FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Fantner, GE Adams, J Turner, P Thurner, PJ Fisher, LW Hansma, PK AF Fantner, Georg E. Adams, Jonathan Turner, Patricia Thurner, Philipp J. Fisher, Larry W. Hansma, Paul K. TI Nanoscale ion mediated networks in bone: Osteopontin can repeatedly dissipate large amounts of energy SO NANO LETTERS LA English DT Article ID SACRIFICIAL BONDS; TRABECULAR BONE; FORCE SPECTROSCOPY; ORGANIC MATRIX; HIDDEN LENGTH; IN-VITRO; FRACTURE; PROTEINS; SIALOPROTEIN; TOUGHNESS AB In the nanocomposite bone, inorganic material is combined with several types of organic molecules, and these complexes have been proposed to increase the bone strength. Here we report on a mechanism of how one of these components, human osteopontin, forms large mechanical networks that can repeatedly dissipate energy through work against entropy by breaking sacrificial bonds and stretching hidden length. The behavior of these in vitro networks is similar to that of organic components in bone, acting as an adhesive layer in between mineralized fibrils. C1 Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. DHHS, NIH, NIDCR, Craniofacial & Skeletal Dis Branch, Bethesda, MD 20892 USA. RP Fantner, GE (reprint author), Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. EM fantner@physics.ucsb.edu RI Fantner, Georg/F-7392-2011; Thurner, Philipp/A-3887-2012; OI Thurner, Philipp/0000-0001-7588-9041 FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM65354] NR 52 TC 65 Z9 65 U1 1 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 J9 NANO LETT JI Nano Lett. PD AUG PY 2007 VL 7 IS 8 BP 2491 EP 2498 DI 10.1021/nl0712769 PG 8 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 198WI UT WOS:000248657800057 PM 17645366 ER PT J AU d'Abbadie, M Hofreiter, M Vaisman, A Loakes, D Gasparutto, D Cadet, J Woodgate, R Paabo, S Holliger, P AF d'Abbadie, Marc Hofreiter, Michael Vaisman, Alexandra Loakes, David Gasparutto, Didier Cadet, Jean Woodgate, Roger Paeaebo, Svante Holliger, Philipp TI Molecular breeding of polymerases for amplification of ancient DNA SO NATURE BIOTECHNOLOGY LA English DT Article ID COMPARTMENTALIZED SELF-REPLICATION; DIRECTED-EVOLUTION; DEOXYRIBONUCLEIC ACID; NEANDERTHAL DNA; EXTENSION; SEQUENCES; TEMPLATE; PROTEIN; ORIGIN; FAMILY AB In the absence of repair, lesions accumulate in DNA. Thus, DNA persisting in specimens of paleontological, archaeological or forensic interest is inevitably damaged(1). We describe a strategy for the recovery of genetic information from damaged DNA. By molecular breeding(2) of polymerase genes from the genus Thermus ( Taq ( Thermus aquaticus), Tth ( Thermus thermophilus) and Tfl ( Thermus flavus)) and compartmentalized self-replication(3,4) selection, we have evolved polymerases that can extend single, double and even quadruple mismatches, process non-canonical primer-template duplexes and bypass lesions found in ancient DNA, such as hydantoins and abasic sites. Applied to the PCR amplification of 47,000-60,000-year-old cave bear DNA, these outperformed Taq DNA polymerase by up to 150% and yielded amplification products at sample dilutions at which Taq did not. Our results demonstrate that engineered polymerases can expand the recovery of genetic information from Pleistocene specimens and may benefit genetic analysis in paleontology, archeology and forensic medicine. C1 MRC, Mol Biol Lab, Cambridge CB2 2QH, England. Max Planck Inst Mol Anthropol, Dept Evolutionary Genet, D-04103 Leipzig, Germany. NICHHD, NIH, Sect DNA Replicat Repair & Mutagenesis, Bethesda, MD 20892 USA. CEA Grenoble, Commiss Energia Atom, Dept Rech Fondamentale Mat Condensee, Lab Lesions Acides Nucl,SCIB UMR 3,CEA UJF, F-38054 Grenoble 9, France. RP Holliger, P (reprint author), MRC, Mol Biol Lab, Hills Rd, Cambridge CB2 2QH, England. EM ph1@mrc-lmb.cam.ac.uk RI Vaisman, Alexandra/C-3766-2013; Hofreiter, Michael/A-3996-2017 OI Vaisman, Alexandra/0000-0002-2521-1467; Hofreiter, Michael/0000-0003-0441-4705 FU Intramural NIH HHS; Medical Research Council [MC_U105178804, U.1051.03.006(78804)] NR 30 TC 73 Z9 73 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD AUG PY 2007 VL 25 IS 8 BP 939 EP 943 DI 10.1038/nbt1321 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 199WL UT WOS:000248725800033 PM 17632524 ER PT J AU Song, SW Finkel, T AF Song, Shiwei Finkel, Toren TI GAPDH and the search for alternative energy SO NATURE CELL BIOLOGY LA English DT Editorial Material ID GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; CELL-DEATH; AUTOPHAGY C1 NHLBI, Cardiol Branch, Bethesda, MD 20892 USA. RP Song, SW (reprint author), NHLBI, Cardiol Branch, Bldg 10-CRC 5-3330 10 Ctr Dr, Bethesda, MD 20892 USA. EM finkelt@nih.gov NR 8 TC 16 Z9 18 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD AUG PY 2007 VL 9 IS 8 BP 869 EP 870 DI 10.1038/ncb0807-869 PG 2 WC Cell Biology SC Cell Biology GA 196MM UT WOS:000248486700004 PM 17671452 ER PT J AU Inglese, J Shamu, CE Guy, RK AF Inglese, James Shamu, Caroline E. Guy, R. Kiplin TI Reporting data from high-throughput screening of small-molecule libraries SO NATURE CHEMICAL BIOLOGY LA English DT Editorial Material ID STATISTICAL PARAMETER; ASSAYS AB Publications reporting results of small-molecule screens are becoming more common as academic researchers increasingly make use of high-throughput screening (HTS) facilities. However, no standards have been formally established for reporting small-molecule screening data, and often key information important for the evaluation and interpretation of results is omitted in published HTS protocols. Here, we propose concise guidelines for reporting small-molecule HTS data. C1 US Natl Inst Hlth, Chem Genom Ctr, Natl Human Genome Inst, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, ICCB, Longwood Screening Facil, Boston, MA 02115 USA. St Jude Childrens Hosp, Dept Chem Biol & Therapeut, Memphis, TN 38105 USA. RP Inglese, J (reprint author), US Natl Inst Hlth, Chem Genom Ctr, Natl Human Genome Inst, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM jinglese@mail.nih.gov RI Guy, Rodney/J-7107-2013 OI Guy, Rodney/0000-0002-9638-2060 FU Intramural NIH HHS NR 7 TC 54 Z9 54 U1 1 U2 11 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1552-4450 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD AUG PY 2007 VL 3 IS 8 BP 438 EP 441 DI 10.1038/nchembio0807-438 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 193VB UT WOS:000248302200004 PM 17637769 ER PT J AU Inglese, J Johnson, RL Simeonov, A Xia, MH Zheng, W Austin, CP Auld, DS AF Inglese, James Johnson, Ronald L. Simeonov, Anton Xia, Menghang Zheng, Wei Austin, Christopher P. Auld, Douglas S. TI High-throughput screening assays for the identification of chemical probes SO NATURE CHEMICAL BIOLOGY LA English DT Review ID PROTEIN-COUPLED RECEPTORS; RESONANCE ENERGY-TRANSFER; SCINTILLATION PROXIMITY-ASSAY; TIME-RESOLVED FLUORESCENCE; CELL-BASED ASSAY; ENZYME FRAGMENT COMPLEMENTATION; DRUG DISCOVERY; KINASE INHIBITORS; BETA-LACTAMASE; LIVING CELLS AB High-throughput screening (HTS) assays enable the testing of large numbers of chemical substances for activity in diverse areas of biology. The biological responses measured in HTS assays span isolated biochemical systems containing purified receptors or enzymes to signal transduction pathways and complex networks functioning in cellular environments. This Review addresses factors that need to be considered when implementing assays for HTS and is aimed particularly at investigators new to this field. We discuss assay design strategies, the major detection technologies and examples of HTS assays for common target classes, cellular pathways and simple cellular phenotypes. We conclude with special considerations for configuring sensitive, robust, informative and economically feasible HTS assays. C1 US Natl Inst Hlth, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Inglese, J (reprint author), US Natl Inst Hlth, Chem Genom Ctr, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM jinglese@mail.nih.gov RI Zheng, Wei/J-8889-2014 OI Zheng, Wei/0000-0003-1034-0757 FU Intramural NIH HHS NR 150 TC 280 Z9 286 U1 14 U2 118 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1552-4450 EI 1552-4469 J9 NAT CHEM BIOL JI Nat. Chem. Biol. PD AUG PY 2007 VL 3 IS 8 BP 466 EP 479 DI 10.1038/nchembio.2007.17 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 193VB UT WOS:000248302200013 PM 17637779 ER PT J AU Illei, GG AF Illei, Gabor G. TI The clinical impact of neuropsychiatric manifestations in early systemic lupus erythematosus SO NATURE CLINICAL PRACTICE RHEUMATOLOGY LA English DT Editorial Material DE diagnosis; neuropsychiatric events; systemic lupus erythematosus ID COHORT; DAMAGE C1 NIDCR, Sjogrens Syndrome Clin, GTTB, NIH, Bethesda, MD 20892 USA. RP Illei, GG (reprint author), NIDCR, Sjogrens Syndrome Clin, GTTB, NIH, Bldg 10,Room 1N-114, Bethesda, MD 20892 USA. EM illeig@mail.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1745-8382 J9 NAT CLIN PRACT RHEUM JI Nat. Clin. Pract. Rheumatol. PD AUG PY 2007 VL 3 IS 8 BP 428 EP 429 DI 10.1038/ncprheum0553 PG 2 WC Rheumatology; Social Issues SC Rheumatology; Social Issues GA 195KZ UT WOS:000248412400004 PM 17579601 ER PT J AU Zanke, BW Greenwood, CMT Rangrej, J Kustra, R Tenesa, A Farrington, SM Prendergast, J Olschwang, S Chiang, T Crowdy, E Ferretti, V Laflamme, P Sundararajan, S Roumy, S Olivier, JF Robidoux, F Sladek, R Montpetit, A Campbell, P Bezieau, S O'Shea, AM Zogopoulos, G Cotterchio, M Newcomb, P McLaughlin, J Younghusband, B Green, R Green, J Porteous, MEM Campbell, H Blanche, H Sahbatou, M Tubacher, E Bonaiti-Pellie, C Buecher, B Riboli, E Kury, S Chanock, SJ Potter, J Thomas, G Gallinger, S Hudson, TJ Dunlop, MG AF Zanke, Brent W. Greenwood, Celia M. T. Rangrej, Jagadish Kustra, Rafal Tenesa, Albert Farrington, Susan M. Prendergast, James Olschwang, Sylviane Chiang, Theodore Crowdy, Edgar Ferretti, Vincent Laflamme, Philippe Sundararajan, Saravanan Roumy, Stephanie Olivier, Jean-Francois Robidoux, Frederick Sladek, Robert Montpetit, Alexandre Campbell, Peter Bezieau, Stephane O'Shea, Anne Marie Zogopoulos, George Cotterchio, Michelle Newcomb, Polly McLaughlin, John Younghusband, Ban Green, Roger Green, Jane Porteous, Mary E. M. Campbell, Harry Blanche, Helene Sahbatou, Mourad Tubacher, Emmanuel Bonaiti-Pellie, Catherine Buecher, Bruno Riboli, Elio Kury, Sebastien Chanock, Stephen J. Potter, John Thomas, Gilles Gallinger, Steven Hudson, Thomas J. Dunlop, Malcolm G. TI Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24 SO NATURE GENETICS LA English DT Article ID PROSTATE-CANCER AB Using a multistage genetic association approach comprising 7,480 affected individuals and 7,779 controls, we identified markers in chromosomal region 8q24 associated with colorectal cancer. In stage 1, we genotyped 99,632 SNPs in 1,257 affected individuals and 1,336 controls from Ontario. In stages 2-4, we performed serial replication studies using 4,024 affected individuals and 4,042 controls from Seattle, Newfoundland and Scotland. We identified one locus on chromosome 8q24 and another on 9p24 having combined odds ratios (OR) for stages 1-4 of 1.18 (trend; P = 1.41 x 10(-8)) and 1.14 (trend; P = 1.32 x 10(-5)), respectively. Additional analyses in 2,199 affected individuals and 2,401 controls from France and Europe supported the association at the 8q24 locus (OR = 1.16, trend; 95% confidence interval (c.i.): 1.07-1.26; P = 5.05 = 10-4). A summary across all seven studies at the 8q24 locus was highly significant (OR = 1.17, c.i.: 1.12-1.23; P = 3.16 x 10(-11)). This locus has also been implicated in prostate cancer(1-3). C1 Ontario Inst Canc Res, Toronto, ON M5G 2L7, Canada. Canc Care Ontario, Toronto, ON M5G 1L7, Canada. Univ Ottawa, Fac Med, Div Hematol, Ottawa, ON K1H 8L6, Canada. Hosp Sick Children, Toronto, ON M5G 1L7, Canada. Univ Toronto, Dept Publ Hlth Sci, Toronto, ON M5T 3M7, Canada. Univ Edinburgh, Canc Res Ctr, Colon Canc Genet Grp, Edinburgh EH4 2XU, Midlothian, Scotland. Western Gen Hosp, Human Genet Unit, UK Med Res Council, Edinburgh EH4 2XU, Midlothian, Scotland. Inst J Paoli I Calmettes, INSERM, U599, F-13009 Marseille, France. McGill Univ, Montreal, PQ H3G 1A4, Canada. Genome Quebec Innovat Ctr, Montreal, PQ H3G 1A4, Canada. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. Univ Toronto, Toronto, ON M5G 1X5, Canada. Ctr Hosp Univ Hotel Dieu, IMAD, F-44093 Nantes 01, France. Ctr Hosp Univ Hotel Dieu, EA3823, F-44093 Nantes 01, France. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Mem Univ Newfoundland, St John, NF A1C 5S7, Canada. Univ Edinburgh, Dept Clin Genet, Edinburgh EH4 2XU, Midlothian, Scotland. Univ Edinburgh, Edinburgh EH8 9AG, Midlothian, Scotland. Ctr Etud Polymorphisme Humain, F-75010 Paris, France. Hop Paul Brousse, INSERM, U535, F-94800 Villejuif, France. Imperial Coll, Fac Med, London W2 1PG, England. NCI, Canc Res Ctr, NIH, DHHS, Gaithersburg, MD 20877 USA. NCI, Div Canc Genet & Epidemiol, NIH, DHHS, Gaithersburg, MD 20877 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Hudson, TJ (reprint author), Ontario Inst Canc Res, 101 Coll St, Toronto, ON M5G 2L7, Canada. EM tom.hudson@oicr.on.ca RI Dunlop, Malcolm/F-1973-2011; Farrington, Susan/C-7319-2013; Olschwang, Sylviane/G-2716-2013; Gallinger, Steven/E-4575-2013; McLaughlin, John/E-4577-2013; KURY, Sebastien/G-5971-2015; Bezieau, stephane/G-5621-2015; OI Sladek, Robert/0000-0002-2730-1204; Dunlop, Malcolm/0000-0002-3033-5851; Prendergast, James/0000-0001-8916-018X; KURY, Sebastien/0000-0001-5497-0465; Bezieau, stephane/0000-0003-0095-1319; Potter, John/0000-0001-5439-1500 FU Chief Scientist Office [CZB/4/449]; Medical Research Council [MC_U127527198]; NCI NIH HHS [U01 CA074783, RFA CA-95-011, U01 CA074794, U01 CA076783] NR 13 TC 474 Z9 492 U1 1 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD AUG PY 2007 VL 39 IS 8 BP 989 EP 994 DI 10.1038/ng2089 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 195XX UT WOS:000248446900016 PM 17618283 ER PT J AU Jankovic, M Nussenzweig, A Nussenzweig, MC AF Jankovic, Mila Nussenzweig, Andre Nussenzweig, Michel C. TI Antigen receptor diversification and chromosome translocations SO NATURE IMMUNOLOGY LA English DT Review ID CLASS-SWITCH RECOMBINATION; INDUCED CYTIDINE DEAMINASE; DOUBLE-STRAND BREAKS; DNA-LIGASE-IV; ATM-DEFICIENT MICE; DEPENDENT PROTEIN-KINASE; LEAKY SCID PHENOTYPE; B-CELL DEVELOPMENT; V(D)J RECOMBINATION; SOMATIC HYPERMUTATION AB Double-stranded DNA breaks (DSBs) can result in chromosomal abnormalities, including deletions, translocations and aneuploidy, which can promote neoplastic transformation. DSBs arise accidentally during DNA replication and can be induced by environmental factors such as ultraviolet light or ionizing radiation, and they are generated during antigen receptor-diversification reactions in lymphocytes. Cellular pathways that maintain genomic integrity use sophisticated mechanisms that recognize and repair all DSBs regardless of their origin. Such pathways, along with DNA-damage checkpoints, ensure that either the damage is properly repaired or cells with damaged DNA are eliminated. Here we review how impaired DNA-repair or DNA-damage checkpoints can lead to genetic instability and predispose lymphocytes undergoing diversification of antigen receptor genes to malignant transformation. C1 Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. RP Nussenzweig, MC (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. EM nussen@mail.rockefeller.edu NR 165 TC 43 Z9 43 U1 1 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD AUG PY 2007 VL 8 IS 8 BP 801 EP 808 DI 10.1038/ni1498 PG 8 WC Immunology SC Immunology GA 191ZB UT WOS:000248169400007 PM 17641661 ER PT J AU Zeisberg, EM Tarnavski, O Zeisberg, M Dorfman, AL McMullen, JR Gustafsson, E Chandraker, A Yuan, XL Pu, WT Roberts, AB Neilson, EG Sayegh, MH Izumo, S Kalluri, R AF Zeisberg, Elisabeth M. Tarnavski, Oleg Zeisberg, Michael Dorfman, Adam L. McMullen, Julie R. Gustafsson, Erika Chandraker, Anil Yuan, Xueli Pu, William T. Roberts, Anita B. Neilson, Eric G. Sayegh, Mohamed H. Izumo, Seigo Kalluri, Raghu TI Endothelial-to-mesenchymal transition contributes to cardiac fibrosis SO NATURE MEDICINE LA English DT Article ID GROWTH-FACTOR-BETA; NITRIC-OXIDE SYNTHESIS; LONG-TERM BLOCKADE; DIASTOLIC DYSFUNCTION; TGF-BETA; CELL-TRANSFORMATION; EMBRYONIC HEART; GENE-EXPRESSION; CRE RECOMBINASE; TRANSGENIC MICE AB Cardiac fibrosis, associated with a decreased extent of microvasculature and with disruption of normal myocardial structures, results from excessive deposition of extracellular matrix, which is mediated by the recruitment of fibroblasts. The source of these fibroblasts is unclear and specific anti-fibrotic therapies are not currently available. Here we show that cardiac fibrosis is associated with the emergence of fibroblasts originating from endothelial cells, suggesting an endothelial-mesenchymal transition (EndMT) similar to events that occur during formation of the atrioventricular cushion in the embryonic heart. Transforming growth factor-beta 1 (TGF-beta 1) induced endothelial cells to undergo EndMT, whereas bone morphogenic protein 7 (BMP-7) preserved the endothelial phenotype. The systemic administration of recombinant human BMP-7 (rhBMP-7) significantly inhibited EndMT and the progression of cardiac fibrosis in mouse models of pressure overload and chronic allograft rejection. Our findings show that EndMT contributes to the progression of cardiac fibrosis and that rhBMP-7 can be used to inhibit EndMT and to intervene in the progression of chronic heart disease associated with fibrosis. C1 Beth Israel Deaconess Med Ctr, Dept Med, Div Matrix Biol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Novartis Inst Biomed Res, Cambridge, MA 02139 USA. Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. Beth Israel Deaconess Med Ctr, Dept Cardiol, Dept Med, Div Cardiovasc, Boston, MA 02215 USA. Lund Univ, Dept Expt Pathol, S-22185 Lund, Sweden. Brigham & Womens Hosp, Transplantat Res Ctr, Boston, MA 02215 USA. Childrens Hosp, Boston, MA 02215 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Med, Nashville, TN 37215 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA. Harvard Mit Div Hlth Sci & Technol, Boston, MA 02215 USA. RP Kalluri, R (reprint author), Beth Israel Deaconess Med Ctr, Dept Med, Div Matrix Biol, Boston, MA 02215 USA. EM rkalluri@bidmc.harvard.edu RI Kalluri, Raghu/E-2677-2015 OI Kalluri, Raghu/0000-0002-2190-547X FU NHLBI NIH HHS [5 F32 HL082436-01]; NIAAA NIH HHS [AA13913]; NIDDK NIH HHS [5K08DK074558-01, DK-46282, DK55001, DK61688, DK62987] NR 50 TC 786 Z9 830 U1 14 U2 74 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD AUG PY 2007 VL 13 IS 8 BP 952 EP 961 DI 10.1038/nm1613 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 199CU UT WOS:000248674600026 PM 17660828 ER PT J AU Atarashi, R Moore, RA Sim, VL Hughson, AG Dorward, DW Onwubiko, HA Priola, SA Caughey, B AF Atarashi, Ryuichiro Moore, Roger A. Sim, Valerie L. Hughson, Andrew G. Dorward, David W. Onwubiko, Henry A. Priola, Suzette A. Caughey, Byron TI Ultrasensitive detection of scrapie prion protein using seeded conversion of recombinant prion protein SO NATURE METHODS LA English DT Article ID CELL-FREE CONVERSION; IN-VITRO; SPONGIFORM ENCEPHALOPATHY; CYCLIC AMPLIFICATION; PROPAGATION; PRP; FEATURES AB The scrapie prion protein isoform, PrPSc, is a prion- associated marker that seeds the conformational conversion and polymerization of normal protease- sensitive prion protein ( PrP- sen). This seeding activity allows ultrasensitive detection of PrPSc using cyclical sonicated amplification ( PMCA) reactions and brain homogenate as a source of PrP- sen. Here we describe a much faster seeded polymerization method ( rPrP- PMCA) which detects >= 50 ag of hamster PrPSc (approximate to 0.003 lethal dose) within 2 - 3 d. This technique uses recombinant hamster PrP- sen, which, unlike brain- derived PrP- sen, can be easily concentrated, mutated and synthetically tagged. We generated protease- resistant recombinant PrP fibrils that differed from spontaneously initiated fibrils in their proteolytic susceptibility and by their infrared spectra. This assay could discriminate between scrapie- infected and uninfected hamsters using 2-mu l aliquots of cerebral spinal fluid. This method should facilitate the development of rapid, ultrasensitive prion assays and diagnostic tests, in addition to aiding fundamental studies of structure and mechanism of PrPSc formation. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. NIAID, Rocky Mt Labs, Electron Microscopy Core Facil, NIH, Hamilton, MT 59840 USA. RP Caughey, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM bcaughey@nih.gov RI Sim, Valerie/C-4137-2013 OI Sim, Valerie/0000-0002-0088-8666 FU Intramural NIH HHS NR 28 TC 161 Z9 171 U1 2 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD AUG PY 2007 VL 4 IS 8 BP 645 EP 650 DI 10.1038/NMETH1066 PG 6 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 195WV UT WOS:000248443900018 PM 17643109 ER PT J AU Dobrovolskaia, MA Mcneil, SE AF Dobrovolskaia, Marina A. Mcneil, Scott E. TI Immunological properties of engineered nanomaterials SO NATURE NANOTECHNOLOGY LA English DT Review ID PLASMA-PROTEIN ADSORPTION; SOLID-LIPID-NANOPARTICLES; ANTITUMOR IMMUNE-RESPONSES; PEG-CHAIN-LENGTH; 2-DIMENSIONAL ELECTROPHORESIS; CARBON-NANOTUBES; DRUG-DELIVERY; IN-VIVO; POLYMERIC NANOPARTICLES; CHITOSAN NANOPARTICLES AB Most research on the toxicology of nanomaterials has focused on the effects of nanoparticles that enter the body accidentally. There has been much less research on the toxicology of nanoparticles that are used for biomedical applications, such as drug delivery or imaging, in which the nanoparticles are deliberately placed in the body. Moreover, there are no harmonized standards for assessing the toxicity of nanoparticles to the immune system ( immunotoxicity). Here we review recent research on immunotoxicity, along with data on a range of nanotechnology- based drugs that are at different stages in the approval process. Research shows that nanoparticles can stimulate and/or suppress the immune responses, and that their compatibility with the immune system is largely determined by their surface chemistry. Modifying these factors can significantly reduce the immunotoxicity of nanoparticles and make them useful platforms for drug delivery. C1 SAIC Frederick, NCI Frederick, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick, MD 21702 USA. RP Dobrovolskaia, MA (reprint author), SAIC Frederick, NCI Frederick, Nanotechnol Characterizat Lab, Adv Technol Program, 1050 Boyles St,Bldg 469, Frederick, MD 21702 USA. EM marina@mail.nih.gov; ncl@ncifcrf.gov RI beyazkilic, pinar/G-6781-2011; Nanotechnology Characterization Lab, NCL/K-8454-2012 FU NCI NIH HHS [N01-CO-12400] NR 100 TC 766 Z9 778 U1 26 U2 353 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1748-3387 J9 NAT NANOTECHNOL JI Nat. Nanotechnol. PD AUG PY 2007 VL 2 IS 8 BP 469 EP 478 DI 10.1038/nnano.2007.223 PG 10 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Science & Technology - Other Topics; Materials Science GA 204RY UT WOS:000249062900010 PM 18654343 ER PT J AU Schoenbaum, G Stalnaker, TA Shaham, Y AF Schoenbaum, Geoffrey Stalnaker, Thomas A. Shaham, Yavin TI A role for BDNF in cocaine reward and relapse SO NATURE NEUROSCIENCE LA English DT Editorial Material ID NEUROTROPHIC FACTOR; WITHDRAWAL; EXPRESSION; TRANSPORT; NEURONS AB Brain-derived neurotrophic factor (BDNF) is important in regulating synaptic plasticity in the brain areas that process reward information. A new study reports that BDNF in the nucleus accumbens, a brain area critical for the rewarding effects of cocaine, promotes persistent cocaine-seeking behaviors and heightens relapse vulnerability. C1 Univ Maryland Baltimore Cty, Dept Psychol, Baltimore, MD 21228 USA. Natl Inst Drug Abuse, Intramural Res Program, Behav Neurosci Branch, US Dept HHS,NIH, Baltimore, MD 21224 USA. RP Schoenbaum, G (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, Dept Psychiat, 20 Penn St,HSF-2 S251, Baltimore, MD 21201 USA. RI shaham, yavin/G-1306-2014 FU NIDA NIH HHS [R01 DA015718-04, R01 DA015718] NR 15 TC 19 Z9 21 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD AUG PY 2007 VL 10 IS 8 BP 935 EP 936 DI 10.1038/nn0807-935 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 194PY UT WOS:000248357500002 PM 17657232 ER PT J AU Aladjem, MI AF Aladjem, Mirit I. TI Replication in context: dynamic regulation of DNA replication patterns in metazoans SO NATURE REVIEWS GENETICS LA English DT Review ID BETA-GLOBIN LOCUS; ORIGIN RECOGNITION COMPLEX; DIHYDROFOLATE-REDUCTASE ORIGIN; EMBRYONIC STEM-CELLS; HEAVY-CHAIN LOCUS; BUDDING YEAST; S-PHASE; SCHIZOSACCHAROMYCES-POMBE; ASYNCHRONOUS REPLICATION; SACCHAROMYCES-CEREVISIAE AB Replication in eukaryotes initiates from discrete genomic regions according to a strict, often tissue-specific temporal programme. However, the locations of initiation events within initiation regions vary, show sequence disparity and are affected by interactions with distal elements. Increasing evidence suggests that specification of replication sites and the timing of replication are dynamic processes that are regulated by tissue-specific and developmental cues, and are responsive to epigenetic modifications. Dynamic specification of replication patterns might serve to prevent or resolve possible spatial and/or temporal conflicts between replication, transcription and chromatin assembly, and facilitate subtle or extensive changes of gene expression during differentiation and development. C1 NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Aladjem, MI (reprint author), NCI, Mol Pharmacol Lab, NIH, Bldg 37,Room 5056,37 Convent Dr, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov RI Aladjem, Mirit/G-2169-2010 OI Aladjem, Mirit/0000-0002-1875-3110 FU Intramural NIH HHS NR 136 TC 134 Z9 134 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1471-0056 J9 NAT REV GENET JI Nat. Rev. Genet. PD AUG PY 2007 VL 8 IS 8 BP 588 EP 600 DI 10.1038/nrg2143 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 191ZO UT WOS:000248170700013 PM 17621316 ER PT J AU Wickner, RB Edskes, HK Shewmaker, F Nakayashiki, T AF Wickner, Reed B. Edskes, Herman K. Shewmaker, Frank Nakayashiki, Toru TI Prions of fungi: inherited structures and biological roles SO NATURE REVIEWS MICROBIOLOGY LA English DT Review ID HET-S PRION; CREUTZFELDT-JAKOB-DISEASE; YEAST SUP35 PROTEIN; SACCHAROMYCES-CEREVISIAE; PSI+ PRION; GUANIDINE-HYDROCHLORIDE; PODOSPORA-ANSERINA; SCRAPIE PRION; HETEROKARYON INCOMPATIBILITY; ANTAGONISTIC INTERACTIONS AB The term 'prion' means an infectious protein that does not need an accompanying nucleic acid. There are six fungal prions, including four self-propagating amyloids and two enzymes that are necessary to activate their inactive precursors. Here we explore the scope of the prion phenomenon, the biological and evolutionary roles of prions, the structural basis of the amyloid prions and the prominent role of chaperones (proteins that affect the folding of other proteins) and other cellular components in prion generation and propagation. C1 Natl Inst Hlth, Inst Diabet Digest & Kidney Dis, Lab Biochem & Genet, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), Natl Inst Hlth, Inst Diabet Digest & Kidney Dis, Lab Biochem & Genet, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU Intramural NIH HHS [Z01 DK024943-14] NR 125 TC 152 Z9 155 U1 1 U2 16 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1740-1526 J9 NAT REV MICROBIOL JI Nat. Rev. Microbiol. PD AUG PY 2007 VL 5 IS 8 BP 611 EP 618 DI 10.1038/nrmicro1708 PG 8 WC Microbiology SC Microbiology GA 191ZS UT WOS:000248171100013 PM 17632572 ER PT J AU Manning-Bog, AB Caudle, WM Perez, XA Reaney, SH Paletzki, R Isla, MZ Chou, VP McCormack, AL Miller, GW Langston, JW Gerfen, CR DiMonte, DA AF Manning-Bog, Amy B. Caudle, W. Michael Perez, Xiomara A. Reaney, Stephen H. Paletzki, Ronald Isla, Martha Z. Chou, Vivian P. McCormack, Alison L. Miller, Gary W. Langston, J. William Gerfen, Charles R. DiMonte, Donato A. TI Increased vulnerability of nigrostriatal terminals in DJ-1-deficient mice is mediated by the dopamine transporter SO NEUROBIOLOGY OF DISEASE LA English DT Article DE DJ-1; Parkinson; dopamine transporter; striatum; MPTP; substantia nigra; transgenic; dopamine ID FAMILIAL PARKINSONS-DISEASE; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE MPTP; NEUROCHEMICAL DEFICITS; PROTEIN STABILITY; DJ-1 MUTATIONS; MOUSE-BRAIN; NEURONS; NEUROTOXICITY; LOCALIZATION; GENE AB Mutations in the gene for DJ-1 have been associated with early-onset autosomal recessive parkinsonism. Previous studies of null DJ-1 mice have shown alterations in striatal dopamine (DA) transmission with no DAergic cell loss. Here we characterize a new line of DJ-1-deficient mice. A subtle locomotor deficit was present in the absence of a change in striatal DA levels. However, increased [(3)H]-DA synaptosomal uptake and [(125)I]-RTI-121 binding were measured in null DJ-1 vs. wild-type mice. Western analyses of synaptosomes revealed significantly higher dopamine transporter (DAT) levels in pre-synaptic membrane fractions. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure exacerbated striatal DA depletion in null DJ-1 mice with no difference in DAergic nigral cell loss. Furthermore, increased 1-methyl-4-phenylpyridinium (MPP(+)) synaptosomal uptake and enhanced MPP+ accumulation were measured in DJ-1-deficient vs. control striatum. Thus, under null DJ-1 conditions, DAT changes likely contribute to altered DA neurotransmission and enhanced sensitivity to toxins that utilize DAT for nigrostriatal entry. (c) 2007 Published by Elsevier Inc. C1 Parkinsons Inst, Dept Basic Res, Sunnyvale, CA 94089 USA. Emory Univ, Ctr Neurodegenerat Dis, Atlanta, GA 30322 USA. NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Manning-Bog, AB (reprint author), Parkinsons Inst, Dept Basic Res, 1170 Morse Ave, Sunnyvale, CA 94089 USA. EM amanning-bog@thepi.org FU Intramural NIH HHS; NIEHS NIH HHS [ES 012077, ES 01268] NR 49 TC 59 Z9 60 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 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD AUG PY 2007 VL 27 IS 2 BP 141 EP 150 DI 10.1016/j.nbd.2007.03.014 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 197VK UT WOS:000248584400003 PM 17560790 ER PT J AU Sanchez-Pernaute, R Jenkins, BG Choi, JK Chen, YCI Isacson, O AF Sanchez-Pernaute, Rosario Jenkins, Bruce G. Choi, Ji-Kyung Chen, Yin-Ching Iris Isacson, Ole TI In vivo evidence of D-3 dopamine receptor sensitization in parkinsonian primates and rodents with L-DOPA-induced dyskinesias SO NEUROBIOLOGY OF DISEASE LA English DT Article DE dyskinesia; Parkinson's disease; dopamine; dopamine receptor; D-3; striatum; phMR1; primate ID LEVODOPA-INDUCED DYSKINESIA; 6-HYDROXYDOPAMINE-TREATED RATS; EXTRACELLULAR DOPAMINE; ACID DECARBOXYLASE; MESSENGER-RNA; BASAL GANGLIA; DISEASE; BRAIN; EXPRESSION; STRIATUM AB A growing body of evidence indicates a role for D-3 receptors in L-DOPA-induced dyskinesias. This involvement could be amenable to non-invasive in viva analysis using functional neuroimaging. With this goal, we examined the hemodynamic response to the dopamine D-3-preferring agonist 7-hydroxy-NN-di-n-propyl-2 aminotetralin (7-OHDPAT) in naive, parkinsonian and L-DOPA-treated, dyskinetic rodents and primates using pharmacological MRI (phMRI) and relative cerebral blood volume (rCBV) mapping. Administration of 7-OHDPAT induced minor negative changes of rCBV in the basal ganglia in naive and parkinsonian animals. Remarkably, the hemodynamic response was reversed (increased rCBV) in the striatum of parkinsonian animals rendered dyskinetic by repeated L-DOPA treatment. Such increase in rCBV is consistent with D, receptor-like signaling occurring in response to D3 stimulation, demonstrates a dysregulation of dopamine receptor function in dyskinesia and provides a potentially novel means for the characterization and treatment of L-DOPA-induced dyskinesia in patients. (c) 2007 Elsevier Inc. All rights reserved. C1 McLean Hosp, Neurogenerat Labs, Belmont, MA 02478 USA. Harvard Univ, McLean Hosp, Udall Parkinsons Dis Res Ctr Excellence, Belmont, MA 02478 USA. Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, MGH NMR Ctr, Boston, MA 02115 USA. RP Sanchez-Pernaute, R (reprint author), McLean Hosp, Neurogenerat Labs, MRC 130,115 Mill St, Belmont, MA 02478 USA. EM rpernaute@hms.harvard.edu FU NCRR NIH HHS [P51 RR000168, P51 RR000168-466888, P51RR00168]; NIDA NIH HHS [R01 DA016187]; NINDS NIH HHS [P50 NS039793-08, P50 NS039793-07, P50 NS-39793, P50 NS039793] NR 44 TC 29 Z9 29 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 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD AUG PY 2007 VL 27 IS 2 BP 220 EP 227 DI 10.1016/j.nbd.2007.04.016 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 197VK UT WOS:000248584400010 PM 17588764 ER PT J AU Kim, SJ Son, TG Kim, K Park, HR Mattson, MP Lee, J AF Kim, So Jung Son, Tae Gen Kim, Keunho Park, Hee Ra Mattson, Mark P. Lee, Jaewon TI Interferon-gamma promotes differentiation of neural progenitor cells via the JNK pathway SO NEUROCHEMICAL RESEARCH LA English DT Article DE ERK; inflammation; neurite outgrowth; neurogenesis ID CENTRAL-NERVOUS-SYSTEM; STEM-CELLS; NEUROTROPHIC FACTOR; NEURONAL DIFFERENTIATION; HIPPOCAMPAL-NEURONS; SIGNAL-TRANSDUCTION; NEURITE OUTGROWTH; PC12 CELLS; IFN-GAMMA; NEUROGENESIS AB It has been reported that interferon-gamma (IFN-gamma) facilitates differentiation of PC-12 cells and murine adult neural stem cells. Here we show that IFN-gamma promotes the differentiation of C17.2 neural progenitor cells (NPC) into a neuronal phenotype characterized by neurite outgrowth and the expression of the neuronal marker protein beta-III tubulin. IFN-gamma induced an increase in the activity c-jun N-terminal kinase (JNK) without affecting activities of extracellular signal-regulated kinases (ERKs 1 and 2). An inhibitor of JNK blocked the ability of IFN-gamma to promote differentiation of NPC into neurons, whereas an inhibitor of ERKs 1 and 2 did not. Our findings show that the pro-inflammatory cytokine, IFN-gamma has the potential to stimulate neurogenesis, suggesting roles for this cytokine in development and repair of the nervous system. C1 Pusan Natl Univ, Coll Pharm, Dept Pharm, Longev Life Sci & Technol Inst, Pusan 609735, South Korea. Pusan Natl Univ, Res Inst Drug Dev, Longev Life Sci & Technol Inst, Pusan 609735, South Korea. NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. RP Lee, J (reprint author), Pusan Natl Univ, Coll Pharm, Dept Pharm, Longev Life Sci & Technol Inst, Pusan 609735, South Korea. EM neuron@pusan.ac.kr RI Mattson, Mark/F-6038-2012; Lee, Jaewon/N-9064-2013 FU Intramural NIH HHS NR 34 TC 51 Z9 57 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD AUG PY 2007 VL 32 IS 8 BP 1399 EP 1406 DI 10.1007/s11064-007-9323-z PG 8 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 181YP UT WOS:000247472600016 PM 17415631 ER PT J AU Jian, B Vemuri, BC Ozarslan, E Carney, PR Mareci, TH AF Jian, Bing Vemuri, Baba C. Ozarslan, Evren Carney, Paul R. Mareci, Thomas H. TI A novel tensor distribution model for the diffusion-weighted MR signal SO NEUROIMAGE LA English DT Article ID MULTIPLE FIBER ORIENTATIONS; SPHERICAL DECONVOLUTION; WATER DIFFUSION; WHITE-MATTER; HUMAN BRAIN; RESOLUTION; TRACTOGRAPHY; COEFFICIENT; ANISOTROPY; TRACKING AB Diffusion MRI is a non-invasive imaging technique that allows the measurement of water molecule diffusion through tissue in vivo. The directional features of water diffusion allow one to infer the connectivity patterns prevalent in tissue and possibly track changes in this connectivity over time for various clinical applications. In this paper, we present a novel statistical model for diffusion-weighted MR signal attenuation which postulates that the water molecule diffusion can be characterized by a continuous mixture of diffusion tensors. An interesting observation is that this continuous mixture and the MR signal attenuation are related through the Laplace transform of a probability distribution over symmetric positive definite matrices. We then show that when the mixing distribution is a Wishart distribution, the resulting closed form of the Laplace transform leads to a Rigaut-type asymptotic fractal expression, which has been phenomenologically used in the past to explain the MR signal decay but never with a rigorous mathematical justification until now. Our model not only includes the traditional diffusion tensor model as a special instance in the limiting case, but also can be adjusted to describe complex tissue structure involving multiple fiber populations. Using this new model in conjunction with a spherical deconvolution approach, we present an efficient scheme for estimating the water molecule displacement probability functions on a voxel-by-voxel basis. Experimental results on both simulations and real data are presented to demonstrate the robustness and accuracy of the proposed algorithms. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Florida, Dept Comp & Informat Sci & Engn, Gainesville, FL 32611 USA. NICHD, LIMB, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. Univ Florida, Dept Pediat, Gainesville, FL 32610 USA. Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. RP Vemuri, BC (reprint author), Univ Florida, Dept Comp & Informat Sci & Engn, POB 116120, Gainesville, FL 32611 USA. EM vemuri@cise.ufl.edu RI Ozarslan, Evren/B-4858-2013 OI Ozarslan, Evren/0000-0003-0859-1311 FU Intramural NIH HHS; NIBIB NIH HHS [EB004752, EB007082, R01 EB004752, R01 EB007082, R01 EB007082-03]; NINDS NIH HHS [NS42075, R01 NS042075, R01 NS042075-04] NR 50 TC 92 Z9 92 U1 2 U2 7 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 AUG 1 PY 2007 VL 37 IS 1 BP 164 EP 176 DI 10.1016/j.neuroimage.2007.03.074 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 197AY UT WOS:000248526700016 PM 17570683 ER PT J AU Pelled, G Chuang, KH Dodd, SJ Koretsky, AP AF Pelled, Galit Chuang, Kai-Hsiang Dodd, Stephen J. Koretsky, Alan P. TI Functional MRI detection of bilateral cortical reorganization in the rodent brain following peripheral nerve deafferentation SO NEUROIMAGE LA English DT Article DE functional MRI; somatosensory cortex; plasticity; peripheral; nerves; denervation; rat ID PRIMARY SOMATOSENSORY CORTEX; RAT BARREL CORTEX; INTERHEMISPHERIC MODULATION; SUBCORTICAL CONTRIBUTIONS; SENSORY DEPRIVATION; SENSORIMOTOR CORTEX; RECEPTIVE-FIELDS; CORPUS-CALLOSUM; PLASTICITY; FMRI AB Evidence is emerging for significant inter-hemispheric cortical plasticity in humans, opening important questions about the significance and mechanism for this long range plasticity. In this work, peripheral nerve deafferentation was performed on both the rat forepaw and hindpaw and cortical reorganization was assessed using functional MRI (fMRI). Sensory stimulation of the forepaw or the hindpaw in rats that experienced only partial denervation resulted in activation in only the appropriate, contralateral, primary somatosensory cortex (SI). However, 2-3 weeks following complete denervation of the rats' forepaw or hindpaw, stimulation of the intact paw resulted in fMRI activation of ipsilateral as well as contralateral SI. To address whether inter-cortical communication is required for this cortical reorganization, the healthy hindpaw SI representation was stereotaxically lesioned in rats which had the other hindpaw denervated. No fMRI activation was detected in the ipsilateral SI cortex after lesioning of the contralateral cortex. These results indicate that extensive interhemispheric cortical-cortical reorganization can occur in the rodent brain after peripheral nerve deafferentation and that cortical-cortical connections play a role in mediating this inter-hemispheric cortical reorganization. Published by Elsevier Inc. C1 Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD USA. RP Koretsky, AP (reprint author), Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, B1D728,10 Ctr Dr, Bethesda, MD USA. EM KoretskyA@ninds.nih.gov RI Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Chuang, Kai-Hsiang/0000-0002-8356-0657 FU Intramural NIH HHS [Z01 NS002989-08] NR 62 TC 35 Z9 36 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD AUG 1 PY 2007 VL 37 IS 1 BP 262 EP 273 DI 10.1016/j.neuroimage.2007.03.069 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 197AY UT WOS:000248526700025 PM 17544301 ER PT J AU Cornwell, BR Baas, JMP Johnson, L Holroyd, T Carver, FW Lissek, S Grillon, C AF Cornwell, Brian R. Baas, Johanna M. P. Johnson, Linda Holroyd, Tom Carver, Frederick W. Lissek, Shmuel Grillon, Christian TI Neural responses to auditory stimulus deviance under threat of electric shock revealed by spatially-filtered magnetoencephalography SO NEUROIMAGE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; MISMATCH NEGATIVITY MMN; BRAIN; CORTEX; FEAR; REPRESENTATION; AMYGDALA; ANXIETY; FMRI; ERP AB Stimulus novelty or deviance may be especially salient in anxietyrelated states due to sensitization to environmental change, a key symptom of anxiety disorders such as posttraumatic stress disorder (PTSD). We aimed to identify human brain regions that show potentiated responses to stimulus deviance during anticipatory anxiety. Twenty participants (14 men) were presented a passive oddball auditory task in which they were exposed to uniform auditory stimulation of tones with occasional deviations in tone frequency, a procedure that elicits the mismatch negativity (MMN) and its magnetic counterpart (MMNm). These stimuli were presented during threat periods when participants anticipated unpleasant electric shocks, and safe periods when no shocks were anticipated. Neuromagnetic data were collected with a 275-channel whole-head MEG system and eventrelated beamformer analyses were conducted to estimate source power across the brain in response to stimulus deviance. Source analyses revealed greater right auditory and inferior parietal activity to stimulus deviance under threat relative to safe conditions, consistent with locations of MMN and MMNm sources identified in other studies. Structures related to evaluation of threat, left amygdala and right insula, also showed increased activity to stimulus deviance under threat. As anxiety level increased across participants, right and left auditory cortical as well as right amygdala activity increased to stimulus deviance. These findings fit with evidence of a potentiated MMN in PTSD relative to healthy controls, and warrant closer evaluation of how these structures might form a functional network mediating sensitization to stimulus deviance during anticipatory anxiety. (C) 2007 Elsevier Inc. All rights reserved. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NIMH, MEG Core Facil, Bethesda, MD 20892 USA. Univ Utrecht, Dept Psychonom, Utrecht, Netherlands. RP Cornwell, BR (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. EM cornwellb@mail.nih.gov RI Lissek, Shmuel/B-6577-2008; OI Baas, Johanna/0000-0001-6267-8712 FU Intramural NIH HHS [Z01 MH002798-06] NR 46 TC 51 Z9 51 U1 1 U2 9 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 AUG 1 PY 2007 VL 37 IS 1 BP 282 EP 289 DI 10.1016/j.neuroimage.2007.04.055 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 197AY UT WOS:000248526700027 PM 17566766 ER PT J AU Nahas, Z Teneback, C Chae, JH Mu, QW Molnar, C Kozel, FA Walker, J Anderson, B Koola, J Kose, S Lomarev, M Bohning, DE George, MS AF Nahas, Ziad Teneback, Charlotte Chae, Jeong-Ho Mu, Qiwen Molnar, Chris Kozel, Frank A. Walker, John Anderson, Berry Koola, Jejo Kose, Samet Lomarev, Mikhail Bohning, Daryl E. George, Mark S. TI Serial vagus nerve stimulation functional MRI in treatment-resistant depression SO NEUROPSYCHOPHARMACOLOGY LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the American-College-of-Neuropsychopharmacology CY DEC 12-16, 2004 CL San Juan, PR SP Vanderbilt Univ, Sch Med, Dept Psychiat, Amer Coll Neuropsychopharmacol DE vagus nerve stimulation; fMRI; depression; antidepressant ID TRANSCRANIAL MAGNETIC STIMULATION; CEREBRAL-BLOOD-FLOW; MAJOR DEPRESSION; SLEEP-DEPRIVATION; PREFRONTAL CORTEX; BRAIN METABOLISM; PARTIAL EPILEPSY; BOLD FMRI; ANTIDEPRESSANT RESPONSE; GLUCOSE-METABOLISM AB Vagus nerve stimulation (VNS) therapy has shown antidepressant effects in open acute and long-term studies of treatment-resistant major depression. Mechanisms of action are not fully understood, although clinical data suggest slower onset therapeutic benefit than conventional psychotropic interventions. We set out to map brain systems activated by VNS and to identify serial brain functional correlates of antidepressant treatment and symptomatic response. Nine adults, satisfying DSM-IV criteria for unipolar or bipolar disorder, severe depressed type, were implanted with adjunctive VNS therapy (MRI-compatible technique) and enrolled in a 3-month, doubleblind, placebo-controlled, serial-interleaved VNS/functional MRI (fMRI) study and open 20-month follow-up. A multiple regression mixed model with blood oxygenation level dependent (BOLD) signal as the dependent variable revealed that over time, VNS therapy was associated with ventro-medial prefrontal cortex deactivation. Controlling for other variables, acute VNS produced greater right insula activation among the participants with a greater degree of depression. These results suggest that similar to other antidepressant treatments, BOLD deactivation in the ventro-medial prefrontal cortex correlates with the antidepressant response to VNS therapy. The increased acute VNS insula effects among actively depressed participants may also account for the lower dosing observed in VNS clinical trials of depression compared with epilepsy. Future interleaved VNS/fMRI studies to confirm these findings and further clarify the regional neurobiological effects of VNS. C1 Inst Psychiat, Mood Disorders Program, Brain Stimulat Lab, Dept Psychiat, Charleston, SC 29403 USA. Med Univ S Carolina, Dept Radiol, Charleston, SC 29425 USA. Med Univ S Carolina, Ctr Adv Imaging Res, Charleston, SC 29425 USA. Catholic Univ, Dept Psychiat, Seoul, South Korea. NINDS, Bethesda, MD 20892 USA. Ralph H Johson VA Med Ctr, Dept Psychiat, Charleston, SC USA. RP Nahas, Z (reprint author), Inst Psychiat, Mood Disorders Program, Brain Stimulat Lab, Dept Psychiat, 67 President St,Room 502 N, Charleston, SC 29403 USA. EM nahasz@musc.edu RI Kozel, Frank/I-5366-2012 FU NIMH NIH HHS [MH070615-01A1, R01 MH069896-01, R21 MH065630-01]; NINDS NIH HHS [R01 NS40956-01] NR 67 TC 57 Z9 59 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2007 VL 32 IS 8 BP 1649 EP 1660 DI 10.1038/sj.npp.1301288 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 191QU UT WOS:000248146900001 PM 17203016 ER PT J AU Ohnishi, T Yamada, K Ohba, H Iwayama, Y Toyota, T Hattori, E Inada, T Kunugi, H Tatsumi, M Ozaki, N Iwata, N Sakamoto, K Iijima, Y Iwata, Y Tsuchiya, KJ Sugihara, G Nanko, S Osumi, N Detera-Wadleigh, SD Kato, T Yoshikawa, T AF Ohnishi, Tetsuo Yamada, Kazuo Ohba, Hisako Iwayama, Yoshimi Toyota, Tomoko Hattori, Eiji Inada, Toshiya Kunugi, Hiroshi Tatsumi, Masahiko Ozaki, Norio Iwata, Nakao Sakamoto, Kaoru Iijima, Yoshimi Iwata, Yasuhide Tsuchiya, Kenji J. Sugihara, Genichi Nanko, Shinichiro Osumi, Noriko Detera-Wadleigh, Sevilla D. Kato, Tadafumi Yoshikawa, Takeo TI A promoter haplotype of the inositol monophosphatase 2 gene (IMPA2) at 18p11.2 confers a possible risk for bipolar disorder by enhancing transcription SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE lithium; luciferase assay; post-mortem brain; quantitative RT-PCR; allele-specific expression; imprinting ID MANIC-DEPRESSIVE PATIENTS; SUSCEPTIBILITY REGION; GENOMIC STRUCTURE; MOOD DISORDER; CELL-LINES; ASSOCIATION; LITHIUM; SCHIZOPHRENIA; EXPRESSION; POLYMORPHISMS AB Lithium is an effective mood stabilizer for bipolar disorder patients and its therapeutic effect may involve inhibition of inositol monophosphatase activity. In humans, the enzyme is encoded by two genes, IMPA1 and IMPA2. IMPA2 maps to 18p11.2, a genomic interval for which evidence of linkage to bipolar disorder has been supported by several reports. We performed a genetic association study in Japanese cohorts (496 patients with bipolar disorder and 543 control subjects). Interestingly, we observed association of IMPA2 promoter single nucleotide polymorphisms (SNPs) (-461C and -207T) with bipolar disorder, the identical SNPs reported previously in a different population. In vitro promoter assay and genetic haplotype analysis showed that the combination of (-461C) -(-207T) (-185A) drove enhanced transcription and the haplotypes containing (-461C) -(-207T)-(-185A) contributed to risk for bipolar disorder. Expression study on post-mortem brains revealed increased transcription from the IMPA2 allele that harbored (-461 C) (-207T)-(-185A) in the frontal cortex of bipolar disorder patients. The examination of allele- specific expressions in post-mortem brains did not support genomic imprinting of IMPA2, which was suggested nearby genomic locus. Contrasting to a prior report, therapeutic concentrations of lithium could not suppress the transcription of IMPA2 mRNA, and the mood-stabilizing effect of lithium is, if IMPA2 was one of the targets of lithium, deemed to be generated via inhibition of enzymatic reaction rather than transcriptional suppression. In conclusion, the present study suggests that a promoter haplotype of IMPA2 possibly contributes to risk for bipolar disorder by elevating IMPA2 levels in the brain, albeit the genetic effect varies among populations. C1 RIKEN, Brain Sci Inst, Lab Mol Psychiat, Wako, Saitama 3510198, Japan. Teikyo Univ, Sch Med, Med Ctr, Chiba, Japan. Natl Inst Neurosci, Dept Mental Disorder Res, Tokyo, Japan. Yokohama Shinryo Clin, Kanagawa, Japan. Nagoya Univ, Fac Med, Dept Psychiat, Nagoya, Aichi, Japan. Fujita Hlth Univ, Fac Med, Dept Psychiat, Nagoya, Aichi, Japan. Tokyo Womens Med Coll, Dept Psychiat, Tokyo 162, Japan. Hamamatsu Univ Sch Med, Dept Psychiat & Neurol, Shizuoka, Japan. Teikyo Univ, Sch Med, Dept Psychiat, Tokyo 173, Japan. Tohoku Univ, Sch Med, Ctr Translat & Adv Anim Res, Sendai, Miyagi 980, Japan. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Yoshikawa, T (reprint author), RIKEN, Brain Sci Inst, Lab Mol Psychiat, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. EM takeo@brain.riken.go.jp RI Ozaki, Norio/M-8908-2014; Kato, Tadafumi/J-3583-2014; OI Ozaki, Norio/0000-0002-7360-4898; Kato, Tadafumi/0000-0001-7856-3952; Tsuchiya, Kenji/0000-0002-1314-4199; Kunugi, Hiroshi/0000-0002-7209-3790 NR 42 TC 25 Z9 26 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2007 VL 32 IS 8 BP 1727 EP 1737 DI 10.1038/sj.npp.1301307 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 191QU UT WOS:000248146900009 PM 17251911 ER PT J AU Barbier, E Zapata, A Oh, E Liu, Q Zhu, F Undie, A Shippenberg, T Wang, JB AF Barbier, Elisabeth Zapata, Agustin Oh, Eric Liu, Qing Zhu, Fei Undie, Ashiwel Shippenberg, Toni Wang, Jia Bei TI Supersensitivity to amphetamine in protein kinase-C interacting protein/HINT1 knockout mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE schizophrenia; amphetamine-induced hyperactivity; dopamine; PKCI/ HINT1 ID GENE-EXPRESSION; PREFRONTAL CORTEX; MOTOR-ACTIVITY; DOPAMINE; SCHIZOPHRENIA; COCAINE; FAMILY; PHOSPHORYLATION; DESENSITIZATION; TRANSPORTER AB Protein kinase C interacting protein/histidine triad nucleotide binding protein 1 (PKC1/HINT1) is a member of the histidine triad protein family. Although this protein is widely expressed in the mammalian brain including mesocorticolimbic and mesostriatal regions, its physiological function in CNS remains unknown. Recent microarray studies reported decreased mRNA expression of PKC1/HINT1 in the frontal cortex of individuals with schizophrenia, suggesting the possible involvement of this protein in the pathophysiology of the disease. In view of the documented link between dopamine (DA) transmission and schizophrenia, the present study used behavioral and neurochemical approaches to examine the influence of constitutive PKC1/HINT1 deletion upon: (i) basal and amphetamine (AMPH)evoked locomotor activity; (ii) DA dynamics in the dorsal striatum, and (iii) postsynaptic DA receptor function. PKC1/HINT1(-/-) (KO) mice displayed lower spontaneous locomotion relative to wild-type (WT) controls. Acute AMPH administration significantly increased locomotor activity in WT mice; nonetheless, the effect was enhanced in KO mice. Quantitative microdialysis studies revealed no alteration in basal DA dynamics in the striatum or nucleus accumbens of KO mice. The ability of acute AMPH to increase DA levels was unaltered indicating that function in presynaptic DA neurotransmission in these regions do not underlie the behavioral phenotype of KO mice. In contrast to WT mice, systemic administration of the direct-acting DA receptor agonist apomorphine (10 mg/kg) significantly increased locomotor activity in KO mice suggesting that postsynaptic DA function is altered in these animals. These results demonstrate an important role of PKC1/HINT1 in modulating the behavioral response to AMPH. Furthermore, they indicate that the absence of this protein may be associated with dysregulation of postsynaptic DA transmission. C1 Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. NIDA, Intramural Res Program, Integrat Neurosci Sect, Baltimore, MD USA. RP Wang, JB (reprint author), Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, 20 N Pine St, Baltimore, MD 21201 USA. EM jwang@rx.umaryland.edu OI Undieh, Ashiwel/0000-0003-1823-5230 FU NIDA NIH HHS [DA17614, R01 DA017614, DA018722, R01 DA017614-04, DA11925] NR 28 TC 35 Z9 36 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD AUG PY 2007 VL 32 IS 8 BP 1774 EP 1782 DI 10.1038/sj.npp.1301301 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 191QU UT WOS:000248146900013 PM 17203012 ER PT J AU Logan, J Wang, GJ Telang, F Fowler, JS Alexoff, D Zabroski, J Jayne, M Hubbard, B King, P Carter, P Shea, C Xu, Y Muench, L Schlyer, D Learned-Coughlin, S Cosson, V Volkow, ND Ding, YS AF Logan, Jean Wang, Gene-Jack Telang, Frank Fowler, Joanna S. Alexoff, David Zabroski, John Jayne, Millard Hubbard, Barbara King, Payton Carter, Pauline Shea, Colleen Xu, Youwen Muench, Lisa Schlyer, David Learned-Coughlin, Susan Cosson, Valerie Volkow, Nora D. Ding, Yu-Shin TI Imaging the norepinephrine transporter in humans with (S,S)-[C-11]O-methyl reboxetine and PET: problems and progress SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE [C-11](S,S)-MRB; PET; norepinephrine transporter; atomoxetine ID POSITRON-EMISSION-TOMOGRAPHY; H-3 DESMETHYLIMIPRAMINE BINDING; NONHUMAN PRIMATE BRAIN; LOCUS-COERULEUS; ENANTIOMERIC RESOLUTION; PARKINSONS-DISEASE; UPTAKE SITES; RAT-BRAIN; NORADRENALINE; RADIOLIGAND AB Results from human studies with the PET radiotracer (S,S)-[C-11]O-methyl reboxetine ([C-11](S,S)-MRB), a ligand targeting the norepinephrine transporter (NET), are reported. Quantification methods were determined from test/retest studies, and sensitivity to pharmacological blockade was tested with different doses of atomoxetine (ATX), a drug that binds to the NET with high affinity (K-i=2-5 nM). Methods: Twenty-four male subjects were divided into different groups for serial 90-min PET studies with [C-11](S,S)-MRB to assess reproducibility and the effect of blocking with different doses of ATX (25, 50 and 100 mg, po). Region-of-interest uptake data and arterial plasma input were analyzed for the distribution volume (DV). Images were normalized to a template, and average parametric images for each group were formed. Results: [C-11](S,S)-MRB uptake was highest in the thalamus (THL) and the midbrain (MBR) [containing the locus coeruleus (LC)] and lowest for the caudate nucleus (CDT). The CDT, a region with low NET, showed the smallest change on ATX treatment and was used as a reference region for the DV ratio (DVR). The baseline average DVR was 1.48 for both the THL and MBR with lower values for other regions [cerebellum (CB), 1.09; cingulate gyrus (CNG) 1.07]. However, more accurate information about relative densities came from the blocking studies. MBR exhibited greater blocking than THL, indicating a transporter density similar to 40% greater than THL. No relationship was found between DVR change and plasma ATX level. Although the higher dose tended to induce a greater decrease than the lower dose for MBR (average decrease for 25 mg=24 +/- 7%; 100 mg=31 +/- 11%), these differences were not significant. The different blocking between MBR (average decrease=28 +/- 10%) and THL (average decrease= 1 +/- 7 : 10%) given the same baseline DVR indicates that the CDT is not a good measure for non-NET binding in both regions. Threshold analysis of the difference between the average baseline DV image and the average blocked image showed the expected NET distribution with the MBR (LC) and hypothalamus > THL > CNG and CB, as well as a significant change in the supplementary motor area. DVR reproducibility for the different brain regions was similar to 10%, but intersubject variability was large. Conclusions: The highest density of NETs was found in the MBR where the LC is located, followed by THL, whereas the lowest density was found in basal ganglia (lowest in CDT), consistent with the regional localization of NETs in the nonhuman primate brain. While all three doses of ATX were found to block most regions, no significant differences between doses were found for any region, although the average percent change across subjects of the MBR did correlate with ATX dose. The lack of a dose effect could reflect a low signal-to-noise ratio coupled with the possibility that a sufficient number of transporters were blocked at the lowest dose and further differences could not be detected. However, since the lowest (25 mg) dose is less than the therapeutic doses used in children for the treatment of attention-deficit/hyperactivity disorder(similar to 1.0 mg/kg/day), this would suggest that there may be additional targets for ATX's therapeutic actions. Published by Elsevier Inc. C1 Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. GlaxoSmithKline Inc, Res Triangle Pk, NC 27709 USA. Natl Inst Drug Abuse, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06520 USA. RP Logan, J (reprint author), Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. EM logan@bnl.gov OI Logan, Jean/0000-0002-6993-9994 FU Intramural NIH HHS; NIBIB NIH HHS [EB002630]; NIDA NIH HHS [DA-019062] NR 41 TC 45 Z9 45 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD AUG PY 2007 VL 34 IS 6 BP 667 EP 679 DI 10.1016/j.nucmedbio.2007.03.013 PG 13 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 206AW UT WOS:000249157300010 PM 17707807 ER PT J AU Seneca, N Cai, L Liow, JS Zoghbi, SS Gladding, RL Hong, J Pike, VW Innis, RB AF Seneca, Nicholas Cai, Lisheng Liow, Jelh-San Zoghbi, Saini S. Gladding, Robert L. Hong, Jinsoo Pike, Victor W. Innis, Robert B. TI Brain and whole-body imaging in nonhuman primates with [C-11]MeS-IMPY, a candidate radioligand for beta-amyloid plaques SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE positron emission tomography; beta-amyloid plaques; [C-11]MeS-IMPY; dosimetry; kinetic analysis ID PITTSBURGH COMPOUND-B; ALZHEIMERS-DISEASE; PET; BINDING; BIODISTRIBUTION; DOSIMETRY; HUMANS; TRACER; MODEL AB [C-11]MeS-IMPY ([S-methyl-C-11]NN-dimethyl-4-(6-(methylthio)imidazo[1,2-a]pyridine-2-yl)aniline) is a potential radioligand for imaging beta-amyloid plaques with positron emission tomography (PET). The aims of this study were to evaluate [C-11]MeS-IMPY uptake in nonhuman primate brain and to estimate radiation exposure from serial whole-body images. Eight PET studies were performed in rhesus monkeys to measure the brain uptake and washout of [C-11]MeS-IMPY Time-activity data were analyzed with one-tissue and two-tissue compartmental models using radiometabolite-corrected plasma input function. In addition, two whole-body PET scans were acquired for 120 min to determine the biodistribution of C]MeS-IMPY Tomographic PET images were compressed into a single planar image to identify organs with the highest radiation exposures. Estimates of the absorbed dose of radiation were calculated using OLINDA 1.0. Injection of [C-11]MeS-IMPY caused little change in pulse rate, blood pressure, respiratory rate and temperature. [C-11]MeS-IMPY showed high standardized brain uptake values of similar to 500% and 600% between 2 and 3 min in cortical regions and the cerebellum, respectively. The brain uptake of [C-11]MeS-IMPY was widespread and quite uniform across all cortical regions. Activity rapidly washed out of the brain, with 20% of peak activity remaining at 40 min. Thus, all brain regions showed minimal retention of radioactivity, consistent with these healthy young animals having negligible amyloid plaques. Regional brain activity fitted well into a one-tissue compartment model. The average volume of distribution in all brain regions was 7.66 +/- 2.14 ml/cm(3) (n=4). The organs with the highest radiation exposure (mu Sv/MBq) were the gallbladder wall (33.4), urinary bladder (17) and lungs (12.9), with a resulting effective dose of 4.9 mu Sv/MBq (18 mrem/mCi). The high brain uptake, rapid washout and quantifiable volume of distribution in nonhuman primate brain further support the evaluation of [C-11]MeS-IMPY. Calculated dosimetry results are comparable with those for other C-labeled brain imaging radioligands. Published by Elsevier Inc. C1 Natl Inst Mental Hlth, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Seneca, N (reprint author), Natl Inst Mental Hlth, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM nicholasseneca@mail.nih.gov FU Intramural NIH HHS; NIMH NIH HHS [N01MH32004] NR 31 TC 11 Z9 12 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD AUG PY 2007 VL 34 IS 6 BP 681 EP 689 DI 10.1016/j.nucmedbio.2007.06.002 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 206AW UT WOS:000249157300011 PM 17707808 ER PT J AU Imam, SZ Indig, FE Cheng, WH Saxena, SP Stevnsner, T Kufe, D Bohr, VA AF Imam, Syed Z. Indig, Fred E. Cheng, Wen-Hsing Saxena, Satya P. Stevnsner, Tinna Kufe, Donald Bohr, Vilhelm A. TI Cockayne syndrome protein B interacts with and is phosphorylated by c-Abl tyrosine kinase SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-DAMAGE; OXIDATIVE STRESS; APOPTOTIC RESPONSE; INDUCE APOPTOSIS; CELLULAR REPAIR; EXCISION-REPAIR; ACTIVE GENES; 8-HYDROXYADENINE; 8-HYDROXYGUANINE; ACTIVATION AB The Cockayne Syndrome group B (CSB) protein plays important roles in transcription, transcription-coupled nucleotide excision repair and base excision DNA repair. c-Abl kinase also plays a role in DNA repair as a regulator/coordinator of the DNA damage response. This study presents evidence that the N-terminal region of CSB interacts with the SH3 domain of c-Abl in vitro and in vivo. In addition, c-Abl kinase phosphorylates CSB at Tyr932. The subcellular localization of CSB to the nucleus and nucleolus is altered after phosphorylation by c-Abl. c-Abl-dependent phosphorylation of CSB increased in cells treated with hydrogen peroxide and decreased in cells pre-treated with STI-571, a c-Abl-specific protein kinase inhibitor. Activation of the c-Abl kinase in response to oxidative damage is not observed in CSB null cells. These results suggest that c-Abl and CSB may regulate each other in a reciprocal manner in response to oxidative stress. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. NIA, Res Resource Branch, NIH, Baltimore, MD 21224 USA. Univ Aarhus, MBI, Danish Ctr Mol Gerontol, DK-8000 Aarhus, Denmark. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU Intramural NIH HHS NR 39 TC 13 Z9 16 U1 2 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG PY 2007 VL 35 IS 15 BP 4941 EP 4951 DI 10.1093/nar/gkm386 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212QQ UT WOS:000249612300002 PM 17626041 ER PT J AU Henriet, S Sinck, L Bec, G Gorelick, RJ Marquet, R Paillart, JC AF Henriet, S. Sinck, L. Bec, G. Gorelick, R. J. Marquet, R. Paillart, J.-C. TI Vif is a RNA chaperone that could temporally regulate RNA dimerization and the early steps of HIV-1 reverse transcription SO NUCLEIC ACIDS RESEARCH LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; VIRAL-DNA SYNTHESIS; IN-VITRO EVIDENCE; NUCLEOCAPSID PROTEIN; NUCLEOPROTEIN COMPLEXES; STRAND TRANSFER; GENOMIC RNA; NONPERMISSIVE CELLS; SECONDARY STRUCTURE; RESTRICTIVE CELLS AB HIV-1 Vif ( viral infectivity factor) is associated with the assembly complexes and packaged at low level into the viral particles, and is essential for viral replication in non-permissive cells. Viral particles produced in the absence of Vif exhibit structural defects and are defective in the early steps of reverse transcription. Here, we show that Vif is able to anneal primer tRNA(Lys3) to the viral RNA, to decrease pausing of reverse transcriptase during (-) strand strong-stop DNA synthesis, and to promote the first strand transfer. Vif also stimulates formation of loose HIV-1 genomic RNA dimers. These results indicate that Vif is a bona fide RNA chaperone. We next studied the effects of Vif in the presence of HIV-1 NCp, which is a well-established RNA chaperone. Vif inhibits NCp-mediated formation of tight RNA dimers and hybridization of tRNA(Lys3), while it has little effects on NCp-mediated strand transfer and it collaborates with nucleocapsid (NC) to increase RT processivity. Thus, Vif might negatively regulate NC-assisted maturation of the RNA dimer and early steps of reverse transcription in the assembly complexes, but these inhibitory effects would be relieved after viral budding, thanks to the limited packaging of Vif in the virions. C1 Univ Strasbourg 1, CNRS, IBMC, Architecture & React ARN, F-67084 Strasbourg, France. NCI, SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD USA. RP Paillart, JC (reprint author), Univ Strasbourg 1, CNRS, IBMC, Architecture & React ARN, 15 Rue Renes Descartes, F-67084 Strasbourg, France. EM r.marquet@ibmc.u-strasbg.fr; jc.paillart@ibmc.u-strasbg.fr RI Paillart, Jean-Christophe/A-4171-2010; OI Marquet, Roland/0000-0002-4209-3976; Paillart, jean-christophe/0000-0003-1647-8917 FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 86 TC 48 Z9 49 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG PY 2007 VL 35 IS 15 BP 5141 EP 5153 DI 10.1093/nar/gkm542 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212QQ UT WOS:000249612300019 PM 17660191 ER PT J AU Shultzaberger, RK Roberts, LR Lyakhov, IG Sidorov, IA Stephen, AG Fisher, RJ Schneider, TD AF Shultzaberger, Ryan K. Roberts, Lindsey R. Lyakhov, Ilya G. Sidorov, Igor A. Stephen, Andrew G. Fisher, Robert J. Schneider, Thomas D. TI Correlation between binding rate constants and individual information of E-coli Fis binding sites SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-BINDING; TRANSCRIPTION FACTOR; REGULATORY PROTEINS; MATHEMATICAL-THEORY; SEQUENCE LOGOS; PREDICTION; COMPLEXES; PROMOTER; COMMUNICATION; REPLICATION AB Individual protein binding sites on DNA can be measured in bits of information. This information is related to the free energy of binding by the second law of thermodynamics, but binding kinetics appear to be inaccessible from sequence information since the relative contributions of the on- and off-rates to the binding constant, and hence the free energy, are unknown. However, the on-rate could be independent of the sequence since a protein is likely to bind once it is near a site. To test this, we used surface plasmon resonance and electromobility shift assays to determine the kinetics for binding of the Fis protein to a range of naturally occurring binding sites. We observed that the logarithm of the off-rate is indeed proportional to the individual information of the binding sites, as predicted. However, the on- rate is also related to the information, but to a lesser degree. We suggest that the on- rate is mostly determined by DNA bending, which in turn is determined by the sequence information. Finally, we observed a break in the binding curve around zero bits of information. The break is expected from information theory because it represents the coding demarcation between specific and nonspecific binding. C1 NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21782 USA. SAIC Frederick, Prot Chem Lab, Adv Technol Program, Frederick, MD 21782 USA. NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Schneider, TD (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. EM toms@ncifcrf.gov RI Fisher, Robert/B-1431-2009; OI Schneider, Thomas/0000-0002-9841-1531; Sidorov, Igor/0000-0001-6519-4983 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 52 TC 19 Z9 20 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG PY 2007 VL 35 IS 16 BP 5275 EP 5283 DI 10.1093/nar/gkm471 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 227UM UT WOS:000250683300001 PM 17617646 ER PT J AU Weissman, L Jo, DG Sorensen, MM de Souza-Pinto, NC Markesbery, WR Mattson, MP Bohr, VA AF Weissman, Lior Jo, Dong-Gyu Sorensen, Martin M. de Souza-Pinto, Nadja C. Markesbery, William R. Mattson, Mark P. Bohr, Vilhelm A. TI Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment SO NUCLEIC ACIDS RESEARCH LA English DT Article ID POLYMERASE-BETA; OXIDATIVE DAMAGE; AD PATIENTS; URACIL; GLYCOSYLASE; LYMPHOCYTES; NEURONS; RISK; MITOCHONDRIA; HOMOCYSTEINE AB Oxidative stress is thought to play a role in the pathogenesis of Alzheimer's disease (AD) and increased oxidative DNA damage has been observed in brain tissue from AD patients. Base excision repair (BER) is the primary DNA repair pathway for small base modifications such as alkylation, deamination and oxidation. In this study, we have investigated alterations in the BER capacity in brains of AD patients. We employed a set of functional assays to measure BER activities in brain tissue from short post-mortem interval autopsies of 10 sporadic AD patients and 10 age-matched controls. BER activities were also measured in brain samples from 9 amnestic mild cognitive impairment (MCI) subjects. We found significant BER deficiencies in brains of AD patients due to limited DNA base damage processing by DNA glycosylases and reduced DNA synthesis capacity by DNA polymerase beta. The BER impairment was not restricted to damaged brain regions and was also detected in the brains of amnestic MCI patients, where it correlated with the abundance of neurofibrillary tangles. These findings suggest that BER dysfunction is a general feature of AD brains which could occur at the earliest stages of the disease. The results support the hypothesis that defective BER may play an important role in the progression of AD. C1 NIA, NIH, Labs Mol Gerontol, Baltimore, MD 21224 USA. NIA, NIH, Labs Neurosci, Baltimore, MD 21224 USA. Sungkyunkwan Univ, Coll Pharm, Suwon, South Korea. Univ Kentucky, Sanders Brown Ctr Aging, Lexington, KY 40536 USA. Univ Kentucky, Alzheimers Dis Ctr, Lexington, KY 40536 USA. Univ Kentucky, Dept Pathol & Lab Med, Lexington, KY 40536 USA. Univ Kentucky, Dept Neurol, Lexington, KY 40536 USA. RP Bohr, VA (reprint author), NIA, NIH, Labs Mol Gerontol, Baltimore, MD 21224 USA. EM vbohr@nih.gov RI Mattson, Mark/F-6038-2012; Souza-Pinto, Nadja/C-3462-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X FU Intramural NIH HHS; NIA NIH HHS [P30 AG028383] NR 40 TC 131 Z9 132 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD AUG PY 2007 VL 35 IS 16 BP 5545 EP 5555 DI 10.1093/nar/gkm605 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 227UM UT WOS:000250683300026 PM 17704129 ER PT J AU Davis, CD Hartmuller, V Freedman, DM Hartge, P Picciano, MF Swanson, CA Milner, JA AF Davis, Cindy D. Hartmuller, Virginia Freedman, D. Michal Hartge, Patricia Picciano, Mary Frances Swanson, Christine A. Milner, John. A. TI Vitamin D and cancer: Current dilemmas and future needs SO NUTRITION REVIEWS LA English DT Editorial Material C1 NCI, Div Canc Prevent, NIH, DHHS, Rockville, MD 20892 USA. NCI, Div Canc Control & Populat Sci, NIH, Rockville, MD USA. NCI, Div Canc Epidemiol, NIH, Rockville, MD USA. NIH, Off Dietary Supplements, Rockville, MD USA. RP Davis, CD (reprint author), NCI, Div Canc Prevent, NIH, DHHS, 6130 Execut Blvd,Suite 3159, Rockville, MD 20892 USA. EM davisci@mail.nih.gov NR 0 TC 17 Z9 18 U1 0 U2 0 PU INT LIFE SCIENCES INST NORTH AMER PI WASHINGTON PA ONE THOMAS CIRCLE, N W, 9TH FLOOR, WASHINGTON, DC 20005 USA SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD AUG PY 2007 VL 65 IS 8 BP S71 EP S74 DI 10.1111/j.1753-4887.2007.tb00343.x PN 2 PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 203SY UT WOS:000248995500001 PM 17867373 ER PT J AU Tucker, MA AF Tucker, Margaret A. TI Sun exposure measurements in Populations SO NUTRITION REVIEWS LA English DT Article; Proceedings Paper CT Conference on Vitamin D and Cancer - Current Dilemas/Future Needs CY MAY 07-08, 2007 CL NIH, Bethesda, MD HO NIH ID QUESTIONNAIRE; ADOLESCENTS; RADIATION; MELANOMA; RISK C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Tucker, MA (reprint author), NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Human Genet Program, 6120 Execut Blvd,Room 7122, Bethesda, MD 20892 USA. EM tuckerp@mail.nih.gov RI Tucker, Margaret/B-4297-2015 NR 13 TC 5 Z9 5 U1 0 U2 0 PU INT LIFE SCIENCES INST NORTH AMER PI WASHINGTON PA ONE THOMAS CIRCLE, N W, 9TH FLOOR, WASHINGTON, DC 20005 USA SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD AUG PY 2007 VL 65 IS 8 BP S84 EP S86 DI 10.1111/j.1753-4887.2007.tb00347.x PN 2 PG 3 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 203SY UT WOS:000248995500005 PM 17867377 ER PT J AU Nunez, NP Carpenter, CL Perkins, SN Berrigan, D Jaque, SV Ingles, SA Bernstein, L Forman, MR Barrett, JC Hursting, SD AF Nunez, Nomeli P. Carpenter, Catherine L. Perkins, Susan N. Berrigan, David Jaque, S. Victoria Ingles, Sue Ann Bernstein, Leslie Forman, Michele R. Barrett, J. Carl Hursting, Stephen D. TI Extreme obesity reduces bone mineral density: Complementary evidence from mice and women SO OBESITY LA English DT Article DE ovariectomy; bone mineral density; leptin; mice; women ID BODY-COMPOSITION; BREAST-CANCER; LEPTIN; FAT; OVERWEIGHT; ADULTS; MODEL; MASS AB Objective: To evaluate the effects of body adiposity on bone mineral density in the presence and absence of ovarian hormones in female mice and postmenopausal women. Research Methods and Procedures: We assessed percentage body fat, serum leptin levels, and bone mineral density in ovariectomized and non-ovariectomized C57BL/6 female mice that had been fed various calorically dense diets to induce body weight profiles ranging from lean to very obese. Additionally, we assessed percentage body fat and whole body bone mineral density in 37 overweight and extremely obese postmenopausal women from the Women's Contraceptive and Reproductive Experiences study. Results: In mice, higher levels of body adiposity (> 40% body fat) were associated with lower bone mineral density in ovariectomized C57BL/6 female mice. A similar trend was observed in a small sample of postmenopausal women. Discussion: The complementary studies in mice and women suggest that extreme obesity in postmenopausal women may be associated with reduced bone mineral density. Thus, extreme obesity (BMI > 40 kg/m(2)) may increase the risk for osteopenia and osteoporosis. Given the obesity epidemic in the U.S. and in many other countries, and, in particular, the rising number of extremely obese adult women, increased attention should be drawn to the significant and interrelated public health issues of obesity and osteoporosis. C1 NCI, Lab Biochem Canc, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Canc Prevent Fellowship Program, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Ctr Human Nutr, Los Angeles, CA USA. NCI, Appl Res Prog, Div Canc Control & Populat Sci, Bethesda, MD USA. Univ So Calif, Dept Prevent Med, Alhambra, CA USA. RP Hursting, SD (reprint author), Univ Texas, Div Nutr Sci, 1 Univ Stn,A2700, Austin, TX 78712 USA. EM shursting@mail.utexas.edu FU NCI NIH HHS [N01-CO-12400]; NICHD NIH HHS [N01 HD 3-3175] NR 25 TC 46 Z9 50 U1 0 U2 6 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1930-7381 J9 OBESITY JI Obesity PD AUG PY 2007 VL 15 IS 8 BP 1980 EP 1987 DI 10.1038/oby.2007.236 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 203VJ UT WOS:000249001800012 PM 17712115 ER PT J AU Solomon, D Stoler, M Jeronimo, J Khan, M Castle, P Schiffman, M AF Solomon, Diane Stoler, Mark Jeronimo, Jose Khan, Michelle Castle, Philip Schiffman, Mark TI Diagnostic utility of endocervical curettage in women undergoing colposcopy for equivocal or low-grade cytologic abnormalities SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID MANAGEMENT; DEBATE AB Objective: To estimate the diagnostic yield of endocervical curettage (ECC) when performed as part of a colposcopic procedure in the multicenter ASCUS-LSIL Triage Study (ALTS), a randomized trial of management strategies for women with equivocal or mildly abnormal cytology. Methods: A total of 1,119 women in ALTS had colposcopic examinations that included an ECC performed at the discretion of the colposcopist. We compared the results of ECC and concurrent cervical colposcopic evaluation, with or without biopsy, in prediction of final histopathologic diagnosis. This was defined as the worst histopathologic result from that colposcopy or any subsequent procedure during 2 years of follow-up. Results: Overall, 3.7% of ECCs yielded a diagnostic abnormality of cervical intraepithelial neoplasia (CIN) 2+ compared with 21.7% of colposcopically directed biopsies. In women ultimately found to have CIN 2+ in the trial, the overall sensitivity of colposcopically directed biopsy was 72.5%, compared with 12.2% for ECC. In women under 40, the marginal contribution of ECC, independently of biopsy, was only 2.2%. By contrast, among women 40 and older, the sensitivity of biopsy dropped while the sensitivity of ECC improved, resulting in 13.0% increased detection with ECC, independently of biopsy. However, in women 40 and older, the combined sensitivity of ECC and biopsy was only 47.8% for a single colposcopy procedure. Conclusion: As an ancillary diagnostic technique to colposcopically directed biopsy, ECC is of questionable value in younger women. However, in women aged 40 and older, the sensitivity of colposcopic biopsy decreased and the sensitivity of ECC increased. Thus, ECC may be useful in older women undergoing colposcopy for equivocal or mildly abnormal cytology. C1 Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA 22903 USA. NCI, Dept Hlth & Human Serv, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Stoler, M (reprint author), Univ Virginia Hlth Syst, Dept Pathol, 1215 Lee St,Office 3032, Charlottesville, VA 22903 USA. EM mhs2e@virginia.edu FU NCI NIH HHS [CN 55105, CN 55155, CN 55159, CN 55154, CN 55156, CN 55157, CN 55153, CN 55158] NR 11 TC 31 Z9 33 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2007 VL 110 IS 2 BP 288 EP 295 DI 10.1097/01.AOG.0000270154.69879.09 PN 1 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 193QY UT WOS:000248290500010 PM 17666602 ER PT J AU Louis, J Landon, MB Gersnoviez, RJ Leveno, KJ Spong, CY Rouse, DJ Moawad, AH Varner, MW Caritis, SN Harper, M Wapner, RJ Miodovnik, M Carpenter, M Peaceman, AM O'Sullivan, MJ Sibai, BM Langer, O Thorp, JM Ramin, SM Mercer, BM AF Louis, Judette Landon, Mark B. Gersnoviez, Rebecca J. Leveno, Kenneth J. Spong, Catherine Y. Rouse, Dwight J. Moawad, Atef H. Varner, Michael W. Caritis, Steve N. Harper, Margaret Wapner, Ronald J. Miodovnik, Menachem Carpenter, Marshall Peaceman, Alan M. O'Sullivan, Mary J. Sibai, Baha M. Langer, Oded Thorp, John M. Ramin, Susan M. Mercer, Brian M. CA NICHD MFMU Network TI Perioperative morbidity and mortality among human immunodeficiency virus-infected women undergoing cesarean delivery SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID HIV-POSITIVE WOMEN; MATERNAL MORTALITY; POSTPARTUM MORBIDITY; VAGINAL DELIVERY; SOUTH-AFRICA; SECTION; COMPLICATIONS; TRANSMISSION; MODE; PREVENTION AB Objective: To determine whether human immunodeficiency virus (HIV)-infected women have a higher rate of postcesarean morbidity and mortality compared with women without HIV infection. Methods: A secondary analysis was performed of women with singleton gestations undergoing cesarean delivery with known HIV status. Data were collected as part of a prospective 4-year (1999-2002) observational study and analyzed using logistic regression. Women were surveyed for a large number of intraoperative complications, common perioperative morbidities, and uncommon maternal complications. Results: There were 378 HIV-infected and 54,281 uninfected women who met criteria. Patients infected with HIV were more likely to have postpartum endometritis (11.6% compared with 5.8%, P <.001), require a postpartum blood transfusion (4.0% compared with 2.0%, P=.02), develop maternal sepsis (1.1% compared with 0.2%, P <.001), be treated for pneumonia (1.3% compared with 0.3%, P=.001), and to have a maternal death (0.8% compared with 0.1%, P <.001). After controlling for potential confounders, patients with HIV infection were more likely to have one or more postpartum morbidities (odds ratio 1.6, 95% confidence interval 1.2-2.2). Conclusion: Women with HIV infection undergoing cesarean delivery are at increased risk for perioperative morbidity and maternal mortality. C1 Wayne State Univ, Detroit, MI USA. Ohio State Univ, Columbus, OH 43210 USA. George Washington Univ, Biostat Ctr, Washington, DC USA. Univ Texas San Antonio, SW Med Ctr, Dallas, TX USA. NICHHD, Bethesda, MD 20892 USA. Univ Alabama Birmingham, Birmingham, AL USA. Univ Chicago, Chicago, IL 60637 USA. Univ Utah, Salt Lake City, UT USA. Univ Pittsburgh, Pittsburgh, PA USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Univ Cincinnati, Cincinnati, OH USA. Columbia Univ, New York, NY USA. Brown Univ, Providence, RI 02912 USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Miami, Miami, FL 33152 USA. Univ Tennessee, Memphis, TN USA. Univ Texas San Antonio, San Antonio, TX 78285 USA. Univ N Carolina, Chapel Hill, NC USA. Univ Texas San Antonio, Houston, TX USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Louis, J (reprint author), 2500 Metrohlth Dr, Cleveland, OH 44109 USA. EM judettelouis@hotmail.com RI Louis, Judette/E-5130-2013; Varner, Michael/K-9890-2013; OI Louis, Judette/0000-0002-1336-7886; caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973; Peaceman, Alan/0000-0002-4515-4850 FU NICHD NIH HHS [HD 34136, HD 21410, HD 21414, HD 27860, HD 27861, HD 27869, HD 27905, HD 27915, HD 27917, HD 34116, HD 34122, HD 34208, HD 34210, HD 36801, HD 40485, HD 40500, HD 40512, HD 40544, HD 40545, HD 40560] NR 22 TC 23 Z9 25 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2007 VL 110 IS 2 BP 385 EP 390 DI 10.1097/01.AOG.0000275263.81272.fc PN 1 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 193QY UT WOS:000248290500023 PM 17666615 ER PT J AU Livingston, EG Cohn, SE Yang, Y Watts, HD Bardeguez, AD Jones, TB Smith, LM Umbleja, T McComsey, GA AF Livingston, Elizabeth G. Cohn, Susan E. Yang, Yang Watts, Heather D. Bardeguez, Arlene D. Jones, Theodore B. Smith, Laura M. Umbleja, Triin McComsey, Grace A. CA AIDS Clinical Trials Grp A5084 Stu TI Lipids and lactate in human immunodeficiency virus-1-infected pregnancies with or without protease inhibitor-based therapy SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 8th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV CY SEP 24-26, 2006 CL San Francisco, CA ID ANTIRETROVIRAL THERAPY; HIV; ACIDOSIS; WOMEN; FETAL AB Objective: To evaluate the effect of protease inhibitors on lipid and lactate levels and gastrointestinal symptoms in pregnancy. Methods: Acquired Immunodeficiency Syndrome (AIDS) Clinical Trials Group (ACTG) A5084 was an observational cohort study of human immunodeficiency virus (HIV)-infected pregnant women. Women recruited between 20 and 34 weeks of gestation were required to be on a stable, highly active antiretroviral therapy (HAART) regimen, stratified by protease inhibitor compared with no protease inhibitor regimens. Interval history was assessed, and lipid and lactate levels were drawn every 8 weeks during pregnancy and 12 weeks postpartum, with levels closest to delivery and postpartum used for analysis. Statistical comparisons used Kruskal-Wallis and Fisher exact tests. Results: One-hundred fifty-eight women were evaluated. Total cholesterol levels (median 230 mg/dL, inter-quartile range [197, 259], compared with 212 [179, 246] mg/dL, P=.042) and triglycerides (median 224 mg/dL, interquartile range [187, 288], compared with 185 [142, 230] mg/dL, P <.0011 were elevated in the protease inhibitor group during pregnancy and remained higher in this group after delivery (total cholesterol 185 [163, 224] mg/dl compared with 171 [140, 190] mg/dL, P <.004; triglycerides 122 [87, 175] mg/dL compared with 89 [66, 150] mg/dL, P=.02). No difference was seen in lactate levels or rates of gastrointestinal symptoms between groups. Obstetric outcomes were similar between the two groups. A higher number of low birth weight infants were born to women in the highest twentieth percentile of triglycerides compared with the lowest across medication groups. Conclusion: Cholesterol and triglycerides were higher in protease inhibitor-treated women in pregnancy. Lactate and gastrointestinal symptoms were not different. A higher number of low birth weight infants were noted in women with high triglycerides, but other elevated lipid levels did not affect pregnancy outcomes. C1 Duke Univ, Med Ctr, Durham, NC 27710 USA. Univ Rochester, Rochester, NY USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. NIH, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. Wayne State Univ, Detroit, MI USA. Frontier Sci Technol & Res Fdn, Amherst, NY USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Livingston, EG (reprint author), Duke Univ, Med Ctr, Box 3967, Durham, NC 27710 USA. EM livin001@mc.duke.edu FU NCRR NIH HHS [RR 000080]; NIAID NIH HHS [5U01 AI 25883, 1U01 AI 39156, 3U01 AI 38558, 2U01 AI 27658, U01 AI 41089]; NICHD NIH HHS [N01 HD 33345] NR 18 TC 9 Z9 9 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2007 VL 110 IS 2 BP 391 EP 397 DI 10.1097/01.AOG.0000271210.79340.4c PN 1 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 193QY UT WOS:000248290500024 PM 17666616 ER PT J AU Spong, CY AF Spong, Catherine Y. TI Prediction and prevention of recurrent spontaneous preterm birth SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID CERVICOVAGINAL FETAL FIBRONECTIN; RANDOMIZED CONTROLLED-TRIAL; FISH-OIL SUPPLEMENTATION; PLACEBO-CONTROLLED TRIAL; HIGH-RISK; GESTATIONAL-AGE; DOUBLE-BLIND; SHORT CERVIX; 17-ALPHA-HYDROXYPROGESTERONE CAPROATE; INTERPREGNANCY INTERVAL AB Rates of preterm birth have continued to rise despite intensive research efforts over the last several decades. A woman who has a spontaneous preterm birth is at high risk for a subsequent preterm birth. Studies have identified clinical, sonographic, and biochemical markers that help to identify the women at highest risk. Determining cervical length and measuring cervicovaginal fibronectin have been proposed as useful tools for evaluating women at risk of preterm birth and may identify those who might benefit from a timely course of antenatal corticosteroids, but effective interventions to prevent preterm birth remain elusive. In the prevention of recurrent spontaneous preterm birth, recent trials have confirmed the use of progesterone beginning in the second trimester as an effective intervention. Optimal management of women with a history of spontaneous preterm birth includes a thorough review of the obstetric, medical, and social history, with attention to potentially reversible causes of preterm birth (eg, smoking cessation, acute infections, strenuous activities), accurate ultrasound dating, consideration of progesterone therapy beginning at 16-20 weeks of gestation, and close surveillance during the pregnancy for evolving findings. Results from the ongoing trials of cerclage as an interventional therapy and omega-3 fatty acid supplementation as a preventive therapy will provide additional knowledge for the optimal management of these high-risk women. C1 NICHHD, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. RP Spong, CY (reprint author), NICHD, Pregnancy & Perinatol Branch, NIH, 6100 Execut Blvd,Room 4B03,MSC 7510, Bethesda, MD 20892 USA. EM spongc@mail.nih.gov NR 54 TC 102 Z9 109 U1 2 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD AUG PY 2007 VL 110 IS 2 BP 405 EP 415 DI 10.1097/01.AOG.0000275287.08520.4a PN 1 PG 11 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 193QY UT WOS:000248290500026 PM 17666618 ER PT J AU Snyder, KM Mackall, CL AF Snyder, Kristen M. Mackall, Crystal L. TI Highlight SO PEDIATRIC BLOOD & CANCER LA English DT Editorial Material ID TOTAL-BODY IRRADIATION; STEM-CELL TRANSPLANTATION; RISK EWINGS-SARCOMA; HIGH-DOSE THERAPY; BONE; CHEMOTHERAPY; ETOPOSIDE; TUMORS C1 NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, 10-CRC-1W-3940,10 Ctr Dr,MSC 1104, Bethesda, MD 20892 USA. EM cm35c@nih.gov NR 12 TC 3 Z9 4 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD AUG PY 2007 VL 49 IS 2 BP 115 EP 116 DI 10.1002/pbc.21238 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 184BQ UT WOS:000247616500001 PM 17474114 ER PT J AU Mauras, N Beck, RW Kollman, C Chase, HP Tsalikian, E Fox, LA Weinzimer, SA Xing, DY Ruedy, KJ Steffes, MW Borland, TM Singh, R Tamborlane, WV AF Mauras, Nelly Beck, Roy W. Kollman, Craig Chase, H. Peter Tsalikian, Eva Fox, Larry A. Weinzimer, Stuart A. Xing, Dongyuan Ruedy, Katrina J. Steffes, Michael W. Borland, Timothy M. Singh, Ravinder Tamborlane, William V. CA Diabet Res Children Network Study TI Impaired overnight counterregulatory hormone responses to spontaneous hypoglycemia in children with type 1 diabetes SO PEDIATRIC DIABETES LA English DT Article DE epinephrine; GH; hypoglycemia; norepinephrine; T1DM ID ANTECEDENT HYPOGLYCEMIA; SUBSEQUENT HYPOGLYCEMIA; GLUCOSE COUNTERREGULATION; AUTONOMIC FAILURE; NORMAL HUMANS; EXERCISE; MELLITUS; CORTISOL; GLUCAGON; IDDM AB To assess the changes in counterregulatory hormones overnight after an afternoon of structured exercise or sedentary activity in children with type I diabetes mellitus (T1DM), the Diabetes Research in Children Network (DirecNet) studied 50 children (10 to < 18 yr) with TI DM in five clinical research centers on two separate days (with and without an afternoon exercise session) using a crossover design. Glucose, epinephrine. norepinephrine, cortisol, growth hormone (GH), and glucagon concentrations were measured hourly overnight. Nocturnal hypoglycemia [plasma glucose concentrations <= 70 mg/dL (3.9 mmol/L)] occurred more frequently on the nights following exercise (56 vs. 36%; p = 0.008). Mean hourly concentrations of most hormones did not differ between sedentary or exercise nights or between nights with or without hypoglycemia. Spontaneous nocturnal hypoglycemia only stimulated small increases in plasma epinephrine and GH concentrations and failed to cause a rise in norepinephrine, cortisol, or glucagon levels in comparison with values during the hour before or after hypoglycemia or other times during those same nights. Counterregulatory hormone responses to spontaneous nocturnal hypoglycemia were markedly decreased regardless of whether there was antecedent afternoon exercise in children with T1DM. Sleep-induced impairments in counterregulatory hormone responses likely contribute to the increased risk of hypoglycemia during the entire overnight period in youth with T1DM. C1 DirecNet Coordinat Ctr, Jaeb Ctr Hlth Res, Tampa, FL 33647 USA. Univ Minnesota, Cent Lab, Minneapolis, MN 55455 USA. Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. NIH, Bethesda, MD USA. RP Mauras, N (reprint author), DirecNet Coordinat Ctr, Jaeb Ctr Hlth Res, 15310 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM direcnet@jaeb.org NR 23 TC 0 Z9 0 U1 3 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1399-543X EI 1399-5448 J9 PEDIATR DIABETES JI Pediatr. Diabetes PD AUG PY 2007 VL 8 IS 4 BP 199 EP 205 PG 7 WC Endocrinology & Metabolism; Pediatrics SC Endocrinology & Metabolism; Pediatrics GA 196LS UT WOS:000248483900005 ER PT J AU Johnson, SB Bradshaw, CP Wright, JL Haynie, DL Simons-Morton, BG Cheng, TL AF Johnson, Sara B. Bradshaw, Catherine P. Wright, Joseph L. Haynie, Denise L. Simons-Morton, Bruce G. Cheng, Tina L. TI Characterizing the teachable moment - Is an emergency department visit a teachable moment for intervention among assault-injured youth and their parents? SO PEDIATRIC EMERGENCY CARE LA English DT Article DE teachable moment; assault injury; youth violence; intervention ID SMOKING-CESSATION; VIOLENCE; CANCER; HEALTH; RISK AB Objectives: Injury interventions often invoke the teachable moment (TM); however, there is scant empirical research examining this construct with violent injuries. We sought to operationalize the TM construct and to determine whether an emergency department (ED) visit was a TM for intervention among assault-injured adolescents and their parents. Setting and Participants: One hundred sixty-eight youth (age, 10-15 years) and their parents presenting to the ED with interpersonal assault injuries at 2 urban medical centers. Methods and Analysis: Data were collected using ED record abstraction and interviews. Interview questions assessed perceived injury severity, perceived susceptibility, and preventability/ability to avoid future conflict. Data were examined by age, sex, weapon involvement, and time elapsed between injury and interview. Factor analysis was used to identify the components of the TM construct, and a TM index was created for youth and parents. Results: Youth and parents found their trip to the ED moderately stressful, although parents perceived more stress than youth. Older youth (13-15 years old) and the parents of younger youth (10-12 years old) were most likely to see their injuries as preventable. The parent TM index was positively correlated with parent-reported aggression (r = 0.16, P < 0.03); the youth's TM index scores were associated with the time elapsed since the event (r = -0.16, P = 0.03). Conclusions: This study provides preliminary support for the TM after assault injuries. The TM index may be a first step toward an assessment that can differentiate individuals who are amenable to violence prevention intervention from those who are not. C1 Univ Calif San Francisco, San Francisco, CA 94118 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. Johns Hopkins Ctr Prevent Youth Violence, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Childrens Res Inst, Washington, DC USA. George Washington Univ, Sch Med, Washington, DC USA. George Washington Univ, Sch Publ Hlth, Washington, DC USA. Childrens Natl Med Human Dev, Dept Emergency Med, Washington, DC USA. NICHHD, Prevent Res Branch, Bethesda, MD 20892 USA. Johns Hopkins Univ, Div Gen Pediat & Adolescent Med, Baltimore, MD USA. RP Johnson, SB (reprint author), Univ Calif San Francisco, 3333 Calif St,Suite 465, San Francisco, CA 94118 USA. EM sara.johnson@ucsf.edu OI Simons-Morton, Bruce/0000-0003-1099-6617; Haynie, Denise/0000-0002-8270-6079 NR 24 TC 29 Z9 29 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0749-5161 J9 PEDIATR EMERG CARE JI Pediatr. Emerg. Care PD AUG PY 2007 VL 23 IS 8 BP 553 EP 559 DI 10.1097/PEC.0b013e31812c6687 PG 7 WC Emergency Medicine; Pediatrics SC Emergency Medicine; Pediatrics GA 200QE UT WOS:000248777100007 PM 17726415 ER PT J AU Zaoutis, TE Roilides, E Chiou, CC Buchanan, WL Knudsen, TA Sarkisova, TA Schaufele, RL Sein, M Sein, T Prasad, PA Chu, JH Walsh, TJ AF Zaoutis, Theoklis E. Roilides, Emmanuel Chiou, Christine C. Buchanan, Wendy L. Knudsen, Tena A. Sarkisova, Tatyana A. Schaufele, Robert L. Sein, Michael Sein, Tin Prasad, Priya A. Chu, Jaclyn H. Walsh, Thomas J. TI Zygomycosis in children: A systematic review and analysis of reported cases SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Review DE epidemiology; zygomycosis; mucon-nycosis; outcome; risk factors ID SALVAGE THERAPY; POSACONAZOLE; MUCORMYCOSIS; INFECTIONS AB Background: Zygomycosis has emerged as an increasingly important infection with a high mortality especially in immunocompromised patients. No comprehensive analysis of pediatric zygomycosis cases has been published to date. Methods: We used a PUBMED search for English publications of pediatric (0 - 18 years) zygomycosis cases and references from major books as well as single case reports or case series. Individual references were reviewed for additional cases. Data were entered into Filemaker-pro database and analyzed by logistic regression analysis. Results: One hundred fifty-seven cases (64% male) were found with median age 5 years (range, 0.16-13). Underlying conditions included neutropenia (18%), prematurity (17%), diabetes mellitus (15%), ketoacidosis (10%), and no apparent underlying condition (14%). The most common patterns of zygomycosis were cutaneous (27%), gastrointestinal (21%), rhinocerebral (18%), and pulmonary (16%). Among 77 culture-confirmed cases, Rhizopus spp. (44%) and Mucor spp. (15%) were most commonly identified. Of 81 patients who were given antifungal therapy, 73% received an amphotericin B formulation only. The remaining patients received mostly amphotericin B in combination with other antifungal agents. Mortality in patients without antifungal therapy was higher than in those with therapy (88% versus 36%, P < 0.0001). Ninety-two (59%) patients underwent surgery. Cerebral, gastrointestinal, disseminated and cutaneous zygomycosis were associated with mortality rates of 100, 100, 88, and 0%, respectively. Independent risk factors for death were disseminated infection (OR: 7.18; 95% CI: 3.02-36.59) and age < 1 year (OR: 3.85; 95% CI: 1.05-7.43). Antifungal therapy and particularly surgery reduced risk of death by 92% (OR: 0.07; 95% Cl: 0.04-0.25) and 84% (OR: 0.16; 95% CI: 0.09-0.61), respectively. Conclusions: Zygomycosis is a life-threatening infection in children with neutropenia, diabetes mellitus, and prematurity as common predisposing factors, and there is high mortality in untreated disease, disseminated infection, and age < 1 year. Amphotericin B and surgery significantly improve outcome. C1 Childrens Hosp Philadelphia, Div Infect Dis, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Aristotle Univ Thessaloniki, Dept Pediat 3, GR-54006 Thessaloniki, Greece. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Natl Yang Ming Univ, Taipei 112, Taiwan. RP Zaoutis, TE (reprint author), Childrens Hosp Philadelphia, Div Infect Dis, 3535 Market St,Room 1527, Philadelphia, PA 19104 USA. EM zaoutis@email.chop.edu FU Intramural NIH HHS; NIAID NIH HHS [1K23 AI0629753-1] NR 11 TC 89 Z9 96 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2007 VL 26 IS 8 BP 723 EP 727 DI 10.1097/INF.0b013e318062115c PG 5 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 198SJ UT WOS:000248647500011 PM 17848885 ER PT J AU Lin, FYC AF Lin, Feng-Ying C. TI Respiratory distress related to asymptomatic colonization with group B streptococci - Reply SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Letter ID INFECTIONS C1 Natl Inst Child Hlth & Human Dev, NIH, DHHS, Bethesda, MD USA. RP Lin, FYC (reprint author), Natl Inst Child Hlth & Human Dev, NIH, DHHS, Bethesda, MD USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD AUG PY 2007 VL 26 IS 8 BP 765 EP 766 DI 10.1097/INF.0b013e3180cc25f1 PG 2 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 198SJ UT WOS:000248647500028 ER PT J AU McKinney, RE Rodman, J Hu, CC Britto, P Hughes, M Smith, ME Serchuck, LK Kraimer, J Ortiz, AA Flynn, P Yogev, R Spector, S Draper, L Tran, P Scites, M Dickover, R Weinberg, A Cunningham, C Abrams, E Blum, MR Chittick, GE Reynolds, L Rathore, M AF McKinney, Ross E., Jr. Rodman, John Hu, Chengcheng Britto, Paula Hughes, Michael Smith, Mary Elizabeth Serchuck, Leslie K. Kraimer, Joyce Ortiz, Alberto A. Flynn, Patricia Yogev, Ram Spector, Stephen Draper, Linda Tran, Paul Scites, Melissa Dickover, Ruth Weinberg, Adriana Cunningham, Coleen Abrams, Elaine Blum, M. Robert Chittick, Gregory E. Reynolds, Laurie Rathore, Mobeen CA Pediat AIDS Clin Trials Grp Prot TI Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and adolescents: Pediatric AIDS clinical trials group protocol P1021 SO PEDIATRICS LA English DT Article DE agents; antiretroviral; AIDS; child; didanosine; efavirenz; emtricitabine; HIV ID COMBINATION THERAPY; HIV-1-INFECTED ADULTS; RANDOMIZED-TRIAL AB Background. Compliance with complex antiretroviral therapy regimens is a problem for HIV-1-infected children and their families. Simple, safe, and effective regimens are important for long-term therapeutic success. Methods. A novel, once-daily dosing regimen of 3 antiretroviral drugs, emtricitabine, didanosine, and efavirenz, was tested in 37 therapy-naive HIV- infected children and adolescents between 3 and 21 years of age (inclusive). Subjects were followed for >= 96 weeks on an intention-to-treat basis. Signs, symptoms, plasma HIV-1 RNA viral load, CD4 counts, and safety laboratories were followed regularly. End points were the proportion of subjects with plasma HIV < 400 or 50 HIV copies per mL and safety and tolerability of the regimen. Results. Thirty-seven subjects enrolled at 16 sites. Two subjects with rashes during the first 2 weeks of therapy were the only adverse events leading to study-drug discontinuation. Other early (before protocol-scheduled conclusion) study discontinuations included 3 viral failures on treatment and 5 patients who stopped therapy for apparently nonmedical reasons. Possible drug-related adverse events included 1 grade 4 low-glucose and 5 varied grade 3 events. There were no deaths. Virologic outcomes demonstrated that 32 (85%) of 37 subjects achieved viral suppression to < 400 RNA copies per mL, and 26 (72%) of 37 subjects maintained sustained suppression at < 50 copies per mL through week 96. The median baseline CD4 count was 310 per mu L (17%), which increased at week 96 by a median of +329 cells per mu L (by + 18% CD4). Pharmacokinetic results were as predicted for emtricitabine, didanosine, and efavirenz capsules, whereas efavirenz concentrations in children receiving efavirenz oral solution were lower than anticipated, requiring a dose escalation after the planned assessment point. Conclusions. A once-daily regimen of emtricitabine, didanosine, and efavirenz proved to be safe and tolerable and demonstrated good immunologic and virologic efficacy in this 2-year study. C1 Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. NIAID, Div Aids, Bethesda, MD 20892 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, NIH, Bethesda, MD 20892 USA. Social & Sci Syst Inc, Silver Spring, MD USA. Childrens Mem Hosp, Dept Pediat, Chicago, IL 60614 USA. Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. Univ Florida, Hlth Sci Ctr, Dept Pediat, Jacksonville, FL 32209 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Pediat, Los Angeles, CA USA. Univ Colorado, Hlth Sci Ctr, Dept Pediat, Denver, CO 80262 USA. SUNY Hlth Sci Ctr, Dept Pediat, Syracuse, NY 13210 USA. Harlem Hosp Med Ctr, Dept Pediat, New York, NY USA. Gilead Sci Inc, Durham, NC USA. Bristol Myers Squibb Co, Wallingford, CT 06492 USA. RP McKinney, RE (reprint author), Duke Univ, Med Ctr, Dept Pediat, Box 3461, Durham, NC 27710 USA. EM ross.mckinney@duke.edu RI Hu, Chengcheng/A-8391-2017 FU NCRR NIH HHS [5 M01 RR-01271, 5 M01 RR00069]; NIAID NIH HHS [5U01 AI 27560-18] NR 7 TC 30 Z9 31 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2007 VL 120 IS 2 BP E416 EP E423 DI 10.1542/peds.2006-0925 PG 8 WC Pediatrics SC Pediatrics GA 196SY UT WOS:000248503500066 PM 17646352 ER PT J AU Melendi, GA Laham, FR Monsalvo, AC Casellas, JM Israele, V Polack, NR Kleeberger, SR Polack, FP AF Melendi, Guillermina A. Laham, Federico R. Monsalvo, A. Clara Casellas, Javier M. Israele, Victor Polack, Norberto R. Kleeberger, Steven R. Polack, Fernando P. TI Cytokine profiles in the respiratory tract during primary infection with human metapneumovirus, respiratory syncytial virus, or influenza virus in infants SO PEDIATRICS LA English DT Article DE human metapneumovirus; influenza; respiratory syncytial virus; T helper ID VIRAL-INFECTIONS; G-GLYCOPROTEIN; BALB/C MICE; RESPONSES; GAMMA; CHILDREN; IMMUNITY; DISEASE AB Objectives. We characterized the T helper cytokine profiles in the respiratory tract of infants infected with influenza virus, human metapneumovirus, and respiratory syncytial virus to examine whether these agents elicit similar cytokine responses and whether T helper type 2 polarization is associated with wheezing and severe disease. Methods. A prospective study of infants who were seeking medical help for acute upper and/or lower respiratory tract infection symptoms for the first time and were found to be infected with influenza, human metapneumovirus, or respiratory syncytial virus was performed. Respiratory viruses were detected in nasal secretions with reverse transcriptase-polymerase chain reaction assays. The study was performed in emergency departments and outpatient clinics in Buenos Aires, Argentina. T cell cytokine responses were determined in nasal secretions with immunoassays and reverse transcriptase-polymerase chain reaction assays. Results. Influenza elicited higher levels of interferon-gamma, interleukin- 4, and interleukin-2 than did the other agents. Human metapneumovirus had the lowest interferon-gamma/ interleukin- 4 ratio (T helper type 2 bias). However, no association was found between T helper type 2 bias and overall wheezing or hospitalization rates. Conclusions. These findings show that viral respiratory infections in infants elicit different cytokine responses and that the pathogeneses of these agents should be studied individually. C1 Johns Hopkins Univ, Dept Pediat, Sch Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Int Hlth, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Fdn INFANT, Buenos Aires, DF, Argentina. Hosp Materno Infantil San Isidro, Div Infect Dis, Buenos Aires, DF, Argentina. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Melendi, GA (reprint author), Johns Hopkins Univ, Dept Pediat, Sch Med, 615 N Wolfe St,E5202, Baltimore, MD 21205 USA. EM fpolack@jhsph.edu FU Intramural NIH HHS; NIAID NIH HHS [AI-054952] NR 24 TC 29 Z9 30 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD AUG PY 2007 VL 120 IS 2 BP E410 EP E415 DI 10.1542/peds.2006-3283 PG 6 WC Pediatrics SC Pediatrics GA 196SY UT WOS:000248503500065 PM 17671045 ER PT J AU Boudreau, RM Roumani, YF Hanlon, JT Newman, AB Studenski, SA Harris, TB Nevitt, MC Shorr, RI Simonsick, EM AF Boudreau, Robert M. Roumani, Yazan F. Hanlon, Joseph T. Newman, Anne B. Studenski, Stephanie A. Harris, Tamara B. Nevitt, Michael C. Shorr, Ronald I. Simonsick, Eleanor M. TI The impact of benzodiazepine use on mobility in community dwelling elderly SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 UPITT, Grad Sch Publ Hlth, Pittsburgh, PA USA. UPITT, Sch Med, Pittsburgh, PA USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Calif San Francisco, Sch Med, San Francisco, CA USA. N Florida S Georgia VHS, GRECC, Gainesville, FL USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2007 VL 16 SU 2 MA 078 BP S38 EP S38 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 201GT UT WOS:000248820200079 ER PT J AU Covington, DL Tilson, HH Watts, H Sacks, S Vannappagari, V AF Covington, Deborah L. Tilson, Hugh H. Watts, Heather Sacks, Susan Vannappagari, Vani TI Assessing the safety of antiretroviral drugs used during pregnancy: Evolution from voluntary registry to post-marketing commitment SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. Natl Inst Child Hlth & Human Dev, Matern AIDS Branch, Rockville, MD USA. F Hoffman La Roche Ltd, Nutley, NJ USA. GlaxoSmithKline Inc, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2007 VL 16 SU 2 MA 282 BP S134 EP S134 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 201GT UT WOS:000248820200282 ER PT J AU Huang, B Grant, BF Dawson, DA Stinson, FF Chou, SP Pickering, RP AF Huang, Boji Grant, Bridget F. Dawson, Deborah A. Stinson, Frederick F. Chou, S. Patricia Pickering, Roger P. TI Lifetime amphetamine use disorders among obese individuals with and without other substance use disorders and/or mental disorders SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 NIH, Natl Inst Alcohol Abuse & Alcoholism, Lab Epidemiol & Biometry, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2007 VL 16 SU 2 MA 255 BP S121 EP S122 PG 2 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 201GT UT WOS:000248820200256 ER PT J AU Zito, JM Korelitz, JJ Valluri, S Gardner, JF Bethel, J Mattison, DR AF Zito, Julie M. Korelitz, James J. Valluri, Satish Gardner, James F. Bethel, James Mattison, Donald R. TI Comparing prevalence estimates from US claims data by two methods SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Meeting Abstract C1 Univ Maryland, Pharmaceut Hlth Serv Res, Baltimore, MD USA. Ctr Res Mother & Children, NIH, Natl Inst Child Hlth & Human dev, Obstet & Pediat Pharmacol Branch, Bethesda, MD USA. RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD AUG PY 2007 VL 16 SU 2 MA 252 BP S120 EP S120 PG 1 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 201GT UT WOS:000248820200253 ER PT J AU Weinstein, LS Xie, T Zhang, QH Chen, M AF Weinstein, Lee S. Xie, Tao Zhang, Qing-Hong Chen, Min TI Studies of the regulation and function of the G(s)alpha-gene Gnas using gene targeting technology SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE G protein; genomic imprinting; signal transduction; cAMP; obesity; diabetes; hormone ID PROTEIN ALPHA-SUBUNIT; STIMULATORY-G-PROTEIN; ALBRIGHT-HEREDITARY-OSTEODYSTROPHY; PSEUDOHYPOPARATHYROIDISM TYPE IB; RECEPTOR-MEDIATED ACTIVATION; HORMONE-RELATED PEPTIDE; PROGRESSIVE OSSEOUS HETEROPLASIA; INCREASED INSULIN SENSITIVITY; GUANINE-NUCLEOTIDE-BINDING; IMPRINTING CONTROL ELEMENT AB The heterotrimeric G protein a-subunit G,a is ubiquitously expressed and mediates receptor-stimulated intracellular cAMP generation. Its gene Gnas is a complex imprinted gene which uses alternative promoters and first exons to generate other gene products, including the G(s)alpha isoform XL alpha s and the chromogranin-like protein NESP55, which are specifically expressed from the paternal and maternal alleles, respectively. G(s)alpha itself is imprinted in a tissue-specific manner, being biallelically expressed in most tissues but paternally silenced in a few tissues. Gene targeting of specific Gnas transcripts demonstrates that heterozygous mutation of G(s)alpha on the maternal (but not the paternal) allele leads to early lethality, perinatal subcutaneous edema, severe obesity, and multiliontione resistance, while the paternal mutation leads to only mild obesity and insulin resistance. These parent-of-origin differences are the consequence of tissue-specific G(s)alpha imprinting. XL alpha s deficiency leads to a perinatal suckling defect and a lean phenotype with increased insulin sensitivity. The opposite metabolic effects of G(s)alpha and XL alpha s deficiency are associated with decreased and increased sympathetic nervous system activity, respectively. NESP55 deficiency has no metabolic consequences. Other gene targeting experiments have shown Gnas to have 2 independent imprinting domains controlled by 2 different imprinting control regions. Tissue-specific G,a knockout models have identified important roles for G(s)alpha signaling pathways in skeletal development, renal function, and glucose and lipid metabolism. Our present knowledge gleaned from various Gnas gene targeting models are discussed in relation to the pathogenesis of human disorders with mutation or abnormal imprinting of the human orthologue GNAS. Published by Elsevier Inc. C1 NIH, NIDDKD, Metab Dis Branch, Bethesda, MD 20854 USA. RP Weinstein, LS (reprint author), NIH, NIDDKD, Metab Dis Branch, Bethesda, MD 20854 USA. EM leew@amb.niddk.nih.gov OI Weinstein, Lee/0000-0002-1899-5152 FU Intramural NIH HHS [Z01 DK043313-03, Z01 DK043302-14, Z99 DK999999] NR 172 TC 46 Z9 47 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD AUG PY 2007 VL 115 IS 2 BP 271 EP 291 DI 10.1016/j.pharmthera.2007.03.013 PG 21 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 198WA UT WOS:000248657000006 PM 17588669 ER PT J AU Schroeder, JR Schmittner, J Bleiberg, J Epstein, DH Krantz, MJ Preston, KL AF Schroeder, Jennifer R. Schmittner, John Bleiberg, Joseph Epstein, David H. Krantz, Mori J. Preston, Kenzie L. TI Hemodynamic and cognitive effects of lofexidine and methadone coadministration: A pilot study SO PHARMACOTHERAPY LA English DT Article DE methadone; lofexidine; hemodynamic; safety monitoring ID ESSENTIAL-HYPERTENSION; INDUCED REINSTATEMENT; DOSE METHADONE; CLONIDINE; MAINTENANCE; DEPENDENCE; ADDICTION; MODERATE; SEEKING; SAFETY AB Study Objective. To determine the hemodynamic and cognitive effects of lofexidine and methadone coadministration. Design. Prospective, double-blind study Setting. Outpatient drug treatment research clinic. Subjects. Fourteen participants (aged 18-45 yrs) with physical dependence on opioids. Intervention. Subjects were stabilized on methadone maintenance therapy, starting with 30 mg/day and increasing by 10-mg/day increments, based on each subject's tolerability to achieve a target dose of 80 mg/day After 3 weeks of methadone stabilization, lofexidine 0.4 mg/day or matching placebo were coadministered with methadone, in doses escalating by 0.2mg/week increments, to achieve a target dose of 1.6 mg/day over the next 8 weeks. Measurements and Main Results. Acute orthostatic vital signs and neuropsychological effects of lofexidine and methadone coadministration were monitored for 5 hours after the dose on the first day of each new lofexidine dose. Orthostatic vital signs and adverse events were assessed daily thereafter to determine the effects of repeated doses. Lofexidine significantly decreased sitting systolic and diastolic blood pressure (p=0.045 and p=0.033, respectively) compared with placebo (i.e., methadone alone). With lofexidine 0.4 mg/day, mean decreases in systolic and diastolic blood pressure were 27 +/- 17 and 15 +/- 16 mm Hg, respectively. No significant association was noted between changes in orthostatic vital signs and lofexidine dose. Decreased cognitive efficiency was associated with lofexidine administration, and higher lofexidine doses adversely affected performance on a mathematical task compared with placebo (p=0.0035). The rate of adverse events was no higher with lofexidine than with placebo; the majority (54.3%) were common adverse effects of lofexidine. Conclusion. Significant changes in hemodynamic and cognitive efficiency were observed with coadministration of lofexidine and methadone compared with methadone alone. When patients receiving methadone are prescribed lofexidine, they should be closely monitored for cardiovascular and cognitive changes. C1 NIA, Clin Pharmacol & Therapeut Res Branch, NIH, Intramural Res Program, Baltimore, MD 21224 USA. Natl Rehabil Hosp, Ctr Cognit Neurosci, Washington, DC USA. Denver Hlth Med Ctr, Cardiac Risk Reduct Program, Denver, CO USA. RP Schmittner, J (reprint author), NIA, Clin Pharmacol & Therapeut Res Branch, NIH, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM jschmitt@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU Intramural NIH HHS NR 23 TC 6 Z9 6 U1 0 U2 1 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD AUG PY 2007 VL 27 IS 8 BP 1111 EP 1119 DI 10.1592/phco.27.8.1111 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 195IG UT WOS:000248405100004 PM 17655511 ER PT J AU Grandinetti, CA Goldspiel, BR AF Grandinetti, Cheryl A. Goldspiel, Barry R. TI Sorafenib and sunitinib: Novel targeted therapies for renal cell cancer SO PHARMACOTHERAPY LA English DT Review DE sorafenib; sunitimb; SU11248; renal cell cancer; RCC; tyrosine; kinase inhibitors; Raf kinase; von Hippel-Lindau; Ras-Raf/MEK/ERK ID REFRACTORY SOLID TUMORS; GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; DAYS ON/7 DAYS; RAF KINASE; PHASE-I; DOSE INTERLEUKIN-2; PROGNOSTIC-FACTORS; ANTITUMOR-ACTIVITY; CARCINOMA C1 NCI, Pharmaceut Management Branch, Canc Therapy Evaluat Program, Rockville, MD 20852 USA. NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. RP Grandinetti, CA (reprint author), NCI, Pharmaceut Management Branch, Canc Therapy Evaluat Program, 6130 Execut Blvd,Execut Plaza N,Room 7149,MSC 742, Rockville, MD 20852 USA. EM grandinettic@ctep.nci.nih.gov NR 79 TC 67 Z9 74 U1 0 U2 5 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD AUG PY 2007 VL 27 IS 8 BP 1125 EP 1144 DI 10.1592/phco.27.8.1125 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 195IG UT WOS:000248405100006 PM 17655513 ER PT J AU Ackerman, W Montenegro, D Kim, S Romero, R Kim, C Kniss, D AF Ackerman, W. Montenegro, D. Kim, S. Romero, R. Kim, C. Kniss, D. TI Expression of lipid droplet-associated pat family genes in spontaneous term human labor SO PLACENTA LA English DT Meeting Abstract CT 13th International-Federation-of-Placenta-Association Meeting CY AUG 17-22, 2007 CL Kingston, CANADA SP Int Federat Placenta Assoc C1 Ohio State Univ, Columbus, OH 43210 USA. NICHD, Perinatol Res Branch, Detroit, MI USA. RI Ackerman, William/E-2612-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD AUG-SEP PY 2007 VL 28 IS 8-9 BP A78 EP A78 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 199UK UT WOS:000248720500334 ER PT J AU Armant, DR Romero, R Smith, SM Leach, RE AF Armant, D. R. Romero, R. Smith, S. M. Leach, R. E. TI The EGF signaling system and trophoblast survival SO PLACENTA LA English DT Meeting Abstract CT 13th International-Federation-of-Placenta-Association Meeting CY AUG 17-22, 2007 CL Kingston, CANADA SP Int Federat Placenta Assoc C1 Wayne State Univ, Detroit, MI 48201 USA. NICHD, Perinatol Res Branch, DHHS, Bethesda, MD USA. Univ Wisconsin, Madison, WI 53706 USA. Univ Illinois, Chicago, IL 60680 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD AUG-SEP PY 2007 VL 28 IS 8-9 BP A49 EP A49 PG 1 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 199UK UT WOS:000248720500220 ER PT J AU Kryazhimskiy, S Dieckmann, U Levin, SA Dushoff, J AF Kryazhimskiy, Sergey Dieckmann, Ulf Levin, Simon A. Dushoff, Jonathan TI On state-space reduction in multi-strain pathogen models, with an application to antigenic drift in influenza A SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID CROSS-IMMUNITY; INFECTIOUS AGENTS; EVOLUTION; DYNAMICS; HEMAGGLUTININ; VIRUS; PERSISTENCE; DISEASES; DETERMINANTS; DIVERSITY AB Many pathogens exist in phenotypically distinct strains that interact with each other through competition for hosts. General models that describe such multi- strain systems are extremely difficult to analyze because their state spaces are enormously large. Reduced models have been proposed, but so far all of them necessarily allow for coinfections and require that immunity be mediated solely by reduced infectivity, a potentially problematic assumption. Here, we suggest a new state- space reduction approach that allows immunity to be mediated by either reduced infectivity or reduced susceptibility and that can naturally be used for models with or without coinfections. Our approach utilizes the general framework of status- based models. The cornerstone of our method is the introduction of immunity variables, which describe multi- strain systems more naturally than the traditional tracking of susceptible and infected hosts. Models expressed in this way can be approximated in a natural way by a truncation method that is akin to moment closure, allowing us to sharply reduce the size of the state space, and thus to consider models with many strains in a tractable manner. Applying our method to the phenomenon of antigenic drift in influenza A, we propose a potentially general mechanism that could constrain viral evolution to a one- dimensional manifold in a two- dimensional trait space. Our framework broadens the class of multi- strain systems that can be adequately described by reduced models. It permits computational, and even analytical, investigation and thus serves as a useful tool for understanding the evolution and ecology of multi- strain pathogens. C1 Princeton Univ, Program Appl & Computat Math, Princeton, NJ 08544 USA. Int Inst Appl Syst Anal, Program Evolut & Ecol, A-2361 Laxenburg, Austria. Princeton Univ, Dept Ecol & Evolut Biol, Princeton, NJ 08544 USA. Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD USA. RP Kryazhimskiy, S (reprint author), Princeton Univ, Program Appl & Computat Math, Princeton, NJ 08544 USA. EM skryazhi@princeton.edu RI Dieckmann, Ulf/E-1424-2011 OI Dieckmann, Ulf/0000-0001-7089-0393 FU NIGMS NIH HHS [P50 GM071508] NR 40 TC 33 Z9 33 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD AUG PY 2007 VL 3 IS 8 BP 1513 EP 1525 AR e159 DI 10.1371/journal.pcbi.0030159 PG 13 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 214VU UT WOS:000249767100011 PM 17708677 ER PT J AU Xi, HL Shulha, HP Lin, JM Vales, TR Fu, YT Bodine, DM Mckay, RDG Chenoweth, JG Tesar, PJ Furey, TS Ren, B Weng, ZP Crawford, GE AF Xi, Hualin Shulha, Hennady P. Lin, Jane M. Vales, Teresa R. Fu, Yutao Bodine, David M. Mckay, Ronald D. G. Chenoweth, Josh G. Tesar, Paul J. Furey, Terrence S. Ren, Bing Weng, Zhiping Crawford, Gregory E. TI Identification and characterization of cell type-specific and ubiquitous chromatin regulatory structures in the human genome SO PLOS GENETICS LA English DT Article ID I-HYPERSENSITIVE SITES; TRANSCRIPTION FACTORS; BINDING SITES; PROTEIN CTCF; DNA MOTIFS; GENE; EXPRESSION; VERTEBRATE; ELEMENTS; PROMOTERS AB The identification of regulatory elements from different cell types is necessary for understanding the mechanisms controlling cell type-specific and housekeeping gene expression. Mapping DNasel hypersensitive ( HS) sites is an accurate method for identifying the location of functional regulatory elements. We used a high throughput method called DNase-chip to identify 3,904 DNasel HS sites from six cell types across 1% of the human genome. A significant number ( 22%) of DNasel HS sites from each cell type are ubiquitously present among all cell types studied. Surprisingly, nearly all of these ubiquitous DNasel HS sites correspond to either promoters or insulator elements: 86% of them are located near annotated transcription start sites and 10% are bound by CTCF, a protein with known enhancer-blocking insulator activity. We also identified a large number of DNasel HS sites that are cell type specific ( only present in one cell type); these regions are enriched for enhancer elements and correlate with cell type-specific gene expression as well as cell type-specific histone modifications. Finally, we found that approximately 8% of the genome overlaps a DNasel HS site in at least one the six cell lines studied, indicating that a significant percentage of the genome is potentially functional. C1 Boston Univ, Bioinformat Program, Boston, MA 02215 USA. Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. Duke Univ, Inst Genome Sci & Policy, Durham, NC USA. NHGRI, Genet & Mol Biol Branch, Hematopoiesis Sect, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. RP Weng, ZP (reprint author), Boston Univ, Bioinformat Program, Boston, MA 02215 USA. EM zhiping@bu.edu; greg.crawford@duke.edu RI Tesar, Paul/C-9848-2014; OI Tesar, Paul/0000-0003-1532-3155; Furey, Terry/0000-0001-5546-9672 FU Intramural NIH HHS; NHGRI NIH HHS [HG003169, HG03110, K22 HG003169, R01 HG003110] NR 41 TC 140 Z9 145 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2007 VL 3 IS 8 BP 1377 EP 1388 AR e136 DI 10.1371/journal.pgen.0030136 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 214VZ UT WOS:000249767600006 PM 17708682 ER PT J AU Cromie, GA Hyppa, RW Cam, HP Farah, JA Grewal, SIS Smith, GR AF Cromie, Gareth A. Hyppa, Randy W. Cam, Hugh P. Farah, Joseph A. Grewal, Shiv I. S. Smith, Gerald R. TI A discrete class of Intergenic DNA dictates meiotic DNA break hotspots in fission yeast SO PLOS GENETICS LA English DT Article ID DOUBLE-STRAND BREAKS; RECOMBINATION HOT-SPOT; SCHIZOSACCHAROMYCES-POMBE; HUMAN GENOME; SACCHAROMYCES-CEREVISIAE; GENE CONVERSION; HOMOLOGOUS RECOMBINATION; CHIP-CHIP; S.-POMBE; MEIOSIS AB Meiotic recombination is initiated by DNA double-strand breaks (DSBs) made by Spo11 ( Rec12 in fission yeast), which becomes covalently linked to the DSB ends. Like recombination events, DSBs occur at hotspots in the genome, but the genetic factors responsible for most hotspots have remained elusive. Here we describe in fission yeast the genome-wide distribution of meiosis-specific Rec12-DNA linkages, which closely parallel DSBs measured by conventional Southern blot hybridization. Prominent DSB hotspots are located; similar to 65 kb apart, separated by intervals with little or no detectable breakage. Most hotspots lie within exceptionally large intergenic regions. Thus, the chromosomal architecture responsible for hotspots in fission yeast is markedly different from that of budding yeast, in which DSB hotspots are much more closely spaced and, in many regions of the genome, occur at each promoter. Our analysis in fission yeast reveals a clearly identifiable chromosomal feature that can predict the majority of recombination hotspots across a whole genome and provides a basis for searching for the chromosomal features that dictate hotspots of meiotic recombination in other organisms, including humans. C1 Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98104 USA. Natl Canc Inst, NIH, Mol Biol Lab, Bethesda, MD USA. RP Smith, GR (reprint author), Fred Hutchinson Canc Res Ctr, Div Basic Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM gsmith@fhcrc.org OI Smith, Gerald/0000-0002-8747-1352 FU NIGMS NIH HHS [GM031693, R56 GM031693, R01 GM031693] NR 46 TC 59 Z9 60 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD AUG PY 2007 VL 3 IS 8 BP 1496 EP 1507 AR e141 DI 10.1371/journal.pgen.0030141 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 214VZ UT WOS:000249767600016 PM 17722984 ER PT J AU Hemming, ML Patterson, M Reske-Nielsen, C Lin, L Isacson, O Selkoe, DJ AF Hemming, Matthew L. Patterson, Michaela Reske-Nielsen, Casper Lin, Ling Isacson, Ole Selkoe, Dennis J. TI Reducing amyloid plaque burden via ex vivo gene delivery of an a beta-degrading protease: A novel therapeutic approach to Alzheimer Disease SO PLOS MEDICINE LA English DT Article ID CILIARY NEUROTROPHIC FACTOR; NERVE GROWTH-FACTOR; ALZHEIMERS-DISEASE; IN-VIVO; TRANSGENIC MICE; CONVERTING ENZYME; PRECURSOR PROTEIN; ENCAPSULATED CELLS; CLINICAL-TRIAL; FACTOR CNTF AB Background Understanding the mechanisms of amyloid-beta protein ( A beta) production and clearance in the brain has been essential to elucidating the etiology of Alzheimer disease ( AD). Chronically decreasing brain A beta levels is an emerging therapeutic approach for AD, but no such disease-modifying agents have achieved clinical validation. Certain proteases are responsible for the catabolism of brain A beta in vivo, and some experimental evidence suggests they could be used as therapeutic tools to reduce A beta levels in AD. The objective of this study was to determine if enhancing the clearance of A beta in the brain by ex vivo gene delivery of an A beta-degrading protease can reduce amyloid plaque burden. Methods and Findings We generated a secreted form of the A beta-degrading protease neprilysin, which significantly lowers the levels of naturally secreted A beta in cell culture. We then used an ex vivo gene delivery approach utilizing primary fibroblasts to introduce this soluble protease into the brains of beta-amyloid precursor protein ( APP) transgenic mice with advanced plaque deposition. Brain examination after cell implantation revealed robust clearance of plaques at the site of engraftment ( 72% reduction, p = 0.0269), as well as significant reductions in plaque burden in both the medial and lateral hippocampus distal to the implantation site ( 34% reduction, p 0.0020; and 55% reduction, p = 0.0081, respectively). Conclusions Ex vivo gene delivery of an A beta-degrading protease reduces amyloid plaque burden in transgenic mice expressing human APP. These results support the use of A beta-degrading proteases as a means to therapeutically lower A beta levels and encourage further exploration of ex vivo gene delivery for the treatment of Alzheimer disease. C1 Brigham & Womens Hosp, Harvard Med Sch, Ctr Neurol Dis, Boston, MA 02115 USA. Harvard Univ, McLean Hosp, Udall Parkinsons Dis Res Ctr Excellence, Neuroregenerat Lab, Belmont, MA USA. RP Selkoe, DJ (reprint author), Brigham & Womens Hosp, Harvard Med Sch, Ctr Neurol Dis, 75 Francis St, Boston, MA 02115 USA. EM dselkoe@rics.bwh.harvard.edu FU NIA NIH HHS [AG12749, R01 AG012749]; NINDS NIH HHS [NS39793, P50 NS039793] NR 54 TC 79 Z9 84 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD AUG PY 2007 VL 4 IS 8 BP 1405 EP 1416 AR e262 DI 10.1371/journal.pmed.0040262 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 205IT UT WOS:000249107900018 PM 17760499 ER PT J AU Ivanov, AI Bachar, M Babbin, BA Adelstein, RS Nusrat, A Parkos, CA AF Ivanov, Andrei I. Bachar, Moshe Babbin, Brian A. Adelstein, Robert S. Nusrat, Asma Parkos, Charles A. TI A Unique Role for Nonmuscle Myosin Heavy Chain IIA in Regulation of Epithelial Apical Junctions SO PLOS ONE LA English DT Article AB The integrity and function of the epithelial barrier is dependent on the apical junctional complex (AJC) composed of tight and adherens junctions and regulated by the underlying actin filaments. A major F-actin motor, myosin II, was previously implicated in regulation of the AJC, however direct evidence of the involvement of myosin II in AJC dynamics are lacking and the molecular identity of the myosin II motor that regulates formation and disassembly of apical junctions in mammalian epithelia is unknown. We investigated the role of nonmuscle myosin II (NMMII) heavy chain isoforms, A, B, and C in regulation of epithelial AJC dynamics and function. Expression of the three NMMII isoforms was observed in model intestinal epithelial cell lines, where all isoforms accumulated within the perijunctional F-actin belt. siRNA-mediated downregulation of NMMIIA, but not NMMIIB or NMMIIC expression in SK-CO15 colonic epithelial cells resulted in profound changes of cell morphology and cell-cell adhesions. These changes included acquisition of a fibroblast-like cell shape, defective paracellular barrier, and substantial attenuation of the assembly and disassembly of both adherens and tight junctions. Impaired assembly of the AJC observed after NMMIIA knock-down involved dramatic disorganization of perijunctional actin filaments. These findings provide the first direct non-pharmacological evidence of myosin II-dependent regulation of AJC dynamics in mammalian epithelia and highlight a unique role of NMMIIA in junctional biogenesis. C1 [Ivanov, Andrei I.; Bachar, Moshe; Babbin, Brian A.; Nusrat, Asma; Parkos, Charles A.] Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA. [Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Ivanov, AI (reprint author), Emory Univ, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA. EM aiivano@emory.edu OI Adelstein, Robert/0000-0002-8683-2144 FU Crohn's and Colitis Foundation of America; National Institute of Health [DK 61379, DK 72564, HL72124, DK 55679, DK 59888]; Digestive Diseases Minicenter [DK64399] FX This work was supported by a Career Development Award from Crohn's and Colitis Foundation of America (to AII) and by National Institute of Health grants DK 61379, DK 72564 and HL72124 (to CAP), DK 55679, and DK 59888 (to AN) and a Digestive Diseases Minicenter grant DK64399 (epithelial tissue culture and morphology cores). NR 62 TC 87 Z9 89 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 1 PY 2007 VL 2 IS 8 AR e658 DI 10.1371/journal.pone.0000658 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10GK UT WOS:000207452300004 PM 17668046 ER PT J AU Stoddart, CA Bales, CA Bare, JC Chkhenkeli, G Galkina, SA Kinkade, AN Moreno, ME Rivera, JM Ronquillo, RE Sloan, B Black, PL AF Stoddart, Cheryl A. Bales, Cheryl A. Bare, Jennifer C. Chkhenkeli, George Galkina, Sofiya A. Kinkade, April N. Moreno, Mary E. Rivera, Jose M. Ronquillo, Rollie E. Sloan, Barbara Black, Paul L. TI Validation of the SCID-hu Thy/Liv Mouse Model with Four Classes of Licensed Antiretrovirals SO PLOS ONE LA English DT Article AB Background. The SCID-hu Thy/Liv mouse model of HIV-1 infection is a useful platform for the preclinical evaluation of antiviral efficacy in vivo. We performed this study to validate the model with representatives of all four classes of licensed antiretrovirals. Methodology/Principal Findings. Endpoint analyses for quantification of Thy/Liv implant viral load included ELISA for cell-associated p24, branched DNA assay for HIV-1 RNA, and detection of infected thymocytes by intracellular staining for Gag-p24. Antiviral protection from HIV-1-mediated thymocyte depletion was assessed by multicolor flow cytometric analysis of thymocyte subpopulations based on surface expression of CD3, CD4, and CD8. These mice can be productively infected with molecular clones of HIV-1 (e. g., the X4 clone NL4-3) as well as with primary R5 and R5X4 isolates. To determine whether results in this model are concordant with those found in humans, we performed direct comparisons of two drugs in the same class, each of which has known potency and dosing levels in humans. Here we show that second-generation antiretrovirals were, as expected, more potent than their first-generation predecessors: emtricitabine was more potent than lamivudine, efavirenz was more potent than nevirapine, and atazanavir was more potent than indinavir. After interspecies pharmacodynamic scaling, the dose ranges found to inhibit viral replication in the SCID-hu Thy/Liv mouse were similar to those used in humans. Moreover, HIV-1 replication in these mice was genetically stable; treatment of the mice with lamivudine did not result in the M184V substitution in reverse transcriptase, and the multidrug-resistant NY index case HIV-1 retained its drug-resistance substitutions. Conclusion. Given the fidelity of such comparisons, we conclude that this highly reproducible mouse model is likely to predict clinical antiviral efficacy in humans. C1 [Stoddart, Cheryl A.] Univ Calif San Francisco, Dept Med, Div Expt Med, Gladstone Inst Virol & Immunol, San Francisco, CA 94143 USA. [Black, Paul L.] NIAID, Div Aids, Targeted Intervent Branch, NIH, Bethesda, MD 20892 USA. RP Stoddart, CA (reprint author), Univ Calif San Francisco, Dept Med, Div Expt Med, Gladstone Inst Virol & Immunol, San Francisco, CA 94143 USA. EM cheryl.stoddart@ucsf.edu FU NIAID, NIH [N01-AI-05418] FX This project has been funded in whole or in part with Federal funds from NIAID, NIH, under contract no. N01-AI-05418. NR 56 TC 29 Z9 29 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 AUG 1 PY 2007 VL 2 IS 8 AR e655 DI 10.1371/journal.pone.0000655 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10GK UT WOS:000207452300001 PM 17668043 ER PT J AU Yao, YG Bandelt, HJ Young, NS AF Yao, Yong-Gang Bandelt, Hans-Juergen Young, Neal S. TI External Contamination in Single Cell mtDNA Analysis SO PLOS ONE LA English DT Article AB Background. Mitochondrial DNA (mtDNA) variation in single hematopoietic cells, muscle fibers, oocytes, and from tiny amount of tumor tissues and degraded clinical specimens has been reported in many medical publications. External DNA contamination, notoriously difficult to avoid, threatens the integrity of such studies. Methodology/Principal Findings. Employing a phylogenetic approach, we analyzed the geographic origins of mtDNA sequence anomalies observed during multiple studies of mtDNA sequence variation in a total of 7094 single hematopoietic cells. 40 events with irregular mtDNA patterns were detected: eight instances (from seven different haplotypes) could be traced to laboratory personnel; six cases were caused by sample cross-contamination. The sources of the remaining events could not be identified, and the anomalous sequence variation referred to matrilines from East Asia, Africa, or West Eurasia, respectively. These mtDNA sequence anomalies could be best explained by contamination. Conclusions. Using the known world mtDNA phylogeny, we could distinguish the geographic origin of the anomalous mtDNA types, providing some useful information regarding the source of contamination. Our data suggest that routine mtDNA sequence analysis of laboratory personnel is insufficient to identify and eliminate all contaminants. A rate of 0.6% of external contamination in this study, while low, is not negligible: Unrecognized contaminants will be mistaken as evidence of remarkable somatic mutations associated with the development of cancer and other diseases. The effective contamination rate can increase by a factor of more than an order of magnitude in some studies that did not institute high standards. Our results are of particular relevance to mtDNA research in medicine, and such an approach should be adopted to maintain and improve quality control in single-cell analyses. C1 [Yao, Yong-Gang; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Bandelt, Hans-Juergen] Univ Hamburg, Dept Math, Hamburg, Germany. RP Yao, YG (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM yaoy3@nhlbi.nih.gov FU NIH FX This work was supported by the Intramural Research Program of the NIH. NR 64 TC 15 Z9 15 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 AUG 1 PY 2007 VL 2 IS 8 AR e681 DI 10.1371/journal.pone.0000681 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10GK UT WOS:000207452300017 PM 17668059 ER PT J AU Sullivan, HW Klassen, AC AF Sullivan, Helen W. Klassen, Ann C. TI Nutrition-related cancer prevention attitudes in low-income women SO PREVENTIVE MEDICINE LA English DT Article DE cancer prevention; attitudes; nutrition education ID HEALTH INTERVIEW SURVEY; AMERICAN WOMEN; BELIEFS; KNOWLEDGE; EDUCATION; PROGRAM; FRUIT AB Objective. To investigate the nutrition-related cancer prevention attitudes of low-income African American women, determine whether a nutrition education program can alter these attitudes, and determine whether these attitudes are related to diet and dietary changes. Method. One-hundred and fifty-seven African American women from Washington, D.C. public housing communities participated in a nutrition education program from 2001 to 2003. They completed questionnaires assessing their attitudes about the role of nutrition in cancer prevention at baseline, post-intervention, and 4 months later. They also completed 24-hour food recalls at baseline, post-intervention, and 4 months later. Results. Women agreed that good nutrition prevents cancer, especially women with higher literacy, women with fewer children living at home, women who had not had experience with cancer, and women who were worried about their health. Participation in the program increased agreement that good nutrition prevents cancer over 4 months. Women whose agreement increased over the intervention were able to maintain dietary changes they made over 4 months. Conclusion. Nutrition-related cancer prevention attitudes were strong and were strengthened by a nutrition education program. These attitudes may contribute to people's ability to maintain dietary changes. (C) 2007 Elsevier Inc. All rights reserved. C1 NCI, NIH, Div Canc Prevent, Off Prevent Oncol,Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. NCI, NIH, Div Canc Control & Popula Sci, Behav Res Program,Hlth Commun & Informat Res Bran, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. Johns Hopkins Sch Med, Dept Oncol, Baltimore, MD USA. RP Sullivan, HW (reprint author), 6130 Execut Blvd, Bethesda, MD 20892 USA. EM sullivhe@mail.nih.gov NR 27 TC 3 Z9 3 U1 2 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD AUG-SEP PY 2007 VL 45 IS 2-3 BP 139 EP 145 DI 10.1016/j.ypmed.2007.05.006 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 218RP UT WOS:000250032900012 PM 17604830 ER PT J AU Talbot, LA Morrell, CH Fleg, JL Metter, EJ AF Talbot, Laura A. Morrell, Christopher H. Fleg, Jerome L. Metter, E. Jeffrey TI Changes in leisure time physical activity and risk of all-cause mortality in men and women: The Baltimore Longitudinal Study of Aging SO PREVENTIVE MEDICINE LA English DT Article DE all-cause mortality; leisure time physical activity; Aging; exercise ID CORONARY-HEART-DISEASE; COLLEGE ALUMNI; LONGEVITY; EXERCISE; DEATH; PATTERNS; FITNESS; ATTACK AB Background. Higher levels of leisure time physical activity (LTPA) are associated with reduced mortality. However it is unclear how changes in LTPA over time impact all-cause mortality in men and women. Methods. From 1958 to 1996 for men (n = 1316) and 1978 to 1996 for women (n = 776), participants aged 19-90+ years from the Baltimore Longitudinal Study of Aging (Baltimore, MD) were assessed for LTPA at baseline and at similar to 2-year intervals over a mean follow-up of 21.2 +/- 9.4 years for men and 10.2 +/- 5.6 years for women. Death occurred in 538 men and 90 women. LTPA was derived from self-reports of time spent in 97 activities converted into MET-min per 24 h and was further grouped into high-, moderate- and low-intensity LTPA. The longitudinal data was analyzed using mixed effects models to determine the rate of change in LTPA at each assessment. Proportional hazard models were used to assess the associations between LTPA at baseline and rate of change in LTPA with all-cause mortality. Results. In younger (<70 years) men, those who reported increases or negligible declines in total and high-intensity LTPA had lower all-cause mortality compared to those with greater declines in LTPA. In older (>= 70 years) men, the association between rate of change in high-intensity LTPA and mortality was similar to that seen in younger men. For women, longitudinal analyses showed neither rates of change in total, high-, moderate- nor low-intensity LTPA were predictive of mortality. Conclusions. In this health-conscious population, greater longitudinal declines in total and high-intensity LTPA are independent predictors of all-cause mortality in men. Published by Elsevier Inc. C1 Uniformed Serv Univ Hlth Sci, Grad Sch Nursing, Bethesda, MD 20814 USA. Harbar Hosp, NIA, NIH, Intramural Res Program, Baltimore, MD 21225 USA. Loyola Coll, Baltimore, MD 21210 USA. NHLBI, Div Cardiovasc Dis, Bethesda, MD 20892 USA. RP Talbot, LA (reprint author), Uniformed Serv Univ Hlth Sci, Grad Sch Nursing, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM ltalbot@usuhs.mil FU Intramural NIH HHS NR 26 TC 48 Z9 48 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 0091-7435 J9 PREV MED JI Prev. Med. PD AUG-SEP PY 2007 VL 45 IS 2-3 BP 169 EP 176 DI 10.1016/j.ypmed.2007.05.014 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 218RP UT WOS:000250032900017 PM 17631385 ER PT J AU Narasimha, A Watanabe, J Lin, JA Hama, S Langenbach, R Navab, M Fogelman, AM Reddy, ST AF Narasimha, Ajay Watanabe, Junji Lin, James A. Hama, Susan Langenbach, Robert Navab, Mohamad Fogelman, Alan M. Reddy, Srinivasa T. TI A novel anti-atherogenic role for COX-2-potential mechanism for the cardiovascular side effects of COX-2 inhibitors SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article DE atherosclerosis; cardiovascular diseases; cholesterol; COX-2; cytokines; high-density lipoprotein; heart diseases; hyperlipidemia; inflammation; lipoproteins; prostanoids ID HIGH-DENSITY-LIPOPROTEIN; CHOLESTEROL EFFLUX; ANTIINFLAMMATORY PROPERTIES; ATHEROSCLEROTIC LESIONS; OXIDIZED PHOSPHOLIPIDS; APOLIPOPROTEIN-E; TRANSGENIC MICE; HDL; CYCLOOXYGENASE; MACROPHAGES AB Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by lipid accumulation, lipoprotein oxidation, and inflammation. Products of the cyclooxygenase (COX) pathway participate in acute and chronic inflammation. The inducible form of COX, COX-2, generates lipid mediators of inflammation that are pro-inflammatory and COX-2-selective inhibitors are potent anti-inflammatory agents. However, clinical data suggest an increased risk of cardiovascular side effects in patients using COX2-selective inhibitors. In this paper, we sought to determine the effect of COX-2 deficiency on atherosclerosis-related lipoprotein metabolism in mice. We demonstrate that COX-2 deficiency resulted in (i) accumulation of lipids in circulation and liver, (ii) pro-inflammatory properties of HDL as measured by HDL's increased reactive oxygen species (ROS) content, decreased paraoxonase I (PON1) activity, decreased serum apoA-1, reduced ability to efflux cholesterol and to prevent LDL oxidizability, and (iii) increased TXB2 in circulation. Moreover, when placed on an atherogenic diet, COX-2 deficiency resulted in (i) increased lipid deposition in the aorta, (ii) a further dramatic imbalance in circulating eicosanoids, i.e. decreased serum PGI(2) coupled with increased PGE(2) and TXB2, and (iii) a marked elevation of pro-inflammatory cytokines, TNF and IL-6. Our results suggest, for the first time, that COX-2 deficiency contributes to the pro-atherogenic properties of HDL in mice. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Calif Los Angeles, Dept Med Cardiol, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Atherosclerosis Res Unit, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90024 USA. Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC USA. RP Reddy, ST (reprint author), Univ Calif Los Angeles, Dept Med Cardiol, Dept Mol & Med Pharmacol, 650 Charles E Young Dr S,MRL 3736, Los Angeles, CA 90095 USA. EM sreddy@mednet.ucla.edu RI Lin, James/E-4796-2010 FU NCI NIH HHS [CA-16042, P30 CA016042]; NHLBI NIH HHS [HL-30568, 1R01HL71776, P01 HL030568, P01 HL030568-19, P01 HL030568-20, R01 HL071776, R01 HL071776-01, R01 HL082823, R01 HL082823-01A2]; NIAID NIH HHS [AI-28697, P30 AI028697]; NIDDK NIH HHS [5R33DK070328, R33 DK070328] NR 38 TC 15 Z9 15 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD AUG PY 2007 VL 84 IS 1-2 BP 24 EP 33 DI 10.1016/j.prostaglandins.2007.03.004 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 202JT UT WOS:000248898500003 PM 17643885 ER PT J AU Arnold, JT Liu, XX Allen, JD Le, H McFann, KK Blackman, MR AF Arnold, Julia T. Liu, Xunxian Allen, Jeffrey D. Le, Hanh McFann, Kimberly K. Blackman, Marc R. TI Androgen receptor or estrogen receptor-beta blockade alters DHEA-, DHT-, and E-2-induced proliferation and PSA production in human prostate cancer cells SO PROSTATE LA English DT Article DE DHEA; DHT; E-2; AR; ER beta; PSA; Casodex; ICI 182,780 ID ER-BETA; ALPHA; DEHYDROEPIANDROSTERONE; EXPRESSION; CARCINOGENESIS; ANTIESTROGENS; TESTOSTERONE; PROGRESSION; MUTATIONS; STABILITY AB BACKGROUND. Dehydroepiandrosterone (DHEA) is an endogenous steroid that is metabolized to androgens and/or estrogens in the human prostate. DHEA levels decline with age, and use of DHEA supplements to retard the aging process is of unproved effectiveness and safety. LNCaP and LAPC-4 prostate cancer cells were used to determine whether DHEA-modulated proliferation and prostate specific antigen (PSA) production were mediated via the androgen receptor (AR) and/or ER beta. METHODS. Cells were treated with DHEA, DHT, or E-2 and antagonists to AR (Casodex R bicalutamide) or ER (ICI 182,780) or siRNA to the respective receptors. Proliferation was assessed by MTT assay and PSA mRNA and protein secretion were measured by quantitative real-time PCR and ELISA. Associations of AR and ER beta were analyzed by co-immunoprecipitation studies and fluorescent confocal microscopy. RESULTS. DHEA-, T-, and E-2-induced proliferation of LNCaP cells was blunted by Casodex but not by ICI treatment. In LNCaP cells, Casodex and ICI suppressed hormone-induced PSA production. In LAPC-4 cells, DHT-stimulated PSA mRNA was inhibited by Casodex and ICI, and the minimal stimulation by DHEA was inhibited by ICI. Use of siRNAs confirmed involvement of AR and ER beta in hormone-induced PSA production while AR-ER beta co-association was suggested by immunoprecipitation and nuclear co-localization. CONCLUSIONS. These findings support involvement of both AR and ER beta in mediating DHEA-, DHT-, and E2-induced PSA expression in prostate cancer cells. Prostate 67:1152-1162, 2007. (c) 2007 Wiley-Liss, Inc. C1 NIH, Endocrine Sect, LCI, Div Intramural Res,NCCAM, Bethesda, MD 20892 USA. Univ Colorado, Ctr Hlth Sci, Denver, CO 80202 USA. RP Arnold, JT (reprint author), NIH, Endocrine Sect, LCI, Div Intramural Res,NCCAM, 9 Mem Dr,Rm 1N105, Bethesda, MD 20892 USA. EM jarnold@mail.nih.gov FU Intramural NIH HHS; NIMHD NIH HHS [MD20892] NR 40 TC 37 Z9 38 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD AUG 1 PY 2007 VL 67 IS 11 BP 1152 EP 1162 DI 10.1002/pros.20585 PG 11 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 197EN UT WOS:000248537500002 PM 17503469 ER PT J AU Gong, HP Shen, Y Rose, GD AF Gong, Haipeng Shen, Yang Rose, George D. TI Building native protein conformation from NMR backbone chemical shifts using Monte Carlo fragment assembly SO PROTEIN SCIENCE LA English DT Article DE protein structure/folding; NMR spectroscopy; computational analysis ID RESIDUAL DIPOLAR COUPLINGS; GLOBULAR-PROTEINS; DATABASE; CLASSIFICATION; REPLACEMENT; PREDICTION; STABILITY; HOMOLOGY; HELICES AB We have been analyzing the extent to which protein secondary structure determines protein tertiary structure in simple protein folds. An earlier paper demonstrated that three-dimensional structure can be obtained successfully using only highly approximate backbone torsion angles for every residue. Here, the initial information is further diluted by introducing a realistic degree of experimental uncertainty into this process. In particular, we tackle the practical problem of determining three-dimensional structure solely from backbone chemical shifts, which can be measured directly by NMR and are known to be correlated with a protein's backbone torsion angles. Extending our previous algorithm to incorporate these experimentally determined data, clusters of structures compatible with the experimentally determined chemical shifts were generated by fragment assembly Monte Carlo. The cluster that corresponds to the native conformation was then identified based on four energy terms: steric clash, solvent-squeezing, hydrogen-bonding, and hydrophobic contact. Currently, the method has been applied successfully to five small proteins with simple topology. Although still under development, this approach offers promise for high- throughput NMR structure determination. C1 Johns Hopkins Univ, TC Jenkins Dept Biophys, Baltimore, MD 21218 USA. NIDDK, Natl Inst Hlth, Phys Chem Lab, Bethesda, MD 20892 USA. RP Rose, GD (reprint author), Johns Hopkins Univ, TC Jenkins Dept Biophys, 3400 N Charles St, Baltimore, MD 21218 USA. EM grose@jhu.edu RI Shen, Yang/C-3064-2008 OI Shen, Yang/0000-0003-1408-8034 NR 32 TC 26 Z9 26 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2007 VL 16 IS 8 BP 1515 EP 1521 DI 10.1110/ps.072988407 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 194RD UT WOS:000248360600001 PM 17656574 ER PT J AU Lee, D Walsh, JD Migliorini, M Yu, P Cai, T Schwieters, CD Krueger, S Strickland, DK Wang, YX AF Lee, Donghan Walsh, Joseph D. Migliorini, Molly Yu, Ping Cai, Tao Schwieters, Charles D. Krueger, Susan Strickland, Dudley K. Wang, Yun-Xing TI The structure of receptor-associated protein (RAP) SO PROTEIN SCIENCE LA English DT Article DE multidomain protein; receptor-associated protein; global order ID N-TERMINAL DOMAIN; LIGAND-BINDING; LIPOPROTEIN RECEPTORS; MOLECULAR CHAPERONE; DIPOLAR COUPLINGS; SCATTERING DATA; CHEMICAL-SHIFT; NMR ASSIGNMENT; LRP; REFINEMENT AB The receptor-associated protein (RAP) is a molecular chaperone that binds tightly to certain newly synthesized LDL receptor family members in the endoplasmic reticulum (ER) and facilitates their delivery to the Golgi. We have adopted a divide-and-conquer strategy to solve the structures of the individual domains of RAP using NMR spectroscopy. We present here the newly determined structure of domain 2. Based on this structure and the structures of domains 1 and 3, which were solved previously, we utilized experimental small-angle neutron scattering (SANS) data and a novel simulated annealing protocol to characterize the overall structure of RAP. The results reveal that RAP adopts a unique structural architecture consisting of three independent three-helix bundles that are connected by long and flexible linkers. The flexible linkers and the quasi- repetitive structural architecture may allow RAP to adopt various possible conformations when interacting with the LDL receptors, which are also made of repetitive substructure units. C1 NCI, Natl Inst Hlth, Struct Biophys Lab, Nucl Acid Interact Sect, Frederick, MD 21702 USA. Univ Maryland, Sch Med, Ctr Vasc & Inflam Dis, Dept Surg & Physiol, Baltimore, MD 21201 USA. NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. NIDCR, Natl Inst Hlth, Expt Med Sect, Bethesda, MD 20892 USA. Natl Inst Hlth, Ctr Informat Technol, Div Computat Biosci, Bethesda, MD 20892 USA. NIST, Ctr Neutron Res, Natl Inst Stand & Technol, Gaithersburg, MD 20899 USA. RP Wang, YX (reprint author), NCI, Natl Inst Hlth, Struct Biophys Lab, Nucl Acid Interact Sect, Frederick, MD 21702 USA. EM wangyu@ncifcrf.gov RI Lee, Donghan/B-6893-2011; OI Lee, Donghan/0000-0002-6530-8060; Lee, Donghan/0000-0002-3971-986X FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01-CO56000, N01CO12400]; NHLBI NIH HHS [P01 HL054710, HL50784, HL54710, R01 HL050784] NR 57 TC 13 Z9 13 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD AUG PY 2007 VL 16 IS 8 BP 1628 EP 1640 DI 10.1110/ps.072865407 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 194RD UT WOS:000248360600012 PM 17656581 ER PT J AU Zhou, M Veenstra, TD AF Zhou, Ming Veenstra, Timothy D. TI Proteomic analysis of protein complexes SO PROTEOMICS LA English DT Review DE immunofluorescence; interactome; mass spectrometry; protein complexes; yeast two-hybrid ID TANDEM MASS-SPECTROMETRY; SACCHAROMYCES-CEREVISIAE; POLYACRYLAMIDE-GELS; INTERACTION MAP; PHOSPHATASE 2A; YEAST; INTERACTOME; IDENTIFICATION; RECEPTOR; NETWORK AB While it sometimes does not generate the publicity that biomarker discovery does, the identification of protein complexes may be the most popular use of proteomic technology. The partners a protein interacts with is a key component that describes the function of any protein. Basic research has long appreciated the importance of identifying protein interactions through techniques such as Western blotting and colocalization studies using immunofluorescence microscopy. This appreciation has carried over into the field of proteomics and brought with it the development of tools that increase the capabilities to characterize protein complexes to a far greater scale. While advances in technology have had a huge impact, sample preparation issues related to the isolation of protein complexes remains a critical factor in determining the success of these types of studies. C1 SAIC Frederick Inc, NCI Frederick, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), SAIC Frederick Inc, NCI Frederick, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 38 TC 17 Z9 21 U1 2 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1615-9853 J9 PROTEOMICS JI Proteomics PD AUG PY 2007 VL 7 IS 16 BP 2688 EP 2697 DI 10.1002/pmic.200700048 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 208BT UT WOS:000249295500002 PM 17639601 ER PT J AU Meng, Z Veenstra, TD AF Meng, Zhaojing Veenstra, Timothy D. TI Proteomic analysis of serum, plasma, and lymph for the identification of biomarkers SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Review DE biomarker; clinical diagnostics; lymph; plasma; serum ID DYNAMIC-RANGE CHARACTERIZATION; HUMAN BLOOD-SERUM; MASS-SPECTROMETRY; OVARIAN-CANCER; PROTEIN; ELECTROPHORESIS; TECHNOLOGY; SEPARATION; PEPTIDE; CHEMISTRY AB Probably no topic has generated more excitement in the world of proteomics than the search for biomarkers. This excitement has been generated by two realities: the constant need for better biomarkers that can be used for disease diagnosis and prognosis, and the recent developments in proteomic technologies that are capable of scanning the individual proteins within varying complex clinical samples. ideally a biomarker would be assayable from a noninvasively collected sample, therefore, much of the focus in proteomics has been on the analysis of biofluids such as serum, plasma, urine, cerebrospinal fluid, lymph, etc. While the discovery of biomarkers has been elusive, there have been many advances made in the understanding of the proteome content of various bicifluids, and in the technologies used for their analysis, that continues to point the research community toward new methods for achieving the ultimate goal of identifying novel disease-specific biomarkers. In this review, we will describe and discuss many of the proteomic approaches taken in an attempt to find novel biomarkers in serum, plasma, and lymph. C1 SAIC Frederick Inc, Natl Canc Inst, Lab Prote & Analyt Technol, Ft Detrick, MD 21702 USA. RP Veenstra, TD (reprint author), SAIC Frederick Inc, Natl Canc Inst, Lab Prote & Analyt Technol, POB B, Ft Detrick, MD 21702 USA. EM veenstra@ncifcrf.gov NR 40 TC 21 Z9 22 U1 1 U2 4 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD AUG PY 2007 VL 1 IS 8 BP 747 EP 757 DI 10.1002/prca.200700243 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 203VC UT WOS:000249001100004 PM 21136731 ER PT J AU Collins, GT Newman, AH Grundt, P Rice, KC Husbands, SM Chauvignac, C Chen, JY Wang, SM Woods, JH AF Collins, Gregory T. Newman, Amy Hauck Grundt, Peter Rice, Kenner C. Husbands, Stephen M. Chauvignac, Cedric Chen, Jianyong Wang, Shaomeng Woods, James H. TI Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists SO PSYCHOPHARMACOLOGY LA English DT Article DE D2 receptors; D3 receptors; yawning; hypothermia; pramipexole; quinpirole; PG01037; SB-277011A; agonists; antagonists ID VIVO PHARMACOLOGICAL CHARACTERIZATION; D-3 RECEPTOR ANTAGONIST; SEEKING BEHAVIOR; COCAINE-SEEKING; PENILE ERECTION; IN-VIVO; INDUCED REINSTATEMENT; SELECTIVE ANTAGONISM; BODY-TEMPERATURE; BINDING PROFILES AB Rational Identification of behaviors specifically mediated by the dopamine D2 and D3 receptors would allow for the determination of in vivo receptor selectivity and aide the development of novel therapeutics for dopamine-related diseases. Objectives These were aimed at evaluating the specific receptors involved in the mediation of D2/D3 agonist-induced yawning and hypothermia. Materials & Methods The relative potencies of a series of D2-like agonists to produce yawning and hypothermia were determined. The ability of D3-selective and D2-selective antagonists to inhibit the induction of yawning and hypothermia were assessed and a series of D2/D3 antagonists were characterized with respect to their ability to alter yawning induced by a low and high dose of PD-128,907 and sumanirole-induced hypothermia. Results D3-preferring agonists induced yawning at lower doses than those required to induce hypothermia and the D2-preferring agonist, sumanirole, induced hypothermia at lower doses than were necessary to induce yawning. The rank order of D3 selectivity was pramipexole > PD-128,907 = 7-OH-DPAT = quinpirole = quinelorane > apomorphine = U91356A. Sumanirole had only D2 agonist effects. PG01037, SB-277011A, and U99194 were all D3-selective antagonists, whereas haloperidol and L-741,626 were D2-selective antagonists and nafadotride's profile of action was more similar to the D2 antagonists than to the D3 antagonists. Conclusions D3 and D2 receptors have specific roles in the mediation of yawning and hypothermia, respectively, and the analysis of these effects allow inferences to be made regarding the selectivity of D2/D3 agonists and antagonists with respect to their actions at D2 and D3 receptors. C1 Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. Natl Inst Drug Abuse Intramural Res Program, Med Chem Sect, NIH, Baltimore, MD 21224 USA. Natl Inst Drug Abuse Intramural Res Program, Chem Biol Res Branch, NIH, Bethesda, MD 20892 USA. Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England. Univ Michigan, Sch Med, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Med, Dept Med Chem, Ann Arbor, MI 48109 USA. RP Woods, JH (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 MSRB 3,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM jhwoods@umich.edu RI Husbands, Stephen/D-5926-2011; Collins, Gregory/K-3125-2012; OI Husbands, Stephen/0000-0002-9928-6322 FU NIDA NIH HHS [F31 DA019322-03, DA 019322, DA 020669, F31 DA019322, R01 DA020669, R01 DA020669-02]; PHS HHS [F013771] NR 48 TC 79 Z9 79 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2007 VL 193 IS 2 BP 159 EP 170 DI 10.1007/s00213-007-0766-3 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 188PM UT WOS:000247931800001 PM 17393143 ER PT J AU Wang, B You, ZB Rice, KC Wise, RA AF Wang, Bin You, Zhi-Bing Rice, Kenner C. Wise, Roy A. TI Stress-induced relapse to cocaine seeking: roles for the CRF2 receptor and CRF-binding protein in the ventral tegmental area of the rat SO PSYCHOPHARMACOLOGY LA English DT Article DE stress; addiction; cocaine; corticotropin-releasing factor; binding protein; reinstatement ID CORTICOTROPIN-RELEASING-FACTOR; LONG-TERM POTENTIATION; DOPAMINE NEURONS; INDUCED REINSTATEMENT; LIGAND INHIBITOR; NMDA RECEPTORS; DRUG SEEKING; BRAIN; SYNAPSES; CORTICOSTERONE AB Rationale Footshock reinstates cocaine seeking in cocaine-experienced rats by inducing corticotropin-releasing factor (CRF) and glutamate release in the ventral tegmental area (VTA) and thus activating VTA dopaminergic neurons. Footshock-induced VTA glutamate release, dopamine activation and reinstatements are blocked by VTA administration of a alpha-helical CRF, a nonselective CRF receptor antagonist. The effects of selective CRF antagonists have not yet been reported. Objective The present studies were designed to explore the roles of VTA CRF receptor subtypes and CRF-BP in these effects induced by footshock. Methods Rats were first trained to lever-press for intravenous cocaine (1 mg/infusion/0.13 ml, FR-1 schedule), and then tested under extinction conditions until response rates returned to the pretraining baseline. Reinstatements, VTA glutamate and dopamine levels [microdialysis with high performance liquid chromatography (HPLC)] were then assessed, under various pharmacological conditions, after mild inescapable footshock. Results Footshock-induced reinstatement of cocaine seeking and release of VTA glutamate and dopamine were blocked by selective blockade of VTA CRF2 receptors (CRF(2)Rs) but not CRF(1)Rs. VTA perfusion of CRF or CRF2R agonists that have strong affinity for CRF-BP mimicked the effects induced by footshock while CRFR agonists that do not bind CRF-BP were ineffective. CRF6-33, which competes for the CRF binding site on CRF-BP, attenuated the effects of CRF or urocortin I on VTA glutamate and dopamine release and on reinstatement of cocaine seeking. Conclusions The present studies revealed a role of VTA CRF-BP and suggest an involvement of CRF2R in the effectiveness of stress in triggering glutamate and dopamine release and cocaine seeking in drug-experienced animals. C1 NIDA, IRP, Behav Neurosci Branch, NIH, Baltimore, MD 21224 USA. NIDDK, Lab Med Chem, NIH, Bethesda, MD 20892 USA. RP You, ZB (reprint author), NIDA, IRP, Behav Neurosci Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM zyou@intra.nida.nih.gov RI Wise, Roy/A-6465-2012 FU Intramural NIH HHS NR 36 TC 123 Z9 123 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD AUG PY 2007 VL 193 IS 2 BP 283 EP 294 DI 10.1007/s00213-007-0782-3 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 188PM UT WOS:000247931800012 PM 17437087 ER PT J AU Meeske, K Smith, AW Alfano, CM McGregor, BA McTiernan, A Baumgartner, KB Malone, KE Reeve, BB Ballard-Barbash, R Bernstein, L AF Meeske, Kathleen Smith, Ashley Wilder Alfano, Catherine M. McGregor, Bonnie A. McTiernan, Anne Baumgartner, Kathy B. Malone, Kathleen E. Reeve, Bryce B. Ballard-Barbash, Rachel Bernstein, Leslie TI Fatigue in breast cancer survivors two to five years post diagnosis: a HEAL Study report SO QUALITY OF LIFE RESEARCH LA English DT Article DE breast cancer survivors; fatigue; quality of life; Piper Fatigue Scale ID POSTMASTECTOMY PAIN SYNDROME; LONG-TERM SURVIVORS; QUALITY-OF-LIFE; ADJUVANT CHEMOTHERAPY; PREVALENCE; EXERCISE; IMPACT; WOMEN; DEPRESSION; CARCINOMA AB Purpose The purpose of this study was to estimate prevalence of fatigue, identify correlates of fatigue and evaluate the relationship between fatigue and health-related quality of life (HRQOL) in a large cohort of disease-free breast cancer survivors. Methods Participants are enrolled in the HEAL Study, a multi-center prospective study of women diagnosed with in-situ to Stage IIIA breast cancer. HEAL participants (n = 1183) completed a baseline and a 24-month follow-up interview. Women in this report (n = 800) also completed a quality of life questionnaire that included the Piper Fatigue Scale and the RAND SF-36 two to five years after diagnosis. Multivariate regression methods were used to identify significant factors associated with fatigue. SF-36 scores for fatigued survivors were compared to non-fatigued survivor scores and population norms. Results Forty-one percent of the breast cancer survivors were fatigued. Significant correlates of fatigue included pain, cognitive problems, physical inactivity, weight gain/personal appearance and antidepressant use. Fatigue was associated with poorer HRQOL, most notably in areas of role and social functioning. Conclusions This study provides further support for the conclusion that a significant proportion of breast cancer survivors experience fatigue that compromises HRQOL two to five years post-diagnosis. C1 Univ So Calif, Keck Sch Med, Dept Prevent Med, USC Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA. NCI, Div Canc Control & Populat Sci, Appl Res Program, Outcomes Res Branch, Bethesda, MD 20892 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Ohio State Univ, Coll Publ Hlth, Columbus, OH 43210 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Univ Louisville, Sch Publ Hlth & Informat Sci, Louisville, KY 40202 USA. RP Meeske, K (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, USC Norris Comprehens Canc Ctr, 1444 Eastlake Ave,Room 4449, Los Angeles, CA 90033 USA. EM lbern@usc.edu FU NCI NIH HHS [N01-CN-05228, N01-CN-75036-20, N01-PC-67010, T32 CA90661]; NICHD NIH HHS [N01-HD-3-3175] NR 65 TC 65 Z9 67 U1 7 U2 13 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD AUG PY 2007 VL 16 IS 6 BP 947 EP 960 DI 10.1007/s11136-007-9215-3 PG 14 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 196TP UT WOS:000248505400004 PM 17457697 ER PT J AU vom Saal, FS Akingbemi, BT Belcher, SM Birnbaum, LS Crain, DA Eriksen, M Farabollini, F Guillette, LJ Hauser, R Heindel, JJ Ho, SM Hunt, PA Iguchi, T Jobling, S Kanno, J Keri, RA Knudsen, KE Laufer, H LeBlanc, GA Marcus, M McLachlan, JA Myers, JP Nadal, A Newbold, RR Olea, N Prins, GS Richter, CA Rubin, BS Sonnenschein, C Soto, AM Talsness, CE Vandenbergh, JG Vandenberg, LN Walser-Kuntz, DR Watson, CS Welshons, WV Wetherill, Y Zoeller, RT AF vom Saal, Frederick S. Akingbemi, Benson T. Belcher, Scott M. Birnbaum, Linda S. Crain, D. Andrew Eriksen, Marcus Farabollini, Francesca Guillette, Louis J., Jr. Hauser, Russ Heindel, Jerrold J. Ho, Shuk-Mei Hunt, Patricia A. Iguchi, Taisen Jobling, Susan Kanno, Jun Keri, Ruth A. Knudsen, Karen E. Laufer, Hans LeBlanc, Gerald A. Marcus, Michele McLachlan, John A. Myers, John Peterson Nadal, Angel Newbold, Retha R. Olea, Nicolas Prins, Gail S. Richter, Catherine A. Rubin, Beverly S. Sonnenschein, Carlos Soto, Ana M. Talsness, Chris E. Vandenbergh, John G. Vandenberg, Laura N. Walser-Kuntz, Debby R. Watson, Cheryl S. Welshons, Wade V. Wetherill, Yelena Zoeller, R. Thomas TI Chapel Hill bisphenol A expert panel consensus statement: Integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure SO REPRODUCTIVE TOXICOLOGY LA English DT Letter DE bisphenol A; in vitro; in vivo; rat; mouse; aquatic animal; cancer; low dose; non-monotonic dose-response curves; developmental programming ID ESTROGENIC ACTIVITY; PROLACTIN-RELEASE; IN-VIVO; XENOESTROGENS; CHEMICALS; LEACHATE; CELLS; ASSAY C1 Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. Auburn Univ, Dept Anat Physiol & Pharmacol, Auburn, AL 36849 USA. Univ Cincinnati, Ctr Environm Genet, Dept Pharmacol & Cell Biophys, Cincinnati, OH 45267 USA. US EPA, Res Triangle Pk, NC 27709 USA. Maryville Coll, Dept Biol, Maryville, TN 37804 USA. Algalita Marine Res Fdn, Los Angeles, CA 90034 USA. Univ Siena, Dept Physiol, I-53100 Siena, Italy. Univ Florida, Dept Zool, Gainesville, FL 32611 USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. Univ Cincinnati, Dept Environm Hlth, Cincinnati, OH 45267 USA. Washington State Univ, Sch Mol Sci, Pullman, WA 99164 USA. Okazaki Inst Integrat Biosci Bioenvironm Sci, Natl Inst Nat Sci, Okazaki, Aichi 4448787, Japan. Brunel Univ, Dept Biol Sci, Uxbridge UB8 3PH, Middx, England. Natl Inst Hlth Sci, Div Cellular & Mol Toxicol, Tokyo 1588501, Japan. Case Western Reserve Univ, Sch Med, Dept Pharmacol, Cleveland, OH 44106 USA. Univ Cincinnati, Coll Med, Dept Cell & Canc Biol, Cincinnati, OH 45267 USA. Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT 06269 USA. N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. Emory Univ, Rollins Sch Publ Hlth, Dept Epidemiol, Atlanta, GA 30322 USA. Tulane Univ, Ctr Bioenvironm Res, New Orleans, LA 70112 USA. Xavier Univ, New Orleans, LA 70112 USA. Environm Hlth Sci, Charlottesville, VA 22902 USA. Univ Miguel Hernandez, Inst Bioingn, Alicante 03202, Spain. NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. Univ Granada, CIBERESP Hosp Clin, E-18071 Granada, Spain. Univ Illinois, Dept Urol, Chicago, IL 60612 USA. Columbia Environm Res Ctr, USGS, Columbia, MO 65201 USA. Tufts Med Sch, Dept Anat & Cellular Biol, Boston, MA 02111 USA. Tufts Univ, Sch Med, Dept Anat & Cellular Biol, Boston, MA 02111 USA. Charite Univ Med Sch Berlinb, Inst Clin Pharmacol & Toxicol, Dept Toxicol, D-14195 Berlin, Germany. N Carolina State Univ, Dept Zool, Raleigh, NC 27695 USA. Tufts Univ, Sackler Sch Grad Biomed Sci, Boston, MA 02111 USA. Carleton Coll, Dept Biol, Northfield, MN 55057 USA. Univ Texas, Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. Univ Missouri, Dept Biomed Sci, Columbia, MO 65211 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. RP vom Saal, FS (reprint author), Univ Missouri, Div Biol Sci, 105 Lefevre Hall, Columbia, MO 65211 USA. EM vomsaalf@missouri.edu RI Olea, Nicolas/H-3198-2014; Nadal, Angel/G-6721-2014; OI Olea, Nicolas/0000-0002-8938-3743; Nadal, Angel/0000-0003-4178-2152; Richter, Catherine/0000-0001-7322-4206 FU NIEHS NIH HHS [R01 ES016675, ES11283, P30 ES006096, R01 ES011283, R01 ES015584, R01 ES015584-02, R01 ES015768, R01 ES016675-07] NR 25 TC 348 Z9 352 U1 3 U2 49 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD AUG-SEP PY 2007 VL 24 IS 2 BP 131 EP 138 DI 10.1016/j.reprotox.2007.07.005 PG 8 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 220SB UT WOS:000250176500001 PM 17768031 ER PT J AU Richter, CA Birnbaum, LS Farabollini, F Newbold, RR Rubin, BS Talsness, CE Vandenbergh, JG Walser-Kuntz, DR vom Saal, FSV AF Richter, Catherine A. Birnbaum, Linda S. Farabollini, Francesca Newbold, Retha R. Rubin, Beverly S. Talsness, Chris E. Vandenbergh, John G. Walser-Kuntz, Debby R. vom Saal, Frederick S. TI In vivo effects of bisphenol A in laboratory rodent studies SO REPRODUCTIVE TOXICOLOGY LA English DT Review DE behavior; neuroendocrine; endocrine disruptors; immune system; metabolism; mouse; rat; reproduction ID ESTROGEN-RECEPTOR-ALPHA; ADULT OVARIECTOMIZED RATS; SPRAGUE-DAWLEY RATS; UDP-GLUCURONOSYLTRANSFERASE ACTIVITIES; LUTEINIZING-HORMONE SECRETION; BRAIN SEXUAL-DIFFERENTIATION; FEMALE REPRODUCTIVE-TRACT; MATERNAL DIETARY EXPOSURE; MESSENGER-RNA EXPRESSION; DAILY SPERM PRODUCTION AB Concern is mounting regarding the human health and environmental effects of bisphenol A (BPA), a high-production-volume chemical used in synthesis of plastics. We have reviewed the growing literature on effects of low doses of BPA, below 50 mg/(kg day), in laboratory exposures with mammalian model organisms. Many, but not all, effects of BPA are similar to effects seen in response to the model estrogens diethylstilbestrol and ethinylestradiol. For most effects, the potency of BPA is approximately 10-1000-fold less than that of diethylstilbestrol or ethinylestradiol. Based on our review of the literature, a consensus was reached regarding our level of confidence that particular outcomes occur in response to low dose BPA exposure. We are confident that adult exposure to BPA affects the male reproductive tract, and that long lasting, organizational effects in response to developmental exposure to BPA occur in the brain, the male reproductive system, and metabolic processes. We consider it likely, but requiring further confirmation, that adult exposure to BPA affects the brain, the female reproductive system, and the immune system, and that developmental effects occur in the female reproductive system. (C) 2007 Elsevier Inc. All rights reserved. C1 US Geol Survey, Columbia Environm Res Ctr, Columbia, MO 65201 USA. US EPA, Res Triangle Pk, NC 27711 USA. Univ Siena, Dept Physiol, I-53100 Siena, Italy. NIEHS, NIH, DHHS, Res Triangle Pk, NC 27709 USA. Tufts Univ, Sch Med, Dept Anat & Cell Biol, Boston, MA 02111 USA. Charite Univ Med Berlin, Inst Clin Pharmacol & Toxicol, Berlin, Germany. N Carolina State Univ, Dept Zool, Raleigh, NC 27695 USA. Carleton Coll, Dept Biol, Northfield, MN 55057 USA. Univ Missouri, Div Biol Sci, Columbia, MO 65211 USA. RP Richter, CA (reprint author), US Geol Survey, Columbia Environm Res Ctr, 4200 New Haven Rd, Columbia, MO 65201 USA. EM Crichter@usgs.gov OI Richter, Catherine/0000-0001-7322-4206 FU NIEHS NIH HHS [R01 ES011283, R01 ES011283-01A1] NR 199 TC 510 Z9 534 U1 15 U2 123 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD AUG-SEP PY 2007 VL 24 IS 2 BP 199 EP 224 DI 10.1016/j.reprotox.2007.06.004 PG 26 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 220SB UT WOS:000250176500004 PM 17683900 ER PT J AU Newbold, RR Jefferson, WN Padilla-Banks, E AF Newbold, Retha R. Jefferson, Wendy N. Padilla-Banks, Elizabeth TI Long-term adverse effects of neonatal exposure to bisphenol A on the murine female reproductive tract SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE endocrine disruptors; ovary; uterus; reproduction; developmental ID MOUSE GENITAL-TRACT; IN-UTERO EXPOSURE; DEVELOPMENTAL EXPOSURE; DIETHYLSTILBESTROL DES; PERINATAL EXPOSURE; FETAL EXPOSURE; ESTROGEN DIETHYLSTILBESTROL; PROSTATE CARCINOGENESIS; ENDOCRINE DISRUPTORS; PRENATAL EXPOSURE AB The developing fetus is uniquely sensitive to perturbation by chemicals with hormone-like activity. The adverse effects of prenatal diethylstilbestrol (DES) exposure are a classic example. Since concern has been mounting regarding the human health and environmental effects of bisphenol A (BPA), a high-production-volume chemical with estrogenic activity used in the synthesis of plastics, we investigated its long-term effects in an experimental animal model that was previously shown useful in studying the adverse effects of developmental exposure to DES. Outbred female CD-1 mice were treated on days 1-5 with subcutaneous injections of BPA (10, 100 or 1000 mu g/kg/day) dissolved in corn oil or corn oil alone (Control). At 18 months, ovaries and reproductive tract tissues were examined. There was a statistically significant increase in cystic ovaries and cystic endometrial hyperplasia (CEH) in the BPA-100 group as compared to Controls. Progressive proliferative lesion (PPL) of the oviduct and cystic mesonephric (Wolffian) duct remnants were also seen in all of the BPA groups. More severe pathologies of the uterus following neonatal BPA treatment included adenomyosis, leiomyomas, atypical hyperplasia, and stromal polyps. These data suggest that BPA causes long-term adverse effects if exposure occurs during critical periods of differentiation. Published by Elsevier Inc. C1 NIEHS, Dev Endocrinol & Endocrine Disruptor Sect, Mol Toxicol Lab, NIH,DHHS, Res Triangle Pk, NC 27709 USA. RP Newbold, RR (reprint author), NIEHS, Dev Endocrinol & Endocrine Disruptor Sect, Mol Toxicol Lab, NIH,DHHS, MD E4-02,POB 12233, Res Triangle Pk, NC 27709 USA. EM newbold1@niehs.nih.gov FU Intramural NIH HHS [Z01 ES070060-34] NR 50 TC 131 Z9 136 U1 3 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD AUG-SEP PY 2007 VL 24 IS 2 BP 253 EP 258 DI 10.1016/j.reprotox.2007.07.006 PG 6 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 220SB UT WOS:000250176500007 PM 17804194 ER PT J AU Monge, P Wesseling, C Guardado, J Lundberg, I Ahlbom, A Cantor, KP Weideroass, E Partanen, T AF Monge, Patricia Wesseling, Catharina Guardado, Jorge Lundberg, Ingvar Ahlbom, Anders Cantor, Kenneth P. Weideroass, Elisabete Partanen, Tmo TI Parental occupational exposure to pesticides and the risk of childhood leukemia in Costa Rica SO SCANDINAVIAN JOURNAL OF WORK ENVIRONMENT & HEALTH LA English DT Article DE cancer epidemiology; case-control study; childhood cancer; children; developing country; fetal exposure; pregnancy; reproductive effect; tropics ID CANCER; CHILDREN; POPULATION; CALIFORNIA; GERMANY AB Objectives Parental exposure to pesticides and the risk of leukemia in offspring were examined in a population-based case-control study in Costa Rica. Methods All cases of childhood leukemia (N=334), in 1995-2000, were identified at the Cancer Registry and the Children's Hospital. Population controls (N=579) were drawn from the National Birth Registry. Interviews of parents were conducted using conventional and icon-based calendar forms. An exposure model was constructed for 25 pesticides in five time periods. Results Mothers' exposures to any pesticides during the year before conception and during the first and second trimesters were associated with the risk [odds ratio (OR) 2.4, 95% confidence interval (95% CI) 1.0-5.9; OR 22, 95% CI 2.8-171.5; OR 4.5, 95% CI 1.4-14.7, respectively] and during anytime (OR 2.2, 95% CI 1.0-4.8). An association was found for fathers' exposures to any pesticides during the second trimester (OR 1.5, 95% CI 1.0-2.3). An increased risk with respect to organophosphates was found for mothers during the first trimester (OR 3.5,95% CI 1.0-12.2) and for fathers during the year before conception and the first trimester (OR 1.5, 95% CI 1.0-2.2 and OR 1.6, 95% Cl 1.0-2.6, respectively), and benzimidazoles during the first, second, and third trimesters of pregnancy (OR 2.2,95% CI 1.0-4.4; OR 2.2,95% CI 1.0-5.0; OR 2.2,95% CI 1.0-5.2, respectively). There was a suggestion of an exposure-response gradient for fathers as regards picloram, benomyl, and paraquat. Age at diagnosis was positively associated with fathers' exposures and inversely associated with mothers' exposures. Conclusions The results suggest that parental exposure to certain pesticides may increase the risk of leukemia in offspring. C1 Univ Nacl, Cent Amer Inst Studies Tox Subst, Heredia, Costa Rica. Karolinska Inst, Dept Publ Hlth Sci, Stockholm, Sweden. Natl Inst Working Life, Stockholm, Sweden. Karolinska Inst, Natl Inst Environm Med, Stockholm, Sweden. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Canc Registry Norway, Oslo, Norway. RP Monge, P (reprint author), Univ Nacl, Cent Amer Inst Studies Tox Subst, POB 86-3000, Heredia, Costa Rica. EM pmonge@una.ac.cr RI Weiderpass, Elisabete/M-4029-2016 OI Weiderpass, Elisabete/0000-0003-2237-0128 FU FIC NIH HHS [5 D43 TW00642-07]; Intramural NIH HHS NR 52 TC 23 Z9 25 U1 1 U2 10 PU SCAND J WORK ENV HEALTH PI HELSINKI PA TOPELIUKSENKATU 41A, SF-00250 HELSINKI, FINLAND SN 0355-3140 J9 SCAND J WORK ENV HEA JI Scand. J. Work Environ. Health PD AUG PY 2007 VL 33 IS 4 BP 293 EP 303 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 208HD UT WOS:000249309500009 PM 17717622 ER PT J AU Genderson, MR Dickinson, D Diaz-Asper, CM Egan, MF Weinberger, DR Goldberg, TE AF Genderson, Margo R. Dickinson, Dwight Diaz-Asper, Catherine M. Egan, Michael F. Weinberger, Daniel R. Goldberg, Terry E. TI Factor analysis of neurocognitive tests in a large sample of schizophrenic probands, their siblings, and healthy controls SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; factor analysis; neuropsychology ID CONFIRMATORY FACTOR-ANALYSIS; PSYCHOTIC DISORDERS; DEFICITS; INTELLIGENCE; CAPACITY AB Large batteries of neuropsychological tests are typically necessary to identify cognitive deficits in schizophrenia and routinely examine multiple cognitive processes, with many tests often yielding more than one measure of interest. This study investigates the feasibility of a partial solution to the problem of multiple comparisons: the use of factor analysis to reduce the number of phenotypic variables and to better understand the underlying cognitive architecture in schizophrenia. Using a principle components analysis followed by a varimax rotation, we identified factor structures for schizophrenic patients (n = 99), their unaffected siblings (n= 167), and control subjects (n= 13 1), both separately and as a composite group. Exploratory factor analysis of the full sample yielded a 7-factor model that included verbal memory, working memory, visual memory, IQ/speed/fluency, executive function, attention and digit span. A confirmatory factor analysis (CFA) with maximum likelihood estimation revealed that the 7-factor model fit observed data from the three groups adequately. Since we identified a factor structure representative of all groups that reduced 24 original variables to 7 variables of interest, factor analysis was useful in reducing the complexity of large batteries of cognitive measures to more manageable numbers of phenotypic variables. Furthermore, these findings provide the first confirmation that cognitive structure is comparable in family members of schizophrenia patients, as well as in patients themselves and controls. (c) 2007 Published by Elsevier B.V. C1 NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. RP Goldberg, TE (reprint author), Zucker Hillside Hosp, 75-59 263rd St, Glen Oaks, NY 11040 USA. EM TGoldber@NSHS.edu NR 26 TC 34 Z9 36 U1 5 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD AUG PY 2007 VL 94 IS 1-3 BP 231 EP 239 DI 10.1016/j.schres.2006.12.031 PG 9 WC Psychiatry SC Psychiatry GA 198OX UT WOS:000248638500029 PM 17570645 ER PT J AU Fields, RD AF Fields, R. Douglas TI The shark's electric sense SO SCIENTIFIC AMERICAN LA English DT Article AB Sharks and related fish can sense the extremely weak electric fields emitted by animals in the surrounding water, an ability few organisms possess. the ability is made possible by unique electrosensor structure called ampullae of Lorenzini. Sharks use this sixth sense to home in on prey during the final phase of attack. Other potential uses remain to be determined. C1 NIH, Bethesda, MD 20892 USA. RP Fields, RD (reprint author), NIH, Bethesda, MD 20892 USA. NR 0 TC 7 Z9 7 U1 10 U2 44 PU SCI AMERICAN INC PI NEW YORK PA 415 MADISON AVE, NEW YORK, NY 10017 USA SN 0036-8733 J9 SCI AM JI Sci.Am. PD AUG PY 2007 VL 297 IS 2 BP 74 EP 80 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 189KE UT WOS:000247987000032 PM 17894175 ER PT J AU Melendez, JH Giles, JA Yuenger, JD Smith, TD Ghanem, KG Reich, K Zenilman, JM AF Melendez, Johan H. Giles, Julie A. Yuenger, Jeffrey D. Smith, Tukisa D. Ghanem, Khalil G. Reich, Karl Zenilman, Jonathan M. TI Detection and quantification of Y-chromosomal sequences by real-time PCR using the LightCyclerl((R)) system SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID CHAIN-REACTION DETECTION; VAGINAL FLUID C1 Johns Hopkins Univ, Sch Med, Bayview Med Ctr, Div Infect Dis,Dept Med, Baltimore, MD 21224 USA. Digene Corp, Gaithersburg, MD USA. Natl Canc Inst, Gaithersburg, MD USA. Independent Forens, Hillside, IL USA. RP Zenilman, JM (reprint author), Johns Hopkins Univ, Sch Med, Bayview Med Ctr, Div Infect Dis,Dept Med, B3N,4940 Eastern Ave, Baltimore, MD 21224 USA. EM jzenilma@jhmi.edu FU NICHD NIH HHS [R01 HD043674-01] NR 2 TC 15 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD AUG PY 2007 VL 34 IS 8 BP 617 EP 619 DI 10.1097/01.olq.0000258336.65285.31 PG 3 WC Infectious Diseases SC Infectious Diseases GA 193PT UT WOS:000248287200017 PM 17334265 ER PT J AU Ghanem, KG Melendez, JH McNeil-Solis, C Giles, JA Yuenger, J Smith, TD Zenilman, J AF Ghanem, Khalil G. Melendez, Johan H. McNeil-Solis, Corlina Giles, Julie A. Yuenger, Jeffrey Smith, Tukisa D. Zenilman, Jonathan TI Condom use and vaginal Y-chromosome detection: The specificity of a potential biomarker SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID PROSTATE-SPECIFIC ANTIGEN; SEXUALLY-TRANSMITTED-DISEASE; CHAIN-REACTION DETECTION; FACE-TO-FACE; INTERVIEW MODES; PREVENTION; FAILURE; FLUID; SEQUENCES; BREAKAGE AB Objective: Detection of vaginal Y-chromosome sequences (YCS) may be a useful biomarker to validate sexual behavior reporting in women. We describe the effects of condom use on the detection of vaginal YCS. Methods: Fifty-six women were asked to abstain from sexual intercourse for 14 days. On day 15, participants were asked to engage in sexual intercourse with their male partners using condoms. Self-collected vaginal swabs were obtained on days 14, 16, and 17. YCS were detected using the Roche LightCycler with the use of positive controls. Results: Fourty-four of 56 women completed the study. Five women (11.4%) had detectable YCS. The overall specificity of the YCS assay with condom use was 92% (95% CI: 80%-98%). Although women who reported receptive oral sex and digital penetration within 48 hours of swab collection had a higher detection rate of YCS [RR 2.3 (95% CI: 1.1-4.6) and 3.6 (95% CI: 1.6-8.5), respectively], the mean concentration of YCS was much less than that associated with unprotected vaginal intercourse (P <0.001) Conclusions: Condom use during intercourse appears to prevent vaginal YCS detection; this may be a useful biomarker to validate self-reported condom use. C1 Johns Hopkins Univ, Sch Med, Div Infect Dis, Bayview Med Ctr, Baltimore, MD 21205 USA. Digene Corp, Gaithersburg, MD USA. Natl Canc Inst, Core Genotyping Facil, Gaithersburg, MD USA. RP Zenilman, J (reprint author), Johns Hopkins Univ, Sch Med, Div Infect Dis, Bayview Med Ctr, B3N,4940 Eastern Ave, Baltimore, MD 21205 USA. EM jzenilma@jhmi.edu FU NICHD NIH HHS [R01 HD043674-01] NR 24 TC 22 Z9 22 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD AUG PY 2007 VL 34 IS 8 BP 620 EP 623 DI 10.1097/01.olq.0000258318.99606.d9 PG 4 WC Infectious Diseases SC Infectious Diseases GA 193PT UT WOS:000248287200018 PM 17308500 ER PT J AU Spouge, JL AF Spouge, John L. TI Inequalities on the overshoot beyond a boundary for independent summands with differing distributions SO STATISTICS & PROBABILITY LETTERS LA English DT Article DE renewal theory; excess over the boundary; Lorden's inequality ID SEQUENTIAL-ANALYSIS; RENEWAL THEORY AB Let {S-n: n >= 0} (S-0 = 0) denote the successive sums of independent non-negative random variates, of possibly differing distributions. Define: (1) the number N(b) = inf (n >= 0: S-n > b) of sums in the interval [0, b]; and (2) the overshoot Rb = S-N(b) - b. This paper bounds the tail P(R-b > c) and the moments ERbk. Published by Elsevier B.V. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Spouge, JL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM spouge@ncbi.nlm.nih.gov FU Intramural NIH HHS [Z01 LM000088-09] NR 11 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7152 J9 STAT PROBABIL LETT JI Stat. Probab. Lett. PD AUG PY 2007 VL 77 IS 14 BP 1486 EP 1489 DI 10.1016/j.spl.2007.02.013 PG 4 WC Statistics & Probability SC Mathematics GA 206CY UT WOS:000249162700003 PM 19461943 ER PT J AU Hattiangady, B Shuai, B Cai, JL Coksaygan, T Rao, MS Shetty, AK AF Hattiangady, Bharathi Shuai, Bing Cai, Jingli Coksaygan, Turhan Rao, Mahendra S. Shetty, Ashok K. TI Increased dentate neurogenesis after grafting of glial restricted progenitors or neural stem cells in the aging hippocampus SO STEM CELLS LA English DT Article DE adult neurogenesis; doublecortin; neural stem/progenitor cells; stem/progenitor cell transplantation; stem cell aging stem cell differentiation ID TEMPORAL-LOBE EPILEPSY; AGE-RELATED DECLINE; ECTOPIC GRANULE CELLS; ADULT-RAT HIPPOCAMPUS; SONIC HEDGEHOG; COGNITIVE DECLINE; SPINAL-CORD; CA3 REGION; OLD-AGE; GYRUS AB Neurogenesis in the dentate gyrus (DG) declines severely by middle age, potentially because of age-related changes in the DG microenvironment. We hypothesize that providing fresh glial restricted progenitors (GRPs) or neural stem cells (NSCs) to the aging hippocampus via grafting enriches the DG microenvironment and thereby stimulates the production of new granule cells from endogenous NSCs. The GRPs isolated from the spinal cords of embryonic day 13.5 transgenic F344 rats expressing human alkaline phosphatase gene and NSCs isolated from embryonic day 9 caudal neural tubes of Sox-2:EGFP transgenic mice were expanded in vitro and grafted into the hippocampi of middle-aged (12 months old) F344 rats. Both types of grafts survived well, and grafted NSCs in addition migrated to all layers of the hippocampus. Phenotypic characterization revealed that both GRPs and NSCs differentiated predominantly into astrocytes and oligodendrocytic progenitors. Neuronal differentiation of graft-derived cells was mostly absent except in the dentate subgranular zone (SGZ), where some of the migrated NSCs but not GRPs differentiated into neurons. Analyses of the numbers of newly born neurons in the DG using 5'-bromodeoxyuridine and/or doublecortin assays, however, demonstrated considerably increased dentate neurogenesis in animals receiving grafts of GRPs or NSCs in comparison with both naive controls and animals receiving sham-grafting surgery. Thus, both GRPs and NSCs survive well, differentiate predominantly into glia, and stimulate the endogenous NSCs in the SGZ to produce more new dentate granule cells following grafting into the aging hippocampus. Grafting of GRPs or NSCs therefore provides an attractive approach for improving neurogenesis in the aging hippocampus. C1 Duke Univ, Med Ctr, Div Neurosurg, Dept Surg, Durham, NC 27710 USA. Vet Affairs Med Ctr, Med Res Serv, Durham, NC USA. Vet Affairs Med Ctr, Surg Serv, Durham, NC USA. NIA, NIH, Neurosci Lab, Stem Cell Unit, Baltimore, MD 21224 USA. Invitrogen, Corp Res Labs, Carlsbad, CA USA. RP Shetty, AK (reprint author), Duke Univ, Med Ctr, Div Neurosurg, Dept Surg, DUMC Box 3807, Durham, NC 27710 USA. EM Ashok.Shetty@Duke.Edu RI Hattiangady, Bharathi/B-6367-2008; Hattiangady, Bharathi/A-2642-2009; Shetty, Ashok/A-2428-2008; OI Shetty, Ashok/0000-0001-5049-6671; Hattiangady, Bharathi/0000-0002-0432-1894 FU NIA NIH HHS [R01 AG20924]; NINDS NIH HHS [R01 NS054780, R01 NS043507] NR 62 TC 44 Z9 45 U1 0 U2 4 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD AUG PY 2007 VL 25 IS 8 BP 2104 EP 2117 DI 10.1634/stemcells.2006-0726 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 195KL UT WOS:000248411000028 PM 17510219 ER PT J AU Imaizumi, M Briard, E Zoghbi, SS Gourley, JP Hong, J Musachio, JL Gladding, R Pike, VW Innis, RB Fujita, M AF Imaizumi, Masao Briard, Emmanuelle Zoghbi, Sami S. Gourley, Jonathan P. Hong, Jinsoo Musachio, John L. Gladding, Robert Pike, Victor W. Innis, Robert B. Fujita, Masahiro TI Kinetic evaluation in nonhuman primates of two new PET ligands for peripheral benzodiazepine receptors in brain SO SYNAPSE LA English DT Article DE arterial input function; aryloxyanilide; compartmental modeling; distribution volume; positron emission tomography ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; BINDING-SITES; MICROGLIAL ACTIVATION; MULTIPLE-SCLEROSIS; NEURONAL DAMAGE; RAT-BRAIN; DISEASE; LOCALIZATION; VISUALIZATION AB Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia and are, thereby, biomarkers of cellular inflammation in brain.-We recently developed two PET ligands with an aryloxyanilide structure to image PBRs and now evaluate the kinetics of these radiotracers in monkey to determine whether they are suitable to explore in human. Baseline and receptor-blocking scans were performed with [C-11]PBR01 and [F-18]PBR06 in conjunction with serial measurements of the arterial plasma concentration of parent radiotracer separated from radiometabolite. We used brain and plasma data with compartmental modeling to calculate regional brain distribution volume, which is equal to the ratio at equilibrium of the concentration of radioligand in brain to that of plasma. The distribution volume of [C-11]PBR01 was inaccurately estimated in the baseline scans, possibly because of the short half-life of 11C or the presence of radiometabolite in brain. In contrast, the distribution volume of [18F]PBR06 was stably determined within 200 min of scanning, and nondisplaceable uptake was only similar to 10% of total brain uptake. [18F]PBR06 is promising for use in human because brain activity could be quantified with standard compartmental models and showed higher ratios (similar to 10:1) of specific to nonspecific uptake. A critical factor for human use will be whether the tracer has adequately fast wash out from brain relative to the half-life of the radionuclide to obtain stable values of distribution volume. C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Fujita, M (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 31,Room B2B37,31 Ctr Dr, Bethesda, MD 20892 USA. EM fujitam@mail.nih.gov FU Intramural NIH HHS NR 43 TC 48 Z9 48 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD AUG PY 2007 VL 61 IS 8 BP 595 EP 605 DI 10.1002/syn.20394 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 178CO UT WOS:000247199000003 PM 17455247 ER PT J AU Huestis, MA De Martinis, BS Goodwin, RS Gorelick, DA Kolbrich, EA Barnes, AJ AF Huestis, Marilyn A. De Martinis, Bruno S. Goodwin, Robert S. Gorelick, David A. Kolbrich, Erin A. Barnes, Allan J. TI Disposition of MDMA and metabolites in human sweat following controlled MDMA administration SO THERAPEUTIC DRUG MONITORING LA English DT Meeting Abstract CT 10th International Congress of Therapeutic Drug Monitoring and Clinical Toxicology CY SEP 09-14, 2007 CL Nice, FRANCE C1 Natl Inst Drug Abuse, Intramural Res Program, Chem & Drug Metab Sect, Baltimore, MD 21224 USA. Univ Sao Paulo, Fac Med, Dept Pathol, BR-14051140 Ribeirao Preto, Brazil. RI De Martinis, Bruno/I-5388-2012 OI De Martinis, Bruno/0000-0002-2702-5190 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0163-4356 J9 THER DRUG MONIT JI Ther. Drug Monit. PD AUG PY 2007 VL 29 IS 4 MA 15 BP 464 EP 464 PG 1 WC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology SC Medical Laboratory Technology; Pharmacology & Pharmacy; Toxicology GA 194QP UT WOS:000248359200029 ER PT J AU Bertino, P Porta, C Barbone, D Germano, S Busacca, S Pinato, S Tassi, G Favoni, R Gaudino, G Mutti, L AF Bertino, Pietro Porta, Camillo Barbone, Dario Germano, Serena Busacca, Sara Pinato, Sabrina Tassi, Giancarlo Favoni, Roberto Gaudino, Giovanni Mutti, Luciano TI Preliminary data suggestive of a novel translational approach to mesothelioma treatment: Imatinib mesylate with gemcitabine or pemetrexed SO THORAX LA English DT Article ID HUMAN-MALIGNANT MESOTHELIOMA; ENDOTHELIAL GROWTH-FACTOR; PLEURAL MESOTHELIOMA; TYROSINE KINASE; DIFFERENTIAL EXPRESSION; FACTOR PDGF; CELL-LINES; RECEPTOR; CANCER; INHIBITOR AB Background: Malignant mesothelioma is a cancer which is refractory to current treatments. Imatinib mesylate is a selective inhibitor of tyrosine kinases such as bcr-abl, c-Kit, c-Fms and platelet derived growth factor receptor beta (PDGFRb). PDGFRb is often overexpressed in mesothelioma cells and is a therapeutic target for imatinib in some solid tumours. A study was undertaken to assess whether imatinib alone or combined with chemotherapeutic agents may be effective for treating mesothelioma. Methods: Cultures from mesothelioma MMP, REN and ISTMES2 cell lines were treated with imatinib alone or in combination with a chemotherapeutic agent. Results: Imatinib induced cytotoxicity and apoptosis selectively on PDGFRb positive mesothelioma cells via blockade of receptor phosphorylation and interference with the Akt pathway. Of the chemotherapeutic agents tested in combination with imatinib, a synergistic effect was obtained with gemcitabine and pemetrexed. Conclusions: This study provides a rationale for a novel translational approach to the treatment of mesothelioma which relies on enhancement of tumour chemosensitivity by inhibition of Akt. C1 Univ Piemonte Orientale, DISCAFF Dept, I-28100 Novara, Italy. Univ Piemonte Orientale, DFBC Ctr, I-28100 Novara, Italy. San Matteo Univ Hosp, IRCCS, Pavia, Italy. Brescia Hosp, Chest Med Unit, Brescia, Italy. Natl Canc Inst, Genoa, Italy. Local Hlth Unit, I-11 Piemonte, Italy. RP Gaudino, G (reprint author), Univ Piemonte Orientale, DISCAFF Dept, I-28100 Novara, Italy. EM giovanni.gaudino@unipmn.it OI Porta, Camillo/0000-0003-2412-1563 NR 43 TC 30 Z9 30 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD AUG PY 2007 VL 62 IS 8 BP 690 EP 695 DI 10.1136/thx.2006.069872 PG 6 WC Respiratory System SC Respiratory System GA 199IQ UT WOS:000248689800011 PM 17311837 ER PT J AU Orlova, V Chavakis, T AF Orlova, ValeriaV. Chavakis, Trianfyllos TI Regulation of vascular endothelial permeability by junctional adhesion molecules (JAM) SO THROMBOSIS AND HAEMOSTASIS LA English DT Review DE adhesion molecules; cadherins; endothelial cells; inflammation; GTPases ID MEDIATED CELL-ADHESION; NEUTROPHIL TRANSENDOTHELIAL MIGRATION; ISCHEMIA-REPERFUSION INJURY; IMMUNOGLOBULIN SUPERFAMILY; P21-ACTIVATED KINASE; BARRIER FUNCTION; TIGHT JUNCTIONS; VE-CADHERIN; PLATELET-AGGREGATION; MONOCLONAL-ANTIBODY AB lation of the endothelial barrier as well as important participating signaling players, such as the small GTPases RhoA, Rac and Rap I. In this context, we will attempt to analyze and interpret the recent evidence pointing to the role of the family of junctional adhesion molecules (JAMs) in modulating the pathways involved in the regulation of the endothelial barrier.The vascular endothelium forms a barrier between the circulation and the interstitium, and changes in vascular permeability are very important during vascular repair and inflammatory conditions. The regulation of the endothelial barrier depends on actomyosin-related cell contractility as well as the integrity of cell-cell junctions, such as tight and adherens junctions. The present review will introduce the basic pathways involved in the regulation of the endothelial barrier as well as important participating signaling players, such as the small GTPases RhoA, Rac and Rap I. In this context, we will attempt to analyze and interpret the recent evidence pointing to the role of the family of junctional adhesion molecules (JAMs) in modulating the pathways involved in the regulation of the endothelial barrier. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Chavakis, T (reprint author), NCI, Expt Immunol Branch, NIH, 10 Ctr Dr,Rm 4B17, Bethesda, MD 20892 USA. EM chavakist@mail.nih.gov RI Orlova, Valeria/C-6065-2014 OI Orlova, Valeria/0000-0002-1169-2802 NR 92 TC 25 Z9 25 U1 0 U2 1 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 2007 VL 98 IS 2 BP 327 EP 332 DI 10.1160/Th07-03-0206 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 201BZ UT WOS:000248807800011 PM 17721614 ER PT J AU Bouaziz, A Ben Amor, N Woodard, GE Zibidi, H Lopez, JJ Bartegi, A Salido, GM Rosado, JA AF Bouaziz, Aicha Ben Amor, Niclhal Woodard, Geoffrey E. Zibidi, Hanen Lopez, Jose J. Bartegi, Ahgleb Salido, Gines M. Rosado, Juan A. TI Tyrosine phosphorylation/dephosphorylation balance is involved in thrombin-evoked microtubular reorganisation in human platelets SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE thrombin; microtubules; aggregation; platelets; pp60(src); Btk; protein kinases; protein phosphatases; ATP ID HUMAN-BLOOD PLATELETS; CALCIUM-ENTRY; CA2+ ENTRY; IN-VITRO; ACTIVATION; PHOSPHORYLATION; AGGREGATION; RECEPTOR; RELEASE; KINASE AB We have investigated the intracellular mechanisms involved in microtubular remodelling by thrombin and its possible involvement in platelet aggregation and secretion. Platelet stimulation with thrombin induces a time- and concentration-dependent regulation of the microtubular content, which was found to be maximally effective at the concentration 0.1 U/ml. Thrombin (0.1 U/ml) evoked an initial decrease in the microtubule content detectable at 5 seconds (sec) and reached a minimum 10 sec after stimulation. The microtubular content then increased, exceeding basal levels again approximately 30 sec after stimulation. Inhibition of tyrosine phosphatases using vanadate abolished thrombin-induced microtubular depolymerisation while inhibition of tyrosine kinases by methyl-2,5-dihydroxycinnamate prevented microtubule polymerisation. Thrombin activates the cytosolic Bruton's tyrosine kinase (Btk) and Src proteins. Inhibition of Btk or Src by LFM-A13 or PPI, respectively, abolished thrombin-induced microtubular polymerisation, while maintaining intact its ability to induce initial depolymerisation. Microtubular disruption by colchicine significantly reduced thrombin-induced platelet aggregation and ATP secretion. Similar results were observed after inhibition of microtubular disassembly by paclitaxel. These findings indicate that thrombin induces microtubular remodelling by modifying the balance between protein tyrosine phosphorylation and dephosphorylation. The former seems to be required for microtubular polymerisation, while tyrosine dephosphorylation is required for microtubular depolymerisation. Both, initial microtubular disassembly and subsequent polymerisation are required for thrombin-induced platelet aggregation and secretion in human platelets. C1 Univ Extremadura, Dept Physiol, Cell Physiol Res Grp, Caceres 10071, Spain. Inst Super Biotechnol, Unite Rech Biochim, Monastir, Tunisia. NIDDK, Bethesda, MD USA. RP Rosado, JA (reprint author), Univ Extremadura, Dept Physiol, Cell Physiol Res Grp, Av Univ S-N, Caceres 10071, Spain. EM jarosado@unex.es RI Woodard, Geoffrey/A-8608-2009; Salido, Gines/A-4292-2009; rosado, juan/H-3488-2015; LOPEZ, JOSE/F-4602-2016; Ben Amor, Nidhal/Q-8840-2016 OI Salido, Gines/0000-0002-8687-2445; rosado, juan/0000-0002-9749-2325; LOPEZ, JOSE/0000-0002-5234-1478; Ben Amor, Nidhal/0000-0002-6526-415X NR 50 TC 16 Z9 16 U1 0 U2 0 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD AUG PY 2007 VL 98 IS 2 BP 375 EP 384 DI 10.1160/TH07-01-0061 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 201BZ UT WOS:000248807800017 PM 17721620 ER PT J AU Woods, CG Burns, AM Bradford, BU Ross, PK Kosyk, O Swenberg, JA Cunningham, ML Rusyn, I AF Woods, Courtney G. Burns, Amanda M. Bradford, Blair U. Ross, Pamela K. Kosyk, Oksana Swenberg, James A. Cunningham, Michael L. Rusyn, Ivan TI WY-14,643-induced cell proliferation and oxidative stress in mouse liver are independent of NADPH oxidase SO TOXICOLOGICAL SCIENCES LA English DT Article DE Kupffer cells; PPAR alpha; peroxisome proliferators; carcinogenesis ID ACTIVATED RECEPTOR-ALPHA; TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; <4-CHLORO-6-(2,3-XYLIDINO)-2-PYRIMIDINYLTHIO>ACETIC ACID WY-14,643; ACYL COA OXIDASE; PEROXISOME PROLIFERATOR; KUPFFER CELLS; DNA-SYNTHESIS; PPAR-ALPHA; HEPATOCYTE PROLIFERATION AB Long-term exposure of rodents to peroxisome proliferators leads to increases in peroxisomes, hepatocellular proliferation, oxidative damage, suppressed apoptosis, and ultimately results in the development of hepatic adenomas and carcinomas. Peroxisome proliferators-activated receptor (PPAR)alpha was shown to be required for these pleiotropic responses; however, Kupffer cells, resident liver macrophages, were also identified as playing a role in peroxisome proliferators-induced effects, independently of PPAR alpha. Previous studies showed that oxidants from NADPH (nicotinamide adenine dinucleotide phosphate, reduced) oxidase mediate acute effects of peroxisome proliferators in rodent liver. To determine if Kupffer cell oxidants are also involved in chronic effects, NADPH oxidase-deficient (p47(phox)-null) mice were fed 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (WY-14,643)-containing diet (0.1% wt/ wt) for 1 week, 5 weeks, or 5 months along with Ppar alpha-null and wild type mice. As expected, no change in liver size, cell replication rates, or other phenotypic effects of peroxisome proliferators were observed in Ppar alpha-null mice. Through 5 months of treatment, the p47(phox)-null and wild type mice exhibited peroxisome proliferators-induced adverse liver effects, along with increased oxidative DNA damage and increased cell proliferation, a response that is potentially mediated through nuclear factor kappa B (NFkB). Suppressed apoptosis caused by WY-14,643 was dependent on both NADPH oxidase and PPAR alpha. Collectively, these findings suggest that involvement of Kupffer cells in WY-14,643-induced parenchymal cell proliferation and oxidative stress in rodent liver is an acute phenomenon that is not relevant to long-term exposure, but they are still involved in chronic apoptotic responses. These results provide new insight for understanding the mode of hepatocarcinogenic action of peroxisome proliferators. C1 Univ N Carolina, Michael Hooker Res Ctr 0031, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Rusyn, I (reprint author), Univ N Carolina, Michael Hooker Res Ctr 0031, Dept Environm Sci & Engn, CB 7431, Chapel Hill, NC 27599 USA. EM iir@unc.edu RI Rusyn, Ivan/S-2426-2016 FU NIEHS NIH HHS [K22-ES11660, F32-ES13342, P30-ES10126, R01-ES12686, U19-ES11391] NR 51 TC 20 Z9 21 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD AUG PY 2007 VL 98 IS 2 BP 366 EP 374 DI 10.1093/toxsci/kfm104 PG 9 WC Toxicology SC Toxicology GA 194WR UT WOS:000248375000006 PM 17483499 ER PT J AU Yang, ZQ Yang, S Qian, SY Hong, JS Kadiiska, MB Tennant, RW Waalkes, MP Liu, J AF Yang, Zhengqin Yang, Sufen Qian, Steven Y. Hong, Jau-Shyong Kadiiska, Maria B. Tennant, Raymond W. Waalkes, Michael P. Liu, Jie TI Cadmium-induced toxicity in rat primary mid-brain neuroglia cultures: role of oxidative stress from microglia SO TOXICOLOGICAL SCIENCES LA English DT Article DE cadmium; neurotoxicity; neuron-glia cultures; oxidative stress; NF-kappa B and; AP-1; gene expression ID MEDIATED NEUROTOXICITY; INDUCED APOPTOSIS; EPITHELIAL-CELLS; HEME OXYGENASE; OXIDANT STRESS; NITRIC-OXIDE; EXPOSURE; METALLOTHIONEIN; EXPRESSION; INDUCTION AB This study examined the role of oxidative stress in neurotoxic effects of cadmium chloride (Cd) in rat primary mid-brain neuron-glia cultures. Cd accumulated in neuron-glia cultures and produced cytotoxicity in a dose-dependent manner, with IC50 of 2.5 mu M 24 h after exposure. H-3-dopamine uptake into neuron-glia cultures was decreased 7 days after Cd exposure, with IC50 of 0.9 mu M, indicative of the sensitivity of dopaminergic neurons to Cd toxicity. To investigate the role of microglia in Cd-induced toxicity to neurons, microglia-enriched cultures were prepared. Cd significantly increased intracellular reactive oxygen species production in microglia-enriched cultures, as evidenced by threefold increases in 2',7'-dichlorofluorescein signals. Using 5,5-dimethyl-l-pyrroline N-oxide as a spin-trapping agent, Cd increased electron spin resonance signals by 3.5-fold in microglia-enriched cultures. Cd-induced oxidative stress to microglia-enriched cultures was further evidenced by activation of redox-sensitive transcription factor nuclear factor kappa B and activator protein-1 (AP-1), and the increased expression of oxidative stress-related genes, such as metallothionein, heme oxygenase-1, glutathione S-transferase pi, and metal transport protein-1, as determined by gel-shift assays and real-time reverse transcription-PCR, respectively, in microglia-enriched cultures. In conclusion, Cd is toxic to neuronglia cultures, and the oxidative stress from microglia may play important roles in Cd-induced damage to dopaminergic neurons. C1 NIEHS, NCI, Comparat Carcinogenesis Lab, Inorgan Carcinogenesis Sect, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. Zhengzhou Univ, Coll Pharm, Zhengzhou 450001, Peoples R China. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. N Dakota State Univ, Dept Pharmaceut Sci, Fargo, ND 58105 USA. RP Liu, J (reprint author), NIEHS, NCI, Comparat Carcinogenesis Lab, Inorgan Carcinogenesis Sect, POB 12233, Res Triangle Pk, NC 27709 USA. EM liu6@niehs.nih.gov FU Intramural NIH HHS [, NIH0011069698]; PHS HHS [NIH0011069698] NR 38 TC 34 Z9 35 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD AUG PY 2007 VL 98 IS 2 BP 488 EP 494 DI 10.1093/toxsci/kfm106 PG 7 WC Toxicology SC Toxicology GA 194WR UT WOS:000248375000017 PM 17483498 ER PT J AU Cantor, KP Lubin, JH AF Cantor, Kenneth P. Lubin, Jay H. TI Arsenic, internal cancers, and issues in inference from studies of low-level exposures in human populations SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article; Proceedings Paper CT International Workshop on Research and Risk Assessment for Arsenic CY MAY 31-JUN 02, 2006 CL Shepherdstown, WV SP US Environm Protect Agcy DE arsenic; drinking water; epidemiology; human risk; exposure misclassification ID DRINKING-WATER; BLADDER-CANCER; LUNG-CANCER; NEW-ENGLAND; FOLLOW-UP; SMELTER WORKERS; COPPER SMELTER; KIDNEY CANCER; UNITED-STATES; WELL WATER AB Epidemiologic data from regions of the world with very high levels of arsenic in drinking water (> 150 mu g/L)show a strong association between arsenic exposure and risk of several internal cancers. A causal interpretation of the data is warranted based on the strength and consistency of study findings. At lower levels of exposure (< 100 mu g/L), in the absence of unambiguous human data, extrapolation from the high-exposure studies has been used to estimate risk. Misclassification of exposure usually results in depressing observed levels of risk, and studies conducted in populations with exposures below 100 mu g/L have been limited by the challenge of estimating past exposures, a critically important aspect of studying relative small increases in risk. Relatively small study size contributes to the variability of findings in most studies and makes interpretation of results all the more challenging. The effects on risk estimates of exposure misclassification and small study size under various scenarios are graphically illustrated. Efforts are underway to improve exposure assessment in a large case-control study of bladder cancer in a region of the United States with moderately elevated levels of arsenic in drinking water. Published by Elsevier Inc. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Cantor, KP (reprint author), NCI, Div Canc Epidemiol & Genet, 8106 EPS, Bethesda, MD 20892 USA. EM cantork@nih.gov FU Intramural NIH HHS [Z01 CP010125-12] NR 39 TC 59 Z9 61 U1 2 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 1 PY 2007 VL 222 IS 3 BP 252 EP 257 DI 10.1016/j.taap.2007.01.026 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 200YK UT WOS:000248798500003 PM 17382983 ER PT J AU Valenzuela, OL Germolec, DR Borja-Aburto, VH Contreras-Ruiz, J Garcia-Vargas, GG Del Razo, LM AF Valenzuela, Olga L. Germolec, Dori R. Borja-Aburto, Victor H. Contreras-Ruiz, Jose Garcia-Vargas, Gonzalo G. Del Razo, Luz M. TI Chronic arsenic exposure increases TGFalpha concentration in bladder urothelial cells of Mexican populations environmentally exposed to inorganic arsenic SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article; Proceedings Paper CT International Workshop on Research and Risk Assessment for Arsenic CY MAY 31-JUN 02, 2006 CL Shepherdstown, WV SP US Environm Protect Agcy DE transforming growth factor alpha; susceptibility marker; bladder urothelial cells; arsenic; trivalent arsenic; urine metabolites; arsenic-skin lesions; hyperkeratosis; hypo-hyperpigmentation ID TRANSFORMING-GROWTH-FACTOR; DRINKING-WATER; FACTOR-ALPHA; METHYLATED ARSENICALS; CHRONIC STIMULATION; CYTOKINE SECRETION; SKIN NEOPLASIA; CANCER; TRIVALENT; TOXICITY AB Inorganic arsenic (iAs) is a well-established carcinogen and human exposure has been associated with a variety of cancers including those of skin, lung, and bladder. High expression of transforming growth factor alpha (TGF-alpha) has associated with local relapses in early stages of urinary bladder cancer. iAs exposures are at least in part determined by the rate of formation and composition of iAs metabolites (MAsIII, MAsv, DMAsIII, DMAsV). This study examines the relationship between TGF-alpha concentration in exfoliated bladder urothelial cells (BUC) separated from urine and urinary arsenic species in 72 resident women (18-51 years old) from areas exposed to different concentrations of iAs in drinking water (2-378 ppb) in central Mexico. Urinary arsenic species, including trivalent methylated metabolites were measured by hydride generation atomic absorption spectrometry method. The concentration of TGF-alpha in BUC was measured using an ELISA assay. Results show a statistically significant positive correlation between TGF-alpha concentration in BUC and each of the six arsenic species present in urine. The multivariate linear regression analyses show that the increment of TGF-alpha levels in BUC was importantly associated with the presence of arsenic species after adjusting by age, and presence of urinary infection. People from areas with high arsenic exposure had a significantly higher TGF-a concentration in BUC than people from areas of low arsenic exposure (128.8 vs. 64.4 pg/mg protein; p < 0.05). Notably, exfoliated cells isolated from individuals with skin lesions contained significantly greater amount of TGF-a than cells from individuals without skin lesions: 157.7 vs. 64.9 pg/mg protein (p=0.003). These results suggest that TGF-alpha in exfoliated BUC may serve as a susceptibility marker of adverse health effects on epithelial tissue in arsenic-endemic areas. (c) 2006 Elsevier Inc. All rights reserved. C1 Cinvestav IPN, Secc Toxicol, Mexico City 07300, DF, Mexico. NIH, Neurol Sect, Res Triangle Pk, NC 27709 USA. Inst Mexicano Seguro Social, Salud Trabajo, Mexico City, DF, Mexico. Hosp Gen Dr Manuel Gea Gonzalez, Div Dermatol, Mexico City, DF, Mexico. Univ Juarez Estado Durango, Fac Med, Gomex Palacio, Durango, Mexico. RP Del Razo, LM (reprint author), Cinvestav IPN, Secc Toxicol, Av Inst Politecn Nacl 2508,Col Zacatenco, Mexico City 07300, DF, Mexico. EM ldelrazo@cinvestav.mx OI Contreras-Ruiz, Jose/0000-0002-5788-9854 FU Intramural NIH HHS [Z99 ES999999] NR 33 TC 28 Z9 30 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 1 PY 2007 VL 222 IS 3 BP 264 EP 270 DI 10.1016/j.taap.2006.12.015 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 200YK UT WOS:000248798500005 PM 17267001 ER PT J AU Waalkes, MP Liu, J Diwan, BA AF Waalkes, Michael P. Liu, Jie Diwan, Bhalchandra A. TI Transplacental arsenic carcinogenesis in mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article; Proceedings Paper CT International Workshop on Research and Risk Assessment for Arsenic CY MAY 31-JUN 02, 2006 CL Shepherdstown, WV SP US Environm Protect Agcy DE arsenic; carcinogenesis; liver; bladder; adrenal; ovary ID ABERRANT GENE-EXPRESSION; MALE F344 RATS; IN-UTERO; DIMETHYLARSINIC ACID; URINARY-BLADDER; MOUSE SKIN; POSTNATAL DIETHYLSTILBESTROL; DIAPLACENTAL INITIATION; ULTRAVIOLET-RADIATION; PROLIFERATIVE LESIONS AB Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show that a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from days 8 to 18 of gestation, and the offspring were observed for up to 2 years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol- 13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD I mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD I mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloina, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans and investigating a potential transplacental component of the human carcinogenic response to arsenic should be a research priority. Published by Elsevier Inc. C1 NIEHS, NCI, Comparat Carcinogenesis Lab, Inorgan Carcinogenesis Sect, Res Triangle Pk, NC 27709 USA. Natl Canc Inst Frederick, SAIC, Basic Res Program, Frederick, MD 21702 USA. RP Waalkes, MP (reprint author), NIEHS, NCI, Comparat Carcinogenesis Lab, Inorgan Carcinogenesis Sect, 1111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU Intramural NIH HHS [Z01 BC005488-21, Z99 ES999999]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 61 TC 104 Z9 108 U1 1 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD AUG 1 PY 2007 VL 222 IS 3 BP 271 EP 280 DI 10.1016/j.taap.2006.12.034 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 200YK UT WOS:000248798500006 PM 17306315 ER PT J AU Al-Awadi, AR Karam, MV Molyneux, DH Breman, JG AF Al-Awadi, Abdul Rahman Karam, Marc V. Molyneux, David H. Breman, Joel G. TI The other 'neglected' eradication programme: achieving the final mile for Guinea worm disease eradication? SO TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE LA English DT Article DE dracunculiasis; Guinea worm; eradication; Africa; WHO AB Guinea worm disease is one of two diseases targeted for eradication, the other being polio. Since the late 1980s, the number of new cases per year has been reduced from approximately one million to some 25 000 in 2006. However, there was an increase from 2005 owing to improved surveillance in Sudan and problems in Ghana. The International Commission argues that more resources are required to ensure that the goat of eradication is completed. Elimination of transmission throughout Asia has now been confirmed and the disease is now confined to a small number of African countries requiring increased efforts to achieve the global goat. (c) 2007 Royal Society of Tropical Medicine and Hygiene. Published by Elsevier Ltd. All rights reserved. C1 Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. Islam Org Med Sci, Int Commiss Certificat Dracunculiasis Eradicat, Sulaiblkhat 90803, Kuwait. Int Commiss Certificat Dracunculiasis Eradicat, F-01170 Crozet, France. NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Molyneux, DH (reprint author), Univ Liverpool, Liverpool Sch Trop Med, Pembroke Pl, Liverpool L3 5QA, Merseyside, England. EM david.molyneux@tiv.ac.uk NR 5 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0035-9203 J9 T ROY SOC TROP MED H JI Trans. Roy. Soc. Trop. Med. Hyg. PD AUG PY 2007 VL 101 IS 8 BP 741 EP 742 DI 10.1016/j.trstmh.2007.04.002 PG 2 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 192LW UT WOS:000248204300001 PM 17507066 ER PT J AU Ambrose, Z KewalRamani, VN Bieniasz, PD Hatziioannou, T AF Ambrose, Zandrea KewalRamani, Vineet N. Bieniasz, Paul D. Hatziioannou, Theodora TI HIV/AIDS: in search of an animal model SO TRENDS IN BIOTECHNOLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFECTIOUS MOLECULAR CLONES; HIV-1/SIV CHIMERIC VIRUS; AIDS-LIKE DISEASE; RHESUS MACAQUES; NEUTRALIZING ANTIBODIES; GASTROINTESTINAL-TRACT; HIV-INFECTION; ENVELOPE GLYCOPROTEINS; REVERSE-TRANSCRIPTASE AB AIDS is among the most devastating diseases of our time, claiming the lives of approximately 3 million people per year. The primary cause of AIDS, human immunodeficiency virus type 1 (HIV-1), is a pathogen that is highly specific for humans and generally does not infect or cause disease in other species. This property complicates the generation of animal models that are urgently needed to test new antiretroviral therapies and vaccines. The most practical animal models developed to date consist of infection of rhesus macaques with a simian immunodeficiency virus (SIV) or chimeric HIV/SIV viruses. Although these models are useful for particular applications, the fact that SIV is a distinct virus compared with HIV-1 represents a significant limitation to their use. Here, we discuss the uses and limitations of existing models and recent advances that might lead to better animal models for HIV/AIDS. C1 Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. Rockefeller Univ, New York, NY 10016 USA. NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Hatziioannou, T (reprint author), Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. EM thatziio@adarc.org NR 50 TC 49 Z9 55 U1 0 U2 8 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0167-7799 J9 TRENDS BIOTECHNOL JI Trends Biotechnol. PD AUG PY 2007 VL 25 IS 8 BP 333 EP 337 DI 10.1016/j.tibtech.2007.05.004 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 199JN UT WOS:000248692100002 PM 17574286 ER PT J AU Raman, VK Lederman, RJ AF Raman, Venkatesh K. Lederman, Robert J. TI Interventional cardiovascular magnetic resonance imaging SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Review ID GUIDED BALLOON ANGIOPLASTY; SWINE MODEL; STENT PLACEMENT; CARDIAC-CATHETERIZATION; CAROTID ARTERIES; MR-ANGIOGRAPHY; PIG MODEL; FEASIBILITY; TRACKING; GUIDANCE AB Magnetic resonance imaging provides structural and functional cardiovascular information with excellent soft tissue contrast. Real-time magnetic resonance imaging can guide transcatheter cardiovascular interventions in large animal models and may prove superior to x-ray and adjunct modalities for peripheral vascular, structural heart, and cardiac electrophysiology applications. We describe technical considerations, preclinical work, and early clinical studies in this emerging field. C1 NHLBI, Cardiovasc Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, Washington, DC 20422 USA. RP Lederman, RJ (reprint author), NHLBI, Cardiovasc Branch, Div Intramural Res, NIH, Bldg 10,Room 2c713,MSC1538, Bethesda, MD 20892 USA. EM lederman@nih.gov FU Intramural NIH HHS [Z01 HL005062-05] NR 37 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD AUG PY 2007 VL 17 IS 6 BP 196 EP 202 DI 10.1016/j.tcm.2007.05.003 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 200TR UT WOS:000248786200003 PM 17662914 ER PT J AU Cote, JF Vuori, K AF Cote, Jean-Francois Vuori, Kristiina TI GEF what? Dock 180 and related proteins help Rac to polarize cells in new ways SO TRENDS IN CELL BIOLOGY LA English DT Review ID NUCLEOTIDE EXCHANGE FACTOR; FAMILY KINASE HCK; MYOBLAST CITY; RHO-GTPASES; CAENORHABDITIS-ELEGANS; DOCK180; MIGRATION; ACTIVATION; DOMAIN; IDENTIFICATION AB Rho GTPase activation, which is mediated by guanine nucleotide exchange factors (GEFs), is tightly regulated in time and space. Although Rho GTPases have a significant role in many biological events, they are best known for their ability to restructure the actin cytoskeleton profoundly through the activation of specific downstream effectors. Two distinct families of GEFs for Rho GTPases have been reported so far, based on the features of their catalytic domains: firstly, the classical GEFs, which contain a DbI homology-pleckstrin homology domain module with GEF activity, and secondly, the Dock180-related GEFs, which contain a Dock homology region-2 domain that catalyzes guanine nucleotide exchange on Rho GTPases. Recent exciting data suggest key roles for the DHR-2 domain-containing GEFs in a wide variety of fundamentally important biological functions, including cell migration, phagocytosis of apoptotic cells, myoblast fusion and neuronal polarization. C1 Univ Montreal, Inst Rech Clin Montreal, Cytoskeletal Org & Cell Migrat Lab, Montreal, PQ H2W1R7, Canada. NCI, Ctr Canc, Burnham Inst Med Res, La Jolla, CA 92037 USA. RP Cote, JF (reprint author), Univ Montreal, Inst Rech Clin Montreal, Cytoskeletal Org & Cell Migrat Lab, 110 Pine Ave W, Montreal, PQ H2W1R7, Canada. EM Jean-Francois.Cote@ircm.qc.ca; kvuori@burnham.org FU Canadian Institutes of Health Research [77591] NR 53 TC 180 Z9 181 U1 0 U2 8 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0962-8924 J9 TRENDS CELL BIOL JI Trends Cell Biol. PD AUG PY 2007 VL 17 IS 8 BP 383 EP 393 DI 10.1016/j.tcb.2007.05.001 PG 11 WC Cell Biology SC Cell Biology GA 219YU UT WOS:000250124900004 PM 17765544 ER PT J AU Bajenoff, M Egen, JG Qi, H Huan, AYC Castellino, F Germain, RN AF Bajenoff, Marc Egen, Jackson G. Qi, Hai Huan, Alex Y. C. Castellino, Flora Germain, Ronald N. TI Highways, byways and breadcrumbs: directing lymphocyte traffic in the lymph node SO TRENDS IN IMMUNOLOGY LA English DT Review ID T-CELL MOTILITY; HIGH ENDOTHELIAL VENULES; DENDRITIC CELLS; IN-VIVO; ANTIGEN; MIGRATION; IMMUNITY; ACTIVATION; MECHANISMS; CHEMOKINES AB The lymph node (LN) is charged with a crucial function in the mammalian immune system: to facilitate physical interactions between extremely rare cells arriving from different tissue compartments. Paramount to carrying out this function is its unique placement at the interface between the blood and lymphatic systems, thus enabling tissue-derived antigen and antigen-presenting cells, especially dendritic cells (DCs) to gather in close proximity to blood-derived antigen-specific motile lymphocytes. A generally held view is that this accumulation of cells, coupled with stochastic migration, is itself sufficient to facilitate a physiologically adequate frequency of cell-cell contacts due to random migration within the confined space of the LN. Based on recent data, we propose an expanded model of LN function in which unique architectural features and chemical signals together provide a means of enhancing otherwise unlikely encounters between sparse DCs and rare antigen-specific lymphocytes. C1 NIH, NIAID, Immunol Lab, Lymphocyte Biol Sect, Bethesda, MD 20892 USA. Univ Nice Sophia Antipolis, CNRS, Inst Pharmacol Mol & Cellulaire, INSERM U344, Valbonne, France. Case Western Reserve Univ, Sch Med, Rainbow Babies & Childrens Hosp, Div Pediat Hematol Oncol, Cleveland, OH 44106 USA. Novartis Vaccines, I-53100 Siena, Italy. RP Germain, RN (reprint author), NIH, NIAID, Immunol Lab, Lymphocyte Biol Sect, Bldg 10, Bethesda, MD 20892 USA. EM rgermain@niaid.nih.gov RI Qi, Hai/A-3955-2009; OI Egen, Jackson/0000-0003-2053-0837; Huang, Alex/0000-0002-5701-4521 FU Intramural NIH HHS NR 34 TC 83 Z9 84 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD AUG PY 2007 VL 28 IS 8 BP 346 EP 352 DI 10.1016/j.it.2007.06.005 PG 7 WC Immunology SC Immunology GA 202DZ UT WOS:000248883500004 PM 17625969 ER PT J AU Heilig, M Koob, GF AF Heilig, Markus Koob, George F. TI A key role for corticotropin-releasing factor in alcohol dependence SO TRENDS IN NEUROSCIENCES LA English DT Review ID ANXIETY-LIKE BEHAVIOR; WITHDRAWAL-INDUCED ANXIETY; CHRONIC ETHANOL EXPOSURE; STRESS-INDUCED RELAPSE; PREFERRING MSP RATS; NEUROPEPTIDE-Y; RECEPTOR ANTAGONIST; SEEKING BEHAVIOR; DRUG-ADDICTION; HYDROCHLORIDE SSR125543A AB Recent data indicate that alcohol dependence induces long-term neuroadaptations that recruit a negative emotional state. This leads to excessive alcohol ingestion motivated by relief of negative emotionality. A key mechanism in this transition to negative reinforcement is a recruitment of corticotropin-releasing factor (CRF) signaling within the amygdala. Long term upregulation, of CRF, receptors is observed in the amygdala following a history of dependence, and CRF antagonists selectively block emotionality, excessive alcohol drinking and stress-induced reinstatement of alcohol-seeking in post-dependent animals. Innate upregulation of CRF, receptor expression mimics the post-dependent phenotype, both with regard to emotional responses and ethanol self-administration. Therefore, the CRF system is emerging as a key element of the neuroadaptive changes driving alcoholism and as a major target for its treatment. C1 NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, Comm Neurobiol Addict Disorders, La Jolla, CA 92037 USA. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,1-5334, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov RI koob, george/P-8791-2016; OI Heilig, Markus/0000-0003-2706-2482 FU NIAAA NIH HHS [P50 AA006420, AA06420, AA08459, P60 AA006420, P60 AA006420-24, R01 AA008459, R01 AA008459-17, R37 AA008459]; NIDDK NIH HHS [DK26741, P01 DK026741, P01 DK026741-280004] NR 71 TC 257 Z9 257 U1 2 U2 11 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD AUG PY 2007 VL 30 IS 8 BP 399 EP 406 DI 10.1016/j.tins.2007.06.006 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 202QW UT WOS:000248919100005 PM 17629579 ER PT J AU Maeda, K Mitsuya, H AF Maeda, Kenji Mitsuya, Hiroaki TI Development of therapeutics for AIDS: Structure-based molecular targeting SO TUBERCULOSIS LA English DT Article; Proceedings Paper CT 10th International Conference on Emerging Infectious Diseases in the Pacific Rim CY DEC 07-10, 2004 CL kyoto, JAPAN SP US-Japan Cooperat Med Sci Program DE chemotherapeutics for HIV/AIDS; antiretroviral therapy; CCR5 inhibitors; darunavir ID DRUG-RESISTANCE; PROTEASE INHIBITOR; POTENT ACTIVITY; IN-VITRO; HIV; CCR5; DESIGN; ENTRY AB Novel anti-HIV agents that target different stages of the human immunodeficiency virus type 1 (HIV-1) replication cycle are now in clinical trials and have signs of improving our ability to manage HIV-1. This chapter, and the Conference presentation, dealt with the challenges encountered in realizing the optimal benefits of the newer therapeutics to individuals with AIDS and HIV-1 infection receiving highly active antiretroviral therapy (HAART). Emphasis was on the G-protein-coupled seven-transmembrane chemokine receptor, CCR5, as a potentially new therapeutic target and experience with novel CCR5 inhibitors, and the promise from further advancement through structural and molecular analysis of CCR5 inhibitor-CCR5 interactions. The promise in some of the newer protease inhibitors was also discussed. Published by Elsevier Ltd. C1 NCI, HIV & AIDS Malignancy Branch, Expt Retrovirol Sect, Bethesda, MD 20892 USA. Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, Dept Hematol, Kumamoto 8608556, Japan. Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, Dept Infect Dis, Kumamoto 8608556, Japan. RP Maeda, K (reprint author), NCI, HIV & AIDS Malignancy Branch, Expt Retrovirol Sect, Bethesda, MD 20892 USA. EM maedak@mail.nih.gov NR 17 TC 3 Z9 3 U1 0 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1472-9792 J9 TUBERCULOSIS JI Tuberculosis PD AUG PY 2007 VL 87 SU 1 BP S31 EP S34 DI 10.1016/j.tube.2007.05.009 PG 4 WC Immunology; Microbiology; Respiratory System SC Immunology; Microbiology; Respiratory System GA 216OR UT WOS:000249888400008 PM 17625972 ER PT J AU Hamada, A Danesi, R Price, DK Sissung, T Chau, C Venzon, D Sparreboom, A Dahut, WL Figg, WD AF Hamada, Akinobu Danesi, Romano Price, Douglas K. Sissung, Tristan Chau, Cindy Venzon, David Sparreboom, Alex Dahut, William L. Figg, William D. TI Association of a CYP17 polymorphism with overall survival in caucasian patients with androgen-independent prostate cancer SO UROLOGY LA English DT Article ID HORMONE-LEVELS; RISK; SRD5A2; GENE; MEN AB OBJECTIVES To investigate the association between a cytochrome P450 17 alpha-hydroxylase gene (CYP17) polymorphism and survival in Caucasian patients with androgen- independent prostate cancer (AIPC). METHODS The study used 222 samples acquired from Caucasian patients with AIPC. The CYP17 polymorphism (-34T >>C) was analyzed using polymerase chain reaction amplification followed by restriction fragment length polymorphism detection. RESULTS No significant differences were observed in the frequencies of the CYP17 genotype in relation to categorized Gleason scores, age at diagnosis, or hormone therapy. The median survival was significantly longer in 126 patients with the CYP17 A2 allele (8.9 years) genotype than in 96 patients with the Al allele (6.7 years) genotype (P = 0.040 by log-rank test). Similarly, the estimated survival probability at 10 years (24% in Al allele versus 43% in A2 allele) showed a statistically significant difference between the two groups (P = 0.002 by the permutation test). CONCLUSIONS These results suggest that the CYP17 polymorphism is associated with overall survival in patients with AIPC. C1 NCI, Bethesda, MD 20892 USA. Natl Canc Inst, Natl Inst Hlth, Clin Pharmacol Res Core, Mol Pharmacol Sect, Bethesda, MD USA. Natl Canc Inst, Natl Inst Hlth, Ctr Canc Res, Med Oncol Branch,Data Management Sect, Bethesda, MD USA. Kumamoto Univ, Dept Clin Pharmaceut Sci, Kumamoto, Japan. Univ Pisa, Div Pharmacol & Chemotherapy, Pisa, Italy. RP Figg, WD (reprint author), NCI, Bldg 10-Room,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 FU Intramural NIH HHS [Z01 BC010453-05, Z99 CA999999] NR 15 TC 24 Z9 25 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0090-4295 J9 UROLOGY JI Urology PD AUG PY 2007 VL 70 IS 2 BP 217 EP 220 DI 10.1016/j.urology.2007.06.1097 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 211WV UT WOS:000249554900001 PM 17826473 ER PT J AU Beigel, J Kohl, KS Khuri-Bulos, N Bravo, L Nell, P Marcy, SM Warschaw, K Ong-Lim, A Poerschke, G Weston, W Lindstrom, JA Stoltman, G Maurer, T AF Beigel, John Kohl, Katrin S. Khuri-Bulos, Najwa Bravo, Lulu Nell, Patricia Marcy, S. Michael Warschaw, Karen Ong-Lim, Anna Poerschke, Gabriele Weston, William Lindstrom, Jill A. Stoltman, Gillian Maurer, Toby CA Brighton Collaboration Rash TI Rash including mucosal involvement: Case definition and guidelines for collection, analysis, and presentation of immunization safety data SO VACCINE LA English DT Article DE rash; mucocutaneous; adverse event; immunization; guidelines; case definition ID STATEMENT; QUALITY; TRIALS C1 Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Natl Inst Hlth, Bethesda, MD USA. Jordan Univ Hosp, Amman, Jordan. Univ Philippines, Manila, Philippines. USAF, Sturgeon Bay, WI USA. Univ So Calif, Panorama, CA USA. Univ Calif Los Angeles, Sch Med, Kaiser Fdn Hosp, Panorama, CA USA. Mayo Clin, Scottsdale, AZ USA. Merck Sharp & Dohme Asia Ltd, Hong Kong, Hong Kong, Peoples R China. Univ Colorado, Aurora, CO USA. US FDA, Rockville, MD 20857 USA. Michigan Dept Commun Hlth, Lansing, MI USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Kohl, KS (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. EM secretariat@brightoncollaboration.org RI Beigel, John/A-7111-2009 NR 10 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 1 PY 2007 VL 25 IS 31 BP 5697 EP 5706 DI 10.1016/j.vaccine.2007.02.066 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 198QZ UT WOS:000248643900004 PM 17403561 ER PT J AU Beigel, J Kohl, KS Brinley, F Graham, PL Khuri-Bulos, N LaRussa, PS Nell, P Norton, S Stoltman, G Tebaa, A Warschaw, K AF Beigel, John Kohl, Katrin S. Brinley, Floyd Graham, Philip L. Khuri-Bulos, Najwa LaRussa, Philip S. Nell, Patricia Norton, Scott Stoltman, Gillian Tebaa, Amina Warschaw, Karen CA Brighton Collaboration Vaccinia Vi TI Generalized vaccinia as an adverse event following exposure to vaccinia virus: Case definition and guidelines for data collection, analysis, and presentation of immunization safety data SO VACCINE LA English DT Article DE generalized vaccinia; adverse event; vaccinia virus; smallpox vaccine; immunization; guidelines; case definition ID SMALLPOX VACCINATION; COMPLICATIONS; BIOTERRORISM; STATEMENT; QUALITY; TRIALS C1 Ctr Dis Control & Prevent, Off Chief Sci Officer, Immunizat Safety Off, Atlanta, GA 30333 USA. Natl Inst Hlth, NIG Clin Ctr, Bethesda, MD USA. Natl Inst Hlth, Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. Columbia Univ, New York Presbyterian Hosp, Coll Phys & Surg, Dept Pediat,Dept Epidemiol, New York, NY USA. Jordan Univ Hosp, Div Pediat Infect Dis, Amman, Jordan. USAF, Sturgeon Bay, WI USA. Walter Reed Army Med Ctr, Washington, DC USA. Michigan Dept Commun Hlth, Div Communicable Dis & Immunizat, Lansing, MI USA. Ctr Antipoison & Pharmacovigilance, Rabat, Morocco. Mayo Clin Scottsdale, Dept Dermatol, Scottsdale, AZ USA. Mayo Clin Scottsdale, Dept Pathol, Scottsdale, AZ USA. RP Kohl, KS (reprint author), Ctr Dis Control & Prevent, Off Chief Sci Officer, Immunizat Safety Off, Atlanta, GA 30333 USA. EM secretariat@brightoncollaboration.org RI Beigel, John/A-7111-2009 NR 21 TC 6 Z9 6 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 1 PY 2007 VL 25 IS 31 BP 5745 EP 5753 DI 10.1016/j.vaccine.2007.02.086 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 198QZ UT WOS:000248643900009 PM 17537552 ER PT J AU Tapiainen, T Prevots, R Izurieta, HS Abramson, J Bilynsky, R Bonhoeffer, J Bonnet, MC Center, K Galama, J Gillard, P Griot, M Hartmann, K Heininger, U Hudson, M Koller, A Khetsuriani, N Khuri-Bulos, N Marcy, SM Matulionyte, R Schondorf, I Sejvar, J Steele, R AF Tapiainen, Terhi Prevots, Rebecca Izurieta, Hector S. Abramson, Jon Bilynsky, Roman Bonhoeffer, Jan Bonnet, Marie-Claude Center, Kimberly Galama, Jochem Gillard, Paul Griot, Monika Hartmann, Katharina Heininger, Ulrich Hudson, Michael Koller, Annette Khetsuriani, Nino Khuri-Bulos, Najwa Marcy, S. Michael Matulionyte, Raimonda Schoendorf, Ines Sejvar, James Steele, Russell CA Brighton Collaboration Aseptic Men TI Aseptic meningitis: Case definition and guidelines for collection, analysis and presentation of immunization safety data SO VACCINE LA English DT Article DE aseptic meningitis; adverse event; immunization; guidelines; case definition ID MUMPS-RUBELLA VACCINATION; NORMAL CEREBROSPINAL-FLUID; C-REACTIVE PROTEIN; BACTERIAL-MENINGITIS; MASS VACCINATION; MMR VACCINE; VIRAL MENINGITIS; ADVERSE EVENTS; GRAM STAIN; WILD-TYPE C1 Univ Childrens Hosp, Basel, Switzerland. Univ Oulu, Dept Pediat, SF-90100 Oulu, Finland. Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Bethesda, MD USA. US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Pediat, Winston Salem, NC 27103 USA. Patterson Army Hlth Ctr, Ft Monmouth, NJ USA. Aventis Pasteur, Lyon, France. Wyeth Pharmaceut, Collegeville, PA USA. Univ Med Ctr, Dept Med Microbiol, Nijmegen, Netherlands. GlaxoSmithKline Inc, Rixensart, Belgium. Berna Biotech, Kusnacht, Switzerland. Ctr Emergency Preparedness & Response, Hlth Protect Agcy, Salisbury, Wilts, England. Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Div Viral & Rickettsial Dis, Atlanta, GA USA. Univ So Calif, Panorama, CA USA. Univ Calif Los Angeles, Kaiser Fdn Hosp, Sch Med, Panorama, CA USA. Vilnius State Univ, Dept Infect Dis, Vilnius, Lithuania. Novartis Vaccines, Marburg, Germany. LSU Med Sch, Dept Pediat, New Orleans, LA USA. RP Bonhoeffer, J (reprint author), Univ Childrens Hosp, Basel, Switzerland. EM secretariat@brightoncollaboration.org RI Bonhoeffer, Jan/E-5903-2014 NR 75 TC 24 Z9 24 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 1 PY 2007 VL 25 IS 31 BP 5793 EP 5802 DI 10.1016/j.vaccine.2007.04.058 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 198QZ UT WOS:000248643900013 PM 17574313 ER PT J AU Toubaji, A Hill, S Terabe, M Qian, JH Floyd, T Simpson, RM Berzofsky, JA Khleif, SN AF Toubaji, Antoun Hill, Sarah Terabe, Masaki Qian, Jiahua Floyd, Tamara Simpson, R. Mark Berzofsky, Jay A. Khleif, Samir N. TI The combination of GM-CSF and IL-2 as local adjuvant shows synergy in enhancing peptide vaccines and provides long term tumor protection SO VACCINE LA English DT Article DE adjuvant; immunotherapy; GM-CSF; IL-2 ID COLONY-STIMULATING FACTOR; T-CELLS; MULTIPEPTIDE VACCINE; METASTATIC MELANOMA; IMMUNE-RESPONSE; INTERLEUKIN-2; CYTOKINES; ANTIGEN; RESPONSIVENESS; IMMUNIZATION AB Many strategies have been used to enhance the peptide vaccine immune response and to establish therapeutic benefits. This includes the utilization of cytokines to improve antigen presentation or enhance T cell response. Here, we have tested the combination of GM-CSF and IL-2 as locally administered adjuvant to enhance the immune response to the HPV16 E7 peptide. Female C57BL/6 mice were immunized intradermally with a 9-mer HPV16 E7 peptide (aa: 49-57) alone, or in combination with GM-CSF, IL-2, or both cytokines. Specific immune responses were measured by ELISA and Chromium-Release Assays. Furthermore, therapeutic effects of these vaccines and long term tumor protection were assessed in mice bearing established tumors. We showed that GM-CSF and IL-2, when co-administered locally in an emulsion with peptide, exert a synergistic effect in enhancing the immune response to the antigen. This combination induced higher CTL and cytokine release responses and did not increase the T-reg population. Therapeutic intervention with this synergistic combination led to a complete response of established tumors. Furthermore, this combination induced a memory response which protected mice against subsequent additional tumor challenge. We identified a new vaccine adjuvant, a local combination of GM-CSF and IL-2, which is synergistic in enhancing peptide specific immune response through local effect without increasing T-reg cells. This immune response was found to be long lasting and protective in tumor bearing mice. Published by Elsevier Ltd. C1 NIH, NCI, Vaccine Branch, Canc Vaccine Sect, Bethesda, MD 20892 USA. NIH, NCI, Vaccine Branch, Mol Immungenet & Vaccine Res Sect, Bethesda, MD 20892 USA. NIH, NCI, CCR, Mol Pathol Unit, Bethesda, MD 20892 USA. RP Khleif, SN (reprint author), NIH, NCI, Vaccine Branch, Canc Vaccine Sect, Bldg 10, Bethesda, MD 20892 USA. EM khleif@nih.gov FU Intramural NIH HHS NR 33 TC 30 Z9 32 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD AUG 1 PY 2007 VL 25 IS 31 BP 5882 EP 5891 DI 10.1016/j.vaccine.2007.05.040 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 198QZ UT WOS:000248643900019 PM 17602804 ER PT J AU Doyle, L Espina, V Petricoin, E Liotta, L Winters, M Stephens, R Keeling, N Kelleher, D Muldoon, C Gaffney, E AF Doyle, Leona Espina, Virginia Petricoin, Emanuel Liotta, Lance Winters, Mary Stephens, Richard Keeling, Napoleon Kelleher, Dermot Muldoon, Cian Gaffney, Eoin TI Confluent basal apoptosis in colonic adenomas: Morphology, potential functional significance, and preliminary reverse phase microarray findings for apoptosis-related proteins SO VIRCHOWS ARCHIV LA English DT Meeting Abstract C1 St James Hosp, Dept Histopathol, Dublin 8, Ireland. George Mason Univ, Ctr Appl Proteom & Mol Med, Manassas, VA USA. NIH, Bethesda, MD 20892 USA. St James Hosp, Dept Surg, Dublin 8, Ireland. St James Hosp, Dept Gastroenterol, Dublin 8, Ireland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD AUG PY 2007 VL 451 IS 2 BP 169 EP 169 PG 1 WC Pathology SC Pathology GA 210KH UT WOS:000249454600161 ER PT J AU Achim, W Liu, JH Irene, C David, L AF Achim, Weber Liu Juhong Irene, Collins David, Levens TI The FUSE/FBP/FIR/TFIIH-system is a molecular machinery equipped to control the expression of the c-myc proto-oncogene by sensing DNA-conformation of the promoter and fine-tuning transcriptional output SO VIRCHOWS ARCHIV LA English DT Meeting Abstract C1 Univ Zurich, Inst Clin Pathol, Dept Pathol, Zurich, Switzerland. NCI, Gene Regulat Sect, Pathol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD AUG PY 2007 VL 451 IS 2 MA OP28-8 BP 187 EP 188 PG 2 WC Pathology SC Pathology GA 210KH UT WOS:000249454600208 ER PT J AU Stamatelli, A Bei, TA Saetta, AA Stergiopoulos, S Boikos, S Patsouris, E Aroni, K Stratakis, CA AF Stamatelli, Angeliki Bei, Thaleia. A. Saetta, Angelika. A. Stergiopoulos, Sotirios Boikos, Sosipatros Patsouris, Efstratios Aroni, Kiriaki Stratakis, Constantine A. TI Loss of heterozygosity (LOH) for the 17Q22-24 locus, PRKAR1A gene mutations and microsatellite instability (MSI) in basal cell carcinoma (BCC) SO VIRCHOWS ARCHIV LA English DT Meeting Abstract C1 Univ Athens, Sch Med, Dept Pathol 1, Athens, Greece. NICHHD, Sect Endocrinol & Genet, DEB, NIH, Bethesda, MD 20892 USA. RI Aroni, Kyriaki/B-8331-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD AUG PY 2007 VL 451 IS 2 MA OP28-7 BP 187 EP 187 PG 1 WC Pathology SC Pathology GA 210KH UT WOS:000249454600207 ER PT J AU Quezado, M Santi, M Rushing, E Begnami, M AF Quezado, Martha Santi, Mariarita Rushing, Elisabeth Begnami, Maria TI EGFR status in pediatric ependymomas using immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) SO VIRCHOWS ARCHIV LA English DT Meeting Abstract C1 NCI, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Washington, DC USA. AFIP, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD AUG PY 2007 VL 451 IS 2 BP 237 EP 238 PG 2 WC Pathology SC Pathology GA 210KH UT WOS:000249454600368 ER PT J AU Kupesiz, GY Sakr, W Cher, M Banerjee, M Pontes, E Parnes, H Kucuk, O AF Kupesiz, Gokben Yildirim Sakr, Wael Cher, Michael Banerjee, Mousumi Pontes, Edson Parnes, Howard Kucuk, Omer TI Effect of soy isoflavone supplementation on prostate tissue, markers of proliferation and apoptosts and histopathological endpoints of tumor grade, volume and stage SO VIRCHOWS ARCHIV LA English DT Meeting Abstract C1 Akdeniz Univ, Dept Pathol, Antalya, Turkey. Wayne State Univ, Barbara Ann Karmanos Canc Inst, Dept Pathol, Detroit, MI 48202 USA. Wayne State Univ, Barbara Ann Karmanos Canc Inst, Dept Urol, Detroit, MI 48202 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. NCI, Div Canc Prevent, Rockville, MD USA. Wayne State Univ, Barbara Ann Karmanos Canc Inst, Dept Hematol & Oncol, Detroit, MI 48202 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD AUG PY 2007 VL 451 IS 2 BP 412 EP 412 PG 1 WC Pathology SC Pathology GA 210KH UT WOS:000249454600914 ER PT J AU Rhodes, G Jeffery, L Clifford, CWG Leopold, DA AF Rhodes, Gillian Jeffery, Linda Clifford, Colin W. G. Leopold, David A. TI The timecourse of higher-level face aftereffects SO VISION RESEARCH LA English DT Article DE visual perception; face perception; adaptation; aftereffects ID ORIENTATION DISCRIMINATION; ADAPTATION; PERCEPTION; AREA; CONTRAST; MOTION; REPRESENTATION; RECOGNITION; DURATION; IDENTITY AB Perceptual aftereffects for simple visual attributes processed early in the cortical hierarchy increase logarithmically with adapting duration and decay exponentially with test duration. This classic timecourse has been reported recently for a face identity aftereffect [Leopold, D. A., Rhodes, G., Muller, K.-M., & Jeffery, L. (2005). The dynamics of visual adaptation to faces. Proceedings of the Royal Society of London, Series B, 272, 897-904], suggesting that the dynamics of visual adaptation may be similar throughout the visual system. An alternative interpretation, however, is that the classic timecourse is a flow-on effect of adaptation of a low-level, retinotopic component of the face identity aftereffect. Here, we examined the timecourse of the higher-level (size-invariant) components of two face aftereffects, the face identity aftereffect and the figural face aftereffect. Both showed the classic pattern of logarithmic build-up and exponential decay. These results indicate that the classic timecourse of face aftereffects is not a flow-on effect of low-level retinotopic adaptation, and support the hypothesis that dynamics of visual adaptation are similar at higher and lower levels of the cortical visual hierarchy. They also reinforce the perceptual nature of face aftereffects, ruling out demand characteristics and other post-perceptual factors as plausible accounts. (c) 2007 Elsevier Ltd. All rights reserved. C1 Univ Western Australia, Sch Psychol, Nedlands, WA 6009, Australia. Univ Sydney, Sch Psychol, Sydney, NSW 2006, Australia. NIMH, Neuropsychol Lab, Unit Cognit Neurophysiol & Imaging, Bethesda, MD 20892 USA. RP Rhodes, G (reprint author), Univ Western Australia, Sch Psychol, 35 Stirling Highway, Nedlands, WA 6009, Australia. EM gill@psy.uwa.edu.au RI Jeffery, Linda/H-5127-2014; OI Jeffery, Linda/0000-0002-3980-5864; Leopold, David/0000-0002-1345-6360 NR 43 TC 62 Z9 63 U1 2 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD AUG PY 2007 VL 47 IS 17 BP 2291 EP 2296 DI 10.1016/j.visres.2007.05.012 PG 6 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 205VB UT WOS:000249141600006 PM 17619045 ER PT J AU Klein, HG Anderson, D Bernardi, MJ Cable, R Carey, W Hoch, JS Robitaille, N Sivilotti, MLA Smaill, F AF Klein, H. G. Anderson, D. Bernardi, M.-J. Cable, R. Carey, W. Hoch, J. S. Robitaille, N. Sivilotti, M. L. A. Smaill, F. TI Pathogen inactivation: making decisions about new technologies - preliminary report of a consensus conference SO VOX SANGUINIS LA English DT Article DE blood transfusion; pathogen reduction ID BLOOD; TRANSFUSION C1 NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. QE II Hlth Sci Ctr, Halifax, NS, Canada. CRIR, Montreal, PQ, Canada. Amer Red Cross, Blood Serv, Farmington, CT USA. St Michaels Hosp, Toronto, ON M5B 1W8, Canada. CHU St Justine, Montreal, PQ, Canada. Queens Univ, Kingston, ON, Canada. McMaster Univ Hlth Sci, Hamilton, ON, Canada. RP Klein, HG (reprint author), NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. EM hklein@dtm.cc.nih.gov OI Hoch, Jeffrey/0000-0002-4880-4281 NR 9 TC 17 Z9 18 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0042-9007 J9 VOX SANG JI Vox Sang. PD AUG PY 2007 VL 93 IS 2 BP 179 EP 182 DI 10.1111/j.1423-0410.2007.00937.x PG 4 WC Hematology SC Hematology GA 205PC UT WOS:000249126100012 PM 17683364 ER PT J AU Joy, T Keogh, HM Hadigan, C Lee, H Dolan, SE Fitch, K Liebau, J Lo, J Johnsen, S Hubbard, J Anderson, EJ Grinspoon, S AF Joy, Tisha Keogh, Hester M. Hadigan, Colleen Lee, Hang Dolan, Sara E. Fitch, Kathleen Liebau, James Lo, Janet Johnsen, Stine Hubbard, Jane Anderson, Ellen J. Grinspoon, Steven TI Dietary fat intake and relationship to serum lipid levels in HIV-infected patients with metabolic abnormalities in the HAART era SO AIDS LA English DT Article DE HIV; hypertriglyceridemia; metabolic abnormalities; nutrition; saturated fat ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; CORONARY-HEART-DISEASE; PROTEASE INHIBITOR THERAPY; RESTING ENERGY-EXPENDITURE; LIPODYSTROPHY SYNDROME; MYOCARDIAL-INFARCTION; CARDIOVASCULAR RISK; INSULIN-RESISTANCE; BODY-COMPOSITION AB Objective: To evaluate dietary intake and its relationship to lipid parameters in HIV-infected patients with metabolic abnormalities. Method: We prospectively determined dietary intake (4-day food records or 24-h recall) in 356 HIV-infected patients and 162 community-derived HIV-negative controls evaluated for metabolic studies between 1998-2005. Differences in dietary intake between HIV-infected patients and non-HIV-infected controls, in relation to the established 2005 USDA (United States Department of Agriculture) Recommended Dietary Guidelines, were determined. The relationship between dietary fat intake and serum lipid levels among HIV-infected individuals was also evaluated. Results: Assessment of dietary intake in this group of HIV-infected patients demonstrated increased intake of total dietary fat (P < 0.05), saturated fat (P=0.006), and cholesterol (P=0.006) as well as a greater percentage of calories from saturated fat (P=0.002) and from trans fat (P=0.02), despite similar caloric intake to the control individuals. A significantly higher percentage of HIV-infected patients were above the 2005 USDA Recommended Dietary Guidelines for saturated fat (> 10%/day) (76.0% HIV vs. 60.9% controls, P=0.003), and cholesterol (> 300 mg/day) (49.7% HIV vs. 37.9% controls, P=0.04). Saturated fat intake was strongly associated with triglycericle level [triglyceride level increased 8.7 mg/dl (parameter estimate) per gram of increased saturated fat intake, P=0.005] whereas total fat was inversely associated with triglyceride level [triglycericle level decreased 3.0 mg/dl (parameter estimate) per gram of increased total fat intake, P=0.02] among HIV-infected individuals. Conclusions: Increased intake of saturated fat is seen and contributes to hypertrigly-ceridemia among HIV-infected patients who have developed metabolic abnormalities. Increased saturated fat intake should be targeted for dietary modification in this population. (c) 2007 Lippincott Williams & Wilkins. C1 Massachusetts Gen Hosp, Program Nutr Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, MGH Biostat Ctr, Boston, MA 02114 USA. Massachusetts Gen Hosp, Gen Clin Res Ctr, Boston, MA 02114 USA. RP Grinspoon, S (reprint author), Massachusetts Gen Hosp, Program Nutr Med, Boston, MA 02114 USA. EM sgrinspoon@partners.org FU NCRR NIH HHS [M01 RR001066, M01 RR 01066]; NICHD NIH HHS [T32 HD052961, T32 HD 052961]; NIDDK NIH HHS [R01 DK 49302, P30 DK040561, P30 DK040561-12, DK 02844, K23 DK002844, R01 DK059535] NR 52 TC 24 Z9 25 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 31 PY 2007 VL 21 IS 12 BP 1591 EP 1600 DI 10.1097/QAD.0b013e32823644ff PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 196PV UT WOS:000248495400012 PM 17630554 ER PT J AU Melendez-Morales, L Konkle, BA Preiss, L Zhang, MD Mathew, P Eyster, ME Goedert, JJ AF Melendez-Morales, Lehida Konkle, Barbara A. Preiss, Liliana Zhang, Mingdong Mathew, Prasad Eyster, M. Elaine Goedert, James J. TI Chronic hepatitis B and other correlates of spontaneous clearance of hepatitis C virus among HIV-infected people with hemophilia SO AIDS LA English DT Article DE hemophilia; hepatitis B virus (HBV); hepatitis C virus (HCV) ID HUMAN-IMMUNODEFICIENCY-VIRUS; NATURAL-HISTORY; VIRAL CLEARANCE; LIVER-DISEASE; UNITED-STATES; POPULATION; PREVALENCE; LOAD AB Objective: To identify correlates of spontaneous hepatitis C virus (HCV) clearance among people with human immunodeficiency virus (HIV) co-infection. Design: Baseline (2001-2004) analysis of a cohort study of people with hemophilia. Methods: Detailed questionnaire data were used to identify dates of primary HCV and HIV infections and to categorize sex; race; alcohol use; interferon treatment; hepatitis B virus (HBV) status; and HIV/AIDS history, treatment and current status. Spontaneous HCV clearance was defined as nondetection of HCV RNA by polymerase chain reaction assay in paired annual plasma, excluding those treated with interferon. Chi-squared, Fisher exact test, and logistic regression were used to identify correlates of clearance. Results: Among 478 HIV-infected participants, 61 (12.8%) had cleared HCV. Among the 31 participants with chronic HBV (as well as HIV), 16 (51.6%) had cleared HCV. With chronic HBV, HCV clearance was increased 11.2-fold (95% confidence interval, 5.1-24.8), after adjusting for sex, race, and hemophilia severity. Excluding the participants with chronic HBV, the prevalence of HCV clearance was 10.1%; and it was significantly reduced among males (9.7%, P=0.05), blacks (1.6%, P=0.01), and participants with severe hemophilia (8.2%, P=0.02). HCV clearance was not associated with HIV RNA detection in plasma, CD4 cell count, anti-HIV therapy, AIDS history, ages at or years of HIV or HCV infection, or alcohol consumption. Conclusions: HCV clearance is unambiguously and markedly increased with chronic HBV infection among HIV co-infected people. (c) 2007 Lippincott Williams & Wilkins. C1 NCI, Viral Epidemiol Branch, DCEG, Rockville, MD 20852 USA. Ctr Dis Control & Prevent, Emerging Leaders Program, Natl Ctr HIV Hepatitis STD & TB Prevent, Atlanta, GA USA. Univ Penn, Dept Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. Res Triangle Inst Int, Rockville, MD USA. FDA, CDRH, OSB, DPS,Epidemiol Branch, Rockville, MD USA. Univ New Mexico, Dept Pediat, Albuquerque, NM 87131 USA. Penn State Univ, Coll Med, Div Hematol & Oncol, Dept Med, Hershey, PA 17033 USA. RP Goedert, JJ (reprint author), NCI, Viral Epidemiol Branch, DCEG, 6120 Execut Blvd,Room 7066, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov FU NCI NIH HHS [N01 CP 01004, N01 CO 12400] NR 17 TC 10 Z9 11 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 31 PY 2007 VL 21 IS 12 BP 1631 EP 1636 DI 10.1097/QAD.0b013e32826fb6d9 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 196PV UT WOS:000248495400017 PM 17630559 ER PT J AU Anderson, LA Goedert, JJ AF Anderson, Lesley A. Goedert, James J. TI Tumor markers and treatments for Kaposi sarcoma SO AIDS LA English DT Editorial Material DE Africa; antiviral therapy; cancer chemotherapy; HIV/AIDS; human herpesvirus 8; Kaposi sarcoma; transplantation; virus load ID ACTIVE ANTIRETROVIRAL THERAPY; HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN-HERPESVIRUS-8 DNA; PERIPHERAL-BLOOD; STAGING SYSTEM; RISK-FACTORS; AIDS; HERPESVIRUS; PROGRESSION; CANCER C1 NCI, Div Clin Epidemiol & Genet, Viral Epidemiol Branch, Rockville, MD USA. NCI, Diov Canc Prevent, Canc Prevent Fellowship Program, Rockville, MD USA. RP Goedert, JJ (reprint author), 6120 Execut Blvd,Room 7066, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov NR 35 TC 2 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 31 PY 2007 VL 21 IS 12 BP 1637 EP 1639 DI 10.1097/QAD.0b013e32826fb721 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 196PV UT WOS:000248495400018 PM 17630560 ER PT J AU McCulloch, SD Wood, A Garg, P Burgers, PMJ Kunkel, TA AF McCulloch, Scott D. Wood, Adam Garg, Parie Burgers, Peter M. J. Kunkel, Thomas A. TI Effects of accessory proteins on the bypass of a cis-syn thymine-thymine dimer by Saccharomyces cerevisiae DNA polymerase eta SO BIOCHEMISTRY LA English DT Article ID PIGMENTOSUM VARIANT CELLS; MISMATCH-REPAIR PROTEIN; ESCHERICHIA-COLI DINB; SINGLE-STRANDED-DNA; XERODERMA-PIGMENTOSUM; CRYSTAL-STRUCTURE; LESION-BYPASS; POL-ETA; ULTRAVIOLET-IRRADIATION; SULFOLOBUS-SOLFATARICUS AB Among several hypotheses to explain how translesion synthesis (TLS) by DNA polymerase eta (pol eta) suppresses ultraviolet light-induced mutagenesis in vivo despite the fact that pol eta copies DNA with low fidelity, here we test whether replication accessory proteins enhance the fidelity of TLS by pol eta. We first show that the single-stranded DNA binding protein RPA, the sliding clamp PCNA, and the clamp loader RFC slightly increase the processivity of yeast pol eta and its ability to recycle to new template primers. However, these increases are small, and they are similar when copying an undamaged template and a template containing a cis-syn TT dimer. Consequently, the accessory proteins do not strongly stimulate the already robust TT dimer bypass efficiency of pol eta. We then perform a comprehensive analysis of yeast pol eta fidelity. We show that it is much less accurate than other yeast DNA polymerases and that the accessory proteins have little effect on fidelity when copying undamaged templates or when bypassing a TT dimer. Thus, although accessory proteins clearly participate in pol eta functions in vivo, they do not appear to help suppress UV mutagenesis by improving pol eta bypass fidelity per se. C1 Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. Nat Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Kunkel, TA (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Intramural NIH HHS [Z01 ES065070-17]; NIGMS NIH HHS [R01 GM032431, GM32431] NR 76 TC 21 Z9 21 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 31 PY 2007 VL 46 IS 30 BP 8888 EP 8896 DI 10.1021/bi700234t PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 192UV UT WOS:000248229800020 PM 17608453 ER PT J AU Dhingra, R Sullivan, L Jacques, PF Wang, TJ Fox, CS Meigs, JB D'Agostino, RB Gaziano, JM Vasan, RS AF Dhingra, Ravi Sullivan, Lisa Jacques, Paul F. Wang, Thomas J. Fox, Caroline S. Meigs, James B. D'Agostino, Ralph B. Gaziano, J. Michael Vasan, Ramachandran S. TI Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community SO CIRCULATION LA English DT Article DE diabetes mellitus; metabolic syndrome; epidemiology; obesity; risk factors; carbonated beverages ID FOOD FREQUENCY QUESTIONNAIRE; TYPE-2 DIABETES-MELLITUS; WEIGHT-GAIN; CARDIOVASCULAR-DISEASE; BEVERAGE CONSUMPTION; SWEETENED BEVERAGES; INSULIN-RESISTANCE; CHILDHOOD OBESITY; SUGAR; FRUCTOSE AB Background - Consumption of soft drinks has been linked to obesity in children and adolescents, but it is unclear whether it increases metabolic risk in middle-aged individuals. Methods and Results - We related the incidence of metabolic syndrome and its components to soft drink consumption in participants in the Framingham Heart Study (6039 person-observations, 3470 in women; mean age 52.9 years) who were free of baseline metabolic syndrome. Metabolic syndrome was defined as the presence of >= 3 of the following: waist circumference >= 35 inches (women) or >= 40 inches ( men); fasting blood glucose >= 100 mg/dL; serum triglycerides >= 150 mg/dL; blood pressure >= 135/85 mm Hg; and high-density lipoprotein cholesterol < 40 mg/dL ( men) or < 50 mg/dL ( women). Multivariable models included adjustments for age, sex, physical activity, smoking, dietary intake of saturated fat, trans fat, fiber, magnesium, total calories, and glycemic index. Cross-sectionally, individuals consuming >= 1 soft drink per day had a higher prevalence of metabolic syndrome ( odds ratio [ OR], 1.48; 95% CI, 1.30 to 1.69) than those consuming < 1 drink per day. On follow-up ( mean of 4 years), new-onset metabolic syndrome developed in 765 ( 18.7%) of 4095 participants consuming < 1 drink per day and in 474 (22.6%) of 2059 persons consuming >= 1 soft drink per day. Consumption of >= 1 soft drink per day was associated with increased odds of developing metabolic syndrome (OR, 1.44; 95% CI, 1.20 to 1.74), obesity ( OR, 1.31; 95% CI, 1.02 to 1.68), increased waist circumference (OR, 1.30; 95% CI, 1.09 to 1.56), impaired fasting glucose (OR, 1.25; 95% CI, 1.05 to 1.48), higher blood pressure ( OR, 1.18; 95% CI, 0.96 to 1.44), hypertriglyceridemia (OR, 1.25; 95% CI, 1.04 to 1.51), and low high-density lipoprotein cholesterol (OR, 1.32; 95% CI 1.06 to 1.64). Conclusions - In middle-aged adults, soft drink consumption is associated with a higher prevalence and incidence of multiple metabolic risk factors. C1 VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Duv Aging, Boston, MA 02115 USA. Alice Peck Day Mem Hosp, Lebanon, NH USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. Tufts Univ, Nutr Res Ctr Aging, Medford, MA 02155 USA. Harvard Univ, Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA. Natl Heart Lung & blood Inst, Bethesda, MD USA. Brigham & Womens Hosp, Div Prevent Med & Cardiovasc Med, Boston, MA 02115 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Boston, MA 02215 USA. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970; Sullivan, Lisa/0000-0003-0726-7149 FU NCI NIH HHS [R01 CA097193]; NHLBI NIH HHS [1R01HL67288, 2K24HL04334, K23HL74077, N01-HC-25195] NR 43 TC 395 Z9 405 U1 9 U2 78 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 31 PY 2007 VL 116 IS 5 BP 480 EP 488 DI 10.1161/CIRCULATIONAHA.107.689935 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 196BG UT WOS:000248456000005 PM 17646581 ER PT J AU Bougdour, A Gottesman, S AF Bougdour, Alexandre Gottesman, Susan TI ppGpp regulation of RpoS degradation via anti-adaptor protein IraP SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE phosphate starvation; sigma(38); SpoT ID SIGMA-FACTOR SIGMA(S); SPOT-DEPENDENT ACCUMULATION; ESCHERICHIA-COLI; GUANOSINE TETRAPHOSPHATE; STATIONARY-PHASE; RNA-POLYMERASE; HISTIDINE OPERON; STRESS-RESPONSE; ACID STARVATION; IN-VIVO AB lraP is a small protein that interferes with the delivery of os (RpoS) to the ClpXP protease by blocking the action of RssB, an adaptor protein for os degradation. lraP was previously shown to mediate stabilization of os during phosphate starvation. Here, we show that iraP is transcribed in response to phosphate starvation; this response is mediated by ppGpp. The iraP promoter is positively regulated by ppGpp, dependent on the discriminator region of the iraP promoter. Sensing of phosphate starvation requires SpoT but not RelA. The results demonstrate a target for positive regulation by ppGpp and suggest that the cell use of ppGpp to mediate a variety of starvation responses operates in part by modulating sigma(s) levels. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM susang@helix.nih.gov RI Bougdour, Alexandre/K-3795-2014 OI Bougdour, Alexandre/0000-0002-5895-0020 FU Intramural NIH HHS NR 44 TC 60 Z9 62 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 31 PY 2007 VL 104 IS 31 BP 12896 EP 12901 DI 10.1073/pnas.0705561104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 198CF UT WOS:000248603900055 PM 17640895 ER PT J AU van Niekerk, EA Willis, DE Chang, JH Reumann, K Heise, T Twiss, JL AF van Niekerk, Erna A. Willis, Dianna E. Chang, Jay H. Reumann, Kerstin Heise, Tilman Twiss, Jeffery L. TI Sumoylation in axons triggers retrograde transport of the RNA-binding protein La SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE axonal transport; La/SSB; RNA localization; small ubiquitin-like modifying polypeptide ID HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEINS; MESSENGER-RNAS; SS-B; TRANSLATION; AUTOANTIGEN; SUMO; TRANSCRIPTION; LOCALIZATION; REGENERATION; SYNTHETASE AB A surprisingly large population of mRNAs has been shown to localize to sensory axons, but few RNA-binding proteins have been detected in these axons. These axonal mRNAs include several potential binding targets for the La RNA chaperone protein. La is transported into axonal processes in both culture and peripheral nerve. Interestingly, La is posttranslationally modified in sensory neurons by sumoylation. In axons, small ubiquitin-like modifying polypeptides (SUMO)-La interacts with dynein, whereas native La interacts with kinesin. Lysine 41 is required for sumoylation, and sumoylation-incompetent La-K41R shows only anterograde transport, whereas WT La shows both anterograde and retrograde transport in axons. Thus, sumoylation of La determines the directionality of its transport within the axonal compartment, with SUMO-La likely recycling to the cell body. C1 Univ Delaware, Dept Biol Sci, Newark, DE 19713 USA. Alfred I Dupont Hosp Children, Wilmington, DE 19803 USA. NICHHD, NIH, Lab Cellular & Synapt Neurophysiol, Dev Neurol & Plast Sect, Bethesda, MD 20892 USA. Univ Hamburg, Heinrich Pette Inst Expt Virol & Immunol, D-20251 Hamburg, Germany. Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. RP Twiss, JL (reprint author), Univ Delaware, Dept Biol Sci, Newark, DE 19713 USA. EM twiss@medsci.udel.edu FU NINDS NIH HHS [NS 041596, R01 NS041596] NR 33 TC 57 Z9 57 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 JUL 31 PY 2007 VL 104 IS 31 BP 12913 EP 12918 DI 10.1073/pnas.0611562104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 198CF UT WOS:000248603900058 PM 17646655 ER PT J AU Sharma, SK Nirenberg, M AF Sharma, Shail K. Nirenberg, Marshall TI Silencing of genes in cultured Drosophila neurons by RNA interference SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ELAV; insulin receptor; neurites ID WINGLESS SIGNALING PATHWAY; NERVOUS-SYSTEM DEVELOPMENT; INSULIN-RECEPTOR; CELL-CULTURES; SCREEN; COMPONENTS; PROTEIN; GROWTH; DIFFERENTIATION; TRANSDUCTION AB Cultures of neuroblasts that generate abundant neurons were established from Drosophila embryos to study silencing of genes by RNA interference (RNAi). Cultured cells expressed ELAV, a marker of neurons, Futsch, a marker of neurites, and Synapsin, Synaptobrevin, and Synaptogamin, proteins involved in neurotransmitter secretion. Conditions were found for efficient trans-fection of cells with siRNAs for ELAV or the insulin-like receptor, which resulted in marked decreases in neurons that express ELAV and Futsch. Cells also were successfully transfected with long-chain Sox-Neuro dsRNA resulting in a 55% reduction of neurons expressing Futsch. The results suggest that this cultured neural cell system can be used to study RNAi-dependent silencing of genes involved in many kinds of neural functions. C1 NHLBI, Biochim Genet Lab, NIH, Bethesda, MD 20892 USA. RP Nirenberg, M (reprint author), NHLBI, Biochim Genet Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mnirenberg@nih.gov NR 31 TC 4 Z9 5 U1 1 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 JUL 31 PY 2007 VL 104 IS 31 BP 12925 EP 12930 DI 10.1073/pnas.0704299104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 198CF UT WOS:000248603900060 PM 17646657 ER PT J AU Fang, J Brzostowski, JA Ou, S Isik, N Nair, V Jin, T AF Fang, Jun Brzostowski, Joseph A. Ou, Stephen Isik, Nilgun Nair, Vinod Jin, Tian TI A vesicle surface tyrosine kinase regulates phagosome maturation SO JOURNAL OF CELL BIOLOGY LA English DT Article ID TOLL-LIKE RECEPTORS; ATP-BINDING SITE; DICTYOSTELIUM-DISCOIDEUM; PATHOGENIC MYCOBACTERIA; FUNCTIONALLY DISTINCT; SIGNALING PATHWAYS; INSULIN-RECEPTOR; PHAGOCYTOSIS; MACROPHAGES; DYNAMICS AB Phagocytosis is crucial for host defense against microbial pathogens and for obtaining nutrients in Dictyostelium discoideum. Phagocytosed particles are delivered via a complex route from phagosomes to lysosomes for degradation, but the molecular mechanisms involved in the phagosome maturation process are not well understood. Here, we identify a novel vesicle-associated receptor tyrosine kinase-like protein, VSK3, in D. discoideum. We demonstrate how VSK3 is involved in phagosome maturation. VSK3 resides on the membrane of late endosomes/lysosomes with its C-terminal kinase domain facing the cytoplasm. Inactivation of VSK3 by gene disruption reduces the rate of phagocytosis in cells, which is rescued by re-expression of VSK3. We found that the in vivo function of VSK3 depends on the presence of the kinase domain and vesicle localization. Furthermore, VSK3 is not essential for engulfment, but instead, is required for the fusion of phagosomes with late endosomes/lysosomes. Our findings suggest that localized tyrosine kinase signaling on the surface of endosome/lysosomes represents a control mechanism for phagosome maturation. C1 NIAID, Lab Immunogenet, NIH, Rockville, MD 20852 USA. NIAID, RTB Rocky Mt Labs, Res Technol Sect, NIH, Hamilton, MT 59840 USA. RP Jin, T (reprint author), NIAID, Lab Immunogenet, NIH, Rockville, MD 20852 USA. EM tjin@niaid.nih.gov NR 53 TC 9 Z9 9 U1 1 U2 2 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 JUL 30 PY 2007 VL 178 IS 3 BP 411 EP 423 DI 10.1083/jcb.200701023 PG 13 WC Cell Biology SC Cell Biology GA 197HF UT WOS:000248544500010 PM 17664333 ER PT J AU Conklin, SM Harris, JI Manuck, SB Yao, JK Hibbeln, JR Muldoon, MF AF Conklin, Sarah M. Harris, Jennifer I. Manuck, Stephen B. Yao, Jeffrey K. Hibbeln, Joseph R. Muldoon, Matthew F. TI Serum omega-3 fatty acids are associated with variation in mood, personality and behavior in hypercholesterolemic community volunteers SO PSYCHIATRY RESEARCH LA English DT Article DE polyunsaturated fatty acids (PUFA); depression; impulsivity; personality ID POLYUNSATURATED FATTY-ACIDS; PLACEBO-CONTROLLED TRIAL; AMERICAN-HEART-ASSOCIATION; HEALTH-CARE PROFESSIONALS; PRELIMINARY DOUBLE-BLIND; BLOOD-CELL MEMBRANES; DOCOSAHEXAENOIC ACID; FISH CONSUMPTION; MAJOR DEPRESSION; CARDIOVASCULAR-DISEASE AB Low dietary intake of omega-3 polyunsaturated fatty acids has been linked to several features of psychiatric symptomatology, including depression, disorders of impulse control, and hostility. Preliminary intervention trials of omega-3 fatty acid supplementation for clinical depression and other disorders have reported benefit. However, few studies have investigated the relationships between these fatty acids and normative variability in mood, behavior and personality. Participants were 105 hypercholesterolemic, but otherwise healthy, non-smoking adults. Fasting serum alpha-linolenic (alpha-LNA), eicosapentaenoic (EPA) and docosahexacnoic acid (DHA) were assayed with gas chromatography. Participants completed the Beck Depression Inventory (BDI), the NEO Five Factor Personality Inventory (NEO-FFI) and the Barratt Impulsiveness Scale (BIS). In multivariate analyses, higher levels of the long chain omega-3 PUFAs, EPA and DHA, were associated with significantly reduced odds of scoring >= 10 on the BDI. Similarly, DHA and EPA covaried inversely with NEO-Neuroticism scores, whereas DHA was positively associated with NEO-Agreeableness. On the BIS, DHA was inversely related to cognitive impulsivity and alpha-LNA was inversely related to motor and total impulsivity. These findings suggest that omega-3 fatty acid status is associated with variability in affect regulation, personality and impulse control. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Psychiat, Cardiovasc Behav Med Postdoctoral Training Progra, Pittsburgh, PA USA. Brown Univ, Dept Psychol, Providence, RI 02912 USA. Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Psychiat & Pharmaceut Sci, VA Pittsburgh Healthcare syst, Pittsburgh, PA USA. Natl Inst Alcohol Abuse & Alcoholism, Bethesda, MD USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Conklin, SM (reprint author), Univ Pittsburgh, Dept Psychiat, 506 Old Engn Hall, Pittsburgh, PA 15260 USA. EM conklinsm@upmc.edu FU NHLBI NIH HHS [HL46328, HL07560] NR 72 TC 43 Z9 45 U1 2 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD JUL 30 PY 2007 VL 152 IS 1 BP 1 EP 10 DI 10.1016/j.psychres.2006.10.006 PG 10 WC Psychiatry SC Psychiatry GA 198UO UT WOS:000248653200001 PM 17383013 ER PT J AU Fucic, A Znaor, A Strnad, M van der Hel, O Aleksandrov, A Miskov, S Grah, J Sedlar, M Jazbec, AM Ceppi, M Vermeulen, R Boffetta, P Norppa, H Bonassi, S AF Fucic, Aleksandra Znaor, Ariana Strnad, Marija van der Hel, Olga Aleksandrov, Anastasija Miskov, Snjezana Grah, Josip Sedlar, Miljenko Jazbec, Ana Marija Ceppi, Marcello Vermeulen, Roel Boffetta, Paolo Norppa, Hannu Bonassi, Stefano TI Chromosome damage and cancer risk in the workplace: The example of cytogenetic surveillance in Croatia SO TOXICOLOGY LETTERS LA English DT Article; Proceedings Paper CT 36th Annual Meeting of the European-Environmental-Mutagen-Society CY JUL 03, 2006 CL Prague, CZECH REPUBLIC SP European Environm Mutagen Soc DE biomarkers; cancer; chromosome aberration; micronucleus; occupational exposure ID PERIPHERAL-BLOOD LYMPHOCYTES; PREDICT HUMAN CANCER; GENOMIC INSTABILITY; ABERRATIONS; BIOMARKERS; FREQUENCY; HUMANS; TRANSLOCATION; HEALTH; COHORT AB The use of cytogenetic assays in the surveillance of populations occupationally exposed to genotoxic carcinogens originates from the assumption that chromosomal alterations might be causally involved in early stages of carcinogenesis. Historical cohort studies have since 1990s consistently reported an association between the level of chromosomal aberrations (CA) in peripheral lymphocytes of healthy subjects and the risk of cancer. Only in few cases, have these results been transformed into a regulatory tool for improving occupational safety. The cytogenetic surveillance program adopted for more than two decades in the Republic of Croatia is one of these few examples. Croatian workers exposed to genotoxic agents were systematically screened for CA, to identify occupational settings needing a priority intervention. Significant increases of mean CA frequency were observed in groups exposed to ionizing radiation, chemical agents, and mixed exposures when compared with a group of unexposed referents. CA data on 736 men and 584 women, monitored between 1987 and 2000, have been associated with cancer incidence. Although the small size of the cohort did not allow for reaching statistical significance, the medium tertile of the CA frequency distribution was associated with a doubling of cancer incidence rate ratio (IRR = 2.40; 95% CI 0.85-6.77) when compared with the lowest tertile. For chromosome-type CA, IRR was non-significantly increased for both the medium (IRR 1.53, 95% CI 0.58-3.99) and high categories (IRR 1.69; 95% CI 0.61-4.72). Recommendations for future strategies comprise the inclusion of predictive biomarkers in surveillance programs, the definition of a regulatory framework, and their possible use for the identification of individual risk profiles. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 Inst Med Res & Occupat Hlth, Zagreb, Croatia. Croatian Natl Inst Publ Hlth, Croatian Natl Canc Reg, Zagreb 10000, Croatia. Int Agcy Res Canc, Lyon, France. Univ Zagreb, Univ Hosp, Gynecol Canc Ctr, Zagreb 10000, Croatia. Univ Zagreb, Univ Hosp, Gynecol Canc Ctr, Zagreb 10000, Croatia. Univ Zagreb, Clin Hosp Sestre Milosrdnice, Zagreb, Croatia. Univ Zagreb, Univ Hosp Tumours, Zagreb, Croatia. Univ Zagreb, Fac Forestry, Zagreb, Croatia. Natl Canc Inst, Occupat & Environm Epidemiol, Rockville, MD USA. Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. Finnish Inst Occupat Hlth, FI-00250 Helsinki, Finland. Natl Canc Res Inst, Unit Mol Epidemiol, I-16132 Genoa, Italy. RP Fucic, A (reprint author), Inst Med Res & Occupat Hlth, Ksaverska 2, Zagreb, Croatia. EM afucic@imi.hr RI Vermeulen, Roel/F-8037-2011; OI Vermeulen, Roel/0000-0003-4082-8163; bonassi, stefano/0000-0003-3833-6717 NR 36 TC 9 Z9 10 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 EI 1879-3169 J9 TOXICOL LETT JI Toxicol. Lett. PD JUL 30 PY 2007 VL 172 IS 1-2 BP 4 EP 11 DI 10.1016/j.toxlet.2007.05.015 PG 8 WC Toxicology SC Toxicology GA 206GB UT WOS:000249170800002 PM 17651925 ER PT J AU Choi, E Lee, J Oh, J Park, I Han, C Yi, C Kim, DH Cho, BN Eddy, EM Cho, C AF Choi, Eunyoung Lee, Jiae Oh, Jungsu Park, Inju Han, Cecil Yi, Chongil Kim, Do Han Cho, Byung-Nam Eddy, Edward M. Cho, Chunghee TI Integrative characterization of germ cell-specific genes from mouse spermatocyte UniGene library SO BMC GENOMICS LA English DT Article ID SPERMATOGENIC CELLS; POSTNATAL-DEVELOPMENT; SPERM MOTILITY; MALE-FERTILITY; EXPRESSION; CLONING; LOCALIZATION; ACROSOME; TESTIS; IDENTIFICATION AB Background: The primary regulator of spermatogenesis, a highly ordered and tightly regulated developmental process, is an intrinsic genetic program involving male germ cell-specific genes. Results: We analyzed the mouse spermatocyte UniGene library containing 2155 gene-oriented transcript clusters. We predict that 11% of these genes are testis-specific and systematically identified 24 authentic genes specifically and abundantly expressed in the testis via in silico and in vitro approaches. Northern blot analysis disclosed various transcript characteristics, such as expression level, size and the presence of isoform. Expression analysis revealed developmentally regulated and stage-specific expression patterns in all of the genes. We further analyzed the genes at the protein and cellular levels. Transfection assays performed using GC-2 cells provided information on the cellular characteristics of the gene products. In addition, antibodies were generated against proteins encoded by some of the genes to facilitate their identification and characterization in spermatogenic cells and sperm. Our data suggest that a number of the gene products are implicated in transcriptional regulation, nuclear integrity, sperm structure and motility, and fertilization. In particular, we found for the first time that Mm. 333010, predicted to contain a trypsin-like serine protease domain, is a sperm acrosomal protein. Conclusion: We identify 24 authentic genes with spermatogenic cell-specific expression, and provide comprehensive information about the genes. Our findings establish a new basis for future investigation into molecular mechanisms underlying male reproduction. C1 Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. Gwangju Inst Sci & Technol, Res Ctr Biomol Nanotechnol, Kwangju 500712, South Korea. Catholic Univ Korea, Dept Life Sci, Puchon 421743, South Korea. NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Cho, C (reprint author), Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. EM ibbnida@hotmail.com; reslee@hanmail.net; tornado94@hanmail.net; seafood0980@hanmail.net; yakcecil@hanmail.net; yici@gist.ac.kr; dhkim@gist.ac.kr; ocean@catholic.ac.kr; eddy@niehs.nih.gov; choch@gist.ac.kr FU Intramural NIH HHS NR 39 TC 16 Z9 17 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 28 PY 2007 VL 8 AR 256 DI 10.1186/1471-2164-8-256 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 204ZP UT WOS:000249082800001 PM 17662146 ER PT J AU Gray, RH Makumbi, F Serwadda, D Lutalo, T Nalugoda, F Opendi, P Kigozi, G Reynolds, SJ Sewankambo, NK Wawer, MJ AF Gray, Ronald H. Makumbi, Fredrick Serwadda, David Lutalo, Tom Nalugoda, Fred Opendi, Pius Kigozi, Godfrey Reynolds, Steven J. Sewankambo, Nelson K. Wawer, Maria J. TI Limitations of rapid HIV-1 tests during screening for trials in Uganda: diagnostic test accuracy study SO BRITISH MEDICAL JOURNAL LA English DT Article AB Objective To evaluate the limitations of rapid tests for HIV-1. Design Diagnostic test accuracy study. Setting Rural Rakai, Uganda. Participants 1517 mates aged 15-49 screened for trials of circumcision for HIV prevention. Main outcome measures Sensitivity, specificity, negative predictive values, and positive predictive values of an algorithm using three rapid tests for HIV, compared with the results of enzyme immunoassay and western blotting as the optimal methods. Results Rapid test results were evaluated by enzyme immunoassay and western blotting. Sensitivity was 97.7%. Among 639 samples where the strength of positive bands was coded if the sample showed positivity for HIV, the algorithm had low specificity (94.1%) and a low positive predictive value (74.0%). Exclusion of 37 samples (5.8%) with a weak positive band improved the specificity (99.6%) and positive predictive value (97.7%.). Conclusion Weak positive bands on rapid tests for HIV should be confirmed by enzyme immunoassay and western blotting before disclosing the diagnosis. Programmes using rapid tests routinely should use standard serological assays for quality control. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. Uganda Virus Res Inst, Rakai Hlth Sci Program, Entebbe, Uganda. Makerere Univ, Inst Publ Hlth, Kampala, Uganda. NIH, NIAID, Entebbe, Uganda. Makerere Univ, Sch Med, Kampala, Uganda. RP Gray, RH (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. EM rgray@jhsph.edu OI Sewankambo, Nelson/0000-0001-9362-053X FU FIC NIH HHS [2D43TW00001019-AITRP]; NIAID NIH HHS [UO1 AI11171-01-02] NR 5 TC 49 Z9 52 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD JUL 28 PY 2007 VL 335 IS 7612 BP 188 EP 190 DI 10.1136/bmj.39210.582801.BE PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 198YA UT WOS:000248662200029 PM 17545184 ER PT J AU Krekelberg, WP Mittal, J Ganesan, V Truskett, TM AF Krekelberg, William P. Mittal, Jeetain Ganesan, Venkat Truskett, Thomas M. TI How short-range attractions impact the structural order, self-diffusivity, and viscosity of a fluid SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID UNIVERSAL SCALING LAW; HARD-SPHERE FLUID; SUPERCOOLED LIQUIDS; GLASS-TRANSITION; TRANSPORT-COEFFICIENTS; O-TERPHENYL; DYNAMICS; EQUILIBRIUM; BREAKDOWN; ROTATION AB We present molecular simulation data for viscosity, self-diffusivity, and the local structural ordering of (i) a hard-sphere fluid and (ii) a square-well fluid with short-range attractions. The latter fluid exhibits a region of dynamic anomalies in its phase diagram, where its mobility increases upon isochoric cooling, which is found to be a subset of a larger region of structural anomalies, in which its pair correlations strengthen upon isochoric heating. This "cascade of anomalies" qualitatively resembles that found in recent simulations of liquid water. The results for the hard-sphere and square-well systems also show that the breakdown of the Stokes-Einstein relation upon supercooling occurs for conditions where viscosity and self-diffusivity develop different couplings to the degree of pairwise structural ordering of the liquid. We discuss how these couplings reflect dynamic heterogeneities. Finally, we note that the simulation data suggest how repulsive and attractive glasses may generally be characterized by two distinct levels of short-range structural order. (c) 2007 American Institute of Physics. C1 Univ Texas, Dept Chem Engn, Austin, TX 78712 USA. NIDDK, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. Univ Texas, Inst Theoret Chem, Austin, TX 78712 USA. RP Krekelberg, WP (reprint author), Univ Texas, Dept Chem Engn, Austin, TX 78712 USA. EM krekel@che.utexas.edu; jeetain@helix.nih.gov; venkat@che.utexas.edu; truskett@che.utexas.edu RI Truskett, Thomas/D-4624-2009; Ganesan, Venkat/B-9912-2011; Truskett, Thomas/C-4996-2014 OI Truskett, Thomas/0000-0002-6607-6468; NR 40 TC 51 Z9 51 U1 0 U2 22 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD JUL 28 PY 2007 VL 127 IS 4 AR 044502 DI 10.1063/1.2753154 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 196ME UT WOS:000248485900030 PM 17672702 ER PT J AU Lu, FL Jiang, HY Ding, JH Mu, JB Valenzuela, JG Ribeiro, JMC Su, XZ AF Lu, Fangli Jiang, Hongying Ding, Jinhui Mu, Jianbing Valenzuela, Jesus G. Ribeiro, Jose M. C. Su, Xin-Zhuan TI cDNA sequences reveal considerable gene prediction inaccuracy in the Plasmodium falciparum genome SO BMC GENOMICS LA English DT Article ID HUMAN MALARIA PARASITE; FULL-LENGTH CDNAS; DROSOPHILA-MELANOGASTER; FUNCTIONAL ANNOTATION; ANTISENSE TRANSCRIPTS; LIFE-CYCLE; EXPRESSION; ERYTHROCYTES; COLLECTION; IDENTIFICATION AB Background: The completion of the Plasmodium falciparum genome represents a milestone in malaria research. The genome sequence allows for the development of genome-wide approaches such as microarray and proteomics that will greatly facilitate our understanding of the parasite biology and accelerate new drug and vaccine development. Designing and application of these genome-wide assays, however, requires accurate information on gene prediction and genome annotation. Unfortunately, the genes in the parasite genome databases were mostly identified using computer software that could make some erroneous predictions. Results: We aimed to obtain cDNA sequences to examine the accuracy of gene prediction in silico. We constructed cDNA libraries from mixed blood stages of P. falciparum parasite using the SMART cDNA library construction technique and generated 17332 high-quality expressed sequence tags (EST), including 2198 from primer-walking experiments. Assembly of our sequence tags produced 2548 contigs and 2671 singletons versus 5220 contigs and 5910 singletons when our EST were assembled with EST in public databases. Comparison of all the assembled EST/ contigs with predicted CDS and genomic sequences in the PlasmoDB database identified 356 genes with predicted coding sequences fully covered by EST, including 85 genes (23.6%) with introns incorrectly predicted. Careful automatic software and manual alignments found an additional 308 genes that have introns different from those predicted, with 152 new introns discovered and 182 introns with sizes or locations different from those predicted. Alternative spliced and antisense transcripts were also detected. Matching cDNA to predicted genes also revealed silent chromosomal regions, mostly at subtelomere regions. Conclusion: Our data indicated that approximately 24% of the genes in the current databases were predicted incorrectly, although some of these inaccuracies could represent alternatively spliced transcripts, and that more genes than currently predicted have one or more additional introns. It is therefore necessary to annotate the parasite genome with experimental data, although obtaining complete cDNA sequences from this parasite will be a formidable task due to the high AT nature of the genome. This study provides valuable information for genome annotation that will be critical for functional analyses. C1 NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Sun Yat Sen Univ, Zhongshan Sch Med, Dept Parasitol, Guangzhou 510080, Guangdong, Peoples R China. NIA, PRoC, NIH, Bethesda, MD 20892 USA. NIA, Bioinformat Unit, NIH, Bethesda, MD 20892 USA. RP Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM fanglilu@yahoo.com; hojiang@niaid.nih.gov; dingj@mail.nih.gov; jmu@niaid.nih.gov; jvalenzuela@niaid.nih.gov; jribeiro@niaid.nih.gov; xsu@niaid.nih.gov OI Su, Xinzhuan/0000-0003-3246-3248; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS NR 45 TC 39 Z9 40 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD JUL 27 PY 2007 VL 8 AR 255 DI 10.1186/1471-2164-8-255 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 212KA UT WOS:000249594000001 PM 17662120 ER PT J AU Chang, CR Blackstone, C AF Chang, Chuang-Rung Blackstone, Craig TI Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EFFECTOR DOMAIN; DYNAMIN; FISSION; OLIGOMERIZATION; ENDOCYTOSIS AB Mitochondria in cells comprise a tubulovesicular reticulum shaped by dynamic fission and fusion events. The multimeric dynamin-like GTPase Drp1 is a critical protein mediating mitochondrial division. It harbors multiple motifs including GTP-binding, middle, and GTPase effector (GED) domains that are important for both intramolecular and intermolecular interactions. As for other members of the dynamin superfamily, such interactions are critical for assembly of higher-order structures and cooperative increases in GTPase activity. Although the functions of Drp1 in cells have been extensively studied, mechanisms underlying its regulation remain less clear. Here, we have identified cAMP-dependent protein kinase-dependent phosphorylation of Drp1 within the GED domain at Ser(637) that inhibits Drp1 GTPase activity. Mechanistically, this change in GTPase activity likely derives from decreased interaction of GTP-binding/middle domains with the GED domain since the phosphomimetic S637D mutation impairs this intramolecular interaction but not Drp1-Drp1 intermolecular interactions. Using the phosphomimetic S637D substitution, we also demonstrate that mitochondrial fission is prominently inhibited in cells. Thus, protein phosphorylation at Ser(637) results in clear alterations in Drp1 function and mitochondrial morphology that are likely involved in dynamic regulation of mitochondrial division in cells. C1 NINDS, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. RP Blackstone, C (reprint author), NINDS, Cellular Neurol Unit, NIH, Bldg 35,Rm 2C-913,9000 Rockville Pike, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov RI Chang, Chuang-Rung /C-1815-2012 FU Intramural NIH HHS NR 20 TC 263 Z9 268 U1 3 U2 17 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 JUL 27 PY 2007 VL 282 IS 30 BP 21583 EP 21587 DI 10.1074/jbc.C700083200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 192JG UT WOS:000248196800003 PM 17553808 ER PT J AU Kebache, S Ash, J Annis, MG Hagan, J Huber, M Hassard, J Stewart, CL Whiteway, M Nantel, A AF Kebache, Sem Ash, Josee Annis, Matthew G. Hagan, John Huber, Maria Hassard, Jennifer Stewart, Colin L. Whiteway, Malcolm Nantel, Andre TI Grb10 and active Raf-1 kinase promote bad-dependent cell survival SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR-I; PROTEIN-KINASE; ADAPTER PROTEIN; SIGNALING PATHWAYS; C-RAF-1 GENE; PHOSPHORYLATION; APOPTOSIS; DEATH; RECEPTOR; AKT AB The proapoptotic protein Bad is a key player in cell survival decisions, and is regulated post-translationally by several signaling networks. We expressed Bad in mouse embryonic fibroblasts to sensitize them to apoptosis, and tested cell lines derived from knock-out mice to establish the significance of the interaction between the adaptor protein Grb10 and the Raf-1 protein kinase in anti-apoptotic signaling pathways targeting Bad. When compared with wild-type cells, both Grb10 and Raf-1 deficient cells exhibit greatly enhanced sensitivity to apoptosis in response to Bad expression. Structure-function analysis demonstrates that, in this cellular model, the SH2, proline-rich, and pleckstrin homology domains of Grb10, as well as its Akt phosphorylation site and consequent binding by 14-3-3, are all necessary for its anti-apoptotic functions. As for Raf-1, its kinase activity, its ability to be phosphorylated by Src on Tyr-340/341 and the binding of its Ras-associated domain to the Grb10 SH2 domain are all necessary to promote cell survival. Silencing the expression of either Grb10 or Raf-1 by small interfering RNAs as well as mutagenesis of specific serine residues on Bad, coupled with signaling inhibitor studies, all indicate that Raf-1 and Grb10 are required for the ability of both the phosphatidylinositol 3-kinase/Akt and MAP kinase pathways to modulate the phosphorylation and inactivation of Bad. Because total Raf-1, ERK,andAktkinaseactivities are not impaired in the absence of Grb10, we propose that this adapter protein creates a subpopulation of Raf-1 with specific anti-apoptotic activity. C1 Natl Res Council Canada, Biotechnol Res Inst, Montreal, PQ H4P 2R2, Canada. McGill Univ, Dept Biol, Montreal, PQ H3A 2B2, Canada. McGill Univ, Dept Anat, Montreal, PQ H3A 2B2, Canada. McGill Univ, Dept Cell Biol, Montreal, PQ H3A 2B2, Canada. NCI, NIH, Canc & Dev Biol Lab, Ft Detrick, MD 21702 USA. RP Nantel, A (reprint author), Natl Res Council Canada, Biotechnol Res Inst, 6100 Royalmount Ave, Montreal, PQ H4P 2R2, Canada. EM andre.nantel@cnrc-nrc.gc.ca OI Hagan, John/0000-0003-0295-4898 NR 58 TC 25 Z9 25 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 27 PY 2007 VL 282 IS 30 BP 21873 EP 21883 DI 10.1074/jbc.M611066200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 192JG UT WOS:000248196800035 PM 17535812 ER PT J AU Bao, JJ Ma, XF Liu, CY Adelstein, RS AF Bao, Jianjun Ma, Xuefei Liu, Chengyu Adelstein, Robert S. TI Replacement of nonmuscle myosin II-B with II-A rescues brain but not cardiac defects in mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAVY CHAIN-B; DILATED CARDIOMYOPATHY; MOLECULAR-MECHANISMS; NERVOUS-SYSTEM; HEART-FAILURE; MESSENGER-RNA; CELL-ADHESION; CYTOKINESIS; EXPRESSION; ISOFORMS AB The purpose of these studies was to learn whether one isoform of nonmuscle myosin II, specifically nonmuscle myosin II-A, could functionally replace a second one, nonmuscle myosin II-B, in mice. To accomplish this, we used homologous recombination to ablate nonmuscle myosin heavy chain (NMHC) II-B by inserting cDNA encoding green fluorescent protein (GFP)NMHC II-A into the first coding exon of the Myh10 gene, thereby placing GFP-NMHC II-A under control of the endogenous II-B promoter. Similar to B-/B- mice, most B-a*/B-a* mice died late in embryonic development with structural cardiac defects and impaired cytokinesis of the cardiac myocytes. However, unlike B-/B- mice, 15 B-a*/B-a* mice of 172 F2 generation mice survived embryonic lethality but developed a dilated cardiomyopathy as adults. Surprisingly none of the B-a*/B-a* mice showed evidence for hydrocephalus that is always found in B-/B- mice. Rescue of this defect was due to proper localization and function of GFP-NMHC II-A in place of NMHC II-B in a cell-cell adhesion complex in the cells lining the spinal canal. Restoration of the integrity and adhesion of these cells prevents protrusion of the underlying cells into the spinal canal where they block circulation of the cerebral spinal fluid. However, abnormal migration of facial and pontine neurons found in NMHC II-B mutant and ablated mice persisted in B-a*/B-a* mice. Thus, although NMHC II-A can substitute for NMHC II-B to maintain integrity of the spinal canal, NMHC II-B plays an isoform-specific role during cytokinesis in cardiac myocytes and in migration of the facial and pontine neurons. C1 NIH, Mol Cardiol Lab, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Adelstein, RS (reprint author), NIH, Mol Cardiol Lab, Bldg 10,Rm 8N202,10 Ctr Dr MSC 1762, Bethesda, MD 20892 USA. EM adelster@nhlbi.nih.gov OI Adelstein, Robert/0000-0002-8683-2144 NR 42 TC 50 Z9 50 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 JUL 27 PY 2007 VL 282 IS 30 BP 22102 EP 22111 DI 10.1074/jbc.M702731200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 192JG UT WOS:000248196800057 PM 17519229 ER PT J AU Trujillo, CA Majumder, P Gonzalez, FA Moaddel, R Ulrich, H AF Trujillo, Cleber A. Majumder, Paromita Gonzalez, Fernando A. Moaddel, Ruin Ulrich, Henning TI Immobilized P2X(2) purinergic receptor stationary phase for chromatographic determination of pharmacological properties and drug screening SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE purinergic receptor; affinity chromatography; drug screening; SELEX; aptamer ID NICOTINIC ACETYLCHOLINE-RECEPTOR; IN-VITRO SELECTION; RNA APTAMERS; NUCLEOTIDE RECEPTOR; TNP-ATP; DNA; SURAMIN; BINDING; PROTEIN; PURINOCEPTORS AB The purinergic receptor signaling system plays an important role in communication between cells in the nervous system and opens new opportunities for screening of potential drugs. Our objective was to explore the pharmacological properties and establish a new methodology for ligand screening for the P2X(2) receptor, which has been developed by the combinatorial library approach Systematic Evolution of Ligands by Exponential enrichment (SELEX). To this end, membranes of 1321N1 cells stably transfected with rat P2X(2) receptors were resuspended in 2% cholate detergent and subsequently coupled onto an immobilized artificial membrane (JAM). The IAM-cholate-P2X(2) mixture was then dialyzed, centrifuged and packed into a FPLC column. Equilibrium binding to the receptor and competition between ATP and the purinergic antagonists suramin and 2'3'-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate (TNP-ATP) were analyzed by a chromatographic assay using (32)P alpha ATP as a radioligand. Our data indicate that suramin does not compete with ATP for the ligand binding site and TNP-ATP is a competitive antagonist. confirming previous studies [C.A. Trujillo, A.A. Nery, A.H. Martins, P. Majumder, F.A. Gonzalez, H. Ulrich, Biochemistry 45 (2006) 224-233]. In addition, we demonstrate that this assay can be used in in vitro selection procedures for RNA aptamers binding to P2X(2) receptors. The results demonstrate that the receptor can be immobilized in a stable format and reused over an extended period of time, facilitating the exploration of ligand-receptor interactions and screening of combinatorial pools for possible ligands. (c) 2007 Elsevier B.V. All rights reserved. C1 Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508900 Sao Paulo, Brazil. Univ Puerto Rico, Dept Chem, Rio Piedras, PR 00931 USA. NIA, Natl Inst Hlth, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Ulrich, H (reprint author), Univ Sao Paulo, Inst Quim, Dept Bioquim, BR-05508900 Sao Paulo, Brazil. EM henning@iq.usp.br RI Ulrich, Henning/C-5245-2013 OI Ulrich, Henning/0000-0002-2114-3815 FU NIGMS NIH HHS [GM-08102] NR 44 TC 3 Z9 4 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD JUL 27 PY 2007 VL 44 IS 3 SI SI BP 701 EP 710 DI 10.1016/j.jpba.2007.03.006 PG 10 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 200BF UT WOS:000248738200011 PM 17481842 ER PT J AU Driscoll, CA Menotti-Raymond, M Roca, AL Hupe, K Johnson, WE Geffen, E Harley, EH Delibes, M Pontier, D Kitchener, AC Yamaguchi, N O'Brien, SJ Macdonald, DW AF Driscoll, Carlos A. Menotti-Raymond, Marilyn Roca, Alfred L. Hupe, Karsten Johnson, Warren E. Geffen, Eli Harley, Eric H. Delibes, Miguel Pontier, Dominique Kitchener, Andrew C. Yamaguchi, Nobuyuki O'Brien, Stephen J. Macdonald, David W. TI The Near Eastern origin of cat domestication SO SCIENCE LA English DT Article ID FELIS-SILVESTRIS; WILD; POPULATIONS; RADIATION AB The world's domestic cats carry patterns of sequence variation in their genome that reflect a history of domestication and breed development. A genetic assessment of 979 domestic cats and their wild progenitors-Felis silvestris silvestris ( European wildcat), F. s. lybica ( Near Eastern wildcat), F. s. ornata ( central Asian wildcat), F. s. cafra ( southern African wildcat), and F. s. bieti ( Chinese desert cat)indicated that each wild group represents a distinctive subspecies of Felis silvestris. Further analysis revealed that cats were domesticated in the Near East, probably coincident with agricultural village development in the Fertile Crescent. Domestic cats derive from at least five founders from across this region, whose descendants were transported across the world by human assistance. C1 NCI, Lab Genom Divers, Frederick, MD 21702 USA. Univ Oxford, Dept Zool, Wildlife Conservat Res Unit, Oxford OX1 3PS, England. NCI, Lab Genom Divers, SAIC Frederick Inc, Frederick, MD 21702 USA. JagdEinrichtungsBuro, D-37170 Furstenhagen, Germany. Tel Aviv Univ, Dept Zool, IL-69978 Tel Aviv, Israel. Univ Cape Town, Div Chem Pathol, Observ, ZA-7925 Cape Town, South Africa. CSIC, Dept Appl Biol, Estac Biol Donana, Seville 41013, Spain. Univ Lyon 1, CNRS, Biometrie & Biol Evolut UMR 5558, F-69622 Villeurbanne, France. Natl Museums Scotland, Dept Nat Sci, Edinburgh EH1 1JF, Midlothian, Scotland. Univ Edinburgh, Inst Geog, Sch Geosci, Edinburgh EH8 9XP, Midlothian, Scotland. RP Macdonald, DW (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM driscoll@ncifcrf.gov; obrien@ncifcrf.gov; david.macdonald@zoology.oxford.ac.uk RI Johnson, Warren/D-4149-2016; CSIC, EBD Donana/C-4157-2011; Delibes, Miguel/K-2744-2014; OI Johnson, Warren/0000-0002-5954-186X; CSIC, EBD Donana/0000-0003-4318-6602; Delibes, Miguel/0000-0002-3569-567X; Driscoll, Carlos/0000-0003-2392-505X FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 31 TC 169 Z9 179 U1 23 U2 141 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 JUL 27 PY 2007 VL 317 IS 5837 BP 519 EP 523 DI 10.1126/science.1139518 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 194JD UT WOS:000248339800047 PM 17600185 ER PT J AU Hall, MD Mellor, HR Callaghan, R Hambley, TW AF Hall, Matthew D. Mellor, Howard R. Callaghan, Richard Hambley, Trevor W. TI Basis for design and development of Platinum(IV) anticancer complexes SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CANCER-CELL-LINES; IN-VITRO; ANTITUMOR-ACTIVITY; OXIDATION-STATE; CISPLATIN RESISTANCE; CARBOXYLATE LIGANDS; ACQUIRED-RESISTANCE; PLASMA-PROTEINS; PT(IV) COMPLEX; DNA-DAMAGE C1 Univ Sydney, Ctr Heavy Met Res, Sch Chem, Sydney, NSW 2006, Australia. NCI, Cell Biol Lab, NIH, Bethesda, MD 20893 USA. Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Lab Sci, Oxford Drug Resistance Grp, Oxford OX3 9DU, England. RP Hall, MD (reprint author), Univ Sydney, Ctr Heavy Met Res, Sch Chem, Sydney, NSW 2006, Australia. EM hallma@mail.nih.gov; t.hambley@chem.usyd.edu.au RI Hall, Matthew/B-2132-2010; Callaghan, Richard/B-7032-2012 OI Callaghan, Richard/0000-0001-6136-3532 NR 81 TC 216 Z9 220 U1 11 U2 73 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 JUL 26 PY 2007 VL 50 IS 15 BP 3403 EP 3411 DI 10.1021/jm070280u PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 191HD UT WOS:000248121300001 PM 17602547 ER PT J AU Choi, Y Pu, Y Peach, ML Kang, JH Lewin, NE Sigano, DM Garfield, SH Blumberg, PM Marquez, VE AF Choi, Yongseok Pu, Yongmei Peach, Megan L. Kang, Ji-Hye Lewin, Nancy E. Sigano, Dina M. Garfield, Susan H. Blumberg, Peter M. Marquez, Victor E. TI Conformationally constrained analogues of diacylglycerol (DAG). 28. DAG-dioxolanones reveal a new additional interaction site in the C1b domain of PKC delta SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; PHORBOL ESTER BINDING; 5-DISUBSTITUTED TETRAHYDRO-2-FURANONE TEMPLATE; 12-MYRISTATE 13-ACETATE; MEDICINAL LEADS; DOWN-REGULATION; BRYOSTATIN 1; SIDE-CHAIN; ACTIVATION; LACTONES AB Diacylglycerol (DAG) lactones have provided a powerful platform for structural exploration of the interactions between ligands and the C1 domains of protein kinase C (PKC). In this study, we report that DAG-dioxolanones, novel derivatives of DAG-lactones, exploit an additional point of contact (glutamine 27) in their binding with the C1b domain of PKC delta. Mutation of this point of contact to glutamate selectively impairs binding of the DAG-dioxolanones compared to that of the corresponding DAG-lactones (1200- to 3000-fold versus 35- to 55-fold, respectively). The differential response of this mutated C1b domain to the DAG-dioxolanones relative to the DAG-lactones provides a unique tool to probe the role of the C1b domain in PKC delta function, where the response to the DAG-lactones affords a positive control for retained function. Using this approach, we show that the C1b domain of PKC delta plays the predominant role in the translocation of PKC delta to the membrane in the presence of DAG. C1 NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. SAIC Frederick Inc, NCI Frederick, Basic Res Program, Frederick, MD 21702 USA. RP Blumberg, PM (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ychoi@korea.ac.kr; blumberp@dc37a.nci.nih.gov; marquezv@mail.nih.gov RI Sigano, Dina/M-6144-2014; Choi, Yongseok/F-8375-2012 OI Sigano, Dina/0000-0001-7489-9555; Choi, Yongseok/0000-0002-3622-3439 FU Intramural NIH HHS; NCI NIH HHS [N01-CO12400] NR 63 TC 6 Z9 7 U1 0 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 JUL 26 PY 2007 VL 50 IS 15 BP 3465 EP 3481 DI 10.1021/jm0702579 PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 191HD UT WOS:000248121300011 PM 17591763 ER PT J AU Simpson, DS Katavic, PL Lozama, A Harding, WW Parrish, D Deschamps, JR Dersch, CM Partilla, JS Rothman, RB Navarro, H Prisinzano, TE AF Simpson, Denise S. Katavic, Peter L. Lozama, Anthony Harding, Wayne W. Parrish, Damon Deschamps, Jeffrey R. Dersch, Christina M. Partilla, John S. Rothman, Richard B. Navarro, Hernan Prisinzano, Thomas E. TI Synthetic studies of neoclerodane diterpenes from Salvia divinorum: Preparation and opioid receptor activity of salvinicin analogues SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SALVINORIN-A; AGONIST; MINT; HALLUCINOGEN; LIGANDS; TARGET; MICE AB Further modification of salvinorin A (1a), the major active component of Salvia divinorum, has resulted in the synthesis of novel neoclerodane diterpenes with opioid receptor affinity and activity. We report in this study that oxadiazole 11a and salvidivin A (12a), a photooxygenation product of 1a, have been identified as the first neoclerodane diterpenes with kappa antagonist activity. This indicates that additional structural modifications of 1a may lead to analogues with higher potency and utility as drug abuse medications. C1 Univ Iowa, Coll Pharm, Div Med & Nat Prod Chem, Iowa City, IA 52242 USA. USN, Res Lab, Washington, DC USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NIDA, Clin Psychopharmacol Sect, IRP, NIH,DHHS, Baltimore, MD 21224 USA. RP Prisinzano, TE (reprint author), Univ Iowa, Coll Pharm, Div Med & Nat Prod Chem, Iowa City, IA 52242 USA. EM thomas-prisinzano@uiowa.edu RI Prisinzano, Thomas/B-7877-2010; OI Deschamps, Jeffrey/0000-0001-5845-0010 FU Intramural NIH HHS; NIDA NIH HHS [DA018151, R01 DA018151, R01 DA018151-01A2, R01 DA018151-02S1, Y1-DA6002] NR 35 TC 29 Z9 30 U1 0 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 JUL 26 PY 2007 VL 50 IS 15 BP 3596 EP 3603 DI 10.1021/jm070393d PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 191HD UT WOS:000248121300021 PM 17580847 ER PT J AU Mishra, BK Wu, T Belfer, I Hodgkinson, CA Cohen, LG Kiselycznyk, C Kingman, A Keller, RB Yuan, Q Goldman, D Atlas, SJ Max, MB AF Mishra, Bikash K. Wu, Tianxia Belfer, Inna Hodgkinson, Colin A. Cohen, Leonardo G. Kiselycznyk, Carly Kingman, Albert Keller, Robert B. Yuan, Qiaoping Goldman, David Atlas, Steven J. Max, Mitchell B. TI Do motor control genes contribute to interindividual variability in decreased movement in patients with pain? SO MOLECULAR PAIN LA English DT Article ID LOW-BACK-PAIN; CHRONIC MUSCULOSKELETAL PAIN; BED REST; RECEPTOR GENE; ADRENERGIC-RECEPTOR; FEAR-AVOIDANCE; LUMBAR SPINE; POLYMORPHISM; ASSOCIATION; MODEL AB Background: Because excessive reduction in activities after back injury may impair recovery, it is important to understand and address the factors contributing to the variability in motor responses to pain. The current dominant theory is the "fear-avoidance model", in which the some patients' heightened fears of further injury cause them to avoid movement. We propose that in addition to psychological factors, neurochemical variants in the circuits controlling movement and their modification by pain may contribute to this variability. A systematic search of the motor research literature and genetic databases yielded a prioritized list of polymorphic motor control candidate genes. We demonstrate an analytic method that we applied to 14 of these genes in 290 patients with acute sciatica, whose reduction in movement was estimated by items from the Roland-Morris Disability Questionnaire. Results: We genotyped a total of 121 single nucleotide polymorphisms (SNPs) in 14 of these genes, which code for the dopamine D2 receptor, GTP cyclohydrolase I, glycine receptor alpha 1 subunit, GABA-A receptor alpha 2 subunit, GABA-A receptor beta 1 subunit, alpha-adrenergic 1C, 2A, and 2C receptors, serotonin 1A and 2A receptors, cannabinoid CB-1 receptor, M1 muscarinic receptor, and the tyrosine hydroxylase, and tachykinin precursor-1 molecules. No SNP showed a significant association with the movement score after a Bonferroni correction for the 14 genes tested. Haplotype analysis of one of the blocks in the GABA-A receptor beta 1 subunit showed that a haplotype of 11% frequency was associated with less limitation of movement at a nominal significance level value (p = 0.0025) almost strong enough to correct for testing 22 haplotype blocks. Conclusion: If confirmed, the current results may suggest that a common haplotype in the GABA-A beta 1 subunit acts like an "endogenous muscle relaxant" in an individual with subacute sciatica. Similar methods might be applied a larger set of genes in animal models and human laboratory and clinical studies to understand the causes and prevention of pain-related reduction in movement. C1 Natl Inst Dent & Craniofacial Res, Clin Pain Res Sect, Lab Sensory Biol, NIH,DHHS, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, NIH, DHHS, Rockville, MD 20852 USA. Natl Inst Dent & Craniofacial Res, Div Populat & Hlth Promot Sci, NIH, DHHS, Bethesda, MD USA. NINDS, Human Cort Physiol Sect, NIH, DHHS, Rockville, MD USA. Maine Spine & Rehabil, Portland, ME USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Med Serv,Gen Med Div, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Med Serv,Clin Epidemiol Unit, Boston, MA USA. RP Max, MB (reprint author), Natl Inst Dent & Craniofacial Res, Clin Pain Res Sect, Lab Sensory Biol, NIH,DHHS, Bethesda, MD 20892 USA. EM mbikashkumar@hotmail.com; wuti@mail.nih.gov; ibelfer@mail.nih.gov; chodg@mail.nih.gov; cohenl@ninds.nih.gov; kiselycznykc@mail.nih.gov; kingmana@mail.nih.gov; rbkeller@wildblue.net; qyuan@mail.nih.gov; dgneuro@mail.nih.gov; satlas@partners.org; mm77k@nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU AHRQ HHS [HS-06344, HS-08194, HS-09804, R01 HS009804]; Intramural NIH HHS [Z99 AA999999]; NIAAA NIH HHS [Z01 AA000303]; NIDCR NIH HHS [Z01 DE000366] NR 55 TC 7 Z9 7 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD JUL 26 PY 2007 VL 3 AR 20 DI 10.1186/1744-8069-3-20 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 229UA UT WOS:000250829700001 PM 17655760 ER PT J AU Ousman, SS Tomooka, BH van Noort, JM Wawrousek, EF O'Connor, KC Hafler, DA Sobel, RA Robinson, WH Steinman, L AF Ousman, Shalina S. Tomooka, Beren H. van Noort, Johannes M. Wawrousek, Eric F. O'Connor, Kevin C. Hafler, David A. Sobel, Raymond A. Robinson, William H. Steinman, Lawrence TI Protective and therapeutic role for alpha B-crystallin in autoimmune demyelination SO NATURE LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; LENS EPITHELIAL-CELLS; NF-KAPPA-B; MULTIPLE-SCLEROSIS; CANDIDATE AUTOANTIGEN; A-CRYSTALLIN; APOPTOSIS; EXPRESSION; DISEASE; ENCEPHALOMYELITIS AB alpha B-crystallin (CRYAB) is the most abundant gene transcript present in early active multiple sclerosis lesions, whereas such transcripts are absent in normal brain tissue(1). This crystallin has anti-apoptotic(2-7) and neuroprotective(8) functions. CRYAB is the major target of CD4(+) T-cell immunity to the myelin sheath from multiple sclerosis brain(9,10). The pathophysiological implications of this immune response were investigated here. We demonstrate that CRYAB is a potent negative regulator acting as a brake on several inflammatory pathways in both the immune system and central nervous system (CNS). Cryab(-/-) mice showed worse experimental autoimmune encephalomyelitis (EAE) at the acute and progressive phases, with higher Th1 and Th17 cytokine secretion from T cells and macrophages, and more intense CNS inflammation, compared with their wild-type counterparts. Furthermore, Cryab(-/-) astrocytes showed more cleaved caspase-3 and more TUNEL staining, indicating an anti-apoptotic function of Cryab. Antibody to CRYAB was detected in cerebrospinal fluid from multiple sclerosis patients and in sera from mice with EAE. Administration of recombinant CRYAB ameliorated EAE. Thus, the immune response against a negative regulator of inflammation, CRYAB, in multiple sclerosis, would exacerbate inflammation and demyelination. This can be countered by giving CRYAB itself for therapy of ongoing disease. C1 Stanford Univ, Dept Neurol & Neurol Sci, Sch Med, Stanford, CA 94305 USA. Stanford Univ, Div Rheumatol & Immunol, Sch Med, Stanford, CA 94305 USA. Vet Affairs Palo Alto Hlth Care Syst, Lab Serv, Palo Alto, CA 94304 USA. Vet Affairs Palo Alto Hlth Care Syst, GRECC, Palo Alto, CA 94304 USA. TNO Qual Life, Dept Biosci, NL-2301 CE Leiden, Netherlands. NEI, NIH, Bethesda, MD 20892 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. RP Steinman, L (reprint author), Stanford Univ, Dept Neurol & Neurol Sci, Sch Med, Stanford, CA 94305 USA. EM steinman@stanford.edu RI Wawrousek, Eric/A-4547-2008; OI van Noort, Johannes/0000-0002-9060-5921 FU Multiple Sclerosis Society [835] NR 30 TC 283 Z9 293 U1 1 U2 20 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 26 PY 2007 VL 448 IS 7152 BP 474 EP U7 DI 10.1038/nature05935 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 193VG UT WOS:000248302700047 PM 17568699 ER PT J AU Nurieva, R Yang, XXO Martinez, G Zhang, YL Panopoulos, AD Ma, L Schluns, K Tian, Q Watowich, SS Jetten, AM Dong, C AF Nurieva, Roza Yang, Xuexian O. Martinez, Gustavo Zhang, Yongliang Panopoulos, Athanasia D. Ma, Li Schluns, Kimberly Tian, Qiang Watowich, Stephanie S. Jetten, Anton M. Dong, Chen TI Essential autocrine regulation by IL-21 in the generation of inflammatory T cells SO NATURE LA English DT Article ID MYELIN OLIGODENDROCYTE GLYCOPROTEIN; AUTOIMMUNE INFLAMMATION; ROR-GAMMA; TH1 CELLS; DIFFERENTIATION; CYTOKINE; EXPRESSION; LINEAGE; T(H)17; ENCEPHALOMYELITIS AB After activation, CD4(+) helper T (T-H) cells differentiate into distinct effector subsets that are characterized by their unique cytokine expression and immunoregulatory function(1,2). During this differentiation, T(H)1 and T(H)2 cells produce interferon-gamma and interleukin (IL)-4, respectively, as autocrine factors necessary for selective lineage commitment. A distinct T-H subset, termed THIL-17, T(H)17 or inflammatory T-H (T(H)i), has been recently identified as a distinct T-H lineage mediating tissue inflammation(3,4). T(H)17 differentiation is initiated by transforming growth factor-beta and IL-6 (refs 5 - 7) and reinforced by IL-23 ( ref. 8), in which signal transduction and activators of transcription ( STAT) 3 and retinoic acid receptor-related orphan receptor (ROR)-gamma mediate the lineage specification(8-10). T(H)17 cells produce IL-17, IL-17F and IL-22, all of which regulate inflammatory responses by tissue cells but have no importance in T(H)17 differentiation(11-14). Here we show that IL-21 is another cytokine highly expressed by mouse T(H)17 cells. IL-21 is induced by IL-6 in activated T cells, a process that is dependent on STAT3 but not ROR-gamma. IL-21 potently induces T(H)17 differentiation and suppresses Foxp3 expression, which requires STAT3 and ROR-gamma, which is encoded by Rorc. IL-21 deficiency impairs the generation of T(H)17 cells and results in protection against experimental autoimmune encephalomyelitis. IL-21 is therefore an autocrine cytokine that is sufficient and necessary for T(H)17 differentiation, and serves as a target for treating inflammatory diseases. C1 Univ Texas, MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. Inst Syst Engn, Seattle, WA 98103 USA. NIEHS, Cell Biol Sect, LRB, NIH, Res Triangle Pk, NC 27709 USA. RP Nurieva, R (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Immunol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM rnurieva@mdanderson.org; cdong@mdanderson.org RI dong, chen /B-3181-2009; OI dong, chen /0000-0002-0084-9130; Jetten, Anton/0000-0003-0954-4445; Watowich, Stephanie/0000-0003-1969-659X FU Intramural NIH HHS NR 28 TC 912 Z9 983 U1 5 U2 36 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 26 PY 2007 VL 448 IS 7152 BP 480 EP U8 DI 10.1038/nature05969 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 193VG UT WOS:000248302700048 PM 17581589 ER PT J AU Albanes, D AF Albanes, Demetrius TI Antioxidant supplements and mortality SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID CANCER; TRIALS C1 NCI, Div Canc Epiodemiol & Genet, Bethesda, MD 20892 USA. RP Albanes, D (reprint author), NCI, Div Canc Epiodemiol & Genet, Bethesda, MD 20892 USA. EM daa@nih.gov RI Albanes, Demetrius/B-9749-2015 NR 5 TC 3 Z9 3 U1 0 U2 1 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 JUL 25 PY 2007 VL 298 IS 4 BP 400 EP 400 DI 10.1001/jama.298.4.400-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 193JA UT WOS:000248269100012 PM 17652290 ER PT J AU Taylor, PR Dawsey, S AF Taylor, Philip R. Dawsey, Sanford TI Antioxidant supplements and mortality SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID NUTRITION INTERVENTION TRIALS; DISEASE-SPECIFIC MORTALITY; CANCER INCIDENCE; BETA-CAROTENE; LUNG-CANCER; VITAMIN; LINXIAN; CHINA C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Taylor, PR (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM ptaylor@mail.nih.gov NR 5 TC 2 Z9 4 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 JUL 25 PY 2007 VL 298 IS 4 BP 401 EP 402 DI 10.1001/jama.298.4.401-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 193JA UT WOS:000248269100015 PM 17652291 ER PT J AU Burton, RA Tsurupa, G Hantgan, RR Tjandra, N Medved, L AF Burton, Robert A. Tsurupa, Galina Hantgan, Roy R. Tjandra, Nico Medved, Leonid TI NMR solution structure, stability, and interaction of the recombinant bovine fibrinogen alpha C-domain fragment SO BIOCHEMISTRY LA English DT Article ID HEREDITARY RENAL AMYLOIDOSIS; SEDIMENTATION-VELOCITY DATA; CRYSTAL-STRUCTURE; AMINO-ACIDS; ELECTRON-MICROSCOPY; FACTOR-XIII; OLIGOMERIZATION; CHAIN; SITES; IDENTIFICATION AB According to the existing hypothesis, in fibrinogen, the COOH-terminal portions of two AR chains are folded into compact RC-domains that interact intramolecularly with each other and with the central region of the molecule; in fibrin, the alpha C-domains switch to an intermolecular interaction resulting in RC-polymers. In agreement, our recent NMR study identified within the bovine fibrinogen A alpha 374-538 alpha C-domain fragment an ordered compact structure including a,beta-hairpin restricted at the base by a 423-453 disulfide linkage. To establish the complete structure of the RC-domain and to further test the hypothesis, we expressed a shorter RC-fragment, AR406-483, and performed detailed analysis of its structure, stability, and interactions. NMR experiments on the AR406-483 fragment identified a second loose, beta-hairpin formed by residues 459-476, yielding a structure consisting of an intrinsically unstable mixed parallel/antiparallel, beta-sheet. Size-exclusion chromatography and sedimentation velocity experiments revealed that the AR406-483 fragment forms soluble oligomers whose fraction increases with an increase in concentration. This was confirmed by sedimentation equilibrium analysis, which also revealed that the addition of each monomer to an assembling alpha C-oligomer substantially increases its stabilizing free energy. In agreement, unfolding experiments monitored by CD established that oligomerization of AR406-483 results in increased thermal stability. Altogether, these experiments establish the complete NMR solution structure of the AR406- 483 beta C-domain fragment, provide direct evidence for the intra-and intermolecular interactions between the beta C-domains, and confirm that these interactions are thermodynamically driven. C1 NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. Wake Forest Univ, Sch Med, Dept Biochem, Winston Salem, NC 27157 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, 50 Ctr Dr, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [HL-56051, R01 HL056051, R01 HL056051-08] NR 58 TC 26 Z9 29 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 24 PY 2007 VL 46 IS 29 BP 8550 EP 8560 DI 10.1021/bi700606v PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 190QE UT WOS:000248073200006 PM 17590019 ER PT J AU Wu, QQ Blakeley, LR Cornwall, MC Crouch, RK Wiggert, BN Koutalos, Y AF Wu, Qingqing Blakeley, Lorie R. Cornwall, M. Carter Crouch, Rosalie K. Wiggert, Barbara N. Koutalos, Yiannis TI Interphotoreceptor retinoid-binding protein is the physiologically relevant carrier that removes retinol from rod photoreceptor outer segments SO BIOCHEMISTRY LA English DT Article ID ALL-TRANS-RETINOL; VISUAL PIGMENT REGENERATION; VERTEBRATE PHOTORECEPTORS; METARHODOPSIN-III; SERUM-ALBUMIN; KNOCKOUT MICE; RHODOPSIN; CYCLE; IRBP; RPE65 AB Light detection by vertebrate rod photoreceptor outer segments results in the destruction of the visual pigment, rhodopsin, as its retinyl moiety is photoisomerized from 11-cis to all-trans. The regeneration of rhodopsin is necessary for vision and begins with the release of the all-trans retinal and its reduction to all-trans retinol. Retinol is then transported out of the rod outer segment for further processing. We used fluorescence imaging to monitor retinol fluorescence and quantify the kinetics of its formation and clearance after rhodopsin bleaching in the outer segments of living isolated frog (Rana pipiens) rod photoreceptors. We independently measured the release of all-trans retinal from bleached rhodopsin in frog rod outer segment membranes and the rate of all-trans retinol removal by the lipophilic carriers interphotoreceptor retinoid binding protein (IRBP) and serum albumin. We find that the kinetics of all-trans retinol formation in frog rod outer segments after rhodopsin bleaching are to a good first approximation determined by the kinetics of all-trans retinal release from the bleached pigment. For the physiological concentrations of carriers, the rate of retinol removal from the outer segment is determined by IRBP concentration, whereas the effect of serum albumin is negligible. The results indicate the presence of a specific interaction between IRBP and the rod outer segment, probably mediated by a receptor. The effect of different concentrations of IRBP on the rate of retinol removal shows no cooperativity and has an EC50 of 40 mu mol/L. C1 Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29425 USA. Sun Yat Sen Univ, Dept Nephrol, Affiliated Hosp 1, Guangzhou, Peoples R China. Boston Univ, Sch Med, Dept Physiol & Biophys, Boston, MA 02215 USA. NEI, Retinal Cell & Mol Biol Lab, Bethesda, MD 20892 USA. RP Koutalos, Y (reprint author), Med Univ S Carolina, Dept Ophthalmol, 171 Ashley Ave, Charleston, SC 29425 USA. EM koutalo@musc.edu OI Cornwall, M./0000-0002-0847-939X FU Intramural NIH HHS; NEI NIH HHS [EY14850, EY01157, EY04939, EY14793, R01 EY001157, R01 EY001157-34, R01 EY004939, R01 EY004939-25, R01 EY014850, R01 EY014850-03, R24 EY014793, Z01 EY000070] NR 64 TC 36 Z9 36 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 24 PY 2007 VL 46 IS 29 BP 8669 EP 8679 DI 10.1021/bi7004619 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 190QE UT WOS:000248073200017 PM 17602665 ER PT J AU Ingelsson, E Sullivan, LM Fox, CS Murabito, JM Benjamin, EJ Polak, JF Meigs, JB Keyes, MJ O'Donnell, CJ Wang, TJ D'Agostino, RB Wolf, PA Vasan, RS AF Ingelsson, Erik Sullivan, Lisa M. Fox, Caroline S. Murabito, Joanne M. Benjamin, Emelia J. Polak, Joseph F. Meigs, James B. Keyes, Michelle J. O'Donnell, Christopher J. Wang, Thomas J. D'Agostino, Ralph B. Wolf, Philip A. Vasan, Ramachandran S. TI Burden and prognostic importance of subclinical cardiovascular disease in overweight and obese individuals SO CIRCULATION LA English DT Article DE atherosclerosis; cardiovascular diseases; epidemiology; obesity; risk factors ID LEFT-VENTRICULAR HYPERTROPHY; CORONARY-HEART-DISEASE; BODY-MASS INDEX; BLOOD-PRESSURE; PLASMA HOMOCYSTEINE; RISK-FACTORS; ATHEROSCLEROSIS; ADULTS; ASSOCIATION; PREVALENCE AB Background - The burden and prognostic importance of subclinical cardiovascular disease (CVD) in obesity has not been investigated systematically. Methods and Results - We examined prevalence of subclinical disease in 1938 Framingham Study participants (mean age, 57 years; 59% women) by use of 5 tests (electrocardiography, echocardiography, carotid ultrasound, ankle-brachial pressure, and urinary albumin excretion) and stratified by body mass index (BMI) ( normal, < 25; overweight, 25 to < 30.0; obese, >= 30 kg/m(2)) and waist circumference (WC) ( increased, >= 88 cm for women or >= 102 cm for men). We investigated risk of overt CVD associated with adiposity according to presence versus absence of subclinical disease on any of the 5 tests. Prevalence of subclinical disease was higher in overweight (40.0%; adjusted odds ratio, 1.68) and obese individuals (49.7%; odds ratio, 2.82) compared with individuals with normal BMI (29.3%) and in individuals with increased WC (44.9%; odds ratio, 1.67) compared with normal WC (31.9%). On follow-up (mean 7.2 years), 139 participants had developed overt CVD. Presence of subclinical disease was associated with > 2-fold risk of overt CVD in all BMI and WC strata, with no evidence of an interaction between BMI and subclinical disease. CVD risk was attenuated in participants with obesity or increased WC but without subclinical disease ( adjusted hazard ratio for obesity, 1.57; 95% confidence interval, 0.74 to 3.33; adjusted hazard ratio for increased WC, 1.22; 95% confidence interval, 0.69 to 2.15), compared with individuals with normal BMI or WC and no subclinical disease, respectively. Conclusions - In our community-based sample, overweight and obesity were associated with high prevalence of subclinical disease, which partly contributed to the increased risk of overt CVD in these strata. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Boston Univ, Dept Biostat, Boston, MA 02215 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. Boston Univ, Sch Med, Div Cardiol, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. Tufts Univ New England Med Ctr, Dept Radiol, Boston, MA 02111 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. NHLBI, Bethesda, MD 20892 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM vasan@bu.edu OI Murabito, Joanne/0000-0002-0192-7516; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Sullivan, Lisa/0000-0003-0726-7149 FU NHLBI NIH HHS [1R01HL080124, 2K24HL04334, K23-HL074077-01, N01-HC-25195] NR 34 TC 34 Z9 41 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 24 PY 2007 VL 116 IS 4 BP 375 EP 384 DI 10.1161/CIRCULATIONAHA.107.688788 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 193AA UT WOS:000248244300004 PM 17620505 ER PT J AU Sachdev, V Machado, RF Blackwelder, WC Kato, GJ Gladwin, MT AF Sachdev, Vandana Machado, Roberto F. Blackwelder, William C. Kato, Gregory J. Gladwin, Mark T. TI Diastolic dysfunction is an independent risk factor for death in patients with sickle cell disease - Reply SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter ID IRON OVERLOAD; THALASSEMIA C1 NHLBI, Natl Inst Hlth, Div Intramural Res, Bethesda, MD 20892 USA. RP Sachdev, V (reprint author), NHLBI, Natl Inst Hlth, Div Intramural Res, 10 Ctr Dr, Bethesda, MD 20892 USA. EM sachdevv@nhlbi.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 5 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 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD JUL 24 PY 2007 VL 50 IS 4 BP 378 EP 379 DI 10.1016/j.jacc.2007.04.039 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 193CR UT WOS:000248251800014 ER PT J AU Wang, DW Jao, LE Zheng, NZ Dolan, K Ivey, J Zonles, S Wu, XL Wu, KM Yang, HB Meng, QC Zhu, ZY Zhang, B Lin, S Burgess, SM AF Wang, Dongmei Jao, Li-En Zheng, Naizhong Dolan, Kyle Ivey, Jessica Zonles, Seth Wul, Xiaolin Wu, Kangmai Yang, Hongbo Meng, Qingchao Zhu, Zuoyan Zhang, Bo Lin, Shuo Burgess, Shawn M. TI Efficient genome-wide mutagenesis of zebrafish genes by retroviral insertions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genetics; retrovirus ID GERM-LINE TRANSMISSION; FUNCTIONAL GENOMICS; POSITIONAL CLONING; CELL-LINES; HIGH-TITER; VECTOR; INTEGRATION; MUTATIONS; MOUSE AB Using a combination of techniques we developed, we infected zebrafish embryos using pseuclotyped retroviruses and mapped the genomic locations of the proviral integrations in the F, offspring of the infected fish. From F, fish, we obtained 2,045 sequences representing 933 unique retroviral integrations. A total of 599 were mappable to the current genomic assembly (Zv6), and 233 of the integrations landed within genes. By inbreeding fish carrying proviral integrations in 25 different genes, we were able to demonstrate that in approximate to 50% of the gene "hits," the mRNA transcript levels were reduced by >= 70%, with the highest probability for mutation occurring if the integration was in an exon or first intron. Based on these data, the mutagenic frequency for the retrovirus is nearly one in five integrations. In addition, a strong mutagenic effect is seen when murine leukemia virus integrates specifically in the first intron of genes but not in other introns. Three of 19 gene inactivation events had embryonic defects. Using the strategy we outlined, it is possible to identify 1 mutagenic event for every 30 sequencing reactions done on the F, fish. This is a 20- to 30-fold increase in efficiency when compared with the current resequencing approach [targeting induced local lesions in genomes (TILLING)] used in zebrafish for identifying mutations in genes. Combining this increase in efficiency with cryopreservation of sperm samples from the F, fish, it is now possible to create a stable resource that contains mutations in every known zebrafish gene. C1 Peking Univ, Key Lab Cell Proliferat & Differentiat, Ctr Dev Biol & Genet, Coll Life Sci,Minist Educ, Beijing 100871, Peoples R China. NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. NCI, Lab Mol Technol, SAIC, Frederick, MD 21701 USA. Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90095 USA. RP Zhang, B (reprint author), Peking Univ, Key Lab Cell Proliferat & Differentiat, Ctr Dev Biol & Genet, Coll Life Sci,Minist Educ, Beijing 100871, Peoples R China. EM bzhang@pku.edu.cn; shuolin@ucla.edu; burgess@mail.nih.gov RI Zhang, Bo/K-7162-2012; OI Burgess, Shawn/0000-0003-1147-0596 FU Intramural NIH HHS; NCRR NIH HHS [R01 RR013227, R24 RR013227, RR13227] NR 25 TC 70 Z9 78 U1 0 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 JUL 24 PY 2007 VL 104 IS 30 BP 12428 EP 12433 DI 10.1073/pnas.0705502104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 196HK UT WOS:000248472100036 PM 17640903 ER PT J AU Marutle, A Ohmitsu, M Nilbratt, M Greig, NH Nordberg, A Sugaya, K AF Marutle, Amelia Ohmitsu, Masao Nilbratt, Mats Greig, Nigel H. Nordberg, Agneta Sugaya, Kiminobu TI Modulation of human neural stem cell differentiation in Alzheimer (APP23) transgenic mice by phenserine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE amyloid precursor protein; transplantation; immunohistochernistry; neurogenesis; Alzheimer's disease ID AMYLOID PRECURSOR PROTEIN; PROGENITOR CELLS; BETA-PEPTIDE; EXPRESSION PATTERN; MESSENGER-RNA; RAT-BRAIN; IN-VITRO; DISEASE; NEUROGENESIS; PHOSPHORYLATION AB In a previous study, we found that human neural stem cells (HNSCs) exposed to high concentrations of secreted amyloid-precursor protein (sAPP) in vitro differentiated into mainly astrocytes, suggesting that pathological alterations in APP processing during neurodegenerative conditions such as Alzheimer's disease (AD) may prevent neuronal differentiation of HNSCs. Thus, successful neuroplacement therapy for AD may require regulating APP expression to favorable levels to enhance neuronal differentiation of HNSCs. Phenserine, a recently developed cholinesterase inhibitor (ChEI), has been reported to reduce APP levels in vitro and in vivo. In this study, we found reductions of APP and glial fibrillary acidic protein (GFAP) levels in the hippocampus of APP23 mice after 14 days treatment with (+)-phenserine (25 mg/kg) lacking ChEI activity. No significant change in APP gene expression was detected, suggesting that (+)-phenserine decreases APP levels and reactive astrocytes by posttranscription regulation. HNSCs transplanted into (+)-phenserine-treated APP23 mice followed by an additional 7 days of treatment with (+)-phenserine migrated and differentiated into neurons in the hippocampus and cortex after 6 weeks. Moreover, (+)-phenserine significantly increased neuronal differentiation of implanted HNSCs in hippocampal and cortical regions of APP23 mice and in the CA1 region of control mice. These results indicate that (+)-phenserine reduces APP protein in vivo and increases neuronal differentiation of HNSCs. Combination use of HNSC transplantation and treatment with drugs such as (+)phenserine that modulate APP levels in the brain may be a useful tool for understanding mechanisms regulating stem cell migration and differentiation during neurodegenerative conditions in AD. C1 Karolinska Univ Hosp Huddinge, Div Alzheimer Neurobiol, Dept Neurobiol Care Sci & Soc, Karolinska Inst, S-14186 Huddinge, Sweden. NIA, Sect Drug Design & Delivery, Lab Neurosci, NIH, Baltimore, MD 21224 USA. Univ Cent Florida, Biomol Sci Ctr, Burnett Coll Biomed Sci, Orlando, FL 32816 USA. RP Marutle, A (reprint author), Karolinska Univ Hosp Huddinge, Div Alzheimer Neurobiol, Dept Neurobiol Care Sci & Soc, Karolinska Inst, S-14186 Huddinge, Sweden. EM amelia.marutle@ki.se FU NIA NIH HHS [R01 AG023472, AG 23472] NR 48 TC 51 Z9 65 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 JUL 24 PY 2007 VL 104 IS 30 BP 12506 EP 12511 DI 10.1073/pnas.0705346104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 196HK UT WOS:000248472100050 PM 17640880 ER PT J AU Tan, HY Chen, Q Sust, S Buckholtz, JW Meyers, JD Egan, MF Mattay, VS Meyer-Lindenberg, A Weinberger, DR Callicott, JH AF Tan, Hao-Yang Chen, Qiang Sust, Steven Buckholtz, Joshua W. Meyers, John D. Egan, Michael F. Mattay, Venkata S. Meyer-Lindenberg, Andreas Weinberger, Daniel R. Callicott, Joseph H. TI Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dopamine; functional MRI; genetics; schizophrenia ID DORSOLATERAL PREFRONTAL CORTEX; GLUTAMATE-RECEPTOR AGONIST; CORTICAL PYRAMIDAL NEURONS; EVENT-RELATED FMRI; DOPAMINE MODULATION; PERSISTENT ACTIVITY; COMT GENOTYPE; SCHIZOPHRENIA; COGNITION; ATTENTION AB Dopaminergic and glutamatergic systems are critical components responsible for prefrontal signal-to-noise tuning in working memory. Recent functional MRI (fMRl) studies of genetic variation in these systems in catechol-O-methyltransferase (COMT) and in metabotropic glutamate receptor mgluR3 (GRM3), respectively, suggest that these genes influence prefrontal physiological signal-to-noise in humans. Here, using fMRI, we extend these individual gene findings to examine the combined effects of COMT and GRM3 on dissociable components of the frontoparietal working memory network. We observed an apparent epistatic interaction of these two genes on the engagement of prefrontal cortex during working memory. Specifically, the GRM3 genotype putatively associated with suboptimal glutamatergic signaling was significantly associated with inefficient prefrontal engagement and altered prefrontal-parietal coupling on the background of COMT Val-homozygous genotype. Conversely, COMT Met-homozygous background mediated against the effect of GRM3 genotype. These findings extend putative brain dopaminergic and glutamatergic relationships indexed by COMT and GRM3 to a systems-level interaction in human cortical circuits implicated in working memory dysfunction such as in schizophrenia. C1 NIMH, Inramural Res Program, NIH, Genes Cognit & Psyosis Program,Clin Brain Disorde, Bethesda, MD 20892 USA. RP Callicott, JH (reprint author), Bldg 10,Ctr Dr,Room 4C-216,MSC 1364, Bethesda, MD 20892 USA. EM callicottj@mail.nih.gov RI Buckholtz, Joshua /E-7299-2010; Callicott, Joseph/C-9102-2009; Meyer-Lindenberg, Andreas/H-1076-2011 OI Buckholtz, Joshua /0000-0002-9418-8686; Callicott, Joseph/0000-0003-1298-3334; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU Intramural NIH HHS NR 67 TC 125 Z9 128 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 24 PY 2007 VL 104 IS 30 BP 12536 EP 12541 DI 10.1073/pnas.0610125104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 196HK UT WOS:000248472100055 PM 17636131 ER PT J AU Skupsky, R McCann, C Nossal, R Losert, W AF Skupsky, Ron McCann, Colin Nossal, Ralph Losert, Wolfgang TI Bias in the gradient-sensing response of chemotactic cells SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE gradient-sensing; chemotaxis; phosphoinositides; linear stability theory ID EUKARYOTIC CHEMOTAXIS; DICTYOSTELIUM-DISCOIDEUM; PATTERN-FORMATION; POLYMORPHONUCLEAR LEUKOCYTES; CHEMICAL GRADIENTS; SIGNALING EVENTS; STOCHASTIC-MODEL; ARP2/3 COMPLEX; LIVING CELLS; BETA-GAMMA AB We apply linear stability theory and perform perturbation studies to better characterize, and to generate new experimental predictions from, a model of chemotactic gradient sensing in eukaryotic cells. The model uses reaction-diffusion equations to describe 3 ' phosphoinositide signaling and its regulation at the plasma membrane. It demonstrates a range of possible gradient-sensing mechanisms and captures such characteristic behaviors as strong polarization in response to static gradients, adaptation to differing mean levels of stimulus, and plasticity in response to changing gradients. An analysis of the stability of polarized steady-state solutions indicates that the model is most sensitive to off-axis perturbations. This biased sensitivity is also reflected in responses to localized external stimuli, and leads to a clear experimental prediction, namely, that a cell which is polarized in a background gradient will be most sensitive to transient point-source stimuli lying within a range of angles that are oblique with respect to the polarization axis. Stimuli at angles below this range will elicit responses whose directions overshoot the stimulus angle, while responses to stimuli applied at larger angles will undershoot the stimulus angle. We argue that such a bias is likely to be a general feature of gradient sensing in highly motile cells, particularly if they are optimized to respond to small gradients. Finally, an angular bias in gradient sensing might lead to preferred turn angles and zigzag movements of cells moving up chemotactic gradients, as has been noted under certain experimental conditions. (C) 2007 Elsevier Ltd. All rights reserved. C1 Univ Maryland, Dept Phys, College Pk, MD 20742 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Losert, W (reprint author), Univ Maryland, Dept Phys, College Pk, MD 20742 USA. EM wlosert@umd.edu FU Intramural NIH HHS [Z01 HD008841-01] NR 58 TC 6 Z9 6 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 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD JUL 21 PY 2007 VL 247 IS 2 BP 242 EP 258 DI 10.1016/j.jtbi.2007.02.016 PG 17 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 186SG UT WOS:000247797900003 PM 17462672 ER PT J AU Hibbeln, JR Davis, JM Steer, C Emmet, P Golding, J AF Hibbeln, Joseph R. Davis, John M. Steer, Colin Emmet, Pauline Golding, Jean TI Maternal seafood consumption and children's development - Reply SO LANCET LA English DT Letter ID METHYLMERCURY C1 NIAAA, Bethesda, MD 20952 USA. RP Hibbeln, JR (reprint author), NIAAA, 31 Ctr Dr,Rm 31-1B58,MSC 2088, Bethesda, MD 20952 USA. EM jihbbeln@mail.nih.gov NR 5 TC 1 Z9 1 U1 2 U2 3 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 21 PY 2007 VL 370 IS 9583 BP 218 EP 218 DI 10.1016/S0140-6736(07)61118-0 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 194MG UT WOS:000248347900020 ER PT J AU Shin, SH Murray, GJ Kluepfel-Stahl, S Cooney, AM Quirk, JM Schiffmann, R Brady, RO Kaneski, CR AF Shin, Sang-Hoon Murray, Gary J. Kluepfel-Stahl, Stefanie Cooney, Adele M. Quirk, Jane M. Schiffmann, Raphael Brady, Roscoe O. Kaneski, Christine R. TI Screening for pharmacological chaperones in Fabry disease SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE lysosomal storage disorder; chaperone therapy; lysosomal enzyme; Fabry disease ID ALPHA-GALACTOSIDASE; ENZYME REPLACEMENT; THERAPY; STORAGE; DEFECT AB As a prerequisite for clinical trials of pharmacological chaperone therapy (PCT) for Fabry disease, we developed a rapid screening assay for enhancement of endogenous, alpha-galactosidase A (alpha-Gal A) in patient-derived cells. We used a T-cell based system to screen 11 mutations causing Fabry disease for enhanceability using 1-deoxygalactonojirimycin (DGJ). When patient-derived T-cells were grown in the presence of DGJ, alpha-Gal A activity increased to more than 50%, of normal in several mutations but was unaffected in others. In addition to the mutation R301Q, reported previously, A97V, R112H, R112C, A143T, and L300P were enhanceable, but R356W, G132R, A143P, R220X, and 30delG were not. The level of alpha-Gal A activity achieved provides a basis for the therapeutic trial of DGJ in patients with similarly enhanceable enzyme. This assay method has general utility in other disorders in assessing the degree of enhancement of activity of mutated proteins by PCT. Published by Elsevier Inc. C1 Natl Inst Neurol Disorders & Stroke, NIH, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. RP Murray, GJ (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Dev & Metab Neurol Branch, 10 Ctr Dr, Bldg 10, Bethesda, MD 20892 USA. EM murrayg@ninds.nih.gov OI Kaneski, Christine/0000-0003-1453-2502 FU Intramural NIH HHS [Z01 NS002982-09] NR 21 TC 30 Z9 31 U1 0 U2 1 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 JUL 20 PY 2007 VL 359 IS 1 BP 168 EP 173 DI 10.1016/j.bbrc.2007.05.082 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 178YZ UT WOS:000247257600027 PM 17532296 ER PT J AU Remaley, AT AF Remaley, Alan T. TI Old drug, new tricks - The unexpected effect of doxazosin on high-density lipoprotein SO CIRCULATION RESEARCH LA English DT Editorial Material DE cholesterol; atherosclerosis; HDL; doxazosin; ABCA1 ID ANTIHYPERTENSIVE DRUG; HYPERTENSIVE PATIENTS; CHOLESTEROL; EXPRESSION; TRIAL; ABCA1; BIOGENESIS; INCREASES; DISEASE; BINDING C1 NHLBI, NIH, Vasc Med Branch, Lipoprot Metab Sect, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NHLBI, NIH, Vasc Med Branch, Lipoprot Metab Sect, 10 Ctr Dr,Bldg 10,Rm 2C-433, Bethesda, MD 20892 USA. EM aremaley@nih.gov NR 27 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 20 PY 2007 VL 101 IS 2 BP 116 EP 118 DI 10.1161/CIRCRESAHA.107.157404 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 192BO UT WOS:000248175900003 PM 17641233 ER PT J AU Um, JH Yang, ST Yamazaki, S Kang, H Viollet, B Foretz, M Chung, JH AF Um, Jee Hyun Yang, Shutong Yamazaki, Shin Kang, Hyeog Viollet, Benoit Foretz, Marc Chung, Jay H. TI Activation of 5 '-AMP-activated kinase with diabetes drug metformin induces casein kinase I epsilon (CKI epsilon)-dependent degradation of clock protein mPer2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CIRCADIAN GENE-EXPRESSION; PHOSPHORYLATION; FIBROBLASTS; MAMMALS; FAMILY; LIVER; MICE; TAU; CKI AB Metformin is one of the most commonly used first line drugs for type II diabetes. Metformin lowers serum glucose levels by activating 5'-AMP-activated kinase (AMPK), which maintains energy homeostasis by directly sensing the AMP/ATP ratio. AMPK plays a central role in food intake and energy metabolism through its activities in central nervous system and peripheral tissues. Since food intake and energy metabolism is synchronized to the light-dark (LD) cycle of the environment, we investigated the possibility that AMPK may affect circadian rhythm. We discovered that the circadian period of Rat-1 fibroblasts treated with metformin was shortened by 1 h. One of the regulators of the period length is casein kinase I epsilon (CKI epsilon), which by phosphorylating and inducing the degradation of the circadian clock component, mPer2, shortens the period length. AMPK phosphorylates Ser-389 of CKI epsilon, resulting in increased CKI epsilon activity and degradation of mPer2. In peripheral tissues, injection of metformin leads to mPer2 degradation and a phase advance in the circadian expression pattern of clock genes in wild-type mice but not in AMPK alpha 2 knock-out mice. We conclude that metformin and AMPK have a previously unrecognized role in regulating the circadian rhythm. C1 NHLBI, Natl Inst Hlth, Lab Biochem Genet, Bethesda, MD 20892 USA. Vanderbilt Univ, Dept Biol Sci, Nashville, TN 37235 USA. Inst Cochin, Dept Endocrinol Metab & Canc, F-75014 Paris, France. INSERM, U567, F-75014 Paris, France. CNRS, UMR 8104, F-75014 Paris, France. Univ Paris 05, Fac Med Rene Descartes, UM 3, F-75014 Paris, France. Univ Paris 05, Inst Cochin, CNRS, UMR 8104, F-75014 Paris, France. RP Chung, JH (reprint author), NHLBI, Natl Inst Hlth, Lab Biochem Genet, Bldg 10,Rm 7D14,10 Ctr Dr, Bethesda, MD 20892 USA. EM chungj@nhlbi.nih.gov FU Intramural NIH HHS NR 27 TC 89 Z9 90 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 JUL 20 PY 2007 VL 282 IS 29 BP 20794 EP 20798 DI 10.1074/jbc.C700070200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 190GP UT WOS:000248047500003 PM 17525164 ER PT J AU Free, RB Hazelwood, LA Cabrera, DM Spalding, HN Namkung, Y Rankin, ML Sibley, DR AF Free, R. Benjamin Hazelwood, Lisa A. Cabrera, David M. Spalding, Heather N. Namkung, Yoon Rankin, Michele L. Sibley, David R. TI D-1 and D-2 dopamine receptor expression is regulated by direct interaction with the chaperone protein calnexin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-SURFACE EXPRESSION; N-LINKED GLYCOSYLATION; ENDOPLASMIC-RETICULUM; QUALITY-CONTROL; COUPLED RECEPTORS; DRUG DISCOVERY; ASSOCIATION; TRAFFICKING; DESENSITIZATION; D1 AB As for all proteins, G protein-coupled receptors (GPCRs) undergo synthesis and maturation within the endoplasmic reticulum (ER). The mechanisms involved in the biogenesis and trafficking of GPCRs from the ER to the cell surface are poorly understood, but they may involve interactions with other proteins. We have now identified the ER chaperone protein calnexin as an interacting protein for both D-1 and D-2 dopamine receptors. These protein-protein interactions were confirmed using Western blot analysis and co-immunoprecipitation experiments. To determine the influence of calnexin on receptor expression, we conducted assays in HEK293T cells using a variety of calnexin-modifying conditions. Inhibition of glycosylation either through receptor mutations or treatments with glycosylation inhibitors partially blocks the interactions with calnexin with a resulting decrease in cell surface receptor expression. Confocal fluorescence microscopy reveals the accumulation of D-1-green fluorescent protein and D-2-yellow fluorescent protein receptors within internal stores following treatment with calnexin inhibitors. Overexpression of calnexin also results in a marked decrease in both D-1 and D-2 receptor expression. This is likely because of an increase in ER retention because confocal microscopy revealed intracellular clustering of dopamine receptors that were co-localized with an ER marker protein. Additionally, we show that calnexin interacts with the receptors via two distinct mechanisms, glycan-dependent and glycan-independent, which may underlie the multiple effects (ER retention and surface trafficking) of calnexin on receptor expression. Our data suggest that optimal receptor-calnexin interactions critically regulate D-1 and D-2 receptor trafficking and expression at the cell surface, a mechanism likely to be of importance for many GPCRs. C1 NINDS, Mol Neuropharmacol Sect, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Sibley, DR (reprint author), NINDS, Mol Neuropharmacol Sect, Natl Inst Hlth, 5625 Fishers Ln,Rm 4S-04,MSC 9405, Bethesda, MD 20892 USA. EM sibley@helix.nih.gov RI Cabrera, David/I-1013-2014 FU Intramural NIH HHS NR 48 TC 51 Z9 51 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 JUL 20 PY 2007 VL 282 IS 29 BP 21285 EP 21300 DI 10.1074/jbc.M701555200 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 190GP UT WOS:000248047500057 PM 17395585 ER PT J AU Shoji, A Yanagida, A Shindo, H Ito, Y Shibusawa, Y AF Shoji, Atsushi Yanagida, Akio Shindo, Heisaburo Ito, Yoichiro Shibusawa, Yoichi TI Counter-current chromatographic estimation of hydrophobicity of Z-(cis) and E-(trans) enalapril and kinetics of cis/trans isomerization SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE enalapril; cis/trans isomerizatiom; high-speed counter-current chromatography; log P-O/W ID CIS-TRANS ISOMERIZATION; NUCLEAR-MAGNETIC-RESONANCE; MICROEMULSION ELECTROKINETIC CHROMATOGRAPHY; PERFORMANCE LIQUID-CHROMATOGRAPHY; WATER PARTITION-COEFFICIENTS; CONVERTING ENZYME-INHIBITORS; CAPILLARY-ELECTROPHORESIS; SEPARATION; PROLINE; OLIGOPEPTIDES AB The kinetics of Z-(cis)/E-(trans) isomerization of enalapril was investigated by reversed phase high-performance liquid chromatography (RP-HPLC) using a monolith ODS column under a series of different temperature and pH conditions. At a neutral pH 7, the rate (k(obs)) of Z-(cis)/E-(trans) isomerization of enalapril at 4 degrees C (9.4 x 10(-3) min(-1)) is much lower than at 23 degrees C (1.8 x 10(-1) min(-1)), while the fractional concentration of Z-(cis) isomer is always higher than that of E-(trans) isomer in the pH range 2-7. The fractional concentration of the E-(trans) isomer becomes a maximum (about 40%) in the pH range 3-6, where enalapril exists as a zwitterion. The hydrophobicity (log P-O/W) of both isomers was estimated by highspeed counter-current chromatography (HSCCC). Normal phase HSCCC separation using a tert-butyl methyl ether-acetonitrile-20 mM potassium phosphate buffer (pH 5) two-phase solvent system (2:2:3, v/v/v) at 4 degrees C was effective in partially separating the isomers, and the partition coefficient (K) of each isomer was directly calculated from the retention volume (V-R). The log P-O/W values of Z-(cis) and E-(trans) isomers were -0.46 and -0.65, respectively. (c) 2007 Elsevier B.V. All rights reserved. C1 Tokyo Univ Pharm & Life Sci, Sch Pharm, Div Struct Biol & Anal Sci, Tokyo 1920392, Japan. NIH, NHLBI, Ctr Biochem & Biophys, Bethesda, MD 20892 USA. RP Shibusawa, Y (reprint author), Tokyo Univ Pharm & Life Sci, Sch Pharm, Div Struct Biol & Anal Sci, 1432-1 Horinouchi,Hachioji, Tokyo 1920392, Japan. EM sibusawa@ps.toyaku.ac.jp NR 34 TC 11 Z9 11 U1 0 U2 8 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 JUL 20 PY 2007 VL 1157 IS 1-2 BP 101 EP 107 DI 10.1016/j.chroma.2007.04.027 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 191CK UT WOS:000248107200014 PM 17467722 ER PT J AU Thompson, IM Ankerst, DP Chi, C Goodman, PJ Tangen, CM Lippman, SM Lucia, MS Parnes, HL Coltman, CA AF Thompson, Ian M. Ankerst, Donna Pauler Chi, Chen Goodman, Phyllis J. Tangen, Catherine M. Lippman, Scott M. Lucia, M. Scott Parnes, Howard L. Coltman, Charles A., Jr. TI Prediction of prostate cancer for patients receiving finasteride: Results from the prostate cancer prevention trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RISK; ANTIGEN; MEN; LEVEL; PSA AB Purpose Using data from men in the finasteride group of the Prostate Cancer Prevention Trial ( PCPT), we evaluated the impact of prostate-specific antigen ( PSA) and other risk factors on the risk of prostate cancer. Methods Four thousand four hundred forty men in the finasteride group of the PCPT underwent prostate biopsy, had at least one PSA and a digital rectal exam ( DRE) during the year before biopsy, had at least two PSA values from the 3 years before biopsy, and were on finasteride at the time of PSA evaluation. Logistic regression was conducted using the variables age, race, family history of prostate cancer, PSA, PSA velocity, and DRE adjusting for history of prior prostate biopsy. Results Six hundred forty-nine ( 14.6%) of 4,440 men were diagnosed with prostate cancer; 250 had Gleason 7 or higher cancer. Factors associated with an increased risk of prostate cancer included high PSA value and a rising PSA ( 24.9% risk for PSA value of 1.0 ng/mL and 24.8% risk for a rising PSA), family history of prostate cancer, abnormal DRE result, African American race, and older age. Factors associated with an increased risk of Gleason 7 or higher grade prostate cancer included PSA, abnormal DRE, and older age. A prior negative biopsy was associated with decreased risk of prostate cancer and high-grade prostate cancer. Conclusion Risk factors for prostate cancer on biopsy for men receiving finasteride include PSA, DRE, age, race, family history, and history of a prior negative biopsy. With the exception of the approximate reduction of PSA by half with finasteride, the impact of these risk factors is similar to men who do not receive finasteride. C1 Univ Texas, Hlth Sci Ctr, Dept Urol, San Antonio, TX 78229 USA. SW Oncol Grp, San Antonio, TX USA. Univ Texas, Dept Clin Canc Prevent, Anderson Canc Ctr, Houston, TX USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Colorado, Dept Pathol, Hlth Sci Ctr, Denver, CO 80202 USA. Natl Canc Inst, Dept Canc Prevent, Washington, DC USA. RP Thompson, IM (reprint author), Univ Texas, Hlth Sci Ctr, Dept Urol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM thompsoni@uthscsa.edu FU NCI NIH HHS [CA35178, CA45808, 5UO1CA86402-04, CA37429] NR 13 TC 55 Z9 57 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD JUL 20 PY 2007 VL 25 IS 21 BP 3076 EP 3081 DI 10.1200/JCO.2006.07.6836 PG 6 WC Oncology SC Oncology GA 200DJ UT WOS:000248743800015 PM 17634486 ER PT J AU Sabate, R Baxa, U Benkemouni, L de Groot, NS Coulary-Salin, B Maddelein, ML Malato, L Ventura, S Steven, AC Saupe, SJ AF Sabate, Raimon Baxa, Ulrich Benkemouni, Laura Sanchez de Groot, Natalia Coulary-Salin, Benedicte Maddelein, Marie-Lise Malato, Laurent Ventura, Salvador Steven, Alasdair C. Saupe, Sven J. TI Prion and non-prion amyloids of the HET-s prion forming domain SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE prion; amyloid; Podospora anserina; fungi; thioflavine T ID SOLID-STATE NMR; YEAST PRION; PODOSPORA-ANSERINA; HYDROGEN/DEUTERIUM EXCHANGE; ELECTRON-MICROSCOPY; MASS-SPECTROMETRY; BETA-SHEETS; IN-VITRO; PROTEIN; FIBRILS AB HET-s is a prion protein of the fungus Podospora anserina. A plausible structural model for the infectious amyloid fold of the HET-s prion-forming domain, HET-s(218-289), makes it an attractive system to study structure-function relationships in amyloid assembly and prion propagation. Here, we report on the diversity of HET-s(218-289) amyloids formed in vitro. We distinguish two types formed at pH 7 from fibrils formed at pH 2, on morphological grounds. Unlike pH 7 fibrils, the pH 2 fibrils show very little if any prion infectivity. They also differ in ThT-binding, resistance to denaturants, assembly kinetics, secondary structure, and intrinsic fluorescence. Both contain 5 nm fibrils, either bundled or disordered (pH 7) or as tightly twisted protofibrils (pH 2). We show that electrostatic interactions are critical for the formation and stability of the infectious prion fold given in the current model. The altered properties of the amyloid assembled at pH 2 may arise from a perturbation in the subunit fold or fibrillar stacking. (c) 2007 Elsevier Ltd. All rights reserved. C1 Univ Bordeaux 2, Lab Genet Mol Champignons, Inst Biochim & Genet Cellulaire, CNRS,UMR 5095, F-33077 Bordeaux, France. NIAMSD, Struct Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Autonoma Barcelona, Inst Biotecnol & Biomed, E-08193 Barcelona, Spain. RP Saupe, SJ (reprint author), Univ Bordeaux 2, Lab Genet Mol Champignons, Inst Biochim & Genet Cellulaire, CNRS,UMR 5095, F-33077 Bordeaux, France. EM sven.saupe@ibgc.u-bordeaux2.fr RI Ventura, Salvador/C-7021-2008; MADDELEIN, Marie-Lise/G-5395-2010; Sanchez de Groot, Natalia/J-8212-2014; OI Ventura, Salvador/0000-0002-9652-6351; Sanchez de Groot, Natalia/0000-0002-0492-5532; saupe, sven/0000-0002-5589-721X; sabate, raimon/0000-0003-3894-2362 FU Intramural NIH HHS NR 51 TC 45 Z9 45 U1 1 U2 9 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUL 20 PY 2007 VL 370 IS 4 BP 768 EP 783 DI 10.1016/j.jmb.2007.05.014 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 188FI UT WOS:000247904400013 PM 17532341 ER PT J AU Elbina, H Levin, HL AF Elbina, Hirotaka Levin, Henry L. TI Stress management: How cells take control of their transposons SO MOLECULAR CELL LA English DT Editorial Material ID YEAST RETROTRANSPOSON; SILENT CHROMATIN; INTEGRATION AB In this issue of Molecular Cell, Dai et al. (2007) describe their exciting discovery that, in Saccharomyces cerevisiae, the integrase of retrotransposon Ty5 is phosphorylated, and this modification stabilizes the interaction between integrase and Sir4p that directs integration to heterochromatin. C1 NICHHD, NIH, Lab Gene Regulat & Dev, Sect Eukaryot Transposable Elements, Bethesda, MD 20892 USA. RP Levin, HL (reprint author), NICHHD, NIH, Lab Gene Regulat & Dev, Sect Eukaryot Transposable Elements, Bethesda, MD 20892 USA. EM henry_levin@nih.gov NR 8 TC 5 Z9 6 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD JUL 20 PY 2007 VL 27 IS 2 BP 180 EP 181 DI 10.1016/j.molcel.2007.07.004 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 195OD UT WOS:000248420600005 PM 17643368 ER PT J AU Christensen, ST Ott, CM AF Christensen, Soren Tvorup Ott, Carolyn Marie TI A ciliary signaling switch SO SCIENCE LA English DT Editorial Material ID INTRAFLAGELLAR TRANSPORT; SONIC HEDGEHOG; PRIMARY CILIUM C1 Univ Copenhagen, Dept Mol Biol, DK-2100 Copenhagen, Denmark. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Christensen, ST (reprint author), Univ Copenhagen, Dept Mol Biol, DK-2100 Copenhagen, Denmark. EM stchristensen@aki.ku.dk; ottcarol@mail.nih.gov RI Christensen, Soren/N-3049-2014 OI Christensen, Soren/0000-0001-5004-304X NR 12 TC 28 Z9 29 U1 0 U2 2 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 JUL 20 PY 2007 VL 317 IS 5836 BP 330 EP 331 DI 10.1126/science.1146180 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 191RR UT WOS:000248150200033 PM 17641189 ER PT J AU Mullen, GED Aebig, JA Dobrescu, G Rausch, K Lambert, L Long, CA Miles, AP Saul, A AF Mullen, Gregory E. D. Aebig, Joan A. Dobrescu, Gelu Rausch, Kelly Lambert, Lynn Long, Carole A. Miles, Aaron P. Saul, Allan TI Enhanced antibody production in mice to the malaria antigen AMA 1 by CPG 7909 requires physical association of CpG and antigen SO VACCINE LA English DT Article DE vaccine; formulation; malaria antigen; CPG 7909; antibody response ID PLASMODIUM-FALCIPARUM MALARIA; APICAL MEMBRANE ANTIGEN-1; BACTERIAL-DNA; IN-VITRO; VACCINE; OLIGODEOXYNUCLEOTIDE; ADJUVANT; IMMUNOGENICITY; RESPONSES; ADULTS AB CpG oligodeoxynucleotides are potent immunostimulants. In this study, CPG 7909 was formulated with the recombinant Plasmodium falciparum protein AMA1-C1 adsorbed to Alhydrogel (aluminum hydroxide) and used to immunize mice. Mice receiving free CPG 7909 in a separate same site injection to the AMA1-C1/Alhydrogel had the same antibody responses as mice receiving AMA1 -C1/Alhydrogel alone. For mice immunized with CPG 7909 bound to the AMA1-C1/Alhydrogel formulation, there was a bell shaped CPG 7909 dose-response curve with the highest antibody response co-incident with the concentration of CPG 7909 that saturated binding to the Alhydrogel. At a higher CPG 7909 dose where 74% was unbound, there was no enhancement of response over AMA1-C1/Alhydrogel alone. Our results suggest that the adjuvant effects of CpGs are optimal when adsorbed to Alhydrogel and highlight the need for careful characterization of the vaccine formulation. (c) 2007 Elsevier Ltd. All rights reserved. C1 NIAID, NIH, Malaria Vaccine Dev Branch, Rockville, MD 20852 USA. RP Aebig, JA (reprint author), NIAID, NIH, Malaria Vaccine Dev Branch, 5640 Fishers Lane, Rockville, MD 20852 USA. EM jaebig@niaid.nih.gov RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 FU Intramural NIH HHS [Z99 AI999999] NR 14 TC 19 Z9 19 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD JUL 20 PY 2007 VL 25 IS 29 BP 5343 EP 5347 DI 10.1016/j.vaccine.2007.05.007 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 194QQ UT WOS:000248359300017 PM 17566616 ER PT J AU Morchon, R Roca, F Lopez-Belmonte, J Genchi, A Venco, L Rodriguez-Barbero, A Simon, F AF Morchon, R. Roca, F. Lopez-Belmonte, J. Genchi, A. Venco, L. Rodriguez-Barbero, A. Simon, F. TI Changes in the levels of eicosanoids in cats naturally and experimentally infected with Dirofilaria immitis SO VETERINARY PARASITOLOGY LA English DT Article DE Dirofilaria immitis; cats; eicosanoids; prostaglandin E-2; thromboxane B-2; leukotriene B-4 ID FILARIAL PARASITES; WOLBACHIA; PROSTAGLANDIN-E2; NEUTROPHILS; DIAGNOSIS; CELLS; IGG AB Feline heartworm (Dirofilaria immitis) infection is a severe, life-threatening disease. The eicosanoids are lipid mediators derived from the metabolism of the arachidonic acid, involved in the regulation of the immune response and of inflammatory reactions. In this study, naturally infected cats showed significant higher levels of prostaglandin E-2 (PGE2), thromboxane B-2 (TXB2) and leukotriene B-4 (LTB4) than uninfected cats. Changes in the levels of eicosanoids during the infection were observed in experimentally infected cats. PGE2 increased significantly during the first 60 days post-infection, then progressively decreased until day 180 post-infection. At this time, PGE2 values are still significantly higher than those observed before the infection. TxB2 and LTB4 increased progressively from the beginning of infection and reached their maximum levels 180 days post-infection. In experimentally infected, ivermectin-treated cats, 15 days after treatment (45 days after infection) both PGE2 and LTB4 levels were similar to those observed in experimentally infected, untreated cats. No significant differences of PGE2 levels were found before the infection and at the end of the experiment (165 days post-treatment, 195 days post-infection). Increased levels of LTB4 were found 15 days post-treatment. afterward they progressively decreased. These data show that A immitis infection influences the production of intravascular eicosanoids in cats. The high levels of PGE2 observed in the early phase of infection could be related to the survival of the worms. while those of TxB2 and LTB4 detected at the end of the study could mediate the inflammatory reactions and thrombi formation during the feline dirofilariosis. (c) 2007 Elsevier B.V. All rights reserved. C1 Univ Salamanca, Fac Farm, Lab Parasitol, Salamanca, Spain. Univ Puerto Rico, Escuela Med, MHIRT Program, NIH, San Juan, PR 00936 USA. Univ Milan, Dipartimento Di Patol Anim Igiene & Sanita Publ V, I-20122 Milan, Italy. Clin Vet Citta Pavia, Pavia, Italy. Univ Salamanca, Dept Fisiol & Farmacol, Inst Reina Sofia Invest Nefrol, E-37008 Salamanca, Spain. RP Simon, F (reprint author), Univ Salamanca, Fac Farm, Lab Parasitol, Ave Campo charro SN, Salamanca, Spain. EM fersimon@usal.es RI 2007, Secribsal/A-1556-2012; Rodriguez-Barbero, Alicia /A-7583-2017; OI Rodriguez-Barbero, Alicia /0000-0002-6774-7147; Genchi, Marco/0000-0003-3768-2482 NR 22 TC 10 Z9 10 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4017 J9 VET PARASITOL JI Vet. Parasitol. PD JUL 20 PY 2007 VL 147 IS 3-4 BP 271 EP 275 DI 10.1016/j.vetpar.2007.04.010 PG 5 WC Parasitology; Veterinary Sciences SC Parasitology; Veterinary Sciences GA 191KS UT WOS:000248130700010 PM 17544219 ER PT J AU Huang, Y Staschke, K De Francesco, R Tan, SL AF Huang, Ying Staschke, Kirk De Francesco, Raffaele Tan, Seng-Lai TI Phosphorylation of hepatitis C virus NS5A nonstructural protein: A new paradigm for phosphorylation-dependent viral RNA replication? SO VIROLOGY LA English DT Review DE hepatitis C virus; nonstructural protein NS5A; casein kinase 1; protein phosphorylation; viral RNA replication ID SENSITIVITY-DETERMINING REGION; CELL-CULTURE; ALPHA-INTERFERON; 5A PROTEIN; IN-VITRO; TRANSCRIPTIONAL ACTIVATOR; MEMBRANE ASSOCIATION; SIGNALING CASCADE; BINDING PROTEIN; CORE PROTEIN AB The hepatitis C virus (HCV) nonstructural 5A (NS5A) phosphoprotein has been intensely studied due to its ability to subvert the host interferon-induced antiviral response. However, more recent studies suggest that it may also play an important regulatory role in HCV RNA replication as well as modulate host intracellular signaling pathways. Phosphorylation of NS5A appears to be a highly regulated process and several cellular protein kinases responsible for NS5A phosphorylation have been identified in vitro. Studies utilizing the HCV replicon cell culture system have suggested a provocative role for the differential phosphorylation of NS5A in the regulation of viral RNA replication through its association with the viral replication complex, including several host cell factors. Importantly, recent in vivo data linking loss of NS5A hyperphosphorylation to nonproductive HCV replication in the chimpanzee model have provided high validation for targeting the cellular kinases involved, particularly the kinases responsible for NS5A phosphorylation, for antiviral therapeutic intervention. Understanding the process of NS5A phosphorylation and the definite identification of the culprit cellular protein kinase(s) will shed light on the mechanisms of HCV RNA replication and/or pathogenesis. (C) 2007 Elsevier Inc. All rights reserved. C1 Amgen Inc, Seattle, WA 98119 USA. NIH, NIDDK, Liver Dis Branch, Bethesda, MD 20892 USA. Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. Ist Ric Biol Mol P Angeletti, Rome, Italy. RP Tan, SL (reprint author), Amgen Inc, 1201 Amgen Court W, Seattle, WA 98119 USA. EM sengt@amgen.com RI De Francesco, Raffaele/J-6003-2012 OI De Francesco, Raffaele/0000-0001-8754-5123 NR 76 TC 96 Z9 99 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 JUL 20 PY 2007 VL 364 IS 1 BP 1 EP 9 DI 10.1016/j.virol.2007.01.042 PG 9 WC Virology SC Virology GA 178CG UT WOS:000247198200001 PM 17400273 ER PT J AU Larkin, JD Bhat, KL Markham, GD Brooks, BR Lai, JH Bock, CW AF Larkin, Joseph D. Bhat, Krishna L. Markham, George D. Brooks, Bernard R. Lai, Jack H. Bock, Charles W. TI A computational investigation of the geometrical structure and protodeboronation of boroglycine, H2N-CH2-B(OH)(2) SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Review ID BORONATE AFFINITY-CHROMATOGRAPHY; CROSS-COUPLING REACTIONS; CORRELATED MOLECULAR CALCULATIONS; POLARIZABLE CONTINUUM MODEL; METHYL TRANSFER-REACTIONS; ALPHA-AMINOBORONIC ACIDS; GAUSSIAN-BASIS SETS; BORIC-ACID; PHENYLBORONIC ACID; WAVE-FUNCTIONS AB In this article the geometrical structure of the simple, achiral, alpha-amino boronic acid boroglycine, H2N-CH2-B(OH)(2), was investigated using density functional theory (DFT), second-order Moller-Plesset (MP2) perturbation theory, and coupled cluster methodology with single- and double-excitations (CCSD); the effects of an aqueous environment were incorporated into the results by using a few explicit water molecules and/or self-consistent reaction field (SCRF) calculations with the IEF polarizable continuum model (PCM). Neutral reaction mechanisms were investigated for the direct protodeboronation (hydrolysis) of boroglycine (H2O + H2N-CH2-B(OH)(2) -> B(OH)(3) + H2N-CH3), for which Delta H-298 degrees was -21.9 kcal/mol at the MP2(FC)/aug-cc-pVDZ level, and for the 1,2-carbon-to-nitrogen shift of the -B(OH)(2) moiety (H2N-CH2-B(OH)(2) -> H3C-NH-B(OH)(2)), for which the corresponding value of Delta H-298 degrees was -18.2 kcal/mol. A boron-oxygen double-bonded intermediate was found to play an important role in the 1,2-rearrangement mechanism. C1 Bloomsburg Univ Penn, Dept Chem, Bloomsburg, PA 17815 USA. Philadelphia Univ, Sch Sci & Hlth, Dept Chem & Biochem, Philadelphia, PA 19144 USA. Fox Chase Canc Ctr, Inst Canc Res, Philadelphia, PA 19111 USA. NHLBI, NIH, Bethesda, MD 20851 USA. Tufts Univ, Sch Med, Dept Biochem, Boston, MA 02111 USA. Widener Univ, Dept Chem, Chester, PA 19013 USA. RP Larkin, JD (reprint author), Bloomsburg Univ Penn, Dept Chem, Bloomsburg, PA 17815 USA. EM jlarkin@bloomu.edu FU Intramural NIH HHS; NCI NIH HHS [CA06927]; NIGMS NIH HHS [GM31186] NR 105 TC 7 Z9 7 U1 2 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD JUL 19 PY 2007 VL 111 IS 28 BP 6489 EP 6500 DI 10.1021/jp0700682 PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 189CM UT WOS:000247966600047 PM 17595064 ER PT J AU Hallett, M AF Hallett, Mark TI Transcranial magnetic stimulation: A primer SO NEURON LA English DT Review ID HUMAN MOTOR CORTEX; REACTION-TIME PARADIGMS; FRONTAL EYE FIELDS; PARKINSONS-DISEASE; VISUAL-CORTEX; PREFRONTAL CORTEX; PREMOTOR CORTEX; CORTICOSPINAL EXCITABILITY; INTRACORTICAL INHIBITION; CORTICAL EXCITABILITY AB Transcranial magnetic stimulation (TMS) is a technique for noninvasive stimulation of the human brain. Stimulation is produced by generating a brief, high-intensity magnetic field by passing a brief electric current through a magnetic coil. The field can excite or inhibit a small area of brain below the coil. All parts of the brain just beneath the skull can be influenced, but most studies have been of the motor cortex where a focal muscle twitch can be produced, called the motor-evoked potential. The technique can be used to map brain function and explore the excitability of different regions. Brief interference has allowed mapping of many sensory, motor, and cognitive functions. TMS has some clinical utility, and, because it can influence brain function if delivered repetitively, it is being developed for various therapeutic purposes. C1 Natl Inst Neurol Disorders & Stroke, NIH, Human Motor Control Sect, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Human Motor Control Sect, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov OI Hallett, Mark/0000-0002-3180-6811 NR 117 TC 450 Z9 480 U1 13 U2 84 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD JUL 19 PY 2007 VL 55 IS 2 BP 187 EP 199 DI 10.1016/j.neuron.2007.06.026 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 198NW UT WOS:000248635800005 PM 17640522 ER PT J AU Malozowski, S Sahlroot, JT AF Malozowski, Saul Sahlroot, Jon Todd TI Interleukin-1-receptor antagonist in type 2 diabetes mellitus SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIDDKD, Bethesda, MD 20892 USA. Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Malozowski, S (reprint author), NIDDKD, Bethesda, MD 20892 USA. EM sm87j@nih.gov NR 1 TC 13 Z9 16 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 JUL 19 PY 2007 VL 357 IS 3 BP 302 EP 303 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 191FH UT WOS:000248115100018 PM 17634469 ER PT J AU Tran, HA Kang, E Becker, D AF Tran, Henry A. Kang, Eunice Becker, Daniel TI Omeprazole before endoscopy in patients with gastrointestinal bleeding SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIDDKD, Bethesda, MD 20892 USA. Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. RP Tran, HA (reprint author), NIDDKD, Bethesda, MD 20892 USA. EM hat7e@hotmail.com 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 JUL 19 PY 2007 VL 357 IS 3 BP 303 EP 304 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 191FH UT WOS:000248115100021 PM 17644833 ER PT J AU Meng, LH Kohn, KW Pommier, Y AF Meng, L-H Kohn, K. W. Pommier, Y. TI Dose-response transition from cell cycle arrest to apoptosis with selective degradation of Mdm2 and p21(WAF1/CIP1) in response to the novel anticancer agent, aminoflone (NSC 686288) SO ONCOGENE LA English DT Article DE p53; proteasome; Akt; apoptosis; histone H2AX; DNA damage ID ATM-DEPENDENT PHOSPHORYLATION; MOLECULAR INTERACTION MAP; DNA-DAMAGE; AMINOFLAVONE NSC-686288; ADENOCARCINOMA CELLS; IONIZING-RADIATION; TOPOISOMERASE-I; P53 ACTIVATION; CANCER CELLS; KINASE AB Aminoflavone (AF, NSC 686288) is beginning clinical trials. It induces replication-mediated histone H2AX phosphorylation, DNA-protein crosslinks and activates p53. Here, we studied p21(CIP1/WAF1) and Mdm2 responses to AF. Although p53 stabilization and phosphorylation at serine 15 increased with dose and time of exposure, Mdm2 and p21(CIP1/WAF1) protein levels displayed a biphasic response, as they accumulated at submicromolar doses and then decreased with increasing AF. As both Mdm2 and p21(CIP1/WAF1) mRNA levels increased with AF concentration without reduction at higher concentrations, we measured the half- lives of Mdm2 and p21(CIP1/WAF1) proteins. Mdm2 and p21(CIP1/WAF1) half-lives were shortened with increasing AF concentrations. Proteasomal degradation appears responsible for the decrease of both Mdm2 and p21(CIP1/WAF1), as MG-132 prevented their degradation and revealed AF-induced Mdm2 polyubiquitylation. AF also induced protein kinase B (Akt) activation, which was reduced with increasing AF concentrations. Suppression of Akt by small interfering RNA was associated with downregulation of Mdm2 and p21(CIP1/WAF1) and with enhanced apoptosis. These results suggest that the cellular responses to AF are determined at least in part by Mdm2 and p21(CIP1/WAF1) protein levels, as well as by Akt activity, leading either to cell cycle arrest when Mdm2 and p21(CIP1/WAF1) are elevated, or to apoptosis when Mdm2 and p21(CIP1/WAF1) are degraded by the proteasome and Akt insufficiently activated to protect against apoptosis. C1 NCI, Canc Res Ctr, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Canc Res Ctr, Mol Pharmacol Lab, NIH, 37 Convent Dr,Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Intramural NIH HHS NR 40 TC 19 Z9 19 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 19 PY 2007 VL 26 IS 33 BP 4806 EP 4816 DI 10.1038/sj.onc.1210283 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 191ZL UT WOS:000248170400005 PM 17297446 ER PT J AU Chen, M Rahman, L Voeller, D Kastanos, E Yang, SX Feigenbaum, L Allegra, C Kaye, FJ Steeg, P Zajac-Kaye, M AF Chen, M. Rahman, L. Voeller, D. Kastanos, E. Yang, S. X. Feigenbaum, L. Allegra, C. Kaye, F. J. Steeg, P. Zajac-Kaye, M. TI Transgenic expression of human thymidylate synthase accelerates the development of hyperplasia and tumors in the endocrine pancreas SO ONCOGENE LA English DT Article DE thymidylate synthase; transgenic model; islet cell adenoma; endocrine pancreas ID DEPENDENT KINASE INHIBITORS; GENE-EXPRESSION; BREAST-CANCER; DNA-SYNTHESIS; MOUSE MODEL; C-MYC; K-RAS; P53; MICE; 5-FLUOROURACIL AB Thymidylate synthase ( TS) is an essential enzyme for DNA synthesis and repair and elevated levels of TS have been identified as an important prognostic biomarker for colorectal cancer and several other common human malignancies. In addition, TS gene expression has been linked with cell-cycle regulation and cell proliferation through the ability of retinoblastoma protein to repress the transcriptional activation of E2F target genes such as TS. Therefore, overproduction of TS could participate in the progression to a neoplastic phenotype. Consistent with this model, a recent study has suggested that ectopic TS express ion can induce a transformed phenotype in mammalian cells. To investigate the role of deregulated TS activity in tumor development, we generated transgenic mice that express high levels of catalytically active human TS( hTS) exclusively in the pancreas and low levels of hTS in multiple other tissues. Analyses of pancreatic tissue in TS transgenic mice revealed abnormalities within the endocrine pancreas, ranging from pancreatic islet hyperplasia to the detection of islet cell tumors. Overexpression of hTS in murine islets provides a new model to study genetic alterations associated with the progression from normal cells to hyperplasia to islet cell tumors, and suggests that this mouse model may be useful for regulating TS activity in vivo for development of cancer prevention and new therapies. C1 Ctr Canc Res, Mol Therapeut Program, Bethesda, MD USA. Natl Clin Target Validat Lab, Div Canc Treatment & Diag, Bethesda, MD USA. NCI, Frederick Canc Res, Lab Anim Sci, Frederick, MD 21701 USA. NCI, Genet Branch, Bethesda, MD 20892 USA. RP Zajac-Kaye, M (reprint author), NCI, NIH, Bldg 37 RM 1122,37 Convent Dr, Bethesda, MD 20892 USA. EM kayem@exchange.nih.gov RI kaye, frederic/E-2437-2011 FU Intramural NIH HHS NR 35 TC 15 Z9 18 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 19 PY 2007 VL 26 IS 33 BP 4817 EP 4824 DI 10.1038/sj.onc.1210273 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 191ZL UT WOS:000248170400006 PM 17297449 ER PT J AU Ma, X Kalakonda, S Srinivasula, SM Reddy, SP Platanias, LC Kalvakolanu, DV AF Ma, X. Kalakonda, S. Srinivasula, S. M. Reddy, S. P. Platanias, L. C. Kalvakolanu, D. V. TI GRIM-19 associates with the serine protease HtrA2 for promoting cell death SO ONCOGENE LA English DT Article DE cytokines; vitamins; cancer; cell death; growth; suppression ID RETINOIC ACID; TUMOR-DEVELOPMENT; CASPASE ACTIVITY; IFN-GAMMA; APOPTOSIS; INHIBITOR; OMI/HTRA2; MITOCHONDRIA; REGULATOR; INTERACTS AB We have isolated a novel interferon (IFN)-retinoid regulated cell death regulatory protein genes associated with retinoid-IFN-induced mortality (GRIM)-19 earlier. To understand its mechanism of action, we have employed a yeast-two-hybrid screen and identified serine protease HtrA2 as its binding partner. GRIM-19 physically interacts with HtrA2 and augments cell death in an IFN/all-trans retinoic acid (RA)-dependent manner. In the presence of GRIM-19, the HtrA2-driven destruction of the antiapoptotic protein X-linked inhibitor of apoptosis (XIAP) is augmented. These interactions were disrupted by an human herpes virus-8 (HHV-8)-coded oncoprotein, vIRF1, and conferred resistance to IFN/RA-induced cell death. These data show a critical role of HtrA2 in a cytokine-induced cell death response for the. rst time and its inhibition by a viral protein. C1 Univ Maryland, Greenbaum Canc Ctr, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA. NCI, Lab Immune Cell Biol, Bethesda, MD 20892 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. Northwestern Univ, Sch Med, Lurie Canc Ctr, Div Hematol & Oncol, Chicago, IL 60611 USA. RP Kalvakolanu, DV (reprint author), Univ Maryland, Greenbaum Canc Ctr, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA. EM dkalvako@umaryland.edu FU NCI NIH HHS [CA105005] NR 28 TC 25 Z9 26 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD JUL 19 PY 2007 VL 26 IS 33 BP 4842 EP 4849 DI 10.1038/sj.onc.1210287 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 191ZL UT WOS:000248170400009 PM 17297443 ER PT J AU Goff, DC Gerstein, HC Ginsberg, HN Cushman, WC Margolis, KL Byington, RP Buse, JB Genuth, S Probstfield, JL Simons-Morton, DG AF Goff, David C., Jr. Gerstein, Hertzel C. Ginsberg, Henry N. Cushman, William C. Margolis, Karen L. Byington, Robert P. Buse, John B. Genuth, Saul Probstfield, Jeffrey L. Simons-Morton, Denise G. CA ACCORD Study Grp TI Prevention of cardiovascular disease in persons with type 2 diabetes mellitus: Current knowledge and rationale for the action to control cardiovascular risk in diabetes (ACCORD) trial SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Review ID CORONARY-HEART-DISEASE; ACUTE MYOCARDIAL-INFARCTION; RANDOMIZED CONTROLLED-TRIAL; BLOOD-PRESSURE CONTROL; SCANDINAVIAN-SIMVASTATIN-SURVIVAL; DENSITY LIPOPROTEIN TRIGLYCERIDE; AVERAGE CHOLESTEROL LEVELS; APOLIPOPROTEIN-B KINETICS; INSULIN-GLUCOSE INFUSION; PLACEBO-CONTROLLED TRIAL AB Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates 2-4 times higher than patients without diabetes but with similar demographic characteristics. The prevalence of diabetes is increasing in the United States and, thus, the prevention of CVD in patients with diabetes poses an urgent public health challenge. The objective of this report is to review the current knowledge base for the prevention of CVD in patients with diabetes, with particular emphasis on the control of glycemia, lipids, and blood pressure. Epidemiologic analyses suggest that each 1% increase in glycosylated hemoglobin increases the risk for CVD by approximately 18%; however, evidence from the randomized trials that have examined whether glucose lowering reduces this risk is conflicting. Randomized trials have shown that lowering low-density lipoprotein cholesterol reduces CVD event rates by 17%-43% in patients with diabetes. Limited data support a role for lowering triglycerides and increasing high-density lipoprotein cholesterol in the prevention of CVD. Evidence from clinical trials shows that reducing systolic blood pressure to < 140 mm Hg results in 30%-60% reductions in CVD events; however, epidemiologic evidence suggests that lowering to optimal systolic blood pressure levels (< 120 mm Hg) may be additionally beneficial. Important questions regarding prevention of CVD in patients with diabetes remain unresolved, including the benefits of near-normal glycemic control, comprehensive therapy for diabetes-related dyslipidemia, and optimal blood pressure control. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial will test hypotheses to address these unanswered questions. (c) 2007 Elsevier Inc. All rights reserved. C1 Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. Wake Forest Univ, Sch Med, Dept Internal Med, Winston Salem, NC USA. McMaster Univ, Hamilton Hlth Sci, Populat Hlth Res Inst, Dept Med, Hamilton, ON, Canada. Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA. Vet Affairs Med Ctr, Memphis, TN USA. Hennepin Cty Med Ctr, Berman Ctr Outcomes & Clin Res, Minneapolis, MN 55415 USA. Univ N Carolina, Sch Med, Dept Med, Div Gen Med Clin Epidemiol, Chapel Hill, NC USA. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. Univ Washington, Med Ctr, Dept Med, Div Cardiol, Seattle, WA USA. NHLBI, Div Prevent & Populat Sci, Clin Applicat & Prevent Branch, Bethesda, MD 20892 USA. RP Goff, DC (reprint author), Wake Forest Univ, Sch Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM dgoff@wfubmc.edu FU NHLBI NIH HHS [N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95183, N01-HC-95184, Y1-HC-1010, Y1-HC-9035] NR 116 TC 37 Z9 39 U1 1 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 18 PY 2007 VL 99 IS 12A SU S BP 4I EP 20I DI 10.1016/j.amjcard.2007.03.002 PG 17 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188RV UT WOS:000247937900002 PM 17599424 ER PT J AU Cushman, WC Grimm, RH Cutler, JA Evans, GW Capes, S Corson, MA Sadler, LS Alderman, MH Peterson, K Bertoni, A Basile, JN AF Cushman, William C. Grimm, Richard H., Jr. Cutler, Jeffrey A. Evans, Gregory W. Capes, Sarah Corson, Marshall A. Sadler, Laurie S. Alderman, Michael H. Peterson, Kevin Bertoni, Alain Basile, Jan N. CA ACCORD Study Grp TI Rationale and design for the blood pressure intervention of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LIPID-LOWERING TREATMENT; JOINT NATIONAL COMMITTEE; MICROVASCULAR COMPLICATIONS; HYPERTENSIVE PATIENTS; ANTIHYPERTENSIVE TREATMENT; SYSTOLIC HYPERTENSION; DISEASE RISK; 7TH REPORT; OUTCOMES; MELLITUS AB The Action to Control Cardiovascular Disease in Diabetes (ACCORD) blood pressure trial is an unmasked, open-label, randomized trial with a sample size of 4,733 participants. This report describes the rationale, design, and methods of the blood pressure interventions in ACCORD. Participants eligible for the blood pressure trial are randomized to 1 of 2 groups with different treatment goals: systolic blood pressure < 120 mm Hg for the more intensive goal and systolic blood pressure < 140 mm Hg for the less intensive goal. The primary outcome measure for the trial is the first occurrence of a major cardiovascular disease (CVD) event, specifically nonfatal myocardial infarction or stroke, or cardiovascular death during a follow-up period ranging from 4-8 years. The ACCORD blood pressure trial should provide the first definitive clinical trial data on the possible benefit of treating to a more aggressive systolic blood pressure goal in reducing CVD events in patients with diabetes mellitus. (c) 2007 Elsevier Inc. All rights reserved. C1 Vet Affairs Med Ctr, Memphis, TN USA. Hennepin Cty Med Ctr, Berman Ctr Outcomes & Clin Res, Div Clin Epidemiol, Minneapolis, MN 55415 USA. NHLBI, Div Cardiovasc Dis, Vasc Biol & Hypertens Branch, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. McMaster Univ, Dept Med, Hamilton, ON, Canada. Univ Washington, Med Ctr, Dept Med, Div Cardiol, Seattle, WA 98195 USA. St Vincent Charity Hosp, Lipid Res Ctr, Cleveland, OH USA. Albert Einstein Coll Med, Dept Med & Epidemiol, Bronx, NY 10467 USA. Univ Minnesota, Phalen Village Clin, Minneapolis, MN USA. Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC USA. RP Cushman, WC (reprint author), Vet Affairs Med Ctr, Prevent Med Sect 111Q, 1030 Jefferson Ave, Memphis, TN 38104 USA. EM william.cushman@va.gov OI Peterson, Kevin/0000-0002-6914-8586 FU NHLBI NIH HHS [N01-HC-95183, Y1-HC-9035, N01-HC-95178, N01-HC-95182, N01-HC-95184, N01-HC-95179, N01-HC-95181, N01-HC-95180, Y1-HC-1010] NR 33 TC 17 Z9 18 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 18 PY 2007 VL 99 IS 12A SU S BP 44I EP 55I DI 10.1016/j.amjcard.2007.03.005 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188RV UT WOS:000247937900005 PM 17599425 ER PT J AU Ginsberg, HN Bonds, DE Lovato, LC Crouse, JR Elam, MB Linz, PE O'Connor, PJ Leiter, LA Weiss, D Lipkin, E Fleg, JL AF Ginsberg, Henry N. Bonds, Denise E. Lovato, Laura C. Crouse, John R. Elam, Marshall B. Linz, Peter E. O'Connor, Patrick J. Leiter, Lawrence A. Weiss, Daniel Lipkin, Edward Fleg, Jerome L. CA ACCORD Study Grp TI Evolution of the lipid trial protocol of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; FENOFIBRATE INCREASES CREATININEMIA; AVERAGE CHOLESTEROL LEVELS; PLACEBO-CONTROLLED TRIAL; HIGH BLOOD CHOLESTEROL; NCEP EXPERT PANEL; PRIMARY-PREVENTION; RANDOMIZED-TRIAL; EVENTS; SIMVASTATIN AB The Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial aims to test whether a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) plus a fibrate is more efficacious in reducing cardiovascular events than a statin plus placebo in patients with type 2 diabetes mellitus with defined glycemic control. This is a blinded component in a 5,518-patient subset of the ACCORD cohort. These participants were randomized to either be (1) treated with simvastatin (titrated to 40 mg/day if necessary to achieve a goal low-density lipoprotein [LDL] cholesterol level of < 2.59 mmol/L [100 mg/dL]) plus placebo or (2) treated to the same goal LDL cholesterol level with the statin plus active fenofibrate 160 mg/day or its bioequivalent (or 54 mg/day if the estimated glomerular filtration rate ranges from 30 to < 50 mL/min per 1.73 m(2)). Setting an upper limit of LDL cholesterol qualifying for randomization excluded patients who would not likely achieve the LDL cholesterol goal. Recruitment for ACCORD began in January 2001, and follow-up is scheduled to end in June 2009. Since recruitment began, several clinical trials and consensus statements have been published that led to changes in the details of the lipid treatment algorithm and protocol. This report describes the design of the lipid protocol and modifications to the protocol during the course of the study in response to and in anticipation of these developments. The current protocol is designed to provide an ethically justifiable test of combined statin plus fibrate treatment consistent with the highest level of safety and lipid treatment standards of care. (c) 2007 Elsevier Inc. All rights reserved. C1 Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA. Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC 27109 USA. Wake Forest Univ, Sch Med, Dept Med, Winston Salem, NC USA. Univ Tennessee, Ctr Hlth Sci, Dept Med, Vet Affairs Med Ctr, Memphis, TN 38163 USA. Naval Med Ctr, San Diego, CA USA. Hlth Partners Res Fdn, Minneapolis, MN USA. Univ Toronto, St Michaels Hosp, Dept Med, Toronto, ON M5B 1W8, Canada. Univ Washington, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA 98195 USA. NHLBI, Div Cardiovasc Dis, Atherothrombosis & Coronary Artery Dis Branch, Bethesda, MD USA. RP Crouse, JR (reprint author), Wake Forest Univ, Sch Med, Dept Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jrcrouse@wfubmc.edu FU NHLBI NIH HHS [N01-HC-95178, N01-HC-95181, N01-HC-95183, Y1-HC-9035, N01-HC-95179, N01-HC-95180, N01-HC-95182, N01-HC-95184, Y1-HC-1010] NR 28 TC 15 Z9 17 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 18 PY 2007 VL 99 IS 12A SU S BP 56I EP 67I DI 10.1016/j.amjcard.2007.03.024 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188RV UT WOS:000247937900006 PM 17599426 ER PT J AU Kingry, C Bastien, A Booth, G Geraci, TS Kirpach, BR Ms, L Margolis, KL Sperl-Hillen, JM Vargo, L Williamson, JD Probstfield, JL AF Kingry, Connie Bastien, Arnaud Booth, Gillian Geraci, Therese S. Kirpach, Brenda R. Ms, Lovato Margolis, Karen L. Sperl-Hillen, JoAnne M. Vargo, Laura Williamson, Jeff D. Probstfield, Jeffrey L. CA ACCORD Study Grp TI Recruitment strategies in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PREVENTION; RATIONALE; CANCER; DESIGN AB The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is a randomized, multicenter clinical trial using a double 2 x 2 factorial design in 10,251 participants with type 2 diabetes mellitus at high risk for cardiovascular disease (CVD) events. ACCORD is testing 3 complementary medical treatment strategies that may reduce high rates of major CVD morbidity and mortality in patients with type 2 diabetes. The ACCORD vanguard phase, conducted at 59 clinics in the United States and Canada, recruited 1,174 participants in 20 weeks from January through June I ' 2001, with a recruitment efficiency (R-factor) of 0.65. The recruitment strategies used in this vanguard phase were almost exclusively chart and database review within clinical practices and institutions. Recruitment for the main trial began in February 2003, involved 77 clinics, and resulted in an additional 9,077 participants by October 29, 2005 (total, 10,251). The R-factor during main trial recruitment was 0.96. Although new and refined recruitment strategies were formulated from the vanguard experience, the most powerful determinant of improved recruitment efficiency was the immediate start of enrollment by most clinics at the beginning of the main trial. Recruitment in the main trial required only a brief extension of 3 months and facilitated the nearly*complete capture of the expected number of person-years of observation. Described herein are vanguard and main trial recruitment activities, including strategy implementation, screening procedures, randomization results, problems encountered, and lessons learned. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Washington, Med Ctr, Dept Med, Div Cardiol, Seattle, WA 98103 USA. Copper Univ Hosp, Clin Trials Ctr, Dept Internal Med, Camden, NJ USA. St Michaels Hosp, Ctr Hlth, Div Endocrinol & Metab, Toronto, ON M5B 1W8, Canada. Vet Affairs Med Ctr, Memphis, TN USA. Berman Ctr Outcomes & Clin Res, Minneapolis, MN USA. Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC USA. Wake Forest Univ, Sch Med, Ctr Mem & Cognit Res, Winston Salem, NC USA. NHLBI, Div Cardiovasc Dis, Atherothrombosis & Coronary Artery Dis Branch, Bethesda, MD USA. Hennepin Cty Med Ctr, Berman Ctr Outcomes & Clin Res, Minneapolis, MN USA. Case Western Reserve Univ, Div Clin & Mol Endocrinol, Cleveland, OH 44106 USA. RP Kingry, C (reprint author), Univ Washington, Med Ctr, Dept Med, Div Cardiol, 146 N Canal St,Suite 200, Seattle, WA 98103 USA. EM ckingry@u.washington.edu FU NHLBI NIH HHS [Y1-HC-1010, N01-HC-95181, N01-HC-95180, N01-HC-95178, N01-HC-95182, Y1-HC-9035, N01-HC-95179, N01-HC-95184, N01-HC-95183] NR 26 TC 9 Z9 9 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 18 PY 2007 VL 99 IS 12A SU S BP 68I EP 79I DI 10.1016/j.amjcard.2007.03.025 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188RV UT WOS:000247937900007 PM 17599427 ER PT J AU Bonds, DE Kurashige, EM Bergenstal, R Brillon, D Domanski, M Felicetta, JV Fonseca, VA Hall, K Hramiak, I Miller, ME Osei, K Simons-Morton, DG AF Bonds, Denise E. Kurashige, Ella Mae Bergenstal, Richard Brillon, David Domanski, Michael Felicetta, James V. Fonseca, Vivian A. Hall, Kathleen Hramiak, Irene Miller, Michael E. Osei, Kwame Simons-Morton, Denise G. CA ACCORD Study Grp TI Severe hypoglycemia monitoring and risk management procedures in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID GLYCEMIC CONTROL; COMPLICATIONS; PROGRESSION; MELLITUS; TYPE-1 AB Hypoglycemia is a potentially serious side effect of blood glucose lowering in diabetes mellitus. The intensive glycemia treatment arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is designed to treat patients with type 2 diabetes with target glycemia within the normal range (ie, glycosylated hemoglobin < 6%). Because it is known that treating glycemia to such a low level in patients with diabetes will result in episodes of hypoglycemia, it is necessary to address prevention and treatment of such episodes to ensure patient safety, Thus, several approaches are being taken in the ACCORD trial to prevent initial episodes of severe hypoglycemia, to monitor the frequency of episodes that do occur, and to prevent recurrence. This report describes the processes used in the ACCORD trial, including the definition of severe hypoglycemia, the type of education provided to participants and staff members to prevent initial and subsequent episodes of severe hypoglycemia, and the monitoring systems implemented to identify severe hypoglycemia and prevent its recurrence. The ACCORD trial conducts review and oversight of individual cases of severe hypoglycemia and monitors rates of severe hypoglycemia by clinical site and treatment arm. If the ACCORD intensive glycemia treatment is found to be efficacious in preventing cardiovascular disease events, assessment of the risk and benefit will be essential. In addition, translation of the principles behind the monitoring of severe hypoglycemia in ACCORD into feasible strategies for use in clinical practice will be needed. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Int Diabet Ctr, Minneapolis, MN USA. Cornell Univ, Weill Med Coll, Dept Med, Div Endocrinol, New York, NY USA. Atherothrombosis & Coronary Artery Dis Branch, Bethesda, MD USA. Div Cardiovasc Dis, Bethesda, MD USA. NHLBI, Div Prevent & Populat Sci, Clin Applicat & Prevent Branch, Bethesda, MD 20892 USA. Vet Affairs Med Ctr, Phoenix, AZ USA. Tulane Univ, Hlth Sci Ctr, Sect Endocrinol & Metab, New Orleans, LA 70118 USA. Univ Minnesota, Hennepin Cty Med Ctr, Dept Med, Berman Ctr Outcomes & Clin Res, Minneapolis, MN USA. Univ Western Ontario, St Josephs Hlth Care, Dept Med, London, ON, Canada. Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC USA. Ohio State Univ, Dept Internal Med, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. RP Bonds, DE (reprint author), Univ Virginia, Sch Med, Dept Publ Hlth Sci, Box 800717, Charlottesville, VA 22908 USA. EM dbonds@virginia.edu FU NCRR NIH HHS [M01RR0004741, 5M01RR05096]; NHLBI NIH HHS [N01-HC-95179, N01-HC-95182, Y1-HC-9035, N01-HC-95184, Y1-HC-1010, N01-HC-95178, N01-HC-95181, N01-HC-95180, N01-HC-95183] NR 13 TC 10 Z9 12 U1 4 U2 7 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 18 PY 2007 VL 99 IS 12A SU S BP 80I EP 89I DI 10.1016/j.amjcard.2007.03.026 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188RV UT WOS:000247937900008 PM 17599428 ER PT J AU Sullivan, MD Anderson, RT Aron, D Atkinson, HH Bastien, A Chen, GJ Feeney, P Gafni, A Hwang, W Katz, LA Narayan, KMV Nwachuku, C O'Connor, PJ Zhang, P AF Sullivan, Mark D. Anderson, Roger T. Aron, David Atkinson, Hal H. Bastien, Arnaud Chen, G. John Feeney, Patricia Gafni, Amiram Hwang, Wenke Katz, Lois A. Narayan, K. M. Venkat Nwachuku, Chuke O'Connor, Patrick J. Zhang, Ping CA ACCORD Study Grp TI Health-related quality of life and cost-effectiveness components of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial: Rationale and design SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID GLYCEMIC CONTROL; MELLITUS; VALIDATION; THERAPY; UTILITY AB Diabetes mellitus affects not only life expectancy but also quality of life. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial's health-related quality of life (HRQOL) and cost-effectiveness components will enable the assessment of the relative importance of the various outcomes from the point of view of patients, provide an understanding of the balance between the burdens and benefits of the intervention strategies, and offer valuable insights into adherence. The HRQOL measures used include the Diabetes Symptoms Distress Checklist; the 36-Item Short Form Health Survey, Version 2 (SF-36) (RAND Corporation, Santa Monica, CA); the Patient Health Questionnaire (PHQ) depression measure (Pfizer Inc, New York, NY); the World Health Organization (WHO) Diabetes Treatment Satisfaction Questionnaire (DTSQ); and the EuroQol Feeling Thermometer (EuroQol Group, Rotterdam, Netherlands). The cost-effectiveness analysis (CEA) in ACCORD will provide information about the relative economic efficiency of the different interventions being compared in the trial. Effectiveness will be measured in terms of cardiovascular event-free years gained and quality-adjusted life-years gained (using the Health Utilities Index Mark 3 [HUI-3] [Health Utilities Inc., Dundas, Ontario, Canada] to measure health-state utility). Costs will be direct medical costs assessed from the perspective of a single-payer health system collected by means of patient and clinic cost forms and hospital discharge summaries. The primary HRQOL and CEA hypotheses mirror those in the main ACCORD trial, addressing the effects of the 3 main ACCORD interventions considered separately. There are also secondary. (pairwise reference case) comparisons that do not assume independence of treatment effects on HRQOL. CEA will be done on a subsample of 4,311 ACCORD participants and HRQOL on a subsample of 2,053 nested within the CEA subsample. Most assessments will occur through questionnaires at baseline and at 12, 36, and 48 months. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. Wake Forest Univ, Sch Med, Dept Social Sci & Hlth Policy, Winston Salem, NC USA. Wake Forest Univ, Sch Med, Dept Geriatr Gerontol, Winston Salem, NC USA. Case Western Reserve Univ, Sch Med, Ctr Qual Improvement Res, Louis Stokes Cleveland Dept Vet Affairs Med Ctr, Cleveland, OH 44106 USA. Cooper Univ Hosp, Clin Trials Ctr, Dept Internal Med, Camden, NJ USA. McMaster Univ, Med Ctr, Dept Clin Epidemiol & Biostat, Hamilton, ON, Canada. NY Harbor Healthcare Syst, New York, NY USA. Ctr Dis Control & Prevent, Atlanta, GA USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. HlthPartners Res Fdn, Minneapolis, MN USA. RP Sullivan, MD (reprint author), Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Box 356560,1959 NE Pacific St, Seattle, WA 98195 USA. EM sullimar@u.washington.edu RI Narayan, K.M. Venkat /J-9819-2012 OI Narayan, K.M. Venkat /0000-0001-8621-5405 NR 22 TC 5 Z9 5 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 18 PY 2007 VL 99 IS 12A SU S BP 90I EP 102I DI 10.1016/j.amjcard.2007.03.027 PG 13 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188RV UT WOS:000247937900009 ER PT J AU Chew, EY Ambrosius, WT Howard, LT Greven, CM Johnson, S Danis, RP Davis, MD Genuth, S Domanski, M AF Chew, Emily Y. Ambrosius, Walter T. Howard, Letitia T. Greven, Craig M. Johnson, Samantha Danis, Ronald P. Davis, Matthew D. Genuth, Saul Domanski, Michael CA ACCORD Study Grp TI Rationale, design, and methods of the Action to Control Cardiovascular Risk in Diabetes Eye Study (ACCORD-EYE) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID BLOOD-PRESSURE CONTROL; MICROVASCULAR COMPLICATIONS; PROLIFERATIVE RETINOPATHY; UNITED-STATES; HARD EXUDATE; PROGRESSION; MELLITUS; ONSET; UKPDS; EPIDEMIOLOGY AB Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus. The Action to Control Cardiovascular Risk in Diabetes Eye Study (ACCORD-EYE), a prospective study of a subset of patients in the randomized controlled clinical ACCORD trial, is being conducted at enrollment and after 4 years of follow-up to assess the progression of DR with standardized comprehensive eye exams and fundus photography of 7 standard stereoscopic fields. This study aims to assess the effects of the ACCORD medical treatment strategies of tight control of glycemia and blood pressure and management of dyslipidemia on the course of DR in patients with type 2 diabetes. Photographs will be evaluated at a centralized location using the modified Early Treatment Diabetic Retinopathy Study (ETDRS) classification. The primary outcome of ACCORD-EYE, which will measure the development and progression of DR, is a composite of (1) progression of DR (>= 3 steps on the ETDRS scale), (2) photocoagulation for DR, or (3) vitrectomy for DR. Specifically, the following questions will be addressed: (1) Does a therapeutic strategy targeting a glycosylated hemoglobin (HbA(1c)) level < 6.0% reduce development and progression of DR more than one targeting an HbA(1c) level of 7.0%-7.9% (target median level, 7.5%)? (2) In the context of good glycemic control, does a strategy using a fibrate to increase high-density lipoprotein cholesterol and lower triglyceride levels and a statin to maintain the level of low-density lipoprotein (LDL) cholesterol at < 2.59 mmol/L (100 mg/dL) reduce development and progression of DR compared with one using placebo and a statin to treat LDL cholesterol? (3) In the context of good glycemic control, does a strategy targeting a systolic blood pressure level < 120 mm Hg reduce development and progression of DR compared with one targeting a level < 140 mm Hg? Secondary outcome variables include various levels of loss of visual acuity at 4 years versus baseline, cataract extraction, and the development or progression of diabetic macular edema. Methods to measure DR progression have been incorporated into ACCORD, and complete baseline data have been collected on 3,537 participants. These data will provide valuable information regarding the effects of medical treatment on the prevention and progression of DR. (c) 2007 Elsevier Inc. All rights reserved. C1 NEI, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. Wake Forest Univ, Sch Med, Dept Ophthalmol, Winston Salem, NC USA. Univ Wisconsin, Dept Ophthalmol, Madison, WI USA. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. NHLBI, Div Cardiovasc Dis, Atherothrombosis & Coronary Artery Dis Branch, Bethesda, MD 20892 USA. RP Chew, EY (reprint author), NEI, Div Epidemiol & Clin Res, Bldg 10,CRC,Room 3-2531,10 Ctr Dr MSC-1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU Intramural NIH HHS [ZIA EY000410-04, Z99 EY999999]; NHLBI NIH HHS [Y1-HC-9035, N01-HC-95178, N01-HC-95182, N01-HC-95184, N01-HC-95183, N01-HC-95179, N01-HC-95181, Y1-HC-1010, N01-HC-95180] NR 26 TC 15 Z9 16 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 18 PY 2007 VL 99 IS 12A SU S BP 103I EP 111I DI 10.1016/j.amjcard.2007.03.028 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188RV UT WOS:000247937900010 PM 17599420 ER PT J AU Williamson, JD Miller, ME Bryan, RN Lazar, RM Coker, LH Johnson, J Cukierman, T Horowitz, KR Murray, A Launer, LJ AF Williamson, Jeff D. Miller, Michael E. Bryan, R. Nick Lazar, Ronald M. Coker, Laura H. Johnson, Janice Cukierman, Tali Horowitz, Karen R. Murray, Anne Launer, Lenore J. CA ACCORD Study Grp TI The action to control cardiovascular risk in diabetes memory in diabetes study (ACCORD-MIND): Rationale, design, and methods SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID COGNITIVE IMPAIRMENT; ALZHEIMERS-DISEASE; WOMENS HEALTH; DEMENTIA; MELLITUS; POPULATION; BRAIN; INTERFERENCE; DETERMINANTS; DECLINE AB Type 2 diabetes mellitus and cognitive impairment are 2 of the most common chronic conditions found in persons aged >= 60 years. Clinical studies have shown a greater prevalence of global cognitive impairment, incidence of cognitive decline, and incidence of Alzheimer disease in patients with type 2 diabetes. To date, there have been no randomized trials of the effects of long-term glycemic control on cognitive function and structural brain changes in patients with type 2 diabetes. The primary aim of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Memory in Diabetes Study (ACCORD-MIND) is to test whether there is a difference in the rate of cognitive decline and structural brain change in patients with diabetes treated with standard-care guidelines compared with those treated with intensive-care guidelines. This comparison will be made in a subsample of 2,977 patients with diabetes participating in the ongoing ACCORD trial, a clinical trial sponsored by the National Heart, Lung, and Blood Institute (NHLBI) with support from the National Institute on Aging (NIA). Data from this ACCORD substudy on the possible beneficial or adverse effects of intensive treatment on cognitive function will be obtained from a 30-minute test battery, administered at baseline and 20-month and 40-month visits. In addition, full-brain magnetic resonance imaging will be performed on 630 participants at baseline and at 40 months to assess the relation between the ACCORD treatments and structural brain changes. The general aim of ACCORD-MIND is to determine whether the intensive treatment of diabetes, a major risk factor for Alzheimer disease and vascular dementia, can reduce the early decline in cognitive function that could later evolve into more cognitively disabling conditions. This report presents the design, rationale, and methods of the ACCORD-MIND substudy. (c) 2007 Elsevier Inc. All rights reserved. C1 Wake Forest Univ, Sch Med, Ctr Mem Cognit Res, Dept Internal Med, Winston Salem, NC USA. Wake Forest Univ, Sch Med, Dept Biostat Sci, Div Publ Hlth Sci, Winston Salem, NC USA. Wake Forest Univ, Sch Med, Dept Social Sci & Hlth Policy, Winston Salem, NC USA. Univ Penn, Sch Med, Dept Radiol, Philadelphia, PA 19104 USA. Columbia Univ, Coll Phys & Surg, Dept Neurol, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Neurosurg, New York, NY USA. Univ Washington, Med Ctr, Seattle, WA 98195 USA. McMaster Univ, Hamilton Hlth Sci, Hamilton, ON, Canada. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. NIH, NIA, Intramural Res Program, Bethesda, MD 20892 USA. RP Launer, LJ (reprint author), NIH, Intramural Res Program, Bethesda, MD 20892 USA. EM LaunerL@exmur.nia.nih.gov RI Hegele, Robert/G-3301-2011 FU NHLBI NIH HHS [N01-HC-95183, HC-99-16, N01-HC-95178, N01-HC-95179, N01-HC-95180, N01-HC-95181, N01-HC-95182, N01-HC-95184, Y1-HC-1010, Y1-HC-9035] NR 35 TC 22 Z9 22 U1 0 U2 3 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 18 PY 2007 VL 99 IS 12A SU S BP 112I EP 122I DI 10.1016/j.amjcard.2007.03.029 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188RV UT WOS:000247937900011 PM 17599421 ER PT J AU Koo, TH Eipper, BA Donaldson, JG AF Koo, Tae Hyeon Eipper, Betty A. Donaldson, Julie G. TI Arf6 recruits the Rac GEF Kalirin to the plasma membrane facilitating Rac activation SO BMC CELL BIOLOGY LA English DT Article ID GUANINE-NUCLEOTIDE EXCHANGE; CELL-MIGRATION; FACTOR DOMAINS; DOWNSTREAM ACTIVATION; NEURITE OUTGROWTH; ENDOGENOUS ARF6; RHO; PROTEIN; TRIO; ACTIN AB Background: Many studies implicate Arf6 activity in Rac-mediated membrane ruffling and cytoskeletal reorganization. Although Arf6 facilitates the trafficking of Racl to the plasma membrane and in many cases Arf6 activation leads to the activation of Racl, the details of how Arf6 influences Rac function remain to be elucidated. Results: We demonstrate in binding assays and by co-immunoprecipitation that GDP-bound Arf6 binds to Kalirin5, a Rho family guanine nucleotide exchange factor, through interaction with the spectrin repeat region. In cells, expression of wild type Arf6 recruits spectrin repeat 5 and Kalirin to the plasma membrane and leads to enhanced Kalirin5-induced ruffling. By contrast, expression of an Arf6 mutant that cannot become activated, Arf6 T27N, still recruits spectrin repeat 5 and Kalirin to membranes but inhibits Kalirin5-induced ruffling in HeLa cells. Kalirin5-induced Racl activation is increased by the expression of wild type Arf6 and decreased by Arf6T27N. Furthermore, expression of a catalytically-inactive mutant of Kalirin5 inhibits cytoskeletal changes observed in cells expressing EFA6, an Arf6 guanine nucleotide exchange factor that leads to activation of Rac. Conclusion: We show here with over-expressed proteins that the GDP-bound form of Arf6 can bind to the spectrin repeat regions in Kalirin Rho family GEFs thereby recruiting Kalirin to membranes. Although Kalirin is recruited onto membranes by Arf6-GDP, subsequent Rac activation and membrane ruffling requires Arf6 activation. From these results, we suggest that Arf6 can regulate through its GTPase cycle the activation of Rac. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Connecticut, Ctr Hlth, Dept Neurosci, Farmington, CT 06030 USA. RP Donaldson, JG (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 50,Rm 2503, Bethesda, MD 20892 USA. EM gutae@kfda.go.kr; Eipper@uchc.edu; jdonalds@helix.nih.gov FU Intramural NIH HHS; NIDDK NIH HHS [DK32948, R01 DK032948, R56 DK032948] NR 39 TC 36 Z9 36 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2121 J9 BMC CELL BIOL JI BMC Cell Biol. PD JUL 18 PY 2007 VL 8 AR 29 DI 10.1186/1471-2121-8-29 PG 10 WC Cell Biology SC Cell Biology GA 199PD UT WOS:000248706800002 PM 17640372 ER PT J AU Coates, PM AF Coates, Paul M. TI Evidence-based reviews in support of health policy decisions SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material C1 NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Coates, PM (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Rm 3B01, Bethesda, MD 20892 USA. EM pc6ls@nih.gov NR 4 TC 3 Z9 3 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 18 PY 2007 VL 99 IS 14 BP 1059 EP 1059 DI 10.1093/jnci/djm049 PG 1 WC Oncology SC Oncology GA 200BD UT WOS:000248738000001 PM 17623794 ER PT J AU Mangiameli, DP Blansfield, JA Kachala, S Lorang, D Schafer, PH Muller, GW Stirling, DI Libutti, SK AF Mangiameli, David P. Blansfield, Joseph A. Kachala, Stephan Lorang, Dominique Schafer, Peter H. Muller, George W. Stirling, David I. Libutti, Steven K. TI Combination therapy targeting the tumor microenvironment is effective in a model of human ocular melanoma SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID MULTIPLE-MYELOMA CELLS; THALIDOMIDE ANALOGS; IN-VITRO; PHOSPHORYLATION; GENE; MICE AB Background: Ocular melanoma is the leading intraocular malignancy. There is no effective treatment for metastatic ocular melanoma. We sought a treatment targeting the tumor microenvironment as well as the tumor cells. Methods: Migration of HUVEC cells, the ability of HUVEC cells to form tubes, and proliferative capacity of a human ocular melanoma cell line were tested in the presence of lenalidomide and sorafenib alone and in combination. The compounds were also tested in a rat aortic ring assay and were tested in a highly aggressive human ocular melanoma xenograft model. Results: Lenalidomide and Sorafenib inhibit HUVEC ability to migrate and form tubes and when used in combination the inhibition is increased. The agents alone and in combination inhibit outgrowth in the rat aortic ring model. The combination of the agents improved the inhibition over either single agent. In a xenograft model, combination therapy inhibited tumor growth over inhibition by single agent alone in a significant fashion ( p < 0.004: lenalidomide and p < 0.0035: sorafenib). Furthermore, spontaneous lung metastasis development was completely inhibited in the combination treated animals. Sixty percent of vehicle treated animals developed lung metastases compared to 50% of lenalidomide treated animals, and 33% of sorafenib treated animals. Conclusion: Lenalidomide and sorafenib are effective at targeting endothelial cells, inhibiting growth of ocular melanoma cells and can inhibit growth of tumors in a xenograft model as well as inhibit development of metastases. Combining these agents works in an additive to synergistic way to inhibit the growth of tumors and development of metastases. C1 NCI, NIH, Surg Branch, Tumor Angiogenesis Sect, Bethesda, MD 20892 USA. Celgene Corp, Summit, NJ USA. RP Libutti, SK (reprint author), NCI, NIH, Surg Branch, Tumor Angiogenesis Sect, Bethesda, MD 20892 USA. EM david_mangiameli@nih.gov; joseph_blansfield@nih.gov; stephan_kachala@nih.gov; dominique_lorang@nih.gov; pschafer@celgene.com; gmuller@celgene.com; dstirling@celgene.com; libuttis@mail.nih.gov NR 19 TC 23 Z9 24 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUL 18 PY 2007 VL 5 AR 38 DI 10.1186/1479-5876-5-38 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 198UG UT WOS:000248652400001 PM 17640369 ER PT J AU Wu, T Zang, YF Wang, L Long, XY Hallett, M Chen, Y Li, KC Chan, P AF Wu, Tao Zang, Yufeng Wang, Liang Long, Xiangyu Hallett, Mark Chen, Yi Li, Kuncheng Chan, Piu TI Aging influence on functional connectivity of the motor network in the resting state SO NEUROSCIENCE LETTERS LA English DT Article DE aging; functional connectivity; motor network; resting state ID POSITRON EMISSION TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; PREMOTOR AREAS; MOVEMENTS; CORTEX; MRI; DISEASE; IMAGES; BRAIN; FMRI AB We used functional MRI (fMRI) to study the aging influence on functional connectivity of the motor network in the resting state. A network model based on graph theory was used to measure functional connectivity. The total connectivity degree of each region within the motor network was calculated and compared between aged and young groups. We found that the pattern of functional connectivity was changed in aged subjects, including a significant decrease in the functional connectivity degree of the right cingulate motor area and left premotor area compared to young subjects. Our study demonstrates that normal aging modulates the functional connectivity of motor network in the resting state. We postulate that this abnormal functional connectivity of motor network in the baseline state is an important reason contributing to the deteriorated motor ability in aged subjects. (c) 2007 Elsevier Ireland Ltd. All rights reserved. C1 Capital Med Univ, Xuanwu Hosp, Dept Neurol, Beijing Inst Geriatr, Beijing 100053, Peoples R China. Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. Capital Med Univ, Xuanwu Hosp, Dept Radiol, Beijing, Peoples R China. NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Chan, P (reprint author), Capital Med Univ, Xuanwu Hosp, Dept Neurol, Beijing Inst Geriatr, 45 Changchun St, Beijing 100053, Peoples R China. EM pbchan@bjsap.org RI Wang, Liang/E-8652-2011; ZANG, Yu-Feng/J-1558-2012 OI ZANG, Yu-Feng/0000-0003-1833-8010 NR 24 TC 44 Z9 45 U1 0 U2 6 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 JUL 18 PY 2007 VL 422 IS 3 BP 164 EP 168 DI 10.1016/j.neulet.2007.06.011 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 203MV UT WOS:000248979600004 PM 17611031 ER PT J AU Goh, SH Josleyn, M Lee, YT Danner, RL Gherman, RB Cam, MC Miller, JL AF Goh, Sung-Ho Josleyn, Matthew Lee, Y. Terry Danner, Robert L. Gherman, Robert B. Cam, Maggie C. Miller, Jeffery L. TI The human reticulocyte transcriptome SO PHYSIOLOGICAL GENOMICS LA English DT Article DE microarray; erythropoiesis; hemoglobin; malaria; iron ID ERYTHROID-DIFFERENTIATION; GLOBIN GENE; PROTEIN; BLOOD; IDENTIFICATION; APOPTOSIS; MEMBRANE AB RNA from circulating blood reticulocytes was utilized to provide a robust description of genes transcribed at the final stages of erythroblast maturation. After depletion of leukocytes and platelets, Affymetrix HG- U133 arrays were hybridized with probe generated from the reticulocyte total RNA ( blood obtained from 14 umbilical cords and 14 healthy adult humans). Among the cord and adult reticulocyte profiles, 698 probe sets ( 488 named genes) were detected in each of the 28 samples. Among the highly expressed genes, promoter analyses revealed a subset of transcription factor binding motifs encoded at higher than expected frequencies including the hypoxia- related arylhydrocarbon receptor repressor family. Over 100 probe sets demonstrated differential expression between the cord and adult reticulocyte samples. For verification, the array expression patterns for 21 genes were confirmed by real-time PCR ( correlation coefficient 0.98). Only four transcripts ( MAP17, FLJ32009, ARRB2, and FLJ27365) were identified as being upregulated in the adult blood transcriptome. Further analysis revealed that the lipid-regulating protein MAP17 was present in the membrane fraction of adult erythrocytes, but not detected in cord blood erythrocytes. Combined with other clinical and experimental data, these reticulocyte transcriptome profiles should be useful to better understand the molecular bases of terminal erythroid differentiation, hemoglobin switching, iron metabolism and malarial patho-genesis. C1 Natl Inst Hlth, Mol Med Branch, Natl Inst Diabet Digest & Kidney, Bethesda, MD 20892 USA. Natl Inst Hlth, Microarray Core Facil, Bethesda, MD USA. Natl Naval Med Ctr, Bethesda, MD USA. RP Miller, JL (reprint author), Natl Inst Hlth, Mol Med Branch, Natl Inst Diabet Digest & Kidney, 10 Ctr Dr,Bldg 10,Rm 9B 17, Bethesda, MD 20892 USA. EM jm7f@nih.gov FU Intramural NIH HHS NR 22 TC 50 Z9 50 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD JUL 18 PY 2007 VL 30 IS 2 BP 172 EP 178 DI 10.1152/physiolgenomics.00247.2006 PG 7 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 201OL UT WOS:000248841700008 PM 17405831 ER PT J AU Baena, A Mootnick, AR Falvo, JV Tsytsykova, AV Ligeiro, F Diop, OM Brieva, C Gagneux, P O'Brien, SJ Ryder, OA Goldfeld, AE AF Baena, Andres Mootnick, Alan R. Falvo, James V. Tsytsykova, Alla V. Ligeiro, Filipa Diop, Ousmane M. Brieva, Claudia Gagneux, Pascal O'Brien, Stephen J. Ryder, Oliver A. Goldfeld, Anne E. TI Primate TNF Promoters Reveal Markers of Phylogeny and Evolution of Innate Immunity SO PLOS ONE LA English DT Article ID TUMOR-NECROSIS-FACTOR; FACTOR-ALPHA GENE; SINGLE-NUCLEOTIDE POLYMORPHISMS; COMPARATIVE SEQUENCE-ANALYSIS; TRANSCRIPTION FACTOR-BINDING; MONKEY SAIMIRI-SCIUREUS; NEW-WORLD MONKEYS; DNA EVIDENCE; EXPRESSION PATTERNS; MOLECULAR PHYLOGENY AB Background. Tumor necrosis factor (TNF) is a critical cytokine in the immune response whose transcriptional activation is controlled by a proximal promoter region that is highly conserved in mammals and, in particular, primates. Specific single nucleotide polymorphisms (SNPs) upstream of the proximal human TNF promoter have been identified, which are markers of human ancestry. Methodology/Principal findings. Using a comparative genomics approach we show that certain fixed genetic differences in the TNF promoter serve as markers of primate speciation. We also demonstrate that distinct alleles of most human TNF promoter SNPs are identical to fixed nucleotides in primate TNF promoters. Furthermore, we identify fixed genetic differences within the proximal TNF promoters of Asian apes that do not occur in African ape or human TNF promoters. Strikingly, protein-DNA binding assays and gene reporter assays comparing these Asian ape TNF promoters to African ape and human TNF promoters demonstrate that, unlike the fixed differences that we define that are associated with primate phylogeny, these Asian ape-specific fixed differences impair transcription factor binding at an Sp1 site and decrease TNF transcription induced by bacterial stimulation of macrophages. Conclusions/significance. Here, we have presented the broadest interspecies comparison of a regulatory region of an innate immune response gene to date. We have characterized nucleotide positions in Asian ape TNF promoters that underlie functional changes in cell type-and stimulus-specific activation of the TNF gene. We have also identified ancestral TNF promoter nucleotide states in the primate lineage that correspond to human SNP alleles. These findings may reflect evolution of Asian and African apes under a distinct set of infectious disease pressures involving the innate immune response and TNF. C1 [Baena, Andres; Falvo, James V.; Tsytsykova, Alla V.; Ligeiro, Filipa; Goldfeld, Anne E.] Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA. [Mootnick, Alan R.] Gibbon Conservat Ctr, Santa Clarita, CA USA. [Diop, Ousmane M.] Inst Pasteur, Lab Retrovirol, Dakar, Senegal. [Brieva, Claudia] Univ Nacl Colombia, Fac Med Vet & Zootecn, Unidad Rescate & Rehabil Anim Silvestres, Bogota, Colombia. [Gagneux, Pascal] Univ Calif San Diego, Dept Med & Cellular & Mol Med, Project Explaining Origin Humans, Glycobiol Res & Training Ctr, La Jolla, CA 92093 USA. [O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21701 USA. [Ryder, Oliver A.] Zool Soc San Diego, San Diego, CA USA. [Ryder, Oliver A.] Univ Calif San Diego, Div Biol Sci, La Jolla, CA 92093 USA. RP Goldfeld, AE (reprint author), Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA. EM goldfeld@cbrinstitute.org FU NIH [GM076685, HL59838]; NSF [0094993] FX This work was supported by grants from the NIH to A. E. G. (GM076685 and HL59838) and an NSF grant (0094993) to O.A.R. NR 111 TC 17 Z9 17 U1 2 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD JUL 18 PY 2007 VL 2 IS 7 AR e621 DI 10.1371/journal.pone.0000621 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10GI UT WOS:000207452100011 PM 17637837 ER PT J AU Jimenez, M Rivas, G Minton, AP AF Jimenez, Mercedes Rivas, German Minton, Allen P. TI Quantitative characterization of weak self-association in concentrated solutions of immunoglobulin G via the measurement of sedimentation equilibrium and osmotic pressure SO BIOCHEMISTRY LA English DT Article ID PROTEINS; CHALLENGES; DEPENDENCE; MODEL AB The sedimentation equilibrium of solutions of immunoglobulin G in saline buffer, over a concentration range up to 125 g/L, was measured and analyzed in the context of a model that takes into account the possibility of attractive intermolecular interaction leading to the reversible formation of oligomeric species and repulsive intermolecular interaction leading to nonideal solution behavior. Additionally, previously published data on the concentration dependence of the osmotic pressure of immunoglobulin G under similar conditions, over a concentration range up to 400 g/L, were analyzed in the context of a newly developed thermodynamic formalism describing the osmotic pressure of a solution containing multiple nondiffusible solute species at an arbitrary concentration. Both sets of data are quantitatively accounted for by a model in which IgG self-associates at very high concentration to form (predominantly) trimers under the conditions of these experiments. C1 NIDDKD, Lab Biochem & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. CSIC, Dept Prot Sci, Ctr Invest Biol, E-28040 Madrid, Spain. RP Minton, AP (reprint author), NIDDKD, Lab Biochem & Genet, NIH, US Dept Hlth & Human Serv, Bldg 8,Room 226, Bethesda, MD 20892 USA. EM minton@helix.nih.gov RI Jimenez Sarmiento, Mercedes/K-2691-2014; OI Jimenez Sarmiento, Mercedes/0000-0003-2006-1903; Minton, Allen/0000-0001-8459-1247; Rivas, German/0000-0003-3450-7478 FU Intramural NIH HHS NR 26 TC 31 Z9 31 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 17 PY 2007 VL 46 IS 28 BP 8373 EP 8378 DI 10.1021/bi7005515 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 188BI UT WOS:000247893000016 PM 17590018 ER PT J AU Omland, T Sabatine, MS Jablonski, KA Rice, MM Hsia, J Wergeland, R Landaas, S Rouleau, JL Domanski, MJ Hall, C Pfeffer, MA Braunwald, E AF Omland, Torbjorn Sabatine, Marc S. Jablonski, Kathleen A. Rice, Madeline Murguia Hsia, Judith Wergeland, Ragnhild Landaas, Sverre Rouleau, Jean L. Domanski, Michael J. Hall, Christian Pfeffer, Marc A. Braunwald, Eugene CA PEACE Investigators TI Prognostic value of B-Type natriuretic peptides in patients with stable coronary artery disease - The PEACE trial SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID AMINO-TERMINAL PROBNP; C-REACTIVE PROTEIN; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; HEART-FAILURE; CLINICAL-PRACTICE; CARDIAC-FUNCTION; NT-PROBNP; RISK; PLASMA AB Objectives The purpose of this study was to assess the association between B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the incidence of specific cardiovascular events in low-risk patients with stable coronary disease, the incremental prognostic information obtained from these two biomarkers compared with traditional risk factors, and their ability to identify patients who may benefit from angiotensin-converting enzyme (ACE) inhibition. Background The prognostic value of BNPs in low-risk patients with stable coronary artery disease remains unclear. Methods Baseline plasma BNP and NT-proBNP concentrations were measured in 3,761 patients with stable coronary artery disease and preserved left ventricular function participating in the PEACE (Prevention of Events With Angiotensin-Converting Enzyme Inhibition) study, a placebo-controlled trial of trandolapril. Multivariable Cox regression was used to assess the association between natriuretic peptide concentrations and the incidence of cardiovascular mortality, fatal or nonfatal myocardial infarction, heart failure, and stroke. Results The BNP and NT-proBNP levels were strongly related to the incidence of cardiovascular mortality, heart failure, and stroke but not to myocardial infarction. In multivariable models, BNP remained associated with increased risk of heart failure, whereas NT-proBNP remained associated with increased risk of cardiovascular mortality, heart failure, and stroke. By C-statistic calculations, BNP and NT-proBNP significantly improved the predictive accuracy of the best available model for incident heart failure, and NT-proBNP also improved the model for cardiovascular death. The magnitude of effect of ACE inhibition on the likelihood of experiencing cardiovascular end points was similar, regardless of either BNP or NT-proBNP baseline concentrations. Conclusions In low-risk patients with stable coronary artery disease and preserved ventricular function, BNPs provide strong and incremental prognostic information to traditional risk factors. C1 Akershus Univ Hosp, Dept Med, NO-1478 Lorenskog, Norway. Univ Oslo, Fac Med, Oslo, Norway. Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. George Washington Univ, Rockville, MD USA. George Washington Univ, Washington, DC USA. Rikshosp Radiumhosp Med Ctr, Dept Med Biochem, Oslo, Norway. Ullevaal Univ Hosp, Dept Clin Chem, Oslo, Norway. Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada. NHLBI, Bethesda, MD 20892 USA. RP Omland, T (reprint author), Akershus Univ Hosp, Dept Med, NO-1478 Lorenskog, Norway. EM torbjorn.omland@medisin.uio.no FU NHLBI NIH HHS [N01HC65149] NR 34 TC 113 Z9 119 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 JUL 17 PY 2007 VL 50 IS 3 BP 205 EP 214 DI 10.1016/j.jacc.2007.03.038 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 192YY UT WOS:000248241200001 PM 17631211 ER PT J AU Zhu, ZY Chakraborti, S He, Y Roberts, A Sheahan, T Xiao, XD Hensley, LE Prabakaran, P Rockx, B Sidorov, IA Corti, D Vogel, L Feng, Y Kim, JO Wang, LF Baric, R Lanzavecchia, A Curtis, KM Nabel, GJ Subbarao, K Jiang, S Dimitrov, DS AF Zhu, Zhongyu Chakraborti, Samitabh He, Yuxian Roberts, Anjeanette Sheahan, Tim Xiao, Xiaodong Hensley, Lisa E. Prabakaran, Ponraj Rockx, Barry Sidorov, Igor A. Corti, Davide Vogel, Leatrice Feng, Yang Kim, Jae-Ouk Wang, Lin-Fa Baric, Ralph Lanzavecchia, Antonio Curtis, Kristopher M. Nabel, Gary J. Subbarao, Kanta Jiang, Shibo Dimitrov, Dimiter S. TI Potent cross-reactive neutralization of SARS coronavirus isolates by human monoclonal antibodies SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE epitope; paratope; vaccine; therapeutic ID ACUTE RESPIRATORY SYNDROME; RECEPTOR-BINDING DOMAIN; GOLDEN SYRIAN-HAMSTERS; S-GLYCOPROTEIN; SPIKE PROTEIN; PALM CIVET; INFECTION; COV; REPLICATION; EVOLUTION AB The severe acute respiratory syndrome coronavirus (SARS-CoV) caused a worldwide epidemic in late 2002/early 2003 and a second outbreak in the winter of 2003/2004 by an independent animal-to-human transmission. The GD03 strain, which was isolated from an index patient of the second outbreak, was reported to resist neutralization by the human monoclonal antibodies (hmAbs) 80R and S3.1, which can potently neutralize isolates from the first outbreak. Here we report that two hmAbs, m396 and S230.15, potently neutralized GD03 and representative isolates from the first SARS outbreak (Urbani, Tor2) and from palm civets (SZ3, SZ16). These antibodies also protected mice challenged with the Urbani or recombinant viruses bearing the GD03 and SZ16 spike (S) glycoproteins. Both antibodies competed with the SARS-CoV receptor, ACE2, for binding to the receptor-binding domain (RBD), suggesting a mechanism of neutralization that involves interference with the SARS-CoV-ACE2 interaction. Two putative hot-spot residues in the RBD (Ile-489 and Tyr-491) were identified within the SARS-CoV spike that likely contribute to most of the m396-binding energy. Residues Ile-489 and Tyr-491 are highly conserved within the SARS-CoV spike, indicating a possible mechanism of the m396 cross-reactivity. Sequence analysis and mutagenesis data show that m396 might neutralize all zoonotic and epidemic SARS-CoV isolates with known sequences, except strains derived from bats. These antibodies exhibit cross-reactivity against isolates from the two SARS outbreaks and palm civets and could have potential applications for diagnosis, prophylaxis, and treatment of SARSCoV infections. C1 NIH, Natl Canc Inst, Ctr Canc Res Nanobiol Program, Ft Detrick, MD 21702 USA. NIH, Ctr Canc Res Nanobiol Program, Protein Interact Grp, Ft Detrick, MD 21702 USA. NIH, NCI, SAIC Frederick Inc, Basic Res Program, Ft Detrick, MD 21702 USA. New York Blood Ctr, Lindsley F Kimball Res Inst, Lab Viral Immunol, New York, NY 10021 USA. NIH, NIAID, Lab Infect Dis, Bethesda, MD 20892 USA. NIH, NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. United States Army Med Res Inst Infect Dis, Div Virol, Ft Detrick, MD 21702 USA. Inst Res Biomed, CH-6500 Bellinzona, Switzerland. CSIRO, Livestock Ind, Australian Biosecur Cooperat Res Ctr Emerging Inf, Australian Anim Hlth Lab, Geelong, Vic 3220, Australia. RP Dimitrov, DS (reprint author), NIH, Natl Canc Inst, Ctr Canc Res Nanobiol Program, PO Box B,Bldg 469,Room 150B, Ft Detrick, MD 21702 USA. EM dimitrov@ncifcrf.gov RI Jiang, Shibo/L-4500-2014; Ponraj, Prabakaran/D-6325-2011; OI Sidorov, Igor/0000-0001-6519-4983 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [R01 AI059136, AI059434, AI059136, P01 AI059443] NR 42 TC 61 Z9 68 U1 1 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 JUL 17 PY 2007 VL 104 IS 29 BP 12123 EP 12128 DI 10.1073/pnas.0701000104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 192KA UT WOS:000248199200047 PM 17620608 ER PT J AU White, JF Grodnitzky, J Louis, JM Trinh, LB Shiloach, J Gutierrez, J Northup, JK Grisshammer, R AF White, Jim F. Grodnitzky, Justin Louis, John M. Trinh, Loc B. Shiloach, Joseph Gutierrez, Joanne Northup, John K. Grisshammer, Reinhard TI Dimerization of the class A G protein-coupled neurotensin receDtor NTS1 alters G protein interaction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE dimer; G protein activation; G protein-coupled receptor; monomer ID TRANSDUCIN-ALPHA-SUBUNIT; ESCHERICHIA-COLI; GAMMA-SUBUNIT; BETA-GAMMA; RECEPTOR HOMODIMERIZATION; LIGHT-SCATTERING; RHODOPSIN; ACTIVATION; MEMBRANES; PURIFICATION AB G protein-coupled receptors (GPCRs) have been found as monomers but also as dimers or higher-order oligomers in cells. The relevance of the monomeric or dimeric receptor state for G protein activation is currently under debate for class A rhodopsin-like GPCRs. Clarification of this issue requires the availability of well defined receptor preparations as monomers or dimers and an assessment of their ligand-binding and G protein-coupling properties. We show by pharmacological and hydrodynamic experiments that purified neurotensin receptor NTS1, a class A GPCR, dimerizes in detergent solution in a concentration-dependent manner, with an apparent affinity in the low nanomolar range. At low receptor concentrations, NTS1 binds the agonist neurotensin with a Hill slope of approximate to 1; at higher receptor concentrations, neurotensin binding displays positive cooperativity with a Hill slope of approximate to 2. NTS1 monomers activate GaqB(1 gamma 2), whereas receptor dimers catalyze nucleotide exchange with lower affinity. Our results demonstrate that NTS1 dimerization per se is not a prerequisite for G protein activation. C1 NIH, NINDS, Rockville, MD 20852 USA. NINDS, Membrane Protein Struct & Funct Unit, Bethesda, MD 20892 USA. NIH, NIDDKD, Chem Phys Lab, Bethesda, MD 20892 USA. NIH, NIDDKD, Dept Hlth & Human Serv, Biotechnol Unit, Bethesda, MD 20892 USA. NIH, Natl Inst Deafness & Commun Disorders, Dept Hlth & Human Serv, Cell Biol Lab, Rockville, MD 20850 USA. RP Grisshammer, R (reprint author), Iowa State Univ, Dept Biomed Sci, Ames, IA 50011 USA. EM rkgriss@helix.nih.gov RI Grisshammer, Reinhard/C-3089-2015 FU Intramural NIH HHS [Z99 DK999999] NR 51 TC 93 Z9 93 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 17 PY 2007 VL 104 IS 29 BP 12199 EP 12204 DI 10.1073/pnas.0705312104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 192KA UT WOS:000248199200060 PM 17620610 ER PT J AU Mori, T Ito, S Namiki, M Suzuki, T Kobayashi, S Matsubayashi, K Sawaguchi, T AF Mori, Tomohisa Ito, Shinobu Namiki, Mizuho Suzuki, Tadashi Kobayashi, Shizuko Matsubayashi, Kenji Sawaguchi, Toshiko TI Involvement of free radicals followed by the activation of phospholipase A(2) in the mechanism that underlies the combined effects of methamphetamine and morphine on subacute toxicity or lethality in mice: Comparison of the therapeutic potential of fullerene, mepacrine, and cooling SO TOXICOLOGY LA English DT Article DE methamphetamine; morphine; mepacrine; fullerene ID NITRIC-OXIDE SYNTHASE; POLY(ADP-RIBOSE) POLYMERASE; INDUCED NEUROTOXICITY; C-60; TEMPERATURE; SUPEROXIDE; ISCHEMIA; NEURONS; DEATH; CELLS AB An increase in polydrug abuse is a major problem worldwide. The coadministration of methamphetamine and morphine increased subacute toxicity or lethality in rodents. However, the underlying mechanisms by which lethality is increased by the coadministration of methamphetamine and morphine are not yet fully understood. Coadministered methamphetamine and morphine induced lethality by more than 80% in BALB/c mice, accompanied by the rupture of cells in the kidney and liver, and an increase in poly (ADP-ribose) polymerase (PARP)-immunoreactive cells in the heart, kidney and liver. The lethal effect and the increase in the incidence of rupture or PARP-immunoreactive cells induced by the coadministration of methamphetamine and morphine was significantly attenuated by pretreatment with mepacrine (phospholipase A(2) inhibitor) or fullerene (a radical scavenger), or by cooling from 30 to 90 min after drug administration. Furthermore, based on the results of the electron spin resonance spin-trapping technique, hydroxyl radicals were increased by the administration of methamphetamine and morphine, and these increased hydroxyl radicals were potently attenuated by fullerene and cooling. These results suggest that hydroxyl radicals plays an important role in the increased lethality induced by the coadministration of methamphetamine plus morphine. The potency of cooling or drugs for decreasing the subacute toxicity or lethality induced by the coadministration of methamphetamine and morphine was in the order fullerene = cooling > mepacrine. These results indicate that fullerene and cooling are beneficial for preventing death that is induced by the coadministration of methamphetamine and morphine. (C) 2007 Published by Elsevier Ireland Ltd. C1 Tokyo Womens Med Univ, Dept Legal Med, Shinjuku Ku, Tokyo 1628666, Japan. Tokyo Womens Med Univ, Dept Emergency Med, Shinjuku Ku, Tokyo 1628666, Japan. Kyoritsu Univ Pharm, Dept Mol Physiol, Minato Ku, Tokyo 1058512, Japan. Mitsubishi Electr Corp, Technol & Business Dev Dept, Chiyoda Ku, Tokyo 1008086, Japan. Natl Inst Drug Abuse, Cellular Pathobiol Unit, Dev Plastic Sect,DHHS, Cellular Neurobiol Res Branch,IRP,NIH, Baltimore, MD 21224 USA. RP Sawaguchi, T (reprint author), Tokyo Womens Med Univ, Dept Legal Med, Shinjuku Ku, 8-1 Kawada Cho, Tokyo 1628666, Japan. EM tsawagu@research.twmu.ac.jp NR 36 TC 11 Z9 12 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD JUL 17 PY 2007 VL 236 IS 3 BP 149 EP 157 DI 10.1016/j.tox.2007.03.027 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 195AP UT WOS:000248385200001 PM 17553606 ER PT J AU Magaki, S Mueller, C Yellon, SM Fox, J Kim, J Snissarenko, E Chin, V Ghosh, MC Kirsch, WM AF Magaki, Shino Mueller, Claudius Yellon, Steven M. Fox, James Kim, Joseph Snissarenko, Eugene Chin, Vernon Ghosh, Manik C. Kirsch, Wolff M. TI Regional dissection and determination of loosely bound and non-heme iron in the developing mouse brain SO BRAIN RESEARCH LA English DT Article DE iron regulatory protein 2; neuroclegeneration; microdissection; iron ID REGULATORY PROTEIN; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; NEURODEGENERATIVE DISORDERS; THERAPEUTIC IMPLICATIONS; MOLECULAR CONTROL; KNOCKOUT MICE; REDOX METALS; RAT-BRAIN; HOMEOSTASIS AB Iron is a trace metal essential for normal brain development but toxic in excess as it is capable of generating highly reactive radicals that damage cells and tissue. Iron is stringently regulated by the iron regulatory proteins, IRP1 and IRP2, which regulate proteins involved in iron homeostasis at the posttranscriptional level. in this study, 12 distinct regions were microdissected from the mouse brain and regional changes in the levels of loosely bound and non-heme iron that occur with development were measured. We examined 6, 12, and 24 week old wildtype C57BL/6 mice and mice with a targeted deletion of iron regulatory protein 2 (IRP2-/-) that have been reported to develop neurodegenerative symptoms in adulthood. In wildtype mice, levels of loosely bound iron decreased while non-heme iron increased with development. In contrast, an increase in loosely bound and a more pronounced increase in non-heme iron was seen in IRP2-/- mice between 6 and 12 weeks of age, stemming from lower levels at 6 weeks (the youngest age examined) compared to wildtype. These results have implications for understanding the increase in regional brain iron that is associated with normal aging and is postulated to be exacerbated in neurodegenerative disorders. (c) 2007 Elsevier B.V. All rights reserved. C1 Loma Linda Univ, Sch Med, Neurosurg Ctr Res, Training Educ, Loma Linda, CA 92350 USA. Loma Linda Univ, Sch Med, Dept Physiol, Ctr Perinatal Biol, Loma Linda, CA 92350 USA. NICHHD, US Natl Inst Hlth, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Kirsch, WM (reprint author), Loma Linda Univ, Sch Med, Neurosurg Ctr Res, Training Educ, Coleman Pavilion,11175 Campus St,Suite 11113, Loma Linda, CA 92350 USA. EM wkirsch@llu.edu RI Mueller, Claudius/A-4459-2012 OI Mueller, Claudius/0000-0003-4499-4724 FU NIA NIH HHS [R01 AG020948-05, R01 AG020948-04, R01 AG020948-01, AG20948, R01 AG020948-03, R01 AG020948, R01 AG020948-02] NR 39 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 16 PY 2007 VL 1158 BP 144 EP 150 DI 10.1016/j.brainres.2007.05.004 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 199QN UT WOS:000248710400015 PM 17560557 ER PT J AU Kim, JA Kruhlak, M Dotiwala, F Nussenzweig, A Haber, JE AF Kim, Jung-Ae Kruhlak, Michael Dotiwala, Farokh Nussenzweig, Andre Haber, James E. TI Heterochromatin is refractory to gamma-H2AX modification in yeast and mammals SO JOURNAL OF CELL BIOLOGY LA English DT Article ID DOUBLE-STRAND-BREAK; DNA-DAMAGE CHECKPOINT; SISTER-CHROMATID RECOMBINATION; RESOLUTION STRUCTURAL-ANALYSIS; HISTONE H2AX PHOSPHORYLATION; SACCHAROMYCES-CEREVISIAE; GENOMIC INSTABILITY; CELL-CYCLE; IN-VIVO; REPAIR AB Double-strand break (DSB) damage in yeast and mammalian cells induces the rapid ATM (ataxia telanglectasia mutated)/ATR (ataxia telangiectasia and Rad3 related)-dependent phosphorylation of histone H2AX (gamma-H2AX). In budding yeast, a single endonuclease-induced DSB triggers gamma-H2AX modification of 50 kb on either side of the DSB. The extent of gamma-H2AX spreading does not depend on the chromosomal sequences. DNA resection after DSB formation causes the slow, progressive loss of gamma-H2AX from single-stranded DNA and, after several hours, the Mecl (ATR)-dependent spreading of gamma-H2AX to more distant regions. Heterochromatic sequences are only weakly modified upon insertion of a 3-kb silent HMR locus into a gamma-H2AX-covered region. The presence of heterochromatin does not stop the phosphorylation of chromatin more distant from the DSB. In mouse embryo fibroblasts, gamma-H2AX distribution shows that gamma-H2AX foci increase in size as chromatin becomes more accessible. In yeast, we see a high level of constitutive gamma-H2AX in telomere regions in the absence of any exogenous DNA damage, suggesting that yeast chromosome ends are transiently detected as DSBs. C1 Brandeis Univ, Rosenstiel Ctr, Waltham, MA 02454 USA. Brandeis Univ, Dept Biol, Waltham, MA 02454 USA. NIH, NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Haber, JE (reprint author), Brandeis Univ, Rosenstiel Ctr, Waltham, MA 02454 USA. EM haber@brandeis.edu RI Dotiwala, Farokh/C-7068-2009 FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM061766-07, GM20056, GM61799, R01 GM020056, R01 GM061766, R01 GM061766-06, R01 GM061766-08, R37 GM020056] NR 40 TC 146 Z9 149 U1 1 U2 7 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 JUL 16 PY 2007 VL 178 IS 2 BP 209 EP 218 DI 10.1083/jcb.200612031 PG 10 WC Cell Biology SC Cell Biology GA 191SE UT WOS:000248151500004 PM 17635934 ER PT J AU Cho, H Kehrl, JH AF Cho, Hyeseon Kehrl, John H. TI Localization of G(i alpha) proteins in the centrosomes and at the midbody: implication for their role in cell division SO JOURNAL OF CELL BIOLOGY LA English DT Article ID HETEROTRIMERIC G-PROTEIN; BETA-GAMMA; G-ALPHA; SIGNALING PROTEINS; ACTIVATION; RGS14; CYTOKINESIS; SUBUNITS; NUMA; ORIENTATION AB At the plasma membrane, heterotrimeric G proteins act as molecular switches to relay signals from G protein-coupled receptors; however, G(alpha) subunits also have receptor-independent functions at intracellular sites. Regulator of G protein signaling (RGS) 14, which enhances the intrinsic GTPase activity of G(i alpha) proteins, localizes in centrosomes, which suggests the coexpression of G(i alpha). We show expression of G(i alpha 1), G(i alpha 2), and G(i alpha 3) in the centrosomes and at the midbody. Fluorescence resonance energy transfer analysis confirms a direct interaction between RGS14 and G(i alpha 1) in centrosomes. Expression of GTPase-deficient G(i alpha 1) results in defective cytokinesis, whereas that of wild-type or GTPase-deficient G(i alpha 3) causes prolonged mitosis. Cells treated with pertussis toxin, with reduced expression of G(i alpha 1), G(i alpha 2), and G(i alpha 3) or with decreased expression of RGS14 also exhibit cytokinesis defects. These results suggest that G(i alpha) proteins and their regulators at these sites may play essential roles during mammalian cell division. C1 NIAID, Immunoregulat Lab, B Cell Mol Immunol Sect, Bethesda, MD 20892 USA. RP Cho, H (reprint author), NIAID, Immunoregulat Lab, B Cell Mol Immunol Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM hcho@niaid.nih.gov; kehrl@niaid.nih.gov FU Intramural NIH HHS NR 32 TC 36 Z9 44 U1 0 U2 3 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 JUL 16 PY 2007 VL 178 IS 2 BP 245 EP 255 DI 10.1083/jcb.200604114 PG 11 WC Cell Biology SC Cell Biology GA 191SE UT WOS:000248151500007 PM 17635935 ER PT J AU Spletter, ML Liu, J Liu, J Su, H Giniger, E Komiyama, T Quake, S Luo, LQ AF Spletter, Maria Lynn Liu, Jian Liu, Justin Su, Helen Giniger, Edward Komiyama, Takaki Quake, Stephen Luo, Liqun TI Lola regulates Drosophila olfactory projection neuron identity and targeting specificity SO NEURAL DEVELOPMENT LA English DT Article ID REPRESSIBLE CELL MARKER; TRANSCRIPTION FACTORS; WIRING SPECIFICITY; AXON GUIDANCE; ZINC-FINGER; MOSAIC ANALYSIS; ANTENNAL LOBE; MAP; PROTEIN; REPRESENTATION AB Background: Precise connections of neural circuits can be specified by genetic programming. In the Drosophila olfactory system, projection neurons (PNs) send dendrites to single glomeruli in the antenna lobe (AL) based upon lineage and birth order and send axons with stereotyped terminations to higher olfactory centers. These decisions are likely specified by a PN-intrinsic transcriptional code that regulates the expression of cell-surface molecules to instruct wiring specificity. Results: We find that the loss of longitudinals lacking (lola), which encodes a BTB-Zn-finger transcription factor with 20 predicted splice isoforms, results in wiring defects in both axons and dendrites of all lineages of PNs. RNA in situ hybridization and quantitative RT-PCR suggest that most if not all lola isoforms are expressed in all PNs, but different isoforms are expressed at widely varying levels. Overexpression of individual lola isoforms fails to rescue the lola null phenotypes and causes additional phenotypes. Loss of lola also results in ectopic expression of Gal4 drivers in multiple cell types and in the loss of transcription factor gene lim1 expression in ventral PNs. Conclusion: Our results indicate that lola is required for wiring of axons and dendrites of most PN classes, and suggest a need for its molecular diversity. Expression pattern changes of Gal4 drivers in lola(-/-) clones imply that lola normally represses the expression of these regulatory elements in a subset of the cells surrounding the AL. We propose that Lola functions as a general transcription factor that regulates the expression of multiple genes ultimately controlling PN identity and wiring specificity. C1 [Spletter, Maria Lynn; Liu, Justin; Su, Helen; Komiyama, Takaki; Luo, Liqun] Stanford Univ, Howard Hughes Med Inst, Dept Biol Sci, Stanford, CA 94305 USA. [Liu, Jian; Quake, Stephen] Stanford Univ, Howard Hughes Med Inst, Dept Bioengn, Stanford, CA 94305 USA. [Liu, Jian] Emory Univ, Dept Biomed Engn, Atlanta, GA 30322 USA. [Su, Helen; Komiyama, Takaki] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Giniger, Edward] Nat Inst Neurol Disorders & Stroke, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Luo, LQ (reprint author), Stanford Univ, Howard Hughes Med Inst, Dept Biol Sci, Stanford, CA 94305 USA. EM spletter@stanford.edu; jliu44@emory.edu; jliu85@stanford.edu; suh@janelia.hhmi.org; ginigere@ninds.nih.gov; komiyamat@janelia.hhmi.org; quake@stanford.edu; lluo@stanford.edu RI Liu, Jian/G-2422-2010; Giniger, Edward/C-1764-2015; OI Giniger, Edward/0000-0002-8340-6158; Spletter, Maria/0000-0002-2068-3350; Liu, Jian/0000-0002-0095-8978 FU Howard Hughes Medical Institute; NIDCD NIH HHS [F31 DC008277] NR 42 TC 40 Z9 40 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1749-8104 J9 NEURAL DEV JI Neural Dev. PD JUL 16 PY 2007 VL 2 AR 14 DI 10.1186/1749-8104-2-14 PG 19 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 345FJ UT WOS:000258981200001 PM 17634136 ER PT J AU Khan, MA Goila-Gaur, R Opi, S Miyagi, E Takeuchi, H Kao, S Strebel, K AF Khan, Mohammad A. Goila-Gaur, Ritu Opi, Sandrine Miyagi, Eri Takeuchi, Hiroaki Kao, Sandra Strebel, Klaus TI Analysis of the contribution of cellular and viral RNA to the packaging of APOBEC3G into HIV-1 virions SO RETROVIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; SIGNAL RECOGNITION PARTICLE; ROUS-SARCOMA VIRUS; POLYNUCLEOTIDE (DEOXY)CYTIDINE DEAMINASES; EDITING ENZYME APOBEC3G; MOLECULAR-WEIGHT RNAS; MESSENGER-RNA; VIF PROTEIN; RETROVIRUS PARTICLES; NUCLEOCAPSID PROTEIN AB Background: Efficient incorporation of the cellular cytidine deaminase APOBEC3G ( APO3G) into HIV-1 virions is necessary for its antiviral activity. Even though cellular RNAs are known to be non-specifically incorporated into virus particles, we have previously found that encapsidation of APO3G into HIV-1 virions is specifically enhanced by viral genomic RNA. Intracellularly, APO3G was found to form large RNA-protein complexes involving a variety of cellular RNAs. The goal of this study was to investigate the possible contribution of host RNAs recently identified in intracellular APO3G ribonucleoprotein complexes to APO3G's encapsidation into HIV-1 virions. Results: Our results show that 7SL RNA, a component of signal recognition particles, and hY1, hY3, hY4, hY5 RNAs were present in intracellular APO3G complexes and were packaged into HIV-1 particles lacking viral genomic RNA unlike APO3G, which was not packaged in significant amounts into genomic RNA-deficient particles. These results indicate that packaging of 7SL or hY RNAs is not sufficient for the packaging of APO3G into HIV-1 virions. We also tested the encapsidation of several other cellular RNAs including beta-actin, GAPDH, alpha-tubulin, and small nuclear RNAs and determined their effect on the packaging of APO3G into nascent virions. Again, we were unable to observe any correlation between APO3G encapsidation and the packaging of any of these cellular RNAs. Conclusion: The results from this study support our previous conclusion that viral genomic RNA is a critical determinant for APO3G incorporation into HIV-1 virions. While most cellular RNAs tested in this study were packaged into viruses or virus-like particles we failed to identify a correlation between APO3G encapsidation and the packaging of these cellular RNAs. C1 NIH, NIAID, Mol Microbiol Lab, Viral Biochem Sec, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIH, NIAID, Mol Microbiol Lab, Viral Biochem Sec, Bldg 4,Rm 310,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. EM mkhan@niaid.nih.gov; rgaur@niaid.nih.gov; opi@marseille.inserm.fr; emiyagi@niaid.nih.gov; htake@ims.u-tokyo.ac.jp; skao@niaid.nih.gov; kstrebel@niaid.nih.gov RI Takeuchi, Hiroaki/F-9728-2012 FU Intramural NIH HHS NR 54 TC 47 Z9 47 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD JUL 16 PY 2007 VL 4 AR 48 DI 10.1186/1742-4690-4-48 PG 11 WC Virology SC Virology GA 204EQ UT WOS:000249026900001 PM 17631688 ER PT J AU Park, Y Subar, AF Kipnis, V Thompson, FE Mouw, T Hollenbeck, A Leitzmann, MF Schatzkin, A AF Park, Yikyung Subar, Amy F. Kipnis, Victor Thompson, Frances E. Mouw, Traci Hollenbeck, Albert Leitzmann, Michael F. Schatzkin, Arthur TI Fruit and vegetable intakes and risk of colorectal cancer in the NIH-AARP diet and health study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; colorectal neoplasms; fruit; vegetables ID WOMENS HEALTH; PROSPECTIVE COHORT; COLON-CANCER; CONSUMPTION; QUESTIONNAIRES; ASSOCIATION; FIBER; JAPAN AB The authors examined the associations between fruit and vegetable intakes and risk of colorectal cancer in the NIH-AARP Diet and Health Study. Diet was assessed with a food frequency questionnaire at baseline. Relative risks and 95% confidence intervals were estimated by using the Cox proportional hazards model. During 5-year follow-up of 488,043 men and women aged 50-71 years, 2,972 incident colorectal cancer cases were identified. The respective 10th and 90th percentiles of total fruit and vegetable intake (servings/1,000 kcal per day) were 1.4 and 5.2 for men and 1.8 and 6.5 for women. Compared with that for the lowest quintile of vegetable intake, the multivariate relative risk for the highest quintile was 0.82 (95% confidence interval: 0.71, 0.94) for men and 1. 12 (95% confidence interval: 0.90, 1.38) for women. Increased risk of colorectal cancer was observed for very low intake of total fruits and vegetables by men (multivariate relative risk for < 1 vs. > 2.0 servings/1,000 kcal per day = 1.26, 95% confidence interval: 1.03, 1.54). Among subgroups of vegetables, green leafy vegetables were associated with a lower risk of colorectal cancer for men (multivariate relative risk for the highest quintile vs. the lowest = 0.86, 95% confidence interval: 0.74, 0.99). Intake of fruits was not related to risk of colorectal cancer in men or women. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20852 USA. NCI, Div Canc Prevent, Bethesda, MD 20852 USA. AARP, Washington, DC USA. RP Park, Y (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20852 USA. EM parkyik@mail.nih.gov OI Park, Yikyung/0000-0002-6281-489X FU Intramural NIH HHS NR 38 TC 38 Z9 40 U1 1 U2 14 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 JUL 15 PY 2007 VL 166 IS 2 BP 170 EP 180 DI 10.1093/aje/kwm067 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 187UA UT WOS:000247872800008 PM 17485731 ER PT J AU Chodick, G Bhatti, P Sigurdson, AJ AF Chodick, G. Bhatti, P. Sigurdson, A. J. TI Re: "Chromosomal aberrations and cancer risk: Results of a cohort study from central Europe" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth Human Serv, Bethesda, MD 20852 USA. RP Chodick, G (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth Human Serv, Bethesda, MD 20852 USA. EM chodickg@mail.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 15 PY 2007 VL 166 IS 2 BP 239 EP 240 DI 10.1093/aje/kwm166 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 187UA UT WOS:000247872800020 PM 17535830 ER PT J AU Makishima, T Madeo, AC Brewer, CC Zalewski, CK Butman, JA Sachdev, V Arai, AE Holbrook, BM Rosing, DR Griffith, AJ AF Makishima, Tomoko Madeo, Anne C. Brewer, Carmen C. Zalewski, Christopher K. Butman, John A. Sachdev, Vandana Arai, Andrew E. Holbrook, Brenda M. Rosing, Douglas R. Griffith, Andrew J. TI Nonsyndromic hearing loss DFNA10 and a novel mutation of EYA4: Evidence for correlation of normal cardiac phenotype mutations of the with truncating Eya domain SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE deafness; cardiomyopathy; ear; EYA4; hearing; hearing loss ID DILATED CARDIOMYOPATHY; SENSORINEURAL DEAFNESS; FAMILY; LOCUS; GENE; IMPAIRMENT; MAPS AB Dominant, truncating mutations of eyes absent 4 (EYA4) on chromosome 6q23 can cause either nonsyndromic hearing loss DFNA10 or hearing loss with dilated cardiomyopathy (DCM). It has been proposed that truncations of the C-terminal Eya domain cause DFNA10 whereas upstream truncations of the N-terminal variable region cause hearing loss with DCM. Here we report an extended family cosegregating autosomal dominant, postlingual-onset, progressive, sensorineural hearing loss (SNHL) with a novel frame-shift mutation, 1490insAA, of EYA4. The 1490insAA allele is predicted to encode a truncated protein with an intact N-terminal variable region, but lacking the entire C-terminal Eya domain. Clinical studies including electrocardiography, echocardiography, and magnetic resonance imaging (MRI) of the heart in nine affected family members revealed no DCM or associated abnormalities and confirmed their nonsyndromic phenotype. These are the first definitive cardiac evaluations of DFNA10 hearing loss to support a correlation of EYA4 mutation position with the presence or absence of DCM. These results will facilitate the counseling of patients with these phenotypes and EYA4 mutations. Published 2007 Wiley-Liss, Inc.(dagger) C1 NIDCD, Otolaryngol Branch, NIH, Rockville, MD 20850 USA. NIH, Diagnost Radiol Branch, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Cardiac Energet, NIH, Bethesda, MD 20892 USA. RP Griffith, AJ (reprint author), NIDCD, Otolaryngol Branch, NIH, 5 Res Court,Room 2A-01, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov RI Butman, John/A-2694-2008; Madeo, Anne/K-2880-2012 FU Intramural NIH HHS NR 14 TC 18 Z9 21 U1 0 U2 1 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 JUL 15 PY 2007 VL 143A IS 14 BP 1592 EP 1598 DI 10.1002/ajmg.a.31793 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 186EB UT WOS:000247760800010 PM 17567890 ER PT J AU Carey, MA Card, JW Voltz, JW Jacobs, ER Dakhama, A Larsen, G Gelfand, EW Zeldin, DC AF Carey, Michelle A. Card, Jeffrey W. Voltz, James W. Jacobs, Elizabeth R. Dakhama, Azzedine Larsen, Gary Gelfand, Erwin W. Zeldin, Darryl C. TI Airway responsiveness should be a measurement of the responsiveness of airways - Reply SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Letter ID HYPERRESPONSIVENESS; MICE C1 NIH, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. Natl Jewish Med & Res Ctr, Denver, CO USA. RP Carey, MA (reprint author), NIH, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 15 PY 2007 VL 176 IS 2 BP 215 EP 216 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 191NP UT WOS:000248138300021 ER PT J AU Vitorino, R Ferreira, R Neuparth, M Guedes, S Williams, J Tomer, KB Domingues, PM Appell, HJ Duarte, JA Amado, FML AF Vitorino, Rui Ferreira, Rita Neuparth, Maria Guedes, Sofia Williams, Jason Tomer, Kenneth B. Domingues, Pedro M. Appell, Hans J. Duarte, Jose A. Amado, Francisco M. L. TI Subcellular proteomics of mice gastrocnemius and soleus muscles SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE skeletal muscle; subcellular fractionation; proteomics ID TWITCH SKELETAL-MUSCLES; MASS-SPECTROMETRY; SLOW-TWITCH; RAT SOLEUS; PROTEINS; EXPRESSION; ISOFORMS; PHOSPHORYLATION; IDENTIFICATION; TRANSITIONS AB A proteomics characterization of mice soleus and gastrocnemius white portion skeletal muscles was performed using nuclear, mitochondrial/membrane, and cytosolic subcellular fractions. The proposed methodology allowed the elimination of the cytoskeleton proteins from the cytosolic fraction and of basic proteins from the nuclear fraction. The subsequent protein separation by two-dimensional gel electrophoresis prior to mass spectrometry analysis allowed the detection of more than 600 spots in each muscle. In the gastrocnemius muscle fractions, it was possible to identify 178 protein spots corresponding to 108 different proteins. In the soleus muscle fractions, 103 different proteins were identified from 253 positive spot identifications. A bulk of cytoskeleton proteins such as actin, myosin light chains, and troponin were identified in the nuclear fraction, whereas mainly metabolic enzymes were detected in the cytosolic fraction. Transcription factors and proteins associated with protein biosynthesis were identified in skeletal muscles for the first time by proteomics. In addition, proteins involved in the mitochondrial redox system, as well as stress proteins, were identified. Results confirm the potential of this methodology to study the differential expressions of contractile proteins and metabolic enzymes, essential for generating functional diversity of muscles and muscle fiber types. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Aveiro, Dept Chem, P-3810193 Aveiro, Portugal. Univ Porto, Fac Sport, CIAFEL, P-4200450 Oporto, Portugal. NIH, Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Dept Physiol & Anat, D-50927 Cologne, Germany. RP Amado, FML (reprint author), Univ Aveiro, Dept Chem, P-3810193 Aveiro, Portugal. EM famado@dq.ua.pt RI Amado, Francisco/M-5337-2015; Tomer, Kenneth/E-8018-2013; Domingues, Pedro/E-5202-2010; Neuparth, Maria Joao/L-8805-2013; Duarte, Jose/F-1443-2013; PTMS, RNEM/C-1589-2014; Vitorino, Rui/G-7356-2014; Ferreira, Rita/C-4020-2014; OI Amado, Francisco/0000-0001-8256-1749; Domingues, Pedro/0000-0002-8060-7675; Neuparth, Maria Joao/0000-0002-1464-8700; Duarte, Jose/0000-0003-4756-5917; Vitorino, Rui/0000-0003-3636-5805; Ferreira, Rita/0000-0002-6872-4051; Guedes, Sofia de Morais/0000-0001-9556-3639 FU Intramural NIH HHS [Z01 ES050171-08] NR 31 TC 28 Z9 30 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD JUL 15 PY 2007 VL 366 IS 2 BP 156 EP 169 DI 10.1016/j.ab.2007.04.009 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 187QL UT WOS:000247863000007 PM 17540331 ER PT J AU Moaddel, R Marszall, MP Bighi, F Yang, Q Duan, X Wainer, IW AF Moaddel, R. Marszall, M. P. Bighi, F. Yang, Q. Duan, X. Wainer, I. W. TI Automated ligand fishing using human serum albumin-coated magnetic beads SO ANALYTICAL CHEMISTRY LA English DT Article ID CHROMATOGRAPHIC STATIONARY-PHASE; PROTEINS; PURIFICATION; BIOSENSOR; RECOVERY; CELLS AB Human serum albumin, HSA, was immobilized onto the surface of silica-based magnetic beads. The beads were used to isolate known HSA ligands from a mixture containing ligands and nonligands. The separation was accomplished manually and was also automated. The results indicate that an automated "ligand-fishing" technique can be developed using magnetic beads containing an immobilized protein. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. PSS Bio Instruments Inc, Gaithersburg, MD 20877 USA. RP Moaddel, R (reprint author), NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. EM Moaddelru@grc.nia.nih.gov RI Marszall, Michal/G-8936-2014 FU Intramural NIH HHS NR 15 TC 42 Z9 42 U1 2 U2 27 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD JUL 15 PY 2007 VL 79 IS 14 BP 5414 EP 5417 DI 10.1021/ac070268+ PG 4 WC Chemistry, Analytical SC Chemistry GA 189MI UT WOS:000247992600040 PM 17579480 ER PT J AU Colozo, AT Park, PSH Sum, CS Pisterzi, LF Wells, JW AF Colozo, Alejandro T. Park, Paul S. -H. Sum, Chi Shing Pisterzi, Luca F. Wells, James W. TI Cholesterol as a determinant of cooperativity in the M-2 muscarinic cholinergic receptor SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE M-2 muscarinic cholinergic receptor; G protein-coupled receptor; cholesterol; oligomers; cooperativity; mechanistic models ID BETA-ADRENERGIC RECEPTORS; PROTEIN-COUPLED RECEPTORS; HUMAN OXYTOCIN RECEPTOR; CAVEOLIN-1 ENRICHED DOMAINS; H-2 HISTAMINIC RECEPTORS; RAT CEREBRAL-CORTEX; NEGATIVE COOPERATIVITY; ACETYLCHOLINE-RECEPTOR; ADENYLATE-CYCLASE; MULTIPLE STATES AB M-2 muscarinic receptor extracted from Sf9 cells in cholate-NaCl differs from that extracted from porcine sarcolemma. The latter has been shown to exhibit an anomalous pattern in which the capacity for N-[H]methylscopolamine (NMS) is only 50% of that for [H-3]quinuclidinylbenzilate (QNB), yet unlabeled NMS exhibits high affinity for all of the sites labeled by [H-3]QNB. The effects can be explained in terms of cooperativity within a receptor that is at least tetravalent [Park PS, Sum CS, Pawagi AB, Wells JW. Cooperativity and oligomeric status of cardiac muscarinic cholinergic receptors. Biochemistry 2002;41:5588-6041. In contrast, M-2 receptor extracted from Sf9 membranes exhibited no shortfall in the capacity for [H-3]NMS at either 30 or 4 degrees C, although there was a time-dependent inactivation during incubation with [3H]NMS at 30 degrees C; also, any discrepancies in the affinity of NMS were comparatively small. The level of cholesterol in Sf9 membranes was only 4% of that in sarcolemmal membranes, and it was increased to about 100% by means of cholesterol- methyl- beta -cyclodextrin. M2 receptors extracted from treated Sf9 membranes were stable at 30 and 4 degrees C and resembled those from heart. Cholesterol induced a marked heterogeneity detected in the binding of both radioligands, including a shortfall in the apparent capacity for [3H]NMS, and there were significant discrepancies in the apparent affinity of NMS as estimated directly and via the inhibition of [3 H]QNB. The data can be described quantitatively in terms of cooperative effects among six or more interacting sites. Cholesterol therefore appears to promote cooperativity in the binding of antagonists to the M-2 muscarinic receptor. (C) 2007 Elsevier Inc. All rights reserved. C1 Case Western Reserve Univ, Dept Pharmacol, Cleveland, OH 44106 USA. NIH, NIDDK, Clin Endocrinol Branch, Bethesda, MD 20892 USA. Univ Toronto, Leslie Dan Fac Pharm, Dept Pharmaceut Sci, Toronto, ON M5S 3M2, Canada. RP Wells, JW (reprint author), Case Western Reserve Univ, Dept Pharmacol, 10900 Euclid Ave,BRB909B, Cleveland, OH 44106 USA. EM jwells@phm.utoronto.ca NR 71 TC 13 Z9 13 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD JUL 15 PY 2007 VL 74 IS 2 BP 236 EP 255 DI 10.1016/j.bcp.2007.04.009 PG 20 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 191VS UT WOS:000248160700006 PM 17521619 ER PT J AU Sean, D Meltzer, PS AF Sean, Davis Meltzer, Paul S. TI GEOquery: a bridge between the gene expression omnibus (GEO) and BioConductor SO BIOINFORMATICS LA English DT Article AB Microarray technology has become a standard molecular biology tool. Experimental data have been generated on a huge number of organisms, tissue types, treatment conditions and disease states. The Gene Expression Omnibus ( Barrett et al., 2005), developed by the National Center for Bioinformatics (NCBI) at the National Institutes of Health is a repository of nearly 140 000 gene expression experiments. The BioConductor project (Gentleman et al., 2004) is an open-source and open-development software project built in the R statistical programming environment (R Development core Team, 2005) for the analysis and comprehension of genomic data. The tools contained in the BioConductor project represent many state-of-the-art methods for the analysis of microarray and genemics data. We have developed a software tool that allows access to the wealth of information within GEO directly from BioConductor, eliminating many the formatting and parsing problems that have made such analyses labor-intensive in the past. The software, called GEOquery, effectively establishes a bridge between GEO and BioConductor. Easy access to GEO data from BioConductor will likely lead to new analyses of GEO data using novel and rigorous statistical and bioinformatic tools. Facilitating analyses and meta-analyses of microarray data will increase the efficiency with which biologically important conclusions can be drawn from published genomic data. C1 Natl Canc Inst, Natl Inst Hlth, Genet Branch, Bethesda, MD 20892 USA. RP Sean, D (reprint author), Natl Canc Inst, Natl Inst Hlth, Genet Branch, Bethesda, MD 20892 USA. EM sdavis2@mail.nih.gov NR 4 TC 66 Z9 71 U1 1 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD JUL 15 PY 2007 VL 23 IS 14 BP 1846 EP 1847 DI 10.1093/bioinformatics/btm254 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 207JV UT WOS:000249248300022 ER PT J AU Velazquez, CA Rao, PNP Citro, ML Keefer, LK Knaus, EE AF Velazquez, Carlos A. Rao, P. N. Praveen Citro, Michael L. Keefer, Larry K. Knaus, Edward E. TI O-2-Acetoxymethyl-protected diazeniumdiolate-based NSAIDs (NONO-NSAIDs): Synthesis, nitric oxide release, and biological evaluation studies SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE nitric oxide donors; diazeniumdiolates; non-ulcerogenic NSAIDs; anti-inflammatories; cyclooxygenase inhibition ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; RANDOMIZED TRIALS; NITRATE TOLERANCE; GASTROPATHY; PREVENTION; DONORS; DERIVATIVES; MECHANISMS; THERAPY; FAILURE AB A novel group of O-2-acetoxymethyl-protected diazeniumdiolate-based non-steroidal anti-inflammatory prodrugs (NONO-NSAIDs) were synthesized by esterifying the carboxylate group of aspirin, ibuprofen, or indomethacin with O-2-acetoxymethyl 1-[N-(2-hydroxyethyl)-N-methylamino]diazeniumdiolate. The resulting nitric oxide ((NO)-N-center dot)-releasing prodrugs (7-9) did not exhibit in vitro cyclooxygenase (COX) inhibitory activity against the COX-1 and COX-2 isozymes (IC50S > 100 mu M), In contrast, prodrugs 7 and 8 significantly decreased carrageenan-induced rat paw edema showing enhanced in vivo anti-inflammatory activities (ID50's = 552 and 174 mu mol/kg, respectively) relative to those of the parent NSAIDs aspirin (ID50 = 714 mu mol/kg) and ibuprofen (ID50 = 326 mu mol/kg). The rate of porcine liver esterase-mediated (NO)-N-center dot release from prodrugs 7-9 (2 mol of (NO)-N-center dot/mol of test compound in 0.6-6.5 min) was substantially higher compared to that observed without enzymatic catalysis (about 1 mol of (NO)-N-center dot/mol of test compound in 40-48 h). These incubation studies suggest that both (NO)-N-center dot and the parent NSAID would be released upon in vivo activation (hydrolysis) by esterases. Data acquired in an in vivo ulcer index (UI) assay showed that NONO-aspirin (UI = 0.8), NONO-indomethacin (UI = 1.3), and particularly NONO-ibuprofen (UI = 0) were significantly less ulcerogenic compared to the parent drugs aspirin (UI = 57), ibuprofen (UI = 46) or indomethacin (UI = 34) at equimolar doses. The release of aspirin and (NO)-N-center dot from the NONO-aspirin (7) prodrug constitutes a potentially beneficial property for the prophylactic prevention of thrombus formation and adverse cardiovascular events such as stroke and myocardial infarction. Published by Elsevier Ltd. C1 Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. NCI, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. SAIC Frederick Inc, NCI, Basic Res Program, Frederick, MD 21702 USA. RP Knaus, EE (reprint author), Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. EM eknaus@pharmacy.ualberta.ca RI Velazquez, Carlos/C-4224-2008; Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU Intramural NIH HHS [ZIA BC005673-19]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 38 TC 45 Z9 47 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD JUL 15 PY 2007 VL 15 IS 14 BP 4767 EP 4774 DI 10.1016/j.bmc.2007.05.009 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 183OY UT WOS:000247583300008 PM 17509888 ER PT J AU Chen, JY Nikolovska-Coleska, Z Yang, CY Gomez, C Gao, W Krajewski, K Jiang, S Roller, P Wang, SM AF Chen, Jianyong Nikolovska-Coleska, Zaneta Yang, Chao-Yie Gomez, Cindy Gao, Wei Krajewski, Krzysztof Jiang, Sheng Roller, Peter Wang, Shaomeng TI Design and synthesis of a new, conformationally constrained, macrocyclic small-molecule inhibitor of STAT3 via 'click chemistry' SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE STAT3; conformationally; constrained mimetic; click chemistry ID CANCER; TARGETS AB STAT3 is a promising molecular target for the design of new anticancer drugs. In this paper, we report the design and synthesis of a conformationally constrained macrocyclic peptidomimetic 2 via click chemistry. Compound 2 was determined to bind to STAT3 with a K, value of 7.3 mu M in a competitive fluorescence-polarization-based binding assay, representing a promising initial lead compound for further optimization. (C) 2007 Elsevier Ltd. All rights reserved. C1 Univ Michigan, Dept Internal Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Pharmacol & Med Chem, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. RP Wang, SM (reprint author), Univ Michigan, Dept Internal Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. EM shaomeng@umich.edu NR 12 TC 39 Z9 40 U1 1 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 JUL 15 PY 2007 VL 17 IS 14 BP 3939 EP 3942 DI 10.1016/j.bmcl.2007.04.096 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 190QS UT WOS:000248074600026 PM 17513110 ER PT J AU Sakamoto, N Tsuji, K Muul, LM Lawler, AM Petricoin, EF Candotti, F Metcalf, JA Tavel, JA Lane, HC Urba, WJ Fox, BA Varki, A Lunney, JK Rosenberg, AS AF Sakamoto, Norihisa Tsuji, Kazuhide Muul, Linda M. Lawler, Ann M. Petricoin, Emanuel F. Candotti, Fabio Metcalf, Julia A. Tavel, Jorge A. Lane, H. Clifford Urba, Walter J. Fox, Bernard A. Varki, Ajit Lunney, Joan K. Rosenberg, Amy S. TI Bovine apolipoprotein B-100 is a dominant immunogen in therapeutic cell populations cultured in fetal calf serum in mice and humans SO BLOOD LA English DT Article ID EMBRYONIC STEM-CELLS; BREAST-CANCER; STROMAL CELLS; GENE-THERAPY; SIALIC-ACID; T-CELLS; ANTIBODIES; EXPANSION; IDENTIFICATION; VACCINATION AB Recent studies have demonstrated that cell populations intended for therapeutic purposes that are cultured in heterologous animal products can acquire xenoantigens, potentially limiting their utility. In investigations of the immune response to murine embryonic stem cells, we found that a strong antibody response was generated after the second infusion. Both polyclonal and monoclonal antibody responses, derived from immunized mice, were found to be specific for bovine apolipoprotein B-100, which binds to abundant low-density lipoprotein receptors on the cell surface and is internalized. Here we show that in the majority of patients administered 3 different types of cell-based therapies using cells grown in fetal calf serum-containing media, an antibody response to bovine apolipoprotein B-100 develops after the second infusion and is the dominant specificity. The known and potential clinical effects of such antibodies are discussed. C1 US FDA, Ctr Drug Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. Okayama Univ, Sch Med & Dent & Pharmaceut Sci, Dept Dermatol, Okayama 7008530, Japan. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD USA. Johns Hopkins Univ, Sch Med, Transgen Mouse Facil, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21218 USA. George Mason Univ, Ctr Appl Proteom & Mol Med, Dept Mol & Microbiol, Manassas, VA 22030 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Robert W Franz Canc Res Ctr, Lab Mol & Tumor Immunol, Earle Chiles Res Inst, Providence Portland Med Ctr, Portland, OR USA. Univ Calif San Diego, Glycobiol Res & Training Ctr, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. USDA, Anim Parasit Dis Lab, ARS, Beltsville, MD 20705 USA. RP Rosenberg, AS (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. EM amy.rosenberg@fda.gov FU Intramural NIH HHS NR 35 TC 28 Z9 29 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 JUL 15 PY 2007 VL 110 IS 2 BP 501 EP 508 DI 10.1182/blood-2007-07-066522 PG 8 WC Hematology SC Hematology GA 191EH UT WOS:000248112400011 PM 17395779 ER PT J AU Morton, LM Turner, JJ Cerhan, JR Linet, MS Treseler, PA Clarke, CA Jack, A Cozen, W Maynadie, M Spinelli, JJ Costantini, AS Rudiger, T Scarpa, A Zheng, TZ Weisenburger, DD AF Morton, Lindsay M. Turner, Jennifer J. Cerhan, James R. Linet, Martha S. Treseler, Patrick A. Clarke, Christina A. Jack, Andrew Cozen, Wendy Maynadie, Marc Spinelli, John J. Costantini, Adele Seniori Ruediger, Thomas Scarpa, Aldo Zheng, Tongzhang Weisenburger, Dennis D. TI Pro-posed classification of lymphoid neoplasms for epidemiologic research from the Pathology Working Group of the International Lymphoma Epidemiology Consortium (InterLymph) SO BLOOD LA English DT Article ID NON-HODGKINS-LYMPHOMA; B-CELL LYMPHOMA; EUROPEAN-AMERICAN CLASSIFICATION; UNITED-STATES; RISK-FACTORS; MALIGNANT-LYMPHOMAS; T(14/18) SUBTYPES; CANCER REGISTRY; POOLED ANALYSIS; SURVEILLANCE AB Recent evidence suggests that there is etiologic heterogeneity among the various subtypes of lymphoid neoplasms. However, epidemiologic analyses by disease subtype have proven challenging due to the numerous clinical and pathologic schemes used to classify lymphomas and lymphoid leukemias over the last several decades. On behalf of the International Lymphoma Epidemiology Consortium (InterLymph) Pathology Working Group, we present a proposed nested classification of lymphoid neoplasms to facilitate the analysis of lymphoid neoplasm subtypes in epidemiologic research. The proposed classification is based on the World Health Organization classification of lymphoid neoplasms and the International Classification of Diseases-Oncology, Third Edition (ICD-O-3). We also provide a translation into the proposed classification from previous classifications, including the Working Formulation, Revised European-American Lymphoma (REAL) classification, and ICD-O-2. We recommend that epidemiologic studies include analyses by lymphoma subtype to the most detailed extent allowable by sample size. The standardization of groupings for epidemiologic research of lymphoma subtypes is essential for comparing subtype-specific reports in the literature, harmonizing cases within a single study diagnosed using different systems, as well as combining data from multiple studies for the purpose of pooled analysis or metaanalysis, and will probably prove to be critical for elucidating etiologies of the various lymphoid neoplasms. C1 NCI, Hormonal & Reproduct Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. No Calif Canc Ctr, Fremont, CA USA. Leeds Teaching Hosp, Natl Hlth Serv NHS Trust, Dept Haematol, Haematol Malignancy Diagnost Serv, Leeds, W Yorkshire, England. Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. Univ Hosp Dijon, Haematol Lab, Dijon, France. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Sci Inst Tuscany, Ctr Study & Prevent Canc, Occupat & Environm Epidemiol Unit, Florence, Italy. Univ Wurzburg, Inst Pathol, D-97070 Wurzburg, Germany. Univ Verona, Osped Policlin, Dept Pathol, I-37100 Verona, Italy. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68182 USA. RP Morton, LM (reprint author), NCI, Hormonal & Reproduct Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Execut Blvd,EPS-550, Rockville, MD 20852 USA. EM mortonli@mail.nih.gov RI Spinelli, John/B-6210-2013; Morton, Lindsay/B-5234-2015; scarpa, aldo/K-6832-2016; OI Morton, Lindsay/0000-0001-9767-2310; scarpa, aldo/0000-0003-1678-739X; Cerhan, James/0000-0002-7482-178X FU Intramural NIH HHS; NCI NIH HHS [CA62006-05, N01-CN-35136, P50 CA097274, P50 CA97274, R01 CA062006, R01 CA092153, R01 CA92153] NR 55 TC 224 Z9 238 U1 0 U2 7 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 JUL 15 PY 2007 VL 110 IS 2 BP 695 EP 708 DI 10.1182/blood-2006-11-051672 PG 14 WC Hematology SC Hematology GA 191EH UT WOS:000248112400033 PM 17389762 ER PT J AU Kiziltepe, T Hideshima, T Ishitsuka, K Ocio, EM Raje, N Catley, L Li, CQ Trudel, LJ Yasui, H Vallet, S Kutok, JL Chauhan, D Mitsiades, CS Saavedra, JE Wogan, GN Keefers, LK Shami, PJ Anderson, KC AF Kiziltepe, Tanyel Hideshima, Teru Ishitsuka, Kenji Ocio, Enrique M. Raje, Noopur Catley, Laurence Li, Chun-Qi Trudel, Laura J. Yasui, Hiroshi Vallet, Sonia Kutok, Jeffery L. Chauhan, Dharminder Mitsiades, Constantine S. Saavedra, Joseph E. Wogan, Gerald N. Keefers, Larry K. Shami, Paul J. Anderson, Kenneth C. TI JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells SO BLOOD LA English DT Article ID PROTEASOME INHIBITOR PS-341; HUMAN LYMPHOBLASTOID-CELLS; OVERCOMES DRUG-RESISTANCE; MOLECULAR-MECHANISMS; S-TRANSFERASE; CAM-DR; KINASE; INTERLEUKIN-6; REPAIR; ATM AB Here we investigated the cytotoxicity of JS-K, a prodrug designed to release nitric oxide (NO center dot) following reaction with glutathione S-transferases, in multiple myeloma (MM). JS-K showed significant cytotoxicity in both conventional therapy-sensitive and -resistant MM cell lines, as well as patient-derived MM cells. JS-K induced apoptosis in MM cells, which was associated with PARP, caspase-8, and caspase-9 cleavage; increased Fas/ CD95 expression; Mcl-1 cleavage; and Bcl-2 phosphorylation, as well as cytochrome c, apoptosis-inducing factor (AIF), and endonuclease G (EndoG) release. Moreover, JS-K overcame the survival advantages conferred by interieukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1), or by adherence of MM cells to bone marrow stromal cells. Mechanistic studies revealed that JS-K-induced cytotoxicity was mediated via NO center dot in MM cells. Furthermore, JS-K induced DNA doublestrand breaks (DSBs) and activated DNA damage responses, as evidenced by neutral comet assay, as well as H2AX, Chk2 and p53 phosphorylation. JS-K also activated c-Jun NH2-terminal kinase (JNK) in MM cells; conversely, inhibition of JNK markedly decreased JS-K-induced cytotoxicity. Importantly, bortezomib significantly enhanced JS-K-induced cytotoxicity. Finally, JS-K is well tolerated, inhibits tumor growth, and prolongs survival in a human MM xenograft mouse model. Taken together, these data provide the preclinical rationale for the clinical evaluation of JS-K to improve patient outcome in MM. C1 Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. MIT, Biol Engn Div, Cambridge, MA 02139 USA. MIT, Dept Chem, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. SAIC Frederick, Frederick, MD USA. NCI, Comparat Carcinogenesis Lab, NIH, Frederick, MD 21701 USA. Univ Utah, Div Med Oncol, Salt Lake City, UT USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, 44 Binney St, Boston, MA 02115 USA. EM tanyel_kiziltepe@dfci.harvard.edu; kenneth_anderson@dfci.harvard.edu RI li, Chunqi/D-9650-2011; Catley, Laurence/E-5313-2013 FU Intramural NIH HHS; NCI NIH HHS [N01-CO12400, N01CO12400, P0-1 CA78373, P50 CA100707]; PHS HHS [R0-1 A50947] NR 54 TC 78 Z9 83 U1 1 U2 11 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 JUL 15 PY 2007 VL 110 IS 2 BP 709 EP 718 DI 10.1182/blood-2006-10-052845 PG 10 WC Hematology SC Hematology GA 191EH UT WOS:000248112400034 PM 17384201 ER PT J AU Yong, ASM Rezvani, K Savani, BN Eniafe, R Mielke, S Goldman, JM Barrett, AJ AF Yong, Agnes S. M. Rezvani, Katayoun Savani, Bipin N. Eniafe, Rhoda Mielke, Stephan Goldman, John M. Barrett, A. John TI High PR3 or ELA2 expression by CD34(+) cells in advanced-phase chronic myeloid leukemia is associated with improved outcome following allogeneic stem cell transplantation and may improve PR1 peptide-driven graft-versus-leukemia effects SO BLOOD LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; BONE-MARROW-TRANSPLANTATION; DONOR LYMPHOCYTE INFUSIONS; T-CELLS; PERIPHERAL-BLOOD; MOLECULAR REMISSION; IMATINIB MESYLATE; INTERFERON-ALPHA; PROTEINASE-3; SURVIVAL AB The primary granule proteins elastase (ELA2) and proteinase 3 (PR3) both contain the nonapeptide PR1, which can induce cytotoxic T lymphocyte (CTL) responses against chronic myeloid leukemia (CML) cells. To investigate whether eradication of CML after allogeneic stem cell transplantation (SCT) was influenced by PR3 and ELA2 gene expression or PR1 -specific CTL responses, we studied cells from 87 CML patients and 27 HLA-A*0201(+) donors collected prior to T-cell-depleted HLA-identical sibling SCT. For patients in advanced phase (AdP), a higher expression of both PR3 and ELA2 in CD34(+) progenitors before SCT was associated with a lower incidence of relapse-related death, improved leukemia-free survival (LFS), and overall survival (OS); in chronic phase patients, no differences were observed. PR1-CTL responses were detected in 7 of 27 HLA-identical sibling donors, and associated with improved LFS and OS after SCT on follow-up. PR1-CTL responses detected in 7 of 28 CML patients before transplantation were not predictive of outcome and correlated inversely with PR3 and ELA2 expression. These findings suggest that assessment of PR3 and ELA2 expression in leukemic progenitors is useful for predicting posttransplantation outcome in AdP patients undergoing SCT. The presence of a donor immune response against PR1 may be advantageous and could be exploited therapeutically. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Yong, ASM (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Hatfield CRC,Rm 3-5140,10 Ctr Dr,MSC 1202, Bethesda, MD 20892 USA. EM yonga@nhlbi.nih.gov NR 33 TC 26 Z9 29 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 JUL 15 PY 2007 VL 110 IS 2 BP 770 EP 775 DI 10.1182/blood-2007-02-071738 PG 6 WC Hematology SC Hematology GA 191EH UT WOS:000248112400041 PM 17412886 ER PT J AU Posadas, EM Kwitkowski, V Kotz, HL Espina, V Minasian, L Tchabo, N Premkumar, A Hussain, MM Chang, R Steinberg, SM Kohn, EC AF Posadas, Edwin M. Kwitkowski, Virginia Kotz, Herbert L. Espina, Virginia Minasian, Lori Tchabo, Nana Premkumar, Ahalya Hussain, Mahrukh M. Chang, Richard Steinberg, Seth M. Kohn, Elise C. TI A prospective analysis of imatinib-induced c-KIT modulation in ovarian cancer - A phase II clinical study with proteomic profiling SO CANCER LA English DT Article DE ovarian cancer; c-kit; proteomics; protein arrays; clinical trial ID ENDOTHELIAL GROWTH-FACTOR; CHRONIC MYELOGENOUS LEUKEMIA; CHRONIC MYELOID-LEUKEMIA; GASTROINTESTINAL STROMAL TUMORS; EPITHELIAL OVARIAN; FACTOR-RECEPTOR; MUTATIONAL ANALYSIS; SURFACE EPITHELIUM; FACTOR EXPRESSION; SEROUS CARCINOMA AB BACKGROUND. c-Kit and platelet-derived growth factor receptor (PDGFR) are potential molecular targets in epithelial ovarian cancer (EOC). Imatimb inhibits the kinase domain and subsequent downstream signaling of these receptor tyrosine kinases. The objective of this study was to investigate biochemical and biologic effects of imatinib on EOC. METHODS. Patients with recurrent EOC who had received no more than 4 prior regimens and who had good end-organ function were eligible. Imatimb was administered orally at a dose of 400 mg twice daily in continuous, 28-day cycles with reassessment imaging studies obtained every other cycle. Tumor core biopsies were obtained prior to and at 4 weeks into therapy; microdissected tumor and stroma were subjected to protein lysate array analysis. Blood samples were obtained monthly for cytokine measurements. RESULTS. Twenty-three patients were enrolled, including 16 patients who received imatinib 600 mg daily because of gastrointestinal (GI) toxicity and fluid accumulation at the starting dose. The median time to disease progression was 2 months (range, 2-14 months). Common grade 3 toxicities included edema/ascites/pleural effusions in 11 patients (48%), GI complaints in 8 patients (35%), fatigue in 3 patients (13%), and grade 2 and 3 cytopenias in 10 patients and 3 patients (43% and 13%), respectively. Increased circulating levels of interleukin 6 were associated with grade >= 2 fluid collection (P =.02). A statistically significant trend was observed between pretreatment phosphorylated-kit levels in microdissected tumor and stroma and GI toxicity (P <.01), between tumor levels of epidermal growth factor receptor (EGFR) and PDGFR with grade of fatigue (P <=.005), and EGFR and phosphorylated-AKT levels with grade of ascites and edema (P <.01). CONCLUSIONS. The results of this study indicated imatinib had minimal activity as a single agent in ECC. Its ability to modulate its molecular targets suggests that it may be considered in combinatorial therapy. C1 NCI, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Canc Res Ctr, Bethesda, MD 20892 USA. Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD USA. RP Kohn, EC (reprint author), NCI, Pathol Lab, Canc Res Ctr, 10 Ctr Dr,MSC1500, Bethesda, MD 20892 USA. EM eklb@nih.gov OI Espina, Virginia/0000-0001-5080-5972 FU Intramural NIH HHS NR 49 TC 40 Z9 45 U1 0 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD JUL 15 PY 2007 VL 110 IS 2 BP 309 EP 317 DI 10.1002/cncr.22757 PG 9 WC Oncology SC Oncology GA 189JQ UT WOS:000247985600010 PM 17559139 ER PT J AU Yan, J Kim, YS Yang, XP Li, LP Liao, G Xia, F Jetten, AM AF Yan, Jun Kim, Yong-Sik Yang, Xiao-Ping Li, Li-Ping Liao, Grace Xia, Fen Jetten, Anton M. TI The ubiquitin-interacting motif-containing protein RAP80 interacts with BRCA1 and functions in DNA damage repair response SO CANCER RESEARCH LA English DT Article ID ATM-DEPENDENT PHOSPHORYLATION; STRAND BREAK REPAIR; HISTONE H2AX; CHECKPOINT; PATHWAY; MONOUBIQUITINATION; RECOGNITION; INSTABILITY; RECEPTOR; REPEATS AB In this study, we examine the potential role of receptor-associated protein 80 (RAP80), a nuclear protein containing two ubiquitin-interacting motifs (UIM), in DNA damage response and double-strand break (DSB) repair. We show that following ionizing radiation and treatment with DNA-damaging agents, RAP80 translocates to discrete nuclear foci that colocalize with those of gamma-H2AX. The UIMs and the region of amino acids 204 to 304 are critical for the relocalization of RAP80 to ionizing radiation-induced foci (IRIF). These observations suggest that RAP80 becomes part of a DNA repair complex at the sites of IRIF. We also show that RAP80 forms a complex with the tumor repressor BRCA1 and that this interaction is mediated through the BRCA1 COOH-terminal repeats of BRCA1. The UlMs are not required for the interaction of RAP80 with BRCA1. Knockdown of RAP80 in HEK293 cells significantly reduced DSB-induced homologydirected recombination (HDR). Moreover, inhibition of RAP80 expression by small interfering RNA increased radiosensitivity, whereas increased radioresistance was observed in human breast cancer MCF-7 cells with overexpression of RAP80. Taken together, our data suggest that RAP80 plays an important role in DNA damage response signaling and HDR-mediated DSB repair. We further show that RAP80 can function as a substrate of the ataxia-telangiectasia mutated protein kinase in vitro, 2 402 which phosphorylates RAP80 at Ser(205) and Ser(402). We show that this phosphorylation is not required for the migration of RAP80 to IRIF. C1 NIEHS, Div Intramural Res, Cell Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. Vanderbilt Univ, Med Ctr, Dept Radiat Oncol, Nashville, TN USA. RP Jetten, AM (reprint author), NIEHS, Div Intramural Res, Cell Biol Sect, NIH, MD2-01,Bldg 101, Res Triangle Pk, NC 27713 USA. EM jetten@niehs.nih.gov RI Xia, Fen/G-3708-2013; OI Jetten, Anton/0000-0003-0954-4445 FU Intramural NIH HHS [Z01 ES101586-05] NR 44 TC 95 Z9 101 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 JUL 15 PY 2007 VL 67 IS 14 BP 6647 EP 6656 DI 10.1158/0008-5472.CAN-07-0924 PG 10 WC Oncology SC Oncology GA 194BN UT WOS:000248319000017 PM 17621610 ER PT J AU Jiang, JG Ning, YG Chen, C Ma, D Liu, ZJ Yang, SL Zhou, JF Xiao, X Zhang, XA Edin, ML Card, JW Wang, JN Zeldin, DC Wang, DW AF Jiang, Jian-Gang Ning, Yao-Gui Chen, Chen Ma, Ding Liu, Zhen-Jun Yang, Shilin Zhou, Jianfeng Xiao, Xiao Zhang, Xin A. Edin, Matthew L. Card, Jeffrey W. Wang, Jianing Zeldin, Darryl C. Wang, Dao Wen TI Cytochrome P450 epoxygenase promotes human cancer metastasis SO CANCER RESEARCH LA English DT Article ID PLASMINOGEN-ACTIVATOR SYSTEM; KAI1/CD82 GENE-EXPRESSION; BREAST-CANCER; PROTEIN-KINASE; MATRIX METALLOPROTEINASES; SIGNALING PATHWAYS; COLORECTAL-CANCER; CARCINOMA-CELLS; HYALURONIC-ACID; CD44 CLEAVAGE AB Cytochrome P450 (CYP) epoxygenases convert arachidonic acid to four regioisomeric epoxycicosatrienoic acids (EET), which exert diverse biological activities in a variety of systems. We previously reported that the CYP2J2 epoxygenase is overexpressed in human cancer tissues and cancer cell lines and that EETs enhance tumor growth, increase carcinoma cell proliferation, and prevent apoptosis of cancer cells. Herein, we report that CYP epoxygenase overexpression or EET treatment. promotes tumor metastasis independent of effects on tumor growth. In four different human cancer cell lines in vitro, overexpression of CYP2J2 or CYP102 F87V with an associated increase in EET production or addition of synthetic EETs significantly induced Transwell migration (4.5- to 5.5-fold), invasion of cells (3- to 3.5-fold), cell adhesion to fibronectin, and colony formation in soft agar. In contrast, the epoxygenase inhibitor 17-ODYA or infection with the antisense recombinant adeno-associated viral vector (rAAV)-CYP2J2 vector inhibited cell migration, invasion, and adhesion with an associated reduction in EET production. CYP overexpression also enhanced metastatic potential in vivo in that rAAV-CYP2J2-infected MDA-MB-231 human breast carcinoma cells showed 60% more lung metastases in athymic BALB/c mice and enhanced angiogenesis in and around primary tumors compared with control cells. Lung metastasis was abolished by infection with the antisense rAAV-CYP2J2 vector. CYP epoxygenase overexpression or EET treatment up-regulated the prometastatic matrix metalloproteinases and CD44 and down-regulated the antimetastatic genes CD82 and nm-23. Together, these data suggest that CYP epoxygenase inhibition may represent a novel approach to prevent metastasis of human cancers. C1 Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Inst Hypertens,Dept Internal Med, Wuhan 430074, Peoples R China. Univ N Carolina, Sch Med, Chapel Hill, NC USA. Univ Tennessee, Hlth Sci Ctr, Vasc Biol Ctr, Dept Med,Dept Mol Sci, Memphis, TN USA. NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Internal Med, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.edu.cn OI Edin, Matthew/0000-0002-7042-500X FU Intramural NIH HHS NR 46 TC 86 Z9 91 U1 3 U2 31 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 JUL 15 PY 2007 VL 67 IS 14 BP 6665 EP 6674 DI 10.1158/0008-5472.CAN-06-3643 PG 10 WC Oncology SC Oncology GA 194BN UT WOS:000248319000019 PM 17638876 ER PT J AU Loomis, KD Zhu, S Yoon, K Johnson, PF Smart, RC AF Loomis, Kari D. Zhu, Songyun Yoon, Kyungsil Johnson, Peter F. Smart, Robert C. TI Genetic ablation of CCAAT/Enhancer binding protein alpha in epidermis reveals its role in suppression of epithelial tumorigenesis SO CANCER RESEARCH LA English DT Article ID TRANSCRIPTION FACTORS C/EBP; MOUSE SKIN CARCINOGENESIS; ACUTE MYELOID LEUKEMIAS; CELL-PROLIFERATION; TUMOR-DEVELOPMENT; DOWN-REGULATION; GROWTH ARREST; ONCOGENIC RAS; STEM-CELLS; HA-RAS AB CCAAT/enhancer binding protein alpha (C/EBP alpha) is a basic leucine zipper transcription factor that inhibits cell cycle progression and regulates differentiation in various cell types. C/EBP alpha is inactivated by mutation in acute myeloid leukemia (AmL) and is considered a human tumor suppressor in AML. Although C/EBP alpha mutations have not been observed in malignancies other than AML, greatly diminished expression of C/EBP alpha occurs in numerous human epithelial cancers including lung, liver, endometrial, skin, and breast, suggesting a possible tumor suppressor function. However, direct evidence for C/EBP alpha as an epithelial tumor suppressor is lacking due to the absence of C/EBP alpha mutations in epithelial tumors and the lethal effect of C/EBP alpha deletion in mouse model systems. To examine the function of C/EBP alpha in epithelial tumor development, an epidermal-specific C/EBP alpha knockout mouse was generated. The epidermal-specific C/EBPa knockout mice survived and displayed no detectable abnormalities in epidermal keratinocyte proliferation, differentiation, or apoptosis, showing that C/EBP alpha is dispensable for normal epidermal homeostasis. In spite of this, the epidermal-specific C/EBP(x knockout mice were highly susceptible to skin tumor development involving oncogenic Ras. These mice displayed decreased tumor latency and striking increases in tumor incidence, multiplicity, growth rate, and the rate of malignant progression. Mice hemizygous for C/EBP alpha displayed an intermediate-enhanced tumor phenotype. Our results suggest that decreased expression of C/EBP alpha. contributes to deregulation of tumor cell proliferation. C/EBP alpha had been proposed to block cell cycle progression through inhibition of E2F activity. We observed that C/EBPa blocked Ras-induced and epidermal growth factor-induced E2F activity in keratinocytes and also blocked Ras-induced cell transformation and cell cycle progression. Our study shows that C/EBP alpha is dispensable for epidermal homeostasis and provides genetic evidence that C/EBP alpha is a suppressor of epithelial tumorigenesis. C1 N Carolina State Univ, Dept Environm & Mol Toxicol, Cell Signaling & Canc Grp, Raleigh, NC 27695 USA. N Carolina State Univ, Funct Genom Program, Raleigh, NC 27695 USA. NCI, Lab Prot Dynam & Signaling, Frederick, MD 21701 USA. RP Smart, RC (reprint author), N Carolina State Univ, Dept Environm & Mol Toxicol, Cell Signaling & Canc Grp, Campus Box 7633, Raleigh, NC 27695 USA. EM rcsmart@ncsu.edu RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 FU NCI NIH HHS [CA 46637, R01 CA046637]; NIEHS NIH HHS [ES 12473, R01 ES012473] NR 59 TC 25 Z9 27 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2007 VL 67 IS 14 BP 6768 EP 6776 DI 10.1158/0008-5472.CAN-07-0139 PG 9 WC Oncology SC Oncology GA 194BN UT WOS:000248319000031 PM 17638888 ER PT J AU Neutzner, M Lopez, T Feng, X Bergmann-Leitner, ES Leitner, WW Udey, MC AF Neutzner, Melanie Lopez, Theresa Feng, Xu Bergmann-Leitner, Elke S. Leitner, Wolfgancr W. Udey, Mark C. TI MFG-E8/lactadherin promotes tumor growth in an angiogenesis-dependent transgenic mouse model of multistage carcinogenesis SO CANCER RESEARCH LA English DT Article ID DEVELOPMENTAL ENDOTHELIAL LOCUS-1; BETA-CELL CARCINOGENESIS; APOPTOTIC CELLS; INTEGRIN; MICE; RECEPTOR; PROTEIN; NEOVASCULARIZATION; ALPHA-V-BETA-3; IDENTIFICATION AB The relevance of angiogenesis in tumor biology and as a therapeutic target is well established. MFG-E8 (also termed lactadherin) and developmental endothelial locus 1 (Del1) constitute a two-gene family of alpha(v)beta(3)/beta(5) ligands that regulate angiogenesis. After detecting MFG-E8 mWNA in murine tumor cell lines, we sought to determine if MFG-ES influenced tumorigenesis in Rip1-Tag2 transgenic mice, a cancer model in which angiogenesis is critical. MFG-E8 mRNA and protein were increased in angiogenic islets and tumors in Rip1-Tag2 mice compared with normal pancreas. Frequencies of angiogenic islets and tumor burdens were decreased in MFGE8-deficient Rip1-Tag2 mice compared with those in control Rip1-Tag2 mice. Invasive carcinomas were modestly under-represented in MFG-E8-deficient mice, but tumor frequencies and survivals were comparable in these two strains. Absence of MFG-E8 also led to decreases in tumor vascular permeability without obvious changes in vascular morphology. Decreased proliferation was noted in angiogenic islets and increases in apoptotic cells were detected in islets and tumors. Compensaton increases in mmRNA encoding proangiogenic proteins, including FGF2, in angiogenic islets, and Dell, in angiogenic islets and tumors, were also detected in MFG-E8-deficient mice. MFG-ES and its homologue Dell may represent relevant targets in cancer and other diseases in which angiogenesis is prominent. C1 NCI, Dermatol Branch, Canc Res Ctr, Dermatol Branch,NIH, Bethesda, MD 20892 USA. NCI, Dermatol Branch, Canc Res Ctr, Basic Res Lab,NIH, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Dept Immunol, Silver Spring, MD USA. RP Udey, MC (reprint author), NCI, Dermatol Branch, Canc Res Ctr, Dermatol Branch,NIH, Bldg 10,Room 12N238, Bethesda, MD 20892 USA. EM udey@helix.nih.gov RI Bergmann-Leitner, Elke/B-3548-2011; Leitner, Wolfgang/F-5741-2011 OI Bergmann-Leitner, Elke/0000-0002-8571-8956; Leitner, Wolfgang/0000-0003-3125-5922 FU Intramural NIH HHS NR 32 TC 49 Z9 51 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 JUL 15 PY 2007 VL 67 IS 14 BP 6777 EP 6785 DI 10.1158/0008-5472.CAN-07-0165 PG 9 WC Oncology SC Oncology GA 194BN UT WOS:000248319000032 PM 17638889 ER PT J AU Davis, DA Singer, KE Reynolds, IP Haque, M Yarchoan, R AF Davis, David A. Singer, Kathleen E. Reynolds, Irene P. Haque, Muzarnmel Yarchoan, Robert TI Hypoxia enhances the phosphorylation and cytotoxicity of ganciclovir and zidovudine in Kaposi's sarcoma-associated herpesvirus-infected cells SO CANCER RESEARCH LA English DT Article ID PRIMARY EFFUSION LYMPHOMA; MULTICENTRIC CASTLEMANS-DISEASE; AIDS-RELATED MALIGNANCIES; NERVOUS-SYSTEM LYMPHOMA; NF-KAPPA-B; PROTEIN-KINASE; DNA-SEQUENCES; NUCLEOSIDE ANALOGS; INDUCED APOPTOSIS; THYMIDINE KINASE AB Primary effusion lymphoma (PEL) is a rare B-cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). PEL is poorly responsive to standard cytotoxic chemotherapy and portends a poor survival. Consequently, new effective treatment options are urgently needed. It is known that KSHV encodes two lytic genes, ORF36 (phosphotransferase) and KSHV ORF21 (thymidine kinase), which can phosphorylate ganciclovir and azidothymidine, respectively. Here, we have explored whether these genes can be used as therapeutic targets for PEL. PEL arises in pleural spaces and other effusions that provide a hypoxic environment. Based on Northern blot analysis, exposure of PEL cells to hypoxia up-regulated the expression of both ORF36 and ORF21. Using a newly developed nonradioactive reverse-phase high-performance liquid chromatography/mass spectrometry method to separate and quantify the phosphorylated forms of ganciclovir and azidothymidine, we found that PEL cells exposed to hypoxia produced increased amounts of the toxic triphosphates of these drugs Moreover, we found that hypoxia increased the cell toxicity of ganciclovir and azidothymidine in PEL cells but had no significant effect on the herpesvirus-negative cell line CA46. These findings may have clinical applicability in the development of effective therapies for PEL or other KSHV-related malignancies. C1 NCI, Ctr Canc Res, NIH, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Davis, DA (reprint author), NCI, Ctr Canc Res, NIH, HIV & AIDS Malignancy Branch, Room 10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dadavis@helix.nih.gov FU Intramural NIH HHS NR 51 TC 13 Z9 14 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 J9 CANCER RES JI Cancer Res. PD JUL 15 PY 2007 VL 67 IS 14 BP 7003 EP 7010 DI 10.1158/0008-5472.CAN-07-0939 PG 8 WC Oncology SC Oncology GA 194BN UT WOS:000248319000056 PM 17638913 ER PT J AU Raines, KW Bonini, MG Campbell, SL AF Raines, Kimberly W. Bonini, Marcelo G. Campbell, Sharon L. TI Nitric oxide cell signaling: S-nitrosation of Ras superfamily GTPases SO CARDIOVASCULAR RESEARCH LA English DT Review DE nitric oxide; redox signaling; small GTPases ID GUANINE-NUCLEOTIDE EXCHANGE; SMOOTH-MUSCLE-CELLS; GTP-BINDING PROTEINS; RHO FAMILY GTPASES; NITROGEN-DIOXIDE; THIYL RADICALS; SERUM-ALBUMIN; ACTIVE-SITE; TYROSINE PHOSPHORYLATION; ENDOTHELIAL-CELLS AB The Ras superfamily of small GTPases cycle between inactive GDP-bound and active GTP-bound states to modulate a diverse array of processes involved in cellular growth control. While the basic mechanisms by which GTPase regulatory proteins regulate GTPase substrates have been revealed through numerous studies, detailed studies into the mechanism(s) of free radical-mediated GTPase regulation have only more recently been tackled. This article reviews the mechanism of free radical-mediated GTPase regulation and shows nitric oxide can serve as important regulator of small GTPase proteins (i.e. Ras and RhoA) through protein modifications such as S-nitrosation. (c) 2007 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. NIEHS, Natl Inst Hlth, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Campbell, SL (reprint author), Univ N Carolina, Lineberger Comprehens Canc Ctr, 530 Mary Ellen Jones Bldg, Chapel Hill, NC 27599 USA. EM campbesl@med.unc.edu NR 125 TC 35 Z9 37 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD JUL 15 PY 2007 VL 75 IS 2 BP 229 EP 239 DI 10.1016/j.cardiores.2007.04.013 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 193TA UT WOS:000248296300004 PM 17559822 ER PT J AU Dezfulian, C Raat, N Shiva, S Gladwin, MT AF Dezfulian, Cameron Raat, Nicolaas Shiva, Sruti Gladwin, Mark T. TI Role of the anion nitrite in ischemia-reperfusion cytoprotection and therapeutics SO CARDIOVASCULAR RESEARCH LA English DT Review DE nitric oxide; ischemia; reperfusion ID K-ATP CHANNELS; CYTOCHROME-C-OXIDASE; DEPENDENT HYPOXIC VASODILATION; PERMEABILITY TRANSITION PORE; RAT-HEART MITOCHONDRIA; MYOCARDIAL-ISCHEMIA; IN-VIVO; DIETARY NITRATE; ISCHEMIA/REPERFUSION INJURY; XANTHINE OXIDOREDUCTASE AB The anion nitrite (NO2-) constitutes a biochemical reservoir for nitric oxide (NO). Nitrite reduction to NO may be catalyzed by hemoglobin, myoglobin or other metal-containing enzymes and occurs at increasing rates under conditions of physiologic hypoxia or ischemia. A number of laboratories have now demonstrated in animal models the ability of nitrite to provide potent cytoprotection following focal ischemia-reperfusion (IR) injury of the heart, liver, brain, and kidney. While the mechanism of nitrite-mediated cytoprotection remains to be fully characterized, the release of nitrite-derived NO following IR appears to be central to this mechanism. The evidence of nitrite-mediated cytoprotection against IR injury in multiple animal models opens the door to potential therapeutic opportunities in human disease. Here we review the mechanisms for nitrite formation in blood and tissue, its metabolic equilibrium with NO, nitrate, and NO-modified proteins, the evidence supporting nitrite-mediated cytoprotection, and the potential mechanisms driving cytoprotection, and we explore the opportunities for the therapeutic application of nitrite for human disease. Published by Elsevier B.V. C1 NHLBI, Natl Inst Hlth, Vasc Med Branch, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. Johns Hopkins Univ Hosp, Div Pediat Anesthesia & Crit Care Med, Baltimore, MD 21287 USA. RP Gladwin, MT (reprint author), NHLBI, Natl Inst Hlth, Vasc Med Branch, Bldg 10 CRC,Room 5-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM mgladwin@mail.nih.gov OI Dezfulian, Cameron/0000-0002-4486-0446 FU Intramural NIH HHS [Z99 CL999999] NR 114 TC 124 Z9 129 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD JUL 15 PY 2007 VL 75 IS 2 BP 327 EP 338 DI 10.1016/j.cardiores.2007.05.001 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 193TA UT WOS:000248296300013 PM 17568573 ER PT J AU Marini, JC Cabral, WA Barnes, AM Chang, W AF Marini, Joan C. Cabral, Wayne A. Barnes, Aileen M. Chang, Weizhong TI Components of the collagen prolyl 3-hydroxylation complex are crucial for normal bone development SO CELL CYCLE LA English DT Article DE recessive bone dysplasia; osteogenesis imperfecta type VII; osteogenesis imperfecta type VIII; leprecan; prolyl 3-hydroxylase 1; cartilage-associated protein; cyclophilin B; type I collagen ID CARTILAGE-ASSOCIATED PROTEIN; MEMBRANE-ASSOCIATED PROTEOGLYCAN; TRIPLE-HELIX FORMATION; CIS-TRANS-ISOMERASE; OSTEOGENESIS IMPERFECTA; TETRATRICOPEPTIDE REPEAT; CYCLOPHILIN-B; CDNA CLONING; I COLLAGEN; DISEASE AB Prolyl 3-hydroxylase 1 (P3H1), cartilage-associated protein (CRTAP) and cyclophilin B (CyPB) form a complex in the endoplasmic reticulum which is responsible for 3-hydroxylation of a limited number of proline residues in types I, II and V collagens. In this complex, CRTAP serves the role of helper protein, while P3H1 provides the enzymatic activity for the modification. In type I collagen, the major protein of the extracellular matrix of bone, the complex 3-hydroxylates only the alpha 1(I) Pro986 residue. P3H1 and CRTAP each also have independent roles as components of matrix. Furthermore, the two proteins have significant homology with each other. The critical importance of the components of the complex for normal bone development has been revealed by a Crtap knock-out mouse and by infants and children with null mutations of CRTAP and LEPRE1, the gene that encodes P3H1. On a clinical level, defects in the components of the prolyl 3-hydroxylation complex have been shown to be the long-sought cause of severe and lethal recessive osteogenesis imperfecta. C1 NICHHD, Natl Inst Hlth, Bone Extracellular Matrix Branch, Bethesda, MD 20892 USA. RP Marini, JC (reprint author), NICHHD, Natl Inst Hlth, Bone Extracellular Matrix Branch, Bldg 10, Rm 10N260, Bethesda, MD 20892 USA. EM oidoc@helix.nih.gov NR 37 TC 48 Z9 51 U1 0 U2 3 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD JUL 15 PY 2007 VL 6 IS 14 BP 1675 EP 1681 PG 7 WC Cell Biology SC Cell Biology GA 205CR UT WOS:000249091300001 PM 17630507 ER PT J AU Rios, M Daniel, S Chancey, C Hewlett, IK Stramer, SL AF Rios, Maria Daniel, Sylvester Chancey, Caren Hewlett, Indira K. Stramer, Susan L. TI West Nile virus adheres to human red blood cells in whole blood SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID UNITED-STATES; TRANSFUSION; HIV-1; RNA; TRANSMISSION; INFECTION; DISEASE; ASSAYS; DUFFY AB Background. West Nile virus ( WNV) is endemic in the United States. It is transmissible by blood transfusion, and the nation's blood supply is currently screened for WNV. Documented transmission of WNV infection through red blood cell ( RBC) units in which the plasma co-component had a low viral load could be explained, in at least 1 instance, by cell-association of WNV; in this case, the RBC unit was released as negative by minipool nucleic acid testing ( NAT) performed on plasma but was intermittently NAT-positive when subsequently tested as an individual sample. We hypothesized that a proportion of WNV bound to blood cells and was not measured by NAT performed on plasma samples. We have investigated whether WNV binds to RBCs, leading to reduction of WNV RNA detection by NAT performed on plasma samples. Methods. Equal volumes of leukoreduced RBCs and their corresponding plasma components from 20 blood donors with NAT results that were positive for WNV were tested in 5 replicates by reverse-transcriptase polymerase chain reaction TaqMan for WNV. In addition, aliquots from 8 of the RBC units were tested by infectivity assays using Vero cells. Results. The reverse-transcriptase polymerase chain reaction TaqMan assay showed that the viral load in the RBC components exceeded that in the corresponding plasma units by 1 order of magnitude. In addition, viruses associated with the RBCs were infectious in Vero cell cultures. Conclusions. These observations reinforce the notion that extraction of viral RNA from whole blood could improve assay sensitivity for blood donor screening and further reduce the residual risk of WNV transmission through transfusion. C1 US FDA, Lab Mol Virol, Div Emerging & Transfus Transmitted Dis, Off Blood Res & Review,Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. Amer Red Cross, Gaithersburg, MD USA. RP Rios, M (reprint author), 8800 Rockville Pike,NIH Bldg 29,Rm 131, Bethesda, MD 20892 USA. EM Maria.Rios@fda.hhs.gov NR 26 TC 23 Z9 24 U1 0 U2 2 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 JUL 15 PY 2007 VL 45 IS 2 BP 181 EP 186 DI 10.1086/518850 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 180EC UT WOS:000247343900006 PM 17578776 ER PT J AU Mofenson, LM Laughon, BE AF Mofenson, Lynne M. Laughon, Barbara E. TI Human immunodeficiency virus, Mycobacterium tuberculosis, and pregnancy: A deadly combination SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID ACTIVE ANTIRETROVIRAL THERAPY; SOUTH-AFRICA; MATERNAL MORTALITY; PREVENTIVE THERAPY; INFECTION; WOMEN; TRANSMISSION; DISEASE; RISK; COINFECTION C1 NICHHD, NIH, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, Bethesda, MD 20892 USA. NIAID, NIH, Complicat & Coinfect Res Branch, Therapeut Res Program,Div AIDS, Bethesda, MD 20892 USA. RP Mofenson, LM (reprint author), NICHHD, NIH, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Children, 6100 Execut Blvd,Rm 4B11, Bethesda, MD 20892 USA. EM lm65d@nih.gov OI Mofenson, Lynne/0000-0002-2818-9808 NR 42 TC 15 Z9 15 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 JUL 15 PY 2007 VL 45 IS 2 BP 250 EP 253 DI 10.1086/518975 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 180EC UT WOS:000247343900017 PM 17578787 ER PT J AU Estrada, B Maeland, AD Gisselbrecht, SS Bloor, JW Brown, NH Michelson, AM AF Estrada, Beatriz Maeland, Anne D. Gisselbrecht, Stephen S. Bloor, James W. Brown, Nicholas H. Michelson, Alan M. TI The MARVEL domain protein, Singles Bar, is required for progression past the pre-fusion complex stage of myoblast fusion SO DEVELOPMENTAL BIOLOGY LA English DT Article DE cell-cell fusion; myoblast fusion; mesoderm; myogenesis; muscle; development; Drosophila; MARVEL domain ID DROSOPHILA EMBRYONIC MESODERM; CANINE KIDNEY-CELLS; MUSCLE DEVELOPMENT; GENETIC-ANALYSIS; ROLLING-PEBBLES; BLOWN-FUSE; MYOGENESIS; EXPRESSION; NOTCH; RAS AB Multinucleated myotubes develop by the sequential fusion of individual myoblasts. Using a convergence of genomic and classical genetic approaches, we have discovered a novel gene, singles bar (sing), that is essential for myoblast fusion. sing encodes a small multipass transmembrane protein containing a MARVEL domain, which is found in vertebrate proteins involved in processes such as tight junction formation and vesicle trafficking where-as in myoblast fusion-membrane apposition occurs. sing is expressed in both founder cells and fusion competent myoblasts, preceding and during myoblast fusion. Examination of embryos injected with double-stranded sing RNA or embryos homozygous for ethane methyl sulfonate-induced sing alleles revealed an identical phenotype: replacement of multinucleated myofibers by groups of single, myosin-expressing myoblasts at a stage when formation of the mature muscle pattern is complete in wild-type embryos. Unfused sing mutant myoblasts form clusters, suggesting that early recognition and adhesion of these cells are unimpaired. To further investigate this phenotype, we undertook electron microscopic ultrastructural studies of fusing myoblasts in both sing and wild-type embryos. These experiments revealed that more sing mutant myoblasts than wild-type contain pre-fusion complexes, which are characterized by electron-dense vesicles paired on either side of the fusing plasma membranes. In contrast, embryos mutant for another muscle fusion gene, blown fuse (blow), have a normal number of such complexes. Together, these results lead to the hypothesis that sing acts at a step distinct from that of blow, and that sing is required on both founder cell and fusion-competent myoblast membranes to allow progression past the pre-fusion complex stage of myoblast fusion, possibly by mediating fusion of the electron-dense vesicles to the plasma membrane. Published by Elsevier Inc. C1 Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Cambridge, Gurdon Inst, Cambridge CB2 1QN, England. Univ Cambridge, Dept Physiol, Dept Neurosci, Cambridge CB2 1QN, England. RP Michelson, AM (reprint author), Natl Heart Lung & Blood Inst, NIH, 31 Ctr Dr,Room 5A48C, Bethesda, MD 20892 USA. EM michelsonam@nhlbi.nih.gov OI Gisselbrecht, Stephen/0000-0001-8723-902X FU Intramural NIH HHS [Z99 HL999999]; Wellcome Trust [31315, 43015] NR 62 TC 33 Z9 35 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2007 VL 307 IS 2 BP 328 EP 339 DI 10.1016/j.ydbio.2007.04.045 PG 12 WC Developmental Biology SC Developmental Biology GA 189WK UT WOS:000248019100014 PM 17537424 ER PT J AU Sharova, LV Sharov, AA Piao, Y Shaik, N Sullivan, T Stewart, CL Hogan, BLM Ko, MSH AF Sharova, Lioudmila V. Sharov, Alexei A. Piao, Yulan Shaik, Nabeebi Sullivan, Terry Stewart, Colin L. Hogan, Brigid L. M. Ko, Minoru S. H. TI Global gene expression profiling reveals similarities and differences among mouse pluripotent stem cells of different origins and strains SO DEVELOPMENTAL BIOLOGY LA English DT Article DE microarray; gene expression; embryonic stem cells; embryonic germ cells; LIF; retinoic acid; differentiation; ES cells; EG cells; mouse strains; C57BL/6 mouse; 129 mouse; pluripotency; stem cells ID PRIMORDIAL GERM-CELLS; IN-VITRO; DEAD-END; LINES; MICE; BLASTOCYSTS; MICROARRAY; EMBRYOS; CULTURE; GROWTH AB Pluripotent stem cell lines with similar phenotypes can be derived from both blastocysts (embryonic stem cells, ESC) and primordial germ cells (embryonic germ cells, EGC). Here, we present a compendium DNA microarray analysis of multiple mouse ESCs and EGCs from different genetic backgrounds (strains 129 and C57BL/6) cultured under standard conditions and in differentiation-promoting conditions by the withdrawal of Leukemia Inhibitory Factor (LIF) or treatment with retinoic acid (RA). All pluripotent cell lines showed similar gene expression patterns, which separated them clearly from other tissue stem cells with lower developmental potency. Differences between pluripotent lines derived from different sources (ESC vs. EGC) were smaller than differences between lines derived from different mouse strains (129 vs. C57BL/6). Even in the differentiation-promoting conditions, these pluripotent cells showed the same general trends of gene expression changes regardless of their origin and genetic background. These data indicate that ESCs and EGCs are indistinguishable based on global gene expression patterns alone. On the other hand, a detailed comparison between a group of ESC lines and a group of EGC lines identified 20 signature genes whose average expression levels were consistently higher in ESC lines, and 84 signature genes whose average expression levels were consistently higher in EGC lines, irrespective of mouse strains. Similar analysis identified 250 signature genes whose average expression levels were consistently higher in a group of 129 cell lines, and 337 signature genes whose average expression levels were consistently higher in a group of C57BL/6 cell lines. Although none of the genes was exclusively expressed in either ESCs versus EGCs or 129 versus C57BL/6, in combination these signature genes provide a reliable separation and identification of each cell type. Differentiation-promoting conditions also revealed some minor differences between the cell lines. For example, in the presence of RA, EGCs showed a lower expression of muscle- and cardiac-related genes and a higher expression of gonad-related genes than ESCs. Taken together, the results provide a rich source of information about the similarities and differences between ESCs and EGCs as well as 129 lines and C57BL/6 lines. Such information will be crucial to our understanding of pluripotent stem cells. The results also underscore the importance of studying multiple cell lines from different strains when making comparisons based on gene expression analysis. (c) 2007 Elsevier Inc. All rights reserved. C1 NIA, Lab Genet, NIH, Baltimore, MD 21224 USA. NCI, Ctr Dev Biol Lab, NIH, Frederick, MD 21702 USA. Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. RP Ko, MSH (reprint author), NIA, Lab Genet, NIH, 333 Cassell Dr,Suite 3000, Baltimore, MD 21224 USA. EM kom@mail.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU Intramural NIH HHS [Z01 AG000662-07] NR 69 TC 73 Z9 76 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2007 VL 307 IS 2 BP 446 EP 459 DI 10.1016/j.ydbio.2007.05.004 PG 14 WC Developmental Biology SC Developmental Biology GA 189WK UT WOS:000248019100023 PM 17560561 ER PT J AU Falco, G Lee, SL Stanghellini, I Bassey, UC Hamatani, T Ko, MSH AF Falco, Geppino Lee, Sung-Lim Stanghellini, Ilaria Bassey, Uwem C. Hamatani, Toshio Ko, Minoru S. H. TI Zscan4: A novel gene expressed exclusively in late 2-cell embryos and embryonic stem cells SO DEVELOPMENTAL BIOLOGY LA English DT Article DE preimplantation embryos; ES cells; expression profiling; zygotic genorne activation; stage-specific gene expression; paralogs; mouse genome ID PREIMPLANTATION MOUSE EMBRYO; ZYGOTIC GENOME ACTIVATION; SHORT INTERFERING RNAS; TRANSCRIPTION FACTOR; OOCYTES; MICE; DATABASE; PATTERNS; REPAIR; PCR AB The first wave of transcription, called zygotic genome activation (ZGA), begins during the 2-cell stage in mouse preimplantation development and marks a vital transition from the maternal genetic to the embryonic genetic program. Utilizing DNA microarray data, we looked for genes that are expressed only during ZGA and found Zscan4, whose expression is restricted to late 2-cell stage embryos. Sequence analysis of genomic DNA and cDNA clones revealed nine paralogous genes tightly clustered in 0.85 Mb on mouse chromosome 7. Three genes are not transcribed and are thus considered pseudogenes. Among the six expressed genes named Zscan4a-Zscan4f, three - Zscan4c, Zscan4d, and Zscan4f - encode full-length ORFs with 506 amino acids. Zscan4d is a predominant transcript at the late 2-cell stage, whereas Zscan4c is a predominant transcript in embryonic stein (ES) cells. No transcripts of any Zscan4 genes are detected in any other cell types. Reduction of Zscan4 transcript levels by siRNAs delays the progression from the 2-cell to the 4-cell stage and produces blastocysts that fail to implant or proliferate in blastocyst outgrowth culture. Zscan4 thus seems to be essential for preimplantation development. Published by Elsevier Inc. C1 NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Ko, MSH (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Baltimore, MD 21224 USA. EM kom@mail.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU Intramural NIH HHS [Z01 AG000655-09] NR 51 TC 67 Z9 71 U1 2 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD JUL 15 PY 2007 VL 307 IS 2 BP 539 EP 550 DI 10.1016/j.ydbio.2007.05.003 PG 12 WC Developmental Biology SC Developmental Biology GA 189WK UT WOS:000248019100028 PM 17553482 ER PT J AU Pezza, RJ Voloshin, ON Vanevski, F Camerini-Otero, RD AF Pezza, Roberto J. Voloshin, Oleg N. Vanevski, Filip Camerini-Otero, R. Daniel TI Hop2/Mnd1 acts on two critical steps in Dmc1-promoted homologous pairing SO GENES & DEVELOPMENT LA English DT Article DE DNA repair; Dmc1 recombinase; homologous recombination; strand invasion; synaptic complex ID DNA STRAND EXCHANGE; RECA PROTEIN; MEIOTIC RECOMBINATION; ESCHERICHIA-COLI; SACCHAROMYCES-CEREVISIAE; HOP2 PROTEIN; MEIOSIS; DMC1; COMPLEX; MND1 AB Meiotic recombination between homologous chromosomes ensures their proper segregation at the first division of meiosis and is the main force shaping genetic variation of genomes. The HOP2 and MND1 genes are essential for this recombination: Their disruption results in severe defects in homologous chromosome synapsis and an early-stage failure in meiotic recombination. The mouse Hop2 and Mnd1 proteins form a stable heterodimer (Hop2/Mnd1) that greatly enhances Dmc1-mediated strand invasion. In order to elucidate the mechanism by which Hop2/Mnd1 stimulates Dmc1, we identify several intermediate steps in the homologous pairing reaction promoted by Dmc1. We show that Hop2/Mnd1 greatly stimulates Dmc1 to promote synaptic complex formation on long duplex DNAs, a step previously revealed only for bacterial homologous recombinases. This synaptic alignment is a consequence of the ability of Hop2/Mnd1 to (1) stabilize Dmc1-single-stranded DNA (ssDNA) nucleoprotein complexes, and (2) facilitate the conjoining of DNA molecules through the capture of double-stranded DNA by the Dmc1-ssDNA nucleoprotein filament. To our knowledge, Hop2/Mnd1 is the first homologous recombinase accessory protein that acts on these two separate and critical steps in mammalian meiotic recombination. C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Camerini-Otero, RD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM camerini@ncifcrf.gov FU Intramural NIH HHS NR 47 TC 53 Z9 58 U1 1 U2 5 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 JUL 15 PY 2007 VL 21 IS 14 BP 1758 EP 1766 DI 10.1101/gad.1562907 PG 9 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 190SE UT WOS:000248078600008 PM 17639081 ER PT J AU Hilton, EN Manson, FDC Urquhart, JE Johnston, JJ Slavotinek, AM Hedera, P Stattin, EL Nordgren, A Biesecker, LG Black, GCM AF Hilton, Emma N. Manson, Forbes D. C. Urquhart, Jill E. Johnston, Jennifer J. Slavotinek, Anne M. Hedera, Peter Stattin, Eva-Lena Nordgren, Ann Biesecker, Leslie G. Black, Graeme C. M. TI Left-sided embryonic expression of the BCL-6 corepressor, BCOR, is required for vertebrate laterality determination SO HUMAN MOLECULAR GENETICS LA English DT Article ID CONGENITAL HEART-DISEASE; LEFT-RIGHT ASYMMETRY; CARDIAC DEFECTS; XENOPUS-LAEVIS; MUTATIONS; GENE; HETEROTAXY; PITX2; ABNORMALITIES; MORPHOGENESIS AB Oculofaciocardiodental (OFCD) syndrome is an X-linked male lethal condition encompassing cardiac septal defects, as well as ocular and dental anomalies. The gene mutated in OFCD syndrome, the BCL-6 corepressor (BCOR), is part of a transcriptional repression complex whose transcriptional targets remain largely unknown. We reviewed cases of OFCD syndrome and identified patients exhibiting defective lateralization including dextrocardia, asplenia and intestinal malrotation, suggesting that BCOR is required in normal laterality determination. To study the function of BCOR, we used morpholino oligonucleotides (MOs) to knockdown expression of xtBcor in Xenopus tropicalis, thus creating an animal model for OFCD syndrome. The resulting tadpoles had cardiac and ocular features characteristic of OFCD syndrome. Reversed cardiac orientation and disorganized gut patterning were seen when MOs were injected into the left side of embryos, demonstrating a left-sided requirement for xtBcor in lateral determination in Xenopus. Ocular defects displayed no left-right bias and included anterior and posterior segment disorders such as microphthalmia and coloboma. Expression of xtPitx2c was shown to be downregulated when xtBcor was depleted. This identifies a pathway in which xtBcor is required for lateral specification, a process intrinsically linked to correct cardiac septal development. C1 St Marys Hosp, Acad Unit Med Genet, Manchester M13 0JH, Lancs, England. St Marys Hosp, Reg Genet Serv, Manchester M13 0JH, Lancs, England. Univ Manchester, Ctr Mol Med, Manchester M13 9PL, Lancs, England. Cent Manchester & Manchester Childrens Univ Hosp, Manchester Royal Eye Hosp, Manchester M13 0JH, Lancs, England. Natl Human Genome Res Inst, Genet Dis Res Branch, NIH, Bethesda, MD USA. Univ Calif San Francisco, Div Genet, Dept Pediat, San Francisco, CA 94143 USA. Vanderbilt Univ, Dept Neurol, Nashville, TN 37232 USA. Univ Umea Hosp, Dept Clin Genet, S-90185 Umea, Sweden. Karolinska Inst, Dept Mol Med, Clin Genet Unit, Stockholm, Sweden. RP Black, GCM (reprint author), Cent Manchester & Manchester Childrens Univ Hosp, St Marys Hosp, Dept Clin Genet, Hatersage Rd, Manchester M13 0JH, Lancs, England. EM gblack@man.ac.uk RI Manson, Forbes/G-2222-2015; Urquhart, Jill/G-2282-2015; Nordgren, Ann/N-4057-2013; OI Manson, Forbes/0000-0002-8342-660X; Urquhart, Jill/0000-0002-5788-5511; Nordgren, Ann/0000-0003-3285-4281; Hilton, Emma/0000-0002-3750-577X; Black, Graeme/0000-0001-8727-6592 FU Intramural NIH HHS; Wellcome Trust [GR067443MA] NR 36 TC 30 Z9 31 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD JUL 15 PY 2007 VL 16 IS 14 BP 1773 EP 1782 DI 10.1093/hmg/ddm125 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 196LP UT WOS:000248483500012 PM 17517692 ER PT J AU Yu, YRA Fong, AM Combadiere, C Gao, JL Murphy, PM Patel, DD AF Yu, Yen-Rei A. Fong, Alan M. Combadiere, Christophe Gao, Ji-Liang Murphy, Philip M. Patel, Dhavalkumar D. TI Defective antitumor responses in CX3CR1-deficient mice SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE CX3CR1; monocytes; NK cells; migration ID NATURAL-KILLER-CELLS; FRACTALKINE RECEPTOR CX(3)CR1; NK CELLS; IN-VIVO; CHEMOKINE FRACTALKINE; CYTOKINE EXPRESSION; METASTATIC SPREAD; IMMUNE-RESPONSE; LUNG-CANCER; IFN-GAMMA AB Innate immunity is critically important for tumor surveillance and regulating tumor metastasis. Fractalkine (FKN, CX3CL1), operating through the receptor CX3CR1, is an effective chemoattractant and adhesion receptor for NK cells and monocytes, important constituents of the innate immune response. Previous studies have shown that over-expression of CX3CL1 by tumor cells enhances antitumor responses. However, since most tumors do not express CX3CL1, it remains unclear if CX3CL1/CX3CR1 has a role in tumor immunity in the absence of ligand over-expression. To determine the role of CX3CL1 and CX3CR1 in regulating antitumor immune responses, we tested the response of wildtype and CX3CR1-deficient animals to unmanipulated B16 melanoma that does not express CX3CL1. We studied the distribution and trafficking of mononuclear cells (MNC) under homeostatic conditions and in the presence of B16 metastatic melanoma, cytotoxic activity, and cytokine production in wild-type and CX3CR1-deficient animals. We found that B16-treated CX3CR1-/- mice had increased lung tumor burden and cachexia. There was a selective reduction of monocytes and NK cells in the lungs of CX3CR1-deficient animals under homeostatic conditions and in response to B16. CX3CR1-deficient NK cells effectively killed B16 cells in cytotoxicity assays. However, CX3CR1-deficient NK cells exhibited a tumorigenic cytokine production profile with defective IFN-gamma expression and enhanced IL-6 production in response to TLR3 activation with polyIC. Our studies indicate that CX3CR1 is an important contributor to innate immunity at multiple levels. Its role in tumor immunity is not limited by expression of CX3CL1 by tumor cells. (C) 2007 Wiley-Liss, Inc. C1 Univ N Carolina, Thurston Arthrit Res Ctr, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Med, Chapel Hill, NC 27599 USA. Duke Univ, Dept Immunol, Durham, NC USA. Hop La Pitie Salpetriere, INSERM, U543, Lab Immunol Cellulaire & Tissulaire, Paris, France. NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Yu, YRA (reprint author), Univ N Carolina, Thurston Arthrit Res Ctr, CB 7280,3330 Thurston Bldg, Chapel Hill, NC 27599 USA. EM afong@med.unc.edu RI Combadiere, Christophe/I-5639-2013 OI Combadiere, Christophe/0000-0002-1755-4531 FU NCI NIH HHS [CA098110] NR 41 TC 40 Z9 41 U1 0 U2 2 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 JUL 15 PY 2007 VL 121 IS 2 BP 316 EP 322 DI 10.1002/ijc.22660 PG 7 WC Oncology SC Oncology GA 177LQ UT WOS:000247155000012 PM 17372897 ER PT J AU Lee, WJ Sandler, DP Blair, A Samanic, C Cross, AJ Alavanja, MCR AF Lee, Won Jin Sandler, Dale P. Blair, Aaron Samanic, Claudine Cross, Amanda J. Alavanja, Michael C. R. TI Pesticide use and colorectal cancer risk in the Agricultural Health Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE agriculture; colorectal cancer; farmers; insecticides; occupational exposure; pesticides ID ALACHLOR MANUFACTURING WORKERS; COLON-CANCER; MULTIPLE COMPARISONS; OCCUPATIONAL RISK; RECTAL-CANCER; EPIDEMIOLOGIC DATA; ASBESTOS EXPOSURE; PHYSICAL-ACTIVITY; MORTALITY; APPLICATORS AB We investigated the relationship between agricultural pesticides and colorectal cancer incidence in the Agricultural Health Study. A total of 56,813 pesticide applicators with no prior history of colorectal cancer were included in this analysis. Detailed pesticide exposure and other information were obtained from self-administered questionnaires completed at the time of enrollment (1993-1997). Cancer incidence was determined through population-based cancer registries from enrollment through December 31, 2002. A total of 305 incident colorectal cancers (212 colon, 93 rectum) were diagnosed during the study period, 1993-2002. Although most of the 50 pesticides studied were not associated with colorectal cancer risk, chlorpyrifos use showed significant exposure response trend (p for trend = 0.008) for rectal cancer, rising to a 2.7-fold (95% confidence interval: 1.2-6.4) increased risk in the highest exposure category. Aldicarb was associated with a significantly increased risk of colon cancer (p for trend = 0.001), based on a small number of exposed cases, with the highest exposure category resulting in a 4.1-fold increased risk (95% confidence interval: 1.3-12.8). In contrast, dichlorophenoxyacetic acid showed a significant inverse association with colon cancer but the association was not monotonic. Our findings should be interpreted cautiously since the literature suggesting that pesticides are related to colorectal cancer is limited. Nonetheless the possibility of an association between exposure to certain pesticides and incidence of colorectal cancer among pesticide applicators deserves further evaluation. (C) 2007 Wiley-Liss, Inc. C1 NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. Korea Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Alavanja, MCR (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 8000, Rockville, MD 20852 USA. EM alavanjm@mail.nih.gov OI Sandler, Dale/0000-0002-6776-0018 FU Intramural NIH HHS [Z01 ES049030-11, Z01 CP010119-12] NR 64 TC 42 Z9 44 U1 1 U2 12 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 JUL 15 PY 2007 VL 121 IS 2 BP 339 EP 346 DI 10.1002/ijc.22635 PG 8 WC Oncology SC Oncology GA 177LQ UT WOS:000247155000015 PM 17390374 ER PT J AU Troisi, R Hatch, EE Titus-Ernstoff, L Hyer, M Palmer, JR Robboy, SJ Strohsnitter, WC Kaufman, R Herbst, AL Hoover, RN AF Troisi, Rebecca Hatch, Elizabeth E. Titus-Ernstoff, Linda Hyer, Marianne Palmer, Julie R. Robboy, Stanley J. Strohsnitter, William C. Kaufman, Raymond Herbst, Arthur L. Hoover, Robert N. TI Cancer risk in women prenatally exposed to diethylstilbestrol SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE diethylstilbestrol; estrogen; cancer ID CLEAR-CELL ADENOCARCINOMA; BREAST-CANCER; IN-UTERO; ENDOCRINE DISRUPTION; VAGINA; STILBESTROL; MOTHERS; CERVIX AB Prenatal diethylstilbestrol (DES) exposure is associated with excess risks of clear cell adenocarcinoma (CCA), and breast cancer in older women. Whether overall cancer risk is also elevated is unclear. Total and site-specific cancer risks were evaluated in the DES Combined Cohort Follow-up Study using age- and calendar-year specific standardized incidence rate ratios (SIR), and age-adjusted incidence rate ratios (RR) comparing DES exposed and unexposed women. A total of 143 and 49 cancer cases occurred in 97,831 and 34,810 person-years among the exposed and unexposed, respectively. There was no overall excess risk among exposed women when compared with external rates (SIR 1.01; 95% confidence interval [CI] 0.86-1.2). The overall RR comparing exposed with unexposed women was 1.32 (95% CI 0.94-1.8). Breast cancer risk was elevated only among women over 40 years (RR 1.83; 95% CI 1.1-3.2). The CCA SIR among exposed women was nearly 40, and the estimated attack rate through age 39 was 1.6/1,000 women. CCA incidence decreased by over 80% after age 25 when compared with 20-24 years. Excluding CCA and breast cancer, the overall RR was 1.21 (95% CI 0.74-2.0). DES was not associated with excess risks of either endometrial or ovarian cancer. These data suggest that the DES associated increase in CCA incidence remains elevated through the reproductive years. There was no consistent evidence of risk excesses for cancers other than CCA, and breast cancer in older women. Given that the population is still young, continued follow-up is necessary to assess the overall carcinogenic impact of prenatal DES exposure. (C) 2007 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, NIH, US Dept HHS, Bethesda, MD USA. Dartmouth Coll Sch Med, Dept Community & Family Med, Hanover, NH USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA USA. Informat Management Serv Inc, Rockville, MD USA. Boston Univ, Slone Epidemiol Unit, Boston, MA 02215 USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC 27710 USA. Tufts Univ New England Med Ctr, Dept Obstet & Gynecol, Boston, MA 02111 USA. Methodist Hosp, Obstet & Gynecol Phys Org, Houston, TX 77030 USA. Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. RP Troisi, R (reprint author), Dartmouth Hitchcock Med Ctr, Room 854,7297 Rubin Bldg,1 Med Ctr Dr, Lebanon, NH 03756 USA. EM troisir@mail.nih.gov OI Palmer, Julie/0000-0002-6534-335X; Hatch, Elizabeth/0000-0001-7901-3928 NR 16 TC 71 Z9 74 U1 3 U2 8 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 JUL 15 PY 2007 VL 121 IS 2 BP 356 EP 360 DI 10.1002/ijc.22631 PG 5 WC Oncology SC Oncology GA 177LQ UT WOS:000247155000017 PM 17390375 ER PT J AU Schmitz, A Bayer, J Dechamps, N Goldin, L Thomas, G AF Schmitz, Annette Bayer, Jan Dechamps, Nathalie Goldin, Lynn Thomas, Gilles TI Heritability of susceptibility to ionizing radiation-induced apoptosis of human lymphocyte subpopulations SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Article DE individual radiosensitivity; radiation biology; family studies; apoptosis ID PERIPHERAL-BLOOD; T-LYMPHOCYTE; BREAST-CANCER; RADIOSENSITIVITY; DAMAGE; CELLS; ASSAY; PREDISPOSITION; SENSITIVITY; REPAIR AB Purpose: To evaluate the heritability of intrinsic radiosensitivity, the induction of apoptosis in lymphocyte subpopulations; was determined on samples from related individuals belonging to large kindred families. Methods and Materials: Quiescent lymphocytes from 334 healthy individuals were gamma-irradiated in vitro. Apoptosis was determined 18 h after irradiation by eight-color flow cytometry. Radiosensitivity was quantified from dose-effect curves. Intrafamilial correlations and heritability were computed for 199 father-mother-offspring trios using the programs SOLAR (Sequential Oligogenic Linkage Analysis Routines) and SAGE (Statistical Analysis for Genetic Epidemiology). Segregation analyses were conducted using SAGE. Results: Marked differential susceptibility of naive and memory T lymphocytes was demonstrated. Also, although age and gender were significant covariates, their effects only accounted for a minor part of the inter-individual variation. Parent-offspring and sib-sib correlations were significant for the radiosensitivity of B cells, T4, and T8 and of effector memory T4 and T8 subpopulations. In the T4-effector memory subpopulation, the phenotype showed correlations most consistent with dominant or additive genetic effects, and the results of the segregation analysis were consistent with the contribution of a bi-allelic dominant locus. Conclusions: Heritability was demonstrated for the susceptibility to ionizing radiation-induced apoptosis of lymphocyte populations, and the segregation of the T4-effector memory radiosensitivity phenotype was consistent with a simple mendelian transmission model involving one major gene. (C) 2007 Elsevier Inc. C1 CEA, DSV, iRCM, F-92265 Fontenay Aux Roses, France. Fdn Jean Dausset, Ctr Etud Polymorphisme Humain, Paris, France. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Schmitz, A (reprint author), CEA, DSV, iRCM, BP 6, F-92265 Fontenay Aux Roses, France. EM annette.schmitz@cea.fr FU Intramural NIH HHS [Z99 CA999999] NR 27 TC 21 Z9 21 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD JUL 15 PY 2007 VL 68 IS 4 BP 1169 EP 1177 DI 10.1016/j.ijrobp.2007.03.050 PG 9 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 185ZU UT WOS:000247749700030 PM 17637392 ER PT J AU Kuriyama, R Terada, Y Lee, KS Wang, CLC AF Kuriyama, Ryoko Terada, Yasuhiko Lee, Kyung S. Wang, Christopher L. C. TI Centrosome replication in hydroxyurea-arrested CHO cells expressing GFP-tagged centrin2 SO JOURNAL OF CELL SCIENCE LA English DT Article DE centrosomes; centrioles; pericentriolar material; GFP-centrin; CHO cells; time-lapse fluorescence microscopy; hydroxyurea ID HAMSTER OVARY CELLS; GAMMA-TUBULIN; MICROTUBULE ORGANIZATION; MAMMALIAN-CELLS; ANIMAL-CELLS; HELA-CELLS; PTK2 CELLS; CYCLIN-A; DUPLICATION; PROTEIN AB Centrosome duplication is tightly coupled with the cell cycle and neither too many nor too few centrosomes are induced in a normal cell. To study how centrosome assembly is regulated, we analyzed the abnormal process of multiple centrosome replications in Chinese hamster ovary (CHO) cells induced by hydroxyurea (HU), which is known to uncouple the centrosome cycle from the cell cycle. Green fluorescent protein (GFP)-tagged centrin2 expressed in CHO cells labels both centrioles and the pericentriolar material (PCM). Counting fluorescent spots of GFP-centrin in synchronized cells showed that in G(1)/S-arrested cells, centrioles are initially duplicated in a template manner. Further treatment with HU overrides the suppression of excess centriole/centrosome replication in a cell where the full complement of centrioles/centrosomes already exists. Time- lapse fluorescence microscopy revealed that small centrin- containing foci emerged in the cytoplasm during HU treatment. These foci are surrounded by a PCM cloud and their number continuously increases as cells are exposed to HU for longer periods of time. Both the centrosome and cytoplasmic foci are highly mobile, continuously changing their position in a manner dependent on microtubules/microtubule dynamics. The centrosome number increases as small foci grow in size and resolve into recognizable centrosomes. As this occurs in a random fashion, the cells arrested longer with HU induced highly heterogeneous numbers of centrosomes. C1 Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. NCI, Ctr Canc Res, Dept Genet, NIH, Bethesda, MD 20892 USA. RP Kuriyama, R (reprint author), Univ Minnesota, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. EM kuriy001@umn.edu FU Intramural NIH HHS; NIGMS NIH HHS [GM55735] NR 36 TC 23 Z9 23 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 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD JUL 15 PY 2007 VL 120 IS 14 BP 2444 EP 2453 DI 10.1242/jcs.008938 PG 10 WC Cell Biology SC Cell Biology GA 185TC UT WOS:000247732300016 PM 17606999 ER PT J AU Woodcock, HL Hodoscek, M Gilbert, ATB Gill, PMW Schaefer, HF Brooks, BR AF Woodcock, H. Lee, III Hodoscek, Milan Gilbert, Andrew T. B. Gill, Peter M. W. Schaefer, Henry F., III Brooks, Bernard R. TI Interfacing Q-chem and CHARMM to perform QM/MM reaction path calculations SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Review DE QM/MM; CHARMM; Q-Chem; reaction path; chorismate mutase ID DENSITY-FUNCTIONAL THEORY; TRANSITION-STATE STABILIZATION; MINIMUM-ENERGY PATHS; ELASTIC BAND METHOD; MOLECULAR-DYNAMICS SIMULATIONS; ELECTRONIC-STRUCTURE CALCULATIONS; CHORISMATE MUTASE REACTION; MODEL S(N)2 REACTIONS; FAST MULTIPOLE METHOD; SPIN-FLIP APPROACH AB A hybrid quantum mechanical/molecular inechanical (QM/MM) potential energy function with Hartree-Fock, density functional theory (DFT), and post-HF (RIMP2, MP2, CCSD) capability has been implemented in the CHARMM and Q-Chem software packages. In addition, we have modified CHARMM and Q-Chem to take advantage of the newly introduced replica path and the nudged elastic band methods, which are powerful techniques for studying reaction pathways in a highly parallel (i.e., parallel/parallel) fashion, with each pathway point being distributed to a different node of a large cluster. To test our implementation, a series of systems were studied and comparisons were made to both full QM calculations and previous QM/MM studies and experiments. For instance, the differences between HF, DFT, MP2, and CCSD QM/MM calculations of H2O center dot center dot center dot H2O, H2O center dot center dot center dot Na+, and H2O center dot center dot center dot Cl- complexes have been explored. Furthermore, the recently implemented polarizable Drude water model was used to make comparisons to the popular TIP3P and TIP4P water models for doing QM/MM. calculations. We have also computed the energetic profile of the chorismate mutase catalyzed Claisen rearrangement at various QM/MM levels of theory and have compared the results with previous studies. Our best estimate for the activation energy is 8.20 kcal/mol and for the reaction energy is -23.1 kcal/mol, both calculated at the MP2/6-31+G(d)//MF2/6-31 +G(d)/C22 level of theory. (C) 2007 Wiley Periodicals, Inc. C1 NHLBI, NIH, Bethesda, MD 20892 USA. Natl Inst Chem, Ctr Mol Modeling, SI-1000 Ljubljana, Slovenia. Australian Natl Univ, Res Sch Chem, Canberra, ACT 0200, Australia. Univ Georgia, Ctr Computat Chem, Athens, GA 30602 USA. RP Woodcock, HL (reprint author), NHLBI, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hlwood@nih.gov RI Gill, Peter/A-1201-2010; Gilbert, Andrew/D-1468-2010; Woodc, Henry/D-9275-2011; OI Gill, Peter/0000-0003-1042-6331; Woodcock, Henry/0000-0003-3539-273X NR 114 TC 120 Z9 120 U1 3 U2 46 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD JUL 15 PY 2007 VL 28 IS 9 BP 1485 EP 1502 DI 10.1002/jcc.20587 PG 18 WC Chemistry, Multidisciplinary SC Chemistry GA 169EM UT WOS:000246575500004 PM 17334987 ER PT J AU Yamashita, Y Charles, N Furumoto, Y Odom, S Yamashita, T Gilfillan, AM Constant, S Bower, MA Ryan, JJ Rivera, J AF Yamashita, Yumi Charles, Nicolas Furumoto, Yasuko Odom, Sandra Yamashita, Toshiyuki Gilfillan, Alasdair M. Constant, Stephanie Bower, Molly A. Ryan, John J. Rivera, Juan TI Cutting edge: Genetic variation influences Fc epsilon RI-induced mast cell activation and allergic responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LYN; FYN; DEGRANULATION; 3-KINASE; SIGNALS; ASTHMA; KINASE; BTK AB Mast cell responses are influenced by a diverse array of environmental factors, but little is known about the effect of genetic background. In this study, we report that 129/Sv mice had high levels of circulating IgE, increased expression of the high-affinity receptor for IgE (Fc epsilon RI), and greater sensitivity to anaphylaxis when compared with C57BL/6 mice. Bone marrow-derived mast cells (BMMCs) fro in 129/Sv mice showed more robust degranulation upon the engagement of Fc epsilon RI. Deficiency of the Src family kinase Lyn enhanced degranulation in 129/Sv BMMCs but inhibited this response in C57BL/6 cells. C57BL/6 lyn(-/-) BMMCs bad reduced expression of the Src family kinase Fyn, and increasing its expression markedly enhanced degranulation. In human mast cells the silencing of Lyn or Fyn expression resulted in hyperdegranulation or bypodegranulation, respectively. The findings demonstrate a genetic influence on the extent of a mast cell's response and identify Fyn kinase as a contributory determinant. C1 NIAMSD, Mol Immunol & Inflammat Branch, Mol Inflammat Sect, Bethesda, MD 20892 USA. NIH, NIAID, Allerg Dis Res Lab, Bethesda, MD 20892 USA. George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. RP Rivera, J (reprint author), NIH, NIAMSD, Bldg 10,Room 9N228, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov RI Charles, Nicolas/P-5430-2014 OI Charles, Nicolas/0000-0002-5416-5834 FU Intramural NIH HHS; NIAID NIH HHS [AI059638, AI067254] NR 19 TC 51 Z9 51 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 JUL 15 PY 2007 VL 179 IS 2 BP 740 EP 743 PG 4 WC Immunology SC Immunology GA 186AS UT WOS:000247752100006 PM 17617561 ER PT J AU Frasca, D Landin, AM Alvarez, JP Blackshear, PJ Riley, RL Blomberg, BB AF Frasca, Daniela Landin, Ana Marie Alvarez, Juan P. Blackshear, Perry J. Riley, Richard L. Blomberg, Bonnie B. TI Tristetraprolin, a negative regulator of mRNA stability, is increased in old B cells and is involved in the degradation of E47 mRNA SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; ACTIVATED PROTEIN-KINASE; TRANSCRIPTION FACTOR ACTIVITY; RICH ELEMENT; POSTTRANSCRIPTIONAL REGULATION; BINDING-PROTEIN; GENE-EXPRESSION; TNF-ALPHA; AGED MICE; NONLYMPHOID CELLS AB We have previously shown that the E2A-encoded transcription factor E47, which regulates class switch in splenic B cells, is down-regulated in old B cells, due to increased E47 mRNA decay. At least part of the decreased stability of E47 mRNA seen in aged B cells is mediated by proteins. We have herein looked at the specific proteins responsible for the degradation of the E47 mRNA and found that tristetraprolin (TTP), a physiological regulator of mRNA expression and stability, is involved in the degradation of the E47 mRNA. Although many studies have characterized TTP expression and function in macrophages, monocytes, mast cells, and T cells, little is known about the expression and function of TTP in primary B cells. We show herein that TTP mRNA and protein expression are induced by LPS in B cells from young and old mice, the levels of TTP in old B cells always being higher than those in young B cells. Although TTP mRNA is degraded at a significantly higher rate in old B cells, TTP mRNA expression is higher in old than in young, likely due to its increased transcription. Like in macrophages, TTP protein expression and function in B cells are dependent upon p38 MAPK. We found that there is less phospho-TTP (inactive form), as well as phospho-p38, in old than in young splenic-activated B cells. This is the first report showing that TTP is involved in the degradation of the E47 mRNA and is up-regulated in old B cells. C1 Univ Miami, Miler Sch Med, Dept Microbiol & Immunol, Miami, FL 33101 USA. Univ Roma La Sapienza, Grad Sch Cell Biol & Dev, Rome, Italy. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Blomberg, BB (reprint author), Univ Miami, Miler Sch Med, Dept Microbiol & Immunol, PO Box 016960,R-138, Miami, FL 33101 USA. EM bblomber@med.miami.edu FU NIA NIH HHS [AG-025256, AG-17618, AG-23717]; NIAID NIH HHS [AI-064591] NR 70 TC 55 Z9 55 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 JUL 15 PY 2007 VL 179 IS 2 BP 918 EP 927 PG 10 WC Immunology SC Immunology GA 186AS UT WOS:000247752100028 PM 17617583 ER PT J AU Dai, XZ Chen, YH Di, L Podd, A Li, GQ Bunting, KD Hennighausen, L Wen, RR Wang, DM AF Dai, Xuezhi Chen, Yuhong Di, Lie Podd, Andrew Li, Geqiang Bunting, Kevin D. Hennighausen, Lothar Wen, Renren Wang, Demin TI Stat5 is essential for early B cell development but not for B cell maturation and function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERLEUKIN-2-RECEPTOR GAMMA-CHAIN; SEVERE COMBINED IMMUNODEFICIENCY; COMMON LYMPHOID PROGENITORS; TRANSCRIPTION FACTOR GATA-1; MICE LACKING JAK3; DEFICIENT MICE; IL-7 RECEPTOR; FETAL LIVER; INDUCED TRANSFORMATION; LINEAGE COMMITMENT AB The two closely related Stat5 (Stat5A and Stat5B) proteins are activated by a broad spectrum of cytokines. However, with the complication of the involvement of Stat5A/5B in stem cell function, the role of Stat5A/513 in the development and function of lymphocytes, especially B cells, is not fully understood. In this study, we demonstrated that Stat5A/5B(-/-) fetal liver cells had severe diminution of B cell progenitors but clearly had myeloid progenitors. Consistently, the mutant fetal liver cells could give rise to hemopoietic progenitors and myeloid cells but not B cells beyond pro-B cell progenitors in lethally irradiated wild-type or Jak3(-/-) mice. Deletion of Stat5A/513 in vitro directly impaired IL-7-mediated B cell expansion. Of note, reintroduction of Stat5A back into Stat5A/513(-/-) fetal liver cells restored their abilities to develop B cells. Importantly, CD19-Cre-mediated deletion of Stat5A/513 in the B cell compartment specifically impaired early B cell development but not late B cell maturation. Moreover, the B cell-specific deletion of Stat5A/5B did not impair splenic B cell survival, proliferation, and Ig production. Taken together, these data demonstrate that Stat5A/5B directly control IL-7-mediated early B cell development but are not required for B cell maturation and Ig production. C1 Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Nanjing 210008, Peoples R China. Blood Ctr Wisconsin, Blood Res Inst, Milwaukee, WI 53226 USA. Case Western Reserve Univ, Dept Med, Cleveland, OH 44106 USA. NIDDK, NIH, Bethesda, MD 20892 USA. Med Coll Wisconsin, Dept Microbiol & Mol Genet, Milwaukee, WI 53226 USA. RP Wang, DM (reprint author), Blood Res Inst, 8727 Watertown Plank Rd, Milwaukee, WI 53226 USA. EM demin.wang@bcw.edu FU NHLBI NIH HHS [R01 HL073284]; NIAID NIH HHS [R01 AI52327]; NIDDK NIH HHS [R01 DK059380, R01 DK059830] NR 78 TC 29 Z9 31 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 JUL 15 PY 2007 VL 179 IS 2 BP 1068 EP 1079 PG 12 WC Immunology SC Immunology GA 186AS UT WOS:000247752100044 PM 17617599 ER PT J AU Gomos-Klein, J Harrow, F Alarcon, J Ortiz, BD AF Gomos-Klein, Janette Harrow, Faith Alarcon, Jemma Ortiz, Benjamin D. TI CTCF-independent, but not CTCF-dependent, elements significantly contribute to TCR-alpha locus control region activity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID T-CELL-RECEPTOR; ENHANCER-BLOCKING ACTIVITY; BETA-GLOBIN GENE; ALPHA/DELTA LOCUS; TRANSGENIC MICE; APOPTOTIC DEATH-1; PROTEIN CTCF; DAD1 GENES; HIGH-LEVEL; 3' END AB The mouse TCR alpha/TCR delta/Dad1 gene locus bears a locus control region (LCR) that drives high-level, position-independent, thymic transgene expression in chromatin. It achieves this through DNA sequences that enhance transcription and protect transgene expression from integration site-dependent position effects. The former activity maps to a classical enhancer region (E alpha). In contrast, the elements supporting the latter capacity that suppresses position effects are incompletely understood. Such elements likely play important roles in their native locus and may resemble insulator/boundary sequences. Insulators support enhancer blocking and/or chromatin barrier activity. Most vertebrate enhancer-blocking insulators are dependent on the CTCF transcription factor and its cognate DNA binding site. However, studies have also revealed CTCF-independent enhancer blocking and barrier insulator activity in the vertebrate genome. The TCR alpha LCR contains a CTCF-dependent and multiple CTCF-independent enhancer-blocking regions whose roles in LCR activity are unknown. Using randomly integrated reporter transgenes in mice, we find that the CTCF region plays a very minor role in LCR function. In contrast, we report the in vivo function of two additional downstream elements located in the region of the LCR that supports CTCF-independent enhancer- blocking activity in cell culture. Internal deletion of either of these elements significantly impairs LCR activity. These results reveal that the position-effect suppression region of the TCR alpha LCR harbors an array of CTCF-independent, positive-acting gene regulatory elements, some of which share characteristics with barrier-type insulators. These elements may help manage the separate regulatory programs of the TCR alpha and Dad1 genes. C1 CUNY Hunter Coll, Dept Biol Sci, New York, NY 10021 USA. RP Ortiz, BD (reprint author), Natl Inst Hlth, Natl HUman Genom Res Inst, Baltimore, MD 21205 USA. EM ortiz@genectr.hunter.cuny.edu FU NCRR NIH HHS [RR-03037]; NIAID NIH HHS [AI-053050]; NIGMS NIH HHS [GM-060655] NR 50 TC 13 Z9 15 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2007 VL 179 IS 2 BP 1088 EP 1095 PG 8 WC Immunology SC Immunology GA 186AS UT WOS:000247752100046 PM 17617601 ER PT J AU Qian, L Tan, KS Wei, SJ Wu, HM Xu, ZL Wilson, B Lu, RB Hong, JS Flood, PM AF Qian, Li Tan, Kai Soo Wei, Sung-Jen Wu, Hung-Ming Xu, Zongli Wilson, Belinda Lu, Ru-Bin Hong, Jau-Shyong Flood, Patrick M. TI Microglia-mediated neurotoxicity is inhibited by morphine through an opioid receptor-independent reduction of NADPH oxidase activity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; NIGRAL DOPAMINERGIC-NEURONS; NF-KAPPA-B; PARKINSONS-DISEASE; RESPIRATORY BURST; HUMAN-NEUTROPHILS; TETRAZOLIUM SALT; DEXTRO-MORPHINE; LEVO-MORPHINE; SPINAL-CORD AB Recent studies have shown that morphine modulates the function of glia cells through both opioid receptor dependent and independent mechanisms. However, the mechanism by which morphine regulates neuronal disorders through the alteration of microglia activity remains unclear. In this study, using rat primary mesencephalic neuron-glia cultures, we report that both 1-morphine and its synthetic stereoenantiomer, d-morphine, an ineffective opioid receptor agonist, significantly reduced LPS- or 1-methyl-4-phenylpyridinium-induced dopaminergic neurotoxicity with similar efficacy, indicating a nonopioid receptor-mediated effect. In addition, using reconstituted neuron and glia cultures, subpicomolar concentrations of morphine were found to be neuroprotective only in the presence of microglia, and significantly inhibited the production of inflammatory mediators from LPS-stimulated microglia cells. Mechanistic studies showed that both l- and d- morphine failed to protect dopaminergic neurons in cultures from NADPH oxidase (PHOX) knockout mice and significantly. reduced LPS-induced PHOX cytosolic subunit p47(phox)translocation to the cell membrane by inhibiting ERK phosphorylation. Taken together, our results demonstrate that morphine, even at subpicomolar concentrations, exerts potent anti-inflammatory and neuroprotective effects either through the inhibition of direct microglial activation by LPS or through the inhibition of reactive microgliosis elicited by 1-methyl-4-phenylpyridinium. Furthermore, our study reveals that inhibition of PHOX is a novel site of action for the mu-opioid receptor-independent effect of morphine. C1 Univ N Carolina, Comprehens Ctr Inflammatory Disorders, Chapel Hill, NC 27599 USA. NIEHS, NIH, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NIEHS, NIH, La Pharmacol & Chem, Neuropharmacol Sect, Res Triangle Pk, NC 27709 USA. Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore 117548, Singapore. NIEHS, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. Natl Cheng Kung Univ, Coll Med & Hosp, Dept Psychiat, Tainan 70101, Taiwan. RP Flood, PM (reprint author), Univ N Carolina, Comprehens Ctr Inflammatory Disorders, Chapel Hill, NC 27599 USA. EM pat_flood@dentistry.unc.edu OI Tan, Kai Soo/0000-0002-9865-9828; xu, zongli/0000-0002-9034-8902 FU Intramural NIH HHS; NIDCR NIH HHS [DE-13079] NR 62 TC 53 Z9 55 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUL 15 PY 2007 VL 179 IS 2 BP 1198 EP 1209 PG 12 WC Immunology SC Immunology GA 186AS UT WOS:000247752100058 PM 17617613 ER PT J AU Biragyn, A Schiavo, R Olkhanud, P Sumitomo, K King, A McCain, M Indig, FE Almanzar, G Baatar, D AF Biragyn, Arya Schiavo, Roberta Olkhanud, Purevdorj Sumitomo, Kenya King, Alan McCain, Megan Indig, Fred E. Almanzar, Giovanni Baatar, Dolgor TI Tumor-associated embryonic antigen-expressing vaccines that target CCR6 elicit potent CD8(+) T cell-mediated protective and therapeutic antitumor immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMATURE LAMININ RECEPTOR; COLONY-STIMULATING FACTOR; DENDRITIC CELLS; ONCOFETAL ANTIGEN; PROTOTYPE PROTEIN; CANCER VACCINES; DNA VACCINES; IN-VIVO; LYMPHOMA; CHEMOKINES AB Despite its potency, the wider use of immunotherapy for B cell malignancies is hampered by the lack of well-defined tumor-specific Ags. In this study, we demonstrate that an evolutionarily conserved 37-kDa immature laminin receptor protein (OFA-iLRP), a nonimmunogenic embryonic Ag expressed by a variety of tumors, is rendered immunogenic if targeted to the APCs using the CCR6 ligands MIP3 alpha/CCL20 and mDF2 beta. The CCR6 targeting facilitated efficient Ag cross-presentation and induction of tumorneutralizing CTLs. Although the Ag targeting alone, without activation of dendritic cells (DCs), is proposed to induce tolerance, and MIP3 alpha does not directly activate DCs, the MIP3 alpha-based vaccine efficiently induced protective and therapeutic antitumor responses. The responses were as strong as those elicited by the OFA-iLRP fusions with moieties that activated DCs and Th1-type cytokine responses, mDF2 beta, or mycobacterial Hsp70 Ag. Although the same cDNA encodes the dimerized high-affinity mature 67-kDa mLRP that is expressed in normal tissues to stabilize the binding of laminin to cell surface integrins, the vaccines expressing OFA-iLRP elicited long-term protective CD8(+) T cell-mediated memory responses against syngeneic B cell lymphoma, indicating the potential application of these simple vaccines as preventive and therapeutic formulations for human use. C1 NIH, NIA, Gerontol Res Ctr, Immunol Lab, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, Immunol Lab, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, Res Resources Branch, Baltimore, MD 21224 USA. Cyto Pulse Sci, Glen Burnie, MD 21061 USA. RP Biragyn, A (reprint author), Osped Niguarda Ca Granda, Falck Div Med Oncol, Milan, Italy. EM biragyna@mail.nih.gov FU Intramural NIH HHS [Z01 AG000770-04] NR 42 TC 16 Z9 17 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 JUL 15 PY 2007 VL 179 IS 2 BP 1381 EP 1388 PG 8 WC Immunology SC Immunology GA 186AS UT WOS:000247752100076 PM 17617631 ER PT J AU Engels, EA Atkinson, JO Graubard, BI McQuillan, GM Gamache, C Mbisa, G Cohn, S Whitby, D Goedert, JJ AF Engels, Eric A. Atkinson, Jonnae O. Graubard, Barry I. McQuillan, Geraldine M. Gamache, Christine Mbisa, Georgina Cohn, Silvia Whitby, Denise Goedert, James J. TI Risk factors for human herpesvirus 8 infection among adults in the United States and evidence for sexual transmission SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SARCOMA-ASSOCIATED HERPESVIRUS; KAPOSIS-SARCOMA; HOMOSEXUAL-MEN; SEROLOGIC ASSAYS; BLOOD-DONORS; SEROPREVALENCE; WOMEN; SEROPOSITIVITY; PREVALENCE AB Background. Human herpesvirus 8 ( HHV- 8) causes Kaposi sarcoma. In the United States, transmission routes for HHV- 8 are uncertain. Methods. The National Health and Nutrition Examination Survey III sampled individuals from the US general population ( 1988 - 1994). We used enzyme immunoassays ( EIAs) to measure HHV- 8 antibodies ( K8.1 and open reading frame [ ORF] 73 antigens) in 13,894 surveyed adults. HHV- 8 seroprevalence was examined according to sexual history and viral coinfection markers. Results. Overall, seroprevalence was low when a highly specific cutoff was used ( K8.1, 1.6%; ORF73, 1.5%) but was higher when a less- specific cutoff was used ( K8.1, 7.1%; ORF73, 7.4%). When the more- specific approach was used, K8.1 seroprevalence was similar in men and women. Men who have sex with men ( MSM) had a higher K8.1 seroprevalence ( 8.2%). Among other men, K8.1 seroprevalence was marginally associated with duration of heterosexual activity (P=.1) and was positively associated with the lifetime number of sex partners (P=.04) and with coinfections with hepatitis B virus ( 6.1% vs. 1.2% without coinfection;) and herpes simplex P <.001 virus 2 ( 2.7% vs. 1.0%; P=.003). Among women, K8.1 seroprevalence was not significantly related to duration Pp. 003 of sexual activity, the lifetime number of sex partners, or viral coinfections. The ORF73 EIA revealed similar but less clear- cut patterns. Conclusions. Among men, HHV- 8 transmission may occur through sexual activity, particularly sex with other men. No evidence was observed for heterosexual transmission to women. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RTI Int, Rockville, MD USA. Natl Ctr Hlth Stat, Hyattsville, MD USA. Natl Canc Inst, SAIC Frederick, Viral Epidemiol Sect, AIDS Vaccine Program, Frederick, MD USA. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7076, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov NR 37 TC 61 Z9 66 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 JUL 15 PY 2007 VL 196 IS 2 BP 199 EP 207 DI 10.1086/518791 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 186UF UT WOS:000247803100006 PM 17570106 ER PT J AU Jenkins, FJ Hayes, RB Jackson, A Pizza, G Mbisa, G Whitby, D Goedert, JJ AF Jenkins, F. J. Hayes, R. B. Jackson, A. Pizza, G. Mbisa, G. Whitby, D. Goedert, J. J. TI Human herpesvirus 8 seroprevalence among prostate cancer case patients and control subjects SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID KAPOSIS-SARCOMA; BLOOD-DONORS; EPIDEMIOLOGY; INFECTION; CARCINOMA; DISEASE AB To investigate a possible association between human herpesvirus 8 ( HHV- 8) and prostate cancer, we evaluated HHV-8 seroprevalence in 2 case- control studies. HHV- 8 antibodies were detected by immunofluorescence with cells expressing lytic viral proteins and by enzyme immunoassays with recombinant viral structural protein ( K8.1) and latent protein ( latency- associated nuclear antigen - 1; open reading frame 73), respectively. HHV- 8 seroprevalence tended to be lower in patients with prostate cancer than in control subjects, but there was no significant difference in either study. These data imply that HHV- 8 is not a major prevalent cause of prostate cancer. C1 Univ Pittsburgh, Inst Canc, Dept Pathol, Pittsburgh, PA 15213 USA. NCI, NIH, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, NIH, Viral Epidemiol Branch, AIDS Vaccine Program, Bethesda, MD 20892 USA. Howard Univ, Dept Urol, Washington, DC 20059 USA. S Orsola Malpighi, Dept Urol, Bologna, Italy. RP Jenkins, FJ (reprint author), Univ Pittsburgh, Inst Canc, Dept Pathol, G 17B Hillman Canc Res Pavil,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM fjenkins@pitt.edu RI Jenkins, Frank/A-8529-2009; OI Hayes, Richard/0000-0002-0918-661X FU NCI NIH HHS [N01-CO-12400] NR 16 TC 15 Z9 16 U1 0 U2 0 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 JUL 15 PY 2007 VL 196 IS 2 BP 208 EP 211 DI 10.1086/518790 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 186UF UT WOS:000247803100007 PM 17570107 ER PT J AU Gulick, RM Su, ZH Flexner, C Hughes, MD Skolnik, PR Wilkin, TJ Gross, R Krambrink, A Coakley, E Greaves, WL Zolopa, A Reichman, R Godfrey, C Hirsch, M Kuritzkes, DR AF Gulick, Roy M. Su, Zhaohui Flexner, Charles Hughes, Michael D. Skolnik, Paul R. Wilkin, Timothy J. Gross, Robert Krambrink, Amy Coakley, Eoin Greaves, Wayne L. Zolopa, Andrew Reichman, Richard Godfrey, Catherine Hirsch, Martin Kuritzkes, Daniel R. CA AIDS Clinical Trials Grp 5211 Team TI Phase 2 study of the safety and efficacy of vicriviroc, a CCR5 inhibitor, in HIV-1-infected, treatment experienced patients: AIDS clinical trials group 5211 SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 16th International AIDS Conference CY AUG 13-18, 2006 CL Toronto, CANADA ID ACTIVE ANTIRETROVIRAL THERAPY; ENTRY INHIBITORS; HIV-INFECTION; MALIGNANCIES; FUSION; INDIVIDUALS; ENFUVIRTIDE; ANTAGONIST; MUTATION; DISEASE AB Background. Vicriviroc, an investigational CCR5 inhibitor, demonstrated short- term antiretroviral activity in a phase 1 study. Methods. The present study was a double- blind, randomized phase 2 study of vicriviroc in treatment- experienced, human immunodeficiency virus ( HIV) - infected subjects experiencing virologic failure while receiving a ritonavir- containing regimen with an HIV- 1 RNA level >= 5000 copies/ mL and CCR5- using virus. Vicriviroc at 5, 10, or 15 mg or placebo was added to the failing regimen for 14 days, after which the antiretroviral regimen was optimized. The primary end point was the change in plasma HIV- 1 RNA levels at day 14; secondary end points included safety/ tolerability and HIV- 1 RNA changes at week 24. Results. One hundred eighteen subjects were randomized with a median HIV- 1 RNA level of 36,380 ( 4.56 log 10) copies/ mL and a median CD4 cell count of 146 cells/ mm(3). At 14 days and 24 weeks, mean changes in HIV1 RNA level ( log 10 copies/ mL) were greater in the vicriviroc groups ( - 0.87 and - 1.51 [ 5 mg], - 1.15 and - 1.86 [ 10 mg], and - 0.92 and - 1.68 [ 15 mg]) than in the placebo group (+ 0.06 and - 0.29) (P < 0,29). Grade 3/ 4 adverse events were similar across groups. Malignancies occurred in 6 subjects randomized to vicriviroc and in 2 to placebo. Conclusions. In HIV- 1 - infected, treatment- experienced patients, vicriviroc demonstrated potent virologic suppression through 24 weeks. The relationship of vicriviroc to malignancy is uncertain. Further development of vicriviroc in treatment- experienced patients is warranted. C1 Cornell Univ, Weill Med Coll, Cornell HIV Clin Trials Unit, New York, NY 10021 USA. Univ Rochester, Med Ctr, Rochester, NY 14642 USA. Harvard Univ, Sch Publ Hlth, Cambridge, MA 02138 USA. Boston Univ, Med Ctr, Boston, MA 02215 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. Johns Hopkins Univ, Baltimore, MD USA. NIH, Div AIDS, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Monogram Biosci Inc, San Francisco, CA USA. Stanford Univ, Palo Alto, CA 94304 USA. Schering Plough Res Inst, Kenilworth, NJ USA. RP Gulick, RM (reprint author), Cornell Univ, Weill Med Coll, Cornell HIV Clin Trials Unit, Box 566,525 E 68th St, New York, NY 10021 USA. EM rgulick@med.cornell.edu FU NCRR NIH HHS [M01-RR00047, M01-RR00052, M01-RR00096, M01-RR00046, M01-RR00044, M01-RR00051]; NIAID NIH HHS [AI-27661, AI-39439, AI-46370, AI-46381, AI-69418, AI-69423, AI-69432, AI-69434, AI-69450, AI-69465, AI-69472, AI-69474, AI-69494, AI-69502, P30-AI-50410, U01-AI-68636, AI-25859, AI-32783, AI-34853, AI-68634, AI-69411, AI-69419, AI-69424, AI-69471, AI-69495, AI-69501, AI-69532, AI-69556, K23 AI-55038, K24-AI-51966, P30-AI-45008] NR 28 TC 190 Z9 201 U1 0 U2 3 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 JUL 15 PY 2007 VL 196 IS 2 BP 304 EP 312 DI 10.1086/518797 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 186UF UT WOS:000247803100019 PM 17570119 ER PT J AU Fayuk, D Yakel, JL AF Fayuk, Dmitriy Yakel, Jerrel L. TI Dendritic Ca2+ signalling due to activation of alpha 7-containing nicotinic acetylcholine receptors in rat hippocampal neurons SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID LONG-TERM POTENTIATION; CALCIUM PERMEABILITY; SYNAPTIC PLASTICITY; CA1 INTERNEURONS; CHANNEL; MUTATIONS; SUBTYPE; CHOLINE; REGION; BRAIN AB Neuronal nicotinic acetylcholine receptors (nAChRs) are in the superfamily of Cys-loop ligand-gated ion channels, which are widely expressed in the brain. Among the many different subtypes of nAChRs known to be expressed in the rat brain, the alpha 7-containing nAChRs are considered to be the most permeable to Ca2+. Utilizing highly localized and rapid iontophoretic agonist delivery, combined with patch-clamp electrophysiology and fura-2 fluorescence imaging techniques, we examined the alpha 7 nAChR-mediated currents and [Ca2+](i) transients in the dendrites of rat hippocampal CA1 interneurons in the slice. We found that in the dendrites, whereas the amplitudes of the current responses were smaller and the decay kinetics faster than the responses in the soma, the amplitudes of the [Ca2+](i) signals were significantly larger. Cultured hippocampal neurons were studied since the dendritic field lies in the same focal plane, which allowed for a broader investigation of the spatiotemporal dynamics of [Ca2+](i) signalling. In cultured neurons, the [Ca2+](i) signals in the dendrites were similar to those in slices. Interestingly in cultures, even though the amplitude of the alpha 7 nAChR-mediated currents dramatically decreased with distance from the soma (from similar to 20-250 mu m), the amplitude of the [Ca2+](i) signals did not correlate with distance. This indicates that the relative efficacy of alpha 7 nAChR activation to increase [Ca2+](i) levels in dendrites increased severalfold with distance from the soma. These results may have implications for the role that alpha 7 nAChRs have in regulating various signal transduction cascades, synaptic plasticity, and memory processes, via significant changes in [Ca2+](i) levels. C1 NIEHS, Neurobiol Lab, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, Dept Hlth & Human Serv, F2-08,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov FU Intramural NIH HHS NR 40 TC 27 Z9 31 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUL 15 PY 2007 VL 582 IS 2 BP 597 EP 611 DI 10.1113/jphysiol.2007.135319 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 187AK UT WOS:000247819500016 PM 17510177 ER PT J AU Fueger, PT Li, CY Ayala, JE Shearer, J Bracy, DP Charron, MJ Rottman, JN Wasserman, DH AF Fueger, Patrick T. Li, Candice Y. Ayala, Julio E. Shearer, Jane Bracy, Deanna P. Charron, Maureen J. Rottman, Jeffrey N. Wasserman, David H. TI Glucose kinetics and exercise tolerance in mice lacking the GLUT4 glucose transporter SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID CORTICOTROPIN-RELEASING HORMONE; SKELETAL-MUSCLE; PHOSPHORYLATION CAPACITY; CONSCIOUS MOUSE; INSULIN; DEFICIENCY; HYPERGLYCEMIA; METABOLISM; GLYCOGEN; OVEREXPRESSION AB The absence of GLUT4 severely impairs basal glucose uptake in vivo, but does not alter glucose homeostasis or circulating insulin. Glucose uptake in isolated contracting skeletal muscle (MGU) is also impaired by the absence of GLUT4, and onset of muscle fatigue is hastened. Whether the body can compensate and preserve glucose homeostasis during exercise, as it does in the basal state, is unknown. One aim was to test the effectiveness of glucoregulatory compensation for the absence of GLUT4 in vivo. The absence of GLUT4 was also used to further define the role of hexokinase (HK) II, which catalyses glucose phosphorylation after it is transported in the cell. HK II increases MGU during exercise, as well as exercise endurance. In the absence of GLUT4, HK II expression will not affect MGU. A second aim was to test whether, in the absence of GLUT4, HK II retains its ability to increase exercise endurance. Wild-type (WT), GLUT4 null (GLUT4(-/-)), and GLUT4 null overexpressing HK II (GLUT4(-/-)HK(Tg)) mice were studied using a catheterized mouse model that allows blood sampling and isotope infusions during treadmill exercise. The impaired capacity of working muscle to take up glucose in GLUT4(-/-) is partially offset by an exaggerated increase in the glucagon: insulin ratio, increased liver glucose production, hyperglycaemia, and a greater capillary density in order to increase the delivery of glucose to the exercising muscle of GLUT4(-/-). Hearts of GLUT4(-/-) also exhibited a compensatory increase in HK II expression and a paradoxical increase in glucose uptake. Exercise tolerance was reduced in GLUT4(-/-) compared to WT. As expected, MGU in GLUT4(-/-)HK(Tg) was the same as in GLUT4(-/-). However, HK II overexpression retained its ability to increase exercise endurance. In conclusion, unlike the basal state where glucose homeostasis is preserved, hyperglycaemia results during exercise in GLUT4(-/-) due to a robust stimulation of liver glucose release in the face of severe impairments in MGU. Finally, studies in GLUT4(-/-)HK(Tg) show that HK II improves exercise tolerance, independent of its effects on MGU. C1 Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Internal Med, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37232 USA. Yeshiva Univ Albert Einstein Coll Med, Dept Biochem, Bronx, NY 10461 USA. RP Fueger, PT (reprint author), Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, 4321 Med Pk Dr,Suite 200, Durham, NC 27704 USA. EM patrick.fueger@duke.edu RI Fueger, Patrick/G-8956-2013 FU NIDDK NIH HHS [R01 DK050277, R01 DK50277, R01 DK54902, R01 DK047425, R01 DK054902, R01 DK47425, U24 DK059637, U24 DK59637] NR 44 TC 30 Z9 31 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD JUL 15 PY 2007 VL 582 IS 2 BP 801 EP 812 DI 10.1113/jphysiol.2007.132902 PG 12 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 187AK UT WOS:000247819500031 PM 17495042 ER PT J AU Lenroot, RK Gogtay, N Greenstein, DK Wells, EM Wallace, GL Clasen, LS Blumenthal, JD Lerch, J Zijdenbos, AP Evans, AC Thompson, PM Giedd, JN AF Lenroot, Rhoshel K. Gogtay, Nitin Greenstein, Deanna K. Wells, Elizabeth Molloy Wallace, Gregory L. Clasen, Liv S. Blumenthal, Jonathan D. Lerch, Jason Zijdenbos, Alex P. Evans, Alan C. Thompson, Paul M. Giedd, Jay N. TI Sexual dimorphism of brain developmental trajectories during childhood and adolescence SO NEUROIMAGE LA English DT Article ID MRI DATA; TESTOSTERONE; MATURATION; PATTERNS; ABILITY; MATTER; MODEL AB Human total brain size is consistently reported to be similar to 8-10% larger in males, although consensus on regionally specific differences is weak. Here, in the largest longitudinal pediatric neuroimaging study reported to date (829 scans from 387 subjects, ages 3 to 27 years), we demonstrate the importance of examining size-by-age trajectories of brain development rather than group averages across broad age ranges when assessing sexual dimorphism. Using magnetic resonance imaging (MRI) we found robust male/female differences in the shapes of trajectories with total cerebral volume peaking at age 10.5 in females and 14.5 in males. White matter increases throughout this 24-year period with males having a steeper rate of increase during adolescence. Both cortical and subcortical gray matter trajectories follow an inverted U shaped path with peak sizes I to 2 years earlier in females. These sexually dimorphic trajectories confirm the importance of longitudinal data in studies of brain development and underline the need to consider sex matching in studies of brain development. (C) 2007 Elsevier Inc. All rights reserved. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20814 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2T5, Canada. Univ Calif Los Angeles, Lab Neuro Imaging, Los Angeles, CA 90024 USA. RP Lenroot, RK (reprint author), NIMH, Child Psychiat Branch, 10 Ctr Dr,Room 4C110, Bethesda, MD 20814 USA. EM lenrootr@mail.nih.gov RI Gogtay, Nitin/A-3035-2008; Giedd, Jay/A-3080-2008; Wallace, Gregory/A-4789-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Wallace, Gregory/0000-0003-0329-5054; Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU Intramural NIH HHS [Z01 MH002794-06, Z99 MH999999] NR 31 TC 487 Z9 494 U1 13 U2 63 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2007 VL 36 IS 4 BP 1065 EP 1073 DI 10.1016/j.neuroimage.2007.03.053 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 191SN UT WOS:000248152400002 PM 17513132 ER PT J AU Oishi, N Mima, T Ishii, K Bushara, KO Hiraoka, T Uekl, Y Fukuyama, H Hallett, M AF Oishi, N. Mima, T. Ishii, K. Bushara, K. O. Hiraoka, T. Uekl, Y. Fukuyama, H. Hallett, M. TI Neural correlates of regional EEG power change SO NEUROIMAGE LA English DT Article DE neural networks; positron emission tomography (PET); regional cerebral blood flow; sensorimotor; visual ID EVENT-RELATED DESYNCHRONIZATION; CEREBRAL-BLOOD-FLOW; PARTIAL COHERENCE ANALYSIS; CENTRAL NERVOUS-SYSTEM; FRONTAL MIDLINE THETA; CORTICAL MOTOR AREAS; ALZHEIMERS-DISEASE; PREFRONTAL CORTEX; ALPHA RHYTHMS; HUMAN BRAIN AB To clarify the physiological significance of task-related change of the regional electroencephalogram (EEG) rhythm, we quantitatively evaluated the correlation between regional cerebral blood flow (rCBF) and EEG power. Eight subjects underwent (H2O)-O-15 positron emission tomography scans simultaneously with EEG recording during the following tasks: rest condition with eyes closed and open, self-paced movements of the right and left thumb and right ankle. EEG signals were recorded from the occipital and bilateral sensorimotor areas. Cortical activation associated with EEG rhythm generation was studied by the correlation between rCBF and EEG power. There were significant negative correlations between the sensorimotor EEG rhythm at 10-20 Hz on each side and the ipsilateral sensorimotor rCBF and between the occipital EEG rhythm at 10-20 Hz and the occipital rCBF. The occipital EEG rhythm showed a positive correlation with the bilateral medial prefrontal rCBF, while the right sensorimotor EEG rhythm showed a positive correlation with the left prefrontal rCBF. In conclusion, decrease in the regional EEG rhythm at 10-20 Hz might represent the neuronal activation of the cortex underlying the electrodes, at least for the visual and sensorimotor areas. The neural network including the prefrontal cortex could play an important role to generate the EEG rhythm. (C) 2007 Elsevier Inc. All rights reserved. C1 Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Kyoto 606, Japan. Tokyo Metropolitan Inst Gerontol, Positron Med Ctr, Tokyo 173, Japan. Vet Adm Med Ctr, Neurol Serv, Minneapolis, MN 55417 USA. NIH, NINDS, Bethesda, MD 20892 USA. Kyoto City Hosp, Dept Radiol, Nakagyo Ku, Kyoto 604, Japan. RP Mima, T (reprint author), Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Sakyo Ku, 54 Kawahara-cho, Kyoto 606, Japan. EM mima@kuhp.kyoto-u.ac.jp OI Mima, Tatsuya/0000-0001-7787-4855 NR 96 TC 22 Z9 22 U1 3 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUL 15 PY 2007 VL 36 IS 4 BP 1301 EP 1312 DI 10.1016/j.neuroimage.2007.04.030 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 191SN UT WOS:000248152400024 PM 17524671 ER PT J AU Saas, P Bonnefoy, F Kury-Paulin, S Kleinclauss, F Perruche, S AF Saas, Philippe Bonnefoy, Francis Kury-Paulin, Stephanie Kleinclauss, Francois Perruche, Sylvain TI Mediators involved in the immunomodulatory effects of apoptotic cells SO TRANSPLANTATION LA English DT Article; Proceedings Paper CT 6th Beaune Seminar in Transplant Research CY OCT 19-20, 2006 CL Beaune, FRANCE SP Roche, AMGEN, Wolters Kluwer Hlth, Lippincott Williams & Wilkins DE apoptotic cells; dendritic cells; macrophages; TGF-beta; regulatory T cells ID REGULATORY T-CELLS; TGF-BETA; DENDRITIC CELLS; INTRAVENOUS-INFUSION; ALLOGRAFT TOLERANCE; IMMUNE-RESPONSES; GROWTH-FACTOR; PHAGOCYTOSIS; TRANSFUSION; NEUTROPHILS AB Immunomodulatory properties are attributed to apoptotic cells. These properties have been used to modulate allogeneic immune responses in experimental transplantation settings. In independent studies, apoptotic cell infusion has been shown to favor hematopoietic cell engraftment, to increase heart graft survival, and to delay the lethal onset of graft-versus-host disease (GVHD). The goal of this review was to discuss how apoptotic cell infusion interferes with graft rejection or host rejection (i.e., GVHD) and to focus on the potential mediators or "perpetuators" involved in apoptotic cell-induced immunomodulation. Particular emphasis on apoptotic cell phagocytosis, transforming growth factor (TGF)-ss secretion, and regulatory T cell induction was performed. Stimulating "naturally" immunosuppressive molecules (i.e., TGF-ss) or immunomodulatory cells ("alternatively-activated" macrophages, certain dendritic cell subsets, or regulatory T cells) in a physiological manner by using apoptotic cell infusion can be a promising way to induce tolerance. C1 Etablissement Francais Sang Bourgogne Franche Com, F-25020 Besancon, France. Univ Besancon, INSERM, U645, Etablissement Francais Sang, F-25030 Besancon, France. NIH, NIDCR, Mucosal Immunol Unit, Bethesda, MD 20892 USA. RP Saas, P (reprint author), Etablissement Francais Sang Bourgogne Franche Com, 1 Blvd A Fleming,BP1937, F-25020 Besancon, France. EM philippe.saas@efs.sante.fr RI SAAS, Philippe/M-3550-2015; OI SAAS, Philippe/0000-0002-8857-9939 NR 28 TC 18 Z9 21 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD JUL 15 PY 2007 VL 84 IS 1 SU S BP S31 EP S34 DI 10.1097/01.tp.0000269113.59857.d6 PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 191SH UT WOS:000248151800009 PM 17632410 ER PT J AU Sturm-Ramirez, K Miller, MA AF Sturm-Ramirez, Katherine Miller, Mark A. TI Eradication versus control for poliomyelitis SO LANCET LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Miller, MA (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM millermark@nih.gov NR 5 TC 0 Z9 0 U1 3 U2 3 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD JUL 14 PY 2007 VL 370 IS 9582 BP 132 EP 133 DI 10.1016/S0140-6736(07)61082-4 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 190WP UT WOS:000248091600023 PM 17630031 ER PT J AU Callen, E Jankovic, M Difilippantonio, S Daniel, JA Chen, HT Celeste, A Pellegrini, M McBride, K Wangsa, D Bredemeyer, AL Sleckman, BP Ried, T Nussenzweig, M Nussenzweig, A AF Callen, Elsa Jankovic, Mila Difilippantonio, Simone Daniel, Jeremy A. Chen, Hua-Tang Celeste, Arkady Pellegrini, Manuela McBride, Kevin Wangsa, Danny Bredemeyer, Andrea L. Sleckman, Barry P. Ried, Thomas Nussenzweig, Michel Nussenzweig, Andre TI ATM prevents the persistence and propagation of chromosome breaks in lymphocytes SO CELL LA English DT Article ID CLASS-SWITCH RECOMBINATION; DOUBLE-STRAND BREAKS; CYTIDINE DEAMINASE AID; B-CELL DEVELOPMENT; HEAVY-CHAIN LOCUS; GENOMIC INSTABILITY; V(D)J RECOMBINATION; DEFICIENT MICE; IONIZING-RADIATION; GENE AMPLIFICATION AB DNA double- strand breaks ( DSBs) induce a signal transmitted by the ataxia- telangiectasia mutated ( ATM) kinase, which suppresses illegitimate joining of DSBs and activates cell- cycle checkpoints. Here we show that a significant fraction of mature ATM- deficient lymphocytes contain telomere- deleted ends produced by failed end joining during V( D) J recombination. These RAG- 1/ 2 endonuclease- dependent, terminally deleted chromosomes persist in peripheral lymphocytes for at least 2 weeks in vivo and are stable over several generations in vitro. Restoration of ATM kinase activity in mature lymphocytes that have transiently lostATM function leads to loss of cells with terminally deleted chromosomes. Thus, maintenance of genomic stability in lymphocytes requires faithful end joining as well a checkpoint that prevents the long- term persistence and transmission of DSBs. Silencing this checkpoint permits DNA ends produced by V( D) J recombination in a lymphoid precursor to serve as substrates for translocations with chromosomes subsequently damaged by other means in mature cells. C1 Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. Howard Hughes Med Inst, New York, NY 10021 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Sect Canc Genom, NIH, Genet Branch, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63110 USA. RP Nussenzweig, M (reprint author), Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. EM andre_nussenzweig@nih.gov; nussen@mail.rockefeller.edu RI Daniel, Jeremy/S-4729-2016; mcbride, kevin/E-8230-2011 OI Daniel, Jeremy/0000-0002-1981-5571; Bredemeyer, Andrea/0000-0003-2970-5998; FU Intramural NIH HHS NR 52 TC 128 Z9 129 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD JUL 13 PY 2007 VL 130 IS 1 BP 63 EP 75 DI 10.1016/j.cell.2007.06.016 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 197WK UT WOS:000248587000011 PM 17599403 ER PT J AU Ozato, K Tailor, P Kubota, T AF Ozato, Keiko Tailor, Prafullakumar Kubota, Toru TI The interferon regulatory factor family in host defense: Mechanism of action SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SEQUENCE-BINDING-PROTEIN; PLASMACYTOID DENDRITIC CELLS; INNATE ANTIVIRAL RESPONSE; TOLL-LIKE RECEPTORS; CRYSTAL-STRUCTURE; NEGATIVE REGULATION; TRANSCRIPTIONAL ACTIVATION; GENE-EXPRESSION; NUCLEAR-BODIES; MYELOID CELLS AB Transcription factors of the interferon regulatory factor (IRF) family commands the entire type I interferon (IFN) system from induction of IFNs to diverse IFN responses, thereby providing a principal basis for host resistance against pathogens. However, the family has various additional roles. Regulating the development of the immune system, IRFs shape the establishment and execution of innate and adaptive immunity. IRFs also regulate growth and differentiation of many cell types, thus playing a role in leukemia and other cancers. In addition, evidence indicates that IRFs confer antiviral mechanisms not directly ascribed to the IFN system. This review deals with the diverse roles of IRFs in host defense and discusses the molecular mechanisms by which they regulate target gene transcription. C1 NIH, NICHD, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NIH, NICHD, Lab Mol Growth Regulat, Bldg 10, Bethesda, MD 20892 USA. EM ozatok@nih.gov FU Intramural NIH HHS NR 54 TC 98 Z9 109 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 13 PY 2007 VL 282 IS 28 BP 20065 EP 20069 DI 10.1074/jbc.R700003200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 187AI UT WOS:000247819300006 PM 17502370 ER PT J AU Jang, SI Lee, EJ Hart, PS Ramaswami, M Pallos, D Hart, TC AF Jang, Shyh-Ing Lee, Eun-Jin Hart, P. Suzanne Ramaswami, Mukundhan Pallos, Debora Hart, Thomas C. TI Germ line gain of function with SOS1 mutation in hereditary gingival fibromatosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE EXCHANGE FACTOR; EPIDERMAL-GROWTH-FACTOR; ACTIVATED PROTEIN-KINASE; EARLY GENE-PRODUCTS; MAP KINASE; SIGNAL-TRANSDUCTION; EGF RECEPTOR; PC12 CELLS; NUCLEAR TRANSLOCATION; TRANSCRIPTION FACTORS AB Mutation of human SOS1 is responsible for hereditary gingival fibromatosis type 1, a benign overgrowth condition of the gingiva. Here, we investigated molecular mechanisms responsible for the increased rate of cell proliferation in gingival fibroblasts caused by mutant SOS1 in vitro. Using ectopic expression of wild-type and mutant SOS1 constructs, we found that truncated SOS1 could localize to the plasma membrane, without growth factor stimuli, leading to sustained activation of Ras/MAPK signaling. Additionally, we observed an increase in the magnitude and duration of ERK signaling in hereditary gingival fibromatosis gingival fibroblasts that was associated with phosphorylation of retinoblastoma tumor suppressor protein and the up-regulation of cell cycle regulators, including cyclins C, D, and E and the E2F/DP transcription factors. These factors promote cell cycle progression from G1 to S phase, and their up-regulation may underlie the increased gingival fibroblast proliferation observed. Selective depletion of wild-type and mutant SOS1 through small interfering RNA demonstrates the link between mutation of SOS1, ERK signaling, cell proliferation rate, and the expression levels of Egr-1 and proliferating cell nuclear antigen. These findings elucidate the mechanisms for gingival overgrowth mediated by SOS1 gene mutation in humans. C1 NIH, NIDCR, Sect Human & Craniofacial Genet, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Univ Taubate, Dept Dent, Periodont Res & Grad Studies Div, BR-12020 Sao Paulo, Brazil. RP Hart, TC (reprint author), NIH, NIDCR, Sect Human & Craniofacial Genet, Bldg 10, Bethesda, MD 20892 USA. EM thart@mail.nih.gov FU Intramural NIH HHS NR 57 TC 18 Z9 18 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 JUL 13 PY 2007 VL 282 IS 28 BP 20245 EP 20255 DI 10.1074/jbc.M701609200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 187AI UT WOS:000247819300027 PM 17510059 ER PT J AU Cho, YW Hong, T Hong, S Guo, H Yu, H Kim, D Guszczynski, T Dressler, GR Copeland, TD Kalkum, M Ge, K AF Cho, Young-Wook Hong, Teresa Hong, SunHwa Guo, Hong Yu, Hong Kim, Doyeob Guszczynski, Tad Dressler, Gregory R. Copeland, Terry D. Kalkum, Markus Ge, Kai TI PTIP associates with MLL3-and MLL4-containing histone H3 lysine 4 methyltransferase complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; DROSOPHILA-TRITHORAX; ACTIVE CHROMATIN; SET1 COMPLEX; TARGET GENES; METHYLATION; PROTEIN; COACTIVATOR; GROWTH; MLL2 AB PTIP, a protein with tandem BRCT domains, has been implicated in DNA damage response. However, its normal cellular functions remain unclear. Here we show that while ectopically expressed PTIP is capable of interacting with DNA damage response proteins including 53BP1, endogenous PTIP, and a novel protein PA1 are both components of a Set1-like histone methyltransferase (HMT) complex that also contains ASH2L, RBBP5, WDR5, hDPY-30, NCOA6, SET domain-containing HMTsMLL3 and MLL4, and substoichiometric amount of JmjC domain-containing putative histone demethylase UTX. PTIP complex carries robust HMT activity and specifically methylates lysine 4 (K4) on histone H3. Furthermore, PA1 binds PTIP directly and requires PTIP for interaction with the rest of the complex. Moreover, we show that hDPY-30 binds ASH2L directly. The evolutionarily conserved hDPY-30, ASH2L, RBBP5, and WDR5 likely constitute a subcomplex that is shared by all human Set1-likeHMTcomplexes. In contrast, PTIP, PA1, and UTX specifically associate with the PTIP complex. Thus, in cells without DNA damage agent treatment, the endogenous PTIP associates with a Set1-like HMT complex of unique subunit composition. As histone H3 K4 methylation associates with active genes, our study suggests a potential role of PTIP in the regulation of gene expression. C1 NIDDK, NIH, Nucl Receptor Biol Sect, Bethesda, MD 20892 USA. City Hope Natl Med Ctr, Beckman Res Inst, Div Immunol, Duarte, CA 91010 USA. Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. NCI, Natl Inst Hlth, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. RP Ge, K (reprint author), NIDDK, NIH, Nucl Receptor Biol Sect, Bethesda, MD 20892 USA. EM kaig@niddk.nih.gov RI Cho, Young-Wook /F-8269-2011; OI Ge, Kai/0000-0002-7442-5138 FU Intramural NIH HHS [Z01 DK047055-01, Z01 DK075003-04, Z99 DK999999]; NIDDK NIH HHS [ZIADK047055-03, ZIADK075003-06, ZIADK075017-01] NR 40 TC 266 Z9 281 U1 0 U2 9 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 13 PY 2007 VL 282 IS 28 BP 20395 EP 20406 DI 10.1074/jbc.M701574200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 187AI UT WOS:000247819300042 PM 17500065 ER PT J AU Marseille, E Dandona, L Marshall, N Gaist, P Bautista-Arredondo, S Rollins, B Bertozzi, SM Coovadia, J Saba, J Lioznov, D Du Plessis, JA Krupitsky, E Stanley, N Over, M Peryshkina, A Kumar, P Muyingo, S Pitter, C Lundberg, M Kahn, JG AF Marseille, Elliot Dandona, Lalit Marshall, Nell Gaist, Paul Bautista-Arredondo, Sergio Rollins, Brandi Bertozzi, Stefano M. Coovadia, Jerry Saba, Joseph Lioznov, Dmitry Du Plessis, Jo-Ann Krupitsky, Evgeny Stanley, Nicci Over, Mead Peryshkina, Alena Kumar, Prem Muyingo, Sowedi Pitter, Christian Lundberg, Mattias Kahn, James G. TI HIV prevention costs and program scale: data from the PANCEA project in five low and middle-income countries SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID UP HEALTH INTERVENTIONS; SUB-SAHARAN AFRICA; ANDHRA-PRADESH; SEX WORKERS; INDIA; EFFICIENCY; TRANSMISSION AB Background: Economic theory and limited empirical data suggest that costs per unit of HIV prevention program output ( unit costs) will initially decrease as small programs expand. Unit costs may then reach a nadir and start to increase if expansion continues beyond the economically optimal size. Information on the relationship between scale and unit costs is critical to project the cost of global HIV prevention efforts and to allocate prevention resources efficiently. Methods: The "Prevent AIDS: Network for Cost-Effectiveness Analysis" (PANCEA) project collected 2003 and 2004 cost and output data from 206 HIV prevention programs of six types in five countries. The association between scale and efficiency for each intervention type was examined for each country. Our team characterized the direction, shape, and strength of this association by fitting bivariate regression lines to scatter plots of output levels and unit costs. We chose the regression forms with the highest explanatory power (R-2). Results: Efficiency increased with scale, across all countries and interventions. This association varied within intervention and within country, in terms of the range in scale and efficiency, the best fitting regression form, and the slope of the regression. The fraction of variation in efficiency explained by scale ranged from 26%-96%. Doubling in scale resulted in reductions in unit costs averaging 34.2% (ranging from 2.4% to 58.0%). Two regression trends, in India, suggested an inflection point beyond which unit costs increased. Conclusion: Unit costs decrease with scale across a wide range of service types and volumes. These country and intervention-specific findings can inform projections of the global cost of scaling up HIV prevention efforts. C1 Univ Calif San Francisco, Inst Hlth Policy Studies, San Francisco, CA 94143 USA. George Inst Int Hlth India, Hyderabad, Andhra Pradesh, India. Adm Staff Coll India, Ctr Human Dev, Hlth Studies Area, Hyderabad, Andhra Pradesh, India. Univ Sydney, Sch Publ Hlth, Sydney, NSW 2006, Australia. Univ Sydney, George Inst Int Hlth, Sydney, NSW 2006, Australia. NIH, Off AIDS Res, Bethesda, MD 20892 USA. Inst Nacl Salud Publ, Cuernavaca, Morelos, Mexico. HIVAN, Ctr HIV AIDS Networking, Durban, South Africa. Axios Int, Paris, France. St Petersburg Pavlov State Med Univ, St Petersburg, Russia. Elizabeth Glaser Pediad AIDS Fdn, Washington, DC USA. Ctr Global Dev, Washington, DC USA. AIDS Infoshare, Moscow, Russia. George Inst Int Hlth India, Hyderabad, Andhra Pradesh, India. Adm Staff Coll India, Ctr Human Dev, Hlth Studies Area, Hyderabad, Andhra Pradesh, India. Axios Int, Kampala, Uganda. World Bank, Washington, DC 20433 USA. RP Marseille, E (reprint author), Univ Calif San Francisco, Inst Hlth Policy Studies, San Francisco, CA 94143 USA. EM emarseille@comcast.net; LDandona@george.org.in; nell.marshall@ucsf.edu; gaistp@od31em1.od.nih.gov; sbautista@correo.insp.mx; brandi@healingourchildren.org; sbertozzi@correo.insp.mx; coovadiah@nu.ac.za; sabaj@axiosint.com; lioznov@spmu.rssi.ru; maxduplessis@mac.com; kru@ek3506.spb.edu; stazig@yahoo.com; mover@cgdev.org; alena@infoshare.ru; sg.premkumar@george.org.in; muyingos@axiosint.com; cpitter@pedaids.org; mlundberg@worldbank.org; jgkahn@itsa.ucsf.edu RI Bautista-Arredondo, Sergio/N-7305-2016; Lioznov, Dmitry/J-2539-2013 OI Bautista-Arredondo, Sergio/0000-0001-8910-3011; Lioznov, Dmitry/0000-0003-3643-7354 FU NIDA NIH HHS [R01 DA015612, R01 DA15612]; PHS HHS [282-98-0026] NR 22 TC 42 Z9 44 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD JUL 12 PY 2007 VL 7 AR 108 DI 10.1186/1472-6963-7-108 PG 9 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 196KO UT WOS:000248480500001 PM 17626616 ER PT J AU Longart, M Chatani-Hinze, M Gonzalez, CM Vullhorst, D Buonanno, A AF Longart, M. Chatani-Hinze, M. Gonzalez, C. M. Vullhorst, D. Buonanno, A. TI Regulation of ErbB-4 endocytosis by neuregulin in GABAergic hippocampal interneurons SO BRAIN RESEARCH BULLETIN LA English DT Article DE ErbB-4; NRG-1; PSD-95; trafficking; GABAergic intememons; surface protein biotinylation ID RECEPTOR TYROSINE KINASE; NERVOUS-SYSTEM; SCHWANN-CELL; SYNAPSES; CLEAVAGE; PROTEINS; SCHIZOPHRENIA; TRAFFICKING; EXPRESSION; ASSOCIATION AB Neuregulin (NRG)/ErbB receptor signaling pathways have recently been implicated in the reversal of long-term potentiation at hippocampal glutamatergic synapses. Moreover, polymorphisms in NRG-1 and ErbB-4 genes have been linked to an increased risk for developing schizophrenia. ErbB-4 is highly expressed at glutamatergic synapses where it binds to PSD-95 via its carboxyl terminal T-V-V sequence. Here we investigated the expression, localization and trafficking of ErbB-4 in cultured hippocampal neurons by immunocytochemistry, surface protein biotinylation, and live labeling of native receptors. We show that neuronal ErbB-4 is detected at its highest levels in GABAergic interneurons, as observed in vivo. ErbB-4 immunoreactivity precedes PSD-95 expression, with ErbB-4 cluster initially forming in the absence of, but later associating with, PSD-95-positive puncta. By surface protein biotinylation, the fraction of ErbB-4 receptors on the plasma membrane increases from 30% to 65% between 6 and 16 days in vitro (DIV). Interestingly, 30 min of NRG stimulation triggers measurable ErbB-4 receptor internalization at DIV 16, despite increased colocalization with PSD-95. We also investigated the role of TNF alpha-converting enzyme (TACE)-mediated receptor processing in regulating ErbB-4 surface expression. We found that the cleavage-resistant JM-b isoform accounts for 80% of all ErbB-4 transcripts in cultured hippocampal neurons. Receptor stimulation or treatment with phorbol esters does not induce detectable ErbB-4 processing, indicating that neurons mostly rely on endocytosis of the intact receptor to regulate ErbB-4 surface expression. These results enhance our understanding of the regulation of ErbB-4-mediated signaling at glutamatergic synapses. Published by Elsevier Inc. C1 NICHD, Mol Neurobiol Sect, Bethesda, MD 20892 USA. Inst Estudios Avanzados, Ctr Biociencias & Med Mol, Mol Neurobiol Unit, Caracas, Venezuela. RP Buonanno, A (reprint author), Mol Neurobiol Sect, 35 Lincoln Dr, Bethesda, MD 20892 USA. EM mlongart@idea.gob.ve; mayumich@starpower.net; gonzalca@mail.nih.gov; vullhord@mail.nih.gov; buonanno@helix.nih.gov FU Intramural NIH HHS [Z99 HD999999, Z01 HD000711-18] NR 40 TC 19 Z9 22 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD JUL 12 PY 2007 VL 73 IS 4-6 BP 210 EP 219 DI 10.1016/j.brainresbull.2007.02.014 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 186JM UT WOS:000247775000003 PM 17562386 ER PT J AU Jeong, LS Choe, SA Gunaga, P Kim, HO Lee, HW Lee, SK Tosh, DK Patel, A Palaniappan, KK Gao, ZG Jacobson, KA Moon, HR AF Jeong, Lak Shin Choe, Seung Ah Gunaga, Prashantha Kim, Hea Ok Lee, Hyuk Woo Lee, Sang Kook Tosh, Dilip K. Patel, Amit Palaniappan, Krishnan K. Gao, Zhan-Guo Jacobson, Kenneth A. Moon, Hyung Ryong TI Discovery of a new nucleoside template for human A(3) adenosine receptor ligands: D-4 '-thioadenosine derivatives without 4 '-hydroxymethyl group as highly potent and selective antagonists SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID A3 RECEPTORS; ACTIVATION; AGONISTS; RELEASE; INJURY; CELLS; FLUID AB Truncated D-4'-thioadenosine derivatives lacking the 4'-hydroxymethylene moiety were synthesized starting from D-mannose, using cyclization to the 4-thiosugar and one-step conversion of the diol to the acetate as key steps. At the human A(3) adenosine receptor (AR), N(6)-substituted purine analogues bound potently and selectively and acted as antagonists in a cyclic AMP functional assay. An N(6)-(3-chlorobenzyl)purine analogue 9b displayed a K(i) value of 1.66 nM at the human A(3) AR. Thus, truncated D-4'-thioadenosine is an excellent template for the design of novel A(3) AR antagonists to act at both human and murine species. C1 Ewha Womans Univ, Coll Pharm, Lab Med Chem, Seoul 120750, South Korea. NIDDKD, Mol Regulat Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. Pusan Natl Univ, Coll Pharm, Pusan 609753, South Korea. RP Jeong, LS (reprint author), Ewha Womans Univ, Coll Pharm, Lab Med Chem, Seoul 120750, South Korea. EM lakjeong@ewha.ac.kr RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 22 TC 43 Z9 43 U1 0 U2 4 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 JUL 12 PY 2007 VL 50 IS 14 BP 3159 EP 3162 DI 10.1021/jm070259t PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 186DX UT WOS:000247760400001 PM 17555308 ER PT J AU Tang, GZ Ding, K Nikolovska-Coleska, Z Yang, CY Qiu, S Shangary, S Wang, RX Guo, J Gao, W Meagher, J Stuckey, J Krajewski, K Jiang, S Roller, PP Wang, SM AF Tang, Guozhi Ding, Ke Nikolovska-Coleska, Zaneta Yang, Chao-Yie Qiu, Su Shangary, Sanjeev Wang, Renxiao Guo, Jie Gao, Wei Meagher, Jennifer Stuckey, Jeanne Krajewski, Krzysztof Jiang, Sheng Roller, Peter P. Wang, Shaomeng TI Structure-based design of flavonoid compounds as a new class of small-molecule inhibitors of the anti-apoptotic bcl-2 proteins SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID FAMILY PROTEINS; CELL-DEATH; DISCOVERY; REGULATORS; BCL-X(L) AB Structure-based strategy was employed to design flavonoid compounds to mimic the Bim BH3 peptide as a new class of inhibitors of the anti-apoptotic Bcl-2 proteins. The most potent compound, 4 (BI-33), binds to Bcl-2 and Mcl-1 with K-i values of 17 and 18 nM, respectively. Compound 4 inhibits cell growth in the MDA-MB-231 breast cancer cell line with an IC50 value of 110 nM and effectively induces apoptosis. C1 Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. Natl Canc Inst Hlth, Lab Med Chem, Frederick, MD USA. RP Wang, SM (reprint author), Univ Michigan, Ctr Comprehens Canc, 15009 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM shaomeng@umich.edu RI Wang, Shaomeng/E-9686-2010; Ding, Ke/B-3257-2010; OI ding, ke/0000-0001-8167-0476; Tang, Guozhi/0000-0002-7131-4678; Ding, Ke/0000-0001-9016-812X FU Intramural NIH HHS; NCI NIH HHS [U19 CA113317-030001, U19 CA113317, U19 CA113317-01, U19 CA113317-010001, U19 CA113317-015118, U19 CA113317-02, U19 CA113317-020001, U19 CA113317-03, U19 CA113317-04, U19 CA113317-040001, U19CA113317] NR 23 TC 38 Z9 46 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 12 PY 2007 VL 50 IS 14 BP 3163 EP 3166 DI 10.1021/jm070383c PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 186DX UT WOS:000247760400002 PM 17552510 ER PT J AU Xu, H Regino, CAS Bernardo, M Koyama, Y Kobayashi, H Choyke, PL Brechbiel, MW AF Xu, Heng Regino, Celeste A. S. Bernardo, Marcelino Koyama, Yoshinori Kobayashi, Hisataka Choyke, Peter L. Brechbiel, Martin W. TI Toward improved syntheses of dendrimer-based magnetic resonance imaging contrast agents: New bifunctional diethylenetriaminepentaacetic acid ligands and nonaqueous conjugation chemistry SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IN-VIVO; METAL-COMPLEXES; ANTIBODY; RADIOIMMUNOTHERAPY; BIODISTRIBUTION; RELAXIVITY; EXCHANGE; CANCER; CORE; SIZE AB Two different fourth-generation (G4) polyaminonamido dendrimer-based magnetic resonsance (MR) agents were prepared by a new synthetic approach wherein tert-butyl-protected forms of 2-(4-isothiocyanatobenzyl)-6-methyldiethylenetriamine pentaacetic acid (1B4M-DTPA), bearing either an isothiocyanate or a succinimidyl ester moiety, respectively, were conjugated to the primary amines of the dendrimer. Purification was facilitated using a solid phase, N-(2-aminoethyl)aminomethyl polystyrene. After Gd(III) incorporation, molar relaxivity measurements of both new dendrimer-based agents as compared to a G4 agent prepared by an aqueous chemistry route indicated no significant changes in relaxivity. Comparative MR imaging revealed equivalent enhancement of the vessels and organs such as the kidney and liver, although slightly different vascular clearance rates were observed. This general synthesis provides a procedure for preparation of dendrimer-based MR agents for clinical applications with higher yields and efficiency while enhancing versatility. The latter aspect is further demonstrated by preparation of a novel maleimide analog of 1B4M-DTPA from a key synthetic intermediate aniline derivative. C1 NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, SAIC Frederick Inc, Res Technol Program, Frederick, MD 21702 USA. RP Brechbiel, MW (reprint author), NCI, Radiat Oncol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM martinwb@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 34 TC 47 Z9 50 U1 2 U2 12 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 JUL 12 PY 2007 VL 50 IS 14 BP 3185 EP 3193 DI 10.1021/jm061324m PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 186DX UT WOS:000247760400005 PM 17552504 ER PT J AU Costanzi, S Tikhonova, IG Ohno, M Roh, EJ Joshi, BV Colson, AO Houston, D Maddileti, S Harden, TK Jacobson, KA AF Costanzi, Stefano Tikhonova, Irina G. Ohno, Michihiro Roh, Eun Joo Joshi, Bhalchandra V. Colson, Anny-Odile Houston, Dayle Maddileti, Savitri Harden, T. Kendall Jacobson, Kenneth A. TI P2Y(1) antagonists: Combining receptor-based modeling and QSAR for a quantitative prediction of the biological activity based on consensus scoring SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NUCLEOTIDE RECEPTORS; PLATELET-AGGREGATION; POTENT ANTAGONISTS; BINDING-AFFINITY; PHOSPHOLIPASE-C; RATIONAL DESIGN; ANALOGS; AGONISTS; NUCLEOSIDES; DERIVATIVES AB P2Y(1) is an ADP-activated G protein-coupled receptor (GPCR). Its antagonists impede platelet aggregation in vivo and are potential antithrombotic agents. Combining ligand and structure-based modeling we generated a consensus model (LIST-CM) correlating antagonist structures with their potencies. We docked 45 antagonists into our rhodopsin-based human P2Y(1) homology model and calculated docking scores and free binding energies with the Linear Interaction Energy (LIE) method in continuum-solvent. The resulting alignment was also used to build QSAR based on CoMFA, CoMSIA, and molecular descriptors. To benefit from the strength of each technique and compensate for their limitations, we generated our LIST-CM with a PLS regression based on the predictions of each methodology. A test set featuring untested substituents was synthesized and assayed in inhibition of 2-MeSADP-stimulated PLC activity and in radioligand binding. LIST-CM outperformed internal and external predictivity of any individual model to predict accurately the potency of 75% of the test set. C1 NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27515 USA. RP Costanzi, S (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM stefanoc@mail.nih.gov; kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; Costanzi, Stefano/G-8990-2013; OI Jacobson, Kenneth/0000-0001-8104-1493; Costanzi, Stefano/0000-0003-3183-7332 FU Intramural NIH HHS NR 42 TC 28 Z9 29 U1 0 U2 9 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 JUL 12 PY 2007 VL 50 IS 14 BP 3229 EP 3241 DI 10.1021/jm0700971 PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 186DX UT WOS:000247760400010 PM 17564423 ER PT J AU Simeon, FG Brown, AK Zoghbi, SS Patterson, VM Innis, RB Pike, VW AF Simeon, Fabrice G. Brown, Amira K. Zoghbi, Sami S. Patterson, Velvet M. Innis, Robert B. Pike, Victor W. TI Synthesis and simple F-18-labeling of 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile as a high affinity radioligand for imaging monkey brain metabotropic glutamate subtype-5 receptors with positron emission tomography SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MGLUR5 ANTAGONIST MPEP; POTENT; COCAINE; C-11-ABP688; ANALOGS; RELAPSE; SEEKING; PET AB 2-Fluoromethyl analogs of (3-[(2-methyl-1,3-thiazol-4yl)ethynyl]pyridine) were synthesized as potential ligands for metabotropic glutamate subtype-5 receptors (mGluR5s). One of these, namely, 3-fluoro-5-(2-(2-(fluoromethyl)thiazol-4-yl)ethynyl)benzonitrile (3), was found to have exceptionally high affinity (IC50 = 36 pM) and potency in a phosphoinositol hydrolysis assay (IC50 = 0.714 pM) for mGluR5. Compound 3 was labeled with fluorine-18 (t(1/2) = 109.7 min) in high radiochemical yield (87%) by treatment of its synthesized bromomethyl analog (17) with [F-18]fluoride ion and its radioligand behavior was assessed with positron emission tomography (PET). Following intravenous injection of [F-18]3 into rhesus monkey, radioactivity was avidly taken up into brain with high uptake in mGluR5 receptor-rich regions such as striata. [F-18]3 was stable in monkey plasma and human whole blood in vitro and in monkey and human brain homogenates. In monkey in vivo, a single polar radiometabolite of [F-18]3 appeared rapidly in plasma. [F-18]3 merits further evaluation as a PET radioligand for mGluR5 in human subjects. C1 NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Simeon, FG (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3,C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM simeonf@mail.nih.gov FU Intramural NIH HHS; NIMH NIH HHS [N01MH32004] NR 36 TC 58 Z9 58 U1 0 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 JUL 12 PY 2007 VL 50 IS 14 BP 3256 EP 3266 DI 10.1021/jm0701268 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 186DX UT WOS:000247760400012 PM 17571866 ER PT J AU Barinka, C Rovenska, M Mlcochova, P Hlouchova, K Plechanovova, A Majer, P Tsukamoto, T Slusher, BS Konvalinka, J Lubkowski, J AF Barinka, Cyril Rovenska, Miroslava Mlcochova, Petra Hlouchova, Klara Plechanovova, Anna Majer, Pavel Tsukamoto, Takashi Slusher, Barbara S. Konvalinka, Jan Lubkowski, Jacek TI Structural insight into the pharmacophore pocket of human glutamate carboxypeptidase II SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID LINKED ACIDIC DIPEPTIDASE; ASPARTYL-L-GLUTAMATE; THIOL-BASED INHIBITORS; N-ACETYLASPARTYLGLUTAMATE; BIOLOGICAL EVALUATION; MEMBRANE ANTIGEN; QUISQUALIC ACID; RAT-BRAIN; ELECTRON-DENSITY; NAALADASE AB Inhibition of glutamate carboxypeptidase II (GCPII) has been shown to be neuroprotective in multiple preclinical models in which dysregulated glutamatergic transmission is implicated. Herein, we report crystal structures of the human GCPII complexed with three glutamate mimetics/derivatives, 2-(phosphonomethyl)pentanedioic acid (2-PMPA), quisqualic acid (QA), and L-serine O-sulfate (L-SOS), at 1.72, 1.62, and 2.10 angstrom resolution, respectively. Despite the structural differences between the distal parts of the inhibitors, all three compounds share similar binding modes in the pharmacophore (i.e., S1') pocket of GCPII, where they are stabilized by a combination of polar and van der Waals interactions. The structural diversity of the distal parts of the inhibitors leads to rearrangements of the S1' site that are necessary for efficient interactions between the enzyme and an inhibitor. The set of structures presented here, in conjunction with the available biochemical data, illustrates a flexibility of the GCPII pharmacophore pocket and highlights the structural features required for potent GCPII inhibition. These findings could facilitate the rational structure-based drug design of new GCPII inhibitors in the future. C1 NCI, Ctr Canc Res, Frederick, MD 21702 USA. Acad Sci Czech Republ, Inst Organ Chem & Biochem, Gilead Sci & IOCB Res Ctr, CR-10400 Prague, Czech Republic. MGI Pharma Inc, Baltimore, MD 21224 USA. RP Lubkowski, J (reprint author), NCI, Macromol Crystallog Lab, 539 botles St, Frederick, MD 21702 USA. EM jacek@ncifcrf.gov RI Konvalinka, Jan/G-7518-2014; Barinka, Cyril/G-9803-2014; OI Konvalinka, Jan/0000-0003-0695-9266; Hlouchova, Klara/0000-0002-5651-4874 FU Intramural NIH HHS NR 45 TC 45 Z9 46 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD JUL 12 PY 2007 VL 50 IS 14 BP 3267 EP 3273 DI 10.1021/jm070133w PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 186DX UT WOS:000247760400013 PM 17567119 ER PT J AU Deola, S Scaramuzza, S Birolo, RS Cergnul, M Ficara, F Dando, J Voena, C Vai, S Monari, M Pogliani, E Corneo, G Peccatori, J Selleri, S Bordignon, C Roncarolo, MG Aiuti, A Bregni, M AF Deola, Sara Scaramuzza, Samantha Birolo, Roberto Sciarretta Cergnul, Massimiliano Ficara, Francesca Dando, Jonathan Voena, Claudia Vai, Sergio Monari, Marta Pogliani, Enrico Corneo, Gianmarco Peccatori, Jacopo Selleri, Silvia Bordignon, Claudio Roncarolo, Maria Grazia Aiuti, Alessandro Bregni, Marco TI Molecular purging of multiple myeloma cells by ex-vivo culture and retroviral transduction of mobilized-blood CD34(+) cells SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID HIGH-DOSE CHEMOTHERAPY; HEMATOPOIETIC PROGENITOR CELLS; BONE-MARROW TRANSPLANTATION; HSV-TK GENE; PERIPHERAL-BLOOD; STEM-CELLS; TUMOR-CELLS; FREE SURVIVAL; PLASMA-CELLS; ENGRAFTMENT AB Background: Tumor cell contamination of the apheresis in multiple myeloma is likely to affect disease-free and overall survival after autografting. Objective: To purge myeloma aphereses from tumor contaminants with a novel culture-based purging method. Methods: We cultured myeloma-positive CD34(+) PB samples in conditions that retained multipotency of hematopoietic stem cells, but were unfavourable to survival of plasma cells. Moreover, we exploited the resistance of myeloma plasma cells to retroviral transduction by targeting the hematopoietic CD34+ cell population with a retroviral vector carrying a selectable marker (the truncated form of the human receptor for nerve growth factor,Delta NGFR). We performed therefore a further myeloma purging step by selecting the transduced cells at the end of the culture. Results: Overall recovery of CD34(+) cells after culture was 128.5%; Delta NGFR transduction rate was 28.8% for CD34(+) cells and 0% for CD138-selected primary myeloma cells, respectively. Recovery of CD34(+) cells after Delta NGFR selection was 22.3%. By patient-specific Ig-gene rearrangements, we assessed a decrease of 0.7 -1.4 logs in tumor load after the CD34(+) cell selection, and up to 2.3 logs after culture and.NGFR selection. Conclusion: We conclude that ex-vivo culture and retroviral-mediated transduction of myeloma leukaphereses provide an efficient tumor cell purging. C1 Sci Inst HS Raffaele, San Raffaele Telethon Inst Gene Therapy, Milan, Italy. Sci Inst HS Raffaele, Hematol & BMT Unit, Milan, Italy. Hosp S Gerardo, Hematol & Bone Marrow Transplant Unit, Monza, Italy. NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Univ Turin, Dept Biomed Sci & Human Oncol, Turin, Italy. Univ Turin, Ctr Expt Res & Clin Studies, Turin, Italy. Univ Milan, Dept Human Morphol, Milan, Italy. RP Deola, S (reprint author), Sci Inst HS Raffaele, San Raffaele Telethon Inst Gene Therapy, Milan, Italy. EM deola.sara@hsr.it; scaramuzza.samantha@hsr.it; roberto.sciarretta@molmed.it; maxcergnul@yahoo.it; fficara@stanford.edu; jonathan.dando@spr-r.it; clavoe@katamail.com; vai.sergio@libero.it; monari.marta@hsr.it; enrico.pogliani@unimib.it; gianmarco.corneo@unimib.it; peccatori.jacopo@hsr.it; selleris@mail.nih.gov; bordignon.claudio@hsr.it; roncarolo.mariagrazia@hsr.it; aiuti.alessandro@hsr.it; bregni.marco@hsr.it RI AIUTI, ALESSANDRO/K-3918-2016; Ficara, Francesca/M-4624-2016; OI AIUTI, ALESSANDRO/0000-0002-5398-1717; Ficara, Francesca/0000-0003-1873-1189; bregni, marco/0000-0002-3789-1199; RONCAROLO, Maria Grazia/0000-0002-2193-9186 FU Telethon [TGT06S01] NR 33 TC 4 Z9 4 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD JUL 12 PY 2007 VL 5 AR 35 DI 10.1186/1479-5876-5-35 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 204FZ UT WOS:000249030500001 PM 17626627 ER PT J AU Tesar, PJ Chenoweth, JG Brook, FA Davies, TJ Evans, EP Mack, DL Gardner, RL McKay, RDG AF Tesar, Paul J. Chenoweth, Josh G. Brook, Frances A. Davies, Timothy J. Evans, Edward P. Mack, David L. Gardner, Richard L. McKay, Ronald D. G. TI New cell lines from mouse epiblast share defining features with human embryonic stem cells SO NATURE LA English DT Article ID IN-VITRO; CLONAL ANALYSIS; SELF-RENEWAL; GERM-LINE; DIFFERENTIATION; PLURIPOTENCY; ORIGIN; GENOME; DERIVATION; NETWORK AB The application of human embryonic stem (ES) cells in medicine and biology has an inherent reliance on understanding the starting cell population. Human ES cells differ from mouse ES cells and the specific embryonic origin of both cell types is unclear. Previous work suggested that mouse ES cells could only be obtained from the embryo before implantation in the uterus(1-5). Here we show that cell lines can be derived from the epiblast, a tissue of the post-implantation embryo that generates the embryo proper. These cells, which we refer to as EpiSCs (post-implantation epiblast-derived stem cells), express transcription factors known to regulate pluripotency, maintain their genomic integrity, and robustly differentiate into the major somatic cell types as well as primordial germ cells. The EpiSC lines are distinct from mouse ES cells in their epigenetic state and the signals controlling their differentiation. Furthermore, EpiSC and human ES cells share patterns of gene expression and signalling responses that normally function in the epiblast. These results show that epiblast cells can be maintained as stable cell lines and interrogated to understand how pluripotent cells generate distinct fates during early development. C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Oxford, Dept Zool, Mammalian Dev Lab, Oxford OX1 3PS, England. NCI, Stem Cell Biol Sect, NIH, Bethesda, MD 20892 USA. RP McKay, RDG (reprint author), NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM paultesar@ninds.nih.gov; mckayr@ninds.nih.gov RI Tesar, Paul/C-9848-2014; jia, xu/A-8386-2016 OI Tesar, Paul/0000-0003-1532-3155; FU Intramural NIH HHS; Wellcome Trust NR 38 TC 1039 Z9 1060 U1 2 U2 89 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD JUL 12 PY 2007 VL 448 IS 7150 BP 196 EP U10 DI 10.1038/nature05972 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 188QN UT WOS:000247934500043 PM 17597760 ER PT J AU Hartge, P AF Hartge, Patricia TI Genes, cancer risks, and clinical outcomes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID BREAST-CANCER; MUTATION CARRIERS; SURVIVAL C1 NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. RP Hartge, P (reprint author), NCI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. NR 9 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 JUL 12 PY 2007 VL 357 IS 2 BP 175 EP 176 DI 10.1056/NEJMe078093 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 188NX UT WOS:000247927700013 PM 17625130 ER PT J AU Liang, TJ AF Liang, T. Jake TI Shortened therapy for hepatitis C virus genotype 2 or 3 - Is less more? SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID PEGINTERFERON ALPHA-2B; PLUS RIBAVIRIN; INFECTION; GENE; IDENTIFICATION; CANCER C1 NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Liang, TJ (reprint author), NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. NR 18 TC 5 Z9 5 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 JUL 12 PY 2007 VL 357 IS 2 BP 176 EP 178 DI 10.1056/NEJMe078092 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 188NX UT WOS:000247927700014 PM 17625131 ER PT J AU Marcus, PM AF Marcus, Pamela M. TI MRI evaluation of breast cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Marcus, PM (reprint author), NCI, Bethesda, MD 20892 USA. EM pm145q@nih.gov NR 0 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 JUL 12 PY 2007 VL 357 IS 2 BP 192 EP 192 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 188NX UT WOS:000247927700022 PM 17632894 ER PT J AU Vitiello, B Goodkin, K Ashtana, D Shapshak, P Atkinson, JH Heseltine, PNR Eaton, E Heaton, R Lyman, WD AF Vitiello, Benedetto Goodkin, Karl Ashtana, Deshratn Shapshak, Paul Atkinson, J. Hampton Heseltine, Peter N. R. Eaton, Elaine Heaton, Robert Lyman, William D. TI HIV-1 RNA concentration and cognitive performance in a cohort of HIV-positive people SO AIDS LA English DT Article DE cognitive impairment; cerebrospinal fluid; HIV-1; viral load ID PLACEBO-CONTROLLED TRIAL; CEREBROSPINAL-FLUID; NEUROPSYCHOLOGICAL IMPAIRMENT; ANTIRETROVIRAL THERAPY; DOUBLE-BLIND; INFECTION; DEMENTIA; INDIVIDUALS; BRAIN; RISK AB Objective: To determine whether higher viral concentrations in the cerebrospinal fluid (CSF) and/or peripheral blood were associated with greater severity of cognitive impairment in HIV-1-seropositive subjects with cognitive-motor impairment. Methods: Cognitive performance measurements and viral load were obtained from HIV-1 -seropositive individuals with cognitive-motor impairment entering a clinical trial before the introduction of highly active antiretroviral therapy (HAART). CSF viral load (UltraSensitive Roche HIV-1 Monitor test with detection limit of 50copies/ml) was available from 179 patients, and peripheral (plasma or serum) viral load from ill patients. Of these patients, 62% met the 1993 Centers for Disease Control (CDC) criteria for AIDS, and 19% had clinically significant cognitive impairment (i.e., global deficit score >= 0.5). Possible associations between viral load and cognitive scores were examined with general linear regression models with and without adjustment for age, education, study site, antiretroviral use, CD4 cell count, and CDC stage. Results: The mean CSF viral load was 2.83log(10)/ml +/- 0.94 (SD) (undetectable in 19.5%). Mean peripheral viral load was 4.11 log(10)/ml +/- 0.90 (SID). No statistically significant associations emerged between either CSF or peripheral viral load and the global deficit score, or any of the seven cognitive domain deficit scores. Conclusions: Among these HIV-1 -sero-positive individuals with mainly minor HIV-1 associated cognitive deficits and not receiving HAART, no association between CSF or blood concentration of HIV-1 RNA and cognitive performance could be found. These results suggest that the severity of HIV-1 -associated cognitive impairment is not directly related to concurrent viral concentration in the CSF or the peripheral blood. (c) 2007 Lippincott Williams & Wilkins. C1 NIMH, Bethesda, MD 20892 USA. Univ Miami, Sch Med, Dept Psychiat & Behav Sci, Miami, FL USA. Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. Univ So Calif, Dept Med, Los Angeles, CA 90089 USA. Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. Childrens Hosp Michigan, Detroit, MI 48201 USA. RP Vitiello, B (reprint author), NIMH, Room 7147,6001 Execut Blvd, Bethesda, MD 20892 USA. EM bvitiell@mail.nih.gov FU NIMH NIH HHS [N01MH00013, N01MH20007, N01MH20004] NR 23 TC 7 Z9 10 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD JUL 11 PY 2007 VL 21 IS 11 BP 1415 EP 1422 DI 10.1097/QAD.0b013e328220e71a PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 190XI UT WOS:000248093600004 PM 17589187 ER PT J AU Peng, M Litman, R Xie, J Sharma, S Brosh, RM Cantor, SB AF Peng, Min Litman, Rachel Xie, Jenny Sharma, Sudha Brosh, Robert M., Jr. Cantor, Sharon B. TI The FANCJ/MutL alpha interaction is required for correction of the cross-link response in FA-J cells SO EMBO JOURNAL LA English DT Article DE BRIP1/BACH1; FANCJ; fanconi anemia; interstrand crosslinks; mismatch repair; MutL alpha (MLH1/PMS2) ID FANCONI-ANEMIA POLYPEPTIDE; MISMATCH REPAIR PROTEINS; DNA-DAMAGE RESPONSE; S-PHASE; HOMOLOGOUS RECOMBINATION; HELICASE BRIP1; BREAST-CANCER; STRAND BREAK; MUTS-ALPHA; IN-VITRO AB FANCJ also called BACH1/BRIP1 was first linked to hereditary breast cancer through its direct interaction with BRCA1. FANCJ was also recently identified as a Fanconi anemia (FA) gene product, establishing FANCJ as an essential tumor suppressor. Similar to other FA cells, FANCJ-null (FA-J) cells accumulate 4N DNA content in response to DNA interstrand crosslinks (ICLs). This accumulation is corrected by reintroduction of wild-type FANCJ. Here, we show that FANCJ interacts with the mismatch repair complex MutL alpha composed of PMS2 and MLH1. Specifically, FANCJ directly interacts with MLH1 independent of BRCA1, through its helicase domain. Genetic studies reveal that FANCJ helicase activity and MLH1 binding, but not BRCA1 binding, are essential to correct the FA-J cells' ICL-induced 4N DNA accumulation and sensitivity to ICLs. These results suggest that the FANCJ/MutL alpha interaction, but not FANCJ/BRCA1 interaction, is essential for establishment of a normal ICL-induced response. The functional role of the FANCJ/MutL alpha complex demonstrates a novel link between FA and MMR, and predicts a broader role for FANCJ in DNA damage signaling independent of BRCA1. C1 Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Dept Canc Biol, Womens Canc Program, Worcester, MA 01605 USA. NIA, NIH, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Cantor, SB (reprint author), Univ Massachusetts, Sch Med, Dept Canc Biol, 364 Plantat St, LRB 415, Worcester, MA 01605 USA. EM Sharon.Cantor@umassmed.edu NR 48 TC 109 Z9 112 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD JUL 11 PY 2007 VL 26 IS 13 BP 3238 EP 3249 DI 10.1038/sj.emboj.7601754 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 190DP UT WOS:000248038500018 PM 17581638 ER PT J AU Wasko, MCM Hubert, HB Lingala, VB Elliott, JR Luggen, ME Fries, JF Ward, MM AF Wasko, Mary Chester M. Hubert, Helen B. Lingala, Vijaya Bharathi Elliott, Jennifer R. Luggen, Michael E. Fries, James F. Ward, Michael M. TI Hydroxychloroquine and risk of diabetes in patients with rheumatoid arthritis SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID LIFE-STYLE INTERVENTION; RANDOMIZED-TRIAL; MELLITUS; PREVENTION; METFORMIN; WOMEN; CLASSIFICATION; DIAGNOSIS; ESTROGEN; RAMIPRIL AB Context Hydroxychloroquine, a commonly used antirheumatic medication, has hypoglycemic effects and may reduce the risk of diabetes mellitus. Objective To determine the association between hydroxychloroquine use and the incidence of self-reported diabetes in a cohort of patients with rheumatoid arthritis. Design, Setting, and Patients A prospective, multicenter observational study of 4905 adults with rheumatoid arthritis ( 1808 had taken hydroxychloroquine and 3097 had never taken hydroxychloroquine) and no diagnosis or treatment for diabetes in outpatient university-based and community-based rheumatology practices with 21.5 years of follow-up ( January 1983 through July 2004). Main Outcome Measures Diabetes by self-report of diagnosis or hypoglycemic medication use. Results During the observation period, incident diabetes was reported by 54 patients who had taken hydroxychloroquine and by 171 patients who had never taken hydroxychloroquine, with incidence rates of 5.2 per 1000 patient-years of observation compared with 8.9 per 1000 patient-years of observation, respectively ( P <. 001). In time-varying multivariable analysis with adjustments for possible confounding factors, the hazard ratio for incident diabetes among patients who had taken hydroxychloroquine was 0.62 (95% confidence interval, 0.42-0.92) compared with those who had not taken hydroxychloroquine. In Poisson regression, the risk of incident diabetes was significantly reduced with increased duration of hydroxychloroquine use ( P <. 001 for trend); among those taking hydroxychloroquine for more than 4 years (n= 384), the adjusted relative risk of developing diabetes was 0.23 ( 95% confidence interval, 0.11-0.50; P <. 001), compared with those who had not taken hydroxychloroquine. Conclusion Among patients with rheumatoid arthritis, use of hydroxychloroquine is associated with a reduced risk of diabetes. C1 Univ Pittsburgh, Div Clin Immunol & Rheumatol, Pittsburgh, PA 15261 USA. Stanford Univ, Med Ctr, Palo Alto, CA 94304 USA. Univ Cincinnati, Div Immunol, Cincinnati, OH USA. NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Wasko, MCM (reprint author), Univ Pittsburgh, Div Clin Immunol & Rheumatol, 3500 Terrace St,BST 704 S, Pittsburgh, PA 15261 USA. EM wasko@pitt.edu RI Fries, James/F-6271-2011 FU Intramural NIH HHS NR 32 TC 98 Z9 103 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 JUL 11 PY 2007 VL 298 IS 2 BP 187 EP 193 DI 10.1001/jama.298.2.187 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 188HI UT WOS:000247910600024 PM 17622600 ER PT J AU Antoniadis, EA Winslow, JT Davis, M Amaral, DG AF Antoniadis, Elena A. Winslow, James T. Davis, Michael Amaral, David G. TI Role of the primate amygdala in fear-potentiated startle: Effects of chronic lesions in the rhesus monkey SO JOURNAL OF NEUROSCIENCE LA English DT Article DE primate; amygdala; fear-potentiated startle; fear conditioning; rhesus monkey; emotional learning; learning and memory ID BASOLATERAL AMYGDALA; CONDITIONED-STIMULUS; PREPULSE INHIBITION; MULATTA; MODULATION; NUCLEUS; MACACA; BRAIN; RATS AB In experiment 1, we assessed the role of the primate amygdala and hippocampus in the acquisition of learned fear measured with fear-potentiated startle. Three groups of six rhesus monkeys were prepared with bilateral ibotenic acid lesions of the amygdaloid complex and the hippocampus or were sham operated. Selective ibotenic acid lesions of the amygdala, but not the hippocampus, blocked the acquisition of fear-potentiated startle. In experiment 2, we assessed the role of the primate amygdala in the expression of fear-potentiated startle. Surprisingly, animals that sustained amygdala damage after they successfully learned fear-potentiated startle expressed normal fear-potentiated startle, despite a complete amygdala lesion based on magnetic resonance imaging assessments. These results suggest that although the amygdala is necessary for the initial acquisition of fear-potentiated startle, it is not necessary for the retention and expression of fear-potentiated startle. These findings are discussed in relation to the role of the amygdala in emotional learning and in cross-species comparisons of emotional behavior. C1 Univ Calif Davis, Med Invest Neurodev Disorders Inst, Davis, CA 95817 USA. Dept Psychiat & Behav Sci, Davis, CA USA. California Natl Primate Res Ctr, Davis, CA USA. NIMH, Bethesda, MD 20842 USA. Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30320 USA. Emory Univ, Dept Psychiat & Behav Sci, Ctr Behav Neurosci, Atlanta, GA 30320 USA. RP Amaral, DG (reprint author), Univ Calif Davis, Med Invest Neurodev Disorders Inst, 2825 50th St, Davis, CA 95817 USA. EM dgamaral@ucdavis.edu FU NCRR NIH HHS [RR00169]; NIMH NIH HHS [R37 MH057502, 2P50 MH058922, R37 MH47840] NR 35 TC 33 Z9 34 U1 2 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 11 PY 2007 VL 27 IS 28 BP 7386 EP 7396 DI 10.1523/JNEUROSCI.5643-06.2007 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 191RD UT WOS:000248147900003 PM 17626199 ER PT J AU Samanta, J Burke, GM McGuire, T Pisarek, AJ Mukhopadhyay, A Mishina, Y Kessler, JA AF Samanta, Jayshree Burke, Gordon M. McGuire, Tammy Pisarek, Anna J. Mukhopadhyay, Abhishek Mishina, Yuji Kessler, John A. TI BMPR1a signaling determines numbers of oligodendrocytes and calbindin-expressing interneurons in the cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE BMPR1a; Olig1; calbindin; knock-out mice; oligodendrocyte; stem cell ID BONE MORPHOGENETIC PROTEIN; DEVELOPING CEREBRAL-CORTEX; CORTICAL GABAERGIC NEURONS; SONIC HEDGEHOG; TRANSCRIPTION FACTORS; SUBVENTRICULAR ZONE; PROGENITOR CELLS; NERVOUS-SYSTEM; MOUSE EMBRYOGENESIS; NEUROTROPHIC FACTOR AB Progenitor cells that express the transcription factor olig1 generate several neural cell types including oligodendrocytes and GABAergic interneurons in the dorsal cortex. The fate of these progenitor cells is regulated by a number of signals including bone morphogenetic proteins (BMPs) secreted in the dorsal forebrain. BMPs signal by binding to heteromeric serine-threonine kinase receptors formed by type I (BMPR1a, BMPR1b, Alk2) and type II (BMPRII) subunits. To determine the specific role of the BMPR1a subunit in lineage commitment by olig1-expressing cells, we used a cre/loxP genetic approach to ablate BMPR1a in these cells while leaving signaling from other subunits intact. There was a reduction in numbers of immature oligodendrocytes in the BMPR1a-null mutant brains at birth. However, by postnatal day 20, the BMPR1a-null mice had a significant increase in the number of mature and immature oligodendrocytes compared with wild-type littermates. There was also an increase in the proportion of calbindin-positive interneurons in the dorsomedial cortex of BMPR1a- null mice at birth without any change in the number of parvalbumin- or calretinin-positive cells. These effects were attributable, at least in part, to a decrease in the length of the cell cycle in subventricular zone progenitor cells. Thus, our findings indicate that BMPR1a mediates the suppressive effects of BMP signaling on oligodendrocyte lineage commitment and on the specification of calbindin-positive interneurons in the dorsomedial cortex. C1 Northwestern Univ, Feinberg Sch Med, Dept Neurol, Chicago, IL 60611 USA. Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Kessler, JA (reprint author), 303 E Chicago Ave,Ward 10-233, Chicago, IL 60611 USA. EM jakessler@northwestern.edu OI Samanta, Jayshree/0000-0003-1240-3395; Burke, Gordon/0000-0002-4724-6548 NR 86 TC 40 Z9 41 U1 1 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 11 PY 2007 VL 27 IS 28 BP 7397 EP 7407 DI 10.1523/JNEUROSCI.1434-07.2007 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 191RD UT WOS:000248147900004 PM 17626200 ER PT J AU Ng, BK Chen, L Mandemakers, W Cosgaya, JM Chan, JR AF Ng, Benjamin K. Chen, Lian Mandemakers, Wilhelm Cosgaya, Jose M. Chan, Jonah R. TI Anterograde transport and secretion of brain-derived neurotrophic factor along sensory axons promote schwann cell myelination SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Schwann cell; myelination; dorsal root ganglion neurons; neurotrophins; anterograde; BDNF ID FUNCTIONAL RECOVERY; SPINAL-CORD; NEURONS; MIGRATION; PATHWAY; ACTIVATION; EXPRESSION; P75(NTR); SYSTEM; GROWTH AB The neurotrophin brain-derived neurotrophic factor ( BDNF) inhibits Schwann cell (SC) migration and promotes myelination via the p75 neurotrophin receptor (NTR). Despite these recent findings, the expression, localization, and mechanism of BDNF action has yet to be determined. Here we demonstrate that the sensory neurons of the dorsal root ganglion (DRG) are a major source of BDNF during postnatal development. The expression of BDNF is initially elevated before myelination and decreases dramatically after the onset of myelination. BDNF expression is controlled in part by transcriptional regulation and the increased expression of the truncated TrkB receptor on SCs. To investigate the possible mechanism of BDNF transport and release, multicompartment Campenot chambers were used. DRG neurons transported and secreted endogenous BDNF along the surface of axons in anterograde fashion. In an attempt to enhance myelination by SCs, DRG neurons were transduced with an adenovirus to overexpress BDNF. BDNF was transported and secreted along the axons and enhanced myelination when compared with control cocultures. Together, the events surrounding the expression, localization, and mechanism of BDNF action in DRG neurons may hint at potential therapeutic implications to efficiently promote remyelination. C1 Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA. NIH, NICHHD, Bethesda, MD 20892 USA. Katholieke Univ Leuven, Dept Human Genet, B-3000 Louvain, Belgium. Univ Autonoma Madrid, Consejo Super Invest, Inst Invest Biomed, E-28029 Madrid, Spain. RP Chan, JR (reprint author), Univ So Calif, Keck Sch Med, Zilkha Neurogenet Inst, Dept Biochem & Mol Biol, Los Angeles, CA 90033 USA. EM jonah.chan@usc.edu RI Cosgaya, Jose/B-4936-2008; OI Cosgaya, Jose Miguel/0000-0002-6005-2916 NR 33 TC 56 Z9 61 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 11 PY 2007 VL 27 IS 28 BP 7597 EP 7603 DI 10.1523/JNEUROSCI.0563-07.2007 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 191RD UT WOS:000248147900025 PM 17626221 ER PT J AU Zhang, N Appella, DH AF Zhang, Ning Appella, Daniel H. TI Colorimetric detection of anthrax DNA with a peptide nucleic acid sandwich-hybridization assay SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID BACILLUS-ANTHRACIS AB Technologies for genomic detection most commonly use DNA probes to hybridize to target sequences. To achieve required sensitivity, the use of PCR to amplify target sequences has remained standard practice in many labs. Direct detection methods that eliminate the requirement for a PCR step could afford faster and simpler devices that can be used outside of a laboratory. We have developed a sandwich-hybridization DNA detection system in which the DNA detection probes are replaced with a class of synthetic nucleic acid mimics called peptide nucleic acids (PNAs). There are numerous advantages to using PNA instead of DNA probes in hybridization assays, including complete resistance to degradation by enzymes, increased sequence specificity to complementary DNA, and higher stability when bound with complementary DNA. In this communication, several different strategies are described to improve and fine-tune the properties of PNA so that anthrax DNA can be detected at a 10 zmol limit. Key to the success of these strategies is the ability to introduce chemical modifications into the PNA to improve thermal stability and to increase the number of biotin groups to which a horseradish peroxidase-avidin conjugate can bind. C1 NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Appella, DH (reprint author), NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov FU Intramural NIH HHS NR 7 TC 60 Z9 61 U1 3 U2 24 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD JUL 11 PY 2007 VL 129 IS 27 BP 8424 EP + DI 10.1021/ja072744j PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 186DN UT WOS:000247759400013 PM 17569540 ER PT J AU Chloupkova, M Pickert, A Lee, JY Souza, S Trinh, YT Connelly, SM Dumont, ME Dean, M Urbatsch, IL AF Chloupkova, Maja Pickert, Amanda Lee, Jyh-Yeuan Souza, Shiloe Trinh, Yenphuong T. Connelly, Sara M. Dumont, Mark E. Dean, Michael Urbatsch, Ina L. TI Expression of 25 human ABC transporters in the yeast Pichia pastoris and characterization of the purified ABCC3 ATPase activity SO BIOCHEMISTRY LA English DT Article ID MULTIDRUG-RESISTANCE PROTEIN-3; HUMAN P-GLYCOPROTEIN; TRANSMEMBRANE CONDUCTANCE REGULATOR; CYSTIC-FIBROSIS; MICE LACKING; FUNCTIONAL-CHARACTERIZATION; INCREASED SENSITIVITY; ESCHERICHIA-COLI; ANTICANCER DRUGS; BILE-ACIDS AB Human ATP-binding cassette (ABC) transporters comprise a family of 48 membrane-spanning transport proteins, many of which are associated with genetic diseases or multidrug resistance of cancers. In this study, we present a comprehensive approach for the cloning, expression, and purification of human ABC transporters in the yeast Pichia pastoris. We analyzed the expression of 25 proteins and demonstrate that 11 transporters, including ABCC3, ABCB6, ABCD1, ABCG1, ABCG4, ABCG5, ABCG8, ABCE1, ABCF1, ABCF2, and ABCF3, were expressed at high levels comparable to that of ABCB1 (P-glycoprotein). As an example of the purification strategy via tandem affinity chromatography, we purified ABCC3 (MRP3) whose role in the transport of anticancer drugs, bile acids, and glucuronides has been controversial. The yield of ABCC3 was 3.5 mg/100 g of cells in six independent purifications. Purified ABCC3, activated with PC lipids, exhibited significant ATPase activity with a V-max of 82 +/- 32 nmol min(-1) mg(-1). The ATPase activity was stimulated by bile acids and glucuronide conjugates, reaching 170 +/- 28 nmol min(-1) mg(-1), but was not stimulated by a variety of anticancer drugs. The glucuronide conjugates ethinylestradiol-3-glucuronide and 17 beta-estradiol-17-glucuronide stimulated the ATPase with relatively high affinities (apparent K-m values of 2 and 3 mu M, respectively) in contrast to bile acids (apparent K-m values of > 130 mu M), suggesting that glucuronides are the preferred substrates for this transporter. Overall, the availability of a purification system for the production of large quantities of active transporters presents a major step not only toward understanding the role of ABCC3 but also toward future structure-function analysis of other human ABC transporters. C1 Texas Tech Univ, Hlth Sci Ctr, Dept Cell Biol & Biochem, Lubbock, TX 79430 USA. Univ Rochester, Med Ctr, Dept Biochem & Biophys, Rochester, NY 14642 USA. NCI Frederick, Lab Genom Divers, Ft Detrick, MD 21702 USA. RP Urbatsch, IL (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Cell Biol & Biochem, Lubbock, TX 79430 USA. EM ina.urbatsch@ttuhsc.edu RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU Intramural NIH HHS; NIGMS NIH HHS [P50GM64655] NR 62 TC 34 Z9 35 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 10 PY 2007 VL 46 IS 27 BP 7992 EP 8003 DI 10.1021/bi700020m PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 184YE UT WOS:000247677700007 PM 17569508 ER PT J AU Wang, DQ Wang, Q Awasthi, S Simons, SS AF Wang, Dongqing Wang, Qi Awasthi, Smita Simons, S. Stoney, Jr. TI Amino-terminal domain of TIF2 is involved in competing for corepressor binding to glucocorticoid and progesterone receptors SO BIOCHEMISTRY LA English DT Article ID NUCLEAR HORMONE-RECEPTORS; PARTIAL AGONIST ACTIVITY; DOSE-RESPONSE CURVE; ANDROGEN RECEPTOR; ESTROGEN-RECEPTOR; ANTAGONIST COMPLEXES; INDUCTION PROPERTIES; GENE-EXPRESSION; CO-REPRESSOR; N-COR AB Both agonist- and antagonist-bound glucocorticoid receptors (GRs) and progesterone receptors (PRs) regulate gene transcription with the assistance of corepressors (NCoR and SMRT) and coactivators (TIF2/GRIP1, SRC1, and AIB1). Receptor binding of these cofactors is competitive and is considered to involve interactions between the C-terminal ligand binding domain of receptors and receptor interaction domains (RIDs) in the middle and C-terminus of coactivators and corepressors, respectively. Therefore, our recent finding that an amino terminal fragment of TIF2 (TIF2.0 = amino acids 1-627) competed for GR and PR interactions with corepressors in mammalian two-hybrid assays was unexpected. Here, we use biochemical approaches (mammalian two-hybrid, pull-down, and coimmunoprecipitation assays) to locate an N-terminal GR region that is sufficient to bind TIF2.0. In contrast, an N-terminal sequence of PR-B that is largely missing in the shorter PR-A is necessary but not sufficient for TIF2.0 binding. Mutagenesis studies of NCoR establish that the more amino-terminal RID#1, but not RID#2, is necessary for binding to both GR and PR agonist and antagonist complexes. ChIP assays indicate that PR and NCoR each selectively localize to the enhancer element (PRE) of a transiently transfected PREtkLUC reporter in the presence of antagonist steroid, whereas exogenous TIF2.0 reduces the amount of PRE-associated NCoR. Importantly, exogenous TIF2.0 also inhibits the biological responses to added NCoR under the same conditions as those used in the ChIP assays. These results suggest that both N-terminal and middle sequences of TIF2 participate in competing with corepressor for regulating the gene transcriptional responses of GRs and PRs. C1 NIDDK, CEB, Steroid Hormones Sect, NIH, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, CEB, Steroid Hormones Sect, NIH, Bldg 10,Room 8N-307B, Bethesda, MD 20892 USA. EM steroids@helix.nih.gov FU Intramural NIH HHS NR 65 TC 20 Z9 22 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD JUL 10 PY 2007 VL 46 IS 27 BP 8036 EP 8049 DI 10.1021/bi7004575 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 184YE UT WOS:000247677700011 PM 17571860 ER PT J AU Owens, DS Plehn, JF AF Owens, David S. Plehn, Jonathan F. TI Recognizing unrecognized risk - The evolving role of ventricular functional assessment in population-based studies SO CIRCULATION LA English DT Editorial Material ID CONGESTIVE-HEART-FAILURE; WAVE MYOCARDIAL-INFARCTION; MAGNETIC-RESONANCE; CARDIOVASCULAR HEALTH; URBAN-POPULATION; DYSFUNCTION; ELECTROCARDIOGRAM; ENHANCEMENT; FRAMINGHAM; PROGNOSIS C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. Univ Washington, Div Cardiol, Seattle, WA 98195 USA. George Washington Univ, Washington, DC 20052 USA. RP Plehn, JF (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10,CRC 5-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM plehnj@nhlbi.nih.gov OI Owens, David/0000-0002-7293-9688 NR 25 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 10 PY 2007 VL 116 IS 2 BP 126 EP 130 DI 10.1161/CIRCULATIONAHA.107.712364 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 188ES UT WOS:000247902600001 PM 17620518 ER PT J AU Magnusson, A Goransson, M Heilig, M AF Magnusson, Asa Goransson, Mona Heilig, Markus TI Hazardous alcohol users during pregnancy: Psychiatric health and personality traits SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE preganancy; alcohol; hazardous use; fetal alcohol spectrum disorders; personality; impulsivity; novelty seeking ID IDENTIFICATION TEST AUDIT; SCREENING INSTRUMENTS; SPONTANEOUS-ABORTION; MODERATE DRINKING; CONSUMPTION; WOMEN; RISK; PREVALENCE; LIFE; CARE AB Background: We examined alcohol use disorders, psychiatric symptoms and personality traits in women reporting alcohol use during pregnancy. Methods: In a pilot cohort (n = 139), subjects were screened for alcohol use disorders, and assessed for psychopathology, personality traits, and alcohol use during the first trimester. Those reporting consumption exceeding a conservative threshold for harmful use were offered a diagnostic psychiatric interview. The main findings of the pilot study were replicated using a large sample of women in the third trimester (n = 715), who were screened for alcohol use disorders, had their consumption during pregnancy assessed, and were assessed for personality traits. Results: In the pilot cohort, only a minority of women who consumed significant amounts of alcohol during pregnancy fulfilled alcohol dependence criteria, or had scores on the Alcohol Use Disorder Identification Test typically associated with such a diagnosis. Psychiatric morbidity was also unremarkable as assessed by self-reported symptom intensity. The distinguishing feature was high novelty seeking. The results were robustly confirmed in the replication study. Conclusions: Most women with significant alcohol consumption during pregnancy do not seem to be alcohol dependent. Instead, use during pregnancy may reflect impulsive personality traits, and be correlated with additional risk behaviors. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 Karolinska Univ, Huddinge Hosp, Dept Clin Neurosci, S-14186 Stockholm, Sweden. NIAAA, NIH, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. RP Heilig, M (reprint author), Karolinska Univ, Huddinge Hosp, Dept Clin Neurosci, S-14186 Stockholm, Sweden. EM markus.heilig@mail.nih.gov OI Heilig, Markus/0000-0003-2706-2482 NR 32 TC 11 Z9 11 U1 2 U2 4 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 JUL 10 PY 2007 VL 89 IS 2-3 BP 275 EP 281 DI 10.1016/j.drugalcdep.2007.01.015 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 176QB UT WOS:000247098900022 PM 17363194 ER PT J AU Bruni, AC Momeni, P Bernardi, L Tomaino, C Frangipane, F Elder, J Kawarai, T Sato, C Pradella, S Wakutani, Y Anfossi, M Gallo, M Geracitano, S Costanzo, A Smirne, N Curcio, SAM Mirabelli, M Puccio, G Colao, R Maletta, RG Kertesz, A St George-Hyslop, P Hardy, J Rogaeva, E AF Bruni, A. C. Momeni, P. Bernardi, L. Tomaino, C. Frangipane, F. Elder, J. Kawarai, T. Sato, C. Pradella, S. Wakutani, Y. Anfossi, M. Gallo, M. Geracitano, S. Costanzo, A. Smirne, N. Curcio, S. A. M. Mirabelli, M. Puccio, G. Colao, R. Maletta, R. G. Kertesz, A. St. George-Hyslop, P. Hardy, J. Rogaeva, E. TI Heterogeneity within a large kindred with frontotemporal dementia - A novel progranulin mutation SO NEUROLOGY LA English DT Article ID LOBAR DEGENERATION; TAU; VARIABILITY; TAUOPATHIES; ASSOCIATION; INCLUSIONS; CRITERIA; DISEASE; CHMP2B; 17Q21 AB Background: Frontotemporal dementia (FTD) in several 17q21-linked families was recently explained by truncating mutations in the progranulin gene (GRN). Objective: To determine the frequency of GRN mutations in a cohort of Caucasian patients with FTD without mutations in known FTD genes. Methods: GRN was sequenced in a series of 78 independent FTD patients including 23 familial subjects. A different Calabrian dataset ( 109 normal control subjects and 96 FTD patients) was used to establish the frequency of the GRN mutation. Results: A novel truncating GRN mutation (c.1145insA) was detected in a proband of an extended consanguineous Calabrian kindred. Segregation analysis of 70 family members revealed 19 heterozygous mutation carriers including 9 patients affected by FTD. The absence of homozygous carriers in a highly consanguineous kindred may indicate that the loss of both GRN alleles might lead to embryonic lethality. An extremely variable age at onset in the mutation carriers ( more than five decades apart) is not explained by APOE genotypes or the H1/H2 MAPT haplotypes. Intriguingly, the mutation was excluded in four FTD patients belonging to branches with an autosomal dominant mode of inheritance of FTD, suggesting that another novel FTD gene accounts for the disease in the phenocopies. It is difficult to clinically distinguish phenocopies from GRN mutation carriers, except that language in mutation carriers was more severely compromised. Conclusion: The current results imply further genetic heterogeneity of frontotemporal dementia, as we detected only one GRN-linked family (about 1%). The value of discovering large kindred includes the possibility of a longitudinal study of GRN mutation carriers. C1 Ctr Reg Neurogenet, I-88046 Lamezia Terme, CZ, Italy. Univ Florence, Dept Neurol & Psychiat, Florence, Italy. Texas Tech Univ, Hlth Sci Ctr, Dept Neurol, Lubbock, TX 79409 USA. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. Univ Toronto, Toronto Western Hosp, Res Inst, Dept Med,Ctr Res Neurodegenerat Dis, Toronto, ON M5T 2S8, Canada. Univ Hlth Network, Dept Med, Toronto, ON, Canada. Univ Toronto, Div Neurol, Toronto, ON, Canada. Univ Western Ontario, St Josephs Hlth Ctr, Dept Clin Neurol Sci, London, ON N6A 4V2, Canada. RP Bruni, AC (reprint author), Ctr Reg Neurogenet, AS6m,Viale A Perugini, I-88046 Lamezia Terme, CZ, Italy. EM bruni@arn.it RI Hardy, John/C-2451-2009; , raffaele/K-4421-2016 OI , raffaele/0000-0002-0758-1835 FU Intramural NIH HHS; Medical Research Council [G0701075] NR 23 TC 49 Z9 51 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 JUL 10 PY 2007 VL 69 IS 2 BP 140 EP 147 DI 10.1212/01.wnl.0000265220.64396.b4 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 188ER UT WOS:000247902500004 PM 17620546 ER PT J AU van der Knaap, MS Linnankivi, T Paetau, A Feigenbaum, A Wakusawa, K Haginoya, K Kohler, W Henneke, M Dinopoulos, A Grattan-Smith, P Brockmann, K Schiffmann, R Blaser, S AF van der Knaap, M. S. Linnankivi, T. Paetau, A. Feigenbaum, A. Wakusawa, K. Haginoya, K. Kohler, W. Henneke, M. Dinopoulos, A. Grattan-Smith, P. Brockmann, K. Schiffmann, R. Blaser, S. TI Hypomyelination with atrophy of the basal ganglia and cerebellum - Follow-up and pathology SO NEUROLOGY LA English DT Article ID PELIZAEUS-MERZBACHER DISEASE; SOX10 MUTATION; BRAIN; HYPODONTIA; MATURATION; MYELIN AB Background and objective: Hypomyelination with atrophy of the basal ganglia and cerebellum is a recently defined disorder. Only a few patients have been described. We report on 11 additional patients and new MRI findings and provide histopathologic confirmation of the MRI interpretation. Methods: We reviewed the patients' clinical history and present findings. We scored the MRI abnormalities. The histopathology of one patient was re-examined. Results: The patients' early psychomotor development was normal or delayed, followed by increasing extrapyramidal movement abnormalities, ataxia, and spasticity. Mental capacities were variably affected. MRI showed hypomyelination with, on follow-up, evidence of further myelin loss and variable white matter atrophy. The putamen was small or, more often, absent; the head of the caudate nucleus was decreased in size. In contrast, the thalamus and globus pallidus remained normal. Cerebellar atrophy was invariably present. Histopathology confirmed the myelin deficiency, probably related to both lack of deposition and low-grade further loss. The degeneration of putamen was subtotal. The cerebellar cortex was affected, particularly the granular layer. Conclusion: Hypomyelination with atrophy of the basal ganglia and cerebellum is a syndrome diagnosed by distinctive MRI findings. Histopathology confirms hypomyelination, low-grade further myelin loss, subtotal degeneration of the putamen, and cerebellar cortical atrophy. All known patients are sporadic, and the mode of inheritance is unclear. C1 Vrije Univ Amsterdam, Med Ctr, Dept Child Neurol, NL-1007 MB Amsterdam, Netherlands. Univ Helsinki, Hosp Childrens & Adolescents, Dept Pediat Neurol, Helsinki, Finland. Univ Helsinki, Cent Hosp, Dept Pathol, Helsinki, Finland. Hosp Sick Children, Dept Neuroradiol, Toronto, ON M5G 1X8, Canada. Tohoku Univ, Sch Med, Dept Pediat, Sendai, Miyagi, Japan. Sach Krankenhaus Hubertusburg, Dept Neurol, Wermsdorf, Germany. Univ Gottingen, Dept Pediat & Pediat Neurol, Gottingen, Germany. Childrens Hosp, Med Ctr, Dept Pediat Neurol, Cincinnati, OH 45229 USA. Sydney Childrens Hosp, Dept Neurol, Randwick, NSW, Australia. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP van der Knaap, MS (reprint author), Vrije Univ Amsterdam, Med Ctr, Dept Child Neurol, POB 7057, NL-1007 MB Amsterdam, Netherlands. EM ms.vanderknaap@vumc.nl NR 18 TC 26 Z9 27 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 10 PY 2007 VL 69 IS 2 BP 166 EP 171 DI 10.1212/01.wnl.0000265592.74483.a6 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 188ER UT WOS:000247902500007 PM 17620549 ER PT J AU Azurmendi, HF Vionnet, J Wrightson, L Trinh, LB Shiloach, J Freedberg, DI AF Azurmendi, Hugo F. Vionnet, Justine Wrightson, Lauren Trinh, Loc B. Shiloach, Joseph Freedberg, Daron I. TI Extracellular structure of polysialic acid explored by on cell solution NMR SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE carbohydrate structure; isotopically labeled carbohydrates; in vivo kinetics; triple resonance NMR ID ESCHERICHIA-COLI K1; B MENINGOCOCCAL POLYSACCHARIDE; MENINGITIDIS GROUP-B; NEISSERIA-MENINGITIDIS; CAPSULAR POLYSACCHARIDE; SEROGROUP-B; SIALIC-ACID; ANTIBODY-RESPONSES; VACCINES; SPECTROSCOPY AB The capsular polysaccharide of the pathogens Neisseria meningitidis serogroup B and of Escherichia coli K1, alpha(2 -> 8) polysialic acid (PSA), is unusual, because when injected into adult humans, it generates little or no antibody. in contrast, people infected with these pathogens generate specific serum antibodies. A structural study on cells is used to address this anomaly by characterizing antigen structures in vivo. We introduce on cell multidimensional solution NMR spectroscopy for direct observation of PSA on E. coli bacteria. Using C-13,N-15-labeled PSA, we applied a combination of heteronuclear NMR methods, such as heteronuclear single quantum coherence, HNICA, and HNCO, in vivo. Analysis reveals that free and cell-bound PSA are structurally similar, indicating that the poor immunogenicity of PSA is not due to major structural differences between cells and purified IPSA. The C-13 linewidths of PSA on cells are 2 to 3 times larger than the corresponding ones in free PSA. The possible implications of the differences between free and on cell PSA are discussed. In addition, we demonstrate the suitability of the method for in vivo kinetic studies. C1 NIDDKD, Biotechnol Unit, MSC 5522, NIH, Bethesda, MD 20892 USA. Ctr Biol Evaluat & Res, Food & Drug Adm, Lab Bacterial Polysaccharides, Bethesda, MD 20892 USA. RP Freedberg, DI (reprint author), NIDDKD, Biotechnol Unit, MSC 5522, NIH, Bethesda, MD 20892 USA. EM daron.freedberg@fda.hhs.gov NR 44 TC 29 Z9 30 U1 3 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 10 PY 2007 VL 104 IS 28 BP 11557 EP 11561 DI 10.1073/pnas.0704404104 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 190MQ UT WOS:000248063400010 PM 17609375 ER PT J AU Duyn, JH van Gelderen, P Li, TQ de Zwart, JA Koretsky, AP Fukunaga, M AF Duyn, Jeff H. van Gelderen, Peter Li, Tie-Qiang de Zwart, Jacco A. Koretsky, Alan P. Fukunaga, Masaki TI High-field MRI of brain cortical substructure based on signal phase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anatomy; contrast mechanism; cortex ID HIGH-RESOLUTION MRI; HUMAN CEREBRAL-CORTEX; NON-HAEMIN IRON; WHITE-MATTER; ALZHEIMERS-DISEASE; MOTION CORRECTION; AMYLOID PLAQUES; GRAY-MATTER; 8 TESLA; SUSCEPTIBILITY AB The ability to detect brain anatomy and pathophysiology with MRI is limited by the contrast-to-noise ratio (CNR), which depends on the contrast mechanism used and the spatial resolution. In this work, we show that in MRI of the human brain, large improvements in contrast to noise in high-resolution images are possible by exploiting the MRI signal phase at high magnetic field strength. Using gradient-echo MRI at 7.0 tesla and a multichannel detector, a nominal voxel size of 0.24 x 0.24 x 1.0 mm(3) (58 nl was achieved. At this resolution, a strong phase contrast was observed both between as well as within gray matter (GM) and white matter (WM). In gradient-echo phase images obtained on normal volunteers at this high resolution, the CNR between GM and WM ranged from 3:1 to 20:1 over the cortex. This CNR is an almost 10-fold improvement over conventional MRI techniques that do not use image phase, and it is an approximate to 100-fold improvement when including the gains in resolution from high-field and multichannel detection. Within WM, phase contrast appeared to be associated with the major fiber bundles, whereas contrast within GM was suggestive of the underlying layer structure. The observed phase contrast is attributed to local variations in magnetic susceptibility, which, at least in part, appeared to originate from iron stores. The ability to detect cortical substructure from MRI phase contrast at high field is expected to greatly enhance the study of human brain anatomy in vivo. C1 Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, Lab Adv MRI, NIH, Bethesda, MD 20892 USA. RP Duyn, JH (reprint author), Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, Lab Adv MRI, NIH, Bldg 10 Room B1D-728, Bethesda, MD 20892 USA. EM jhd@helix.nih.gov RI Duyn, Jozef/F-2483-2010; Fukunaga, Masaki/F-6441-2013; Koretsky, Alan/C-7940-2015 OI Fukunaga, Masaki/0000-0003-1010-2644; Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS002989-08] NR 63 TC 358 Z9 365 U1 1 U2 19 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD JUL 10 PY 2007 VL 104 IS 28 BP 11796 EP 11801 DI 10.1073/pnas.0610821104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 190MQ UT WOS:000248063400051 PM 17586684 ER PT J AU Personius, KE Chang, Q Mentis, GZ O'Donovan, MJ Balice-Gordon, RJ AF Personius, Kirkwood E. Chang, Qiang Mentis, George Z. O'Donovan, Michael J. Balice-Gordon, Rita J. TI Reduced gap junctional coupling leads to uncorrelated motor neuron firing and precocious neuromuscular synapse elimination SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MAMMALIAN SPINAL-CORD; RAT SKELETAL-MUSCLE; NEONATAL-RAT; POLYNEURONAL INNERVATION; SYNCHRONIZATION; MOTONEURONS; COMPETITION; DEPRESSION; EXPRESSION; UNITS AB During late embryonic and early postnatal life, neuromuscular junctions undergo synapse elimination that is modulated by patterns of motor neuron activity. Here, we test the hypothesis that reduced spinal neuron gap junctional coupling decreases temporally correlated motor neuron activity that, in turn, modulates neuromuscular synapse elimination, by using mutant mice lacking connexin 40 (Cx40), a developmentally regulated gap junction protein expressed in motor and other spinal neurons. In Cx40(-/-) mice, electrical coupling among lumbar motor neurons, measured by whole-cell recordings, was reduced, and single motor unit recordings in awake, behaving neonates showed that temporally correlated motor neuron activity was also reduced. Immunostaining and intracellular recording showed that the neuromuscular synapse elimination was accelerated in muscles from Cx40(-/-) mice compared with WT littermates. Our work shows that gap junctional coupling modulates neuronal activity patterns that, in turn, mediate synaptic competition, a process that shapes synaptic circuitry in the developing brain. C1 Univ Penn, Sch Med, Dept Neurosci, Philadelphia, PA 19104 USA. SUNY Buffalo, Sch Publ Hlth & Hlth Prof, Dept Rehabil Sci, Buffalo, NY 14214 USA. Porter Neurosci Ctr, NIH, Bethesda, MD 20892 USA. RP Balice-Gordon, RJ (reprint author), Univ Penn, Sch Med, Dept Neurosci, 215 Stemmler Hall, Philadelphia, PA 19104 USA. EM rbaliceg@mail.med.tipenn.edu RI o'donovan, michael/A-2357-2015 OI o'donovan, michael/0000-0003-2487-7547 FU Intramural NIH HHS; NIGMS NIH HHS [GM37751, R01 GM037751]; NINDS NIH HHS [NS38517] NR 44 TC 46 Z9 49 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 JUL 10 PY 2007 VL 104 IS 28 BP 11808 EP 11813 DI 10.1073/pnas.0703357104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 190MQ UT WOS:000248063400053 PM 17609378 ER PT J AU Foster, MC Hwang, SJ Larson, MG Parikh, NI Meigs, JB Vasan, RS Wang, TJ Levy, D Fox, CS AF Foster, Meredith C. Hwang, Shih-Jen Larson, Martin G. Parikh, Nisha I. Meigs, James B. Vasan, Ramachandran S. Wang, Thomas J. Levy, Daniel Fox, Caroline S. TI Cross-classification of microalbuminuria and reduced glomerular filtration rate - Associations between cardiovascular disease risk factors and clinical outcomes SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CHRONIC KIDNEY-DISEASE; CHRONIC RENAL-INSUFFICIENCY; CORONARY HEART-DISEASE; ENDOTHELIAL FUNCTION; SERUM CREATININE; NONDIABETIC INDIVIDUALS; HEMODIALYSIS-PATIENTS; GENERAL-POPULATION; OXIDATIVE STRESS; ALBUMINURIA AB Background: Chronic kidney disease is defined by reduced estimated glomerular filtration rate (reduced eGFR) or by microalbuminuria (MA). Concordance between reduced eGFR and MA and associated cardiovascular disease (CVD) and all-cause mortality according to these definitions is uncertain. Methods: Participants (n = 2966 [52.6% were women], mean age, 59 years) were drawn from the Framingham Offspring Cohort. Participants were classified into 4 groups based on the presence or absence of reduced eGFR (eGFR < 59 mL/min/ 1.73 m(2) in women, < 64 mL/min/ 1.73 m(2) in men or MA (spot urinary albumin to creatinine ratio of at least 30 mg/g). Cox proportional hazard models were used to determine the combined risk of CVD events and all-cause mortality for each group. Results: Of the participants, 9.9% (n = 295) had reduced eGFR, and 12.2% (n = 362) had MA. Among those with reduced eGFR, 28% had MA. Those with reduced eGFR and with MA were at increased risk for combined CVD and all cause mortality compared with those with neither condition (hazard ratio [HR] 1.7, 95% confidence interval [CI], 1.1-2.4; P = .009), whereas those with reduced eGFR and without MA and those without reduced eGFR and with MA had similar HRs (1.3 and 1.2, respectively). Those with reduced eGFR and with MA, as well as those with reduced eGFR and without MA, were at significantly increased risk of all-cause mortality (HR 2.2 [95% CI, 1.4-3.6] and HR 1.7 [95% CI, 1.1-2.6], respectively). Conclusions: Reduced eGFR and MA are relatively common conditions with different risk factor profiles. The coexistence of reduced eGFR and MA was present in 2.8% of the study sample and conferred substantial increased risk for CVD and all-cause mortality, in part because of a heavy burden of CVD risk factors. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. NHLBI, NIH, Framingham, MA 01702 USA. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Boston Univ, Sch Med, Boston, MA 02215 USA. Harvard Univ, Sch Med, Div Gen Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div Cardiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Endocrinol Diabet & Hypertens, Brigham & Womens Hosp, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [N01-HC-25195] NR 45 TC 96 Z9 101 U1 0 U2 2 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 JUL 9 PY 2007 VL 167 IS 13 BP 1386 EP 1392 DI 10.1001/archinte.167.13.1386 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 188AT UT WOS:000247891500008 PM 17620532 ER PT J AU Ehirchiou, D Xiong, Y Xu, GW Chen, WJ Shi, YF Zhang, L AF Ehirchiou, Driss Xiong, Ying Xu, Guangwu Chen, Wanjun Shi, Yufang Zhang, Li TI CD11b facilitates the development of peripheral tolerance by suppressing Th17 differentiation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID REGULATORY T-CELLS; GROWTH-FACTOR-BETA; DENDRITIC CELLS; AUTOIMMUNE INFLAMMATION; ORAL TOLERANCE; ANTIGEN; LINEAGE; LFA-1; MICE; RESPONSES AB Antigen-induced immune suppression, like T cell activation, requires antigen-presenting cells (APCs); however, the role of APCs in mediating these opposing effects is not well understood, especially in vivo. We report that genetic inactivation of CD11b, which is a CD1 8 subfamily of integrin receptors that is highly expressed on APCs, abolishes orally induced peripheral immune tolerance (oral tolerance) without compromising APC maturation or antigen-specific immune activation. The defective oral tolerance in CD11 b(-/-) mice can be restored by adoptive transfer of wild-type APCs. CD11 b deficiency leads to enhanced interleukin (IL) 6 production by APCs, which subsequently promotes preferential differentiation of naive T cells to T helper 17 (Th17) cells, which are a T cell lineage characterized by their production of IL-17. Consequently, antigen feeding and immunization of CD11b(-/-)mice results in significant production of IL-17 within the draining lymph nodes that interferes with the establishment of oral tolerance. Together, we conclude that CD11b facilitates oral tolerance by suppressing Th17 immune differentiation. C1 Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Dept Physiol, Baltimore, MD 21201 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Mol Genet Microbiol & Immunol, Piscataway, NJ 08854 USA. Natl Inst Dent & Craniiofacial Res, NIH, Mucosal Immun Unit, Bethesda, MD 20892 USA. RP Zhang, L (reprint author), Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Dept Physiol, Baltimore, MD 21201 USA. EM lizhang@som.umaryland.edu FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL061589, 2P01 HL 54710, P01 HL054710, R01 HL 61589]; NIAID NIH HHS [AI 43384, AI 50222, R01 AI043384, R01 AI050222, R21 AI043384] NR 27 TC 81 Z9 85 U1 1 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 9 PY 2007 VL 204 IS 7 BP 1519 EP 1524 DI 10.1084/jem.20062292 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 189OI UT WOS:000247998000004 PM 17562817 ER PT J AU Kim, HP Leonard, WJ AF Kim, Hyoung-Pyo Leonard, Warren J. TI CREB/ATF-dependent T cell receptor-induced FoxP3 gene expression: a role for DNA methylation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ALPHA-CHAIN GENE; TRANSCRIPTION; IL-2; MICE; INTERLEUKIN-2; INDUCTION; PROMOTER; SIGNALS; BETA; CD28 AB Regulatory T cells (T reg cells) are a population of Cll T cells that limit immune responses. FoxP3 is a master control transcription factor for development and function of these cells, but its regulation is poorly understood. We have identified a T cell receptor-responsive enhancer in the FoxP3 first intron that is dependent on a cyclic-AMP response element binding protein (CREB)/activating transcription factor (ATF) site overlapping a CpG island. Methylation of this island inversely correlates with CREB binding and Ill expression. Interestingly, transforming growth factor-P, which induces T reg cell formation, decreases methylation of the CpG island and increases Ill expression. Similarly, inhibiting methylation with 5-azacytidine or knocking down the DNA methyltransferase Dnmt1 also induces Ill expression. Conversely, methylation of the CpG island, which decreases CREB binding or expression of dominant-negative CREB, decreases FoxP3 gene expression. Thus, T cell receptor-induced Ill expression in T reg cells is controlled both by sequence-specific binding of CREB/ATF and by DNA methylation of a CpG island. C1 NHLBI, NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, NIH, Lab Mol Immunol, Bldg 10, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov FU Intramural NIH HHS NR 30 TC 304 Z9 318 U1 0 U2 8 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 9 PY 2007 VL 204 IS 7 BP 1543 EP 1551 DI 10.1084/jem.20070109 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 189OI UT WOS:000247998000007 PM 17591856 ER PT J AU Roberts, ZJ Goutagny, N Perera, PY Kato, H Kumar, H Kawai, T Akira, S Savan, R van Echo, D Fitzgerald, KA Young, HA Ching, LM Vogel, SN AF Roberts, Zachary J. Goutagny, Nadege Perera, Pin-Yu Kato, Hiroki Kumar, Himanshu Kawai, Taro Akira, Shizuo Savan, Ram van Echo, David Fitzgerald, Katherine A. Young, Howard A. Ching, Lai-Ming Vogel, Stefanie N. TI The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NF-KAPPA-B; 5,6-DIMETHYLXANTHENONE-4-ACETIC ACID DMXAA; INTERFERON REGULATORY FACTOR-3; FLAVONE ACETIC-ACID; DOUBLE-STRANDED-RNA; VASCULAR DISRUPTING AGENT; DOMAIN-CONTAINING ADAPTER; INNATE IMMUNE-RESPONSE; GENE-EXPRESSION; ANTIVASCULAR AGENT AB Vascular disrupting agents (VDAs) represent a novel approach to the treatment of cancer, resulting in the collapse of tumor vasculature and tumor death. 5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a VDA currently in advanced phase 11 clinical trials, yet its precise mechanism of action is unknown despite extensive preclinical and clinical investigations. Our data demonstrate that DMXAA is a novel and specific activator of the TANK-binding kinase I (TBK1)-interferon (IFN) regulatory factor 3 (IRF-3) signaling pathway. DMXAA treatment of primary mouse macrophages resulted in robust IRF-3 activation and similar to 750-fold increase in IFN-P mRNA, and in contrast to the potent Toll-like receptor 4 (TLR4) agonist lipopolysaccharide (LPS), signaling was independent of mitogen-activated protein kinase (MAPK) activation and elicited minimal nuclear factor kappa B-dependent gene expression. DMXAA-induced signaling was critically dependent on the IRF-3 kinase, TBK1, and IRF-3 but was myeloid differentiation factor 88-, Toll-interleukin 1 receptor domain-containing adaptor inducing IFN-beta-, IFN promoter-stimulator 1-, and inhibitor of KB kinase-independent, thus excluding all known TLRs and cytosolic helicase receptors. DMXAA pretreatment of mouse macrophages induced a state of tolerance to LPS and vice versa. In contrast to LPS stimulation, DMXAA-induced IRF-3 dimerization and IFN-P expression were inhibited by salicylic acid. These findings detail a novel pathway for TBK1 mediated IRF-3 activation and provide new insights into the mechanism of this new class of chemotherapeutic drugs. C1 Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. Univ Massachusetts, Sch Med, Div Infect Dis, Worcester, MA 01605 USA. Vet Adm Med Ctr, Washington, DC 20422 USA. Osaka Univ, Res Inst Microbial Dis, Dept Host Def, Osaka 5650871, Japan. Natl Canc Inst, Expt Immunol Lab, Frederick, MD 21702 USA. Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc Res Ctr, Auckland 1000, New Zealand. RP Vogel, SN (reprint author), Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. EM svogel@som.umaryland.edu RI Young, Howard/A-6350-2008; Akira, Shizuo/C-3134-2009; Kumar, Himanshu/A-8070-2010; Kumar, Himanshu/J-4494-2012 OI Young, Howard/0000-0002-3118-5111; Kumar, Himanshu/0000-0001-5246-2694 FU NIAID NIH HHS [AI 067497, AI 18797, AI 44936, R01 AI018797, R01 AI044936, R01 AI067497, R37 AI018797, R37 AI067497, R56 AI018797, R56 AI067497, T32 AI 007540, T32 AI007540] NR 69 TC 76 Z9 76 U1 1 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD JUL 9 PY 2007 VL 204 IS 7 BP 1559 EP 1569 DI 10.1084/jem.20061845 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 189OI UT WOS:000247998000009 PM 17562815 ER PT J AU Booth, BW Sandifer, T Martin, EL Martin, LD AF Booth, Brian W. Sandifer, Tracy Martin, Erika L. Martin, Linda D. TI IL-13-induced proliferation of airway epithelial cells: mediation by intracellular growth factor mobilization and ADAM17 SO RESPIRATORY RESEARCH LA English DT Article ID ALPHA-CONVERTING-ENZYME; AMYLOID PRECURSOR PROTEIN; IN-VITRO; SUBCELLULAR-LOCALIZATION; TRANSGENIC MICE; TNF-ALPHA; TGF-ALPHA; FACTOR RECEPTOR; ASTHMA; INTERLEUKIN-13 AB Background: The pleiotrophic cytokine interleukin (IL)-13 features prominently in allergic and inflammatory diseases. In allergic asthma, IL-13 is well established as an inducer of airway inflammation and tissue remodeling. We demonstrated previously that IL-13 induces release of transforming growth factor-alpha (TGF alpha) from human bronchial epithelial cells, with proliferation of these cells mediated by the autocrine/paracrine action of this growth factor. TGFa exists as an integral membrane protein and requires proteolytic processing to its mature form, with a disintegrin and metalloproteinase ( ADAM) 17 responsible for this processing in a variety of tissues. Methods: In this study, normal human bronchial epithelial (NHBE) cells grown in air/liquid interface (ALI) culture were used to examine the mechanisms whereby IL-13 induces release of TGFa and cellular proliferation. Inhibitors and antisense RNA were used to examine the role of ADAM17 in these processes, while IL-13-induced changes in the intracellular expression of TGFa and ADAM17 were visualized by confocal microscopy. Results: IL-13 was found to induce proliferation of NHBE cells, and release of TGF alpha, in an ADAM17-dependent manner; however, this IL-13-induced proliferation did not appear to result solely from ADAM17 activation. Rather, IL-13 induced a change in the location of TGFa expression from intracellular to apical regions of the NHBE cells. The apical region was also found to be a site of significant ADAM17 expression, even prior to IL-13 stimulation. Conclusion: Results from this study indicate that ADAM17 mediates IL-13-induced proliferation and TGF alpha shedding in NHBE cells. Furthermore, they provide the first example wherein a cytokine ( IL-13) induces a change in the intracellular expression pattern of a growth factor, apparently inducing redistribution of intracellular stores of TGF alpha to the apical region of NHBE cells where expression of ADAM17 is prominent. Thus, IL-13-induced, ADAM17-mediated release of TGF alpha, and subsequent epithelial cell proliferation, could contribute to the epithelial hypertrophy, as well as other features, associated with airway remodeling in allergic asthma. C1 N Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27695 USA. NCI, Mammary Biol & Tumorignesis Lab, NIH, Bethesda, MD 20892 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. RP Martin, LD (reprint author), N Carolina State Univ, Dept Mol Biomed Sci, Raleigh, NC 27695 USA. EM boothbr@mail.nih.gov; tks5@u.washington.edu; ljej@earthlink.net; linda_martin@ncsu.edu FU NHLBI NIH HHS [R01 HL66236, R01 HL066236] NR 53 TC 26 Z9 26 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1465-9921 J9 RESP RES JI Respir. Res. PD JUL 9 PY 2007 VL 8 AR 51 DI 10.1186/1465-9921-8-51 PG 12 WC Respiratory System SC Respiratory System GA 212SO UT WOS:000249617300001 PM 17620132 ER PT J AU Thomas, JW AF Thomas, John W. TI National Heart, Lung, and Blood Institute resources and programs for cell-based therapies SO CIRCULATION RESEARCH LA English DT Editorial Material C1 NHLBI, Div Blood Dis & Resources, Rockledge Ctr 2, NIH, Bethesda, MD 20892 USA. RP Thomas, JW (reprint author), NHLBI, Div Blood Dis & Resources, Rockledge Ctr 2, NIH, Room 10154,6701 Rockledge Dr,Mail Stop 7950, Bethesda, MD 20892 USA. EM ThomasJ@nhlbi.nih.gov NR 8 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 6 PY 2007 VL 101 IS 1 BP 1 EP 6 DI 10.1161/CIRCRESAHA.106.013001 PG 6 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 186VC UT WOS:000247805500001 PM 17615375 ER PT J AU Capell, BC Collins, FS Nabel, EG AF Capell, Brian C. Collins, Francis S. Nabel, Elizabeth G. TI Mechanisms of cardiovascular disease in accelerated aging syndromes SO CIRCULATION RESEARCH LA English DT Review DE premature aging; progeria; Werner syndrome; genome instability ID HUTCHINSON-GILFORD-PROGERIA; LAMIN A/C GENE; A-TYPE LAMINS; COMPOUND HETEROZYGOUS MUTATIONS; GIRDLE MUSCULAR-DYSTROPHY; CHROMATIN BINDING-SITE; WRN HELICASE ACTIVITY; WERNER-SYNDROME GENE; SMOOTH-MUSCLE-CELLS; PRELAMIN-A AB In the past several years, remarkable progress has been made in the understanding of the mechanisms of premature aging. These rare, genetic conditions offer valuable insights into the normal aging process and the complex biology of cardiovascular disease. Many of these advances have been made in the most dramatic of these disorders, Hutchinson - Gilford progeria syndrome. Although characterized by features of normal aging such as alopecia, skin wrinkling, and osteoporosis, patients with Hutchinson - Gilford progeria syndrome are affected by accelerated, premature arteriosclerotic disease that leads to heart attacks and strokes at a mean age of 13 years. In this review, we highlight recent advances in the biology of premature aging uncovered in Hutchinson - Gilford progeria syndrome and other accelerated aging syndromes, advances that provide insight into the mechanisms of cardiovascular diseases ranging from atherosclerosis to arrhythmias. C1 NHLBI, NIH, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, NIH, Bldg 31,Room 5A48,31 Ctr Dr,MSC 2486, Bethesda, MD 20892 USA. EM nabele@nih.gov OI Capell, Brian/0000-0002-7036-8359 FU Intramural NIH HHS NR 147 TC 68 Z9 69 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD JUL 6 PY 2007 VL 101 IS 1 BP 13 EP 26 DI 10.1161/CIRCRESAHA.106.153692 PG 14 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 186VC UT WOS:000247805500004 PM 17615378 ER PT J AU Zou, GZ de Leeuw, E Li, C Pazgier, M Li, CQ Zeng, PY Lu, WY Lubkowski, J Lu, WY AF Zou, Guozhang de Leeuw, Erik Li, Chong Pazgier, Marzena Li, Changqing Zeng, Pengyun Lu, Wei-Yue Lubkowski, Jacek Lu, Wuyuan TI Toward understanding the cationicity of defensins - Arg and Lys versus their noncoded analogs SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN ALPHA-DEFENSINS; HUMAN BETA-DEFENSINS; ANTIMICROBIAL PEPTIDES; HUMAN BETA-DEFENSIN-3; HOST-DEFENSE; AMINO-ACIDS; ANTIBACTERIAL ACTIVITY; MAMMALIAN DEFENSINS; HUMAN-NEUTROPHILS; MESSENGER-RNA AB Human defensins are a family of small antimicrobial proteins found predominantly in leukocytes and epithelial cells that play important roles in the innate and adaptive immune defense against microbial infection. The most distinct molecular feature of defensins is cationicity, manifested by abundant Arg and/or Lys residues in their sequences. Sequence analysis indicates that Arg is strongly selected over Lys in alpha-defensins but not in alpha-defensins. To understand this Arg/Lys disparity in defensins, we chemically synthesized human alpha-defensin 1 (HNP1) and several HNP1 analogs where three Arg residues were replaced by each of the following six alpha-amino acids: Lys, ornithine (Orn), diaminobutyric acid ( Dab), diaminopropionic acid (Dap), N, N-dimethyl-Lys ((diMe)Lys), and homo-Arg ((homo)Arg). In addition, we prepared human alpha-defensin 1 (hBD1) and (Lys3 -> Arg)hBD1 in which all four Lys residues were substituted for Arg. Bactericidal activity assays revealed the following. 1) Arg-containing HNP1 and (Lys3 -> Arg)hBD1 are functionally better than Lys-HNP1 and hBD1, respectively; the difference between Arg and Lys is more evident in the alpha-defensin than in the beta-defensin and is more evident at low salt concentrations than at high salt concentrations. 2) For HNP1, the Arg/Lys disparity is much more pronounced with Staphylococcus aureus than with Escherichia coli, and the Arg-rich HNP1 kills bacteria faster than its Lys-rich analog. 3) Arg and Lys appear to have optimal chain lengths for bacterial killing as shortening Lys or lengthening Arg in HNP1 invariably becomes functionally deleterious. Our findings provide insights into the Arg/Lys disparity in defensins, and shed light on the cationicity of defensins with respect to their antimicrobial activity and specificity. C1 Univ Maryland, Inst Biotechnol, Inst Human Virol, Baltimore, MD 21201 USA. Fudan Univ, Sch Pharm, Fudan PharmCo Drug Target Res Ctr, Shanghai 200032, Peoples R China. NIH, NCI, Macromol Assembly Struct & Cell Signaling Sect, Frederick, MD 21702 USA. RP Lubkowski, J (reprint author), Univ Maryland, Inst Biotechnol, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. EM jacek@ncifcrf.gov; luw@umbi.umd.edu RI Lu, Wuyuan/B-2268-2010; Li, Chong/H-2515-2011; Pazgier, Marzena/B-7295-2012; Lu, Weiyue/E-7938-2010 FU Intramural NIH HHS; NIAID NIH HHS [AI056264, AI061482] NR 75 TC 77 Z9 81 U1 3 U2 16 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 JUL 6 PY 2007 VL 282 IS 27 BP 19653 EP 19665 DI 10.1074/jbc.M611003200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 184OF UT WOS:000247650600040 PM 17452329 ER PT J AU Ji, JY Lee, RT Vergnes, L Fong, LG Stewart, CL Reue, K Young, SG Zhang, QP Shanahan, CM Lammerding, J AF Ji, Julie Y. Lee, Richard T. Vergnes, Laurent Fong, Loren G. Stewart, Colin L. Reue, Karen Young, Stephen G. Zhang, Qiuping Shanahan, Catherine M. Lammerding, Jan TI Cell nuclei spin in the absence of lamin B1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DREIFUSS MUSCULAR-DYSTROPHY; MEMBRANE-PROTEIN; MAMMALIAN-CELLS; GENE-EXPRESSION; INTERPHASE NUCLEI; ENVELOPE PROTEINS; CHROMATIN MOTION; BUILDING-BLOCKS; PORE COMPLEXES; LIVING CELLS AB Mutations of the nuclear lamins cause a wide range of human diseases, including Emery-Dreifuss muscular dystrophy and Hutchinson-Gilford progeria syndrome. Defects in A-type lamins reduce nuclear structural integrity and affect transcriptional regulation, but few data exist on the biological role of B-type lamins. To assess the functional importance of lamin B1, we examined nuclear dynamics in fibroblasts from Lmnb1(Delta/Delta) and wild-type littermate embryos by time-lapse videomicroscopy. Here, we report that Lmnb1(Delta/Delta) cells displayed striking nuclear rotation, with similar to 90% of Lmnb1(Delta/Delta) nuclei rotating at least 90 during an 8-h period. The rotation involved the nuclear interior as well as the nuclear envelope. The rotation of nuclei required an intact cytoskeletal network and was eliminated by expressing lamin B1 in cells. Nuclear rotation could also be abolished by expressing larger nesprin isoforms with long spectrin repeats. These findings demonstrate that lamin B1 serves a fundamental role within the nuclear envelope: anchoring the nucleus to the cytoskeleton. C1 Partners Res Facil, Cambridge, MA 02139 USA. Brigham & Womens Hosp, Div Cardiovasc, Cambridge, MA 02139 USA. NCI, NIH, Frederick, MD 21702 USA. Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90073 USA. Univ Cambridge, Addenbrookes Hosp, Dept Med, Div Cardiovasc Med, Cambridge CB2 2QQ, England. RP Lammerding, J (reprint author), Partners Res Facil, 65 Landsdowne St, Cambridge, MA 02139 USA. EM jlammerding@rics.bwh.harvard.edu RI Lammerding, Jan/A-9498-2016 OI Lammerding, Jan/0000-0003-4335-8611 FU NHLBI NIH HHS [HL079862, HL073809, HL082792, HL64858, R01 HL082792]; NIAMS NIH HHS [AR050200]; NINDS NIH HHS [R01 NS059348] NR 57 TC 54 Z9 55 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD JUL 6 PY 2007 VL 282 IS 27 BP 20015 EP 20026 DI 10.1074/jbc.M611094200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 184OF UT WOS:000247650600075 PM 17488709 ER PT J AU Pursell, ZF Isoz, I Lundstrom, EB Johansson, E Kunkel, TA AF Pursell, Zachary F. Isoz, Isabelle Lundstroem, Else-Britt Johansson, Erik Kunkel, Thomas A. TI Yeast DNA polymerase epsilon participates in leading-strand DNA replication SO SCIENCE LA English DT Article ID SACCHAROMYCES-CEREVISIAE; S-PHASE; POL EPSILON; CHECKPOINT; REPAIR; ERRORS; FORK AB Multiple DNA polymerases participate in replicating the leading and lagging strands of the eukaryotic nuclear genome. Although 50 years have passed since the first DNA polymerase was discovered, the identity of the major polymerase used for leading-strand replication is uncertain. We constructed a derivative of yeast DNA polymerase e that retains high replication activity but has strongly reduced replication fidelity, particularly for thymine-deoxythymidine 5'-monophosphate (T-dTMP) but not adenine-deoxyadenosine 5'-monophosphate (A-dAMP) mismatches. Yeast strains with this DNA polymerase e allele have elevated rates of T to A substitution mutations. The position and rate of these substitutions depend on the orientation of the mutational reporter and its location relative to origins of DNA replication and reveal a pattern indicating that DNA polymerase e participates in leading-strand DNA replication. C1 NIEHS, Mol Genet Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI Pursell, Zachary/0000-0001-5871-7192 FU Intramural NIH HHS [Z01 ES065070-17] NR 14 TC 254 Z9 262 U1 4 U2 15 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 JUL 6 PY 2007 VL 317 IS 5834 BP 127 EP 130 DI 10.1126/science.1144067 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 186KD UT WOS:000247776700068 PM 17615360 ER PT J AU Fanous, AH Neale, MC Webb, BT Straub, RE Amdur, RL O'Neill, FA Walsh, D Riley, BP Kendler, KS AF Fanous, Ayman H. Neale, Michael C. Webb, B. Todd Straub, Richard E. Amdur, Richard L. O'Neill, F. Anthony Walsh, Dermot Riley, Brien P. Kendler, Kenneth S. TI A genome-wide scan for modifier loci in schizophrenia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE schizophrenia; linkage; clinical features ID AFFECTED SIBLING PAIRS; SUSCEPTIBILITY LOCUS; BIPOLAR DISORDER; LINKAGE ANALYSIS; CLINICAL-FEATURES; FOLLOW-UP; GENETIC-HETEROGENEITY; VULNERABILITY LOCUS; MAJOR PSYCHOSES; COMPLEX TRAITS AB The purpose of this study was to detect genetic loci that influence clinical features of, but not necessarily susceptibility to, psychotic illness. In the Irish Study of High-Density Schizophrenia Families (n = 270 families, n = 1,408 individuals), subjects with non-affective psychosis were rated using the Operational Criteria Checklist for Psychotic Illness. Factor analysis identified hallucinations, delusions, and negative, manic, and depressive symptom factors. We performed autosomal genome-wide multipoint non-parametric quantitative trait locus linkage analysis, in affected individuals only, using these five factors, as well as age at onset, and course of illness. Determination of empirical significance and correction for multiple testing was implemented using 200 simulated genome scans. We also tested for pleiotropic loci by examining the sums of -log(10)'s of the empirical P values of multiple traits in selected regions. LODs of 2.42 and 2.35 were obtained near D9S934 (9q33.1) and D14S587 (14q24.2), respectively, for course of illness, and of 2.26 between D6S1040-D6S2420 (6q23.1-25.1) and age at onset. No other regions met criteria for suggestive linkage to any one trait. No loci were significant after correction for multiple testing. On 6q, however, the joint linkage of age of onset, course, delusions, and depressive symptoms resulted in a genome-wide P = 0.06. We conclude that genes located near 9q33.1 and 14q24.2 may modify the clinical course and severity of schizophrenia. A gene in 6q may affect several clinical features of illness. (c) 2007 Wiley-Liss, Inc. C1 Washington VA Med Ctr, Washington, DC 20422 USA. Virginia Commonwealth Univ, Georgetown Univ, Ctr Med, Richmond, VA USA. Virginia Commonwealth Univ, Dept Psychiat, Richmond, VA USA. Virginia Commonwealth Univ, Dept Human Genet, Richmond, VA USA. NIMH, NIH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. Queens Univ Belfast, Belfast, Antrim, North Ireland. Hlth Res Board, Dublin, Ireland. RP Fanous, AH (reprint author), Washington VA Med Ctr, 50 Irving St,NW, Washington, DC 20422 USA. EM ayman.fanous@med.va.gov RI Neale, Michael/B-1418-2008; O'Neill, Francis/C-5582-2008; Webb, Bradley/B-1459-2009; OI Webb, Bradley/0000-0002-0576-5366; O'Neill, Francis Anthony/0000-0002-7531-7657 FU NIMH NIH HHS [MH-52537, IT-32 MH-20030, MH-41953, MH-45390] NR 55 TC 17 Z9 17 U1 2 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD JUL 5 PY 2007 VL 144B IS 5 BP 589 EP 595 DI 10.1002/ajmg.b.30442 PG 7 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 187QU UT WOS:000247864000002 PM 17262803 ER PT J AU Woodcock, HL Hodoscek, M Brooks, BR AF Woodcock, H. Lee Hodoscek, Milan Brooks, Bernard R. TI Exploring SCC-DFTB paths for mapping QM/MM reaction mechanisms SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article; Proceedings Paper CT 232nd National Meeting of the American-Chemical-Society CY SEP 10-14, 2006 CL San Francisco, CA SP Amer Chem Soc ID ELASTIC BAND METHOD; TRANSITION-STATE STABILIZATION; MINIMUM-ENERGY PATHS; MONOFUNCTIONAL CHORISMATE MUTASE; FAST MULTIPOLE METHOD; SEMIEMPIRICAL METHODS; BACILLUS-SUBTILIS; ENZYME CATALYSIS; CLAISEN REARRANGEMENT; MOLECULAR-DYNAMICS AB A new first-order procedure for locating transition structures (TS) that employs hybrid quantum mechanical/molecular mechanical (QM/MM) potentials has been developed. This new technique (RPATh+RESD) combines the replica path method (RPATh) and standard reaction coordinate driving (RCD) techniques in an approach that both efficiently determines reaction barriers and successfully eliminates two key weaknesses of RCD calculations (i.e., hysteresis/discontinuities in the path and the sequential nature of the RCD procedure). In addition, we have extended CHARMM's QM/MM reaction pathway methods, the RPATh and nudged elastic band (NEB) methods, to incorporate SCC-DFTB wave functions. This newly added functionality has been applied to the chorismate mutase-catalyzed interconversion of chorismate to prephenate, which is a key step in the shikimate pathway of bacteria, fungi, and other higher plants. The RPATh+RESD barrier height (Delta E = 5.7 kcal/mol) is in good agreement with previous results from full-energy surface mapping studies (Zhang, X.; Zhang, X.; Bruice, T. C. Biochemistry 2005, 44, 10443-10448). Full reaction paths were independently mapped with RPATh and NEB methods and showed good agreement with the final transition state from the RPATh+RESD "gold standard" and previous high-level QM/MM transition states (Woodcock, H. L.; Hodoscek, M.; Gilbert, T. B.; Gill, P. M. W.; Schaefer, H. F.; Brooks, B. R. J. Comput. Chem. 2007, 28, 1485-1502). The SCC-DFTB TS geometry most closely approximates the MP2/6-31+G(d) QM/MM result. However, the barrier height is underestimated and possibly points to an area for improvement in SCC-DFTB parametrization. In addition, the steepest descents (SD) minimizer for the NEB method was modified to uncouple the in-path and off-path degrees of freedom during the minimization, which significantly improved performance. The convergence behavior of the RPATh and NEB was examined for SCC-DFTB wave functions, and it was determined that, in general, both methods converge at about the same rate, although the techniques used for convergence may be different. For instance, RPATh can effectively use the adopted basis Newton-Raphson (ABNR) minimizer, where NEB seems to require a combination of SD and ABNR. C1 NHLBI, Natl Inst Hlth, Lab Computat Biol, Bethesda, MD 20892 USA. Natl Inst Chem, Ctr Mol Modeling, SL-1000 Ljubljana, Slovenia. RP Woodcock, HL (reprint author), NHLBI, Natl Inst Hlth, Lab Computat Biol, Bethesda, MD 20892 USA. RI Woodc, Henry/D-9275-2011; OI Woodcock, Henry/0000-0003-3539-273X FU Intramural NIH HHS NR 70 TC 44 Z9 44 U1 0 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD JUL 5 PY 2007 VL 111 IS 26 BP 5720 EP 5728 DI 10.1021/jp0714217 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 183LF UT WOS:000247573600017 PM 17555303 ER PT J AU Chin, MPS Chen, JB Nikolaitchik, OA Hu, WS AF Chin, Mario P. S. Chen, Jianbo Nikolaitchik, Olga A. Hu, Wei-Shau TI Molecular determinants of HIV-1 intersubtype recombination potential SO VIROLOGY LA English DT Article DE HIV-1; subtype; recombination rate; dimerization initiation signal; heterozygous virus; RNA packaging ID IMMUNODEFICIENCY-VIRUS TYPE-1; INJECTING DRUG-USERS; FULL-LENGTH CLONES; CIRCULATING RECOMBINANT; SUBTYPE-C; GENETIC-RECOMBINATION; REFERENCE SEQUENCES; VIRAL REPLICATION; RNA DIMERIZATION; KISSING COMPLEX AB Sequence differences in the dimerization initiation signal (DIS) affect the rate of recombination between subtype B and subtype C HIV-1. To test the hypothesis that DIS sequences can be used to predict intersubtype recombination potentials, we measured the recombination rate between CRF01_A/E (AE) and B, which contain mismatches in the DIS, and between AE and C, which have an identical DIS. Compared with the intrasubtype recombination rate, the recombination rate between AE and subtype B virus was 9-fold lower, and the rate between AE and subtype C virus was 2-fold lower. Thus, DIS sequences can be used to predict the recombination potential between HIV-1 subtypes. Further analyses revealed that the 2-fold lower recombination rate between AE and C viruses can be restored to the intrasubtype recombination rate by matching a part of the LTR and a portion of the viral genome. Therefore, the lower intersubtype recombination rate between AE and C is not caused by a given region but is a cumulative effect by more than one region. Published by Elsevier Inc. C1 Natl Canc Inst, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Hu, WS (reprint author), Natl Canc Inst, HIV Drug Resistance Program, PO Box B Bldg 535, Frederick, MD 21702 USA. EM whu@ncifcrf.gov RI Chen, Jianbo/N-3737-2014 OI Chen, Jianbo/0000-0001-6491-6577 FU Intramural NIH HHS NR 47 TC 30 Z9 31 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD JUL 5 PY 2007 VL 363 IS 2 BP 437 EP 446 DI 10.1016/j.virol.2007.01.034 PG 10 WC Virology SC Virology GA 176BQ UT WOS:000247058100019 PM 17336363 ER PT J AU Huestis, MA Gustafson, RA Moolchan, ET Barnes, A Bourland, JA Sweeney, SA Hayes, EF Carpenter, PM Smith, ML AF Huestis, Marilyn A. Gustafson, Richard A. Moolchan, Eric T. Barnes, Allan Bourland, James A. Sweeney, Stacy A. Hayes, Eugene F. Carpenter, Patrick M. Smith, Michael L. TI Cannabinoid concentrations in hair from documented cannabis users SO FORENSIC SCIENCE INTERNATIONAL LA English DT Article DE cannabinoids; hair; ELISA; GCMSMS; controlled administration ID TESTING HUMAN HAIR; MASS-SPECTROMETRY; THC-COOH; COCAINE; METABOLITES; CODEINE; COLOR; BIAS; NCI AB Fifty-three head hair specimens were collected from 38 males with a history of cannabis use documented by questionnaire, urinalysis and controlled, double blind administration of Delta(9)-tetrahydrocannabinol (THC) in an institutional review board approved protocol. The subjects completed a questionnaire indicating daily cannabis use (N = 18) or non-daily use, i.e. one to five cannabis cigarettes per week (N = 20). Drug use was also documented by a positive cannabinoid urinalysis, a hair specimen was collected from each subject and they were admitted to a closed research unit. Additional hair specimens were collected following smoking of two 2.7% THC cigarettes (N = 13) or multiple oral doses totaling 116 mg THC (N = 2). Cannabinoid concentrations in all hair specimens were determined by ELISA and GCMSMS. Pre- and post-dose detection rates did not differ statistically, therefore, all 53 specimens were considered as one group for further comparisons. Nineteen specimens (36%) had no detectable THC or 11-nor-9-carboxy-THC (THCCOOH) at the GCNISMS limits of quantification (LOQ) of 1.0 and 0.1 pg/mg hair, respectively. Two specimens (3.8%) had measurable THC only, 14 (26%) THCCOOH only, and 18 (34%) both cannabinoids. Detection rates were significantly different (p < 0.05, Fishers' exact test) between daily cannabis users (85%) and non-daily users (52%). There was no difference in detection rates between African-American and Caucasian subjects (p > 0.3, Fisher's exact test). For specimens with detectable cannabinoids, concentrations ranged from 3.4 to > 100 pg THC/mg and 0. 10 to 7.3 pg THCCOOH/mg hair. THC and THCCOOH concentrations were positively correlated (r = 0.38, p < 0.01, Pearson's product moment correlation). Using an immunoassay cutoff concentration of 5 pg THC equiv./mg hair, 83% of specimens that screened positive were confirmed by GCMSMS at a cutoff concentration of 0. 1 pg THCCOOH/mg hair. Published by Elsevier Ireland Ltd. C1 Natl Inst Drug Abuse, Intramural Res Program, Natl Inst Hlth, Baltimore, MD 21224 USA. Navy Drug Screening Lab, Jacksonville, FL 32212 USA. Quest Diagnost Inc, Las Vegas, NV 89119 USA. Off Armed Forces Med Examiner, Rockville, MD 20850 USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Natl Inst Hlth, Baltimore, MD 21224 USA. EM mhuestis@irp.nida.nih.gov FU Intramural NIH HHS [Z01 DA000413-10, Z01 DA000414-10, Z01 DA000412-10] NR 24 TC 53 Z9 53 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0379-0738 J9 FORENSIC SCI INT JI Forensic Sci.Int. PD JUL 4 PY 2007 VL 169 IS 2-3 BP 129 EP 136 DI 10.1016/j.forsciint.2006.08.005 PG 8 WC Medicine, Legal SC Legal Medicine GA 185FN UT WOS:000247696900004 PM 16963215 ER PT J AU Butman, JA Kim, HJ Baggenstos, M Ammerman, JM Dambrosia, J Patsalides, A Patronas, NJ Oldfield, EH Lonser, RR AF Butman, John A. Kim, H. Jeffrey Baggenstos, Martin Ammerman, Joshua M. Dambrosia, James Patsalides, Athos Patronas, Nicholas J. Oldfield, Edward H. Lonser, Russell R. TI Mechanisms of morbid hearing loss associated with tumors of the endolymphatic sac in von Hippel-Lindau disease SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; NATURAL-HISTORY; VHL GENE; HEMANGIOBLASTOMAS; IDENTIFICATION; ADENOCARCINOMA; MANAGEMENT AB Context Endolymphatic sac tumors (ELSTs) are associated with von Hippel-Lindau disease and cause irreversible sensorineural hearing loss (SNHL) and vestibulopathy. The underlying mechanisms of audiovestibular morbidity remain unclear and optimal timing of treatment is not known. Objective To define the mechanisms underlying audiovestibular pathophysiology associated with ELSTs. Design, Setting, and Patients Prospective and serial evaluation of patients with von Hippel-Lindau disease and ELSTs at the National Institutes of Health between May 1990 and December 2006. Main Outcome Measures Clinical findings and audiologic data were correlated with serial magnetic resonance imaging and computed tomography imaging studies to determine mechanisms underlying audiovestibular dysfunction. Results Thirty-five patients with von Hippel-Lindau disease and ELSTs in 38 ears (3 bilateral ELSTs) were identified. Tumor invasion of the otic capsule was associated with larger tumors (P = .01) and occurred in 7 ears (18%) causing SNHL (100%). No evidence of otic capsule invasion was present in the remaining 31 ears (82%). SNHL developed in 27 of these 31 ears (87%) either suddenly (14 ears; 52%) or gradually (13 ears; 48%) and 4 ears had normal hearing. Intralabyrinthine hemorrhage was found in 11 of 14 ears with sudden SNHL (79%; P < .001) but occurred in none of the 17 ears with gradual SNHL or normal hearing. Tumor size was not related to SNHL (P = .23) or vestibulopathy (P = .83). Conclusions ELST-associated SNHL and vestibulopathy may occur suddenly due to tumor-associated intralabyrinthine hemorrhage, or insidiously, consistent with endolymphatic hydrops. Both of these pathophysiologic mechanisms occur with small tumors that are not associated with otic capsule invasion. C1 NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. Natl Inst Hlth & Other Commun Disorders, Neurootol Branch, NIH, Bethesda, MD USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Butman, JA (reprint author), NIH, Dept Diagnost Radiol, Ctr Clin, Bldg 10,Room 1C365, Bethesda, MD 20892 USA. EM jbutman@nih.gov RI Butman, John/A-2694-2008; OI Butman, John/0000-0002-1547-9195 FU Intramural NIH HHS NR 26 TC 29 Z9 30 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 JUL 4 PY 2007 VL 298 IS 1 BP 41 EP 48 DI 10.1001/jama.298.1.41 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 185OU UT WOS:000247721100020 PM 17609489 ER PT J AU Laine, C Horton, R DeAngelis, CD Drazen, JM Frizelle, FA Godlee, F Haug, C Hebert, PC Kotzin, S Marusic, A Sahni, P Schroeder, TV Sox, HC Van der Weyden, MB Verheugt, FWA AF Laine, Christine Horton, Richard DeAngelis, Catherine D. Drazen, Jeffrey M. Frizelle, Frank A. Godlee, Fiona Haug, Charlotte Hebert, Paul C. Kotzin, Sheldon Marusic, Ana Sahni, Peush Schroeder, Torben V. Sox, Harold C. Van der Weyden, Martin B. Verheugt, Freek W. A. TI Clinical trial registration looking back and moving ahead SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 Natl Lib Med, MEDLINE, Bethesda, MD 20894 USA. RI Marusic, Ana/E-7683-2013; Verheugt, F.W.A./H-8105-2014; OI Marusic, Ana/0000-0001-6272-0917; Schroeder, Torben/0000-0002-9827-9438 NR 4 TC 39 Z9 40 U1 0 U2 5 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 JUL 4 PY 2007 VL 298 IS 1 BP 93 EP 94 DI 10.1001/jama.298.1.93-94 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 185OU UT WOS:000247721100027 PM 17548375 ER PT J AU Cai, Q Pan, PY Sheng, ZH AF Cai, Qian Pan, Ping-Yue Sheng, Zu-Hang TI Syntabulin-kinesin-1 family member 5B-mediated axonal transport contributes to activity-dependent presynaptic assembly SO JOURNAL OF NEUROSCIENCE LA English DT Article DE axonal transport; microtubules; presynaptic assembly; synaptogenesis; presynaptic plasticity; active zone precursor; kinesin-1 motor ID LONG-TERM POTENTIATION; SYNAPTIC VESICLE LOCALIZATION; ZONE PROTEIN BASSOON; KINESIN HEAVY-CHAIN; LASTING POTENTIATION; EXCITATORY SYNAPSES; HIPPOCAMPAL-NEURONS; MEMBRANE-PROTEINS; CORTICAL CIRCUITS; SILENT SYNAPSES AB The mechanism by which microtubule-based axonal transport regulates activity-dependent presynaptic plasticity in developing neurons remains mostly unknown. Our previous studies established that syntabulin is an adaptor capable of conjoining the kinesin family member 5B (KIF5B) motor and syntaxin-1. We now report that the complex of syntaxin-1-syntabulin-KIF5B mediates axonal transport of the active zone (AZ) components essential for presynaptic assembly. Syntabulin associates with AZ precursor carriers and colocalizes and comigrates with green fluorescent protein (GFP)-Bassoon-labeled AZ transport cargos within developing axons. Knock-down of syntabulin or disruption of the syntaxin-1-syntabulin-KIF5B complex impairs the anterograde transport of GFP-Bassoon out of the soma and reduces the axonal densities of synaptic vesicle (SV) clusters and FM4-64 [N-(3-triethylammoniumpropyl)-4-(p-dibutylaminostyryl) pyridinium, dibromide] loading. Furthermore, syntabulin loss of function results in a reduction in both the amplitude of postsynaptic currents and the frequency of asynchronous quantal events, and abolishes the activity-induced recruitment of new GFP-Bassoon into the axons and subsequent coclustering with SVs. Consequently, syntabulin loss of function blocks the formation of new presynaptic boutons during activity-dependent synaptic plasticity in developing neurons. These studies establish that a kinesin motor adaptor complex is critical for the anterograde axonal transport of AZ components, thus contributing to activity-dependent presynaptic assembly during neuronal development. C1 NINCDS, Natl Inst Hlth, Porter Neurosci Res Ctr, Synapt Funct Unit, Bethesda, MD 20892 USA. RP Sheng, ZH (reprint author), NINCDS, Natl Inst Hlth, Porter Neurosci Res Ctr, Bldg 35,Rm 3B203,35 Convent Dr, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov FU Intramural NIH HHS NR 75 TC 74 Z9 74 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD JUL 4 PY 2007 VL 27 IS 27 BP 7284 EP 7296 DI 10.1523/JNEUROSCI.0731-07.2007 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 186BP UT WOS:000247754400022 PM 17611281 ER PT J AU Dreher, MR Chilkoti, A AF Dreher, Matthew R. Chilkoti, Ashutosh TI Toward a systems engineering approach to cancer drug delivery SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID HUMAN TUMOR XENOGRAFT; ELASTIN-LIKE POLYPEPTIDE; BINDING-SITE BARRIER; SOLID TUMORS; BLOOD-VESSELS; MACROMOLECULAR THERAPEUTICS; VASCULAR-PERMEABILITY; ACCUMULATION; HYPERTHERMIA; TRANSPORT C1 NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Duke Univ, Dept Biochem Engn, Durham, NC USA. RP Chilkoti, A (reprint author), Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA. EM chilkoti@duke.edu FU Intramural NIH HHS NR 54 TC 13 Z9 13 U1 0 U2 3 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 JUL 4 PY 2007 VL 99 IS 13 BP 983 EP 985 DI 10.1093/jnci/djm042 PG 3 WC Oncology SC Oncology GA 191GF UT WOS:000248118900001 PM 17596569 ER PT J AU Jiang, W Freidlin, B Simon, R AF Jiang, Wenyu Freidlin, Boris Simon, Richard TI Biomarker-adaptive threshold design: A procedure for evaluating treatment with possible biomarker-defined subset effect SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CLINICAL-TRIALS; LUNG-CANCER; MULTIPLICITY; ONCOLOGY AB Background Many molecularly targeted anticancer agents entering the definitive stage of clinical development benefit only a subset of treated patients. This may lead to missing effective agents by the traditional broadeligibility randomized trials due to the dilution of the overall treatment effect. We propose a statistically rigorous biomarker-adaptive threshold phase III design for settings in which a putative biomarker to identify patients who are sensitive to the new agent is measured on a continuous or graded scale. Methods The design combines a test for overall treatment effect in all randomly assigned patients with the establishment and validation of a cut point for a prespecified biomarker of the sensitive subpopulation. The performance of the biomarker-adaptive design, relative to a traditional design that ignores the biomarker, was evaluated in a simulation study. The biomarker-adaptive design was also used to analyze data from a prostate cancer trial. Results In the simulation study, the biomarker-adaptive design preserved the power to detect the overall effect when the new treatment is broadly effective. When the proportion of sensitive patients as identified by the biomarker is low, the proposed design provided a substantial improvement in efficiency compared with the traditional trial design. Recommendations for sample size planning and implementation of the biomarker-adaptive design are provided. Conclusions A statistically valid test for a biomarker-defined subset effect can be prospectively incorporated into a randomized phase III design without compromising the ability to detect an overall effect if the intervention is beneficial in a broad population. C1 NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, EPN-8122, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 17 TC 114 Z9 115 U1 2 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 4 PY 2007 VL 99 IS 13 BP 1036 EP 1043 DI 10.1093/jnci/djm022 PG 8 WC Oncology SC Oncology GA 191GF UT WOS:000248118900011 PM 17596577 ER PT J AU Cronin-Fenton, DP Ries, LA Clegg, LX Edwards, BK AF Cronin-Fenton, Deirdre P. Ries, Lynn A. Clegg, Limin X. Edwards, Brenda K. TI Rising incidence rates of breast carcinoma with micrometastatic lymph node involvement SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HORMONE REPLACEMENT THERAPY; EARLY-STAGE MELANOMA; SENTINEL NODE; CANCER INCIDENCE; MULTICENTER TRIAL; BIOPSY; LYMPHADENECTOMY; DISSECTION; TRENDS; VALIDATION AB We investigated the increased incidence of early-stage breast cancer with micrometastatic lymph node involvement. Breast cancer incidence trends from 1990 through 2002 in the US Surveillance, Epidemiology, and End Results Program catchment area were analyzed. Joinpoint regression was used to show the annual percentage change (APC) in breast cancer incidence trends. The overall incidence of breast cancer among women aged 50-64 years increased 1.8% (95% confidence interval [CI] = 1.4% to 2.2%) per annum from 1990 through 2002 but decreased in all other age groups. Stage IIA and stage IIB tumor incidence increased (APC for stage IIA from 1996 to 2002 = 61.9%, 95% Cl = 51.1% to 73.4%, and APC for stage IIB from 1998 to 2002 = 53.7%, 95% Cl = 20.6% to 96.0%). The incidence of micrometastatic lymph node involvement for stage IIA and stage IIB tumors increased during the 1990s, especially after 1997 (APC = 17.3% for both stages), more for estrogen receptor-positive than estrogen receptor-negative disease. Increased use of mammography screening partly explains the increased incidence of early-stage breast cancer. Increases in small tumors with micrometastatic lymph node involvement may be attributable to the increased use of the sentinel lymph node biopsy in community practice. C1 Aarhus Univ Hosp, Dept Clin Epidemiol, DK-8000 Aarhus, Denmark. NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. US Dept Vet Affairs, Off Healthcare Inspect, Off Inspector Gen, Washington, DC USA. RP Cronin-Fenton, DP (reprint author), Aarhus Univ Hosp, Dept Clin Epidemiol, Ole Worms Alle 1150, DK-8000 Aarhus, Denmark. EM dc@dce.au.dk NR 48 TC 15 Z9 15 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 4 PY 2007 VL 99 IS 13 BP 1044 EP 1049 DI 10.1093/jnci/djm026 PG 6 WC Oncology SC Oncology GA 191GF UT WOS:000248118900012 PM 17596573 ER PT J AU Warren, JL Brown, ML AF Warren, Joan L. Brown, Martin L. TI Re: Acute myeloid leukemia or myelodysplastic syndrome following use of granulocyte colony-stimulating factors during breast cancer adjuvant chemotherapy SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID CLAIMS C1 NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Warren, JL (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Execut Plaza N,Rm 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM joan_warren@nih.gov NR 7 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD JUL 4 PY 2007 VL 99 IS 13 BP 1050 EP 1050 DI 10.1093/jnci/djm015 PG 1 WC Oncology SC Oncology GA 191GF UT WOS:000248118900013 PM 17596580 ER PT J AU Menon, V Shlipak, MG Wang, XL Coresh, J Greene, T Stevens, L Kusek, JW Beck, GJ Collins, AJ Levey, AS Sarnak, MJ AF Menon, Vandana Shlipak, Michael G. Wang, Xuelei Coresh, Josef Greene, Tom Stevens, Lesley Kusek, John W. Beck, Gerald J. Collins, Allan J. Levey, Andrew S. Sarnak, Mark J. TI Cystatin C as a risk factor for outcomes in chronic kidney disease SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID GLOMERULAR-FILTRATION-RATE; CORONARY-HEART-DISEASE; EARLY RENAL IMPAIRMENT; CARDIOVASCULAR OUTCOMES; SERUM CREATININE; BIOLOGICAL VARIATION; ELDERLY PERSONS; MARKER; EVENTS; INSUFFICIENCY AB Background: No study has compared cystatin C level, serum creatinine concentration, and estimated glomerular filtration rate (GFR) as risk factors for outcomes in chronic kidney disease (CKD), and none has compared measured GFR with CKD in any population. Objective: To compare cystatin C level with serum creatinine concentration and iothalamate GFR as risk factors for death and kidney failure. Design: Observational study using serum cystatin C assayed from baseline samples of the Modificztion of Diet in Renal Disease Study (1989-1993). Setting: 15 clinical centers in the United States that participated in the Modification of Diet in Renal Disease Study. Participants: 825 trial participants with stage 3 or 4 nondiabetic CKD who had measurements of serum cystatin C. Measurements: All-cause mortality, cardiovascular (CVD) mortality, and kidney failure until December 2000. Results: Mean cystatin C level, creatinine concentration, and GFR were 2.2 mg/L (SD, 0.7), 212.16 mu mol/L (SD, 88.4) (2.4 mg/dL [SD, 1.0]), and 33 mL/min per 1.73 m(2) (SD, 12), respectively. Median follow-up was 10 years. Twenty-five percent of patients (n = 203) died of any cause, 15% (n = 123) died of CVD, and 66% (n = 548) reached kidney failure. In multivariate-adjusted models, 1-SD decreases in 1/creatinine, GFR, and 1/cystatin C were associated with increased risks for all-cause mortality of 1.27 (95% Cl, 1.06 to 1.49), 1.27 (Cl, 1.08 to 1.49), and 1.41 (Cl, 1.18 to 1.67), respectively. For CVD mortality, the increased risks were 1.32 (Cl, 1.05 to 1.64), 1.28 (Cl, 1.04 to 1.59), and 1.64 (Cl, 1.28 to 2.08), respectively. For kidney failure, the increased risks were 2.81 (Cl, 2.48 to 3.18), 2.41 (Cl, 2.15 to 2.70), and 2.36 (Cl, 2.10 to 2.66), respectively. Limitation: The Modification of Diet in Renal Disease Study cohort may not be representative of all patients with nondiabetic CKD because participants were more likely to reach kidney failure than death in follow-up. Conclusion: The association of cystatin C level with all-cause and CVD mortality was as strong as or perhaps stronger than that of iothalamate GFR with these outcomes in stage 3 or 4 CKD. C1 Tufts Univ, New England Med Ctr, Div Nephrol, Boston, MA 02111 USA. Vet Affairs Med Ctr, San Francisco, CA 94121 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. Univ Utah, Salt Lake City, UT USA. Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. RP Sarnak, MJ (reprint author), Tufts Univ, New England Med Ctr, Div Nephrol, 750 Washington St,391, Boston, MA 02111 USA. EM msarnak@tufts-nemc.org FU NHLBI NIH HHS [R01 HL073208-01]; NIDDK NIH HHS [DK53869-05, K23 DK02904, K23 DK067303, R01 DK066488-01, UO1 DK 35073] NR 43 TC 112 Z9 118 U1 0 U2 2 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 JUL 3 PY 2007 VL 147 IS 1 BP 19 EP 27 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 186MN UT WOS:000247782900003 PM 17606957 ER PT J AU Laine, C Horton, R DeAngelis, CD Drazen, JM Frizelle, FA Godlee, F Haug, C Hebert, PC Kotzin, S Marusic, A Sahni, P Schroeder, TV Sox, HC Van der Weyden, MB Verheugt, FWA AF Laine, Christine Horton, Richard DeAngelis, Catherine D. Drazen, Jeffrey M. Frizelle, Frank A. Godlee, Fiona Haug, Charlotte Hebert, Paul C. Kotzin, Sheldon Marusic, Ana Sahni, Peush Schroeder, Torben V. Sox, Harold C. Van der Weyden, Martin B. Verheugt, Freek W. A. TI Clinical trial registration: looking back and moving ahead SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Editorial Material C1 CMAJ, Ottawa, ON K1G 3Y6, Canada. Natl Lib Med, MEDLINE, Bethesda, MD 20894 USA. RP Hebert, PC (reprint author), CMAJ, 1867 Alta Vista Dr, Ottawa, ON K1G 3Y6, Canada. EM paul.hebert@cma.ca RI Marusic, Ana/E-7683-2013; Verheugt, F.W.A./H-8105-2014; OI Marusic, Ana/0000-0001-6272-0917; Schroeder, Torben/0000-0002-9827-9438 NR 5 TC 5 Z9 5 U1 0 U2 2 PU CMA MEDIA INC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD JUL 3 PY 2007 VL 177 IS 1 BP 57 EP 58 DI 10.1503/cmaj.070753 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 181KW UT WOS:000247436600015 PM 17548376 ER PT J AU Aarnoudse, AJLHJ Newton-Cheh, C de Bakker, PIW Straus, SMJM Kors, JA Hofman, A Uitterlinden, AG Witteman, JCM Stricker, BHC AF Aarnoudse, Albert-Jan L. H. J. Newton-Cheh, Christopher de Bakker, Paul I. W. Straus, Sabine M. J. M. Kors, Jan A. Hofman, Albert Uitterlinden, Andre G. Witteman, Jacqueline C. M. Stricker, Bruno H. C. TI Common NOS1AP variants are associated with a prolonged QTc interval in the Rotterdam study SO CIRCULATION LA English DT Article DE arrhythmia; death, sudden; electrocardiography; genetics; long-QT syndrome ID SUDDEN CARDIAC DEATH; NITRIC-OXIDE SYNTHASE; MYOCARDIAL-INFARCTION; HAPLOTYPE RECONSTRUCTION; GENERAL-POPULATION; HEART-FAILURE; RISK-FACTOR; ELECTROCARDIOGRAMS; ARREST; GENOME AB Background - QT prolongation is an important risk factor for sudden cardiac death. About 35% of QT-interval variation is heritable. In a recent genome-wide association study, a common variant (rs10494366) in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene was found to be associated with QT-interval variation. We tested for association of 2 NOS1AP variants with QT duration and sudden cardiac death. Methods and Results - The Rotterdam Study is a population-based, prospective cohort study of individuals >= 55 years of age. The NOS1AP variants rs10494366 T > G and rs10918594 C > G were genotyped in 6571 individuals. Heart rate - corrected QT interval ( QTc) was determined with ECG analysis software on up to 3 digital ECGs per individual ( total, 11 108 ECGs from 5374 individuals). The association with QTc duration was estimated with repeated-measures analyses, and the association with sudden cardiac death was estimated by Cox proportional-hazards analyses. The rs10494366 G allele (36% frequency) was associated with a 3.8-ms (95% confidence interval, 3.0 to 4.6; P = 7.8 x 10(-20)) increase in QTc interval duration for each additional allele copy, and the rs10918594 G allele (31% frequency) was associated with a 3.6-ms ( 95% confidence interval, 2.7 to 4.4; P = 6.9 x 10(-17)) increase per additional allele copy. None of the inferred NOS1AP haplotypes showed a stronger effect than the individual single-nucleotide polymorphisms. There were 233 sudden cardiac deaths over 11.9 median years of follow-up. No significant association was observed with sudden cardiac death risk. Conclusions - Common variants in NOS1AP are strongly associated with QT-interval duration in an elderly population. Larger sample sizes are needed to confirm or exclude an effect on sudden cardiac death risk. C1 Erasmus MC, Dept Epidemiol & Biostat, NL-3000 CA Rotterdam, Netherlands. Erasmus MC, Dept Internal Med, NL-3000 CA Rotterdam, Netherlands. Erasmus MC, Dept Med Informat, NL-3000 CA Rotterdam, Netherlands. Massachusetts Gen Hosp, Dept Biol Mol, Div Cardiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. Inspectorate Hlth Care, The Hague, Netherlands. Dutch Med Evaluat Board, The Hague, Netherlands. RP Stricker, BHC (reprint author), Erasmus MC, Dept Epidemiol & Biostat, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM b.stricker@erasmusmc.nl RI de Bakker, Paul/B-8730-2009 OI de Bakker, Paul/0000-0001-7735-7858 FU NHLBI NIH HHS [K23 HL80025] NR 48 TC 90 Z9 95 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL PY 2007 VL 116 IS 1 BP 10 EP 16 DI 10.1161/CIRCULATIONAHA.106.676783 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 185NZ UT WOS:000247719000004 PM 17576865 ER PT J AU Cao, JJ Arnold, AM Manolio, TA Polak, JF Psaty, BM Hirsch, CH Kuller, LH Cushman, M AF Cao, Jie J. Arnold, Alice M. Manolio, Teri A. Polak, Joseph F. Psaty, Bruce M. Hirsch, Calvin H. Kuller, Lewis H. Cushman, Mary TI Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality - The cardiovascular health study SO CIRCULATION LA English DT Article DE aging; arteriosclerosis; atherosclerosis; cardiovascular diseases; carotid arteries; inflammation ID B-MODE ULTRASONOGRAPHY; RISK PREDICTION; MYOCARDIAL-INFARCTION; ISCHEMIC-STROKE; ATHEROSCLEROSIS; CORONARY; EVENTS; ADULTS; INFLAMMATION; VARIABILITY AB Background - Carotid atherosclerosis, measured as carotid intima-media thickness or as characteristics of plaques, has been linked to cardiovascular disease (CVD) and to C-reactive protein (CRP) levels. We investigated the relationship between carotid atherosclerosis and CRP and their joint roles in CVD prediction. Methods and Results - Of 5888 participants in the Cardiovascular Health Study, an observational study of adults aged >= 65 years, 5020 without baseline CVD were included in the analysis. They were followed up for as long as 12 years for CVD incidence and all-cause mortality after baseline ultrasound and CRP measurement. When CRP was elevated (> 3 mg/L) among those with detectable atherosclerosis on ultrasound, there was a 72% ( 95% CI, 1.46 to 2.01) increased risk for CVD death and a 52% ( 95% CI, 1.37 to 1.68) increased risk for all-cause mortality. Elevated CRP in the absence of atherosclerosis did not increase CVD or all-cause mortality risk. The proportion of excess risk attributable to the interaction of high CRP and atherosclerosis was 54% for CVD death and 79% for all-cause mortality. Addition of CRP or carotid atherosclerosis to conventional risk factors modestly increased in the ability to predict CVD, as measured by the c statistic. Conclusions - In older adults, elevated CRP was associated with increased risk for CVD and all-cause mortality only in those with detectable atherosclerosis based on carotid ultrasound. Despite the significant associations of CRP and carotid atherosclerosis with CVD, these measures modestly improve the prediction of CVD outcomes after one accounts for the conventional risk factors. C1 NHLBI, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. Univ Calif Davis, Davis, CA 95616 USA. Tufts Univ, New England Med Ctr, Boston, MA 02111 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Vermont, Burlington, VT USA. RP Cao, JJ (reprint author), NHLBI, NIH, 10 Ctr Dr,MSC 1061,Bldg 10,Room B1D-416, Bethesda, MD 20892 USA. EM caoj@nhlbi.nih.gov FU NHLBI NIH HHS [N01-HC-85083, N01-HC-15103, N01-HC-35129, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85084, N01-HC-85085, N01-HC-85086] NR 38 TC 179 Z9 186 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL PY 2007 VL 116 IS 1 BP 32 EP 38 DI 10.1161/CIRCULATIONAHA.106.645606 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 185NZ UT WOS:000247719000010 PM 17576871 ER PT J AU Fox, CS Massaro, JM Hoffmann, U Pou, KM Maurovich-Horvat, P Liu, CY Vasan, RS Murabito, JM Meigs, JB Cupples, LA D'Agostino, RB O'Donnell, CJ AF Fox, Caroline S. Massaro, Joseph M. Hoffmann, Udo Pou, Karla M. Maurovich-Horvat, Pal Liu, Chun-Yu Vasan, Ramachandran S. Murabito, Joanne M. Meigs, James B. Cupples, L. Adrienne D'Agostino, Ralph B., Sr. O'Donnell, Christopher J. TI Abdominal visceral and subcutaneous adipose tissue compartments - Association with metabolic risk factors in the Framingham Heart Study SO CIRCULATION LA English DT Article DE abdominal fat; diabetes mellitus; epidemiology; hypertension; intra-abdominal fat; metabolic syndrome X; obesity ID IMPAIRED GLUCOSE-TOLERANCE; ENDOTHELIAL GROWTH-FACTOR; TREATMENT PANEL-III; C-REACTIVE PROTEIN; BETA-CELL FUNCTION; INSULIN-RESISTANCE; JAPANESE-AMERICANS; CARDIOVASCULAR-DISEASE; FAT ACCUMULATION; BODY-FAT AB Background - Visceral adipose tissue ( VAT) compartments may confer increased metabolic risk. The incremental utility of measuring both visceral and subcutaneous abdominal adipose tissue ( SAT) in association with metabolic risk factors and underlying heritability has not been well described in a population-based setting. Methods and Results - Participants (n = 3001) were drawn from the Framingham Heart Study (48% women; mean age, 50 years), were free of clinical cardiovascular disease, and underwent multidetector computed tomography assessment of SAT and VAT volumes between 2002 and 2005. Metabolic risk factors were examined in relation to increments of SAT and VAT after multivariable adjustment. Heritability was calculated using variance-components analysis. Among both women and men, SAT and VAT were significantly associated with blood pressure, fasting plasma glucose, triglycerides, and high-density lipoprotein cholesterol and with increased odds of hypertension, impaired fasting glucose, diabetes mellitus, and metabolic syndrome ( P range < 0.01). In women, relations between VAT and risk factors were consistently stronger than in men. However, VAT was more strongly correlated with most metabolic risk factors than was SAT. For example, among women and men, both SAT and VAT were associated with increased odds of metabolic syndrome. In women, the odds ratio ( OR) of metabolic syndrome per 1 - standard deviation increase in VAT ( OR, 4.7) was stronger than that for SAT ( OR, 3.0; P for difference between SAT and VAT < 0.0001); similar differences were noted for men ( OR for VAT, 4.2; OR for SAT, 2.5). Furthermore, VAT but not SAT contributed significantly to risk factor variation after adjustment for body mass index and waist circumference ( P <= 0.01). Among overweight and obese individuals, the prevalence of hypertension, impaired fasting glucose, and metabolic syndrome increased linearly and significantly across increasing VAT quartiles. Heritability values for SAT and VAT were 57% and 36%, respectively. Conclusions - Although both SAT and VAT are correlated with metabolic risk factors, VAT remains more strongly associated with an adverse metabolic risk profile even after accounting for standard anthropometric indexes. Our findings are consistent with the hypothesized role of visceral fat as a unique, pathogenic fat depot. Measurement of VAT may provide a more complete understanding of metabolic risk associated with variation in fat distribution. C1 NHLBI, Framingham Heart Study, Framingham, MA USA. Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Sch Publ Hlth, Div Biostat, Boston, MA 02215 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA 02115 USA. Semmelweis Univ, H-1085 Budapest, Hungary. Boston Univ, Sch Med, Boston, MA 02215 USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave,Ste 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812; Cupples, L. Adrienne/0000-0003-0273-7965; Murabito, Joanne/0000-0002-0192-7516; Ramachandran, Vasan/0000-0001-7357-5970; Maurovich-Horvat, Pal/0000-0003-0885-736X FU NHLBI NIH HHS [2K24HL04334, N01-HC-25195]; NIDDK NIH HHS [T32 DK007529] NR 75 TC 966 Z9 1007 U1 15 U2 79 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD JUL 3 PY 2007 VL 116 IS 1 BP 39 EP 48 DI 10.1161/CIRCULATIONAHA.106.675355 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 185NZ UT WOS:000247719000012 PM 17576866 ER PT J AU Cheung, N Bluemke, DA Klein, R Sharrett, AR Islam, FMA Cotch, MF Klein, BEK Criqui, MH Wong, TY AF Cheung, Ning Bluemke, David A. Klein, Ronald Sharrett, A. Richey Islam, F. M. Amirul Cotch, Mary Frances Klein, Barbara E. K. Criqui, Michael H. Wong, Tien Yin TI Retinal arteriolar narrowing and left ventricular remodeling - The multi-ethnic study of atherosclerosis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; PRIMARY CORONARY ANGIOPLASTY; CONGESTIVE-HEART-FAILURE; VESSEL DIAMETERS; MICROVASCULAR ABNORMALITIES; CLINICAL-IMPLICATIONS; DIABETIC-RETINOPATHY; HYPERTROPHIC CARDIOMYOPATHY; PROGNOSTIC-SIGNIFICANCE; RISK AB Objectives This study sought to examine the relationships of retinal vascular signs with left ventricular (LV) mass, volume, and concentric remodeling. Background Microvascular disease, reflected as retinopatly lesions, has been shown to predict clinical congestive heart failure. Whether these retinal vascular changes are related to early structural alterations and remodeling of the heart in asymptomatic individuals is unknown. Methods A cross-sectional, population-based study of 4,593 participants ages 45 to 85 years, free of clinical cardiovascular disease. Retinal vascular calibers and retinopathy were graded from retinal photographs according to standardized protocols. The LV mass and volume were measured from cardiac magnetic resonance imaging. Extent of LV concentric remodeling was determined by the ratio of LV mass to end-diastolic volume (M/V ratio). Results After controlling for age, gender, race, center, past and current systolic blood pressure, body mass index, smoking, antihypertensive medications, diabetes, diabetes duration, glycosylated hemoglobin, lipid profile, and C-reactive protein, narrower retinal arteriolar caliber was associated with concentric (highest quintile of M/V ratio) remodeling (odds ratio [OR] 2.06, 95% confidence interval 1.57 to 2.70). This association was seen in men and women, and was present even in those without diabetes, without hypertension, and without significant coronary calcification. In multivariate analysis, the presence of retinopathy (OR 1.31, 95% confidence interval 1.08 to 1.61) was also associated with concentric remodeling. Conclusions Narrower retinal arteriolar caliber is associated with LV concentric remodeling independent of traditional risk factors and coronary atherosclerotic burden, supporting the hypothesis that microvascular disease may contribute to cardiac remodeling. C1 Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. Royal Melbourne Hosp, Melbourne, Vic, Australia. Johns Hopkins Univ, Sch Med, Dept Radiol & Med, Baltimore, MD USA. Univ Wisconsin, Dept Ophthalmol & Visual Sci, Madison, WI USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NEI, NIH, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. Natl Univ Singapore, Yong Loo Lin Sch Med, Eye Res Inst, Singapore 117548, Singapore. RP Wong, TY (reprint author), Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. EM rwong@unimelb.edu.au RI Cheung, Ning Danny/F-2043-2013; OI Cotch, Mary Frances/0000-0002-2046-4350; Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS [ZIA EY000403-09, Z01 EY000403-06, Z01 EY000403-07, Z99 EY999999, ZIA EY000403-08, ZIA EY000403-10]; NHLBI NIH HHS [HL69979-03, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95169, N01HC95159, N01HC95165, N01HC95169, R01 HL069979] NR 44 TC 58 Z9 58 U1 0 U2 3 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 JUL 3 PY 2007 VL 50 IS 1 BP 48 EP 55 DI 10.1080/j.jacc.2007.03.029 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 186AD UT WOS:000247750600008 PM 17601545 ER PT J AU Hardy, J Singleton, A AF Hardy, John Singleton, Andrew TI Reporting and interpretation of genetic variants in cases and controls SO NEUROLOGY LA English DT Editorial Material ID MUTATION C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,Rm 6C103, Bethesda, MD 20892 USA. EM hardyj@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009 FU Medical Research Council [G0701075]; Parkinson's UK [G-0907] NR 4 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 3 PY 2007 VL 69 IS 1 BP 111 EP 112 DI 10.1212/01.wnl.0000265059.56575.a6 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 185NW UT WOS:000247718700018 PM 17606889 ER PT J AU Majeed, K Enam, SA AF Majeed, Kashif Enam, S. Ather TI Recurrent pineal apoplexy in a child SO NEUROLOGY LA English DT Editorial Material ID HEMORRHAGE; THERAPY; REGION; TUMORS C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Enam, SA (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,Rm 6C103, Bethesda, MD 20892 USA. EM ather.enam@aku.edu NR 7 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD JUL 3 PY 2007 VL 69 IS 1 BP 112 EP 114 DI 10.1212/01.wnl.0000265059.56575.a6 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 185NW UT WOS:000247718700019 PM 17606890 ER PT J AU Doyle, SM Hoskins, JR Wickner, S AF Doyle, Shannon M. Hoskins, Joel R. Wickner, Sue TI Collaboration between the ClpB AAA+ remodeling protein and the DnaK chaperone system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ClpA; ClpX; disaggregation; Hsp104; Hsp70 ID HEAT-SHOCK-PROTEIN; ATP-DEPENDENT PROTEASES; ESCHERICHIA-COLI; AGGREGATED PROTEINS; MOLECULAR CHAPERONE; SUBSTRATE RECOGNITION; CRYSTAL-STRUCTURE; HSP100 CHAPERONE; BINDING; DISAGGREGATION AB ClpB and Hsp104, members of the AAA+ superfamily of proteins, protect cells from the devastating effects of protein inactivation and aggregation that arise after extreme heat stress. They exist as a hexameric ring and contain two nucleotide-binding sites per monomer. ClpB and Hsp104 are able to dissolve protein aggregates in conjunction with the DnaK/Hsp70 chaperone system, although the roles of the individual chaperones in disaggregation are not well understood. in the absence of the DnaK/Hsp70 system, ClpB and Hsp104 alone are able to perform protein remodeling when their ATPase activity is asymmetrically slowed either by providing a mixture of ATP and ATP gamma S, a nonphysiological and slowly hydrolyzed ATP analog, or by inactivating one of the two nucleotide-binding domains by mutation. To gain insight into the roles of ClpB and the DnaKsystem in protein remodeling, we tested whether there was a further stimulation by the DnaK chaperone system under conditions that elicited remodeling activity by ClpB alone. Our results demonstrate that ClpB and the DnaK system act synergistically to remodel proteins and dissolve aggregates. The results further show that ATP is required and that both nucleotide-binding sites of ClpB must be able to hydrolyze ATP to permit functional collaboration between ClpB and the DnaK system. C1 NIH, Natl Canc Ctr, Mol Biol Lab, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NIH, Natl Canc Ctr, Mol Biol Lab, Bldg 10, Bethesda, MD 20892 USA. EM wickners@mail.nih.gov FU Intramural NIH HHS NR 47 TC 49 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 JUL 3 PY 2007 VL 104 IS 27 BP 11138 EP 11144 DI 10.1073/pnas.0703980104 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 188DT UT WOS:000247900000005 PM 17545305 ER PT J AU Oberst, A Malatesta, M Aqeilan, RI Rossi, M Salomoni, P Murillas, R Sharma, P Kuehn, MR Orerill, M Croce, CM Bernassola, F Melino, G AF Oberst, Andrew Malatesta, Martina Aqeilan, Rami I. Rossi, Mario Salomoni, Paolo Murillas, Rodolfo Sharma, Prashant Kuehn, Michael R. Orerill, Moshe Croce, Carlo M. Bernassola, Francesca Melino, Gerry TI The Need4-binding partner 1 (N4BP1) protein is an inhibitor of the E3 ligase Itch SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE p53; protein-protein interaction; transcription; ubiquitylation; WW domain ID UBIQUITIN-DEPENDENT DEGRADATION; EPITHELIAL NA+ CHANNEL; WW DOMAINS; NEDD4; PHOSPHORYLATION; STABILITY; P73; JUN; P53; RECOGNITION AB Nedd4-binding partner-1 (N4BP1) has been identified as a protein interactor and a substrate of the homologous to E6AP C terminus [HECT) domain-containing E3 ubiquitin-protein ligase (E3), Nedd4. Here, we describe a previously unrecognized functional interaction between N4BIP1 and Itch, a Nedd4 structurally related E3, which contains four WW domains, conferring substrate-binding activity. We show that N4BP1 association with the second WW domain (WW2) of Itch interferes with E3 binding to its substrates. In particular, we found that N4BP1 and p73a, a target of Itchmediated ubiquitin/proteasome proteolysis, share the same bindling site. By competing with p73a for binding to the WW2 domain, N4BP1 reduces the ability of Itch to recruit and ubiquitylate p73a and inhibits Itch autoubiquitylation activity both in in vitro and in vivo ubiquitylation assays. Similarly, both c-Jun and p63 polyubiquitylation by Itch are inhibited by N4BlP1. As a consequence, genetic and RNAi knockdown of N4lBP1 diminish the steady-state protein levels and significantly impair the transcriptional activity of Itch substrates. Notably, stress-induced induction of c-Jun was impaired in N4BP1-1- cells. These results demonstrate that N41BP1 functions as a negative regulator of Itch. In addition, because inhibition of Itch by N4BP1 results in the stabilization of crucial cell death regulators such as p73a and c-Jun, it is conceivable that N4lBP1 may have a role in regulating tumor progression and the response of cancer cells to chemotherapy. C1 Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. Univ Roma Tor Vergata, Immacolata Ist Ricovero & Cura Caraterre Sci, Biochem Lab, Ist Dermopatico, I-00133 Rome, Italy. Univ Leicester, MRC, Toxicol Unit, Leicester LE1 9HN, Leics, England. Ctr Invest Energet Medioambientales & Technol, Dept Mol & Cellular Biol, Madrid 28040, Spain. NCI, Lab Prot Dynam & Signalling, Frederick, MD 21702 USA. Weizmann Inst Sci, Dept Mol Cell Biol, IL-76100 Rehovot, Israel. RP Bernassola, F (reprint author), Ohio State Univ, Ctr Comprehens Canc, Dept Mol Virol Immunol & Med Genet, Wiseman Hall,Room 385K,400 W 12th Ave, Columbus, OH 43210 USA. EM bernasso@uniroma2.it RI Rossi, Mario/E-7666-2012; Kuehn, Michael/A-4573-2014; Aqeilan, Rami/R-4443-2016 OI Rossi, Mario/0000-0001-6349-8895; Kuehn, Michael/0000-0002-7703-9160; Aqeilan, Rami/0000-0002-6034-023X FU Intramural NIH HHS; Medical Research Council [MC_U132670600, MC_U132670601]; Telethon [GGP04110] NR 29 TC 49 Z9 53 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 JUL 3 PY 2007 VL 104 IS 27 BP 11280 EP 11285 DI 10.1073/pnas.0701773104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 188DT UT WOS:000247900000030 PM 17592138 ER PT J AU Rao, RP Yuan, C Allegood, JC Rawat, SS Edwards, MB Wang, X Merrill, AH Acharya, JK AF Rao, Raghavendra Pralhada Yuan, Changqing Allegood, Jeremy C. Rawat, Satinder S. Edwards, Michael Beth Wang, Xin Merrill, Alfred H., Jr. Acharya, Jairaj K. TI Ceramide transfer protein function is essential for normal oxidative stress response and lifespan SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aging; Drosophila; membrane fluidity; sphingolipids; sphingomyelin ID DROSOPHILA-MELANOGASTER; SPHINGOMYELIN SYNTHESIS; GOLGI-APPARATUS; ENDOPLASMIC-RETICULUM; MITOCHONDRIAL-FUNCTION; MOLECULAR MACHINERY; NEGATIVE GEOTAXIS; CELL; TRAFFICKING; METABOLISM AB Ceramide transfer protein (CERT) transfers ceramide from the encloplasmic reticulum to the Golgi complex, a process critical in synthesis and maintenance of normal levels of sphingolipids in mammalian cells. However, how its function is integrated into development and physiology of the animal is less clear. Here, we report the in vivo consequences of loss of functional CERT protein. We generated Drosophila melanogaster mutant flies lacking a functional CIERT (Dcert) protein using chemical mutagenesis and a Western blot-based genetic screen. The mutant flies die early between days 10 and 30, whereas controls lived between 75 and 90 days. They display >70% decrease in ceramide phosphoethanolamine (the sphingomyelin analog in Drosophila) and ceramide. These changes resulted in increased plasma membrane fluidity that renders them susceptible to reactive oxygen species and results in enhanced oxidative damage to cellular proteins. Consequently, the flies showed reduced thermal tolerance that was exacerbated with aging and metabolic compromise such as decreasing ATP and increasing glucose levels, reminiscent of premature aging. Our studies demonstrate that maintenance of physiological levels of ceramide phosphoethanolamine by CIERT in vivo is required to prevent oxidative damages to cellular components that are critical for viability and normal lifespan of the animal. C1 NCI, Lab Cell & Dev Signalling, Frederick, MD 21702 USA. Georgia Inst Technol, Sch Biol, Atlanta, GA 30332 USA. Georgia Inst Technol, Sch Chem, Atlanta, GA 30332 USA. Georgia Inst Technol, Sch Biochem, Atlanta, GA 30332 USA. Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. RP Acharya, JK (reprint author), NCI, Lab Cell & Dev Signalling, Frederick, MD 21702 USA. EM acharyaj@mail.ncifcrf.gov FU Intramural NIH HHS; NEI NIH HHS [R01 EY016469, R01EY16469]; NIGMS NIH HHS [GM69338, U54 GM069338] NR 48 TC 59 Z9 63 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 JUL 3 PY 2007 VL 104 IS 27 BP 11364 EP 11369 DI 10.1073/pnas.0705049104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 188DT UT WOS:000247900000044 PM 17592126 ER PT J AU Tarasenko, T Kole, HK Chi, AW Mentink-Kane, MM Wynn, TA Bolland, S AF Tarasenko, Tatyana Kole, Hemanta K. Chi, Anthony W. Mentink-Kane, Margaret M. Wynn, Thomas A. Bolland, Silvia TI T cell-specific deletion of the inositol phosphatase SHIP reveals its role in regulating Th1/Th2 and cytotoxic responses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cytotoxicity; T-bet ID 5-PHOSPHATASE SHIP; B-LYMPHOCYTES; IFN-GAMMA; RECEPTOR; ACTIVATION; BET; MACROPHAGES; MICE; 5'-PHOSPHATASE; INFLAMMATION AB The 5'-phosphoinositol phosphatase SHIP negatively regulates signaling pathways triggered by antigen, cytokine and Fc receptors in both lymphocytes and myeloid cells. Mice with germ-line (null) deletion of SHIP develop a myeloproliferative-like syndrome that causes early lethality. Lymphocyte anomalies have been observed in SHIP-null mice, but it is unclear whether they are due to an intrinsic requirement of SHIP in these cells or a consequence of the severe myeloid pathology. To precisely address the function of SHIP in T cells, we have generated mice with T cell-specific deletion of SHIP. In the absence of SHIP, we found no differences in thymic selection or in the activation state and numbers of regulatory T cells in the periphery. In contrast, SHIP-deficientT cells do not skew efficiently to Th2 in vitro. Mice with T cell-specific deletion of SHIP show poor antibody responses on Alum/NP-CGG immunization and diminished Th2 cytokine production when challenged with Schistosoma mansoni eggs. The failure to skew to Th2 responses may be the consequence of increased basal levels of the Thlassociated transcriptional factor T-bet, resulting from enhanced sensitivity to cytokine-mediated T-bet induction. SHIP-deficient CD8(+) cells show enhanced cytotoxic responses, consistent with elevated T-bet levels in these cells. Overall our experiments indicate that in T cells SHIP negatively regulates cytokine-mediated activation in a way that allows effective Th2 responses and limits T cell cytotoxicity. C1 NIAID, NIH, Immunogenet Lab, Rockville, MD 20852 USA. NIAID, NIH, Parasit Dis Lab, Rockville, MD 20852 USA. RP Bolland, S (reprint author), NIAID, NIH, Immunogenet Lab, Rockville, MD 20852 USA. EM sbolland@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU Intramural NIH HHS NR 35 TC 65 Z9 67 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 JUL 3 PY 2007 VL 104 IS 27 BP 11382 EP 11387 DI 10.1073/pnas.0704853104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 188DT UT WOS:000247900000047 PM 17585010 ER PT J AU Jean-Xavier, C Mentis, GZ O'Donovan, MJ Cattaert, D Vinay, L AF Jean-Xavier, Celine Mentis, George Z. O'Donovan, Michael J. Cattaert, Daniel Vinay, Laurent TI Dual personality of GABA/glycine-mediated depolarizations in immature spinal cord SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chloride homeostasis; facilitation; inhibition; synaptic integration ID DEVELOPING HYPOTHALAMIC NEURONS; RAT DORSAL-HORN; CHICK-EMBRYO; IN-VITRO; INTRACELLULAR CHLORIDE; POSTNATAL MATURATION; DEVELOPING NETWORKS; LUMBAR MOTONEURONS; EXCITATORY ACTIONS; ACTION-POTENTIALS AB The inhibitory action of glycine and GABA in adult neurons consists of both shunting incoming excitations and moving the membrane potential away from the action potential (AP) threshold. By contrast, in immature neurons, inhibitory postsynaptic potentials (IPSPs) are depolarizing; it is generally accepted that, despite their depolarizing action, these IPSPs are inhibitory because of the shunting action of the Cl- conductance increase. Here we investigated the integration of depolarizing IPSPs (dIPSPs) with excitatory inputs in the neonatal rodent spinal cord by means of both intracellular recordings from lumbar motoneurons and a simulation using the compartment model program "Neuron." We show that the ability of IPSPs to suppress suprathreshold excitatory events depends on E-cl, and the location of inhibitory synapses. The depolarization outlasts the conductance changes and spreads electrotonically in the somatodendritic tree, whereas the shunting effect is restricted and local. As a consequence, dIPSPs facilitated AP generation by subthreshold excitatory events in the late phase of the response. The window of facilitation became wider as E-cl was more depolarized and started earlier as inhibitory synapses were moved away from the excitatory input. GAD65/67 immunohistochemstry demonstrated the existence of distal inhibitory synapses on motoneurons in the neonatal rodent spinal cord. This study demonstrates that mall dIPSPs can either inhibitor facilitate excitatory inputs depending on timing and location. Our results raise the possibility that inhibitory synapses exert a facilitatory action on distant excitatory inputs and slight changes of Ecl may have important consequences for network processing. C1 Aix Marseille Univ, CNRS, Lab Plast & Physio Pathol Motricite, F-13402 Marseille 20, France. Univ Bordeaux, CNRS, Lab Neurobiol Reseaux, F-33405 Talence, France. NINDS, NIH, Neural Control Lab, Bethesda, MD 20892 USA. RP Vinay, L (reprint author), Aix Marseille Univ, CNRS, Lab Plast & Physio Pathol Motricite, 31 Chemin Joseph Aiguier, F-13402 Marseille 20, France. EM vinay@dpm.cnrs-mrs.fr RI Cattaert, Daniel/D-8630-2014; o'donovan, michael/A-2357-2015; OI o'donovan, michael/0000-0003-2487-7547; Jean-Xavier, Celine/0000-0003-0500-1099 FU Intramural NIH HHS NR 47 TC 55 Z9 56 U1 1 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 JUL 3 PY 2007 VL 104 IS 27 BP 11477 EP 11482 DI 10.1073/pnas.0704832104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 188DT UT WOS:000247900000063 PM 17592145 ER PT J AU Burroughs, AM Balaji, S Iyer, LM Aravind, L AF Burroughs, A. Maxwell Balaji, S. Iyer, Lakshminarayan M. Aravind, L. TI Small but versatile: the extraordinary functional and structural diversity of the beta-grasp fold SO BIOLOGY DIRECT LA English DT Review ID MULTIPLE SEQUENCE ALIGNMENT; PROTEIN CONJUGATION SYSTEM; TRANSFER-RNA SYNTHETASES; CASPASE-ACTIVATED DNASE; UBIQUITIN-LIKE PROTEIN; X-RAY CRYSTALLOGRAPHY; INITIATION-FACTOR IF3; NUCLEAR-PORE COMPLEX; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI AB Background: The beta-grasp fold (beta-GF), prototyped by ubiquitin (UB), has been recruited for a strikingly diverse range of biochemical functions. These functions include providing a scaffold for different enzymatic active sites ( e. g. NUDIX phosphohydrolases) and iron- sulfur clusters, RNA- soluble- ligand and co- factor- binding, sulfur transfer, adaptor functions in signaling, assembly of macromolecular complexes and post- translational protein modification. To understand the basis for the functional versatility of this small fold we undertook a comprehensive sequence- structure analysis of the fold and developed a natural classification for its members. Results: As a result we were able to define the core distinguishing features of the fold and numerous elaborations, including several previously unrecognized variants. Systematic analysis of all known interactions of the fold showed that its manifold functional abilities arise primarily from the prominent beta- sheet, which provides an exposed surface for diverse interactions or additionally, by forming open barrel- like structures. We show that in the beta- GF both enzymatic activities and the binding of diverse co- factors ( e. g. molybdopterin) have independently evolved on at least three occasions each, and iron- sulfur- cluster- binding on at least two independent occasions. Our analysis identified multiple previously unknown large monophyletic assemblages within the beta- GF, including one which unifies versions found in the fasciclin- 1 superfamily, the ribosomal protein L25, the phosphoribosyl AMP cyclohydrolase ( Hisl) and glutamine synthetase. We also uncovered several new groups of beta- GF domains including a domain found in bacterial flagellar and fimbrial assembly components, and 5 new UB- like domains in the eukaryotes. Conclusion: Evolutionary reconstruction indicates that the beta- GF had differentiated into at least 7 distinct lineages by the time of the last universal common ancestor of all extant organisms, encompassing much of the structural diversity observed in extant versions of the fold. The earliest beta- GF members were probably involved in RNA metabolism and subsequently radiated into various functional niches. Most of the structural diversification occurred in the prokaryotes, whereas the eukaryotic phase was mainly marked by a specific expansion of the ubiquitin- like beta- GF members. The eukaryotic UB superfamily diversified into at least 67 distinct families, of which at least 19 - 20 families were already present in the eukaryotic common ancestor, including several protein and one lipid conjugated forms. Another key aspect of the eukaryotic phase of evolution of the beta- GF was the dramatic increase in domain architectural complexity of proteins related to the expansion of UB- like domains in numerous adaptor roles. Reviewers: This article was reviewed by Igor Zhulin, Arcady Mushegian and Frank Eisenhaber. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Boston Univ, Bioinformat Program, Boston, MA 02215 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM burrough@ncbi.nlm.nih.gov; sbalaji@ncbi.nlm.nih.gov; lakshmin@ncbi.nlm.nih.gov; aravind@ncbi.nlm.nih.gov NR 130 TC 92 Z9 94 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD JUL 2 PY 2007 VL 2 AR 18 DI 10.1186/1745-6150-2-18 PG 28 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 202TV UT WOS:000248927600001 PM 17250770 ER PT J AU Bi, LL Pan, G Atkinson, TP Zheng, LX Dale, JK Makris, C Reddy, V McDonald, JM Siegel, RM Puck, JM Lenardo, MJ Straus, SE AF Bi, Lilia L. Pan, George Atkinson, T. Prescott Zheng, Lixin Dale, Janet K. Makris, Christopher Reddy, Vishnu McDonald, Jay M. Siegel, Richard M. Puck, Jennifer M. Lenardo, Michael J. Straus, Stephen E. TI Dominant inhibition of Fas ligand-mediated apoptosis due to a heterozygous mutation associated with autoimmune lymphoproliferative syndrome (ALPS) Type Ib SO BMC MEDICAL GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; GENE POLYMORPHISMS; BREAST-CANCER; T-LYMPHOCYTES; DISEASE; DEFECTS; VARIANT; CELLS; CASPASE-10; FAMILIES AB Background: Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of lymphocyte homeostasis and immunological tolerance due primarily to genetic defects in Fas (CD95/APO-1; TNFRSF6), a cell surface receptor that regulates apoptosis and its signaling apparatus. Methods: Fas ligand gene mutations from ALPS patients were identified through cDNA and genomic DNA sequencing. Molecular and biochemical assessment of these mutant Fas ligand proteins were carried out by expressing the mutant FasL cDNA in mammalian cells and analysis its effects on Fas- mediated programmed cell death. Results: We found an ALPS patient that harbored a heterozygous A530G mutation in the FasL gene that replaced Arg with Gly at position 156 in the protein's extracellular Fas-binding region. This produced a dominant-interfering FasL protein that bound to the wild-type FasL protein and prevented it from effectively inducing apoptosis. Conclusion: Our data explain how a naturally occurring heterozygous human FasL mutation can dominantly interfere with normal FasL apoptotic function and lead to an ALPS phenotype, designated Type Ib. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. NIAMS, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. Univ Alabama, Dept Pediat, Birmingham, AL 35294 USA. Birmingham Vet Adm Med Ctr, Birmingham, AL USA. RP Bi, LL (reprint author), NIAID, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bi@cber.fda.gov; gpan@uab.edu; PAtkinson@peds.uab.edu; LZHENG@niaid.nih.gov; JDALE@niaid.nih.gov; cmakris@uab.edu; vreddy@uab.edu; mcdonald@uab.edu; SiegelR@mail.nih.gov; puckj@peds.ucsf.edu; lenardo@nih.gov; LZHENG@niaid.nih.gov RI Siegel, Richard/C-7592-2009; OI Siegel, Richard/0000-0001-5953-9893; Reddy, Vishnu/0000-0001-5474-3289 FU Intramural NIH HHS NR 40 TC 36 Z9 36 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD JUL 2 PY 2007 VL 8 AR 41 DI 10.1186/1471-2350-8-41 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 196KF UT WOS:000248479500001 PM 17605793 ER PT J AU Romanowska, M Ostrowska, M Komoszynski, MA AF Romanowska, Malgorzata Ostrowska, Marta Komoszynski, Michal A. TI Adenosine ecto-deaminase (ecto-ADA) from porcine cerebral cortex synaptic membrane SO BRAIN RESEARCH LA English DT Article DE ecto-adenosine; adenosine ecto-deaminase; central nervous system; synaptosomes ID CENTRAL-NERVOUS-SYSTEM; A(1) RECEPTORS; BRAIN CORTEX; RAT-BRAIN; PURIFICATION; CELLS; INHIBITION; NEURONS; DESENSITIZATION; CHROMATOGRAPHY AB We have purified and investigated the role of adenosine ecto-deaminase (ecto-ADA) in porcine brain synaptic membranes and found a low activity of ecto-ADA in synaptic preparations from the cerebral cortex, hippocampus, striatum and medulla oblongata in the presence of purine transport inhibitors (NBTI, dipyridamole and papaverine). The purification procedure with affinity chromatography on epoxy-Toyopearl gel/purine riboside column as a crucial step of purification allowed a 214-fold purification of synaptic ecto-ADA with a yield of 30%. Gel filtration chromatography revealed a molecular mass estimated at 42.4 +/- 3.9 kDa. The enzyme had a broad optimum pH and was not affected by mono- and divalent cations. Ecto-ADA revealed a low affinity to adenosine (Ado) and 2'-deoxyadenosine (2'-dAdo) (K-M=286.30 +/- 40.38 mu M and 287.14 +/- 46.50 mu M, respectively). We compared the affinity of ecto-ADA to the substrates with the physiological and pathological concentrations of the extracellular Ado in brains that do not exceed a low micromolar range even during ischemia. and hypoxia, and with the affinity of adenosine receptors to Ado not exceeding a low nanomolar (A(1) and A(2A) receptors) or low micromolar (A(2B) and A(3)) range. Taken together, our data suggest that the role of synaptic ecto-ADA in the regulation of the ecto-Ado level in the brain and in the termination of adenosine receptor signaling is questionable. The porcine brain synapses must have other mechanisms for the ecto-Ado removal from the synaptic cleft and synaptic ecto-ADA may also play an extra-enzymatic role in cell adhesion and non-enzymatic regulation of adenosine receptor activity. (c) 2007 Elsevier B.V. All rights reserved. C1 Nicholas Copernicus Univ, Fac Biol & Earth Sci, Dept Biochem, PL-87100 Torun, Poland. RP Romanowska, M (reprint author), NCI, Lab Comprehens Carcinogenesis, Cellular Pathogenesis Sect, Bldg 538,Room 206, Frederick, MD 21702 USA. EM malgromanowska@interia.pl NR 47 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD JUL 2 PY 2007 VL 1156 BP 1 EP 8 DI 10.1016/j.brainres.2007.04.037 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 193EL UT WOS:000248257000001 PM 17499224 ER PT J AU Karbowski, M Neutzner, A Youle, RJ AF Karbowski, Mariusz Neutzner, Albert Youle, Richard J. TI The mitochondrial E3 ubiquitin ligase MARCH5 is required for Drp1 dependent mitochondrial division SO JOURNAL OF CELL BIOLOGY LA English DT Article ID DYNAMIN-RELATED GTPASE; WD REPEAT PROTEIN; SACCHAROMYCES-CEREVISIAE; MAMMALIAN-CELLS; OUTER-MEMBRANE; NMR STRUCTURE; FISSION; APOPTOSIS; FUSION; DNM1P AB We identify a mitochondrial E3 ubiquitin ligase, MARCH5, as a critical regulator of mitochondrial fission. MARCH5 RING mutants and MARCH5 RNA interference induce an abnormal elongation and interconnection of mitochondria indicative of an inhibition of mitochondrial division. The aberrant mitochondrial phenotypes in MARCH5 RING mutant-expressing cells are reversed by ectopic expression of Drp1, but not another mitochondrial fission protein Fis1. Moreover, as indicated by abnormal clustering and mitochondrial accumulation of Drp1, as well as decreased cellular mobility of YFP-Drp1 in cells expressing MARCH5 RING mutants, MARCH5 activity regulates the subcellular trafficking of Drp1, likely by impacting the correct assembly at scission sites or the disassembly step of fission complexes. Loss of this activity may account for the observed mitochondrial division defects. Finally, MARCH5 RING mutants and endogenous Drp1, but not wild-type MARCH5 or Fis1, co-assemble into abnormally enlarged clusters in a Drp1 GTPase-dependent manner, suggesting molecular interactions among these proteins. Collectively, our data suggest a model in which mitochondrial division is regulated by a MARCH5 ubiquitin-dependent switch. C1 NINDS, NIH, Surg Neurol Branch, Bethesda, MD 20852 USA. Univ Maryland, Inst Biotechnol, Ctr Med Biotechnol, Baltimore, MD 21201 USA. RP Youle, RJ (reprint author), NINDS, NIH, Surg Neurol Branch, Bethesda, MD 20852 USA. EM youler@ninds.nih.gov OI Neutzner, Albert/0000-0001-9254-5558 FU Intramural NIH HHS NR 49 TC 228 Z9 236 U1 1 U2 9 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 JUL 2 PY 2007 VL 178 IS 1 BP 71 EP 84 DI 10.1083/jcb.200611064 PG 14 WC Cell Biology SC Cell Biology GA 187QX UT WOS:000247864300008 PM 17606867 ER PT J AU Xu, X Meier-Schellersheim, M Yan, J Jin, T AF Xu, Xuehua Meier-Schellersheim, Martin Yan, Jianshe Jin, Tian TI Locally controlled inhibitory mechanisms are involved in eukaryotic GPCR-mediated chemosensing SO JOURNAL OF CELL BIOLOGY LA English DT Article ID DIRECTIONAL CELL-MOVEMENT; CAMP SIGNALING RESPONSE; CYCLIC 3',5'-AMP RELAY; DICTYOSTELIUM-DISCOIDEUM; CHEMOTACTIC CELLS; LEADING-EDGE; LIVING CELLS; BETA-GAMMA; G-PROTEINS; POLARITY AB G protein-coupled receptor (GPCR) signaling mediates a balance of excitatory and inhibitory activities that regulate Dictyostelium chemosensing to cAMP. The molecular nature and kinetics of these inhibitors are unknown. We report that transient CAMP stimulations induce PIP3 responses without a refractory period, suggesting that GPCR-mediated inhibition accumulates and decays slowly. Moreover, exposure to CAMP gradients leads to asymmetric distribution of the inhibitory components. The gradients induce a stable accumulation of the PIP3 reporter PHCrac-GFP in the front of cells near the cAMP source. Rapid withdrawal of the gradient led to the re-association of G protein subunits, and the return of the PIP3 phosphatase PTEN and PHCrac-GFP to their pre-stimulus distribution. Reapplication of CAMP stimulation produces a clear PHCrac-GFP translocation to the back but not to the front, indicating that a stronger inhibition is maintained in the front of a polarized cell. Our study demonstrates a novel spatiotemporal feature of currently unknown inhibitory mechanisms acting locally on the PI3K activation pathway. C1 NIAID, NIH, Chemotaxis Signal Sect, Immunogenet Lab, Rockville, MD 20852 USA. NIAID, NIH, Immunol Lab, Program Syst Immunol & Infect Dis Modeling, Bethesda, MD 20892 USA. RP Jin, T (reprint author), NIAID, NIH, Chemotaxis Signal Sect, Immunogenet Lab, Rockville, MD 20852 USA. EM tjin@niaid.nih.gov FU Intramural NIH HHS NR 48 TC 37 Z9 38 U1 1 U2 5 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD JUL 2 PY 2007 VL 178 IS 1 BP 141 EP 153 DI 10.1083/jcb.200611096 PG 13 WC Cell Biology SC Cell Biology GA 187QX UT WOS:000247864300014 PM 17606871 ER PT J AU Bartlett, EJ Castano, A Surman, SR Collins, PL Skiadopoulos, MH Murphy, BR AF Bartlett, Emmalene J. Castano, Adam Surman, Sonja R. Collins, Peter L. Skiadopoulos, Mario H. Murphy, Brian R. TI Attenuation and efficacy of human parainfluenza virus type I (HPIVI) vaccine candidates containing stabilized mutations in the P/C and L genes SO VIROLOGY JOURNAL LA English DT Article ID L-POLYMERASE PROTEIN; ACUTE OTITIS-MEDIA; REVERSE GENETICS; INFLUENZA-A; HETEROLOGOUS PARAMYXOVIRUSES; RESPIRATORY VIRUSES; LIVE; REPLICATION; GENERATION; BOVINE AB Background: Two recombinant, live attenuated human parainfluenza virus type I (rHPIVI) mutant viruses have been developed, using a reverse genetics system, for evaluation as potential intranasal vaccine candidates. These rHPIVI vaccine candidates have two non-temperature sensitive (non-ts) attenuating (att) mutations primarily in the P/C gene, namely (CHNT553A)-H-R84G (two point mutations used together as a set) and C-Delta 170 ( a short deletion mutation), and two ts att mutations in the L gene, namely L-Y942A (a point mutation), and L Delta 1710-11 (a short deletion), the last of which has not been previously described. The latter three mutations were specifically designed for increased genetic and phenotypic stability. These mutations were evaluated on the HPIVI backbone, both individually and in combination, for attenuation, immunogenicity, and protective efficacy in African green monkeys (AGMs). Results: The rHPIVI mutant bearing the novel L Delta 1710-11 mutation was highly ts and attenuated in AGMs and was immunogenic and efficacious against HPIVI wt challenge. The rHPIVI-(CHNLY942A)-H-R84G/Delta 170-L-T553A and rHPIVI-(CHNL Delta 1710-11)-H-R84G/Delta 170-L-T553A vaccine candidates were highly ts, with shut-off temperatures of 38 C and 35 C, respectively, and were highly attenuated in AGMs. Immunization with rHPIVI-(CHNLY942A)-H-R84G/Delta 170-L-T553A protected against HPIVI wt challenge in both the upper and lower respiratory tracts. In contrast, rHPIVI-(CHNL Delta 1710-11)-H-R84G/Delta 170-L-T553A was not protective in AGMs due to over-attenuation, but it is expected to replicate more efficiently and be more immunogenic in the natural human host. Conclusion: The rHPIVI-(CHNLY942A)-H-R84G/Delta 170-L-T553A and rHPIVI-C-R84G/Delta 170HN(T553A)L(Delta 1710-11) vaccine candidates are clearly highly attenuated in AGMs and clinical trials are planned to address safety and immunogenicity in humans. C1 NIAID, Lab Infectious Dis, Resp Viruses Sect, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Bartlett, EJ (reprint author), NIAID, Lab Infectious Dis, Resp Viruses Sect, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM ebartlett@niaid.nih.gov; adam.castano@gmail.com; SBarbagallo@niaid.nih.gov; PCOLLINS@niaid.nih.gov; mskiadopoulos@niaid.nih.gov; bmurphy@niaid.nih.gov FU Intramural NIH HHS NR 32 TC 16 Z9 16 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD JUL 2 PY 2007 VL 4 AR 67 DI 10.1186/1743-422X-4-67 PG 13 WC Virology SC Virology GA 198SN UT WOS:000248647900001 PM 17605811 ER PT J AU Ouimet, MC Brown, TG Nadeau, L Lepage, M Pelletier, M Couture, S Tremblay, J Legault, L Dongier, M Gianoulakis, C Kin, NMKNY AF Ouimet, Marie Claude Brown, Thomas G. Nadeau, Louise Lepage, Martin Pelletier, Marc Couture, Sophie Tremblay, Jacques Legault, Lucie Dongier, Maurice Gianoulakis, Christina Kin, N. M. K. Ng Ying TI Neurocognitive characteristics of DUI recidivists SO ACCIDENT ANALYSIS AND PREVENTION LA English DT Article DE driving while impaired; neurocognitive function; neuropsychology; assessment; alcohol ID COGNITIVE IMPAIRMENT; TIMELINE FOLLOWBACK; PERSONALITY-TRAITS; ALCOHOL DEPENDENCE; SELF-REGULATION; DWI OFFENDERS; INDIVIDUALS; RELIABILITY; PERFORMANCE; PREVALENCE AB Individuals who drive under the influence (DUI) of alcohol may be at greater risk for neurocognitive impairment because of their exposure to multiple sources of neurological risk. This could contribute to the persistence of DUI behaviour and influence the effectiveness of remedial interventions. The objectives of this study were to clarify the neurocognitive characteristics of DUI recidivists and the nature of potential impairments, and to explore relationships between these characteristics and the frequency of past DUI convictions. One hundred male recidivists were evaluated for visuospatial constructional abilities and visual memory, verbal fluency, attention skills, cognitive flexibility, spatial planning, and verbal and movement inhibition. Results indicated that a majority of recidivists showed signs of neurocognitive impairment on several dimensions. Impairment was most marked on visuospatial constructional abilities and visual memory. In contrast to previous studies, no participants were found to have impulse control problems. Measures of memory and cognitive efficiency were significantly associated with the frequency of past convictions. Finally, exploratory analyses of two potential sources of impairment, alcohol exposure and head trauma, suggested the role of excessive alcohol use as the most obvious associated factor. Overall, the findings indicate that neurocognitive impairments are a common feature in recidivists and may contribute to DUI persistence. Development of a DUI-specific neurocognitive assessment and greater understanding of how neurocognitive status influences DUI risk could lead to remediation strategies better adapted to the individual characteristics of recidivists. (c) 2006 Elsevier Ltd. All rights reserved. C1 Douglas Hosp, Res Ctr, Addict Res Program, Verdun, PQ H4H 1R3, Canada. NICHHD, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20892 USA. McGill Univ, Dept Psychiat, Montreal, PQ, Canada. Pavillon Foster Addict Treatment Program, St Philippe De Laprairie, PQ, Canada. Univ Montreal, Dept Psychol, Montreal, PQ H3C 3J7, Canada. RP Brown, TG (reprint author), Douglas Hosp, Res Ctr, Addict Res Program, 6875 Lasalle Blvd,Perry 4, Verdun, PQ H4H 1R3, Canada. EM thomas.brown@mcgill.ca NR 55 TC 16 Z9 16 U1 4 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0001-4575 J9 ACCIDENT ANAL PREV JI Accid. Anal. Prev. PD JUL PY 2007 VL 39 IS 4 BP 743 EP 750 DI 10.1016/j.aap.2006.11.005 PG 8 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA 186JU UT WOS:000247775800011 PM 17229395 ER PT J AU Wang, JW Wlodawer, A Dauter, Z AF Wang, Jiawei Wlodawer, Alexander Dauter, Zbigniew TI What happens when the signs of anomalous differences or the handedness of substructure are inverted? SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article AB Proper solution of a macromolecular crystal structure based on anomalous scattering and/or isomorphous differences requires that the anomalous differences in reflection amplitudes be measured properly and that the correct enantiomer of the substructure be selected. If this information is wrong then the resulting electron-density maps will not show the correct structural features, but the reflection phases and map features will be related to the correct ones in a specific way. This text aims to explain how misinterpretation of the Bijvoet differences or of the substructure affects the resulting phases and electron -density maps. C1 Argonne Natl Lab, Natl Canc Inst, MCL, Synchrotron Radiat Res Sect, Argonne, IL 60439 USA. SAIC Federick Inc, Basic Res Program, Argonne Natl Lab, Argonne, IL 60439 USA. NCI, MCL, Prot Struct Sect, Frederick, MD 21702 USA. RP Dauter, Z (reprint author), Argonne Natl Lab, Natl Canc Inst, MCL, Synchrotron Radiat Res Sect, 9700 S Cass Ave, Argonne, IL 60439 USA. EM dauter@anl.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 11 TC 5 Z9 5 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD JUL PY 2007 VL 63 BP 751 EP 758 DI 10.1107/S0907444907025620 PN 7 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 189HX UT WOS:000247981100001 PM 17582166 ER PT J AU Pequegnat, W Rosser, BRS Bowen, AM Bull, SS DiClemente, RJ Bockting, WO Elford, J Fishbein, M Gurak, L Horvath, K Konstan, J Noar, SM Ross, MW Sherr, L Spiegel, D Zimmerman, R AF Pequegnat, Willo Rosser, B. R. Simon Bowen, Anne M. Bull, Sheana S. DiClemente, Ralph J. Bockting, Walter O. Elford, Jonathan Fishbein, Martin Gurak, Laura Horvath, Keith Konstan, Joseph Noar, Seth M. Ross, Michael W. Sherr, Lorraine Spiegel, David Zimmerman, Rick TI Conducting Internet-based HIV/STD prevention survey research: Considerations in design and evaluation SO AIDS AND BEHAVIOR LA English DT Review DE HIV/STD prevention; Internet methodology ID SEXUALLY-TRANSMITTED-DISEASES; HEPATITIS-B VACCINATION; WORLD-WIDE-WEB; HIV PREVENTION; LATINO MEN; PSYCHOLOGICAL-RESEARCH; HEALTH INFORMATION; RISK BEHAVIORS; REAL-LIFE; GAY MEN AB The aim of this paper is to advance rigorous Internet-based HIV/STD Prevention quantitative research by providing guidance to fellow researchers, faculty supervising graduates, human subjects' committees, and review groups about some of the most common and challenging questions about Internet-based HIV prevention quantitative research. The authors represent several research groups who have gained experience conducting some of the first Internet-based HIV/STD prevention quantitative surveys in the US and elsewhere. Sixteen questions specific to Internet-based HIV prevention survey research are identified. To aid rigorous development and review of applications, these questions are organized around six common criteria used in federal review groups in the US: significance, innovation, approach (broken down further by research design, formative development, procedures, sampling considerations, and data collection); investigator, environment and human subjects' issues. Strategies promoting minority participant recruitment, minimizing attrition, validating participants, and compensating participants are discussed. Throughout, the implications on budget and realistic timetabling are identified. C1 Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55410 USA. NIMH, Ctr Mental Hlth Res AIDS, Bethesda, MD 20892 USA. Univ Wyoming, Dept Psychol, Laramie, WY 82071 USA. Univ Colorado, Colorado Hlth Outcomes Program, Denver, CO 80202 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Emory Univ, Sch Publ Hlth, Dept Behav Sci & Hlth Educ, Atlanta, GA 30322 USA. Univ Minnesota, Dept Family Med & Community Hlth, Sch Med, Minneapolis, MN 55410 USA. City Univ London, Inst Hlth Sci, London EC1V 0HB, England. Univ Penn, Annenberg Publ Policy Ctr, Annenberg Sch Commun, Philadelphia, PA 19104 USA. Univ Minnesota, Dept Sci & Tech Writing, Coll Agr Food Sci & Environm Studies, St Paul, MN 55108 USA. Univ Minnesota, Inst Technol, Dept Comp Sci & Engn, Minneapolis, MN USA. Univ Kentucky, Dept Commun, Lexington, KY 40506 USA. Univ Texas, Sch Publ Hlth, Ctr Hlth Promot & Prevent Res, Houston, TX USA. UCL, Dept Primary Care & Populat Sci, RFUCMS, London, England. Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA USA. RP Rosser, BRS (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN 55410 USA. EM rosser@umn.edu NR 78 TC 87 Z9 87 U1 3 U2 20 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD JUL PY 2007 VL 11 IS 4 BP 505 EP 521 DI 10.1007/s10461-006-9172-9 PG 17 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 178ST UT WOS:000247241100001 PM 17053853 ER PT J AU Joglekar, N Joshi, S Kakde, M Fang, G Cianciola, M Reynolds, S Mehendale, S AF Joglekar, N. Joshi, S. Kakde, M. Fang, G. Cianciola, M. Reynolds, S. Mehendale, S. CA HPTN 047 Protocol Team TI Acceptability of PRO2000 vaginal gel among HIV un-infected women in Pune, India SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article ID PHASE-I; PRO-2000 GEL; MICROBICIDE; TRIAL AB Acceptability of PRO2000 Gel, a candidate vaginal microbicide, among participants of its Phase I safety study in Pune, India is reported here. Forty-two eligible women were enrolled in a study requiring twice daily intra-vaginal product use for 14 consecutive days between menses. Acceptability was assessed at study exit through structured questionnaires among 41 participants who completed the product use, and five focus group discussions involving 31 study participants. The participants generally liked the product (40/41, 97.2%), especially its colour (40, 97.2%) and consistency (35, 85.3%). Thirty-four participants reported sexual intercourse within one hour of product use, at least once during the study period and sexual pleasure was reported to be better or unaffected among (30, 88.2%) participants. Nearly 70% did not like its smell and mentioned preference for a product that would be unnoticeable to the male partner. Participating women were concerned about privacy in usage and storage of the product. Acceptability of PRO2000 vaginal gel was good, but its smell will have to be improved. Counselling to address women's concerns about privacy and storage will be crucial. Women's preference for unnoticeable product indicates their empowerment and willingness to accept female-controlled options for HIV prevention. C1 Indian Council Med Res, Natl AIDS Res Inst, Pune 411026, Maharashtra, India. NIAID, NIH, Bethesda, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. RP Joglekar, N (reprint author), Indian Council Med Res, Natl AIDS Res Inst, G-73,MIDC,Post Box 1895, Pune 411026, Maharashtra, India. EM joglekarneelam@yahoo.com NR 15 TC 31 Z9 32 U1 0 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD JUL PY 2007 VL 19 IS 6 BP 817 EP 821 DI 10.1080/09540120601133576 PG 5 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 187SW UT WOS:000247869800014 PM 17573603 ER PT J AU Chougnet, CA Shearer, GM AF Chougnet, Claire A. Shearer, Gene M. TI Regulatory T cells (T-reg) and HIV/AIDS: Summary of the September 7-8, 2006 Workshop SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; TRANSCRIPTION FACTOR FOXP3; DENDRITIC CELLS; TGF-BETA; RETROVIRAL INFECTION; CUTTING EDGE; IN-VITRO; CD4(+); INDUCTION AB A workshop entitled "Regulatory T cells (T-reg) and HIV/AIDS" was held in Cincinnati, OH, September 7-8, 2006. This workshop was the first completely dedicated to T-reg in HIV infection, and gathered investigators working on different aspects of T-reg biology, and on HIV pathogenesis. We report here the major topics of discussion of this workshop, the goal of which was to summarize what is known and not known about the role of T-reg in HIV immune responses and pathogenesis; and to foster discussion on the means of manipulating Treg in HIV-infected subjects. Workshop participants also debated the research priorities in the field, which emerged as follows: (1) to arrive at a consensus on T-reg definition and to standardize assays aimed at characterizing T-reg number and function; (2) to study T-reg biology in tissues, notably in mucosal tissues, and at different stages of infection; (3) to examine Treg function in vivo in animal models, as well as to test strategies to target or modulate T-reg cell function in these models; (4) to investigate the effect of viral factors on T,eg biology, and conversely to study whether T-reg activity affects the level of HIV replication; (5) to conduct longitudinal studies of T-reg number and function; and (6) to determine the effect of coinfections on T-reg biology. C1 Cincinnati Childrens Hosp Res Fdn, Div Mol Immunol, Cincinnati, OH 45229 USA. Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Chougnet, CA (reprint author), Cincinnati Childrens Hosp Med Ctr, Div Mol Immunol ML 7021, 3333 Burnet Ave, Cincinnati, OH 45229 USA. NR 53 TC 17 Z9 17 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD JUL PY 2007 VL 23 IS 7 BP 945 EP 952 DI 10.1089/aid.2006.0259 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 197GG UT WOS:000248542000015 PM 17678480 ER PT J AU Greenberger, PA Yucha, CB Janson, S Huss, K AF Greenberger, Paul A. Yucha, Carolyn B. Janson, Susan Huss, Karen TI Using rare diseases as models for biobehavioral research: Allergic bronchopulmonary aspergillosis SO ALLERGY AND ASTHMA PROCEEDINGS LA English DT Article DE ABPA; aspergillosis; biobehavioral; disease model; interdisciplinary; natural history; prevalence; staging; susceptibility; treatment ID CYSTIC-FIBROSIS; ASTHMA; PREVALENCE; FUMIGATUS; DIAGNOSIS; PATIENT; ABPA; BRONCHIECTASIS; CRITERIA; CHILDREN AB Biobehavioral science explores links between biological, psychosocial, and behavioral factors and health. Maintaining positive health outcomes over time and across a variety of populations and settings requires understanding interactions among biological, behavioral, and social risk factors as well as other variables that influence behavior. Some barriers to biobehavioral research are related to performing biobehavioral research along the natural history of an illness, limitations in existing methodologies to assess the biological impact of behavior, the unknowns relating to impact of behavior on biology, and lack of valid and reliable biobehavioral methods to assess outcomes. A rare disease, such as allergic bronchopulmonary aspergillosis (ABPA) can be used as a model of biobehavioral research. ABPA complicates asthma and cystic fibrosis. It is a hypersensitivity reaction to Aspergillus fumigatus in most cases. ABPA can be classified into five stages: acute, remission, exacerbation, steroid-dependent asthma, and fibrotic or end stage. Because of its rarity, there can be delays in diagnosis. Treatment has used oral corticosteroids and antifungal agents in addition to management of asthma or cystic fibrosis. The National Institute Of Nursing Research held an invitational 2-day working group meeting on July 15-16, 2004 with biobehavioral, biological, and immunologic science experts to examine current knowledge of biobehavioral research and to provide recommendations for additional research. Thefocus was on biobehavioral methods of measurement and analysis with interdisciplinary/biobehavioral approaches. This article is an outcome of this meeting. C1 Northwestern Univ, Feinberg Sch Med, Dept Med, Div Allergy Immunol, Chicago, IL 60611 USA. Univ Calif San Francisco, Dept Community Hlth Syst, San Francisco, CA 94143 USA. Univ Nevada, Coll Nursing, Las Vegas, NV 89154 USA. Natl Inst Nursing Res, Off Extramural Programs, NIH, Bethesda, MD USA. RP Greenberger, PA (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Med, Div Allergy Immunol, 676 N St Clair,14018, Chicago, IL 60611 USA. EM p-greenberger@northwestern.edu NR 37 TC 3 Z9 4 U1 0 U2 3 PU OCEAN SIDE PUBLICATIONS INC PI PROVIDENCE PA 95 PITMAN ST, PROVIDENCE, RI 02906 USA SN 1088-5412 J9 ALLERGY ASTHMA PROC JI Allergy Asthma Proc. PD JUL-AUG PY 2007 VL 28 IS 4 BP 489 EP 496 DI 10.2500/aap.2007.28.3023 PG 8 WC Allergy SC Allergy GA 204DV UT WOS:000249024700017 PM 17883921 ER PT J AU Morgan, MD Mielke, MM O'Brien, R Troncoso, JC Zonderman, AB Lyketsos, CG AF Morgan, Melissa D. Mielke, Michelle M. O'Brien, Richard Troncoso, Juan C. Zonderman, Alan B. Lyketsos, Constantine G. TI Rates of depression in individuals with Pathologic but not clinical Alzheimer disease are lower than those in individuals without the disease: Findings from the Baltimore longitudinal study on aging (BLSA) SO ALZHEIMER DISEASE & ASSOCIATED DISORDERS LA English DT Article DE Alzheimer disease; dementia; depression; autopsy ID LATE-LIFE DEPRESSION; MAJOR DEPRESSION; HIPPOCAMPAL ATROPHY; COGNITIVE DECLINE; SYMPTOMS; DEMENTIA; RISK; AD; ASSOCIATION; NETHERLANDS AB The prevalence of major depression is increased in Alzheimer disease (AD), but currently the basis of this association remains unclear. The present study examined rates of depression in 4 groups of participants with postmortem examination from the Baltimore Longitudinal Study of Aging: (1) cognitively normal controls with no Alzheimer pathology, (2) cognitively normal individuals with Alzheimer pathology, (3) individuals with mild cognitive impairment plus Alzheimer pathology, (4) individuals with clinical diagnoses of dementia plus Alzheimer pathology. Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression Scale. Individuals with Alzheimer pathology but no cognitive decline before death had significantly lower rates of depression than cognitively normal controls with no Alzheimer pathology and individuals with Alzheimer pathology plus clinical diagnoses of dementia. These findings suggest that depression is a risk factor for AD in the presence of AD pathology, but depression is not a risk factor for AD pathology. C1 Johns Hopkins Univ, Dept Psychiat, Baltimore, MD 21224 USA. NIA, Baltimore, MD 21224 USA. RP Lyketsos, CG (reprint author), Johns Hopkins Univ, Dept Psychiat, Johns Hopkins Baybiew,4840 E Ave,A4 Ctr,Room 458, Baltimore, MD 21224 USA. EM kostas@jhmi.edu OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS; NIA NIH HHS [P50 AG005146-25, P50 AG005146-25S1]; PHS HHS [5 PO1 AGO5146] NR 40 TC 7 Z9 7 U1 3 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0893-0341 J9 ALZ DIS ASSOC DIS JI Alzheimer Dis. Assoc. Dis. PD JUL-SEP PY 2007 VL 21 IS 3 BP 199 EP 204 DI 10.1097/WAD.0b013e3181461932 PG 6 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 208IQ UT WOS:000249313400002 PM 17804951 ER PT J AU Ruggiero, C Cherubini, A Miller, E Maggio, M Najjar, SS Lauretani, F Bandinelli, S Senin, U Ferrucci, L AF Ruggiero, Carmelinda Cherubini, Antonio Miller, Edgar, III Maggio, Marcello Najjar, Sarner S. Lauretani, Fulvio Bandinelli, Stefania Senin, Umberto Ferrucci, Luigi TI Usefulness of uric acid to predict changes in c-reactive protein and interleukin-6 in 3-year period in Italians aged 21 to 98 years SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CHRONIC HEART-FAILURE; CARDIOVASCULAR-DISEASE; RISK; HYPERTENSION; MORTALITY; MEN; ALLOPURINOL; INCHIANTI; PROGRAM; MARKERS AB The role of uric acid (UA) in the process of atherothrombosis is controversial. Although serum UA has powerful antioxidant properties, epidemiological studies showed that UA was a risk factor for cardiovascular diseases and was positively associated with proinflammatory markers. Relations between baseline UA and changes in UA circulating levels with C-reactive protein (CRP) and interleukin-6 (IL-6) after 3 years of follow-up in a cohort of 892 Italian men and women aged 21 to 98 years was investigated. Subjects had complete baseline and follow-up data for UA, inflammatory markers, and covariates. An autoregressive approach was used to study such a relation. In adjusted analyses, baseline UA and changes in UA predicted a 3-year change in CRP (p = 0.028), but not IL-6 (p = 0.101). The relation between UA and CRP persisted after adjustment for baseline IL-6. Subjects with high UA at baseline had a progressively higher probability of developing clinically relevant increased IL-6 (>2.5 pg/ml) and CRP (>3 mg/L) during 3 years. In conclusion, our study suggests that in a population-based cohort, baseline UA and changes in circulating UA during 3 years of follow-up predict changes in circulating CRP independent of relevant confounders, including baseline IL-6. (C) 2007 Elsevier Inc. All rights reserved. C1 NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. NIA, Human Cardiovasc Studies Unit, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Univ Perugia, Sch Med, Dept Clin & Expt Med, Inst Gerontol & Geriatr, I-06100 Perugia, Italy. Tuscany Reg Hlth Agcy, Florence, Italy. ASF Geriatr Rehabil, Florence, Italy. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. EM FerrucciLu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016; OI Lauretani, Fulvio/0000-0002-5287-9972; Cherubini, Antonio/0000-0003-0261-9897 FU Intramural NIH HHS [Z99 AG999999]; NIA NIH HHS [N01-AG-821336, N01-AG-916413]; NIMHD NIH HHS [R01 MD009164] NR 30 TC 43 Z9 46 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD JUL 1 PY 2007 VL 100 IS 1 BP 115 EP 121 DI 10.1016/j.amjcard.2007.02.065 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 188LQ UT WOS:000247921800022 PM 17599452 ER PT J AU Purohit, V Abdelmalek, MF Barve, S Benevenga, NJ Halsted, CH Kaplowitz, N Kharbanda, KK Liu, QY Lu, SC McClain, CJ Swanson, C Zakhari, S AF Purohit, Vishnudutt Abdelmalek, Manal F. Barve, Shirish Benevenga, Norlin J. Halsted, Charles H. Kaplowitz, Neil Kharbanda, Kusunt K. Liu, Qi-Ying Lu, Shelly C. McClain, Craig J. Swanson, Christine Zakhari, Samir TI Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Review DE alcohol; betaine; S-adenosylmethionine; folate; liver disease ID ADENOSYL-L-METHIONINE; PHOSPHATIDYLETHANOLAMINE N-METHYLTRANSFERASE; ENDOPLASMIC-RETICULUM STRESS; ETHANOL-FED MICROPIG; RAT-LIVER; HEPATIC METHIONINE; TNF-ALPHA; NONALCOHOLIC STEATOHEPATITIS; HEPATOCELLULAR-CARCINOMA; ADENOSYLTRANSFERASE 1A AB This report is a summary of a symposium on the role of S-adenosylmethionine (SAM), betaine, and folate in the treatment of alcoholic liver disease (ALD), which was organized by the National Institute on Alcohol Abuse and Alcoholism in collaboration with the Office of Dietary Supplements and the National Center for Complementary and Alternative Medicine of the National Institutes of Health (Bethesda, MD) and held on 3 October 2005. SAM Supplementation may attenuate ALD by decreasing oxidative stress through the up-regulation of glutathione synthesis, reducing inflammation via the down-regulation of tumor necrosis factor-a and the up-regulation of interleukin-10 synthesis, increasing the ratio of SAM to S-adenosylhomocysteine (SAH), and inhibiting the apoptosis of normal hepatocytes and stimulating the apoptosis of liver cancer cells. Folate deficiency may accelerate or promote ALD by increasing hepatic homocysteine and SAH concentrations; decreasing hepatic SAM and glutathione concentrations and the SAM-SAH ratio; increasing cytochrome P4502E1 activation and lipid peroxidation; up-regulating endoplasmic reticulum stress markers, including sterol regulatory element-binding protein-1 and proapoptotic gene caspase-12; and decreasing global DNA methylation. Betaine may attenuate ALD by increasing the synthesis of SAM and, eventually, glutathione, decreasing the hepatic concentrations of homocysteine and SAH, and increasing the SAM-SAH ratio, which can trigger a cascade of events that lead to the activation of phosphatidylethanolamine methyltransferase, increased phosphatidylcholine synthesis, and formation of VLDL for the export of triacylglycerol from the liver to the circulation. Additionally, decreased concentrations of homocysteine can down-regulate endoplasmic reticulum stress, which leads to the attenuation of apoptosis and fatty acid synthesis. C1 NIAAA, Div Metab & Hlth Effects, Bethesda, MD USA. Duke Univ, Ctr Med, Div Gastroenterol Hepatol, Durham, NC 27706 USA. Univ Louisville, Dept Med, Louisville, KY 40292 USA. Univ Wisconsin, Dept Anim Sci, Madison, WI 53706 USA. Univ Calif Davis, Clin Nutr Res Unit, Genome & Biomed Sci Facil, Davis, CA 95616 USA. Univ So Calif, Keck Sch Med, Los Angeles, CA 90089 USA. VA Med Ctr, Liver Study Unit, Omaha, NE USA. Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. NIH, Off dietary Supplements, Bethesda, MD 20892 USA. RP Purohit, V (reprint author), 5635 Fishers Lane,Room 2035,MSC 9304, Bethesda, MD 20892 USA. EM vpurohit@mail.nih.gov FU NCCIH NIH HHS [R01 AT01576]; NIAAA NIH HHS [R01 AA014428, R01 AA014145, R37 AA010762, R01 AA014371, R01 AA010496, P50 AA11999, R01 AA015970, R01 AA012677, R01 AA013847]; NIDDK NIH HHS [R01 DK051719, P30 DK048522, R01 DK071765] NR 91 TC 84 Z9 97 U1 4 U2 17 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 JUL PY 2007 VL 86 IS 1 BP 14 EP 24 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 189IF UT WOS:000247981900005 PM 17616758 ER PT J AU Padayatty, SJ Doppman, JL Chang, R Wang, Y Gill, J Papanicolaou, DA Levine, M AF Padayatty, Sebastian J. Doppman, John L. Chang, Richard Wang, Yaohui Gill, John Papanicolaou, Dimitris A. Levine, Mark TI Human adrenal glands secrete vitamin C in response to adrenocorticotrophic hormone SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT 86th Annual Meeting of the Endocrine-Society CY JUN 12-15, 2004 CL New Orleans, LA SP Endocrine Soc DE vitamin C; adrenal gland; stress response; cortisol; paracrine secretion ID RECOMMENDED DIETARY ALLOWANCE; ASCORBIC-ACID; DEHYDROASCORBIC ACID; CHROMAFFIN GRANULES; PHARMACOKINETICS; CORTICOSTEROIDS; KINETICS; SYSTEMS; BLOOD; ACTH AB Background: When vitamin C intake is from foods, fasting plasma concentrations do not exceed 80 mu mol/L. We postulated that such tight control permits a paracrine function of vitamin C. Objective: The purpose of this study was to determine whether paracrine secretion of vitamin C from the adrenal glands occurs. Design: During diagnostic evaluation of 26 patients with hyperaldosteronism, we administered adrenocorticotrophic hormone intravenously and measured vitamin C and cortisol in adrenal and peripheral veins. Results: Adrenal vein vitamin C concentrations increased in all cases and reached a peak of 176 +/- 71 mu mol/L at 1-4 min, whereas the corresponding peripheral vein vitamin C concentrations were 35 +/- 15 mu mol/L (P < 0.0001). Mean adrenal vein vitamin C increased from 39 +/- 15 mu mol/L at 0 min, rose to 162 +/- 101 mu mol/L at 2 min, and returned to 55 +/- 16 mu mol/L at 15 min. Adrenal vein vitamin C release preceded the release of adrenal vein cortisol, which increased from 1923 +/- 2806 nmol/L at 0 min to 27 +/- 191 16 +/- 161 nmol/L at 15 min (P < 0.0001). Peripheral plasma cortisol increased from 250 +/- 119 nmol/L at 0 min to 506 +/- 189 nmol/L at 15 min (P < 0.0001). Conclusions: Adrenocorticotrophic hormone stimulation increases adrenal vein but not peripheral vein vitamin C concentrations. These data are the first in humans showing that hormone-regulated vitamin secretion occurs and that adrenal vitamin C paracrine secretion is part of the stress response. Tight control of peripheral vitamin C concentration is permissive of higher local concentrations that may have paracrine functions. C1 NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Hlth, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD USA. NHLBI, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, Bethesda, MD 20892 USA. RP Levine, M (reprint author), NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bldg 10,Room 4D52-MSC 1372, Bethesda, MD 20892 USA. EM markl@intra.niddk.nih.gov RI Padayatty, Sebastian/A-8581-2012 OI Padayatty, Sebastian/0000-0001-8758-3170 FU NIDDK NIH HHS [Z01 DK 54506] NR 18 TC 23 Z9 24 U1 0 U2 5 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 JUL PY 2007 VL 86 IS 1 BP 145 EP 149 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 189IF UT WOS:000247981900021 PM 17616774 ER PT J AU Wright, ME Lawson, KA Weinstein, SJ Albanes, D AF Wright, Margaret E. Lawson, Karla A. Weinstein, Stephanie J. Albanes, Demetrius TI Evidence-based medicine and vitamin E supplementation - Reply SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter ID BETA-CAROTENE; MORTALITY; CANCER C1 Univ Illinois, Coll Med, Dept Pathol, Chicago, IL 60612 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Wright, ME (reprint author), Univ Illinois, Coll Med, Dept Pathol, 840 S Wood St,Room 130, Chicago, IL 60612 USA. EM mewright@uic.edu RI Albanes, Demetrius/B-9749-2015 NR 7 TC 0 Z9 0 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 JUL PY 2007 VL 86 IS 1 BP 262 EP 263 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 189IF UT WOS:000247981900039 ER PT J AU Fisher, ER Land, SR Saad, RS Fisher, B Wickerham, DL Wang, MH Costantino, JP Wolmark, N AF Fisher, Edwin R. Land, Stephanie R. Saad, Reda S. Fisher, Bernard Wickerham, D. Lawrence Wang, Meihua Costantino, Joseph P. Wolmark, Norman TI Pathologic variables predictive of breast events in patients with ductal carcinoma in situ SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE breast; ductal carcinoma in situ; pathology; comedo necrosis ID SURGICAL ADJUVANT BREAST; INTRADUCTAL-CARCINOMA; RADIATION-THERAPY; PROTOCOL B-17; CANCER; LUMPECTOMY; FAILURE; UPDATE; DCIS AB Central pathology review of ductal carcinoma in situ from 1,456patients enrolled in National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-24 was performed to determine predictors for ipsilateral breast tumor recurrences and contralateral breast cancers. Findings after a median follow-up time of 10.5 years revealed ductal comedo necrosis, micropapillary histologic tumor type, and multifocality to be independent high riskjactorsfor ipsilateral breast tumor recurrence. Risk increasedfor slight comedo necrosis vs absent andfor moderate to marked comedo necrosis vs slight. The presence of a micropapillary tumor type and gross tumor size (2TO cm) were independently found as riskfactorsfor contralateral breast cancers. Although 4 7% of ipsilateral and 66% of contralateral events were invasive carcinomas, overall mortality was only 2.3%, a conundrum possibly related to the small size of the latter The similar predictive role of comedo necrosis in this study and that reported previouslyfrom NSABP B-1 7 (total of 2,079 patients) strongly supports its role as a simple high- risk predictor for ipsilateral breast tumor recurrences. C1 Allegheny Gen Hosp, Ctr Canc, Dept Human Oncol, Pittsburgh, PA 15212 USA. NSABP, Pittsburgh, PA USA. Allegheny Gen Hosp, NSABP Dept Pathol, W Penn Allegheny Hlth Syst, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, NSABP Biostat Ctr, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RP Fisher, ER (reprint author), Allegheny Gen Hosp, Ctr Canc, Dept Human Oncol, 5th Floor,320 E North Ave, Pittsburgh, PA 15212 USA. FU NCI NIH HHS [U24-CA-114732, U-10-CA 69651, U10-CA 12027] NR 20 TC 37 Z9 39 U1 0 U2 0 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD JUL PY 2007 VL 128 IS 1 BP 86 EP 91 DI 10.1309/WH9LA543NR76Y29J PG 6 WC Pathology SC Pathology GA 180VR UT WOS:000247394900007 PM 17580274 ER PT J AU Adams, KF Leltzmann, MF Albanes, D Kipnis, V Mouw, T Hollenbeck, A Schatzkin, A AF Adams, Kenneth F. Leltzmann, Michael F. Albanes, Demetrius Kipnis, Victor Mouw, Traci Hollenbeck, Al Schatzkin, Arthur TI Body mass and colorectal cancer risk in the NIH-AARP cohort SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body mass index; colonic neoplasms; colorectal neoplasms; humans; obesity; overweight; rectal neoplasms ID COLON-CANCER; PHYSICAL-ACTIVITY; RECTAL-CANCER; UNITED-STATES; ENERGY-BALANCE; US ADULTS; OBESITY; INDEX; WOMEN; WEIGHT AB in most studies, body mass index (BMI) has been associated with increased risk of colorectal or colon cancer in men, but the relation is weaker and less consistent for women, possibly because of interactions with age or hormone replacement therapy. The authors examined the relation between BMI and colorectal cancer incidence in a large, prospective US cohort of 307,708 men and 209,436 women from the NIH-AARP Diet and Health Study. During follow-up of the cohort from 1995 to 2000,2,314 cases of colorectal cancer were observed in men and 1,029 in women. BMI was related to increased risk of incident colon cancer, but not rectal cancer, for both men and women. For men, relative risks of colon cancer for a BMI of 18.5-< 23, 23-< 25, 25-< 27.5, 27.5-< 30, 30-< 32.5, 32.5-< 35, 35-< 40, and >= 40 kg/m(2) were 1.0 (referent), 1.11, 1.22, 1.44, 1.53, 1.57, 1.71, and 2.39, respectively (95% confidence interval: 1.59, 3.58; p-trend < 0.0005). Corresponding relative risks for women were 1.0, 1.20, 1.29, 1.31, 1.28, 1.13, 1.46, and 1.49 (95% confidence interval: 0.98, 2.25; p-trend = 0.02). BMI was related to colon cancer risk for younger (aged 50-66 years) but not older (aged 67-71 years) women. The association was not modified by hormone replacement therapy in women or physical activity in men or women. C1 NCI, Natl Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. NCI, Biometry Res Grp, Div Canc Prevent, NIH,Dept Hlth & Human Serv, Rockville, MD USA. AARP, Washington, DC USA. RP Adams, KF (reprint author), 6120 Execut Blvd, Rockville, MD 20852 USA. EM adamske@mail.nih.gov RI Albanes, Demetrius/B-9749-2015 NR 48 TC 52 Z9 55 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2007 VL 166 IS 1 BP 36 EP 45 DI 10.1093/aje/kwm049 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 182UV UT WOS:000247530400007 PM 17449892 ER PT J AU Ha, M Mabuchi, K Sigurdson, AJ Freedman, DM Linet, MS Doody, MM Hauptmann, M AF Ha, Mina Mabuchi, Kiyohiko Sigurdson, Alice J. Freedman, D. Michal Linet, Martha S. Doody, Michele Morin Hauptmann, Michael TI Smoking cigarettes before first childbirth and risk of breast cancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE breast neoplasms; reproduction; smoking ID RADIOLOGIC TECHNOLOGISTS; UNITED-STATES; PASSIVE SMOKING; WOMEN; HEALTH AB Inconsistent epidemiologic findings on cigarette smoking and female breast cancer risk may reflect insufficient assessment of smoking onset and amount relative to reproductive events. To determine the risk of breast cancer associated with smoking during different periods of reproductive life, the authors evaluated 906 incident breast cancer cases in a nationwide cohort of 56,042 female US radiologic technologists (1983-1998) who responded to two questionnaire surveys. After they accounted for age, birth cohort, and established breast cancer risk factors, smoking-related breast cancer risks differed by smoking during three reproductive time periods (p = 0.003), with a statistically significant 3% increase per pack-year of smoking between menarche and first childbirth (relative risk = 1.03, 95% confidence interval: 1.02, 1.05) and no significant association for smoking after first childbirth. Risk also increased with younger age at smoking initiation (p-trend = 0.06), after adjustment for pack-years of smoking before and after first childbirth, indicating an independent effect of age at smoking initiation. The findings from this study suggest that sensitivity of the female breast to tobacco carcinogens is increased during adolescence and early adulthood but decreases after first childbirth, when most breast tissue has terminally differentiated. C1 Dankook Univ, Coll Med, Dept Prevent Med, Cheonan 330714, Chungnam, South Korea. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Netherlands Canc Inst, Amsterdam, Netherlands. RP Ha, M (reprint author), Dankook Univ, Coll Med, Dept Prevent Med, San 29 Anseo Dong, Cheonan 330714, Chungnam, South Korea. EM minaha@dankook.ac.kr FU Intramural NIH HHS NR 17 TC 35 Z9 36 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2007 VL 166 IS 1 BP 55 EP 61 DI 10.1093/aje/kwm045 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 182UV UT WOS:000247530400009 PM 17426039 ER PT J AU Hsu, CC Chow, WH Boffetta, P Moore, L Zaridze, D Moukeria, A Janout, V Kollarova, H Bencko, V Navratilova, M Szeszenia-Dabrowska, N Mates, D Brennan, P AF Hsu, Charles C. Chow, Wong-Ho Boffetta, Paolo Moore, Lee Zaridze, David Moukeria, Anush Janout, Vladimir Kollarova, Helena Bencko, Vladimir Navratilova, Marie Szeszenia-Dabrowska, Neonilia Mates, Dana Brennan, Paul TI Dietary risk factors for kidney cancer in Eastern and Central Europe SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE carcinoma; renal cell; diet; dietary supplements; Europe; Europe; eastern; kidney neoplasms; risk factors ID RENAL-CELL CARCINOMA; ALCOHOL-CONSUMPTION; UNITED-STATES; POSTMENOPAUSAL WOMEN; NETHERLANDS COHORT; NUTRITION; MORTALITY; EPIDEMIOLOGY; VEGETABLES; SHANGHAI AB The authors examined the role of diet in the high-risk population of Central Europe among 1,065 incident kidney cancer cases and 1,509 controls in Russia, Romania, Poland, and the Czech Republic. They observed an increased association with kidney cancer for consumption of milk (odds ratio (OR) = 1.46, 95% confidence interval (Cl): 1.15, 1.84) and yogurt (OR = 1.34, 95% Cl: 1.07, 1.67), as well as all meat (OR = 1.27, 95% Cl: 1.06, 1.51 compared with the lowest tertile). High consumption of all vegetables (OR = 0.64, 95% Cl: 0.51, 0.80) and cruciferous vegetables (OR = 0.68, 95% Cl: 0.55, 0.84) was inversely associated with kidney cancer. In addition, high consumption of preserved vegetables increased the risk of kidney cancer (OR = 1.66, 95% Cl: 1.24, 2.21). Alcohol consumption did not appear to be associated with kidney cancer. This 1999-2003 study provides further evidence that diet may play a role in the development of kidney cancer, with a particularly strong protective association for high vegetable intake. The increased risk associated with dairy products, preserved vegetables, and red meat provides clues to the high rates of kidney cancer in this population. C1 Int Agcy Res Canc, F-69372 Lyon, France. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. Palacky Univ, Fac Med, Dept Prevent Med, CR-77147 Olomouc, Czech Republic. Charles Univ Prague, Inst Hyg & Epidemiol, Fac Med 1, Prague, Czech Republic. Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. Inst Occupat Med, Dept Epidemiol, Lodz, Poland. Inst Publ Hlth, Bucharest, Romania. RP Brennan, P (reprint author), Genet Epidemiol Grp, 150 Cours Albert Thomas, F-69008 Lyon, France. EM brennan@iarc.fr RI Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; OI mates, dana/0000-0002-6219-9807 NR 62 TC 41 Z9 45 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD JUL 1 PY 2007 VL 166 IS 1 BP 62 EP 70 DI 10.1093/aje/kwm043 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 182UV UT WOS:000247530400010 PM 17456477 ER PT J AU Hamilton, FA AF Hamilton, Frank A. TI Health care in minority patients with IBD SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Editorial Material ID DISPARITIES; DISEASE C1 NIDDK, MPH Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. RP Hamilton, FA (reprint author), NIDDK, MPH Div Digest Dis & Nutr, NIH, 6707 Democracy Blvd Democracy 2,Room 669, Bethesda, MD 20892 USA. NR 8 TC 2 Z9 2 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD JUL PY 2007 VL 102 IS 7 BP 1350 EP 1351 DI 10.1111/j.1572-0241.2007.01367.x PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 181ZE UT WOS:000247474100002 PM 17593156 ER PT J AU Hirsch, GA Inglkanisorn, WP Schulman, SR Gerstenblith, G Dyke, CK Rhoads, KL Thompson, R Aletras, AH Arai, AE AF Hirsch, Glenn A. Inglkanisorn, W. Patricia Schulman, Steven R. Gerstenblith, Gary Dyke, Christopher K. Rhoads, Kenneth L. Thompson, Richard Aletras, Anthony H. Arai, Andrew E. TI Age-related vascular stiffhess and left ventricular size after myocardial infarction SO AMERICAN JOURNAL OF GERIATRIC CARDIOLOGY LA English DT Article ID END-SYSTOLIC VOLUME; ESSENTIAL-HYPERTENSION; AORTIC DISTENSIBILITY; EXERCISE; PREDICTOR; MORTALITY; SURVIVAL; THROMBOLYSIS; ASSOCIATION; PRESSURE AB Aortic stiffness increases with age and may contribute to adverse remodeling after myocardial infarction (MI). The authors examined whether vascular stiffness affects left ventricular (LP) size after MI using contrast-enhanced cardiac magnetic resonance imaging. Despite similar infarct sizes, patients aged 60 years or older (n = 30) had a lower ejection fraction (42+/-15 vs 53+/-11%, P<.01) and greater end-systolic volume index (75+/-47 vs 44+/-18 mL/m(2), P<.01) than younger patients (n = 19). As infarct size increased, LV end-systolic volumes (P<.0001) and ejection fraction (P<.0001) in the older participants were progressively greater. Participants with greater aortic stiffness had greater end-systolic volume indices (P<.0001) and lower ejection fraction (P<.0001) with increasing infarct size. Using multivariate analysis, MI size (P<.001) and aortic distensibility (P = .02) were significant predictors of end-systolic volume index. Older patients have increased LV size after MI compared with younger patients, possibly related to age-related decreases in aortic distensibility affecting LV remodeling. C1 NHLBI, Cardiac Energet Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Suburban Hosp, Baltimore, MD USA. Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. RP Hirsch, GA (reprint author), Carnegie 568,600 N Wolfe St, Baltimore, MD 21287 USA. EM ghirsch@jhmi.edu FU Intramural NIH HHS; NHLBI NIH HHS [HL70059]; NIA NIH HHS [N0-1AG82109] NR 30 TC 7 Z9 7 U1 0 U2 1 PU LE JACQ LTD PI DARIEN PA 3 PARKLANDS DRIVE, DARIEN, CT 06820 USA SN 1076-7460 J9 AM J GERIATR CARDIOL JI Am. J. Geriatr. Cardiol. PD JUL-AUG PY 2007 VL 16 IS 4 BP 222 EP 228 DI 10.1111/j.1076-7460.2007.05849.x PG 7 WC Cardiac & Cardiovascular Systems; Geriatrics & Gerontology SC Cardiovascular System & Cardiology; Geriatrics & Gerontology GA 187YV UT WOS:000247886200003 PM 17617748 ER PT J AU Hurd, AL Augustson, EM Backinger, CL Deaton, C Bright, MA AF Hurd, Ami L. Augustson, Erik M. Backinger, Cathy L. Deaton, Candace Bright, Mary Anne TI Impact of national ABC promotion on 1-800-QUIT-NOW SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Article DE tobacco cessation; quitline; promotion; mass media; prevention research ID TELEPHONE QUITLINE; SMOKERS AB Purpose. ABC's World News Tonight (WNT) promotion of 800-QUIT-NOW allowed for a nationwide introduction of the QUIT-NOW number; this study examined the impact on call volume. Design. Pre-postassessment. Setting. National health promotion campaign Subjects. U.S. population (smokers). Measures. Monthly call attempts to the quitline at national and state levels Intervention. During November 2005 ABC's WNT highlighted the National Network Tobacco Cessation Quitlines' toll-free number, 8000-QUIT-NOW, during the month-long series, "Quit to Live: Fighting Lung Cancer." Analysis. We compared changes in call volume prepromotion, during promotion, and postpromotion by percent and regional differences, range, and average number of calls. Results: Overall call volume in the United States (49 states and the District of Columbia) increased markedly in November; 37,049 calls compared with 16,145 in October. Although there was large variability across states, there was an average of 317 calls prepromotion, 726 calls during the promotion, and 397 calls postpromotion. Conclusion: The promotion highlighted the need for capacity building in terms of both sustained promotion and ability of quitlines to provide service as the number of calls increased, as well as the importance of coordinating efforts so adjustments to individual state quitlines can be made. The series served as the first national promotion and drew attention to the potential impact on the National Network of Tobacco Cessation Quitlines. C1 SAIC Frederick, NCI, Tobacco Control Res Branch,DCCPS, Behav Res Program,Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Canc Informat Serv, Bethesda, MD 20892 USA. RP Augustson, EM (reprint author), SAIC Frederick, NCI, Tobacco Control Res Branch,DCCPS, Behav Res Program,Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4039B, Bethesda, MD 20892 USA. EM augustse@mail.nih.gov FU NCI NIH HHS [N02-PC-54418] NR 10 TC 5 Z9 5 U1 0 U2 0 PU AMER J HEALTH PROMOTION INC PI KEEGO HARBOR PA 1660 CASS LAKE RD, STE 104, KEEGO HARBOR, MI 48320 USA SN 0890-1171 J9 AM J HEALTH PROMOT JI Am. J. Health Promot. PD JUL-AUG PY 2007 VL 21 IS 6 BP 481 EP 483 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 188AQ UT WOS:000247891200002 PM 17674633 ER PT J AU Lin, JP O'Donnell, CJ Jin, L Fox, C Yang, Q Cupples, LA AF Lin, Jing-Ping O'Donnell, Christopher J. Jin, Li Fox, Caroline Yang, Qiong Cupples, L. Adrienne TI Evidence for linkage of red blood cell size and count: Genome-wide scans in the Framingham Heart Study SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE red blood cell; mean corpuscular volume; mean corpuscular hemoglobin; genome scan; linkage ID ERYTHROPOIETIN RECEPTOR GENE; KRUPPEL-LIKE FACTOR; BETA-GLOBIN GENE; TRANSCRIPTION FACTOR; TRAIT LOCI; EKLF; HEMATOCRIT; MUTATION; ELEMENT; RISK AB Red blood cell (RBC) count and size are major criteria for evaluating anemia and related hematology disease diagnoses. While environmental factors influence RBC count (RBCC) and size, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH), studies have indicated that each of these measures has a substantial genetic component. So far, no linkage analysis or genome scan has been reported. We carried out 10 cM genome-wide scans on RBCC, MCV, and MCH in a community-based Caucasian cohort, the Framingham Heart Study, using 325 pedigrees with 1,144 individuals genotyped and phenotyped. Using variance-component linkage methods, heritabilities were estimated as 56, 52, and 52% after covariate adjusted for RBCC, MCV, and IVICH, respectively. For RBCC, we found a maximum LOD score of 3.2 on chromosome 19, 24 cM (7.0 Mbp). Near this region, there lie a few important candidate genes, including erythropoietin receptor and erythroid Kruppel-like factor. For linkage analyses for MCV and IVICH, there were coinciding maximized LOD scores on chromosome 11, 9 cM (5.2 Mbp) with values of 3.8 and 3.6, respectively. Under the peak resides the hemoglobin beta cluster - several beta-like genes, which are important candidates for RBC size. In subsequent analyses, we excluded individuals with low MCV to assess the possible influence of beta-thalassemia carriers, and there continued to be evidence for linkage in the same region on chromosome 11p15 (LOD scores of 2.6 and 2.7 for MCV and IVICH, respectively). For MCV, we also identified a new region on chromosome 6q24 with a LOD score of 2.9. These findings suggest that further studies are warranted to identify potential causal genetic variants for RBC size and count and related erythrocyte indices. C1 NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. NHLBI, Framingham Heart Study, Off Director, Framingham, MA USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. Univ Cincinnati, Ctr Genom Informat, Cincinnati, OH USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. RP Lin, JP (reprint author), NHLBI, Off Biostat Res, NIH, 6701 Rockledge Dr Suite 8110, Bethesda, MD 20892 USA. EM linj@nhlbi.nih.gov RI Jin, Li/C-1468-2009; Yang, Qiong/G-5438-2014; OI Jin, Li/0000-0002-4546-2415; Cupples, L. Adrienne/0000-0003-0273-7965 FU NHLBI NIH HHS [N01 HC25195] NR 31 TC 24 Z9 24 U1 1 U2 2 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 JUL PY 2007 VL 82 IS 7 BP 605 EP 610 DI 10.1002/ajh.20868 PG 6 WC Hematology SC Hematology GA 183EO UT WOS:000247555700001 PM 17211848 ER PT J AU Kim, YJ Dale, JK Noel, P Brown, MR Nutman, TB Straus, SE Klion, AD AF Kim, Yae-Jean Dale, Janet K. Noel, Pierre Brown, Margaret R. Nutman, Thomas B. Straus, Stephen E. Klion, Amy D. TI Eosinophilia is associated with a higher mortality rate among patients with autoimmune lymphoproliferative syndrome SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE eosinophil; apoptosis; lymphadenopathy; autoimmunity; ALPS ID T-CELLS; HYPEREOSINOPHILIC SYNDROME; LYMPHOCYTE APOPTOSIS; BLOOD EOSINOPHILIA; FAS MUTATIONS; LYMPHADENOPATHY; FOLLICULITIS; EXPRESSION; LYMPHOMAS; FEATURES AB Autoimmune lymphoproliferative syndrome (ALPS) is a disorder associated with heritable defects in lymphocyte apoptosis that result in chronic nonmalignant lymphadenopathy, splenomegaly, and autoimmunity. To examine the prevalence, mechanisms, and potential implications of eosinophilia in ALPS, we reviewed data retrospectively from 187 consecutive ALPS patients and their family members studied at the National Institutes of Health. ALPS patients with eosinophilia were compared with ALPS patients without eosinophilia with respect to their clinical and immunologic phenotype. Potential mechanisms for the eosinophilia, including abnormal Fas-mediated eosinophil apoptosis, increased production of eosinophilopoietic cytokines, and presence of anti-eosinophilic autoantibodies were also explored in a small number of patients from whom samples were available. Analysis of data from 68 ALPS patients and 119 of their relatives identified a distinct subgroup of patients with prominent and persisting eosinophilia that proved to be associated with increased numbers of peripheral blood leukocytes (PBL) of multiple lineages and a trend towards increased serum IgE levels. Eosinophilic ALPS patients also had a significantly higher risk of death due to infectious complications. Although the specific etiology of the eosinophilia in these patients remains uncertain, it does not appear to be associated with an altered serum cytokine profile, increased survival responsiveness of eosinophils to IL-5, defective Fas-mediated eosinophil apoptosis, or anti-eosinophil antibodies. Eosinophilia defines a distinct subgroup of ALPS patients with increased serum IgE levels, increased numbers of PBL of multiple lineages, and higher mortality from infectious complications. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD 20892 USA. RP Klion, AD (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr,Room 4-126, Bethesda, MD 20892 USA. EM aklion@niaid.nih.gov OI Klion, Amy/0000-0002-4986-5326 FU Intramural NIH HHS NR 27 TC 15 Z9 15 U1 2 U2 6 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 JUL PY 2007 VL 82 IS 7 BP 615 EP 624 DI 10.1002/ajh.20851 PG 10 WC Hematology SC Hematology GA 183EO UT WOS:000247555700003 PM 17266055 ER PT J AU Shi, M Umbach, DM Weinberg, CR AF Shi, Min Umbach, David M. Weinberg, Clarice R. TI Identification of risk-related haplotypes with the use of multiple SNPs from nuclear families SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID CASE-PARENT TRIADS; LINKAGE DISEQUILIBRIUM; GENOTYPE ASYMMETRIES; GENETIC ASSOCIATION; TRANSMISSION TEST; TESTS; TRAITS; POLYMORPHISMS; REGRESSION; FETAL AB Family-based association studies offer robustness to population stratification and can provide insight into maternally mediated and parent-of-origin effects. Usually, such studies investigate multiple markers covering a gene or chromosomal region of interest. We propose a simple and general method to test the association of a disease trait with multiple, possibly linked SNP markers and, subsequently, to nominate a set of "risk-haplotype-tagging alleles." Our test, the max_Z(2) test, uses only the genotypes of affected individuals and their parents without requiring the user to either know or assign haplotypes and their phases. It also accommodates sporadically missing SNP data. In the spirit of the pedigree disequilibrium test, our procedure requires only a vector of differences with expected value 0 under the null hypothesis. To enhance power against a range of alternatives when genotype data are complete, we also consider a method for combining multiple tests; here, we combine max_ Z(2) and Hotelling's T-2. To facilitate discovery of risk-related haplotypes, we develop a simple procedure for nominating risk-haplotype-tagging alleles. Our procedures can also be used to study maternally mediated genetic effects and to explore imprinting. We compare the statistical power of several competing testing procedures through simulation studies of case-parents triads, whose diplotypes are simulated on the basis of draws from the HapMap-based known haplotypes of four genes. In our simulations, the max_ Z(2) test and the max_TDT (transmission/ disequilibrium test) proposed by McIntyre et al. perform almost identically, but max_ Z2, unlike max_ TDT, extends directly to the investigation of maternal effects. As an illustration, we reanalyze data from a previously reported orofacial cleft study, to now investigate both fetal and maternal effects of the IRF6 gene. C1 Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), Natl Inst Environm Hlth Sci, Biostat Branch, NIH, Dept Hlth & Human Serv, Mail Drop A3-03 101-A315, Res Triangle Pk, NC 27709 USA. EM weinber2@niehs.nih.gov FU Intramural NIH HHS NR 29 TC 32 Z9 32 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD JUL PY 2007 VL 81 IS 1 BP 53 EP 66 DI 10.1086/518670 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 175UO UT WOS:000247039700005 PM 17564963 ER PT J AU Sika, M Lewis, J Douglas, J Erlinger, T Dowie, D Lipkowitz, M Lash, J Cornish-Zirker, D Peterson, G Toto, R Kusek, J Appel, L Kendrick, C Gassman, J AF Sika, Mohammed Lewis, Julia Douglas, Janice Erlinger, Thomas Dowie, Donna Lipkowitz, Michael Lash, James Cornish-Zirker, Denise Peterson, Gail Toto, Robert Kusek, John Appel, Lawrence Kendrick, Cynthia Gassman, Jennifer CA AASK Grp TI Baseline characteristics of participants in the African American Study of Kidney Disease and Hypertension (AASK) Clinical Trial and Cohort Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE African Americans; hypertension; kidney disease; baseline ID GLOMERULAR-FILTRATION RATE; DIABETIC NEPHROPATHY; TYPE-2 DIABETES/; BLOOD-PRESSURE; RENAL-FUNCTION; PROGRESSION; OUTCOMES; DECLINE; NEPHROSCLEROSIS; INHIBITION AB Background: African Americans are at increased risk of kidney failure caused by hypertension. The primary objective of the African American Study of Kidney Disease and Hypertension (AASK) Cohort Study is to identify risk factors for progressive kidney disease in African Americans with hypertensive chronic kidney disease in the setting of recommended anti hypertensive therapy. Study Design, Setting, & Participants: On completion of the AASK Trial, a randomized, double-blind, 3 X 2 factorial trial, participants who had not yet begun dialysis treatment or undergone kidney transplantation were invited to enroll in a prospective Cohort Study. Cohort Study participants received recommended anti hypertensive drug therapy, including high rates of angiotensin-converting enzyme-inhibitor (73%) and angiotensin receptor blocker (10%) use with a blood pressure goal of less than 130/80 mm Hg. Predictor, Outcomes, & Measurements: Baseline clinical and demographic characteristics are described separately at the baseline of the AASK Trial and Cohort Study. Results: Of 1,094 persons enrolled in the AASK Trial (June 1995 to September 2001; mean age, 55 years; 61% men), 691 enrolled in the AASK Cohort Study (April 2002 to present), 299 died or reached dialysis therapy or transplantation, and 104 declined to participate in the AASK Cohort Study. Mean baseline systolic/diastolic blood pressures were 150/96 mm Hg in the Trial and 136/81 mm Hg in the Cohort Study. Cohort Study participants had greater serum creatinine levels at the start of the Cohort Study (2.3 versus 1.8 mg/dL [203 versus 159 mu mol/L]), corresponding to an estimated glomerular filtration rate of 43.8 versus 50.3 mL/min/1.73 m(2) (0.73 versus 0.84 mL/s/1.73 m(2)), than Trial participants and greater urine protein-creatinine ratios (0.38 versus 0.19 mg/mg, respectively). Individuals who were eligible, but declined to participate in the Cohort Study, had greater systolic blood pressure, but similar kidney function. Limitations: Some parameters, such as iothalamate glomerular filtration rate, urinary albumin level, echocardiogram, and ambulatory blood pressure, were not performed in both the Trial and the Cohort Study, limiting the ability to evaluate changes in these parameters over time. Conclusion: Despite well-controlled blood pressure in the AASK Trial, Cohort Study participants still had evidence of progressive chronic kidney disease. Thus, the AASK Cohort Study is well positioned to address its primary objective. C1 Vanderbilt Univ, Med Ctr, Nephrol Clin Trials Ctr, Nashville, TN 37232 USA. Univ Texas, Med Branch, Austin, TX 78712 USA. Harlem Hosp Med Ctr, New York, NY 10037 USA. Univ Illinois, Chicago, IL USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. NIDDK, NIH, Bethesda, MD USA. Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. Cleveland Clin, Cleveland, OH 44106 USA. Case Western, Cleveland, OH USA. Mt Sinai, New York, NY USA. RP Sika, M (reprint author), Vanderbilt Univ, Med Ctr, Nephrol Clin Trials Ctr, 1211 21st Ave S,215 MAB, Nashville, TN 37232 USA. EM mohammed.sika@vanderbilt.edu FU NCRR NIH HHS [RR-11104, 5M01RR00071, RR 00052, RR-00032, RR-00071, RR-00080, RR-00827, RR-11145, RR00095]; NIDDK NIH HHS [5U01DK045388, DK 2818] NR 23 TC 28 Z9 28 U1 1 U2 2 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 JUL PY 2007 VL 50 IS 1 BP 78 EP 89 DI 10.1053/j.ajkd.2007.03.004 PG 12 WC Urology & Nephrology SC Urology & Nephrology GA 197QJ UT WOS:000248570400010 PM 17591527 ER PT J AU Kranz, C Sun, LW Eklund, EA Krasnewich, D Casey, JR Freeze, HH AF Kranz, Christian Sun, Liangwu Eklund, Erik A. Krasnewich, Donna Casey, Janet R. Freeze, Hudson H. TI CDG-Id in two siblings with partially different phenotypes SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE ALG3 deficiency; axial hypotonia; congenital disorder of glycosylation (CDG); disaccharidase deficiency; microcephaly ID DEFICIENT GLYCOPROTEIN SYNDROME; CAUSES CONGENITAL DISORDER; GLYCOSYLATION TYPE IG; MANNOSE; MANNOSYLTRANSFERASE; HYPOGLYCEMIA; DIAGNOSIS; MUTATION; PROTEIN; GENE AB We present two sibs with congenital disorder of glycosylation (CDG) type Id. Each shows severe global delay, failure to thrive, seizures, microcephaly, axial hypotonia, and disaccharidase deficiency. One sib has more severe digestive issues, while the other is more neurologically impaired. Each is compound heterozygous for a novel point mutation and an already known Mutation in the ALG3 gene that leads to the synthesis of a severely truncated oligosaccharide precursor for N-glycans. The defect is corrected by introduction of a normal ALG3 cDNA. CDG should be ruled out in all patients with severe seizures and failure to thrive. (c) 2007 Wiley-Liss, Inc. C1 Burnham Inst Med Res, Glycobiol & Carbohydrate Chem Program, La Jolla, CA 92037 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Univ Rochester, Med Ctr, Dept Pediat, Rochester, NY 14642 USA. RP Freeze, HH (reprint author), Burnham Inst Med Res, Glycobiol & Carbohydrate Chem Program, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM hudson@burnham.org OI Freeze, Hudson/0000-0001-6316-0501 FU NIDDK NIH HHS [F32 DK 072890, R01 DK 55615] NR 26 TC 24 Z9 24 U1 0 U2 0 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 JUL 1 PY 2007 VL 143A IS 13 BP 1414 EP 1420 DI 10.1002/ajmg.a.31796 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 186DZ UT WOS:000247760600003 PM 17551933 ER PT J AU Al-Rahawan, MM Chute, DJ Sol-Church, K Gripp, KW Stabley, DL McDaniel, NL Wilson, WG Waldron, PE AF Al-Rahawan, Mohamad M. Chute, Deborah J. Sol-Church, Katia Gripp, Karen W. Stabley, Deborah L. McDaniel, Nancy L. Wilson, William G. Waldron, Peter E. TI Hepatoblastoma and heart transplantation in a patient with cardio-facio-cutaneous syndrome SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE cardo-facio-cutaneous; Costello syndrome; cancer; transplant; autopsy; MEK1 ID HRAS MUTATION ANALYSIS; COSTELLO-SYNDROME; CARDIOFACIOCUTANEOUS SYNDROME; PHENOTYPE CORRELATION; GERMLINE MUTATIONS; ABNORMALITIES; GENOTYPE AB Cardio-facio-cutaneous syndrome (CFC) and Costello syndrome (CS) are disorders with an overlapping spectrum of congenital anomalies. Mutations in the RAS-MAPK pathway have recently been reported in both of these syndromes, with HRAS mutations characteristic for CS and BRAF and MEK1/2 mutations for CFC. We report on a 3-year-old boy who underwent a cardiac transplant at age 8 months for hypertrophic cardiomyopathy; lie was subsequently suspected to have CS. At age 35 months he presented with an intra-cardiac mass that was diagnosed as Metastatic hepatoblastoma. Although hepatoblastoma is not known to have in increased frequency in immunocompromised patients, questions were raised as whether the post-transplant immuno-suppressive therapy played a role in tumor development. The patient died shortly thereafter and his post-mortem DNA analysis revealed a MEK1 limitation (Y130C) previously reported in CFC. While CS is associated with increased cancer risk, only a single case of leukemia has been reported in a patient with CFC, making this the first case of a solid tumor reported in a patient with CFC. (c) 2007 Wiley-Liss, Inc. C1 Univ Virginia Hlth Syst, Dept Pediat, Charlottesville, VA USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Univ Virginia Hlth Syst, Dept Pathol, Charlottesville, VA USA. Alfred I duPont Hosp Children, Div Med Genet, Wilmington, DE USA. Alfred I duPont Hosp Children, Dept Biomed Res, Nemours Childrens Clin, Wilmington, DE USA. Thomas Jefferson Univ, Dept Pediat, Philadelphia, PA USA. RP Al-Rahawan, MM (reprint author), NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS Rm 7013, Rockville, MD 20852 USA. EM almohama@mail.nih.gov FU NCRR NIH HHS [RR 020173-01] NR 19 TC 24 Z9 29 U1 0 U2 1 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 JUL 1 PY 2007 VL 143A IS 13 BP 1481 EP 1488 DI 10.1002/ajmg.a.31819 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 186DZ UT WOS:000247760600011 PM 17567882 ER PT J AU Cobain, MR Pencina, MJ D'Agostino, RB Vasan, RS AF Cobain, Mark R. Pencina, Michael J. D'Agostino, Ralph B. Vasan, Ramachandran S. TI Lifetime risk for developing dyslipidemia: The Framingham Offspring Study SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE cholesterol; cohort studies; coronary heart disease prevention; epidemiology; HDL; LDL; lifetime risk ID DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY-HEART-DISEASE; BLOOD CHOLESTEROL; PLASMA; PREVENTION; WOMEN; MEN; AVERAGE; EVENTS; BURDEN AB BACKGROUND: High serum low-density lipoprotein (LDL) cholesterol and low high-density lipoprotein (HDL) cholesterol are major vascular risk factors. National surveys indicate that 40% of individuals in the United States have borderline-high LDL cholesterol, and 13-34% have low HDL. The lifetime risk of developing dyslipidemia is unknown, however. METHODS: We estimated the 10- to 30-year long-term risks of developing "borderline-high" LDL cholesterol (>= 130 mg/dL [3.4 mmol/L]), "high" LDL cholesterol (>= 160 mg/ dL [4.1 mmol/L]) and "low" HDL cholesterol (< 40 mg/dL [1.0 mmol/L]) in 4701 Framingham Offspring Study participants (53% women) who attended at least 2 examinations between 1971 and 2000. We performed sex-specific analyses (for age groups 30-34, 40-44, 50-54 years), and estimated risks conditional on surviving without the lipid abnormality up to the baseline age. We also estimated risks accounting for baseline prevalence of dyslipidemia (elevated LDL, low HDL). RESULTS: Over a 30-year period, approximately 6 of 10 participants developed borderline-high LDL, 4 of 10 people developed high LDL, and 2 (women) to 4 (men) of 10 individuals developed low HDL levels; estimates were generally similar for different age groups. Adjustment for baseline prevalence of dyslipidemia increased these estimates: 30-year risks exceeded 80% for borderline-high LDL, 50% for high LDL, and 25% (women) to 65% (men) for low HDL; 20-50% had or developed a low HDL along with a high LDL level. The 30-year estimates approximate the lifetime risk in 50-year-olds. CONCLUSIONS: The long term risks of developing dyslipidemia are substantial in both sexes, and considerably exceed prevalence estimates from cross-sectional surveys. (c) 2007 Elsevier Inc. All rights reserved. C1 Boston Univ, Dept Math Stat & Biostat, Boston, MA 02215 USA. Corp Res, Unilever Res, Bedford, England. Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. Boston Univ, Sch Med, Dept Med, Cardiol Sect, Boston, MA 02118 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [2K24HL04334, N01-HC-25195] NR 34 TC 9 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD JUL PY 2007 VL 120 IS 7 BP 623 EP U3 DI 10.1016/j.amjmed.2006.12.015 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 184WA UT WOS:000247672100015 PM 17602937 ER PT J AU Fine, P Burgio, K Borello-France, D Richter, H Whitehead, W Weber, A Brown, M AF Fine, Paul Burgio, Kathryn Borello-France, Diane Richter, Holly Whitehead, William Weber, Anne Brown, Morton TI Teaching and practicing of pelvic floor muscle exercises in primiparous women during pregnancy and the postpartum period SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 27th Annual Meeting of the American-Urogynecologic-Society CY OCT 19-21, 2006 CL Palm Springs, CA SP Amer Urogynecol Soc DE incontinence; pelvic floor muscle (PFM) exercise; performance; postpartum; primiparous; teaching ID RANDOMIZED CONTROLLED-TRIAL; URINARY-INCONTINENCE; STRESS-INCONTINENCE; FOLLOW-UP; PHYSIOTHERAPY; PREDICTORS; ADHERENCE; THERAPY AB OBJECTIVE: The purpose of this study was to describe the teaching and practicing of pelvic floor muscle exercise (PFME) before and after delivery. STUDY DESIGN: This was a secondary data analysis from a prospective multicenter cohort study, the Childbirth and Pelvic Symptoms study, by the Pelvic Floor Disorders Network. Primiparous women (n = 759) with term singleton delivery were interviewed 6 months after delivery. RESULTS: Sixty-four percent of the women had been taught PFME, most with verbal (76%) and/or written instructions (55%) and a few (10%) during pelvic examination. Women with anal sphincter tears were not more likely to receive instruction or reminders after delivery. More white women (75%) were taught PFME than were Asian women (48%), African American women (36%), or Hispanic women (39%; P < .0001). More women with college education (74%) were taught, compared with women without a college education (37%; P < .0001). Of those women who were taught, 68% performed PFME after delivery, and 63% were still performing the exercises 6 months after delivery. CONCLUSION: Results reveal tremendous potential for the improvement of PFME education and targeting at-risk women in the peripartum period. C1 Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. Baylor Coll Med, Dept Urol, Houston, TX 77030 USA. Univ Alabama, Geriatr Res Educ & Clin Ctr, Birmingham Atlanta VA Med Ctr, Dept Med, Birmingham, AL USA. Duquesne Univ, Dept Phys Therapy, Pittsburgh, PA USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. Univ N Carolina, Sch Med, Dept Med, Div Digest Dis, Chapel Hill, NC USA. NICHHD, Pelv Floor Disorders Network, Bethesda, MD 20892 USA. Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. RP Fine, P (reprint author), 5121 Oak Ct, Dickinson, TX 77539 USA. EM pfine@bcm.edu FU NICHD NIH HHS [U10 HD41250, U10 HD41268, U10 HD41269, U10 HD41263, U10 HD41248, U10 HD041261, U01 HD41249, U10 HD41267, U10 HD41261] NR 28 TC 3 Z9 3 U1 2 U2 13 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 JUL PY 2007 VL 197 IS 1 AR 107.e1 DI 10.1016/j.ajog.2007.02.052 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 188HH UT WOS:000247910500050 PM 17618779 ER PT J AU Jeronimo, J Massad, LS Schiffman, M AF Jeronimo, Jose Massad, L. Stewart Schiffman, Mark CA NIH ASCCP Res Grp TI Visual appearance of the uterine cervix: correlation with human papillomavirus detection and type SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE colposcopy; cervical cancer; human papillomavirus (HPV); intraepithelial lesion ID ATYPICAL SQUAMOUS-CELLS; ASCUS-LSIL TRIAGE; INTRAEPITHELIAL NEOPLASIA; UNDETERMINED SIGNIFICANCE; COLPOSCOPIC INDEX; CANCER; WOMEN; INFECTION; BIOPSY; RISK AB OBJECTIVE: Infection with carcinogenic human papillomaviruses (HPVs) is necessary for cervical precancer and cancer, but the effects of type- specific HPV infection on cervical appearance are poorly understood. STUDY DESIGN: Twenty expert colposcopists evaluated a total of 939 digitized cervigrams that were obtained during the ASCUS (a typical squamous cells of undetermined significance)-LSIL (low-grade squamous intraepithelial lesion) Triage study after the application of 5% acetic acid. Each reviewer rated the number and severity of lesions in 112 pictures that were matched on histologic diagnoses and HPV typing results so that >= 2 reviewers rated each image. We used standard tests of association and correlation to relate HPV type and visual appearance. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. So Illinois Univ, Sch Med, Dept Obstet & Gynecol, Springfield, IL 62794 USA. RP Jeronimo, J (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7234, Bethesda, MD 20892 USA. EM guibovij@mail.nih.gov NR 24 TC 4 Z9 4 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 JUL PY 2007 VL 197 IS 1 AR 47.e2 DI 10.1016/j.ajog.2007.02.047 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 188HH UT WOS:000247910500024 ER PT J AU Whitehead, WE Bradley, CS Brown, MB Brubaker, L Gutman, RE Varner, RE Visco, AG Weber, AM Zyczynski, H AF Whitehead, William E. Bradley, Catherine S. Brown, Morton B. Brubaker, Linda Gutman, Robert E. Varner, R. Edward Visco, Anthony G. Weber, Anne M. Zyczynski, H. TI Gastrointestinal complications following abdominal sacrocolpopexy for advanced pelvic organ prolapse SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 27th Annual Meeting of the American-Urogynecologic-Society CY OCT 19-21, 2006 CL Palm Springs, CA SP Amer Urogynecol Soc DE ileus; nausea; sacrocolpopexy; small bowel obstruction ID POSTOPERATIVE NAUSEA; SURGERY; PREVENTION; PREVALENCE; IMPACT AB OBJECTIVE: The aims of this secondary analysis of the "Colpopexy And Urinary Reduction Efforts" (CARE) study were to estimate the incidence of postoperative gastrointestinal complications and identify risk factors. STUDY DESIGN: We prospectively identified gastrointestinal complications and serious adverse events (SAE) for 12 months after sacrocolpopexy. Two surgeons independently reviewed reports of ileus or small bowel obstruction (SBO). RESULTS: Eighteen percent of 322 women (average age 61.3 years) reported "nausea, emesis, bloating, or ileus" during hospitalization and 9.8% at 6 weeks. Nineteen women (5.9%; Cl 3.8%, 9.1%) had a possible ileus or SBO that generated SAE reports: 4 (1.2%, Cl 0.5%, 3.2%) were reoperated for SBO, 11 ( 3.4%, Cl 1.9%, 6.1%) were readmitted for medical management, and 4 had a prolonged initial hospitalization. Older age (P < .001) was a risk factor for ileus or SBO. CONCLUSION: One in 20 women experiences significant gastrointestinal morbidity after sacrocolpopexy. This information will aid preoperative counseling. C1 Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Dept Obstet & Gynecol, Chapel Hill, NC USA. Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Obstet & Gynecol, Iowa City, IA USA. Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. Loyola Univ, Med Ctr, Dept Obstet & Gynecol, Maywood, IL 60153 USA. Loyola Univ, Med Ctr, Dept Urol, Maywood, IL 60153 USA. Johns Hopkins Univ, Sch Med, Dept Obstet & Gynecol, Baltimore, MD 21205 USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35294 USA. NICHHD, Contracept & Reprod Hlth Branch, Pelv Floor Disorders Program, NIH, Bethesda, MD USA. Univ Pittsburgh, Sch Med, Dept Obstet & Gynecol, Pittsburgh, PA USA. RP Whitehead, WE (reprint author), Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC 27599 USA. FU NICHD NIH HHS [U01 HD041249-06, U10 HD041261, U10 HD041250, U10 HD041250-06, U10 HD41267, U10 HD41263, U01 HD041249, U10 HD041263, U10 HD041269, U10 HD041263-05, U10 HD041269-03, U10 HD41250, U10 HD041268, U10 HD041267, U10 HD41261, U10 HD41268, U10 HD41249, U10 HD41248, U10 HD041248, U10 HD041248-05, U10 HD041261-06, U10 HD041267-06, U10 HD41269, U10 HD041268-05] NR 15 TC 4 Z9 7 U1 0 U2 3 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 JUL PY 2007 VL 197 IS 1 AR 78.e1 DI 10.1016/j.ajog.2007.02.046 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 188HH UT WOS:000247910500038 PM 17618767 ER PT J AU Freitas, VM Vilas-Boas, VF Pimenta, DC Loureiro, V Juliano, MA Carvalho, MR Pinheiro, JJV Camargo, ACM Moriscot, AS Hoffman, MP Jaeger, RG AF Freitas, Vanessa M. Vilas-Boas, Vanessa F. Pimenta, Daniel C. Loureiro, Vania Juliano, Maria A. Carvalho, Marcia R. Pinheiro, Joao J. V. Camargo, Antonio C. M. Moriscot, Anselmo S. Hoffman, Matthew P. Jaeger, Ruy G. TI SIKVAV, a laminin alpha 1-derived peptide, interacts with: Integrins and increases protease activity of a human salivary gland adenoid cystic carcinoma cell, line through the ERK 1/2 signaling pathway SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID CHAIN SYNTHETIC PEPTIDE; A-CHAIN; EXTRACELLULAR-MATRIX; BASEMENT-MEMBRANE; IN-VITRO; BINDING SEQUENCES; NEURITE OUTGROWTH; IKVAV SEQUENCE; ALPHA-1 CHAIN; N-CAM AB Adenoid cystic carcinoma is a frequently occurring malignant salivary gland neoplasm. We studied the induction of protease activity by the laminin-derived peptide, SIKVAV, in cells (CAC2) derived from this neoplasm. Laminin alpha 1 and matrix metalloproteinases (MMPs) 2 and 9 were immunolocalized in adenoid cystic carcinoma cells in vivo and in vitro. CAC2 cells cultured on SIKVAV showed a dose-dependent increase of MMP9 as detected by zymography and colocalization of alpha 3 and alpha 6 integrins. Small interfering RNA (siRNA) knockdown of integrin expression in CAC2 cells resulted in decreased adhesion to the peptide. SIKVAV affinity chromatography and immunoblot analysis showed that alpha 3, alpha 6, and beta 1 integrins; were eluted from the SIKVAV column, which was confirmed by mass spectrometry and a solid-phase binding, assay. Small interfering RNA experiments also showed that these integrins, through extracellular signal-regulated kinase (ERK) 1/2 signaling, regulate MMP secretion induced by SIKVAV in CAC2 cells. We propose that SIKVAV increases protease activity of a human salivary gland adenoid cystic carcinoma cell line through alpha 3 beta b and alpha 6 beta 1 integrins and the ERK 1/2 signaling pathway. C1 Univ Sao Paulo, Inst Ciencias Biomed, Dept Biol Celular & Desenvolovimento, BR-05508900 Sao Paulo, Brazil. Butantan Inst, Ctr Appl Toxinol, Sao Paulo, Brazil. Univ Metropolitana Santos, Sao Paulo, Brazil. Univ Fed Sao Paulo, Dept Biophys, Sao Paulo, Brazil. Fed Univ Para, Sch Dent, Dept Oral Pathol, BR-66059 Belem, Para, Brazil. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Jaeger, RG (reprint author), Univ Sao Paulo, Inst Ciencias Biomed, Dept Biol Celular & Desenvolovimento, Av Prof Lineu Prestes 1524,Ed Biomed 1,Sala 405, BR-05508900 Sao Paulo, Brazil. EM rgjaeger@usp.br RI Moriscot, Anselmo/C-4506-2012; Freitas, Vanessa/D-7897-2012; Moriscot, Anselmo/H-6985-2012; Jaeger, Ruy/G-8230-2011; Pimenta, Daniel/B-4361-2008; Pinheiro, Joao/H-2653-2012 OI Freitas, Vanessa/0000-0001-9613-8626; Pimenta, Daniel/0000-0003-2406-0860; Pinheiro, Joao/0000-0002-6914-6441 NR 69 TC 28 Z9 28 U1 0 U2 8 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 JUL PY 2007 VL 171 IS 1 BP 124 EP 138 DI 10.2353/ajpath.2007.051264 PG 15 WC Pathology SC Pathology GA 185LO UT WOS:000247712700015 PM 17591960 ER PT J AU Saika, S Yamanaka, O Okada, Y Miyamoto, T Kitano, A Flanders, KC Ohnishi, Y Nakajima, Y Kao, WWY Ikeda, K AF Saika, Shizuya Yamanaka, Osamu Okada, Yuka Miyamoto, Takeshi Kitano, Ai Flanders, Kathleen C. Ohnishi, Yoshitaka Nakajima, Yuji Kao, Winston W. -Y. Ikeda, Kazuo TI Effect of overexpression of ppar gamma on the healing process of corneal alkali burn in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE peroxisome proliferator-activated receptor-gamma; gene therapy; macrophage; fibroblast; Smad ID PROLIFERATOR-ACTIVATED RECEPTORS; GROWTH-FACTOR-BETA; HEPATIC STELLATE CELLS; AMNIOTIC MEMBRANE TRANSPLANTATION; EPITHELIAL-MESENCHYMAL TRANSITION; MATRIX METALLOPROTEINASES; GENE-TRANSFER; TGF-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; MYOFIBROBLAST DIFFERENTIATION AB Wound healing involves both local cells and inflammatory cells. Alkali burn of ocular surface tissue is a serious clinical problem often leading to permanent visual impairment resulting from ulceration, scarring and neovascularization during healing. Behaviors of corneal cells and inflammatory cells are orchestrated by growth factor signaling networks that have not been fully uncovered. Here we showed that adenoviral gene introduction of peroxisome proliferator-activated receptor-gamma (PPAR gamma) inhibits activation of ocular fibroblasts and macrophages in vitro and also induced anti-inflammatory and anti-fibrogenic responses in an alkali-burned mouse cornea. PPAR gamma overexpression suppressed upregulation of inflammation/ scarring-related growth factors and matrix metalloproteinases (MMPs) in macrophages. It also suppressed expression of such growth factors and collagen I alpha 2 and myofibroblast generation upon exposure to TGF beta 1. Exogenous PPAR gamma did not alter phosphorylation of Smad2, but inhibited its nuclear translocation. PPAR gamma overexpression enhanced proliferation of corneal epithelial cells, but not of fibroblasts in vitro. Epithelial cell expression of MMP-2/-9 and TGF beta 1 and its migration were suppressed by PPAR gamma overexpression. In vivo experiments showed that PPAR gamma gene introduction suppressed monocytes/macrophages invasion and suppressed the generation of myofibroblasts, as well as upregulation of cytokines/growth factors and MMPs in a healing cornea. In vivo re-epitheliazation with basement membrane reconstruction in the healing, burned, cornea was accelerated by PPAR gamma-Ad expression, although PPAR gamma overexpression was considered to be unfavorable for cell migration. Together, these data suggest that overexpression of PPAR gamma may represent an effective new strategy for treatment of ocular surface burns. C1 Wakayama Med Univ, Dept Ophthalmol, Wakayama 6410012, Japan. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD USA. Osaka City Univ, Grad Sch Med, Dept Anat, Abeno, Osaka, Japan. Univ Cincinnati, Med Ctr, Dept Ophthalmol, Cincinnati, OH 45267 USA. RP Saika, S (reprint author), Wakayama Med Univ, Dept Ophthalmol, 811-1 Kimiidera, Wakayama 6410012, Japan. EM shizuya@wakayama-med.ac.jp FU NEI NIH HHS [EY-13755] NR 67 TC 38 Z9 41 U1 1 U2 3 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 JUL PY 2007 VL 293 IS 1 BP C75 EP C86 DI 10.1152/ajpcell.00332.2006 PG 12 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 189DF UT WOS:000247968900010 PM 17625041 ER PT J AU Koska, J Ortega, E Bogardus, C Krakoff, J Bunt, JC AF Koska, Juraj Ortega, Emilio Bogardus, Clifton Krakoff, Jonathan Bunt, Joy C. TI The effect of insulin on net lipid oxidation predicts worsening of insulin resistance and development of type 2 diabetes mellitus SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE diabetes mellitus; euglycemic clamp; indirect calorimetry ID IMPAIRED GLUCOSE-TOLERANCE; FATTY-ACID METABOLISM; HUMAN SKELETAL-MUSCLE; PIMA-INDIANS; SECRETORY DYSFUNCTION; OBESITY; PATHOGENESIS; PIOGLITAZONE; SENSITIVITY; ADIPOCYTE AB Suppression of lipid oxidation (L-ox) by insulin is impaired in obesity and type 2 diabetes mellitus (T2DM). Here we tested whether high L-ox represents a primary or acquired characteristic in the pathogenesis of T2DM. Hood-indirect calorimetry was performed under postabsorptive conditions and during a two-step hyperinsulinemic euglycemic clamp (insulin infusion rates in mU(.)m(-2.)min(-1): 40 low and 400 high) in 465 Pima Indians: 317 with normal glucose tolerance (NGT), 117 with impaired glucose tolerance (IGT), and 31 with T2DM. The predictive effect of net lipid oxidation (L..) on development of T2DM was assessed in 296 subjects (51 of whom developed T2DM), whereas the predictive effect of L., on followup changes in insulin-mediated glucose disposal (M) and acute insulin response (AIR) was studied in 190 subjects with NGT at baseline. Cross-sectionally, after adjustment for age, sex, body fat (BF), and M low, L., low was increased in T2DM compared with NGT and IGT subjects (P < 0.05). Prospectively, after adjustment for followup duration, age, sex, BF, M, and AIR, increased clamp L., predicted T2DM [hazard rate ratios (95% Cl): L., low, 1.5 (1.1, 2.0), P < 0.01; L-ox high, 1.3 (1.0, 1.8), P = 0.05]. High L-ox low at baseline was also associated with subsequent worsening of M low (P = 0.04). These data indicate that the inability of insulin to suppress L-ox may represent an early risk marker for insulin resistance and T2DM that is independent of adiposity, acute insulin secretion, and insulin action on glucose uptake. C1 NIDDKD, Obes & Diabet Res Sect, NIH, DHHS, Phoenix, AZ 85016 USA. RP Koska, J (reprint author), NIDDKD, Obes & Diabet Res Sect, NIH, DHHS, 4212 N 16th St,Rm 5-35, Phoenix, AZ 85016 USA. EM jkoska@mail.nih.gov FU Intramural NIH HHS NR 43 TC 5 Z9 6 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD JUL PY 2007 VL 293 IS 1 BP E264 EP E269 DI 10.1152/ajpendo.00662.2006 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 190OJ UT WOS:000248068200034 PM 17616607 ER PT J AU Zhu, Q Thomson, CW Zhang, GF Stampfli, M McDermott, MR Collins, SM Gauldie, J AF Zhu, Qing Thomson, Christopher W. Zhang, Guofeng Stampfli, Martin McDermott, Mark R. Collins, Stephen M. Gauldie, Jack TI Eosinophilia is induced in the colon of Th2-sensitized mice upon exposure to locally expressed antigen SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE mucosal; eosinophil; adenovirus; intrarectal ID HAPTEN-INDUCED COLITIS; ULCERATIVE-COLITIS; INTESTINAL-MUCOSA; GASTROINTESTINAL-TRACT; TRANSGENE EXPRESSION; TISSUE EOSINOPHILIA; LYMPHOID-TISSUE; LAMINA PROPRIA; IMMUNE-SYSTEM; MURINE MODEL AB Eosinophilic inflammation is a feature of a variety of gastrointestinal ( GI) disorders including eosinophil- associated GI disorder, allergy, inflammatory bowel disease, and parasite infection. Elucidating the mechanisms of eosinophil infiltration into the GI tract is important to the understanding of multiple disease processes. We hypothesize that eosinophilia in the large intestine ( colon) can be induced by an antigen in a host that is associated with Th2- skewed antigen- specific immune responses. To investigate the importance of antigenic triggering, we established polarized antigen- specific Th2 type responses in BALB/ c mice, using ovalbumin in conjunction with aluminum hydroxide. Upon challenge at the colonic mucosa through transient ( 3 - 4 days) expression of the antigen gene encoded in an adenovirus vector, sensitized animals developed significant subepithelial colonic inflammation, characterized by marked eosinophilic infiltration, and the presence of enlarged and increased numbers of lymphoid follicles. The alterations peaked around day 5 and resolved over the next 5 - 10 days, and no epithelial cell damage was detected through the entire course. Administration of a control ( empty) adenovirus vector did not lead to any pathological changes. These data suggest that colonic eosinophilia can be induced by exposure to an antigen associated with preexisting Th2- skewed responses. Thus the model established here may provide a useful tool to study GI and, in particular, colonic inflammation with respect to underlying mechanisms involved in the recruitment and the immediate function of eosinophils. C1 Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. McMaster Univ, Ctr Gene Therapeut, Dept Pathol & Mol Med, Hamilton, ON L8S 4L8, Canada. McMaster Univ, Dept Med, Hamilton, ON L8S 4L8, Canada. RP Zhu, Q (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM zhuq@mail.nih.gov NR 58 TC 1 Z9 1 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD JUL PY 2007 VL 293 IS 1 BP G383 EP G390 DI 10.1152/ajpgi.00341.2006 PG 8 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 190QX UT WOS:000248075100043 PM 17431215 ER PT J AU Rajesh, M Mukhopadhyay, P Batkai, S Hasko, G Liaudet, L Drel, VR Obrosova, IG Pacher, P AF Rajesh, Mohanraj Mukhopadhyay, Partha Batkai, Sandor Hasko, Gyorgy Liaudet, Lucas Drel, Viktor R. Obrosova, Irina G. Pacher, Pal TI Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE oxidative stress; peroxynitrite; cannabinoids; endocannabinoids; inflammation; atherosclerosis ID INTERCELLULAR-ADHESION MOLECULE-1; NITRIC-OXIDE SYNTHASE; DIABETIC COMPLICATIONS; POLY(ADP-RIBOSE) POLYMERASE; SUPEROXIDE-PRODUCTION; FOAM CELLS; IN-VITRO; ACTIVATION; EXPRESSION; PHOSPHORYLATION AB A nonpsychoactive cannabinoid cannabidiol (CBD) has been shown to exert potent anti-inflammatory and antioxidant effects and has recently been reported to lower the incidence of diabetes in nonobese diabetic mice and to preserve the blood-retinal barrier in experimental diabetes. In this study we have investigated the effects of CBD on high glucose (HG)-induced, mitochondrial superoxide generation, NF-kappa B activation, nitrotyrosine formation, inducible nitric oxide synthase (iNOS) and adhesion molecules ICAM-1 and VCAM-1 expression, monocyte-endothelial adhesion, transendothelial migration of monocytes, and disruption of endothelial barrier function in human coronary artery endothelial cells (HCAECs). HG markedly increased mitochondrial superoxide generation (measured by flow cytometry using MitoSOX), NF-kappa B activation, nitrotyrosine formation, upregulation of iNOS and adhesion molecules ICAM-1 and VCAM-1, transendothelial migration of monocytes, and monocyte-endothelial adhesion in HCAECs. HG also decreased endothelial barrier function measured by increased permeability and diminished expression of vascular endothelial cadherin in HCAECs. Remarkably, all the above mentioned effects of HG were attenuated by CBD pretreatment. Since a disruption of the endothelial function and integrity by HG is a crucial early event underlying the development of various diabetic complications, our results suggest that CBD, which has recently been approved for the treatment of inflammation, pain, and spasticity associated with multiple sclerosis in humans, may have significant therapeutic benefits against diabetic complications and atherosclerosis. C1 NIAAA, Lab Physiol Studies, NIH, Bethesda, MD USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. Univ Lausanne Hosp, Dept Intens Care Med, Lausanne, Switzerland. Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. RP Pacher, P (reprint author), NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, 5625 Fishers Ln,MSC-9413, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov RI Batkai, Sandor/G-3889-2010; MUKHOPADHYAY, PARTHA/G-3890-2010; Pacher, Pal/B-6378-2008; Drel, Viktor/G-8883-2016; Batkai, Sandor/H-7983-2014; Liaudet, Lucas/E-1322-2017 OI MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Pacher, Pal/0000-0001-7036-8108; Drel, Viktor/0000-0003-4542-0132; Liaudet, Lucas/0000-0003-2670-4930 FU Intramural NIH HHS [Z01 AA000375-02] NR 55 TC 67 Z9 70 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 JUL PY 2007 VL 293 IS 1 BP H610 EP H619 DI 10.1152/ajpheart.00236.2007 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 189DE UT WOS:000247968800074 PM 17384130 ER PT J AU Yang, SL Lin, L Chen, JX Lee, CR Seubert, JM Wang, Y Wang, H Chao, ZR Tao, DD Gong, JP Lu, ZY Wang, DW Zeldin, DC AF Yang, Shilin Lin, Li Chen, Ji-Xiong Lee, Craig R. Seubert, John M. Wang, Yan Wang, Hong Chao, Zhong-Ren Tao, De-Ding Gong, Jian-Ping Lu, Zai-Ying Wang, Dao Wen Zeldin, Darryl C. TI Cytochrome P-450 epoxygenases protect endothelial cells from apoptosis induced by tumor necrosis factor-alpha via MAPK and PI3K/Akt signaling pathways SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE epoxyeicosatrienoic acid; arachidonic acid ID ARACHIDONIC-ACID METABOLISM; NITRIC-OXIDE; EPOXYEICOSATRIENOIC ACIDS; TYROSINE PHOSPHORYLATION; HYPERPOLARIZING FACTOR; INHIBITS APOPTOSIS; SMOOTH-MUSCLE; GROWTH-FACTOR; UP-REGULATION; KINASE AB Endothelial cells play a vital role in the maintenance of cardiovascular homeostasis. Epoxyeicosatrienoic acids (EETs), cytochrome P-450 (CYP) epoxygenase metabolites of arachidonic acid in endothelial cells, possess potent and diverse biological effects within the vasculature. We evaluated the effects of overexpression of CYP epoxygenases on tumor necrosis factor-alpha (TNF-alpha)-induced apoptosis in bovine aortic endothelial cells. CYP epoxygenase overexpression significantly increased endothelial cell viability and inhibited TNF-alpha induction of endothelial cell apoptosis as evaluated by morphological analysis of nuclear condensation, DNA laddering, and fluorescent-activated cell sorting ( FACS) analysis. CYP epoxygenase overexpression also significantly inhibited caspase-3 activity and downregulation of Bcl-2 expression induced by TNF-alpha. The antiapoptotic effects of CYP epoxygenase overexpression were significantly attenuated by inhibition of the phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK signaling pathways; however, inhibition of endothelial nitric oxide synthase activity had no effect. Furthermore, CYP epoxygenase overexpression significantly attenuated the extent of TNF-alpha-induced ERK1/2 dephosphorylation in a time-dependent manner and significantly increased PI3K expression and Akt phosphorylation in both the presence and absence of TNF-alpha. Collectively, these results suggest that CYP epoxygenase overexpression, which is known to increase EET biosynthesis, significantly protects endothelial cells from apoptosis induced by TNF-alpha. This effect is mediated, at least in part, through inhibition of ERK dephosphorylation and activation of PI3K/Akt signaling. C1 Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Inst Hypertens & Dept Internal Med, Wuhan 430030, Peoples R China. Natl Inst Environm Hlth Sci, Div Intramural Res, Res Triangle Pk, NC USA. Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada. Beijing Univ, Life Sci Coll, Beijing 100871, Peoples R China. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Inst Hypertens & Dept Internal Med, 1095 Jie Fang Da Dao Ave, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.edu.cn FU Intramural NIH HHS [Z01 ES025034-13] NR 49 TC 73 Z9 78 U1 4 U2 15 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 JUL PY 2007 VL 293 IS 1 BP H142 EP H151 DI 10.1152/ajpheart.00783.2006 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 189DE UT WOS:000247968800021 PM 17322420 ER PT J AU Brass, DM Hollingsworth, JW McElvania-Tekippe, E Garantziotis, S Hossain, I Schwartz, DA AF Brass, David M. Hollingsworth, John W. McElvania-Tekippe, Erin Garantziotis, Stavros Hossain, Imtaz Schwartz, David A. TI CD14 is an essential mediator of LPS-induced airway disease SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE lipopolysaccharide; airways hyperresponsiveness; tumor necrosis factor; inflammation ID NECROSIS-FACTOR-ALPHA; TOLL-LIKE RECEPTOR-4; ACUTE LUNG INJURY; SOLUBLE CD14; EPITHELIAL-CELLS; BINDING-PROTEIN; INHALED ENDOTOXIN; ENDOTHELIAL-CELLS; GENE-EXPRESSION; TRANSGENIC MICE AB Chronic lipopolysaccharide ( LPS) inhalation in rodents recapitulates many classic features of chronic obstructive pulmonary disease seen in humans, including airways hyperresponsiveness, neutrophilic inflammation, cytokine production in the lung, and small airways remodeling. CD14- deficient mice ( C57BL/6(CD14-/-)) have an altered response to systemic LPS, and yet the role of CD14 in the response to inhaled LPS has not been defined. We observed that C57BL/6(CD14-/-) mice demonstrate no discernable physiological or inflammatory response to a single LPS inhalation challenge. However, the physiological ( airways hyperresponsiveness) and inflammatory ( presence of neutrophils and TNF-alpha whole lung lavage fluid) responsiveness to inhaled LPS in C57BL/ 6(CD14-/-) mice was restored by instilling soluble CD14 intratracheally. Intratracheal instillation of wild- type macrophages into C57BL/6(CD14-/-) mice restored neutrophilic inflammation only and failed to restore airways hyperresponsiveness or TNF-alpha protein in whole lung lavage. These findings demonstrate that CD14 is critical to LPS- induced airway disease and that macrophage CD14 is sufficient to initiate neutrophil recruitment into the airways but that CD14 may need to interact with other cell types as well for the development of airways hyperresponsiveness and for cytokine production. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Duke Univ, Div Pulm Allergy & Crit Care Med, Med Ctr, Durham, NC USA. RP Brass, DM (reprint author), NIEHS, POB 12233,Rall Bldg,Rm C224,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM brassd@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU NIEHS NIH HHS [ES-101945, ES-101946, ES-101947] NR 45 TC 31 Z9 31 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD JUL PY 2007 VL 293 IS 1 BP L77 EP L83 DI 10.1152/ajplung.00282.2006 PG 7 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 188FT UT WOS:000247905500011 PM 17384086 ER PT J AU Li, CL Wang, WD Norregaard, R Knepper, MA Nielsen, S Frokiaer, J AF Li, Chunling Wang, Weidong Norregaard, Rikke Knepper, Mark A. Nielsen, Soren Frokiaer, Jorgen TI Altered expression of epithelial sodium channel in rats with bilateral or unilateral ureteral obstruction SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE collecting duct; distal convoluted tube; sodium transport; sodium reabsorption; obstructive nephropathy ID CORTICAL COLLECTING DUCT; DOWN-REGULATION; MEDIATED REGULATION; TARGET TISSUE; GAMMA-SUBUNIT; BETA-SUBUNIT; RENAL WATER; NA+ CHANNEL; ALPHA-ENAC; KIDNEY AB The roles of epithelial sodium channel (ENaC) subunits (alpha, beta, and gamma) in the impaired renal reabsorption of sodium and water were examined in rat models with bilateral (BUO) or unilateral ureteral obstruction (UUO) for 24 h or with BUO followed by release of obstruction and 3 days of observation (BUO-3dR). In BUO rats, plasma osmolality was increased dramatically, whereas plasma sodium concentration was decreased. Immunoblotting revealed a significantly decreased expression of alpha-ENaC (57 +/- 7%), beta-ENaC (19 +/- 5%), and gamma-ENaC (51 +/- 10%) as well as 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) in the cortex and outer medulla (C + OM) compared with sham-operated controls. This was confirmed by immunohistochemistry. BUO-3dR was associated with polyuria and impaired renal sodium handling. The protein abundance and the apical labeling of alpha-ENaC were significantly increased, whereas beta- and gamma-ENaC as well as 11 beta-HSD2 expression remained decreased. In UUO rats, expression of alpha- and beta-ENaC and 11 beta-HSD2 decreased in the C + OM in the obstructed kidney. In contrast, the abundance and the apical labeling of alpha-ENaC in the nonobstructed kidneys were markedly increased, suggesting compensatory upregulation in this kidney. In conclusion, alpha-, beta-, and gamma-ENaC expression levels are downregulated in the obstructed kidney. The expression and apical labeling of alpha-ENaC were increased in BUO-3dR rats and in the nonobstructed kidneys from UUO rats. These results suggest that altered expression of alpha-, beta-, and gamma-ENaC may contribute to impaired renal sodium and water handling in response to ureteral obstruction. C1 Univ Aarhus, Water & Salt Res Ctr, Inst Clin Med, Dept Clin Physiol,Hosp Skejby, DK-8230 Aarhus N, Denmark. Univ Aarhus, Dept Cell Biol, Inst Anat, Aarhus C, Denmark. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Frokiaer, J (reprint author), Univ Aarhus, Water & Salt Res Ctr, Inst Clin Med, Dept Clin Physiol,Hosp Skejby, Brendstrupgaardsvej, DK-8230 Aarhus N, Denmark. EM jf@ki.au.dk FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 40 TC 6 Z9 6 U1 0 U2 3 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 JUL PY 2007 VL 293 IS 1 BP F333 EP F341 DI 10.1152/ajprenal.00372.2006 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 187LZ UT WOS:000247850500043 PM 17475897 ER PT J AU Nusing, RM Schweer, H Fleming, I Zeldin, DC Wegmann, M AF Nuesing, Rolf M. Schweer, Horst Fleming, Ingrid Zeldin, Darryl C. Wegmann, Markus TI Epoxyeicosatrienoic acids affect electrolyte transport in renal tubular epithelial cells: dependence on cyclooxygenase and cell polarity SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE kidney; CYP450; prostaglandin; collecting duct ID CORTICAL COLLECTING DUCT; ARACHIDONIC-ACID; ENDOTHELIAL-CELLS; 5,6-EPOXYEICOSATRIENOIC ACID; RAT-KIDNEY; MOLECULAR-CLONING; CALCIUM INFLUX; ANGIOTENSIN-II; PRINCIPAL CELL; K+ CHANNEL AB We investigated the effects of epoxyeicosatrienoic acids (EETs) on ion transport in the polarized renal distal tubular cell line, Madin-Darby canine kidney (MDCK) C7. Of the four EET regioisomers (5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET) studied, only apical, but not basolateral, application of 5,6-EET increased short-circuit current (I(sc)) with kinetics similar to those of arachidonic acid. The ion transport was blocked by preincubation with the cyclooxygenase inhibitor indomethacin or with the chloride channel blocker NPPB. Furthermore, both a Cl(-)-free bath solution and the Ca(2+) antagonist verapamil blocked 5,6-EET-induced ion transport. Although the presence of the PGE(2) receptors EP2, EP3, and EP4 was demonstrated, apically added PGE(2) was ineffective and basolaterally added PGE(2) caused a different kinetics in ion transport compared with 5,6-EET. Moreover, PGE(2) sythesis in MDCK C7 cells was unaffected by 5,6-EET treatment. GC/MS/MS analysis of cell supernatants revealed the presence of the biologically inactive 5,6-dihydroxy-PGE1 in 5,6-EET-treated cells, but not in control cells. Indomethacin suppressed the formation of 5,6-dihydroxy-PGE1. 5,6-Epoxy-PGE(1), the precursor of 5,6-dihydroxy-PGE1, caused a similar ion transport as 5,6-EET. Cytochrome P-450 enzymes homolog to human CYP2C8, CYP2C9, and CYP2J2 protein were detected immunologically in the MDCK C7 cells. Our findings suggest that 5,6-EET affects Cl(-) transport in renal distal tubular cells independent of PGE2 but by a mechanism, dependent on its conversion to 5,6-epoxy-PGE(1) by cyclooxygenase. We suggest a role for this P450 epoxygenase product in the regulation of electrolyte transport, especially as a saluretic compound acting from the luminal side of tubular cells in the mammalian kidney. C1 Univ Frankfurt, Inst Clin Pharmacol, D-60590 Frankfurt, Germany. Univ Marburg, Dept Pediat, Marburg, Germany. Univ Frankfurt, Inst Cardiovasc Physiol, Vasc Signalling Grp, D-60590 Frankfurt, Germany. Natl Inst Environm Hlth Sci, Div Intramural Res, NIH, Res Triangle Pk, NC USA. RP Nusing, RM (reprint author), Univ Frankfurt, Inst Clin Pharmacol, Bldg 75,Theodor Stern Kai 7, D-60590 Frankfurt, Germany. EM r.m.nuesing@med.uni-frankfurt.de RI Schweer, Horst/C-6240-2008; Fleming, Ingrid/L-1225-2014 OI Fleming, Ingrid/0000-0003-1881-3635 FU Intramural NIH HHS [Z01 ES025034-13] NR 46 TC 11 Z9 11 U1 0 U2 3 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 JUL PY 2007 VL 293 IS 1 BP F288 EP F298 DI 10.1152/ajprenal.00171.2006 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 187LZ UT WOS:000247850500038 PM 17494091 ER PT J AU Oppermann, M Hansen, PB Castrop, H Schnermann, J AF Oppermann, Mona Hansen, Pernille B. Castrop, Hayo Schnermann, Jurgen TI Vasodilatation of afferent arterioles and paradoxical increase of renal vascular resistance by furosemide in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE renal blood flow; superficial blood flow; candesartan; decapsulation; tubular pressure; NKCC1 knockout ID BLOOD-FLOW AUTOREGULATION; THICK ASCENDING LIMB; TUBULOGLOMERULAR FEEDBACK; MYOGENIC AUTOREGULATION; PROSTAGLANDIN SYSTEM; BARTTERS-SYNDROME; ARACHIDONIC-ACID; ANGIOTENSIN-II; LOOP DIURETICS; NITRIC-OXIDE AB Loop diuretics like furosemide have been shown to cause renal vasodilatation in dogs and humans, an effect thought to result from both a direct vascular dilator effect and from inhibition of tubuloglomerular feedback. In isolated perfused afferent arterioles preconstricted with angiotensin II or N(G)-nitro-L-arginine methyl ester, furosemide caused a dose-dependent increase of vascular diameter, but it was without effect in vessels from NKCC1(-/-) mice suggesting that inhibition of NKCC1 mediates dilatation in afferent arterioles. In the intact kidney, however, furosemide (2 mg/kg iv) caused a 50.5 +/- 3% reduction of total renal blood flow (RBF) and a 27% reduction of superficial blood flow (SBF) accompanied by a marked and immediate increase of tubular pressure and volume. At 10 mg/kg, furosemide reduced RBF by 60.4 +/- 2%. Similarly, NKCC1(-/-) mice responded to furosemide with a 45.4% decrease of RBF and a 29% decrease of SBF. Decreases in RBF and SBF and increases of tubular pressure by furosemide were ameliorated by renal decapsulation. In addition, pretreatment with candesartan (2 mg/kg) or indomethacin (5 mg/kg) attenuated the reduction of RBF and peak urine flows caused by furosemide. Our data indicate that furosemide, despite its direct vasodilator potential in isolated afferent arterioles, causes a marked increase in flow resistance of the vascular bed of the intact mouse kidney. We suggest that generation of angiotensin II and/or a vasoconstrictor prostaglandin combined with compression of peritubular capillaries by the expanding tubular compartment are responsible for the reduction of RBF in vivo. C1 NIDDK, NIH, Bethesda, MD 20892 USA. Univ So Denmark, Dept Physiol & Pharmacol, Odense, Denmark. Univ Regensburg, Inst Physiol, D-8400 Regensburg, Germany. RP Schnermann, J (reprint author), NIDDK, NIH, Bldg 10,Rm 4D51,10 Ctr Dr MSC 1370, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov FU Intramural NIH HHS NR 44 TC 27 Z9 27 U1 1 U2 1 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 JUL PY 2007 VL 293 IS 1 BP F279 EP F287 DI 10.1152/ajprenal.00484.2006 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 187LZ UT WOS:000247850500037 PM 17494095 ER PT J AU Klabunde, CN Meissner, HI Wooten, KG Breen, N Singleton, JA AF Klabunde, Carrie N. Meissner, Helen I. Wooten, Karen G. Breen, Nancy Singleton, James A. TI Comparing colorectal cancer screening and immunization status in older Americans SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HEALTH INTERVIEW SURVEY; PNEUMOCOCCAL VACCINATION; RACIAL/ETHNIC DISPARITIES; PREVENTIVE SERVICES; UNITED-STATES; INFLUENZA; MEDICARE; CARE; VALIDATION; TELEPHONE AB Background: This study examined patterns of use of three adult preventive services-influenza vaccination, pneumococcal polysaccharide vaccination, and colorectal cancer (CRC) screening; factors associated with different use patterns; and reasons for non-use. Methods: Data from 3675 individuals aged 65 and older responding to the 2004 National Adult Immunization Survey, which included a CRC screening module, were analyzed in 2005-2006. Descriptive statistics were used to characterize patterns of use of preventive services, and to assess reasons for non-use. Polytomous logistic regression modeling was used to identify predictors of specific use patterns. Results: Thirty-seven percent of respondents were current with all three preventive services; 10% were not current with any. Preventive services rise varied by demographic and healthcare utilization characteristics. Having a recent visit to a doctor or other health provider was the most consistent predictor of use. Concern about side effects was the most frequently cited reason for not having an influenza vaccination (25%), while not knowing that the preventive service was needed was the most common reason for non-use of pneumonia vaccination (47%) and CRC tests (44% FOBT, 51% sigmoidoscopy, 47% colonoscopy). Conclusions: Rates of influenza and pneumonia vaccination and CRC screening are suboptimal. This is especially apparent when examining the combined use of these services. Patient and provider activation and the new "Welcome to Medicare" benefit are among the strategies that may improve use of these services among older Americans. Ongoing monitoring and further research are required to determine the most effective approaches. C1 NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Appl Canc Screening Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Immunizat & Resp Dis, Atlanta, GA USA. RP Klabunde, CN (reprint author), NCI, Hlth Serv & Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, EPN 4005,6130 Execut Blvd, Bethesda, MD 20892 USA. EM klabtmdc@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [Y01 PC004037, Y1-PC-4037] NR 33 TC 29 Z9 29 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD JUL PY 2007 VL 33 IS 1 BP 1 EP 8 DI 10.1016/j.amepre.2007.02.043 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 184WF UT WOS:000247672600001 PM 17572304 ER PT J AU McMahon, FJ AF McMahon, Francis J. TI A success at the end of an era, and a glimpse of things to come SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID BIPOLAR DISORDER; LINKAGE; CHROMOSOME-18; FAMILIES; ILLNESS; G72/G30; LOCUS C1 NIMH, Genet Basis Mood & Anxiety Disorders, Bethesda, MD 20892 USA. RP McMahon, FJ (reprint author), NIMH, Genet Basis Mood & Anxiety Disorders, 35 Convent Dr,Bldg 35,Rm 1A202, Bethesda, MD 20892 USA. EM mcmahonf@mail.nih.gov RI McMahon, Francis/A-7290-2009; OI McMahon, Francis/0000-0002-9469-305X FU Intramural NIH HHS NR 10 TC 1 Z9 2 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUL PY 2007 VL 164 IS 7 BP 999 EP 1001 DI 10.1176/appi.ajp.164.7.999 PG 3 WC Psychiatry SC Psychiatry GA 187TZ UT WOS:000247872700004 PM 17606647 ER PT J AU Buchsbaum, MS Buchsbaum, BR Hazlett, EA Haznedar, MM Newmark, R Tang, CY Hof, PR AF Buchsbaum, Monte S. Buchsbaum, Bradley R. Hazlett, Erin A. Haznedar, M. Mehmet Newmark, Randall Tang, Cheuk Y. Hof, Patrick R. TI Relative glucose metabolic rate higher in white matter in patients with schizophrenia SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; SCHIZOTYPAL PERSONALITY-DISORDER; MULTIPLE-SCLEROSIS; PREFRONTAL CORTEX; BASAL GANGLIA; RADIATION MYELOPATHY; MEDIODORSAL NUCLEUS; FRONTAL-CORTEX; SPINAL-CORD; FDG-PET AB Objective: There is increasing evidence demonstrating that circuits involving the frontal lobe, striatum, temporal lobe, and cerebellum are abnormal in individuals with schizophrenia, which suggests that metabolic activity in the white matter connecting these areas should be investigated. Method- The authors obtained [F-18]fluorodeoxyglucose(FDG) positron emission tomography (PET) and matching T1-weighted magnetic resonance imaging (MRI) on 170 subjects. Participants were 103 normal volunteers and 67 unmedicated patients with schizophrenia (N=61) or schizoaffective disorder (N=6). The images were coregistered and warped to standard space for significance probability mapping. Results: Compared with normal volunteers, patients showed higher relative metabolic rates in the frontal white matter, corpus callosum, superior longitudinal fasciculus, and white matter core of the temporal lobe. Elevated activity in white matter was most pronounced in the center of large white matter tracts, especially the frontal parts of the brain and the internal capsule. The white matter elevation did not appear to be entirely related to changes in gray matter/white matter brain proportions, whole brain metabolic rate bias, or excess head motion in patients, but this cannot be ruled out without absolute glucose determinations. Patients also showed significantly lower relative glucose metabolism in the frontal and temporal lobes, caudate nucleus, cingulate gyrus, and mediodorsal nucleus of the thalamus relative to normal volunteers, which is consistent with earlier studies. Conclusions: In comparisons of unmedicated schizophrenia patients with normal volunteers, relative metabolic increases are apparent in white matter in patients with schizophrenia as well as decreases in gray matter. Inefficiency in brain circuitry, defects in white matter leading to enhanced energy need, white matter damage, and alterations in axon packing density are among the possible explanations for these schizophrenia-related findings of relatively increased metabolism in white matter. C1 Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Mt Sinai Sch Med, Dept Radiol, New York, NY USA. Mt Sinai Sch Med, Dept Neurosci, New York, NY USA. NIMH, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. RP Buchsbaum, MS (reprint author), Mt Sinai Med Ctr, Neurosci PET Lab, Box 1505,1 Gustave L Levy Pl, New York, NY 10029 USA. EM monte.buchsbaum@mssm.edu FU NCRR NIH HHS [RR-0071]; NIMH NIH HHS [MH40071, MH66392, MH60023] NR 58 TC 50 Z9 51 U1 1 U2 1 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD JUL PY 2007 VL 164 IS 7 BP 1072 EP 1081 DI 10.1176/appi.ajp.164.7.1072 PG 10 WC Psychiatry SC Psychiatry GA 187TZ UT WOS:000247872700018 PM 17606659 ER PT J AU McCormack, FX Moss, J AF McCormack, Francis X. Moss, Joel TI S-LAM in a man? SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID TUBEROUS SCLEROSIS COMPLEX; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; MUTATION ANALYSIS; TSC2; LYMPHANGIOMYOMATOSIS; WOMEN; CELLS; SERUM C1 Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP McCormack, FX (reprint author), Univ Cincinnati, Coll Med, Cincinnati, OH 45221 USA. OI McCormack, Francis/0000-0001-7168-9464 NR 19 TC 5 Z9 5 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 1 PY 2007 VL 176 IS 1 BP 3 EP 5 DI 10.1164/rccm.200703-514ED PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 183CH UT WOS:000247549800003 PM 17586762 ER PT J AU Hoshino, T Kato, S Oka, N Imaoka, H Kinoshita, T Takei, S Kitasato, Y Kawayama, T Imaizumi, T Yamada, K Young, HA Aizawa, H AF Hoshino, Tomoaki Kato, Seiya Oka, Naoki Imaoka, Haruki Kinoshita, Takashi Takei, Satoko Kitasato, Yasuhiko Kawayama, Tomotaka Imaizumi, Tsutomu Yamada, Kentaro Young, Howard A. Aizawa, Hisamichi TI Pulmonary inflammation and emphysema - Role of the Cytokines IL-18 and IL-13 SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE emphysema; IFN-gamma; IL-13; IL-18; transgenic mouse ID ADULT MURINE LUNG; CHRONIC-BRONCHITIS; PROINFLAMMATORY CYTOKINE; AIRWAY OBSTRUCTION; TRANSGENIC MICE; POTENTIAL ROLE; T-LYMPHOCYTES; DISEASE; EXPRESSION; INTERLEUKIN-18 AB Rationale: Chronic obstructive pulmonary disease (COPD) is believed to be an inflammatory cytokine-driven disease, but a causal basis that can be associated with a specific cytokine has not been directly demonstrated. We have previously reported that proinflammatory cytokine IL-18 expression is important in the pathogenesis of pulmonary inflammation and lung injury in mice. Our results demonstrate that IL-18 overproduction in the lungs can induce lung diseases, such as pulmonary inflammation, lung fibrosis, and COPD. Objectives: We analyzed the role of IL-18 in the pathogenesis of COPD. Methods: Using the human surfactant protein C promoter to drive expression of mature mouse IL-18 cDNA, we developed two different lines of transgenic (Tg) mice that overproduced mouse mature IL-18 in the lungs either constitutively or in response to doxycycline. Measurements and Main Results: Constitutive overproduction of IL-18 in the lungs resulted in the increased production of IFN-gamma, IL-5, and IL-13, and chronic pulmonary lung inflammation with the appearance of CD8(+) T cells, macrophages, neutrophils, and eosinophils. Increased lung volume, severe emphysematous change, dilatation of the right ventricle, and mild pulmonary hypertension were observed in (more than 15-wk-old) Tg mice. Interestingly, disruption of the IL-13 gene, but not the IFN-gamma gene, prevented emphysema and pulmonary inflammation in Tg mice. Moreover, when IL-18 production was induced in lung tissues for 4 weeks through the use of a doxycycline-dependent surfactant protein C promoter, interstitial inflammation was induced. Conclusions: Our results indicate that IL-18 and IL-13 may have an important role in the pathogenesis of COPD. C1 Kurume Univ, Sch Med, Dept Internal Med 1, Kurume, Fukuoka 8300011, Japan. Kurume Univ, Sch Med, Dept Pathol, Kurume, Fukuoka, Japan. Ctr Canc Res, Natl Canc Inst, Expt Immunol Lab, Frederick, MD USA. Kurume Univ, Sch Med, Cardiovasc Res Inst, Kurume, Fukuoka, Japan. Univ Ryukyus, Fac Med, Grad Sch, Div Pathol & Cell Biol, Okinawa, Japan. RP Hoshino, T (reprint author), Kurume Univ, Sch Med, Dept Internal Med 1, 67 Asahi-machi, Kurume, Fukuoka 8300011, Japan. EM hoshino@med.kurume-u.ac.jp NR 44 TC 69 Z9 73 U1 0 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD JUL 1 PY 2007 VL 176 IS 1 BP 49 EP 62 DI 10.1164/rccm.200603-316OC PG 14 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 183CH UT WOS:000247549800010 PM 17400729 ER PT J AU Reddy, NM Kleeberger, SR Cho, HY Yamamoto, M Kensler, TW Biswal, S Reddy, SP AF Reddy, Narsa M. Kleeberger, Steven R. Cho, Hye-Youn Yamamoto, Masayuki Kensler, Thomas W. Biswal, Shyam Reddy, Sekhar P. TI Deficiency in Nrf2-GSH signaling impairs type II cell growth and enhances sensitivity to oxidants SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE oxidative stress; lung; antioxidants; cell proliferation ID OXIDATIVE STRESS; CYCLE PROGRESSION; GLUTATHIONE; LUNG; MICE; SUSCEPTIBILITY; INFLAMMATION; INHIBITION; PROTECTS; SURVIVAL AB Redox imbalance has been implicated in the pathogenesis of many acute and chronic lung diseases. The b-Zip transcription factor Nrf2 acts via an antioxidant/electrophilic response element to regulate antioxidants and maintain cellular redox homeostasis. Our previous studies have shown that Nrf2-deficient mice (Nrf2(-/-)) show reduced pulmonary expression of several antioxidant enzymes, which renders them highly susceptible to hyperoxia-induced lung injury. To better understand the physiologic significance of Nrf2-induced redox signaling, we have used primary cells isolated from the lungs of Nrf2(+/+) and Nrf2(-/-) mice. Our studies were focused on type II cells because these cells are constantly exposed to the oxidant environment and play key roles in host defense, injury, and repair processes. Using this system, we now report that an Nrf2 deficiency leads to defects in type II cell proliferation and greatly enhances the cells' sensitivity to oxidant-induced cell death. These defects were closely associated with high levels of reactive oxygen species (ROS) and redox imbalance in Nrf2(-/-) cells. Glutathione (GSIH) supplementation rescued these phenotypic defects associated with the Nrf2 deficiency. Intriguingly, although the antioxidant N-acetylcysteine drastically squelched ROS levels, it was unable to counteract growth arrest in Nrf2(-/-) cells. Moreover, despite their elevated levels of ROS, Nrf2(-/-) type II cells were viable and, like their wildtype counterparts, exhibited normal differentiation characteristics. Our data suggest that dysfunctional Nrf2-regulated GSH-induced signaling is associated with deregulation of type II cell proliferation, which contributes to abnormal injury and repair and leads to respiratory impairment. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 305, Japan. Univ Tsukuba, Inst Basic Med Sci, Tsukuba, Ibaraki 305, Japan. RP Reddy, SP (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Rm E7547,615 N Wolfe St, Baltimore, MD 21205 USA. EM sreddy@jhsph.edu RI Yamamoto, Masayuki/A-4873-2010; Kensler, Thomas/D-8686-2014 OI Kensler, Thomas/0000-0002-6676-261X FU NHLBI NIH HHS [HL 66109, P50 HL 073994] NR 28 TC 61 Z9 66 U1 0 U2 4 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD JUL PY 2007 VL 37 IS 1 BP 3 EP 8 DI 10.1165/rcmb.2007-0004RC PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 184SE UT WOS:000247661500002 PM 17413030 ER PT J AU Sogoba, N Doumbia, S Vounatsou, P Baber, I Keita, M Maiga, M Traore, SF Toure, A Dolo, G Smith, T Ribeiro, JMC AF Sogoba, Nafomon Doumbia, Seydou Vounatsou, Penelope Baber, Ibrahima Keita, Moussa Maiga, Mamoudou Traore, Sekou F. Toure, Abdoulaye Dolo, Guimogo Smith, Thomas Ribeiro, Jose M. C. TI Monitoring of larval habitats and mosquito densities in the Sudan savanna of Mali: Implications for malaria vector control SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID ANOPHELES-GAMBIAE; DRY SEASON; POPULATION-SIZE; TRANSMISSION; AFRICA; SUPPRESSION; MANAGEMENT; KENYA; AREA AB In Mali, anopheline mosquito populations increase sharply during the rainy season, but are barely detectable in the dry season. This study attempted to identify the dry season mosquito breeding population in and near the village of Bancoumana, Mali, and in a fishing hamlet 5 km from this village and adjacent to the Niger River. In Bancoumana, most larval habitats were human made, and dried out in January-February. In contrast, in the fishing hamlet, productive larval habitats were numerous and found mainly during the dry season (January-May) as the natural result of drying riverbeds. Adult mosquitoes were abundant during the dry season in the fishermen hamlet and rare in Bancoumana. To the extent that the fishermen hamlet mosquito population seeds Bancoumana with the advent of the rainy season, vector control in this small hamlet may be a cost-effective way to ameliorate malaria transmission in the 40-times larger village. C1 NIAID, NIH, Lab Malaria & Vector Res, Rockville, MD 20892 USA. Univ Bamako, Fac Med, Malaria Res & Training Ctr, Bamako, Mali. Swiss Trop Inst, CH-4002 Basel, Switzerland. RP Ribeiro, JMC (reprint author), NIAID, NIH, Lab Malaria & Vector Res, 12735 Twinbrook Pkwy, Rockville, MD 20892 USA. EM nafomon@mrtcbko.org; sdoumbi@mrtcbko.org; baber@mrtcbko.org; moussa@mrtcbko.org; maigam@mrtcbko.org; cheick@mrtcbko.org; atoure@mrtcbko.org; guimogo@mrtcbko.org; Thomas-A.Smith@unibas.ch; jribeiro@niaid.nih.gov RI Smith, Thomas/B-5569-2015; OI Smith, Thomas/0000-0002-3650-9381; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS NR 21 TC 19 Z9 20 U1 1 U2 5 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 JUL PY 2007 VL 77 IS 1 BP 82 EP 88 PG 7 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 189HK UT WOS:000247979800013 PM 17620634 ER PT J AU Pace, NL Stylianou, MP AF Pace, Nathan L. Stylianou, Mario P. TI Advances in and limitations of up-and-down methodology - A precis of clinical use, study design, and dose estimation in anesthesia research SO ANESTHESIOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-of-Anesthesiologists CY OCT 22-26, 2005 CL Atlanta, GA SP Amer Soc Anesthesiologists ID MINIMUM ALVEOLAR CONCENTRATION; LOCAL ANALGESIC CONCENTRATION; EPIDURAL BUPIVACAINE; LABOR ANALGESIA; SEVOFLURANE CONCENTRATION; INTRATHECAL FENTANYL; SMALL SAMPLES; LEVOBUPIVACAINE; MAC; ROPIVACAINE AB Sequential design methods for binary response variables exist for determination of the concentration or dose associated with the 50% point along the dose-response curve; the up-and-down method of Dixon and Mood is now commonly used in anesthesia research. There have been important developments in statistical methods that (1) allow the design of experiments for the measurement of the response at any point (quantile) along the dose-response curve, (2) demonstrate the risk of certain statistical methods commonly used in literature reports, (3) allow the estimation of the concentration or dose-the target dose-associated with the chosen quantile without the assumption of the symmetry of the tolerance distribution, and (4) set bounds on the probability of response at this target dose. This article details these developments, briefly surveys current use of the up-and-down method in anesthesia research, reanalyzes published reports using the up-and-down method for the study of the epidural relief of pain during labor, and discusses appropriate inferences from up-and-down method studies. C1 Univ Utah, Dept Anesthesiol, Salt Lake City, UT 84132 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD USA. RP Pace, NL (reprint author), Univ Utah, Dept Anesthesiol, 30 N 1900 E,3C444, Salt Lake City, UT 84132 USA. EM n.l.pace@utah.edu NR 43 TC 123 Z9 134 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-3022 J9 ANESTHESIOLOGY JI Anesthesiology PD JUL PY 2007 VL 107 IS 1 BP 144 EP 152 DI 10.1097/01.anes.0000267514.42592.2a PG 9 WC Anesthesiology SC Anesthesiology GA 184AK UT WOS:000247613300022 PM 17585226 ER PT J AU Gregorio, DI Huang, L Dechello, LM Samociuk, H Kulldorff, M AF Gregorio, David I. Huang, Lan Dechello, Laurie M. Samociuk, Holly Kulldorff, Martin TI Place of residence effect on likelihood of surviving prostate cancer SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE prostate cancer; survival; geography AB PURPOSE: To examine geographic variation in survival time of men diagnosed with prostate cancer, adjusted for patient and disease characteristics. METHOD: Survival times for a geographically referenced database of 27,189 incident prostate cancer cases (ICD-O-2: C61.9) from Connecticut, 1984-1998, were evaluated using a newly developed extension of the spatial scan statistic for survival data. RESULTS: Statewide, median survival time was 4.6 years following diagnosis, Age-adjusted survival times across most locales around Connecticut did not differ markedly from the statewide pattern, but our analysis revealed 3 zones with noteworthy differences. Analysis of survival times adjusted for age as well as tumor grade and stage produced only two locations with significant results, and further adjustment for racial composition of cases yielded only one location with significant distinct (lower) survival times. Among cases within that place, the likelihood of dying was estimated to be 1.39-times greater than that of cases different from those diagnosed elsewhere around the state (P = 0.009). CONCLUSION: The prognosis for men with prostate cancer may differ, in part, by virtue of where they live when diagnosed. Measuring geographic differences in survival time should facilitate the targeting of clinical and ancillary services to persons at high risk of poor outcomes. C1 Univ Connecticut, Sch Med, Dept Commun Med & Hlth Care, Farmington, CT 06030 USA. Natl Canc Inst, Div Canc Control & Populat Studies, Stat Applicat & Res Branch, Boston, MA USA. Harvard Univ, Sch Med, Dept Ambulatory Cre & Prevent, Boston, MA USA. Harvard Pilgrim Hlth Care, Boston, MA USA. RP Gregorio, DI (reprint author), Univ Connecticut, Sch Med, Dept Commun Med & Hlth Care, Farmington, CT 06030 USA. EM gregorio@nso.uchc.edu RI Kulldorff, Martin/H-4282-2011; OI Kulldorff, Martin/0000-0002-5284-2993 FU PHS HHS [U50/CCU300860] NR 13 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 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD JUL PY 2007 VL 17 IS 7 BP 520 EP 524 DI 10.1016/j.annepidem.2006.12.003 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 187ZV UT WOS:000247888900006 PM 17448679 ER PT J AU Smith, SR Wahed, AS Kelley, SS Conjeevaram, HS Robuck, PR Fried, MW AF Smith, Scott R. Wahed, Abdus S. Kelley, Stephanie S. Conjeevaram, Hari S. Robuck, Patricia R. Fried, Michael W. CA Virahep-C Study Grp TI Assessing the validity of self-reported medication adherence in hepatitis C treatment SO ANNALS OF PHARMACOTHERAPY LA English DT Article DE hepatitis C; measurement; medication adherence ID RIBAVIRIN TREATMENT; THERAPY; PHYSICIAN AB OBJECTIVE: To assess the validity of self-reported medication adherence provided by individuals in treatment for hepatitis C virus (HCV) infection with a regimen of peginterferon and ribavirin. METHODS: Adherence was evaluated prospectively among 196 African American and 205 white subjects enrolled in Virahep-C (Viral Resistance to Antiviral Thearpy of Chronic Hepatitis C), a treatment study for genotype 1 HCV infection. Adherence to the prescribed dose was measured by 2 methods: self-report questions administered during multiple clinic visits, using a touch screen computer; and recordings of bottle openings, using an electronic monitor placed inside the cap of prescription containers. Self-reported responses were compared with the electronic monitor data. Nonparametric tests were used to test the association between adherence measures at 4, 12, 24, 36, and 48 weeks of treatment. RESULTS: The estimated proportion of participants who were adherent prior to a given visit ranged from 85% to 97% (ribavirin) and 97% to 100% (peginterferon) by self report and from 69% to 90% (ribavirin) and 84% to 100% (peginterferon) by electronic monitors. For ribavirin, the percentage of cases in which the 2 measurement methods agreed varied from 68% to 90%; peginterferon agreement was from 84% to 100%. Overall, adherence was higher for peginterferon than for ribavirin but decreased over time for both medications. Self-reported adherence was usually higher than that assessed by electronic measures, and the level of descrepancy increased during the course of treatment. CONCLUTIONS: Adherence to peginterferon and ribavirin decreased gradually during therapy but remained relatively high. Simple self-reported measures can be used to screen for nonadherence to HCV drug therapy, but should be considered as overestimation of the actual amounts taken. C1 Univ N Carolina, Sch Pharm, Chapel Hill, NC USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Univ Michigan, Ann Arbor, MI 48109 USA. NIDDK, Bethesda, MD USA. Univ N Carolina, Virahep C Study Grp, Chapel Hill, NC 27515 USA. Ctr Outcomes & Evidence, US Dept Hlth & Human Serv, Agcy Healthcare Res & Qual, Rockville, MD 20850 USA. RP Smith, SR (reprint author), Ctr Outcomes & Evidence, US Dept Hlth & Human Serv, Agcy Healthcare Res & Qual, 540 Gaither Rd, Rockville, MD 20850 USA. EM Scott.Smith@ahrq.hhs.gov RI Wahed, Abdus/A-6441-2008; OI Wahed, Abdus/0000-0001-6911-7221 NR 11 TC 31 Z9 32 U1 0 U2 0 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD JUL-AUG PY 2007 VL 41 IS 7-8 BP 1116 EP 1123 DI 10.1345/aph.1K024 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 193MW UT WOS:000248279100003 PM 17519299 ER PT J AU Lipsky, PE AF Lipsky, P. E. TI B cells and autoimmunity: A new target for intervention SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2007) CY JUN 13-16, 2007 CL Barcelona, SPAIN SP European League Against Rheumatism C1 [Lipsky, P. E.] NIH, Natl Inst Arthritis & Musculoskeletal & Skin Dis, NIAMS, Autoimmunity Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2007 VL 66 SU 2 BP 11 EP 11 PG 1 WC Rheumatology SC Rheumatology GA 261SU UT WOS:000253101100034 ER PT J AU Ferreiro-Neira, I Alonso-Perez, E Calaza, M Marchini, M Scorza, R Sebastiani, GD Blanco, F Rego, I Pullmann, R Pullmann, R Kallenberg, CG Bijl, M Skopouli, FN Mavromali, M Migliaresi, S D'Alfonso, S Ruzickova, S Dostal, C Schmidt, RE Witte, T Papasteriades, C Kappou-Rigatou, I Endreffy, E Gomez-Reino, JJ Gonzalez, A AF Ferreiro-Neira, I. Alonso-Perez, E. Calaza, M. Marchini, M. Scorza, R. Sebastiani, G. D. Blanco, F. Rego, I. Pullmann, R., Jr. Pullmann, R. Kallenberg, C. G. Bijl, M. Skopouli, F. N. Mavromali, M. Migliaresi, S. D'Alfonso, S. Ruzickova, S. Dostal, C. Schmidt, R. E. Witte, T. Papasteriades, C. Kappou-Rigatou, I. Endreffy, E. Gomez-Reino, J. J. Gonzalez, A. TI Separate association with susceptibility or protection to systemic lupus erythematosus of interferon regulatory factor 5 (IRF5) polymorphisms SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2007) CY JUN 13-16, 2007 CL Barcelona, SPAIN SP European League Against Rheumatism C1 [Ferreiro-Neira, I.; Alonso-Perez, E.; Calaza, M.; Gomez-Reino, J. J.; Gonzalez, A.] Univ Santiago, Hosp Clin, Rheumatol Unit, Lab Invest 2, Santiago De Compostela, Spain. [Marchini, M.; Scorza, R.] Univ Milan, Fdn IRCCS Osped Magiorre Policlin, Milan, Italy. [Sebastiani, G. D.] Osped S Camillo Forlanini, UO Complessa Reumatol, Rome, Italy. [Blanco, F.; Rego, I.] CH Univ Juan Canalejo, Serv Reumatol, La Coruna, Spain. [Pullmann, R., Jr.] NIH, NIA, Gerontol Res Ctr, Baltimore, MD USA. [Pullmann, R.] Martin Fac Hosp, Inst Clin Biochem, Martin, Slovakia. [Kallenberg, C. G.; Bijl, M.] Univ Groningen, Univ Med Ctr Groningen, Dept Rheumatol & Clin Immunol, Groningen, Netherlands. [Skopouli, F. N.; Mavromali, M.] Univ Athens, Sch Med, Pathophys Dept, Athens, Greece. [Migliaresi, S.] Univ Naples 2, Rheumatol Unit, Naples, Italy. [D'Alfonso, S.] Eastern Piedmont Univ, IRCAD, Dept Med Sci, Novara, Italy. [Ruzickova, S.; Dostal, C.] Inst Rheumatol, Mol Biol & Immunogenet Dept, Prague, Czech Republic. [Schmidt, R. E.; Witte, T.] Hannover Med Sch, Div Clin Immunol, Hannover, Germany. [Papasteriades, C.; Kappou-Rigatou, I.] Evangelismos Med Ctr, Dept Histocompatibility & Immunol, Athens, Greece. [Endreffy, E.] Univ Szeged, Dept Pediat, Szeged, Hungary. RI D'Alfonso, Sandra/K-7295-2014; Witte, Torsten/B-5783-2016; Rego-Perez, Ignacio/B-1665-2012 OI D'Alfonso, Sandra/0000-0002-3983-9925; Rego-Perez, Ignacio/0000-0003-1754-1164 NR 3 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2007 VL 66 SU 2 BP 112 EP 113 PG 2 WC Rheumatology SC Rheumatology GA 261SU UT WOS:000253101100356 ER PT J AU Reveille, JD Zhou, X Bradbury, LA Cardon, LR Davis, JC Deloukas, P Evans, DM Keniry, A McGinnis, R Pointon, J Ward, MM Weisman, MH Wordsworth, P Brown, MA AF Reveille, J. D. Zhou, X. Bradbury, L. A. Cardon, L. R. Davis, J. C. Deloukas, P. Evans, D. M. Keniry, A. McGinnis, R. Pointon, J. Ward, M. M. Weisman, M. H. Wordsworth, P. Brown, M. A. TI Il-23r is a major determinant of ankylosing spondylitis risk - The tasc study SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2007) CY JUN 13-16, 2007 CL Barcelona, SPAIN SP European League Against Rheumatism C1 [Reveille, J. D.] Univ Texas Houston, Sch Med, Houston, England. [Zhou, X.] Univ Texas Houston, Sch Med, Houston, TX USA. [Bradbury, L. A.; Brown, M. A.] Univ Queensland, Diamantina Res Inst, Brisbane, Qld, Australia. [Cardon, L. R.; Evans, D. M.] Wellcome Trust Ctr Human Genet, Oxford, England. [Davis, J. C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Deloukas, P.; Keniry, A.; McGinnis, R.] Sanger Ctr, Human Genet Grp, Cambridge, England. [Pointon, J.; Wordsworth, P.] Univ Oxford, Botnar Res Ctr, Oxford, England. [Ward, M. M.] NIH, Natl Inst Arthritis & Musculoskeletal & Skin Dis, Washington, DC USA. [Weisman, M. H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RI Deloukas, Panos/B-2922-2013; Evans, David/H-6325-2013 OI Deloukas, Panos/0000-0001-9251-070X; NR 0 TC 5 Z9 5 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2007 VL 66 SU 2 BP 112 EP 112 PG 1 WC Rheumatology SC Rheumatology GA 261SU UT WOS:000253101100355 ER PT J AU Neugebauer, K Herzog, C Pundt, N Meyer, L Kollas, G Blackshear, PJ Schett, G Pap, T Echtermeyer, F AF Neugebauer, K. Herzog, C. Pundt, N. Meyer, L. Kollas, G. Blackshear, P. J. Schett, G. Pap, T. Echtermeyer, F. TI Syndecan-4 is highly expressed in human RA and in TNF-alpha dependent models of destructive arthritis and regulates cytokines-induced expression of MMP in arhtritic synovial fibroblasts via ERK SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2007) CY JUN 13-16, 2007 CL Barcelona, SPAIN SP European League Against Rheumatism C1 [Neugebauer, K.; Pundt, N.; Meyer, L.; Echtermeyer, F.] Div Mol Med Musculoskeletal Tissue, Munster, Germany. [Herzog, C.] Univ Hosp Munster, Dept Anat, Munster, Germany. [Kollas, G.] Biomed Sci Res Ctr, Inst Immunol, Vari, Greece. [Blackshear, P. J.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. [Schett, G.] Univ Erlangen Nurnberg, Dept Rheumatol, D-8520 Erlangen, Germany. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2007 VL 66 SU 2 BP 115 EP 116 PG 2 WC Rheumatology SC Rheumatology GA 261SU UT WOS:000253101100366 ER PT J AU Fragouli, E Eliopoulos, E Petraki, E Galanakis, E Sidiropoulos, P Aksentijevich, I Kritikos, H Fragiadakis, G Boumpas, DT Goulielmos, G AF Fragouli, E. Eliopoulos, E. Petraki, E. Galanakis, E. Sidiropoulos, P. Aksentijevich, I. Kritikos, H. Fragiadakis, G. Boumpas, D. T. Goulielmos, G. TI Familial mediterranean fever (FMF): A genetic apphuagh in the cretan population and structural implications of the pyrin pryspry domain interactions SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2007) CY JUN 13-16, 2007 CL Barcelona, SPAIN SP European League Against Rheumatism C1 [Eliopoulos, E.] Univ Agr Athens, Agr Biotechnol, Athens, Greece. [Petraki, E.; Galanakis, E.; Sidiropoulos, P.; Kritikos, H.; Boumpas, D. T.; Goulielmos, G.] Univ Crete, Sch Med, Iraklion, Greece. [Aksentijevich, I.] NIAMSD, Genet Sect, Bethesda, MD USA. [Fragiadakis, G.] Asklipieion Hosp, Iraklion, Greece. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2007 VL 66 SU 2 BP 128 EP 128 PG 1 WC Rheumatology SC Rheumatology GA 261SU UT WOS:000253101100403 ER PT J AU Valencia, X Yarboro, C Illei, G Lipsky, P AF Valencia, X. Yarboro, C. Illei, G. Lipsky, P. TI Defective suppressor function of CD4+CD25HI T regulatory cells in active SLE SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2007) CY JUN 13-16, 2007 CL Barcelona, SPAIN SP European League Against Rheumatism C1 [Valencia, X.; Lipsky, P.] Autoimmunity Branch, Bethesda, MD USA. [Yarboro, C.] Off Clin Director, NIAMS, NIH, Bethesda, MD USA. [Illei, G.] NIDCR, NIH, Gene Therapy & Therapeut Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2007 VL 66 SU 2 BP 317 EP 317 PG 1 WC Rheumatology SC Rheumatology GA 261SU UT WOS:000253101101293 ER PT J AU Smolen, JS Aletaha, D van den Heijde, DM St Clair, EW Gathany, T Yan, S Baker, D AF Smolen, J. S. Aletaha, D. van den Heijde, D. M. St Clair, E. W. Gathany, T. Yan, S. Baker, D. TI Patterns of erosion and joint space narrowing development in patients with early rheumatoid arthritis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2007) CY JUN 13-16, 2007 CL Barcelona, SPAIN SP European League Against Rheumatism C1 [Smolen, J. S.] Med Univ Vienna, Hietzing Hosp, Vienna, Austria. [Aletaha, D.] Med Univ Vienna, Natl Inst Arthritis & Musculoskeletal & Skin Dis, Vienna, Austria. [van den Heijde, D. M.] Univ Hosp, Maastricht, Netherlands. [St Clair, E. W.] Duke Univ, Med Ctr, Durham, NC USA. [Baker, D.] Centocor Res & Dev Inc, Malvern, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2007 VL 66 SU 2 BP 368 EP 368 PG 1 WC Rheumatology SC Rheumatology GA 261SU UT WOS:000253101101460 ER PT J AU Bar Yehuda, S Jacobson, KA Joshi, B Gau, Z Ochaion, A Cohen, S Barer, F Zabutti, A Del-Valle, L Perez-Liz, G Fishman, P AF Bar Yehuda, S. Jacobson, K. A. Joshi, B. Gau, Z. Ochaion, A. Cohen, S. Barer, F. Zabutti, A. Del-Valle, L. Perez-Liz, G. Fishman, P. TI The anti-inflammatory effect of a new A3 adenosine receptor agonist MRS3558: Involvement of the NF-KAPPA B signal transduction pathway SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT Annual European Congress of Rheumatology (EULAR 2007) CY JUN 13-16, 2007 CL Barcelona, SPAIN SP European League Against Rheumatism C1 [Bar Yehuda, S.; Ochaion, A.; Cohen, S.; Barer, F.; Zabutti, A.; Fishman, P.] Can Fite BioPharma, Petah Tiqwa, Israel. [Jacobson, K. A.; Joshi, B.; Gau, Z.] Natl Inst Hlth, Bethesda, MD USA. [Del-Valle, L.; Perez-Liz, G.] Temple Univ, Sch Med, Neuropathol Core & Ctr Neurovirol, Philadelphia, PA 19122 USA. RI Del Valle, Luis/J-4085-2015 OI Del Valle, Luis/0000-0003-3894-9206 NR 2 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD JUL PY 2007 VL 66 SU 2 BP 441 EP 441 PG 1 WC Rheumatology SC Rheumatology GA 261SU UT WOS:000253101101695 ER PT J AU Stone, ND Dunaway, SB Flexner, C Tierney, C Calandra, GB Becker, S Cao, YJ Wiggins, IP Conley, J MacFarland, RT Park, JG Lalama, C Snyder, S Kallungal, B Klingman, KL Hendrix, CW AF Stone, Nimalie D. Dunaway, Shelia B. Flexner, Charles Tierney, Camlin Calandra, Gary B. Becker, Stephen Cao, Ying-Jun Wiggins, Ilene P. Conley, Jeanne MacFarland, Ron T. Park, Jeong-Gun Lalama, Christina Snyder, Sally Kallungal, Beatrice Klingman, Karin L. Hendrix, Craig W. TI Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; AMD3100; MOBILIZATION; ANTAGONIST; VOLUNTEERS; ENTRY AB AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P < 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0- to 2.1-fold) in an E-max model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070. C1 Johns Hopkins Univ, Sch Med, Div Clin Pharmacol, Baltimore, MD 21287 USA. Univ Washington, Sch Med, Harborview Med Ctr, Seattle, WA 98104 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Anormed Inc, Langley, BC V2Y 1N55, Canada. Social & Sci Syst Inc, Silver Spring, MD USA. NIH, NIAID, Div Aids, Bethesda, MD 20892 USA. RP Hendrix, CW (reprint author), Emory Univ, Sch Med, Div Infect Dis, Woodruff Mem Bldg 2101,1639 Pierce Dr, Atlanta, GA 30322 USA. EM chendrix@jhmi.edu RI Hendrix, Craig/G-4182-2014 OI Hendrix, Craig/0000-0002-5696-8665 FU NCRR NIH HHS [M01RR000052, M01RR00037, M01 RR000037, M01 RR000052]; NIAID NIH HHS [U01AI27664, U01 AI027664, AI038855, U01AI027668, U01 AI038855, U01 AI027668] NR 11 TC 68 Z9 75 U1 2 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD JUL PY 2007 VL 51 IS 7 BP 2351 EP 2358 DI 10.1128/AAC.00013-07 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 184TS UT WOS:000247665800009 PM 17452489 ER PT J AU Wang, SM AF Wang, Shumin TI Numerical examinations of the stability of FDTD subgridding schemes SO APPLIED COMPUTATIONAL ELECTROMAGNETICS SOCIETY JOURNAL LA English DT Article DE FDTD method; subgridding; stability ID FINITE-DIFFERENCE METHOD; EQUATIONS; ALGORITHM AB The stability of two-dimensional Finite-Difference Time-Domain subgridding schemes was numerically examined. Both the same-time-step and the multiple-time-step schemes were considered. Results show that the multiple-time-step subgridding scheme is late-time unstable due to larger-than-unity eigenvalues. As to the same-time-step subgridding schemes, stability is related to the treatment of corner regions. C1 Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Wang, SM (reprint author), Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,10 B1D728, Bethesda, MD 20892 USA. EM james.wang@ieee.org NR 11 TC 3 Z9 3 U1 0 U2 2 PU APPLIED COMPUTATIONAL ELECTROMAGNETICS SOCIETY PI UNIVERSITY PA UNIV MISSISSIPPI, DEPT ELECTRICAL ENGINEERING, UNIVERSITY, MS 38677 USA SN 1054-4887 J9 APPL COMPUT ELECTROM JI Appl. Comput. Electromagn. Soc. J. PD JUL PY 2007 VL 22 IS 2 BP 189 EP 194 PG 6 WC Engineering, Electrical & Electronic; Telecommunications SC Engineering; Telecommunications GA 189UM UT WOS:000248014100001 ER PT J AU Lee, YC Jackson, PL Jablonsky, MJ Muccio, DD AF Lee, Yi-Chien Jackson, Patricia L. Jablonsky, Michael J. Muccio, Donald D. TI Conformation of 3'CMP bound to RNase a using TrNOESY SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE tansferred nuclear Overhauser effect spectroscopy; nuclear Overhauser effect; pseudorotational phase angle; 3'CMP; R Nase A ID OVERHAUSER EFFECT SPECTROSCOPY; NUCLEAR-MAGNETIC-RESONANCE; TRANSFERRED NOE EXPERIMENTS; RIBONUCLEASE-A; 3'-CYTIDINE MONOPHOSPHATE; EXCHANGE PROCESSES; NMR-SPECTROSCOPY; CROSS-RELAXATION; SPIN-DIFFUSION; ACTIVE-SITE AB The conditions for accurately determining distance constraints from TrNOESY data on a small ligand (3'CMP) bound to a small protein (RNase A, <14 kDa) are described. For small proteins, normal TrNOESY conditions of 10:1 ligand:protein or greater can lead to inaccurate structures for the ligand-bound conformation due to the contribution of the free ligand to the TrNOESY signals. By using two ligand:protein ratios (2:1 and 5:1), which give the same distance constraints, a conformation of 3'CMP bound to RNase A was determined (glycosidic torsion angle, chi= -166 degrees; pseudorotational phase angle, 0 degrees <= P <= 36 degrees). Ligand-protein NOESY cross peaks were also observed and used to dock 3'CMP into the binding pocket of the apo-protein (7rsa). After energy minimization, the conformation of the 3'CMP:RNase A complex was similar to the X-ray structure (1rpf) except that a C3'-endo conformation for the ribose ring (rather than C2'-exo conformation) was found in the TrNOESY structure. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Alabama, Dept Chem, Birmingham, AL 35294 USA. NCI, Med Chem Lab, Frederick, MD 21702 USA. Univ Alabama, Dept Physiol & Biophys, Birmingham, AL 35294 USA. RP Muccio, DD (reprint author), Univ Alabama, Dept Chem, 901 14th St S, Birmingham, AL 35294 USA. EM muccio@uab.edu NR 56 TC 2 Z9 2 U1 0 U2 0 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 JUL 1 PY 2007 VL 463 IS 1 BP 37 EP 46 DI 10.1016/j.abb.2007.02.034 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 181EG UT WOS:000247419100005 PM 17416340 ER PT J AU Gogtay, N Greenstein, D Lenane, M Clasen, L Sharp, W Gochman, P Butler, P Evans, A Rapoport, J AF Gogtay, Nitin Greenstein, Deanna Lenane, Marge Clasen, Liv Sharp, Wendy Gochman, Pete Butler, Philip Evans, Alan Rapoport, Judith TI Cortical brain development in nonpsychotic siblings of patients with childhood-onset schizophrenia SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID 1ST EPISODE SCHIZOPHRENIA; AUTOMATED 3-D EXTRACTION; HIGH-RISK; TWINS DISCORDANT; UNAFFECTED RELATIVES; HIPPOCAMPAL VOLUME; GRAY-MATTER; OBSTETRIC COMPLICATIONS; PERSONALITY-DISORDERS; PSYCHOTIC SYMPTOMS AB Context: Cortical gray matter ( GM) loss is marked and progressive in childhood-onset schizophrenia (COS) during adolescence but becomes more circumscribed by early adulthood. Nonpsychotic siblings of COS probands could help evaluate whether the cortical GM abnormalities are familial/trait markers. Objective: To map cortical development in nonpsychotic siblings of COS probands. Design: Using an automated measurement and prospectively acquired anatomical brain magnetic resonance images, we mapped cortical GM thickness in healthy full siblings (n = 52, 113 scans; age 8 through 28 years) of patients with COS, contrasting them with age-, sex-, and scan interval-matched healthy controls (n = 52, 108 scans). The false-discovery rate procedure was used to control for type I errors due to multiple comparisons. Setting: An ongoing COS study at the National Institute of Mental Health. Participants: Fifty-two healthy full siblings of patients with COS, aged 8 through 28 years, and 52 healthy controls. Main Outcome Measures: Longitudinal trajectories of cortical GM development in healthy siblings of patients with COS compared with matched healthy controls and exploratory measure of the relationship between developmental GM trajectories and the overall functioning as defined by the Global Assessment Scale (GAS) score. Results: Younger, healthy siblings of patients with COS showed significant GM deficits in the left prefrontal and bilateral temporal cortices and smaller deficits in the right prefrontal and inferior parietal cortices compared with the controls. These cortical deficits in siblings disappeared by age 20 years and the process of deficit reduction correlated with overall functioning (GAS scores) at the last scan. Conclusions: Prefrontal and temporal GM loss in COS appears to be a familial/trait marker. Amelioration of regional GM deficits in healthy siblings was associated with higher global functioning ( GAS scores), suggesting a relationship between brain plasticity and functional outcome for these nonpsychotic, nonspectrum siblings. C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. Montreal Neurol Inst, Montreal, PQ, Canada. RP Gogtay, N (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Room 3N202,10 Ctr Dr,MSC1600, Bethesda, MD 20892 USA. EM gogtayn@mail.nih.gov RI Gogtay, Nitin/A-3035-2008 NR 68 TC 100 Z9 102 U1 4 U2 7 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 JUL PY 2007 VL 64 IS 7 BP 772 EP 780 DI 10.1001/archpsyc.64.7.772 PG 9 WC Psychiatry SC Psychiatry GA 185GF UT WOS:000247698700002 PM 17606811 ER PT J AU Hu, XZ Rush, AJ Charney, D Wilson, AF Sorant, AJM Papanicolaou, GJ Fava, M Trivedi, MH Wisniewski, SR Laje, G Paddock, S McMahon, FJ Manji, H Lipsky, RH AF Hu, Xian-Zhang Rush, A. John Charney, Dennis Wilson, Alexander F. Sorant, Alexa J. M. Papanicolaou, George J. Fava, Maurizio Trivedi, Madhukar H. Wisniewski, Stephen R. Laje, Gonzalo Paddock, Silvia McMahon, Francis J. Manji, Husseini Lipsky, Robert H. TI Association between a functional serotonin transporter promoter polymorphism and citalopram treatment in adult outpatients with major depression SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID SEQUENCED TREATMENT ALTERNATIVES; STAR-ASTERISK-D; DIAGNOSTIC SCREENING QUESTIONNAIRE; REUPTAKE INHIBITORS; ANTIDEPRESSANT TREATMENT; FLUOXETINE TREATMENT; QUICK INVENTORY; DRUG RESPONSE; RATING-SCALE; GENE AB Context: The HTTLPR, a functional polymorphism of the serotonin transporter gene solute carrier family 6 ( neurotransmitter transporter, serotonin), member 4 (SLC6A4), promoter, affects transcription and may be involved in antidepressant drug treatment outcome, although response rates with antidepressants can be lower in patients who experience adverse effects. Objective: To test the hypothesis that HTTLPR is associated with treatment outcome to citalopram. Design: A clinical effectiveness trial, Sequenced Treatment Alternatives to Relieve Depression, collected DNA samples from outpatients with nonpsychotic major depressive disorder who received citalopram in the first treatment step. The triallelic HTTLPR locus was genotyped in 1775 samples to discriminate between long ( L) and short (S) alleles, followed by the A > G substitution. The low-expression S and LG alleles were grouped together compared with the high-expression L-A allele. Setting: Eighteen primary care and 23 psychiatric care sites across the United States. Participants: Ages 18 to 75 years, meeting criteria for single or recurrent nonpsychotic major depression. Main Outcome Measures: Categorical response, remission, tolerance, and adverse effect burden. Results: Expression-based grouping produced a significant finding of association between the LA allele and adverse effect burden in the entire sample (P = .004 [genotype frequency]; P < .001 [allele frequency]). To control for bias from population stratification, a white American subsample was analyzed. A lesser adverse effect burden was associated with LALA genotype frequency (P = .03) or LA allele frequency ( P = .007). These findings in white patients did not hold when the L allele was undifferentiated. No association was observed between treatment outcome phenotypes and HTTLPR. Development of diarrhea and the presence of the low-expression S or L-G alleles were the strongest risk factors associated with adverse effect burden. Conclusions: The HTTLPR polymorphism is associated with citalopram adverse effects. Because the LA allele confers increased SLC6A4 transcription, increased serotonin transporter levels in brain and other tissues may lead to fewer adverse effects for antidepressant medications that target the transporter. C1 NIAAA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NIMH, Genet Basis Mood & Anxiety Disorders, Mood & Anxiety Program, NIH, Bethesda, MD 20892 USA. NIMH, Mol Pathophysiol Lab, Mood & Anxiety Program, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75230 USA. Mt Sinai Hosp, Albert Einstein Sch Med, Dept Psychiat, New York, NY 10029 USA. NHGRI, Genometr Sect, Inherited Dis Res Branch, NIH, Baltimore, MD USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. RP Lipsky, RH (reprint author), NIAAA, Mol Genet Sect, Neurogenet Lab, NIH, 5625 Fishers Ln,Room 3S32,MSC 9412, Bethesda, MD 20892 USA. EM rlipsky@mail.nih.gov RI McMahon, Francis/A-7290-2009; Wilson, Alexander/C-2320-2009; Laje, Gonzalo/L-2654-2014; OI Laje, Gonzalo/0000-0003-2763-3329; Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382; Lipsky, Robert/0000-0001-7753-1473; McMahon, Francis/0000-0002-9469-305X FU Intramural NIH HHS; NIMH NIH HHS [N01MH90003] NR 46 TC 141 Z9 148 U1 3 U2 5 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 JUL PY 2007 VL 64 IS 7 BP 783 EP 792 DI 10.1001/archpsyc.64.7.783 PG 10 WC Psychiatry SC Psychiatry GA 185GF UT WOS:000247698700003 PM 17606812 ER PT J AU Hasin, DS Stinson, FS Ogburn, E Grant, BF AF Hasin, Deborah S. Stinson, Frederick S. Ogburn, Elizabeth Grant, Bridget F. TI Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States - Results from the National Epidemiologic Survey on Alcohol and Related Conditions SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Review ID SUBSTANCE USE DISORDERS; DIAGNOSTIC-INTERVIEW-SCHEDULE; RANDOMIZED CONTROLLED-TRIAL; GENERAL-POPULATION SAMPLE; R PSYCHIATRIC-DISORDERS; BRIEF PHYSICIAN ADVICE; PRIMARY-HEALTH-CARE; MENTAL-DISORDERS; DRUG-USE; LIFETIME PREVALENCE AB Context: Epidemiologic information is important to inform etiological research and service delivery planning. However, current information on the epidemiology of alcohol use disorders in the United States is lacking. Objectives: To present nationally representative findings on the prevalence, correlates, psychiatric comorbidity, and treatment of DSM-IV alcohol abuse and dependence. Design, Setting, and Participants: Face-to-face interviews with a representative US adult sample (N= 43 093). Main Outcome Measures: Lifetime and 12-month DSM-IV alcohol abuse and dependence. Results: Prevalence of lifetime and 12-month alcohol abuse was 17.8% and 4.7%; prevalence of lifetime and 12-month alcohol dependence was 12.5% and 3.8%. Alcohol dependence was significantly more prevalent among men, whites, Native Americans, younger and unmarried adults, and those with lower incomes. Current alcohol abuse was more prevalent among men, whites, and younger and unmarried individuals while lifetime rates were highest among middle-aged Americans. Significant disability was particularly associated with alcohol dependence. Only 24.1% of those with alcohol dependence were ever treated, slightly less than the treatment rate found 10 years earlier. Strong associations between other substance use disorders and alcohol use disorders (odds ratios, 2.0-18.7) were lower but remained strong and significant (odds ratios, 1.8-7.5) when controlling for other comorbidity. Significant associations between mood, anxiety, and personality disorders and alcohol dependence (odds ratios, 2.1-4.8) were reduced in number and magnitude (odds ratios, 1.5-2.0) when controlling for other comorbidity. Conclusions: Alcohol abuse and dependence remain highly prevalent and disabling. Comorbidity of alcohol dependence with other substance disorders appears due in part to unique factors underlying etiology for each pair of disorders studied while comorbidity of alcohol dependence with mood, anxiety, and personality disorders appears more attributable to factors shared among these other disorders. Persistent low treatment rates given the availability of effective treatments indicate the need for vigorous education efforts for the public and professionals. C1 NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. Columbia Univ, Coll Phys & Surg, New York, NY USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,Dept Hlth & Human Serv, MS 9304,5635 Fishers Ln, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov FU Intramural NIH HHS; NIAAA NIH HHS [K05 AA 014223] NR 129 TC 1051 Z9 1060 U1 17 U2 122 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 JUL PY 2007 VL 64 IS 7 BP 830 EP 842 DI 10.1001/archpsyc.64.7.830 PG 13 WC Psychiatry SC Psychiatry GA 185GF UT WOS:000247698700008 PM 17606817 ER PT J AU Motta, M Malaguarnera, M Ferrari, E Mauro, VN Ferrucci, L Rapisarda, R Tomasello, FB Basile, G Ferlito, L Passamonte, M Bennati, E AF Motta, M. Malaguarnera, M. Ferrari, E. Mauro, V. Nicita Ferrucci, L. Rapisarda, R. Tomasello, F. B. Basile, G. Ferlito, L. Passamonte, M. Bennati, E. TI Genealogy of centenarians and their relatives: A study of 12 families SO ARCHIVES OF GERONTOLOGY AND GERIATRICS LA English DT Article DE genealogical tree of centenarians; medium life span of the Italian population; genetic basis of longevity ID MORTALITY; LONGEVITY AB The longevity is a complex phenomenon in which specific genetic properties seem to play a role. The present study intended to reconstruct the genealogical tree of 12 subjects, being residents of one Northern and one Southern province of Italy, in order to establish the longevity of the ancestors. Detailed studies have been performed in the registry offices and the historic archives. The research method started from the identification of the centenarians on the basis of the documentation of the relevant birth document, it was continued by identifying the documents of birth, marriages and death of the parents of the centenarians. This way we proceeded systematically backwards in time. In addition, we verified the medium life span of the Italian population in the given periods of time, when the centenarians and their ascending lines had lived. These results offer clear historic-statistical evidences for the genetic basis of longevity. (C) 2006 Published by Elsevier Ireland Ltd. C1 Univ Catania, Cannizzaro Hosp, Dept Senescence Sci, I-95126 Catania, Italy. Univ Messina, Azienda Osped, Sch Specializat Geriatr, Policlin G Martino, I-98125 Messina, Italy. Univ Pavia, Geriatr Unit, Dept Internal Med & Med Therapy, I-27100 Pavia, Italy. Harbor Hosp, NIA, Clin Res Branch, Longitudinal Studies Sect,NIH, Baltimore, MD USA. RP Motta, M (reprint author), Univ Catania, Cannizzaro Hosp, Dept Senescence Sci, Via Messina,829, I-95126 Catania, Italy. EM mmotta@unict.it OI MALAGUARNERA, Mariano/0000-0002-5171-7963; BASILE, Giorgio/0000-0002-0040-8618 FU Intramural NIH HHS [Z99 AG999999] NR 12 TC 5 Z9 6 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-4943 J9 ARCH GERONTOL GERIAT JI Arch. Gerontol. Geriatr. PD JUL-AUG PY 2007 VL 45 IS 1 BP 97 EP 102 DI 10.1016/j.archger.2006.10.004 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 173HR UT WOS:000246864600010 PM 17196681 ER PT J AU Davis, PL Rambaut, A Bourhy, H Holmes, EC AF Davis, P. L. Rambaut, A. Bourhy, H. Holmes, E. C. TI The evolutionary dynamics of canid and mongoose rabies virus in southern Africa SO ARCHIVES OF VIROLOGY LA English DT Article ID MOLECULAR EPIDEMIOLOGY; CYNICTIS-PENICILLATA; NUCLEOPROTEIN GENE; LYSSAVIRUS; DIVERSITY; INFECTION; GLYCOPROTEIN; SUBSTITUTION; VARIANTS; REGION AB Two variants of rabies virus (RABV) currently circulate in southern Africa: canid RABV, mainly associated with dogs, jackals, and bat-eared foxes, and mongoose RABV. To investigate the evolutionary dynamics of these variants, we performed coalescent-based analyses of the G-L inter-genic region, allowing for rate variation among viral lineages through the use of a relaxed molecular clock. This revealed that mongoose RABV is evolving more slowly than canid RABV, with mean evolutionary rates of 0.826 and 1.676 x 10-3 nucleotide substitutions per site, per year, respectively. Additionally, mongoose RABV exhibits older genetic diversity than canid RABV, with common ancestors dating to 73 and 30 years, respectively, and while mongoose RABV has experienced exponential population growth over its evolutionary history in Africa, populations of canid RABV have maintained a constant size. Hence, despite circulating in the same geographic region, these two variants of RABV exhibit striking differences in evolutionary dynamics which are likely to reflect differences in their underlying ecology. C1 Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, Mueller Lab, University Pk, PA 16802 USA. Univ Oxford, Dept Zool, Oxford OX1 3PS, England. Inst Pasteur, UPRE Lyssavirus Dynam & Host Adaptat, WHO, Collaborating Ctr Reference & Res Rabies, Paris, France. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Davis, PL (reprint author), Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, Mueller Lab, University Pk, PA 16802 USA. EM ech15@psu.edu RI Bourhy, Herve/F-5272-2010; OI Rambaut, Andrew/0000-0003-4337-3707; Holmes, Edward/0000-0001-9596-3552 NR 30 TC 27 Z9 29 U1 2 U2 5 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 JUL PY 2007 VL 152 IS 7 BP 1251 EP 1258 DI 10.1007/s00705-007-0962-9 PG 8 WC Virology SC Virology GA 185UD UT WOS:000247735000002 PM 17401615 ER PT J AU Gelderman, MP Schiffmann, R Simak, J AF Gelderman, Monique P. Schiffmann, Raphael Simak, Jan TI Elevated endothelial microparticles in fabry children decreased after enzyme replacement therapy SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Letter ID DISEASE; TRIAL C1 FDA, CBER, Rockville, MD USA. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Gelderman, MP (reprint author), FDA, CBER, Rockville, MD USA. RI Simak, Jan/C-1153-2011 NR 6 TC 14 Z9 14 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD JUL PY 2007 VL 27 IS 7 BP E138 EP E139 DI 10.1161/ATVBAHA.107.143511 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 180XN UT WOS:000247401400027 PM 17581828 ER PT J AU Li, N Shigihara, T Tzioufas, AG Notkins, AL Yoon, JW Jun, HS AF Li, Na Shigihara, Toshikatsu Tzioufas, Athanasios G. Notkins, Abner L. Yoon, Ji-Won Jun, Hee-Sook TI Human chorionic gonadotropin prevents Sjogren's syndrome-like exocrinopathy in mice SO ARTHRITIS AND RHEUMATISM LA English DT Article ID TUMOR-NECROSIS-FACTOR; KAPOSIS-SARCOMA; NOD MICE; KAPPA-B; ACTIVATION; PREGNANCY; APOPTOSIS; DISEASE; SYSTEM; CELLS AB Objective. Results of recent studies suggest that human chorionic gonadotropin (HCG), a placental glycoprotein hormone required for the maintenance of pregnancy, may have immunomodulatory properties. Primary Sjogren's syndrome (SS), a chronic autoimmune disorder of unknown etiology, affects multiple exocrine glands including the salivary and lacrimal glands. The purpose of the present study was to determine whether HCG could prevent the development of salivary gland exocrinopathy in NOD mice, an experimental model of Sjogren's-like syndrome. Methods. Female NOD mice were treated with HCG from 6 weeks of age to 12 weeks of age. At 14 weeks, tissue samples were evaluated for inflammatory lesions and cytokine messenger RNA by real-time polymerase chain reaction. At 18 weeks, the salivary flow rate was measured. Results. Treatment with HCG resulted in a significant decrease in lymphocyte infiltration and parenchymal cell damage in the submandibular salivary glands. Messenger RNA levels of interferon-gamma, tumor necrosis factor a, interleukin-1 beta, and interleukin-10, as well as inducible nitric oxide synthase and matrix metalloproteinase 9, were significantly decreased. Function studies revealed a marked increase in the salivary flow rate in HCG-treated mice compared with that in phosphate buffered saline-treated mice. Conclusion. In NOD mice, HCG acts as an immune modulator and prevents the development of salivary gland exocrinopathy. These findings suggest that HCG, a naturally occurring reproductive hormone, may be useful in the treatment of Sjogren's syndrome and other human autoimmune diseases. C1 Rosalind Franklin Univ Med & Sci, Rosalind Franklin Comprehens Diabet Ctr, Chicago Med Sch, N Chicago, IL 60064 USA. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. RP Jun, HS (reprint author), Rosalind Franklin Univ Med & Sci, Rosalind Franklin Comprehens Diabet Ctr, Chicago Med Sch, 3333 Green Bay Rd, N Chicago, IL 60064 USA. EM hee-sook.jeon@rosalindfranklin.edu NR 24 TC 3 Z9 6 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 JUL PY 2007 VL 56 IS 7 BP 2211 EP 2215 DI 10.1002/art.22737 PG 5 WC Rheumatology SC Rheumatology GA 190PP UT WOS:000248071600013 PM 17599739 ER PT J AU Lunemann, JD Schmidt, J Dalakas, MC Munz, C AF Lunemann, Jan D. Schmidt, Jens Dalakas, Marinas C. Munz, Christian TI Macroautophagy as a pathomechanism in sporadic inclusion body myositis SO AUTOPHAGY LA English DT Article DE sporadic inclusion body myositis; beta-amyloid; macroautophagy; LC3/Atg8; vacuolar myopathy ID AUTOPHAGY; DISEASE; BETA; EXPRESSION; MICE; INHIBITION; CHEMOKINES; ANTIGEN; CELLS AB Skeletal muscle fibers show a high level of constitutive and starvation-induced macroautophagy. Sporadic Inclusion Body Myositis (sIBM) is the most common acquired skeletal muscle disease in patients above the age of 50 years and is characterized by inflammation and intracellular accumulation of aggregate-prone proteins such as amyloid precursor protein (APP)/beta-amyloid, hyperphosphorylated tau, and presenilin. In a recent study, we found that muscle fibers of sIBM patients show increased frequencies of Atg8/ LC3(+) autophagosomes and that intracellular APP/(i-amyloid colocalized with Atg8/LC3 in degenerating fibers. Colocalization of APP/beta-amyloid with LC3(+) autophagosomes was further associated with upregulation of major histocompatibility complex (MHC) class I and class II molecules and T cell infiltration. These findings indicate that APP/beta-amyloid is a substrate for autophagy in skeletal muscle fibers and suggest that degradation of aggregate-prone proteins via macroautophagy can be linked with both immune-mediated and degenerative tissue damage. A better understanding of this pathway in skeletal muscle and in the inflammatory environment of sIBM might provide a rationale for novel therapeutic strategies targeting pathogenic protein aggregation. C1 Rockefeller Univ, Lab Viral Immunobiol, Christopher H Browne Ctr Immunol & Immune Dis, New York, NY 10021 USA. Univ Gottingen, Muscle Immunobiol Grp, Dept Neuroimmunol, D-3400 Gottingen, Germany. Univ Gottingen, Dept Neurol, D-3400 Gottingen, Germany. NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Munz, C (reprint author), Rockefeller Univ, Lab Viral Immunobiol, Christopher H Browne Ctr Immunol & Immune Dis, Box 390,1230 York Ave, New York, NY 10021 USA. EM munzc@rockefeller.edu RI Schmidt, Jens/B-5791-2013; Lunemann, Jan/G-8729-2011 OI Lunemann, Jan/0000-0002-3007-708X NR 18 TC 15 Z9 17 U1 0 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD JUL-AUG PY 2007 VL 3 IS 4 BP 384 EP 386 PG 3 WC Cell Biology SC Cell Biology GA 183DY UT WOS:000247554100019 PM 17438365 ER PT J AU Butter, EM AF Butter, Eric M. CA RUPP Autism Network TI Parent training for children with pervasive developmental disorders: A multi-site feasibility trial SO BEHAVIORAL INTERVENTIONS LA English DT Article ID ABERRANT BEHAVIOR CHECKLIST; ADAPTIVE-BEHAVIOR; PRESCHOOL-CHILDREN; AUTISTIC-CHILDREN; RISPERIDONE; INDIVIDUALS; DOMAINS; SYMPTOMS; VERSION; STRESS AB The primary purpose of this study was to evaluate the feasibility of a structured, manual-based parent training (PT) program designed to reduce noncompliant behavior and enhance adaptive behavior in children with Pervasive Developmental Disorders (PDD) who were taking medication for irritability, tantrums, aggression, and self-injury. Children (N = 17, mean age 7.7 +/- 2.6 years) with PDD were enrolled in a 24-week structured PT protocol. Parental attendance to sessions (93%), satisfaction with the program (92%), and adherence to PT assignments (80%) were excellent. The program was adequately implemented with a mean treatment integrity rate of 94%. Parent-reported rates of noncompliance were reduced by 39%; irritability was reduced by 34%; and daily living skills were enhanced by 19%. Parenting stress was also reduced by 14%. However, these results must be interpreted with caution because the study did not include a control group. The study supports feasibility of the PT program, which will be used in an randomized clinical trials (RCT). Copyright (c) 2007 John Wiley & Sons, Ltd. C1 Ohio State Univ, Columbus, OH 43210 USA. Yale Univ, New Haven, CT USA. Indiana Univ, Sch Med, Indianapolis, IN USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. NIMH, Bethesda, MD 20892 USA. RP Butter, EM (reprint author), Ohio State Univ, Columbus Childrens Hosp, Autism Ctr, Dept Psychol, 187 W Schrock Rd, Westerville, OH 43081 USA. EM buttere@chi.osu.edu NR 47 TC 27 Z9 27 U1 2 U2 6 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1072-0847 J9 BEHAV INTERVENT JI Behav. Intervent. PD JUL PY 2007 VL 22 IS 3 BP 179 EP 199 DI 10.1002/bin.236 PG 21 WC Psychology, Clinical SC Psychology GA 196WN UT WOS:000248513800001 ER PT J AU Johnson, CR Handen, BL Butter, E Wagner, A Mulick, J Sukhodolsky, DG Williams, S Swiezy, NA Arnold, LE Aman, MG Scahill, L Stigler, KA McDougle, CJ Vitiello, B Smith, T AF Johnson, Cynthia R. Handen, Benjamin L. Butter, Eric Wagner, Ann Mulick, James Sukhodolsky, Denis G. Williams, Susan Swiezy, Naomi A. Arnold, L. Eugene Aman, Michael G. Scahill, Lawrence Stigler, Kimberly A. McDougle, Christopher J. Vitiello, Benedetto Smith, Tristram TI Development of a parent training program for children with pervasive developmental disorders SO BEHAVIORAL INTERVENTIONS LA English DT Article ID INTENSIVE EARLY INTERVENTION; RANDOMIZED CONTROLLED-TRIAL; YOUNG-CHILDREN; BEHAVIORAL TREATMENT; PSYCHOSOCIAL INTERVENTIONS; PRESCHOOL-CHILDREN; AUTISM; RISPERIDONE; SYMPTOMS; PHARMACOTHERAPY AB Parent delivered interventions based on applied behavior analysis (ABA) for children with Pervasive Developmental Disorders (PDDs) have been evaluated using primarily single-subject design methodology or small case series. While the results of these evaluations are encouraging, an important next step is to standardize the interventions to allow for replication across sites, in studies with large samples and measures of long-term, clinically meaningful outcomes such as improvements in children's functioning and their relationships with parents. Accordingly, the Research Units on Pediatric Psychopharmacology and Psychosocial Interventions (RUPP Autism Network) assembled a detailed manual for a structured behavioral parent training (PT) program, developed treatment fidelity and training procedures, and conducted a pilot, feasibility study. The PT program is part of a large scale, multisite study intended to determine the efficacy of combined pharmacological treatment and behavioral intervention to improve behavior and adaptive ftincfioning in children with PDD. This paper discusses the rationale for this project. A companion paper provides the results of our feasibility study on the PT program. Copyright (c) 2007 John Wiley & Sons, Ltd. C1 Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Autism Ctr, Pittsburgh, PA 15213 USA. Ohio State Univ, Columbus, OH 43210 USA. NIMH, Bethesda, MD 20892 USA. Yale Univ, New Haven, CT 06520 USA. Indiana Univ, Sch Med, Bloomington, IN 47405 USA. Univ Rochester, Med Ctr, Rochester, NY 14627 USA. RP Johnson, CR (reprint author), Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Autism Ctr, 3705 5th Ave, Pittsburgh, PA 15213 USA. EM Cynthia.Johnson@chp.edu OI Sukhodolsky, Denis/0000-0002-5401-792X; Scahill, Lawrence/0000-0001-5073-1707 NR 85 TC 24 Z9 24 U1 2 U2 11 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1072-0847 J9 BEHAV INTERVENT JI Behav. Intervent. PD JUL PY 2007 VL 22 IS 3 BP 201 EP 221 DI 10.1002/bin.237 PG 21 WC Psychology, Clinical SC Psychology GA 196WN UT WOS:000248513800002 ER PT J AU Lau, JYF Viding, EM AF Lau, Jennifer Y. F. Viding, Essi M. TI Anxiety-related biases in children's avoidant responses to a masked angry face SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE anxiety; avoidance; children; facial expressions; fear conditioning ID CHILDHOOD ANXIETY; DISORDERS; SCREEN AB While anxious children often show escape and withdrawal behaviours towards threats, few studies have experimentally assessed avoidance. The present study examined whether children with high levels of anxiety showed more avoidant responses to a neutral conditioned cue (CS+) that was paired with an unconditioned threat stimulus (UCS), a masked angry facial expression. Thirty-six 10 and 11 year-olds participated in a task, which involved choosing between two CS card stimuli of different colours to win points. Whilst both cards awarded the same number of points, one colour was systematically paired with a masked angry face (CS+), whilst the other colour was paired with a masked neutral face (CS-). Children with higher anxiety scores had an overall tendency to choose the card associated with the neutral face, with some evidence suggesting that this tendency emerged gradually across trials. These results suggest a relationship between anxiety and stimulus-response learning for CS + -UCS associations that support behavioural avoidance. (c) 2006 Elsevier Ltd. All rights reserved. C1 Kings Coll London, Inst Psychiat, MRC Social Genet & Dev Psychiat Ctr, London WC2R 2LS, England. RP Lau, JYF (reprint author), NIMH, Mood & Anxiety Program, NIH, Bethesda, MD 20892 USA. EM lauj@mail.nih.gov NR 18 TC 4 Z9 4 U1 1 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 J9 BEHAV RES THER JI Behav. Res. Ther. PD JUL PY 2007 VL 45 IS 7 BP 1639 EP 1645 DI 10.1016/j.brat.2006.08.006 PG 7 WC Psychology, Clinical SC Psychology GA 182OT UT WOS:000247514600018 PM 17007809 ER PT J AU Cromer, KR Schmidt, NB Murphy, DL AF Cromer, Kiara R. Schmidt, Norman B. Murphy, Dennis L. TI An investigation of traumatic life events and obsessive-compulsive disorder SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE obsessive-compulsive disorder; traumatic stress; symptom dimensions ID ANXIETY DISORDERS; NATURAL-HISTORY; COMORBIDITY; PERSONALITY; DEPRESSION; STRESS; ADOLESCENTS; PREVALENCE; SYMPTOMS; CHILDREN AB Obsessive-compulsive disorder (OCD), like most other psychiatric disorders, is suspected of being influenced by an interaction between life events and genes, both with regard to onset and course of illness. To date, no specific genes have been identified as playing a frequent role, and only a relatively few empirical studies have assessed the association between stressful life events (SLEs) and OCD. The present study builds on past research by examining the potential contributions from traumatic life events (TLEs) on the severity and symptom features in 265 individuals with Structured Clinical Interview for DSM-IV (SCID)-diagnosed OCD. Of these participants 54% endorsed having experienced at least one TLE in their life time. The presence of one or more TLEs was associated with increased OCD symptom severity. This relationship remained significant despite controlling for key variables including age, OCD age-of-onset, comorbidity, and depressive symptoms. In addition, obsessions/checking and symmetry/ordering were two of four symptom factors that were specifically associated with the occurrence of TLEs. These results are generally supportive of a pathoplastic relationship between TLEs and OCD symptomatology and thus suggest the need for greater systematic consideration of life stresses in research focused on the nature and treatment of OCD. (c) 2006 Published by Elsevier Ltd. C1 Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. NIMH, Clin Sci Lab, Bethesda, MD 20894 USA. RP Cromer, KR (reprint author), Florida State Univ, Dept Psychol, Tallahassee, FL 32306 USA. EM cromer@psy.fsu.edu RI Timpano, Kiara/C-8760-2012 NR 42 TC 45 Z9 45 U1 2 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 J9 BEHAV RES THER JI Behav. Res. Ther. PD JUL PY 2007 VL 45 IS 7 BP 1683 EP 1691 DI 10.1016/j.brat.2006.08.018 PG 9 WC Psychology, Clinical SC Psychology GA 182OT UT WOS:000247514600023 PM 17067548 ER PT J AU Li, JX Rice, KC France, CP AF Li, Jun-Xu Rice, Kenner C. France, Charles P. TI Behavioral effects of dipropyltryptamine in rats: evidence for 5-HT1A and 5-HT2A agonist activity SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE dipropyltryptamine; drug discrimination; flat body posture; lower-lip retraction; rat; serotonin ID DISCRIMINATIVE STIMULUS; SEROTONIN SYNDROME; RECEPTORS; 5-METHOXY-N,N-DIMETHYLTRYPTAMINE; PSYCHOTHERAPY; DERIVATIVES; ANTAGONISM; DRUGS; LSD; DOM AB These studies investigated the role of serotonin-1A (5-HTIA) and 5-HT2A receptors in the behavioral effects of dipropyltryptarnine (DPT). Eight rats discriminated 0.56 mg/kg 2,5-dimethoxy-4-methylamphetamine (DOM) from saline and responded under a fixed ratio 5 schedule of food presentation; 12 other rats were used for observational studies. DOM and DPT increased responding on the DOM lever with 3.2 mg/kg DPT producing greater than 95% responding on the DOM lever; this effect of DPT was antagonized by the 5-HT2A receptor antagonist MDL10090Z In another study, the 5-HT1A and 5-HT7 receptor agonist 8-OH-DPAT produced lower-lip retraction and, at larger doses, flat body posture; DPT alone produced flat body posture and not lower-lip retraction; MDL100907 alone did not produce either effect. Pretreatment with DPT blocked 8-OH-DPAT-elicited lower-lip retraction, suggesting antagonist activity of DPT at 5-HT1A receptors; however, in the presence of MDL100907 DPT produced not only flat body posture but also lower-lip retraction, suggesting that agonist activity of DPT at 5-HT2A receptors masked agonist activity at 5-HT1A receptors. Lower-lip retraction and flat body posture by DPT in the presence of MDL100907 were attenuated by the 5-HT1A receptor antagonist WAY100635. These findings suggest that DPT has agonist activity at 5-HT1A and 5-HT2A receptors and that effects at 5-HT2A receptors mask effects at 5-HT1A receptors. C1 Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX 78229 USA. NIDDK, Med Chem Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP France, CP (reprint author), Univ Texas, Hlth Sci Ctr, Dept Pharmacol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM france@uthscsa.edu RI Li, Jun-Xu/K-9192-2013 FU NIDA NIH HHS [K05 DA017918, K05 DA17918] NR 24 TC 11 Z9 11 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD JUL PY 2007 VL 18 IS 4 BP 283 EP 288 DI 10.1097/FBP.0b013e3281f19ca0 PG 6 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 181FQ UT WOS:000247422800004 PM 17551320 ER PT J AU Balaji, S Aravind, L AF Balaji, S. Aravind, L. TI The two faces of short-range evolutionary dynamics of regulatory modes in bacterial transcriptional regulatory networks SO BIOESSAYS LA English DT Article ID ESCHERICHIA-COLI AB Studies on the conservation of the inferred transcriptional regulatory network of prokaryotes have suggested that specific transcription factors are less-widely conserved in comparison to their target genes. This observation implied that, at large evolutionary distances, the turnover of specific transcription factors through loss and non-orthologous displacement might be a major factor in the adaptive radiation of prokaryotes. However, the recent work of Hershberg and Margalit((1)) suggests that, at shorter phylogenetic scales, the evolutionary dynamics of the bacterial transcriptional regulatory network might exhibit distinct patterns. The authors find previously unnoticed relationships between the regulatory mode (activation or repression), the number of regulatory interactions and their conservation patterns in gamma-proteobacteria. These relationships might be shaped by the differences in the adaptive value and mode of operation of different regulatory interactions. C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Balaji, S (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM sbalaji@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 10 TC 2 Z9 2 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD JUL PY 2007 VL 29 IS 7 BP 625 EP 629 DI 10.1002/bies.20600 PG 5 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 183ED UT WOS:000247554600002 PM 17563073 ER PT J AU Megarbane, B Bittoun, P Amir-Aslani, A AF Megarbane, Bruno Bittoun, Patrick Amir-Aslani, Arsia TI Surrenal gland illnesses SO BIOFUTUR LA French DT Editorial Material C1 Univ Zurich, CH-8006 Zurich, Switzerland. Univ Minnesota, Minneapolis, MN 55455 USA. NCI, Bethesda, MD 20892 USA. Princess Margaret Hosp, Hong Kong, Hong Kong, Peoples R China. RP Megarbane, B (reprint author), Univ Zurich, CH-8006 Zurich, Switzerland. EM a.amir-aslani@araxes-associates.com NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0294-3506 J9 BIOFUTUR JI Biofutur PD JUL-AUG PY 2007 IS 279 BP 63 EP 64 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 196SO UT WOS:000248502500016 ER PT J AU Csuros, M Holey, JA Rogozin, IB AF Csuroes, Miklos Holey, J. Andrew Rogozin, Igor B. TI In search of lost introns SO BIOINFORMATICS LA English DT Article; Proceedings Paper CT 15th Conference on Intelligent Systems for Molecular Biology/6th European Conference on Computation Biology CY JUL 21-25, 2007 CL Vienna, AUSTRIA ID MAXIMUM-LIKELIHOOD APPROACH; SPLICEOSOMAL INTRONS; EUKARYOTIC EVOLUTION; PHYLOGENETIC TREES; GENES; CONSERVATION; ALIGNMENTS; ALGORITHM; PATTERNS; MODELS AB Many fundamental questions concerning the emergence and subsequent evolution of eukaryotic exon-intron organization are still unsettled. Genome-scale comparative studies, which can shed light on crucial aspects of eukaryotic evolution, require adequate computational tools. We describe novel computational methods for studying spliceosomal intron evolution. Our goal is to give a reliable characterization of the dynamics of intron evolution. Our algorithmic innovations address the identification of orthologous introns, and the likelihood-based analysis of intron data. We discuss a compression method for the evaluation of the likelihood function, which is noteworthy for phylogenetic likelihood problems in general. We prove that after O(nl) preprocessing time, subsequent evaluations take O(nl/logl) time almost surely in the Yule-Harding random model of n-taxon phylogenies, where l is the input sequence length. We illustrate the practicality of our methods by compiling and analyzing a data set involving 18 eukaryotes, which is more than in any other study to date. The study yields the surprising result that ancestral eukaryotes were fairly intron-rich. For example, the bilaterian ancestor is estimated to have had more than 90% as many introns as vertebrates do now. C1 Univ Montreal, Dept Comp Sci & Operat Res, Quebec City, PQ, Canada. St Johns Univ, Dept Comp Sci, Collegeville, MN 56321 USA. Coll St Benedict, Collegeville, MN USA. NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Csuros, M (reprint author), Univ Montreal, Dept Comp Sci & Operat Res, Quebec City, PQ, Canada. EM csuros@iro.umontreal.ca FU Intramural NIH HHS NR 51 TC 11 Z9 12 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD JUL 1 PY 2007 VL 23 IS 13 BP I87 EP I96 DI 10.1093/bioinformatics/btm190 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 198IN UT WOS:000248620400035 PM 17646350 ER PT J AU Chuang, DM Manji, HK AF Chuang, De-Maw Manji, Husseini K. TI In search of the holy grail for the treatment of neurodegenerative disorders: Has a simple cation been overlooked? SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID GLYCOGEN-SYNTHASE KINASE-3; ALZHEIMERS-DISEASE; GLUTAMATE EXCITOTOXICITY; NEUROTROPHIC FACTOR; SIGNALING PATHWAY; MOOD STABILIZERS; BIPOLAR DISORDER; CORTICAL-NEURONS; HUMAN BRAIN; IN-VIVO C1 NIMH, Mol Neurobiol Sect, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, Mood & Anxiety Disorders Program, NIH, Bldg 10,Room 4C-206,10 Ctr Dr MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 29 TC 49 Z9 49 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 JUL 1 PY 2007 VL 62 IS 1 BP 4 EP 6 DI 10.1016/j.biopsych.2007.04.008 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 184PH UT WOS:000247653500002 PM 17572175 ER PT J AU Wolff, GS Chiang, PJ Smith, SM Romero, R Armant, DR AF Wolff, Garen S. Chiang, Po Jen Smith, Susan M. Romero, Roberto Armant, D. Randall TI Epidermal growth factor-like growth factors prevent apoptosis of alcohol-exposed human placental cytotrophoblast cells SO BIOLOGY OF REPRODUCTION LA English DT Article DE apoptosis; growth factors; placenta; toxicology; trophoblast ID INTRAUTERINE GROWTH; HUMAN TROPHOBLAST; OXIDATIVE STRESS; IMMUNOHISTOCHEMICAL LOCALIZATION; VILLOUS CYTOTROPHOBLAST; HUMAN ENDOMETRIUM; HB-EGF; ETHANOL; EXPRESSION; RAT AB Maternal alcohol abuse during pregnancy can produce an array of birth defects comprising fetal alcohol syndrome. A hallmark of fetal alcohol syndrome is intrauterine growth retardation, which is associated with elevated apoptosis of placental cytotrophoblast cells. Using a human first trimester cytotrophoblast cell line, we examined the relationship between exposure to ethanol and cytotrophoblast survival, as well as the ameliorating effects of epidermal growth factor (EGF)-like growth factors produced by human cytotrophoblast cells. After exposure to 0-100 mM ethanol, cell death was quantified by the TUNEL method, and expression of the nuclear proliferation marker, Ki67, was measured by immunohistochemistry. The mode of cell death was determined by assessing annexin V binding, caspase 3 activation, pyknotic nuclear morphology, reduction of TUNEL by caspase inhibition, and cellular release of lactate dehydrogenase. Ethanol significantly reduced proliferation and increased cell death approximately 2.5-fold through the apoptotic pathway within 1-2 h of exposure to 50 mM alcohol. Exposure to 25-50 mM ethanol significantly increased transforming growth factor alpha (TGFA) and heparin-binding EGF-like growth factor (HBEGF), but not EGF or amphiregulin (AREG). When cytotrophoblasts were exposed concurrently to 100 mM ethanol and 1 nM HBEGF or TGFA, the increase in apoptosis was prevented, while EGF ameliorated at 10 nM and AREG was weakly effective. HBEGIF survival-promoting activity required ligation of either of its cognate receptors, HER1 or HER4. These findings reveal the potential for ethanol to rapidly induce cytotrophoblast apoptosis. However, survival factor induction could provide cytotrophoblasts with an endogenous cytoprotective mechanism. C1 Wayne State Univ, Sch Med, Dept Obstet & Gynecol, CS Mott Ctr Human Growth & Dev, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Anat & Cell Biol, Detroit, MI 48201 USA. Univ Wisconsin, Dept Nutrit Sci, Madison, WI 53706 USA. NICHHD, Perinatol Res Branch, DHHS, NIH, Bethesda, MD 20892 USA. RP Armant, DR (reprint author), Wayne State Univ, Sch Med, Dept Obstet & Gynecol, CS Mott Ctr Human Growth & Dev, 275 E Hancock Ave, Detroit, MI 48201 USA. EM d.armant@wayne.edu OI Armant, D. Randall/0000-0001-5904-9325 FU Intramural NIH HHS; NIAAA NIH HHS [AA11085, R01 AA012057-04, R01 AA011085, AA12057, R29 AA011085, R37 AA011085, R01 AA012057, R01 AA011085-10] NR 53 TC 22 Z9 22 U1 0 U2 2 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 JUL PY 2007 VL 77 IS 1 BP 53 EP 60 DI 10.1095/biolreprod.106.057984 PG 8 WC Reproductive Biology SC Reproductive Biology GA 180RA UT WOS:000247382000007 PM 17392498 ER PT J AU Mueller, GA DeRose, EF Kirby, TW London, RE AF Mueller, Geoffrey A. DeRose, Eugene F. Kirby, Thomas W. London, Robert E. TI NMR assignment of polymerase beta labeled with H-2, C-13, and N-15 in complex with substrate DNA SO BIOMOLECULAR NMR ASSIGNMENTS LA English DT Article DE polymerase beta; base excision repair ID SEQUENTIAL ASSIGNMENT; LARGER PROTEINS; SPECTROSCOPY; SENSITIVITY; RESONANCES; BACKBONE; SPECTRA; DOMAIN AB DNA Polymerase beta is a multifunctional enzyme involved in base excision repair of nuclear DNA in vertebrate cells. We present here the first assignments of the full-length protein (335 residues, 39 kDa) in the presence of a double gap-double hairpin DNA (22 nucleotides, 7 kDa). C1 [Mueller, Geoffrey A.; DeRose, Eugene F.; Kirby, Thomas W.; London, Robert E.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 23455 USA. RP London, RE (reprint author), Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 23455 USA. EM london@niehs.nih.gov FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 13 TC 4 Z9 4 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1874-2718 J9 BIOMOL NMR ASSIGM JI Biomol. NMR Assign. PD JUL PY 2007 VL 1 IS 1 BP 33 EP 35 DI 10.1007/s12104-007-9007-2 PG 3 WC Biophysics; Spectroscopy SC Biophysics; Spectroscopy GA 341AO UT WOS:000258686800011 PM 19421423 ER PT J AU de Alba, E AF de Alba, Eva TI H-1, N-15 and C-13 backbone and side chain chemical shifts of human ASC (apoptosis-associated speck-like protein containing a CARD domain) SO BIOMOLECULAR NMR ASSIGNMENTS LA English DT Article DE apoptosis; ASC; TMS-1; cancer; NMR ID ADAPTER AB The backbone and side chain resonance assignments of human ACS (similar to 22 KD), apoptosis-associated speck-like protein containing a caspase recruitment domain and a pyrin domain, have been determined by triple-resonance NMR techniques. C1 [de Alba, Eva] CSIC, Biol Res Ctr, Dept Prot Sci, Madrid 28040, Spain. [de Alba, Eva] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP de Alba, E (reprint author), CSIC, Biol Res Ctr, Dept Prot Sci, Ramiro de Maeztu 9, Madrid 28040, Spain. EM dealbae@cib.csic.es FU ASC FX I am indebted to Dr. Nico Tjandra for his support and encouragement, and grateful to Professor Gabriel Nunez for providing the cDNA of ASC. NR 11 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1874-2718 J9 BIOMOL NMR ASSIGM JI Biomol. NMR Assign. PD JUL PY 2007 VL 1 IS 1 BP 135 EP 137 DI 10.1007/s12104-007-9036-x PG 3 WC Biophysics; Spectroscopy SC Biophysics; Spectroscopy GA 341AO UT WOS:000258686800040 PM 19636848 ER PT J AU Woodcock, HL Moran, D Pastor, RW MacKerell, AD Brooks, BR AF Lee Woodcock, H. Moran, Damian Pastor, Richard W. MacKerell, Alexander D., Jr. Brooks, Bernard R. TI Ab initio modeling of glycosyl torsions and anomeric effects in a model carbohydrate: 2-Ethoxy tetrahydropyran SO BIOPHYSICAL JOURNAL LA English DT Article ID COMPLETE BASIS-SET; CONFORMATIONAL-ANALYSIS; GEOMETRY OPTIMIZATION; SYSTEMATIC SEQUENCES; AQUEOUS-SOLUTION; WAVE-FUNCTIONS; GAUSSIAN-3 G3; SIMULATIONS; ENERGIES; DYNAMICS AB A range of ab initio calculations were carried out on the axial and equatorial anomers of the model carbohydrate 2-ethoxy tetrahydropyran to evaluate the level of theory required to accurately evaluate the glycosyl dihedral angle and the anomeric ratio. Vacuum CCSD(T)/CBS extrapolations at the global minimum yield DE = E-equatorial -E-axial = 1.42 kcal/mol. When corrected for solvent (by the IEFPCM model), zero-point vibrations and entropy, Delta G(298) = 0.49 kcal/mol, in excellent agreement with the experimental value of 0.47 +/- 6 0.3 kcal/mol. A new additivity scheme, the layered composite method (LCM), yields DE to within 0.1 kcal/mol of the CCSD(T)/CBS result at a fraction of the computer requirements. Anomeric ratios and one-dimensional torsional surfaces generated by LCM and the even more ef. cient MP2/cc-pVTZ level of theory are in excellent agreement, indicating that the latter is suitable for force-. eld parameterization of carbohydrates. Hartree-Fock and density functional theory differ from CCSD(T)/CBS for DE by similar to 1 kcal/mol; they show similar deviations in torsional surfaces evaluated from LCM. A comparison of vacuum and solvent-corrected one-and two-dimensional torsional surfaces indicates the equatorial form of 2-ethoxy tetrahydropyran is more sensitive to solvent than the axial. C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. Macquarie Univ, Dept Chem & Biomol Sci, Sydney, NSW 2109, Australia. Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. RP Woodcock, HL (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM hlwood@nih.gov RI Woodc, Henry/D-9275-2011; OI Moran, Damian/0000-0002-8316-8823; Woodcock, Henry/0000-0003-3539-273X; MacKerell, Alex/0000-0001-8287-6804 FU Intramural NIH HHS; NIGMS NIH HHS [GM 70855] NR 43 TC 27 Z9 27 U1 0 U2 4 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUL PY 2007 VL 93 IS 1 BP 1 EP 10 DI 10.1529/biophysj.106.099986 PG 10 WC Biophysics SC Biophysics GA 176CW UT WOS:000247061500005 PM 17554075 ER PT J AU Haspel, N Zanuy, D Zheng, J Aleman, C Wolfson, H Nussinov, R AF Haspel, Nurit Zanuy, David Zheng, Jie Aleman, Carlos Wolfson, Haim Nussinov, Ruth TI Changing the charge distribution of beta-helical-based nanostructures can provide the conditions for charge transfer SO BIOPHYSICAL JOURNAL LA English DT Article ID AMYLOID FIBRIL FORMATION; MOLECULAR-DYNAMICS; HUMAN CALCITONIN; SEQUENCE; PEPTIDES; PROTEINS; DESIGN; MODEL AB In this work we present a computational approach to the design of nanostructures made of structural motifs taken from left-handed beta-helical proteins. Previously, we suggested a structural model based on the self-assembly of motifs taken from Escherichia coli galactoside acetyltransferase (Protein Data Bank 1krr, chain A, residues 131-165, denoted krr1), which produced a very stable nanotube in molecular dynamics simulations. Here we modify this model by changing the charge distribution in the inner core of the system and testing the effect of this change on the structural arrangement of the construct. Our results demonstrate that it is possible to generate the proper conditions for charge transfer inside nanotubes based on assemblies of krr1 segment. The electronic transfer would be achieved by introducing different histidine ionization states in selected positions of the internal core of the construct, in addition to specific mutations with charged amino acids that altogether will allow the formation of coherent networks of aromatic ring stacking, salt-bridges, and hydrogen bonds. C1 Tel Aviv Univ, Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. Univ Barcelona, Dept Chem Engn, Escola Tech Super Engn Ind, Politecn Catalunya, E-08028 Barcelona, Spain. NCI, Natl Canc Inst, Ctr Canc Res Nanobiol Program, Basic Res Program Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. RP Zanuy, D (reprint author), Tel Aviv Univ, Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. EM david.zanuy@upc.edu; ruthn@ncifcrf.gov RI Wolfson, Haim/A-1837-2011; Zheng, Jie/B-5057-2013; Zanuy, David/G-3930-2014; Haspel, Nurit/D-1961-2017 OI Zheng, Jie/0000-0003-1547-3612; Zanuy, David/0000-0001-7704-2178; FU Intramural NIH HHS; NCI NIH HHS [N01-CO12400, N01CO12400] NR 28 TC 12 Z9 13 U1 1 U2 4 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD JUL PY 2007 VL 93 IS 1 BP 245 EP 253 DI 10.1529/biophysj.106.100644 PG 9 WC Biophysics SC Biophysics GA 176CW UT WOS:000247061500028 PM 17416628 ER PT J AU Che, Y Brooks, BR Marshall, GR AF Che, Ye Brooks, Bernard R. Marshall, Garland R. TI Protein recognition motifs: Design of peptidomimetics of helix surfaces SO BIOPOLYMERS LA English DT Article DE alpha-helix; peptidomimetic; template design; privileged structure; conformational analysis; side-chain ID ALPHA-HELIX; BETA-PEPTIDE; FORMING PROPENSITIES; MIMETICS; PROTEOMIMETICS; ENTROPY; MIMICRY; DERIVATIVES; TEMPLATE; PEPTOIDS AB Helices represent one of the most common recognition motifs in proteins. The design of nonpeptidic scaffolds, such as the 3,2';2"-tris-substituted terphenyl, that can imitate the side-chain orientation along one face of an ahelix potentially provides an effective means to modulate helix-recognition functions. Here, based on theoretical arguments, we described novel alpha-helix mimetics which are more effective than the terphenyl at constraining the aryl-aryl torsion angles to those associated with structures suitable for mimicking the alpha-helical twist for side-chain orientation and for superimposing the side chains of residues i, i + 3 or i + 4, i + 7 when compared with the alpha-beta side-chain vectors of the regular alpha-helix with an improved root mean square deviation (RMSD) of approximately 0.5 angstrom. In addition, this study suggests that rotamer distributions around the C-alpha- C-beta bonds of these helix mimetics are similar to those of alpha-helices, except that these rotamer distributions show an r approximately 60 degrees shift compared to those of alpha-helices when the mimetic axis is superimposed upon the helix axis.,This change in rotamer orientation complicates mimicry of the helix surface. (c) 2007 Wiley Periodicals, Inc. C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. Washington Univ, Ctr Computat Biol, St Louis, MO 63110 USA. Washington Univ, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Che, Y (reprint author), NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM chey@nhlbi.nih.gov RI Che, Ye/A-3449-2008; OI Marshall, Garland/0000-0002-3098-0332 FU Intramural NIH HHS; NIGMS NIH HHS [GM 68460] NR 35 TC 20 Z9 20 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0006-3525 J9 BIOPOLYMERS JI Biopolymers PD JUL PY 2007 VL 86 IS 4 BP 288 EP 297 DI 10.1002/bip.20744 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 183LZ UT WOS:000247575600005 PM 17443711 ER PT J AU He, HJ Pires, R Zhu, TN Zhou, A Gaigalas, AK Zou, S Wang, LL AF He, Hua-Jun Pires, Rick Zhu, Tie-Nian Zhou, Anhong Gaigalas, Adolfas K. Zou, Sige Wang, Lili TI Fluorescence resonance energy transfer-based method for detection of DNA binding activities of nuclear factor kappa B SO BIOTECHNIQUES LA English DT Article ID GEL-ELECTROPHORESIS; PROTEINS; ALPHA; PHOSPHORYLATION; KINETICS; REGIONS; ASSAY AB The DNA binding protein nuclear factor KB (NF-kappa B) and the cellular signaling pathways in which it participates are the central coordinators of many biological processes, including innate and adaptive immune responses, oxidative stress response, and aging. NF-kappa B also plays a key role in diseases, for example, cancer A simple, convenient, and high-throughput detection of NF-kappa B activation is therefore important for systematicall, studying signaling pathways and for screening therapeutic drug targets. We describe a method based on fluorescence resonance energy transfer (FRET) to directly measure the amount of activated NF-kappa B More specifically a double-stranded DNA (dsDNA) probe was designed to contain a pair of FRET fluorophores at the saine end of the probe and an endonuclease binding site within the NF-kappa B consensus sequence. The activated NF-kappa B was detected by FRET following the restriction enzyme digestion. Using three different analyte materials - (i) purified recombinant NF-kappa B p50, (ii) nuclear extracts, and (iii) whole cell lysates-we demonstrated that this assay is as sensitive as the traditional, widely used electrophoretic mobility shift assay (EMSA), but much less labor intensive for measuring NF-kappa B DNA binding activities. In addition, this FRET-based assay can be easily adapted for high-throughput screening of NF-kappa B activation. C1 Natl Inst Stand & Technol, Div Biochem Sci, Gaithersburg, MD 20899 USA. Montgomery Coll, Germantown, MD USA. NIA, Baltimore, MD 21224 USA. Utah State Univ, Logan, UT 84322 USA. RP Wang, LL (reprint author), Natl Inst Stand & Technol, Div Biochem Sci, 100 Bur Dr,Stop 8312, Gaithersburg, MD 20899 USA. EM zous@grc.nia.nih-gov; lili.wang@nist.gov FU Intramural NIH HHS NR 24 TC 15 Z9 16 U1 0 U2 3 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD JUL PY 2007 VL 43 IS 1 BP 93 EP 98 DI 10.2144/000112475 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 192MV UT WOS:000248207100020 PM 17695258 ER PT J AU Chinen, J Davis, J De Ravin, SS Hay, BN Hsu, AP Linton, GF Naumann, N Nomicos, EYH Silvin, C Ulrick, J Whiting-Theobald, NL Malech, HL Puck, JM AF Chinen, Javier Davis, Joie De Ravin, Suk See Hay, Beverly N. Hsu, Amy P. Linton, Gilda F. Naumann, Nora Nomicos, Effie Y. H. Silvin, Christopher Ulrick, Jean Whiting-Theobald, Narda L. Malech, Harry L. Puck, Jennifer M. TI Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; CHRONIC GRANULOMATOUS-DISEASE; STEM-CELL TRANSPLANTATION; T-CELL; CD34(+) CELLS; TRANSDUCTION; SCID-X1; SURVIVAL; MODEL; IL2RG AB Retroviral gene therapy can restore immunity to infants with X-linked severe combined immunodeficiency (XSCID) caused by mutations in the IL2RG gene encoding the common gamma chain (gamma c) of receptors for interleukins 2 (IL-2), -4, -7, -9, -15, and -21. We investigated the safety and efficacy of gene therapy as salvage treatment for older XSCID children with inadequate immune reconstitution despite prior bone marrow transplant from a parent. Subjects received retrovirus-transduced autologous peripherally mobilized CD34(+) hematopoletic cells. T-cell function significantly improved in the youngest subject (age 10 years), and multilineage retroviral marking occurred in all 3 children. C1 NIAID, Host Def Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NHGRI, Genet & Mol Biol Branch, NIAID, NIH,DHHS, Bethesda, MD 20892 USA. RP Chinen, J (reprint author), NIAID, Host Def Lab, NIH, Dept Hlth & Human Serv, Bldg 10-CRC 5 W Labs,Room 5-3750,10 Ctr Dr MSC 14, Bethesda, MD 20892 USA. OI Malech, Harry/0000-0001-5874-5775 FU Intramural NIH HHS NR 32 TC 54 Z9 54 U1 2 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 JUL 1 PY 2007 VL 110 IS 1 BP 67 EP 73 DI 10.1182/blood-2006-11-058933 PG 7 WC Hematology SC Hematology GA 183ZN UT WOS:000247611000016 PM 17369490 ER PT J AU Chen, Z Naveiras, O Balduini, A Mammoto, A Conti, MA Adelstein, RS Ingber, D Daley, GQ Shivdasani, RA AF Chen, Zhao Naveiras, Olaia Balduini, Alessandra Mammoto, Akiko Conti, Mary Anne Adelstein, Robert S. Ingber, Donald Daley, George Q. Shivdasani, Ramesh A. TI The May-Hegglin anomaly gene MYH9 is a negative regulator of platelet biogenesis modulated by the Rho-ROCK pathway SO BLOOD LA English DT Article ID MYOSIN HEAVY-CHAIN; PROPLATELET FORMATION; MOLECULAR-MECHANISMS; HUMAN MEGAKARYOCYTES; BLOOD-PLATELETS; LIGHT-CHAIN; STEM-CELLS; IN-VITRO; MUTATIONS; MARROW AB The gene implicated in the May-Hegglin anomaly and related macrothrombocytopenias, MYH9, encodes myosin-IIA, a protein that enables morphogenesis in diverse cell types. Defective myosin-IIA complexes are presumed to perturb megakaryocyte (MK) differentiation or generation of proplatelets. We observed that Myh9(-/-) mouse embryonic stem (ES) cells differentiate into MKs that are fully capable of proplatelet formation (PPF). In contrast, elevation of myosin-IIA activity, by exogenous expression or by mimicking constitutive phosphorylation of its regulatory myosin light chain (MLC), significantly attenuates PPF. This effect occurs only in the presence of myosin-IIA and implies that myosin-IIA influences thrombopoiesis negatively. MLC phosphorylation in MKs is regulated by Rho-associated kinase (ROCK), and consistent with our model, ROCK inhibition enhances PPF. Conversely, expression of AV14, a constitutive form of the ROCK activator Rho, blocks PPF, and this effect is rescued by simultaneous expression of a dominant inhibitory MLC form. Hematopoietic transplantation studies in mice confirm that interference with the putative Rho-ROCK-myosin-IIA pathway selectively decreases the number of circulating platelets. Our studies unveil a key regulatory pathway for platelet biogenesis and hint at Sdf-1/CXCL12 as one possible extracellular mediator. The unexpected mechanism for Myh9-associated thrombocytopenia may lead to new molecular approaches to manipulate thrombopoiesis. C1 Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. Childrens Hosp, Div Hematol & Oncol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA. Univ Pavia, Dept Biochem, Fdn Ist Ricovero & Cura Carattere Sci Policlin Sa, I-27100 Pavia, Italy. Childrens Hosp, Vasc Biol Program, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA. NHLBI, Mol Cardiol Lab, Bethesda, MD 20892 USA. RP Chen, Z (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 1 Jimmy Fund Way, Boston, MA 02115 USA. RI Balduini, Alessandra/K-6802-2016; OI Balduini, Alessandra/0000-0003-3145-1245; Adelstein, Robert/0000-0002-8683-2144 FU NCI NIH HHS [CA55883]; NHLBI NIH HHS [R01 HL063143, HL63143, R56 HL063143]; Telethon [GGP06177] NR 51 TC 90 Z9 91 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD JUL 1 PY 2007 VL 110 IS 1 BP 171 EP 179 DI 10.1182/blood-2007-02-071589 PG 9 WC Hematology SC Hematology GA 183ZN UT WOS:000247611000028 PM 17392504 ER PT J AU Peng, G Greenwell-Wild, T Nares, S Jin, W Lei, KJ Rangel, ZG Munson, PJ Wahl, SM AF Peng, Gang Greenwell-Wild, Teresa Nares, Salvador Jin, Wenwen Lei, Ke Jian Rangel, Zoila G. Munson, Peter J. Wahl, Sharon M. TI Myeloid differentiation and susceptibility to HIV-1 are linked to APOBEC3 expression SO BLOOD LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; LEUKOCYTE PROTEASE INHIBITOR; CD4(+) T-CELLS; RETROVIRAL RESTRICTION; CYTIDINE DEAMINATION; POTENT INHIBITORS; ENZYME APOBEC3G; FAMILY PROTEINS; DENDRITIC CELLS; VIF PROTEIN AB HIV-1 recognition by, interaction with, and/or infection of CD4(+)CCR5(+) tissue macrophages and dendritic cells (DCs) play important roles in HIV-1 transmission and pathogenesis. By comparison, circulating CD4(+)CCR5(+) monocytes appear relatively resistant to HIV-1, and a fundamental unresolved question involves deciphering restriction factors unique to this precursor population. Not only do monocytes, relative to macrophages, possess higher levels of the innate resistance factor APOBEC3G, but we uncovered APOBEC3A, not previously associated with anti-HIV activity, as being critical in monocyte resistance. Inversely correlated with susceptibility, silencing of APOBEC3A renders monocytes vulnerable to HIV-1. Differences in promiscuity of monocytes, macrophages, and DCs can be defined, at least partly, by disparities in APOBEC expression, with implications for enhancing cellular defenses against HIV-1. C1 NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 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 Intramural NIH HHS NR 52 TC 114 Z9 115 U1 2 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 JUL 1 PY 2007 VL 110 IS 1 BP 393 EP 400 DI 10.1182/blood-2006-10-051763 PG 8 WC Hematology SC Hematology GA 183ZN UT WOS:000247611000057 PM 17371941 ER PT J AU Seggewiss, R Lore, K Guenaga, FJ Pittaluga, S Mattapallil, J Chow, CK Koup, RA Camphausen, K Nason, MC Meier-Schellersheim, M Donahue, RE Blazar, BR Dunbar, CE Douek, DC AF Seggewiss, Ruth Lore, Karin Guenaga, F. Javier Pittaluga, Stefania Mattapallil, Joseph Chow, Catherine K. Koup, Richard A. Camphausen, Kevin Nason, Martha C. Meier-Schellersheim, Martin Donahue, Robert E. Blazar, Bruce R. Dunbar, Cynthia E. Douek, Daniel C. TI Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; T-CELLS; GASTROINTESTINAL-TRACT; NONHUMAN-PRIMATES; REGENERATION; MICE; AGE; REPERTOIRE; EXPRESSION AB Opportunistic infections contribute to morbidity and mortality after peripheral blood progenitor cell (PBPC) transplantation and are related to a deficient T-cell compartment. Accelerated T-cell reconstitution may therefore be clinically beneficent. Keratinocyte growth factor (KGF) has been shown to protect thymic epithelial cells in mice. Here, we evaluated immune reconstitution after autologous CD34(+) PBPC transplantation in rhesus macaques conditioned with myeloablative total body irradiation in the absence or presence of single pretotal body irradiation or repeated peritransplant KGF administration. All KGF-treated animals exhibited a well-preserved thymic architecture 12 months after graft. In contrast, thymic atrophy was observed in the majority of animals in the control group. The KGF-treated animals showed higher frequencies of naive T cells in lymph nodes after transplantation compared with the control animals. The animals given repeated doses of KGF showed the highest levels of T-cell receptor excision circles (TRECs) and the lowest frequencies of Ki67(+) T cells, which suggest increased thymic-dependent reconstitution in these animals. Of note, the humoral response to a T-cell-dependent neo-antigen was significantly higher in the KGF-treated animals compared with the control animals. Thus, our findings suggest that KGF may be a useful adjuvant therapy to augment T-cell reconstitution after human PBPC transplantation. C1 NIAID, Human Immunol Sect, Vaccine Res Ctr, DHHS,NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Hematopathol Sect, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIAID, Biostat Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Minnesota, Ctr Canc, Dept Pediat, Div Blood & Marrow Transplantat, Minneapolis, MN 55455 USA. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, Vaccine Res Ctr, DHHS,NIH,Dept Hlth & Human Serv, 40 Convent Dr,Rm 3509, Bethesda, MD 20892 USA. EM ddouek@nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL073794] NR 47 TC 61 Z9 72 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 JUL 1 PY 2007 VL 110 IS 1 BP 441 EP 449 DI 10.1182/blood-2006-12-065623 PG 9 WC Hematology SC Hematology GA 183ZN UT WOS:000247611000063 PM 17374737 ER PT J AU Kochenderfer, JN Simpson, JL Chien, CD Gress, RE AF Kochenderfer, James N. Simpson, Jessica L. Chien, Christopher D. Gress, Ronald E. TI Vaccination regimens incorporating CpG-containing oligodeoxynucleotides and IL-2 generate antigen-specific antitumor immunity from T-cell populations undergoing homeostatic peripheral expansion after BMT SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; BLOOD STEM-CELL; COLONY-STIMULATING FACTOR; PULSED DENDRITIC CELLS; ACUTE MYELOID-LEUKEMIA; LOW-DOSE INTERLEUKIN-2; INTENSIVE CHEMOTHERAPY; B16 MELANOMA; PEPTIDE VACCINE; TUMOR VACCINES AB Development of CD8(+) T-cell responses targeting tumor-associated antigens after autologous stem cell transplantations (ASCTs) might eradicate residual tumor cells and decrease relapse rates. Because thymic function dramatically decreases with aging, T-cell reconstitution in the first year after ASCT in middle-aged patients occurs primarily by homeostatic peripheral expansion (HPE) of mature T cells. To study antigen-specific T-cell responses during HPE, we performed syngeneic bone marrow transplantations (BMTs) on thymectomized mice and then vaccinated the mice with peptides plus CpG-containing oligodeoxynucleotides (CpGs) in incomplete Freund adjuvant and treated the mice with systemic interleukin-2 (IL-2). When CD8(+) T-cell responses were measured ex vivo, up to 9.1% of CD8(+) T cells were specific for tumor-associated epitopes. These large T-cell responses were generated by synergism between CpG and IL-2. When we injected mice subcutaneously with tumor cells 14 days after BMT and then treated them with peptide + CpG-containing vaccines plus systemic IL-2, survival was increased and tumor growth was inhibited in an epitope-specific manner. Depletion of CD8(+) T cells eliminated epitope-specific antitumor immunity. This is the first report to demonstrate that CD8(+) T-cell responses capable of executing antitumor immunity can be elicited by CpG-containing vaccines during HPE. C1 NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Kochenderfer, JN (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, 10 Ctr Dr CRC 3-3288, Bethesda, MD 20892 USA. EM kochendj@mail.nih.gov FU Intramural NIH HHS NR 57 TC 16 Z9 17 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 JUL 1 PY 2007 VL 110 IS 1 BP 450 EP 460 DI 10.1182/blood-2006-11-057935 PG 11 WC Hematology SC Hematology GA 183ZN UT WOS:000247611000064 PM 17371943 ER PT J AU Frattali, C Hanna, R McGinty, AS Gerber, L Wesley, R Grafman, J Coelho, C AF Frattali, Carol Hanna, Rebecca McGinty, Anita Shukla Gerber, Lynn Wesley, Robert Grafman, Jordan Coelho, Carl TI Effect of prefrontal cortex damage on resolving lexical ambiguity in text SO BRAIN AND LANGUAGE LA English DT Article DE suppression; prefrontal cortex damage; lexical ambiguity; text comprehension; inhibitory control; aging effects ID GENERAL COMPREHENSION SKILL; DISCOURSE COMPREHENSION; SENTENCE COMPREHENSION; RIGHT-HEMISPHERE; CORTICAL AREAS; ALZHEIMER-TYPE; SUPPRESSION; RETRIEVAL; MEMORY; MECHANISMS AB The function of suppression of context-inappropriate meanings during lexical ambiguity resolution was examined in 25 adults with prefrontal cortex damage (PFCD) localized to the left (N = 8), right (N = 6), or bilaterally (N = 11); and 21 matched Controls. Results revealed unexpected inverse patterns of suppression between PFCD and Control groups, with measures suggesting decreased interference across time in the PFCD group and increased interference in the Control group. The PFCD group, however, had significantly lower accuracy rates for the context-inappropriate condition. Results suggest a loss of the control aspects of inhibitory processes in lexical ambiguity resolution following PFCD. An aging effect on suppression function is also suggested. (C) 2006 Elsevier Inc. All rights reserved. C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. NIH, Dept Rehabil Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Univ Maryland, Dept Speech & Hearing Sci, College Stn, TX USA. Univ Connecticut, Dept Commun Sci, Storrs, CT 06268 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457 NR 62 TC 1 Z9 2 U1 3 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD JUL PY 2007 VL 102 IS 1 BP 99 EP 113 DI 10.1016/j.bandl.2006.09.007 PG 15 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 184KO UT WOS:000247640500010 PM 17092552 ER PT J AU Solomou, EE Wong, S Visconte, V Gibellini, F Young, NS AF Solomou, Elena E. Wong, Susan Visconte, Valeria Gibellini, Federica Young, Neal S. TI Decreased TCR zeta-chain expression in T cells from patients with acquired aplastic anaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE aplastic anaemia; T cells; bone marrow failure ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; DOWN-REGULATION; PHOSPHORYLATION; INTERFERON; PROMOTER AB In aplastic anaemia, T cells have a central role in the pathophysiology of bone marrow destruction. This study showed that T cells from patients with aplastic anaemia expressed decreased T-cell receptor (TCR) zeta-chain protein and mRNA levels compared to healthy controls. Patients with decreased TCR zeta-chain showed an abnormal response in intracellular calcium following stimulation through the TCR. We also observed an altered pattern of the transcription factors CREM alpha and Elf-1 that are implicated in zeta-chain transcription. We concluded that TCR zeta-chain expression was decreased in the majority of patients with aplastic anaemia, regardless of disease activity or treatment status. RP Solomou, EE (reprint author), Natl Heart Lung & Blood Inst, Hematol Branch, NIH, Bldg 10 CRC,Rm 3E5216,10 Ctr Dr, Bethesda, MD 20892 USA. EM solomoue@nhlbi.nih.gov FU Intramural NIH HHS NR 12 TC 10 Z9 10 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD JUL PY 2007 VL 138 IS 1 BP 72 EP 76 DI 10.1111/j.1365-2141.2007.06627.x PG 5 WC Hematology SC Hematology GA 176UV UT WOS:000247111300007 PM 17555449 ER PT J AU Ren, H Salous, AK Paul, JM Lipsky, RH Peoples, RW AF Ren, H. Salous, A. K. Paul, J. M. Lipsky, R. H. Peoples, R. W. TI Mutations at F637 in the NMDA receptor NR2A subunit M3 domain influence agonist potency, ion channel gating and alcohol action SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE glutamate receptor; ethanol; electrophysiology; mutant; desensitization; affinity ID D-ASPARTATE RECEPTORS; MEMBRANE-ASSOCIATED DOMAIN; GAMMA-AMINOBUTYRIC-ACID; SINGLE-CHANNEL; ETHANOL INHIBITION; GLYCINE RECEPTORS; MOLECULAR VOLUME; NERVOUS-SYSTEM; BINDING-SITE; DESENSITIZATION AB Background and purpose: NMDA receptors are important molecular targets of ethanol action in the CNS. Previous studies have identified a site in membrane-associated domain 3 ( M3) of the NR1 subunit and two sites in M4 of the NR2A subunit that influence alcohol action; the sites in NR2A M4 also regulate ion channel gating. The purpose of this study was to determine whether mutations at the site in the NR2A subunit corresponding to the NR1 M3 site influence alcohol action and ion channel gating. Experimental approach: We investigated the effects of mutations at phenylalanine ( F) 637 of the NR2A subunit using whole-cell and single-channel patch-clamp electrophysiological recording in transiently-transfected HEK 293 cells. Key results: Mutations at F637 in the NR2A subunit altered peak and steady-state glutamate EC50 values, maximal steady- state to peak current ratios ( I-ss: I-p), mean open time, and ethanol IC50 values. Differences in glutamate potency among the mutants were not due to changes in desensitization. Ethanol IC50 values were significantly correlated with glutamate EC50 values, but not with maximal I-ss: I-p or mean open time. Ethanol IC50 values were linearly and inversely related to molecular volume of the substituent. Conclusions and implications: These results demonstrate that NR2A(F637) influences NMDA receptor affinity, ion channel gating, and ethanol sensitivity. The changes in NMDA receptor affinity are likely to be the result of altered ion channel gating. In contrast to the cognate site in the NR1 subunit, the action of ethanol does not appear to involve occupation of a critical volume at NR2A(F637). C1 Marquette Univ, Dept Biomed Sci, Milwaukee, WI 53233 USA. NIAAA, Mol Genet Sect, Neurogenet Lab, Rockville, MD 20852 USA. RP Peoples, RW (reprint author), Marquette Univ, Dept Biomed Sci, SC426,PO Box 1881, Milwaukee, WI 53201 USA. EM robert.peoples@marquette.edu OI Lipsky, Robert/0000-0001-7753-1473 FU NIAAA NIH HHS [AA15203-01A1, R01 AA015203] NR 28 TC 20 Z9 20 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD JUL PY 2007 VL 151 IS 6 BP 749 EP 757 DI 10.1038/sj.bjp.0707254 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 190TW UT WOS:000248084500005 PM 17519952 ER PT J AU Eckstein, DJ Oberholtzer, JC AF Eckstein, David J. Oberholtzer, J. Carl TI NCI responds to "no K01 offered from the NCI - What's the message?" SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material C1 NCI, OCTR OD, Bethesda, MD 20892 USA. RP Oberholtzer, JC (reprint author), NCI, OCTR OD, 6116 Execut Blvd,Suite 7000, Bethesda, MD 20892 USA. EM oberholtzerc@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL PY 2007 VL 6 IS 7 BP 1003 EP 1004 PG 2 WC Oncology SC Oncology GA 229LQ UT WOS:000250805900012 ER PT J AU Karakas, B Weeraratna, AT Abukhdeir, AM Konishi, H Gustin, JP Vitolo, MI Bachman, KE Park, BH AF Karakas, Bedri Weeraratna, Ashani T. Abukhdeir, Abde M. Konishi, Hiroyuki Gustin, John P. Vitolo, Michele I. Bachman, Kurtis E. Park, Ben Ho TI p21 gene knock down does not identify genetic effectors seen with gene knock out SO CANCER BIOLOGY & THERAPY LA English DT Article DE RNAi; gene knock down; gene knock out; p21; TGF beta ID RNA INTERFERENCE SCREENS; CANCER-CELLS; HYPERMETHYLATION; SIRNAS; DNMT1 AB RNA interference (RNAi) has become a popular tool for analyzing gene function in cancer research. The feasibility of using RNAi in cellular and animal models as an alternative to conventional gene knock out approaches has been demonstrated. Although these studies show that RNAi can recapitulate phenotypes seen in knock out animals and their derived cell lines, a systematic study rigorously comparing downstream effector genes between RNAi and gene knock out has not been performed. Here we present data contrasting the phenotypic and genotypic changes that occur with either stable knock down via RNAi of the cyclin dependent kinase inhibitor p21 versus its somatic cell knock out counterpart in the human mammary epithelial cell line MCF-10A. Our results demonstrate that p21 knock down clones display a growth proliferative response upon exposure to Transforming Growth Factor-Beta Type 1 (TGF beta) similar to p21 knock out clones. However, gene expression profiles were significantly different in p21 knock down cells versus p21 knock out clones. Importantly p21 knock down clones did not display increased gene expression of interleukin-1 alpha (IL-1 alpha), a critical effector of this growth response previously validated in p21 knock out cells. We conclude that gene knock out can yield additional vital information that may be missed with gene knock down strategies. C1 Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr John Hopkins, Baltimore, MD USA. NIA, Immunol Lab, Baltimore, MD 21224 USA. Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Park, BH (reprint author), Dept Oncol, 1650 Orleans St,Room 1M42, Baltimore, MD 21231 USA. EM bpark2@jhmi.edu FU Intramural NIH HHS [Z01 AG000442-04]; NCI NIH HHS [R55 CA109274, R01 CA109274, T32 CA067751, CA109274, T32CA67751] NR 26 TC 6 Z9 6 U1 0 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL PY 2007 VL 6 IS 7 BP 1025 EP 1030 PG 6 WC Oncology SC Oncology GA 229LQ UT WOS:000250805900017 PM 17611398 ER PT J AU Shaheduzzaman, S Vishwanath, A Furusato, B Cullen, J Chen, YM Banez, L Nau, M Ravindranath, L Kim, KH Mohammed, A Chen, YD Ehrich, M Srikantan, V Sesterhenn, IA McLeod, DG Vahey, M Petrovics, Y Dobi, A Srivastava, S AF Shaheduzzaman, Syed Vishwanath, Anu Furusato, Bungo Cullen, Jennifer Chen, Yongmei Banez, Lionel Nau, Martin Ravindranath, Lakshmi Kim, Kee-Hong Mohammed, Ahmed Chen, Yidong Ehrich, Mathias Srikantan, Vasantha Sesterhenn, Isabell A. McLeod, David G. Vahey, Maryanne Petrovics, Yorgy Dobi, Albert Srivastava, Shiv TI Silencing of Lactotransferrin expression by methylation in prostate cancer progression SO CANCER BIOLOGY & THERAPY LA English DT Article DE LTF; downregulation; methylation; PSA doubling time; chemoprevention ID CYCLIN-DEPENDENT KINASES; BOVINE LACTOFERRIN; RADICAL PROSTATECTOMY; COLON CARCINOGENESIS; GROWTH ARREST; CELLS; RECURRENCE; PREVENTION; APOPTOSIS; GENE AB Background: Cancer cells gain selection advantages by the coordinated silencing of protective and by the activation of cell proliferation/cell survival genes. Evaluations of epithelial cell transcriptome of benign and malignant prostate glands by laser capture microdissection (LCM) identified Lactotransferrin (LTF) as the most significantly downregulated gene in prostate cancer (CaP) cells (p < 10(-6)). Frequent downregulation, significant association of LTF with PSA recurrence-free survival in CaP patients and the established anti-tumorigenic effects of LTF in experimental cancer models have provided impetus to evaluate LTF expression features and mechanisms in CaP specimens. Methods: LTF mRNA expression analysis was performed in LCM derived benign and malignant prostate epithelial cells by using Affymetrix GeneChip and QRT-PCR. LTF protein expression was assessed in tissue specimens by immunohistochemistry and in serum samples from CaP patients compared to healthy male control by using ELISA. Mechanism of LTF downregulation was analyzed in 5-azadeoxycytidine treated LNCaP and LAPC4 cells using MALDI-TOF MS. Proliferation and cell cycle analysis of CaP cells by FACS flow cytrometry was assessed in LNCaP cell cultures. Results: Quantitative analysis of LTF mRNA expression in tumor cells revealed marked downregulation of LTF with significant associations to decreased PSA recurrence-free survival of CaP patients (n = 100, p <= 0.0322). Moreover, low levels of LTF protein expression was observed in tumor tissues as well as in sera from CaP patients (p <= 0.0001). LTF promoter downstream CpG island methylation was found in LNCaP and LAPCA cells. Furthermore, replenishing of LTF by supplementing growth media with LTF protein resulted in reduced cell growth. Cell cycle analysis revealed robust increases in apoptosis in response to LTF treatment. Conclusion: This study highlights the potential for LTF in chemoprevention and to become a biologically relevant prognostic marker of CaP, suggesting that silencing of the LTF gene may be causally linked to CaP progression. C1 Uniformed Serv Univ Hlth Sci, US Mil Canc Inst, Dept Surg, Ctr Prostate Dis Res, Rockville, MD 20852 USA. Armed Forces Inst Pathol, Dept Genitourinary Pathol, Washington, DC 20306 USA. Walter Reed Army Med Ctr, Urol Serv, Washington, DC 20307 USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. WRAIR, Div Retrovirol, Rockville, MD USA. SEQUENOM Inc, San Diego, CA USA. RP Dobi, A (reprint author), Uniformed Serv Univ Hlth Sci, US Mil Canc Inst, Dept Surg, Ctr Prostate Dis Res, 1530 E Jefferson St, Rockville, MD 20852 USA. EM ADobi@cpdr.org; SSrivastava@cpdr.org OI Furusato, Bungo/0000-0003-4614-9882 FU NIDDK NIH HHS [R01 DK065977] NR 33 TC 18 Z9 20 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD JUL PY 2007 VL 6 IS 7 BP 1088 EP 1095 PG 8 WC Oncology SC Oncology GA 229LQ UT WOS:000250805900026 PM 17568188 ER PT J AU Pawarode, A Shukla, S Minderman, H Fricke, SM Pinder, EM O'Loughlin, KL Ambudkar, SV Baer, MR AF Pawarode, Attaphol Shukla, Suneet Minderman, Hans Fricke, Stacy M. Pinder, Elaine M. O'Loughlin, Kieran L. Ambudkar, Suresh V. Baer, Maria R. TI Differential effects of the immunosuppressive agents cyclosporin A, tacrolimus and sirolimus on drug transport by multidrug resistance proteins SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE cyclosporin A; tacrolimus; sirolimus; P-glycoprotein; multidrug resistance protein-1; breast cancer resistance protein; lung resistance protein ID ACUTE MYELOID-LEUKEMIA; RENAL-TRANSPLANT RECIPIENTS; SOUTHWEST-ONCOLOGY-GROUP; P-GLYCOPROTEIN; GENE-EXPRESSION; ATPASE ACTIVITY; CANCER; ABCG2; CELLS; PHARMACOKINETICS AB Purpose We sought to determine the effects of the immunosuppressants, cyclosporin A (CsA), tacrolimus and sirolimus, on drug transport by the ATP-binding cassette proteins, P-glycoprotein (Pgp; ABCB1), multidrug resistance protein-1 (MRP-1; ABCC1) and breast cancer resistance protein (BCRP; ABCG2), and the major vault protein lung resistance protein (LRP). Methods Cellular content of mitoxantrone, a Pgp, MRP-1 and BCRP substrate, was measured by flow cytometry in cells overexpressing these proteins following incubation with and without CsA, tacrolimus or sirolimus. Interaction of BCRP with these compounds was studied by photolabeling and ATPase assays. Nuclear-cytoplasmic distribution of doxorubicin was studied by confocal microscopy in cells overexpressing LRP. Results CsA increased cellular drug uptake in cells overexpressing Pgp, MRP-1 or BCRP and nuclear drug uptake in cells overexpressing LRP at the clinically achievable concentration of 2.5 mu M. Tacrolimus enhanced cellular drug uptake at 1 mu M, but not at 0.08 mu M, its clinically achievable concentration, and did not enhance nuclear drug uptake. Sirolimus enhanced cellular drug uptake in cells overexpressing Pgp, MRP-1 and BCRP with optimal effects at 2.5 mu M, but was effective at its clinically achievable concentration of 0.25 mu M if cells were pre-incubated for at least 30 min before drug exposure, and also enhanced nuclear drug uptake at 0.25 mu M. BCRP modulation by all three immunosuppressive agents was associated with competitive binding to the drug transport sites. Conclusion CsA, tacrolimus and sirolimus modulate drug transport by Pgp, MRP-1 and BCRP and CsA and sirolimus modulate drug transport by LRP at concentrations that differ from immunosuppressive concentrations and maximum tolerated concentrations. C1 New York State Dept Hlth, Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. NCI, Canc Res Ctr, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. New York State Dept Hlth, Roswell Pk Canc Inst, Dept Mol Pharmacol & Canc Therapeut, Buffalo, NY 14263 USA. RP Baer, MR (reprint author), New York State Dept Hlth, Roswell Pk Canc Inst, Dept Med, Elm & Carlton St, Buffalo, NY 14263 USA. EM maria.baer@roswellpark.org RI shukla, suneet/B-4626-2012 FU Intramural NIH HHS; NCI NIH HHS [P30 CA16056, R21 CA 98457, T32 CA 09072-31] NR 46 TC 36 Z9 37 U1 0 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD JUL PY 2007 VL 60 IS 2 BP 179 EP 188 DI 10.1007/s00280-006-0357-8 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 166MZ UT WOS:000246384300003 PM 17031644 ER PT J AU Kopelovich, L Fay, JR Sigman, CC Crowell, JA AF Kopelovich, Levy Fay, Judith R. Sigman, Caroline C. Crowell, James A. TI The mammalian target of rapamycin pathway as a potential target for cancer chemoprevention SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID TUBEROUS SCLEROSIS COMPLEX; TUMOR-SUPPRESSOR GENE; HUMAN PROSTATE-CANCER; FACTOR-KAPPA-B; EPIDERMAL-GROWTH-FACTOR; PHOSPHOINOSITIDE 3-KINASE/AKT/MAMMALIAN TARGET; HER-2/NEU TRANSGENIC MICE; CARCINOMA CELL-GROWTH; GREEN TEA CATECHINS; HUMAN BREAST-CANCER AB The mammalian target of rapamycin (mTOR) is a key signaling node coordinating cell cycle progression and cell growth in response to genetic, epigenetic, and environmental conditions. Pathways involved in mTOR signaling are dysregulated in precancerous human tissues. These findings, together with the intriguing possibility that mTOR suppression may be associated with antitumor actions of caloric restriction, suggest that mTOR signaling may be an important target for chemopreventive drugs. C1 NCI, NIH, Div Canc Prevent, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. CCs Assoc, Mountain View, CA USA. RP Kopelovich, L (reprint author), NCI, NIH, Div Canc Prevent, Chemoprevent Agent Dev Res Grp, 6130 Execut Blvd, Bethesda, MD 20892 USA. EM lk94c@nih.gov NR 193 TC 40 Z9 41 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 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2007 VL 16 IS 7 BP 1330 EP 1340 DI 10.1158/1055-9965.EPI-07-0045 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 192BD UT WOS:000248174800002 PM 17626998 ER PT J AU Franzmann, EJ Reategui, EP Pedroso, F Pernas, FG Karakullukcu, BM Carraway, KL Hamilton, K Singal, R Goodwinl, WJ AF Franzmann, Elizabeth J. Reategui, Erika P. Pedroso, Felipe Pernas, Francisco G. Karakullukcu, Baris M. Carraway, Kermit L. Hamilton, Kara Singal, Rakesh Goodwinl, W. Jarrard TI Soluble CD44 is a potential marker for the early detection of head and neck cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SQUAMOUS-CELL CARCINOMA; ORAL-CANCER; MATRIX-METALLOPROTEINASE; AERODIGESTIVE TRACT; ADHESION MOLECULES; MEDICAL PROGRESS; PROSTATE-CANCER; TUMOR-MARKERS; FOLLOW-UP; EXPRESSION AB Introduction: Head and neck squamous cell carcinoma (HNSCC) is a devastating and deadly disease, largely because it is diagnosed in late stage. Cure rates, currently at 50%, could increase to > 80% with early detection. In this study, we evaluate soluble CD44 (solCD44) as an early detection tool for HNSCC by determining whether it reliably distinguishes HNSCC from benign disease of the upper aerodigestive tract. Methods: We carried out the solCD44 ELISA on oral rinses from 102 patients with HNSCC and 69 control patients with benign diseases of upper aerodigestive tract to determine the sensitivity and specificity of the test for differentiating HNSCC from benign disease. Furthermore, we did a pilot study using methylation-specific PCR primers on oral rinses from 11 HNSCC patients with low solCD44 levels and 10 benign disease controls. Results: Mean salivary solCD44 levels were 24.4 +/- 32.0 ng/mL for HNSCC patients (range, 0.99-201 ng/mL) and 9.9 +/- 16.1 ng/mL (range, 0.73-124 ng/mL) for the patients with benign disease (P < 0.0001). Depending on cutoff point and HNSCC site, sensitivity ranged from 62% to 70% and specificity ranged from 75% to 88%. Nine of 11 HNSCC and 0 of 10 controls with low solCD44 levels showed hypermethylation of the CD44 promoter. Conclusions: SolCD44 is elevated in the majority of HNSCC and distinguishes cancer from benign disease with high specificity. Whereas the solCD44 test lacks sensitivity by itself, methylation status of the CD44 gene seems to complement the solCD44 test. Our pilot data indicate that, together, these markers will detect HNSCC with very high sensitivity and specificity. C1 Univ Miami, Sylvester Comprehens Canc Ctr, Div Biostat, Miami, FL 33152 USA. Univ Miami, Dept Otolaryngol, Miami, FL 33152 USA. Univ Miami, Dept Cell Biol & Anat, Miami, FL 33152 USA. Univ Miami, Div Med Oncol, Dept Internal Med, Miami, FL 33152 USA. Natl Inst Deafness & Other Commun, NIH, Bethesda, MD 20892 USA. RP Franzmann, EJ (reprint author), E Room 1028,1500 NW 12th Ave, Miami, FL 33136 USA. EM efranzman@med.miami.edu FU NCI NIH HHS [CA107828] NR 56 TC 55 Z9 58 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 JUL PY 2007 VL 16 IS 7 BP 1348 EP 1355 DI 10.1158/1055-9965.EPI-06-0011 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 192BD UT WOS:000248174800004 PM 17627000 ER PT J AU Melikian, AA Djordjevic, MV Chen, S Richie, J Stellman, SD AF Melikian, Assieh A. Djordjevic, Mirjana V. Chen, Shuquan Richie, John, Jr. Stellman, Steven D. TI Effect of delivered dosage of cigarette smoke toxins on the levels of urinary biomarkers of exposure SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CHROMATOGRAPHY-MASS SPECTROMETRY; DOSE-RESPONSE RELATIONSHIP; S-PHENYLMERCAPTURIC ACID; TOBACCO-RELATED CANCERS; LUNG-CANCER; 1-HYDROXYPYRENE GLUCURONIDE; RACIAL-DIFFERENCES; NICOTINE; METABOLITES; RISK AB Urinary metabolites of tobacco smoke toxins are often used as biomarkers for the evaluation of active and passive exposure to cigarette smoke toxins. In a study of healthy smokers, we investigated concentrations of urinary biomarkers in relation to concentrations of selected toxins in mainstream cigarette smoke as determined by machine smoking of cigarettes in a manner that mimics an individual's smoking behavior (topography). Concentrations of nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, and benzo(a)pyrene, in mainstream smoke determined under human smoking conditions, and their urinary metabolites cotinine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, and 1-hydroxypyrene were established for 257 individuals who smoked low-yield (0.1-0.8 mg Federal Trade Commission nicotine/cigarette; mean, 0.66; n = 87), medium-yield (0.9-1.2 mg nicotine/cigarette; mean, 1.1; n = 109), and high-yield cigarettes (nicotine, > 1.3 mg nicotine/cigarette; mean, 1.41; n = 61). Levels of urinary metabolites expressed per unit of delivered parent compounds decreased with increased smoke emissions. In smokers of low-, medium-, and high-yield cigarettes, the respective cotinine (ng/mg creatinine)-to-nicotine (mg/d) ratios were 89.4, 77.8, and 57.1 (low versus high; P = 0.06); the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (pmol/mg creatinine)-to-4-(methylnitrosamino)-1-(3-pyridyl)-1-buta- none (ng/d) ratios were 0.81, 0.55, and 0.57 (low versus high; P = 0.05); and the 1-hydroxypyrene (pg/mg creatinine)to-benzo(a)pyrene (ng/d) ratios were 1.55, 1.13, and 0.97 (low versus high; P = 0.008). Similarly, means of cotinine per unit of delivered nicotine in smokers who consumed < 20 cigarettes per day was 3.5-fold higher than in those who smoked > 20 cigarettes per day. Likewise, a negative correlation was observed between cotinine-to-nicotine ratios and delivered doses of nicotine in subgroups of smokers who used the identical brand of cigarette, namely a filter tip-vented Marlboro (r = -0.59), which is a popular brand among Euro-Americans, and Newport (r = -0.37), a menthol-flavored cigarette without filter tip vents that is preferred by African-Americans. Thus, the intensity of the exposures significantly affects the levels of urinary biomarkers of exposure and should be taken into account in the evaluation of human exposure to cigarette smoke toxins. C1 NYU, Sch Med, Dept Environm Med, Tuxedo Pk, NY 10987 USA. NCI, Tobacco Control Res Branch, Bethesda, MD USA. Former Amer hlth Fdn, Valhalla, NY USA. Penn State Univ, Hershey Med Ctr, Hershey, PA 17033 USA. Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Melikian, AA (reprint author), NYU, Sch Med, Dept Environm Med, Tuxedo Pk, NY 10987 USA. EM Melikian@med.nyu.edu FU NCI NIH HHS [CA-68384, CA-70972] NR 37 TC 24 Z9 27 U1 1 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 JUL PY 2007 VL 16 IS 7 BP 1408 EP 1415 DI 10.1158/1055-9965.EPI-06-1097 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 192BD UT WOS:000248174800012 PM 17627005 ER PT J AU Couch, FJ Sinilnikova, O Vierkant, RA Pankratz, VS Fredericksen, ZS Stoppa-Lyonnet, D Coupier, I Hughes, D Hardouin, A Berthet, P Peock, S Cook, M Baynes, C Hodgson, S Morrison, PJ Porteous, ME Jakubowska, A Lubinski, J Gronwald, J Spurdle, AB KConFab Schmutzler, R Versmold, B Engel, C Meindl, A Sutter, C Horst, J Schaefer, D Offit, K Kirchhoff, T Andrulis, IL Ilyushik, E Glendon, G Devilee, P Vreeswijk, MPG Vasen, HFA Borg, A Backenhorn, K Struewing, JP Greene, MH Neuhausen, SL Rebbeck, TR Nathanson, K Domchek, S Wagner, T Garber, JE Szabo, C Zikan, M Foretova, L Olson, JE Sellers, TA Lindor, N Ll, HN Tommiska, J Aittomaki, K Hamann, U Rashid, MU Torres, D Simard, J Durocher, F Guenard, F Lynch, HT Isaacs, C Weitzel, J Olopade, OI Narod, S Daly, MB Godwin, AK Tomlinson, G Easton, DF Chenevix-Trench, G Antoniou, AC AF Couch, Fergus J. Sinilnikova, Olga Vierkant, Robert A. Pankratz, V. Shane Fredericksen, Zachary S. Stoppa-Lyonnet, Dominique Coupier, Isabelle Hughes, David Hardouin, Agnes Berthet, Pascaline Peock, Susan Cook, Margaret Baynes, Caroline Hodgson, Shirley Morrison, Patrick J. Porteous, Mary E. Jakubowska, Anna Lubinski, Jan Gronwald, Jacek Spurdle, Amanda B. kConFab Schmutzler, Rita Versmold, Beatrix Engel, Christoph Meindl, Alfons Sutter, Christian Horst, Jurgen Schaefer, Dieter Offit, Kenneth Kirchhoff, Tomas Andrulis, Irene L. Ilyushik, Eduard Glendon, Gordon Devilee, Peter Vreeswijk, Maaike P. G. Vasen, Hans F. A. Borg, Ake Backenhorn, Katja Struewing, Jeffery P. Greene, Mark H. Neuhausen, Susan L. Rebbeck, Timothy R. Nathanson, Katherine Domchek, Susan Wagner, Theresa Garber, Judy E. Szabo, Csilla Zikan, Michal Foretova, Lenka Olson, Janet E. Sellers, Thomas A. Lindor, Noralane Ll, Heli Nevanlinna Tommiska, Johanna Aittomaki, Kristiina Hamann, Ute Rashid, Muhammad U. Torres, Diana Simard, Jacques Durocher, Francine Guenard, Frederic Lynch, Henry T. Isaacs, Claudine Weitzel, Jeffrey Olopade, Olufunmilayo I. Narod, Steven Daly, Mary B. Godwin, Andrew K. Tomlinson, Gail Easton, Douglas F. Chenevix-Trench, Georgia Antoniou, Antonis C. CA CIM Brca1 2 TI AURKA F31I polymorphism and breast cancer risk in BRCA1 and BRCA2 mutation carriers: A consortium of investigators of modifiers of BRCA1/2 study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID UNKNOWN CLINICAL-SIGNIFICANCE; DNA-SEQUENCE VARIANTS; AURORA-A; SUSCEPTIBILITY GENE; MOUSE AB The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 individuals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 311 allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91; 95% confidence interval (95% CI), 0.77-1.061. Similarly, no significant association was seen in BRCA1 (HR, 0.90; 95% Cl, 0.75-1.08) or BRCA2 carriers (HR, 0.93; 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. C1 Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN 55905 USA. Mayo Clin, Coll Med, Dept Med Genet, Rochester, MN 55905 USA. Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN 55905 USA. Hospices Civils, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. IARC, Lyon, France. Inst Curie, Serv Genet Oncol, Inst Natl Sante & Rech Med, U509, Paris, France. Ctr Francois Baclesse, Caen, France. Univ Cambridge, Canc Res UK, Genet Epidemiol Unit, Dept Publ Hlth, Cambridge CB2 1TN, England. Univ Cambridge, Human Canc Genet Grp, Dept Oncol, Cambridge CB2 1TN, England. St George Hosp, SW Thames Reg Genet Serv, London, England. Belfast City Hosp, Canc Genet Serv, No Ireland Reg Genet Ctr, Belfast BT9 7AD, Antrim, North Ireland. Western Gen Hosp, SE Scotland Clin Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland. Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. Queensland Inst Med Res, Brisbane, Qld 4006, Australia. Kathleen Cuningham Fdn Consortium Res Familial Br, Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. Univ Cologne, Div Mol Gynecooncol, D-5000 Cologne 41, Germany. Univ Leipzig, Inst Med Informat Stat & Epidemiol, D-7010 Leipzig, Germany. Tech Univ Munich, Dept Gynaecol & Obstet, D-8000 Munich, Germany. Univ Heidelberg, Inst Human Genet, D-6900 Heidelberg, Germany. Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. Univ Munster, Munster, Germany. Univ Frankfurt, Inst Human Genet, D-6000 Frankfurt, Germany. Mem Sloan Kettering Canc Ctr, Clin Genet Serv, New York, NY 10021 USA. Ctr Res Womens Hlth, Toronto, ON, Canada. Leiden Univ, Ctr Med, Dept Human Genet, NL-2300 RA Leiden, Netherlands. Fdn Detect Hereditary Tumors, Leiden, Netherlands. Lund Univ Hosp, Dept Oncol, Lund, Sweden. NCI, Clin Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. Univ Calif Irvine, Dept Med, Div Epidemiol, Irvine, CA 92717 USA. Univ Penn, Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. Med Univ Vienna, Div Senol, Vienna, Austria. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Charles Univ Prague, Fac Med 1, Dept Biochem & Expt Oncol, CR-11636 Prague, Czech Republic. Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. H Lee Moffitt Canc Ctr & Res Inst, Div Canc Prevent & Control, Tampa, FL USA. Univ Helsinki, Dept Obstet & Gynecol, FIN-00014 Helsinki, Finland. Univ Helsinki, Dept Clin Genet, FIN-00014 Helsinki, Finland. Univ Laval, Quebec City, PQ G1K 7P4, Canada. Univ Quebec, Cent Hosp, Canc Genom Lab, Quebec City, PQ, Canada. Univ Quebec, Cent Hosp, Oncol & Mol Endocrinol Res Ctr, Quebec City, PQ, Canada. Creighton Univ, Dept Prevent Med & Publ Hlth, Omaha, NE 68178 USA. City Hope Canc Ctr, Duarte, CA USA. Georgetown Univ, Lombardi Canc Ctr, Washington, DC 20057 USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. Univ Chicago, Chicago, IL 60637 USA. RP Couch, FJ (reprint author), Mayo Clin, Coll Med, Dept Lab Med & Pathol, 200 1st St SW, Rochester, MN 55905 USA. EM Couch.fergus@mayo.edu RI Spurdle, Amanda/A-4978-2011; Andrulis, Irene/E-7267-2013; Jakubowska, Anna/O-8050-2014; Struewing, Jeffery/I-7502-2013; Gronwald, Jacek/A-4576-2017; OI Spurdle, Amanda/0000-0003-1337-7897; Tommiska, Johanna/0000-0001-7958-8262; Evans, Gareth/0000-0002-8482-5784; Struewing, Jeffery/0000-0002-4848-3334; Gronwald, Jacek/0000-0002-3643-2871; Nathanson, Katherine/0000-0002-6740-0901; Vierkant, Robert/0000-0001-6242-5221; Nevanlinna, Heli/0000-0002-0916-2976; Kirchhoff, Tomas/0000-0002-9055-2364 FU NCI NIH HHS [R01 CA102776-04, P50 CA116201, P50 CA116201-030002, P50-CA116201, R01 CA074415, R01 CA074415-10, R01 CA083855, R01 CA083855-08, R01 CA102776, R01-CA083855, R01-CA102776, R01-CA74415]; NCRR NIH HHS [M01 RR000043, M01 RR000043-440791, M01-RR00043] NR 19 TC 26 Z9 26 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 JUL PY 2007 VL 16 IS 7 BP 1416 EP 1421 DI 10.1158/1055-9965.EPI-07-0129 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 192BD UT WOS:000248174800013 PM 17627006 ER PT J AU Matsuno, RK Anderson, WF Yamamoto, S Tsukuma, H Pfeiffer, RM Kobayashi, K Devesa, SS Levine, PH AF Matsuno, Rayna K. Anderson, William F. Yamamoto, Seiichiro Tsukuma, Hideaki Pfeiffer, Ruth M. Kobayashi, Ken Devesa, Susan S. Levine, Paul H. TI Early- and late-onset breast cancer types among women in the United States and Japan SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FEMALE BREAST; AGE-INCIDENCE; RISK; MORTALITY; PATTERNS; TRENDS; PREVALENCE; CARCINOMA; MIGRATION; HAWAII AB Background: Although differences in breast cancer incidence among Occidental and Asian populations are often attributed to variations in environmental exposures and/or lifestyle, fewer studies have systematically examined the effect of age-related variations. Methods: To further explore age-related geographic breast cancer variations, we compared age-specific incidence patterns among cases of female invasive breast cancer from the Surveillance, Epidemiology, and End Results (SEER) program and the Osaka Cancer Registry (1978-1997). Results: In SEER, there were 236,130 Whites, 21,137 Blacks, and 3,304 Japanese-Americans in Hawaii with invasive breast cancer. In Osaka, there were 25,350 cases. Incidence rates per 100,000 woman-years ranged from 87.6 among Whites to 21.8 in Osaka. Age-specific incidence rates increased rapidly until age 50 years for all race/ethnicity groups, and then continued to increase more slowly for Whites, Blacks, and Japanese/Americans in Hawaii but plateaud for Osaka. Age-specific incidence rates in SEER reflected bimodal (early-onset and late-onset) breast cancer populations, whereas Osaka had only an early-onset age distribution. These age-specific differences in incidence among SEER and Osaka persisted after adjustment for calendar-period and birth-cohort effects using age-period-cohort models. Conclusions: Results confirm striking age-specific differences among Occidental and native Japanese breast cancer populations, probably due to complex age-related biological and/or environmental variations among Occidental and Asian breast cancer populations. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. Osaka Med Ctr Canc & Cardiovasc Dis, Dept Canc Control & Stat, Osaka, Japan. Novartis Pharma KK, Oncol Early Clin Dev, Tokyo, Japan. George Washington Univ, Dept Epidemiol & Biostat, Washington, DC 20037 USA. RP Matsuno, RK (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 8105, Rockville, MD 20852 USA. EM matsunora@mail.nih.gov FU Intramural NIH HHS NR 42 TC 32 Z9 32 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 JUL PY 2007 VL 16 IS 7 BP 1437 EP 1442 DI 10.1158/1055-9965.EPI-07-0329 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 192BD UT WOS:000248174800016 PM 17627009 ER PT J AU Baird, DD Travlos, GS AF Baird, Donna Day Travlos, Gregory S. TI Obesity and insulin-like growth factor-I in African Americans and Whites SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter C1 NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. NIEHS, Clin Pathol Grp, NIH, Res Triangle Pk, NC USA. RP Baird, DD (reprint author), NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC USA. RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD JUL PY 2007 VL 16 IS 7 BP 1526 EP 1526 DI 10.1158/1055-9965.EPI-07-0309 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 192BD UT WOS:000248174800031 PM 17627022 ER PT J AU Lim, U Hartge, P Morton, LM Schatzkin, A AF Lim, Unhee Hartge, Patricia Morton, Lindsay M. Schatzkin, Arthur TI Aspartame consumption and incidence of hematopoietic and brain cancers - In response SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter ID FOOD FREQUENCY QUESTIONNAIRE; RISK; ENERGY; COHORT C1 NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. RP Lim, U (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. RI Morton, Lindsay/B-5234-2015 OI Morton, Lindsay/0000-0001-9767-2310 NR 17 TC 0 Z9 0 U1 2 U2 12 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 JUL PY 2007 VL 16 IS 7 BP 1528 EP 1529 DI 10.1158/1055-9965.EPI-07-0492 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 192BD UT WOS:000248174800036 ER PT J AU Merchant, MS Melchionda, F Sinha, M Khanna, C Helman, L Mackall, CL AF Merchant, Melinda S. Melchionda, Fraia Sinha, Manoj Khanna, Chand Helman, Lee Mackall, Crystal L. TI Immune reconstitution prevents metastatic recurrence of murine osteosarcoma SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article ID STEM-CELL TRANSPLANTATION; EARLY LYMPHOCYTE RECOVERY; TUMOR SURVEILLANCE; INTERFERON-GAMMA; T-CELLS; HOMEOSTATIC PROLIFERATION; PROLONGED SURVIVAL; CARCINOMA CELLS; DENDRITIC CELLS; DEFICIENT MICE AB Primary tumors developing in immunocompetent hosts escape immunosurveillance by acquiring immune evasive properties. This raises the prospect that metastases derived from such tumors will also evade immunity. To investigate whether immune surveillance plays a role in preventing metastases, we studied a murine model which mimics the clinical progression of osteosarcoma: primary tumor growth in the lower extremity, amputation, minimal residual disease followed by the development of overt metastases. K7M2 implants readily escaped immune surveillance since normal BALB/c mice, T cell deficient SCID and T/NK cell deficient SCID-bg mice showed no difference in the rate of growth of primary osteosarcomas. However, both SCID and SCID-bg mice had higher rates of metastases than immunocompetent mice. Similarly, immune reconstitution following transfer of naive T cells to SCID or SCID-bg mice did not impact primary tumor growth, but significantly diminished metastatic recurrence. T cells in osteosarcoma bearing mice produced IFN gamma in response to tumor and IFN gamma production by immune reconstituting T cells was required to prevent metastases. These results demonstrate an important role for T cell based immune surveillance in preventing metastases, even when metastases develop from tumors that adeptly evade immunosurveillance. The results further suggest that T cell depleting cancer therapies may eliminate beneficial immune responses and that immune reconstitution of lymphopenic cancer patients could prevent metastatic recurrence of solid tumors. C1 Univ Bologna, S Orsola Hosp, Dept Pediat Hematol & Oncol, Bologna, Italy. NCI, Canc Res Ctr, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Mackall, CL (reprint author), 10 CRC,1W-3940,10 Ctr Dr,MSC 1104, Bethesda, MD 20892 USA. EM cm35c@nih.gov FU Intramural NIH HHS NR 44 TC 19 Z9 19 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD JUL PY 2007 VL 56 IS 7 BP 1037 EP 1046 DI 10.1007/s00262-006-0257-0 PG 10 WC Oncology; Immunology SC Oncology; Immunology GA 162NO UT WOS:000246094800009 PM 17149595 ER PT J AU Provenzano, M Selleri, S Jin, P Wang, E Werden, R Slezak, S Adams, SD Panelli, MC Leitman, SF Stroncek, DF Marincola, FM AF Provenzano, Maurizio Selleri, Silvia Jin, Ping Wang, Ena Werden, Rosemary Slezak, Stephanie Adams, Sharon D. Panelli, Monica C. Leitman, Susan F. Stroncek, David F. Marincola, Francesco M. TI Comprehensive epitope mapping of the Epstein-Barr virus latent membrane protein-2 in normal, non tumor-bearing individuals SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE tumor immunity; T cells; cell activation; antigens/peptides/epitopes ID POSTTRANSPLANT LYMPHOPROLIFERATIVE DISEASE; CYTOTOXIC T-CELLS; POSITIVE NASOPHARYNGEAL CARCINOMA; PEPTIDE-BASED IMMUNOTHERAPY; BLOOD MONONUCLEAR-CELLS; HLA-A LOCUS; CLASS-I; MELANOMA PATIENTS; PERIPHERAL-BLOOD; QUANTITATIVE PCR AB Latent membrane protein (LMP)-2 is one of the Epstein-Barr virus (EBV)-encoded proteins consistently expressed by nasopharyngeal carcinoma (NPC). EBV-transformed lymphoblastoid cell lines (LCL) have been used in patients with NPC to induce LMP-2-recognizing T cell lines which have been in turn utilized for protein-wide mapping of T cell epitopes. However, comprehensive mapping of naturally recognized LMP-2 epitopes in non tumor-bearing individuals has not been reported. Here, we applied a low sensitivity epitope-defining technique for the identification of LMP-2 CTL responses detectable ex vivo in EBV-experienced individuals. This screening tool has been previously validated by analyzing memory CTL responses to Flu, cytomegalovirus (CMV), and the melanoma associated antigen gp100/Mel17. Peripheral blood monocytes (PBMC) from ten Caucasian and ten Chinese individuals were stimulated ex vivo with pools of nonamer (9-mer) peptides overlapping in a stepwise fashion each single amino acid of the LMP-2 sequence. No obvious differences were observed between the immune response of the two ethnic groups save for those related to the divergence in the ethnic prevalence of HLA haplotypes. Several novel and known LMP-2 epitopes were identified. Reactivity toward at least one LMP-2 epitope was detected in 18 of the 20 donors but no prevalent human leukocyte antigen (HLA)/epitope combination was observed confirming that LMP-2 reactivity in the context of common HLA alleles is more pleiotropic than that of FLU and CMV. We believe that the usefulness of these epitopes occurring naturally in non-cancer bearing patients as reagents for the immunization of patients with early or advanced stage NPC deserves further evaluation. C1 Ctr Clin, Dept Transfus Med, NIH, Bethesda, MD 20892 USA. Univ Hosp ZLF, Dept Surg, Immune Oncol Sect, CH-4031 Basel, Switzerland. Univ Milan, Dept Human Morphol, I-20133 Milan, Italy. RP Marincola, FM (reprint author), Ctr Clin, Dept Transfus Med, NIH, Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM FMarincola@cc.nih.gov NR 83 TC 6 Z9 7 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD JUL PY 2007 VL 56 IS 7 BP 1047 EP 1063 DI 10.1007/s00262-006-0246-3 PG 17 WC Oncology; Immunology SC Oncology; Immunology GA 162NO UT WOS:000246094800010 PM 17124584 ER PT J AU Kakinuma, T Nadiminti, H Lonsdorf, AS Murakami, T Perez, BA Kobayashi, H Finkelstein, SE Pothiawala, G Belkaid, Y Hwang, ST AF Kakinuma, Takashi Nadiminti, Hari Lonsdorf, Anke S. Murakami, Takashi Perez, Bradford A. Kobayashi, Hisataka Finkelstein, Steven E. Pothiawala, Gulnar Belkaid, Yasmine Hwang, Sam T. TI Small numbers of residual tumor cells at the site of primary inoculation are critical for anti-tumor immunity following challenge at a secondary location SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE tumorigenesis; regulatory T cells; CD4 ID REGULATORY T-CELLS; MAGNETIC RESONANCE LYMPHANGIOGRAPHY; LEISHMANIA-MAJOR; MELANOMA; IMMUNOTHERAPY; CANCER; LYMPHOCYTES; PERSISTENCE; METASTASIS; INDUCTION AB Luciferase-transduced B16 murine melanoma cells (luc-B16) inoculated in ear skin do not form tumors but prevent tumor formation by luc-B16 cells injected into the footpad. To determine the requirements for such immunity, we followed the fate of luc-B16 cells following ear injection. Surprisingly, small numbers of viable luc-B16 cells were detected in tumor-free mouse skin for up to 60 days post-inoculation. After 1 week, the number of Foxp3(+)CD4(+)CD25(+) T cells (along with foxp3 mRNA expression) increased rapidly in the injected ear skin. Residual tumor cells in ears were reduced in mice treated with anti-CD25 mAb and in CD4-deficient mice, but increased in CD8-deficient mice. Strikingly, the loss of luc-B16 cells in the ear skin, either spontaneously or following amputation of the injected ear, resulted in significantly enhanced tumor formation by parental and luciferase-expressing B16 cells after footpad injection. These studies suggest that small numbers of tumor cells (possibly regulated by CD4(+)CD25(+) regulatory T cells expressing Foxp3) are required for effective host anti-tumor responses at alternate inoculation sites. C1 NCI, Canc Res Ctr, Dermatol Branch, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. NCI, Metab Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Surg Branch, Bethesda, MD 20892 USA. RP Hwang, ST (reprint author), NCI, Canc Res Ctr, Dermatol Branch, Bldg 10-Rm 12N246,10 Ctr Dr, Bethesda, MD 20892 USA. EM hwangs@mail.nih.gov NR 32 TC 13 Z9 13 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD JUL PY 2007 VL 56 IS 7 BP 1119 EP 1131 DI 10.1007/s00262-006-0253-4 PG 13 WC Oncology; Immunology SC Oncology; Immunology GA 162NO UT WOS:000246094800016 PM 17139493 ER PT J AU Giubellino, A Gao, Y Lee, SM Lee, MJ Vasselli, JR Medepalli, S Trepel, JB Burke, TR Bottaro, DP AF Giubellino, Alessio Gao, Yang Lee, Sunmin Lee, Min-Jung Vasselli, James R. Medepalli, Sampath Trepel, Jane B. Burke, Terrence R., Jr. Bottaro, Donald P. TI Inhibition of tumor metastasis by a growth factor receptor bound protein 2 Src homology 2 domain-binding antagonist SO CANCER RESEARCH LA English DT Article ID BRANCHING MORPHOGENESIS; CANCER METASTASIS; N-CADHERIN; MET; MOTILITY; INVASION; GRB2 AB Metastasis, the primary cause of death in most forms of cancer, is a multistep process whereby cells from the primary tumor spread systemically and colonize distant new sites. Blocking critical steps in this process could potentially inhibit tumor metastasis and dramatically improve cancer survival rates; however, our understanding of metastasis at the molecular level is still rudimentary. Growth factor receptor binding protein 2 (Grb2) is a widely expressed adapter protein with roles in epithelial cell growth and morphogenesis, as well as angiogenesis, making it a logical target for anticancer drug development. We have previously shown that a potent antagonist of Grb2 Src homology-2 domain-binding, C90, blocks growth factor-driven cell motility in vitro and angiogenesis in vivo. We now report that C90 inhibits metastasis in vivo in two aggressive tumor models, without affecting primary tumor growth rate. These results support the potential efficacy of this compound in reducing the metastatic spread of primary solid tumors and establish a critical role for Grb2 Src homology-2 domain-mediated interactions in this process. C1 NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Lab Med Chem, Frederick, MD 21701 USA. RP Bottaro, DP (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bldg 10,CRC 1 W,Room 3961,10 Ctr Dr,MS 1107, Bethesda, MD 20892 USA. EM dbottaro@helix.nih.gov RI Bottaro, Donald/F-8550-2010; Burke, Terrence/N-2601-2014; OI Bottaro, Donald/0000-0002-5057-5334; Giubellino, Alessio/0000-0002-5352-0662 FU Intramural NIH HHS NR 18 TC 30 Z9 30 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 JUL 1 PY 2007 VL 67 IS 13 BP 6012 EP 6016 DI 10.1158/0008-5472.CAN-07-0022 PG 5 WC Oncology SC Oncology GA 186II UT WOS:000247772000004 PM 17616655 ER PT J AU Palmer, MB Majumder, P Green, MR Wade, PA Boss, JM AF Palmer, Matthew B. Majumder, Parimal Green, Myesha R. Wade, Paul A. Boss, Jeremy M. TI A 3' enhancer controls snail expression in melanoma cells SO CANCER RESEARCH LA English DT Article ID EPITHELIAL-MESENCHYMAL TRANSITION; E-CADHERIN EXPRESSION; TRANSCRIPTION FACTOR; UP-REGULATION; TUMOR-CELLS; HISTONE H3; CANCER; SLUG; TRANSFORMATION; REPRESSORS AB The snail gene encodes a transcriptional repressor that functions during animal development and in cancer progression to promote epithelial-mesenchymal transitions. Strict spatial and temporal boundaries of Snail expression in development imply precise transcriptional control, which becomes inappropriately activated in many cancer subtypes. To gain insight into the molecular mechanism(s) governing transcriptional control of Snail, we analyze chromatin structural changes associated with Snail transcription in melanoma cells. Regardless of transcriptional status, the Snail promoter displays three constitutive DNase hypersensitive sites (HS) and a moderate level of historic H3 Lys(4) dimethylation. A robust HS is found in the 3 ' region of A375 melanoma cells, in which Snail is highly expressed, but is absent in cells not expressing Snail. This element is conserved throughout the mammalian lineage and strongly activates expression of a reporter in A375 and Colo829 melanoma cells, but not in keratinocytes or primary melanocytes. Activity of this enhancer is associated with enrichment of H3 Lys(4) dimethylation and H3 acetylation at both the enhancer and the promoter. Additionally, enhancer activity is associated with H3 Lys(4) trimethylation at the promoter. A physical interaction between the 3 ' enhancer and promoter was observed in Snail-expressing cells, demonstrating a direct role for the enhancer in Snail expression. These results suggest a model in which the Snail promoter is constitutively packaged in a poised chromatin structure that can be activated in melanoma cells by a tissue-specific enhancer, which physically contacts the promoter. C1 Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. Natl Inst Environm Hlth Sci, Lab Mol Carcinogenesis, Res Triangle Pk, NC USA. RP Boss, JM (reprint author), Emory Univ, Sch Med, Dept Microbiol & Immunol, 1510 Clifton Rd, Atlanta, GA 30322 USA. EM wadep2@niehs.nih.gov FU Intramural NIH HHS; NIDDK NIH HHS [DK065961] NR 45 TC 22 Z9 22 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 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2007 VL 67 IS 13 BP 6113 EP 6120 DI 10.1158/0008-5472.CAN-06-4256 PG 8 WC Oncology SC Oncology GA 186II UT WOS:000247772000017 PM 17616667 ER PT J AU Ramalingam, S Honkanen, P Young, L Shimura, T Austin, J Steeg, PS Nishizuka, S AF Ramalingam, Sundhar Honkanen, Peter Young, Lynn Shimura, Tsutomu Austin, John Steeg, Patricia S. Nishizuka, Satoshi TI Quantitative assessment of the p53-Mdm2 feedback loop using protein lysate microarrays SO CANCER RESEARCH LA English DT Article ID ATM-DEPENDENT PHOSPHORYLATION; DNA-DAMAGE; P53 ACTIVATION; MDM2; DEUBIQUITINATION; STABILIZATION; OSCILLATIONS; DEGRADATION; HAUSP; HDMX AB Mathematical simulations of the p53-Mdm2 feedback loop suggest that both proteins will exhibit impulsive expression characteristics in response to high cellular stress levels. However, little quantitative experimental evaluation has been done, particularly of the phosphorylated forms. To evaluate the mathematical models experimentally, we used lysate microarrays from an isogenic pair of gamma-ray-irradiated cell lysates from HCT116 (p53(+/+), and p53(-/-)). Both p53 and Mdm2 proteins showed expected pulses in the wild type, whereas no pulses were seen in the knockout. Based on experimental observations, we determined model parameters and generated an in silico "knockout," reflecting the experimental data, including phosphorylated proteins. C1 NCI, Mol Therapeut Program, NIH, Bethesda, MD 20892 USA. NCI, Lab Mol Pharmacol, NIH, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Aushon BioSyst, Burlington, MA USA. Sci Applicat Int Corp Frederick Inc, Lab Proteom & Analyt Technol, Res Technol Program, Natl Canc Inst, Frederick, MD USA. RP Nishizuka, S (reprint author), Iwate Med Univ, Sch Med, Dept Surg, 19-1 Uchimaru, Morioka, Iwate 0208505, Japan. EM nishizus@mail.nih.gov FU NCI NIH HHS [N01-CO12400] NR 22 TC 24 Z9 25 U1 0 U2 5 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 JUL 1 PY 2007 VL 67 IS 13 BP 6247 EP 6252 DI 10.1158/0008-5472.CAN-07-0342 PG 6 WC Oncology SC Oncology GA 186II UT WOS:000247772000032 PM 17616682 ER PT J AU Mi, LX Wang, XT Govind, S Hood, BL Veenstra, TD Conrads, TP Saha, DT Goldman, R Chung, FL AF Mi, Lixin Wang, Xiantao Govind, Sudha Hood, Brian L. Veenstra, Timothy D. Conrads, Thomas P. Saha, Daniel T. Goldman, Radoslav Chung, Fung-Lung TI The role of protein binding in induction of apoptosis by phenethyl isothiocyanate and sulforaphane in human non-small lung cancer cells SO CANCER RESEARCH LA English DT Article ID N-TERMINAL KINASE; BENZYL ISOTHIOCYANATE; ANTICARCINOGENIC ISOTHIOCYANATES; MEDIATED APOPTOSIS; SIGNALING PATHWAYS; GROWTH-INHIBITION; PHASE-2 ENZYMES; A/J MICE; ACTIVATION; MECHANISMS AB Induction of apoptosis underlies a mechanism for inhibiting tumorigenesis by phenethyl isothiocyanate (PEITC) and sulforaphane (SFN). However, the upstream events by which isothiocyanates (ITC) induce apoptosis have not been fully investigated. As electrophiles, ITCs could trigger apoptosis by binding to DNA or proteins or by inducing oxidative stress. To better understand the molecular mechanisms of apoptosis by ITCs, we examined, as a first step, the role of these events in human non-small lung cancer A549 cells. PEITC was a more potent inducer than SFN; it induced apoptosis at 20 mu mol/L, whereas SFN induced at 40 mu mol/L but not at 20 mu mol/L. To study binding with cellular proteins and DNA, cells were treated with C-14-ITCs; the initial protein binding by PEITC was almost 3-fold than that of SFN. The binding by PEITC increased with time, whereas binding by SFN remained low. Therefore, 4 It after incubation proteins became the predominant targets for PEITC with a 6-fold binding than that of SFN. To characterize the chemical nature of binding by the ITCs, we used bovine serum albumin (BSA) as a surrogate protein. PEITC also modified BSA covalently to a greater extent than SFN occurring exclusively at cysteine residues. Surprisingly, neither PEITC nor SFN bound to DNA or RNA at detectable levels or caused significant DNA strand breakage. The levels of oxidative damage in cells, measured as reactive oxygen species, 8-oxo-deoxygnanosine, and protein carbonyls formation, were greater in cells treated with SFN than PEITC. Because PEITC is a stronger inducer of apoptosis than SFN, these results indicate that direct covalent binding to cellular proteins is an important early event in the induction of apoptosis by the ITCs. C1 Georgetown Univ, Med Ctr, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. NCI, Lab Proteom & Analyt Technol, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Chung, FL (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, Lombardi Comprehens Canc Ctr, LL 128A,Box 571465, Washington, DC 20057 USA. EM flc6@georgetown.edu FU NCI NIH HHS [CA100853] NR 44 TC 88 Z9 93 U1 1 U2 7 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 JUL 1 PY 2007 VL 67 IS 13 BP 6409 EP 6416 DI 10.1158/0008-5472.CAN-07-0340 PG 8 WC Oncology SC Oncology GA 186II UT WOS:000247772000051 PM 17616701 ER PT J AU Adachi, S Nagao, T Ingolfsson, HI Maxfield, FR Andersen, OS Kopelovich, L Weinstein, IB AF Adachi, Seiji Nagao, Tomokazu Ingolfsson, Helgi I. Maxfield, Frederick R. Andersen, Olaf S. Kopelovich, Levy Weinstein, I. Bernard TI The inhibitory effect of (-)-epigallocatechin gallate on activation of the epidermal growth factor receptor is associated with altered lipid order in HT29 colon cancer cells SO CANCER RESEARCH LA English DT Article ID LIGAND-INDEPENDENT ACTIVATION; EPSILON-RI EXPRESSION; FACTOR-I RECEPTOR; CHOLESTEROL DEPLETION; CARCINOMA-CELLS; TEA POLYPHENOL; SIGNALING PATHWAYS; PROSTATE-CANCER; EXTRACELLULAR SIGNALS; DOMAIN SEGREGATION AB (-)-Epigallocatechin gallate (EGCG), a major biologically active constituent of green tea, inhibits activation of the epidermal growth factor (EGF) receptor (EGFR) and downstream signaling pathways in several types of human cancer cells, but the precise mechanism is not known. Because several plasma membrane-associated receptor tyrosine kinases (RTK) including FGFR are localized in detergent-insoluble ordered membrane domains, so-called "lipid rafts; we examined whether the inhibitory effect of EGCG on activation of the EGFR is associated with changes in membrane lipid order in HT29 colon cancer cells. First, we did cold Triton X-100 solubility assays. Phosphorylated (activated) EGFR was found only in the Triton X-100-insoluble (lipid raft) fraction, whereas total cellular EGFR was present in the Triton X-100-soluble fraction. Pretreatment with EGCG inhibited the binding of Alexa Fluor 488-labeled EGF to the cells and also inhibited EGF-induced dimerization of the EGFR. To examine possible effects of EGCG on membrane lipid organization, we labeled the cells with the fluorescent lipid analogue 1, 1 '-dihexadecyl-3,3,3 ',3 '-tetramethylindocarbocyanine perchlorate, which preferentially incorporates into ordered membrane domains in cells and found that subsequent treatment with EGCG caused a marked reduction in the Triton X-100-resistant membrane fraction. Polyphenon E, a mixture of green tea catechins, had a similar effect but (similar to)-epicatechin (EC), the biologically inactive compound, did not significantly alter the Triton X-100 solubility properties of the membrane. Furthermore, we found that EGCG but not EC caused dramatic changes in the function of bilayer-incorporated gramicidin channels. Taken together, these findings suggest that EGCG inhibits the binding of EGF to the EGFR and the subsequent dimerization and activation of the EGFR by altering membrane organization. These effects may also explain the ability of EGCG to inhibit activation of other membrane-associated RTKs, and they may play a critical role in the anticancer effects of this and related compounds. C1 Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA. Columbia Univ, Med Ctr, Dept Med, New York, NY 10032 USA. Cornell Univ, Dept Biochem, Weill Med Coll, New York, NY USA. Cornell Univ, Dept Physiol & Biophys, Weill Med Coll, New York, NY USA. NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Weinstein, IB (reprint author), Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, HHSC-1509,701 W 168th St, New York, NY 10032 USA. EM ibw1@columbia.edu RI Maxfield, Fred/A-1718-2011; OI Maxfield, Frederick/0000-0003-4396-8866 FU NIDDK NIH HHS [DK27083]; NIGMS NIH HHS [GM21342, R01 GM021342] NR 50 TC 123 Z9 125 U1 1 U2 4 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 JUL 1 PY 2007 VL 67 IS 13 BP 6493 EP 6501 DI 10.1158/0008-5472.CAN-07-0411 PG 9 WC Oncology SC Oncology GA 186II UT WOS:000247772000061 PM 17616711 ER PT J AU Engels, EA Wu, XF Gu, J Dong, Q Liu, J Spitz, MR AF Engels, Eric A. Wu, Xifeng Gu, Jian Dong, Qiong Liu, Jun Spitz, Margaret R. TI Systematic evaluation of genetic variants in the inflammation pathway and risk of lung cancer SO CANCER RESEARCH LA English DT Article ID RECEPTOR ANTAGONIST GENE; COLONY-STIMULATING FACTOR; REACTIVE PROTEIN-LEVELS; INTERLEUKIN-1-BETA GENE; GM-CSF; AIRWAY HYPERRESPONSIVENESS; COMMON POLYMORPHISMS; ASSOCIATION; METAANALYSIS; POPULATION AB Inflammatory responses to environmental exposures, such as tobacco smoke, may play a role in lung carcinogenesis. To test this hypothesis, we studied genetic polymorphisms in the inflammation pathway in relation to lung cancer risk. We evaluated a panel of 59 single nucleotide polymorphisms (SNP) in 37 inflammation-related genes among non-Hispanic Caucasian lung cancer cases (N = 1,553) and controls (N = 1,730) from Houston, Texas. Logistic regression was used to assess associations with lung cancer under a dominant genetic model adjusted for sex, age, and smoking. Haplotypes were estimated with the expectation-maximization algorithm. False-positive report probabilities (FPRP) were calculated for significant associations. Interleukin 1 beta (IL1B) C3954T was associated with lung cancer [odds ratio (OR), 1.27; 95% confidence interval (95% CI), 1.10-1.47; FPRP 0.148]. Two ILIA SNPs (C-889T and Ala(114)Ser) were also related to lung cancer (OR, 1.18-1.22), although FPRPs were higher. One IL1A-IL1B haplotype, containing only the IL1B 3954T allele, was associated with elevated lung cancer risk (OR, 1.80; 95% CI, 1.24-2.61). These associations were stronger in heavy smokers, particularly for IL1B C3954T (OR, 1.59; 95% CI, 1.28-1.97; FPRP 0.004). Lung cancer risk was unrelated to polymorphisms in IL1 receptor or antagonist genes. Associations with lung cancer were also seen for SNPs in granulocyte macrophage colony stimulating factor and peroxisome proliferator-activated factor-delta, but FPRPs were high. IL1A and IL1B polymorphisms are associated with increased lung cancer risk, especially among heavy smokers. IL1A and IL1B are critical signals in initiating inflammation. Our results suggest that a dysregulated inflammatory response to tobacco-induced lung damage promotes carcinogenesis. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7076, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov FU Intramural NIH HHS; NCI NIH HHS [CA070907, CA111646, CA55769, CA70609, P50 CA070907] NR 39 TC 86 Z9 89 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD JUL 1 PY 2007 VL 67 IS 13 BP 6520 EP 6527 DI 10.1158/0008-5472.CAN-07-0370 PG 8 WC Oncology SC Oncology GA 186II UT WOS:000247772000064 PM 17596594 ER PT J AU Cao, L Xu, XL Cao, LYL Wang, RH Coumoul, X Kim, SS Deng, CX AF Cao, Liu Xu, Xiaoling Cao, Longyue L. Wang, Rui-Hong Coumoul, Xavier Kim, Sang S. Deng, Chu-Xia TI Absence of full-length Brca1 sensitizes mice to oxidative stress and carcinogen-induced tumorigenesis in the esophagus and forestomach SO CARCINOGENESIS LA English DT Article ID DNA-DAMAGE RESPONSE; CANCER SUSCEPTIBILITY; GENOMIC INSTABILITY; BARRETTS ESOPHAGEAL; MUTATION CARRIERS; TUMOR-FORMATION; CELL-CYCLE; LIFE-SPAN; P53; BREAST AB Environmental and genetic factors are important both in affecting life span and neoplastic transformation. We have shown previously that mice, which are homozygous for full-length breast cancer-associated gene-1 (Brca1) deletion and heterozygous for a p53-null mutation (Brca1(Delta 11/Delta 11)p53(+/-)), display premature aging and high frequency of spontaneous lymphoma and mammary tumor formation. To investigate the role of Brca1 in regulation of organ homeostasis and susceptibility of Brca1 deficiency to environmental carcinogens, we examined biological function of Brca1 in maintaining organ homeostasis and carcinogen-induced tumorigenesis. Brca1(Delta 11/Delta 11)p53(+/-) mice showed altered gastrointestinal tract homeostasis, including hyperkeratosis in the esophagus and forestomach. At 6 months of age, most mutant mice displayed hyperplasia in their forestomach and esophagus, leading to dysplasia and carcinoma formation in older animals. Brca1 mutant mice exhibited increased expression of Redd1, elevated reactive oxygen species and are more sensitive to oxidative stress induced lethality. Upon methyl-N-amylnitrosaniine (MNAN) treatment, 70% Brca1 mutant mice developed tumors within 4 months whereas only 14% control animals developed tumor at the same period of the time. Our further analysis revealed that the tumorigenesis is accompanied by the loss of p53 and increased expression of a number of oncogenes, including Cyclin D1, phosphorylated form of Akt, beta-catenin, Runx-2 and c-Myc. These results suggest that Brca1 is involved in renewable organ homeostasis, linking the environmental and genetic factors in carcinogenesis and aging, and providing new insights into genomic instability in organism maintenance and tumorigenesis. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, 10-9N105,10 Ctr Dr, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU Intramural NIH HHS NR 51 TC 24 Z9 28 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2007 VL 28 IS 7 BP 1401 EP 1407 DI 10.1093/carcin/bgm060 PG 7 WC Oncology SC Oncology GA 199XX UT WOS:000248729600004 PM 17363841 ER PT J AU Gunter, MJ Divi, RL Kulldorff, M Vermeulen, R Haverkos, KJ Kuo, MM Strickland, P Poirier, MC Rothman, N Sinha, R AF Gunter, Marc J. Divi, Rao L. Kulldorff, Martin Vermeulen, Roel Haverkos, Kathryn J. Kuo, Maryanne M. Strickland, Paul Poirier, Miriam C. Rothman, Nathaniel Sinha, Rashmi TI Leukocyte polycyclic aromatic hydrocarbon-DNA adduct formation and colorectal adenoma SO CARCINOGENESIS LA English DT Article ID WHITE BLOOD-CELLS; LUNG-CANCER; RISK; MEAT; CONSUMPTION; BEEF AB Consumption of charbroiled red meat and meat-derived polycyclic aromatic hydrocarbons (PAHs) has been associated with risk of colorectal adenoma, a precursor of colorectal cancer. Furthermore, leukocyte PAH-DNA adduct levels have been demonstrated to increase in response to charbroiled red meat intake but to date there have been no studies that have investigated the relationship between leukocyte PAH-DNA adduct levels and risk of colorectal adenoma. We investigated the relation of leukocyte PAH-DNA adduct formation and colorectal adenoma in a clinic-based case-control study of colorectal adenomas. The study comprised 82 cases of colorectal adenoma and 111 polyp-free controls, none of whom were current smokers. Leukocyte PAH-DNA adducts were measured by a sensitive chemiluminescence immunoassay using an antiserum elicited against DNA modified with (+/-)-7 beta, 8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydro-benzo[a]pyrene that recognizes several PAHs bound to human DNA. Leukocyte PAH-DNA adduct levels were higher among colorectal adenoma cases (median, 1.4 adducts per 10(8) nucleotides) than polyp-free controls (median, 1.2 adducts per 10(8) nucleotides) (P = 0.02). There was a positive association between PAH-DNA adduct level and adenoma prevalence: each unit increase in PAH-DNA adduct level (per 108 nucleotides) was associated with an odds ratio (OR) of 1.5 [95% confidence interval (CI), 1.1-2.2]. In addition, a comparison of the lowest quartile for PAH-DNA adduct level with the highest quartile yielded an OR of 2.8 (95% CI, 1.2-6.5; P-trend = 0.048) for risk of colorectal adenoma. These data support a link between PAH exposure and colorectal adenoma. C1 NCI, Div Canc Epidemiol & Genet, NIH, Div Hlth & Human Serv, Bethesda, MD 20852 USA. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10461 USA. NCI, NIH, Canc Res Ctr, Carcinogen DNA Interact Sect,Div Hlth & Human Ser, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02115 USA. Harvard Pilgrim Hlth Care, Boston, MA 02115 USA. Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, NL-3508 TD Utrecht, Netherlands. Johns Hopkins Univ, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Gunter, MJ (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Div Hlth & Human Serv, Bethesda, MD 20852 USA. EM mgunter@aecom.yu.edu RI Kulldorff, Martin/H-4282-2011; Vermeulen, Roel/F-8037-2011; Sinha, Rashmi/G-7446-2015; OI Vermeulen, Roel/0000-0003-4082-8163; Sinha, Rashmi/0000-0002-2466-7462; Kulldorff, Martin/0000-0002-5284-2993 FU Intramural NIH HHS NR 18 TC 32 Z9 33 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2007 VL 28 IS 7 BP 1426 EP 1429 DI 10.1093/carcin/bgm022 PG 4 WC Oncology SC Oncology GA 199XX UT WOS:000248729600007 PM 17277232 ER PT J AU Lee, KM Shen, M Chapman, RS Yeager, M Welch, R He, XZ Zheng, TZ Hosgood, HD Yang, DY Berndt, SI Chanock, S Lan, Q AF Lee, Kyoung-Mu Shen, Min Chapman, Robert S. Yeager, Meredith Welch, Robert He, Xingzhou Zheng, Tongzhang Hosgood, H. Dean Yang, Dongyun Berndt, Sonja I. Chanock, Stephen Lan, Qing TI Polymorphisms in immunoregulatory genes, smoky coal exposure and lung cancer risk in Xuan Wei, China SO CARCINOGENESIS LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; INTERLEUKIN-1-BETA GENE; GASTRIC-CANCER; LINKAGE DISEQUILIBRIUM; SUSCEPTIBILITY LOCUS; ASTHMA; INFLAMMATION; ASSOCIATION; IL-8; EPIDEMIOLOGY AB We conducted a population-based case-control study in Xuan Wei, China, where lung cancer rates are among the highest in China due to exposure to indoor coal combustion products, to evaluate the association between polymorphisms in immunoregulatory genes and lung cancer risk. A total of 122 incident primary lung cancer cases and 122 individually matched controls were enrolled in Xuan Wei, China. Fifty single-nucleotide polymorphisms (SNPs) in 23 immunoregulatory genes involved in inflammation were genotyped and analyzed by logistic regression to assess the risk of lung cancer. A global test of association for 42 SNPs, which excluded eight SNPs that were in very tight linkage disequilibrium with other SNPs, was statistically significant (P = 0.01), suggesting that overall genetic variation in this pathway contributes to lung cancer risk. In addition, the IL1B - 1060TT (i.e. -511TT) genotype was associated with increased lung cancer risk compared with the CC genotype [odds ratio (OR) = 2.27, 95% confidence interval (CI) = 1.05-4.91]. The IL8RA Ex2+860 GC or CC (OR = 0.27, 95% CI = 0.11-0.67), ICAMI Ex2+100 AT or TT (OR 0.39, 95% CI 0.18-0.88) and IL12A Ex7+277 GA or AA (OR 0.43, 95% CI 0.22-0.84) genotypes were associated with decreased lung cancer risk. The protective effect of the IL8RA variant was stronger among subjects with high cumulative smoky coal use (>= 130 tons) (OR = 0.11, 95% CI = 0.03-0.44; P-interaction = 0.03). In conclusion, genetic variation in immunoregulatory genes may play an important role in the development of lung cancer in this population. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Chulalongkorn Univ, Coll Publ Hlth, Bangkok 10330, Thailand. Chinese Acad Prevent Med, Inst Environm Hlth & Engn, Beijing 100050, Peoples R China. Yale Univ, Yale Sch Publ Hlth, New Haven, CT 06520 USA. Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Los Angeles, CA 90089 USA. RP Lee, KM (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM leekyou@mail.nih.gov NR 42 TC 38 Z9 43 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2007 VL 28 IS 7 BP 1437 EP 1441 DI 10.1093/carcin/bgm030 PG 5 WC Oncology SC Oncology GA 199XX UT WOS:000248729600009 PM 17361014 ER PT J AU Li, L Tao, LH Lubet, RA Steele, VE Pereira, MA AF Li, Long Tao, Lianhui Lubet, Ronald A. Steele, Vernon E. Pereira, Michael A. TI Modulation by budesonide of a CpG endonuclease in mouse lung tumors SO CARCINOGENESIS LA English DT Article ID FEMALE A/J MICE; DNA METHYLATION; PULMONARY CARCINOGENESIS; AEROSOLIZED BUDESONIDE; HYPOMETHYLATION; CHEMOPREVENTION; PREVENTION; CANCER; COLON; GENE AB CpG endonuclease activity was identified in nuclear extracts obtained from mouse lung tumors. Enzyme activity was determined using a 333 bp polymerase chain reaction product of the estrogen receptor-alpha gene that contained either radiolabeled cytosine or tritium-labeled methyl groups at CpG sites. Activity was measured as the release of radioactivity from the substrate. The product of the nuclease activity was identified by high pressure liquid chromatography (HPLC) as either 5-methyl-2'-deoxycytidine when the CpG sites in the substrate were methylated or 2'-deoxycytidine when the CpG sites were not methylated. The CpG endonuclease activity was dependent on nuclear protein and temperature, had a proclivity for double-stranded over single-stranded DNA and was inhibited by ethylenediaminetetraacetic acid or 2-mer-captoethanol. Strain A/J mouse lung tumors induced by vinyl carbarnate had a greater level of CpG endonuclease activity than non-involved lung tissue. Budesonide, a potent chemopreventive agent in mouse lung, not only prevented an increase in CpG endonuclease activity in lung tumors but, when administered to mice with established tumors, also decreased the level of endonuclease activity in the tumors. The effect of budesonide on CpG endonuclease activity in lung tumors was inversely related to its published effect on DNA methylation in mouse lung tumors, i.e. the drug decreased CpG endonuclease activity and increased the methylation of DNA. The increased CpG endonuclease activity in mouse lung tumors and its inhibition by budesonide would suggest this endonuclease as a potential molecular target for chemoprevention. C1 Med Univ Ohio, Dept Biochem & Canc Biol, Toledo, OH 43614 USA. Ohio State Univ, Coll Med, Dept Internal Med, Div Hematol & Oncol, Columbus, OH 43210 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Pereira, MA (reprint author), Med Univ Ohio, Dept Biochem & Canc Biol, 3055 Arlington Ave, Toledo, OH 43614 USA. EM michael.pereira@osumc.edu FU NCI NIH HHS [N01-CN-25126, R01 CA-096129, R03 CA-117520] NR 22 TC 6 Z9 6 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2007 VL 28 IS 7 BP 1499 EP 1503 DI 10.1093/carcin/bgm056 PG 5 WC Oncology SC Oncology GA 199XX UT WOS:000248729600018 PM 17361011 ER PT J AU Budhu, A Chen, Y Kim, JW Forgues, M Valerie, K Harris, CC Wang, XW AF Budhu, A. Chen, Y. Kim, J. W. Forgues, M. Valerie, K. Harris, C. C. Wang, X. W. TI Induction of a unique gene expression profile in primary human hepatocytes by hepatitis C virus core, NS3 and NS5A proteins SO CARCINOGENESIS LA English DT Article ID HEPATOCELLULAR-CARCINOMA; X PROTEIN; MOLECULAR SIGNATURE; IDENTIFICATION; CELLS; TRANSCRIPTION; PATHOGENESIS; INFECTION; FIBROSIS; MARKERS AB Hepatocellular carcinoma (HCC) is a fatal disease and hepatitis B and C viruses (HBV and HCV) are considered as major causative factors for the development of HCC. We have conducted gene expression profiling studies to search for potential target genes responsible for HCV-mediated HCC. Adenoviruses encoding core (HCV structural protein), NS3 and NS5A [HCV non-structural (NS) proteins] were generated and infected individually or together in freshly isolated primary human hepatocytes. An adenovirus harboring the oncogenic HBV protein, HBx, was included for comparison. A microarray platform of over 22 000 human oligos was analyzed to seek out significant differentially expressed genes among these viral proteins. We also compared these gene expression profiles with those obtained from HCV-infected liver samples from chronic liver disease (CLD) patients and HCV-related HCC. We found that HCV-related proteins largely induce unique genes when compared with RBx. In particular, interferon-inducible gene 27 (IFI27) was highly expressed in HCV or core-infected hepatocytes and HCV-related CLD or HCC, but was not significantly expressed in HBx-infected hepatocytes or HBV-related CLD or HCC, indicating that IFI27 may play a role in HCV-mediated HCC. In conclusion, our results suggest that HBV and HCV promote HCC development mainly through different mechanisms. C1 NCI, NIH, Ctr Canc Res, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. NCI, NIH, Ctr Canc Res, Genet Branch, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Radiat Oncol, Richmond, VA 23298 USA. RP Wang, XW (reprint author), NCI, NIH, Ctr Canc Res, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. EM xw3u@nih.gov RI Wang, Xin/B-6162-2009 NR 34 TC 20 Z9 20 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD JUL PY 2007 VL 28 IS 7 BP 1552 EP 1560 DI 10.1093/carcin/bgm075 PG 9 WC Oncology SC Oncology GA 199XX UT WOS:000248729600025 PM 17404395 ER PT J AU Even-Ram, S Yamada, KM AF Even-Ram, Sharona Yamada, Kenneth M. TI Of Mice and Men Relevance of Cellular and Molecular Characterizations of Myosin IIA to MYH9-Related Human Disease SO CELL ADHESION & MIGRATION LA English DT Article DE myosin IIA; MYH9; microtubules; actin; cytoskeleton; platelets; cell-cell adhesion AB Non-muscle myosin II has diverse functions in cell contractility, morphology, cytokinesis and migration. Mammalian cells have three isoforms of non-muscle myosin II, termed IIA, IIB and IIC, encoded by three different genes. These isoforms share considerable homology and some overlapping functions, yet they exhibit differences in enzymatic properties, subcellular localization, molecular interaction and tissue distribution.(1-6) Our studies have focused on the IIA isoform, and they reveal unique regulatory roles in cell-cell adhesion and cell migration that are associated with cross-talk of the actomyosin system with microtubules. In humans, various mutations in the MYH9 gene that encodes the myosin IIA heavy chain cause autosomal dominant disease, whereas in mice, the complete deficiency is embryonic lethal but heterozygous mice are nearly normal. We discuss here the differences between mouse and human phenotypes and how the wealth of mechanistic knowledge about myosin II based on in vitro studies and mouse models can help us understand the molecular and cellular pathophysiology of myosin IIA deficiency in humans. C1 [Even-Ram, Sharona] Hadassah Univ Hosp, Stem Cell Ctr, Goldyn Savad Inst Gene Therapy, IL-91120 Jerusalem, Israel. [Even-Ram, Sharona; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD USA. RP Yamada, KM (reprint author), 30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM kenneth.yamada@nih.gov OI Even-Ram, Sharona/0000-0002-5540-3822; Yamada, Kenneth/0000-0003-1512-6805 FU NIDCR, NIH FX We thank Deborah Steiner and Jacob Rachmilewitz for helpful comments and the Intramural Research Program, NIDCR, NIH for support. NR 29 TC 13 Z9 13 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6918 J9 CELL ADHES MIGR JI Celll Adhes. Migr. PD JUL-SEP PY 2007 VL 1 IS 3 BP 152 EP 155 DI 10.4161/cam.1.3.5089 PG 4 WC Cell Biology SC Cell Biology GA V21US UT WOS:000208233100011 PM 19262128 ER PT J AU Anderson, JM Valenzuela, JG AF Anderson, Jennifer M. Valenzuela, Jesus G. TI Spit-acular entry: Borrelia gets help from a tick salivary protein to move from the mammalian host to the arthropod vector SO CELL HOST & MICROBE LA English DT Editorial Material ID IXODES-SCAPULARIS AB In vector-host-pathogen interactions, vector saliva plays a key role in the successful acquisition of blood and in facilitating the establishment of pathogens in mammalian hosts. In this issue of Cell Host & Microbe, Narasimhan et al. describe how a tick salivary antioxidant neutralizes reactive oxygen species at the tick-host interface and facilitates the tick vector's acquisition of Borrelia burgdorferi bacteria from an infected mammalian host. C1 NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Valenzuela, JG (reprint author), NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM jvalenzuela@niaid.nih.gov NR 11 TC 4 Z9 4 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD JUL PY 2007 VL 2 IS 1 BP 3 EP 4 DI 10.1016/j.chom.2007.06.007 PG 2 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 221BW UT WOS:000250203400002 PM 18005711 ER PT J AU Huss, JM Imahashi, KI Dufour, CR Weinheimer, CJ Courtois, M Kovacs, A Giguere, V Murphy, E Kelly, DP AF Huss, Janice M. Imahashi, Ken-ichi Dufour, Catherine R. Weinheimer, Carla J. Courtois, Michael Kovacs, Atilla Giguere, Vincent Murphy, Elizabeth Kelly, Daniel P. TI The nuclear receptor ERR alpha is required for the bioenergetic and functional adaptation to cardiac pressure overload SO CELL METABOLISM LA English DT Article ID PROLIFERATOR-ACTIVATED RECEPTOR; FATTY-ACID OXIDATION; ENERGY-METABOLISM; HEART-FAILURE; CREATINE-KINASE; GENE-EXPRESSION; HYPERTROPHIC CARDIOMYOPATHY; TRANSCRIPTIONAL CONTROL; MYOCARDIAL HYPERTROPHY; FAILING HEART AB Downregulation and functional deactivation of the transcriptional coactivator PGC-1 alpha has been implicated in heart failure pathogenesis. We hypothesized that the estrogen-related receptor alpha (ERR alpha), which recruits PGC-1 alpha to metabolic target genes in heart, exerts protective effects in the context of stressors known to cause heart failure. ERR alpha(-/-) mice subjected to left ventricular (LV) pressure overload developed signatures of heart failure including chamber dilatation and reduced LV fractional shortening. P-31-NMR studies revealed abnormal phosphocreatine depletion in ERR alpha(-/-) hearts subjected to hemodynamic stress, indicative of a defect in ATP reserve. Mitochondrial respiration studies demonstrated reduced maximal ATP synthesis rates in ERR alpha(-/-) hearts. Cardiac ERR alpha target genes involved in energy substrate oxidation, ATP synthesis, and phosphate transfer were downregulated in ERR alpha(-/-) mice at baseline or with pressure overload. These results demonstrate that the nuclear receptor ERR alpha is required for the adaptive bioenergetic response to hemodynamic stressors known to cause heart failure. C1 Washington Univ, Sch Med, Cardiovasc Res Ctr, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. McGill Univ, Ctr Hlth, Montreal, PQ H3A 1A1, Canada. RP Kelly, DP (reprint author), Washington Univ, Sch Med, Cardiovasc Res Ctr, St Louis, MO 63110 USA. EM dkelly@im.wustl.edu FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL058493]; NIDDK NIH HHS [K01 DK063051, P30 DK056341, P30 DK056341-06, P30 DK056341-07, P60 DK20579, R01 DK074700] NR 54 TC 135 Z9 136 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD JUL PY 2007 VL 6 IS 1 BP 25 EP 37 DI 10.1016/j.cmet.2007.06.005 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 189JJ UT WOS:000247984900005 PM 17618854 ER PT J AU Walz, HA Wierup, N Vikman, J Manganiello, VC Degerman, E Eliasson, L Holst, LS AF Walz, Helena A. Wierup, Nils Vikman, Jenny Manganiello, Vincent C. Degerman, Eva Eliasson, Lena Holst, Lena Stenson TI beta-cell PDE3B regulates Ca2+-stimulated exocytosis of insulin SO CELLULAR SIGNALLING LA English DT Article DE phosphodiesterase 3B; exocytosis; beta-cell; insulin; cAMP ID CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE; PERFUSED RAT PANCREAS; GLUCOSE-INTOLERANCE; GRANULE EXOCYTOSIS; ALPHA-CELLS; B-CELLS; SECRETION; CAMP; PROTEIN; ISLET AB cAMP signaling is important for the regulation of insulin secretion in pancreatic beta-cells. The level of intracellular cAMP is controlled through its production by adenylyl cyclases and its breakdown by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE3B is involved in the regulation of nutrient-stimulated insulin secretion. Here, aiming at getting deeper functional insights, we have examined the role of PDE3B in the two phases of insulin secretion as well as its localization in the beta-cell. Depolarization-induced insulin secretion was assessed and in models where PDE3B was overexpressed [islets from transgenic RIP-PDE3B/7 mice and adenovirally (AdPDE3B) infected INS-I (832/13) cells], the first phase of insulin secretion, occurring in response to stimulation with high K+ for 5 min, was significantly reduced (similar to 25% compared to controls). In contrast, in islets from PDE3B(-/-) mice the response to high K+ was increased. Further, stimulation of isolated beta-cells from RIP-PDE3B/7 islets, using successive trains of voltage-clamped depolarizations, resulted in reduced Ca2+-triggered first phase exocytotic response as well as reduced granule mobilization-dependent second phase, compared to wild-type beta-cells. Using sub-cellular fractionation, confocal microscopy and transmission electron microscopy of isolated mouse islets and INS-1 (832/13) cells, we show that endogenous and overexpressed PDE3B is localized to insulin granules and plasma membrane. We conclude that PDE3B, through hydrolysis of cAMP in pools regulated by Ca2+, plays a regulatory role in depolarization-induced insulin secretion and that the enzyme is associated with the exocytotic machinery in beta-cells. (c) 2007 Elsevier Inc. All rights reserved. C1 Lund Univ, Biomed Ctr, Dept Expt Med Sci, SE-22184 Lund, Sweden. Lund Univ, Clin Res Ctr, Dept Clin Sci, SE-20502 Malmo, Sweden. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Walz, HA (reprint author), Lund Univ, Biomed Ctr, Dept Expt Med Sci, C11, SE-22184 Lund, Sweden. EM Helena.Walz@med.lu.se RI Jones, Helena/C-8847-2013; OI Jones, Helena/0000-0002-3948-161X; Eliasson, Lena/0000-0002-6467-5029 NR 45 TC 21 Z9 22 U1 0 U2 0 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 JUL PY 2007 VL 19 IS 7 BP 1505 EP 1513 DI 10.1016/j.cellsig.2007.01.030 PG 9 WC Cell Biology SC Cell Biology GA 184XI UT WOS:000247675500014 PM 17368848 ER PT J AU Hahn, B Ross, TJ Stein, EA AF Hahn, Britta Ross, Thomas J. Stein, Elliot A. TI Cingulate activation increases dynamically with response speed under stimulus unpredictability SO CEREBRAL CORTEX LA English DT Article DE anterior cingulate; attention; bottom-up; intertrial variability; posterior cingulate; reaction time ID EVENT-RELATED FMRI; COGNITIVE CONTROL; MACAQUE MONKEY; SELECTIVE ATTENTION; VISUAL-ATTENTION; ERROR-DETECTION; DEFAULT MODE; MOTOR AREAS; STROOP TASK; CORTEX AB Functional magnetic resonance imaging studies of cognition require repeated and consistent engagement of the cognitive process under investigation. Activation is generally averaged across trials that are assumed to tax a specific mental operation or state, whereas intraindividual variability in performance between trials is usually considered error variance. A more recent analysis approach postulates that these fluctuations can reflect variation in the very process taxed by the particular trial type. In the present study, participants responded to targets presented randomly in 1 of 4 peripheral locations. By employing a function of reaction time (RT) of individual trials as a linear regressor, brain regions were identified whose activation varied with RT on a trial-by-trial basis. Wholebrain analysis revealed that the anterior cingulate, posterior cingulate, and left angular/superior temporal gyri were more active in trials with faster RT but only when the target location was unpredictable. No such association was seen in trials where the target location was predicted by a central cue. These results suggest a role for the cingulate and angular gyri in the dynamic regulation of attention to unpredictable events. This is in accordance with the function of a default network that is active in the absence of top-down-focused attention and is thought to continuously provide resources for broad and spontaneous information gathering. Exploiting intertrial performance variability may be particularly suitable for capturing such spontaneous and elusive phenomena as stimulus-driven processes of attention. C1 Natl Inst Drug Abuse, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Hahn, B (reprint author), Natl Inst Drug Abuse, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM bhahn@intra.nida.nih.gov RI Ross, Thomas/B-7469-2008; Stein, Elliot/C-7349-2008; Hahn, Britta/G-4593-2012 OI Ross, Thomas/0000-0002-7745-3572; FU Intramural NIH HHS [Z99 DA999999] NR 49 TC 90 Z9 93 U1 3 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD JUL PY 2007 VL 17 IS 7 BP 1664 EP 1671 DI 10.1093/cercor/bhl075 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 180FX UT WOS:000247349000016 PM 16963517 ER PT J AU Palma, N Cinelli, S Sapora, O Wilson, SH Dogliotti, E AF Palma, Nieves Cinelli, Serena Sapora, Orazio Wilson, Samuel H. Dogliotti, Eugenia TI Ochratoxin A-induced mutagenesis in mammalian cells is consistent with the production of oxidative stress SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID CHINESE-HAMSTER CELLS; SPONTANEOUSLY OCCURRING MUTATIONS; UNSCHEDULED DNA-SYNTHESIS; BLADDER EPITHELIAL-CELLS; HUMAN UROTHELIAL CELLS; MYCOTOXIN OCHRATOXIN; HPRT GENE; SALMONELLA-TYPHIMURIUM; KIDNEY-CELLS; RAT-KIDNEY AB Ochratoxin A (OTA) is a widespread mycotoxin in food and a powerful nephrocarcinogen in rats. The mutagenicity of OTA has been extensively investigated but with conflicting results, thus leaving open the mechanistic question for OTA carcinogenicity. Here, we examined the mutagenicity of OTA by using well-standardized mutation assays such as the hypoxanthine-guanine phosphoribosyltransferase (HPRT) assay in Chinese hamster V79 cells and the thymidine kinase assay in mouse lymphoma LY5178 cells. OTA-induced HPRT mutations were characterized at the molecular level. In V79 cells, OTA produced a dose- and time-related decrease in cell number as a consequence of the transitory cytostatic effect mediated by G(2)/M cell cycle arrest. In both mutation assays, OTA was weakly mutagenic and this effect was independent of biotransformation. OTA-induced mutations were characterized by point mutations (48%) and a lack of a detectable reverse-transcription polymerase chain reaction product (52%). The pattern of OTA-induced point mutations was similar to that of spontaneous mutants, suggesting that OTA induced an increase of the endogenous oxidative metabolism but not covalent DNA adducts. Our data support a model where OTA is mutagenic via oxidative DNA damage induction. C1 Ist Super Sanita, Dept Environm & Primary Prevent, I-00161 Rome, Italy. Res Toxicol Ctr, I-00040 Monte Porzio Catone, Italy. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Dogliotti, E (reprint author), Ist Super Sanita, Dept Environm & Primary Prevent, Viale Regina Elena 299, I-00161 Rome, Italy. EM eugenia.dogliotti@iss.it FU Intramural NIH HHS [Z01 ES050159-11] NR 81 TC 55 Z9 56 U1 0 U2 3 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 JUL PY 2007 VL 20 IS 7 BP 1031 EP 1037 DI 10.1021/tx700027j PG 7 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 189UO UT WOS:000248014300007 PM 17567156 ER PT J AU Siraki, AG Bonini, MG Jiang, JJ Ehrenshaft, M Mason, RP AF Siraki, Arno G. Bonini, Marcelo G. Jiang, JinJie Ehrenshaft, Marilyn Mason, Ronald P. TI Aminoglutethimide-induced protein free radical formation on myeloperoxidase: A potential mechanism of agranulocytosis SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID CUTANEOUS PHOTOSENSITIZING AGENTS; HUMAN NEUTROPHIL MYELOPEROXIDASE; HYDROGEN-PEROXIDE; HORSERADISH-PEROXIDASE; 4-AMINOBENZOIC ACID; PHOTOLYSIS PRODUCTS; NITROXIDE METHOD; INACTIVATION; OXIDATION; CELLS AB Aminoglutethimide (AG) is a first-generation aromatase inhibitor used for estrogen-dependent breast cancer. Unfortunately, its use has also been associated with agranulocytosis. We have investigated the metabolism of AG by myeloperoxidase (MPO) and the formation of an MPO protein free radical. We hypothesized that AG oxidation by MPO/H2O2 would produce an AG cation radical that, in the absence of a biochemical reductant, would lead to the oxidation of MPO. We utilized a novel anti-DMPO antibody to detect DMPO (5,5-dimethyl-1-pyrroline N-oxide) covalently bound to protein, which forms only by the reaction of DMPO with a protein free radical. We found that AG metabolism by MPO/H2O2 induced the formation of DMPO-MPO, which was inhibited by MPO inhibitors and ascorbate. Glutethimide, a congener of AG that lacks the aromatic amine, did not cause DMPO-MPO formation, indicating the necessity of oxidation of the aniline moiety in AG. When analyzed by electron spin resonance spectroscopy, we detected a phenyl radical adduct, derived from AG, which may be involved in the free radical formation on MPO. Furthermore, we also found protein-DMPO adducts in MPO-containing, intact human promyelocytic leukemia cells (HL-60). MPO was affinity-purified from HL-60 cells treated with AG/H2O2 and was found to contain DMPO. These findings were also supported by the detection of protein free radicals with electron spin resonance in the cellular cytosolic lysate. The formation of an MPO protein free radical is believed to be mediated by one of two free radical drug metabolites of AG, one of which was characterized by spin trapping with 2-methyl-2-nitrosopropane. These results are the first demonstration of MPO free-radical detection by the anti-DMPO antibody that results from drug oxidation. We propose that drug-dependent free radical formation on MPO may play a role in the origin of agranulocytosis. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Siraki, AG (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM sirakia@niehs.nih.gov FU Intramural NIH HHS [, NIH0012013023]; PHS HHS [NIH0012013023] NR 51 TC 23 Z9 23 U1 1 U2 6 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 JUL PY 2007 VL 20 IS 7 BP 1038 EP 1045 DI 10.1021/tx6003562 PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 189UO UT WOS:000248014300008 PM 17602675 ER PT J AU Meyer-Lindenberg, A Zink, CF AF Meyer-Lindenberg, Andreas Zink, Caroline F. TI Imaging genetics for neuropsychiatric disorders SO CHILD AND ADOLESCENT PSYCHIATRIC CLINICS OF NORTH AMERICA LA English DT Article ID WILLIAMS-SYNDROME; SEROTONIN TRANSPORTER; MONOAMINE-OXIDASE; DEVELOPMENTAL TRAJECTORIES; FUNCTIONAL POLYMORPHISM; PROMOTER POLYMORPHISM; AMYGDALA INTERACTIONS; PREFRONTAL CORTEX; NEURAL MECHANISMS; COMPLEX TRAITS AB Many neuropsychiatric disorders of childhood and adolescence have a strong genetic component, and all present challenging questions about the neural abnormalities that underlie complex and unique behavioral and cognitive phenotypes. A useful research strategy in this setting is imaging genetics, a relatively new approach that combines genetic assessment with multimodal neuroimaging to discover neural systems linked to genetic abnormalities or variation. In this article, the authors review this strategy as applied to two areas. First, the authors present results on dissecting neural mechanisms underlying the complex neuropsychiatric phenotype of Williams syndrome. Second, they examine neural systems that are linked to candidate gene genetic variation that mediate risk for psychiatric disorders in a gene by environmental interaction. These data provide convergent evidence for neural circuitry mediating emotional regulation and social cognition under genetic control in humans. C1 Unit Syst Neurosci Psychiat, Bethesda, MD 20892 USA. Neuroimaging Core Facil, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH,DHHS, Bethesda, MD 20892 USA. RP Meyer-Lindenberg, A (reprint author), Unit Syst Neurosci Psychiat, 9000 Rockville Pike,Bldg 10,Room 3C101, Bethesda, MD 20892 USA. EM andreasm@mail.nih.gov RI Meyer-Lindenberg, Andreas/H-1076-2011 OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123 NR 85 TC 18 Z9 18 U1 2 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1056-4993 J9 CHILD ADOL PSYCH CL JI Child Adolesc. Psychiatr. N. Am. PD JUL PY 2007 VL 16 IS 3 BP 581 EP + DI 10.1016/j.chc.2007.02.005 PG 18 WC Psychiatry SC Psychiatry GA 188UI UT WOS:000247944400005 PM 17562580 ER PT J AU Orbach, Y Lamb, ME AF Orbach, Yael Lamb, Michael E. TI Young children's references to temporal attributes of allegedly experienced events in the course of forensic interviews SO CHILD DEVELOPMENT LA English DT Article ID INVESTIGATIVE UTTERANCE TYPES; BEHAVIORAL FREQUENCY; EYEWITNESS TESTIMONY; PRESCHOOL-CHILDREN; AGE-DIFFERENCES; ABUSE VICTIMS; TIME CONCEPTS; QUESTION TYPE; PAST EVENTS; MEMORY AB Developmental differences in references to temporal attributes of allegedly experienced events were examined in 250 forensic interviews of 4- to 10-year-old alleged victims of sexual abuse. Children's ages, the specific temporal attributes referenced, and the types of memory tapped by the interviewers' questions significantly affected the quantity and quality of temporal references produced. The findings documented age-related increases in 4- to 10-year-olds' references to temporal attributes, using the appropriate relational terminology, both spontaneously and in response to temporal requests. More references to temporal attributes were elicited from recall than from recognition memory, highlighting spontaneous reporting capabilities. Implications for theories concerning the developing understanding of temporal concepts and for the design of effective, age-appropriate, forensic interview techniques are discussed. C1 Univ Cambridge, Fac Social & Polit Sci, Cambridge CB2 3RQ, England. NICHHD, Bethesda, MD 20892 USA. RP Lamb, ME (reprint author), Univ Cambridge, Fac Social & Polit Sci, Free Sch Lane, Cambridge CB2 3RQ, England. EM mel37@cam.ac.uk NR 92 TC 42 Z9 42 U1 12 U2 18 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0009-3920 J9 CHILD DEV JI Child Dev. PD JUL-AUG PY 2007 VL 78 IS 4 BP 1100 EP 1120 DI 10.1111/j.1467-8624.2007.01055.x PG 21 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 197AH UT WOS:000248524600005 PM 17650128 ER PT J AU Belsky, J Steinberg, LD Houts, RM Friedman, SL DeHart, G Cauffman, E Roisman, GI Halpern-Felsher, BL Susman, E AF Belsky, Jay Steinberg, Laurence D. Houts, Renate M. Friedman, Sarah L. DeHart, Ganie Cauffman, Elizabeth Roisman, Glenn I. Halpern-Felsher, Bonnie L. Susman, Elisabeth TI Family rearing antecedents of pubertal timing SO CHILD DEVELOPMENT LA English DT Review ID EARLY CHILD-CARE; SECONDARY SEX CHARACTERISTICS; ANDROGEN RECEPTOR GENE; FATHER ABSENCE; REPRODUCTIVE DEVELOPMENT; INDIVIDUAL-DIFFERENCES; MENARCHEAL AGE; ATTACHMENT SECURITY; INFANT ATTACHMENT; STRESS REACTIVITY AB Two general evolutionary hypotheses were tested on 756 White children (397 girls) studied longitudinally: (1) rearing experiences would predict pubertal timing; and (2) children would prove differentially susceptible to rearing. Analysis of pubertal measurements, including some based on repeated physical assessments, showed that mothering and fathering, earlier and later in childhood, predicted pubertal development, but only for girls, with negative parenting appearing most influential; maternal harsh control predicted earlier menarche. Rearing effects varied by infant negative emotionality, proving stronger (and opposite) for girls who in infancy were lower rather than higher in negativity. Maternal menarche, controlled in all analyses, was a stronger predictor than rearing. Findings are discussed in terms of theory development, genetic and nutritional influences, and sample restrictions. C1 Birkbeck Univ London, Inst Study Children Families & Social Issues, London WC1B 3RA, England. RTI Int, Res Triangle Pk, NC USA. Temple Univ, Philadelphia, PA 19122 USA. SUNY Coll Geneseo, Geneseo, NY 14454 USA. Univ Calif Irvine, Irvine, CA USA. Univ Illinois, Urbana, IL 61801 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Penn State Univ, University Pk, PA 16802 USA. NICHD, Early Child Care Res Network, Bethesda, MD USA. RP Belsky, J (reprint author), Birkbeck Univ London, Inst Study Children Families & Social Issues, 7 Bedford Sq, London WC1B 3RA, England. EM j.belsky@bbk.ac.uk OI Belsky, Jay/0000-0003-2191-2503 NR 104 TC 119 Z9 121 U1 26 U2 58 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-3920 J9 CHILD DEV JI Child Dev. PD JUL-AUG PY 2007 VL 78 IS 4 BP 1302 EP 1321 DI 10.1111/j.1467-8624.2007.01067.x PG 20 WC Psychology, Educational; Psychology, Developmental SC Psychology GA 197AH UT WOS:000248524600017 PM 17650140 ER PT J AU Jo, SA Kim, EK Park, MH Han, C Park, HY Jang, Y Song, BJ Jo, I AF Jo, Sangmee Ahn Kim, Eun-Kyung Park, Moon Ho Han, Changsu Park, Hyun-Young Jang, Yangsoo Song, Byung Joon Jo, Inho TI A Glu487Lys polymorphism in the gene for mitochondrial aldehyde dehydrogenase 2 is associated with myocardial infarction in elderly Korean men SO CLINICA CHIMICA ACTA LA English DT Article DE aldehyde dehydrogenase 2; polymorphism; myocardial infarction; Koreans ID ALDEHYDE DEHYDROGENASE POLYMORPHISM; ALZHEIMERS-DISEASE; RISK-FACTOR; RED WINE; ALCOHOL; HYPERTENSION; JAPANESE; ANSAN; POPULATION; DEFICIENCY AB Background: A homozygous mutant (ALDH2*2/*2) of the gene for mitochondrial aldehyde dehydrogenase 2 (ALDH2) at codon 487 was reported to be associated with myocardial infarction (MI) among Japanese men. However, such an association has never been studied in a Korean population. Method: The subjects consisted of 122 men (60-81 y) with MI recruited randomly from Yonsei University Medical Center, Korea. A total of 439 men (60-84 y) without MI were selected as controls from the Ansan Geriatric Study. ALDH2 genotypes were determined using the TaqMan fluorogenic 5' nuclease polymerase chain reaction assay. Results: Genotypes carrying the mutant ALDH2 allele (ALDH2*1/*2 plus ALDH2*2/*2) were significantly more frequent in patients with MI than in the controls (42.6% vs. 30.5%, P=0.0163). Multiple logistic regression analysis revealed that ALDH2*1/*2 plus ALDH2*2/*2, together with abnormal high density lipoprotein cholesterol and elevated body mass index, was an independent risk factor for MI in elderly Korean men (odds ratio = 1.976, 95% CI: 1.202-3.248). Conclusions: ALDH2 polymorphisms may play an important role in the pathogenesis of MI in elderly Korean men. (c) 2007 Published by Elsevier B.V. C1 Natl Inst Hlth, Ctr Biomed Sci, Seoul 122701, South Korea. Univ Korea Hosp, Geriartr Hlth Clin & Res Inst, Ansan 425707, South Korea. Yonsei Univ, Med Ctr, Cardiovasc Res Inst, Seoul 120752, South Korea. NIH, NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. RP Jo, I (reprint author), Natl Inst Hlth, Ctr Biomed Sci, 194 Tongil-ro, Seoul 122701, South Korea. EM inhojo@nih.go.kr OI Park, Hyun-Young/0000-0002-6698-7368 NR 36 TC 46 Z9 54 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD JUL PY 2007 VL 382 IS 1-2 BP 43 EP 47 DI 10.1016/j.cca.2007.03.016 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 185KU UT WOS:000247710700008 PM 17459359 ER PT J AU Slater, JE James, R Pongracic, JA Liu, AH Sarpong, S Sampson, HA Satinover, SM Woodfolk, JA Mitchell, HE Gergen, PJ Eggleston, PA AF Slater, J. E. James, R. Pongracic, J. A. Liu, A. H. Sarpong, S. Sampson, H. A. Satinover, S. M. Woodfolk, J. A. Mitchell, H. E. Gergen, P. J. Eggleston, P. A. TI Biological potency of German cockroach allergen extracts determined in an inner city population SO CLINICAL AND EXPERIMENTAL ALLERGY LA English DT Article DE allergen; asthma; cockroach; immunotherapy; standardization ID CHILDREN; ASTHMA; EXPOSURE; IGE AB Background Cockroach allergy is an important cause of inner city asthma. To perform valid studies on the diagnosis and treatment of cockroach allergy, biological potencies of test extracts need to be established, and a surrogate in vitro test for biological potency should be chosen. Methods Sixty-two cockroach-allergic adult subjects were recruited for quantitative skin testing with three commercial German cockroach extracts. The intradermal D50 values were determined using linear interpolation, and the biologic potencies were determined from D50 data. The extracts were also analysed for relative potency, using a competition ELISA, and for specific allergen content, using a two-site ELISA. Results Estimates of each extract's D50 were analysable in 48-55 subjects, with D50s between 10.3 and 11.8. All three extracts were bioequivalent using pre-set criteria. The biological potencies of the extracts were 1738-8570 bioequivalent allergy units (BAU)/mL (geometric mean=3300), and these relative potencies were similar to those estimated by competition ELISA and specific allergen content. IgE against cockroach allergens were detected in sera from 34 subjects with analysable D50s, and 17 subjects had IgE directed against specific cockroach allergens. Although the presence of anti-Bla g 5 correlated with the subjects' skin test responses for 2/3 extracts, no single allergen was immunodominant. Antibody responses among the subjects were heterogeneous. Conclusions Although commercial cockroach extracts are relatively low in potency, immunotherapeutic doses should be achievable. Biological potency may be estimated using D50 testing, a combination of specific allergen determinations, or by an overall potency assay such as the competition ELISA. Capsule Summary The biological potency of three German cockroach allergen extracts, determined in an inner city population, was 1738-8570 BAU/mL. No one allergen was immunodominant, and surrogate in vitro testing methods were examined. C1 US FDA, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. Rho Inc, Chapel Hill, NC USA. Childrens Mem Hosp, Chicago, IL 60614 USA. Natl Jewish Med & Res Ctr, Denver, CO USA. Howard Univ, Washington, DC 20059 USA. Mt Sinai Sch Med, New York, NY USA. Univ Virginia, Hlth Syst, Charlottesville, VA 22903 USA. NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. RP Slater, JE (reprint author), US FDA, Ctr Biol Evaluat & Res, 1401 Rockville Pike, Rockville, MD 20852 USA. EM jay.slater@fda.hhs.gov NR 20 TC 23 Z9 24 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0954-7894 J9 CLIN EXP ALLERGY JI Clin. Exp. Allergy PD JUL PY 2007 VL 37 IS 7 BP 1033 EP 1039 DI 10.1111/j.1365-2222.2007.02751.x PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 180WQ UT WOS:000247398300009 PM 17581196 ER PT J AU Kurup, SK Levy-Clarke, G Calvo, KR Jaffe, ES Nussenblatt, RB Chan, CC AF Kurup, Shree K. Levy-Clarke, Grace Calvo, Katherine R. Jaffe, Elaine S. Nussenblatt, Robert B. Chan, Chi-Chao TI Primary diffuse large B-cell lymphoma of the spleen with coincident serous retinal detachments responsive to corticosteroids SO CLINICAL AND EXPERIMENTAL OPHTHALMOLOGY LA English DT Article DE corticosteroids; malignancy; serous retinal detachment ID KOYANAGI-HARADA-DISEASE; NERVOUS-SYSTEM LYMPHOMA AB Non-Hodgkin's lymphoma is the sixth leading cause of cancer death in the USA. Herein, a patient is presented with primary diffuse large B-cell lymphoma whose initial complaint was blurred vision and who presented with corticosteroid-responsive serous retinal detachments mimicking Vogt-Koynagi-Harada. Extensive clinical examination including imaging and blood testing was negative. Splenectomy led to a diagnosis of splenic lymphoma C1 NEI, Immunol Lab, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Kurup, SK (reprint author), Wake Forest Univ, Ctr Eye, Dept Ophthalmol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM skk100@pol.net RI Calvo, Katherine/A-8109-2009; OI Calvo, Katherine/0000-0002-0771-4191 FU Intramural NIH HHS [Z01 EY000222-22] NR 10 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1442-6404 J9 CLIN EXP OPHTHALMOL JI Clin. Exp. Ophthalmol. PD JUL PY 2007 VL 35 IS 5 BP 468 EP 472 DI 10.1111/j.1442-9071.2007.01517.x PG 5 WC Ophthalmology SC Ophthalmology GA 197BY UT WOS:000248529600013 PM 17651253 ER PT J AU Schlom, J Arlen, PM Gulley, JL AF Schlom, Jeffrey Arlen, Philip M. Gulley, James L. TI Cancer vaccines: Moving beyond current paradigms SO CLINICAL CANCER RESEARCH LA English DT Review ID RENAL-CELL CARCINOMA; PROSTATE-SPECIFIC ANTIGEN; COLONY-STIMULATING FACTOR; HIGH-DOSE INTERLEUKIN-2; ACTIVATED KILLER-CELLS; PHASE-III TRIAL; CARCINOEMBRYONIC ANTIGEN; METASTATIC MELANOMA; TUMOR-IMMUNOTHERAPY; ANTITUMOR IMMUNITY AB The field of cancer vaccines is currently in an active state of preclinical and clinical investigations. Although no therapeutic cancer vaccine has to date been approved by the Food and Drug Administration, several new paradigms are emerging from recent clinical findings both in the use of combination therapy approaches and, perhaps more importantly, in clinical trial design and end point analyses. This article will review recent clinical trials involving several different cancer vaccines from which data are emerging contrasting classic "tumor response" (Response Evaluation Criteria in Solid Tumors) criteria with "patient response" in the manifestation of increased patient survival post-vaccine therapy. Also described are several strategies in which cancer vaccines can be exploited in combination with other agents and therapeutic modalities that are quite unique when compared with "conventional" combination therapies. This is most likely due to the phenomena that (a) cancer vaccines initiate a dynamic immune process that can be exploited in subsequent therapies and (b) both radiation and certain chemotherapeutic agents have been shown to alter the phenotype of tumor cells as to render them more susceptible to T-cell-mediated killing. Consequently, evidence is emerging from several studies in which patient cohorts who first receive a cancer vaccine (as contrasted with control cohorts) benefit clinically from subsequent therapies. C1 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, Room 8B09,10 Ctr Dr, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS [Z01 BC010598-04] NR 54 TC 127 Z9 133 U1 2 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD JUL 1 PY 2007 VL 13 IS 13 BP 3776 EP 3782 DI 10.1158/1078-0432.CCR-07-0588 PG 7 WC Oncology SC Oncology GA 186IT UT WOS:000247773100005 PM 17606707 ER PT J AU Monti, P Ciribilli, Y Jordan, J Menichini, P Umbach, DM Resnick, MA Luzzatto, L Inga, A Fronza, G AF Monti, Paola Ciribilli, Yari Jordan, Jennifer Menichini, Paola Umbach, David M. Resnick, Michael A. Luzzatto, Lucio Inga, Alberto Fronza, Gilberto TI Transcriptional functionality of germ line p53 mutants influences cancer phenotype SO CLINICAL CANCER RESEARCH LA English DT Article ID FRAUMENI-SYNDROME; MUTATION ANALYSIS; TP53 DATABASE; TUMOR; TRANSACTIVATION; YEAST; PROMOTERS; GAIN; ASSAY; POLYMORPHISM AB Purpose: The TP53 tumor suppressor gene encodes a sequence-specific transcription factor that is able to transactivate several sets of genes, the promoters of which include appropriate response elements. Although human cancers frequently contain mutated p53, the alleles as well as the clinical expression are often heterogeneous. Germ line mutations of TP53 result in cancer proneness syndromes known as Li-Fraumeni, Li-Fraumeni-like, and nonsyndromic predisposition with or without family history. p53 mutants can be classified as partial deficiency alleles or severe deficiency alleles depending on their ability to transactivate a set of human target sequences, as measured using a standardized yeast-based assay (see http://www.umd.be:2072/ index. html). We have investigated the extent to which the functional features of p53 mutant alleles determine clinical features in patients who have inherited these alleles and have developed cancer. Experimental Design: We retrieved clinical data from the IARC database (see http:// www.p53.iarc.fr/Germline.html) for all cancer patients with germ line p53 mutations and applied stringent statistical evaluations to compare the functional classification of p53 alleles with clinical phenotypes. Results: Our analyses reveal that partial deficiency alleles are associated with a milder family history (P = 0.007), a lower numbers of tumors (P = 0.007), and a delayed disease onset (median, 31 versus 15 years; P = 0.007) which could be related to distinct tumor spectra. Conclusions: These findings establish for the first time significant correlations between the residual transactivation function of individual TP53 alleles and clinical variables in patients with inherited p53 mutations who develop cancer. C1 Natl Canc Res Inst IST, Dept Translat Oncol, Mol Mutagenesis Unit, I-16132 Genoa, Italy. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Chromosome Stabil Sect, NIH, Res Triangle Pk, NC 27709 USA. Ist Toscano Tumori, Florence, Italy. RP Inga, A (reprint author), Natl Canc Res Inst IST, Dept Translat Oncol, Mol Mutagenesis Unit, Largo R Benzi 10, I-16132 Genoa, Italy. EM alberto.inga@istge.it; gilberto.fronza@istge.it FU Intramural NIH HHS [Z01 ES065079-14] NR 34 TC 22 Z9 22 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 JUL 1 PY 2007 VL 13 IS 13 BP 3789 EP 3795 DI 10.1158/1078-0432.CCR-06-2545 PG 7 WC Oncology SC Oncology GA 186IT UT WOS:000247773100007 PM 17606709 ER PT J AU Ruhayel, Y Malm, G Haugen, TB Henrichsen, T Bjorsvik, C Grotmol, T Saether, T Malm, J Figenschau, Y Rylander, L Levine, RJ Giwercman, A AF Ruhayel, Yasir Malm, Gunilla Haugen, Trine B. Henrichsen, Trine Bjorsvik, Cathrine Grotmol, Tom Saether, Thomas Malm, Johan Figenschau, Yngve Rylander, Lars Levine, Richard J. Giwercman, Aleksander TI Seasonal variation in serum concentrations of reproductive hormones and urinary excretion of 6-sulfatoxymelatonin in men living north and south of the Arctic Circle: a longitudinal study SO CLINICAL ENDOCRINOLOGY LA English DT Article ID FOLLICLE-STIMULATING-HORMONE; PLASMA TESTOSTERONE; LUTEINIZING-HORMONE; CIRCADIAN-RHYTHMS; BINDING GLOBULIN; HUMAN MELATONIN; HUMAN-FERTILITY; SEMEN QUALITY; INHIBIN-B; SUMMER AB Objective Seasonal variation in photoperiod or temperature may influence human reproductive biology. The present study evaluated whether seasonal changes occurred in the levels of reproductive hormones and the major melatonin metabolite, 6-sulfatoxymelatonin (aMT6s), in populations exposed to extreme variation in photoperiod and temperature. Design Two separate cohorts of Norwegian men were recruited from the general population in either of two locations: Tromso (69.5 degrees N, n = 92) or Oslo (60 degrees N, n = 112), located north and south of the Arctic Circle (66.5 degrees N), respectively. Measurements Four blood and 12-h overnight urine samples were obtained on separate occasions over a 12-month period, including during the photoperiod maximum and minimum. Serum concentrations of FSH, LH, testosterone (T), oestradiol (E-2), SHBG and the urinary excretion of aMT6s were assessed. Results Statistical analysis using generalized estimating equations indicated that LH levels were lowest during early winter in both locations (both P = 0.01). In Tromso, free T and E-2 concentrations peaked during early winter (P = 0.02 and 0.003, respectively). In Oslo, free T levels were lowest during early winter (P = 0.06) whereas E-2 levels were lowest during late summer (P < 0.001). Urinary aMT6s concentrations were lowest during early summer in Tromso and Oslo. Concentrations peaked during early winter in Tromso (P < 0.001) and during late winter in Oslo (P < 0.001). Conclusion LH levels exhibited similar changes in both locations, whereas the patterns of changes of the sex steroid concentrations differed, possibly indicating different underlying mechanisms. Excretion of aMT6s was lowest during early summer in both locations, indicating that the long natural photoperiod was sufficient to cause suppression of melatonin secretion. Whether these changes have any biological significance remains uncertain. C1 Lund Univ, Malmo Univ Hosp, CRC, Dept Clin Sci, SE-20502 Malmo, Sweden. Rikshosp Univ Hosp, Androl Lab, Dept Obstet & Gynaecol, Oslo, Norway. Oslo Univ Coll, Fac Hlth Sci, Oslo, Norway. Canc Registry Norway, Inst Populat Based Canc Res, Oslo, Norway. Lund Univ, Malmo Univ Hosp, Dept Lab Med, Div Clin Chem, Malmo, Sweden. Univ Hosp N Norway, Dept Clin Chem, Tromso, Norway. Lund Univ, Div Occupat & Environm Med & Psychiat Epidemiol, Dept Labor Med, Lund, Sweden. NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Ruhayel, Y (reprint author), Lund Univ, Malmo Univ Hosp, CRC, Dept Clin Sci, Bldg 91,Level 10,Entrance 72,UMAS, SE-20502 Malmo, Sweden. EM yasir.ruhayel@med.lu.se RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X NR 49 TC 14 Z9 14 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0300-0664 J9 CLIN ENDOCRINOL JI Clin. Endocrinol. PD JUL PY 2007 VL 67 IS 1 BP 85 EP 92 DI 10.1111/j.1365-2265.2007.02843.x PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 180DC UT WOS:000247339300013 PM 17547693 ER PT J AU Adriani, M Aoki, J Horai, R Thornton, AM Konno, A Kirby, M Anderson, SM Siegel, RM Candotti, F Schwartzberg, PL AF Adriani, Marsilio Aoki, Joseph Horai, Reiko Thornton, Angela M. Konno, Akihiro Kirby, Martha Anderson, Stacie M. Siegel, Richard M. Candotti, Fabio Schwartzberg, Pamela L. TI Impaired in vitro regulatory T cell function associated with Wiskott-Aldrich syndrome SO CLINICAL IMMUNOLOGY LA English DT Article DE Wiskott-Aldrich syndrome; regulatory T cells; autoimmunity ID SYNDROME PROTEIN; SUPPRESSOR FUNCTION; CYTOSKELETAL REARRANGEMENT; IMMUNOLOGICAL SYNAPSE; FOXP3; ACTIVATION; AUTOIMMUNITY; EXPRESSION; WASP; POLYMERIZATION AB Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency characterized by the contradictory coexistence of impaired T-cell function and exaggerated T-cell-mediated pathology, including autoimmunity and eczema. WAS protein (WASp)-deficient mice are also immunodeficient and can develop autoimmune disease. Since defects in regulatory T-cells (Treg) are associated with autoimmunity, we examined the presence and function of these cells in WAS patients and WASP-deficient mice. We found that CD4(+)CD25(+)FOXP3(+) Treg cells can develop in the absence of WASP expression. However, Treg cells both from WASP-deficient mice and from four out of five WAS patients studied showed impaired in vitro suppressor function. In WASP-deficient mice, this defect could be partially rescued by pre-activation with IL-2, suggesting that inadequate cell activation may play a role in WASP-deficient Treg dysfunction. These findings may provide insights into the complex pathophysiology and paradoxical phenotypes of WAS and suggest new therapeutic modalities for autoimmunity in these patients. Published by Elsevier Inc. C1 NHGRI, NIH, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. Natl Inst Musculoskeletal & Skin Dis, NIH, Bethesda, MD 20892 USA. RP Candotti, F (reprint author), NHGRI, NIH, Genet & Mol Biol Branch, 49 Convent Dr,Blg 49,Rm 3A20, Bethesda, MD 20892 USA. EM fabio@nhgri.nih.gov RI Adriani, Marsilio/F-2553-2013; OI Siegel, Richard/0000-0001-5953-9893 FU Intramural NIH HHS [Z01 HG000123-10, Z99 HG999999, Z01 HG000122-10, Z01 AR041133-06] NR 49 TC 55 Z9 59 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUL PY 2007 VL 124 IS 1 BP 41 EP 48 DI 10.1016/j.clim.2007.02.001 PG 8 WC Immunology SC Immunology GA 187OJ UT WOS:000247857300008 PM 17512803 ER PT J AU Koczwara, K Muller, D Achenbach, P Ziegler, AG Bonifacio, E AF Koczwara, Kerstin Muller, Daniela Achenbach, Peter Ziegler, Anette-G. Bonifacio, Ezio TI Identification of insulin autoantibodies of IgA isotype that preferentially target non-human insulin SO CLINICAL IMMUNOLOGY LA English DT Article DE type 1 diabetes; autoimmunity; insulin autoantibodies; antibody isotypes; IgA; IgG ID ISLET AUTOANTIBODIES; COWS MILK; TYPE-1; RISK; AUTOIMMUNITY; APPEARANCE; CHILDHOOD; INFANTS; EXPOSURE; BABYDIAB AB Insulin autoantibodies (IAA) precede clinical type 1 diabetes in children. Immunization events leading to IAA are unknown. The aim of this study was to determine whether some IAA result from mucosal immunization. IgA-IAA and binding of IAA to non-human insulin were examined in selected high and low affinity IAA-positive samples and in first IAA-positive samples from children aged < 2 years. High affinity IAA (> 10(9)L/mol) bound strongly to human insulin and poorly to chicken insulin. In contrast, 12/13 lower affinity IAA were chicken insulin-reactive, binding equally to human and chicken insulin (n=4), or preferentially binding chicken insulin (n=8). IgA-IAA were found in association with chicken insulin-reactive IAA, and included cases where IgA-IAA predominated over IgG-IAA. Among 20 IAA-positive children aged < 2 years, one had early IgA-chicken insulin-reactive IAA that were replaced by high affinity IgG-IAA. The findings suggest that some IAA can result from immunization against molecules other than human insulin at mucosal sites. (c) 2007 Elsevier Inc. All rights reserved. C1 Diabet Res Inst, D-80804 Munich, Germany. NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacio, E (reprint author), Diabet Res Inst, Koelner Pl 1, D-80804 Munich, Germany. EM ezio.bonifacio@lrz.uni-muenchen.de RI Ziegler, Anette-Gabriele/M-4614-2014; Bonifacio, Ezio/E-7700-2010; Achenbach, Peter/M-9867-2014 OI Ziegler, Anette-Gabriele/0000-0002-6290-5548; Bonifacio, Ezio/0000-0002-8704-4713; Achenbach, Peter/0000-0001-6720-2684 NR 17 TC 5 Z9 5 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD JUL PY 2007 VL 124 IS 1 BP 77 EP 82 DI 10.1016/j.clim.2007.03.545 PG 6 WC Immunology SC Immunology GA 187OJ UT WOS:000247857300012 PM 17524809 ER PT J AU Kirk, GD Merlo, C O' Driscoll, P Mehta, SH Galai, N Vlahov, D Samet, J Engels, EA AF Kirk, Gregory D. Merlo, Christian O' Driscoll, Peter Mehta, Shruti H. Galai, Noya Vlahov, David Samet, Jonathan Engels, Eric A. TI HIV infection is associated with an increased risk for lung cancer, independent of smoking SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; UNITED-STATES; RESPIRATORY-DISEASE; NONSMOKING WOMEN; IMMUNODEFICIENCY; AIDS; COHORT; ERA; PEOPLE; IMMUNOSUPPRESSION AB Background. Human immunodeficiency virus ( HIV)-infected persons have an elevated risk for lung cancer, but whether the increase reflects solely their heavy tobacco use remains an open question. Methods. The Acquired Immunodeficiency Syndrome ( AIDS) Link to the Intravenous Experience Study has prospectively observed a cohort of injection drug users in Baltimore, Maryland, since 1988, using biannual collection of clinical, laboratory, and behavioral data. Lung cancer deaths were identified through linkage with the National Death Index. Cox proportional hazards regression was used to examine the effect of HIV infection on lung cancer risk, controlling for smoking status, drug use, and clinical variables. Results. Among 2086 AIDS Link to the Intravenous Experience Study participants observed for 19,835 person-years, 27 lung cancer deaths were identified; 14 of the deaths were among HIV-infected persons. All but 1 ( 96%) of the patients with lung cancer were smokers, smoking a mean of 1.2 packs per day. Lung cancer mortality increased during the highly active antiretroviral therapy era, compared with the pre-highly active antiretroviral therapy period ( mortality rate ratio, 4.7; 95% confidence interval, 1.7-16). After adjusting for age, sex, smoking status, and calendar period, HIV infection was associated with increased lung cancer risk ( hazard ratio, 3.6; 95% confidence interval, 1.6-7.9). Preexisting lung disease, particularly noninfectious diseases and asthma, displayed trends for increased lung cancer risk. Illicit drug use was not associated with increased lung cancer risk. Among HIV-infected persons, smoking remained the major risk factor; CD4 cell count and HIV load were not strongly associated with increased lung cancer risk, and trends for increased risk with use of highly active antiretroviral therapy were not significant. Conclusions. HIV infection is associated with significantly increased risk for developing lung cancer, independent of smoking status. C1 Johns Hopkins Univ, Dept Epidemiol, Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. NCI, Viral Epidemiol Branch, NIH, Rockville, MD USA. New York Acad Med, New York, NY USA. RP Kirk, GD (reprint author), Johns Hopkins Univ, Dept Epidemiol, Johns Hopkins Bloomberg Sch Publ Hlth, 615 N Wolfe St,E-6533, Baltimore, MD 21205 USA. EM gkirk@jhsph.edu RI Kirk, Gregory/A-8484-2009 FU NHLBI NIH HHS [R01 HL090483]; NIDA NIH HHS [DA04334, DA12568, R01 DA004334, R01 DA012568, R37 DA004334, R56 DA004334, R56 DA012568] NR 39 TC 182 Z9 183 U1 1 U2 9 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 JUL 1 PY 2007 VL 45 IS 1 BP 103 EP 110 DI 10.1086/518606 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 175RC UT WOS:000247029700019 PM 17554710 ER PT J AU Kopp, JB Ball, LK Cohen, A Kenney, RJ Lempert, KD Miller, PE Muntner, P Qureshi, N Yelton, SA AF Kopp, Jeffrey B. Ball, Lynda K. Cohen, Andrew Kenney, Robert J. Lempert, Kenneth D. Miller, Paul E. Muntner, Paul Qureshi, Nauman Yelton, Sarah A. TI Kidney patient care in disasters: Lessons from the hurricanes and earthquake of 2005 SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE-RENAL-FAILURE; TASK-FORCE; MANAGEMENT; INJURIES; VICTIMS; DISEASE; MARMARA; IRAN AB The active 2005 hurricane season alerted Americans to the pressing need for a more effective response to mass casualty incidents. The kidney patient community was particularly affected. Ninety-four dialysis facilities in the Gulf Coast states closed for at least 1 wk in the aftermath of Hurricane Katrina, and additional units were affected by evacuation of dialysis patients. Dialysis units along the Gulf Coast were also affected by Hurricanes Rita and Wilma. Existing emergency response plans were inadequate in providing continuity of care for kidney patients. The Kashmir, South Asia, earthquake of October 2005 killed 97,000 individuals. Building collapse was associated with widespread crush injury, and many patients required temporary hemodialysis. Several regions of the United States have the potential for catastrophic earthquakes. The Kidney Community Emergency Response Coalition has recently issued recommendations for patients, dialysis facilities, and providers, with a goal to improve care of kidney patients in future domestic disasters. With suitable planning, the nephrology community can do much to ensure the continuity of medical care for kidney patients in the face of a wide range of possible natural and human-made disasters. C1 NIDDK, Kidney Dis Sect, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NW Renal Network, Seattle, WA USA. Ochsner Clin & Alton Ochsner Med Fdn, Dept Nephrol, New Orleans, LA USA. Renal Associates Baton Rouge, Baton Rouge, LA USA. Nephrol Consultants NW Ohio, Toledo, OH USA. Miller Dialysis Acadiana Reg, Ville Platte, LA USA. Tulane Univ, Dept Epidemiol, New Orleans, LA 70118 USA. Univ Alabama, Huntsville, AL 35899 USA. Heartland Kidney Network, ESRD Network 12, Kansas City, MO USA. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, NIH, Dept Hlth & Human Serv, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU Intramural NIH HHS NR 19 TC 34 Z9 35 U1 0 U2 1 PU AMERICAN SOCIETY NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JUL PY 2007 VL 2 IS 4 BP 814 EP 824 DI 10.2215/CJN.03481006 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 184AE UT WOS:000247612700028 PM 17699499 ER PT J AU Kopp, JB Ball, LK Cohen, A Kenney, RJ Lempert, KD Miller, PE Muntner, P Qureshi, N Yelton, SA AF Kopp, Jeffrey B. Ball, Lynda K. Cohen, Andrew Kenney, Robert J. Lempert, Kenneth D. Miller, Paul E. Muntner, Paul Qureshi, Nauman Yelton, Sarah A. TI Kidney patient care in disasters: Emergency planning for patients and dialysis facilities SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article AB The catastrophic 2005 hurricane season alerted Americans to the need for a more effective response to mass casualty incidents. To address the needs of the nephrology community, the Kidney Community Emergency Response Coalition (KCERC) was formed, with representatives from more than 50 governmental agencies and private organizations. After completing phase 1 of its work, the KCERC issued recommendations for patients, dialysis units, and providers. During phase 2, the KCERC will promote implementation of those recommendations. During a disaster, the KCERC will host a daily conference call on which dialysis facilities, the End-Stage Renal Disease Networks, and emergency response officials will coordinate disaster response. Predisaster preparation for kidney patients should stress identification of alternative dialysis facilities, education about the renal emergency diet, and plans for early evacuation from the disaster area and for evacuating with medical documents and medications. Dialysis facilities are required to have a disaster plan; regular revision and rehearsal are essential. Critical issues for dialysis facilities include identification of partner facilities, a robust communications plan that takes into account the limitations of telephones and broadband access, staff shortages in the face of a possible influx of new patients, the delivery of service in the face of compromised utilities (water, power), and the recovery of a dialysis facility that experiences flooding or structural damage. A timeline to safety for dialysis patients can be visualized; if specific tasks are accomplished at each disaster stage, then it is likely that the health of these vulnerable patients can be protected. C1 NIDDK, Kidney Dis Sect, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NW Renal Network, ESRD Network 16, Seattle, WA USA. Ochsner Clin & Alton Ochsner Med Fdn, Dept Nephrol, New Orleans, LA USA. Renal Associates Baton Rouge, Baton Rouge, LA USA. Nephrol Consultants NW Ohio, Toledo, OH USA. Miller Dialysis Acadiana Reg, Ville Platte, LA USA. Tulane Univ, Dept Epidemiol, New Orleans, LA 70118 USA. Univ Alabama, Huntsville, AL 35899 USA. Heartland Kidney Network, ESRD Network 12, Kansas City, MO USA. RP Kopp, JB (reprint author), NIDDK, Kidney Dis Sect, NIH, Dept Hlth & Human Serv, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X NR 17 TC 28 Z9 28 U1 0 U2 3 PU AMERICAN SOCIETY NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JUL PY 2007 VL 2 IS 4 BP 825 EP 838 DI 10.2215/CJN.01220307 PG 14 WC Urology & Nephrology SC Urology & Nephrology GA 184AE UT WOS:000247612700029 PM 17699500 ER PT J AU Waldman, M Kopp, JB AF Waldman, Meryl Kopp, Jeffrey B. TI Parvovirus B19 and the kidney SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the American-Society-of-Nephrology CY NOV 14-19, 2006 CL San Diego, CA SP Amer Soc Nephrol ID RENAL-TRANSPLANT RECIPIENTS; SICKLE-CELL-DISEASE; ENDOCAPILLARY PROLIFERATIVE GLOMERULONEPHRITIS; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; ERYTHROCYTE-P-ANTIGEN; BONE-MARROW; APLASTIC-ANEMIA; NONSTRUCTURAL PROTEIN; PERSISTENT ANEMIA; IMMUNE-RESPONSES AB Infection with parvovirus B19 causes several clinical syndromes (fifth disease, transient aplastic crisis, pure red cell aplasia, and hydrops fetalis) and may contribute to other illnesses. B19 has been linked to renal disease in three settings: As a cause of acute glomerulopathy and as a cause of anemia in ESRD and kidney transplantation. Case reports implicate parvovirus in the pathogenesis of proliferative glomerulonephritis and collapsing glomerulopathy, but a causal relationship has not been established. A proposed role for B19 infection is based on the temporal association of renal findings with viral infection, positive serology, and identification of the viral genome in the glomerulus. Mechanisms may include cytopathic effects on glomerular epithelial cells and/or endothelial cells and glomerular deposition of immune complexes. Patients who require dialysis may have increased susceptibility to acute and chronic anemia after parvoviral infection. Factors that predispose this population to complications of B19 infection include impaired immune response, deficient erythropoietin production, and possibly decreased erythrocyte survival. The clinical burden of parvovirus B19 infection in renal transplant recipients may be underestimated; these individuals may develop persistent viremia as a result of a dysfunctional immune response. Chronic anemia and pure red blood cell aplasia are the most common complications of parvovirus infection in this population; the diagnosis should be considered in transplant recipients with unexplained anemia or pancytopenia. Allograft rejection and dysfunction have been reported in association with infection, but a cause-effect relationship has not been proved. Further investigation of the relationship between B19 and kidney disease is warranted. C1 NIDDK, Kidney Dis Sect, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Waldman, M (reprint author), NIDDK, Kidney Dis Sect, NIH, Dept Hlth & Human Serv, 10 Ctr Dr,Clin Res Bldg 10, Bethesda, MD 20892 USA. EM merylw@.niddk.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU Intramural NIH HHS NR 107 TC 33 Z9 37 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-905X J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD JUL PY 2007 VL 2 SU 1 BP S47 EP S56 DI 10.2215/CJN.01060307 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 196MR UT WOS:000248487200008 PM 17699510 ER PT J AU Thapinta, D Jenkins, RA AF Thapinta, Darawan Jenkins, Richard A. TI Starting from scratch: Program development and lessons learned from HIV vaccine trial counseling in Thailand SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE HIV vaccine trials; risk reduction counseling; Thailand ID RISK BEHAVIOR; NORTHERN THAILAND; SOCIAL-ISSUES; VOLUNTEERS; PARTICIPATE; EFFICACY; INTERVENTIONS; PSYCHOTHERAPY; WILLINGNESS; PSYCHOLOGY AB Counseling for participants in preventive HIV vaccine trials has been an area of continuing concern because of the need to address possible behavioral side effects (e.g., increased risk behavior because trial participants believe they may have received an active, effective vaccine) and social harms (e.g., discrimination in health care or employment because of vaccine-induced scropositivity, on commercial HIV tests). Yet, the data on behavioral effects and social harms are limited and rather little detail has been provided regarding the counseling provided in current or past trials. This paper summarizes conceptual, cultural, and practical considerations in the development of a counseling program for HIV vaccine trials and provides examples from work done in the context of Phase I/II vaccine trials in Thailand. (c) 2006 Elsevier Inc. All rights reserved. C1 Chiang Mai Univ, Fac Nursing, Chang Mai, Thailand. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Jenkins, RA (reprint author), Natl Inst Drug Abuse, Prevent Res Branch, 6001 Execut Blvd,Rm 5185,MSC 9589, Bethesda, MD 20892 USA. EM jenkinsri@mail.nih.gov NR 75 TC 3 Z9 4 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JUL PY 2007 VL 28 IS 4 BP 409 EP 422 DI 10.1016/j.cct.2006.11.005 PG 14 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 178MD UT WOS:000247223900011 PM 17196444 ER PT J AU Resnik, DB Tinkle, SS AF Resnik, David B. Tinkle, Sally S. TI Ethical issues in clinical trials involving nanomedicine SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE nanomedicine; nanotechnology; ethics; clinical trials ID THERAPEUTIC MISCONCEPTION; ULTRAFINE PARTICLES; ANIMAL-MODELS; DRUG SAFETY; NANOTECHNOLOGY; RISKS; NANOTOXICOLOGY; CONSENT AB Nanomedicine shows tremendous promise for improving medical diagnosis, treatment, and prevention, but it also raises a variety of ethical concerns. Because of the paucity of data on the physicochemical properties of nanoscale materials in biological systems, clinical trials of nanomedicine products present some unique challenges related to risk minimization, management and communication involving human subjects. Although these clinical trials do not raise any truly novel ethical issues, the rapid development of nanotechnology and its potentially profound social and environmental impacts, add a sense of urgency to the problems that arise. (c) 2006 Elsevier Inc. All rights reserved. C1 NIEHS, Cellular Organ & Syst Pathobiol Branch, Div Extramural Res & Training, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, Cellular Organ & Syst Pathobiol Branch, Div Extramural Res & Training, NIH, Box 12233,Mail Drop NH06, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 45 TC 32 Z9 34 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JUL PY 2007 VL 28 IS 4 BP 433 EP 441 DI 10.1016/j.cct.2006.11.001 PG 9 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 178MD UT WOS:000247223900013 PM 17166777 ER PT J AU Wu, CQ Liu, AY AF Wu, Chengqing Liu, Aiyi TI An adaptive approach for bivariate phase II clinical trial designs SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE phase II clinical trials; adaptive design; bivariate binary endpoints; odds ratio; sample size recalculation AB In designing a phase II cancer clinical trial monitoring simultaneously the response and toxicity rate of a therapeutic agent, the odds ratio has to be specified. The false positive or Type I error rate, however, can be substantially inflated if the specified value is considerably larger than the true odds ratio. To overcome the sensitivity of the error rates to the odds ratio, an adaptive procedure is proposed which allows the sample size to be re-estimated based on observed odds ratio. Simulation results show that the procedure is robust against the odds ratio assumptions and controls effectively the Type I error rate. (c) 2007 Elsevier Inc. All rights reserved. C1 NICHHD, Biometry & Math Stat Branch, DESPR, DHHS, Rockville, MD 20852 USA. RP Liu, AY (reprint author), NICHHD, Biometry & Math Stat Branch, DESPR, DHHS, 6100 Execut Blvd, Rockville, MD 20852 USA. EM Liua@mail.nih.gov RI Poulopoulou, Stavroula/F-2952-2011; OI Liu, Aiyi/0000-0002-6618-5082 FU Intramural NIH HHS NR 8 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD JUL PY 2007 VL 28 IS 4 BP 482 EP 486 DI 10.1016/j.cct.2007.01.005 PG 5 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 178MD UT WOS:000247223900018 PM 17303476 ER PT J AU Shaheed, G Malkovska, V Mendoza, J Patel, M Rees, J Wesley, R Merryman, P Horne, M AF Shaheed, Gurvinder Malkovska, Vera Mendoza, Jose Patel, Mehool Rees, John Wesley, Robert Merryman, Paula Horne, McDonald TI PF4 ENHANCED assay for the diagnosis of heparin-induced thrombocytopenia in complex medical and surgical patients SO CRITICAL CARE MEDICINE LA English DT Article DE heparin; thrombocytopenia; enzyme-linked immunosorbent assay; diagnosis; sensitivity ID LINKED-IMMUNOSORBENT-ASSAY; PLATELET-AGGREGATION TEST; CLINICAL-SIGNIFICANCE; LABORATORY DIAGNOSIS; ANTIBODIES; MANAGEMENT; THROMBOSIS AB Objective: To evaluate the sensitivity and specificity of the PF4 ENHANCED (GTI Diagnostics, Waukesha, WI) enzyme-linked immunosorbent assay for heparin-induced thrombocytopenia using the carbon-14 serotonin-release assay as the reference method. Design: A total of 34 patients were prospectively enrolled with a variety of diagnoses and suspected heparin-induced thrombocytopenia. They were clinically scored and underwent testing with the C-14-serotonin-release assay. Enzyme-linked immunosorbent assay and C-14-serotonin-release assay results were also available from 21 medical and surgical patients who had previously been tested. Main Results: With the 14 C-serotonin-release assay as the reference method, the sensitivity and specificity of the enzyme-linked immunosorbent assay were 93% and 65%, respectively. There was only one false-negative enzyme-linked immunosorbent assay. The clinical scores were frequently misleading, largely because of difficulty excluding other causes of thrombocytopenia. Conclusion: Because of its high sensitivity, we believe the PF4 ENHANCED enzyme-linked immunosorbent assay should be used to identify heparin-induced thrombocytopenia in patients with multiple potential causes of thrombocytopenia, although false-positive results will not be uncommon. C1 Washington Hosp Ctr, Hematol Oncol Sect, Dept Med, Washington, DC 20010 USA. Washington Hosp Ctr, Sect Coagulat & Flow Cytometry, Dept Pathol, Washington, DC 20010 USA. NIH, Warren G Magnuson Clin Ctr, Biostat & Clin Epidemiol Serv, Off Director, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Hematol Serv, Dept Lab Med, Bethesda, MD 20892 USA. RP Horne, M (reprint author), Washington Hosp Ctr, Hematol Oncol Sect, Dept Med, Washington, DC 20010 USA. EM mhorne@mail.nih.gov FU Intramural NIH HHS NR 20 TC 16 Z9 16 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 JUL PY 2007 VL 35 IS 7 BP 1691 EP 1695 DI 10.1097/01.CCM.0000268057.62578.3A PG 5 WC Critical Care Medicine SC General & Internal Medicine GA 181GB UT WOS:000247424100010 PM 17507826 ER PT J AU Bassi, GL Zanella, A Curto, F Cressoni, M Kolobow, T AF Bassi, Gianluigi Li Zanella, Alberto Curto, Francesco Cressoni, Massimo Kolobow, Theodor TI Slurping at the inside - Do not forget to clean the outside too - Reply SO CRITICAL CARE MEDICINE LA English DT Letter ID TRACHEAL TUBE CUFF; MUCUS SLURPER C1 Osped Maggiore, UO Anesthesia & Rianimaz, I-20122 Milan, Italy. NIH, NHLBI, Bethesda, MD 20892 USA. Azienda Osped Niguarda Ca Granda, Milan, Italy. RP Bassi, GL (reprint author), Osped Maggiore, UO Anesthesia & Rianimaz, Via F Sforza 35, I-20122 Milan, Italy. RI Cressoni, Massimo/B-7315-2017 NR 5 TC 0 Z9 0 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 JUL PY 2007 VL 35 IS 7 BP 1803 EP 1804 DI 10.1097/01.CCM.0000269348.84357.DE PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 181GB UT WOS:000247424100048 ER PT J AU Wu, Y Beddall, MH Marsh, JW AF Wu, Yuntao Beddall, Margaret H. Marsh, Jon W. TI Rev-dependent indicator T cell line SO CURRENT HIV RESEARCH LA English DT Article DE reporter; HIV; Rev; GFP ID HUMAN-IMMUNODEFICIENCY-VIRUS; MONOCYTE-DERIVED MACROPHAGES; HIV-INFECTED CELLS; GENE-EXPRESSION; DENDRITIC CELLS; HTLV-III; TYPE-1; ACTIVATION; CCR5; STRAINS AB Measuring virion infectivity is critical for studying and monitoring the process of HIV-1 infection. The easiest and the most common method utilizes reporter cell lines based on the HIV LTR promoter. The early HIV gene product Tat amplifies expression from the LTR; however, there is a background transcriptional activity that is independent of Tat. Furthermore, LTR activity can be influenced by cellular activation states. We have recently constructed a Rev-dependent expression vector, and as a test of this construct's functionality, we have integrated this vector into a continuous T cell line. This novel indicator cell has no measurable background signal, is not affected by elevated metabolic states, and yet responds robustly to the presence of HIV. The line is able to complete TCID50 assays in 3-5 days, and appears sensitive to both CCR5- and CXCR4-utilizing viruses. C1 Natl Inst Mental Hlth, Sect Mol Virol, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. George Mason Univ, Natl Ctr Biodef & Infect Dis, Dept Mol & Microbiol, Manassas, VA USA. RP Marsh, JW (reprint author), Natl Inst Mental Hlth, Sect Mol Virol, Lab Cellular & Mol Regulat, Bldg 49,Room 5A60,49 Convent Dr,MSC 4483, Bethesda, MD 20892 USA. EM marshj@mail.nih.gov FU Intramural NIH HHS; NINDS NIH HHS [R21 NS051130-01A1, R21 NS051130-02, 5R21NS51130-2, R21 NS051130] NR 34 TC 19 Z9 19 U1 1 U2 4 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-162X J9 CURR HIV RES JI Curr. HIV Res. PD JUL PY 2007 VL 5 IS 4 BP 394 EP 402 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 191DZ UT WOS:000248111600003 PM 17627502 ER PT J AU Osei-Hyiaman, D AF Osei-Hyiaman, Douglas TI Endocannabinoid system in cancer cachexia SO CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE LA English DT Article DE appetite; cancer-cahexia; cannabinoids; CB1 receptor; lipogenesis ID LIPOPROTEIN LIPASE ACTIVITY; ELEMENT-BINDING PROTEIN-1; ADIPOCYTE DIFFERENTIATION; ADIPOSE-TISSUE; FOOD-INTAKE; MOLECULAR-MECHANISMS; CANNABINOIDS; EXPRESSION; ANOREXIA; LIPOGENESIS AB Purpose or review More than 60% advanced cancer patients suffer from anorexia and cahexia. This review focuses on the posssible mechanisms by which the endocannabinoid system antagonizes cachexia-anorexia processes in cancer patients and how it can be tapped for therapeutic applicatins. Recent findings Cannabinoids stimulate appetite and food intake. Hepatocytes express functional cannbinoid type 1 receptors, activation of which increases the expression of lipogenic genes (e.g those encoding sterol regulatory element binding protein 1c, acetyl-coenzyme A carboxylase-1, and fatty acid synthese in the liver and hypothalamus) and increase de-novo fatty acid synthesis, which contibutes to development of diet-induced obesity. Both ghrelin and cannabinoids stimulate AMP-activeated protein kinase in the hypothalamus, whereas they inhibit it in the liver and adipose tissues. Both anandamide and synthetic cannabinoid type 1 receptor agnoists such as HU210 and the plant-derived cannabinoid tetrahydro-cannbinol also significantly inhibit tumor necrosis factor-alpha Summary Cannabinoid type 1 receptor activation stimulates appetite and promotes lipogenesis and energy storage. Further study of cancer-cachexia pathophysiology and the role of endocannabinoids will help us to develop cannabinoids without psychotropic properties, which will help cancer patients suffering from cachexia and improve outcomes of clinical antitumor therapy. C1 NIAAA, Lab Physiol Studies, Sect NeuroEndocrinol, Div Intramural Clin & Biol Res,Natl Inst Hlth, Bethesda, MD 20892 USA. RP Osei-Hyiaman, D (reprint author), NIAAA, Lab Physiol Studies, Sect NeuroEndocrinol, Div Intramural Clin & Biol Res,Natl Inst Hlth, 5625 Fishers Lane MSC-9413,Room 2S18, Bethesda, MD 20892 USA. EM dhyiaman@gmail.com NR 45 TC 11 Z9 11 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1363-1950 J9 CURR OPIN CLIN NUTR JI Curr. Opin. Clin. Nutr. Metab. Care PD JUL PY 2007 VL 10 IS 4 BP 443 EP 448 DI 10.1097/MCO.0b013e3281900ecc PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 318HG UT WOS:000257081600010 PM 17563462 ER PT J AU Muniyappa, R Quon, MJ AF Muniyappa, Ranganath Quon, Michael J. TI Insulin action and insulin resistance in vascular endothelium SO CURRENT OPINION IN CLINICAL NUTRITION AND METABOLIC CARE LA English DT Article DE endothelial dysfunction; insulin resistance; metabolic syndrome; nitric oxide ID NITRIC-OXIDE SYNTHASE; TYPE-2 DIABETIC-PATIENTS; SPONTANEOUSLY HYPERTENSIVE-RATS; ACTIVATED PROTEIN-KINASE; GLYCATION END-PRODUCTS; C-REACTIVE PROTEIN; SKELETAL-MUSCLE; IN-VIVO; CAPILLARY RECRUITMENT; GLUCOSE-UPTAKE AB Purpose of review Vasodilator actions of insulin are mediated by phosphatidylinositol 3-kinase dependent insulin signaling pathways in endothelium, which stimulate production of nitric oxide. Insulin-stimulated nitric oxide mediates capillary recruitment, vasodilation, increased blood flow, and subsequent augmentaion of glucose disposal in skeletal muscle. Distinct mitogen-activated protein kinase dependent insulin signaling pathways regulate secretion of the vasoconstictor endothelin-1 from endothelium. These vascular actions of insulin contribute to the coupling of metabolic and hemodynamic homeostatis that occurs under healthy conditions. Insulin resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase dependent signaling in both metabolic and vascular insulin target tissues. Here we discuss consequences and therapeutic interventions targeting this selective impairment. Recent findings Shared causal factors such as glucotoxicity, lipotoxicity, and inflammation selectively impair phosphatidylinostitol 3-kinase dependent insulin signaling pathways, creating reciprocal relationships between insulin resistance and endothelial dysfunction. Diet, exercise, cardiovascular drugs, and insulin sensitizers simultaneously modulate phosphatidylinosito 3-kinase and mitogen-activated protein kinase dependent pathways, improving metabolic and vascular actions of insulin. Summary Pathwya-specific impairment in insulin action contributes to reciprocal relationships between endothelial dysfunction and insulin resistance, fostering clustering of metabolic and cardiovascular diseases in insulin-resistant states. Therapeutic interventions that target this selective impairment often simultaneously improve both metabolic and vascular function. C1 [Muniyappa, Ranganath; Quon, Michael J.] NCCAM, Diabet Unit, NIH, Bethesda, MD 20892 USA. RP Quon, MJ (reprint author), NCCAM, Diabet Unit, NIH, 10 Ctr Dr,Bldg 10,Room 6C-205, Bethesda, MD 20892 USA. EM quonm@nih.gov RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 FU Intramural NIH HHS NR 51 TC 80 Z9 81 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1363-1950 J9 CURR OPIN CLIN NUTR JI Curr. Opin. Clin. Nutr. Metab. Care PD JUL PY 2007 VL 10 IS 4 BP 523 EP 530 DI 10.1097/MCO.0b013e32819f8ecd PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 318HG UT WOS:000257081600022 PM 17563474 ER PT J AU Dunleavy, K Wilson, WH Jaffe, ES AF Dunleavy, Kieron Wilson, Wyndham H. Jaffe, Elaine S. TI Angioimmunoblastic T cell lymphoma: pathobiological insights and clinical implications SO CURRENT OPINION IN HEMATOLOGY LA English DT Article DE chemokines; Epstein-Barr virus; immunoregulation; peripheral T cell lymphoma; T cells ID EPSTEIN-BARR-VIRUS; ENDOTHELIAL GROWTH-FACTOR; ANGIO-IMMUNOBLASTIC LYMPHADENOPATHY; ACUTE MYELOID-LEUKEMIA; NON-HODGKINS-LYMPHOMA; B-CELL; GENE REARRANGEMENTS; FREE SURVIVAL; HELPER-CELLS; EXPRESSION AB Purpose of review Angioimmunoblastic T cell lymphoma is a complex lymphoproliferative disorder. While recent evidence suggests that the Epstein-Barr virus and B cell disregulation are implicated in the disease's pathogenesis, their mechanistic roles remain largely unknown. The prognosis with traditional chemotherapy has been poor, but improved understanding of the disease's pathobiology has led to several promising novel therapeutic strategies. Recent findings The recent finding of overexpression of the chemokine CXCL13 by the neoplastic cells of angioimmunoblastic T cell lymphoma suggests that it is derived from follicular helper T cells. In addition, gene-expression profiling has demonstrated overexpression of several genes characteristic of follicular helper T cells. Vascular endothelial growth factor-A is also highly expressed. Novel therapeutic strategies including immunomodulation with agents like cyclosporine and angiogenesis inhibition with drugs such as bevacizumab are being investigated, and show early promise in this disease. Summary Diseases such as angioimmunoblastic T cell lymphoma can help illuminate the biology of the normal immune system. Significant progress has been made in understanding the biology of angioimmunoblastic T cell lymphoma. This has paved the way for the development of new therapeutic strategies and these have shown interesting results. C1 NCI, Hematopathol Sect, CCR, Bethesda, MD 20892 USA. NCI, Pathol Lab, CCR, Bethesda, MD 20892 USA. NCI, Metab Branch, CCR, Bethesda, MD 20892 USA. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, CCR, 10 Room 2N202,10 Ctr Dr MSC-1500, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov NR 50 TC 50 Z9 61 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1065-6251 J9 CURR OPIN HEMATOL JI Curr. Opin. Hematol. PD JUL PY 2007 VL 14 IS 4 BP 348 EP 353 DI 10.1097/MOH.0b013e328186ffbf PG 6 WC Hematology SC Hematology GA 177PA UT WOS:000247163800007 PM 17534160 ER PT J AU Merikangas, KR Kalaydjian, A AF Merikangas, Kathleen R. Kalaydjian, Amanda TI Magnitude and impact of comorbidity of mental disorders from epidemiologic surveys SO CURRENT OPINION IN PSYCHIATRY LA English DT Article DE community surveys; comorbidity; epidemiology; mental disorders ID SUBSTANCE USE DISORDERS; ANXIETY DISORDERS; BIPOLAR DISORDER; HEALTH SURVEY; CO-MORBIDITY; DSM-IV; EATING-DISORDERS; PREVALENCE; DEPRESSION; ALCOHOL AB Purpose of review To consider comorbidity across multiple classes of disorders in data derived from recent large scale community surveys. Recent findings There has been substantial recent progress in our understanding of patterns and implications of comorbidity of mental disorders. There is now converging evidence on the magnitude and specific patterns of comorbidity in international studies worldwide. There is increasing recognition of comorbidity of mental and physical disorders. Comorbidity of mental disorders and substance abuse has now been recognized universally, and the results of treatment and prevention studies incorporating comorbidity are now beginning to emerge. Summary Comorbidity has been shown to be an index of more severe course and outcome of mental disorders. Systematic inclusion of comorbidity into clinical evaluation and treatment will enhance the effectiveness of intervention with these conditions. Prevention of the development of secondary conditions as a consequence of primary disorders should reduce the impact of these conditions on both the individual and society. C1 NIMH, Intramural Res Program, Bethesda, MD 20892 USA. RP Merikangas, KR (reprint author), NIMH, Intramural Res Program, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM kathleen.merikangas@nih.gov NR 39 TC 50 Z9 50 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7367 J9 CURR OPIN PSYCHIATR JI Curr. Opin. Psychiatr. PD JUL PY 2007 VL 20 IS 4 BP 353 EP 358 DI 10.1097/YCO.0b013e3281c61dc5 PG 6 WC Psychiatry SC Psychiatry GA 186IR UT WOS:000247772900008 PM 17551350 ER PT J AU Alt, C Harrison, T Fujita, N Shew, K Tran, T Matsukawa, A Litterst, C Mirsalis, J D'Andrea, A AF Alt, Carsten Harrison, Travis Fujita, Nahoko Shew, Kenneth Tran, Thuy Matsukawa, Akihiro Litterst, Charles Mirsalis, Jon D'Andrea, Annalisa TI CCL2/monocyte-chemoattractant protein-1 as a novel biomarker for the safety evaluation of microbicide-induced vaginal irritation SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Alt, Carsten; Harrison, Travis; Fujita, Nahoko; Shew, Kenneth; Tran, Thuy; Mirsalis, Jon; D'Andrea, Annalisa] SRI Int, Biosci Div, Menlo Pk, CA 94025 USA. [Matsukawa, Akihiro] Okayama Univ, Dept Pathol & Expt Med, Okayama, Japan. [Matsukawa, Akihiro] NIAID, Div Aids, Bethesda, MD 20892 USA. RI D'Andrea, Annalisa/F-9836-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 4 BP 1 EP 2 DI 10.1016/j.cyto.2007.07.009 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500005 ER PT J AU Cataliamo, M Di Mascio, M Tagaya, Y Sriniasula, S Thaker, V Adelsberger, J Rupert, A Baseler, M Roby, G Rehm, C Lane, C AF Cataliamo, Marta Di Mascio, Michele Tagaya, Yutaka Sriniasula, Sharat Thaker, V. Adelsberger, Joseph Rupert, Adam Baseler, Michael Roby, Gregg Rehm, Catherine Lane, Clifford TI HIV infection leads to increased immune activation by 2 distinct pathways that differentially affect CD4 and CD8 T cells SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Cataliamo, Marta; Di Mascio, Michele; Sriniasula, Sharat; Thaker, V.; Adelsberger, Joseph; Rupert, Adam; Roby, Gregg; Rehm, Catherine; Lane, Clifford] NIAID, CMRS, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Tagaya, Yutaka] NCI, Metab Branch, CCR, NIH, Bethesda, MD 20892 USA. [Adelsberger, Joseph; Rupert, Adam; Baseler, Michael] Sci Applicat Int Corp, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 16 BP 5 EP 5 DI 10.1016/j.cyto.2007.07.021 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500017 ER PT J AU Chen, J Petrus, M Bryant, B Nguyen, VP Starner, M Goldman, C Bamford, R Morris, JC Janik, JE Waldmarm, TA AF Chen, Jing Petrus, Mike Bryant, Bonita Nguyen, Vinh Phue Starner, Mindy Goldman, Carolyn Bamford, Richard Morris, John C. Janik, John E. Waldmarm, Thomas A. TI Induction of the IL-9 gene by HTLV-I tax stimulates the spontaneous proliferation of primary ATL cells by a paracrine mechanism SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Chen, Jing; Petrus, Mike; Bryant, Bonita; Nguyen, Vinh Phue; Starner, Mindy; Goldman, Carolyn; Morris, John C.; Janik, John E.; Waldmarm, Thomas A.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Bamford, Richard; Waldmarm, Thomas A.] Transponics, Mt Wolf, PA 17437 USA. NR 0 TC 3 Z9 5 U1 2 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 18 BP 5 EP 6 DI 10.1016/j.cyto.2007.07.023 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500019 ER PT J AU Durum, SK Warming, S Lawrence, SM Ishii, M Abshari, M Feigenbaum, L Washington, AV Warner, AC Sims, DJ Li, WQ Hixon, JA Gray, DHD Rich, BE Morrow, M Anver, MR Cherry, J Naf, D Sternberg, LR MeVicar, DW Farr, AG Germain, RN Rogers, K Copeland, NG Mazzucchelli, R AF Durum, Scott K. Warming, Soren Lawrence, Scott M. Ishii, Masaru Abshari, Mehrnoosh Feigenbaum, Lionel Washington, A. Valance Warner, Andrew C. Sims, David J. Li, Wen Qing Hixon, Julie A. Gray, Daniel H. D. Rich, Benjamin E. Morrow, Matthew Anver, Miriam R. Cherry, James Naf, Dieter Sternberg, Lawrence R. MeVicar, Daniel W. Farr, Andrew G. Germain, Ronald N. Rogers, Keith Copeland, Neal G. Mazzucchelli, Renata TI Visualization and identification of IL-7 producing cells SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Durum, Scott K.; Li, Wen Qing; Hixon, Julie A.; Mazzucchelli, Renata] NCI, Natl Inst Hlth, Ctr & Inflammat Program, Mol Immunoregulat Lab, Frederick, MD 21701 USA. [Warming, Soren] SAIC, LASP, Pathol Histotechnol Lab, Frederick, MD USA. [Lawrence, Scott M.; Rogers, Keith] NIAID, NIH, Immunol Lab, Lymphocyte Biol Sect, Bethesda, MD 20892 USA. [Ishii, Masaru; Germain, Ronald N.] NCI, Ctr Canc Res, SAIC, Lab Anim Sci Program, Frederick, MD 21701 USA. [Abshari, Mehrnoosh] Natl Canc Inst, Mol Pathol Lab PHL, SAIC Frederick, Frederick, MD USA. [Feigenbaum, Lionel] SAIC Frederick, AMDL, LASP, Frederick, MD USA. [Washington, A. Valance] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Warner, Andrew C.; Sternberg, Lawrence R.] NCI, Canc Res Ctr, Vaccine Branch, Human Retrovirus Sect, Frederick, MD USA. [Sims, David J.; Naf, Dieter] NCI Frederick, SAIC Frederick Inc, Gene Express lab, Frederick, MD USA. [Gray, Daniel H. D.] NCI, Natl Inst Hlth, Canc Res Ctr, Expt Immunol Lab, Frederick, MD 21701 USA. [Rich, Benjamin E.] Univ Washington, Dept Immunol, Seattle, WA 98195 USA. [Morrow, Matthew] Biopolis Dr Proteos, Singapore, Singapore. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 33 BP 9 EP 10 DI 10.1016/j.cyto.2007.07.038 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500034 ER PT J AU Hansen, AM Rachitskya, A Horai, R Caspi, RR AF Hansen, Anna M. Rachitskya, Aleksandra Horai, Raiko Caspi, Rachel R. TI NKT cells constitutively express IL-23 receptor and can rapidly produce IL-17 independently of IL-6 following IL-23 or T cell receptor ligation SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Hansen, Anna M.; Rachitskya, Aleksandra; Horai, Raiko; Caspi, Rachel R.] NIH, NEI, Immunol Lab, Bethesda, MD 20892 USA. [Rachitskya, Aleksandra] HHMI NIH Res Scholars Program, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 49 BP 14 EP 14 DI 10.1016/j.cyto.2007.07.054 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500050 ER PT J AU Hodge, DL Berthet, C Subleski, J Pascal, V Bere, W Chen, X Buschman, M Wolfe, T Young, HA AF Hodge, Deborah L. Berthet, Cyril Subleski, Jeff Pascal, Veronique Bere, William Chen, Xin Buschman, Matthew Wolfe, Thomas Young, Howard A. TI Challenging evolution: eliminating the IFN-gamma 3 ARE effects T cell homenstasis SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Hodge, Deborah L.; Berthet, Cyril; Subleski, Jeff; Pascal, Veronique; Bere, William; Chen, Xin; Buschman, Matthew; Wolfe, Thomas; Young, Howard A.] Natl Canc Inst, Ctr Canc Res, Expt Immunol Lab, Ft Detrick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 54 BP 15 EP 16 DI 10.1016/j.cyto.2007.07.059 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500055 ER PT J AU Howard, OMZ Oppenheim, JJ Chen, X AF Howard, O. M. Zack Oppenheim, Joost J. Chen, Xin TI Biological regulators of CD4+CD25+FOXP3+regulatory T-cells SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Howard, O. M. Zack; Oppenheim, Joost J.] Canc Res Ctr, Natl Canc Inst, Natl Inst Hlth, Mol Immunoregulat Canc & Inflammat Program, Bethesda, MD 20892 USA. [Chen, Xin] SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. RI Howard, O M Zack/B-6117-2012; Chen, Xin/I-6601-2015 OI Howard, O M Zack/0000-0002-0505-7052; Chen, Xin/0000-0002-2628-4027 NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 56 BP 16 EP 16 DI 10.1016/j.cyto.2007.07.061 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500057 ER PT J AU Ishida, Y Gao, JL Murphy, PM AF Ishida, Yuko Gao, Ji-Liang Murphy, Philip M. TI Regulation of skin wound healing by chemokine receptor CX3CR1 in mice SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Ishida, Yuko; Gao, Ji-Liang; Murphy, Philip M.] Natl Inst Hlth, NIAID, Lab Mol Immunol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 61 BP 17 EP 17 DI 10.1016/j.cyto.2007.07.066 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500062 ER PT J AU Ju, W Zhang, M Chen, J Thomas, CJ Waldmann, TA AF Ju, Wei Zhang, Meili Chen, Jing Thomas, Craig J. Waldmann, Thomas A. TI The drug CP690550 inhibits the JAK3/STAT5 pathway in vitro and in vivo SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Ju, Wei; Zhang, Meili; Chen, Jing; Waldmann, Thomas A.] Ctr Canc Res, Natl Canc Inst, NIH, Metab Branch, Bethesda, MD 20892 USA. [Thomas, Craig J.] NIDDK, NIH, Chem Biol Core Facil, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 67 BP 19 EP 19 DI 10.1016/j.cyto.2007.07.072 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500068 ER PT J AU Kim, HP Leonard, WJ AF Kim, Hyoung-Pyo Leonard, Warren J. TI CREB/ATF-Dependent T-cell receptor-induced FoxP3 gene expression: A role for DNA methylation SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Kim, Hyoung-Pyo; Leonard, Warren J.] NHLBI, Natl Inst Hlth, Lab Mol Immunol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 73 BP 20 EP 21 DI 10.1016/j.cyto.2007.07.078 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500074 ER PT J AU Kim, JY Anderson, ED Ozato, K AF Kim, Ji Young Anderson, Eric David Ozato, Keiko TI Proteomic approach to identifying ubiquitinated nuclear proteins in stimulated macrophages SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Kim, Ji Young; Ozato, Keiko] NICHHD, NIH, Bethesda, MD 20892 USA. [Anderson, Eric David] NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 74 BP 21 EP 21 DI 10.1016/j.cyto.2007.07.079 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500075 ER PT J AU Kramer, JM Hanel, W Shen, F Isik, N Malone, JP Maitra, A Sigurdson, W Swart, D Tocker, J Jin, T Gaffen, SL AF Kramer, Jill M. Hanel, Walter Shen, Fang Isik, Nilgun Malone, James P. Maitra, Amarnath Sigurdson, Wade Swart, David Tocker, Joel Jin, Tian Gaffen, Sarah L. TI Dissecting the IL-17 receptor: Identification of a pre-ligand assembly domain (PLAD) and ligand binding site in IL-17RA SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Kramer, Jill M.; Hanel, Walter; Shen, Fang; Malone, James P.; Maitra, Amarnath; Gaffen, Sarah L.] SUNY Buffalo, Dept Oral Biol, Buffalo, NY USA. [Gaffen, Sarah L.] SUNY Buffalo, Dept Microbiol & Immunol, Buffalo, NY USA. [Sigurdson, Wade] SUNY Buffalo, Confocal Microscope Facil, Buffalo, NY USA. [Isik, Nilgun; Jin, Tian] NIAID, Immunogenet Lab, Rockville, MD USA. [Swart, David; Tocker, Joel] Amgen Inc, Dept Inflammat Res, Seattle, WA USA. RI Gaffen, Sarah/B-1560-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 78 BP 22 EP 22 DI 10.1016/j.cyto.2007.07.083 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500079 ER PT J AU Liu, Y Perruche, S Li, J Kulkarni, A Deng, C Chen, W AF Liu, Yongzhon Perruche, Sylvain Li, Jun Kulkarni, Ashok Deng, Chuxia Chen, WanJun TI Differential requirement of TGF-beta receptor I and smad4 in T cells in response to TGF-beta signaling in vivo SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Liu, Yongzhon; Perruche, Sylvain; Li, Jun; Chen, WanJun] NIH, OIIB, Mucosal Immun Unit, Bethesda, MD 20892 USA. [Kulkarni, Ashok] NIH, NIDCR, CDBRB, Bethesda, MD 20892 USA. [Deng, Chuxia] NIH, NIDDK, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 0 TC 2 Z9 2 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 91 BP 25 EP 25 DI 10.1016/j.cyto.2007.07.096 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500092 ER PT J AU Luger, D Silver, PB Tang, J Cua, D Chen, Z Iwakura, Y Bowman, EP Sgambellone, N Chan, CC Caspi, RR AF Luger, Dror Silver, Phyllis B. Tang, Jun Cua, Daniel Chen, Zoe Iwakura, Yoichiro Bowman, Edward P. Sgambellone, Nicole Chan, Chi-Chao Caspi, Rachel R. TI Essential role for IL-23 but not for the Th17 effector response in pathogenesis of experimental ocular autoimmunity SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Luger, Dror; Silver, Phyllis B.; Tang, Jun; Caspi, Rachel R.] Univ Tokyo, Tokyo, Japan. [Cua, Daniel; Chen, Zoe; Bowman, Edward P.; Sgambellone, Nicole] DNAX Palo Alto, Palo Alto, CA USA. [Iwakura, Yoichiro] NIH, NEI, Immunol Lab, Bethesda, MD USA. RI Iwakura, Yoichiro/E-5457-2011 OI Iwakura, Yoichiro/0000-0002-9934-5775 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 93 BP 26 EP 26 DI 10.1016/j.cyto.2007.07.098 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500094 ER PT J AU Nurieva, R Yang, XO Martinez, G Zhang, Y Panopoulos, AD Ma, L Schluns, K Tian, Q Watowich, SS Jetten, AM Dong, C AF Nurieva, Roza Yang, Xuexian O. Martinez, Gustavo Zhang, Yongliang Panopoulos, Athanasia D. Ma, Li Schluns, Kimberly Tian, Qiang Watowich, Stephanie S. Jetten, Anton M. Dong, Chen TI Essential autocrine regulation by IL-21 in the generation of inflammatory T cells SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Nurieva, Roza; Yang, Xuexian O.; Martinez, Gustavo; Zhang, Yongliang; Panopoulos, Athanasia D.; Schluns, Kimberly; Watowich, Stephanie S.; Dong, Chen] Univ Texas, MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77030 USA. [Ma, Li; Tian, Qiang] Inst Syst Biol, Seattle, WA 98103 USA. [Jetten, Anton M.] NIEHS, NIH, LRB, Cell Biol Sect, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 112 BP 31 EP 31 DI 10.1016/j.cyto.2007.07.117 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500113 ER PT J AU Park, JH Adoro, S Lucas, PJ Sarafova, SD Alag, A Doan, LL Erman, B Liu, X Ellmeier, W Bosselut, R Feigenbaum, L Singer, A AF Park, Jung-Hyun Adoro, Stanley Lucas, Philip J. Sarafova, Sophia D. Alag, Amala Doan, Loretta L. Erman, Batu Liu, Xiaolong Ellmeier, Wilfried Bosselut, Remy Feigenbaum, Lionel Singer, Alfred TI Coreceptor tuning: IL-7 signals transcriptionally tailor CD8 coreceptor expression in CD8 T cells to the self-specificity of their TCR SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Park, Jung-Hyun; Adoro, Stanley; Sarafova, Sophia D.; Alag, Amala; Doan, Loretta L.; Singer, Alfred] NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. [Lucas, Philip J.] NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Erman, Batu] Sabanci Univ, Fac Engn & Nat Sci, Biol Sci & Bioengn Program, Istanbul, Turkey. [Liu, Xiaolong; Bosselut, Remy] NCI, NIH, Immune Cell Biol Branch, Bethesda, MD 20892 USA. [Ellmeier, Wilfried] Med Univ Vienna, Inst Immunol, Vienna, Austria. [Feigenbaum, Lionel] NCI, Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD USA. [Adoro, Stanley] Univ Penn, Immunol Grad Grp, Philadelphia, PA 19104 USA. NR 0 TC 7 Z9 7 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 118 BP 32 EP 32 DI 10.1016/j.cyto.2007.07.123 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500119 ER PT J AU Round, JL Humphries, LA Tommasian, T Mittelstadt, P Zhang, M Micelil, MC AF Round, J. L. Humphries, L. A. Tommasian, T. Mittelstadt, P. Zhang, M. Micelil, M. C. TI MAGUK family member Dlgh1 coordinates TCR-dependent p38 activation, specifically linking TCR engagement to activation of NFAT but not NF-kappa B SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Round, J. L.; Humphries, L. A.; Zhang, M.; Micelil, M. C.] Univ Calif Los Angeles, Los Angeles, CA 90066 USA. [Tommasian, T.; Micelil, M. C.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90066 USA. [Mittelstadt, P.; Micelil, M. C.] NCI, Ctr Canc Res, Lab Immune Cell Biol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 130 BP 36 EP 36 DI 10.1016/j.cyto.2007.07.135 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500131 ER PT J AU Sa-Nunes, A Bafica, A Lucas, DA Conrads, TP Veenstra, TD Andersen, JF Mather, TN Ribeiro, JMC Francischetti, IMB AF Sa-Nunes, Anderson Bafica, Andre Lucas, David A. Conrads, Thomas P. Veenstra, Timothy D. Andersen, John F. Mather, Thomas N. Ribeiro, Jose M. C. Francischetti, Ivo M. B. TI Prostaglandin E-2 is a major inhibitor of dendritic cell maturation and function in Ixodes scapularis saliva SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Sa-Nunes, Anderson; Andersen, John F.; Ribeiro, Jose M. C.; Francischetti, Ivo M. B.] NIAID, NIH, Lab Malaria & Vector Res, Sect Vector Biol, Rockville, MD USA. [Bafica, Andre] NIAID, NIH, Parasit Dis Lab, Immunol Sect, Bethesda, MD 20892 USA. [Lucas, David A.] Univ Fed Santa Catarina, Dept Microbiol & Parasitol, Div Immunol, Florianopolis, SC, Brazil. [Lucas, David A.; Conrads, Thomas P.; Veenstra, Timothy D.] SAIC Frederick Inc, NCI, NIH, Lab Proteom & Analyt Technol, Frederick, MD USA. [Lucas, David A.] Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA USA. [Conrads, Thomas P.] Univ Pittsburgh, Hillman Canc Ctr, Inst Canc, Pittsburgh, PA USA. [Mather, Thomas N.] Univ Rhode Isl, Ctr Vector Borne Dis, Kingston, RI 02881 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 133 BP 37 EP 37 DI 10.1016/j.cyto.2007.07.138 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500134 ER PT J AU Sato, N Waldmann, TA Tagaya, Y AF Sato, Noriko Waldmann, Thomas A. Tagaya, Yutaka TI Accessory cells enable cytokine response of naive T cells through cellular contact without antigen SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Sato, Noriko; Waldmann, Thomas A.; Tagaya, Yutaka] NCI, NIH, Med Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 134 BP 37 EP 37 DI 10.1016/j.cyto.2007.07.140 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500135 ER PT J AU Simon, A Maddipatti, R Park, H Komarow, H Kastner, DL Siegel, RM AF Simon, Anna Maddipatti, Ravikanth Park, Heiyoung Komarow, Hirsh Kastner, Daniel L. Siegel, Richard M. TI Mutated TNF-receptor type 1 in TNF-receptor associated periodic syndrome (TRAPS): TNF-independent hyper-responsiveness through ER-retained, misfolded receptors SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Simon, Anna; Kastner, Daniel L.] NIAMSD, NIH, Genom Branch, Bethesda, MD 20892 USA. [Maddipatti, Ravikanth; Park, Heiyoung; Komarow, Hirsh; Siegel, Richard M.] NIAMSD, NIH, Autoimmun Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 141 BP 39 EP 39 DI 10.1016/j.cyto.2007.07.146 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500142 ER PT J AU Stumhofer, JS Silver, J Laurence, A Porrett, PM Turka, LA Ernst, M Saris, CJM O'Shea, JJ Hunter, CA AF Stumhofer, Jason S. Silver, Jonathan Laurence, Arian Porrett, Paige M. Turka, Laurence A. Ernst, Matthias Saris, Christiaan J. M. O'Shea, John J. Hunter, Christopher A. TI A central role for interleukin 27 and IL-6 mediated activation of STAT3 in T cell production of IL-10 SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Stumhofer, Jason S.; Silver, Jonathan; Hunter, Christopher A.] Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. [Laurence, Arian; O'Shea, John J.] NIAMSD, NIH, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Porrett, Paige M.; Turka, Laurence A.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Ernst, Matthias] Ludwig Inst Canc Res, Parkville, Vic 3050, Australia. [Saris, Christiaan J. M.] Amgen Inc, Dept Inflammat Res, Newbury Pk, CA 91320 USA. RI Laurence, Arian/A-8770-2009; Ernst, Matthias/D-5111-2012 OI Laurence, Arian/0000-0003-0942-8292; NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 146 BP 40 EP 41 DI 10.1016/j.cyto.2007.07.151 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500147 ER PT J AU Tsuno, T Mejido, J Schmeisser, H Fey, S Morrow, A Nie, H Zhao, T Bekisz, J Goldman, N Zoon, K AF Tsuno, Takaya Mejido, Josef Schmeisser, Hana Fey, Samuel Morrow, Angel Nie, Huiqin Zhao, Tongmao Bekisz, Joseph Goldman, Neil Zoon, Kathryn TI Synthesis of IRF-9 is important in the antiproliferative response to IFN-alpha in Jak-Stat signaling pathway of OVCAR3 cells SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Tsuno, Takaya; Mejido, Josef; Schmeisser, Hana; Fey, Samuel; Morrow, Angel; Nie, Huiqin; Zhao, Tongmao; Bekisz, Joseph; Goldman, Neil; Zoon, Kathryn] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 155 BP 43 EP 43 DI 10.1016/j.cyto.2007.07.160 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500156 ER PT J AU van Panhuy, N Scarlet, D Camberis, M Roberts, J Prout, M Tang, SC Li, JH Min, B Paul, W Le Gros, G AF van Panhuy, Nicholas Scarlet, Debbie Camberis, Mali Roberts, Joanna Prout, Melanie Tang, Schiau-Choot Li, Jane Hu Min, Booki Paul, William Le Gros, Graham TI Rewriting the paradigm for IL4/STAT6 and th2 differentiation. New rules for in vivo commitment SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 Malaghan Inst Med Res, Wellington, New Zealand. Cleveland Clin, Cleveland, OH 44106 USA. NIAID, NIH, Immunol Lab, Bethesda, MD 20892 USA. RI Le Gros, Graham/C-6725-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 159 BP 44 EP 44 DI 10.1016/j.cyto.2007.07.164 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500160 ER PT J AU Vivekanandhan, A Klinman, DM AF Vivekanandhan, Aravindhan Klinman, Dennis M. TI Contribution of MPAK and NF-kB signaling to TLR mediated MCP-1 secretion SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Vivekanandhan, Aravindhan; Klinman, Dennis M.] Natl Canc Inst, Expt Immunol Lab, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 162 BP 45 EP 45 DI 10.1016/j.cyto.2007.07.167 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500163 ER PT J AU Zarember, KA DeLeo, FR Whitney, AR Shoffner, AR Dorward, DW Gallin, JI Holland, SM Greenberg, DE AF Zarember, Kol A. DeLeo, Frank R. Whitney, Addie R. Shoffner, Adam R. Dorward, David W. Gallin, John I. Holland, Steven M. Greenberg, David E. TI Comparatively diminished cytokine and superoxide induction by the emerging pathogen Granulibacter bethesdensis: Implications for pathogenesis SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Zarember, Kol A.; Gallin, John I.] NIAID, NIH, Host Def Lab, Bethesda, MD 20892 USA. [DeLeo, Frank R.; Whitney, Addie R.] NIAID, NIH, Rocky Mt Labs, Lab Human Bacterial Pathogenes, Hamilton, MT 59840 USA. [Shoffner, Adam R.; Holland, Steven M.; Greenberg, David E.] NIAID, NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Dorward, David W.] Res Technol Branch, Hamilton, MT USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 172 BP 47 EP 48 DI 10.1016/j.cyto.2007.07.177 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500173 ER PT J AU Zeng, R Spolski, R Casas, E Zhu, W Levy, DE Leonard, WJ AF Zeng, Rong Spolski, Rosanne Casas, Esther Zhu, Wei Levy, David E. Leonard, Warren J. TI Multiple signaling pathways are involved in IL-21-mediated proliferation SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Zeng, Rong; Spolski, Rosanne; Leonard, Warren J.] NHLBI, NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. [Casas, Esther; Levy, David E.] NYU, Sch Med, Dept Pathol, New York, NY USA. [Casas, Esther; Zhu, Wei; Levy, David E.] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 174 BP 48 EP 48 DI 10.1016/j.cyto.2007.07.179 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500175 ER PT J AU Zhou, L Ivanov, II Spolski, R Min, R Shenderov, K Egawa, T Levy, DE Leonard, WJ Littman, DR AF Zhou, Liang Ivanov, Ivaylo I. Spolski, Rosanne Min, Roy Shenderov, Kevin Egawa, Takeshi Levy, David E. Leonard, Warren J. Littman, Dan R. TI IL-6 programs TH-17 cell differentiation by promoting the sequential engagement of the IL-21 and IL-23 pathways SO CYTOKINE LA English DT Meeting Abstract CT 15th Annual Meeting of the International-Cytokine-Society CY OCT 26-30, 2007 CL San Francisco, CA SP Int Cytokine Soc C1 [Zhou, Liang; Ivanov, Ivaylo I.; Min, Roy; Shenderov, Kevin; Egawa, Takeshi; Littman, Dan R.] NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst, New York, NY USA. [Min, Roy; Littman, Dan R.] NYU, Sch Med, Howard Hughes Med Inst, New York, NY USA. [Levy, David E.; Littman, Dan R.] NYU, Sch Med, Dept Pathol, New York, NY USA. [Levy, David E.; Littman, Dan R.] NYU, Sch Med, Dept Microbiol, New York, NY USA. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD JUL PY 2007 VL 39 IS 1 MA 176 BP 49 EP 49 DI 10.1016/j.cyto.2007.07.181 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 224BV UT WOS:000250421500177 ER PT J AU Que, J Okubo, T Goldenring, JR Nam, KT Kurotani, R Morrisey, EE Taranova, O Pevny, LH Hogan, BLM AF Que, Jianwen Okubo, Tadashi Goldenring, James R. Nam, Ki-Taek Kurotani, Reiko Morrisey, Edward E. Taranova, Olena Pevny, Larysa H. Hogan, Brigid L. M. TI Multiple dose-dependent roles for Sox2 in the patterning and differentiation of anterior foregut endoderm SO DEVELOPMENT LA English DT Article DE Sox2; Nkx2.1; p63; mouse embryo; mutant; foregut development; tracheoesophageal fistula; metaplasia ID EPITHELIAL-MESENCHYMAL INTERACTIONS; GASTROINTESTINAL-TRACT; CHICKEN-EMBRYO; TRANSCRIPTIONAL REGULATION; MOLECULAR-MECHANISMS; STOMACH DEVELOPMENT; CELL-PROLIFERATION; LUNG MORPHOGENESIS; BARRETTS-ESOPHAGUS; CAUSE ANOPHTHALMIA AB Sox2 is expressed in developing foregut endoderm, with highest levels in the future esophagus and anterior stomach. By contrast, Nkx2.1 (Titf1) is expressed ventrally, in the future trachea. In humans, heterozygosity for SOX2 is associated with anopthalmia-esophageal-genital syndrome (OMIM 600992), a condition including esophageal atresia (EA) and tracheoesophageal fistula (TEF), in which the trachea and esophagus fail to separate. Mouse embryos heterozygous for the null allele, Sox2(EGFP), appear normal. However, further reductions in Sox2, using Sox2(LP) and Sox2(COND) hypomorphic alleles, result in multiple abnormalities. Approximately 60% of Sox2(EGFP/COND) embryos have EA with distal TEF in which Sox2 is undetectable by immunohistochemistry or western blot. The mutant esophagus morphologically resembles the trachea, with ectopic expression of Nkx2.1, a columnar, ciliated epithelium, and very few p63(+) basal cells. By contrast, the abnormal foregut of Nkx2.1-null embryos expresses elevated Sox2 and p63, suggesting reciprocal regulation of Sox2 and Nkx2.1 during early dorsal/ventral foregut patterning. Organ culture experiments further suggest that FGF signaling from the ventral mesenchyme regulates Sox2 expression in the endoderm. In the 40% Sox2(EGFP/COND) embryos in which Sox2 levels are similar to 18% of wild type there is no TEF. However, the esophagus is still abnormal, with luminal mucus-producing cells, fewer p63(+) cells, and ectopic expression of genes normally expressed in glandular stomach and intestine. In all hypomorphic embryos the forestomach has an abnormal phenotype, with reduced keratinization, ectopic mucus cells and columnar epithelium. These findings suggest that Sox2 plays a second role in establishing the boundary between the keratinized, squamous esophagus/forestomach and glandular hindstomach. C1 Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. Vanderbilt Univ, Med Ctr, Nashville VA Med Ctr, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Surg, Nashville, TN 37232 USA. Vanderbilt Univ, Med Ctr, Dept Cell & Dev Biol, Nashville, TN 37232 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. Univ N Carolina, Dept Genet, Ctr Neurosci, Chapel Hill, NC 27599 USA. RP Hogan, BLM (reprint author), Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. EM b.hogan@cellbio.duke.edu FU Intramural NIH HHS; NHLBI NIH HHS [HL071303, R01 HL071303, R37 HL071303]; NIDDK NIH HHS [K99 DK082650, R00 DK082650]; NIMH NIH HHS [MH 641798-01] NR 47 TC 208 Z9 211 U1 0 U2 9 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD JUL 1 PY 2007 VL 134 IS 13 BP 2521 EP 2531 DI 10.1242/dev.003855 PG 11 WC Developmental Biology SC Developmental Biology GA 193WN UT WOS:000248306000014 PM 17522155 ER PT J AU Keller, MJ Chitnis, AB AF Keller, Michael J. Chitnis, Ajay B. TI Insights into the evolutionary history of the vertebrate zic3 locus from a teleost-specific zic6 gene in the zebrafish, Danio rerio SO DEVELOPMENT GENES AND EVOLUTION LA English DT Article DE fishes; zic; evolution; gene expression; synteny ID GLI PROTEINS; CONSERVATION; PATTERN; FAMILY AB The Zic gene family of zinc-finger transcription factors includes five orthologues, zic1-5, that are common to the Euteleostian vertebrates (fish, frogs, birds, and mammals). The Zic genes have been implicated as regulators of a number of critical developmental processes, including neurulation, neuronal differentiation, neural crest specification, the establishment of left-right asymmetry, and regulation of cell proliferation. The different Zic genes encode proteins that are expressed in broadly overlapping spatial domains, have conserved DNA-binding domains that recognize a common motif, are capable of physical interactions, and can co-regulate one another's transcription. Thus, the transcriptional regulation of individual proteins and their effects on downstream targets must be assessed within the context of co-expression with other family members. We describe a novel gene, zic6, that is specific to the teleost fishes and lacks the lateral and rostral expression domains typical of the other Zic family members. We present evidence that zic6 is an ancestral locus arising by chromosomal duplication early in the Euteleostomi that was subsequently lost in the terrestrial vertebrates. C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Keller, MJ (reprint author), NICHD, Mol Genet Lab, NIH, 6 Ctr Dr,6B-3B315, Bethesda, MD 20892 USA. EM kellermi@mail.nih.gov NR 15 TC 8 Z9 8 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0949-944X J9 DEV GENES EVOL JI Dev. Genes Evol. PD JUL PY 2007 VL 217 IS 7 BP 541 EP 547 DI 10.1007/s00427-007-0161-4 PG 7 WC Cell Biology; Evolutionary Biology; Developmental Biology SC Cell Biology; Evolutionary Biology; Developmental Biology GA 191ZD UT WOS:000248169600005 PM 17503076 ER PT J AU Puligilla, C Feng, F Ishikawa, K Bertuzzi, S Dabdoub, A Griffith, AJ Fritzsch, B Kelley, MW AF Puligilla, Chandrakala Feng, Feng Ishikawa, Kotaro Bertuzzi, Stefano Dabdoub, Alain Griffith, Andrew J. Fritzsch, Bernd Kelley, Matthew W. TI Disruption of Fibroblast growth factor receptor 3 signaling results in defects in cellular differentiation, neuronal patterning, and hearing impairment SO DEVELOPMENTAL DYNAMICS LA English DT Article DE hair cell; cochlea; BMP4; Prox1; innervation; Deiters' cells; Pillar cells; microtubules; stria vascularis ID FIBROBLAST-GROWTH-FACTOR; EAR SENSORY EPITHELIA; MAMMALIAN INNER-EAR; HAIR CELL; TRANSCRIPTION FACTORS; COCHLEAR INNERVATION; SYSTEM DEVELOPMENT; DEAFNESS GENE; NULL MICE; MOUSE AB Deletion of fibroblast growth factor receptor 3 (Fgfr3) leads to hearing impairment in mice due to defects in the development of the organ of Corti, the sensory epithelium of the Cochlea. To examine the role of FGFR3 in auditory development, cochleae from Fgfr(3-/-) mice were examined using anatomical and physiological methods. Deletion of Fgfr3 leads to the absence of inner pillar cells and an increase in other cell types, suggesting that FGFR3 regulates cell fate. Defects in outer hair cell differentiation were also observed and probably represent the primary basis for hearing loss. Furthermore, innervation defects were detected consistent with changes in the fiber guidance properties of pillar cells. To elucidate the mechanisms underlying the effects of FGFR3, we examined the expression of Bmp4, a known target. Bmp4 was increased in Fgfr3(-/-) cochleae, and exogenous application of bone morphogenetic protein 4 (BMP4) onto cochlear explants induced a significant increase in the outer hair cells, suggesting the Fgf and Bmp signaling act in concert to pattern the cochlea. Developmental Dynamics 236:1905-1917, 2007. Published 2007 Wiley-Liss, Inc. C1 NIDCD, Sect Dev Neurosc, NIH, Bethesda, MD 20892 USA. Creighton Univ, Dept Biomed Sci, Omaha, NE USA. NIDCD, Otolaryngol Branch, NIH, Rockville, MD USA. NIDCD, Mammalian Dev Sect, NIH, Bethesda, MD USA. RP Puligilla, C (reprint author), NIDCD, Sect Dev Neurosc, NIH, Bldg 35,Room 2A-205,Convent Dr, Bethesda, MD 20892 USA. EM puligillac@nidcd.nih.gov OI Fritzsch, Bernd/0000-0002-4882-8398 FU NIDCD NIH HHS [R01 DC005590, R01 DC005590-01] NR 45 TC 77 Z9 79 U1 1 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD JUL PY 2007 VL 236 IS 7 BP 1905 EP 1917 DI 10.1002/dvdy.21192 PG 13 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 190EO UT WOS:000248041000017 PM 17557302 ER PT J AU Paul, SM Siegel, KL Malley, J Jaeger, RJ AF Paul, Scott M. Siegel, Karen Lohmann Malley, James Jaeger, Robert J. TI Evaluating interventions to improve gait in cerebral palsy: a meta-analysis of spatiotemporal measures SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Review ID ANKLE-FOOT ORTHOSES; SELECTIVE DORSAL RHIZOTOMY; RECTUS FEMORIS TRANSFER; GROSS MOTOR FUNCTION; BOTULINUM-TOXIN-A; SPASTIC DIPLEGIA; ENERGY-EXPENDITURE; YOUNG-ADULTS; CHILDREN; SURGERY AB A number of interventions to improve gait in individuals with cerebral palsy (CP) have been reported in the literature. The aim of this study was to perform a meta-analysis of these studies to determine the overall efficacy of these interventions. Effect sizes (Hedge's g) for spatiotemporal measures of gait (velocity, cadence, stride length) pre- and postintervention were analyzed. Sixty-three studies were included, and the overall effect size was statistically significant for both fixed effects and random models. Types of interventions were grouped into spasticity treatments, orthopedic (bony and soft tissue) surgery, lower extremity orthoses, or 'other'. When the data were analyzed in subgroups by type of intervention, each intervention had a statistically significant effect size with the exception of the 'other'. More importantly, the present study indicates the need to address participant inclusion criteria and power analysis more adequately in future research studies of interventions to improve gait in CP. C1 Natl Sci Fdn, Res Aid Persons Disabil Program, Arlington, VA 22230 USA. NIH, Dept Rehabil Med, US Dept HHS, Bethesda, MD 20892 USA. NIH, Phys Disabil Branch, US Dept HHS, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, US Dept HHS, Bethesda, MD 20892 USA. RP Jaeger, RJ (reprint author), Natl Sci Fdn, Res Aid Persons Disabil Program, 4201 Wilson Blvd,Room 545-21, Arlington, VA 22230 USA. EM rjaeger@nsf.gov RI Siegel, Karen Lohmann/B-5898-2008; OI Paul, Scott/0000-0003-1274-6670; Siegel, Karen Lohmann/0000-0002-0788-6612 NR 73 TC 10 Z9 12 U1 0 U2 12 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0012-1622 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD JUL PY 2007 VL 49 IS 7 BP 542 EP 549 PG 8 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 181ZX UT WOS:000247476000016 PM 17593129 ER PT J AU Bornstein, MH Putnick, DL AF Bornstein, Marc H. Putnick, Diane L. TI Chronological age, cognitions, and practices in European American mothers: A multivariate study of parenting SO DEVELOPMENTAL PSYCHOLOGY LA English DT Review DE age; maternal behaviors; maternal beliefs; parenting ID ADOLESCENT MOTHERS; PERSONALITY-INVENTORY; CHILD INTERACTION; MATERNAL AGE; PARENTHOOD; FAMILY; PLAY; DETERMINANTS; ASSOCIATIONS; COMPETENCE AB The authors studied multiple parenting cognitions and practices in European American mothers (N = 262) who ranged from 15 to.47 years of age. All were Ist-time parents of 20-month-old children. Some age effects were 0; others were linear or nonlinear. Nonlinear age effects determined by spline regression showed significant associations to a "knot" age (-30 years), with little or no association afterward. For parenting cognitions and practices that are age-sensitive, a 2-phase model of parental development is proposed. The findings stress the importance of considering maternal chronological age as a factor in developmental study. C1 NICHHD, Bethesda, MD 20892 USA. RP Bornstein, MH (reprint author), NICHHD, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@njh.gov RI Putnick, Diane/B-1707-2009; OI Putnick, Diane/0000-0002-6323-749X FU Intramural NIH HHS NR 115 TC 18 Z9 18 U1 2 U2 6 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD JUL PY 2007 VL 43 IS 4 BP 850 EP 864 DI 10.1037/0012-1649.43.4.850 PG 15 WC Psychology, Developmental SC Psychology GA 187HW UT WOS:000247839400004 PM 17605519 ER PT J AU Pi, JB Bai, YS Zhang, Q Wong, V Floering, LM Daniel, K Reece, JM Deeney, JT Andersen, ME Corkey, BE Collins, S AF Pi, Jingbo Bai, Yushi Zhang, Qiang Wong, Victoria Floering, Lisa M. Daniel, Kiefer Reece, Jeffrey M. Deeney, Jude T. Andersen, Melvin E. Corkey, Barbara E. Collins, Sheila TI Reactive oxygen species as a signal in glucose-stimulated insulin secretion SO DIABETES LA English DT Article ID PANCREATIC BETA-CELLS; SENSITIVE K+ CHANNELS; OXIDATIVE STRESS; HYDROGEN-PEROXIDE; GLUTATHIONE-PEROXIDASE; SUPEROXIDE-PRODUCTION; GENE-EXPRESSION; TOXICITY; ACTIVATION; RELEASE AB One of the unique features of P-cells is their relatively low expression of many antioxidant enzymes. This could render P-cells susceptible to oxidative damage but may also provide a system that is sensitive to reactive oxygen species as signals. In isolated mouse islets and INS-1(832/13) cells, glucose increases intracellular accumulation of H2O2. In both models, insulin secretion could be stimulated by provision of either exogenous H2O2 or diethyl maleate, which raises intracellular H2O2 levels. Provision of exogenous H2O2 scavengers, including cell permeable catalase and N-acetyl-L-cysteine, inhibited glucose-stimulated H2O2 accumulation and insulin secretion (GSIS). In contrast, cell permeable superoxide dismutase, which metabolizes superoxide into H2O2, had no effect on GSIS. Because oxidative stress is an important risk factor for beta-cell dysfunction in diabetes, the relationship between glucose-induced H-2,O-2, generation and GSIS was investigated under various oxidative stress conditions. Acute exposure of isolated mouse islets or INS-1(832/ 13) cells to oxidative stressors, including arsenite, 4-hydroxynonenal, and methylglyoxal, led to decreased GSIS. This impaired GSIS was associated with increases in a battery of endogenous antioxidant enzymes. Taken together, these findings suggest that H2O2 derived from glucose metabolism is one of the metabolic signals for insulin secretion, whereas oxidative stress may disturb its signaling function. C1 Hamner Inst Hlth Sci, Endocrine Biol Program, Res Triangle Pk, NC 27709 USA. Hamner Inst Hlth Sci, Div Computat Biol, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Lab Signal Transduct, Res Triangle Pk, NC USA. Boston Univ, Sch Med, Obes Res Ctr, Boston, MA 02215 USA. RP Collins, S (reprint author), Hamner Inst Hlth Sci, Endocrine Biol Program, 6 Davis Dr, Res Triangle Pk, NC 27709 USA. EM jpi@thehamner.org; scollins@thehamner.org OI Corkey, Barbara/0000-0002-5467-1630; Andersen, Melvin/0000-0002-3894-4811; Deeney, Jude/0000-0003-0988-9419 FU NIDDK NIH HHS [DK-35914, DK-54024] NR 50 TC 228 Z9 242 U1 2 U2 23 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD JUL PY 2007 VL 56 IS 7 BP 1783 EP 1791 DI 10.2337/db06-1601 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 186GV UT WOS:000247768000004 PM 17400930 ER PT J AU Pavkov, ME Hanson, RL Knowler, WC Bennett, PH Kpakoff, J Nelson, RG AF Pavkov, Meda E. Hanson, Robert L. Knowler, William C. Bennett, Peter H. Kpakoff, Jonathan Nelson, Robert G. TI Changing patterns of type 2 diabetes incidence among Pima Indians SO DIABETES CARE LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; LIFE-STYLE; PREVALENCE; EPIDEMIC; MELLITUS; CHILDREN; OBESITY; TRENDS; ADULTS AB OBJECTIVE - The rising prevalence of obesity and high prevalence of diabetes among Pima Indians suggest that the incidence of diabetes has risen over time. We examined trends in the incidence rate of type 2 diabetes among Pima Indians between 1965 and 2003. RESEARCH DESIGN AND METHODS - incidence rates were computed independently in three 13-year time periods in Pima Indians aged >= 5 years. Diabetes was defined by the presence of at least one of two criteria: 1) 2-h plasma glucose concentration >= 200 mg/dl (11.1 mmol/l) or 2) hypoglycemic treatment. RESULTS - Among 8,236 subjects without diabetes at baseline, 1,005 incident cases occurred during follow-up. Age- and sex-adjusted incidence rates of diabetes were 25.3 cases/1,000 patient-years (95% CI 22.5-28.0) in 1965-1977, 22.9 cases/1,000 patient years (20.0-25.8) in 1978-1990, and 23.5 cases/1,000 patient years (20.5-26.5) in 1991-2003 (P = 0.3). The incidence rate in subjects aged 5-14 years was 5.7 (1.9-17.4) times as high in the last as in the first period, but the rate declined in those aged 25-34 years (incidence rate ratio 0.6 [0.4-0.81). Sex-adjusted prevalence increased significantly over time only in those aged 5-24 years (P-trend < 0.0001). CONCLUSIONS - The overall incidence of diabetes among Pima Indians remained stable over the past four decades, with a significant rise occurring only in the youth. C1 NIDDKD, Diabet Epidemiol & Clin Res Sect, NIH, Phoenix, AZ 85014 USA. RP Pavkov, ME (reprint author), NIDDKD, Diabet Epidemiol & Clin Res Sect, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM mpavkov@phx.niddk.nih.gov RI Nelson, Robert/B-1470-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU Intramural NIH HHS NR 30 TC 58 Z9 60 U1 1 U2 11 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 JUL PY 2007 VL 30 IS 7 BP 1758 EP 1763 DI 10.2337/dc06-2010 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 186GZ UT WOS:000247768400013 PM 17468358 ER PT J AU Landon, MB Thom, E Spong, CY Carpente, M Mele, L Johnson, F Tillinghast, J Anderson, G AF Landon, Mark B. Thom, Elizabeth Spong, Catherine Y. Carpente, Marshall Mele, Lisa Johnson, Francee Tillinghast, Joann Anderson, Garland TI The national institute of child health and human development maternal-fetal medicine unit network randomized clinical trial in progress SO DIABETES CARE LA English DT Article; Proceedings Paper CT 5th International Workshop-Conference on Gestational Diabetes CY NOV 11-13, 2005 CL Chicago, IL SP Amer Diabet Assoc ID GESTATIONAL DIABETES-MELLITUS; GLUCOSE-TOLERANCE; PREGNANCY; CRITERIA C1 Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Columbus, OH 43210 USA. George Washington Biostat Ctr, Washington, DC USA. NICHHD, Bethesda, MD 20892 USA. Brown Univ, Providence, RI 02912 USA. Univ Texas, Galveston, TX 77555 USA. RP Landon, MB (reprint author), Ohio State Univ, Coll Med, Dept Obstet & Gynecol, Means Hall,5th Floor,1654 Upham Dr, Columbus, OH 43210 USA. EM landon.l@osu.edu NR 20 TC 11 Z9 12 U1 0 U2 1 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 JUL PY 2007 VL 30 SU 2 BP S194 EP S199 DI 10.2337/dc07-s215 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 187WK UT WOS:000247879600015 PM 17596471 ER PT J AU Gellar, LA Schrader, K Nansel, TR AF Gellar, Lauren A. Schrader, Kelly Nansel, Tonja R. TI Healthy eating practices - Perceptions, facilitators, and barriers among youth with diabetes SO DIABETES EDUCATOR LA English DT Article ID CARDIOVASCULAR-DISEASE; RISK-FACTORS; ENVIRONMENTAL-INFLUENCES; PHYSICAL-ACTIVITY; ADOLESCENTS; FOOD; PREVALENCE; NUTRITION; CHILDREN; SEARCH AB Purpose The purpose of this study was to explore the perceptions of healthy eating by youth with diabetes as well as facilitators of and barriers to healthy eating behavior. Methods One hundred forty youth aged 7 to 16 years with diabetes participated in 18 focus groups. Sample race/ethnicity was 71% white, 18% African American, 6% Hispanic, and 5% other; 69% of the participants were female. Results Healthy eating was defined primarily in terms of eating fruits and vegetables, low fat, low sugar, and eating to keep blood sugar in range. However, there were notable differences in perceptions of healthy eating versus perceptions of eating practices good for diabetes management. Specifically, "free" foods (foods high in fat but low in carbohydrate) were commonly reported as being good for diabetes management. Major barriers to healthy eating included widespread availability of unhealthy foods, preparation time, and social situations. Parental behaviors, including monitoring food choices and positive modeling, were the most commonly reported facilitators of healthy eating. Conclusion Findings suggest that youth with diabetes have a general understanding of healthy eating and face similar barriers and facilitators to healthy eating as nondiabetic children do. However, the diabetes regimen may influence their understanding of healthy eating, sometimes negatively. Diabetes nutrition education sessions should emphasize the connection between healthy eating and both short- and long-term diabetes outcomes, and they should highlight strategies to reduce saturated fat consumption while avoiding excessive carbohydrate consumption. The diabetes educator can play an integral role in promoting healthy dietary practices by facilitating parental involvement, designing action plans for managing social situations, and increasing awareness of healthier alternatives to widely available unhealthy foods. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Columbia Univ, Coll Teachers, Dept Hlth & Behav Studies, New York, NY 10027 USA. George Washington Univ, Sch Publ Hlth & Hlth Serv, Washington, DC USA. RP Nansel, TR (reprint author), NICHHD, Prevent Res Branch, 6100 Execut Blvd,Room 7B13R, Bethesda, MD 20892 USA. EM Nanselt@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595 FU Intramural NIH HHS [Z99 HD999999] NR 24 TC 23 Z9 24 U1 1 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0145-7217 J9 DIABETES EDUCATOR JI Diabetes Educ. PD JUL-AUG PY 2007 VL 33 IS 4 BP 671 EP 679 DI 10.1177/0145721707303807 PG 9 WC Endocrinology & Metabolism; Public, Environmental & Occupational Health SC Endocrinology & Metabolism; Public, Environmental & Occupational Health GA 196HP UT WOS:000248472600009 PM 17684168 ER PT J AU Gorman, GS Coward, L Kerstner-Wood, C Cork, L Kapetanovic, IM Brouillette, WJ Muccio, DD AF Gorman, Gregory S. Coward, Lori Kerstner-Wood, Corenna Cork, Lea Kapetanovic, Izet M. Brouillette, Wayne J. Muccio, Donald D. TI In vitro metabolic characterization, phenotyping, and kinetic studies of 9cUAB30, a retinoid X receptor-specific retinoid SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID BREAST-CANCER CELLS; HUMAN-LIVER; ACID 4-HYDROXYLATION; SELECTIVE RETINOIDS; DRUG-METABOLISM; CARCINOMA CELLS; GROWTH; IDENTIFICATION; GLUCURONIDATION; TESTOSTERONE AB The present study was conducted to compare the in vitro phase I and phase II metabolic profiles of ( 2E, 4E, 6Z, 8E)- 8-( 3', 4'- dihydro-1 '( 2'H)- naphthalen-1'-ylidene)- 3,7- dimethyl- 2,4,6-octatrienoic acid (9cUAB30) in human, rat, and dog microsomes and to characterize and identify the associated metabolic kinetics and specific isozymes from human liver microsomes ( HLM) responsible for metabolism, respectively. Data from these experiments revealed that nine (M1 - M9) phase I metabolites along with a single glucuronide conjugate were observed across the species investigated. With the exception of glucuronidation, no evidence of metabolism was detected for phase II enzymes ( data not shown). Significant differences between species with regard to metabolic profile, stability, and gender were noted. For the eight phase I metabolites detected in HLM, the specific isozymes responsible for the biotransformations were CYP2C8, CYP2C9, and CYP2C19, with minor contributions from CYP1A2 and CYP2B6. For the glucuronide conjugate, UGT1A9 was the major catalyzing enzyme, with a minor contribution from UGT1A3. Kinetic analysis of eight of the detected metabolites indicated that four seemed to follow classical hyperbolic kinetics, whereas the remaining four showed evidence of either autoactivation or substrate inhibition. C1 So Res Inst, Birmingham, AL 35205 USA. NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Alabama, Dept Chem, Birmingham, AL 35294 USA. RP Gorman, GS (reprint author), So Res Inst, 2000 9th Ave S, Birmingham, AL 35205 USA. EM gorman@sri.org NR 30 TC 14 Z9 14 U1 0 U2 1 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 JUL PY 2007 VL 35 IS 7 BP 1157 EP 1164 DI 10.1124/dmd.106.013938 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 180OB UT WOS:000247373800020 PM 17446266 ER PT J AU Wolf, KK Wood, SG Allard, JL Hunt, JA Gorman, N Walton-Strong, BW Szakacs, JG Duan, SX Hao, Q Court, MH von Moltke, LL Greenblatt, DJ Kostrubsky, V Jeffery, EH Wrighton, SA Gonzalez, FJ Sinclair, PR Sinclair, JF AF Wolf, Kristina K. Wood, Sheryl G. Allard, Jenna L. Hunt, Jane A. Gorman, Nadia Walton-Strong, Brooke W. Szakacs, Juliana G. Duan, Su X. Hao, Qin Court, Michael H. von Moltke, Lisa L. Greenblatt, David J. Kostrubsky, Vsevolod Jeffery, Elizabeth H. Wrighton, Steven A. Gonzalez, Frank J. Sinclair, Peter R. Sinclair, Jacqueline F. TI Role of CYP3A and CYP2E1 in alcohol-mediated increases in acetaminophen hepatotoxicity: Comparison of wild-type and Cyp2e1(-/-) mice SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID HUMAN LIVER-MICROSOMES; SHORT-TERM TREATMENT; IN-VITRO METABOLISM; UROPORPHYRIN ACCUMULATION; PROTECTIVE ROLE; CHICKEN LIVER; RAT-LIVER; ETHANOL; CYTOCHROME-P-450; IDENTIFICATION AB CYP2E1 is widely accepted as the sole form of cytochrome P450 responsible for alcohol-mediated increases in acetaminophen (APAP) hepatotoxicity. However, we previously found that alcohol [ethanol and isopentanol (EIP)] causes increases in APAP hepatotoxicity in Cyp2e1(-/-) mice, indicating that CYP2E1 is not essential. Here, using wild-type and Cyp2e1(-/-) mice, we investigated the relative roles of CYP2E1 and CYP3A in EIP-mediated increases in APAP hepatotoxicity. We found that EIP-mediated increases in APAP hepatotoxicity occurred at lower APAP doses in wild-type mice (300 mg/kg) than in Cyp2e1(-/-) mice (600 mg/kg). Although this result suggests that CYP2E1 has a role in the different susceptibilities of these mouse lines, our findings that EIP-mediated increases in CYP3A activities were greater in wild-type mice compared with Cyp2e1(-/-) mice raises the possibility that differential increases in CYP3A may also contribute to the greater APAP sensitivity in EIP-pretreated wild-type mice. At the time of APAP administration, which followed an 11 h withdrawal from the alcohols, alcohol-induced levels of CYP3A were sustained in both mouse lines, whereas CYP2E1 was decreased to constitutive levels in wild-type mice. The CYP3A inhibitor triacetyloleandomycin (TAO) decreased APAP hepatotoxicity in EIP-pretreated wild-type and Cyp2e1(-/-) mice. TAO treatment in vivo resulted in inhibition of microsomal CYP3A-catalyzed activity, measured in vitro, with no inhibition of CYP1A2 and CYP2E1 activities. In conclusion, these findings suggest that both CYP3A and CYP2E1 contribute to APAP hepatotoxicity in alcohol-treated mice. C1 Vet Adm Med Ctr, White River Jct, VT USA. Dartmouth Med Sch, Dept Pharmacol & Toxicol, Hanover, NH USA. Dartmouth Med Sch, Dept Biochem, Hanover, NH USA. Harvard Vanguard Med Associates, Dept Pathol, Boston, MA USA. Tufts Univ, Sch Med, Dept Pharmacol & Expt Therapeut, Boston, MA 02111 USA. Tufts Univ New England Med Ctr, Boston, MA 02111 USA. Pfizer Global Res & Dev, Dept Safety Sci, Ann Arbor, MI USA. Univ Illinois, Dept Food Sci & Human Nutr, Urbana, IL 61801 USA. Lilly Res Labs, Dept Drug Disposit, Indianapolis, IN USA. Natl Canc Inst, Bethesda, MD USA. RP Sinclair, JF (reprint author), Vet Adm Med Ctr, Res 151,215 N Main St, White River Jct, VT USA. EM jsinc@dartmouth.edu FU NCCIH NIH HHS [AT01381]; NIA NIH HHS [AG17880]; NIAAA NIH HHS [AA12898]; NIAID NIH HHS [AI58784]; NIDA NIH HHS [DA05258, DA58496]; NIGMS NIH HHS [GM74396, GM61834]; NIMH NIH HHS [MH58435]; SAMHSA HHS [OA13834] NR 51 TC 34 Z9 36 U1 0 U2 7 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 EI 1521-009X J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD JUL PY 2007 VL 35 IS 7 BP 1223 EP 1231 DI 10.1124/dmd.107.014738 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 180OB UT WOS:000247373800029 PM 17392391 ER PT J AU Chung, JU Kim, SY Lim, JO Choi, HK Kang, SU Yoon, HS Ryu, H Kang, DW Lee, J Kang, B Choi, S Toth, A Pearce, LV Pavlyukovets, VA Lundberg, DJ Blumberg, PM AF Chung, Jae-Uk Kim, Su Yeon Lim, Ju-Ok Choi, Hyun-Kyung Kang, Sang-Uk Yoon, Hae-Seok Ryu, HyungChul Kang, Dong Wook Lee, Jeewoo Kang, Bomi Choi, Sun Toth, Attila Pearce, Larry V. Pavlyukovets, Vladimir A. Lundberg, Daniel J. Blumberg, Peter M. TI alpha-Substituted N-(4-t-butylbenzyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues as potent and stereospecific TRPV1 antagonists SO DRUGS OF THE FUTURE LA English DT Meeting Abstract C1 Seoul Natl Univ, Coll Pharm, Med Chem Lab, Seoul 151742, South Korea. Ewha Womans Univ, Coll Pharm, Seoul 120750, South Korea. Ewha Womans Univ, Natl Core Res Ctr Cell Signaling & Drug Discovery, Seoul 120750, South Korea. NCI, Lab Canc Biol & Genet, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PROUS SCIENCE, SA PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0377-8282 J9 DRUG FUTURE JI Drug Future PD JUL PY 2007 VL 32 SU A BP 46 EP 46 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 199IC UT WOS:000248688400098 ER EF