarone, Angelo] Univ Messina, Dipartimento Neurosci Sci Psichiatr & Anestesiol, UOC Neuropatol, AOU G Martino, I-98125 Messina, Italy. [Classen, Joseph] Univ Wurzburg, Dept Neurol, Human Cort Physiol & Motor Control Lab, D-97070 Wurzburg, Germany. [Rosenkranz, Karin] Inst Neurol, Sobell Dept Motor Neurosci & Movement Disorders, London WC1N 3BG, England. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Quartarone, A (reprint author), Univ Messina, Dipartimento Neurosci Sci Psichiatr & Anestesiol, UOC Neuropatol, AOU G Martino, I-98125 Messina, Italy. EM angelo.quartarone@unime.it RI Morgante, Francesca/E-8717-2010; OI QUARTARONE, Angelo/0000-0003-1485-6590; MORGANTE, FRANCESCA/0000-0002-9834-3639 NR 96 TC 8 Z9 8 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1935-861X J9 BRAIN STIMUL JI Brain Stimul. PD APR PY 2009 VL 2 IS 2 BP 108 EP 117 DI 10.1016/j.brs.2008.09.010 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 445RD UT WOS:000266068300007 PM 20633408 ER PT J AU Patel, GK Yee, CL Vogel, JC AF Patel, G. K. Yee, C. L. Vogel, J. C. TI The identification of primary human cutaneous squamous cell carcinoma stem cells SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Meeting Abstract CT Annual Meeting of the British-Society-for-Investigative-Dermatology CY MAR 30-APR 01, 2009 CL Royal Agr Coll, Cirencester, ENGLAND SP British Soc Invest Dermatol HO Royal Agr Coll C1 [Patel, G. K.] Cardiff Univ, Sch Med, Dept Dermatol, Cardiff, S Glam, Wales. [Yee, C. L.; Vogel, J. C.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. EM patelgk@cardiff.ac.uk NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD APR PY 2009 VL 160 IS 4 BP 905 EP 905 PG 1 WC Dermatology SC Dermatology GA 421FL UT WOS:000264344700043 ER PT J AU O'Connor, OA Moskowitz, C Portlock, C Hamlin, P Straus, D Dumitrescu, O Sarasohn, D Gonen, M Butos, J Neylon, E Hamelers, R Mac-Gregor Cortelli, B Blumel, S Zelenetz, AD Gordon, L Wright, JJ Vose, J Cooper, B Winter, J AF O'Connor, Owen A. Moskowitz, Craig Portlock, Carol Hamlin, Paul Straus, David Dumitrescu, Otilia Sarasohn, Debra Gonen, Mithat Butos, John Neylon, Ellen Hamelers, Rachel Mac-Gregor Cortelli, Barbara Blumel, Susan Zelenetz, Andrew D. Gordon, Leo Wright, John J. Vose, Julie Cooper, Brenda Winter, Jane TI Patients with chemotherapy-refractory mantle cell lymphoma experience high response rates and identical progression-free survivals compared with patients with relapsed disease following treatment with single agent bortezomib: results of a multicentre phase 2 clinical trial SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE bortezomib; mantle cell lymphoma; non-Hodgkin lymphoma; proteasome inhibition ID NON-HODGKINS-LYMPHOMA; PROTEASOME INHIBITOR BORTEZOMIB; MALIGNANCIES; ACTIVATION; SYNERGIZES; EXPRESSION AB The recent approval of bortezomib for the treatment of mantle cell lymphoma (MCL) by the US Food and Drug Administration is based on the results of the multicentre PINNACLE study with supportive data from a number of single and multicentre Phase 2 studies. This multicentre Phase 2 study enroled 40 patients with heavily pretreated MCL. The overall response rate (ORR) was 47%, including 5 complete remissions and 14 partial remissions. Overall, these remissions are relatively durable. The ORR in relapsed and refractory patients was 50% and 43% respectively (P = 0.74), while both populations of patients exhibited essentially similar progression-free survival (PFS; 5.6 months vs. 3.9 months, P = 0.81). Responding patients experienced a PFS from bortezomib that was similar to their line of prior therapy (7.8 months vs. 8.4 months, respectively). The data showed similar responses in relapsed and refractory patients as well as remission durations similar to prior therapy, suggesting that there may be little cross-resistance with other conventional cytotoxic agents. Importantly, these data suggest that MCL patients with refractory or poorly responsive disease may still derive meaningful clinical benefit from treatment with bortezomib. C1 [O'Connor, Owen A.] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Lymphoma Serv, Lymphoid Dev & Malignancy Program, New York, NY 10032 USA. [O'Connor, Owen A.; Neylon, Ellen; Hamelers, Rachel; Mac-Gregor Cortelli, Barbara] Columbia Univ, New York Presbyterian Hosp, Coll Phys & Surg, New York, NY USA. [Moskowitz, Craig; Portlock, Carol; Hamlin, Paul; Straus, David; Butos, John; Zelenetz, Andrew D.] Mem Sloan Kettering Canc Ctr, Dept Med, Div Hematol Oncol, New York, NY 10021 USA. [Dumitrescu, Otilia; Sarasohn, Debra] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Gonen, Mithat] Mem Sloan Kettering Canc Ctr, Dept Stat, New York, NY 10021 USA. [Blumel, Susan; Vose, Julie] Univ Nebraska, Dept Med, Omaha, NE 68182 USA. [Gordon, Leo; Winter, Jane] Northwestern Univ, Dept Med, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. [Wright, John J.] NCI, CTEP, Bethesda, MD 20892 USA. [Cooper, Brenda] Case Western Reserve Univ, Univ Hosp Cleveland, Ctr Comprehens Canc, Dept Med, Cleveland, OH 44106 USA. RP O'Connor, OA (reprint author), Columbia Univ, Herbert Irving Comprehens Canc Ctr, Lymphoma Serv, Lymphoid Dev & Malignancy Program, 1130 St Nicholas Ave,Room 216, New York, NY 10032 USA. EM oo2130@columbia.edu RI Sarasohn, Debra/A-1863-2010; Gonen, Mithat/E-4826-2012 FU NCI Phase II [UO1 CA 69913]; [K23 CA109613] FX OAO is the recipient of the Leukemia and Lymphoma Society Scholar in Research Award. This work was supported under a NCI Phase II Grant (UO1 CA 69913). AME is supported in part by K23 CA109613. We would also like to thank Shereen Mohammed for her assistance in the preparation of this manuscript. NR 16 TC 43 Z9 43 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD APR PY 2009 VL 145 IS 1 BP 34 EP 39 DI 10.1111/j.1365-2141.2008.07466.x PG 6 WC Hematology SC Hematology GA 417OH UT WOS:000264085100004 PM 19220284 ER PT J AU Jiang, LY Yuan, CM Hubacheck, J Janik, JE Wilson, W Morris, JC Jasper, GA Stetler-Stevenson, M AF Jiang, Liuyan Yuan, Constance M. Hubacheck, Julia Janik, John E. Wilson, Wyndham Morris, John C. Jasper, Gregory A. Stetler-Stevenson, Maryalice TI Variable CD52 expression in mature T cell and NK cell malignancies: implications for alemtuzumab therapy SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE alemtuzumab; CD52; flow cytometry; NK cell lymphoma; T cell lymphoma ID ANTI-CD52 MONOCLONAL-ANTIBODY; CHRONIC LYMPHOCYTIC-LEUKEMIA; COMPLEMENT-MEDIATED LYSIS; PROLYMPHOCYTIC LEUKEMIA; CAMPATH-1H; CHEMOTHERAPY; LYMPHOMA; ANTIGEN; TRANSPLANTATION; MARROW AB The anti-CD52 antibody alemtuzumab has been explored as a novel targeted therapy in T cell malignancies. To assess the suitability of alemtuzumab therapy, we carried out a comprehensive study of CD52 expression using flow cytometry (FC) in 78 untreated patients diagnosed with mature T/natural killer (NK) cell neoplasms, including 34 adult T cell leukaemia/lymphomas (ATLL), two anaplastic large cell lymphomas (ALCL), three angioimmunoblastic T cell lymphomas (AITL), 16 cutaneous T cell lymphomas (CTCL), four extra-nodal T/NK cell lymphomas (ENT/NKCL), four hepatosplenic T cell lymphomas (HSTCL), 13 peripheral T cell lymphomas, not otherwise specified (PTCL-NOS) and two T-prolymphocytic leukaemia (T-PLL). The level of CD52 expression was quantified using QuantiBRITE standard beads. The level of CD52 expression varied widely within each diagnostic category. All AITL, HSTCL and T-PLL cases were CD52-positive and the frequency of CD52 expression was high in PTCL-NOS (92.3%), ATLL (94.1%) and CTCL (87.5%), implying a rational role for alemtuzumab in the treatment of these diseases; however, CD52 expression was low in ALCL (50%) and ENT/NKCL (25%). FC testing for cell surface expression of CD52 is indicated in patients with T/NK cell malignancies being considered for alemtuzumab therapy. Further studies are necessary to determine if the level of CD52 expression correlates with response to therapy. C1 [Jiang, Liuyan; Yuan, Constance M.; Hubacheck, Julia; Jasper, Gregory A.; Stetler-Stevenson, Maryalice] NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Janik, John E.; Wilson, Wyndham; Morris, John C.] NCI, Metab Branch, Ctr Canc Res, NIH,Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Stetler-Stevenson, M (reprint author), NCI, Flow Cytometry Unit, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 2A-33,10 Ctr Dr, Bethesda, MD 20892 USA. EM stetler@mail.nih.gov FU Intramural NIH HHS [Z01 BC011104-01] NR 27 TC 32 Z9 35 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD APR PY 2009 VL 145 IS 2 BP 173 EP 179 DI 10.1111/j.1365-2141.2009.07606.x PG 7 WC Hematology SC Hematology GA 424JS UT WOS:000264563600003 PM 19236377 ER PT J AU Lencz, T Lipsky, RH DeRosse, P Burdick, KE Kane, JM Malhotra, AK AF Lencz, Todd Lipsky, Robert H. DeRosse, Pamela Burdick, Katherine E. Kane, John M. Malhotra, Anil K. TI Molecular differentiation of schizoaffective disorder from schizophrenia using BDNF haplotypes SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID NEUROTROPHIC FACTOR BDNF; FAMILY-BASED ASSOCIATION; FACTOR VAL66MET POLYMORPHISM; GENOME-WIDE ASSOCIATION; BIPOLAR DISORDER; RISK-FACTOR; GENE; SUSCEPTIBILITY; LOCUS; VARIANTS AB Background Allelic variation in the gene encoding brain-derived neurotrophic factor (BDNF) has been associated with affective disorders, but generally not schizophrenia. Brain-derived neurotrophic factor variants may help clarify the status of schizoaffective disorder. Aims To test the hypothesis that BDNF haplotypes are associated with psychiatric illness marked by a prominent affective component. Method Frequencies of a 5-marker BDNF haplotype were examined in 600 White participants across four diagnostic categories and healthy controls. Results Individuals with schizoaffective disorder and other affective disorders were significantly more likely to carry two copies of the most common BDNF haplotype (containing the valine allele of the Val66Met polymorphism) compared with healthy volunteers. Moreover, when compared with people with schizophrenia, individuals with schizoaffective disorder were significantly more likely to carry two copies of the common haplotype. Conclusions To our knowledge, this is the first candidate gene study to demonstrate association with schizoaffective disorder but not schizophrenia. Variation in the BDNF gene may be associated with the clinical phenotype of affective dysregulation across several DSM-IV diagnostic categories. C1 [Lencz, Todd; Burdick, Katherine E.; Kane, John M.; Malhotra, Anil K.] Zucker Hillside Hosp, Ctr Translat Psychiat, Feinstein Inst Med Res, Glen Oaks, NY 11004 USA. [Lencz, Todd; DeRosse, Pamela; Burdick, Katherine E.; Malhotra, Anil K.] Zucker Hillside Hosp, Div Psychiat Res, Glen Oaks, NY 11004 USA. [Lipsky, Robert H.] NIAAA, Neurogenet Lab, Bethesda, MD USA. [Kane, John M.] Zucker Hillside Hosp, Dept Psychiat, Glen Oaks, NY 11004 USA. RP Lencz, T (reprint author), Zucker Hillside Hosp, Ctr Translat Psychiat, Feinstein Inst Med Res, 75-59 263rd St, Glen Oaks, NY 11004 USA. EM lencz@lij.edu RI Burdick, Katherine/G-6124-2012; Lencz, Todd/J-3418-2014; OI Lencz, Todd/0000-0001-8586-338X; Lipsky, Robert/0000-0001-7753-1473 FU National Institute of Mental Health [K01 MH65580, P30 MH60575, K23 MH01760]; General Clinical Research Center [M01 RR18535]; National Alliance for Research on Schizophrenia and Depression FX This work was supported by the following grants from the National Institute of Mental Health: K01 MH65580 (T.L.), P30 MH60575 (J.M.K.), K23 MH01760 (A.K.M.), and a General Clinical Research Center (M01 RR18535) to the North Shore - Long Island Jewish Health System. This work was also supported by the National Alliance for Research on Schizophrenia and Depression (T.L. and A.K.M.). NR 50 TC 32 Z9 32 U1 1 U2 2 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD APR PY 2009 VL 194 IS 4 BP 313 EP 318 DI 10.1192/bjp.bp.108.050401 PG 6 WC Psychiatry SC Psychiatry GA 433HR UT WOS:000265195400005 PM 19336781 ER PT J AU Shainberg, A Yitzhaki, S Golan, O Jacobson, KA Hochhauser, E AF Shainberg, Asher Yitzhaki, Smadar Golan, Or Jacobson, Kenneth A. Hochhauser, Edith TI Involvement of UTP in protection of cardiomyocytes from hypoxic stress SO CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY LA English DT Article; Proceedings Paper CT NATO Advanced Research Workshop on Translational Knowledge for Heart Health CY MAY 12-16, 2008 CL Istanbul, TURKEY SP NATO Sci Peace & Security Programme, Int Ctr Gent Engn & Biotechnol, Int Acad Cardiovasc Sci, Cmmat Ltd, DATEKS Co Ltd, Leica Resolut DE calcium; cardioprotection; cardiac cell culture; heart; hypoxia; ischemia; nucleotides; preconditioning; pyrimidines ID CARDIAC MYOCYTES; VENTRICULAR MYOCYTES; RECEPTOR ACTIVATION; RAT CARDIOMYOCYTES; EXTRACELLULAR ATP; ADENOSINE A(1); HEART; ISCHEMIA; SURVIVAL; AGONIST AB Massive amounts of nucleotides are released during ischemia in the cardiovascular system. Although the effect of the purine nucleotide ATP has been intensively studied in myocardial infarction, the cardioprotective role of the pyrimidine nucleotide UTP is still unclear, especially in the cardiovascular system. The purpose of our study was to elucidate the protective effects of UTP receptor activation and describe the downstream cascade for the cardioprotective effect. Cultured cardiomyocytes and left anterior descending (LAD)-ligated rat hearts were pretreated with UTP and exposed to hypoxia-ischemia. In vitro experiments revealed that UTP reduced cardiomyocyte death induced by hypoxia, an effect that was diminished by suramin. UTP caused several effects that could trigger a cardioprotective response: a transient increase of [Ca(2+)](i), an effect that was abolished by PPADS or RB2; phosphorylation of the kinases ERK and Akt, which was abolished by U0126 and LY294002, respectively; and reduced mitochondrial calcium elevation after hypoxia. In vivo experiments revealed that UTP maintained ATP levels, improved mitochondrial activity, and reduced infarct size. In conclusion, UTP administrated before ischemia reduced infarct size and improved myocardial function. Reduction of mitochondrial calcium overload can partially explain the protective effect of UTP after hypoxic-ischemic injury. C1 [Shainberg, Asher; Yitzhaki, Smadar; Golan, Or] Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. [Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Hochhauser, Edith] Tel Aviv Univ, Rabin Med Ctr, FMRC, IL-69978 Tel Aviv, Israel. RP Shainberg, A (reprint author), Bar Ilan Univ, Fac Life Sci, IL-52900 Ramat Gan, Israel. EM shaina@mail.biu.ac.il RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031116-21, Z99 DK999999] NR 34 TC 11 Z9 11 U1 0 U2 3 PU NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS PI OTTAWA PA BUILDING M 55, OTTAWA, ON K1A 0R6, CANADA SN 0008-4212 J9 CAN J PHYSIOL PHARM JI Can. J. Physiol. Pharmacol. PD APR PY 2009 VL 87 IS 4 BP 287 EP 299 DI 10.1139/Y09-010 PG 13 WC Pharmacology & Pharmacy; Physiology SC Pharmacology & Pharmacy; Physiology GA 439CU UT WOS:000265606000005 PM 19370082 ER PT J AU Mirabello, L Troisi, RJ Savage, SA AF Mirabello, Lisa Troisi, Rebecca J. Savage, Sharon A. TI Osteosarcoma Incidence and Survival Rates From 1973 to 2004 Data From the Surveillance, Epidemiology, and End Results Program SO CANCER LA English DT Article DE osteosarcoma; bone cancer; epidemiology; Surveillance; Epidemiology; and End Results; incidence; survival ID CHILDHOOD-CANCER SURVIVAL; OSTEOGENIC-SARCOMA; UNITED-STATES; BONE CANCERS; EWINGS-SARCOMA; AGE; CHILDREN; TRENDS; SEX; CHONDROSARCOMA AB BACKGROUND: Osteosarcoma, which is the most common primary bone tumor, occurs most frequently in adolescents, but there is a second incidence peak among individuals aged >60 years. Most osteosarcoma epidemiology studies have been embedded in large analyses of all bone tumors or focused on cases occurring in adolescence. Detailed descriptions of osteosarcoma incidence and survival with direct comparisons among patients of all ages and ethnicities are not available. METHODS: Frequency, incidence, and survival rates for 3482 patients with osteosarcoma from the National Cancer Institute's population-based Surveillance, Epidemiology, and End Results (SEER) Program between 1973 and 2004 were investigated by age (ages 0-24 years, 25-59 years, and 60 to >= 185 years), race, sex, pathology subtype, stage, and anatomic site. RESULTS: There were large differences in incidence and survival rates by age. There was a high percentage of osteosarcoma with Paget disease and osteosarcoma as a second or later cancer among the elderly. There was a high percentage of osteosarcoma among patients with Paget disease and osteosarcoma as a second or later cancer among the elderly. Tumor site differences among age groups were noted. Survival rates varied by anatomic site and disease stage and did not improve significantly from 1984 to 2004. CONCLUSIONS: This comprehensive, population-based description of osteosarcoma, identified important differences in incidence, survival, pathologic subtype, and anatomic site among age groups, and quantified the impact of osteosarcoma in patients with Paget disease or as a second cancer on incidence and mortality rates. These findings may have implications in understanding osteosarcoma biology and epidemiology. Cancer 2009;115:1531-43. (C) 2009 American Cancer Society. C1 [Mirabello, Lisa; Savage, Sharon A.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Troisi, Rebecca J.] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Troisi, Rebecca J.] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. RP Savage, SA (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7018, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Intramural Research Program of the National Institutes of Health; National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 53 TC 464 Z9 496 U1 8 U2 35 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD APR 1 PY 2009 VL 115 IS 7 BP 1531 EP 1543 DI 10.1002/cncr.24121 PG 13 WC Oncology SC Oncology GA 422ME UT WOS:000264431600019 PM 19197972 ER PT J AU Howard, RA Leitzmann, MF Linet, MS Freedman, DM AF Howard, Regan A. Leitzmann, Michael F. Linet, Martha S. Freedman, D. Michal TI Physical activity and breast cancer risk among pre- and postmenopausal women in the US Radiologic Technologists cohort SO CANCER CAUSES & CONTROL LA English DT Article DE Breast cancer; Physical activity; Cohort studies; Hormones ID PREMENOPAUSAL WOMEN; CONSTRUCT-VALIDITY; UNITED-STATES; FOLLOW-UP; HEALTH; MECHANISMS; POPULATION; LIFE AB To clarify aspects of the association between physical activity and breast cancer, such as activity intensity required, and possible effect modification by factors such as menopausal hormone therapy (MHT) use. We prospectively examined physical activity in relation to breast cancer risk among 45,631 women participating in the U.S. Radiologic Technologists cohort. Participants provided information at baseline regarding hours spent per week engaging in strenuous activity, walking/hiking for exercise, and walking at home or work. We estimated multivariable relative risks (RR) and 95% confidence intervals (CI) of breast cancer using Cox regression. We identified 864 incident-invasive breast cancers. Greatest risk reduction was observed among women who reported walking/hiking for exercise 10 or more hours per week (RR, 0.57; 95% CI, 0.34-0.95) compared with those reporting no walking/hiking. The association between walking/hiking for exercise and breast cancer was modified by MHT use (p for interaction = 0.039). Postmenopausal women who never used MHT had reduced risks of breast cancer associated with physical activity whereas no relation was observed among ever users of MHT. Our study suggests moderate intensity physical activity, such as walking, may protect against breast cancer. Further, the relation between physical activity and breast cancer may be modified by MHT use. C1 [Howard, Regan A.; Linet, Martha S.; Freedman, D. Michal] NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, NIH,DHHS, Bethesda, MD 20892 USA. [Leitzmann, Michael F.] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. RP Freedman, DM (reprint author), NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, NIH,DHHS, Execut Plaza S,Suite 7036, Bethesda, MD 20892 USA. EM freedmam@mail.nih.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Division of Cancer Epidemiology and Genetics FX We are indebted to Jeremy Miller, Information Management Services, Rockville, MD, for expert computer support and data management. This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 45 TC 24 Z9 25 U1 0 U2 6 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2009 VL 20 IS 3 BP 323 EP 333 DI 10.1007/s10552-008-9246-2 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 413IO UT WOS:000263787000006 PM 18941914 ER PT J AU Figueroa, JD Terry, MB Gammon, MD Vaughan, TL Risch, HA Zhang, FF Kleiner, DE Bennett, WP Howe, CL Dubrow, R Mayne, ST Fraumeni, JF Chow, WH AF Figueroa, Jonine D. Terry, Mary Beth Gammon, Marilie D. Vaughan, Thomas L. Risch, Harvey A. Zhang, Fang-Fang Kleiner, David E. Bennett, William P. Howe, Christine L. Dubrow, Robert Mayne, Susan T. Fraumeni, Joseph F., Jr. Chow, Wong-Ho TI Cigarette smoking, body mass index, gastro-esophageal reflux disease, and non-steroidal anti-inflammatory drug use and risk of subtypes of esophageal and gastric cancers by P53 overexpression SO CANCER CAUSES & CONTROL LA English DT Article DE P53; Esophageal cancer; Body mass index; Tobacco; NSAIDs; GERD ID SQUAMOUS-CELL CARCINOMA; TUMOR-SUPPRESSOR GENE; HUMAN LUNG-CANCER; PROTEIN ACCUMULATION; BARRETTS-ESOPHAGUS; MOLECULAR EPIDEMIOLOGY; ADENOCARCINOMA; CARDIA; MUTATION; ASSOCIATION AB A number of risk factors for esophageal and gastric cancers have emerged, yet little is known whether risk factors map to molecular tumor markers such as overexpression of the tumor suppressor TP53. Using a US multicenter, population-based case-control study (170 cases of esophageal adenocarcinomas, 147 gastric cardia adenocarcinomas, 220 non-cardia gastric adenocarcinomas, and 112 esophageal squamous cell carcinomas), we examined whether the risk associated with cigarette smoking, body mass index (BMI), gastroesophageal reflux disease (GERD), and non-steroidal anti-inflammatory drug (NSAID) use varied by P53 overexpression. We defined P53 overexpression through immunohistochemistry of paraffin-embedded tumor tissues, using cutpoints based on percent of cells positive. Polytomous logistic regression was used to assess differences between each case group (defined by tumor subtype and P53 expression) and the control group by risk factors. The proportion of cases overexpressing P53 by tumor subtype was 72% for esophageal adenocarcinoma, 69% for gastric cardia adenocarcinoma, 52% for non-cardia gastric adenocarcinoma, and 67% for esophageal squamous cell carcinoma. For most tumor subtypes, we found little difference in risk factors by tumor P53 overexpression. For non-cardia gastric cancer however, an association with cigarette smoking was suggested for tumors that do not overexpress P53, whereas larger BMI was related to adenocarcinomas that overexpress P53 versus no overexpression. Overall, this study did not find a clear relationship between P53 protein overexpression and the known risk factors for subtypes of esophageal and gastric cancers. Further research on these tumors is needed to identify molecular markers associated with variations in the risk factor profiles. C1 [Figueroa, Jonine D.; Fraumeni, Joseph F., Jr.; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Figueroa, Jonine D.] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, NIH, Bethesda, MD 20892 USA. [Terry, Mary Beth; Zhang, Fang-Fang] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Gammon, Marilie D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. [Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Vaughan, Thomas L.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Risch, Harvey A.; Dubrow, Robert; Mayne, Susan T.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Kleiner, David E.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Bennett, William P.] City Hope Natl Med Ctr, Dept Thorac Surg, Duarte, CA 91010 USA. [Howe, Christine L.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. RP Figueroa, JD (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM figueroaj@mail.nih.gov OI Kleiner, David/0000-0003-3442-4453 FU Public Health Service [U01-CA57983, U01-CA57049, U01-CA57923]; National Cancer Institute; National Institutes of Health; Department of Health and Human Services FX Jonine Figueroa would like to thank the Cancer Prevention Fellowship Program, Office of Preventive Oncology, NCI, DHHS for their support. We thank the following: data manager Shelley Niwa (Westat) and field supervisors Patricia Owens (Connecticut), Tom English (New Jersey), and Berta Nicol-Blades (Washington) for data collection and processing; the Yale Cancer Center Rapid Case Ascertainment Shared Resource; the 178 hospitals in Connecticut, New Jersey, and Washington for their participation in the study; and the study participants. Supported in part by Public Health Service grants U01-CA57983 (M. D. Gammon), U01-CA57049 (T. L. Vaughan), and U01-CA57923 (H. A. Risch) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. The work was supported in part by the Intramural Research Program of the National Institutes of Health, Division of Cancer Epidemiology and Genetics. NR 35 TC 16 Z9 18 U1 2 U2 7 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2009 VL 20 IS 3 BP 361 EP 368 DI 10.1007/s10552-008-9250-6 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 413IO UT WOS:000263787000010 PM 18989634 ER PT J AU Nemesure, B Wu, SY Hennis, A Leske, MC AF Nemesure, Barbara Wu, Suh-Yuh Hennis, Anselm Leske, M. Cristina CA Barbados Natl Canc Study Grp TI Body size and breast cancer in a black population-The Barbados National Cancer Study SO CANCER CAUSES & CONTROL LA English DT Article DE Height; Weight; Body circumferences; Breast cancer; African ancestry ID WAIST-HIP RATIO; NIGERIAN WOMEN; UNITED-STATES; RISK-FACTORS; WHITE WOMEN; HEIGHT; WEIGHT; OBESITY; HEALTH; AGE AB To evaluate the relationship between body size and incident breast cancer in an African-origin Caribbean population. This investigation is based on 222 incident breast cancer cases and 454 controls from the Barbados National Cancer Study (BNCS) in whom body size variables that included height, weight, body-mass index (BMI), waist and hip circumferences (WC, HC), and waist-hip ratio (WHR) were compared. Multivariate-adjusted logistic regression analyses were performed and the findings are presented as odds ratios (ORs) with 95% confidence intervals (CI). Although 33% of cases and 39% of controls were obese (BMI a parts per thousand yen 30 kg/m(2)), BMI was not found to be a significant predictor of breast cancer in the multivariate analyses. Tall stature increased risk among women a parts per thousand yen50 years (OR = 2.16, 95% CI (1.02, 4.58)), and a dual effect with age was suggested for both WC and WHR (decreased risk for those aged a parts per thousand currency sign50 years; increased risk among those a parts per thousand yen50 years). Body size appears to influence the risk of breast cancer in this population of African origin. The BNCS data suggest that a few, but not all body size factors play a role in breast cancer risk, and that age may affect these relationships. C1 [Nemesure, Barbara; Wu, Suh-Yuh; Hennis, Anselm; Leske, M. Cristina] SUNY Stony Brook, Dept Prevent Med, Stony Brook, NY 11794 USA. [Hennis, Anselm] Univ W Indies, Chron Dis Res Ctr, Bridgetown, Barbados. [Hennis, Anselm] Minist Hlth, Bridgetown, Barbados. Univ W Indies, Fac Chem & Biol Sci, Bridgetown, Barbados. Translat Genom, Phoenix, AZ USA. [Barbados Natl Canc Study Grp] NHGRI, Bethesda, MD 20892 USA. RP Nemesure, B (reprint author), SUNY Stony Brook, Dept Prevent Med, L3 HSC Room 086, Stony Brook, NY 11794 USA. EM bnemesure@notes.cc.sunysb.edu RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU NHGRI/NIH, Bethesda, MD [N01HG25487] FX Funded by: N01HG25487, NHGRI/NIH, Bethesda, MD. NR 37 TC 12 Z9 12 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD APR PY 2009 VL 20 IS 3 BP 387 EP 394 DI 10.1007/s10552-008-9253-3 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 413IO UT WOS:000263787000013 PM 18987981 ER PT J AU Kosakowska-Cholody, T Cholody, WM Hariprakasha, HK Monks, A Kar, S Wang, MF Michejda, CJ Carr, BI AF Kosakowska-Cholody, Teresa Cholody, Wieslaw M. Hariprakasha, Humcha K. Monks, Anne Kar, Siddhartha Wang, Meifang Michejda, Christopher J. Carr, Brian I. TI Growth inhibition of hepatocellular carcinoma cells in vitro and in vivo by the 8-methoxy analog of WMC79 SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Anti-cancer activity; Hepatocellular carcinoma; Replication arrest; Cdc6; Cdc7 ID DNA-REPLICATION; ANTITUMOR-ACTIVITY; GENE-EXPRESSION; CANCER-CELLS; CDC7 KINASE; MECHANISM; POTENT; AGENT; PHASE; CYCLE AB HKH40A (RTA 502), an optimized 8-methoxy analog of the unsymmetrical bifunctional antitumor agent WMC79, was found to be potently active against liver cancer cell growth in vitro and in vivo. Studies on selected human hepatocellular carcinoma (HCC) cell lines with differing p53 status (HepG2, Hep3B, and PLC/PRF/5), revealed that drug-mediated growth inhibition was independent of p53 status. FACS analysis showed an accumulation of cells in S-phase within 24 h of treatment with 100 nM HKH40A. Subsequent incubation of cells, either in the presence of drug or without, caused cell cycle block at the S and G2/M checkpoints, which was consistent with the observed up-regulation of p21, cyclin A, cyclin B1, sustained phosphorylation of Cdk1, and down-regulation of Cdc6, Cdc7, and RRM2. This irreversible growth arrest eventually led to apoptosis. HKH40A completely suppressed growth of the rat transplantable HCC cell line (JM-1) in an orthotopic model in Fisher 344 rats in vivo, without evidence of toxicity. HKH40A may be a useful agent for new therapeutic strategies focusing on inhibition of HCC cell proliferation. C1 [Wang, Meifang; Carr, Brian I.] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA. [Kosakowska-Cholody, Teresa; Cholody, Wieslaw M.; Hariprakasha, Humcha K.; Michejda, Christopher J.] Ctr Canc Res, Struct Biophys Lab, Frederick, MD USA. [Monks, Anne] NCI, Screening Technol Branch, Lab Funct Genom, Sci Applicat Int Corp, Frederick, MD 21701 USA. [Kar, Siddhartha] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA. RP Carr, BI (reprint author), Thomas Jefferson Univ, Kimmel Canc Ctr, 233 S 10th St,Room 519A, Philadelphia, PA 19107 USA. EM brian.carr@kimmelcancercenter.org FU National Institutes of Health [CA 82723] FX We thank Guity Mohammadi for Xow cytometric analysis and Edward Cho for confocal microscopy images. This research was supported in part by the Intramural Research Program, the National Institutes of Health, and by NIH grant # CA 82723 ( to BIC). NR 25 TC 7 Z9 7 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD APR PY 2009 VL 63 IS 5 BP 769 EP 778 DI 10.1007/s00280-008-0801-z PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 413IU UT WOS:000263787600002 PM 18641988 ER PT J AU Brell, JM Krishnamurthi, SS Javle, M Saltzman, J Wollner, I Pelley, R Dowlati, A Kantharaj, BN Schluchter, MD Rath, L Ivy, SP Remick, SC AF Brell, Joanna M. Krishnamurthi, Smitha S. Javle, Milind Saltzman, Joel Wollner, Ira Pelley, Robert Dowlati, Afshin Kantharaj, Belagodu N. Schluchter, Mark D. Rath, Linda Ivy, S. Percy Remick, Scot C. TI A multi-center phase II study of oxaliplatin, irinotecan, and capecitabine in advanced gastric/gastroesophageal junction carcinoma SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE Gastric cancer; Phase II; Chemotherapy; Metastatic ID ADVANCED GASTRIC-CANCER; ADVANCED ESOPHAGOGASTRIC CANCER; HIGH-DOSE METHOTREXATE; INFUSIONAL FLUOROURACIL; EUROPEAN-ORGANIZATION; COOPERATIVE GROUP; FOLINIC ACID; TRIAL; CISPLATIN; DOXORUBICIN AB There is no standard first-line therapy for advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma and the prognosis remains poor. Our institution conducted a phase I study of oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule. The regimen was tolerated; pharmacodynamic studies revealed no drug interactions, and there was one confirmed response in a gastric cancer patient. We performed a phase II trial in advanced gastric and GEJ adenocarcinoma to determine response rate and response duration. This was a multi-center single treatment arm study involving six sites. Only prior adjuvant therapy was allowed. Patients had ECOG performance status of 0-2, adequate organ function, and were able to tolerate oral medications. All patients received oxaliplatin 60 mg/m(2) intravenously (IV) and irinotecan 50 mg/m(2) IV weekly times 4 weeks with a 2-week rest period. Capecitabine 450 mg bid orally was received on days 1 through 5 every week for 4 weeks, followed by a 2-week rest. Patients were assessed for response after the first two cycles; response duration, overall survival, and adverse events were also recorded. We estimated an improvement in historical response rate by 30% would have clinical meaning. A total of 39 patients were accrued and all were assessed for toxicity; 30 patients were evaluable for response. The median age was 57.8 years (31-79 years) and 74% were male. Two patients had a complete response, with nine patients achieving a partial response. The total response rate was 28%, with nine patients not evaluable for response. The median response duration was noted at 5.97 months and median overall survival was 8.98 months. There were no grade 5 treatment related events, with all deaths secondary to disease progression. Only five grade 4 events occurred (neutropenia, hyperkalemia, hypokalemia (2), thrombosis/embolism) without grade 4 diarrhea or sensory neuropathy. Oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule does induce responses in advanced gastric and GEJ adenocarcinoma. However, the total response rate is modest and not an improvement over other regimens. C1 [Brell, Joanna M.; Krishnamurthi, Smitha S.; Dowlati, Afshin; Rath, Linda] Univ Hosp Case Med Ctr, Dept Med, Cleveland, OH 44106 USA. [Brell, Joanna M.; Krishnamurthi, Smitha S.; Dowlati, Afshin; Rath, Linda] Case Comprehens Canc Ctr, Dev Therapeut Program, Cleveland, OH USA. [Javle, Milind] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Saltzman, Joel] Lake Univ, Ireland Canc Ctr, Mentor, OH USA. [Wollner, Ira] Henry Ford Hlth Syst, Detroit, MI USA. [Pelley, Robert] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Kantharaj, Belagodu N.] Community Hlth Partners, Elyria, OH USA. [Schluchter, Mark D.] Case Comprehens Canc Ctr, Div Biostat, Cleveland, OH USA. [Ivy, S. Percy] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Remick, Scot C.] W Virginia Univ, Mary Babb Randolph Canc Ctr, Morgantown, WV 26506 USA. RP Brell, JM (reprint author), Univ Hosp Case Med Ctr, Dept Med, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM Joanna.Brell@UHhospitals.org; sremick@hsc.wvu.edu FU NIH [U01 CA62502] FX Supported by NIH grant U01 CA62502. NR 28 TC 8 Z9 9 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD APR PY 2009 VL 63 IS 5 BP 851 EP 857 DI 10.1007/s00280-008-0807-6 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 413IU UT WOS:000263787600011 PM 18670776 ER PT J AU Schatzkin, A Subar, AF Moore, S Park, Y Potischman, N Thompson, FE Leitzmann, M Hollenbeck, A Morrissey, KG Kipnis, V AF Schatzkin, Arthur Subar, Amy F. Moore, Steven Park, Yikyung Potischman, Nancy Thompson, Frances E. Leitzmann, Michael Hollenbeck, Albert Morrissey, Kerry Grace Kipnis, Victor TI Observational Epidemiologic Studies of Nutrition and Cancer: The Next Generation (with Better Observation) SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID FOOD FREQUENCY QUESTIONNAIRE; PHYSICAL-ACTIVITY; BREAST-CANCER; NATIONAL-INSTITUTES; ENERGY-EXPENDITURE; MEASUREMENT ERROR; SELF-REPORTS; DIETARY-FAT; COHORT; ABANDON AB It would be of enormous public health importance if diet and physical activity, both modifiable behavioral factors, were causally related to cancer. Nevertheless, the nutritional epidemiology of cancer remains problematic, in part because of persistent concerns that standard questionnaires measure diet and physical activity with too much error. We present a new strategy for addressing this measurement error problem. First, as background, we note that food frequency and physical activity questionnaires require respondents to report "typical" diet or activity over the previous year or longer. Multiple 24-hour recalls (24HR), based on reporting only the previous day's behavior, offer potential cognitive advantages over the questionnaires, and biomarker evidence suggests the 24-hour dietary recall is more accurate than the food frequency questionnaire. The expense involved in administering multiple 24HRs in large epidemiologic studies, however, has up to now been prohibitive. In that context, we suggest that Internet-based 24HRs, for both diet and physical activity, represent a practical and cost-effective approach for incorporating multiple recalls in large epidentiologic studies. We discuss (1) recent efforts to develop such Internet-based instruments and their accompanying software support systems; (2) ongoing studies to evaluate the feasibility of using these new instruments in cohort studies; (3) additional investigations to gauge the accuracy of the Internet-based recalls vis-A-vis standard instruments and biomarkers; and (4) new statistical approaches for combining the new instruments with standard assessment tools and biomarkers The incorporation of Internet-based 24HRs into large epidemiologic studies may help advance our understanding of the nutritional determinants of cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1026-32) C1 [Schatzkin, Arthur; Moore, Steven; Park, Yikyung; Leitzmann, Michael] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Subar, Amy F.; Potischman, Nancy; Thompson, Frances E.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Kipnis, Victor] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. [Morrissey, Kerry Grace] WESTAT Corp, Rockville, MD 20850 USA. RP Schatzkin, A (reprint author), 6120 Execut Blvd,Suite 320, Rockville, MD 20886 USA. EM Schatza@mail.nih.gov RI Moore, Steven/D-8760-2016; OI Moore, Steven/0000-0002-8169-1661; Park, Yikyung/0000-0002-6281-489X FU Intramural NIH HHS [Z01 CP010196-01] NR 43 TC 64 Z9 65 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1026 EP 1032 DI 10.1158/1055-9965.EPI-08-1129 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000002 PM 19336550 ER PT J AU Mariotto, AB Rowland, JH Yabroff, KR Scoppa, S Hachey, M Ries, L Feuer, EJ AF Mariotto, Angela B. Rowland, Julia H. Yabroff, K. Robin Scoppa, Steve Hachey, Mark Ries, Lynn Feuer, Eric J. TI Long-Term Survivors of Childhood Cancers in the United States SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ADULT SURVIVORS; PREVALENCE; OUTCOMES AB Purpose: To estimate the number of individuals in the United States diagnosed with cancer as children (ages 0-19 years) as of 2005, with a focus on those surviving for >30 years. Methods: To estimate the national prevalence of survivors of childhood cancers, we used data from the Surveillance Epidemiology and End Results program from 1975 to 2004. Long-term childhood cancer survivors, diagnosed before 1975, were estimated using incidence and survival models extrapolated into years before 1975. Results: We estimated that there are a total of 328,652 survivors of childhood cancer in the United States as of January 1, 2005, of these, 24% have survived >30 years since diagnosis. The cancer sites with the largest number of survivors are brain (51,650), acute lymphoblastic leukemia (49,271), germ cell tumors (34,169), and Hodgkin lymphoma (31,598). Sites with higher proportions of survivors diagnosed >30 years ago are germ cell (43%), soft tissue (38%), renal (34%), and bone (26%). Historical trends from Connecticut data show major improvements in survival for all of the childhood cancer sites. Conclusion: The number of survivors of childhood cancers is expected to increase in the future consequent to the lifesaving advances in treatment introduced after 1970, especially for acute lymphoblastic leukemia. Because this population is at increased risk for illness-related morbidity and mortality, appreciating the number of survivors who were treated as children is important both to determining the national cancer burden and planning for the future health care needs of these individuals. (Cancer Epidemiol Biornarkers Prev 2009;18(4):1033-40) C1 [Mariotto, Angela B.] NCI, Stat Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Scoppa, Steve; Hachey, Mark] Informat Management Syst Inc, Rockville, MD USA. RP Mariotto, AB (reprint author), NCI, Stat Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Suite 504,MSC 8317,6116 Executive Blvd,MSC 7344, Bethesda, MD 20892 USA. EM mariotta@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 NR 20 TC 168 Z9 170 U1 2 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1033 EP 1040 DI 10.1158/1055-9965.EPI-08-0988 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000003 PM 19336557 ER PT J AU Korde, LA Wu, AH Fears, T Nomura, AMY West, DW Kolonel, LN Pike, MC Hoover, RN Ziegler, RG AF Korde, Larissa A. Wu, Anna H. Fears, Thomas Nomura, Abraham M. Y. West, Dee W. Kolonel, Laurence N. Pike, Malcolm C. Hoover, Robert N. Ziegler, Regina G. TI Childhood Soy Intake and Breast Cancer Risk in Asian American Women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SUPPRESSES MAMMARY-CANCER; GENISTEIN EXPOSURES; MENOPAUSAL STATUS; EARLY ADULTHOOD; SOYFOOD INTAKE; YOUNG-WOMEN; BODY-SIZE; ADOLESCENCE; WEIGHT; POPULATION AB Introduction: Historically, breast cancer incidence has been substantially higher in the United States than in Asia. When Asian women migrate to the United States, their breast cancer risk increases over several generations and approaches that for U.S. Whites. Thus, modifiable factors, such as diet, may be responsible. Methods: In this population-based case-control study of breast cancer among women of Chinese, Japanese, and Filipino descent, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California) and Oahu (Hawaii), we interviewed 597 cases (70% of those eligible) and 966 controls (75%) about adolescent and adult diet and cultural practices. For subjects with mothers living in the United States (39% of participants), we interviewed mothers of 99 cases (43% of eligible) and 156 controls (40%) about the daughter's childhood exposures. Seventy-three percent of study participants were premenopausal at diagnosis. Results: Comparing highest with lowest tertiles, the multivariate relative risks (95% confidence interval) for childhood, adolescent, and adult soy intake were 0.40 (0.18-0.83; P(trend) = 0.03), 0.80 (0.59-1.08; P(trend) = 0.12), and 0.76 (0.56-1.02; P(trend) = 0.04), respectively. Inverse associations with childhood intake were noted in all three races, all three study sites, and women born in Asia and the United States. Adjustment for measures of westernization attenuated the associations with adolescent and adult soy intake but did not affect the inverse relationship with childhood soy intake. Discussion: Soy intake during childhood, adolescence, and adult life was associated with decreased breast cancer risk, with the strongest, most consistent effect for childhood intake. Soy may be a hormonally related, early-life exposure that influences breast cancer incidence. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1050-9) C1 [Korde, Larissa A.] NCI, Clin Genet Branch, Bethesda, MD 20892 USA. [Fears, Thomas; Hoover, Robert N.; Ziegler, Regina G.] NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. [Wu, Anna H.] Univ So Calif, Sch Med, Los Angeles, CA USA. [Nomura, Abraham M. Y.; Kolonel, Laurence N.] Univ Hawaii, Program Epidemiol, Honolulu, HI 96822 USA. [West, Dee W.] No Calif Canc Ctr, Fremont, CA USA. RP Korde, LA (reprint author), 6120 Execut Blvd,Room 7030, Rockville, MD 20852 USA. EM kordel@mail.nih.gov FU intramural research program of the NIH; National Cancer Institute FX The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. We thank Information Management Services for analytic support, Westat for study management and data preparation, all the study subjects for willingness to participate, and the staff at the three study centers for careful work and enthusiasm. This work was supported in part by the intramural research program of the NIH and the National Cancer Institute. NR 50 TC 86 Z9 93 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1050 EP 1059 DI 10.1158/1055-9965.EPI-08-0405 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000005 PM 19318430 ER PT J AU Kilfoy, BA Devesa, SS Ward, MH Zhang, YW Rosenberg, PS Holford, TR Anderson, WF AF Kilfoy, Briseis A. Devesa, Susan S. Ward, Mary H. Zhang, Yawei Rosenberg, Philip S. Holford, Theodore R. Anderson, William F. TI Gender is an Age-Specific Effect Modifier for Papillary Cancers of the Thyroid Gland SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID REPRODUCTIVE FACTORS; TEMPORAL VARIATION; HORMONAL FACTORS; POOLED ANALYSIS; COHORT MODELS; RATES; PERIOD; MORTALITY; PATTERNS; DISEASE AB Background: Thyroid cancer incidence rates have increased worldwide for decades, although more for papillary carcinomas than other types and more for females than males. There are few known thyroid cancer risk factors except female gender, and the reasons for the increasing incidence and gender differences are unknown. Methods: We used the National Cancer Institute's Surveillance, Epidemiology, and End Results 9 Registries Database for cases diagnosed during 1976-2005 to develop etiological clues regarding gender-related differences in papillary thyroid cancer incidence. Standard descriptive epidemiology was supplemented with age-period-cohort (APC) models, simultaneously adjusted for age, calendar-period and birth-cohort effects. Results: The papillary thyroid cancer incidence rate among females was 2.6 times that among males (9.2 versus 3.6 per 100,000 person-years, respectively), with a widening gender gap over time. Age-specific rates were higher among women than men across all age groups, and the female-to-male rate ratio declined quite consistently from more than five at ages 20-24 to 3.4 at ages 35-44 and approached one at ages 80+. APC models for papillary thyroid cancers confirmed statistically different age-specific effects among women and men (P <.001 for the null hypothesis of no difference by gender), adjusted for calendar-period and birth-cohort effects. Conclusion: Gender was an age-specific effect modifier for papillary thyroid cancer incidence. Future analytic studies attempting to identify the risk factors responsible for rising papillary thyroid cancer incidence should be designed with adequate power to assess this age-specific interaction among females and males. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1092-100) C1 [Kilfoy, Briseis A.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv,EPS, Rockville, MD 20852 USA. [Devesa, Susan S.; Rosenberg, Philip S.; Anderson, William F.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Kilfoy, Briseis A.; Zhang, Yawei; Holford, Theodore R.] Yale Univ, Yale Sch Publ Hlth, New Haven, CT USA. RP Kilfoy, BA (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv,EPS, Room 8091,6120 Execut Blvd, Rockville, MD 20852 USA. EM kilfoyb@mail.nih.gov RI Aschebrook-Kilfoy, Briseis/A-2537-2012 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute FX Intramural Research Program of the National Institutes of Health, National Cancer Institute. The authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. NR 27 TC 67 Z9 70 U1 2 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1092 EP 1100 DI 10.1158/1055-9965.EPI-08-0976 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000010 PM 19293311 ER PT J AU McKean-Cowdin, R Barnholtz-Sloan, J Inskip, PD Ruder, AM Butler, M Rajaraman, P Razavi, P Patoka, J Wiencke, JK Bondy, ML Wrensch, M AF McKean-Cowdin, Roberta Barnholtz-Sloan, Jill Inskip, Peter D. Ruder, Avima M. Butler, MaryAnn Rajaraman, Preetha Razavi, Pedram Patoka, Joe Wiencke, John K. Bondy, Melissa L. Wrensch, Margaret TI Associations between Polymorphisms in DNA Repair Genes and Glioblastoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID EXCISION-REPAIR; BRAIN-TUMORS; POLY(ADP-RIBOSE) POLYMERASE-1; NERVOUS-SYSTEM; HUMAN GLIOMAS; CANCER; RISK; ERCC2; SUSCEPTIBILITY; EPIDEMIOLOGY AB A pooled analysis was conducted to examine the association between select variants in DNA repair genes and glioblastoma multiforme, the most common and deadliest form of adult brain tumors. Genetic data for similar to 1,000 glioblastoma multiforme cases and 2,000 controls were combined from four centers in the United States that have conducted case-control studies on adult glioblastoma multiforme, including the National Cancer Institute, the National Institute for Occupational Safety and Health, the University of Texas M. D. Anderson Cancer Center, and the University of California at San Francisco. Twelve DNA repair single-nucleotide polymorphisms were selected for investigation in the pilot collaborative project. The C allele of the PARP1 rs1136410 variant was associated with a 20% reduction in risk for glioblastoma multiforme (odds ratio(CT) (or) (CC), 0.80; 95% confidence interval, 0.67-0.95). A 44% increase in risk for glioblastoma multiforme was found for individuals homozygous for the G allele of the PRK-DC rs7003908 variant (odds ratioGG, 1.44; 95% confidence interval, 1.13-1.84); there was a statistically significant trend (P = 0.009) with increasing number of G alleles. A significant, protective effect was found when three single-nucleotide polymorphisms (ERCC2 rs13181, ERCC1 rs3212986, and GLTSCR1 rs1035938) located near each other on chromosome 19 were modeled as a haplotype. The most common haplotype (AGC) was associated with a 23% reduction in risk (P = 0.03) compared with all other haplotypes combined. Few studies have reported on the associations between variants in DNA repair genes and brain tumors, and few specifically have examined their impact on glioblastoma multiforme. Our results suggest that common variation in DNA repair genes may be associated with risk for glioblastoma multiforme. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1118-26) C1 [McKean-Cowdin, Roberta] Univ So Calif, Norris Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Barnholtz-Sloan, Jill] Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH USA. [Inskip, Peter D.; Rajaraman, Preetha] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ruder, Avima M.; Butler, MaryAnn] NIOSH, Cincinnati, OH 45226 USA. [Patoka, Joe; Wiencke, John K.; Wrensch, Margaret] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. [Bondy, Melissa L.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. RP McKean-Cowdin, R (reprint author), Univ So Calif, Norris Canc Ctr, Keck Sch Med, Dept Prevent Med, Mailstop 44,Room 4419,1441 Eastlake Ave, Los Angeles, CA 90033 USA. EM mckeanco@usc.edu RI Barnholtz-Sloan, Jill/A-4817-2011; Ruder, Avima/I-4155-2012 OI Ruder, Avima/0000-0003-0419-6664 FU The National Brain Tumor Foundation, National Cancer Institute [R01CA52689, P50CA097257]; Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health operating funds, National Cancer Institute [R01CA070917]; the Ron Ross, MD Memorial Cancer Research Fund; Intramural Research Program of the National Cancer Institute, NIH, Department of Health and Human Services FX The National Brain Tumor Foundation, National Cancer Institute R01CA52689 and P50CA097257 (M. Wrensch, principal investigator); Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health operating funds, National Cancer Institute R01CA070917 (M. Bondy, principal investigator); the Ron Ross, MD Memorial Cancer Research Fund; and the Intramural Research Program of the National Cancer Institute, NIH, Department of Health and Human Services. NR 51 TC 61 Z9 62 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1118 EP 1126 DI 10.1158/1055-9965.EPI-08-1078 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000013 PM 19318434 ER PT J AU Jiao, L Flood, A Subar, AF Hollenbeck, AR Schatzkin, A Stolzenberg-Solomon, R AF Jiao, Li Flood, Andrew Subar, Amy F. Hollenbeck, Albert R. Schatzkin, Arthur Stolzenberg-Solomon, Rachael TI Glycemic Index, Carbohydrates, Glycemic Load, and the Risk of Pancreatic Cancer in a Prospective Cohort Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; INSULIN-RESISTANCE; NATIONAL-INSTITUTES; MALE SMOKERS; URIC-ACID; METABOLIC SYNDROME; BINDING PROTEIN-3; GROWTH; GLUCOSE AB Diets with high glycemic index and glycemic load have been associated with insulin resistance. Insulin resistance has been implicated in the etiology of pancreatic cancer. We prospectively investigated the associations between glycemic index, carbohydrates, glycemic load, and available carbohydrates dietary constituents (starch and simple sugar) intake and the risk of pancreatic cancer. We followed the participants in the NIH-AARP Diet and Health Study from 1995/1996 through December 2003. A baseline self-administered food frequency questionnaire was used to assess the dietary intake and exposure information. A total of 1,151 exocrine pancreatic cancer cases were identified from 482,362 participants after excluding first-year of follow-up. We used multivariate Cox proportional hazards regression models to calculate relative risks (RR) and 95% confidence intervals (95% CI) for pancreatic cancer. There were no associations between glycemic index, total or available carbohydrates, gycemic load, and pancreatic cancer risk. Participants with high free fructose and glucose intake were at a greater risk of developing pancreatic cancer (highest compared with lowest quintile, RR, 1.29; 95% CI, 1.04-1.59; P trend = 0.004 and RR, 1.35; 95% CI, 1.101.67; P trend = 0.005, respectively). There were no statistically significant interactions by body mass index, physical activity, or smoking status. Our results do not support an association between glycemic index, total or available carbohydrate intake, and glycemic load and pancreatic cancer risk. The higher risk associated with high free fructose intake needs further confirmation and elucidation. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1144-51) C1 [Jiao, Li; Schatzkin, Arthur; Stolzenberg-Solomon, Rachael] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20852 USA. [Subar, Amy F.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20852 USA. [Flood, Andrew] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Flood, Andrew] Univ Minnesota, Mason Canc Ctr, Minneapolis, MN USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Jiao, L (reprint author), NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, 6120 Execut Blvd,Room 3032, Bethesda, MD 20852 USA. EM jiaol@mail.nih.gov FU Intramural Research Program of the NIH; National Cancer Institute, Division of Cancer Epidemiology and Genetics FX Intramural Research Program of the NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics. NR 53 TC 29 Z9 29 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1144 EP 1151 DI 10.1158/1055-9965.EPI-08-1135 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000016 PM 19336549 ER PT J AU Dolle, JM Daling, JR White, E Brinton, LA Doody, DR Porter, PL Malone, KE AF Dolle, Jessica M. Daling, Janet R. White, Emily Brinton, Louise A. Doody, David R. Porter, Peggy L. Malone, Kathleen E. TI Risk Factors for Triple-Negative Breast Cancer in Women Under the Age of 45 Years SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ORAL-CONTRACEPTIVE USE; PROGESTERONE-RECEPTOR STATUS; GENE-EXPRESSION PATTERNS; ESTROGEN-RECEPTOR; HORMONE-RECEPTOR; YOUNG-WOMEN; ADJUVANT CHEMOTHERAPY; REPRODUCTIVE FACTORS; MOLECULAR SUBTYPES; AFRICAN-AMERICAN AB Little is known about the etiologic profile of triple-negative breast cancer (negative for estrogen receptor/progesterone receptor/human epidermal growth factor), a breast cancer subtype associated with high mortality and inadequate therapeutic options. We undertook this study to assess the risk for triple-negative breast cancer among women 45 years of age and younger in relation to demographic/lifestyle factors, reproductive history, and oral contraceptive use. Study participants were ascertained in two previous population-based, case-control studies. Eligible cases included all primary invasive breast cancers among women ages 20 to 45 years in the Seattle-Puget Sound area, diagnosed between January 1983 and December 1992, for whom complete data was obtained for estrogen receptor, progesterone receptor, and human epidermal growth factor status (n = 897; including n = 187 triple-negative breast cancer cases). Controls were age matched and ascertained via random digit dialing. Oral contraceptive use l year was associated with a 2.5-fold increased risk for triple-negative breast cancer (95% confidence interval, 1.4-4.3) and no significantly increased risk for non-triple-negative breast cancer (P(heterogeneity) = 0.008). Furthermore, the risk among oral contraceptive users conferred by longer oral contraceptive duration and by more recent use was significantly greater for triple-negative breast cancer than non-triple-negative breast cancer (P(heterogeneity) = 0.02 and 0.01, respectively). Among women :<= 40 years, the relative risk for triple-negative breast cancer associated with oral contraceptive use >= 1 year was 4.2 (95% confidence interval, 1.9-9.3), whereas there was no significantly increased risk with oral contraceptive use for non-triple-negative breast cancer among women <= 40 years, nor for triplenegative breast cancer or non-triple-negative breast cancer among women 41 to 45 years of age. In conclusion, significant heterogeneity exists for the association of oral contraceptive use and breast cancer risk between triple-negative breast cancer and non-triple-negative breast cancer among young women, lending support to a distinct etiology. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1157-66) C1 [Dolle, Jessica M.; Daling, Janet R.; White, Emily; Doody, David R.; Malone, Kathleen E.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Porter, Peggy L.] Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. [White, Emily; Malone, Kathleen E.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Malone, KE (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, POB 19024,M4-C308, Seattle, WA 98109 USA. EM kmalone@fhcrc.org RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU [R01 CA59736]; [N01-CP-95671]; [R01 CA-41416]; [R01 CA0988858-03]; [N01-PC35142] FX R01 CA59736, N01-CP-95671, R01 CA-41416, R01 CA0988858-03, and N01-PC35142, which supported case ascertainment through the Cancer Surveillance System. NR 53 TC 91 Z9 92 U1 1 U2 14 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1157 EP 1166 DI 10.1158/1055-9965.EPI-08-1005 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000018 PM 19336554 ER PT J AU Cook, MB Dawsey, SM Freedman, ND Inskip, PD Wichner, SM Quraishi, SM Devesa, SS McGlynn, KA AF Cook, Michael B. Dawsey, Sanford M. Freedman, Neal D. Inskip, Peter D. Wichner, Sara M. Quraishi, Sabah M. Devesa, Susan S. McGlynn, Katherine A. TI Sex Disparities in Cancer Incidence by Period and Age SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUMAN-PAPILLOMAVIRUS INFECTION; RENAL-CELL CARCINOMA; MALIGNANT-MELANOMA; RISK-FACTORS; ESOPHAGEAL ADENOCARCINOMA; HEPATOCELLULAR-CARCINOMA; OROPHARYNGEAL CANCER; BARRETTS-ESOPHAGUS; GENDER-DIFFERENCES; REFLUX DISEASE AB Background: Cancer epidemiology articles often point out that cancer rates tend to be higher among males than females yet rarely is this theme the subject of investigation. Methods: We used the Surveillance, Epidemiology and End Results program data to compute age-adjusted (2000 U.S. standard population) sex-specific incidence rates and male-to-female incidence rate ratios (IRR) for specific cancer sites and histologies for the period 1975 to 2004. Results: The 10 cancers with the largest male-to-female IRR were Kaposi sarcoma (28.73), lip (7.16), larynx (5.17), mesothelioma (4.88), hypopharynx (4.13), urinary bladder (3.92), esophagus (3.49), tonsil (3.07), oropharynx (3.06), and other urinary organs (2.92). Only 5 cancers had a higher incidence in females compared with males: breast (0.01), peritoneum, omentum, and mesentery (0.18), thyroid (0.39), gall-bladder (0.57), and anus, anal canal, and anorecturn (0.81). Between 1975 and 2004, the largest consistent increases in male-to-female IRR were for cancers of the tonsil, oropharynx, skin excluding basal and squamous, and esophagus, whereas the largest consistent decreases in IRR were for cancers of the lip and lung and bronchus. Male-to-female IRRs varied considerably by age, the largest increases of which were for ages 40 to 59 years for tonsil cancer and hepatocellular carcinoma. The largest decreases in male-to-female IRR by age, meanwhile, were for ages 30 to 49 years for thyroid cancer, ages >70 years for esophageal squamous cell carcinoma, and ages >30 years for lung and bronchus cancer. Conclusion: These observations emphasize the importance of sex in cancer etiopathogenesis and may suggest novel avenues of investigation. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1174-82) C1 [Cook, Michael B.; Dawsey, Sanford M.; Freedman, Neal D.; Inskip, Peter D.; Wichner, Sara M.; Quraishi, Sabah M.; Devesa, Susan S.; McGlynn, Katherine A.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20852 USA. RP Cook, MB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS Suite 550,Room 5012, Bethesda, MD 20852 USA. EM cookmich@mail.nih.gov RI Cook, Michael/A-5641-2009; Freedman, Neal/B-9741-2015 OI Cook, Michael/0000-0002-0533-7302; Freedman, Neal/0000-0003-0074-1098 FU Intramural Program of the National Cancer Institute,; NIH; Department of Health and Human Services FX Intramural Program of the National Cancer Institute, NIH, Department of Health and Human Services. NR 59 TC 126 Z9 127 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1174 EP 1182 DI 10.1158/1055-9965.EPI-08-1118 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000020 PM 19293308 ER PT J AU Schenk, JM Riboli, E Chatterjee, N Leitzmann, MF Ahn, J Albanes, D Reding, DJ Wang, YH Friesen, MD Hayes, RB Peters, U AF Schenk, Jeannette M. Riboli, Elio Chatterjee, Nilanjan Leitzmann, Michael F. Ahn, Jiyoung Albanes, Demetrius Reding, Douglas J. Wang, Yinghui Friesen, Marlin D. Hayes, Richard B. Peters, Ulrike TI Serum Retinol and Prostate Cancer Risk: a Nested Case-Control Study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BETA-CAROTENE; ALPHA-TOCOPHEROL; VITAMIN-A; FOLLOW-UP; ACID; MICRONUTRIENTS; ASSOCIATION; EXPRESSION; RECEPTORS; NUTRITION AB Vitamin A (retinol) plays a key role in the regulation of cell growth and differentiation, and has been studied as a potential chemopreventive agent for prostate cancer. However, findings from epidemiologic studies on the association between circulating retinol concentrations and the risk of prostate cancer are inconsistent. We examined whether serum concentrations of retinol were associated with the risk of prostate cancer in a nested case-control study using 692 prostate cancer cases and 844 matched controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. We estimated the risk of prostate cancer using multivariate, conditional logistic regression to calculate odds ratios and 95% confidence intervals for overall prostate cancer and aggressive disease (stage III or IV or Gleason >7; n = 269). Serum retinol concentrations were not associated with overall prostate cancer risk; however, the highest versus lowest concentrations of serum retinol were associated with a 42% reduction in aggressive prostate cancer risk (P-trend = 0.02), with the strongest inverse association for high-grade disease (Gleason sum >7; odds ratio, 0.52; 95% confidence interval, 0.32-0.84; P-trend = 0-01). Our results suggest that higher circulating concentrations of retinol are associated with a decreased risk of aggressive prostate cancer. Further research is needed to better understand the significance of elevations in serum retinol concentrations and the possible biological mechanisms through which retinol affects prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1227-31) C1 [Schenk, Jeannette M.; Wang, Yinghui; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Prevent Program, Seattle, WA 98109 USA. [Riboli, Elio] Int Agcy Res Canc, Nutr & Canc Unit, F-69372 Lyon, France. [Chatterjee, Nilanjan; Ahn, Jiyoung; Albanes, Demetrius; Hayes, Richard B.] NCI, NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Leitzmann, Michael F.] Univ Regensburg, Inst Epidemiol & Prevent Med, Regensburg, Germany. [Reding, Douglas J.] Marshfield Clin Fdn Res, Marshfield, WI USA. [Friesen, Marlin D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. RP Schenk, JM (reprint author), Fred Hutchinson Canc Res Ctr, Prevent Program, 1100 Fairview Ave N,M4-B402 POB 19024, Seattle, WA 98109 USA. EM jschenk@fhcrc.org RI Friesen, Marlin/D-7328-2012; Albanes, Demetrius/B-9749-2015; OI Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute [R25 CA94880] FX National Cancer Institute R25 CA94880. NR 29 TC 13 Z9 13 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1227 EP 1231 DI 10.1158/1055-9965.EPI-08-0984 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000028 PM 19336558 ER PT J AU Loud, JT Thiebaut, ACM Abati, AD Filie, AC Nichols, K Danforth, D Giusti, R Prindiville, SA Greene, MH AF Loud, Jennifer T. Thiebaut, Anne C. M. Abati, Andrea D. Filie, Armando C. Nichols, Kathryn Danforth, David Giusti, Ruthann Prindiville, Sheila A. Greene, Mark H. TI Ductal Lavage in Women from BRCA1/2 Families: Is There a Future for Ductal Lavage in Women at Increased Genetic Risk of Breast Cancer? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FINE-NEEDLE-ASPIRATION; BILATERAL PROPHYLACTIC MASTECTOMY; MUTATION CARRIERS; NIPPLE ASPIRATE; OVARIAN-CANCER; INHERITED MUTATIONS; CYTOLOGIC ATYPIA; FLUID; OOPHORECTOMY; PREVENTION AB Purpose: Ductal lavage has been used for risk stratification and biomarker development and to identify intermediate endpoints for risk-reducing intervention trials. Little is known about patient characteristics associated with obtaining nipple aspirate fluid (NAF) and adequate cell counts (>= 10 cells) in ductal lavage specimens from BRCA mutation carriers. Methods: We evaluated patient characteristics associated with obtaining NAF and adequate cell counts in ductal lavage specimens from the largest cohort of women from BRCA families yet studied (BRCA1/2 = 146, mutation-negative = 23, untested = 2). Fisher's exact test was used to evaluate categorical variables; Wilcoxon nonparametric test was used to evaluate continuous variables associated with NAF or ductal lavage cell count adequacy. Logistic regression was used to identify independent correlates of NAF and ductal lavage cell count adequacy. Results: From 171 women, 45 (26%) women had NAF and 70 (41%) women had ductal lavage samples with >= 10 cells. Postmenopausal women with intact ovaries compared with premenopausal women [odds ratio (OR), 4.8; P = 0.03] and women without a prior breast cancer history (OR, 5.2; P = 0.04) had an increased likelihood of yielding NAF. Having breast-fed (OR, 3.4; P = 0.001), the presence of NAF before ductal lavage (OR, 3.2; P = 0.003), and being premenopausal (OR, 3.0; P = 0.003) increased the likelihood of ductal lavage cell count adequacy. In known BRCA1/2 mutation carriers, only breast-feeding (OR, 2.5; P = 0.01) and the presence of NAF (OR, 3.0; P = 0.01) were independent correlates of ductal lavage cell count adequacy. Conclusions: Ductal lavage is unlikely to be useful in breast cancer screening among BRCA1/2 mutation carriers because the procedure fails to yield adequate specimens sufficient for reliable cytologic diagnosis or to support translational research activities. (Cancer Epidemiol Biomarkers Prev 2009; 18(4):1243-51) C1 [Loud, Jennifer T.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Abati, Andrea D.; Filie, Armando C.; Danforth, David] NCI, Div Clin Sci, NIH, Rockville, MD 20852 USA. [Prindiville, Sheila A.] NCI, Off Director, NIH, Rockville, MD 20852 USA. [Thiebaut, Anne C. M.] Inst Pasteur, INSERM, U657, F-75724 Paris, France. [Nichols, Kathryn] WESTAT Corp, Rockville, MD USA. [Giusti, Ruthann] Ctr Biol Evaluat & Res, Food & Drug Adm, Dept Hlth & Human Serv, Rockville, MD USA. RP Loud, JT (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Plaza Blvd,EPS 7028, Rockville, MD 20852 USA. EM LondJ@mail.nih.gov FU U.S. National Cancer Institute; Westat support services [NO2-CP-11019-50, N02-CP-65504] FX Intramural Research Program of the U.S. National Cancer Institute and Westat support services contracts NO2-CP-11019-50 and N02-CP-65504. NR 38 TC 13 Z9 13 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1243 EP 1251 DI 10.1158/1055-9965.EPI-08-0795 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000031 PM 19336560 ER PT J AU Morton, LM Purdue, MP Zheng, TZ Wang, SS Armstrong, B Zhang, YW Menashe, I Chatterjee, N Avis, S Lan, Q Vajdic, CM Severson, RK Holford, TR Kricker, A Cerhan, JR Leaderer, B Grulich, A Yeager, M Cozen, W Zahm, SH Chanock, SJ Rothman, N Hartge, P AF Morton, Lindsay M. Purdue, Mark P. Zheng, Tongzhang Wang, Sophia S. Armstrong, Bruce Zhang, Yawei Menashe, Idan Chatterjee, Nilanjan Avis, Scott Lan, Qing Vajdic, Claire M. Severson, Richard K. Holford, Theodore R. Kricker, Anne Cerhan, James R. Leaderer, Brian Grulich, Andrew Yeager, Meredith Cozen, Wendy Zahm, Shelia Hoar Chanock, Stephen J. Rothman, Nathaniel Hartge, Patricia TI Risk of Non-Hodgkin Lymphoma Associated with Germline Variation in Genes that Regulate the Cell Cycle, Apoptosis, and Lymphocyte Development SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID EPIDEMIOLOGY CONSORTIUM INTERLYMPH; SINGLE-NUCLEOTIDE POLYMORPHISMS; FAMILY-MEMBER BIM; FOLLICULAR LYMPHOMA; CHROMOSOMAL TRANSLOCATION; BURKITT-LYMPHOMA; PROTEIN BIM; B-CELLS; EXPRESSION; SURVIVAL AB Chromosomal translocations are the hallmark genetic aberration in non-Hodgkin lymphoma (NHL), with specific translocations often selectively associated with specific NHL subtypes. Because many NHL-associated translocations involve cell cycle, apoptosis, and lymphocyte development regulatory genes, we evaluated NHL risk associated with common genetic variation in 20 candidate genes in these pathways. Genotyping of 203 tag single nucleotide polymorphisms (SNP) was conducted in 1,946 NHL cases and 1,808 controls pooled from 3 independent population-based case-control studies. We used logistic regression to compute odds ratios (OR) and 95% confidence intervals (CI) for NHL and four major NHL subtypes in relation to tag SNP genotypes and haplotypes. We observed the most striking associations for tag SNPs in the proapoptotic gene BCL2L11 (BIM) and BCL7A, which is involved in a rare NHL-associated translocation. Variants in BCL2L11 were strongly related to follicular lymphoma only, particularly rs3789068 (OR(AG), 1.41; 95% CI, 1.10-1.81; OR(GG), 1.65; 95% CI, 1.25-2.19; P(trend) = 0.0004). Variants in BCL7A were strongly related to diffuse large B-cell lymphoma only, particularly rs1880030 (OR(AG), 1.34; 95% CI, 1.08-1.68; OR(AA), 1.60; 95% CI, 1.22-2.08; P(trend) = 0.0004). The associations for both variants were similar in all three studies and supported by haplotype analyses. We also observed notable associations for variants in BCL6, CCND1, and MYC. Our results support the role of common genetic variation in cell cycle, apoptosis, and lymphocyte development regulatory genes in lymphomagenesis, and suggest that effects may vary by NHL subtype. Replication of our findings and further study to identify functional SNPs are warranted. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1259-70) C1 [Morton, Lindsay M.; Purdue, Mark P.; Wang, Sophia S.; Menashe, Idan; Chatterjee, Nilanjan; Lan, Qing; Zahm, Shelia Hoar; Rothman, Nathaniel; Hartge, Patricia] NCI, Div Can Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Zheng, Tongzhang; Zhang, Yawei; Holford, Theodore R.; Leaderer, Brian] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Vajdic, Claire M.] Univ New S Wales, Canc Res Ctr, Prince Wales Clin Sch, Sydney, NSW 2052, Australia. [Armstrong, Bruce; Kricker, Anne] Univ Sydney, Sch Publ Hlth, Sydney, NSW 2006, Australia. [Grulich, Andrew] Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. [Avis, Scott] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Avis, Scott] Univ Washington, Seattle, WA USA. [Severson, Richard K.] Wayne State Univ, Dept Family Med, Detroit, MI USA. [Severson, Richard K.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Cerhan, James R.] Mayo Clin, Coll Med, Rochester, MN USA. [Yeager, Meredith; Chanock, Stephen J.] NCI, Core Genotyping Facil, Adv Technol Ctr, NIH,DHHS, Gaithersburg, MD USA. [Cozen, Wendy] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90033 USA. RP Morton, LM (reprint author), NCI, Div Can Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7040,MSC 7238, Rockville, MD 20852 USA. EM mortonli@mail.nih.gov RI Zahm, Shelia/B-5025-2015; Morton, Lindsay/B-5234-2015; Armstrong, Bruce/K-9464-2015; Purdue, Mark/C-9228-2016; OI Morton, Lindsay/0000-0001-9767-2310; Armstrong, Bruce/0000-0001-8940-7525; Purdue, Mark/0000-0003-1177-3108; Cerhan, James/0000-0002-7482-178X; Vajdic, Claire/0000-0002-3612-8298 FU NIH (National Cancer Institute) [N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105, CA62006]; National Health and Medical Research Council of Australia [990920]; Cancer Council New South Wales; University of Sydney Medical Foundation FX All genotyping and statistical analysis for this project was supported by the Intramural Research Program of the NIH (National Cancer Institute). The National Cancer Institute-Surveillance, Epidemiology, and End Results study was also supported by the Intramural Research Program of the NIH (National Cancer Institute) and by Public Health Service contracts N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N02-PC-71105. The Connecticut study was also supported by NIH grant CA62006 from the National Cancer Institute, The New South Wales study was also supported by the National Health and Medical Research Council of Australia. [(Bruce Armstrong) Project Grant number 990920], The Cancer Council New South Wales, and The University of Sydney Medical Foundation. NR 56 TC 38 Z9 39 U1 1 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1259 EP 1270 DI 10.1158/1055-9965.EPI-08-1037 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000033 PM 19336552 ER PT J AU Huang, YF Trentham-Dietz, A Garcia-Closas, M Newcomb, PA Titus-Ernstoff, L Hampton, JM Chanock, SJ Haines, JL Egan, KM AF Huang, Yifan Trentham-Dietz, Amy Garcia-Closas, Montserrat Newcomb, Polly A. Titus-Ernstoff, Linda Hampton, John M. Chanock, Stephen J. Haines, Jonathan L. Egan, Kathleen M. TI Association of CYP1B1 Haplotypes and Breast Cancer Risk in Caucasian Women SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GENETIC-VARIATION; POLYMORPHISM; TESTS; DNA AB CYP1B1 is a key enzyme involved in estrogen metabolism and may Play an important role in the development and progression of breast cancer. In a population-based case-control study, we examined eight CYP1B1 haplotype-tagging single nucleotide polymorphisms in relation to invasive breast cancer risk. Analyses were based on 1,655 cases and 1,470 controls; all women were Caucasian. Among the individual single nucleotide polymorphisms, one (rs9341266) was associated with increased risk of breast cancer P(trend) = 0.021), although the association was no longer significant after adjusting for multiple tests. A marginally significant haplotype effect was identified (P(global) = 0.015), with significant associations identified for 2 uncommon haplotypes comprising 4% of the controls. Results suggest that genetic variation in CYP1B1 has at most a minor influence on breast cancer susceptibility among Caucasian women. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1321-3) C1 [Egan, Kathleen M.] H Lee Moffitt Canc Ctr & Res Inst, MRC, CANCONT, Dept Canc Prevent & Control, Tampa, FL 33612 USA. [Huang, Yifan] Biostatist Core, Tampa, FL USA. [Egan, Kathleen M.] Res Inst, Tampa, FL USA. [Trentham-Dietz, Amy; Newcomb, Polly A.] Univ Wisconsin, Dept Populat Hlth Sci, Madison, WI USA. [Trentham-Dietz, Amy; Hampton, John M.] Univ Wisconsin, Paul P Carbone Comprehens Canc Ctr, Madison, WI USA. [Garcia-Closas, Montserrat; Chanock, Stephen J.] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. [Newcomb, Polly A.] Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Seattle, WA 98104 USA. [Titus-Ernstoff, Linda] Norris Cotton Canc Ctr, Dartmouth Med Sch, Lebanon, NH USA. [Haines, Jonathan L.] Vanderbilt Univ, Sch Med, Ctr Human Genet Res, Nashville, TN 37212 USA. RP Egan, KM (reprint author), H Lee Moffitt Canc Ctr & Res Inst, MRC, CANCONT, Dept Canc Prevent & Control, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM Kathleen.Egan@Moffitt.org RI Haines, Jonathan/C-3374-2012; Garcia-Closas, Montserrat /F-3871-2015 OI Garcia-Closas, Montserrat /0000-0003-1033-2650 FU NCI NIH HHS [R01 CA105197, R01 CA105197-01A1] NR 15 TC 4 Z9 4 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD APR PY 2009 VL 18 IS 4 BP 1321 EP 1323 DI 10.1158/1055-9965.EPI-08-0853 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 432HV UT WOS:000265125000041 PM 19293312 ER PT J AU Yang, SX Schlom, J AF Yang, Sixun Schlom, Jeffrey TI Antigen-presenting cells containing multiple costimulatory molecules promote activation and expansion of human antigen-specific memory CD8(+) T cells SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Costimulation; Memory; T cells; Cytotoxic; Human; Cell proliferation ID HUMAN CARCINOEMBRYONIC ANTIGEN; ENHANCED COSTIMULATION; ANTIVIRAL IMMUNITY; PCR-SSP; HLA-A; AVIDITY; CD4(+); REQUIREMENTS; RESPONSES; PEPTIDE AB We have previously demonstrated that multiple immunizations with vector-based vaccines containing transgenes for tumor Ags and a triad of costimulatory molecules (TRICOM) enhance the expansion and functional avidity of Ag-specific memory CD8(+) T cells in a mouse model. However, the effect of enhanced costimulation on human memory CD8(+) T cells is still unclear. The study reported here was an in vitro investigation of the proliferation and function of CEA-specific human memory CD8(+) T cells following enhanced costimulation. Our results demonstrated that TRICOM costimulation enhanced production of multiple cytokines and expansion of CEA-specific memory CD8(+) T cells. The lytic capacity of memory CTLs toward CEA(+) tumors was also significantly enhanced. IL-2R alpha (CD25) was upregulated dramatically following APC-TRICOM stimulation, suggesting that the enhanced expansion of memory CD8(+) T cells may be mediated by increased expression of IL-2R on memory T cells. The enhanced cytokine production and proliferation following TRICOM signaling was completely blocked by the combination of neutralizing Abs against B7-1, ICAM-1, and LFA-3, the costimulatory molecules comprising TRICOM. No difference in T-cell apoptosis was observed between APC-TRICOM and APC-wild-type groups, as determined by annexin V, Bcl-2, and active caspase-3 staining. Results indicated that enhanced costimulation greatly expanded human CEA-specific CD8(+) T cells and enhanced T-cell function, without inducing increased apoptosis of CEA-specific memory CD8(+) T cells. C1 [Yang, Sixun; Schlom, Jeffrey] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bldg 10,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX The authors thank Drs. Claudia Palena and James W. Hodge, Laboratory of Tumor Immunology and Biology, CCR, NCI, for their helpful suggestions, and Debra Weingarten and Bonnie L. Casey for their editorial assistance in the preparation of this manuscript. The authors thank the National Institutes of Health Tetramer Core Facility (Atlanta, GA) for the preparation of tetramers. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 26 TC 6 Z9 6 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD APR PY 2009 VL 58 IS 4 BP 503 EP 515 DI 10.1007/s00262-008-0572-8 PG 13 WC Oncology; Immunology SC Oncology; Immunology GA 401TZ UT WOS:000262966600003 PM 18690438 ER PT J AU Fay, JR Steele, V Crowell, JA AF Fay, Judith R. Steele, Vernon Crowell, James A. TI Energy Homeostasis and Cancer Prevention: The AMP-Activated Protein Kinase SO CANCER PREVENTION RESEARCH LA English DT Review ID FATTY-ACID SYNTHASE; ACETYL-COA-CARBOXYLASE; METABOLIC SYNDROME; MAMMALIAN TARGET; PROSTATE-CANCER; BREAST-CANCER; CELL-GROWTH; IN-VIVO; CALORIE RESTRICTION; TRANSGENIC MICE AB Caloric restriction has long been recognized as an extremely effective cancer preventive. Current population demographics suggest that caloric excess and obesity will lead to increased cancer incidence, underscoring the need to elucidate the molecular mechanisms that couple dysregulated energy homeostasis to aberrant cell growth. The AMP-activated protein kinase (AMPK) is a critical monitor of cellular energy status, largely studied for its importance in metabolic regulation. AMPK also controls processes relevant to tumor development, including cell cycle progression, protein synthesis, cell growth, and survival. Several tumor suppressors impinge on AMPK signaling, and activation of the kinase inhibits tumor growth. However, AMPK can also promote cancer in some settings, necessitating a more complete understanding of the complexities of this signaling network. Because dysregulated energy balance is a nexus for multiple chronic diseases of aging, drugs that target these pathways may find broad utility in aging populations. C1 [Fay, Judith R.] CCS Associates, Mountain View, CA 94043 USA. [Steele, Vernon] NCI, Chemoprevent Agent Dev Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Crowell, James A.] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Fay, JR (reprint author), CCS Associates, 2005 Landings Dr, Mountain View, CA 94043 USA. EM jfay@ccsainc.com NR 84 TC 42 Z9 46 U1 2 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD APR PY 2009 VL 2 IS 4 BP 301 EP 309 DI 10.1158/1940-6207.CAPR-08-0166 PG 9 WC Oncology SC Oncology GA 429CI UT WOS:000264898000006 PM 19336731 ER PT J AU Bertagnolli, MM Eagle, CJ Zauber, AG Redston, M Breazna, A Kim, K Tang, J Rosenstein, RB Umar, A Bagheri, D Collins, NT Burn, J Chung, DC Dewar, T Foley, TR Hoffman, N Macrae, F Pruitt, RE Saltzman, JR Salzberg, B Sylwestrowicz, T Hawk, ET AF Bertagnolli, Monica M. Eagle, Craig J. Zauber, Ann G. Redston, Mark Breazna, Aurora Kim, KyungMann Tang, Jie Rosenstein, Rebecca B. Umar, Asad Bagheri, Donya Collins, Neal T. Burn, John Chung, Daniel C. Dewar, Thomas Foley, T. Raymond Hoffman, Neville Macrae, Finlay Pruitt, Ronald E. Saltzman, John R. Salzberg, Bruce Sylwestrowicz, Thomas Hawk, Ernest T. CA Adenoma Prevention Celecoxib Study TI Five-Year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial SO CANCER PREVENTION RESEARCH LA English DT Article ID COLORECTAL ADENOMAS; GASTROINTESTINAL TOXICITY; RANDOMIZED-TRIAL; ROFECOXIB; NAPROXEN; ASPIRIN; CANCER; RISK; CHEMOPREVENTION; COMPLICATIONS AB The Adenoma Prevention with Celecoxib Trial examined the efficacy and safety of the cyclooxygenase (Cox)-2 inhibitor, celecoxib, for sporadic colorectal adenoma prevention in patients at high risk for colorectal cancer. The trial randomized 2,035 subjects to receive either placebo, celecoxib 200 mg twice daily, or celecoxib 400 mg twice daily. The primary study safety and efficacy analyses involved 3 years of treatment. The results showed significant antitumor effect but also indicated increased cardiovascular adverse events in patients treated with celecoxib compared with placebo. A total of 933 patients participated in an extension of the Adenoma Prevention with Celecoxib Trial, with a planned total treatment and surveillance duration of 5 years. Study medication was stopped early, resulting in a median treatment duration of 3.1 years for those with a year 5 colonoscopy. Patients treated on the placebo arm had a cumulative adenoma incidence of 68.4% over 5 years of observation. This figure was 59.0% (P < 0.0001) for those receiving low-dose celecoxib, and 60.1% (P < 0.0001) for those receiving high-dose celecoxib. The cumulative incidence of advanced adenomas over 5 years was 21.3% of those taking placebo, 12.5% (P < 0.0001) of those taking low dose celecoxib and 15.8% (P < 0.0001) of those taking high-dose celecoxib. Investigator reported treatment emergent adverse events were similar across all treatment groups for categories including renal and hypertensive events and gastrointestinal ulceration and hemorrhage events. For a category composed of cardiovascular and thrombotic events, the risk relative to placebo was 1.6 (95% confidence interval, 1.0, 2.5) for those using 200 mg twice daily celecoxib and 1.9 (95% confidence interval, 1.2, 3.1) for those using 400 mg twice daily celecoxib. Secondary analysis showed an interaction between a baseline history of atherosclerotic heart disease and study drug use with respect to cardiovascular and thrombotic adverse events (P = 0.004). These results confirm the inhibitory effect of celecoxib on colorectal adenoma formation, and provide additional safety data indicating an elevated risk for cardiovascular and thrombotic adverse events, particularly for patients with preexisting atherosclerotic heart disease. C1 [Bertagnolli, Monica M.; Redston, Mark; Saltzman, John R.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Chung, Daniel C.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Eagle, Craig J.; Breazna, Aurora; Tang, Jie; Rosenstein, Rebecca B.; Collins, Neal T.] Pfizer Inc, New York, NY USA. [Zauber, Ann G.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Kim, KyungMann] Univ Wisconsin, Madison, WI USA. [Bagheri, Donya] CCS Associates Inc, Mountain View, CA USA. [Burn, John] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Dewar, Thomas] Harris Methodist Hosp, Ft Worth, TX USA. [Foley, T. Raymond] Reg Gastroenterol Associates Lancaster, Lancaster, PA USA. [Hoffman, Neville] Sir Charles Gairdner Hosp, Perth, WA, Australia. [Macrae, Finlay] Royal Melbourne Hosp, Melbourne, Vic, Australia. [Pruitt, Ronald E.] Nashville Med Res Inst, Nashville, TN USA. [Salzberg, Bruce] Atlanta Gastroenterol Associates, Atlanta, GA USA. [Sylwestrowicz, Thomas] Univ Saskatchewan, St Pauls Hosp, Saskatoon, SK, Canada. [Umar, Asad] NCI, Bethesda, MD 20892 USA. [Hawk, Ernest T.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. RP Bertagnolli, MM (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM mbertagnolli@partners.org RI Leggett, Barbara/D-3579-2011; OI Burn, John/0000-0002-9823-2322 FU National Cancer Institute and Pfizer [N01-CN-95015] FX National Cancer Institute (N01-CN-95015) and Pfizer. NR 23 TC 107 Z9 108 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD APR PY 2009 VL 2 IS 4 BP 310 EP 321 DI 10.1158/1940-6207.CAPR-08-0206 PG 12 WC Oncology SC Oncology GA 429CI UT WOS:000264898000007 PM 19336730 ER PT J AU Han, W Gills, JJ Memmott, RM Lam, S Dennis, PA AF Han, Wei Gills, Joell J. Memmott, Regan M. Lam, Stephen Dennis, Phillip A. TI The Chemopreventive Agent Myoinositol Inhibits Akt and Extracellular Signal-Regulated Kinase in Bronchial Lesions from Heavy Smokers SO CANCER PREVENTION RESEARCH LA English DT Article ID CELL LUNG-CANCER; AIRWAY EPITHELIAL-CELLS; PROTEIN-KINASE; A/J MICE; PROGNOSTIC-SIGNIFICANCE; K-RAS; INOSITOL; NICOTINE; PHOSPHORYLATION; ADENOCARCINOMA AB Myoinositol is an isomer of glucose that has chemopreventive activity in animal models of cancer. In a recent phase I clinical trial, myoinositol administration correlated with a statistically significant regression of preexisting bronchial dysplastic lesions in heavy smokers. To shed light on the potential mechanisms involved, activation of Akt and extracellular signal-regulated kinase (ERK), two kinases that control cellular proliferation and survival, was assessed in 206 paired bronchial biopsies from 21 patients who participated in this clinical trial. Before myoinositol treatment, strongly positive staining for activation of Akt was detected in 27% of hyperplastic/metaplastic lesions and 58% of dysplastic lesions (P = 0.05, chi(2) test). There was also a trend toward increased activation of ERK (28% in regions of hyperplasia/metaplasia to 42% of dysplastic lesions). Following myoinositol treatment, significant decreases in Akt and ERK phosphorylation were observed in dysplastic (P < 0.01 and 0.05, respectively) but not hyperplastic/metaplastic lesions (P > 0.05). In vitro, myoinositol decreased endogenous and tobacco carcinogen-induced activation of Akt and ERK in immortalized human bronchial epithelial cells, which decreased cell proliferation and induced a G(1)-S cell cycle arrest. These results show that the phenotypic progression of premalignant bronchial lesions from smokers correlates with increased activation of Akt and ERK and that these kinases are targets of myoinositol. Moreover, they suggest that myoinositol might cause regression of bronchial dysplastic lesions through inhibition of active Akt and ERK. C1 [Han, Wei; Gills, Joell J.; Memmott, Regan M.; Dennis, Phillip A.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Lam, Stephen] British Columbia Canc Agcy, Dept Resp Med, Vancouver, BC V5Z 4E6, Canada. [Lam, Stephen] British Columbia Canc Agcy, Dept Canc Imaging, Vancouver, BC V5Z 4E6, Canada. [Lam, Stephen] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. RP Dennis, PA (reprint author), USN Med Oncol, NCI, Room 5101,Bldg 8,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM pdennis@nih.gov FU NIH [NO1-CO-12400, N01-CN85188]; National Cancer Institute; Center for Cancer Research FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and federal funds from the National Cancer Institute, NIH, under contract National Cancer Institute Contract NO1-CO-12400 and N01-CN85188. NR 36 TC 21 Z9 21 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD APR PY 2009 VL 2 IS 4 BP 370 EP 376 DI 10.1158/1940-6207.CAPR-08-0209 PG 7 WC Oncology SC Oncology GA 429CI UT WOS:000264898000014 PM 19336734 ER PT J AU Kaposi-Novak, P Libbrecht, L Woo, HG Lee, YH Sears, NC Conner, EA Factor, VM Roskams, T Thorgeirsson, SS AF Kaposi-Novak, Pal Libbrecht, Louis Woo, Hyun Goo Lee, Yun-Han Sears, Nathaniel C. Conner, Elizabeth A. Factor, Valentina M. Roskams, Tania Thorgeirsson, Snorri S. TI Central Role of c-Myc during Malignant Conversion in Human Hepatocarcinogenesis SO CANCER RESEARCH LA English DT Article ID HUMAN HEPATOCELLULAR CARCINOMAS; CANCER; TUMORIGENESIS; SIGNATURES; PATHWAY; TARGET; RAS; CARCINOGENESIS; IDENTIFICATION; ACTIVATION AB Hepatocarcinogenesis is a multistage process in which precursor lesions progress into early hepatocellular carcinomas (eHCC) by sequential accumulation of multiple genetic and epigenetic alterations. To decode the molecular events during early stages of liver carcinogenesis, we performed gene expression profiling on cirrhotic (regenerative) and dysplastic nodules (DN), as well as eHCC. Although considerable heterogeneity was observed at the regenerative and dysplastic stages, overall, 460 differentially expressed genes were detected between DN and eHCC. Functional analysis of the significant gene set identified the MYC oncogene as a plausible driver gene for malignant conversion of the DNs. In addition, gene set enrichment analysis revealed global activation of the MYC up-regulated gene set in eHCC versus dysplasia. Presence of the MYC signature significantly correlated with increased expression of CSN5, as well as with higher overall transcription rate of genes located in the 8q chromosome region. Furthermore, a classifier constructed from MYC target genes could robustly discriminate eHCC from high-grade and low-grade DNs. In conclusion, our study identified unique expression patterns associated with the transition of high-grade DNs into eHCC and showed that activation of the MYC transcription signature is strongly associated with the malignant conversion of preneoplastic liver lesions. [Cancer Res 2009;69(7):2775-82] C1 [Kaposi-Novak, Pal; Woo, Hyun Goo; Lee, Yun-Han; Sears, Nathaniel C.; Conner, Elizabeth A.; Factor, Valentina M.; Thorgeirsson, Snorri S.] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Libbrecht, Louis; Roskams, Tania] Univ Louvain, Dept Morphol, Louvain, Belgium. [Libbrecht, Louis; Roskams, Tania] Univ Louvain, Dept Mol Pathol, Louvain, Belgium. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 4146, Bethesda, MD 20892 USA. EM snorri_s_thorgeirsson@mail.nih.gov RI Coulouarn, Cedric/E-5472-2011 FU NIH FX Grant support: NIH intramural research program. NR 39 TC 82 Z9 84 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD APR 1 PY 2009 VL 69 IS 7 BP 2775 EP 2782 DI 10.1158/0008-5472.CAN-08-3357 PG 8 WC Oncology SC Oncology GA 429GE UT WOS:000264908100014 PM 19276364 ER PT J AU Nishijo, K Chen, QR Zhang, L McCleish, AT Rodriguez, A Cho, MJ Prajapati, SI Gelfond, JAL Chisholm, GB Michalek, JE Aronow, BJ Barr, FG Randall, RL Ladanyi, M Qualman, SJ Rubin, BP LeGallo, RD Wang, CY Khan, J Keller, C AF Nishijo, Koichi Chen, Qing-Rong Zhang, Lei McCleish, Amanda T. Rodriguez, Andrea Cho, Min Jung Prajapati, Suresh I. Gelfond, Jonathan A. L. Chisholm, Gary B. Michalek, Joel E. Aronow, Bruce J. Barr, Frederic G. Randall, R. Lor Ladanyi, Marc Qualman, Stephen J. Rubin, Brian P. LeGallo, Robin D. Wang, Chiayeng Khan, Javed Keller, Charles TI Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma SO CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION; PROGENITOR CELLS; TESTING PROGRAM; PAX3-FKHR; PAX3; FUSION; SKP2; FKHR; TARGET; MUSCLE AB The highly aggressive muscle cancer alveolar rhabdomyosarcoma (ARMS) is one of the most common soft tissue sarcoma of childhood, yet the outcome for the unresectable and metastatic disease is dismal and unchanged for nearly three decades. To better understand the pathogenesis of this disease and to facilitate novel preclinical approaches, we previously developed a conditional mouse model of ARMS by faithfully recapitulating the genetic mutations observed in the human disease, i.e., activation of Pax3.Fkhr fusion gene with either p53 or Cdkn2a inactivation. In this report, we show that this model recapitulates the immunohistochemical profile and the rapid progression of the human disease. We show that Pax3.Fkhr expression increases during late preneoplasia but tumor cells undergoing metastasis are under apparent selection for Pax3.Fkhr expression. At a whole-genome level, a cross-species gene set enrichment analysis and metagene projection study showed that our mouse model is most similar to human ARMS when compared with other pediatric cancers. We have defined an expression profile conserved between mouse and human ARMS, as well as a Pax3.Fkhr signature, including the target gene, SKP2. We further identified 7 "druggable" kinases overexpressed across species. The data affirm the accuracy of this genetically engineered mouse model. [Cancer Res 2009;69(7):2902-11] C1 [Nishijo, Koichi; McCleish, Amanda T.; Rodriguez, Andrea; Cho, Min Jung; Prajapati, Suresh I.; Keller, Charles] Univ Texas Hlth Sci Ctr San Antonio, Greehey Childrens Canc Res Inst, San Antonio, TX 78229 USA. [Gelfond, Jonathan A. L.; Chisholm, Gary B.; Michalek, Joel E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Keller, Charles] Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA. [Keller, Charles] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Chen, Qing-Rong; Khan, Javed] Natl Canc Inst, Pediat Oncol Branch, Oncogenom Sect, Gaithersburg, MD USA. [Chen, Qing-Rong] Sci Applicat Int Corp Frederick Inc, Adv Biomed Comp Ctr, Frederick, MD USA. [Zhang, Lei; Wang, Chiayeng] Univ Illinois, Ctr Mol Biol Oral Dis, Chicago, IL USA. [Aronow, Bruce J.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Barr, Frederic G.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Randall, R. Lor] Univ Utah, Dept Orthoped, Salt Lake City, UT USA. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Dept Pathol & Human Oncol, New York, NY 10021 USA. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Pathogenesis Program, New York, NY 10021 USA. [Rubin, Brian P.] Cleveland Clin, Dept Anat Pathol, Cleveland, OH 44106 USA. [Qualman, Stephen J.; LeGallo, Robin D.] Columbus Childrens Hosp, Childrens Res Inst, Columbus, OH USA. RP Keller, C (reprint author), 8403 Floyd Curl Dr,MC7784, San Antonio, TX 78229 USA. EM kellerc2@uthscsa.edu RI Aronow, Bruce/F-8438-2012; Khan, Javed/P-9157-2014; OI Khan, Javed/0000-0002-5858-0488; Keller, Charles/0000-0003-2505-7487 FU Sarcoma Foundation of America; NIH [CA074907, CA64202]; Alex's Lemonade Stand Foundation; Clinical Trial Research Center [P30CA54174] FX Bradley J. Breidinger Memorial research award from Sarcoma Foundation of America (C. Keller), NIH grant CA074907 (C. Wang), NIH grant CA64202 (F.G. Barr), Alex's Lemonade Stand Foundation grant (K. Nishijo, and Scott Carter), Foundation grant (C. Keller and K. Nishijo). C. Keller is a member of the Clinical Trial Research Center (P30CA54174).; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.; We thank Dr. Peter Houghton for graciously providing Rh30 and Drs. Louis Kunkel and Peter B. Kang for the data sets and their kind review of this manuscript NR 46 TC 49 Z9 51 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD APR 1 PY 2009 VL 69 IS 7 BP 2902 EP 2911 DI 10.1158/0008-5472.CAN-08-3723 PG 10 WC Oncology SC Oncology GA 429GE UT WOS:000264908100030 PM 19339268 ER PT J AU Takikita, M Altekruse, S Lynch, CF Goodman, MT Hernandez, BY Green, M Cozen, W Cockburn, M Saber, MS Topor, M Zeruto, C Abedi-Ardekani, B Reichman, ME Hewitt, SM AF Takikita, Mikiko Altekruse, Sean Lynch, Charles F. Goodman, Mark T. Hernandez, Brenda Y. Green, Mark Cozen, Wendy Cockburn, Myles Saber, Maria Sibug Topor, Marie Zeruto, Chris Abedi-Ardekani, Belmoush Reichman, Marsha E. Hewitt, Stephen M. TI Associations between Selected Biomarkers and Prognosis in a Population-Based Pancreatic Cancer Tissue Microarray SO CANCER RESEARCH LA English DT Article ID EXPRESSION; TUMORS AB Pancreatic cancer is the fourth leading cause of cancer death in the United States. Prognostic biomarkers are lacking, and treatment has limited effect on survival. Tissues from Surveillance, Epidemiology, and End Results registries (Iowa, Hawaii, and Los Angeles) were used to build a tissue microarray of 161 pancreatic tumors (113 resections and 48 biopsies). Proportional hazard models adjusted for age, race, sex, stage, time-period of diagnosis, and treatment. Associations were examined between markers (MUCI, MUC2, MUC5AC, synaptophysin, chromogranin, neuron specific enolase, epidermal growth factor receptor, HER2, CD5, CD138, CK5/6, CK19, CK20, and p53) and survival time from diagnosis. After adjusting for covariates, borderline statistically significant associations were seen between expression of each of the three mucins (MUC1, MUC2, and MUC5AC) and shorter survival time. The associations strengthened for 154 (96%) adenocarcinomas, particularly the 120 (75%) well-differentiated to moderately differentiated ductal adenocarcinomas, a tumor type that occurred more often in the cohort among White cases than cases of other racial origin (P < 0.01). For differentiated ductal adenocarcinomas, associations with shorter survival time were seen for expression of all three mucins combined versus other mucin expression patterns (adjusted hazard ratio, 1.8; 95% confidence interval, 1.2-2.6) and for MUC2(+) versus MUC2(-) expression (adjusted hazard ratio, 1.6; 95% confidence interval, 1.1-2.4). Mucin gene expression, particularly MUC2 expression, may have prognostic value for differentiated adenocarcinomas. Tumor histologies differed in this and Japanese cohorts. The tissue microarray is available to evaluate other biomarkers. Tissue-based surveillance can be used to monitor tumor histology in populations and facilitate applied research. [Cancer Res 2009;69(7):2950-5] C1 [Altekruse, Sean; Reichman, Marsha E.] NCI, Div Canc Control & Populat Sci, Surveillance Res Program, NIH, Bethesda, MD 20892 USA. [Takikita, Mikiko; Abedi-Ardekani, Belmoush; Hewitt, Stephen M.] NCI, Canc Res Ctr, Pathol Lab, Tissue Array Res Program,NIH, Bethesda, MD 20892 USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Goodman, Mark T.; Hernandez, Brenda Y.; Green, Mark] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Cozen, Wendy; Cockburn, Myles] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Saber, Maria Sibug] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Topor, Marie; Zeruto, Chris] Informat Management Serv Inc, Silver Spring, MD USA. RP Reichman, ME (reprint author), NCI, Div Canc Control & Populat Sci, Surveillance Res Program, NIH, 6116 Execut Blvd,Suite 504,Room 5003, Bethesda, MD 20892 USA. EM reichman@mail.nih.gov; genejock@helix.nih.gov RI Abedi-Ardekani, Behnoush/O-7829-2016 OI Abedi-Ardekani, Behnoush/0000-0002-0980-0587 FU NIH; National Cancer Institute [N01-PC-35143, N01-PC-35137, N01-PC-35139]; Center for Cancer Research FX Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The National Cancer Institute contracts for the participating SEER registries were N01-PC-35143 (Iowa), N01-PC-35137 (Hawaii), and N01-PC-35139 (Los Angeles).; The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 17 TC 47 Z9 47 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD APR 1 PY 2009 VL 69 IS 7 BP 2950 EP 2955 DI 10.1158/0008-5472.CAN-08-3879 PG 6 WC Oncology SC Oncology GA 429GE UT WOS:000264908100036 PM 19276352 ER PT J AU Park, SK Andreotti, G Sakoda, LC Gao, YT Rashid, A Chen, J Chen, BE Rosenberg, PS Shen, MC Wang, BS Han, TQ Zhang, BH Yeager, M Chanock, S Hsing, AW AF Park, Sue K. Andreotti, Gabriella Sakoda, Lori C. Gao, Yu-Tang Rashid, Asif Chen, Jinbo Chen, Bingshu E. Rosenberg, Philip S. Shen, Ming-Chang Wang, Bing-Sheng Han, Tian-Quan Zhang, Bai-He Yeager, Meredith Chanock, Stephen Hsing, Ann W. TI Variants in hormone-related genes and the risk of biliary tract cancers and stones: a population-based study in China SO CARCINOGENESIS LA English DT Article ID BILE-DUCT CANCER; GALLBLADDER CANCER; POSTMENOPAUSAL WOMEN; REPRODUCTIVE HISTORY; CYTOCHROME-P450 1A1; REPLACEMENT THERAPY; BINDING GLOBULIN; ESTROGEN; DISEASE; ASSOCIATION AB Biliary tract cancers, encompassing gallbladder, extrahepatic bile duct and ampulla of Vater cancers, are uncommon but often fatal malignancies. Hormone-related factors, including parity, oral contraceptive use, obesity, and gallstones, have been implicated in the etiology of these cancers. To further clarify the role of hormones in biliary tract cancers and biliary stones, we genotyped 18 single-nucleotide polymorphisms (SNPs) in nine genes involved in steroid hormone biosynthesis, metabolism and transport in a population-based case-control study in Shanghai, China. This study included subjects who completed an interview and provided blood, which totaled 411 biliary tract cancer and 893 biliary stone patients and 786 healthy Shanghai residents. The CYP1A1 IVS1 + 606 (rs2606345) T allele was associated with gallbladder [odds ratio (OR) = 2.0, 95% confidence interval (CI), 1.3-3.0] and bile duct cancers (OR = 1.8, 95% CI = 1.1-3.1), whereas the CYP1A1 Ex7 + 131 (rs1048943) G allele was associated with ampulla of Vater cancer (OR = 2.9, 95% CI = 1.5-5.4). After taking into account multiple comparisons for SNPs within each gene, CYP1A1 was significantly associated with gallbladder (P = 0.004) and ampulla of Vater cancers (P = 0.01), but borderline with bile duct cancer (P = 0.06). The effect of CYP1A1 IVS1 + 606 on gallbladder cancer was more pronounced among non-obese (body mass index < 23) (OR = 3.3, 95% CI = 1.8-6.1; P interaction = 0.001). Among women taking oral contraceptives, the effect of SHBG Ex8 + 6 (rs6259) on gallbladder cancer (OR = 6.7, 95% CI = 2.2-20.5; P interaction = 0.001) and stones (OR = 2.3, 95% CI = 1.1-4.9; P-interaction = 0.05) was statistically significant. Our findings suggest that common variants in hormone-related genes contribute to the risk of biliary tract cancers and stones, possibly by modulating hormone metabolism. C1 [Park, Sue K.; Andreotti, Gabriella; Sakoda, Lori C.; Chen, Bingshu E.; Rosenberg, Philip S.; Chanock, Stephen; Hsing, Ann W.] NCI, Natl Inst Hlth, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Park, Sue K.] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul 110799, South Korea. [Sakoda, Lori C.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Rashid, Asif] Dept Pathol, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Chen, Jinbo] Univ Penn, Dept Epidemiol, Philadelphia, PA 19104 USA. [Shen, Ming-Chang] Fudan Univ, Shanghai Tumor Hosp, Shanghai 200433, Peoples R China. [Wang, Bing-Sheng] Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Han, Tian-Quan] Shanghai Med Univ 2, Ruijin Hosp, Dept Surg, Shanghai, Peoples R China. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Zhang, Bai-He] Second Mil Med Univ, Inst Oriental Hepatobiliary Surg, Shanghai, Peoples R China. [Yeager, Meredith; Chanock, Stephen] NCI, Natl Inst Hlth, Gaithersburg, MD 20892 USA. RP Hsing, AW (reprint author), NCI, Natl Inst Hlth, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 5024,MSC 7234, Bethesda, MD 20892 USA. EM suepark@snu.ac.kr; hsinga@mail.nih.gov RI Perez , Claudio Alejandro/F-8310-2010; Park, Sue Kyung/J-2757-2012 OI Perez , Claudio Alejandro/0000-0001-9688-184X; FU National Cancer Institute, National Institutes of Health [N01-CO-12400] FX Federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. NR 46 TC 17 Z9 18 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 EI 1460-2180 J9 CARCINOGENESIS JI Carcinogenesis PD APR PY 2009 VL 30 IS 4 BP 606 EP 614 DI 10.1093/carcin/bgp024 PG 9 WC Oncology SC Oncology GA 428YX UT WOS:000264889100008 PM 19168589 ER PT J AU Lee, KM Kang, D Park, SK Berndt, SI Reding, D Chatterjee, N Chanock, S Huang, WY Hayes, RB AF Lee, Kyoung-Mu Kang, Daehee Park, Sue Kyung Berndt, Sonja I. Reding, Douglas Chatterjee, Nilanjan Chanock, Stephen Huang, Wen-Yi Hayes, Richard B. TI Nitric oxide synthase gene polymorphisms and prostate cancer risk SO CARCINOGENESIS LA English DT Article ID GENOME-WIDE ASSOCIATION; OVARIAN-CANCER; CELLS; EXPRESSION; BLOOD; PHASE; LOCI; 8Q24; ENOS AB Nitric oxide (NO) induces cytotoxicity and angiogenesis, and may play a role in prostate carcinogenesis, potentially modulated by environmental exposures. We evaluated the association of prostate cancer with genetic polymorphisms in two genes related to intracellular NO: NOS2A [inducible nitric oxide synthase (NOS); -2892T > C, Ex16 + 14C > T (S608L), IVS16 + 88T > G and IVS20 + 524G > A] and NOS3 [endothelial NOS; IVS1 - 762C > T, Ex7 - 43C > T (D258D), IVS7 - 26A > G, Ex8 - 63G > T (E298D) and IVS15 - 62G > T]. Prostate cancer cases (n = 1320) from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial were frequency matched to controls (n = 1842), by age, race, time since initial screening and year of blood draw. An antioxidant score [range 3-12; low (3-7) versus high (8-12)] was created by summing the quartile levels of vitamin E, beta-carotene and lycopene, which were coded from 1 to 4, respectively. The global tests for all eight single-nucleotide polymorphisms (SNPs) (excluding NOS2A -2892T > C, with low minor allele frequency) were statistically significant for prostate cancer (P = 0.005), especially for aggressive cancer (stage III-IV or Gleason score >= 7) (P = 0.01). The NOS2A IVS16 + 88 GT/TT was associated with increased prostate caner risk (odds ratio = 1.24, 95% confidence interval = 1.00-1.54), whereas the IVS20 + 524 AG/GG was associated with decreased risk (0.77, 0.66-0.90). The NOS3 IVS7 - 26GG was associated with increased prostate caner risk (1.33, 1.07-1.64). All these SNPs showed significant associations with aggressive cancer and not for non-aggressive cancer. In the evaluation of effect modification, the effect of the NOS2A IVS16 + 88 GT/TT on aggressive cancer was stronger among subjects with higher antioxidant intake (1.61, 1.18-2.19; P(interaction) = 0.01). Our results suggest that NOS gene polymorphisms are genetic susceptibility factors for aggressive prostate cancer. C1 [Lee, Kyoung-Mu; Berndt, Sonja I.; Huang, Wen-Yi; Hayes, Richard B.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kang, Daehee; Park, Sue Kyung] Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. [Reding, Douglas] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. [Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Chanock, Stephen] NCI, Sect Genom Variat, Pediat Oncol Branch, NIH, Gaithersburg, MD USA. RP Lee, KM (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8118, Bethesda, MD 20892 USA. EM leekyou@mail.nih.gov RI Kang, Dae Hee/E-8631-2012; Park, Sue Kyung/J-2757-2012; OI Hayes, Richard/0000-0002-0918-661X FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services FX Intramural Research Program of the Division of Cancer Epidemiology and Genetics and contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 25 TC 32 Z9 34 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD APR PY 2009 VL 30 IS 4 BP 621 EP 625 DI 10.1093/carcin/bgp028 PG 5 WC Oncology SC Oncology GA 428YX UT WOS:000264889100010 PM 19168583 ER PT J AU Liu, SL Li, YH Shi, GY Tang, SH Jiang, SJ Huang, CW Liu, PY Hong, JS Wu, HL AF Liu, Shu-Lin Li, Yi-Heng Shi, Guey-Yueh Tang, Sei-Hui Jiang, Shinn-Jong Huang, Chia-Wei Liu, Ping-Yen Hong, Jau-Shyong Wu, Hua-Lin TI Dextromethorphan reduces oxidative stress and inhibits atherosclerosis and neointima formation in mice SO CARDIOVASCULAR RESEARCH LA English DT Article DE Atherosclerosis; Macrophages; Anti-oxidants ID SUPEROXIDE ANION PRODUCTION; NADPH OXIDASE; DOPAMINERGIC-NEURONS; ACTIVATION; EXPRESSION; NEUTROPHILS; P47PHOX; DISEASE; INJURY; ARTERY AB Macrophage-related oxidative stress plays an important role in the inflammatory process in atherosclerosis. Recently, dextromethorphan (DXM), a common cough-suppressing ingredient with a high safety profile, was found to inhibit the activation of microglia, the resident macrophage in the nervous system. We investigated whether DXM could reduce macrophage production of cytokines and superoxide and the resultant influence on atherosclerosis formation in mice. We used in vitro and in vivo studies to evaluate the DXM inhibitory effect on oxidative stress. Dextromethorphan pretreatment significantly suppressed the production of tumour necrosis factor-alpha, monocyte chemoattractant protein-1, interleukin-6, interleukin-10, and superoxide in macrophage cell culture after stimulation. Indeed, DXM reduced macrophage nicotinamide adenine dinucleotide phosphate oxidase activity by decreasing membrane translocation of p47(phox) and p67(phox) through the inhibition of protein kinase C and extracellular signal-regulated kinase activation. The anti-atherosclerosis effect of DXM was tested using two animal models, apolipoprotein E (apoE)-deficient mice and a mouse carotid ligation model. Dextromethorphan treatment (10-40 mg/kg/day) for 10 weeks in apoE-deficient mice significantly reduced superoxide production in their polymorphonuclear leukocytes and aortas. It significantly decreased the severity of aortic atherosclerosis in the apoE-deficient mice and decreased carotid neointima formation after ligation in C57BL/6 mice. Our data show that DXM, with its novel effect in reducing oxidative stress, significantly reduces atherosclerosis and neointima formation in mice. C1 [Liu, Shu-Lin; Shi, Guey-Yueh; Tang, Sei-Hui; Jiang, Shinn-Jong; Huang, Chia-Wei; Wu, Hua-Lin] Natl Cheng Kung Univ, Coll Med, Dept Biochem & Mol Biol, Tainan 701, Taiwan. [Li, Yi-Heng; Liu, Ping-Yen] Natl Cheng Kung Univ, Coll Med, Dept Internal Med, Tainan 701, Taiwan. [Li, Yi-Heng; Shi, Guey-Yueh; Tang, Sei-Hui; Jiang, Shinn-Jong; Liu, Ping-Yen; Wu, Hua-Lin] Natl Cheng Kung Univ, Cardiovasc Res Ctr, Tainan 701, Taiwan. [Hong, Jau-Shyong] Natl Inst Environm Hlth Sci, Neuropharmacol Sect, Lab Pharmacol & Chem, Res Triangle Pk, NC USA. RP Shi, GY (reprint author), Natl Cheng Kung Univ, Coll Med, Dept Biochem & Mol Biol, Tainan 701, Taiwan. EM gyshi@mail.ncku.edu.tw; halnwu@mail.ncku.edu.tw FU National Science Council, Taipei, Taiwan, Republic of China [NSC 95-2752-B-006-003-PAE, NSC95-2752-B-006-004-PAE, NSC 95-2752-B-006-005-PAE] FX This work was supported by the National Science Council, Taipei, Taiwan, Republic of China ( Grants NSC 95-2752-B-006-003-PAE, NSC95-2752-B-006-004-PAE, and NSC 95-2752-B-006-005-PAE). NR 25 TC 20 Z9 21 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD APR 1 PY 2009 VL 82 IS 1 BP 161 EP 169 DI 10.1093/cvr/cvp043 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 418ZV UT WOS:000264189800021 PM 19189960 ER PT J AU Wu, Y Suhasini, AN Brosh, RM AF Wu, Y. Suhasini, A. N. Brosh, R. M., Jr. TI Welcome the Family of FANCJ-like Helicases to the Block of Genome Stability Maintenance Proteins SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Review DE Fanconi anemia; DNA repair; helicase; genomic stability; G quadruplex; FANCJ; XPD; CHL1; CHLR1; DOG1; RTEL ID SISTER-CHROMATID COHESION; NUCLEOTIDE EXCISION-REPAIR; DNA SUBSTRATE-SPECIFICITY; NONRANDOM CHROMOSOME LOSS; CROSS-LINK REPAIR; SACCHAROMYCES-CEREVISIAE; CAENORHABDITIS-ELEGANS; XERODERMA-PIGMENTOSUM; HOMOLOGOUS RECOMBINATION; TELOMERE LENGTH AB The FANCJ family of DNA helicases is emerging as an important group of proteins for the prevention of human disease, cancer, and chromosomal instability. FANCJ was identified by its association with breast cancer, and is implicated in Fanconi Anemia. Proteins with sequence similarity to FANCJ are important for maintenance of genomic stability. Mutations in genes encoding proteins related to FANCJ, designated ChlR1 in human and Chl1p in yeast, result in sister chromatid cohesion defects. Nematodes mutated in dog-1 show germline as well as somatic deletions in genes containing guanine-rich DNA. Rtel knockout mice are embryonic lethal, and embryonic stem cells show telomere loss and chromosomal instability. FANCJ also shares sequence similarity with human XPD and yeast RAD3 helicases required for nucleotide excision repair. The recently solved structure of XPD has provided new insight to the helicase core and accessory domains of sequence related Superfamily 2 helicases. The functions and roles of members of the FANCJ-like helicase family will be discussed. C1 [Wu, Y.; Suhasini, A. N.; Brosh, R. M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU NIH; National Institute on Aging and the Fanconi Anemia Research Fund FX This work was supported by the Intramural Research program of the NIH, National Institute on Aging and the Fanconi Anemia Research Fund (RMB). We wish to thank Drs. L. Fan and J. Tainer for kindly providing their XPD crystal structure and Elsevier for permission to reproduce their data in Fig. 4A. We thank Dr. Deborah L. Croteau (NIA, NIH) and Dr. Wei Yang (NIDDK, NIH) for critical reading of the manuscript. NR 80 TC 53 Z9 55 U1 1 U2 8 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD APR PY 2009 VL 66 IS 7 BP 1209 EP 1222 DI 10.1007/s00018-008-8580-6 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 425GF UT WOS:000264624300007 PM 19099189 ER PT J AU Berna, MJ Tapia, JA Sancho, V Thill, M Pace, A Hoffmann, KM Gonzalez-Fernandez, L Jensen, RT AF Berna, Marc J. Tapia, Jose A. Sancho, Veronica Thill, Michelle Pace, Andrea Hoffmann, K. Martin Gonzalez-Fernandez, Lauro Jensen, Robert T. TI Gastrointestinal growth factors and hormones have divergent effects on Akt activation SO CELLULAR SIGNALLING LA English DT Review DE Pancreas; Akt; CCK; Phosphorylation; Kinase; Src; Gastrointestinal hormones; PI3K; PK ID PANCREATIC ACINAR-CELLS; PROTEIN-KINASE-C; SMOOTH-MUSCLE-CELLS; STIMULATED TYROSINE PHOSPHORYLATION; SIGNAL-REGULATED KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; HIGH-AFFINITY; FACTOR RECEPTOR; ANGIOTENSIN-II; CYCLIC-AMP AB Akt is a central regulator of apoptosis, cell growth and survival. Growth factors and some G-protein-coupled receptors (GPCR) regulate Akt. Whereas growth-factor activation of Akt has been extensively studied, the regulation of Akt by GPCR's, especially gastrointestinal hormones/neurotransmitters, remains unclear. To address this area, in this study the effects of GI growth factors and hormones/neurotransmitters were investigated in rat pancreatic acinar cells which are high responsive to these agents. Pancreatic acini expressed Akt and 5 of 7 known pancreatic growth-factors stimulate Akt phosphorylation (T308, S473) and translocation. These effects are mediated by p85 phosphorylation and activation of PI3K GI hormones increasing intracellular cAMP had similar effects. However, GI-hormones/neurotransmitters [CCK, bombesin. carbachol] activating phospholipase C (PLC) inhibited basal and growth-factor-stimulated Akt activation. Detailed studies with CCK, which has both physiological and pathophysiological effects on pancreatic acinar cells at different concentrations, demonstrated CCK has a biphasic effect: at low concentrations (pM) stimulating Akt by a Src-dependent mechanism and at higher concentrations (nM) inhibited basal and stimulated Akt translocation, phosphorylation and activation, by de-phosphorylating p85 resulting in decreasing PI3K activity. This effect required activation of both limbs of the PLC-pathway and a protein tyrosine phosphatase, but was not mediated by p44/42 MAPK, Src or activation of a serine phosphatase. Akt inhibition by CCK was also found in vivo and in Panc-1 cancer cells where it inhibited serum-mediated rescue from apoptosis. These results demonstrate that GI growth factors as well as gastrointestinal hormones/neurotransmitters with different cellular basis of action can all regulate Akt phosphorylation in pancreatic acinar cells. This regulation is complex with phospholipase C agents such as CCK, because both stimulatory and inhibitory effects can be seen, which are mediated by different mechanisms. Published by Elsevier Inc. C1 [Berna, Marc J.; Sancho, Veronica; Jensen, Robert T.] NIDDK, NIH, DDB, Bethesda, MD 20892 USA. [Berna, Marc J.; Pace, Andrea] Univ Klinikum Eppendorf, Med Klin 1, D-20246 Hamburg, Germany. [Tapia, Jose A.; Gonzalez-Fernandez, Lauro] Univ Extremadura, Dept Fisiol, Caceres 10071, Spain. [Thill, Michelle] NEI, NIH, Bethesda, MD 20892 USA. [Thill, Michelle] Univ Klinikum Eppendorf, Klin & Poliklin Augenheilkunde, D-20246 Hamburg, Germany. [Hoffmann, K. Martin] Med Univ Graz, Dept Pediat & Adolescent Med, A-8036 Graz, Austria. RP Jensen, RT (reprint author), NIDDK, NIH, DDB, Bldg 10,Rm 9C-103,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov RI Tapia, Jose/C-5181-2008; OI Tapia, Jose/0000-0002-3614-6867; Gonzalez Fernandez, Lauro/0000-0001-5568-548X FU NIDDK; NEI, NIH; Action Vaincre le Cancer - Lions Luxembourg; Ministerio de Educacion y Ciencia-FEDER of Spain [BFU2007-62423]; Ministry of Culture, Higher Education and Research of the Grand-Duchy of Luxembourg; Extremadura-FEDER, Spain FX This work is partially supported by the Intramural Research Program of the NIDDK and NEI, NIH. Marc Berna is supported by a grant from "Action Vaincre le Cancer - Lions Luxembourg". Jose A. Tapia is supported by the "Programa Ramon y Cajal" and by a research grant (BFU2007-62423) from the "Ministerio de Educacion y Ciencia-FEDER" of Spain. Michelle Thill is supported by a "Bourse Formation Recherche (BFR)" grant from the Ministry of Culture, Higher Education and Research of the Grand-Duchy of Luxembourg. Lauro Gonzalez-Fernandez is supported by a "Formacion de personal Investigador (FPI)" grant from the junta de Extremadura-FEDER, Spain. NR 122 TC 19 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD APR PY 2009 VL 21 IS 4 BP 622 EP 638 DI 10.1016/j.cellsig.2009.01.003 PG 17 WC Cell Biology SC Cell Biology GA 419NL UT WOS:000264226200018 PM 19166928 ER PT J AU Zhao, BZ He, YY Chignell, CF Yin, JJ Andley, U Roberts, JE AF Zhao, Baozhong He, Yu-Ying Chignell, Colin F. Yin, Jun-Jie Andley, Usha Roberts, Joan E. TI Difference in Phototoxicity of Cyclodextrin Complexed Fullerene [(gamma-CyD)(2)/C-60] and Its Aggregated Derivatives toward Human Lens Epithelial Cells SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID WATER-SOLUBLE FULLERENES; SINGLET OXYGEN; PROTEIN PEROXIDES; STATE PROPERTIES; PLASMA-MEMBRANE; UV-RADIATION; MALONIC-ACID; C-60; CYTOTOXICITY; LIGHT AB The water-soluble fullerene derivative gamma-cyclodextrin bicapped C-60 [(gamma-CyD)(2)/C-60, CDF0] has several clinical applications, including use as a drug carrier to bypass the blood ocular barriers or a photosensitizer to treat tumors in photodynamic therapy. We have assessed the potential ocular toxicity of (gamma-CyD)(2)/C-60 and its aggregated derivatives induced by UVA and visible light in vitro in human lens epithelial cells (HLE B-3). Cell viability using the MTS assay demonstrated that 2 mu M (gamma-CyD)(2)/C-60 was highly phototoxic to HLE B-3 cells with UVA irradiation, while no effect was observed in the presence of visible light or when maintained in the dark. In contrast, the aggregated derivative (CDF150) showed neither cytotoxicity nor any phototoxic effect even at 30 mu M with either UVA or visible light irradiation. In lens cells treated with (gamma-CyD)(2)/C-60, phototoxicity was manifested as apoptosis. Singlet oxygen production measurement using the EPR/TEMP trapping technique determined that (gamma-CyD)(2)/C60 (CDF0) efficiently produced singlet oxygen. The rate of singlet oxygen production decreased with increased aggregation, with no production by the fully aggregated sample formed after 150 min of heating (CDF150). UVA irradiation of HLE B-3 in the presence of (gamma-CyD)(2)/C-60 resulted in a significant rise in intracellular protein-derived peroxides. The singlet oxygen quenchers sodium azide and histidine each significantly protected lens cells against (gamma-CyD)(2)/C-60 photodamage, but lutein and Trolox (vitamin E) did not. Clearly, singlet oxygen is an important intermediate in the phototoxicity of monomeric (gamma-CyD)(2)/fullerene. Our results also demonstrate that UVA-blocking sunglasses can limit the ocular phototoxicity of this nanomaterial, while nontoxic endogenous antioxidants like lutein or Trolox cannot provide adequate protection. C1 [Roberts, Joan E.] Fordham Univ, Dept Nat Sci, New York, NY 10023 USA. [Yin, Jun-Jie] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Andley, Usha] Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. [Zhao, Baozhong; He, Yu-Ying; Chignell, Colin F.] Natl Inst Environm Hlth Sci, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. RP Roberts, JE (reprint author), Fordham Univ, Dept Nat Sci, 113 W 60th St, New York, NY 10023 USA. EM jroberts@fordham.edu RI Zhao, Baozhong/B-5865-2011; Yin, Jun Jie /E-5619-2014 FU NIH; National Institute of Environmental Health Sciences FX This paper is dedicated to the memory of Dr. Colin F. Chignell. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. We thank Dr. Ann Motten, NIEHS, for help in preparation of this manuscript and Dr. Carl Bortner and Maria Sifre for their assistance with flow cytometry measurements. This manuscript has been reviewed by the National Institutes of Environmental Health Sciences and approved for publication. NR 54 TC 38 Z9 41 U1 3 U2 26 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD APR PY 2009 VL 22 IS 4 BP 660 EP 667 DI 10.1021/tx800478u PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 436KF UT WOS:000265412300009 PM 19281132 ER PT J AU Chen, C Krausz, KW Shah, YM Idle, JR Gonzalez, FJ AF Chen, Chi Krausz, Kristopher W. Shah, Yatrik M. Idle, Jeffrey R. Gonzalez, Frank J. TI Serum Metabolomics Reveals Irreversible Inhibition of Fatty Acid beta-Oxidation through the Suppression of PPAR alpha Activation as a Contributing Mechanism of Acetaminophen-Induced Hepatotoxicity SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID MITOCHONDRIAL PERMEABILITY TRANSITION; ACUTE LIVER-FAILURE; MASS-SPECTROMETRY; EARLY PREDICTOR; MICE; TOXICITY; MOUSE; METABOLISM; IDENTIFICATION; PARACETAMOL AB Metabolic bioactivation, glutathione depletion, and covalent binding are the early hallmark events after acetaminophen (APAP) overdose. However, the subsequent metabolic consequences contributing to APAP-induced hepatic necrosis and apoptosis have not been fully elucidated. In this study, serum metabolomes of control and APAP-treated wild-type and Cyp2e1-null mice were examined by liquid chromatography-mass spectrometry (LC-MS) and multivariate data analysis. A dose-response study showed that the accumulation of long-chain acylcarnitines in serum contributes to the separation of wild-type mice undergoing APAP-induced hepatotoxicity from other mouse groups in a multivariate model. This observation, in conjunction with the increase of triglycerides and free fatty acids in the serum of APAP-treated wild-type mice, suggested that APAP treatment can disrupt fatty acid beta-oxidation. A time-course study further indicated that both wild-type and Cyp2e1-null mice had their serum acylcarnitine levels markedly elevated within the early hours of APAP treatment. While remaining high in wild-type mice, serum acylcarnitine levels gradually returned to normal in Cyp2e1-null mice at the end of the 24 h treatment. Distinct from serum aminotransferase activity and hepatic glutathione levels, the pattern of serum acylcarnitine accumulation suggested that acylcarnitines can function as complementary biomarkers for monitoring the APAP-induced hepatotoxicity. An essential role for peroxisome proliferator-activated receptor a (PPAR alpha) in the regulation of serum acylcarnitine levels was established by comparing the metabolomic responses of wild-type and Ppara-null mice to a fasting challenge. The upregulation of PPAR alpha activity following APAP treatment was transient in wild-type mice but was much more prolonged in Cyp2e1-null mice. Overall, serum metabolomics of APAP-induced hepatotoxicity revealed that the CYP2E1-mediated metabolic activation and oxidative stress following APAP treatment can cause irreversible inhibition of fatty acid oxidation, potentially through suppression of PPAR alpha-regulated pathways. C1 [Chen, Chi; Shah, Yatrik M.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Idle, Jeffrey R.] Charles Univ Prague, Fac Med 1, Inst Pharmacol, Prague 12800, Czech Republic. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov FU NIH FX This study was supported by the NCI Intramural Research Program of the NIH. J.R.I. is grateful to US Smokeless Tobacco Company for a grant for collaborative research. NR 46 TC 86 Z9 90 U1 3 U2 29 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD APR PY 2009 VL 22 IS 4 BP 699 EP 707 DI 10.1021/tx800464q PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 436KF UT WOS:000265412300014 PM 19256530 ER PT J AU Kulemzina, AI Trifonov, VA Perelman, PL Rubtsova, NV Volobuev, V Ferguson-Smith, MA Stanyon, R Yang, FT Graphodatsky, AS AF Kulemzina, Anastasia I. Trifonov, Vladimir A. Perelman, Polina L. Rubtsova, Nadezhda V. Volobuev, Vitaly Ferguson-Smith, Malcolm A. Stanyon, Roscoe Yang, Fengtang Graphodatsky, Alexander S. TI Cross-species chromosome painting in Cetartiodactyla: Reconstructing the karyotype evolution in key phylogenetic lineages SO CHROMOSOME RESEARCH LA English DT Article DE cetaceans; Pecora; hippopotamus; breakpoint reuse; Zoo-FISH; chromosome evolution ID MUNTJAC MUNTIACUS-REEVESI; 16S RIBOSOMAL-RNA; CYTOCHROME-B; COMPARATIVE MAP; MUSK DEER; MOLECULAR EVOLUTION; ORDER ARTIODACTYLA; PLACENTAL MAMMALS; FAMILY BOVIDAE; DOMESTIC PIG AB Recent molecular and morphological studies place Artiodactyla and Cetacea into the order Cetartiodactyla. Within the Cetartiodactyla such families as Bovidae, Cervidae, and Suidae are well studied by comparative chromosome painting, but many taxa that are crucial for understanding cetartiodactyl phylogeny remain poorly studied. Here we present the genome-wide comparative maps of five cetartiodactyl species obtained by chromosome painting with human and dromedary paint probes from four taxa: Cetacea, Hippopotamidae, Giraffidae, and Moschidae. This is the first molecular cytogenetic report on pilot whale, hippopotamus, okapi, and Siberian musk deer. Our results, when integrated with previously published comparative chromosome maps allow us to reconstruct the evolutionary pathway and rates of chromosomal rearrangements in Cetartiodactyla. We hypothesize that the putative cetartiodactyl ancestral karyotype (CAK) contained 25-26 pairs of autosomes, 2n = 52-54, and that the association of human chromosomes 8/9 could be a cytogenetic signature that unites non-camelid cetartiodactyls. There are no unambiguous cytogenetic landmarks that unite Hippopotamidae and Cetacea. If we superimpose chromosome rearrangements on the supertree generated by Price and colleagues, several homoplasy events are needed to explain cetartiodactyl karyotype evolution. Our results apparently favour a model of non-random breakpoints in chromosome evolution. Cetariodactyl karyotype evolution is characterized by alternating periods of low and fast rates in various lineages. The highest rates are found in Suina (Suidae+Tayasuidae) lineage (1.76 rearrangements per million years (R/My)) and the lowest in Cetaceans (0.07 R/My). Our study demonstrates that the combined use of human and camel paints is highly informative for revealing evolutionary karyotypic rearrangements among cetartiodactyl species. C1 [Kulemzina, Anastasia I.; Trifonov, Vladimir A.; Perelman, Polina L.; Rubtsova, Nadezhda V.; Graphodatsky, Alexander S.] Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. [Perelman, Polina L.] NCI, Frederick, MD 21701 USA. [Volobuev, Vitaly] Museum Natl Hist Nat, F-75231 Paris, France. [Ferguson-Smith, Malcolm A.] Cambridge Resource Ctr Comparat Genom, Dept Vet Med, Cambridge, England. [Stanyon, Roscoe] Univ Florence, Dept Evolutionary Biol, Florence, Italy. [Yang, Fengtang] Wellcome Trust Sanger Inst, Cambridge, England. RP Trifonov, VA (reprint author), Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. EM vlad@bionet.nsc.ru RI Trifonov, Vladimir/E-4907-2012; Graphodatsky, Alexander/B-4922-2010; Perelman, Polina/N-8088-2015; OI Trifonov, Vladimir/0000-0003-0454-8359; Graphodatsky, Alexander/0000-0002-8282-1085; Perelman, Polina/0000-0002-0982-5100; Stanyon, Roscoe/0000-0002-7229-1092 FU Russian Fund for Basic Research; Russian Academy of Science; Siberian Branch of the Russian Academy of Science; Wellcome Trust; Italian Ministry of Universities and Research FX R.S. would like to acknowledge Lutz Froenike for discussion and comments on whale phylogenetics. NR 84 TC 27 Z9 30 U1 1 U2 15 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0967-3849 J9 CHROMOSOME RES JI Chromosome Res. PD APR PY 2009 VL 17 IS 3 BP 419 EP 436 DI 10.1007/s10577-009-9032-3 PG 18 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 445VH UT WOS:000266079100011 PM 19350402 ER PT J AU Dehghan, A Yang, Q Peters, A Basu, S Bis, JC Rudnicka, AR Kavousi, M Chen, MH Baumert, J Lowe, GDO McKnight, B Tang, WH de Maat, M Larson, MG Eyhermendy, S McArdle, WL Lumley, T Pankow, JS Hofman, A Massaro, JM Rivadeneira, F Kolz, M Taylor, KD van Duijn, CM Kathiresan, S Illig, T Aulchenko, YS Volcik, KA Johnson, AD Uitterlinden, AG Tofler, GH Gieger, C Psaty, BM Couper, DJ Boerwinkle, E Koenig, W O'Donnell, CJ Witteman, JC Strachan, DP Smith, NL Folsom, AR AF Dehghan, Abbas Yang, Qiong Peters, Annette Basu, Saonli Bis, Joshua C. Rudnicka, Alicja R. Kavousi, Maryam Chen, Ming-Huei Baumert, Jens Lowe, Gordon D. O. McKnight, Barbara Tang, Weihong de Maat, Moniek Larson, Martin G. Eyhermendy, Susana McArdle, Wendy L. Lumley, Thomas Pankow, James S. Hofman, Albert Massaro, Joseph M. Rivadeneira, Fernando Kolz, Melanie Taylor, Kent D. van Duijn, Cornelia M. Kathiresan, Sekar Illig, Thomas Aulchenko, Yurii S. Volcik, Kelly A. Johnson, Andrew D. Uitterlinden, Andre G. Tofler, Geoffrey H. Gieger, Christian Psaty, Bruce M. Couper, David J. Boerwinkle, Eric Koenig, Wolfgang O'Donnell, Christopher J. Witteman, Jacqueline C. Strachan, David P. Smith, Nicholas L. Folsom, Aaron R. CA Wellcome Trust Case Control Consor TI Association of Novel Genetic Loci With Circulating Fibrinogen Levels A Genome-Wide Association Study in 6 Population-Based Cohorts SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE genome-wide association study; fibrinogen; genes; meta-analysis ID INFLAMMATORY-BOWEL-DISEASE; CARDIOVASCULAR-DISEASE; VENOUS THROMBOSIS; PLASMA-FIBRINOGEN; FRAMINGHAM; DESIGN; RISK; EXPRESSION; HEART; OBJECTIVES C1 [Dehghan, Abbas; Kavousi, Maryam; Hofman, Albert; van Duijn, Cornelia M.; Aulchenko, Yurii S.; Witteman, Jacqueline C.] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Yang, Qiong; Larson, Martin G.; Massaro, Joseph M.; Kathiresan, Sekar; Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Dehghan, Abbas; Yang, Qiong; Chen, Ming-Huei] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Chen, Ming-Huei] Boston Univ, Dept Neurol, Boston, MA 02215 USA. [Chen, Ming-Huei] Boston Univ, Framingham Heart Study, Boston, MA 02215 USA. [Basu, Saonli] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [de Maat, Moniek] Erasmus MC, Dept Hematol, NL-3000 CA Rotterdam, Netherlands. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. [Larson, Martin G.; Massaro, Joseph M.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Tang, Weihong; Pankow, James S.; Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Volcik, Kelly A.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. [Volcik, Kelly A.; Boerwinkle, Eric] Univ Texas Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. [Couper, David J.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Rudnicka, Alicja R.; Strachan, David P.] Univ London, Div Community Hlth Sci, London, England. [McArdle, Wendy L.] Univ Bristol, ALSPAC Lab, Bristol, Avon, England. [Lowe, Gordon D. O.] Univ Glasgow, Royal Infirm, Div Cardiovasc & Med Sci, Glasgow, Lanark, Scotland. [Wellcome Trust Case Control Consor] Wellcome Trust Res Labs, Cambridge, England. [Peters, Annette; Baumert, Jens; Kolz, Melanie; Illig, Thomas; Gieger, Christian] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol, Neuherberg, Germany. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiovasc Res Ctr, Boston, MA USA. [Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Human Genet Res, Boston, MA USA. [Tofler, Geoffrey H.] Royal N Shore Hosp, Sydney, NSW, Australia. [Koenig, Wolfgang] Univ Ulm, Dept Internal Med Cardiol 2, Ulm, Germany. [Eyhermendy, Susana] Pontificia Univ Catolica Chile, Dept Stat, Santiago, Chile. [Smith, Nicholas L.] Vet Affairs Off Res & Dev, Seattle Epidemiol Res & Informat Ctr, Seattle, WA USA. [McKnight, Barbara; Lumley, Thomas] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.; Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Bis, Joshua C.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Taylor, Kent D.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. RP Witteman, JC (reprint author), Erasmus MC, Dept Epidemiol, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM odonnellc@nhlbi.nih.gov; j.witteman@erasmusmc.nl RI Johnson, Andrew/G-6520-2013; Aulchenko, Yurii/M-8270-2013; Waldenberger, Melanie/B-5355-2014; Yang, Qiong/G-5438-2014; Peters, Annette/A-6117-2011; Rivadeneira, Fernando/O-5385-2015; Breen, Gerome/A-5540-2010; OI Gieger, Christian/0000-0001-6986-9554; Wallace, Chris/0000-0001-9755-1703; Eyre, Stephen/0000-0002-1251-6974; Pankow, James/0000-0001-7076-483X; Dehghan, Abbas/0000-0001-6403-016X; Larson, Martin/0000-0002-9631-1254; Aulchenko, Yurii/0000-0002-7899-1575; Waldenberger, Melanie/0000-0003-0583-5093; Rivadeneira, Fernando/0000-0001-9435-9441; Breen, Gerome/0000-0003-2053-1792; Massaro, Joseph/0000-0002-2682-4812; Lango Allen, Hana/0000-0002-7803-8688; Zeggini, Eleftheria/0000-0003-4238-659X; Dunger, Professor David/0000-0002-2566-9304 FU Erasmus Medical Center and Erasmus University Rotterdam; Netherlands Organization for Scientific Research [175.010.2005.011, 911.03.012]; Netherlands Organization for Health Research and Development; Research Institute for Diseases in the Elderly [94800022]; Netherlands Heart Foundation; Ministry of Education, Culture and Science; Ministry of Health Welfare and Sports; European Commission; Municipality of Rotterdam; Netherlands Genomics Initiative/Netherlands Organization for Scientific Research [050-060-810]; National Heart, Lung, and Blood Institute [N01-HC-25195, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01-HL-087641, R01-HL-59367, R01-HL-086694, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL 087652]; Affymetrix Inc [N02-HL-6-4278]; National Human Genome Research Institute [U01-HG-004402]; National Institutes of Health [HHSN268200625226C]; NIH Roadmap for Medical Research; National Center for Research Rosources [M01RR00069]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Helmholtz Zentrum Munchen; German Research Center for Environmental Health (Neuherberg, Germany); German Federal Ministry of Education and Research; German National Genome Research Network; [UL1-RR-025005] FX The RS is supported by the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research; the Netherlands Organization for Health Research and Development; the Research Institute for Diseases in the Elderly; the Netherlands Heart Foundation; the Ministry of Education, Culture and Science; the Ministry of Health Welfare and Sports; the European Commission; and the Municipality of Rotterdam. Support for genotyping was provided by the Netherlands Organization for Scientific Research (175.010.2005.011, 911.03.012) and the Research Institute for Diseases in the Elderly. This study was further supported by the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research project 050-060-810. Dr Dehghan is supported by the Netherlands Organization for Scientific Research and the Research Institute for Diseases in the Elderly (94800022).; The FHS was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract N01-HC-25195) and its contract with Affymetrix Inc for genotyping services (contract N02-HL-6-4278).; The ARIC is supported by National Heart, Lung, and Blood Institute contracts N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022 and grants R01-HL-087641, R01-HL-59367, and R01-HL-086694; National Human Genome Research Institute contract U01-HG-004402; and National Institutes of Health contract HHSN268200625226C. The infrastructure was partly supported by grant UL1-RR-025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research.; The Cardiovascular Health Study is supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant numbers U01 HL080295 and R01 HL 087652 from the National Heart, Lung, and Blood Institute (NHLBI), 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. Support was also provided by NHLBI grant HL073410 and the Leducq Foundation, Paris, France for the development of Transatlantic Networks of Excellence in Cardiovascular Research. DNA handling and genotyping was supported in part by National Center for Research Rosources grant M01RR00069 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 MONICA/KORA studies were financed by the Helmholtz Zentrum Munchen, German Research Center for Environmental Health (Neuherberg, Germany) and supported by grants from the German Federal Ministry of Education and Research. Part of this work was financed by the German National Genome Research Network and through additional funds from the University of Ulm. NR 32 TC 56 Z9 59 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD APR PY 2009 VL 2 IS 2 BP 125 EP U91 DI 10.1161/CIRCGENETICS.108.825224 PG 17 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 574HE UT WOS:000275979200005 PM 20031576 ER PT J AU Tarasov, KV Sanna, S Scuteri, A Strait, JB Orru, M Parsa, A Lin, PI Maschio, A Lai, S Piras, MG Masala, M Tanaka, T Post, W O'Connell, JR Schlessinger, D Cao, A Nagaraja, R Mitchell, BD Abecasis, GR Shuldiner, AR Uda, M Lakatta, EG Najjar, SS AF Tarasov, Kirill V. Sanna, Serena Scuteri, Angelo Strait, James B. Orru, Marco Parsa, Afshin Lin, Ping-I Maschio, Andrea Lai, Sandra Piras, Maria Grazia Masala, Marco Tanaka, Toshiko Post, Wendy O'Connell, Jeffrey R. Schlessinger, David Cao, Antonio Nagaraja, Ramaiah Mitchell, Braxton D. Abecasis, Goncalo R. Shuldiner, Alan R. Uda, Manuela Lakatta, Edward G. Najjar, Samer S. TI COL4A1 Is Associated With Arterial Stiffness by Genome-Wide Association Scan SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE arterial stiffness; pulse wave velocity; genome-wide association scan; COL4A1; MAGI1; nonsynomous SNP ID PULSE-WAVE VELOCITY; AORTIC STIFFNESS; BLOOD-PRESSURE; INDEPENDENT PREDICTOR; HYPERTENSIVE PATIENTS; GENE POLYMORPHISMS; COMMON VARIANTS; RISK; DISEASE; ADULTS AB Background-Pulse wave velocity (PWV), a noninvasive index of central arterial stiffness, is a potent predictor of cardiovascular mortality and morbidity. Heritability and linkage studies have pointed toward a genetic component affecting PWV. We conducted a genome-wide association study to identify single-nucleotide polymorphisms (SNPs) associated with PWV. Methods and Results-The study cohort included participants from the SardiNIA study for whom PWV measures were available. Genotyping was performed in 4221 individuals, using either the Affymetrix 500K or the Affymetrix 10K mapping array sets (with imputation of the missing genotypes). Associations with PWV were evaluated using an additive genetic model that included age, age(2), and sex as covariates. The findings were tested for replication in an independent internal Sardinian cohort of 1828 individuals, using a custom chip designed to include the top 43 nonredundant SNPs associated with PWV. Of the loci that were tested for association with PWV, the nonsynonymous SNP rs3742207 in the COL4A1 gene on chromosome 13 and SNP rs1495448 in the MAGI1 gene on chromosome 3 were successfully replicated (P=7.08X10(-7) and P=1.06X10(-5), respectively, for the combined analyses). The association between rs3742207 and PWV was also successfully replicated (P=0.02) in an independent population, the Old-Order Amish, leading to an overall P=5.16X10(-8). Conclusions-A genome-wide association study identified a SNP in the COL4A1 gene that was significantly associated with PWV in 2 populations. Collagen type 4 is the major structural component of basement membranes, suggesting that previously unrecognized cell-matrix interactions may exert an important role in regulating arterial stiffness. (Circ Cardiovasc Genet. 2009; 2: 151-158.) C1 [Tarasov, Kirill V.; Strait, James B.; Lakatta, Edward G.; Najjar, Samer S.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Tarasov, Kirill V.; Strait, James B.; Schlessinger, David; Nagaraja, Ramaiah] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Tanaka, Toshiko] NIA, Clinial Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Sanna, Serena; Orru, Marco; Maschio, Andrea; Lai, Sandra; Piras, Maria Grazia; Masala, Marco; Uda, Manuela] Cittadella Univ Monseratto, CNR, INN, Cagliari, Italy. [Scuteri, Angelo] IRCCS, INRCA, Unita Operat Geriatria, Rome, Italy. [Parsa, Afshin] Univ Maryland, Sch Med, Dept Med, Div Nephrol, Baltimore, MD 21201 USA. [Lin, Ping-I; O'Connell, Jeffrey R.; Mitchell, Braxton D.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. [Lin, Ping-I] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Catonsville, MD 21228 USA. [Post, Wendy] Johns Hopkins Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21218 USA. [Post, Wendy] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. RP Najjar, SS (reprint author), Harbor Hosp, NIA, ASTRA Unit, 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM NajjarSa@mail.nih.gov RI Abecasis, Goncalo/B-7840-2010; Lin, Ping-I (Daniel)/O-2613-2015; OI Tarasov, Kirill/0000-0001-7799-4670; piras, maria grazia/0000-0001-9004-0900; sanna, serena/0000-0002-3768-1749; Abecasis, Goncalo/0000-0003-1509-1825; Lin, Ping-I/0000-0002-9739-7184; Mitchell, Braxton/0000-0003-4920-4744 FU National Institute on Aging [NO1-AG-1-2109]; National Institutes of Health [T32HL072751]; University of Maryland General Clinical Research Center [M01 RR 16500]; National Center for Research Resources; Clinical Nutrition Research Unit of Maryland [P30DK072488]; American Federation of Aging Research; [U01 HL72515] FX The SardiNIA ("ProgeNIA") team was supported by contract NO1-AG-1-2109 from the National Institute on Aging. This work was supported, in part, by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.; The Amish studies were supported by a National Institutes of Health Institutional Training Grant in Cardiac and Vascular Cell Biology (T32HL072751), grant U01 HL72515, the University of Maryland General Clinical Research Center (M01 RR 16500), the National Center for Research Resources, the Clinical Nutrition Research Unit of Maryland (P30DK072488), and the Paul Beeson Physician Faculty Scholars in Aging Program of the American Federation of Aging Research. NR 47 TC 37 Z9 38 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD APR PY 2009 VL 2 IS 2 BP 151 EP U136 DI 10.1161/CIRCGENETICS.108.823245 PG 24 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 574HE UT WOS:000275979200008 PM 20031579 ER PT J AU Savani, BN Goodman, S Barrett, AJ AF Savani, Bipin N. Goodman, Stacey Barrett, A. John TI Can Routine Posttransplant HPV Vaccination Prevent Commonly Occurring Epithelial Cancers after Allogeneic Stem Cell Transplantation? SO CLINICAL CANCER RESEARCH LA English DT Review ID HUMAN-PAPILLOMAVIRUS INFECTION; BONE-MARROW-TRANSPLANTATION; LONG-TERM SURVIVORS; SOLID CANCERS; IMMUNOSUPPRESSIVE THERAPY; NONMELANOMA SKIN; CERVICAL-CANCER; UNITED-STATES; RISK-FACTORS; YOUNG-WOMEN AB The association between squamous cell carcinoma (SCC) of the oral cavity, female genital tract, and skin with human papilloma virus (HPV) subtypes is well established in the general population and in solid organ transplant recipients, but no consistent link has been reported between HPV infection and SCC after allogeneic stem cell transplantation (allo-SCT). Studies are needed to determine if SCC, the most common secondary malignancy after allo-SCT, which is linked to chronic graft versus host disease and immunosuppressive therapy, is HPV related. Consideration should be given to assessing pretransplant HPV antibodies to identify patients at risk for HPV reactivation. If a strong relationship between HPV and second malignancies after SCT exists, studies to evaluate the immunogenicity and efficacy of quadrivalent HPV vaccine (subtypes 6, 11, 16, and 18) should be considered in both male and female long-term survivors after allo-SCT. C1 [Savani, Bipin N.; Goodman, Stacey] Vanderbilt Univ, Nashville, TN USA. [Savani, Bipin N.; Goodman, Stacey] VAMC Transplant Program, Nashville, TN USA. [Barrett, A. John] NHLBI, Stem Cell Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bldg 10,Hatfield CRC,Room 3-5330,10 Ctr Dr,MSC 12, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov FU Intramural NIH HHS [ZIA HL006105-02] NR 28 TC 18 Z9 18 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 EI 1557-3265 J9 CLIN CANCER RES JI Clin. Cancer Res. PD APR 1 PY 2009 VL 15 IS 7 BP 2219 EP 2221 DI 10.1158/1078-0432.CCR-08-3099 PG 3 WC Oncology SC Oncology GA 429YK UT WOS:000264955800004 PM 19293253 ER PT J AU Pernas, FG Allen, CT Winters, ME Yan, B Friedman, J Dabir, B Saigal, K Mundinger, GS Xu, XJ Morris, JC Calvo, KR Van Waes, C Chen, Z AF Pernas, Francisco G. Allen, Clint T. Winters, Mary E. Yan, Bin Friedman, Jay Dabir, Bhavana Saigal, Kunal Mundinger, Gerhard S. Xu, Xiaojiang Morris, John C. Calvo, Katherine R. Van Waes, Carter Chen, Zhong TI Proteomic Signatures of Epidermal Growth Factor Receptor and Survival Signal Pathways Correspond to Gefitinib Sensitivity in Head and Neck Cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMA; NF-KAPPA-B; LUNG-CANCER; CONSTITUTIVE ACTIVATION; SOMATIC MUTATIONS; EGFR GENE; EXPRESSION; PHOSPHORYLATION; THERAPY; MEK AB Purpose: Gefitinib targeting of the epidermal growth factor receptor (EGFR) has shown limited activity in clinical trials of head and neck squamous cell carcinoma (HNSCC). To investigate the underlying molecular mechanism, the proteomic signatures and responses of EGFR and downstream signals have been studied in a panel of HNSCC cell lines and tumor specimens pre- and post-gefitinib treatment. Experimental Design: The IC(50) of gefitinib for HNSCC cell lines were determined using 3-(4,5-dmethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide proliferation assay. The effects of gefitinib on activation of EGFR and downstream signaling molecules were determined by Western blot, ELISA, and reverse-phase protein microarray (RPMA). The biomarkers involved in the signaling pathways were examined in HNSCC tumor specimens from patients in a phase I gefitinib trial. Results: In vitro, gefitinib inhibited cell proliferation with differing IC(50), and suppressed activation of EGFR and downstream signaling molecules protein kinase B (AKT), extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3 (STAT3), and nuclear factor kappa B. The drug sensitivity was statistically correlated with activation of phosphorylated AKT (p-AKT) and phosphorylated STAT3 (p-STAT3) detected by ELISA, and consistent with results measured by RPMA. In patient samples, a broad suppression of activation of EGFR and downstream signaling molecules was observed in a molecular responder patient, in contrast to a lack of inhibition or increased activation of biomarkers in different pathways in nonresponder patients. Conclusions: Gefitinib sensitivity is correlated with p-AKT and p-STAT3 activation in HNSCC cell lines and tumor specimens. p-AKTand p-STAT3 could serve as potentially useful biomarkers and drug targets for further development of novel therapeutic agents for HNSCC. C1 [Pernas, Francisco G.; Allen, Clint T.; Yan, Bin; Friedman, Jay; Saigal, Kunal; Van Waes, Carter; Chen, Zhong] Natl Inst Deafness & Other Commun Disorders, Tumor Biol Sect, Head & Neck Surg Branch, Bethesda, MD USA. [Winters, Mary E.; Dabir, Bhavana; Mundinger, Gerhard S.; Calvo, Katherine R.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Morris, John C.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Xu, Xiaojiang] Univ Virginia, Charlottesville, VA USA. RP Chen, Z (reprint author), NIH NIDCO, Bldg 10,Room 5D55,10 Ctr Dr, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov; chenz@nidcd.nih.gov RI Calvo, Katherine/A-8109-2009; OI Calvo, Katherine/0000-0002-0771-4191 FU Pfizer Pharmaceuticals Group; NIH; NIDCD [Z01-DC-00016]; NCI, Center for Cancer Research FX Clinical Research Training Program, a public-private partnership supported jointly by the NIH and a grant to the Foundation for the NIH from Pfizer Pharmaceuticals Group. Intramural Research Program of the NIH, NIDCD project Z01-DC-00016, and NCI, Center for Cancer Research. NR 50 TC 36 Z9 37 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 APR 1 PY 2009 VL 15 IS 7 BP 2361 EP 2372 DI 10.1158/1078-0432.CCR-08-1011 PG 12 WC Oncology SC Oncology GA 429YK UT WOS:000264955800019 PM 19318490 ER PT J AU Hance, KW Rogers, CJ Zaharoff, DA Canter, D Schlom, J Greiner, JW AF Hance, Kenneth W. Rogers, Connie J. Zaharoff, David A. Canter, Daniel Schlom, Jeffrey Greiner, John W. TI The Antitumor and Immunoadjuvant Effects of IFN-alpha in Combination with Recombinant Poxvirus Vaccines SO CLINICAL CANCER RESEARCH LA English DT Article ID HLA CLASS-I; HUMAN CARCINOEMBRYONIC ANTIGEN; COLONY-STIMULATING FACTOR; CEA TRANSGENIC MICE; INTERFERON-ALPHA; DENDRITIC CELLS; PANCREATIC-CARCINOMA; DIVERSIFIED PRIME; TUMOR-CELLS; EXPRESSION AB Purpose: IFN-alpha is a pleiotropic cytokine possessing immunomodulatory properties that may improve the efficacy of therapeutic cancer vaccines. The aim of this study was to evaluate the effectiveness and compatibility of combining recombinant IFN-alpha with poxvirus vaccines targeting the human carcinoembryonic antigen (CEA) in murine models of colorectal and pancreatic adenocarcinomas, where CEA is a self-antigen. Experimental Design: The phenotypic and functional effects of IFN-alpha were evaluated in the draining inguinal lymph nodes of tumor-free mice. We studied the effect of the site of IFN-alpha administration (local versus distal) on antigen-specific immune responses to poxvirus vaccination. Mechanistic studies were conducted to assess the efficacy of IFN-alpha and CEA-directed poxvirus vaccines in tumor-bearing CEA transgenic mice. Results: We identified a dose and schedule of IFN-alpha that induced a locoregional expansion of the draining inguinal lymph nodes and improved cellular cytotoxicity (natural killer and CD8(+)) and antigen presentation. Suppression of the vaccinia virus was avoided by administering IFN-alpha distal to the site of vaccination. The combination of IFN-alpha and vaccine inhibitd tumor growth, improved survival, and elicited CEA-specific CTL responses in mice with CEA(+) adenocarcinomas. In mice with pancreatic tumors, IFN-alpha slowed tumor growth, induced CTL activity, and increased CD8(+) tumor-infiltrating lymphocytes. Conclusions: These data suggest that IFN-alpha can be used as a biological response modifier with antigen-directed poxvirus vaccines to yield significant therapeutic antitumor immune responses. This study provides the rationale and mechanistic insights to support a clinical trial of this immunotherapeutic strategy in patients with CEA-expressing carcinomas. C1 [Hance, Kenneth W.; Rogers, Connie J.; Zaharoff, David A.; Canter, Daniel; Schlom, Jeffrey; Greiner, John W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Greiner, JW (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B04, Bethesda, MD 20892 USA. EM greinerj@mail.nih.gov FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH FX Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 47 TC 16 Z9 18 U1 0 U2 2 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 APR 1 PY 2009 VL 15 IS 7 BP 2387 EP 2396 DI 10.1158/1078-0432.CCR-08-1752 PG 10 WC Oncology SC Oncology GA 429YK UT WOS:000264955800022 PM 19276249 ER PT J AU O'Mahony, D Morris, JC Stetler-Stevenson, M Matthews, H Brown, MR Fleisher, T Pittaluga, S Raffeld, M Albert, PS Reitsma, D Kaucic, K Hammershaimb, L Waldmann, TA Janik, JE AF O'Mahony, Deirdre Morris, John C. Stetler-Stevenson, Maryalice Matthews, Helen Brown, Margaret R. Fleisher, Thomas Pittaluga, Stefania Raffeld, Mark Albert, Paul S. Reitsma, Dirk Kaucic, Karen Hammershaimb, Luz Waldmann, Thomas A. Janik, John E. TI EBV-Related Lymphoproliferative Disease Complicating Therapy with the Anti-CD2 Monoclonal Antibody, Siplizumab, in Patients with T-Cell Malignancies SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 49th Annual Meeting of the American-Society-of-Hematology CY DEC 08-11, 2007 CL Atlanta, GA SP Amer Soc Hematol ID EPSTEIN-BARR-VIRUS; 3-WEEKLY CHOP CHEMOTHERAPY; NON-HODGKIN-LYMPHOMA; AGGRESSIVE LYMPHOMAS; MURINE MODEL; DISORDERS; TRANSPLANTATION; IMMUNOSUPPRESSION; CLASSIFICATION; INFECTION AB Purpose: We report an increased incidence of EBV-induced B-cell lymphoproliferative disease (LPD) in patients treated with siplizumab, an anti-CD2 antibody. The development of EBV-LPD has been associated with the use of immunosuppressive agents used in solid organ, bone marrow, and stem cell transplantation and in certain congenital immunodeficiencies. Experimental Design: We conducted a single-institution phase I dose-escalation trial of siplizumab, a humanized monoclonal antibody to CD2, in 29 patients with T-cell malignancies. Results: Although initial responses were encouraging, 4 (13.7%) patients developed EBV-LPD and the trial was stopped. Reductions in CD4(+) and CD8(+) cell count numbers in response to therapy were seen in all patients, but in those patients developing EBV-LPD a significantly greater reduction in natural killer (NK) cell number and CD2 expression on Tcells was seen. These findings highlight the importance of NK-cell depletion and CD2 expression in addition to T-cell depletion in the etiology of EBV-LPD. Conclusions: The emergence of EBV-LPD may be associated with the ability of siplizumab to deplete bothT and NK cells without affecting B cells. Agents that depleteT- and NK-cell populations without affecting B cell number should be screened for this potentially serious adverse event. C1 [O'Mahony, Deirdre; Morris, John C.; Matthews, Helen; Waldmann, Thomas A.; Janik, John E.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice; Pittaluga, Stefania; Raffeld, Mark] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Brown, Margaret R.; Fleisher, Thomas] NCI, Dept Lab Med, Bethesda, MD 20892 USA. [Albert, Paul S.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [Reitsma, Dirk; Kaucic, Karen; Hammershaimb, Luz] Medimmune Inc, Gaithersburg, MD 20878 USA. RP Janik, JE (reprint author), Bldg 10 CRC,Roorn 4E-5330,9000 Rockville Pike, Bethesda, MD 20892 USA. EM janikj@mail.nih.gov FU Intramural NIH HHS NR 42 TC 29 Z9 29 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 APR 1 PY 2009 VL 15 IS 7 BP 2514 EP 2522 DI 10.1158/1078-0432.CCR-08-1254 PG 9 WC Oncology SC Oncology GA 429YK UT WOS:000264955800037 PM 19293260 ER PT J AU Solomon, BD Mohan, P Tifft, CJ AF Solomon, Benjamin D. Mohan, Parvathi Tifft, Cynthia J. TI Dysmorphic findings in two cases of abeta/hypobetalipoproteinemia SO CLINICAL DYSMORPHOLOGY LA English DT Article C1 [Solomon, Benjamin D.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Mohan, Parvathi] Childrens Natl Med Ctr, Dept Gastroenterol, Washington, DC 20010 USA. [Tifft, Cynthia J.] Childrens Natl Med Ctr, Dept Genet & Metab, Washington, DC 20010 USA. RP Solomon, BD (reprint author), NHGRI, Med Genet Branch, NIH, Bldg 35,Room 1B-403, Bethesda, MD 20892 USA. EM solomonb@mail.nih.gov FU National Human Genome Research Institute FX Salary support for B.D.S. given in part by the National Human Genome Research Institute. This study was approved by the Children's National Medical Center Office for the Protection of Human Subjects. Supported by the National Human Genome Research Institute. NR 5 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0962-8827 J9 CLIN DYSMORPHOL JI Clin. Dysmorphol. PD APR PY 2009 VL 18 IS 2 BP 90 EP 91 DI 10.1097/MCD.0b013e3283279a0f PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 435MU UT WOS:000265348800005 PM 19282754 ER PT J AU Levens, ED Whitcomb, BW Csokmay, JM Nieman, LK AF Levens, Eric D. Whitcomb, Brian W. Csokmay, John M. Nieman, Lynnette K. TI Selective venous sampling for androgen-producing ovarian pathology SO CLINICAL ENDOCRINOLOGY LA English DT Article ID STEROID CELL TUMOR; ADRENAL VEIN CATHETERIZATION; HUMAN CHORIONIC-GONADOTROPIN; SERTOLI-LEYDIG TUMOR; PREOPERATIVE LOCALIZATION; SEVERE HYPERANDROGENISM; POSTMENOPAUSAL WOMAN; SECRETING TUMORS; HIRSUTE WOMEN; VIRILIZATION AB Multiple diagnostic modalities may be needed to establish the source of excessive androgen production in women. The role of selective venous catheterization in this process has not been established fully. A study of hyperandrogenaemic subjects and literature review. Four hyperandrogenaemic women and an additional 132 previously reported cases with available testing data and a pathological diagnosis were evaluated. Serum androgens, diagnostic imaging and ovarian venous effluent sampling. Criteria to distinguish ovarian tumours from other ovarian conditions and to localize the lesion(s) were evaluated. Basal peripheral testosterone levels >= 4.51 nmol/l (>= 130 ng/dl) discriminated ovarian tumours from benign causes of hyperandrogenism (sensitivity: 93.8%, 95% CI 85.0-98.2; specificity: 77.8%, 95% CI 66.4-86.7). Single lesions produced higher ipsilateral testosterone concentrations (612.6 +/- 162.0 nmol/l; 17 653 +/- 4670 ng/dl) compared to contralateral values (26.4 +/- 5.2 nmol/l; 761 +/- 150 ng/dl). In women with peripheral testosterone >= 4.51 nmol/l, a right-to-left (R:L) ovarian testosterone ratio >= 1.44 correctly identified all 18 women with right-sided tumours and misclassified two with bilateral lesions; 12 out of 14 women with left-sided or bilateral lesions had a lower R:L value. When this criterion was combined with a left-to-right (L:R) ovarian testosterone effluent ratio of > 15 to identify left-sided tumours, overall 66% of women were correctly categorized. Peripheral testosterone concentrations identified ovarian androgen-producing tumours, and venous sampling could correctly localize 66% of these, suggesting a role for sampling when imaging studies are not revealing. C1 [Levens, Eric D.; Csokmay, John M.; Nieman, Lynnette K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD 20892 USA. [Whitcomb, Brian W.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Epidemiol Branch, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bldg 10,CRC,Room E1-3140,10 Ctr Dr, Bethesda, MD 20892 USA. EM niemanl@mail.nih.gov FU Program in Reproductive and Adult Endocrinology; Epidemiology Branch; NICHD; NIH; NIH, Bethesda, MD, USA FX This research was supported, in part, by the Program in Reproductive and Adult Endocrinology and the Epidemiology Branch, NICHD, NIH, Bethesda, MD, USA. NR 47 TC 17 Z9 18 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD APR PY 2009 VL 70 IS 4 BP 606 EP 614 DI 10.1111/j.1365-2265.2008.03389.x PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 414IE UT WOS:000263856300017 PM 18721192 ER PT J AU Loomba, R Wesley, R Bain, A Csako, G Pucino, F AF Loomba, Rohit Wesley, Robert Bain, Andrew Csako, Gyorgy Pucino, Frank TI Role of Fluoroquinolones in the Primary Prophylaxis of Spontaneous Bacterial Peritonitis: Meta-Analysis SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article ID CIRRHOTIC-PATIENTS; ASCITIC FLUID; NORFLOXACIN; RISK; MANAGEMENT; TRIALS AB Background & Aims: The use of antibiotics in the primary prophylaxis for spontaneous bacterial peritonitis (SBP) in patients with cirrhosis is controversial. Our purpose was to determine the beneficial effect of fluoroquinolones as compared with placebo in primary prophylaxis of SBP in high-risk patients with cirrhosis by using meta-analysis. Methods: Medline, Embase, Cochrane, and Web of Science databases were searched in all languages until August 2008 for randomized placebo-controlled studies evaluating the role of fluoroquinolones in primary prevention of SBP in patients with low protein ascites (total ascitic protein, < 1.5 g/dL) and without history of SBP. Two investigators independently performed literature search and data extraction, and then another investigator independently reviewed whether the studies met prespecified criteria and rechecked data extraction. Odds ratios (Peto method) for the risk reduction with fluoroquinolones were calculated for each study and combined by using a random-effects model. Results: Four randomized controlled studies met predefined criteria. The odds ratios for developing first episode of SBP, serious infections, and mortality with fluoroquinolone prophylaxis (n = 194) versus placebo (n = 190) were 0.18 (95% confidence interval [CI], 0.09-0.35), 0.18 (95% Cl, 0.10-0.32), and 0.60 (95% Cl, 0.37-0.97), respectively. All studies were unidirectional in showing the beneficial effect of fluoroquinolone prophylaxis. We were limited by finding few studies with relatively small sample sizes. Conclusions: Daily oral fluoroquinolone prophylaxis reduces the risk of development of first episode of SBP and mortality in cirrhotic patients with low total protein in the ascitic fluid. Fluoroquinolones might be advisable for the primary prophylaxis of SBP in selected high-risk patients with cirrhosis. C1 [Loomba, Rohit; Bain, Andrew] Univ Calif San Diego, Div Gastroenterol, La Jolla, CA 92093 USA. [Wesley, Robert] Hosp Epidemiol, Bethesda, MD USA. [Csako, Gyorgy] NIH, Dept Lab Med, DHHS, Bethesda, MD 20892 USA. [Pucino, Frank] NIH, Dept Pharm, Ctr Clin, DHHS, Bethesda, MD 20892 USA. RP Loomba, R (reprint author), Univ Calif San Diego, Div Gastroenterol, 9500 Gilman Dr,UC 303,MC 063, La Jolla, CA 92093 USA. EM roloomba@ucsd.edu FU Clinical Center, National Institutes of Health; UCSD Digestive Diseases Research Development Center, US PHS [DK080506] FX This work was supported in part by the intramural research program of the Clinical Center, National Institutes of Health and by the UCSD Digestive Diseases Research Development Center, US PHS grant #DK080506. NR 25 TC 30 Z9 30 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD APR PY 2009 VL 7 IS 4 BP 487 EP 493 DI 10.1016/j.cgh.2008.12.018 PG 7 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 430RQ UT WOS:000265006600020 PM 19250986 ER PT J AU Solis, DC Burnichon, N Timmers, HJLM Raygada, MJ Kozupa, A Merino, MJ Makey, D Adams, KT Venisse, A Gimenez-Roqueplo, AP Pacak, K AF Solis, D. C. Burnichon, N. Timmers, H. J. L. M. Raygada, M. J. Kozupa, A. Merino, M. J. Makey, D. Adams, K. T. Venisse, A. Gimenez-Roqueplo, A-P Pacak, K. TI Penetrance and clinical consequences of a gross SDHB deletion in a large family SO CLINICAL GENETICS LA English DT Article DE paraganglioma; penetrance; pheochromocytoma; SDHB deletion; succinate dehydrogenase subunit B ID RENAL-CELL CARCINOMA; GENE-MUTATIONS; MALIGNANT PHEOCHROMOCYTOMAS; GERMLINE MUTATIONS; PARAGANGLIOMA; SUSCEPTIBILITY; FEATURES AB Solis DC, Burnichon N, Timmers HJLM, Raygada MJ, Kozupa A, Merino MJ, Makey D, Adams KT, Venisse A, Gimenez-Roqueplo A-P, Pacak K. Penetrance and clinical consequences of a gross SDHB deletion in a large family.Clin Genet 2009: 75: 354-363. (C) Blackwell Munksgaard, 2009 Mutations in the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) are inherited in an autosomal dominant manner and are associated with hereditary paraganglioma (PGL) and pheochromocytoma. The phenotype of patients with SDHB point mutations has been previously described. However, the phenotype and penetrance of gross SDHB deletions have not been well characterized as they are rarely described. The objective was to describe the phenotype and estimate the penetrance of an exon 1 large SDHB deletion in one kindred. A retrospective and prospective study of 41 relatives across five generations was carried out. The main outcome measures were genetic testing, clinical presentations, plasma catecholamines and their O-methylated metabolites. Of the 41 mutation carriers identified, 11 were diagnosed with PGL, 12 were found to be healthy carriers after evaluation, and 18 were reportedly healthy based on family history accounts. The penetrance of PGL related to the exon 1 large SDHB deletion in this family was estimated to be 35% by age 40. Variable expressivity of the phenotype associated with a large exon 1 SDHB deletion was observed, including low penetrance, diverse primary PGL tumor locations, and malignant potential. C1 [Pacak, K.] NICHHD, Sect Med Neuroendocrinol, Reprod Biol & Med Branch, Reprod & Adult Endocrinol Program, Bethesda, MD 20892 USA. [Burnichon, N.; Venisse, A.; Gimenez-Roqueplo, A-P] Hop Europeen Georges Pompidou, Dept Genet, AP HP, Paris, France. [Burnichon, N.; Gimenez-Roqueplo, A-P] Coll France, INSERM, U772, F-75231 Paris, France. [Burnichon, N.; Gimenez-Roqueplo, A-P] Univ Paris 05, Fac Med, Paris, France. [Timmers, H. J. L. M.] Radboud Univ Nijmegen, Dept Endocrinol, Med Ctr, NL-6525 ED Nijmegen, Netherlands. [Raygada, M. J.] NICHHD, Lab Clin Genet, NIH, Bethesda, MD 20892 USA. [Merino, M. J.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Pacak, K (reprint author), NICHHD, Sect Med Neuroendocrinol, Reprod Biol & Med Branch, Reprod & Adult Endocrinol Program, 10 Ctr Dr,Bldg 10,CRC,RM 1-E 3140,MSC 1109, Bethesda, MD 20892 USA. EM karel@mail.nih.gov FU Intramural NIH HHS [Z01 HD008735-08] NR 24 TC 23 Z9 24 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD APR PY 2009 VL 75 IS 4 BP 354 EP 363 DI 10.1111/j.1399-0004.2009.01157.x PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 433RI UT WOS:000265223100009 PM 19389109 ER PT J AU Hart, PS Becerik, S Cogulu, D Emingil, G Ozdemir-Ozenen, D Han, ST Sulima, PP Firatli, E Hart, TC AF Hart, P. S. Becerik, S. Cogulu, D. Emingil, G. Ozdemir-Ozenen, D. Han, S. T. Sulima, P. P. Firatli, E. Hart, T. C. TI Novel FAM83H mutations in Turkish families with autosomal dominant hypocalcified amelogenesis imperfecta SO CLINICAL GENETICS LA English DT Letter ID ENAMEL C1 [Hart, T. C.] Natl Inst Dent & Craniofacial Res, Human Craniofacial Genet Sect, NIH, Bethesda, MD 20892 USA. [Hart, P. S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Becerik, S.] Ege Univ, Dept Periodontol, Izmir, Turkey. [Cogulu, D.; Emingil, G.] Ege Univ, Dept Pedodont, Sch Dent, Izmir, Turkey. [Ozdemir-Ozenen, D.] Yeditepe Univ, Dept Pedodont, Istanbul, Turkey. [Firatli, E.] Univ Istanbul, Dept Periodontol, Istanbul, Turkey. RP Hart, TC (reprint author), Natl Inst Dent & Craniofacial Res, Human Craniofacial Genet Sect, NIH, 10 Ctr D,Bldg 10,5N-106, Bethesda, MD 20892 USA. EM thart@mail.nih.gov RI Sulima, Pawel/H-8649-2012; FIRATLI, Erhan/E-4241-2013 OI FIRATLI, Erhan/0000-0002-4154-6929 FU Intramural NIH HHS [Z99 HG999999] NR 11 TC 23 Z9 23 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD APR PY 2009 VL 75 IS 4 BP 401 EP 404 DI 10.1111/j.1399-0004.2008.01112.x PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 433RI UT WOS:000265223100014 PM 19220331 ER PT J AU Crandon, S Yancey, MA AF Crandon, Sonja Yancey, Mary Ann TI Sezary Syndrome: A Case Study of Cutaneous T-Cell Lymphoma SO CLINICAL JOURNAL OF ONCOLOGY NURSING LA English DT Editorial Material C1 [Crandon, Sonja; Yancey, Mary Ann] NIH, Med Oncol Branch, Bethesda, MD 20892 USA. RP Crandon, S (reprint author), NIH, Med Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. EM crandons@mail.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOC PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 1092-1095 J9 CLIN J ONCOL NURS JI Clin. J. Oncol. Nurs. PD APR PY 2009 VL 13 IS 2 BP 157 EP 159 DI 10.1188/09.CJON.157-159 PG 3 WC Oncology; Nursing SC Oncology; Nursing GA 432DZ UT WOS:000265115000005 PM 19349262 ER PT J AU Bae, KT Tao, C Zhu, F Bost, JE Chapman, AB Grantham, JJ Torres, VE Guay-Woodford, LM Meyers, CM Bennett, WM AF Bae, Kyongtae T. Tao, Cheng Zhu, Fang Bost, James E. Chapman, Arlene B. Grantham, Jared J. Torres, Vicente E. Guay-Woodford, Lisa M. Meyers, Catherine M. Bennett, William M. CA Consortium Radiologic Imaging Stud TI MRI-based Kidney Volume Measurements in ADPKD: Reliability and Effect of Gadolinium Enhancement SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID MAGNETIC-RESONANCE; RENAL STRUCTURE; CONTRAST-MEDIA; DISEASE; PROGRESSION; STEREOLOGY; CONSORTIUM; COHORT; CYSTS; NSF AB Background and objectives: To evaluate the inter- and intrareader reliability and the effect of gadolinium enhancement on kidney volume measurements obtained from pre- and postgadolinium T1 MR images in patients with autosomal dominant polycystic kidney disease (ADPKD). Design, setting, participants, & measurements: Twenty subjects were randomly selected with approximately equal frequency from three kidney-size groups. Pre- and postgadolinium 3D TI (pre-T1, post-T1) MR images were obtained. The stereology method was applied to segment and measure kidney volumes. The measurement process was repeated at two-wk intervals by two radiologists. Reliability was assessed with correlation coefficients. Intra- and inter-reader bias and measure differences were assessed with paired T-tests. The size effect on the pre- and post-T1 measurements was evaluated with one-way ANOVA. Results: The intra- and inter-reader reliability was extremely high in all measurements. No systematic intrareader bias but a small inter-reader bias for the post-T1 measurements was observed. All kidney volumes measured on the pre- and post-T1 images were highly correlated with each other for both readers. The post-T1 volumes were significantly higher than pre-T1 volumes. While the post-pre volume differences were relatively constant across the three kidney-size groups, the post-pre percent volume differences were significantly smaller as the size of the kidney increased. Conclusions: Kidney volume measurements can be made with minimum intra- and inter-reader variability on both pre- and post-T1 MR images. Kidney volumes measured on the pre-T1 were smaller than those on post-T1, and percent differences between pre-T1 and post-T1 kidney volumes decreased with increasing kidney size. C1 [Bae, Kyongtae T.] Univ Pittsburgh, Sch Med, Dept Radiol, Pittsburgh, PA 15213 USA. [Bost, James E.] Univ Pittsburgh, Dept Gen Internal Med, Pittsburgh, PA 15213 USA. [Chapman, Arlene B.; Bennett, William M.] Emory Univ, Sch Med, Div Renal, Dekalb Cty, GA USA. [Grantham, Jared J.] Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. [Torres, Vicente E.] Mayo Fdn, Rochester, MN USA. [Guay-Woodford, Lisa M.] Univ Alabama, Birmingham, AL USA. [Meyers, Catherine M.] NIDDK, NIH, Bethesda, MD USA. [Bennett, William M.] NW Renal Clin, Portland, OR USA. RP Bae, KT (reprint author), Univ Pittsburgh, Sch Med, Dept Radiol, 3362 5th Ave, Pittsburgh, PA 15213 USA. EM baek@upmc.edu FU National Institute of Diabetes and Digestive and Kidney Diseases [DK56956, DK56943, DK56957, DK56961]; National Institutes of Health FX This study was supported by the CRISP Study U01 cooperative agreements (DK56956, DK56943, DK56957, and DK56961) of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and the institutional GCRCs. We are indebted to the study coordinators who worked with professional grace and high competence to bring this project to conclusion: Beth Stafford, Kristin Cornwell, Diane Watkins, Sharon Langley, and Teresa Chacana. We thank Paul Commean, Stan Philips, Steve Moore, Paul Koppel, and Fred Prior for image data transfer, and Johana Schafer for managerial assistance. ANALYZE software was provided by Dr. Richard Robb of the Mayo Biomedical Imaging Resource in Rochester, MN. NR 33 TC 28 Z9 29 U1 0 U2 4 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD APR PY 2009 VL 4 IS 4 BP 719 EP 725 DI 10.2215/CJN.03750708 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 429RN UT WOS:000264937900010 PM 19339416 ER PT J AU Chakkera, HA Weil, EJ Castro, J Heilman, RL Reddy, KS Mazur, MJ Hamawi, K Mulligan, DC Moss, AA Mekeel, KL Cosio, FG Cook, CB AF Chakkera, Harini A. Weil, E. Jennifer Castro, Janna Heilman, Raymond L. Reddy, Kunam S. Mazur, Marek J. Hamawi, Khaled Mulligan, David C. Moss, Adyr A. Mekeel, Kristin L. Cosio, Fernando G. Cook, Curtiss B. TI Hyperglycemia during the Immediate Period after Kidney Transplantation SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ONSET DIABETES-MELLITUS; RENAL-ALLOGRAFT RECIPIENTS; RISK-FACTORS; CLINICAL INERTIA; INSULIN THERAPY; ILL PATIENTS; CARE; MANAGEMENT AB Background and objectives: Hyperglycemia and new-onset diabetes occurs frequently after kidney transplantation. The stress of surgery and exposure to immunosuppression medications have metabolic effects and can cause or worsen preexisting hyperglycemia. To our knowledge, hyperglycemia in the immediate posttransplantation period has not been studied. Design, setting, participants, & measurements: We conducted a retrospective, observational study to characterize the prevalence and assess the pharmacologic management of hyperglycemia in kidney transplant recipients who underwent transplantation at our center between June 1999 and December 2006. Data were abstracted from electronic and pharmacy databases. Results: The study cohort included 424 patients (mean age 51 yr; 58% men; 25% with pretransplantation diabetes). All patients with and 87% without pretransplantation diabetes had evidence of hyperglycemia (bedside glucose >= 200 mg/dl or physician-instituted insulin therapy), whereas the prevalence of hypoglycemia was low (4.5%). Hyperglycemia was sustained throughout hospitalization. All patients with and 66% without pretransplantation diabetes required insulin at hospital discharge. Patients with pretransplantation diabetes were treated primarily with short-acting insulin during the first 24 h after transplantation but were transitioned to long-acting insulin as the hospital stay progressed. Conclusions: Investigators have historically attempted to identify hyperglycemia after hospital discharge. Our data indicate that a substantial number of patients without pretransplantation diabetes develop hyperglycemia and require insulin during the hospital phase of their care immediately after kidney transplantation. Prospective studies are needed to delineate factors that contribute to development of new-onset diabetes after transplantation among patients with transient hyperglycemia. C1 [Chakkera, Harini A.; Heilman, Raymond L.; Mazur, Marek J.; Hamawi, Khaled] Mayo Clin, Div Nephrol & Transplantat, Scottsdale, AZ USA. [Castro, Janna; Cook, Curtiss B.] Mayo Clin, Div Endocrinol, Scottsdale, AZ USA. [Reddy, Kunam S.; Mulligan, David C.; Moss, Adyr A.; Mekeel, Kristin L.] Mayo Clin, Div Surg, Scottsdale, AZ USA. [Weil, E. Jennifer] NIDDKD, NIH, Phoenix, AZ USA. [Cosio, Fernando G.] Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. RP Chakkera, HA (reprint author), Mayo Clin Hosp, Div Transplantat, 5777 E Mayo Blvd, Phoenix, AZ 85054 USA. EM chakkera.harini@mayo.edu FU National Center for Research Resources (NCRR) [1KL2 RR024151]; National Institutes of Health (NIH); NIH Roadmap for Medical Research FX This publication was made possible by grant 1KL2 RR024151 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. This publication was also supported in part by the intramural research program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. Information on the NCRR is available at http://www.ncrr.nih.gov/. Information on Reengineering the Clinical Research Enterprise can be obtained from http://niliroadmap. nih.gov. NR 29 TC 36 Z9 39 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD APR PY 2009 VL 4 IS 4 BP 853 EP 859 DI 10.2215/CJN.05471C08 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 429RN UT WOS:000264937900028 PM 19339426 ER PT J AU Bazuine, M Stenkula, KG Cam, M Arroyo, M Cushman, SW AF Bazuine, Merlijn Stenkula, Karin G. Cam, Maggie Arroyo, Mathilde Cushman, Samuel W. TI Guardian of corpulence: a hypothesis on p53 signaling in the fat cell SO CLINICAL LIPIDOLOGY LA English DT Review DE adipogenesis; diabetes; lipotoxicity; oxysterol; p53 ID ACTIVATED-RECEPTOR-GAMMA; OXYSTEROL-BINDING-PROTEIN; PROMOTES ADIPOCYTE DIFFERENTIATION; RAT ADIPOSE-CELLS; PPAR-GAMMA; INSULIN-RESISTANCE; LIPID DROPLETS; GENE-EXPRESSION; TRANSCRIPTION-FACTOR; METABOLIC SYNDROME AB Adipocytes provide an organism with fuel in times of caloric deficit, and are an important type of endocrine cell in the maintenance of metabolic homeostasis. In addition, as a lipid-sink, adipocytes serve an equally important role in the protection of organs from the damaging effects of ectopic lipid deposition. For the organism, it is of vital importance to maintain adipocyte viability, yet the fat depot is a demanding extracellular environment with high levels of interstitial free fatty acids and associated lipotoxic effects. These surroundings are less than beneficial for the overall health of any resident cell, adipocyte and preadipocyte alike. In this review, we discuss the process of adipogenesis and the potential involvement of the p53 tumor-suppressor protein in alleviating some of the cellular stress experienced by these cells. In particular, we discuss p53-mediated mechanisms that prevent damage caused by reactive oxygen species and the effects of lipotoxicity. We also suggest the potential for two p53 target genes, START domain-containing protein 4 (StARD4) and oxysterol-binding protein (OSBP), with the concomitant synthesis of the signaling molecule oxysterol, to participate in adipogenesis. C1 [Bazuine, Merlijn; Stenkula, Karin G.; Cam, Maggie; Arroyo, Mathilde; Cushman, Samuel W.] NIDDK, Expt Diabet Metab & Nutr Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Bazuine, M (reprint author), NIDDK, Expt Diabet Metab & Nutr Sect, Diabet Branch, NIH, Bldg 10 CRC,Room 5W-5816,10 Ctr Dr, Bethesda, MD 20892 USA. EM bazuinem@niddk.nih.gov FU Intramural NIH HHS [Z01 DK075014-02, NIH0011646659] NR 139 TC 11 Z9 11 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1758-4299 J9 CLIN LIPIDOL JI Clin. Lipidol. PD APR PY 2009 VL 4 IS 2 BP 231 EP 243 DI 10.2217/CLP.09.2 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 450EF UT WOS:000266383100014 PM 20126301 ER PT J AU Minneci, PC Deans, KJ Eichacker, PQ Natanson, C AF Minneci, P. C. Deans, K. J. Eichacker, P. Q. Natanson, C. TI The effects of steroids during sepsis depend on dose and severity of illness: an updated meta-analysis SO CLINICAL MICROBIOLOGY AND INFECTION LA English DT Review DE Corticosteroids; glucocorticoids; meta-analysis; review; sepsis; septic shock; steroids ID RANDOMIZED CONTROLLED-TRIAL; HYPERDYNAMIC SEPTIC SHOCK; CRITICAL-CARE-MEDICINE; SMOOTH-MUSCLE-CELLS; DOUBLE-BLIND; HYDROCORTISONE THERAPY; AMERICAN-COLLEGE; STIMULATION TEST; CLINICAL-TRIAL; CORTICOSTEROIDS AB A previous meta-analysis determined that the effects of steroids during sepsis were dose-dependent; since then, additional trials have been published. The current analysis updates our previous analysis examining the effects of steroids during sepsis. A literature search from 2004 to 2008 identified seven randomized controlled trials in adult patients; these were added to 14 previously identified trials. The effects of steroids on mortality were highly variable among the 21 trials (p < 0.001, I(2) = 60%). In trials published before 1989, which involved short courses of high-dose steroids, steroids increased mortality (n = 8, I(2) = 14%, OR of death 1.39 (95% CI 1.04-1.86), p 0.03). In trials published after 1997, which involved longer courses of lower-dose steroids, steroids consistently improved shock reversal (n = 7, I(2) = 0%, OR of shock reversal 1.66 [95% CI 1.25-2.20), p < 0.001), but demonstrated a more heterogeneous beneficial effect on mortality (n = 12, I(2) = 25%, OR of death 0.64 (95% CI 0.45-0.93), p 0.02). An inverse linear relationship between severity of illness and the effects of steroids on mortality was identified across all trials (p 0.03) and within the subgroup of trials published after 1997 (p 0.03); steroids were harmful in less severely ill patient populations and beneficial in more severely ill patient populations. There was no effect of response to adrenocorticotrophic hormone (ACTH) stimulation testing concerning the effects of steroids and no increase in steroid-associated adverse events. Low-dose steroids appear to improve mortality rates in patients with septic shock who are at high risk of death; however, additional trials in this subpopulation are necessary to definitively determine the role of low-dose steroids during sepsis. C1 [Minneci, P. C.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Surg,Childrens Inst Surg Sci, Philadelphia, PA 19104 USA. [Eichacker, P. Q.; Natanson, C.] Natl Inst Hlth, Dept Crit Care Med, Bethesda, MD USA. RP Minneci, PC (reprint author), Univ Penn, Childrens Hosp Philadelphia, Sch Med, Dept Surg,Childrens Inst Surg Sci, 34th St & Civic Ctr Blvd,Abramson Res Ctr,Rm 1116, Philadelphia, PA 19104 USA. EM minneci@email.chop.edu FU Intramural NIH HHS [Z99 CL999999] NR 48 TC 47 Z9 55 U1 0 U2 12 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1198-743X J9 CLIN MICROBIOL INFEC JI Clin. Microbiol. Infect. PD APR PY 2009 VL 15 IS 4 BP 308 EP 318 DI 10.1111/j.1469-0691.2009.02752.x PG 11 WC Infectious Diseases; Microbiology SC Infectious Diseases; Microbiology GA 433EA UT WOS:000265185900004 PM 19416302 ER PT J AU Benninger, DH Lomarev, M Wassermann, EM Lopez, G Houdayer, E Fasano, RE Dang, N Hallett, M AF Benninger, David H. Lomarev, Mikhail Wassermann, Eric M. Lopez, Grisel Houdayer, Elise Fasano, Rebecca E. Dang, Nguyet Hallett, Mark TI Safety study of 50 Hz repetitive transcranial magnetic stimulation in patients with Parkinson's disease SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Repetitive transcranial magnetic stimulation (rTMS); Safety study; Parkinson's disease; 50 Hz rTMS ID MOTOR CORTEX EXCITABILITY; HIGH-FREQUENCY; HUMAN-BRAIN; EPILEPSY; TMS; EEG; BURSTS; DRUGS; AREAS; RTMS AB Objective: Repetitive transcranial magnetic stimulation (rTMS) has shown promising results in treating Parkinson's disease (PD), but the best values for rTMS parameters are not established. Fifty Hertz rTMS may be superior to <= 25 Hz rTMS investigated so far. The objective of this study was to determine if 50 Hz rTMS could be delivered safely in PD patients since Current safety limits are exceeded. Methods: Fifty Hertz rTMS was applied with a circular coil on the primary motor cortex (MI). Stimulation intensity was first tested at 60% rest motor threshold [RMT] and 0.5 s train duration and then increased in 0.5 s steps to 2 s, and by 10% steps to 90% RMT. Multi-channel electromyography (EMG) was recorded to control for signs of increasing time-locked EMG activity including correlates of the spread of excitation and after-discharges, or an increase of MI excitability. Pre- and post-50 Hz rTMS assessments included EEG, Unified Parkinson Disease Rating Scale (UPDRS), Grooved Pegboard Test, Serial Reaction Time Task (SRTT), Folstein Mini-Mental Status Examination (MMSE) and Verbal Fluency to control for motor and cognitive side effects. Results: Ten PD patients were investigated. Multi-channel EMG showed no signs of increased time-locked EMG activity including correlates of the spread of excitation and after-discharges, or increased M1 excitability in 9 patients. A PD patient with bi-temporal spikes in the pre-testing EEG had clinical and EMG correlates of spread of excitation at 90% RMT, but no seizure activity. Pre- and post-50 Hz assessment showed no changes. No adverse events were observed. Fifty Hertz rTMS was well tolerated except by 1 patient who wished to terminate the study due to facial muscle stimulation. Conclusion: Fifty Hertz rTMS at an intensity of 90% RMT for 2 s appears safe in patients with PD, but caution should be taken for patients with paroxysrnal EEG activity. For this reason, comprehensive screening should include EEG before higher-frequency rTMS is applied. Significance: This is the first study to investigate safety of 50 Hz rTMS in humans. Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology. C1 [Benninger, David H.; Lomarev, Mikhail; Lopez, Grisel; Houdayer, Elise; Dang, Nguyet; Hallett, Mark] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Wassermann, Eric M.] Natl Inst Neurol Disorders & Stroke, Brain Stimulat Unit, NIH, Bethesda, MD 20892 USA. [Fasano, Rebecca E.] Natl Inst Neurol Disorders & Stroke, EEG Sect, NIH, Bethesda, MD 20892 USA. [Lomarev, Mikhail] St Petersburg VM Bekhterev Psychoneurol Res Inst, St Petersburg, Russia. RP Benninger, DH (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 7D42 MSC1428,Ctr Dr, Bethesda, MD 20892 USA. EM benningerd@ninds.nih.gov RI Benninger, David/A-8157-2015 OI Benninger, David/0000-0002-1049-9533 FU Intramural Research Program of the NINDS; NIH; USAMRMC [W81XWH-06-1-0534]; Fyssen Foundation FX This research was supported by the Intramural Research Program of the NINDS, NIH, and in part by a grant from the USAMRMC (W81XWH-06-1-0534). E.H. was funded by the Fyssen Foundation. NR 34 TC 19 Z9 23 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD APR PY 2009 VL 120 IS 4 BP 809 EP 815 DI 10.1016/j.clinph.2009.01.012 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 440ZJ UT WOS:000265738000025 PM 19285918 ER PT J AU Shin, HW Sohn, YH Hallett, M AF Shin, Hae-Won Sohn, Young H. Hallett, Mark TI Hemispheric asymmetry of surround inhibition in the human motor system SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Handedness; TMS; Motor cortex; Inhibition ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN HANDEDNESS; HAND PREFERENCE; INTRACORTICAL INHIBITION; CORTEX; REPRESENTATION; MUSCLE; INDEPENDENCE; DIGITS; CONNECTIONS AB Objective: Surround inhibition (SI) in the motor system is an essential mechanism for the selective execution of desired movements. To investigate the relationship between the efficiency of SI operation in the motor system and handedness, we performed a transcranial magnetic stimulation (TMS) study in 10 healthy, right-handed volunteers. Methods: TMS was set to be triggered by self-initiated flexion of the index finger at different intervals ranging from 3 to 1000 ms. Average motor evoked potential (MEP) amplitudes obtained from self-triggered TMS were normalized to average MEPs of the control TMS at rest and expressed as a percentage. Normalized MEP amplitudes of the adductor digiti minimi (ADM) and the flexor digitorum superficialis (FDS) muscles were compared between the dominant and non-dominant hands. Results: During index finger flexion, MEP amplitudes of the ADM in the dominant hand were suppressed but not in the non-dominant hand, while MEP amplitudes of the FDS were comparably enhanced in both hands. F-wave amplitudes of ADM were comparably enhanced during index finger flexion in both hands. Conclusion: These results suggest that the functional operation of SI in the motor system is more efficient in the dominant hand than the non-dominant hand. More efficient SI in the dominant hand could lead to greater dexterity in the dominant hand. Significance: Hemispheric asymmetry of SI might be able to serve as a neurophysiological proxy for handedness. (C) 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Shin, Hae-Won; Sohn, Young H.] Yonsei Univ, Coll Med, Brain Res Inst, Dept Neurol, Seoul 120752, South Korea. [Sohn, Young H.] Yonsei Univ, Coll Med, Brain Korea Project Med Sci 21, Seoul 120752, South Korea. [Shin, Hae-Won] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Neurol,Parkinson & Alzheimer Ctr, Seoul, South Korea. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Sohn, YH (reprint author), Yonsei Univ, Coll Med, Brain Res Inst, Dept Neurol, 134 Shinchon Dong, Seoul 120752, South Korea. EM yhsohn62@yuhs.ac FU Yonsei University FX This work was supported by the Brain Korea 21 Project for Medical Science, Yonsei University. NR 28 TC 12 Z9 12 U1 1 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD APR PY 2009 VL 120 IS 4 BP 816 EP 819 DI 10.1016/j.clinph.2009.02.004 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 440ZJ UT WOS:000265738000026 PM 19299196 ER PT J AU Bevilacqua, L Goldman, D AF Bevilacqua, L. Goldman, D. TI Genes and Addictions SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Editorial Material ID ALCOHOL C1 [Bevilacqua, L.; Goldman, D.] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Goldman, D (reprint author), NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. EM davidgoldman@mail.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z01 AA000306-02] NR 5 TC 16 Z9 18 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD APR PY 2009 VL 85 IS 4 BP 359 EP 361 DI 10.1038/clpt.2009.6 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 422VH UT WOS:000264455300008 PM 19295534 ER PT J AU Freidlin, B Korn, EL AF Freidlin, Boris Korn, Edward L. TI Stopping clinical trials early for benefit: impact on estimation SO CLINICAL TRIALS LA English DT Article ID RANDOMIZED-TRIALS; SEQUENTIAL TEST; BIAS AB Background It has been suggested in the literature that the well-known bias of treatment-effect estimators due to the possibility of early stopping for positive results is a major concern with interim monitoring. Purpose To discuss approaches one might use to compare the inflation of the treatment-effect estimator when the trial is stopped early for positive results with the inflation that would be seen in a comparable set of positive trials that used fixed sample sizes with no interim monitoring, and to quantify the relative inflation of monitored trials relative to that of the corresponding subset of positive fixed sample-size trials. Methods Via simulation for some O'Brien-Fleming and Haybittle-Peto monitoring boundaries, the inflation of the treatment-effect estimator when the trial crossed an interim-monitoring boundary for positive results is compared with the preferred approach to estimate the inflation from a comparable set of positive fixed sample-size trials. Results Although the inflation of the treatment-effect estimator when a trial is stopped early can be considerable, only at very early interim analyses (<= 25% of information) is this inflation much larger than the inflation that would be seen for an appropriate subset of similar positive fixed sample-size trials. The treatment-effect inflation from stopping at second or later interim analyses that are not so early is relatively small and similar to that seen in the corresponding subset of fixed sample-size trials. Limitations The results apply to adequately powered trials with well-designed prospectively specified interim-monitoring plans. Conclusions For trials with a well-designed interim-monitoring plan, stopping at 50% or greater information has a negligible impact on estimation. Except for very early interim analyses (<= 25% of the information), concerns about the inflation of the treatment effect should be minor. Clinical Trials 2009; 6: 119-125. http://ctj.sagepub.com C1 [Freidlin, Boris; Korn, Edward L.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, EPN-8122, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 21 TC 29 Z9 29 U1 1 U2 6 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD APR PY 2009 VL 6 IS 2 BP 119 EP 125 DI 10.1177/1740774509102310 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 441GB UT WOS:000265756200002 PM 19342463 ER PT J AU Rosa, C Campbell, A Kleppinger, C Sampson, R Tyson, C Mamay-Gentilin, S AF Rosa, Carmen Campbell, Aimee Kleppinger, Cynthia Sampson, Royce Tyson, Clare Mamay-Gentilin, Stephanie TI Quality assurance of research protocols conducted in the community: The National Institute on Drug Abuse Clinical Trials Network Experience SO CLINICAL TRIALS LA English DT Article AB Background: Quality assurance (QA) of clinical trials is essential to protect the welfare of trial participants and the integrity of the data collected. However, there is little detailed information available on specific procedures and outcomes of QA monitoring for clinical trials. Purpose: This article describes the experience of the National Institute on Drug Abuse's (NIDA) National Drug Abuse Treatment Clinical Trials Network (CTN) in devising and implementing a three-tiered QA model for rigorous multi-site randomized clinical trials implemented in community-based substance abuse treatment programs. The CTN QA model combined local and national resources and was developed to address the unique needs of clinical trial sites with limited research experience. Methods: The authors reviewed internal records maintained by the sponsor, a coordinating site (Lead Nodes), and a local site detailing procedural development, training sessions, protocol violation monitoring, and site visit reporting. Results: Between January 2001 and September 2005, the CTN implemented 21 protocols, of which 18 were randomized clinical trials, one was a quality improvement study and two were surveys. Approximately 160 community-based treatment programs participated in the 19 studies that were monitored, with a total of 6560 participants randomized across the sites. During this time 1937 QA site visits were reported across the three tiers of monitoring and the cost depended on the location of the sites and the salaries of the staff involved. One study reported 109 protocol violations (M=15.6). Examples are presented to highlight training, protocol violation monitoring, site visit frequency and intensity and cost considerations. Limitations: QA data from the entire network were not easily available for review as much of the data were not electronically accessible. The authors reviewed and discussed a representative sample of internal data from the studies and participating sites. Conclusions: The lessons learned from the CTN's experience include the need for balancing thoroughness with efficiency, monitoring early, assessing research staff abilities in order to judge the need for proactive, focused attention, providing targeted training sessions, and developing flexible tools. The CTN model can work for sponsors overseeing studies at sites with limited research experience that require more frequent, in-depth monitoring. We recommend that sponsors not develop a rigid monitoring approach, but work with the study principal investigators to determine the intensity of monitoring needed depending on trial complexity,the risks of the intervention(s), and the experience of the staff with clinical research. After careful evaluation, sponsors should then determine the best approach to site monitoring and what resources will be needed. Clinical Trials 2009; 6: 151-161. http://ctj.sagepub.com C1 [Rosa, Carmen] NIDA, Ctr Clin Trials Network, Bethesda, MD 20892 USA. [Campbell, Aimee] Columbia Univ, Sch Social Work, Social Intervent Grp, New York, NY 10027 USA. [Kleppinger, Cynthia] US FDA, Div Sci Invest, Off Compliance, CDER,Fed Res Ctr, Silver Spring, MD 20993 USA. [Sampson, Royce; Tyson, Clare; Mamay-Gentilin, Stephanie] Med Univ S Carolina, Dept Psychiat, Charleston, SC 29425 USA. RP Rosa, C (reprint author), 6001 Execut Blvd,MSC 9557, Bethesda, MD 20892 USA. EM crosa@nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 11 TC 9 Z9 10 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 J9 CLIN TRIALS JI Clin. Trials PD APR PY 2009 VL 6 IS 2 BP 151 EP 161 DI 10.1177/1740774509102560 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 441GB UT WOS:000265756200007 PM 19342468 ER PT J AU Berman, RM Fava, M Thase, ME Trivedi, MH Swanink, R McQuade, RD Carson, WH Adson, D Taylor, L Hazel, J Marcus, RN AF Berman, Robert M. Fava, Maurizio Thase, Michael E. Trivedi, Madhukar H. Swanink, Rene McQuade, Robert D. Carson, William H. Adson, David Taylor, Leslie Hazel, James Marcus, Ronald N. TI Aripiprazole Augmentation in Major Depressive Disorder: A Double-Blind, Placebo-Controlled Study in Patients with Inadequate Response to Antidepressants SO CNS SPECTRUMS LA English DT Article ID STAR-ASTERISK-D; MEASUREMENT-BASED CARE; ADJUNCTIVE THERAPY; CLINICAL-PRACTICE; SELF-REPORT; OUTPATIENTS; MEDICATION; EFFICACY; OUTCOMES; TRIALS AB Introduction: Effective management of major depressive disorder (MDD) continues to be a challenging task for psychiatrists and primary care physicians. This trial evaluated the efficacy and safety of adjunctive aripiprazole versus antidepressant monotherapy in patients with MDD and independently replicated the positive findings of two similar trials., Methods: Patients (N=1,147) with MDD experiencing a major depressive episode and a history of inadequate response to antidepressant monotherapy were enrolled (week 0); 827 received single-blind adjunctive placebo plus open-label antidepressant (escitalopram, fluoxetine, paroxetine controlled release, sertraline, or venlafaxine extended release) for 8 weeks to confirm inadequate response to antidepressants; 349 patients with inadequate response were randomized (1:1) to double-blind, adjunctive placebo (n=172) or adjunctive aripiprazole (n=177; 2-20 mg/day). Primary outcome was the mean change in Montgomery-angstrom sberg Depression Rating Scale (MADRS) Total score from baseline (week 8) to endpoint (week 14). Results: Clinically significant improvements in depressive symptoms as assessed by decreases in the (MADRS) Total score were greater with adjunctive aripiprazole (-10.1) than placebo (-6.4; P<.001). Remission rates were greater for adjunctive aripiprazole than for adjunctive placebo (week 14, 36.8% vs 18.9%; P<.001). Completion rates with adjunctive aripiprazole and placebo were high (83% vs. 87%) and discontinuations due to adverse events were low (6.2% vs 1.7%). Conclusion: For some patients with MDD who do not obtain adequate symptom relief with antidepressant monotherapy, adjunctive therapies can significantly improve. depressive symptoms. As reported, adjunctive aripiprazole was associated with a two-fold higher remission rate than adjunctive placebo. This, and previous studies, have shown that discontinuations due to adverse events were low and completion rates were high, and has indicated that both antidepressant and aripiprazole in combination, were relatively well-tolerated and safe. This is the third consecutive clinical trial, in the absence of a failed trial, to demonstrate that aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for patients with MDD who do not respond adequately to standard antidepressant monotherapy C1 [Berman, Robert M.; Hazel, James; Marcus, Ronald N.] Bristol Myers Squibb Co, Neurosci Global Clin Res, Wallingford, CT 06492 USA. [Fava, Maurizio] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Fava, Maurizio] Massachusetts Gen Hosp, Depress Clin & Res Program, Boston, MA 02114 USA. [Fava, Maurizio] Harvard Univ, Sch Med, Boston, MA USA. [Thase, Michael E.] Univ Penn, Philadelphia, PA 19104 USA. [Trivedi, Madhukar H.] Univ Texas SW Med Sch Dallas, Mood Disorders Res Program, Dallas, TX USA. [Trivedi, Madhukar H.] Univ Texas SW Med Sch Dallas, NIMH, Depress Trials Network, Dallas, TX USA. [Adson, David] Univ Minnesota, Ambulatory Res Ctr, Minneapolis, MN USA. [Adson, David] Univ Minnesota, Dept Psychiat, Minneapolis, MN 55455 USA. [Taylor, Leslie] Univ Wisconsin, Sch Med, Madison, WI 53706 USA. RP Berman, RM (reprint author), Bristol Myers Squibb Co, Neurosci Global Clin Res, 5 Res Pkwy, Wallingford, CT 06492 USA. EM Robert.Berman@bms.com NR 31 TC 142 Z9 147 U1 6 U2 16 PU M B L COMMUNICATIONS, INC PI NEW YORK PA 333 HUDSON ST, 7TH FLOOR, NEW YORK, NY 10013 USA SN 1092-8529 J9 CNS SPECTRUMS JI CNS Spectr. PD APR PY 2009 VL 14 IS 4 BP 197 EP 206 PG 10 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 439YB UT WOS:000265662600007 PM 19407731 ER PT J AU Gordon, S Lotenberg, S Long, R Antani, S Jeronimo, J Greenspan, H AF Gordon, Shiri Lotenberg, Shelly Long, Rodney Antani, Sameer Jeronimo, Jose Greenspan, Hayit TI Evaluation of uterine cervix segmentations using ground truth from multiple experts SO COMPUTERIZED MEDICAL IMAGING AND GRAPHICS LA English DT Article DE Image segmentation; Evaluation of segmentation; Multi-expert ground truth; Segmentation complexity; Cervical cancer; Uterine cervix images ID IMAGE SEGMENTATION; MEDICAL IMAGES; VALIDATION; ALGORITHMS AB This work is focused on the generation and utilization of a reliable ground truth (GT) segmentation for a large medical repository of digital cervicographic images (cervigrams) collected by the National Cancer Institute (NCI). NCI invited twenty experts to manually segment a set of 939 cervigrams into regions of medical and anatomical interest. Based on this unique data, the objectives of the current work are to: (1) Automatically generate a multi-expert GT segmentation map; (2) Use the GT map to automatically assess the complexity of a given segmentation task; (3) Use the GT map to evaluate the performance of an automated segmentation algorithm. The multi-expert GT map is generated via the STAPLE (Simultaneous Truth and Performance Level Estimation) algorithm, which is a well-known method to generate a GT segmentation from multiple observations. A new measure of segmentation complexity, which relies on the inter-observer variability within the GT map, is defined. This measure is used to identify images that were found difficult to segment by the experts and to compare the complexity of different segmentation tasks. An accuracy measure, which evaluates the performance of automated segmentation algorithms is presented. Two algorithms for cervix boundary detection are compared using the proposed accuracy measure. The measure is shown to reflect the actual segmentation quality achieved by the algorithms. The methods and conclusions presented in this work are general and can be applied to different images and segmentation tasks. Here they are applied to the cervigram database including a thorough analysis of the available data. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Gordon, Shiri; Lotenberg, Shelly; Greenspan, Hayit] Tel Aviv Univ, IL-69978 Tel Aviv, Israel. [Long, Rodney; Antani, Sameer] NIH, Natl Lib Med, Bethesda, MD 20894 USA. [Jeronimo, Jose] NCI, NIH, Bethesda, MD 20852 USA. RP Greenspan, H (reprint author), Tel Aviv Univ, IL-69978 Tel Aviv, Israel. EM hayit@eng.tau.ac.il OI Antani, Sameer/0000-0002-0040-1387 FU National Institutes of Health/American Society for Colposcopy and Cervical Pathology (NIH-ASCCP); U.S. National Institutes of Health; National Library of Medicine; Lister Hill National Center for Biomedical Communications FX We would like to thank Dr. Simon K. Warfield for his notes and support with the STAPLE implementation software. We also would like to acknowledge the medical expert contributions to this work from the National Institutes of Health/American Society for Colposcopy and Cervical Pathology (NIH-ASCCP) Research Group. This research was supported by the Intramural Research Program of the U.S. National Institutes of Health, National Library of Medicine, and Lister Hill National Center for Biomedical Communications. NR 28 TC 11 Z9 11 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0895-6111 J9 COMPUT MED IMAG GRAP JI Comput. Med. Imaging Graph. PD APR PY 2009 VL 33 IS 3 BP 205 EP 216 DI 10.1016/j.compmedimag.2008.12.002 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 425RD UT WOS:000264653900005 PM 19217754 ER PT J AU Beydoun, HA Beydoun, MA Tamim, H AF Beydoun, Hind A. Beydoun, May A. Tamim, Hala TI How does gestational diabetes affect postpartum contraception in nondiabetic primiparous women? SO CONTRACEPTION LA English DT Article DE Gestational diabetes; Contraception; Parity; Epidemiology; United States ID ORAL-CONTRACEPTIVES; RANDOMIZED-TRIAL; LATINO WOMEN; MELLITUS; PREGNANCY; RISK; GLUCOSE; INSULIN AB Background: The aim of the study is to explore the effect of gestational diabetes mellitus (GDM) on postpartum contraception among nondiabetic primiparous women. Study Design: Secondary analyses of 2004-2005 Pregnancy Risk Assessment Monitoring System data from Michigan and Oregon. Methods: Analyses were performed on 2332 women, taking complex survey design into consideration. Crude and adjusted odds ratios (cOR; aOR) and their 95% confidence intervals (CI) were obtained using logistic regression analyses. Results: Postpartum use of hormonal (aOR=1.12, 95% CI: 0.68-1.83) and nonhormonal (aOR=1.18, 95% CI: 0.73-1.92) contraception were not influenced by GDM after controlling for confounders. Female sterilization was more frequently adopted (cOR=4.99, 95% CI: 1.13-22.17) and depomedroxyprogesterone acetate (DMPA) (cOR=0.53, 95% CI: 0.23-1.18), diaphragm/cervical cap/sponge (cOR=0.13, 95% CI: 0.016-0.95) and cervical ring (cOR=0.13, 95% CI: 0.017-0.98) were less frequently adopted by women reporting GDM diagnosis. Conclusion: With few exceptions, GDM does not appear to affect postpartum hormonal and nonhormonal contraception. (c) 2009 Elsevier Inc. All rights reserved. C1 [Beydoun, Hind A.] Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. [Beydoun, Hind A.] Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. [Beydoun, May A.] NIA, Baltimore, MD 21224 USA. [Tamim, Hala] York Univ, Sch Kinesiol & Hlth Sci, Toronto, ON M3J 1P3, Canada. RP Beydoun, HA (reprint author), Eastern Virginia Med Sch, Grad Program Publ Hlth, Norfolk, VA 23501 USA. EM baydouha@evms.edu FU NIH; National Institute on Aging FX We thank Denise D'Angelo, MPH, and the states of Michigan (Violanda Grigorescu, MD, MSPH) and Oregon (Ken Rosenberg, MD, MPH) for their guidance and provision of 2004-2005 PRAMS data. There was no funding provided for this study. This research was supported in part by the intramural research program of the NIH, National Institute on Aging. NR 24 TC 5 Z9 6 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 J9 CONTRACEPTION JI Contraception PD APR PY 2009 VL 79 IS 4 BP 290 EP 296 DI 10.1016/j.contraception.2008.10.013 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 424CQ UT WOS:000264543500006 PM 19272498 ER PT J AU Li, Y Cui, XZ Su, JW Haley, M Macarthur, H Sherer, K Moayeri, M Leppla, SH Fitz, Y Eichacker, PQ AF Li, Yan Cui, Xizhong Su, Junwu Haley, Michael Macarthur, Heather Sherer, Kevin Moayeri, Mahtab Leppla, Stephen H. Fitz, Yvonne Eichacker, Peter Q. TI Norepinephrine increases blood pressure but not survival with anthrax lethal toxin in rats SO CRITICAL CARE MEDICINE LA English DT Article DE Bacillus anthracis lethal toxin; sepsis; vasopressor; treatment; rodent ID DIRECTED MONOCLONAL-ANTIBODY; BACILLUS-ANTHRACIS; SEPTIC SHOCK; PROTECTIVE ANTIGEN; MURINE MACROPHAGES; MEDIATED INHIBITION; NITRIC-OXIDE; SEPSIS; KINASE; MODEL AB Objectives: The response of anthrax lethal toxin (LeTx) induced shock and lethality to conventional therapies has received little study. Previously, fluids worsened outcome in LeTx-challenged rats in contrast to its benefit with lipopolysaccharide (LPS) or Escherichia coli. The current study investigated norepinephrine treatment. Measurements and Main Results. Sprague-Dawley rats (n = 232) weighing between 230 and 250 g were challenged with similar lethal (80%) 24-hour infusions of either LPS or LeTx, or with diluent only. Toxin-challenged animals were also randomized to receive 24-hour infusions with one of three doses of norepinephrine (0.03, 0.3, or 3.0 mu g/kg/min) or placebo started 1 hour after initiation of challenge. All toxin animals received similar volumes of fluid over the 24 hours (equivalent to 4.0-4.3 mL/kg/hr). Although the intermediate norepinephrine dose (0.3 mu g/kg/min for 24 hours) improved survival with LPS (p = 0.04) and increased blood pressure before the onset of lethality with LeTx (p < 0.0001), it did not improve survival with the latter (p = ns). Furthermore, neither increasing nor decreasing norepinephrine doses improved survival with LeTx. Conclusion: Hypotension with LeTx may not be a primary cause of lethality in this model. Rather, LeTx may cause direct cellular injury insensitive to vasopressors. These findings suggest that during anthrax infection and shock, along with hemodynamic support, toxin-directed treatments may be necessary as well. (Crit Care Med 2009; 37:1348-1354) C1 [Li, Yan; Cui, Xizhong; Su, Junwu; Haley, Michael; Sherer, Kevin; Fitz, Yvonne; Eichacker, Peter Q.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Moayeri, Mahtab; Leppla, Stephen H.] NIAID, NIH, Bethesda, MD 20892 USA. [Macarthur, Heather] St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. [Haley, Michael] Carolinas Med Ctr, Dept Internal Med, Charlotte, NC 28203 USA. RP Li, Y (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM peichacker@mail.cc.nih.gov FU Intramural NIH HHS [Z01 CL008090-03, Z01 CL008066-04, Z01 CL008090-02, ZIA CL008090-04] NR 46 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2009 VL 37 IS 4 BP 1348 EP 1354 DI 10.1097/CCM.0b013e31819cee38 PG 7 WC Critical Care Medicine SC General & Internal Medicine GA 426HQ UT WOS:000264699000025 PM 19242337 ER PT J AU Barochia, AV Li, Y Cui, XZ Sweeney, DA Natanson, C Eichacker, PQ AF Barochia, Amisha V. Li, Yan Cui, Xizhong Sweeney, Daniel A. Natanson, Charles Eichacker, Peter Q. TI Antithrombosis Trials: Should we test therapeutic heparin adjusted based on activated partial thromboplastin time in septic shock? SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE heparin; sepsis; treatment ID RANDOMIZED CONTROLLED-TRIAL; FACTOR PATHWAY INHIBITOR; SEVERE SEPSIS; DOUBLE-BLIND; PROTEIN-C; MULTICENTER; SAFETY; EFFICACY C1 [Barochia, Amisha V.; Li, Yan; Cui, Xizhong; Sweeney, Daniel A.; Natanson, Charles; Eichacker, Peter Q.] NIH, Dept Clin Ctr, Bethesda, MD 20892 USA. RP Barochia, AV (reprint author), NIH, Dept Clin Ctr, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CL999999] NR 20 TC 1 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD APR PY 2009 VL 37 IS 4 BP 1486 EP 1487 DI 10.1097/CCM.0b013e31819d2bb4 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 426HQ UT WOS:000264699000044 PM 19318828 ER PT J AU Martinez, A Lahiri, DK Giacobini, E Greig, NH AF Martinez, Ana Lahiri, Debomoy K. Giacobini, Ezio Greig, Nigel H. TI Advances in Alzheimer Therapy: Understanding Pharmacological Approaches to the Disease SO CURRENT ALZHEIMER RESEARCH LA English DT Editorial Material ID DRUG DEVELOPMENT AB Although significant accomplishments have been made in research to understand, diagnose and treat Alzheimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increasing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanistically-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The cross-fertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clinical utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy". C1 [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, NIH, Baltimore, MD 21224 USA. [Martinez, Ana] CSIC, Inst Quim Med, E-28006 Madrid, Spain. [Lahiri, Debomoy K.] Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. [Giacobini, Ezio] Univ Geneva, Univ Hosp Geneva, Sch Med, Dept Geriatr, CH-1226 Thonex Geneva, Switzerland. RP Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Neurosci Lab, NIH, Baltimore, MD 21224 USA. EM greign@grc.nia.nih.gov RI Martinez, Ana/L-6414-2014 OI Martinez, Ana/0000-0002-2707-8110 FU Intramural NIH HHS [Z01 AG000311-08] NR 8 TC 7 Z9 7 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD APR PY 2009 VL 6 IS 2 BP 83 EP 85 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 431TL UT WOS:000265086800001 PM 19355842 ER PT J AU Janka, J O'Grady, NR AF Janka, Jacqueline O'Grady, Naomi R. TI Clostridium difficile infection: current perspectives SO CURRENT OPINION IN CRITICAL CARE LA English DT Review DE Clostridium difficile; Clostridium difficile infection; colitis; diarrhea; North American pulse-field gel electrophoresis type 1; PCR ribotype 027; restriction endonuclease type BI ID PROTON-PUMP INHIBITORS; MOLECULAR ANALYSIS; UNITED-STATES; DISEASE; DIARRHEA; VANCOMYCIN; RISK; MORTALITY; THERAPY; COLITIS AB Purpose of review Clostridium difficile infection (CDI), long-associated with morbidity and mortality in healthcare settings, has evolved in recent years with unprecedented clinical manifestations. Today, CDI is characterized by unusually toxigenic and resistant subtypes, expanded epidemiology, and a growing list of risk factors. In this article, we discuss current trends and research for CDI in critical care settings, and new controversies that influence clinical practice. Recent findings CDI is the focus of intense and comprehensive research. For the critical care practitioner, relevant knowledge includes diagnosis of CDI, defining the severity of disease, the role of proton pump inhibitors, and treatment options for refractory or relapsing disease. Summary Annually, CDI adds billions of dollars to US healthcare costs compared with just a few years ago, and reflects a new and profound pattern of morbidity and mortality. As this disease changes, our knowledge and practice patterns must adjust to meet the current challenge of CDI. C1 [Janka, Jacqueline; O'Grady, Naomi R.] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP O'Grady, NR (reprint author), NIH, Dept Crit Care Med, Bldg 10,Room 2C 142,10 Ctr Dr MSC 1662, Bethesda, MD 20892 USA. EM nogrady@mail.cc.nih.gov NR 35 TC 16 Z9 17 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1070-5295 J9 CURR OPIN CRIT CARE JI Curr. Opin. Crit. Care PD APR PY 2009 VL 15 IS 2 BP 149 EP 153 DI 10.1097/MCC.0b013e328324e6ad PG 5 WC Critical Care Medicine SC General & Internal Medicine GA 432ZB UT WOS:000265171800012 PM 19578325 ER PT J AU Rousset, X Vaisman, B Amar, M Sethi, AA Remaley, AT AF Rousset, Xavier Vaisman, Boris Amar, Marcelo Sethi, Amar A. Remaley, Alan T. TI Lecithin: cholesterol acyltransferase - from biochemistry to role in cardiovascular disease SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Article DE atherosclerosis; cardiovascular disease; cholesterol; high-density lipoprotein; lecithin : cholesterol acyltransferase; reverse cholesterol transport ID HIGH-DENSITY-LIPOPROTEINS; ESTER TRANSFER PROTEIN; APOLIPOPROTEIN-A-I; FISH-EYE DISEASE; CORONARY-ARTERY-DISEASE; FRACTIONAL ESTERIFICATION RATE; DIET-INDUCED ATHEROSCLEROSIS; TISSUE-SPECIFIC EXPRESSION; LECITHINCHOLESTEROL ACYLTRANSFERASE; LCAT DEFICIENCY AB Purpose of review We discuss the latest findings on the biochemistry of lecithin : cholesterol acyltransferase (LCAT), the effect of LCAT on atherosclerosis, clinical features of LCAT deficiency, and the impact of LCAT on cardiovascular disease from human studies. Recent findings Although there has been much recent progress in the biochemistry of LCAT and its effect on high-density lipoprotein metabolism, its role in the pathogenesis of atherosclerosis is still not fully understood. Studies from various animal models have revealed a complex interaction between LCAT and atherosclerosis that may be modified by diet and by other proteins that modify lipoproteins. Furthermore, the ability of LCAT to lower apoB appears to be the best way to predict its effect on atherosclerosis in animal models. Recent studies on patients with LCAT deficiency have shown a modest but significant increase in incidence of cardiovascular disease consistent with a beneficial effect of LCAT on atherosclerosis. The role of LCAT in the general population, however, has not revealed a consistent association with cardiovascular disease. Summary Recent research findings from animal and human studies have revealed a potential beneficial role of LCAT in reducing atherosclerosis but additional studies are necessary to better establish the linkage between LCAT and cardiovascular disease. C1 [Rousset, Xavier; Vaisman, Boris; Amar, Marcelo; Sethi, Amar A.; Remaley, Alan T.] NHLBI, NIH, Pulm & Vasc Med Branch, Lipoprot Metab Sect, Bethesda, MD 20814 USA. RP Remaley, AT (reprint author), NHLBI, NIH, Pulm & Vasc Med Branch, Lipoprot Metab Sect, 10 Ctr Dr Bldg,10-2C 433, Bethesda, MD 20814 USA. EM aremaley@nih.gov RI Rousset, Xavier/B-3352-2008; Rousset, Xavier/H-5490-2015 OI Rousset, Xavier/0000-0002-5830-6577; Rousset, Xavier/0000-0002-5830-6577 FU NHLBI; Danish Agency for Science Technology and Innovation FX X.R., B. V., M. A., and A. T. were supported by intramural NHLBI research funds. A. S. was supported by the Danish Agency for Science Technology and Innovation. NR 119 TC 63 Z9 67 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1752-296X EI 1752-2978 J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD APR PY 2009 VL 16 IS 2 BP 163 EP 171 DI 10.1097/MED.0b013e328329233b PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 691BP UT WOS:000285055600011 PM 19306528 ER PT J AU Wang, ZB Schones, DE Zhao, KJ AF Wang, Zhibin Schones, Dustin E. Zhao, Keji TI Characterization of human epigenomes SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID EMBRYONIC STEM-CELLS; HISTONE ACETYLATION PATTERNS; HUMAN GENOME; DNA METHYLATION; CHROMATIN SIGNATURES; DEVELOPMENTAL REGULATORS; DYNAMIC REGULATION; T-CELLS; PROMOTERS; POLYCOMB AB Histone modifications play a key role in regulating transcription and thus ultimately regulate cellular development and differentiation. To understand how histone modifications influence normal development and disease states, a global catalogue of histone modifications and modifying enzymes in normal and disease states is necessary. The first such systematic mapping experiments using the recently developed ChIP-Sequencing technique have revealed a combinatorial modification 'backbone' consisting of multiple histone modifications associated with active transcription. The human epigenomic datasets that are now being produced provide valuable resources for a better understanding of the functional regulatory elements of transcription and the pathways necessary for normal cellular development and pathological conditions. C1 [Wang, Zhibin; Schones, Dustin E.; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Zhao, KJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute, NIH FX The work in Zhao lab was supported by the Intramural Research Program of National Heart, Lung, and Blood Institute, NIH. NR 55 TC 88 Z9 92 U1 1 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD APR PY 2009 VL 19 IS 2 BP 127 EP 134 DI 10.1016/j.gde.2009.02.001 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 449RE UT WOS:000266346900006 PM 19299119 ER PT J AU Adamson, AS Collins, K Laurence, A O'Shea, JJ AF Adamson, Adewole S. Collins, Kalonji Laurence, Arian O'Shea, John J. TI The Current STATus of lymphocyte signaling: new roles for old players SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID HYPER-IGE SYNDROME; ROR-GAMMA-T; ARYL-HYDROCARBON RECEPTOR; T(H)17 CELL-DIFFERENTIATION; INFLAMMATORY-BOWEL-DISEASE; GENOME-WIDE ASSOCIATION; TGF-BETA; RHEUMATOID-ARTHRITIS; INTERFERON-GAMMA; CROHNS-DISEASE AB Recently, our understanding of helper/effector T cell differentiation has changed significantly. New subsets of T cells continue to be recognized, including Th17, Treg, and Th9 cells. In addition, the signaling pathways that contribute to their generation continue to be refined. It has become clear that STAT family proteins play a major role in these 'new' T cell fates, along with their critical role in more classical fates. Importantly, genetic studies implicate STATs in autoimmune and primary immunodeficiency diseases in humans. Focusing on how STATs work in concert with other transcription factors will hopefully provide a better mechanistic understanding of the pathogenesis of various autoimmune diseases. C1 [Adamson, Adewole S.; Collins, Kalonji; Laurence, Arian; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Adamson, Adewole S.] Harvard Mit Div Hlth Sci & Technol, Boston, MA 02115 USA. RP Adamson, AS (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM adamsona@cc.nih.gov; collinsk2@mail.nih.gov; laurencea@mail.nih.gov; osheaj@arb.niams.nih.gov RI Laurence, Arian/A-8770-2009 OI Laurence, Arian/0000-0003-0942-8292 FU NIH; Pfizer Inc. FX Adewole Adamson's research was made possible through the Clinical Research Training Program. a public-private partnership supported jointly In the NIH and Pfizer Inc. (via a grant to the Foundation for NIH from Pfizer Inc.). NR 50 TC 65 Z9 68 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD APR PY 2009 VL 21 IS 2 BP 161 EP 166 DI 10.1016/j.coi.2009.03.013 PG 6 WC Immunology SC Immunology GA 447WT UT WOS:000266223400008 PM 19362457 ER PT J AU Schumacher, TNM Restifo, NP AF Schumacher, Ton N. M. Restifo, Nicholas P. TI Adoptive T cell therapy of cancer SO CURRENT OPINION IN IMMUNOLOGY LA English DT Editorial Material ID LYMPHOCYTES C1 [Schumacher, Ton N. M.] Netherlands Canc Inst, Div Immunol, NL-1066 CX Amsterdam, Netherlands. [Restifo, Nicholas P.] NCI, Clin Res Ctr, Bethesda, MD 20892 USA. RP Schumacher, TNM (reprint author), Netherlands Canc Inst, Div Immunol, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. EM t.schumacher@nki.nl; restifo@nih.gov RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-02]; NCI NIH HHS [P01 CA094237-08, P01 CA094237, P50 CA126752, P50 CA126752-03] NR 14 TC 19 Z9 20 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD APR PY 2009 VL 21 IS 2 BP 187 EP 189 DI 10.1016/j.coi.2009.03.006 PG 3 WC Immunology SC Immunology GA 447WT UT WOS:000266223400012 PM 19328668 ER PT J AU Muranski, P Restifo, NP AF Muranski, Pawel Restifo, Nicholas P. TI Adoptive immunotherapy of cancer using CD4(+) T cells SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID ROR-GAMMA-T; ANTITUMOR IMMUNITY; IFN-GAMMA; TH1 CELLS; TUMOR-ANTIGEN; HELPER-CELLS; IN-VIVO; METASTATIC MELANOMA; CD8-T-CELL MEMORY; CD4-T-CELL HELP AB CD4(+) T cells are central to the function of the immune system but their role in tumor immunity remains underappreciated. It is becoming clear that there is an enormous diversity of CD4(+) T cell polarization patterns including Th1, Th2, Th17, and regulatory T cells (Tregs). These functionally divergent T cell subsets can have opposing effects - they can trigger tumor rejection or inhibit treatment after adoptive cell transfer. Some polarized CD4(+) cells have plasticity, and their phenotypes and functions can evolve in vivo. Recent advances in understanding of polarization and differentiation of lymphocytes, as well as some intriguing developments in the clinic, indicate that the use of CD4(+) T cell subsets in the immunotherapy of cancer has unrealized potential. C1 [Muranski, Pawel; Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA. RP Muranski, P (reprint author), NCI, NIH, 10-CRC-3-5750,10 Ctr Dr, Bethesda, MD 20892 USA. EM muranskp@mail.nih.gov; restifo@nih.gov RI Restifo, Nicholas/A-5713-2008; Muranski, Pawel/E-5572-2010; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-02] NR 90 TC 135 Z9 137 U1 1 U2 16 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD APR PY 2009 VL 21 IS 2 BP 200 EP 208 DI 10.1016/j.coi.2009.02.004 PG 9 WC Immunology SC Immunology GA 447WT UT WOS:000266223400014 PM 19285848 ER PT J AU Rosenberg, SA Dudley, ME AF Rosenberg, Steven A. Dudley, Mark E. TI Adoptive cell therapy for the treatment of patients with metastatic melanoma SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID TUMOR-INFILTRATING LYMPHOCYTES; CD8(+) T-CELLS; CANCER-IMMUNOTHERAPY; IN-VITRO; AUTOLOGOUS TUMOR; GENE-TRANSFER; REGRESSION; INTERLEUKIN-2; PERSISTENCE; ANTIGEN AB Adoptive cell therapy (ACT) is the best available treatment for patients with metastatic melanoma. In a recent series of three consecutive clinical trials using increasing lymphodepletion before infusion of autologous tumor infiltrating lymphocytes (TIL), objective response rates between 49% and 72% were seen. Persistence of infused cells in the circulation at one month was highly correlated with anti-tumor response as was the mean telomere length of the cells infused and the number of CD8+ CD27+ cells infused. Responses occur at all sites and appear to be durable with many patients in ongoing response beyond three years. In the most recent trial of 25 patients receiving maximum lymphodepletion, seven of the 25 patients (28%) achieved a complete response. Of the 12 patients in the three trials who achieved a complete response all but one are ongoing between 18 and 75 months. We recently demonstrated that ACT using autologous lymphocytes genetically modified to express anti-tumor T cell receptors can mediate tumor regression and this approach is now being applied to patients with common epithelial cancers. C1 [Rosenberg, Steven A.; Dudley, Mark E.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM sar@nih.gov FU Intramural NIH HHS [Z01 BC011020-01] NR 40 TC 360 Z9 370 U1 2 U2 42 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD APR PY 2009 VL 21 IS 2 BP 233 EP 240 DI 10.1016/j.coi.2009.03.002 PG 8 WC Immunology SC Immunology GA 447WT UT WOS:000266223400018 PM 19304471 ER PT J AU Jenal, U Galperin, MY AF Jenal, Urs Galperin, Michael Y. TI Single domain response regulators: molecular switches with emerging roles in cell organization and dynamics SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID BACTERIAL SIGNAL-TRANSDUCTION; MYXOCOCCUS-XANTHUS; CAULOBACTER-CRESCENTUS; GLIDING MOTILITY; RHODOBACTER-SPHAEROIDES; DIGUANYLATE CYCLASE; ESCHERICHIA-COLI; STRUCTURAL BASIS; RECEIVER DOMAIN; PROTEASE COMPLEX AB Single domain response regulators (SD-RRs) are signaling components of two-component phosphorylation pathways that harbor a phosphoryl receiver domain but lack a dedicated output domain. The Escherichia coli protein CheY, the paradigm member of this family, regulates chemotaxis by relaying information between chemoreceptors and the flagellar motor switch. New data provide a more complex picture of CheY-mediated motility control in several bacteria and suggest diverging mechanisms in control of cellular motors. Moreover, advances have been made in understanding cellular functions of SD-RRs beyond chemotaxis. We review recent reports indicating that SD-RRs constitute a family of versatile molecular switches that contribute to cellular organization and dynamics as spatial organizer and/or as allosteric regulators of histidine protein kinases. C1 [Jenal, Urs] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland. [Galperin, Michael Y.] Natl Inst Hlth, NCBI, Natl Lib Med, Bethesda, MD 20894 USA. RP Jenal, U (reprint author), Univ Basel, Biozentrum, Klingelbergstr 50, CH-4056 Basel, Switzerland. EM urs.jenal@unibas.ch; galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 FU Swiss National Science Foundation [3100A0-108186]; National Library of Medicine at the National Institutes of Health FX We would like to thank Tilman Schirmer for his help with Figure 2 and members of the Jenal lab for helpful comments. UJ is supported by Swiss National Science Foundation Fellowship 3100A0-108186. MYG is supported by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health. NR 66 TC 44 Z9 45 U1 1 U2 6 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD APR PY 2009 VL 12 IS 2 BP 152 EP 160 DI 10.1016/j.mib.2009.01.010 PG 9 WC Microbiology SC Microbiology GA 440NR UT WOS:000265707500005 PM 19246239 ER PT J AU Lu, B Wang, KH Nose, A AF Lu, Bai Wang, Kuan Hong Nose, Akinao TI Molecular mechanisms underlying neural circuit formation SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Review ID ACTIVITY-DEPENDENT REGULATION; CELL-ADHESION MOLECULE; SYNAPSE FORMATION; BDNF TRANSCRIPTION; INHIBITORY SYNAPSES; SPINE MORPHOGENESIS; TARGET SPECIFICITY; NEURONAL-ACTIVITY; DENDRITIC GROWTH; VISUAL-CORTEX AB The functions of the nervous system are mediated by neural circuits that are formed during development and modulated by experiences. Central to the assembly of neural circuits is the regulation of synaptic connectivity by synaptic molecules and neuronal activity. Extensive studies have focused on identifying molecules involved in synapse formation. Besides factors promoting synaptogenesis, several antisynaptogenic factors have been discovered. These factors act in concert to ensure the timing and specificity of circuit formation. Moreover, progress has been made in revealing how neuronal activity governs the balance of excitatory and inhibitory synapses. Intriguingly, several transcription factors, as well as activity-dependent transcription of BDNF through promoter IV, have been shown to selectively regulate cortical inhibitory circuits by promoting GABAergic synapse formation. C1 [Lu, Bai] NICHD, Sect Neural Dev & Plast, NIH, Bethesda, MD 20892 USA. [Wang, Kuan Hong] NIMH, Unit Neural Circuits & Adapt Behav, NIH, Bethesda, MD 20892 USA. [Nose, Akinao] Univ Tokyo, Grad Sch Frontier Sci, Dept Complex Sci & Engn, Chiba 2778561, Japan. RP Lu, B (reprint author), NICHD, Sect Neural Dev & Plast, NIH, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Wang, Kuan Hong/J-1150-2016 OI Wang, Kuan Hong/0000-0002-2249-5417 FU MEXT; NICHD; NIMH intramural research programs FX We would like to thank Hiroki Taniguchi for comments and Makiko Shinza-Kameda for the help in Illustration (Figure 1). This article is supported by a Grant-in-Aid to AN for Scientific Research B and for Scientific Research on priority Areas-Molecular Brain Science-from the MEXT, and by the NICHD and NIMH intramural research programs to BL and KHW. NR 38 TC 35 Z9 36 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD APR PY 2009 VL 19 IS 2 BP 162 EP 167 DI 10.1016/j.conb.2009.04.004 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 485GJ UT WOS:000269108900009 PM 19457653 ER PT J AU Theman, TA Collins, MT AF Theman, T. A. Collins, M. T. TI The Role of the Calcium-Sensing Receptor in Bone Biology and Pathophysiology SO CURRENT PHARMACEUTICAL BIOTECHNOLOGY LA English DT Review DE Calcium-sensing receptor; bone; metastasis; calcimimetic; calcilytic ID HORMONE-RELATED PROTEIN; FAMILIAL HYPOCALCIURIC HYPERCALCEMIA; EXTRACELLULAR CA2+-SENSING RECEPTOR; HUMAN BREAST-CANCER; STEM-CELL NICHE; NEONATAL SEVERE HYPERPARATHYROIDISM; PLASMA CA2+ HOMEOSTASIS; ACTIVE PTH/PTHRP RECEPTOR; GROWTH-PLATE CHONDROCYTES; TO-MINUTE REGULATION AB Bone cells, particularly osteoblasts and osteoclasts, exhibit functional responses to calcium (Ca2+). The identification of the calcium-sensing receptor (CaR) in parathyroid glands as the master regulator of parathyroid hormone (PTH) secretion proved that cells could specifically respond to changes in divalent cation concentration. Yet, after many years of study, it remains unclear whether this receptor, which has also been identified in bone, has functional import there. Various knockout and transgenic mouse models have been developed, but conclusions about skeletal phenotypes remain elusive. Complex endocrine feedback loops involving calcium, phosphorus, vitamin D, and PTH confound efforts to isolate the effects of a single mineral, hormone, or receptor and most models fail to account for other local factors such as parathyroid hormone related protein (PTHrP). We review the relevant mouse models and discuss the importance of CaR in chondrogenesis and osteogenesis. We present the evidence for a non-redundant role for CaR in skeletal mineralization, including our experience in patients with activating CaR mutations. Additionally, we review emerging research on the importance of the CaR to the regulation of serum calcium homeostasis independent of PTH, the role of the CaR in the hematopoietic stem cell niche with implications for bone marrow transplant, and early evidence that implies a role for the CaR as a factor in skeletal metastasis from breast and prostate cancer. We conclude with a discussion of drugs that target the CaR directly either as agonists (calcimimetics) or antagonists (calcilytics), and the consequences for bone physiology and pathology. C1 [Theman, T. A.; Collins, M. T.] NIDCR, Skeletal Clin Studies Unit, CSDB, NIH, Bethesda, MD 20892 USA. RP Collins, MT (reprint author), NIDCR, Skeletal Clin Studies Unit, CSDB, NIH, 30 Convent Dr,MSC-4320,Bldg 30,Room 228, Bethesda, MD 20892 USA. EM mc247k@nih.gov FU NIH; NIDCR; Clinical Research Training Program; Pfizer Inc FX This research was supported in part by the Intramural Research Program of the NIH, NIDCR. Author TAT was supported by the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc (via a grant to the Foundation for NIH from Pfizer Inc). NR 145 TC 18 Z9 22 U1 0 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2010 EI 1873-4316 J9 CURR PHARM BIOTECHNO JI Curr. Pharm. Biotechnol. PD APR PY 2009 VL 10 IS 3 BP 289 EP 301 PG 13 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 440KF UT WOS:000265698500004 PM 19355939 ER PT J AU Zheng, WJ Brooks, BR Thirumalai, D AF Zheng, Wenjun Brooks, Bernard R. Thirumalai, D. TI Allosteric Transitions in Biological Nanomachines are Described by Robust Normal Modes of Elastic Networks SO CURRENT PROTEIN & PEPTIDE SCIENCE LA English DT Review DE Allostery; chaperonin; elastic network model; myosin; normal mode analysis; polymerase ID DNA-POLYMERASE-I; COLD-SENSITIVE MUTANTS; SEQUENCE VARIATIONS; CRYSTAL-STRUCTURE; STRUCTURAL MODEL; CHAPERONIN GROEL; LARGE FRAGMENT; MYOSIN MOTOR; AMINO-ACID; O-HELIX AB Allostery forms the basis of intra-molecular communications in various enzymes, however the underlying conformational changes are largely elusive. Recently, we have proposed to employ an elastic model based normal mode analysis to investigate the allosteric transitions in several molecular nanomachines (including myosin II, DNA polymerase and chaperonin GroEL). After combining with bioinformatics analysis of the evolutionary sequence variations, we have been able to identify the highly conserved and robust modes of collective motions that are capable of transmitting molecular signals over long distances. C1 [Zheng, Wenjun] SUNY Buffalo, Dept Phys, Buffalo, NY 14260 USA. [Brooks, Bernard R.] NIH, Lab Computat Biol, NHLBI, Bethesda, MD 20892 USA. [Thirumalai, D.] Univ Maryland, Biophys Program, Inst Phys Sci & Technol, College Pk, MD 20742 USA. RP Zheng, WJ (reprint author), SUNY Buffalo, Dept Phys, Buffalo, NY 14260 USA. EM wjzheng@buffalo.edu FU National Institutes of Health [1R01GM067851-01]; NIH; NHLBI; BRB; University at Buffalo FX This research was supported in part by a grant from the National Institutes of Health (1R01GM067851-01) to DT and by the Intramural Research Program of the NIH, NHLBI to WZ and BRB. WZ is also indebted to the support from the intramural funding of University at Buffalo. NR 44 TC 23 Z9 23 U1 2 U2 11 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2037 J9 CURR PROTEIN PEPT SC JI Curr. Protein Pept. Sci. PD APR PY 2009 VL 10 IS 2 BP 128 EP 132 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 441VH UT WOS:000265798100004 PM 19355980 ER PT J AU Addington, AM Rapoport, JL AF Addington, Anjene M. Rapoport, Judith L. TI The Genetics of Childhood-Onset Schizophrenia: When Madness Strikes the Prepubescent SO CURRENT PSYCHIATRY REPORTS LA English DT Article AB Stratification by age at onset has been useful for genetic studies across all of medicine. For the past 20 years, the National Institute of Mental Health has been systematically recruiting patients with onset of schizophrenia before age 13 years. Examination of familial transmission of known candidate risk genes was carried out, and a 10% rate of cytogenetic abnormalities was found. Most recently, high-density, array-based scans for submicroscopic rare copy number variations (CNVs) have suggested that this kind of genetic variation occurs more frequently than expected by chance in childhood-onset schizophrenia (COS) and at a higher rate than observed in adult-onset disorder. Several CNVs and cytogenetic abnormalities associated with COS are also seen in autism and mental retardation. Populations with COS may have more salient genetic influence than adult-onset cases. The relationship of rare CNVs to prepsychotic development is being studied further. C1 [Addington, Anjene M.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Addington, AM (reprint author), NIMH, Child Psychiat Branch, NIH, 10 Ctr Dr,Bldg 10,Room 3N202, Bethesda, MD 20892 USA. EM addingta@mail.nih.gov FU Intramural NIH HHS [Z01 MH002581-17] NR 43 TC 40 Z9 40 U1 1 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1523-3812 J9 CURR PSYCHIAT REP JI Curr. Psychiatry Rep. PD APR PY 2009 VL 11 IS 2 BP 156 EP 161 PG 6 WC Psychiatry SC Psychiatry GA V16XI UT WOS:000207901900010 PM 19302770 ER PT J AU Savan, R Ravichandran, S Collins, JR Sakai, M Young, HA AF Savan, Ram Ravichandran, Sarangan Collins, Jack R. Sakai, Masahiro Young, Howard A. TI Structural conservation of interferon gamma among vertebrates SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE Interferon gamma; Vertebrates; Evolution; Structure ID IFN-GAMMA; GENOMIC ANALYSIS; CRYSTAL-STRUCTURE; RECEPTOR COMPLEX; ACCESSORY FACTOR; MESSENGER-RNA; C-TERMINUS; NK CELLS; GENE; EXPRESSION AB Interferon gamma (IFN-gamma), being the hallmark of the T-cell T(H)1 response, has been extensively studied with respect to its expression and regulation of immune function. This gene has been extensively characterized in many mammalian species, making it one of the most widely cloned immunoregulatory genes. Recently, the gene has been identified in avian and piscine species and we have identified the gene in the frog genome. Based on these identified DNA sequences, we have constructed an evolutionary history of IFN-gamma that shows this molecule can be traced back more than 450 million years ago. Our analysis shows that type II interferon (IFN-gamma) function evolved before the tetrapod-fish split, a finding that contrasts earlier studies showing its origins in tetrapods. The IFN-gamma gene has undergone a further duplication event in teleosts after the tetrapod-fish split suggesting a specific-evolutionary adaptation in fish. The analyses of IFN-gamma, IL-22 and IL-26 genomic region in mammals, chicken, frog and fish reveal an evolutionary conservation of the loci and several regulatory elements controlling IFN-gamma gene transcription. Furthermore, across the vertebrata, the first intron of IFN-gamma gene contains a polymorphic microsatellite that has been closely correlated with disease susceptibility. Comparative-modeling of IFN-gamma structure revealed differences among the representative species but with an overall conservation of the fold, dimer interface and some interactions with the receptor. The structural and functional conservation of IFN-gamma suggests the presence of an innate, natural killer (NK) like response or even an adaptive T(H)1 immune response in lower vertebrates. Published by Elsevier Ltd. C1 [Savan, Ram; Young, Howard A.] NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Ravichandran, Sarangan; Collins, Jack R.] NCI, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. [Sakai, Masahiro] Miyazaki Univ, Lab Marine Biotechnol, Miyazaki 8892192, Japan. RP Savan, R (reprint author), NCI, Expt Immunol Lab, Canc & Inflammat Program, Ctr Canc Res, Bldg 560,Room 31-93, Frederick, MD 21702 USA. EM savanr@mail.nih.gov; younghow@mail.nih.gov FU National Cancer Institute, NIH FX Author contributions: R.S., S.R., J.R.C., M.S. and H.Y. designed research; R.S., and S.R., performed research; R.S., and S.R., analyzed data; and R.S. wrote the paper. This work was funded by the intramural research program of the National Cancer Institute, NIH. NR 41 TC 45 Z9 53 U1 1 U2 15 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD APR PY 2009 VL 20 IS 2 BP 115 EP 124 DI 10.1016/j.cytogfr.2009.02.006 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 444PP UT WOS:000265993200003 PM 19268624 ER PT J AU Timpano, KR Buckner, JD Richey, JA Murphy, DL Schmidt, NB AF Timpano, Kiara R. Buckner, Julia D. Richey, J. Anthony Murphy, Dennis L. Schmidt, Norman B. TI EXPLORATION OF ANXIETY SENSITIVITY AND DISTRESS TOLERANCE AS VULNERABILITY FACTORS FOR HOARDING BEHAVIORS SO DEPRESSION AND ANXIETY LA English DT Article DE compulsive hoarding; anxiety sensitivity; distress tolerance ID OBSESSIVE-COMPULSIVE DISORDER; PERSONALITY-DISORDER; PANIC DISORDER; DISCOMFORT INTOLERANCE; DIMENSIONS; DEPRESSION; VALIDATION; INVENTORY; GENETICS; THERAPY AB Background: The phenomenon of compulsive boarding, characterized by the acquisition of and failure to discard a large number of possessions, is increasingly recognized as a significant public health burden. Despite the magnitude of the impairment associated with this condition, empirical research is still in the nascent stages and many facets of the phenomenology, underlying vulnerability and risk factors for boarding, are as of yet unknown. Method: The overall aim of the current investigation was to examine the association between boarding behaviors and two potential vulnerability factors-anxiety sensitivity (AS) and distress tolerance (DT). In addition, we investigated the robustness of these associations as well as the interaction between the two hypothesized risk factors. Three studies (total N = 745) involving independent nonclinical samples assessed hoarding, AS, DT, and relevant covariates using a range of measures. Results: Findings revealed that AS and boarding are significantly and robustly associated with one another beyond general depressive, anxiety, and nonhoarding obsessive-compulsive symptoms. Hoarding was also found to be associated with low DT Consistent with prediction, AS and DT interacted such that DT may play a less important role among individuals with low AS. By contrast, low DT appears to increase vulnerability to boarding symptoms among individuals high in AS. Results are discussed with regard to future research and treatment implications. Depression and Anxiety 26:343-353, 2009. Published 2009 Wiley-Liss, Inc.(dagger) C1 [Richey, J. Anthony; Schmidt, Norman B.] Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. [Timpano, Kiara R.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Buckner, Julia D.] Louisiana State Univ, Dept Psychol, Baton Rouge, LA 70803 USA. [Murphy, Dennis L.] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. RP Schmidt, NB (reprint author), Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. EM schmidt@psy.fsu.edu RI Timpano, Kiara/C-8760-2012; OI Timpano, Kiara/0000-0002-0665-8722 FU National Institute of Mental Health [F31 MH080467-01A1]; National Institute of Drug Abuse [F31 DA12457-01]; NIH [RO1 MH064734-04al, P50 HD052120, R21 MH62056] FX This research was partially supported in part by National Research Service Awards from the National Institute of Mental Health F31 MH080467-01A1 (Timpano) and the National Institute of Drug Abuse F31 DA12457-01 (Buckner) as well as NIH awards RO1 MH064734-04al, P50 HD052120, and R21 MH62056 (Schmidt). NR 60 TC 52 Z9 52 U1 5 U2 17 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD APR PY 2009 VL 26 IS 4 BP 343 EP 353 DI 10.1002/da.20469 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 430QD UT WOS:000265002700007 PM 19123454 ER PT J AU Wei, Z Yaguchi, J Yaguchi, S Angerer, RC Angerer, LM AF Wei, Zheng Yaguchi, Junko Yaguchi, Shunsuke Angerer, Robert C. Angerer, Lynne M. TI The sea urchin animal pole domain is a Six3-dependent neurogenic patterning center SO DEVELOPMENT LA English DT Article DE Microarray; Nodal; BMP2/4; Primary axis; Secondary axis; Canonical Wnt signaling; beta-catenin; Gene expression profiling; Neural development; Transcription factor ID EMBRYONIC STEM-CELLS; GENE REGULATORY NETWORKS; NUCLEAR BETA-CATENIN; ORAL-ABORAL AXIS; STRONGYLOCENTROTUS-PURPURATUS; HOMEOBOX GENE; NEURAL DIFFERENTIATION; TRANSCRIPTION FACTORS; ACHAETE-SCUTE; EXPRESSION AB Two major signaling centers have been shown to control patterning of sea urchin embryos. Canonical Wnt signaling in vegetal blastomeres and Nodal signaling in presumptive oral ectoderm are necessary and sufficient to initiate patterning along the primary and secondary axes, respectively. Here we define and characterize a third patterning center, the animal pole domain (APD), which contains neurogenic ectoderm, and can oppose Wnt and Nodal signaling. The regulatory influence of the APD is normally restricted to the animal pole region, but can operate in most cells of the embryo because, in the absence of Wnt and Nodal, the APD expands throughout the embryo. We have identified many constituent APD regulatory genes expressed in the early blastula and have shown that expression of most of them requires Six3 function. Furthermore, Six3 is necessary for the differentiation of diverse cell types in the APD, including the neurogenic animal plate and immediately flanking ectoderm, indicating that it functions at or near the top of several APD gene regulatory networks. Remarkably, it is also sufficient to respecify the fates of cells in the rest of the embryo, generating an embryo consisting of a greatly expanded, but correctly patterned, APD. A fraction of the large group of Six3-dependent regulatory proteins are orthologous to those expressed in the vertebrate forebrain, suggesting that they controlled formation of the early neurogenic domain in the common deuterostome ancestor of echinoderms and vertebrates. C1 [Wei, Zheng; Yaguchi, Junko; Yaguchi, Shunsuke; Angerer, Robert C.; Angerer, Lynne M.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Angerer, LM (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. EM langerer@mail.nih.gov OI Yaguchi, Shunsuke/0000-0002-8326-5762 FU Division of Intramural Research, National Institute for Dental and Craniofacial Research, National Institutes of Health FX This work has benefited from stimulating discussions with Drs Adi Sethi and Diane Adams. We are grateful to Dr Robert Burke for antibodies against synapatotagmin (1e11) and NK2.1 and Dr William Klein for antibodies against Spec1. This work was supported by the Division of Intramural Research, National Institute for Dental and Craniofacial Research, National Institutes of Health. Deposited in PMC for release after 12 months. NR 59 TC 46 Z9 46 U1 3 U2 19 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 APR 1 PY 2009 VL 136 IS 7 BP 1179 EP 1189 DI 10.1242/dev.032300 PG 11 WC Developmental Biology SC Developmental Biology GA 422BN UT WOS:000264402100013 PM 19270175 ER PT J AU Day, K Paterson, B Yablonka-Reuveni, Z AF Day, Kenneth Paterson, Bruce Yablonka-Reuveni, Zipora TI A Distinct Profile of Myogenic Regulatory Factor Detection Within Pax7(+) Cells at S Phase Supports a Unique Role of Myf5 During Posthatch Chicken Myogenesis SO DEVELOPMENTAL DYNAMICS LA English DT Article DE satellite cells; Pax7; Myf5; MyoD; myogenin; myogenesis; S phase; proliferation; differentiation; self-renewal; chicken ID MUSCLE SATELLITE-CELLS; SKELETAL-MUSCLE; TEMPORAL EXPRESSION; SELF-RENEWAL; MYOD; DIFFERENTIATION; MYOBLASTS; PROLIFERATION; FIBERS; SPECIFICATION AB Satellite cells are skeletal muscle stem cells that provide myogenic progeny for myofiber growth and repair. Temporal expression of muscle regulatory factors (MRFs) and the paired box transcription factor Pax7 defines characteristic phases of proliferation (Pax7(+)/MyoD(+)/myogenin(-)) and differentiation (Pax7(-)/MyoD(+)/myogenin(+)) during myogenesis of satellite cells. Here, using bromodeoxyuridine (BrdU) labeling and triple immunodetection, we analyzed expression patterns of Pax7 and the MRFs MyoD, Myf5, or myogenin within S phase myoblasts prepared from posthatch chicken muscle. Essentially, all BrdU incorporation was restricted to Pax7(+) cells, of which the majority also expressed MyoD. The presence of a minor BrdU(+)/Pax7(+)/myogenin(+) population in proliferation stage cultures suggests that myogenin up-regulation is alone insufficient for terminal differentiation. Myf5 was detected strictly within Pax7+ cells and decreased during S phase while MyoD presence persisted in cycling cells. This study provides novel data in support of a unique role for Myf5 during posthatch myogenesis. Developmental Dynamics 238: 1001-1009, 2009. (C) 2009 Wiley-Liss, Inc. C1 [Day, Kenneth; Yablonka-Reuveni, Zipora] Univ Washington, Sch Med, Dept Biol Struct, Seattle, WA 98195 USA. [Paterson, Bruce] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yablonka-Reuveni, Z (reprint author), Univ Washington, Sch Med, Dept Biol Struct, Box 357420,Warren B Magneson Hlth Sci Bldg,1959 N, Seattle, WA 98195 USA. EM reuveni@u.washington.edu FU Cooperative State Research, Education and Extension Service-United States Department of Agriculture National Research Initiative [2003-35206-1.2843]; National Institutes of Health [AG21566, AG13798, T32AG000057] FX Grant sponsor: Cooperative State Research, Education and Extension Service-United States Department of Agriculture National Research Initiative; Grant number: 2003-35206-1.2843; Grant sponsor: National Institutes of Health; Grant numbers: AG21566; AG13798; T32AG000057. NR 46 TC 29 Z9 30 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD APR PY 2009 VL 238 IS 4 BP 1001 EP 1009 DI 10.1002/dvdy.21903 PG 9 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 429LF UT WOS:000264921200020 PM 19301399 ER PT J AU Nelson, KB AF Nelson, Karin B. TI Infection in pregnancy and cerebral palsy SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Editorial Material ID PRETERM INFANTS; RISK-FACTORS; ANTECEDENTS C1 Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. RP Nelson, KB (reprint author), Natl Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. NR 7 TC 8 Z9 9 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0012-1622 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD APR PY 2009 VL 51 IS 4 BP 253 EP 254 DI 10.1111/j.1469-8749.2008.03256.x PG 2 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 421FN UT WOS:000264344900003 PM 19335562 ER PT J AU Concannon, P Chen, WM Julier, C Morahan, G Akolkar, B Erlich, HA Hilner, JE Nerup, J Nierras, C Pociot, F Todd, JA Rich, SS AF Concannon, Patrick Chen, Wei-Min Julier, Cecile Morahan, Grant Akolkar, Beena Erlich, Henry A. Hilner, Joan E. Nerup, Jorn Nierras, Concepcion Pociot, Flemming Todd, John A. Rich, Stephen S. CA Type 1 Diabet Genetics Consortium TI Genome-Wide Scan for Linkage to Type 1 Diabetes in 2,496 Multiplex Families From the Type 1 Diabetes Genetics Consortium SO DIABETES LA English DT Article ID SUSCEPTIBILITY GENES; MELLITUS; ASSOCIATION; LOCUS; IDENTIFICATION; REGIONS; SEARCH; IDDM8; RISK; HLA AB OBJECTIVE-Type I diabetes arises from the actions of multiple genetic and environmental risk factors. Considerable success at identifying common genetic variants that contribute to type 1 diabetes risk has come from genetic association (primarily case-control) studies. However, such studies have limited power to detect genes containing multiple rare variants that contribute significantly to disease risk. RESEARCH DESIGN AND METHODS-The Type I Diabetes Genetics Consortium (T1DGC) has assembled a collection of 2,496 multiplex type I diabetic families from nine geographical regions containing 2,658 affected sib-pairs (ASPs). We describe the results of a genome-wide scan for linkage to type 1 diabetes in the T1DGC family collection. RESULTS-Significant evidence of linkage to type 1 diabetes was confirmed at the HLA region on chromosome 6p21.3 (logarithm of odds [LOD] = 213.2). There was further evidence of linkage to type I diabetes on 6q that could not be accounted for by the major linkage signal at the HLA class H loci on chromosome 6p21. Suggestive evidence of linkage (LOD >= 2.2) was observed near CTLA4 on chromosome 2q32.3 (LOD = 3.28) and near INS (LOD = 3.16) on chromosome 11p15.5. Some evidence for linkage was also detected at two regions on chromosome 19 (LOD = 2.84 and 2.54). CONCLUSIONS-Five non-HLA chromosome regions showed some evidence of linkage to type 1 diabetes. A number of previously proposed type 1 diabetes susceptibility loci, based on smaller ASP numbers, showed limited or no evidence of linkage to disease. Low-frequency susceptibility variants or clusters of loci with common alleles could contribute to the linkage signals observed. Diabetes 58:1018-1022, 2009 C1 [Concannon, Patrick] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22903 USA. [Concannon, Patrick; Chen, Wei-Min; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Chen, Wei-Min] Univ Virginia, Div Biostat & Epidemiol, Dept Publ Hlth Sci, Charlottesville, VA USA. [Julier, Cecile] Ctr Natl Genotypage, INSERM, U730, Evry, France. [Morahan, Grant] Univ Western Australia, Ctr Diabet Res, Western Australian Inst Med Res, Perth, WA 6009, Australia. [Morahan, Grant] Univ Western Australia, Med Res Ctr, Perth, WA 6009, Australia. [Akolkar, Beena] NIDDKD, Div Didabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. [Hilner, Joan E.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Erlich, Henry A.] Roche Mol Syst, Pleasanton, CA USA. [Nerup, Jorn; Pociot, Flemming] Steno Diabet Ctr, DK-2820 Gentofte, Denmark. [Nierras, Concepcion] Juvenile Diabet Res Fdn, New York, NY USA. [Todd, John A.] Univ Cambridge, Juvenile Diabet Res Fdn, Wellcome Trust Diabet & Inflammat Lab, Dept Med Genet,Cambridge Inst Med Res, Cambridge, England. RP Concannon, P (reprint author), Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA 22903 USA. EM patcon@virginia.edu RI Chen, Wei-Min/A-8469-2009; Todd, John/A-3542-2010; Boehm, Bernhard/F-8750-2015; OI Concannon, Patrick/0000-0002-5801-1859; Pociot, Flemming/0000-0003-3274-5448 FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) [DK46635]; National Institute of Allergy and Infectious Diseases (NIAID); National Human Genome Research Institute (NHGRI); National Institute of Child:Health and Human Development (NICHD); Juvenile Diabetes Research Foundation International (JDRF) [U01 DK062418]; Diabetes and Inflammation Laboratory at Cambridge; National Institute for Health Research Cambridge Biomedical Research Centre; National Institutes of Health to the Johns Hopkins University [N01-HG-65403] FX No potential conflicts of interest relevant to this article were reported. NR 23 TC 45 Z9 48 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD APR PY 2009 VL 58 IS 4 BP 1018 EP 1022 DI 10.2337/db08-1551 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 428AH UT WOS:000264819700028 PM 19136655 ER PT J AU Lieb, W Sullivan, LM Harris, TB Roubenoff, R Benjamin, EJ Levy, D Fox, CS Wang, TJ Wilson, PW Kannel, WB Vasan, RS AF Lieb, Wolfgang Sullivan, Lisa M. Harris, Tamara B. Roubenoff, Ronenn Benjamin, Emelia J. Levy, Daniel Fox, Caroline S. Wang, Thomas J. Wilson, Peter W. Kannel, William B. Vasan, Ramachandran S. TI Plasma Leptin Levels and Incidence of Heart Failure, Cardiovascular Disease, and Total Mortality in Elderly Individuals SO DIABETES CARE LA English DT Article ID RAT VENTRICULAR MYOCYTES; RISK-FACTOR; WEIGHT; OBESITY; MICE; HYPERTROPHY; INSULIN; MEN AB OBJECTIVE - Obesity predisposes individuals to congestive heart failure (CHF) and cardiovascular disease (CVD). Leptin regulates energy homeostasis, is elevated in obesity, and influences ventricular and vascular remodeling. We tested the hypothesis that leptin levels are associated With greater risk of CHF, CVD, and mortality in elderly individuals. RESEARCH DESIGN AND METHODS - We evaluated 818 elderly (mean age 79 years, 62% women) Framingham Study participants attending a routine examination at which plasma leptin was assayed. RESULTS - Leptin levels were higher in women and strongly correlated with BMI (P < 0.0001). On follow-up (mean 8.0 years), 129 (of 775 free of CH F) participants developed CHF, 187 (of 532 free of CVD) experienced a first CVD event, and 391 individuals died. In multivariable Cox regression models adjusting for established risk factors, log-leptin was positively associated with incidence of CHF and CVD (hazard ratio [HR] per SD increment 1.26 [95% Cl 1.03-1.55] and 1.28 [1.09-1.50], respectively). Additional adjustment for BMI nullified the association with CHF (0.97 [0.75-1.24]) but only modestly attenuated the. relation to CVD incidence (1.23 [1.00-1.51], P = 0.052). We observed a nonlinear, U-shaped relation between log-leptin and mortality (P = 0.005 for quadratic term) with greater risk of death evident at both low and high leptin levels. CONCLUSIONS - In our moderate-sized community-based elderly sample, higher circulating leptin levels were associated with a greater risk of CHF and CVD, but leptin did not provide incremental prognostic information beyond BMI. Additional investigations are warranted to elucidate the U-shaped relation of leptin to mortality. C1 [Lieb, Wolfgang; Benjamin, Emelia J.; Levy, Daniel; Fox, Caroline S.; Wang, Thomas J.; Kannel, William B.; Vasan, Ramachandran S.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Sullivan, Lisa M.; Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Biostat & Epidemiol, Boston, MA USA. [Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Roubenoff, Ronenn] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Prevent Med & Cardiol Sect, Boston, MA 02118 USA. [Levy, Daniel; Fox, Caroline S.] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol, Boston, MA 02115 USA. [Wang, Thomas J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA USA. [Wilson, Peter W.] Emory Univ, Sch Med, Atlanta, GA USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, Framingham, MA USA. EM vasan@bu.edu RI Lieb, Wolfgang/C-1990-2012; OI Ramachandran, Vasan/0000-0001-7357-5970; Sullivan, Lisa/0000-0003-0726-7149; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health/National Heart, Lung, and Blood Institute [N01-HC25195, N01-HV28178, K24-HL04334, R01-DK080739] FX This work was supported through National Institutes of Health/National Heart, Lung, and Blood Institute Contracts N01-HC25195, N01-HV28178, K24-HL04334, and R01-DK080739. Contract N01-HC25195 funded the performance of examinations at which leptin levels were obtained. The other grants supported the interpretation of data and preparation of the manuscript.; No potential conflicts of interest relevant to this article were reported. NR 25 TC 48 Z9 50 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD APR PY 2009 VL 32 IS 4 BP 612 EP 616 DI 10.2337/dc08-1596 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 428AI UT WOS:000264819800018 PM 19114611 ER PT J AU Van Den Eeden, SK Sarma, AV Rutledge, BN Cleary, PA Kusek, JW Nyberg, LM McVary, KT Wessells, H AF Van Den Eeden, Stephen K. Sarma, Aruna V. Rutledge, Brandy N. Cleary, Patricia A. Kusek, John W. Nyberg, Leroy M. McVary, Kevin T. Wessells, Hunter CA DCCT EDIC Res Grp TI Effect of Intensive Glycemic Control and Diabetes Complications on Lower Urinary Tract Symptoms in Men With Type 1 Diabetes SO DIABETES CARE LA English DT Article ID BENIGN PROSTATIC HYPERPLASIA; OLMSTED COUNTY; INTERVENTIONS; EPIDEMIOLOGY; POPULATION; MELLITUS; COHORT; TRIAL AB OBJECTIVE - Although diabetes is known to result in lower urinary tract symptoms (LUTS) in men, it remains unclear if glycemic control can mitigate urinary symptoms. We studied how diabetic characteristics are related to LUTS in the men who completed the urological assessment component (UroEDIC) of the Epidemiology of Diabetes Interventions and Complications (FDIC) follow-up study of the Diabetes Control and Complications Trial (DCCT) participants. RESEARCH DESIGN AND METHODS - Study participants were men who completed the UroEDIC questionnaire at the year 10 DCCT/EDIC follow-up examination, which included data on genitourinary tract function and the American Urological Association Symptom Index (AUASI). Analyses were conducted to assess how treatment arm and diabetes characteristics were associated with LUTS using logistic regression. RESULTS - Of the 591 men who completed the AUASI questions, nearly 200 (n = 115) had AUASI scores in the moderate to severe category for LUTS (AUASI score >= 8). No associations were observed between LUTS and treatment arm, or A1C levels at the DCCT baseline or end-of-study or at the year 10 FDIC (UrOEDIC) examination. Of the diabetes complications studied, only erectile dysfunction at the UroEDIC examination was associated with LUTS. CONCLUSIONS - These data from the UroEDIC cohort do not support the assumption that intensive glycemic control results in decreased lower urinary tract symptom severity in men with type 1 diabetes. This result may be due to a true lack of effect, or it may be due to other factors, for example, the relatively young age of the cohort. C1 [Van Den Eeden, Stephen K.] Kaiser Permanente, Div Res, Oakland, CA USA. [Sarma, Aruna V.] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Sarma, Aruna V.] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. [Rutledge, Brandy N.; Cleary, Patricia A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Kusek, John W.; Nyberg, Leroy M.] NIDDK, NIH, Bethesda, MD USA. [McVary, Kevin T.] Northwestern Univ, Dept Urol, Chicago, IL 60611 USA. [Wessells, Hunter] Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. [Wessells, Hunter] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. RP Van Den Eeden, SK (reprint author), Kaiser Permanente, Div Res, Oakland, CA USA. EM stephen.vandeneeden@kp.org FU NIDDK NIH HHS [N01 DK062204-A, N01 DK062204, N01 DK062204-007] NR 23 TC 25 Z9 25 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 EI 1935-5548 J9 DIABETES CARE JI Diabetes Care PD APR PY 2009 VL 32 IS 4 BP 664 EP 670 DI 10.2337/dc07-2375 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 428AI UT WOS:000264819800028 PM 19171725 ER PT J AU Barzilay, JI Cotsonis, GA Walston, J Schwartz, AV Satterfield, S Miljkovic, I Harris, TB AF Barzilay, Joshua I. Cotsonis, George A. Walston, Jeremy Schwartz, Ann V. Satterfield, Suzanne Miljkovic, Iva Harris, Tamara B. CA Hlth ABC Study TI Insulin Resistance Is Associated With Decreased Quadriceps Muscle Strength in Nondiabetic Adults Aged >= 70 Years SO DIABETES CARE LA English DT Article ID BODY-COMPOSITION; SKELETAL-MUSCLE; HEALTH; SENSITIVITY; GLUCOSE AB OBJECTIVE - Lower-limb muscle strength is reduced in many people with diabetes. In this Study, we examined whether quadriceps muscle strength is reduced in relation to insulin resistance in well-functioning ambulatory nondiabetic individuals. RESEARCH DESIGN AND METHODS - Participants (age >= 70 years) underwent dual-energy X-ray absorptiometry (DEXA) scanning to ascertain muscle and fat mass, tests of quadriceps strength, computed tomography scanning Of the quadriceps to gauge muscle lipid content, and fasting insulin and glucose level measurements from which homeostasis model assessment of insulin resistance (HOMA-IR) was derived. RESULTS - In regression analysis, quadriceps strength per kilogram of muscle mass was negatively associated (P < 0.0001) with HOMA-IR independent of other factors negatively associated with strength such as increased age, female sex, low-physical activity, impaired fasting glucose, and increased total body fat. Muscle lipid content was not associated with strength. CONCLUSIONS - A shall decrease in quadriceps muscle force is associated with increased HOMA-IR in well-functioning nondiabetic adults, suggesting that diminished quadriceps muscle strength begins before diabetes. C1 [Barzilay, Joshua I.] Kaiser Permanente Georgia, Atlanta, GA USA. [Barzilay, Joshua I.] Emory Univ, Sch Med, Div Endocrinol, Atlanta, GA USA. [Cotsonis, George A.] Emory Univ, Rollins Sch Publ Hlth, Dept Biostat, Atlanta, GA USA. [Walston, Jeremy] Johns Hopkins Med Inst, Dept Geriatr, Baltimore, MD 21205 USA. [Schwartz, Ann V.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Satterfield, Suzanne] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Miljkovic, Iva] Univ Pittsburgh, Ctr Aging & Populat Hlth, Pittsburgh, PA USA. [Harris, Tamara B.] NIA, Geriatr Epidemiol Sect, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Barzilay, JI (reprint author), Kaiser Permanente Georgia, Atlanta, GA USA. EM Joshua.barzilay@kp.org OI Miljkovic, Iva/0000-0002-3155-9777 FU National Institutes of Health; National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] FX No potential conflicts of interest relevant to this article were reported. NR 15 TC 39 Z9 41 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD APR PY 2009 VL 32 IS 4 BP 736 EP 738 DI 10.2337/dc08-1781 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 428AI UT WOS:000264819800041 PM 19171728 ER PT J AU Poehls, J Wassel, CL Harris, TB Havel, PJ Swarbrick, MM Cummings, SR Newman, AB Satterfield, S Kanaya, AM AF Poehls, J. Wassel, C. L. Harris, T. B. Havel, P. J. Swarbrick, M. M. Cummings, S. R. Newman, A. B. Satterfield, S. Kanaya, A. M. TI Association of adiponectin with mortality in older adults: the Health, Aging, and Body Composition Study SO DIABETOLOGIA LA English DT Article DE Adiponectin; Adipose tissue; Body composition; Epidemiology; Mortality ID CORONARY-HEART-DISEASE; ELDERLY-MEN; PROTEIN; WOMEN; RISK AB Despite inverse associations with insulin resistance and adiposity, adiponectin has been associated with both increased and decreased risk of cardiovascular disease. We examined whether adiponectin is associated with total and cardiovascular mortality in older adults with well-characterised body composition. We analysed data from 3,075 well-functioning adults aged 69-79 years at baseline. Mortality data were obtained over 6.6 +/- 1.6 years. We used Cox proportional hazards models adjusting for covariates in stages to examine the association between adiponectin and total and cardiovascular mortality. There were 679 deaths, 36% of which were from cardiovascular disease. Unadjusted levels of adiponectin were not associated with total or cardiovascular mortality. However, after adjusting for sex and race, adiponectin was associated with an increased risk of both total mortality (hazard ratio 1.26, 95% CI 1.15-1.37, per SD) and cardiovascular mortality (hazard ratio 1.35, 95% CI 1.17-1.56, per SD). Further adjustment for study site, smoking, hypertension, diabetes, prevalent heart disease, HDL-cholesterol, LDL-cholesterol, renal function, fasting insulin, triacylglycerol, BMI, visceral fat, thigh intermuscular fat and thigh muscle area did not attenuate this association. This association between adiponectin and increased mortality risk did not vary by sex, race, body composition, diabetes, prevalent cardiovascular disease, smoking or weight loss. Higher levels of adiponectin were associated with increased risks of total and cardiovascular mortality in this study of older persons. C1 [Cummings, S. R.; Kanaya, A. M.] UCSF Womens Hlth Clin Res Ctr, San Francisco, CA 94115 USA. [Poehls, J.] Univ Wisconsin, Madison, WI USA. [Wassel, C. L.] Univ Calif San Diego, San Diego, CA 92103 USA. [Harris, T. B.] NIA, Lab Epidemiol Demog & Biometry, IRP, NIH, Bethesda, MD USA. [Havel, P. J.] Univ Calif Davis, Sch Vet Med, Dept Mol Biosci, Davis, CA 95616 USA. [Swarbrick, M. M.] Garvan Inst Med Res, Diabet & Obes Program, Sydney, NSW, Australia. [Cummings, S. R.] Calif Pacific Med Ctr, San Francisco Coordinating Ctr, Res Inst, San Francisco, CA USA. [Newman, A. B.] Univ Pittsburgh, Pittsburgh, PA USA. [Satterfield, S.] Univ Tennessee, Memphis, TN USA. RP Kanaya, AM (reprint author), UCSF Womens Hlth Clin Res Ctr, 1635 Divisadero St,Suite 600, San Francisco, CA 94115 USA. EM Alka.Kanaya@ucsf.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU National Institutes of Health [K23HL080026, R21DK068608]; National Institute on Aging ( NIA) [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] FX A. M. Kanaya was funded by the National Institutes of Health, grants # K23HL080026 and # R21DK068608. The Health ABC Study was funded through contracts with National Institute on Aging ( NIA) contracts N01-AG-6-2101, N01-AG-6-2103 and N01-AG-6-2106. This research was supported in part by the Intramural Research Program of the NIH, NIA and included substantial involvement of NIA staff in data collection, analysis, interpretation and review, and approval of the manuscript. A. M. Kanaya had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 10 TC 46 Z9 46 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD APR PY 2009 VL 52 IS 4 BP 591 EP 595 DI 10.1007/s00125-009-1261-7 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 413IR UT WOS:000263787300006 PM 19159917 ER PT J AU Stolerman, ES Manning, AK McAteer, JB Fox, CS Dupuis, J Meigs, JB Florez, JC AF Stolerman, E. S. Manning, A. K. McAteer, J. B. Fox, C. S. Dupuis, J. Meigs, J. B. Florez, J. C. TI TCF7L2 variants are associated with increased proinsulin/insulin ratios but not obesity traits in the Framingham Heart Study SO DIABETOLOGIA LA English DT Article DE Body mass index; Proinsulin; TCF7L2; Type 2 diabetes ID ADIPOSE-TISSUE; GENE; POLYMORPHISMS; POPULATION; RISK AB Common variants in the TCF7L2 gene are associated with type 2 diabetes via impaired insulin secretion. One hypothesis is that variation in TCF7L2 impairs insulin processing in the beta cell. In contrast, the association of related TCF7L2 polymorphisms with obesity is controversial in that it has only been shown in cohorts susceptible to ascertainment bias. We reproduced the association of diabetes-associated variants with proinsulin/insulin ratios, and also examined the association of a TCF7L2 haplotype with obesity in the Framingham Heart Study (FHS). We genotyped the TCF7L2 single nucleotide polymorphisms rs7903146 and rs12255372 (previously associated with type 2 diabetes) and rs10885406 and rs7924080 (which tag haplotype A [HapA], a haplotype reported to be associated with obesity) in 2,512 FHS participants. We used age- and sex-adjusted linear mixed-effects models to test for association with glycaemic traits, proinsulin/insulin ratios and obesity measures. As expected, the T risk allele of rs7903146 was associated with higher fasting plasma glucose (p = 0.01). T/T homozygotes had a 23.5% increase in the proinsulin/insulin ratio (p = 1 x 10(-7)) compared with C/C homozygotes. There was no association of HapA with BMI (p = 0.98), waist circumference (p = 0.89), subcutaneous adipose tissue (p = 0.32) or visceral adipose tissue (p = 0.92). We confirmed that the risk allele of rs7903146 is associated with hyperglycaemia and a higher proinsulin/insulin ratio. We did not detect any association of the TCF7L2 HapA with adiposity measures, suggesting that this may have been a spurious association from ascertainment bias, possibly induced by the evaluation of obesity in separate groups of glycaemic cases and controls. C1 [Stolerman, E. S.; McAteer, J. B.; Florez, J. C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Diabet Unit, Boston, MA 02114 USA. [Stolerman, E. S.; McAteer, J. B.; Florez, J. C.] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Stolerman, E. S.; McAteer, J. B.; Florez, J. C.] MIT, Cambridge, MA 02139 USA. [Stolerman, E. S.; Meigs, J. B.; Florez, J. C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Manning, A. K.; Dupuis, J.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Fox, C. S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Endocrinol Diabet & Hypertens, Boston, MA USA. [Fox, C. S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Meigs, J. B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. RP Florez, JC (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, Diabet Unit, Simches Res Bldg-CPZN 5-250, Boston, MA 02114 USA. EM jcflorez@partners.org OI Dupuis, Josee/0000-0003-2871-3603 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Diabetes Association Career Development Award; NIH NCRR Shared Instrumentation [1S10RR163736-01A1]; NIH [T32 GM007748, K23 DK65978-04]; NIDDK [K24 DK080140]; Glaxo-SmithKline; sanofi-aventis FX This study was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study ( contract no. N01-HC-25195), an American Diabetes Association Career Development Award ( J.B. Meigs), and the Boston University Linux Cluster for Genetic Analysis ( LinGA) funded by the NIH NCRR Shared Instrumentation grant ( 1S10RR163736-01A1). E. S. Stolerman is supported by NIH Training Grant T32 GM007748 Training Grant in Genetics. J.B. Meigs is also supported by NIDDK K24 DK080140. J. C. Florez is supported by NIH Research Career Award K23 DK65978-04. J. B. Meigs currently has research grants from Glaxo-SmithKline and sanofi-aventis, and serves on consultancy boards for GlaxoSmithKline, sanofi-aventis, Interleukin Genetics, Kalypsis, and Outcomes Sciences. J. C. Florez has received consulting honoraria from Merck, bioStrategies, XOMA and Publicis Healthcare Communications Group, a global advertising agency engaged by Amylin Pharmaceuticals. NR 20 TC 38 Z9 41 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD APR PY 2009 VL 52 IS 4 BP 614 EP 620 DI 10.1007/s00125-009-1266-2 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 413IR UT WOS:000263787300010 PM 19183934 ER PT J AU Diwan, BA Timofeeva, O Rice, JM Yang, YL Sharma, N Fortini, ME Wang, HH Perantoni, AO AF Diwan, Bhalchandra A. Timofeeva, Olga Rice, Jerry M. Yang, Yili Sharma, Nirmala Fortini, Mark E. Wang, Honghe Perantoni, Alan O. TI Inheritance of susceptibility to induction of nephroblastomas in the Noble rat SO DIFFERENTIATION LA English DT Article DE Nephroblastoma; Wilms tumor; Wt1; Kidney; Tumor susceptibility ID GROWTH-FACTOR RECEPTOR; TUMOR GENE-PRODUCT; WILMS-TUMOR; NERVOUS-SYSTEM; NEPHRO-BLASTOMA; METANEPHRIC MESENCHYME; N-NITROSOETHYLUREA; PROMOTER ACTIVITY; RODENT MODEL; CELL-LINE AB Noble (Nb) strain rats are susceptible to nephroblastoma induction with transplacental exposure to direct-acting alkylating agent N-nitrosoethylurea (ENU), while F344 strain rats are highly resistant. To study the inheritance of susceptibility to induction of these embryonal renal tumors, fetal Nb and F344 rats and F1, F2 and reciprocal backcross hybrids were exposed transplacentally to ENU once on day 18 of gestation. Nephroblastomas developed in 53% of Nb offspring with no apparent gender difference, while no nephroblastomas developed in inbred F344 offspring. F1 and F2 hybrid offspring had intermediate responses, 28% and 30%, respectively. Nephroblastoma incidence in the offspring of F1 hybrids backcrossed to the susceptible strain Nb was 46%, while that in F1 hybrids backcrossed to resistant strain F344 was much lower (16%). Carcinogenic susceptibility is therefore consistent with the involvement of one major autosomal locus; the operation of a gene dosage effect; and a lack of simple Mendelian dominance for either susceptibility or resistance. Since established Wilms tumor-associated suppressor genes, Wt1 and Wtx, were not mutated in normal or neoplastic tissues, genomic profiling was performed on isolated Nb and F344 metanephric progenitors to identify possible predisposing factors to nephroblastoma induction. Genes preferentially elevated in expression in Nb rat progenitors included Wnt target genes Epidermal growth factor receptor, Inhibitor of DNA binding 2, and Jagged 1, which were further increased in nephroblastomas. These studies demonstrate the value of this model for genetic analysis of nephroblastoma development and implicate both the Wnt and Notch pathways in its pathogenesis. Published by Elsevier Ltd. on behalf of International Society of Differentiation C1 [Yang, Yili; Sharma, Nirmala; Fortini, Mark E.; Wang, Honghe; Perantoni, Alan O.] NCI, Ctr Canc Res, Canc & Dev Biol Lab, Frederick, MD 21702 USA. [Timofeeva, Olga; Rice, Jerry M.] NCI, Ctr Canc Res, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. [Diwan, Bhalchandra A.] NCI, Sci Applicat Int Corp Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Perantoni, AO (reprint author), NCI, Ctr Canc Res, Canc & Dev Biol Lab, Frederick, MD 21702 USA. EM peranton@ncifcrf.gov FU Center for Cancer Research, National Cancer Institute; NCI [NO1-CO12400] FX We thank Lee Dove for help in the isolation of the metanephric mesenchymes. These studies have been supported in part by intramural research funds from the Center for Cancer Research, National Cancer Institute, and from NCI Contract no. NO1-CO12400. 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 organization simply endorsement by the US government. NR 55 TC 3 Z9 3 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0301-4681 EI 1432-0436 J9 DIFFERENTIATION JI Differentiation PD APR PY 2009 VL 77 IS 4 BP 424 EP 432 DI 10.1016/j.diff.2008.12.003 PG 9 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 555RL UT WOS:000274531600009 PM 19281789 ER PT J AU Kuo, PH Kalsi, G Prescott, CA Hodgkinson, CA Goldman, D Alexander, J van den Oord, EJ Chen, XN Sullivan, PF Patterson, DG Walsh, D Kendler, KS Riley, BP AF Kuo, Po-Hsiu Kalsi, Gursharan Prescott, Carol A. Hodgkinson, Colin A. Goldman, David Alexander, Jeffry van den Oord, Edwin J. Chen, Xiangning Sullivan, Patrick F. Patterson, Diana G. Walsh, Dermot Kendler, Kenneth S. Riley, Brien P. TI Associations of glutamate decarboxylase genes with initial sensitivity and age-at-onset of alcohol dependence in the Irish Affected Sib Pair Study of Alcohol Dependence SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE GABA; Initial sensitivity; Response to ethanol; Withdrawal; Gender difference ID ACID DECARBOXYLASE; GABA(A) RECEPTORS; ETHANOL WITHDRAWAL; COCAINE ADDICTION; CANDIDATE GENES; FEMALE RATS; DSM-IV; MICE; BRAIN; ABUSE AB Background: The relation of gamma-aminobutyric acid (GABA) to alcohol dependence (AD) has been widely studied. Several previous studies suggest that GABA may be involved in alcohol withdrawal, tolerance, and the symptoms that form an AD ' diagnosis. The genes coding for glutamate decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, are of potential interest for their association to ethanol consumption and AD. There are two isoforms of GAD, GAD1 and GAD2, which were reported to be associated with AD in males of Han Taiwanese (GAD1) and Russian (GAD2) ancestry. The present study examined the association of the two GAD isoforms with AD and relevant alcohol-related traits in the Irish Affected Sib Pair Study of Alcohol Dependence [Prescott, C.A., Sullivan, P.F., Myers, J.M., Patterson, D.G., Devitt, M., Halberstadt, LJ.. Walsh, D., Kendler, K.S., 2005. The Irish Affected Sib Pair Study of Alcohol Dependence: study methodology and validation of diagnosis by interview and family history. Alcohol.-Clin. Exp. Res. 29 (3) 417-429]. Methods: Participants were recruited in Ireland, including 575 independent cases who met DSM-IV AD criteria and 530 controls, screened for heavy drinking. We first conducted case-control analyses of the GAD genes with AD and, within the cases, examined associations with age at onset of AD, withdrawal symptoms, and two quantitative measures: initial sensitivity and tolerance (based on scales from the Self-Rating of the Effects of Ethanol) [Schuckit, M.A., Smith, T.L., Tipp, J.E., 1997. The self-rating of the effects of alcohol (SRE) form as a retrospective measure of the risk for alcoholism. Addiction 92, 979-988]. A total of 29 SNPs were genotyped for CAD1 and GAD2 using the Illumina GoldenGate protocols. Statistical procedures were implemented to control for false discovery rates (FDR). Results: Nine of 29 markers with minor allele frequencies less than 0.01 were removed from standard analysis; the remaining 20 markers were all in Hardy-Weinberg equilibrium. Three markers in the intronic regions of GAD1 were associated with initial sensitivity to alcohol (P = 0.002); the associations remained significant after a FOR based correction for multiple testing. In addition, one marker located 3 kb upstream of GAD1 exhibited association with age at onset of AD (P = 0.0001). Gender specific effects were observed in results of both single marker and haplotype analyses. Conclusion: We found no evidence for the association of GAD genes with AD but significant association of GAD1 with initial sensitivity and age at onset of AD. Our findings suggest that the underlying C1 [Kuo, Po-Hsiu] Natl Cheng Kung Univ, Coll Med, Inst Clin Med, Tainan 70101, Taiwan. [Kuo, Po-Hsiu; Kalsi, Gursharan; Alexander, Jeffry; Chen, Xiangning; Kendler, Kenneth S.; Riley, Brien P.] Virginia Commonwealth Univ, Dept Psychiat, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. [Prescott, Carol A.] Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. [Hodgkinson, Colin A.; Goldman, David] NIAAA, Neurogenet Lab, DICBR, Rockville, MD 20852 USA. [van den Oord, Edwin J.] Virginia Commonwealth Univ, Ctr Biomarker Res & Personalized Med, Richmond, VA USA. [Sullivan, Patrick F.] Univ N Carolina, Carolina Ctr Genome Sci, Dept Genet, Chapel Hill, NC USA. [Sullivan, Patrick F.] Univ N Carolina, Carolina Ctr Genome Sci, Dept Psychiat, Chapel Hill, NC USA. [Patterson, Diana G.] Shaftsbury Sq Hosp, Belfast, Antrim, North Ireland. [Walsh, Dermot] Hlth Res Board, Dublin, Ireland. RP Kuo, PH (reprint author), 12C Natl Cheng Kung Univ Hosp, Inst Clin Med, 138 Sheng Li Rd, Tainan 704, Taiwan. EM pkuo@mail.ncku.edu.tw RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Kuo, Po-Hsiu/0000-0003-0365-3587 FU National Institutes of Health [R01-AA-11408] FX This work was supported by National Institutes of Health grant R01-AA-11408 and the Irish Health Research Board for original data collections and data analysis. Writing of this manuscript was also supported by a Young Investigator award from the National Alliance for Research on Schizophrenia and Depression to Po-Hsiu Kuo. NR 47 TC 22 Z9 24 U1 1 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD APR 1 PY 2009 VL 101 IS 1-2 BP 80 EP 87 DI 10.1016/j.drugalcdep.2008.11.009 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 422KS UT WOS:000264427200012 PM 19111404 ER PT J AU Epstein, DH Schmittner, J Umbricht, A Schroeder, JR Moolchan, ET Preston, KL AF Epstein, David H. Schmittner, John Umbricht, Annie Schroeder, Jennifer R. Moolchan, Eric T. Preston, Kenzie L. TI Promoting abstinence from cocaine and heroin with a methadone dose increase and a novel contingency SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE Contingency management; Polydrug dependence; Methadone dose; DSM diagnoses ID ADDICTION SEVERITY INDEX; CLINICAL-TRIALS NETWORK; SUBSTANCE USE DISORDERS; MAINTENANCE TREATMENT; OPIOID DEPENDENCE; DRUG-ABUSE; OUTPATIENT TREATMENT; REINFORCEMENT; MANAGEMENT; BUPRENORPHINE AB To test whether a combination of contingency management and methadone dose increase would promote abstinence from heroin and cocaine, we conducted a randomized controlled trial using a 2 x 3 (dose x contingency) factorial design in which dose assignment was double-blind. Participants were 252 heroin- and cocaine-abusing outpatients on methadone maintenance. The were randomly assigned to methadone dose (70 or 100 mg/day, double-blind) and voucher condition (noncontingent, contingent on cocaine-negative urines, or "split"). The "split" contingency was a novel contingency that reinforced abstinence from either drug while doubly reinforcing simultaneous abstinence from both: the total value of incentives was "split" between drugs to contain costs. The main outcome measures were percentages of urine specimens negative for heroin. cocaine, and both simultaneously; these were monitored during a 5-week baseline of standard treatment (to determine Study eligibility), a 12-week intervention, and a 10-week maintenance phase (to examine intervention effects in return-to-baseline conditions). DSM-IV criteria for ongoing drug dependence were assessed at study exit. Urine-screen results showed that the methadone dose increase reduced heroin use but not cocaine use. The split 100 mg group was the only group to achieve a longer duration of simultaneous negatives than its same-dose noncontingent control group. The frequency of DSM-IV opiate and cocaine dependence diagnoses decreased in the active intervention groups. For a split contingency to promote simultaneous abstinence from cocaine and heroin, a relatively high dose of methadone appears necessary but not sufficient; an increase in overall incentive amount may also be required. Published by Elsevier Ireland Ltd. C1 [Epstein, David H.; Schmittner, John; Umbricht, Annie; Schroeder, Jennifer R.; Moolchan, Eric T.; Preston, Kenzie L.] Natl Inst Drug Abuse, Treatment Sect, Clin Pharmacol & Therapeut Branch, Intramural Res Branch, Baltimore, MD 21224 USA. RP Epstein, DH (reprint author), Natl Inst Drug Abuse, Treatment Sect, Clin Pharmacol & Therapeut Branch, Intramural Res Branch, 251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM depstein@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU NIDA IRP FX Funding for this Study was provided by the NIDA IRP; NIDA had no further role in Study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. NR 43 TC 25 Z9 26 U1 4 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD APR 1 PY 2009 VL 101 IS 1-2 BP 92 EP 100 DI 10.1016/j.drugalcdep.2008.11.006 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 422KS UT WOS:000264427200014 PM 19101098 ER PT J AU Field, CA Adinoff, B Harris, TR Ball, SA Carroll, KM AF Field, Craig A. Adinoff, Bryon Harris, T. Robert Ball, Samuel A. Carroll, Kathleen M. TI Construct, concurrent and predictive validity of the URICA: Data from two multi-site clinical trials SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE URICA; Motivation to change; Substance dependence; Readiness to Change; Committed Action; Motivational interviewing; Motivational enhancement therapy ID MOTIVATIONAL ENHANCEMENT THERAPY; MATCHING ALCOHOLISM TREATMENTS; TRANSTHEORETICAL MODEL; METHADONE-MAINTENANCE; SUBSTANCE-ABUSE; CLIENT HETEROGENEITY; MEASURING READINESS; DEPENDENT PATIENTS; DRINKING OUTCOMES; SEEKING TREATMENT AB Background: A better understanding of how to measure motivation to change and how it relates to behavior change in patients with drug and alcohol dependence would broaden our understanding of the role of motivation in addiction treatment. Methods: Two multi-site, randomized clinical trials comparing brief motivational interventions with standard care were conducted in the National Institute on Drug Abuse Clinical Trials Network. Patients with primary drug dependence and alcohol dependence entering Outpatient treatment participated in a study of either Motivational Enhancement Therapy (n = 431) or Motivational Interviewing (n = 423), The construct, concurrent, and predictive validity of two composite measures of motivation to change derived from the University of Rhode Island Change Assessment (URICA): Readiness to Change (RTC) and Committed Action (CA) were evaluated. Results: Confirmatory factor analysis confirmed the a priori factor structure of the URICA. RTC was significantly associated with measures of addiction severity at baseline (r = .12-.52, p < .05).Although statistically significant (p < .01), the correlations between treatment outcomes and RTC were low (r = - .15 and 18). Additional analyses did not support a moderating or mediating effect of motivation on treatment retention or substance use. Conclusions: The construct validity of the URICA was confirmed separately in a large sample of drug- and alcohol-dependent patients. However, evidence for the predictive validity of composite scores was very limited and there were no moderating or mediating effects of either measure on treatment outcome. Thus, increased motivation to change, as measured by the composite scores of motivation derived from the URICA, does not appear to influence treatment Outcome. Published by Elsevier Ireland Ltd. C1 [Field, Craig A.] Univ Texas Austin, Sch Social Work, Ctr Social Work Res, Hlth Behav Res & Training Inst, Austin, TX 78703 USA. [Adinoff, Bryon] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Adinoff, Bryon] VA N Texas Hlth Care Syst, Dallas, TX 75216 USA. [Harris, T. Robert] Univ Texas Dallas, Sch Publ Hlth, Dallas, TX 75390 USA. [Ball, Samuel A.] Yale Univ, Sch Med, APT Fdn, New Haven, CT 06511 USA. [Carroll, Kathleen M.] Yale Univ, Psychotherapy Dev Ctr, NIDA, CTN New England Node,VA Connecticut Healthcare Sy, West Haven, CT 06516 USA. RP Field, CA (reprint author), Univ Texas Austin, Sch Social Work, Ctr Social Work Res, Hlth Behav Res & Training Inst, 1717 W 6th St Ste 295, Austin, TX 78703 USA. EM craig.field@austin.utexas.edu RI Carroll, Kathleen/A-7526-2009; OI Carroll, Kathleen/0000-0003-3263-3374 FU NIDA FX Funding for this study was provided by NIDA Clinical Trials Network; NIDA had no further role in study design; in the collection, analysis and interpretation of data; or in the writing of the report. The NIDA Clinical Trials Network publications committee approved submission of this paper for publication. Dr. Adinoffs time is also supported by Veteran Affairs (VA). The VA had no further role in study design; in the collection, analysis and interpretation of data; or in the writing of the report. NR 77 TC 24 Z9 24 U1 3 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD APR 1 PY 2009 VL 101 IS 1-2 BP 115 EP 123 DI 10.1016/j.drugalcdep.2008.12.003 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 422KS UT WOS:000264427200017 PM 19157723 ER PT J AU Buchanan, ML Easterling, TR Carr, DB Shen, DD Risler, LJ Nelson, WL Mattison, DR Hebert, MF AF Buchanan, M. L. Easterling, T. R. Carr, D. B. Shen, D. D. Risler, L. J. Nelson, W. L. Mattison, D. R. Hebert, M. F. TI Clonidine Pharmacokinetics in Pregnancy SO DRUG METABOLISM AND DISPOSITION LA English DT Article; Proceedings Paper CT Annual Meeting of the American-College-of-Clinical-Pharmacy CY OCT 14-17, 2007 CL Denver, CO SP Amer Coll Clin Pharm ID CYP3A AB The objective of this study was to determine the pharmacokinetic parameters of clonidine during pregnancy compared with previously published data in nonpregnant subjects. Serial blood and urine samples were collected in 17 women during mid to late pregnancy over one steady-state dosing interval to determine clonidine noncompartmental pharmacokinetic parameters (n = 17) and creatinine clearance. In six of these pregnant subjects, maternal and umbilical cord (venous and arterial) plasma samples were collected at the time of delivery for measurement of clonidine concentrations. Clonidine apparent oral clearance was found to be 440 +/- 168 ml/min during pregnancy compared with 245 +/- 72 ml/min as previously reported in nonpregnant subjects (p < 0.0001) (Cunningham et al., 1994). There was a strong correlation (r = 0.82, p < 0.001) between clonidine renal clearance, adjusted for variation in glomerular filtration rate, and urine pH. Umbilical cord to maternal plasma clonidine concentration ratios were 1.0 +/- 0.1 (arterial) and 1.0 +/- 0.1 (venous). In conclusion, clonidine is cleared more rapidly in pregnant women than in nonpregnant subjects. At the time of delivery, the fetus is exposed to similar plasma clonidine concentrations as the mother. C1 [Buchanan, M. L.; Shen, D. D.; Hebert, M. F.] Univ Washington, Dept Pharm, Seattle, WA 98195 USA. [Easterling, T. R.; Carr, D. B.; Hebert, M. F.] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Nelson, W. L.] Univ Washington, Dept Med Chem, Seattle, WA 98195 USA. [Shen, D. D.; Risler, L. J.] Fred Hutchinson Canc Res Ctr, Pharmacokinet Lab, Seattle, WA 98104 USA. [Mattison, D. R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. RP Hebert, MF (reprint author), Univ Washington, Dept Pharm, 1959 NE Pacific St,H-375 Hlth Sci Ctr,Box 357630, Seattle, WA 98195 USA. EM mhebert@u.washington.edu RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 FU NCRR NIH HHS [RR023256, M01-RR00037, T32-RR023256]; NICHD NIH HHS [5U10-HD047892] NR 17 TC 28 Z9 28 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD APR PY 2009 VL 37 IS 4 BP 702 EP 705 DI 10.1124/dmd.108.024984 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 421LR UT WOS:000264360900003 PM 19116263 ER PT J AU Cheng, Y Wright, SH Hooth, MJ Sipes, IG AF Cheng, Y. Wright, S. H. Hooth, M. J. Sipes, I. G. TI Characterization of the Disposition and Toxicokinetics of N-Butylpyridinium Chloride in Male F-344 Rats and Female B6C3F1 Mice and Its Transport by Organic Cation Transporter 2 SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID IMIDAZOLIUM IONIC LIQUIDS; 1-BUTYL-3-METHYLIMIDAZOLIUM CHLORIDE; TOXICITY; KIDNEY; EXPRESSION; MULTIDRUG; SOLVENTS; FUTURE; ROLES AB Studies were conducted to characterize the effect of dose and route of administration on the disposition of N-butylpyridinium chloride (NBuPy-Cl), an ionic liquid with solvent properties. Urine was the major route of NBuPy-Cl excretion after intravenous (5 mg/kg), single oral (0.5, 5, or 50 mg/kg), or repeated oral (50 mg/kg/day, 5 days) administration to male F-344 rats and single oral (50 mg/ kg) administration to female B6C3F1 mice. Depending on the vehicle, absorption after dermal application (5 mg/ kg, 125 mu g/cm(2)) was 10 to 35% at 96 h. After the single intravenous dose, the blood concentration of NBuPy-Cl decreased in a biphasic manner with an elimination half-life of 2.2 h and a clearance of 7 ml/min. After single oral administration of NBuPy-Cl (50 mg/ kg), maximum blood concentration was reached at 1.3 h, and the bioavailability was determined to be 47% at 6 h based on the blood toxicokinetics and 67% at 72 h based on urinary excretion. In all the urine and blood samples, only the parent compound was detected. Coadministration of NBuPy-Cl and inulin (by intravenous injection) revealed that the clearance of NBuPy-Cl exceeded the rat glomerular filtration rate. After incubation with Chinese hamster ovary cells expressing human organic cation transporter 2 (hOCT2), NBuPy-Cl was transported effectively (K(t) = 18 mu M), and also a potent inhibitor of hOCT2 mediated tetraethylammonium transport (IC(50) = 2.3 mu M). In summary, NBuPy-Cl is partially absorbed from the gastrointestinal tract and eliminated rapidly in the urine as parent compound most likely by renal glomerular filtration and OCT2-mediated secretion. C1 [Cheng, Y.; Sipes, I. G.] Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA. [Wright, S. H.] Univ Arizona, Coll Med, Dept Physiol, Tucson, AZ 85724 USA. [Hooth, M. J.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Sipes, IG (reprint author), Univ Arizona, Coll Med, Dept Pharmacol, POB 245050, Tucson, AZ 85724 USA. EM sipes@email.arizona.edu FU National Institutes of Health National Institute of Environmental Health Sciences [N01-ES45529, ES06694, ZO1-ES045004-11 BB]; National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [DK58251] FX This work was supported in part by the National Institutes of Health National Institute of Environmental Health Sciences [Grants N01-ES45529, ES06694]; the National Institutes of Health National Institute of Environmental Health Sciences [Grant ZO1-ES045004-11 BB] ( Intramural Research Program, Research Project Number 1); and the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK58251]. NR 34 TC 12 Z9 12 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD APR PY 2009 VL 37 IS 4 BP 909 EP 916 DI 10.1124/dmd.108.022681 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 421LR UT WOS:000264360900029 PM 19171679 ER PT J AU Tolar, P Pierce, SK AF Tolar, Pavel Pierce, Susan K. TI Change we can believe in-of the conformational type Workshop on the Initiation of Antigen Receptor Signaling SO EMBO REPORTS LA English DT Editorial Material DE antigen receptors; immunological synapse; signalling; structure ID T-CELL-RECEPTOR; ACTIVATION; REVEALS; SYNAPSE; LIGAND; THETA; ZETA C1 [Tolar, Pavel; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Pierce, SK (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM spierce@niaid.nih.gov NR 14 TC 1 Z9 1 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1469-221X EI 1469-3178 J9 EMBO REP JI EMBO Rep. PD APR PY 2009 VL 10 IS 4 BP 331 EP 336 DI 10.1038/embor.2009.26 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 426ZN UT WOS:000264747600014 PM 19282883 ER PT J AU John, S Johnson, TA Sung, MH Biddie, SC Trump, S Koch-Paiz, CA Davis, SR Walker, R Meltzer, PS Hager, GL AF John, Sam Johnson, Thomas A. Sung, Myong-Hee Biddie, Simon C. Trump, Saskia Koch-Paiz, Christine A. Davis, Sean R. Walker, Robert Meltzer, Paul S. Hager, Gordon L. TI Kinetic Complexity of the Global Response to Glucocorticoid Receptor Action SO ENDOCRINOLOGY LA English DT Article ID TUMOR VIRUS PROMOTER; ESTROGEN-RECEPTOR; IN-VIVO; MOLECULAR-MECHANISMS; NUCLEAR RECEPTORS; GENE-EXPRESSION; LIVING CELLS; KAPPA-B; TRANSCRIPTION; RECRUITMENT AB We have characterized the kinetic response of gene targets throughout the murine genome to transcriptional modulation by the glucocorticoid receptor (GR). In contrast to a model in which multiple genes are either repressed or activated during the GR response, the vast majority of responsive genes are subject to complex regulation profiles, frequently with alternate activation and repression phases. We also observe that GR binding at response elements does not always correlate with the target gene response profile. Thus, the cellular response to GR stimulation involves a highly orchestrated series of regulatory actions and not simply a binary response to hormone. (Endocrinology 150: 1766-1774, 2009) C1 [John, Sam; Johnson, Thomas A.; Sung, Myong-Hee; Biddie, Simon C.; Koch-Paiz, Christine A.; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Biddie, Simon C.] Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol BS1 3NY, Avon, England. [Trump, Saskia] UFZ Helmholtz Ctr Environm Res, Dept Environm Immunol, D-04318 Leipzig, Germany. [Davis, Sean R.; Walker, Robert; Meltzer, Paul S.] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,Room B602,41 Lib Dr, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov OI Biddie, Simon/0000-0002-8253-0253; Davis, Sean/0000-0002-8991-6458 NR 31 TC 57 Z9 59 U1 1 U2 6 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD APR PY 2009 VL 150 IS 4 BP 1766 EP 1774 DI 10.1210/en.2008-0863 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 422QN UT WOS:000264442900026 PM 19131569 ER PT J AU Finkielstain, GP Forcinito, P Lui, JCK Barnes, KM Marino, R Makaroun, S Nguyen, V Lazarus, JE Nilsson, O Baron, J AF Finkielstain, Gabriela P. Forcinito, Patricia Lui, Julian C. K. Barnes, Kevin M. Marino, Rose Makaroun, Sami Nguyen, Vina Lazarus, Jacob E. Nilsson, Ola Baron, Jeffrey TI An Extensive Genetic Program Occurring during Postnatal Growth in Multiple Tissues SO ENDOCRINOLOGY LA English DT Article ID CATCH-UP GROWTH; FACTOR-II GENE; NERVOUS-SYSTEM DEVELOPMENT; IN-SITU HYBRIDIZATION; PLATE SENESCENCE; MESSENGER-RNA; KIDNEY DEVELOPMENT; MATERNAL-BEHAVIOR; EMBRYONIC GROWTH; SOMATIC GROWTH AB Mammalian somatic growth is rapid in early postnatal life but then slows and eventually ceases in multiple tissues. We hypothesized that there exists a postnatal gene expression program that is common to multiple tissues and is responsible for this coordinate growth deceleration. Consistent with this hypothesis, microarray analysis identified more than 1600 genes that were regulated with age (1 vs. 4 wk) coordinately in kidney, lung, and heart of male mice, including many genes that regulate proliferation. As examples, we focused on three growth-promoting genes, Igf2, Mest, and Peg3, that were markedly down-regulated with age. In situ hybridization revealed that expression occurred in organ-specific parenchymal cells and suggested that the decreasing expression with age was due primarily to decreased expression per cell rather than a decreased number of expressing cells. The declining expression of these genes was slowed during hypothyroidism and growth inhibition (induced by propylthiouracil at 0-5 wk of age) in male rats, suggesting that the normal decline in expression is driven by growth rather than by age per se. We conclude that there exists an extensive genetic program occurring during postnatal life. Many of the involved genes are regulated coordinately in multiple organs, including many genes that regulate cell proliferation. At least some of these are themselves apparently regulated by growth, suggesting that, in the embryo, a gene expression pattern is established that allows for rapid somatic growth of multiple tissues, but then, during postnatal life, this growth leads to negative-feedback changes in gene expression that in turn slow and eventually halt somatic growth, thus imposing a fundamental limit on adult body size. (Endocrinology 150: 1791-1800, 2009) C1 [Baron, Jeffrey] Eunice Kennedy Shriver NICHHD, Dev Endocrinol Branch, NIH, CRC, Bethesda, MD 20892 USA. [Nilsson, Ola] Karolinska Inst, Dept Woman & Child Hlth, Pediat Endocrinol Unit, SE-17176 Stockholm, Sweden. [Nilsson, Ola] Ctr Mol Med, SE-17176 Stockholm, Sweden. [Nilsson, Ola] Karolinska Univ Hosp, SE-17176 Stockholm, Sweden. RP Baron, J (reprint author), Eunice Kennedy Shriver NICHHD, Dev Endocrinol Branch, NIH, CRC, Room 1-3330,10 Ctr Dr,MSC-1103, Bethesda, MD 20892 USA. EM jeffrey.baron@nih.gov RI Lui, Chun Kin Julian/E-2253-2012; OI Nilsson, Ola/0000-0002-9986-8138 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; Swedish Research Council [K2007-52X-20316-01-4]; Swedish Society of Medical Research; HKH Kronprinsessan Lovisas Forening for Barnasjukvard; Sallskapet Barnavard; Stiftelsen Frimurare Barnhuset i Stockholm FX This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. O.N. was supported by grants from the Swedish Research Council (K2007-52X-20316-01-4), the Swedish Society of Medical Research, HKH Kronprinsessan Lovisas Forening for Barnasjukvard, Sallskapet Barnavard, and Stiftelsen Frimurare Barnhuset i Stockholm. NR 61 TC 38 Z9 40 U1 1 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD APR PY 2009 VL 150 IS 4 BP 1791 EP 1800 DI 10.1210/en.2008-0868 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 422QN UT WOS:000264442900029 PM 19036884 ER PT J AU Blume, A Torner, L Liu, Y Subburaju, S Aguilera, G Neumann, ID AF Blume, Annegret Torner, Luz Liu, Ying Subburaju, Sivan Aguilera, Greti Neumann, Inga D. TI Prolactin Activates Mitogen-Activated Protein Kinase Signaling and Corticotropin Releasing Hormone Transcription in Rat Hypothalamic Neurons SO ENDOCRINOLOGY LA English DT Article ID RECEPTOR MESSENGER-RNA; TUBEROINFUNDIBULAR DOPAMINERGIC-NEURONS; NEUROENDOCRINE STRESS RESPONSES; NB2 LYMPHOMA-CELLS; GENE-EXPRESSION; TYROSINE-HYDROXYLASE; MATERNAL-BEHAVIOR; LACTATING RATS; MAP KINASE; PARAVENTRICULAR NUCLEUS AB Prolactin (PRL) modulates maternal behavior and mediates hypothalamic pituitary adrenal axis inhibition during lactation via PRL receptors in the brain. To identify mechanisms mediating these effects, we examined the effects of PRL on signaling and CRH transcription in hypothalamic neurons in vivo and in vitro. Western blot of hypothalamic proteins from rats receiving intracerebro-ventricular PRL injection revealed increases in phosphorylation of the MAPK and ERK. Double-staining immunohistochemistry demonstrated phosphorylated ERK localization in parvocellular CRH neurons as well as magnocellular vasopressin and oxytocin neurons of the hypothalamic paraventricular (PVN) and supraoptic nuclei. PRL also induced ERK phosphorylation in vitro in the hypothalamic cell line, 4B, which expresses PRL receptors, and in primary hypothalamic neuronal cultures. Using reporter gene assays in 4B cells, or quantitative RT-PCR for primary transcript in hypothalamic cell cultures, PRL potentiated forskolin-stimulated CRH transcription through activation of the ERK/MAPK pathway. The effect of PRL in hypothalamic cell cultures was unaffected by tetrodotoxin, suggesting a direct effect on CRH neurons. The data show that PRL activates the ERK/MAPK pathway and facilitates CRH transcription in CRH neurons, suggesting that the inhibitory effect of PRL on hypothalamo-pituitary-adrenal axis activity reported in vivo is indirect and probably mediated through modulation of afferent pathways to the PVN. In addition, the prominent stimulatory action of PRL on the ERK/MAPK pathway in the hypothalamic PVN and supraoptic nucleus is likely to mediate neuroplasticity of the neuroendocrine system during lactation. (Endocrinology 150: 1841-1849, 2009) C1 [Blume, Annegret; Torner, Luz; Neumann, Inga D.] Univ Regensburg, Dept Behav & Mol Neuroendocrinol, Inst Zool, D-93053 Regensburg, Germany. [Torner, Luz] Inst Mexicano Seguro Social, Biochem Res Ctr Michoacan, Morelia, Michoacan, Mexico. [Liu, Ying; Subburaju, Sivan; Aguilera, Greti] NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bethesda, MD USA. RP Neumann, ID (reprint author), Univ Regensburg, Dept Behav & Mol Neuroendocrinol, Inst Zool, Univ Str 31, D-93053 Regensburg, Germany. EM inga.neumann@biologie.uni-regensburg.de FU National Institutes of Health/National Institute of Child Health and Human Development; Bayrische Forschungsstiftung; Deutsche Forschungsgemeinschaft; German Ministry for Education and Research FX This work was partially supported by the Intramural Research Program of the National Institutes of Health/National Institute of Child Health and Human Development (to G. A.), the Bayrische Forschungsstiftung (to A. B. and I. D. N.), the Deutsche Forschungsgemeinschaft (to I. D. N.), and the German Ministry for Education and Research (to I. D. N.). NR 75 TC 30 Z9 30 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD APR PY 2009 VL 150 IS 4 BP 1841 EP 1849 DI 10.1210/en.2008-1023 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 422QN UT WOS:000264442900035 PM 19022892 ER PT J AU Ng, L Hernandez, A He, WX Ren, TY Srinivas, M Ma, M Galton, VA St Germain, DL Forrest, D AF Ng, Lily Hernandez, Arturo He, Wenxuan Ren, Tianying Srinivas, Maya Ma, Michelle Galton, Valerie A. St Germain, Donald L. Forrest, Douglas TI A Protective Role for Type 3 Deiodinase, a Thyroid Hormone-Inactivating Enzyme, in Cochlear Development and Auditory Function SO ENDOCRINOLOGY LA English DT Article ID IODOTHYRONINE DEIODINASE; PRENATAL COCAINE; HEARING-LOSS; RECEPTOR-BETA; GENE; RESISTANCE; EXPRESSION; MATURATION; MICE; RAT AB Thyroid hormone is necessary for cochlear development and auditory function, but the factors that control these processes are poorly understood. Previous evidence indicated that in mice, the serum supply of thyroid hormone is augmented within the cochlea itself by type 2 deiodinase, which amplifies the level of T-3, the active form of thyroid hormone, before the onset of hearing. We now report that type 3 deiodinase, a thyroid hormone-inactivating enzyme encoded by Dio3, is expressed in the immature cochlea before type 2 deiodinase. Dio3(-/-) mice display auditory deficits and accelerated cochlear differentiation, contrasting with the retardation caused by deletion of type 2 deiodinase. The Dio3 mRNA expression pattern in the greater epithelial ridge, stria vascularis, and spiral ganglion partly overlaps with that of thyroid hormone receptor beta (TR beta), the T3 receptor that is primarily responsible for auditory development. The proposal that type 3 deiodinase prevents premature stimulation of TR beta was supported by deleting TR beta, which converted the Dio3(-/-) cochlear phenotype from one of accelerated to one of delayed differentiation. The results indicate a protective role for type 3 deiodinase in hearing. The auditory system illustrates the considerable extent to which tissues can autoregulate their developmental response to thyroid hormone through both type 2 and 3 deiodinases. (Endocrinology 150: 1952-1960, 2009) C1 [Ng, Lily; Ma, Michelle; Forrest, Douglas] NIDDKD, NIH, Clin Endocrinol Branch, Bethesda, MD 20892 USA. [Hernandez, Arturo; Galton, Valerie A.; St Germain, Donald L.] Dartmouth Med Sch, Dept Med, Lebanon, NH 03756 USA. [St Germain, Donald L.] Dartmouth Med Sch, Dept Physiol, Lebanon, NH 03756 USA. [He, Wenxuan; Ren, Tianying] Oregon Hlth & Sci Univ, Dept Otolaryngol Head & Neck Surg, Portland, OR 97239 USA. [Srinivas, Maya] Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA. RP Forrest, D (reprint author), NIDDKD, NIH, Clin Endocrinol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM forrestd@niddk.nih.gov FU March of Dimes Birth Defects Foundation; National Institutes of Health [DC-03441, HD-09020, DK-42271, DC-004554]; National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported in part by March of Dimes Birth Defects Foundation and National Institutes of Health Grants DC-03441 (to D. F.), HD-09020 (to V. A. G.), DK-42271 (to D. L. S.), and DC-004554 (to T. R.), and by the Intramural Program at National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (to D. F.). NR 50 TC 80 Z9 80 U1 2 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 EI 1945-7170 J9 ENDOCRINOLOGY JI Endocrinology PD APR PY 2009 VL 150 IS 4 BP 1952 EP 1960 DI 10.1210/en.2008-1419 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 422QN UT WOS:000264442900048 PM 19095741 ER PT J AU McCarty, KM Santella, RM Steck, SE Cleveland, RJ Ahn, J Ambrosone, CB North, K Sagiv, SK Eng, SM Teitelbaum, SL Neugut, AI Gammon, MD AF McCarty, Kathleen M. Santella, Regina M. Steck, Susan E. Cleveland, Rebecca J. Ahn, Jiyoung Ambrosone, Christine B. North, Kari Sagiv, Sharon K. Eng, Sybil M. Teitelbaum, Susan L. Neugut, Alfred I. Gammon, Marilie D. TI PAH-DNA Adducts, Cigarette Smoking, GST Polymorphisms, and Breast Cancer Risk SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE breast cancer; GST; Long Island; PAH-DNA adducts; smoking ID GLUTATHIONE-S-TRANSFERASE; POLYCYCLIC AROMATIC-HYDROCARBONS; LUNG-CANCER; LONG-ISLAND; GENETIC POLYMORPHISMS; CYTOCHROME-P450 1A1; TOBACCO-SMOKE; M1 GENOTYPE; TISSUE; SUSCEPTIBILITY AB BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) may increase breast cancer risk, and the association may be modified by inherited differences in deactivation of PAH intermediates by glutathione S-transferases (GSTs). Few breast cancer studies have investigated the joint effects of multiple GSTs and a PAH biomarker. OBJECTIVE: We estimated the breast cancer risk associated with multiple polymorphisms in the GST gene (GSTA1, GSTM1, GSTP1, and GSM) and the interaction with PAH-DNA adducts and cigarette smoking. METHODS: We conducted unconditional logistic regression using data from a population-based sample of women (cases/controls, respectively): GST polymorphisms were genotyped using polymerase chain reaction and matrix-assisted laser desorption/ionization time-of-flight assays (n = 926 of 916), PAH-DNA adduct blood levels were measured by competitive enzyme-linked immunosorbent assay (n = 873 of 94 1), and smoking status was assessed by in-person questionnaires (n = 943 of 973). RESULTS: Odds ratios for joint effects on breast cancer risk among women with at least three variant alleles were 1.56 (95% confidence interval (CI), 1.13-2.16] for detectable PAH-DNA adducts and 0.93 (95% CI, 0.56-1.56) for no detectable adducts; corresponding odds ratios for three or more variants were 1.18 (95% CI, 0.82-1.69) for ever smokers and 1.44 (95% CI, 0.97-2.14) for never smokers. Neither interaction was statistically significant (p = 0.43 and 0.62, respectively). CONCLUSION: We found little statistical evidence that PAHs interacted with GSM, GSTM1, GSTP1, and GSTA1 polymorphisms to further increase breast cancer risk. C1 [McCarty, Kathleen M.; Cleveland, Rebecca J.; North, Kari; Sagiv, Sharon K.; Gammon, Marilie D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [McCarty, Kathleen M.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, Div Environm Hlth Sci, New Haven, CT 06510 USA. [Santella, Regina M.] Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA. [Steck, Susan E.] Univ S Carolina, Dept Epidemiol & Biostat, Arnold Sch Publ Hlth, Columbia, SC 29208 USA. [Ahn, Jiyoung] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Eng, Sybil M.] Pfizer Inc, Epidemiol Resources Safety Evaluat & Epidemiol, New York, NY USA. [Teitelbaum, Susan L.] Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. [Neugut, Alfred I.] Columbia Univ, Dept Med, Coll Phys & Surg, New York, NY USA. [Neugut, Alfred I.] Columbia Univ, Dept Epidemiol, Coll Phys & Surg, Mailman Sch Publ Hlth, New York, NY USA. RP McCarty, KM (reprint author), Yale Univ Epidemiol & Publ Hlth, Environm Hlth Sci Div, 60 Coll St,Room 442, New Haven, CT 06520 USA. EM kathleen.mccarcy@yale.edu RI Steck, Susan/G-5736-2013; OI Sagiv, Sharon/0000-0003-2245-1905 FU National Cancer Institute; National Institutes of Health [CA/S66572, P30ES10126, P30ES009089, IK07CA102640, 5T32CA 009330, L30 CA124219-01] FX This work was supported in part by grants from the National Cancer Institute and the National Institutes of Environmental Health Sciences of the National Institutes of Health (grants CA/S66572, P30ES10126, P30ES009089, IK07CA102640, 5T32CA 009330, and L30 CA124219-01). NR 65 TC 32 Z9 37 U1 1 U2 10 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2009 VL 117 IS 4 BP 552 EP 558 DI 10.1289/ehp.0800119 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 426JQ UT WOS:000264704500028 PM 19440493 ER PT J AU Rusiecki, JA Patel, R Koutros, S Beane-Freeman, L Landgren, O Bonner, MR Coble, J Lubin, J Blair, A Hoppin, JA Alavanja, MCR AF Rusiecki, Jennifer A. Patel, Rahulkumar Koutros, Stella Beane-Freeman, Laura Landgren, Ola Bonner, Matthew R. Coble, Joseph Lubin, Jay Blair, Aaron Hoppin, Jane A. Alavanja, Michael C. R. TI Cancer Incidence among Pesticide Applicators Exposed to Permethrin in the Agricultural Health Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE agriculture; cancer; multiple myeloma; occupation; permethrin; pesticide applicator; pesticides; pyrethroid ID CARCINOMA CELL-LINE; MULTIPLE-MYELOMA; PYRETHROID INSECTICIDES; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; RISK; FARMERS; COHORT; RATS; MICE AB BACKGROUND: Permethrin is a synthetic pyrethroid insecticide widely used in agriculture, in public health, and in many U.S. homes and gardens. OBJECTIVE: In this study we evaluated the incidence of cancer among pesticide applicators exposed to permethrin in the Agricultural Health Study (AHS). METHODS: A total of 49,093 pesticide applicators were included in this analysis of the AHS, a prospective cohort study of licensed pesticide applicators in Iowa and North Carolina. Detailed information on pesticide exposure and lifestyle factors was obtained from self-administered questionnaires completed in 1993-1997. Average length of follow-up since applicator enrollment in the cohort was 9.14 years. We used two permethrin exposure metrics: a) lifetime days applicators personally mixed or applied permethrin and b) intensity-weighted lifetime days (lifetime days weighted by estimated intensity of exposure). We used Poisson regression analysis to estimate relative risks (RRs) and 95% confidence intervals (CIs) for malignancies by tertiles of exposure. RESULTS: We found no associations between permethrin and all malignant neoplasms combined, or between permethrin and melanoma, non-Hodgkin lymphoma, leukemia, or cancers of the colon, rectum, lung, or prostate. We found elevated and statistically significant risks for multiple myeloma in the highest tertiles of both lifetime exposure-days (RR = 5.72; 95% CI, 2.76-11.87) and intensity-weighted lifetime exposure-days (RR = 5.01; 95% CI, 2.41-10.42), compared with applicators reporting they never used permethrin; these results are based on only 15 exposed cases. These findings were similar across a variety of alternative exposure metrics, exposure categories, and reference groups. CONCLUSIONS: This study found no association with most cancers analyzed. Although the suggested association with multiple myeloma was based on a small number of cases, it warrants further evaluation. C1 [Rusiecki, Jennifer A.; Patel, Rahulkumar] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. [Koutros, Stella; Beane-Freeman, Laura; Landgren, Ola; Coble, Joseph; Lubin, Jay; Blair, Aaron; Alavanja, Michael C. R.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bonner, Matthew R.] SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. [Hoppin, Jane A.] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Rusiecki, JA (reprint author), Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, 4301 Jones Bridge Rd,PMB Room A1039, Bethesda, MD 20814 USA. EM jrusiecki@usuhs.mil RI Beane Freeman, Laura/C-4468-2015 OI Beane Freeman, Laura/0000-0003-1294-4124 FU National Institutes of Health; National Cancer Institute; Division of Cancer Epidemiology and Genetics [Z01-CP010119]; National Institute of Environmental Health Sciences [Z01-ES049030] FX This research was supported by the Intramural Research Program of the National Institutes of Health: National Cancer Institute, Division of Cancer Epidemiology and Genetics (Z01-CP010119) and National Institute of Environmental Health Sciences (Z01-ES049030). NR 47 TC 47 Z9 49 U1 2 U2 17 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 EI 1552-9924 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2009 VL 117 IS 4 BP 581 EP 586 DI 10.1289/ehp.11318 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 426JQ UT WOS:000264704500032 PM 19440497 ER PT J AU Birnbaum, LS AF Birnbaum, Linda S. TI Leading the World's Premier Environmental Health Organization: A Message from Linda Birnbaum SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Birnbaum, Linda S.] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NTP, NIH, US Dept HHS, Res Triangle Pk, NC USA. RP Birnbaum, LS (reprint author), NIEHS, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD APR PY 2009 VL 117 IS 4 BP A138 EP A138 DI 10.1289/ehp.12670 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 426JQ UT WOS:000264704500001 PM 19440468 ER PT J AU Kaab, S Darbar, D van Noord, C Dupuis, J Pfeufer, A Newton-Cheh, C Schnabel, R Makino, S Sinner, MF Kannankeril, PJ Beckmann, BM Choudry, S Donahue, BS Heeringa, J Perz, S Lunetta, KL Larson, MG Levy, D MacRae, CA Ruskin, JN Wacker, A Schomig, A Wichmann, HE Steinbeck, G Meitinger, T Uitterlinden, AG Witteman, JCM Roden, DM Benjamin, EJ Ellinor, PT AF Kaab, Stefan Darbar, Dawood van Noord, Charlotte Dupuis, Josee Pfeufer, Arne Newton-Cheh, Christopher Schnabel, Renate Makino, Seiko Sinner, Moritz F. Kannankeril, Prince J. Beckmann, Britt M. Choudry, Subbarao Donahue, Brian S. Heeringa, Jan Perz, Siegfried Lunetta, Kathryn L. Larson, Martin G. Levy, Daniel MacRae, Calum A. Ruskin, Jeremy N. Wacker, Annette Schoemig, Albert Wichmann, H.-Erich Steinbeck, Gerhard Meitinger, Thomas Uitterlinden, Andre G. Witteman, Jacqueline C. M. Roden, Dan M. Benjamin, Emelia J. Ellinor, Patrick T. TI Large scale replication and meta-analysis of variants on chromosome 4q25 associated with atrial fibrillation SO EUROPEAN HEART JOURNAL LA English DT Article DE Atrial fibrillation; Genetics; Arrhythmia; Polymorphism; Meta-analysis ID OF-FUNCTION MUTATION; FAMILIAL AGGREGATION; RISK-FACTORS; POPULATION; HEART; PREVALENCE; PITX2; LOCUS; IDENTIFICATION; POLYMORPHISM AB A recent genome-wide association study identified a haplotype block on chromosome 4q25 associated with atrial fibrillation (AF). We sought to replicate this association in four independent cohorts. The Framingham Heart Study and Rotterdam Study are community-based longitudinal studies. The Vanderbilt AF Registry and German AF Network (AFNet) are case-control studies. Participants with AF (n = 3508) were more likely to be male and were older than referent participants (n = 12 173; Framingham 82 +/- 10 vs. 71 +/- 13 years; Rotterdam 73 +/- 8 vs. 69 +/- 9 years; Vanderbilt 54 +/- 14 vs. 57 +/- 14 years; AFNet 62 +/- 12 vs. 49 +/- 14 years). Single nucleotide polymorphism (SNP) rs2200733 was associated with AF in all four cohorts, with odds ratios (ORs) ranging from 1.37 in Rotterdam [95% confidence interval (CI) 1.18-1.59; P = 3.1 x 10(-5)] to 2.52 in AFNet (95% CI 2.22-2.8; P = 1.8 x 10(-49)). There also was a significant association between AF and rs10033464 in Framingham (OR 1.34; 95% CI 1.03-1.75; P = 0.031) and AFNet (OR 1.30; 95% CI 1.13-1.51; P = 0.0002), but not Vanderbilt (OR 1.16; 95% CI 0.86-1.56; P = 0.33). A meta-analysis of the current and prior AF studies revealed an OR of 1.90 (95% CI 1.60-2.26; P = 3.3 x 10(-13)) for rs2200733 and of 1.36 (95% CI 1.26-1.47; P = 6.7 x 10(-15)) for rs10033464. The non-coding SNPs rs2200733 and rs10033464 are strongly associated with AF in four cohorts of European descent. These results confirm the significant relations between AF and intergenic variants on chromosome 4. C1 [Makino, Seiko; Choudry, Subbarao; MacRae, Calum A.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kaab, Stefan; Sinner, Moritz F.; Beckmann, Britt M.; Steinbeck, Gerhard] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Darbar, Dawood] Vanderbilt Univ, Sch Med, Div Cardiol, Nashville, TN 37232 USA. [van Noord, Charlotte; Heeringa, Jan] Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [van Noord, Charlotte] Dutch Med Evaluat Board, The Hague, Netherlands. [Dupuis, Josee; Lunetta, Kathryn L.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee; Newton-Cheh, Christopher; Schnabel, Renate; Lunetta, Kathryn L.; Larson, Martin G.; Levy, Daniel; Benjamin, Emelia J.] Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA USA. [Pfeufer, Arne; Meitinger, Thomas] Tech Univ Munich, Inst Human Genet, Klinikum Rechts Isar, D-81675 Munich, Germany. [Pfeufer, Arne; Meitinger, Thomas] Helmholtz Zentrum Munchen Deutsch Forschungszentr, D-85764 Neuherberg, Germany. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Broad Inst Harvard & MIT, Program Med & Populat Genet, Boston, MA USA. [Donahue, Brian S.] Vanderbilt Univ, Sch Med, Dept Anesthesiol, Nashville, TN 37212 USA. [Perz, Siegfried] Helmholtz Zentrum Munchen Deutsch Forschungszentr, Inst Med Informat, D-85764 Neuherberg, Germany. [Larson, Martin G.] Boston Univ, Dept Math Stat, Boston, MA 02215 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Ruskin, Jeremy N.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA. [Wacker, Annette] Univ Klin Kinder & Jugendmed, Tubingen, Germany. [Schoemig, Albert] Tech Univ Munich, Kardiol Klin, Deutsches Herzzentrum Munchen, D-80636 Munich, Germany. [Wichmann, H.-Erich] Univ Munich, IBE Chair Epidemiol, Munich, Germany. [Wichmann, H.-Erich] Helmholtz Ctr Munich, Inst Epidemiol, Munich, Germany. [Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med & Epidemiol, Rotterdam, Netherlands. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, Emelia J.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Evans Dept Med,Cardiol & Prevent Med Div, Boston, MA 02118 USA. RP Ellinor, PT (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. EM pellinor@partners.org RI Kaab, Stefan/H-3915-2012; Pfeufer, Arne/B-6634-2013; Schnabel, Renate/F-6527-2014; Darbar, Dawood/C-9079-2015; Meitinger, Thomas/O-1318-2015; OI Darbar, Dawood/0000-0002-4103-5977; Lunetta, Kathryn/0000-0002-9268-810X; Larson, Martin/0000-0002-9631-1254; Dupuis, Josee/0000-0003-2871-3603; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K23 HL075266, HL 075266, HL 076784, N01 HC 25195, R01 HL075431, R01 HL104156, U01 HL 65962, U01 HL065962, U01 HL065962-08]; NIA NIH HHS [AG 028321]; NINDS NIH HHS [6R01 NS 17950] NR 46 TC 103 Z9 106 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD APR PY 2009 VL 30 IS 7 BP 813 EP 819 DI 10.1093/eurheartj/ehn578 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 428ZC UT WOS:000264889600016 PM 19141561 ER PT J AU Mahabadi, AA Massaro, JM Rosito, GA Levy, D Murabito, JM Wolf, PA O'Donnell, CJ Fox, CS Hoffmann, U AF Mahabadi, Amir A. Massaro, Joseph M. Rosito, Guido A. Levy, Daniel Murabito, Joanne M. Wolf, Philip A. O'Donnell, Christopher J. Fox, Caroline S. Hoffmann, Udo TI Association of pericardial fat, intrathoracic fat, and visceral abdominal fat with cardiovascular disease burden: the Framingham Heart Study SO EUROPEAN HEART JOURNAL LA English DT Article DE Pericardial fat; Visceral abdominal fat; Cardiovascular disease; Framingham Heart Study; Epidemiology ID EPICARDIAL ADIPOSE-TISSUE; CORONARY-ARTERY-DISEASE; C-REACTIVE PROTEIN; METABOLIC SYNDROME; RISK-FACTORS; INSULIN-RESISTANCE; PLASMA-PROTEIN; OBESITY; ADIPONECTIN; CELL AB The aim of this study was to assess whether pericardial fat, intrathoracic fat, and visceral abdominal adipose tissue (VAT) are associated with the prevalence of cardiovascular disease (CVD). Participants from the Framingham Heart Study Offspring cohort underwent abdominal and chest multidetector computed tomography to quantify volumes of pericardial fat, intrathoracic fat, and VAT. Relations between each fat depot and CVD were assessed using logistic regression. The analysis of 1267 participants (mean age 60 years, 53.8% women, 9.7% with prevalent CVD) demonstrated that pericardial fat [odds ratio (OR) 1.32, 95% confidence interval (CI) 1.11-1.57; P = 0.002] and VAT (OR 1.35, 95% CI 1.11-1.57; P = 0.003), but not intrathoracic fat (OR 1.14, 95% CI 0.93-1.39; P = 0.22), were significantly associated with prevalent CVD in age-sex-adjusted models and after adjustment for body mass index and waist circumference. After multivariable adjustment, associations were attenuated (P > 0.14). Only pericardial fat was associated with prevalent myocardial infarction after adjusting for conventional measures of adiposity (OR 1.37, 95% CI 1.03-1.82; P = 0.03). Pericardial fat and VAT, but not intrathoracic fat, are associated with CVD independent of traditional measures of obesity but not after further adjustment for traditional risk factor. Taken together with our prior work, these findings may support the hypothesis that pericardial fat contributes to coronary atherosclerosis. C1 [Mahabadi, Amir A.; Rosito, Guido A.; Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Cardiac MR PET CT Program, Boston, MA 02114 USA. [Massaro, Joseph M.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Murabito, Joanne M.; Wolf, Philip A.] Boston Univ, Dept Med, Boston, MA 02215 USA. [Murabito, Joanne M.; Wolf, Philip A.] Boston Univ, Dept Neurol, Boston, MA 02215 USA. [Massaro, Joseph M.; Levy, Daniel; Murabito, Joanne M.; Wolf, Philip A.; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Rosito, Guido A.] Fed Fdn Sch Med Sci Porto Alegre, Porto Alegre, RS, Brazil. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02114 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. RP Hoffmann, U (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,Cardiac MR PET CT Program, 165 Charles River Plaza,Suite 400, Boston, MA 02114 USA. EM uhoffmann@partners.org OI Massaro, Joseph/0000-0002-2682-4812; Murabito, Joanne/0000-0002-0192-7516 NR 36 TC 226 Z9 246 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD APR PY 2009 VL 30 IS 7 BP 850 EP 856 DI 10.1093/eurheartj/ehn573 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 428ZC UT WOS:000264889600021 PM 19136488 ER PT J AU Hold, GL Rabkin, CS Gammon, MD Berry, SH Smith, MG Lissowska, J Risch, HA Chow, WH Mowat, NAG Vaughan, TL El-Omar, EM AF Hold, Georgina L. Rabkin, Charles S. Gammon, Marilie D. Berry, Susan H. Smith, Malcolm G. Lissowska, Jolanta Risch, Harvey A. Chow, Wong-Ho Mowat, N. Ashley G. Vaughan, Thomas L. El-Omar, Emad M. TI CD14-159C/T and TLR9-1237T/C polymorphisms are not associated with gastric cancer risk in Caucasian populations SO EUROPEAN JOURNAL OF CANCER PREVENTION LA English DT Article DE gastric cancer; Helicobacter pylori-induced disease; innate immunity; polymorphisms; Toll-like receptor signaling pathways ID BACTERIAL-DNA; CD14 GENE; TLR9; TOLL-LIKE-RECEPTOR-4; EXPRESSION; CARCINOMA; PROMOTER; ALCOHOL; DISEASE AB Host genetic factors play an important role in modifying the risk of human disease, including cancers of the upper gastrointestinal tract, with increasing interest in Toll-like receptor (TLR) signaling and the impact of genetic polymorphisms in these systems. The CD14-159C/T and the TLR9-1237T/C promoter polymorphisms have previously been shown to be associated with various inflammatory conditions including Helicobacter pylori-induced gastritis in Caucasian populations. In this study, we assessed the association of these two functional single nucleotide polymorphisms with gastric cancer in two independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer, initially in 312 noncardia gastric carcinoma cases and 419 controls and then in 184 noncardia gastric carcinomas, 123 cardia carcinomas, 159 esophageal cancers, and 211 frequency-matched controls. Odds ratios were computed from logistic models and adjusted for potential confounding factors. No significant association was found between the CD14-159C/T and the TLR9-1237T/C promoter polymorphisms and increased risk of gastric cancer, Neither single nucleotide polymorphism has been assessed in a Caucasian gastric cancer case-control study before; although the CD14-159C/T polymorphism has been reported to show no apparent association with H. pylori-related gastric malignancy in a Taiwanese Chinese population. In conclusion, although our earlier preliminary studies suggested that the CD14-159C/T and the TLR9-1237T/C promoter polymorphisms increase the risk of precancerous outcomes, they do not seem to increase the risk of gastric cancer itself. This discrepancy merits further examination. European Journal of Cancer Prevention 18:117-119 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [El-Omar, Emad M.] Univ Aberdeen, Inst Med Sci, Dept Med & Therapeut, Aberdeen AB25 2ZD, Scotland. [Rabkin, Charles S.; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gammon, Marilie D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Lissowska, Jolanta] Ctr Canc, Div Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] M Sklodowska Curie Inst Oncol, Warsaw, Poland. [Risch, Harvey A.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Seattle, WA 98104 USA. [Vaughan, Thomas L.] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. RP El-Omar, EM (reprint author), Univ Aberdeen, Inst Med Sci, Dept Med & Therapeut, Aberdeen AB25 2ZD, Scotland. EM e.el-omar@abdn.ac.uk OI Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural NIH HHS [Z01 CP010150-08]; NCI NIH HHS [U01 CA057949, K05 CA124911, U01 CA057949-03] NR 19 TC 34 Z9 39 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-8278 J9 EUR J CANCER PREV JI Eur. J. Cancer Prev. PD APR PY 2009 VL 18 IS 2 BP 117 EP 119 DI 10.1097/CEJ.0b013e3283101292 PG 3 WC Oncology SC Oncology GA 414WQ UT WOS:000263896300004 PM 19337058 ER PT J AU Shea, MK Benjamin, EJ Dupuis, J Massaro, JM Jacques, PF D'Agostino, RB Ordovas, JM O'Donnell, CJ Dawson-Hughes, B Vasan, RS Booth, SL AF Shea, M. K. Benjamin, E. J. Dupuis, J. Massaro, J. M. Jacques, P. F. D'Agostino, R. B., Sr. Ordovas, J. M. O'Donnell, C. J. Dawson-Hughes, B. Vasan, R. S. Booth, S. L. TI Genetic and non-genetic correlates of vitamins K and D SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE vitamin K; phylloquinone; undercarboxylated osteocalcin; vitamin D; heritability; genetics ID FOOD FREQUENCY QUESTIONNAIRE; UNDERCARBOXYLATED OSTEOCALCIN; SERUM 25-HYDROXYVITAMIN-D; BIOCHEMICAL MEASURES; LINKAGE ANALYSIS; HEART-DISEASE; PLASMA; POPULATION; WOMEN; MEN AB Objective: To assess the genetic and nongenetic correlates of circulating measures of vitamins K and D status in a community-based sample of men and women. Subjects/Methods: A cross-sectional study of 1762 participants of the Framingham Offspring Study (919 women; mean age 59 years). Vitamin K status was measured as plasma phylloquinone and serum percent undercarboxylated osteocalcin (ucOC), and vitamin D was measured using plasma 25-hydroxyvitamin D (25(OH)D). Associations between vitamin K status and vitamin D status with biologically plausible nongenetic factors were assessed using stepwise regression. Heritability and linkage were determined using Sequential Oligogenic Linkage Analysis Routines (SOLAR). Results: Nongenetic factors accounted for 20.1 and 12.3% of the variability in plasma phylloquinone in men and women respectively, with triglycerides and phylloquinone intake being the primary correlates. In men 12.2% and in women 14.6% of the variability in %ucOC was explained by nongenetic factors in our models. Heritability estimates for these vitamin K status biomarkers were nonsignificant. Season, vitamin D intake, high-density lipoprotein (HDL) cholesterol and waist circumference explained 24.7% (men) and 24.2% (women) of the variability in plasma 25(OH)D. Of the three vitamins examined, only 25(OH)D was significantly heritable (heritability estimate 28.8%, P < 0.01), but linkage analysis of 25(OH)D did not achieve genome- wide significance. Conclusions: Variability in biomarkers of vitamin K status was attributed to nongenetic factors, whereas plasma 25(OH)D was found to be significantly heritable. Further studies are warranted to investigate genetic loci influencing vitamin D status. C1 [Shea, M. K.; Jacques, P. F.; Ordovas, J. M.; Dawson-Hughes, B.; Booth, S. L.] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Benjamin, E. J.; Massaro, J. M.; D'Agostino, R. B., Sr.; O'Donnell, C. J.; Vasan, R. S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Benjamin, E. J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Benjamin, E. J.; Vasan, R. S.] Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Dept Med, Boston, MA 02118 USA. [Dupuis, J.; Massaro, J. M.; D'Agostino, R. B., Sr.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. RP Booth, SL (reprint author), Tufts Univ, USDA, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM sarah.booth@tufts.edu OI Massaro, Joseph/0000-0002-2682-4812; Ramachandran, Vasan/0000-0001-7357-5970; Dupuis, Josee/0000-0003-2871-3603; Benjamin, Emelia/0000-0003-4076-2336; Ordovas, Jose/0000-0002-7581-5680 FU US Department of Agriculture; Agricultural Research Service [58-1950-001, 58-1950-4-401]; National Institute of Aging [AG14759, AG028321]; American Heart Association [0515605T]; National Heart, Lung and Blood Institute [HL58090, HL076784, 2K24HL04334, T32HL69772-01A1, N01-HC-38038, HC-25195] FX We thank the Framingham Study participants and staff. We also thank James Peterson for his technical contribution. This study was based upon work supported by federal funds from the US Department of Agriculture, Agricultural Research Service under Cooperative Agreement Nos. 58-1950-001 and 58-1950-4-401, National Institute of Aging (AG14759, AG028321), American Heart Association (0515605T) and by the National Heart, Lung and Blood Institute (HL58090, HL076784, 2K24HL04334, T32HL69772-01A1), including the Framingham Heart Study (N01-HC-38038, HC-25195). Any opinions, findings, conclusions or recommendations expressed in this publication are those of the authors, and do not necessarily reflect the view of the US Department of Agriculture. NR 36 TC 96 Z9 98 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD APR PY 2009 VL 63 IS 4 BP 458 EP 464 DI 10.1038/sj.ejcn.1602959 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 427QK UT WOS:000264793600002 PM 18030310 ER PT J AU Little, JA Hauser, KP Martyr, SE Harris, A Maric, I Morris, CR Suh, JH Taylor, J Castro, O Machado, R Kato, G Gladwin, MT AF Little, Jane A. Hauser, Kristine Partovi Martyr, Sabrina E. Harris, Amy Maric, Irina Morris, Claudia R. Suh, Jung H. Taylor, James Castro, Oswaldo Machado, Roberto Kato, Gregory Gladwin, Mark T. TI Hematologic, biochemical, and cardiopulmonary effects of l-arginine supplementation or phosphodiesterase 5 inhibition in patients with sickle cell disease who are on hydroxyurea therapy SO EUROPEAN JOURNAL OF HAEMATOLOGY LA English DT Article DE sickle cell anemia; l-arginine; phosphodiesterase inhibitor ID FETAL-HEMOGLOBIN LEVELS; GLOBIN GENE-EXPRESSION; PULMONARY-HYPERTENSION; NITRIC-OXIDE; ANEMIA; METABOLISM; PRIAPISM; PATHWAY; CYCLASE AB Fetal hemoglobin (HbF) induction involves NO-cGMP signaling pathways. l-arginine, an NO precursor, and the phosphodiesterase (PDE) 5 inhibitor sildenafil, which potentiates cGMP, were studied in adults with sickle cell disease (SCD) who were stably on HU. Twenty four courses of l-arginine (0.1-0.2 g/kg divided TID) or sildenafil (25-100 mg TID), assigned based on gender due to concerns about sildenafil-related priapism, were successfully completed. Biochemical assays, pulmonary pressures, and cardiopulmonary exercise capacity are reported from patients in whom serial values are available. Hematologic responses are reported in 14 subjects with HbSS who had stable baseline HbF levels. l-arginine increased plasma arginine and ornithine, but not citrulline, suggesting diversion by plasma arginase from NO, and citrulline, generation. Glutathione increased only in patients on l-arginine. Sildenafil increased plasma cGMP and citrulline, but not other amino acids. Pulmonary pressures and 6-min walk distances improved only in patients on sildenafil. In subjects with stable baseline HbF levels, HbF levels changed little from a normalized baseline on l-arginine, decreasing by 2.9 +/- 16.1%, n = 6; P = n.s., but increased on sildenafil, by 7.5 +/- 11.7%, n = 8, P < 0.05. Absolute reticulocyte counts initially decreased in patients on sildenafil. l-arginine, at doses that increase plasma arginine levels, altered redox potential in red cells. The lack of clinically detectable efficacy of l-arginine may be due to increased arginine metabolism in SCD patients. In vivo augmentation of the cyclic nucleotide pathway by PDE inhibition may induce HbF slightly, but strikingly improves hemodynamic and functional status in SCD. C1 [Little, Jane A.; Martyr, Sabrina E.; Taylor, James; Castro, Oswaldo; Machado, Roberto; Kato, Gregory; Gladwin, Mark T.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Little, Jane A.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Hauser, Kristine Partovi; Harris, Amy; Taylor, James; Machado, Roberto; Kato, Gregory; Gladwin, Mark T.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Maric, Irina] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Morris, Claudia R.] Childrens Hosp & Res Ctr Oakland, Dept Emergency Med, Oakland, CA USA. [Castro, Oswaldo] Howard Univ, Coll Med, Ctr Sickle Cell Dis, Washington, DC USA. [Suh, Jung H.] Childrens Hosp Oakland Res Inst, Oakland, CA USA. RP Little, JA (reprint author), NHLBI, Pulm & Vasc Med Branch, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 5-5140, Bethesda, MD 20892 USA. EM janelittle@mail.nih.gov RI Kato, Gregory/I-7615-2014; OI Kato, Gregory/0000-0003-4465-3217; Taylor, James/0000-0002-4421-1809 FU NIH; Critical Care Medicine Department; National Heart, Lung and Blood Institute FX This research was supported by the Intramural Research Program of the NIH, Critical Care Medicine Department and The National Heart, Lung and Blood Institute. We acknowledge, with much gratitude, the patients who participated in this study. The contributions made by the clinical team and staff of the Sickle Cell Disease clinic at the National Institutes of Health were invaluable, and this study would not have been possible without their able assistance. NR 32 TC 27 Z9 27 U1 1 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0902-4441 J9 EUR J HAEMATOL JI Eur. J. Haematol. PD APR PY 2009 VL 82 IS 4 BP 315 EP 321 DI 10.1111/j.1600-0609.2009.01210.x PG 7 WC Hematology SC Hematology GA 410TE UT WOS:000263600400010 PM 19215288 ER PT J AU Wong, J Webster, MJ Cassano, H Weickert, CS AF Wong, Jenny Webster, Maree J. Cassano, Hope Weickert, Cynthia S. TI Changes in alternative brain-derived neurotrophic factor transcript expression in the developing human prefrontal cortex SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE brain-derived neurotrophic factor; developmental gene expression; dorsolateral prefrontal cortex; neurotrophin; postmortem; trkB ID FACTOR MESSENGER-RNA; HUMAN CEREBRAL-CORTEX; NERVE GROWTH-FACTOR; ADULT-MOUSE BRAIN; RAT BDNF-GENE; DEVELOPMENTAL EXPRESSION; MULTIPLE PROMOTERS; SPLICE VARIANTS; VISUAL-CORTEX; LIFE-SPAN AB In this study, we determined when and through which promoter brain-derived neurotrophic factor (BDNF) transcription is regulated during the protracted period of human frontal cortex development. Using quantitative real-time polymerase chain reaction, we examined the expression of the four most abundant alternative 5' exons of the BDNF gene (exons I, II, IV, and VI) in RNA extracted from the prefrontal cortex. We found that expression of transcripts I-IX and VI-IX was highest during infancy, whereas that of transcript II-IX was lowest just after birth, slowly increasing to reach a peak in toddlers. Transcript IV-IX was significantly upregulated within the first year of life, and was maintained at this level until school age. Quantification of BDNF protein revealed that levels followed a similar developmental pattern as transcript IV-IX. In situ hybridization of mRNA in cortical sections showed the highest expression in layers V and VI for all four BDNF transcripts, whereas moderate expression was observed in layers II and III. Interestingly, although low expression of BDNF was observed in cortical layer IV, this BDNF mRNA low-zone decreased in prominence with age and showed an increase in neuronal mRNA localization. In summary, our findings show that dynamic regulation of BDNF expression occurs through differential use of alternative promoters during the development of the human prefrontal cortex, particularly in the younger age groups, when the prefrontal cortex is more plastic. C1 [Weickert, Cynthia S.] Univ New S Wales, Prince Wales Med Res Inst, Dept Psychiat, Randwick, NSW 2031, Australia. [Wong, Jenny; Weickert, Cynthia S.] Schizophrenia Res Inst, Sydney, NSW, Australia. [Wong, Jenny; Weickert, Cynthia S.] Univ New S Wales, Prince Wales Med Res Inst, Schizophrenia Res Lab, Randwick, NSW 2031, Australia. [Webster, Maree J.] Stanley Med Res Inst, Rockville, MD USA. [Cassano, Hope; Weickert, Cynthia S.] NIMH, MiNDS Unit, Clin Brain Disorders Branch, IRP,NIH, Bethesda, MD USA. RP Weickert, CS (reprint author), Univ New S Wales, Prince Wales Med Res Inst, Dept Psychiat, Corner Barker & Easy St, Randwick, NSW 2031, Australia. EM c.weickert@powmri.edu.au RI Shannon Weickert, Cynthia/G-3171-2011 NR 47 TC 37 Z9 38 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD APR PY 2009 VL 29 IS 7 BP 1311 EP 1322 DI 10.1111/j.1460-9568.2009.06669.x PG 12 WC Neurosciences SC Neurosciences & Neurology GA 426UE UT WOS:000264732600001 PM 19519623 ER PT J AU Beck, S Shamim, EA Richardson, SP Schubert, M Hallett, M AF Beck, S. Shamim, E. A. Richardson, S. Pirio Schubert, M. Hallett, M. TI Inter-hemispheric inhibition is impaired in mirror dystonia SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE focal hand dystonia; human; inhibition; motor cortex; TMS ID FOCAL HAND DYSTONIA; HUMAN MOTOR CORTEX; INTERHEMISPHERIC INHIBITION; INTRACORTICAL INHIBITION; SURROUND INHIBITION; WRITERS CRAMP; MOVEMENTS; PATHOPHYSIOLOGY; EXCITABILITY; STIMULATION AB Surround inhibition, a neural mechanism relevant for skilled motor behavior, has been shown to be deficient in the affected primary motor cortex (M1) in patients with focal hand dystonia (FHD). Even in unilateral FHD, however, electrophysiological and neuroimaging studies have provided evidence for bilateral M1 abnormalities. Clinically, the presence of mirror dystonia, dystonic posturing when the opposite hand is moved, also suggests abnormal interhemispheric interaction. To assess whether a loss of inter-hemispheric inhibition (IHI) may contribute to the reduced surround inhibition, IHI towards the affected or dominant M1 was examined in 13 patients with FHD (seven patients with and six patients without mirror dystonia, all affected on the right hand) and 12 right-handed, age-matched healthy controls (CON group). IHI was tested at rest and during three different phases of a right index finger movement in a synergistic, as well as in a neighboring, relaxed muscle. There was a trend for a selective loss of IHI between the homologous surrounding muscles in the phase 50 ms before electromyogram onset in patients with FHD. Post hoc analysis revealed that this effect was due to a loss of IHI in the patients with FHD with mirror dystonia, while patients without mirror dystonia did not show any difference in IHI modulation compared with healthy controls. We conclude that mirror dystonia may be due to impaired IHI towards neighboring muscles before movement onset. However, IHI does not seem to play a major role in the general pathophysiology of FHD. C1 [Beck, S.; Shamim, E. A.; Richardson, S. Pirio; Hallett, M.] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Beck, S.] Univ Freiburg, Dept Clin Neurol & Neurophysiol, Freiburg, Germany. [Shamim, E. A.] Georgetown Univ Hosp, Dept Neurol, Washington, DC 20007 USA. [Richardson, S. Pirio] Univ New Mexico, Dept Neurol, Albuquerque, NM 87131 USA. [Schubert, M.] Univ Hosp Balgrist, Spinal Cord Injury Ctr, Zurich, Switzerland. RP Beck, S (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM becksa@ninds.nih.gov FU Deutsche Forschungsgemeinschaft (DFG) [BE-3792/1]; Intramural Research Program of the NINDS, NIH FX We thank D. Schoenberg for skilful editing. This work was supported by the Deutsche Forschungsgemeinschaft (DFG; BE-3792/1) and by the Intramural Research Program of the NINDS, NIH. NR 40 TC 23 Z9 23 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD APR PY 2009 VL 29 IS 8 BP 1634 EP 1640 DI 10.1111/j.1460-9568.2009.06710.x PG 7 WC Neurosciences SC Neurosciences & Neurology GA 433EG UT WOS:000265186500010 PM 19419426 ER PT J AU Yang, M Clarke, AM Crawley, JN AF Yang, Mu Clarke, Andrew M. Crawley, Jacqueline N. TI Postnatal lesion evidence against a primary role for the corpus callosum in mouse sociability SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE autism; agenesis of the corpus callosum; BTBR T plus tf; J mice; mouse models of autism; repetitive self-grooming; social interactions ID AUTISM SPECTRUM DISORDERS; SOCIAL APPROACH BEHAVIORS; ANXIETY-RELATED BEHAVIORS; HIGH-FUNCTIONING AUTISM; BTBR-T+TF/J MICE; WHITE-MATTER; INBRED STRAINS; SYNAPTIC-TRANSMISSION; MATERNAL-CARE; KNOCKOUT MICE AB The BTBR T+tf/J (BTBR) strain is an inbred strain of mice that displays prominent social deficits and repetitive behaviors analogous to the defining symptoms of autism, along with complete congenital agenesis of the corpus callosum (CC). The BTBR strain is genetically distant from the widely used C57BL/6J (B6) strain, which exhibits high levels of sociability, a low level of repetitive behaviors, and an intact CC. Emerging evidence implicates compromised interhemispherical connectivity in some cases of autism. We investigated the hypothesis that the disconnection of CC fiber tracts contributes to behavioral traits in mice that are relevant to the behavioral symptoms of autism. Surgical lesion of the CC in B6 mice at postnatal day 7 had no effect on juvenile play and adult social approaches, and did not elevate repetitive self-grooming. In addition, LP/J, the strain that is genetically closest to the BTBR strain but has an intact CC, displayed juvenile play deficits and repetitive self-grooming similar to those seen in BTBR mice. These corroborative results offer evidence against the hypothesis that the CC disconnection is a primary cause of low sociability and a high level of repetitive behaviors in inbred mice. Our findings indicate that genes mediating other aspects of neurodevelopment, including those whose mutations underlie more subtle disruptions in white matter pathways and connectivity, are more likely to contribute to the aberrant behavioral phenotypes in the BTBR mouse model of autism. C1 [Yang, Mu; Clarke, Andrew M.; Crawley, Jacqueline N.] NIMH, Lab Behav Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. RP Yang, M (reprint author), NIMH, Lab Behav Neurosci, Intramural Res Program, NIH Bldg 35,Room 1C-909,Mail Code 3730, Bethesda, MD 20892 USA. EM yangmu@mail.nih.gov FU National Institute of Mental Health Intramural Research Program FX We thank Professor Douglas Wahlsten for his excellent suggestion to compare the LP/J and BTBR T+tf/J strains, Dr Petko Petkov for information on the LP/J genetic background, and Drs Elliorr Sherr, Lynn Paul and Ralph Adolphs for helpful discussion of the human acallosal syndrome. Mr Timothy Sullivan provided assistance with histological analysis. Ms Janet Stephens, NIH Medical Arts, contributed macrophotography expertise for Fig. 1. This work was supported by the National Institute of Mental Health Intramural Research Program. NR 96 TC 61 Z9 62 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD APR PY 2009 VL 29 IS 8 BP 1663 EP 1677 DI 10.1111/j.1460-9568.2009.06714.x PG 15 WC Neurosciences SC Neurosciences & Neurology GA 433EG UT WOS:000265186500013 PM 19419429 ER PT J AU Coffey, RM Levit, KR Kassed, CA McLellan, AT Chalk, M Brady, TM Vandivort-Warren, R AF Coffey, Rosanna M. Levit, Katharine R. Kassed, Cheryl A. McLellan, A. Thomas Chalk, Mady Brady, Thomas M. Vandivort-Warren, Rita TI Evidence for Substance Abuse Services and Policy Research A Systematic Review of National Databases SO EVALUATION REVIEW LA English DT Review DE substance addiction; data sets; substance use disorders; financing; treatment ID MENTAL-ILLNESS; USE DISORDERS; PREVALENCE AB We reviewed 39 national government- and nongovernment-sponsored data sets related to substance addiction policy. These data sets describe patients with substance use disorders (SUDs), treatment providers and the services they offer, and/or expenditures on treatment. Findings indicate the availability of reliable data on the prevalence of SUD and the characteristics of specialty treatment facilities, but meager data on financing and services. Gaps in information might be filled through agency collaboration to redesign, coordinate, and augment existing substance abuse and general health surveys. Despite noted gaps, these data sets represent an unusually rich set of resources for health services and policy research. C1 [Coffey, Rosanna M.; Levit, Katharine R.; Kassed, Cheryl A.] Healthcare Business Thomson Reuters, Washington, DC 20008 USA. [Brady, Thomas M.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Coffey, RM (reprint author), Healthcare Business Thomson Reuters, 4301 Connecticut Ave NW,Suite 330, Washington, DC 20008 USA. EM rosanna.coffey@thomsonreuters.com NR 22 TC 2 Z9 2 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0193-841X J9 EVALUATION REV JI Eval. Rev. PD APR PY 2009 VL 33 IS 2 BP 103 EP 137 DI 10.1177/0193841X08328126 PG 35 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA 415CU UT WOS:000263912700001 PM 19126788 ER PT J AU Oyugi, DA Luo, X Lee, KS Hill, B Izevbigie, EB AF Oyugi, Daniel A. Luo, Xuan Lee, Ken S. Hill, Brandon Izevbigie, Ernest B. TI Activity Markers of the Anti-Breast Carcinoma Cell Growth Fractions of Vernonia amygdalina Extracts SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE anti-cancer; Vernonia amygdalina; activity prediction; standardization ID ANTICANCER AGENTS; LEAVES; CHIMPANZEES; UGANDA; PLANTS; DRUGS; MICE AB Vernonia amygdalina (VA) is an edible plant of the Asteraceae family used in many herbal formulations prescribed by herbalists for many diseases. We have previously reported that aqueous VA extracts inhibit the growth of estrogen receptor-positive human breast cancerous cells in vitro. Activity markers of the VA extracts have not been previously identified or characterized. Hence, the objective of this study was to identify activity markers of the VA extracts associated with cell growth inhibition. Extraction of VA with multiple solvents of various polarity indexes yielded three fractions (A-1-2, B-1-3) that significantly inhibited cell growth (P < 0.05) at 0.1 mg/ml concentration. At a higher concentration of 1 mg/ml, six fractions of hexane, chloroform, butanol, and ethyl acetate (A-1-3, B-1-4) inhibited DNA synthesis by 76%, 98%, 94%, 98%, 98%, and 96%, respectively. These fractions were UV-detected from 250-730 nm; and all showed three distinct peaks around 410, 431, and 664 rim. Furthermore, HPLC analysis of the fractions revealed similar retention times of 2.213, 2.167, and 2.151 min, respectively. Bioactivity assays showed that HPLC retention of approximately 2 min is required for cell growth-inhibitory activity of VA fractions. Interestingly, all active fractions exhibited HPLC peaks at approximately 2 min. Therefore, the UV and HPLC peaks may be used as predictive tools to determine VA extracts activities. Exp Biol Med 234:410-417, 2009 C1 [Izevbigie, Ernest B.] Jackson State Univ, Lab Cellular Signaling Phytoceut & Canc Prevent &, Coll Sci Engn & Technol, Dept Biol, Jackson, MS 39217 USA. [Luo, Xuan; Lee, Ken S.] Jackson State Univ, Dept Chem, Jackson, MS 39217 USA. [Izevbigie, Ernest B.] Jackson State Univ, NIH Ctr Environm Hlth, Coll Sci Engn & Technol, Jackson, MS 39217 USA. RP Izevbigie, EB (reprint author), Jackson State Univ, Lab Cellular Signaling Phytoceut & Canc Prevent &, Coll Sci Engn & Technol, Dept Biol, Jackson, MS 39217 USA. EM ernest.b.izevbigie@jsums.edu FU NCRR NIH HHS [G122RR13459-07S1, G12 RR013459, G12 RR013459-115539]; NIMHD NIH HHS [P20 MD000534-010001, P20MD000534-01, P20 MD000534] NR 34 TC 7 Z9 8 U1 0 U2 4 PU SOC EXPERIMENTAL BIOLOGY MEDICINE PI MAYWOOD PA 195 WEST SPRING VALLEY AVE, MAYWOOD, NJ 07607-1727 USA SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD APR PY 2009 VL 234 IS 4 BP 410 EP 417 DI 10.3181/0811-RM-325 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 430DU UT WOS:000264969800007 PM 19176872 ER PT J AU Sarcon, AK Deslerto, MJ Zhou, WJ Visconte, V Gibellini, F Chen, JC Young, NS AF Sarcon, Annahita K. Deslerto, Marie J. Zhou, Wenjun Visconte, Valeria Gibellini, Federica Chen, Jichun Young, Neal S. TI Role of perforin-mediated cell apoptosis in murine models of infusion-induced bone marrow failure SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; FAMILIAL HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS; VERSUS-HOST-DISEASE; NEGATIVE T-CELLS; APLASTIC-ANEMIA; GRANZYME-B; TARGET-CELLS; FAS ANTIGEN; MOUSE MODEL; INTERFERON-GAMMA AB Objective. To investigate the role of perforin-mediated cell apoptosis in murine models of immune-mediated bone marrow (BM) failure. Materials and Methods. We compared C57BL/6J (B6) mice carrying a perforin gene deletion (Prf(-/-)) with wild-type (WT) controls for cellular composition in lymphohematopoietic tissues. Lymph node (LN) cells from Prf(-/-) mice were coincubated with BM cells from B10-H2(b)/LilMcdJ (C.B10) mice in an apoptosis assay in vitro. We then infused Prf(-/-) and WT B6 LN cells into sublethally irradiated C.B10 and CByB6F1 recipients with mismatches at the minor and major histocompatibility loci, respectively, in order to induce BM failure. Cellular composition was analyzed by How cytometry. Results. Prf(-/-) mice showed normal lymphoid cell composition, but Prf(-/-) LN cells had reduced ability to induce C.B10 BM cell apoptosis in vitro. Infusion of 5 to 10 x 10(6) Prf(-/-) LN cells produced obvious BM failure in C.B10 and CByB6F1 recipients; pancytopenia and BM hypocellularity were only slightly less severe than those caused by infusion of 5 x 10(6) WT B6 LN cells. Infused Prf(-/-) LN cells showed less T-cell expansion, normal T-cell activation, and higher proportions of T cells expressing gamma-interferon, tissue necrosis factor -alpha, and Fas ligand CD178, in comparison to infused WT B6 LN cells. Fas expression was equally high in residual BM cells in recipient of both Prf(-/-) and B6 LN cells. Conclusion. Perforin deficiency alters T-cell expansion but upregulates T-cell Fas ligand expression. Perforin-mediated cell death appears to play a minor role in mouse models of immune-mediated BM failure. (C) 2009 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. C1 [Sarcon, Annahita K.; Deslerto, Marie J.; Zhou, Wenjun; Visconte, Valeria; Gibellini, Federica; Chen, Jichun; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Chen, JC (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Clin Res Ctr Room 3E-5132,10 Ctr Dr, Bethesda, MD 20892 USA. EM chenji@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 49 TC 7 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD APR PY 2009 VL 37 IS 4 BP 477 EP 486 DI 10.1016/j.exphem.2008.12.001 PG 10 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 426VD UT WOS:000264735300007 PM 19216020 ER PT J AU Dowdell, KC Pesnicak, L Hoffmann, V Steadman, K Remaley, AT Cohen, JI Straus, SE Rao, VK AF Dowdell, Kennichi C. Pesnicak, Lesley Hoffmann, Victoria Steadman, Kenneth Remaley, Alan T. Cohen, Jeffrey I. Straus, Stephen E. Rao, V. Koneti TI Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, diminishes lymphoproliferation in the Fas-deficient MRL/lpr(-/-) murine model of autoimmune lymphoproliferative syndrome (ALPS) SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID CELL-CYCLE ARREST; LYMPHOCYTIC-LEUKEMIA CELLS; ENDOMETRIAL CANCER-CELLS; MRL-LPR/LPR MOUSE; GENE-EXPRESSION; RENAL-DISEASE; APOPTOSIS; MICE; DEATH; ACTIVATION AB Objective. Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of apoptosis, often presenting in childhood. Similarly, MRL/lpr(-/-) mice homozygous for Fas mutations develop an ALPS-like disease with autoimmunity, lymphadenopathy, splenomegaly, and expansion of double-negative T cells. Currently, there are no proven therapies with adequate safety margins for sustained abolition of the lymphoproliferation associated with ALPS. We sought to test the ability of valproic acid (VPA), a histone deacetylase inhibitor, to induce apoptosis and inhibit lymphoproliferation. Materials and Methods. Human peripheral blood mononuclear cells from patients with ALPS and normal controls were tested in vitro to determine the efficacy of VPA at inducing cell death. VPA was used in vivo to control lymphoproliferation in MRL/lpr(-/-) mice, a model for ALPS. Results. VPA induced cell death in vitro, and was partially inhibited by the pan caspase inhibitor, Z-VAD-FMK. MRL/lpr(-/-) mice treated with VPA for 8 weeks showed significant reductions in spleen and lymph node weights and cellularity compared to controls. A concomitant decrease in double-negative T cells was observed in the spleen, lymph nodes, and peripheral blood. Serum levels of VPA peaked I hour after injection, and a 2.5-fold increase in histone acetylation was observed in the spleen at 4 hours after injection. Conclusion. Based on our data, VPA is effective at reducing lymphoproliferation in mice, and is currently being studied in a clinical trial as a lympholytic agent in patients with ALPS. (C) 2009 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. C1 [Dowdell, Kennichi C.; Pesnicak, Lesley; Cohen, Jeffrey I.; Straus, Stephen E.; Rao, V. Koneti] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Hoffmann, Victoria] NIAID, Dept Vet Resources, NIH, Bethesda, MD 20892 USA. [Steadman, Kenneth] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Remaley, Alan T.] NIH, Ctr Clin, Dept Lab, Bethesda, MD 20892 USA. RP Dowdell, KC (reprint author), NIAID, Lab Clin Infect Dis, NIH, 10 Ctr Dr,Room 11N234, Bethesda, MD 20892 USA. EM kdowdell@niaid.nih.gov RI Steadman, Kenneth/J-3883-2013 FU National Institutes of Allergy and Infectious Diseases; National Institutes of Health, Bethesda, MD FX This research was supported by the Intramural Research Program of the National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD. NR 45 TC 23 Z9 23 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD APR PY 2009 VL 37 IS 4 BP 487 EP 494 DI 10.1016/j.exphem.2009.12.002 PG 8 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 426VD UT WOS:000264735300008 PM 19217201 ER PT J AU Jayasooriya, GS Lamont, RF AF Jayasooriya, G. S. Lamont, R. F. TI The use of progesterone and other progestational agents to prevent spontaneous preterm labour and preterm birth SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE birth; labour; prematurity; preterm; prevention; progestagens; progestational agents; progesterone; prophylactic; prophylaxis; tocolysis; tocolytics ID RANDOMIZED CONTROLLED-TRIALS; PLACEBO-CONTROLLED TRIAL; 17-ALPHA-HYDROXYPROGESTERONE CAPROATE; DOUBLE-BLIND; CYCLOOXYGENASE-2 EXPRESSION; THREATENED-ABORTION; PREMATURE LABOR; INCREASED RISK; META-ANALYSIS; DEJA-VU AB Background: Preterm birth is the major cause of perinatal mortality and morbidity in the developed world, making a huge impact on healthcare costs. There is accumulating evidence that the prophylactic use of progestagens is able to reduce significantly the incidence of low birth weight and preterm birth. Objectives: to emphasise the importance of preterm birth; to review the role of progesterone in inducing myometrial quiescence which prevent preterm labour and preterm birth; to review the published literature and planned future research on the use of progestagens for the prevention of preterm birth. Methods: A review of the published literature using accepted search engines. Results/conclusions: Progestagens have been demonstrated to reduce the incidence of low birth weight and preterm birth. Many questions remain unanswered, particularly the long-term safety concerns and also whether the use of progestagens results in improved neonatal and childhood outcomes. C1 [Jayasooriya, G. S.; Lamont, R. F.] Northwick Pk & St Marks NHS Trust, Dept Obstet & Gynaecol, Harrow HA1 3UJ, Middx, England. [Jayasooriya, G. S.; Lamont, R. F.] Northwick Pk & St Marks NHS Trust, Northwick Pk Inst Med Res, Harrow HA1 3UJ, Middx, England. [Jayasooriya, G. S.; Lamont, R. F.] UCL, London, England. [Jayasooriya, G. S.; Lamont, R. F.] Univ London Imperial Coll Sci Technol & Med, London, England. [Lamont, R. F.] Wayne State Univ, Perinatal Res Branch, Natl Inst Child Hlth & Dev, Detroit, MI 48201 USA. RP Lamont, RF (reprint author), Northwick Pk & St Marks NHS Trust, Dept Obstet & Gynaecol, Watford Rd, Harrow HA1 3UJ, Middx, England. EM pauline.mills@nwlh.nhs.uk NR 71 TC 7 Z9 7 U1 0 U2 1 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-6566 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD APR PY 2009 VL 10 IS 6 BP 1007 EP 1016 DI 10.1517/14656560902851403 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 447LC UT WOS:000266191600009 PM 19351272 ER PT J AU Pancrazio, JJ Peckham, PH AF Pancrazio, Joseph J. Peckham, P. Hunter TI Neuroprosthetic devices: how far are we from recovering movement in paralyzed patients? SO EXPERT REVIEW OF NEUROTHERAPEUTICS LA English DT Editorial Material C1 [Pancrazio, Joseph J.] NINDS, NIH, Bethesda, MD 20892 USA. [Peckham, P. Hunter] Case Western Reserve Univ, Dept Biomed Engn, Cleveland, OH 44106 USA. [Peckham, P. Hunter] Vet Affairs Med Ctr, Louis Stokes Cleveland Dept, Ctr Excellence Funct Elect Stimulat, Cleveland, OH USA. RP Pancrazio, JJ (reprint author), NINDS, NIH, NSC 2205,6001 Execut Blvd, Bethesda, MD 20892 USA. EM pancrazj@ninds.nih.gov; pxp2@po.cwru.edu RI Pancrazio, Joseph/M-3206-2015 OI Pancrazio, Joseph/0000-0001-8276-3690 FU FDA HHS [FD-R-002389]; Intramural NIH HHS [NIH0011642045]; NCRR NIH HHS [M01 RR000080, M01-RR00080]; NINDS NIH HHS [R01-NS-29549, R01 NS029549]; PHS HHS [NIH0011642045] NR 38 TC 11 Z9 11 U1 0 U2 0 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1473-7175 EI 1744-8360 J9 EXPERT REV NEUROTHER JI Expert Rev. Neurother. PD APR PY 2009 VL 9 IS 4 BP 427 EP 430 DI 10.1586/ERN.09.12 PG 4 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA V39ZP UT WOS:000209449200001 PM 19344294 ER PT J AU Zakrajsek, JS Shope, JT Ouimet, MC Wang, J Simons-Morton, BG AF Zakrajsek, Jennifer S. Shope, Jean T. Ouimet, Marie Claude Wang, Jing Simons-Morton, Bruce G. TI Efficacy of a Brief Group Parent-Teen Intervention in Driver Education to Reduce Teenage Driver Injury Risk A Pilot Study SO FAMILY & COMMUNITY HEALTH LA English DT Article DE driver education; driving restrictions; group intervention; parent management practices; teen driving risk ID YOUNG DRIVERS; PASSENGERS; RESTRICTIONS; LIMITS; RATES AB The purpose of this study was to test the efficacy of an adapted Checkpoints Program designed to increase parental limits on novice teen independent driving under high-risk conditions. Twenty-seven class sessions with a minimum of 5 dyads each were delivered in driver education to 231 parent-teen dyads. Entire driving school classes were randomized to Checkpoints Program or comparison group sessions, both led by a trained health educator. At licensure, compared with parents in the comparison group, treatment parents had increased awareness of teen driving risk and were more likely to have completed a parent-teen driving agreement and met Checkpoints recommendations for restrictions on teen driving in inclement weather and road types. They were also marginally more likely to have met Checkpoints restrictions on driving with teen passengers. This study indicates that it is feasible to implement the Checkpoints Program in driver education with positive effects on parent management practices. C1 [Zakrajsek, Jennifer S.; Shope, Jean T.] Univ Michigan, Transportat Res Inst, Ann Arbor, MI 48109 USA. [Ouimet, Marie Claude; Wang, Jing; Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Zakrajsek, JS (reprint author), Univ Michigan, Transportat Res Inst, 2901 Baxter Rd, Ann Arbor, MI 48109 USA. EM jzak@umich.edu OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [Z01 HD001707-09] NR 28 TC 15 Z9 15 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0160-6379 J9 FAM COMMUNITY HEALTH JI Fam. Community Health PD APR-JUN PY 2009 VL 32 IS 2 BP 175 EP 188 PG 14 WC Family Studies; Public, Environmental & Occupational Health SC Family Studies; Public, Environmental & Occupational Health GA 424TN UT WOS:000264591300012 PM 19305216 ER PT J AU Morand, S Ueyama, T Tsujibe, S Saito, N Korzeniowska, A Leto, TL AF Morand, Stanislas Ueyama, Takehiko Tsujibe, Satoshi Saito, Naoaki Korzeniowska, Agnieszka Leto, Thomas L. TI Duox maturation factors form cell surface complexes with Duox affecting the specificity of reactive oxygen species generation SO FASEB JOURNAL LA English DT Article DE Dual oxidase; NADPH oxidase; Nox; NIP ID HYDROGEN-PEROXIDE PRODUCTION; AIRWAY EPITHELIAL-CELLS; NADPH OXIDASE; CONGENITAL HYPOTHYROIDISM; DUAL OXIDASE; PLASMA-MEMBRANE; GENE; IDENTIFICATION; ACTIVATION; MUTATIONS AB Dual oxidases (Duox1 and Duox2) are plasma membrane-targeted hydrogen peroxide generators that support extracellular hemoperoxidases. Duox activator 2 (Duoxa2), initially described as an endoplasmic reticulum resident protein, functions as a maturation factor needed to deliver active Duox2 to the cell surface. However, less is known about the Duox1/Duoxa1 homologues. We identified four alternatively spliced Duoxa1 variants and explored their roles in Duox subcellular targeting and reconstitution. Duox1 and Duox2 are functionally rescued by Duoxa2 or the Duoxa1 variants that contain the third coding exon. All active maturation factors are cotransported to the cell surface when coexpressed with either Duox1 or Duox2, consistent with detection of endogenous Duoxa1 on apical plasma membranes of the airway epithelium. In contrast, the Duoxa proteins are retained in the endoplasmic reticulum when expressed without Duox. Duox1/Duoxa1 alpha and Duox2/Duoxa2 pairs produce the highest levels of hydrogen peroxide, as they undergo Golgi-based carbohydrate modifications and form stable cell surface complexes. Cross-functioning pairs that do not form stable complexes produce less hydrogen peroxide and leak superoxide. These findings suggest Duox activators not only promote Duox maturation, but they function as part of the hydrogen peroxide-generating enzyme.-Morand, S., Ueyama, T., Tsujibe, S., Saito, N., Korzeniowska, A., Leto, T. L. Duox maturation factors form cell surface complexes with Duox affecting the specificity of reactive oxygen species generation. FASEB J. 23, 1205-1218 (2009) C1 [Morand, Stanislas; Korzeniowska, Agnieszka; Leto, Thomas L.] NIAID, Host Def Lab, NIH, Rockville, MD 20852 USA. [Ueyama, Takehiko; Tsujibe, Satoshi; Saito, Naoaki] Kobe Univ, Biosignal Res Ctr, Mol Pharmacol Lab, Kobe, Hyogo 657, Japan. RP Leto, TL (reprint author), NIAID, Host Def Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM tleto@nih.gov FU U.S. National Institutes of Health Intramural Research Program, National Institute of Allergy and Infectious Diseases; KAKENHI on Priority Areas and on the GlobalCOE Program in Japan FX We are thankful to Dr. F. Borrego (NIAID/LIG) and Dr. J. Kabat (NIAID/RTB) for their technical assistance in flow cytometry and imaging experiments. This work was supported by the U.S. National Institutes of Health Intramural Research Program, National Institute of Allergy and Infectious Diseases, and KAKENHI on Priority Areas and on the GlobalCOE Program in Japan. NR 39 TC 81 Z9 82 U1 1 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 IS 4 BP 1205 EP 1218 DI 10.1096/fj.08-120006 PG 14 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 453ZO UT WOS:000266651600025 PM 19074510 ER PT J AU Chandler, RJ Zerfas, PM Shanske, S Sloan, J Hoffmann, V DiMauro, S Venditti, CP AF Chandler, Randy J. Zerfas, Patricia M. Shanske, Sara Sloan, Jennifer Hoffmann, Victoria DiMauro, Salvatore Venditti, Charles P. TI Mitochondrial dysfunction in mut methylmalonic acidemia SO FASEB JOURNAL LA English DT Article DE methylmalonyl-CoA mutase; cytochrome c oxidase; glutathione; oxidant stress; vitamin B12 ID LIVER-KIDNEY TRANSPLANTATION; RESPIRATORY-CHAIN; ORGANIC ACIDEMIAS; GLOBUS-PALLIDUS; KNOCKOUT MICE; INBORN ERROR; ACIDURIA; DEFICIENCY; METABOLISM; MANAGEMENT AB Methylmalonic acidemia is an autosomal recessive inborn error of metabolism caused by defective activity of methylmalonyl-CoA mutase (MUT) that exhibits multiorgan system pathology. To examine whether mitochondrial dysfunction is a feature of this organic acidemia, a background-modified Mut-knockout mouse model was constructed and used to examine mitochondrial ultrastructure and respiratory chain function in the tissues that manifest pathology in humans. In parallel, the liver from a patient with mut methylmalonic acidemia was studied in a similar fashion. Megamitochondria formed early in life in the hepatocytes of the Mut(-/-) animals and progressively enlarged. Liver extracts prepared from the mutants at multiple time points displayed respiratory chain dysfunction, with diminished cytochrome c oxidase activity and reduced intracellular glutathione compared to control littermates. Over time, the exocrine pancreas and proximal tubules of the kidney also exhibited megamitochondria, and older mutant mice eventually developed tubulointerstitial renal disease. The patient liver displayed similar morphological and enzymatic findings as observed in the murine tissues. These murine and human studies establish that megamitochondria formation with respiratory chain dysfunction occur in a tissue-specific fashion in methylmalonic acidemia and suggest treatment approaches based on improving mitochondrial function and ameliorating the effects of oxidative stress.-Chandler, R. J., Zerfas, P. M., Shanske, S., Sloan, J., Hoffmann, V., DiMauro, S., Venditti, C. P. Mitochondrial dysfunction in mut methylmalonic acidemia. FASEB J. 23, 1252-1261 (2009) C1 [Chandler, Randy J.; Sloan, Jennifer; Venditti, Charles P.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Zerfas, Patricia M.; Hoffmann, Victoria] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. [Shanske, Sara; DiMauro, Salvatore] Columbia Univ, Dept Neurol, Med Ctr, New York, NY USA. RP Venditti, CP (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bldg 49 Rm 4A62A, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov FU Intramural NIH HHS [Z99 HG999999, Z01 HG200318-04, Z01 HG200318-05]; NICHD NIH HHS [HD32062, P01 HD032062] NR 47 TC 68 Z9 69 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 IS 4 BP 1252 EP 1261 DI 10.1096/fj.08-121848 PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 453ZO UT WOS:000266651600029 PM 19088183 ER PT J AU Abdala, APL Rybak, IA Smith, JC Paton, JFR AF Abdala, Ana Paula Lima Rybak, Ilya A. Smith, Jeffrey C. Paton, Julian F. R. TI Hypercapnia engages parafacial respiratory group (pFRG) neuronal activity coincident with late expiratory motor outflow SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Abdala, Ana Paula Lima; Paton, Julian F. R.] Univ Bristol, Bristol Heart Inst, Bristol, Avon, England. [Rybak, Ilya A.] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. [Smith, Jeffrey C.] NINDS, Cellular & Syst Neurobiol Sect, Neural Control Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 621.13 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621503883 ER PT J AU Adelman, K Gilchrist, D Nechaev, S Dos Santos, G AF Adelman, Karen Gilchrist, Daniel Nechaev, Sergei Dos Santos, Gilberto TI Promoter-proximal pausing of Pol II enhances gene expression SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Adelman, Karen; Gilchrist, Daniel; Nechaev, Sergei; Dos Santos, Gilberto] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 316.2 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621501621 ER PT J AU Ahn, SH Shah, YM Gonzalez, FJ AF Ahn, Sung-Hoon Shah, Yatrik M. Gonzalez, Frank J. TI Hepatocyte Nuclear Factor 4alpha in the Intestinal Epithelial Cells Protects Against Inflammatory Bowel Disease SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Ahn, Sung-Hoon; Shah, Yatrik M.; Gonzalez, Frank J.] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621502674 ER PT J AU Andrews, K Roseland, J Zhao, CW Feinberg, M Middleton, A Holden, J Douglass, L Dwyer, J Picciano, MF Fisher, K Saldanha, L Yetley, E AF Andrews, Karen Roseland, Janet Zhao, Cuiwei Feinberg, Matthew Middleton, Angela Holden, Joanne Douglass, Larry Dwyer, Johanna Picciano, Mary Frances Fisher, Kenneth Saldanha, Leila Yetley, Elizabeth TI First release of the Dietary Supplement Ingredient Database: Nutrient estimates and methodology for 18 vitamins and minerals in adult multivitamin/minerals (MVMs) SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Andrews, Karen; Roseland, Janet; Zhao, Cuiwei; Feinberg, Matthew; Middleton, Angela; Holden, Joanne] ARS, USDA, BHNRC, NDL, Beltsville, MD USA. [Dwyer, Johanna; Picciano, Mary Frances; Fisher, Kenneth; Saldanha, Leila; Yetley, Elizabeth] NIH, DHHS, ODS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 341.4 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621502818 ER PT J AU Archer, TK AF Archer, Trevor Keith TI Nuclear receptor dependent chromatin remodeling SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Archer, Trevor Keith] NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 325.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621504672 ER PT J AU Awasthi, S Simons, SS AF Awasthi, Smita Simons, S. Stoney, Jr. TI Separate Regions of Glucocorticoid Receptor, Coactivator TIF2, and Comodulator STAMP Modify Different Parameters of GR-mediated Gene Induction SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Awasthi, Smita; Simons, S. Stoney, Jr.] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 880.2 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621501006 ER PT J AU Bagattin, A Hugendubler, L Mueller, E AF Bagattin, Alessia Hugendubler, Lynne Mueller, Elisabetta TI Identification of a novel PPAR alpha-interacting protein SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Bagattin, Alessia; Hugendubler, Lynne; Mueller, Elisabetta] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 680.3 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621501511 ER PT J AU Bailey, RL Wilger, J Dodd, K Dwyer, J McDowell, M Burt, V Radimer, K Sempos, C Picciano, MF AF Bailey, Regan Lucas Wilger, Jaime Dodd, Kevin Dwyer, Johanna McDowell, Margaret Burt, Vicki Radimer, Kathy Sempos, Chris Picciano, Mary Frances TI Dietary folate intakes in the United States: Data from the National Health and Nutrition Examination Survey (NHANES) 2001-2004 SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Bailey, Regan Lucas; Dwyer, Johanna; Sempos, Chris; Picciano, Mary Frances] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Wilger, Jaime; McDowell, Margaret; Burt, Vicki; Radimer, Kathy] Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Dodd, Kevin] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 341.8 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621504859 ER PT J AU Bailey, RL Stotts, JL Wall, DE Lohse, BA AF Bailey, Regan Lucas Stotts, Jodi L. Wall, Denise E. Lohse, Barbara A. TI Diet quality is related to eating competence in low-income females in Pennsylvania SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Bailey, Regan Lucas] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Stotts, Jodi L.; Wall, Denise E.; Lohse, Barbara A.] Penn State Univ, University Pk, PA 16802 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 550.7 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621501134 ER PT J AU Basu, NK Basu, M Mitra, PS Banerjee, R Owens, IS AF Basu, Nikhil K. Basu, Mousumi Mitra, Partha S. Banerjee, Rajat Owens, Ida S. TI Association of UDP-Glucuronosyltransferases with 14-3-3 Chaperone Protein and Kinase-dependent Signaling Partners SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Basu, Nikhil K.; Basu, Mousumi; Mitra, Partha S.; Banerjee, Rajat; Owens, Ida S.] NICHD, PDEGEN, SGDDM, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 709.6 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621503201 ER PT J AU Batkai, S Godlewski, G Liu, J Nikas, SP Makriyannis, A Cravatt, BF Pacher, P Kunos, G AF Batkai, Sandor Godlewski, Gregorz Liu, Jie Nikas, Spyros P. Makriyannis, Alexandros Cravatt, Benjamin F. Pacher, Pal Kunos, George TI ANTIHYPERTENSIVE EFFECT OF THE NOVEL FAAH INHIBITOR AM3506 SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Batkai, Sandor; Godlewski, Gregorz; Liu, Jie; Pacher, Pal; Kunos, George] NIAAA NIH, LPS, Bethesda, MD USA. [Nikas, Spyros P.; Makriyannis, Alexandros] Northeastern Univ, Ctr Drug Discovery, Boston, MA 02115 USA. [Cravatt, Benjamin F.] Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. RI Gladyshev, Vadim/A-9894-2013; Batkai, Sandor/H-7983-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 1019.25 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621506554 ER PT J AU Bhaumik, P Xiao, HG Parr, C Yada, R Gustchina, A Wlodawer, A AF Bhaumik, Prasenjit Xiao, Huogen Parr, Charity Yada, Rickey Gustchina, Alla Wlodawer, Alexander TI Crystal structure of histo-aspartic protease (HAP) from Plasmodium falciparum SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Bhaumik, Prasenjit; Gustchina, Alla; Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21701 USA. [Xiao, Huogen; Parr, Charity; Yada, Rickey] Univ Guelph, Dept Food Sci, Guelph, ON N1G 2W1, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 675.4 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621502385 ER PT J AU Blatch, S Harrison, JF AF Blatch, Sydella Harrison, Jon F. TI The Effects of Folic Acid on Endosymbionts, Growth & Metabolites of the Fruit Fly Drosophila melanogaster SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Blatch, Sydella] NICHHD, NIH, Bethesda, MD 20892 USA. [Harrison, Jon F.] Arizona State Univ, Tempe, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 598.5 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621502039 ER PT J AU Blatch, S Harrison, JF AF Blatch, Sydella Harrison, Jon F. TI The Effects of Folic Acid on Endosymbionts, Growth, and Metabolites of the Fruit Fly Drosophila melanogaster SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Blatch, Sydella] NICHHD, NIH, Bethesda, MD 20892 USA. [Harrison, Jon F.] Arizona State Univ, Sch Life Sci, Tempe, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621501806 ER PT J AU Blaylock, BL Gould, RW Newman, AH Nader, MA AF Blaylock, Brandi L. Gould, Robert W. Newman, Amy H. Nader, Michael A. TI Characterization of PG-619, a dopamine D3 receptor partial agonist, on cocaine self-administration and drug-elicited yawning in rhesus monkeys SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Blaylock, Brandi L.; Gould, Robert W.; Nader, Michael A.] Wake Forest Univ Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC USA. [Newman, Amy H.] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 588.4 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621500804 ER PT J AU Boukari, H Zerari, F AF Boukari, Hacene Zerari, Fatima TI Fluorescence Correlation Spectroscopy study of the diffusion of biomolecules in Ficoll solutions SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Boukari, Hacene] NIH, Bethesda, MD 20892 USA. [Zerari, Fatima] Univ Annaba, Annaba, Algeria. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 681.6 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621505417 ER PT J AU Bravo, IJ Ferraris, JD Williams, CK Burg, MB AF Bravo, Ignacio J. Ferraris, Joan D. Williams, Chester K. Burg, Maurice B. TI Role of miRNAs in post-transcriptional gene regulation by high NaCl SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Bravo, Ignacio J.; Ferraris, Joan D.; Williams, Chester K.; Burg, Maurice B.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 1001.2 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621503060 ER PT J AU Burgos, PV Mardones, GA daSilva, LLP Prabhu, Y Bonifacino, JS AF Burgos, Patricia V. Mardones, Gonzalo A. daSilva, Luis L. P. Prabhu, Yogikala Bonifacino, Juan S. TI The AP-4 Complex Mediates Sorting and Processing of the Alzheimer's Disease Amyloid Precursor Protein SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Burgos, Patricia V.; Mardones, Gonzalo A.; daSilva, Luis L. P.; Prabhu, Yogikala; Bonifacino, Juan S.] NICHD, Cell Biol & Metab Program, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 205.3 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621500327 ER PT J AU Call, RJ Ghirlando, R Bell, JK AF Call, R. Jason Ghirlando, Rodolfo Bell, Jessica K. TI Biochemical and structural characterization of innate immunity kinase complex proteins SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Call, R. Jason; Bell, Jessica K.] Virginia Commonwealth Univ, Richmond, VA USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RI Bell, Jessica/I-3893-2013 OI Bell, Jessica/0000-0003-1455-3274 NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 707.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621501472 ER PT J AU Canagarajah, BJ Hummer, G Hurley, JH AF Canagarajah, Bertram J. Hummer, Gerhard Hurley, James H. TI Dynamics of Cholesterol Exchange in the Oxysterol Binding Protein Family SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Canagarajah, Bertram J.; Hurley, James H.] NIDDK, LMB, NIH, Bethesda, MD USA. [Hummer, Gerhard] NIDDK, LCP, NIH, Bethesda, MD USA. RI Gladyshev, Vadim/A-9894-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 512.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621501225 ER PT J AU Carlson, BA Yoo, MH Kim, JY Shrimali, RK Irons, R Park, JM Hatfield, DL AF Carlson, Bradley A. Yoo, Min-Hyuk Kim, Jin Young Shrimali, Rajeev K. Irons, Robert Park, Jin Mo Hatfield, Dolph L. TI Knockout of the selenocysteine tRNA ([Ser]Sec) gene (Trsp) in mouse macrophages SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Carlson, Bradley A.; Yoo, Min-Hyuk; Shrimali, Rajeev K.; Irons, Robert; Hatfield, Dolph L.] NCI, MBSS, LCP, CCR,NIH, Bethesda, MD 20892 USA. [Kim, Jin Young] Seoul Natl Univ, Sch Biol Sci, Lab Mol Genet & Genom, Inst Mol Biol & Genet, Seoul, South Korea. [Park, Jin Mo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Charlestown, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 346.7 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621502483 ER PT J AU Carlson, BA Lee, BJ Hatfield, DL AF Carlson, Bradley A. Lee, Byeong Jae Hatfield, Dolph L. TI Ribosomal frameshifting in response to hypomodified tRNAs in Xenopus oocytes SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Carlson, Bradley A.; Hatfield, Dolph L.] NCI, MBSS, LCP, CCR,NIH, Bethesda, MD 20892 USA. [Lee, Byeong Jae] Seoul Natl Univ, Lab Mol Genet & Genom, Sch Biol Sci, Inst Mol Biol & Genet, Seoul, South Korea. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 847.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621500696 ER PT J AU Chakraborty, K Banerjee, R Basu, M Basu, N Owens, IS AF Chakraborty, Kushal Banerjee, Rajat Basu, Mousumi Basu, Nikhil Owens, Ida S. TI Isolation and characterization of mouse UDP-glucuronosyltransferase homologs of human isozymes that inactivate mutagenizing catechol estrogens SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Chakraborty, Kushal; Banerjee, Rajat; Basu, Mousumi; Basu, Nikhil; Owens, Ida S.] NICHD, SGDDM, PDEGEN, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 678.9 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621506258 ER PT J AU Chen, C Krausz, KW Shah, YM Idle, JR Gonzalez, FJ AF Chen, Chi Krausz, Kristopher W. Shah, Yatrik M. Idle, Jeffrey R. Gonzalez, Frank J. TI LC-MS-based metabolomics of acetaminophen-induced acute toxicity SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Chen, Chi] Univ Minnesota, St Paul, MN 55108 USA. [Krausz, Kristopher W.; Shah, Yatrik M.; Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. [Idle, Jeffrey R.] Charles Univ Prague, Inst Pharmacol, Prague, Czech Republic. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621501451 ER PT J AU Chiluiza, D Callahan, R Rhoads, RE AF Chiluiza, David Callahan, Robert Rhoads, Robert E. TI Effects on translation initiation and malignant transformation of insertion of Mouse Mammary Tumor Virus (MMTV) into the eukaryotic initiation factor 3e (eIF3e) gene SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Chiluiza, David; Rhoads, Robert E.] Louisiana State Univ, Hlth Sci Ctr, Shreveport, LA 71105 USA. [Callahan, Robert] NIH, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 500.4 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621504153 ER PT J AU Chiu, TK Li, M Davies, DR AF Chiu, Thang Kien Li, Min Davies, David R. TI Structure and function of prolyl peptidases SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Chiu, Thang Kien] LSU Hlth Sci Ctr, New Orleans, LA USA. [Li, Min; Davies, David R.] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 504.11 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621505270 ER PT J AU Chow, SA Wilkinson, TA Zhang, M Januszyk, K Phillips, ML Le Grice, SFJ Clubb, RT AF Chow, Samson A. Wilkinson, Thomas A. Zhang, Min Januszyk, Kurt Phillips, Martin L. Le Grice, Stuart F. J. Clubb, Robert T. TI Specific HIV-1 integrase-reverse transcriptase interactions as a mechanism for promoting reverse transcription SO FASEB JOURNAL LA English DT Meeting Abstract C1 [Chow, Samson A.; Wilkinson, Thomas A.; Zhang, Min] UCLA Sch Med, Los Angeles, CA USA. [Januszyk, Kurt; Phillips, Martin L.; Clubb, Robert T.] Univ Calif Los Angeles, Los Angeles, CA USA. [Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD APR PY 2009 VL 23 MA 501.1 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA V27OC UT WOS:000208621506171 ER EF