FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Moore, SP Liti, G Stefanisko, KM Nyswaner, KM Chang, C Louis, EJ Garfinkel, D AF Moore, SP Liti, G Stefanisko, KM Nyswaner, KM Chang, C Louis, EJ Garfinkel, D TI Analysis of a Ty1-less variant of Saccharomyces paradoxus: the gain and loss of Ty1 elements SO YEAST LA English DT Article DE Ty elements; LTR; recombination; phylogeny; Saccharomyces ID MISMATCH REPAIR SYSTEM; TRANSPOSABLE ELEMENTS; ECTOPIC RECOMBINATION; SEQUENCE-ANALYSIS; HOST STRAINS; DNA DAMAGE; CEREVISIAE; YEAST; RETROTRANSPOSONS; GENOME AB Because Ty elements transpose through an RNA intermediate, element accumulation through retrotransposition must be regulated or offset by element loss to avoid uncontrolled genome expansion. Here we examine the fate of Ty sequences in Saccharomyces strain 337, a strain that is reported to lack Ty1 and Ty2 elements, but contains remnant solo long terminal repeats (LTRs). Although strain 337 was initially classified as Saccharomyces cerevisiae, our work indicates that this strain is more closely related to S. paradoxus. Several degenerate Ty1 and Ty2 LTRs were mapped to the same insertion sites as full-length Ty1 and Ty2 elements in S. cerevisiae, suggesting that this strain lost Ty elements by LTR-LTR recombination. Southern analysis indicates that strain 337 also lacks Ty4 and Ty5 elements. We estimated the rates of element gain and loss in this strain by introducing a single transposition-competent Ty1 element. The results indicate that Ty1 retrotransposition occurs at a much higher rate than elimination, suggesting that copy-number-dependent co-factors or environmental conditions contribute to the loss of Ty elements in this genome. Copyright (C) 2004 John Wiley Sons, Ltd. C1 NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. RP Moore, SP (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, POB B, Frederick, MD 21702 USA. EM moores@ncifcrf.gov RI Louis, Edward/B-7920-2008; Liti, Gianni/I-9929-2014; OI Louis, Edward/0000-0003-1157-3608; Liti, Gianni/0000-0002-2318-0775 NR 45 TC 15 Z9 15 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0749-503X J9 YEAST JI Yeast PD JUN PY 2004 VL 21 IS 8 BP 649 EP 660 DI 10.1002/yea.1129 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Microbiology; Mycology GA 830XE UT WOS:000222156700004 PM 15197730 ER PT J AU Lei, B Li, C Zhang, DH Zhou, QF Shung, KK Zhou, CW AF Lei, B Li, C Zhang, DH Zhou, QF Shung, KK Zhou, CW TI Nanowire transistors with ferroelectric gate dielectrics: Enhanced performance and memory effects SO APPLIED PHYSICS LETTERS LA English DT Article ID CRYSTALLINE IN2O3 NANOWIRES; FIELD-EFFECT TRANSISTORS; THIN-FILM TRANSISTORS; SINGLE; TRANSPORT AB Integration of ferroelectric materials into nanoscale field-effect transistors offers enormous promise for superior transistor performance and also intriguing memory effects. In this study, we have incorporated lead zirconate titanate (PZT) into In2O3 nanowire transistors to replace the commonly used SiO2 as the gate dielectric. These transistors exhibited substantially enhanced performance as a result of the high dielectric constant of PZT, as revealed by a 30-fold increase in the transconductance and a 10-fold reduction in the subthreshold swing when compared to similar SiO2-gated devices. Furthermore, memory effects were observed with our devices, as characterized by a counter-clockwise loop in current-versus-gate-bias curves that can be attributed to the switchable remnant polarization of PZT. Our method can be easily generalized to other nanomaterials systems and may prove to be a viable way to obtain nanoscale memories. (C) 2004 American Institute of Physics. C1 Univ So Calif, Dept EE Electrophys, Los Angeles, CA 90089 USA. Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. RP Lei, B (reprint author), Univ So Calif, Dept EE Electrophys, Los Angeles, CA 90089 USA. EM chongwuz@usc.edu RI Zhou, Chongwu/F-7483-2010 NR 19 TC 66 Z9 66 U1 0 U2 38 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0003-6951 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD MAY 31 PY 2004 VL 84 IS 22 BP 4553 EP 4555 DI 10.1063/1.1759069 PG 3 WC Physics, Applied SC Physics GA 822KF UT WOS:000221537500065 ER PT J AU Kim, CH Park, YS Chung, KN Elwood, PC AF Kim, CH Park, YS Chung, KN Elwood, PC TI Sorting of the human folate receptor in MDCK cells SO JOURNAL OF BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE CHO; folate receptor; MDCK; PNH; sorting ID PAROXYSMAL-NOCTURNAL HEMOGLOBINURIA; HUMAN KB CELLS; GLYCOSYL-PHOSPHATIDYLINOSITOL; BINDING-PROTEIN; SCHIZOSACCHAROMYCES-POMBE; ALKALINE-PHOSPHATASE; MOLECULAR-CLONING; ANCHORED PROTEINS; CANCER CELLS; MEMBRANE AB The human folate receptor (hFR) is a glycosylphosphatidylinositol (GPI) linked plasma membrane protein that mediates delivery of folates into cells. We studied the sorting of the hFR using transfection of the hFR cDNA into MDCK cells. MDCK cells are polarized epithelial cells that preferentially sort GPI-linked proteins to their apical membrane. Unlike other GPI-tailed proteins, we found that in MDCK cells, hFR is functional on both the apical and basolateral surfaces. We verified that the same hFR cDNA that transfected into CHO cells produces the hFR protein that is GPI-linked. We also measured the hFR expression on the plasma membrane of type III paroxysmal nocturnal hemoglobinuria (PNH) human erythrocytes. PNH is a disease that is characterized by the inability of cells to express membrane proteins requiring a GPI anchor. Despite this defect, and different from other GPI-tailed proteins, we found similar levels of hFR in normal and type III PNH human erythrocytes. The results suggest the hypothesis that there may be multiple mechanisms for targeting hFR to the plasma membrane. C1 Wonkwang Hlth Sci Coll, Dept Clin Pathol, Iksan 570750, South Korea. Wonkwang Univ, Div Biol Sci, Iksan 570749, South Korea. NIH, Bethesda, MD 20892 USA. RP Kim, CH (reprint author), Wonkwang Hlth Sci Coll, Dept Clin Pathol, Iksan 570750, South Korea. EM chkim@wkhc.ac.kr NR 35 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER-VERLAG SINGAPORE PTE LTD PI SINGAPORE PA #04-01 CENCON I, 1 TANNERY RD, SINGAPORE 347719, SINGAPORE SN 1225-8687 J9 J BIOCHEM MOL BIOL JI J. Biochem. Mol. Biol. PD MAY 31 PY 2004 VL 37 IS 3 BP 362 EP 369 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 825FU UT WOS:000221742200015 PM 15469720 ER PT J AU Berger, VW AF Berger, VW TI Does the Prentice criterion validate surrogate endpoints? SO STATISTICS IN MEDICINE LA English DT Article DE cancer marker; patient benefit; surrogate endpoint; validity ID RANDOMIZED EXPERIMENTS; CLINICAL-TRIALS AB Randomized Phase II or Phase III clinical trials that are powered based on clinical endpoints, such as survival time, may be prohibitively expensive, in terms of both the time required for their completion and the number of patients required. As such, surrogate endpoints, such as objective tumour response or markers including prostate specific antigen or CA-125, have gained widespread popularity in clinical trials. If an improvement in a surrogate endpoint does not itself confer patient benefit, then consideration must be given to the extent to which improvement in a surrogate endpoint implies improvement in the true clinical endpoint of interest. That this is not a trivial issue is demonstrated by the results of an NIH-sponsored trial of anti-arrhythmic drugs, in which the ability to correct an irregular heart beat not only did not correspond to a survival benefit but in fact led to excess mortality. One approach to the validation of surrogate endpoints involves ensuring that a valid between-group analysis of the surrogate endpoint constitutes also a valid analysis of the true clinical endpoint. The Prentice criterion is a set of conditions that essentially specify the conditional independence of the impact of treatment on the true endpoint, given the surrogate endpoint. It is shown that this criterion alone ensures that an observed effect of the treatment on the true endpoint implies a treatment effect also on the surrogate endpoint, but contrary to popular belief, it does not ensure the converse, specifically that the observation of a significant treatment effect on the surrogate endpoint can be used to infer a treatment effect on the true endpoint. Published in 2004 by John Wiley Sons, Ltd. C1 Univ Maryland Baltimore Cty, Biometry Res Grp, NCI, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), Univ Maryland Baltimore Cty, Biometry Res Grp, NCI, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 13 TC 35 Z9 35 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD MAY 30 PY 2004 VL 23 IS 10 BP 1571 EP 1578 DI 10.1002/sim.1780 PG 8 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 818GP UT WOS:000221233900012 PM 15122737 ER PT J AU Borlongan, CV Lind, JG Dillon-Carter, O Yu, GL Hadman, M Cheng, C Carroll, J Hess, DC AF Borlongan, CV Lind, JG Dillon-Carter, O Yu, GL Hadman, M Cheng, C Carroll, J Hess, DC TI Intracerebral xenografts of mouse bone marrow cells in adult rats facilitate restoration of cerebral blood flow and blood-brain barrier SO BRAIN RESEARCH LA English DT Article DE neural transplantation; striatum; stem cell; immunosuppression; cross-species; neuroprotection ID ISCHEMIC RATS; FUNCTIONAL RECOVERY; CYCLOSPORINE-A; STROMAL CELLS; PARKINSONS-DISEASE; NEUROTROPHIC FACTOR; ARTERY LIGATION; NIGRAL GRAFTS; HNT NEURONS; IN-VITRO AB We examined in the present study alterations in cerebral blood flow (CBF) and blood-brain barrier (BBB) permeability following intrastriatal transplantation of mouse bone marrow stromal cells (BMSCs) or saline infusion in adult Sprague-Dawley rats. Laser Doppler revealed that transplanted animals exhibited near normal cerebral blood flow (CBF, 150 perfusion units) at a much earlier period post-transplantation (day 4) compared to animals that received saline infusion (day 12) (p's < 0.05). Similarly, Evans Blue assay demonstrated that transplanted animals exhibited near complete BBB reconstitution at day 5 post-transplantation, whereas animals that received saline infusion continued to display a compromised BBB up to 11 days post-transplantation. Transplanted animals displayed a cell dose-dependent CBF and BBB restoration. Enzyme-linked immunosorbent assay (ELISA) of transplanted BMSCs revealed elevated levels of transforming growth factor-beta superfamily of neurotrophic factors. Moreover, despite the absence of immunosuppression in this cross-species transplantation, at least in the acute phase (12 days post-transplantation), surviving xenografts were detected during periods of restored CBF and BBB permeability. These observations suggest that restoration of CBF and BBB permeability accompanies the reported functional outcomes associated with intracerebral transplantation of BMSCs. Published by Elsevier B.V. C1 Med Coll Georgia, Dept Neurol, Augusta, GA 30912 USA. Med Coll Georgia, Inst Mol Med Genet, Augusta, GA 30912 USA. Med Coll Georgia, Sch Grad Studies, Augusta, GA 30912 USA. Augusta VAMC, Res & Affiliat Serv Line, Augusta, GA USA. NIDA, NIH, Baltimore, MD USA. RP Borlongan, CV (reprint author), Med Coll Georgia, Dept Neurol, Augusta, GA 30912 USA. EM cborlong@neuro.mcg.edu OI Borlongan, Cesar/0000-0002-2966-9782 FU NINDS NIH HHS [R21-NS43439-01, R21-NS43487-01] NR 53 TC 26 Z9 30 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 29 PY 2004 VL 1009 IS 1-2 BP 26 EP 33 DI 10.1016/j.brainres.2004.02.050 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 821TQ UT WOS:000221486000004 PM 15120580 ER PT J AU Franks, ME Macpherson, GR Figg, WD AF Franks, ME Macpherson, GR Figg, WD TI Thalidomide SO LANCET LA English DT Review ID LOW-DOSE THALIDOMIDE; PHASE-II TRIAL; REFRACTORY MULTIPLE-MYELOMA; RENAL-CELL CARCINOMA; NECROSIS-FACTOR-ALPHA; INDEPENDENT PROSTATE-CANCER; TOXIC EPIDERMAL NECROLYSIS; IMMUNODEFICIENCY-VIRUS INFECTION; SYSTEMIC LUPUS-ERYTHEMATOSUS; SINGLE-AGENT THALIDOMIDE C1 NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res,NIH, Bethesda, MD 20030 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res,NIH, 9000 Rockville Pike, Bethesda, MD 20030 USA. EM wdfigg@helix.nih.gov RI Ain, Kenneth/A-5179-2012; Figg Sr, William/M-2411-2016 OI Ain, Kenneth/0000-0002-2668-934X; NR 159 TC 249 Z9 264 U1 5 U2 40 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 29 PY 2004 VL 363 IS 9423 BP 1802 EP 1811 DI 10.1016/S0140-6736(04)16308-3 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 824SD UT WOS:000221705800024 PM 15172781 ER PT J AU Zhou, YH AF Zhou, YH TI Prevalence of non-pneumonic infections with SARS-correlated virus SO LANCET LA English DT Letter ID ACUTE-RESPIRATORY-SYNDROME; CORONAVIRUS C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Zhou, YH (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr MSC-8009, Bethesda, MD 20892 USA. EM yzhou@niaid.nih.gov NR 5 TC 1 Z9 1 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 29 PY 2004 VL 363 IS 9423 BP 1825 EP 1826 DI 10.1016/S0140-6736(04)16313-7 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 824SD UT WOS:000221705800029 PM 15172786 ER PT J AU McKay, RD AF McKay, RD TI Stem cell biology and neurodegenerative disease SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY OF LONDON SERIES B-BIOLOGICAL SCIENCES LA English DT Article DE stem cells; synapses; Parkinson's disease ID CENTRAL-NERVOUS-SYSTEM; IN-VITRO; NEURONAL DIFFERENTIATION; HIPPOCAMPAL-NEURONS; NEURAL PROGENITORS; PARKINSONS-DISEASE; HUMAN BLASTOCYSTS; DOPAMINE NEURONS; PRECURSOR CELLS; DENTATE GYRUS AB The fundamental basis of our work is that organs are generated by multipotent stem cells, whose properties we must understand to control tissue assembly or repair. Central nervous system (CNS) stem cells are now recognized as a well-defined population of precursors that differentiate into cells that are indisputably neurons and glial cells. Work from our group played an important role in defining stem cells of the CNS. Embryonic stem (ES) cells also differentiate to specific neuron and glial types through defined intermediates that are similar to the cellular precursors that normally occur in brain development. There is convincing evidence that the differentiated progeny of ES cells and CNS stem cells show expected functions of neurons and glia. Recent progress has been made on three fundamental developmental processes: (i) cell cycle control; (ii) the control of cell fate; and (iii) early steps in neural differentiation. In addition, our work on CNS stem cells has developed to a stage where there are clinical implications for Parkinson's and other degenerative disorders. These advances establish that stem cell biology contributes to our understanding of brain development and has great clinical promise. C1 NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP McKay, RD (reprint author), NINDS, Mol Biol Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM mckay@codon.nih.gov NR 52 TC 38 Z9 44 U1 0 U2 1 PU ROYAL SOC LONDON PI LONDON PA 6 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T ROY SOC B JI Philos. Trans. R. Soc. Lond. Ser. B-Biol. Sci. PD MAY 29 PY 2004 VL 359 IS 1445 BP 851 EP 856 DI 10.1098/rstb.2004.1472 PG 6 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 821PA UT WOS:000221472900013 PM 15293812 ER PT J AU Kim, EY Hong, YB Lai, ZN Kim, HJ Cho, YH Brady, RO Jung, SC AF Kim, EY Hong, YB Lai, ZN Kim, HJ Cho, YH Brady, RO Jung, SC TI Expression and secretion of human glucocerebrosidase mediated by recombinant lentivirus vectors in vitro and in vivo: implications for gene therapy of Gaucher disease SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Gaucher disease; lentivirus; gene therapy; glucocerbrosidase; mouse; liver ID PLACENTAL BETA-GLUCOCEREBROSIDASE; NONDIVIDING CELLS; RETROVIRAL INFECTION; BONE-MARROW; DELIVERY; TRANSDUCTION; MICE; ENZYME; DNA; MACROPHAGES AB Gaucher disease is a lysosomal storage disorder resulting from a deficiency Of glucocerebrosidase (GC). In this study, we showed that vascular and hepatic delivery of a HIV-1-based lentivirus vector encoding human GC cDNA produced therapeutic levels of GC protein. A high level of expression of GC was produced in Cultured fibroblasts derived from patients with Gaucher disease by transducing the cells with recombinant lentivirus vectors. GC secreted by transduced fibroblasts was taken up by adjacent GC-deficient cells by endocytosis. Intraportal administration of lenti-EF-GC viral vector resulted in efficient transduction and expression of the GC. Vascular delivery of vector resulted in high levels of GC expression in mice that persisted in most organs over the four months. No significant abnormalities were found attributable to recombinant lentivirus vectors in any of the tissues examined. This study represents all initial step toward gene transfer using recombinant lentivirus vectors for treatment of Gaucher disease. (C) 2004 Elsevier Inc. All rights reserved. C1 Natl Inst Hlth, Dept Biomed Sci, Div Genet Dis, Seoul, South Korea. Hanyang Univ, Coll Med, Dept Med Genet, Seoul 133791, South Korea. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Ajou Univ, Sch Med, Dept Med Genet, Suwon 441749, Gyeonggi Do, South Korea. RP Jung, SC (reprint author), Natl Inst Hlth, Dept Biomed Sci, Div Genet Dis, Seoul, South Korea. EM scjung@nih.go.kr OI Jung, Sung-Chul/0000-0002-3174-8965 NR 46 TC 17 Z9 19 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 28 PY 2004 VL 318 IS 2 BP 381 EP 390 DI 10.1016/j.bbrc.2004.04.040 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 819LD UT WOS:000221315500009 PM 15120612 ER PT J AU Geiman, TM Sankpal, UT Robertson, AK Zhao, YX Zhao, YM Robertson, KD AF Geiman, TM Sankpal, UT Robertson, AK Zhao, YX Zhao, YM Robertson, KD TI DNMT3B interacts with hSNF2H chromatin remodeling enzyme, HDACs 1 and 2, and components of the histone methylation system SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE DNMT3B; hSNF2H; chromatin; DNA methylation; historic modifications; HDAC; HP1; epigenetics ID DNA METHYLTRANSFERASE GENE; H3 LYSINE-9 METHYLATION; DE-NOVO METHYLATION; IMMUNODEFICIENCY SYNDROME; MAMMALIAN DEVELOPMENT; CPG METHYLATION; DOMINANT ROLE; COMPLEX; HETEROCHROMATIN; CANCER AB The non-random pattern of genome-wide DNA methylation in mammalian cells is established and maintained by DNA methyltransferases DNMT1, 3A, and 3B. De novo DNA methyltransferase DNMT3B is critical for embryonic development and is mutated in ICF syndrome. Despite its importance in normal cellular functioning, little is known about how DNMT3B operates in the context of chromatin. Here we demonstrate that DNMT3B associates with four chromatin-associated enzymatic activities common to transcriptionally repressed, heterochromatic regions of the genome: DNA methyltransferase, histone deacetylase, ATPase, and histone methylase activities. By immunoprecipitation and GST pull-down, we show that DNMT3B interacts with HDAC1, HDAC2, HP1 proteins, Suv39h1, and the ATP-dependent chromatin remodeling enzyme hSNF2H. Endogenous hSNF2H is also associated with DNA methyltransferase activity. These proteins co-localize extensively with DNMT3B in heterochromatic regions. Our results therefore link DNMT3B to three other components of the epigenetic machinery and provide important insights into how DNA methylation patterns may be established within the chromatin environment. Published by Elsevier Inc. C1 NCI, NIH, LRBGE, Epigenet Gene Regulat & Canc Sect, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX USA. RP Robertson, KD (reprint author), NCI, NIH, LRBGE, Epigenet Gene Regulat & Canc Sect, Bldg 41,Rm C306,41 Lib Dr, Bethesda, MD 20892 USA. EM robertk@mail.nih.gov FU NCI NIH HHS [CA85146] NR 56 TC 64 Z9 67 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 28 PY 2004 VL 318 IS 2 BP 544 EP 555 DI 10.1016/j.bbrc.2004.04.058 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 819LD UT WOS:000221315500032 PM 15120635 ER PT J AU Jang, HH Lee, KO Chi, YH Jung, BG Park, SK Park, JH Lee, JR Lee, SS Moon, JC Yun, JW Choi, YO Kim, WY Kang, JS Cheong, GW Yun, DJ Rhee, SG Cho, MJ Lee, SY AF Jang, HH Lee, KO Chi, YH Jung, BG Park, SK Park, JH Lee, JR Lee, SS Moon, JC Yun, JW Choi, YO Kim, WY Kang, JS Cheong, GW Yun, DJ Rhee, SG Cho, MJ Lee, SY TI Two enzymes in one: Two yeast peroxiredoxins display oxidative stress-dependent switching from a peroxidase to a molecular chaperone function SO CELL LA English DT Article ID CYSTEINE-SULFINIC ACID; HEAT-SHOCK-PROTEIN; SACCHAROMYCES-CEREVISIAE; HYDROGEN-PEROXIDE; CRYSTAL-STRUCTURE; THIOL PEROXIDASE; 2-CYS PEROXIREDOXIN; INACTIVATION; PROTEASES; REDUCTASE AB Although a great deal is known biochemically about peroxiredoxins (Prxs), little is known about their real physiological function. We show here that two cytosolic yeast Prxs, cPrxI and II, which display diversity in structure and apparent molecular weights (MW), can act alternatively as peroxidases and molecular chaperones. The peroxidase function predominates in the lower MW forms, whereas the chaperone function predominates in the higher MW complexes. Oxidative stress and heat shock exposure of yeasts causes the protein structures of cPrxI and II to shift from low MW species to high MW complexes. This triggers a peroxidase-to-chaperone functional switch. These in vivo changes are primarily guided by the active peroxidase site residue, Cys(47), which serves as an efficient "H2O2-sensor" in the cells. The chaperone function of these proteins enhances yeast resistance to heat shock. C1 Gyeongsang Natl Univ, Div Appl Life Sci, Chinju 660701, South Korea. Gyeongsang Natl Univ, Environm Biotechnol Natl Core Res Ctr, Chinju 660701, South Korea. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Lee, SY (reprint author), Gyeongsang Natl Univ, Div Appl Life Sci, Chinju 660701, South Korea. EM sylee@gsnu.ac.kr RI Cho, Moo Je/F-1649-2010 NR 37 TC 406 Z9 428 U1 6 U2 29 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD MAY 28 PY 2004 VL 117 IS 5 BP 625 EP 635 DI 10.1016/j.cell.2004.05.002 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 826VP UT WOS:000221857900009 PM 15163410 ER PT J AU Miko, A Werby, E Sun, H Healey, J Zhang, L AF Miko, A Werby, E Sun, H Healey, J Zhang, L TI A TM2 residue in the beta 1 subunit determines spontaneous opening of homomeric and heteromeric gamma-aminobutyric acid-gated ion channels SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR-BETA SUBUNITS; GENERAL ANESTHETIC ETOMIDATE; GABA-A RECEPTORS; AMINO-ACID; FUNCTIONAL EXPRESSION; CHLORIDE CHANNELS; MOLECULAR VOLUME; ALPHA-SUBUNIT; RAT-BRAIN; DISTINCT AB gamma-Aminobutyric acid type A (GABA(A)) receptors are major inhibitory neurotransmitter-gated ion channels in the central nervous system. GABA(A) receptors consist of multiple subunits and exhibit distinct pharmacological and channel properties. Of all GABA(A) receptor subunits, the beta subunit is thought to be a key component for the functionality of the receptors. Certain types of GABA(A) receptors have been found to be constitutively active. However, the molecular basis for spontaneous opening of channels of these receptors is not totally understood. In this study, we showed that channels that contain the beta1 but not beta3 subunits opened spontaneously when these subunits were expressed homomerically or co-expressed with other types of GABA(A) receptor subunits in Xenopus oocytes. Using subunit chimeras and site-directed mutagenesis, we localized a key amino acid residue, a serine at position 265, that is critical in conferring an open state of the beta1 subunit-containing GABA(A) receptors in the absence of agonist. Moreover, some point mutations of Ser-265 also produced constitutively active channels. The magnitude of spontaneous activity of these receptors was correlated with the molecular volume of the residue at 265 for both homomeric and heteromeric GABA(A) receptors, suggesting that the spontaneous activity of the beta1 subunit-containing GABA(A) receptors may be mediated through a similar molecular mechanism that is dependent on the molecular volume of the residue at 265. C1 NIAAA, Lab Mol & Cellular Neurobiol, NIH, Bethesda, MD 20892 USA. RP Zhang, L (reprint author), NIAAA, Lab Mol & Cellular Neurobiol, NIH, Pk Bldg,Rm 150, Bethesda, MD 20892 USA. EM lzhang@niaaa.nih.gov NR 46 TC 15 Z9 16 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 28 PY 2004 VL 279 IS 22 BP 22833 EP 22840 DI 10.1074/jbc.M402577200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 822WI UT WOS:000221570900008 PM 15014066 ER PT J AU Wu, JE Basso, F Shamburek, RD Amar, MJA Vaisman, B Szakacs, G Joyce, C Tansey, T Freeman, L Paigen, BJ Thomas, F Brewer, HB Santamarina-Fojo, S AF Wu, JE Basso, F Shamburek, RD Amar, MJA Vaisman, B Szakacs, G Joyce, C Tansey, T Freeman, L Paigen, BJ Thomas, F Brewer, HB Santamarina-Fojo, S TI Hepatic ABCG5 and ABCG8 overexpression increases hepatobiliary sterol transport but does not alter aortic atherosclerosis in transgenic mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BILIARY CHOLESTEROL SECRETION; INCREASED SITOSTEROL ABSORPTION; DENSITY-LIPOPROTEIN RECEPTOR; PLASMA RATIO METHOD; DIETARY-CHOLESTEROL; BETA-SITOSTEROLEMIA; XANTHOMATOSIS; MOUSE; PHYTOSTEROLEMIA; ACCUMULATION AB The individual roles of hepatic versus intestinal ABCG5 and ABCG8 in sterol transport have not yet been investigated. To determine the specific contribution of liver ABCG5/G8 to sterol transport and atherosclerosis, we generated transgenic mice that overexpress human ABCG5 and ABCG8 in the liver but not intestine (liver G5/G8-Tg) in three different genetic backgrounds: C57B1/6, apoE-KO, and low density lipoprotein receptor (LDLr)-KO. Hepatic overexpression of ABCG5/G8 enhanced hepatobiliary secretion of cholesterol and plant sterols by 1.5-2-fold, increased the amount of intestinal cholesterol available for absorption and fecal excretion by up to 27%, and decreased the accumulation of plant sterols in plasma by similar to25%. However, it did not alter fractional intestinal cholesterol absorption, fecal neutral sterol excretion, hepatic cholesterol concentrations, or hepatic cholesterol synthesis. Consequently, overexpression of ABCG5/G8 in only the liver had no effect on the plasma lipid profile, including cholesterol, HDL-C, and non-HDL-C, or on the development of proximal aortic atherosclerosis in C57B1/6, apoE-KO, or LDLr-KO mice. Thus, liver ABCG5/G8 facilitate the secretion of liver sterols into bile and serve as an alternative mechanism, independent of intestinal ABCG5/G8, to protect against the accumulation of dietary plant sterols in plasma. However, in the absence of changes in fractional intestinal cholesterol absorption, increased secretion of sterols into bile induced by hepatic overexpression of ABCG5/G8 was not sufficient to alter hepatic cholesterol balance, enhance cholesterol removal from the body or to alter atherogenic risk in liver G5/G8-Tg mice. These findings demonstrate that overexpression of ABCG5/G8 in the liver profoundly alters hepatic but not intestinal sterol transport, identifying distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism. C1 NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Santamarina-Fojo, S (reprint author), NHLBI, Mol Dis Branch, NIH, Bldg 10,Rm 7N115, Bethesda, MD 20892 USA. EM silvia@mdb.nhlbi.nih.gov RI Szakacs, Gergely/A-2580-2009 OI Szakacs, Gergely/0000-0002-9311-7827 NR 51 TC 43 Z9 44 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 MAY 28 PY 2004 VL 279 IS 22 BP 22913 EP 22925 DI 10.1074/jbc.M402838200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 822WI UT WOS:000221570900018 PM 15044450 ER PT J AU Yakovleva, L Handy, CJ Sayer, JM Pirrung, M Jerina, DM Shuman, S AF Yakovleva, L Handy, CJ Sayer, JM Pirrung, M Jerina, DM Shuman, S TI Benzo[c]phenanthrene adducts and nogalamycin inhibit DNA transesterification by vaccinia topoisomerase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SITE-SPECIFIC INTERACTION; CODON 61 SEQUENCE; SOLUTION CONFORMATION; VIRUS TOPOISOMERASE; DIOL EPOXIDE; MINOR-GROOVE; OPPOSITE DT; DUPLEX DNA; BINDING; CLEAVAGE AB Vaccinia DNA topoisomerase forms a covalent DNA-(3'-phosphotyrosyl)-enzyme intermediate at a specific target site 5'-C(+5)C(+4)C(+3)T(+2)T(+1)pdown arrowN(-1) in duplex DNA. Here we study the effects of position-specific DNA intercalators on the rate and extent of single-turnover DNA transesterification. Chiral C-1 R and S trans-opened 3,4-diol 1,2-epoxide adducts of benzo[c] phenanthrene (BcPh) were introduced at single N-2-deoxyguanosine and N-6-deoxyadenosine positions within the 3'-G(+5)G(+4)G(+3)A(+2)A(+1)T(-1)A(-2) sequence of the nonscissile DNA strand. Transesterification was unaffected by BcPh intercalation between the +6 and +5 base pairs, slowed 4-fold by intercalation between the +5 and +4 base pairs, and virtually abolished by BcPh intercalation between the +4 and +3 base pairs and the +3 and +2 base pairs. Intercalation between the +2 and +1 base pairs by the +2R BcPh dA adduct abolished transesterification, whereas the overlapping +1S BcPh dA adduct slowed the rate of transesterification by a factor of 2700, with little effect upon the extent of the reaction. Intercalation at the scissile phosphodiester (between the +1 and -1 base pairs) slowed transesterification by a factor of 450. BcPh intercalation between the -1 and -2 base pairs slowed cleavage by two orders of magnitude, but intercalation between the -2 and -3 base pairs had little effect. The anthracycline drug nogalamycin, a non-covalent intercalator with preference for 5'-TG dinucleotides, inhibited the single-turnover DNA cleavage reaction of vaccinia topoisomerase with an IC50 of 0.7 muM. Nogalamycin was most effective when the drug was preincubated with DNA and when the cleavage target site was 5'-CCCTTdown arrowG instead of 5'-CCCTTdown arrowA. These findings demarcate upstream and downstream boundaries of the functional interface of vaccinia topoisomerase with its DNA target site. C1 Sloan Kettering Inst, Program Mol Biol, New York, NY 10021 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Duke Univ, Dept Chem, Durham, NC 27708 USA. RP Shuman, S (reprint author), Sloan Kettering Inst, Program Mol Biol, New York, NY 10021 USA. EM s-shuman@ski.mskcc.org FU NIAID NIH HHS [AI053471]; NIGMS NIH HHS [GM46330] NR 55 TC 14 Z9 16 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 28 PY 2004 VL 279 IS 22 BP 23335 EP 23342 DI 10.1074/jbc.M401203200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 822WI UT WOS:000221570900068 PM 15044474 ER PT J AU Moody, TW Mantey, SA Pradhan, TK Schumann, M Nakagawa, T Martinez, A Fuselier, J Coy, DH Jensen, RT AF Moody, TW Mantey, SA Pradhan, TK Schumann, M Nakagawa, T Martinez, A Fuselier, J Coy, DH Jensen, RT TI Development of high affinity camptothecin-bombesin conjugates that have targeted cytotoxicity for bombesin receptor-containing tumor cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GASTRIN-RELEASING-PEPTIDE; LUNG-CANCER; EXPRESSED RECEPTORS; DOWN-REGULATION; BINDING-SITES; NEUROMEDIN-B; SUBTYPE 3; GROWTH; INTERNALIZATION; AUTOCRINE AB Mammalian bombesin (BN) receptors are among those most frequently overexpressed by a number of common tumors including prostate, breast, lung, and colon cancers. The aim of this study was to develop a camptothecin-bombesin (CPT-BN) conjugate that interacts with all classes of BN receptors and possibly functions as a prodrug via a labile linker with site-specific cytotoxicity for cancer cells bearing these receptors. CPT was coupled to analogs of [D-Tyr(6), beta-Ala(11), Phe(13), Nle(14)] BN-(6 - 14) (BA0) using carbamate linkers (L1 and L2) with built-in nucleophile-assisted releasing groups for intracellular cleavage of free cytotoxic agents. One conjugate, CPT-L2-BA3, bound to all three BN receptor classes with high affinity and functioned as a full agonist at each. I-125-CPT-L2-BA3 was rapidly internalized by cells expressing each BN receptor class and, using fluorescent imaging, was found to co-localize with BN receptors initially and later to be internalized in cytoplasmic compartments. HPLC analysis of internalized ligand showed that 40% was intact, 25% was metabolized by releasing free CPT, and 35% was metabolized to other breakdown products. CPT-L2-BA3 inhibited the growth of NCI-H1299 non-small cell lung cancer cells in 3-(4,5-dimethylthiazol-2- yl)- 2.5-diphenyl-2H-tetrazolium bromide (MTT) and clonal growth assays. CPT-L2-BA3 was cytotoxic in an MTT assay for cells transfected with each class of BN receptor; however, it had significantly less effect in cells lacking BN receptors. These results indicate that CTP-L2-BA3 is a potent agonist that is cytotoxic for cells overexpressing any of the three BN receptor classes and functions as a prodrug for receptor-mediated cytoxicity. It therefore should be a useful prototype to explore the effectiveness of tumor-specific cytotoxicity delivery using a receptor-mediated mechanism. C1 NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. Tulane Univ, Hlth Sci Ctr, Dept Med, Peptide Res Labs, New Orleans, LA 70112 USA. RP Jensen, RT (reprint author), NIDDK, Digest Dis Branch, NIH, Bldg 10,Rm 9C203,10 Ctr Dr MSC 1804, Bethesda, MD 20892 USA. EM robertj@intra.niddk.nih.gov RI Martinez, Alfredo/A-3077-2013; Schumann, Michael/K-6426-2013 OI Martinez, Alfredo/0000-0003-4882-4044; Schumann, Michael/0000-0001-6391-9979 NR 42 TC 54 Z9 55 U1 3 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 MAY 28 PY 2004 VL 279 IS 22 BP 23580 EP 23589 DI 10.1074/jbc.M401938200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 822WI UT WOS:000221570900098 PM 15016826 ER PT J AU Kim, DJ Akiyama, TE Harman, FS Burns, AM Shan, WW Ward, JM Kennett, MJ Gonzalez, FJ Peters, JM AF Kim, DJ Akiyama, TE Harman, FS Burns, AM Shan, WW Ward, JM Kennett, MJ Gonzalez, FJ Peters, JM TI Peroxisome proliferator-activated receptor beta (delta)-dependent regulation of ubiquitin C expression contributes to attenuation of skin carcinogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PPAR-GAMMA; GENE-EXPRESSION; LIPOPROTEIN METABOLISM; TRANSCRIPTION FACTORS; TARGETED DISRUPTION; LIPID-METABOLISM; CANCER CELLS; FATTY-ACIDS; ADULT-RAT; DELTA AB The role of peroxisome proliferator-activated receptor-beta( PPARbeta) in the molecular regulation of skin carcinogenesis was examined. Increased caspase-3 activity associated with apoptosis was found in the skin of wildtype mice after tumor promotion with 12-O-tetradecanoylphorbol-13- acetate, and this effect was diminished in PPARbeta-null mice. The onset of tumor formation, tumor size, and tumor multiplicity induced from a two-stage carcinogen bioassay ( 7,12-dimethylbenz[a] anthracene/ 12-O-tetradecanoylphorbol-13- acetate) were significantly enhanced in PPARbeta-null mice compared with wild-type mice. To begin to characterize the molecular changes underlying this PPARbeta-dependent phenotype, microarray analysis was performed and a number of differentially regulated gene products were identified including ubiquitin C. Subsequent promoter analysis, reporter gene assays, site-directed mutagenesis, and electrophoretic mobility shift assays provide evidence that PPARbeta regulates ubiquitin C expression, and that ubiquitination of proteins is influenced by PPARbeta. These results strongly suggest that activation of PPARbeta-dependent target genes provides a novel strategy to inhibit tumor promotion and carcinogenesis. C1 Penn State Univ, Dept Vet Sci, Fenske Lab 226, University Pk, PA 16802 USA. Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. Penn State Univ, Grad Program Biochem Microbiol Mol Biol, University Pk, PA 16802 USA. Penn State Univ, Grad Program Genet, University Pk, PA 16802 USA. Penn State Univ, Grad Program Mol Toxicol, Huck Inst Life Sci, University Pk, PA 16802 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. NCI, Vet & Tumor Pathol Sect, Ctr Canc Res, Frederick, MD 21702 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet Sci, Fenske Lab 226, University Pk, PA 16802 USA. EM jmp21@psu.edu RI Peters, Jeffrey/D-8847-2011 FU NCI NIH HHS [R01 CA89607] NR 58 TC 72 Z9 72 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 MAY 28 PY 2004 VL 279 IS 22 BP 23719 EP 23727 DI 10.1074/jbc.M312063200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 822WI UT WOS:000221570900114 PM 15033975 ER PT J AU Baxa, U Ross, PD Wickner, RB Steven, AC AF Baxa, U Ross, PD Wickner, RB Steven, AC TI The N-terminal prion domain of Ure2p converts from an unfolded to a thermally resistant conformation upon filament formation SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE yeast prion; amyloid; prionogenesis; differential scanning calorimetry; electron microscopy ID SACCHAROMYCES-CEREVISIAE; PROTEIN URE2; NITROGEN REGULATION; AMYLOID FORMATION; IN-VITRO; GLUTATHIONE; STABILITY; FIBRILS; REGION; CELLS AB According to the "amyloid backbone" model of Ure2p prionogenesis, the N-terminal domain of Ure2p polymerizes to form an amyloid filament backbone surrounded by the C-terminal domains. The latter domains retain their native glutathione-S-transferase (GST)-like fold but are sterically inactivated from their regulatory role in nitrogen catabolism. We have tested this model by differential scanning calorimetry of soluble and filamentous Ure2p and of soluble C-terminal domains, combined with electron microscopy. As predicted, the C-terminal domains respond to thermal perturbation identically in all three states, exhibiting a single endotherm at 76degreesC. In contrast, no thermal signal was associated with the N-terminal domains: in the soluble state of Ure2p, because they are unfolded; in the filamentous state, because their robust amyloid conformation resists heating to 100 degreesC. Published by Elsevier Ltd. C1 NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. EM alasdair_steven@nih.gov NR 28 TC 20 Z9 20 U1 0 U2 4 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 MAY 28 PY 2004 VL 339 IS 2 BP 259 EP 264 DI 10.1016/j.jmb.2004.03.033 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 822SZ UT WOS:000221561800002 PM 15136031 ER PT J AU Lazar, J Szabo, T Marincsak, R Kovacs, L Blumberg, PM Biro, T AF Lazar, J Szabo, T Marincsak, R Kovacs, L Blumberg, PM Biro, T TI Sensitization of recombinant vanilloid receptor-1 by various neurotrophic factors SO LIFE SCIENCES LA English DT Article DE vanilloid receptor-1; neurotrophins; sensitization; calcium; heterologous expression system ID DEPENDENT PROTEIN-KINASE; GROWTH-FACTOR NGF; SIGNAL-TRANSDUCTION; CAPSAICIN RECEPTOR; SENSORY NEURONS; MICE LACKING; TRK RECEPTORS; NERVE-FIBERS; PAIN PATHWAY; MURINE SKIN AB The vanilloid receptor (VR1) is a central integrator molecule of nociceptive stimuli. In this study, we have measured the effects of various neurotrophins (nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and -4) on recombinant rat VR1-mediated intracellular calcium rise in response to capsaicin in VR1/C6 cells. Our results clearly show that all neurotrophins sensitize the VR1 to capsaicin. Furthermore, using K252a, an inhibitor of tyrosine kinases, we present that actions of neurotrophins are mediated by the trk (A, B, C) receptors expressed in these cells. These data argue for the putative roles of neurotrophins in inducing inflammatory (thermal) hyperalgesia via VR1. (C) 2004 Elsevier Inc. All rights reserved. C1 Hungarian Acad Sci, Dept Physiol, H-4012 Debrecen, Hungary. Univ Debrecen, Med & Hlth Sci Ctr, Res Ctr Mol Med, Dept Pediat, Debrecen, Hungary. NCI, Mol Mech Tumor Promot Sect, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. Hungarian Acad Sci, Cell Physiol Res Grp, H-4012 Debrecen, Hungary. RP Biro, T (reprint author), Hungarian Acad Sci, Dept Physiol, Nagyerdei Krt 98,POB 22, H-4012 Debrecen, Hungary. EM biro@phys.dote.hu NR 41 TC 16 Z9 20 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAY 28 PY 2004 VL 75 IS 2 BP 153 EP 163 DI 10.1016/j.lfs.2003.11.023 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 819MN UT WOS:000221319100003 PM 15120568 ER PT J AU Zerhouni, EA AF Zerhouni, EA TI Global workforce bolsters U.S. science SO SCIENCE LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. RP Zerhouni, EA (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 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 MAY 28 PY 2004 VL 304 IS 5675 BP 1211 EP 1211 DI 10.1126/science.304.5675.1211 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 824EV UT WOS:000221669600001 PM 15166330 ER PT J AU Norbury, CC Basta, S Donohue, KB Tscharke, DC Princiotta, MF Berglund, P Gibbs, J Bennink, JR Yewdell, JW AF Norbury, CC Basta, S Donohue, KB Tscharke, DC Princiotta, MF Berglund, P Gibbs, J Bennink, JR Yewdell, JW TI CD8(+)T cell cross-priming via transfer of proteasome substrates SO SCIENCE LA English DT Article ID ANTIGEN-PRESENTING CELLS; CLASS-I MOLECULES; ENDOPLASMIC-RETICULUM; GENE-PRODUCTS; CTL RESPONSES; CUTTING EDGE; PEPTIDES; VIVO; GENERATION; MECHANISMS AB "Cross-priming" describes the activation of naive CD8(+) T cells by professional antigen-presenting cells that have acquired viral or tumor antigens from "donor" cells. Antigen transfer is believed to be mediated by donor cell-derived molecular chaperones bearing short peptide ligands generated by proteasome degradation of protein antigens. We show here that cross-priming is based on the transfer of proteasome substrates rather than peptides. These findings are potentially important for the rational design of vaccines that elicit CD8(+) T cell responses. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Penn State Univ, Coll Med, Dept Microbiol & Immunol, Hershey, PA 17033 USA. Penn State Univ, Coll Med, Penn State Univ Huck Inst Life Sci, Integrat Biosci Grad Program, Hershey, PA 17033 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jyewdell@niaid.nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012; Tscharke, David/C-9133-2009 OI Tscharke, David/0000-0001-6825-9172 FU NIAID NIH HHS [AI-056094-01] NR 22 TC 217 Z9 218 U1 2 U2 4 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 MAY 28 PY 2004 VL 304 IS 5675 BP 1318 EP 1321 DI 10.1126/science.1096378 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 824EV UT WOS:000221669600053 PM 15166379 ER PT J AU Collins, FS AF Collins, FS TI The case for a US prospective cohort study of genes and environment SO NATURE LA English DT Editorial Material ID ASSOCIATION; DISEASE AB Information from the Human Genome Project will be vital for defining the genetic and environmental factors that contribute to health and disease. Well-designed case-control studies of people with and without a particular disease are essential for this, but rigorous and unbiased conclusions about the causes of diseases and their population-wide impact will require a representative population to be monitored over time ( a prospective cohort study). The time is right for the United States to consider such a project. C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NHGRI, NIH, Bldg 31,Room 4B09,MSC 2152,31 Ctr Dr, Bethesda, MD 20892 USA. EM fc23a@nih.gov NR 14 TC 155 Z9 159 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 27 PY 2004 VL 429 IS 6990 BP 475 EP 477 DI 10.1038/nature02628 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 823WN UT WOS:000221644600051 PM 15164074 ER PT J AU Thompson, IM Pauler, DK Goodman, PJ Tangen, CM Lucia, MS Parnes, HL Minasian, LM Ford, LG Lippman, SM Crawford, ED Crowley, JJ Coltman, CA AF Thompson, IM Pauler, DK Goodman, PJ Tangen, CM Lucia, MS Parnes, HL Minasian, LM Ford, LG Lippman, SM Crawford, ED Crowley, JJ Coltman, CA TI Prevalence of prostate cancer among men with a prostate-specific antigen level <= 4.0 ng per milliliter SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ACID-PHOSPHATASE; PREVENTION TRIAL; ULTRASOUND; MARKERS; DIAGNOSIS; CARCINOMA; MORTALITY; BIOPSY; SERUM AB BACKGROUND: The optimal upper limit of the normal range for prostate-specific antigen (PSA) is unknown. We investigated the prevalence of prostate cancer among men in the Prostate Cancer Prevention Trial who had a PSA level of 4.0 ng per milliliter or less. METHODS: Of 18,882 men enrolled in the prevention trial, 9459 were randomly assigned to receive placebo and had an annual measurement of PSA and a digital rectal examination. Among these 9459 men, 2950 men never had a PSA level of more than 4.0 ng per milliliter or an abnormal digital rectal examination, had a final PSA determination, and underwent a prostate biopsy after being in the study for seven years. RESULTS: Among the 2950 men (age range, 62 to 91 years), prostate cancer was diagnosed in 449 (15.2 percent); 67 of these 449 cancers (14.9 percent) had a Gleason score of 7 or higher. The prevalence of prostate cancer was 6.6 percent among men with a PSA level of up to 0.5 ng per milliliter, 10.1 percent among those with values of 0.6 to 1.0 ng per milliliter, 17.0 percent among those with values of 1.1 to 2.0 ng per milliliter, 23.9 percent among those with values of 2.1 to 3.0 ng per milliliter, and 26.9 percent among those with values of 3.1 to 4.0 ng per milliliter. The prevalence of high-grade cancers increased from 12.5 percent of cancers associated with a PSA level of 0.5 ng per milliliter or less to 25.0 percent of cancers associated with a PSA level of 3.1 to 4.0 ng per milliliter. CONCLUSIONS: Biopsy-detected prostate cancer, including high-grade cancers, is not rare among men with PSA levels of 4.0 ng per milliliter or less -- levels generally thought to be in the normal range. C1 SW Oncol Grp SWOG 9217, Operat Off, San Antonio, TX 78245 USA. Univ Texas, Hlth Sci Ctr, Dept Surg, Div Urol, San Antonio, TX 78284 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. Canc Res & Biostat, Seattle, WA USA. RP Thompson, IM (reprint author), SW Oncol Grp SWOG 9217, Operat Off, 14980 Omicron Dr, San Antonio, TX 78245 USA. FU NCI NIH HHS [CA37429, CA35178, CA45808] NR 32 TC 1216 Z9 1287 U1 6 U2 71 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 27 PY 2004 VL 350 IS 22 BP 2239 EP 2246 DI 10.1056/NEJMoa031918 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 823VP UT WOS:000221641900004 PM 15163773 ER PT J AU Rosing, DR AF Rosing, DR TI Effusive - Constrictive pericarditis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID RESTRICTIVE CARDIOMYOPATHY C1 NIH, Bethesda, MD 20892 USA. RP Rosing, DR (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM rosingd@nhlbi.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 27 PY 2004 VL 350 IS 22 BP 2311 EP 2311 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 823VP UT WOS:000221641900030 ER PT J AU Knockaert, M Blondel, M Bach, S Leost, M Elbi, C Hager, GL Nagy, SR Han, D Denison, M Ffrench, M Ryan, XZP Magiatis, P Polychronopoulos, P Greengard, P Skaltsounis, L Meijer, L AF Knockaert, M Blondel, M Bach, S Leost, M Elbi, C Hager, GL Nagy, SR Han, D Denison, M Ffrench, M Ryan, XZP Magiatis, P Polychronopoulos, P Greengard, P Skaltsounis, L Meijer, L TI Independent actions on cyclin-dependent kinases and aryl hydrocarbon receptor mediate the antiproliferative effects of indirubins SO ONCOGENE LA English DT Article DE aryl hydrocarbon receptor; indirubin; cyclin-dependent kinase; glycogen synthase kinase; GSK-3 beta; kinase inhibitor; cancer ID AH RECEPTOR; CELL-CYCLE; ARYLHYDROCARBON RECEPTOR; RETINOBLASTOMA PROTEIN; CRYSTAL-STRUCTURE; DIOXIN RECEPTOR; HEPATOMA-CELLS; MESSENGER-RNAS; TYRIAN PURPLE; CANCER-CELLS AB Indirubin, a bis-indole obtained from various natural sources, is responsible for the reported antileukemia activity of a Chinese Medicinal recipe, Danggui Longhui Wan. However, its molecular mechanism of action is still not well understood. In addition to inhibition of cyclin-dependent kinases and glycogen synthase kinase-3, indirubins have been reported to activate the aryl hydrocarbon receptor (AhR), a cotranscriptional factor. Here, we confirm the interaction of AhR and indirubin using a series of indirubin derivatives and show that their binding modes to AhR and to protein kinases are unrelated. As reported for other AhR ligands, binding of indirubins to AhR leads to its nuclear translocation. Furthermore, the apparent survival of AhR-/- and +/+ cells, as measured by the MTT assay, is equally sensitive to the kinase-inhibiting indirubins. Thus, the cytotoxic effects of indirubins are AhR-independent and more likely to be linked to protein kinase inhibition. In contrast, a dramatic cytostatic effect, as measured by actual cell counts and associated with a sharp G1 phase arrest, is induced by 1-methyl-indirubins, a subfamily of AhR-active but kinase-inactive indirubins. As shown for TCDD (dioxin), this effect appears to be mediated through the AhR-dependent expression of p27(KIP1). Altogether these results suggest that AhR activation, rather than kinase inhibition, is responsible for the cytostatic effects of some indirubins. In contrast, kinase inhibition, rather than AhR activation, represents the main mechanism underlying the cytotoxic properties of this class of promising antitumor molecules. C1 CNRS, Cell Cycle Grp, F-29682 Roscoff, France. Biol Stn, F-29682 Roscoff, France. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. Univ Calif Davis, Dept Environm Toxicol, Davis, CA 95616 USA. Univ Lyon 1, Lab Cytol Analyt & Cytogenet Mol, F-69373 Lyon 08, France. Rockefeller Univ, Mol & Cellular Neurosci Lab, New York, NY 10021 USA. Univ Athens, Dept Pharm, Div Pharmacognosy & Nat Prod Chem, GR-15771 Athens, Greece. RP Meijer, L (reprint author), CNRS, Cell Cycle Grp, BP 74, F-29682 Roscoff, France. EM meijer@sb-roscoff.fr RI Magiatis, Prokopios/A-2008-2008 FU NIEHS NIH HHS [5P42ES04699] NR 72 TC 78 Z9 82 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 27 PY 2004 VL 23 IS 25 BP 4400 EP 4412 DI 10.1038/sj.onc.1207535 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 824CJ UT WOS:000221661300006 PM 15077192 ER PT J AU Dhar, A Hu, J Reeves, R Resar, LMS Colburn, NH AF Dhar, A Hu, J Reeves, R Resar, LMS Colburn, NH TI Dominant-negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation SO ONCOGENE LA English DT Article DE TAM67 target; AP-1; HMGA1; tumor promoter; transformation; JB6 ID NF-KAPPA-B; INHIBITS AP-1 TRANSACTIVATION; ACTIVATED PROTEIN-KINASE; MAMMARY EPITHELIAL-CELLS; MOUSE EPIDERMAL-CELLS; JB6 CELLS; NEOPLASTIC TRANSFORMATION; TRANSCRIPTION FACTOR; INCREASED EXPRESSION; SKIN CARCINOGENESIS AB Activation of the transcription factor AP-1 (activator protein-1) is required for tumor promotion and maintenance of malignant phenotype. A number of AP-1-regulated genes that play a role in tumor progression have been identified. However, AP-1-regulated genes driving tumor induction are yet to be defined. Previous studies have established that expression of a dominant-negative c-Jun (TAM67) inhibits phorbol 12-tetradecanoyl-13-acetate (TPA)-induced AP-1 transactivation as well as transformation in mouse epidermal JB6/P+ cells and tumor promotion in mouse skin carcinogenesis. In this study, we utilized the tumor promotion-sensitive JB6/P+ cells to identify AP-1-regulated TAM67 target genes and to establish causal significance in transformation for one target gene. A 2700 cDNA microarray was queried with RNA from TPA-treated P+ cells with or without TAM67 expression. Under conditions in which TAM expression inhibited TPA-induced transformation, microarray analysis identified a subset of six genes induced by TPA and suppressed by TAM67. One of the identified genes, the high-mobility group protein A1 (Hmga1) is induced by TPA in P+, but not in transformation-resistant P cells. We show that TPA induction of the architectural transcription factor HMGA1 is inhibited by TAM67, is extracellular-signal-regulated kinase (ERK)-activation dependent, and is mediated by AP-1. HMGA1 antisense construct transfected into P+ cells blocked HMGA1 protein expression and inhibited TPA-induced transformation indicating that HMGA1 is required for transformation. HMGA1 is not however sufficient as HMGA1a or HMGA1b overexpression did not confer transformation sensitivity on P- cells. Although HMGA1 expression is ERK dependent, it is not the only ERK-dependent event required for transformation because it does not suffice to rescue ERK-deficient P- cells. Our study shows (a) TAM 67 when it inhibits AP-1 and transformation, targets a relatively small number of genes; (b) HMGA1, a TAM67 target gene, is causally related to transformation and therefore a potentially important target for cancer prevention. C1 NCI, Gene Regulat Sect, Lab Canc Prevent, CCR, Ft Detrick, MD 21702 USA. Washington State Univ, Sch Mol Biosci, Dept Biochem, Pullman, WA 99164 USA. Johns Hopkins Univ, Sch Med, Div Pediat Hematol, Baltimore, MD 21205 USA. RP Dhar, A (reprint author), NCI, Gene Regulat Sect, Lab Canc Prevent, CCR, Bldg 567,Rm 180,Chandler St, Ft Detrick, MD 21702 USA. EM adhar@ncifcrf.gov RI Hu, Jing/M-3130-2014 NR 68 TC 37 Z9 40 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 MAY 27 PY 2004 VL 23 IS 25 BP 4466 EP 4476 DI 10.1038/sj.onc.1207581 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 824CJ UT WOS:000221661300012 PM 15064752 ER PT J AU Chen, HM Ikeda, SR AF Chen, HM Ikeda, SR TI Modulation of ion channels and synaptic transmission by a human sensory neuron-specific G-protein-coupled receptor, SNSR4/mrgX1, heterologously expressed in cultured rat neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE channel; sympathetic; dorsal root ganglion; nociception; pain; neuropeptide ID DORSAL-ROOT GANGLION; BETA-GAMMA-SUBUNITS; VOLTAGE-DEPENDENT MODULATION; CALCIUM-CHANNELS; SYMPATHETIC NEURONS; CA2+ CHANNELS; NEUROTRANSMITTER RELEASE; PRESYNAPTIC INHIBITION; PERIPHERAL NEURONS; CURRENTS AB Human sensory neuron-specific G-protein-coupled receptors (SNSRs) are expressed solely in small diameter primary sensory neurons. This restricted expression pattern is of considerable therapeutic interest because small nociceptors transmit chronic pain messages. The neuronal function of human SNSRs is difficult to assess because rodent orthologs have yet to be clearly defined, and individual isoforms are found only in a small subset of primary sensory neurons. To circumvent this problem, we expressed human SNSR4 (hSNSR4; also known as Hs.mrgX1) in rat superior cervical ganglion (SCG), dorsal root ganglion (DRG), and hippocampal neurons using nuclear injection or recombinant adenoviruses and examined modulation of ion channels and neurotransmission using whole-cell patch-clamp techniques. BAM8 - 22 (a 15 amino acid C-terminal fragment of bovine adrenal medulla peptide 22), a peptide agonist derived from proenkephalin, inhibited high ( but not low) voltage-activated Ca2+ current in both DRG and SCG neurons expressing hSNSR4, whereas no response was detected in control neurons. The Ca2+ current inhibition was concentration dependent and partially sensitive to Pertussis toxin ( PTX) treatment. Additionally, the peptide was highly effective in modulating current arising from M-type K+ channels in SCG neurons expressing hSNSR4. In hippocampal neurons expressing hSNSR4, BAM8 - 22 induced presynaptic inhibition of transmission that was abolished after PTX treatment. Our data indicate that hSNSR4, when heterologously expressed in rat neurons, can be activated by an opioid-related peptide, couples to G(q/11)-proteins as well as PTX-sensitive G(i/o)-proteins, and modulates neuronal Ca2+ channels, K+ channels, and synaptic transmission. C1 NIAAA, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. RP Ikeda, SR (reprint author), NIAAA, Lab Mol Physiol, NIH, Pk Bldg,Room 150,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. EM sikeda@mail.nih.gov OI Ikeda, Stephen/0000-0002-4088-9508 NR 48 TC 39 Z9 41 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 26 PY 2004 VL 24 IS 21 BP 5044 EP 5053 DI 10.1523/JNEUROSCI.0990-04.2004 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 823ZZ UT WOS:000221654400017 PM 15163697 ER PT J AU Ding, KY Gronenborn, AM AF Ding, KY Gronenborn, AM TI Protein backbone H-1(N)-C-13(alpha) and N-15-C-13(alpha) residual dipolar and J couplings: New constraints for NMR structure determination SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ONE-BOND; SENSITIVITY IMPROVEMENT; ANGULAR-DEPENDENCE; CONSTANTS; IDENTIFICATION; SPECTROSCOPY; ANGLES; PHASE; N-15 C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gronenborn, AM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 2, Bethesda, MD 20892 USA. EM gronenborn@nih.gov NR 19 TC 27 Z9 28 U1 0 U2 4 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 MAY 26 PY 2004 VL 126 IS 20 BP 6232 EP 6233 DI 10.1021/ja049049I PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 822GK UT WOS:000221526800016 PM 15149211 ER PT J AU Kuszewski, J Schwieters, CD Garrett, DS Byrd, RA Tjandra, N Clore, GM AF Kuszewski, J Schwieters, CD Garrett, DS Byrd, RA Tjandra, N Clore, GM TI Completely automated, highly error-tolerant macromolecular structure determination from multidimensional nuclear overhauser enhancement spectra and chemical shift assignments SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; MAGNETIC-RESONANCE SPECTROSCOPY; 3-DIMENSIONAL SOLUTION STRUCTURE; POTATO CARBOXYPEPTIDASE INHIBITOR; PROTEIN-STRUCTURE DETERMINATION; RESTRAINED MOLECULAR-DYNAMICS; IMMUNOGLOBULIN-BINDING DOMAIN; AMBIGUOUS DISTANCE RESTRAINTS; HIV-INACTIVATING PROTEIN; RIGID-BODY MINIMIZATION AB The major rate-limiting step in high-throughput NMR protein structure determination involves the calculation of a reliable initial fold, the elimination of incorrect nuclear Overhauser enhancement (NOE) assignments, and the resolution of NOE assignment ambiguities. We present a robust approach to automatically calculate structures with a backbone coordinate accuracy of 1.0-1.5 Angstrom from datasets in which as much as 80% of the long-range NOE information (i.e., between residues separated by more than five positions in the sequence) is incorrect. The current algorithm differs from previously published methods in that it has been expressly designed to ensure that the results from successive cycles are not biased by the global fold of structures generated in preceding cycles. Consequently, the method is highly error tolerant and is not easily funnelled down an incorrect path in either three-dimensional structure or NOE assignment space. The algorithm incorporates three main features: a linear energy function representation of the NOE restraints to allow maximization of the number of simultaneously satisfied restraints during the course of simulated annealing; a method for handling the presence of multiple possible assignments for each NOE cross-peak which avoids local minima by treating each possible assignment as if it were an independent restraint; and a probabilistic method to permit both inactivation and reactivation of all NOE restraints on the fly during the course of simulated annealing. NOE restraints are never removed permanently, thereby significantly reducing the likelihood of becoming trapped in a false minimum of NOE assignment space. The effectiveness of the algorithm is demonstrated using completely automatically peak-picked experimental NOE data from two proteins: interleulkin-4 (136 residues) and cyanovirin-N (101 residues). The limits of the method are explored using simulated data on the 56-residue 131 domain of Streptococcal protein G. C1 NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Natl Canc Inst, Struct Biophys Lab, Frederick, MD 21702 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kuszewski, J (reprint author), NIH, Div Computat Biosci, Ctr Informat Technol, Bldg 12A, Bethesda, MD 20892 USA. EM john.kuszewski@nih.gov; mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008; Byrd, R. Andrew/F-8042-2015 OI Clore, G. Marius/0000-0003-3809-1027; Byrd, R. Andrew/0000-0003-3625-4232 NR 64 TC 59 Z9 59 U1 1 U2 9 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 MAY 26 PY 2004 VL 126 IS 20 BP 6258 EP 6273 DI 10.1021/ja049786h PG 16 WC Chemistry, Multidisciplinary SC Chemistry GA 822GK UT WOS:000221526800028 PM 15149223 ER PT J AU Morshedi-Meibodi, A Evans, JC Levy, D Larson, MG Vasan, RS AF Morshedi-Meibodi, A Evans, JC Levy, D Larson, MG Vasan, RS TI Clinical correlates and prognostic significance of exercise-induced ventricular premature beats in the community - The Framingham Heart Study SO CIRCULATION LA English DT Article DE exercise; mortality; ventricles; cardiovascular diseases; arrhythmia ID APPARENTLY HEALTHY-VOLUNTEERS; PRACTICE GUIDELINES COMMITTEE; CORONARY-ARTERY DISEASE; ASSOCIATION TASK-FORCE; AMERICAN-COLLEGE; ARRHYTHMIAS; PREVALENCE; DEPOLARIZATIONS; FREQUENT; MORTALITY AB Background - Recent investigations suggest that ventricular premature beats during exercise (EVPBs) are associated with increased cardiovascular mortality in asymptomatic individuals, but mechanisms underlying the association are unclear. Method and Results - We evaluated 2885 Framingham Offspring Study participants ( 1397 men; mean age, 43 years) who were free of cardiovascular disease and who underwent a routine exercise stress test; 792 participants (27%) had development of EVPBs ( median, 0.22/min of exercise). Logistic regression was used to evaluate predictors of EVPBs. Cox models were used to examine the relations of infrequent ( less than or equal to median) and frequent ( greater than median) versus no EVPBs to incidence of hard coronary heart disease (CHD) event ( recognized myocardial infarction, coronary insufficiency, or CHD death) and all-cause mortality, adjusting for vascular risk factors and exercise variables. Age and male sex were key correlates of EVPBs. During follow-up ( mean, 15 years), 142 ( 113 men) had a first hard CHD event and 171 participants ( 109 men) died. EVPBs were not associated with hard CHD events but were associated with increased all-cause mortality rates (multivariable-adjusted hazards ratio, 1.86, 95% CI, 1.24 to 2.79 for infrequent, and 1.71, 95% CI, 1.18 to 2.49 for frequent EVPBs versus none). The relations of EVPBs to mortality risk were not influenced by VPB grade, presence of recovery VPBs, left ventricular dysfunction, or an ischemic ST-segment response. Conclusions - In our large, community-based sample of asymptomatic individuals, EVPBs were associated with increased risk of death at a much lower threshold than previously reported. Additional studies are needed to confirm these findings and to clarify the underlying mechanisms. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Harvard Univ, Sch Med, Beth iSrael Hosp, Div Cardiol, Boston, MA USA. Harvard Univ, Sch Med, Beth iSrael Hosp, Div Clin Epidemiol, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Boston Univ, Sch Med, Dept Prevent Med & Epidemiol, Boston, MA 02118 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 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 Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [K24-HL-04334, N01-HC-25195] NR 26 TC 35 Z9 36 U1 1 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 MAY 25 PY 2004 VL 109 IS 20 BP 2417 EP 2422 DI 10.1161/01.CIR.0000129762.41889.41 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 823IN UT WOS:000221604400011 PM 15148273 ER PT J AU Hammond, CAS Goldstein, LB Horner, RD Gonzalea-Rothi, L Gray-Leithe, L Scharver, C Bolser, DC AF Hammond, CAS Goldstein, LB Horner, RD Gonzalea-Rothi, L Gray-Leithe, L Scharver, C Bolser, DC TI A comparison of routine bedside evaluation and aerodynamic measures of voluntary cough to predict aspiration SO CIRCULATION LA English DT Meeting Abstract CT 5th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke CY MAY 15-17, 2003 CL Washington, DC C1 Duke Univ, Durham VAMC, Durham, NC USA. NIH, Bethesda, MD 20892 USA. Univ Florida, Gainesville, FL USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD MAY 25 PY 2004 VL 109 IS 20 MA P51 BP E241 EP E241 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 823IN UT WOS:000221604400078 ER PT J AU Margolis, KL Hildebrant, C Sereika, SM Bastien, A Lovato, JF Nwachuku, C AF Margolis, KL Hildebrant, C Sereika, SM Bastien, A Lovato, JF Nwachuku, C TI Validity and predictors of adherence to metformin in a multiracial clinical trial SO CIRCULATION LA English DT Meeting Abstract CT 2nd Scientific Conference on Compliance in Healthcare and Research CY MAY 17-19, 2004 CL Washington, DC C1 Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. Univ Pittsburgh, Pittsburgh, PA USA. UMDNJ RWJMS Camden Cooper Hlth Syst, Cherry Hill, NJ USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. NHLBI, Bethesda, MD 20892 USA. 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 0009-7322 J9 CIRCULATION JI Circulation PD MAY 25 PY 2004 VL 109 IS 20 MA P9 BP E285 EP E285 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 823IN UT WOS:000221604400292 ER PT J AU Takesono, A Horai, R Mandai, M Dombroski, D Schwartzberg, PL AF Takesono, A Horai, R Mandai, M Dombroski, D Schwartzberg, PL TI Requirement for Tec kihases in chemokine-induced migration and activation of Cdc42 and Rac SO CURRENT BIOLOGY LA English DT Article ID T-CELL-RECEPTOR; PLECKSTRIN HOMOLOGY DOMAIN; FACTOR-INDUCED RECRUITMENT; TYROSINE KINASE; FAMILY KINASES; HUMAN NEUTROPHILS; ITK; CHEMOTAXIS; PROTEIN; GTPASE AB Cell polarization and migration in response to chemokines is essential for proper development of them immune system and activation of immune responses. Recent studies of chemokine signaling have revealed a critical role for P13-Kinase, which is required for polarized membrane association of pleckstrin homology (PH) domain-containing proteins [1, 2] and activation of Rho family GTPases that are essential for cell polarization and actin reorganization [3, 4]. Additional data argue that tyrosine kinases are also important for chemokine-induced Rac activation [4]. However, how and which kinases participate in these pathways remain unclear [5]. We demonstrate here that the Tec kinases Itk and Rlk play an important role in chemokine signaling in T lymphocytes. Chemokine stimulation induced transient membrane association of Itk and phosphorylation of both Itk and Rlk, and purified T bells from R/k(-/-)Itk(-/-) mice exhibited defective migration to multiple chemokines in vitro and decreased homing to lymph nodes upon transfer to wt mice. Expression of a dominant-negative Itk impaired SDF-1alpha-induced migration, cell polarization, and activation of Rac, and Cdc42. Thus, Tec kinases are critical components of signaling pathways required for actin polarization downstream from both antigen and chemokine receptors in T cells. C1 Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. RP Schwartzberg, PL (reprint author), Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. EM pams@nhgd.nih.gov NR 26 TC 71 Z9 73 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD MAY 25 PY 2004 VL 14 IS 10 BP 917 EP 922 DI 10.1016/j.cub.2004.04.011 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 824JC UT WOS:000221681600030 PM 15186750 ER PT J AU Hwang, K Acharya, MR Sausville, EA Zhai, S Woo, EW Venitz, J Figg, WD Sparreboom, A AF Hwang, K Acharya, MR Sausville, EA Zhai, S Woo, EW Venitz, J Figg, WD Sparreboom, A TI Determination of MS-275, a novel histone deacetylase inhibitor, in human plasma by liquid chromatography-electrospray mass spectrometry SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE MS-275; histone deacetylase inhibitor ID VIVO ANTITUMOR-ACTIVITY; TUMORS; CELLS AB A rapid method was developed for the quantitative determination of the novel histone deacetylase inhibitor, MS-275, in human plasma. Calibration curves were constructed in the range of 1-100 ng/ml, and were analyzed using a weight factor proportional to the nominal concentration. Sample pretreatment involved a one-step protein precipitation with acetonitrile of 0.1 ml samples. The analysis was performed on a column (75 mm x 4.6 mm i.d.) packed with 3.5 mum Phenyl-SB material, using methanol-10 mM ammonium formate (55:45 (v/v)) as the mobile phase. The column effluent was monitored by mass spectrometry with positive electrospray ionization. The values for precision and accuracy were always less than or equal to5.58 and <11.4% relative error, respectively. The method was successfully applied to examine the pharmacokinetics of MS-275 in a cancer patient. (C) 2004 Elsevier B.V. All rights reserved. C1 NCI, Clin Pharmacol Res Core, Med Oncol Clin Res Unit, Ctr Canc Res, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Dept Pharmaceut Sci, Richmond, VA 23298 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Res Core, Med Oncol Clin Res Unit, Ctr Canc Res, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 7 TC 12 Z9 12 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD MAY 25 PY 2004 VL 804 IS 2 BP 289 EP 294 DI 10.1016/j.jchromb.2004.01.023 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 814XY UT WOS:000221008600005 PM 15081922 ER PT J AU Markoglou, N Hsuesh, R Wainer, IW AF Markoglou, N Hsuesh, R Wainer, IW TI Immobilized enzyme reactors based upon the flavoenzymes monoamine oxidase A and B SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE immobilized enzyme reactors; flavoenzymes; monoamine oxidases ID CHROMATOGRAPHIC STATIONARY-PHASE; RAT-LIVER MICROSOMES; LIQUID-CHROMATOGRAPHY; INHIBITION; SUPPORT; DEHYDROGENASE AB Monoamine oxidase (MAO) catalyzes the oxidative deamination of amines. The enzyme exists in two forms, MAO-A and MAO-B, which differ in substrate specificity and sensitivity to various inhibitors. Membrane fractions containing either expressed MAO-A or MAO-B have been non-covalently immobilized in the hydrophobic interface of an immobilized artificial membrane (IAM) liquid chromatographic stationary phase. The MAO-containing stationary phases were packed into glass columns to create on-line immobilized enzyme reactors (IMERs) that retained the enzymatic activity of the MAO. The resulting MAO-IMERs were coupled through a switching valve to analytical high performance liquid chromatographic columns. The multi-dimensional chromatographic system was used to characterize the MAO-A (MAO-A-IMER) and MAO-B (MAO-B-IMER) forms of the enzyme including the enzyme kinetic constants associated with enzyme/substrate and enzyme/inhibitor interactions as well as the determination of IC50 values. The results of the study demonstrate that the MAO-A-IMER and the MAO-B-IMER can be used for the on-line screening of substances for MAO-A and MAO-B substrate/inhibitor properties. (C) 2004 Elsevier B.V. All rights reserved. C1 McGill Univ, Montreal Gen Hosp, Ctr Hlth, Montreal, PQ H3G 1A4, Canada. NIA, Bioanalyt & Drug Discovery Unit, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Wainer, IW (reprint author), McGill Univ, Montreal Gen Hosp, Ctr Hlth, Montreal, PQ H3G 1A4, Canada. EM wainerir@grc.nia.nih.gov NR 27 TC 25 Z9 28 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD MAY 25 PY 2004 VL 804 IS 2 BP 295 EP 302 DI 10.1016/j.jchromb.2004.01.031 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 814XY UT WOS:000221008600006 PM 15081923 ER PT J AU Mackay, MT Weiss, SK Adams-Webber, T Ashwal, S Stephens, D Ballaban-Gill, K Baram, TZ Duchowny, M Hirtz, D Pellock, JM Shields, WD Shinnar, S Wyllie, E Snead, OC AF Mackay, MT Weiss, SK Adams-Webber, T Ashwal, S Stephens, D Ballaban-Gill, K Baram, TZ Duchowny, M Hirtz, D Pellock, JM Shields, WD Shinnar, S Wyllie, E Snead, OC TI Practice parameter: Medical treatment of infantile spasms - Report of the American Academy of Neurology and the Child Neurology Society SO NEUROLOGY LA English DT Article ID VISUAL-FIELD CONSTRICTION; WEST-SYNDROME; ACTH THERAPY; SPONTANEOUS REMISSION; VIGABATRIN TREATMENT; PREDNISONE THERAPY; NATURAL-HISTORY; DOSE ACTH; EFFICACY; DRUG AB Objective: To determine the current best practice for treatment of infantile spasms in children. Methods: Database searches of MEDLINE from 1966 and EMBASE from 1980 and searches of reference lists of retrieved articles were performed. Inclusion criteria were the documented presence of infantile spasms and hypsarrhythmia. Outcome measures included complete cessation of spasms, resolution of hypsarrhythmia, relapse rate, developmental outcome, and presence or absence of epilepsy or an epileptiform EEG. One hundred fifty-nine articles were selected for detailed review. Recommendations were based on a four-tiered classification scheme. Results: Adrenocorticotropic hormone (ACTH) is probably effective for the short-term treatment of infantile spasms, but there is insufficient evidence to recommend the optimum dosage and duration of treatment. There is insufficient evidence to determine whether oral corticosteroids are effective. Vigabatrin is possibly effective for the short-term treatment of infantile spasm and is possibly also effective for children with tuberous sclerosis. Concerns about retinal toxicity suggest that serial ophthalmologic screening is required in patients on vigabatrin; however, the data are insufficient to make recommendations regarding the frequency or type of screening. There is insufficient evidence to recommend any other treatment of infantile spasms. There is insufficient evidence to conclude that successful treatment of infantile spasms improves the long-term prognosis. Conclusions: ACTH is probably an effective agent in the short-term treatment of infantile spasms. Vigabatrin is possibly effective. C1 Cleveland Clin Fdn, Cleveland, OH 44195 USA. Virginia Commonwealth Univ, Med Coll Virginia, Richmond, VA 23298 USA. NINDS, NIH, Washington, DC USA. Miami Childrens Hosp, Miami, FL USA. Univ Calif Los Angeles, Mattel Childrens Hosp, Los Angeles, CA 90024 USA. Univ Calif Irvine, Irvine, CA 92717 USA. Albert Einstein Coll Med, Montefiore Med Ctr, New York, NY USA. Loma Linda Univ, Sch Med, Loma Linda, CA 92350 USA. Univ Toronto, Fac Med, Toronto, ON, Canada. Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Royal Childrens Hosp, Melbourne, Vic, Australia. RP Mackay, MT (reprint author), Amer Acad Neurol, Qual Stand Subcomm, 1080 Montreal Ave, St Paul, MN 55116 USA. RI Adams-Webber, Thomasin/A-4241-2011; Baram, Tallie/J-6447-2014 OI Adams-Webber, Thomasin/0000-0003-4623-7225; FU NINDS NIH HHS [R01 NS028912, R01 NS028912-08, R01 NS028912-09] NR 68 TC 192 Z9 210 U1 2 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 25 PY 2004 VL 62 IS 10 BP 1668 EP 1681 PG 14 WC Clinical Neurology SC Neurosciences & Neurology GA 823IJ UT WOS:000221603900004 PM 15159460 ER PT J AU Miller, DW Hague, SM Clarimon, J Baptista, M Gwinn-Hardy, K Cookson, MR Singleton, AB AF Miller, DW Hague, SM Clarimon, J Baptista, M Gwinn-Hardy, K Cookson, MR Singleton, AB TI alpha-Synuclein in blood and brain from familial Parkinson disease with SNCA locus triplication SO NEUROLOGY LA English DT Article ID DEMENTIA AB The authors recently demonstrated that genetic triplication of the SNCA locus causes Parkinson disease. Here it is shown that SNCA triplication results in a doubling in the amount of alpha-synuclein protein in blood. Examination of brain tissue showed a doubling in the level of SNCA message. However, at the protein level in brain, there was a greater effect on deposition of aggregated forms into insoluble fractions than on net expression of soluble alpha-synuclein. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NINDS, Neurogenet Branch, NIH, Bethesda, MD USA. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Gwinn, Katrina/C-2508-2009; Singleton, Andrew/C-3010-2009; OI Clarimon, Jordi/0000-0002-6824-6942 NR 9 TC 186 Z9 193 U1 2 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 25 PY 2004 VL 62 IS 10 BP 1835 EP 1838 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 823IJ UT WOS:000221603900032 PM 15159488 ER PT J AU Kajava, AV Baxa, U Wickner, RB Steven, AC AF Kajava, AV Baxa, U Wickner, RB Steven, AC TI A model for Ure2p prion filaments and other amyloids: The parallel superpleated beta-structure SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SOLID-STATE NMR; SACCHAROMYCES-CEREVISIAE; FIBRIL FORMATION; IN-VITRO; X-RAY; BORDETELLA-PERTUSSIS; PROTEIN DETERMINANT; ANTIFREEZE PROTEIN; CRYSTAL-STRUCTURE; VIRULENCE FACTOR AB In its prion form, Ure2p, a regulator of nitrogen catabolism in Saccharomyces cerevisiae, polymerizes into filaments whereby its C-terminal regulatory domain is inactivated but retains its native fold. The filament has an amyloid fibril backbone formed by the Asn-rich, N-terminal, "prion" domain. The prion domain is also capable of forming fibrils when alone or when fused to other proteins. We have developed a model for the fibril that we call a parallel superpleated beta-structure. In this model, the prion domain is divided into nine seven-residue segments, each with a four-residue strand and a three-residue turn, that zig-zag in a planar serpentine arrangement. Serpentines are stacked axially, in register, generating an array of parallel beta-sheets, with a small and potentially variable left-hand twist. The interior of the filament is mostly stabilized not by packing of apolar side chains but by H-bond networks generated by the stacking of Asn side chains: charged residues are excluded. The model is consistent with current biophysical, biochemical, and structural data (notably, mass-per-unit-length measurements by scanning transmission electron microscopy that gave one subunit rise per 0.47 nm) and is readily adaptable to other amyloids, for instance the core of Sup35p filaments and glutamine expansions in huntingtin. C1 NIAMSD, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Lab, NIH, Bldg 50,1517,50 South Dr,MSC 8025, Bethesda, MD 20892 USA. EM alasdair_steven@nih.gov RI Kajava, Andrey/E-1107-2014 OI Kajava, Andrey/0000-0002-2342-6886 NR 64 TC 120 Z9 124 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 MAY 25 PY 2004 VL 101 IS 21 BP 7885 EP 7890 DI 10.1073/pnas.0402427101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 823ZC UT WOS:000221652000010 PM 15143215 ER PT J AU Arnoult, D Bartle, LM Skaletskaya, A Poncet, D Zamzami, N Park, PU Sharpe, J Youle, RJ Goldmacher, VS AF Arnoult, D Bartle, LM Skaletskaya, A Poncet, D Zamzami, N Park, PU Sharpe, J Youle, RJ Goldmacher, VS TI Cytomegalovirus cell death suppressor vMIA blocks Bax- but not Bak-mediated apoptosis by binding and sequestering Bax at mitochondria SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYTOCHROME-C RELEASE; ADENOVIRUS E1B 19K; BCL-X-L; LOCALIZED INHIBITOR; VIRAL INHIBITOR; BH3 DOMAINS; MEMBRANE; HOMOLOG; HETERODIMERIZATION; OLIGOMERIZATION AB We report that the cytomegalovirus-encoded cell death suppressor vMIA binds Bax and prevents Bax-mediated mitochondrial membrane permeabilization by sequestering Bax at mitochondria in the form of a vMIA-Bax complex. vMIA mutants with a defective mitochondria-targeting domain retain their Bax-binding function but not their ability to suppress mitochondrial membrane permeabilization or cell death. vMIA does not seem to either specifically associate with Bak or suppress Bak-mediated mitochondrial membrane permeabilization. Recent evidence suggests that the contribution of Bax and Bak in the mitochondrial apoptotic signaling pathway depends on the distinct phenotypes of cells, and it appears from our data that vMIA is capable of suppressing apoptosis in cells in which this pathway is dominated by Bax, but not in cells where Bak also plays a role. C1 ImmunoGen Inc, Cambridge, MA 02139 USA. NINDS, Biochem Sect, NIH, Bethesda, MD 20892 USA. Inst Gustave Roussy, UMR 8125, CNRS, F-94850 Villejuif, France. RP Goldmacher, VS (reprint author), ImmunoGen Inc, 128 Sidney St, Cambridge, MA 02139 USA. EM victor.goldmacher@immunogen.com NR 48 TC 128 Z9 132 U1 3 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 MAY 25 PY 2004 VL 101 IS 21 BP 7988 EP 7993 DI 10.1073/pnas.0401897101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 823ZC UT WOS:000221652000028 PM 15148411 ER PT J AU Saporito, RA Garraffo, HM Donnelly, MA Edwards, AL Longino, JT Daly, JW AF Saporito, RA Garraffo, HM Donnelly, MA Edwards, AL Longino, JT Daly, JW TI Formicine ants: An arthropod source for the pumiliotoxin alkaloids of dendrobatid poison frogs SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE allomones; allopumiliotoxins; cardiotonic activity; chemical defense; myrmicine ants ID SODIUM-CHANNEL; SKIN ALKALOIDS; DIET SPECIALIZATION; SYNTHETIC ANALOGS; VENOM ALKALOIDS; FIRE ANTS; BIOSYNTHESIS; EVOLUTION; AMPHIBIA; TOXICITY AB A remarkable diversity of bioactive lipophilic alkaloids is present in the skin of poison frogs and toads worldwide. Originally discovered in neotropical dendrobatid frogs, these alkaloids are now known from mantellid frogs of Madagascar, certain myobatrachid frogs of Australia, and certain bufonid toads of South America. Presumably serving as a passive chemical defense, these alkaloids appear to be sequestered from a variety of alkaloid-containing arthropods. The pumiliotoxins represent a major, widespread, group of alkaloids that are found in virtually all anurans that are chemically defended by the presence of lipophilic alkaloids. Identifying an arthropod source for these alkaloids has been a considerable challenge for chemical ecologists. However, an extensive collection of neotropical forest arthropods has now revealed a putative arthropod source of the pumiliotoxins. Here we report on the presence of pumiliotoxins in formicine ants of the genera Brachymyrmex and Paratrechina, as well as the presence of these ants in the stomach contents of the microsympatric pumiliotoxin-containing dendrobatid frog, Dendrobates pumilio. These pumiliotoxins are major alkaloids in D. pumilio, and Brachymyrmex and Paratrechina ants now represent the only known dietary sources of these toxic alkaloids. These findings further support the significance of ant-specialization and alkaloid sequestration in the evolution of bright warning coloration in poison frogs and toads. C1 NIDDKD, Bioorgan Chem Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA. Evergreen State Coll, Olympia, WA 98505 USA. RP Daly, JW (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM jdaly@nih.gov NR 41 TC 99 Z9 110 U1 3 U2 25 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 25 PY 2004 VL 101 IS 21 BP 8045 EP 8050 DI 10.1073/pnas.0402365101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 823ZC UT WOS:000221652000038 PM 15128938 ER PT J AU Ruf, RG Xu, PX Silvius, D Otto, EA Beekmann, F Muerb, UT Kumar, S Neuhaus, TJ Kemper, MJ Raymond, RM Brophy, PD Berkman, J Gattas, M Hyland, V Ruf, EM Schwartz, C Chang, EH Smith, RJH Stratakis, CA Weil, D Petit, C Hildebrandt, F AF Ruf, RG Xu, PX Silvius, D Otto, EA Beekmann, F Muerb, UT Kumar, S Neuhaus, TJ Kemper, MJ Raymond, RM Brophy, PD Berkman, J Gattas, M Hyland, V Ruf, EM Schwartz, C Chang, EH Smith, RJH Stratakis, CA Weil, D Petit, C Hildebrandt, F TI SIX1 mutations cause branchio-oto-renal syndrome by disruption of EYA1-SIX1-DNA complexes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BOR SYNDROME; VARIABLE EXPRESSIVITY; EYA1; GENE; LOCUS; FAMILIES; DEAFNESS; DEFECTS; KIDNEY; MICE AB Urinary tract malformations constitute the most frequent cause of chronic renal failure in the first two decades of life. Branchio-otic (BO) syndrome is an autosomal dominant developmental disorder characterized by hearing loss. In branchio-oto-renal (BOR) syndrome, malformations of the kidney or urinary tract are associated. Haploinsufficiency for the human gene EYA1, a homologue of the Drosophila gene eyes absent (eya), causes BOR and BO syndromes. We recently mapped a locus for BOR/BO syndrome (BOS3) to human chromosome 14q23.1. Within the 33-megabase critical genetic interval, we located the SIX1, SIX4, and SIX6 genes, which act within a genetic network of EYA and PAX genes to regulate organogenesis. These genes, therefore, represented excellent candidate genes for BOS3. By direct sequencing of exons, we identified three different SIX1 mutations in four BOR/BO kindreds, thus identifying SIX1 as a gene causing BOR and BO syndromes. To elucidate how these mutations cause disease, we analyzed the functional role of these SIX1 mutations with respect to protein-protein and protein-DNA interactions. We demonstrate that all three mutations are crucial for Eya1-Six1 interaction, and the two mutations within the homeodomain region are essential for specific Six1-DNA binding. Identification of SIX1 mutations as causing BOR/BO offers insights into the molecular basis of otic and renal developmental diseases in humans. C1 McLaughlin Inst Biomed Sci, Great Falls, MT 59405 USA. Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. Univ Dusseldorf, Childrens Hosp, D-40225 Dusseldorf, Germany. Boys Town Natl Res Hosp, Dept Genet, Ctr Hereditary & Commun Disorders, Omaha, NE 68131 USA. Univ Zurich, Childrens Hosp, Kinderspital, CH-8032 Zurich, Switzerland. Royal Childrens Hosp, Queensland Clin Genet Serv, Southport, Qld 4215, Australia. Queensland Hlth Pathol Serv, Mol Genet Lab, Brisbane, Qld 4029, Australia. RCH Fdn Lab, Brisbane, Qld 4029, Australia. Greenwood Genet Ctr, Ctr Mol Studies, JC Self Res Inst, Greenwood, SC 29646 USA. Univ Iowa, Interdepartmental Genet Program, Iowa City, IA 52246 USA. Univ Iowa, Dept Otolaryngol, Iowa City, IA 52246 USA. NICHHD, DEB, Sect Endocrinol & Genet, Rockville, MD 20847 USA. Inst Pasteur, INSERM, U587, F-75015 Paris, France. RP Xu, PX (reprint author), McLaughlin Inst Biomed Sci, Great Falls, MT 59405 USA. EM pxu@po.mri.montana.edu; fhilde@umich.edu OI Otto, Edgar/0000-0002-2387-9973 FU NIDCD NIH HHS [R01 DC003544, R01 DC005824, R01-DC03544, R01-DC05824]; NIDCR NIH HHS [1 R01-DE14090-01, R01 DE014090]; NIDDK NIH HHS [R01-DK64640, R01 DK064640] NR 28 TC 185 Z9 202 U1 3 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 MAY 25 PY 2004 VL 101 IS 21 BP 8090 EP 8095 DI 10.1073/pnas.0308475101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 823ZC UT WOS:000221652000046 PM 15141091 ER PT J AU Sun, K Welniak, LA Panoskaltsis-Mortari, A O'Shaughnessy, MJ Liu, HY Barao, I Riordan, W Sitcheran, R Wysocki, C Serody, JS Blazar, BR Sayers, TJ Murphy, WJ AF Sun, K Welniak, LA Panoskaltsis-Mortari, A O'Shaughnessy, MJ Liu, HY Barao, I Riordan, W Sitcheran, R Wysocki, C Serody, JS Blazar, BR Sayers, TJ Murphy, WJ TI Inhibition of acute graft-versus-host disease with retention of graft-versus-tumor effects by the proteasome inhibitor bortezomib SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NF-KAPPA-B; MINOR HISTOCOMPATIBILITY ANTIGENS; MULTIPLE-MYELOMA CELLS; TNF-ALPHA; ACTIVATION; INTERLEUKIN-12; APOPTOSIS; RESPONSES; MECHANISMS; CARCINOMA AB Graft-versus-host disease (GVHD) represents a major hurdle impeding the efficacy of allogeneic bone marrow transplantation (BMT). Bortezomib is a proteasome inhibitor that was recently approved for treatment of myeloma. We found that bortezomib potently inhibited in vitro mixed lymphocyte responses and promoted the apoptosis of alloreactive T cells. Bortezomib given at the time of allogeneic BMT in mice resulted in significant protection from acute GVHD. Reductions in GVHD-associated parameters and biological evidence of proteasome inhibition were observed with this regimen but with no adverse effects on long-term donor reconstitution. Assessment of graft-versus-tumor responses in advanced leukemia-bearing mice demonstrated that only the combination of allogeneic BMT and T cells with bortezomib promoted significant increases in survival. increased cytotoxic T cell killing of the tumor was also observed. Thus, the combination of proteasome inhibition with selective immune attack can markedly increase the efficacy of BMT in cancer. C1 Univ Nevada, Dept Microbiol & Immunol MS320, Reno, NV 89557 USA. Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Pediat, Div Bone Marrow Transplantat, Minneapolis, MN 55455 USA. Millennium Pharmaceut, Cambridge, MA 02139 USA. Univ N Carolina, Sch Med, Lineberger Canc Ctr, Chapel Hill, NC 27599 USA. NCI, Basic Sci Program, SAIC Frederick, Expt Immunol Lab,Ctr Canc Res, Frederick, MD 21702 USA. RP Murphy, WJ (reprint author), Univ Nevada, Dept Microbiol & Immunol MS320, Reno, NV 89557 USA. EM wmurphy@unr.edu RI Sayers, Thomas/G-4859-2015 FU NCI NIH HHS [N01-CO-12400, N01CO12400, R01 CA72669, R01 CA072669, R01 CA102282]; NHLBI NIH HHS [R37 HL056067, 2 R37 HL56067]; NIAID NIH HHS [R01 AI034495, R01 AI 34495] NR 34 TC 175 Z9 188 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 MAY 25 PY 2004 VL 101 IS 21 BP 8120 EP 8125 DI 10.1073/pnas.0401563101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 823ZC UT WOS:000221652000051 PM 15148407 ER PT J AU Gogtay, N Giedd, JN Lusk, L Hayashi, KM Greenstein, D Vaituzis, AC Nugent, TF Herman, DH Clasen, LS Toga, AW Rapoport, JL Thompson, PM AF Gogtay, N Giedd, JN Lusk, L Hayashi, KM Greenstein, D Vaituzis, AC Nugent, TF Herman, DH Clasen, LS Toga, AW Rapoport, JL Thompson, PM TI Dynamic mapping of human cortical development during childhood through early adulthood SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN BRAIN-DEVELOPMENT; GRAY-MATTER LOSS; COGNITIVE-DEVELOPMENT; ONSET SCHIZOPHRENIA; SYNAPTIC DENSITY; PROSOMERIC MODEL; CEREBRAL-CORTEX; FRONTAL-CORTEX; LIFE-SPAN; ADOLESCENCE AB We report the dynamic anatomical sequence of human cortical gray matter development between the age of 4-21 years using quantitative four-dimensional maps and time-lapse sequences. Thirteen healthy children for whom anatomic brain MRI scans were obtained every 2 years, for 8-10 years, were studied. By using models of the cortical surface and sulcal landmarks and a statistical model for gray matter density, human cortical development could be visualized across the age range in a spatiotemporally detailed time-lapse sequence. The resulting time-lapse "movies" reveal that (i) higher-order association cortices mature only after lower-order somatosensory and visual cortices, the functions of which they integrate, are developed, and (ii) phylogenetically older brain areas mature earlier than newer ones. Direct comparison with normal cortical development may help understanding of some neurodevelopmental disorders such as childhood-onset schizophrenia or autism. C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Dept Neurol, Lab Neuro Imaging, Los Angeles, CA 90095 USA. RP Gogtay, N (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Room 3N 202, Bethesda, MD 20892 USA. EM nitin@codon.nih.gov RI Gogtay, Nitin/A-3035-2008; Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU NCRR NIH HHS [P41 RR013642, P41 RR13642, R21 RR019771, R21 RR19771]; NIBIB NIH HHS [R21 EB001561, EB 001561]; NIMH NIH HHS [P20 MH/DA52176] NR 55 TC 2125 Z9 2159 U1 36 U2 269 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 25 PY 2004 VL 101 IS 21 BP 8174 EP 8179 DI 10.1073/pnas.0402680101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 823ZC UT WOS:000221652000060 PM 15148381 ER PT J AU Ward, IM Reina-San-Martin, B Olaru, A Minn, K Tamada, K Lau, JS Cascalho, M Chen, LP Nussenzweig, A Livak, F Nussenzweig, MC Chen, JJ AF Ward, IM Reina-San-Martin, B Olaru, A Minn, K Tamada, K Lau, JS Cascalho, M Chen, LP Nussenzweig, A Livak, F Nussenzweig, MC Chen, JJ TI 53BP1 is required for class switch recombination SO JOURNAL OF CELL BIOLOGY LA English DT Article DE NHEJ; ATM; H2AX; V(D)J recombination; DNA repair ID DOUBLE-STRAND BREAKS; CELL-CYCLE REGULATION; BRCT PROTEIN 53BP1; DNA-DAMAGE; V(D)J RECOMBINATION; HISTONE H2AX; SOMATIC HYPERMUTATION; CIRCULAR DNA; ANTIBODY DIVERSIFICATION; REGION RECOMBINATION AB 53BPI participates early in the DNA damage response and is involved in cell cycle checkpoint control. Moreover, the phenotype of mice and cells deficient in 53BP1 suggests a defect in DNA repair (Ward et al., 2003b). Therefore, we asked whether or not 53BPI would be required for the efficient repair of DNA double strand breaks. Our data indicate that homologous recombination by gene conversion does not depend on 53BPI. Moreover, 53BPI-deficient mice support normal V(D)J recombination, indicating that 53BP1 is not required for "classic" non-homologous end joining. However, class switch recombination is severely impaired in the absence of 53BP1, suggesting that 53BP1 facilitates DNA end joining in a way that is not required or redundant for the efficient closing of RAG-induced strand breaks. These findings are similar to those observed in mice or cells deficient in the tumor suppressors ATM and H2AX, further suggesting that the functions of ATM, H2AX, and 53BP1 are closely linked. C1 Mayo Clin, Div Oncol Res, Rochester, MN 55905 USA. Mayo Clin, Div Immunol, Rochester, MN 55905 USA. Rockefeller Univ, Howard Hughes Med Inst, Lab Mol Immunol, New York, NY 10021 USA. Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Chen, JJ (reprint author), Mayo Clin, Div Oncol Res, 1306 Guggenheim,200 1St St,SW, Rochester, MN 55905 USA. EM Chen.junjie@mayo.edu RI Reina-San-Martin, Bernardo/I-9484-2016; OI Reina-San-Martin, Bernardo/0000-0003-2083-6166; Cascalho, Marilia/0000-0002-2695-3921 FU NCI NIH HHS [CA100109, R01 CA100109] NR 38 TC 181 Z9 187 U1 1 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 MAY 24 PY 2004 VL 165 IS 4 BP 459 EP 464 DI 10.1083/jcb.200403021 PG 6 WC Cell Biology SC Cell Biology GA 824AP UT WOS:000221656200001 PM 15159415 ER PT J AU Shigesada, K van de Sluis, B Liu, PP AF Shigesada, K van de Sluis, B Liu, PP TI Mechanism of leukemogenesis by the inv(16) chimeric gene CBFB/PEBP2B-MHY11 SO ONCOGENE LA English DT Article DE CBF beta-MYH11; CBF beta-SMMHC; inv(16); leukemia; hematopoiesis ID ACUTE MYELOID-LEUKEMIA; MYOSIN HEAVY-CHAIN; SMOOTH-MUSCLE MYOSIN; CBF-BETA-SMMHC; ZINC-FINGER PROTEIN; TRANSCRIPTION FACTOR; FUSION GENE; DNA-BINDING; RUNT DOMAIN; MYELOGENOUS LEUKEMIA AB Inv(16)(p13q22) is associated with acute myeloid leukemia subtype M4Eo that is characterized by the presence of myelomonocytic blasts and atypical eosinophils. This chromosomal rearrangement results in the fusion of CBFB and MYH11 genes. CBFbeta normally interacts with RUNX1 to form a transcriptionally active nuclear complex. The MYH11 gene encodes the smooth muscle myosin heavy chain. The CBFbeta-SMMHC fusion protein is capable of binding to RUNX1 and form dimers and multimers through its myosin tail. Previous results from transgenic mouse models show that Cbfb-MYH11 is able to inhibit dominantly Runx1 function in hematopoiesis, and is a key player in the pathogenesis of leukemia. In recent years, molecular and cellular biological studies have led to the proposal of several models to explain the function of CBFbeta-SMMHC. In this review, we will first focus our attention on the molecular mechanisms proposed in the recent publications. We will next examine recent gene expression pro. ling studies on inv(16) leukemia cells. Finally, we will describe a recent study from one of our labs on the identification of cooperating genes for leukemogenesis with CBFB-MYH11. C1 Kyoto Univ, Inst Virus Res, Dept Cell Biol, Kyoto 6068507, Japan. NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA. RP Shigesada, K (reprint author), Kyoto Univ, Inst Virus Res, Dept Cell Biol, Kyoto 6068507, Japan. EM kshigesa@virus.kyoto-u.ac.jp; pliu@mail.nih.gov RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X NR 81 TC 48 Z9 49 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 MAY 24 PY 2004 VL 23 IS 24 BP 4297 EP 4307 DI 10.1038/sj.onc.1207748 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 823BZ UT WOS:000221586000015 PM 15156186 ER PT J AU Sha, BE Onorato, M Bartlett, JA Bosch, RJ Aga, E Nokta, M Adams, EM Li, XD Eldridge, J Pollard, RB AF Sha, BE Onorato, M Bartlett, JA Bosch, RJ Aga, E Nokta, M Adams, EM Li, XD Eldridge, J Pollard, RB TI Safety and immunogenicity of a polyvalent peptide C4-V3HIV vaccine in conjunction with IL-12 SO AIDS LA English DT Article ID CLINICAL-TRIALS; INTERLEUKIN-12; IMMUNITY AB We examined the safety and immunogenicity of a human leukocyte antigen-based HIV envelope polyvalent synthetic peptide vaccine, C4-V3, alone and in combination with subcutaneous IL-12 in nine HIV-infected patients. Lymphocyte proliferative responses increased threefold or more to all four peptides at two consecutive post-immunization timepoints for four individuals. Three responders had received IL-12, suggesting a possible adjuvant effect of IL-12. Transient mild injection site reactions (7/9) and systemic symptoms (3/9) occurred. C1 Rush Med Coll, Dept Med, Infect Dis Sect, Chicago, IL 60612 USA. Univ Texas, Div Infect Dis, Galveston, TX 77555 USA. Duke Univ, Div Infect Dis, Med Ctr, Durham, NC USA. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Calif Davis, Div Infect Dis, Med Ctr, Sacramento, CA 95817 USA. Wyeth Lederle Vaccines, Pearl River, NY USA. RP Sha, BE (reprint author), Rush Med Coll, Dept Med, Infect Dis Sect, Chicago, IL 60612 USA. FU NIAID NIH HHS [U01-AI-38858, U01-AI-39156, U01-AI 25915, U01-AI 38855, U01-AI-32782] NR 8 TC 6 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 21 PY 2004 VL 18 IS 8 BP 1203 EP 1206 DI 10.1097/01.aids.0000125948.65819.9c PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 827GR UT WOS:000221888200015 PM 15166537 ER PT J AU El-Armouche, A Jaeckel, E Boheler, KR Boknik, P Hertle, B Neumann, J Eschenhagen, T AF El-Armouche, A Jaeckel, E Boheler, KR Boknik, P Hertle, B Neumann, J Eschenhagen, T TI Ouabain treatment is associated with upregulation of phosphatase inhibitor-1 and Na+/Ca2+-exchanger and beta-adrenergic sensitization in rat hearts SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE cardiac glycosides; rat; gene expression; protein phosphatase inhibitor-1; Na+/Ca2+-exchanger; beta-adrenergic signaling ID SARCOPLASMIC-RETICULUM CA2+-ATPASE; MESSENGER-RNA; PROTEIN PHOSPHATASES; CARDIAC-MUSCLE; VENTRICULAR MYOCYTES; TRANSGENIC MICE; PHOSPHORYLATION; PHOSPHOLAMBAN; EXPRESSION; FAILURE AB Cardiac glycosides are widely used in the treatment of congestive heart failure. While the mechanism of the positive inotropic effect after acute application of cardiac glycosides is explained by blockade of the Na+/K+-pump, little is known about consequences of a prolonged therapy. Here male Wistar rats were treated for 4 days with continuous infusions of ouabain (6.5 mg/kg/day) or 0.9% NaCl (control) via osmotic minipumps. Electrically driven (1 Hz, 35 degreesC) papillary muscles from ouabain-treated rats exhibited shorter relaxation time (-15%) and a twofold increase in the sensitivity for the positive inotropic effect of isoprenaline. The density and affinity of beta(1)- and beta(2)-adrenoceptors as well as mRNA and protein levels of stimulatory (G(salpha)) and inhibitory (G(ialpha-2), G(ialpha-3)) G-proteins were unaffected by ouabain. Similarly, SR-Ca2+ -ATPase 2A, phospholamban, ryanodine-receptor expression as well as the oxalate-stimulated Ca-45-uptake of membrane vesicles remained unchanged. However, mRNA abundance of the protein phosphalase inhibitor-1 (I-1) and the Na+/Ca2+ -exchanger (NCX) were increased by 52% and 26%, respectively. I-1 plays an amplifier role in cardiac signaling. Downregulation of I-1 in human heart failure is associated with desensitization of the beta-adrenergic signaling pathway. The present data suggest that the ouabain-induced increase in I-1 expression might be at least partly responsible for the increased isoprenaline sensitivity and increased expression of NCX for the accelerated relaxation after chronic ouabain in this model. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Hamburg, Hosp Eppendorf, Inst Expt & Clin Pharmacol, D-20246 Hamburg, Germany. Hannover Med Sch, Dept Gastroenterol Hepatol & Endocrinol, D-3000 Hannover, Germany. Univ Munster, Inst Pharmacol & Toxicol, D-4400 Munster, Germany. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Eschenhagen, T (reprint author), Univ Hamburg, Hosp Eppendorf, Inst Expt & Clin Pharmacol, Martinistr 52, D-20246 Hamburg, Germany. EM t.eschenhagen@uke.uni-hamburg.de NR 41 TC 4 Z9 4 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 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 21 PY 2004 VL 318 IS 1 BP 219 EP 226 DI 10.1016/j.bbrc.2004.04.015 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 818OK UT WOS:000221254200033 PM 15110776 ER PT J AU Penrose, KJ Garcia-Alai, M de Prat-Gay, G McBride, AA AF Penrose, KJ Garcia-Alai, M de Prat-Gay, G McBride, AA TI Casein kinase II phosphorylation-induced conformational switch triggers degradation of the papillomavirus E2 protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BOVINE PAPILLOMAVIRUS; MITOTIC CHROMOSOMES; CIRCULAR-DICHROISM; COPY NUMBER; TYPE-1; DNA; E1; TRIFLUOROETHANOL; TRANSACTIVATOR; DETERMINANTS AB The major phosphorylation sites of the bovine papillomavirus E2 transactivator protein are two serine residues, 298 and 301, that are located in a flexible hinge region between the DNA binding and transactivation domains. Phosphorylation of serine residue 301 promotes ubiquitination and rapid degradation of the E2 protein by the proteasome pathway. To understand the mechanism through which phosphorylation regulates the intracellular levels of this unique papillomavirus regulatory protein, we have carried out an extensive mutational analysis of the region surrounding the phosphorylation sites of the E2 protein. Our results indicate that casein kinase II phosphorylates serine 301. However, phosphorylation of serine 301 is not a sufficient recognition motif for proteasomal degradation; other residues that directly surround the phosphorylation sites are crucial for E2 degradation. The phenotypes of E2 proteins mutated in this region indicate that phosphorylation of serine 301 induces a conformational change that leads to degradation of the E2 protein. In support of this model, circular dichroism studies of the conformational tendencies of peptides from this region indicate that phosphorylation at position 301 decreases the local thermodynamic stability of this region. Thus, this region appears to have evolved to display a marginal local thermodynamic stability that can be regulated by phosphorylation, leading to targeted degradation of the E2 protein. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Buenos Aires, Fdn Inst Leloir, RA-1405 Buenos Aires, DF, Argentina. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0455,Bldg 4,Rm 137, Bethesda, MD 20892 USA. EM amcbride@nih.gov OI McBride, Alison/0000-0001-5607-5157 NR 40 TC 37 Z9 37 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 MAY 21 PY 2004 VL 279 IS 21 BP 22430 EP 22439 DI 10.1074/jbc.M314340200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 820VH UT WOS:000221417100092 PM 15014086 ER PT J AU Nesbit, MA Bowl, MR Harding, B Ali, A Ayala, A Crowe, C Dobbie, A Hampson, G Holdaway, I Levine, MA McWilliams, R Rigden, S Sampson, J Williams, AJ Thakker, RV AF Nesbit, MA Bowl, MR Harding, B Ali, A Ayala, A Crowe, C Dobbie, A Hampson, G Holdaway, I Levine, MA McWilliams, R Rigden, S Sampson, J Williams, AJ Thakker, RV TI Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; ZINC-FINGER PROTEIN; X-LINKED THROMBOCYTOPENIA; DNA-BINDING DOMAIN; 2-HYBRID SYSTEM; SENSORINEURAL DEAFNESS; NUCLEAR-LOCALIZATION; EMBRYONIC EXPRESSION; GENE-EXPRESSION; COFACTOR AB The hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. The C-terminal zinc finger (ZnF2) binds DNA, whereas the N-terminal finger (ZnF1) stabilizes this DNA binding and interacts with other zinc finger proteins, such as the Friends of GATA ( FOG). We have investigated seven HDR probands and their families for GATA3 abnormalities and have identified two nonsense mutations (Glu-228 --> Stop and Arg- 367 --> Stop); two intragenic deletions that result in frameshifts from codons 201 and 355 with premature terminations at codons 205 and 370, respectively; one acceptor splice site mutation that leads to a frameshift from codon 351 and a premature termination at codon 367; and two missense mutations (Cys-318 --> Arg and Asn-320 --> Lys). The functional effects of these mutations, together with a previously reported GATA3 ZnF1 mutation and seven other engineered ZnF1 mutations, were assessed by electrophoretic mobility shift, dissociation, yeast two-hybrid and glutathione S-transferase pull-down assays. Mutations involving GATA3 ZnF2 or adjacent basic amino acids resulted in a loss of DNA binding, but those of ZnF1 either lead to a loss of interaction with specific FOG2 ZnFs or altered DNA-binding affinity. These findings are consistent with the proposed three-dimensional model of ZnF1, which has separate DNA and protein binding surfaces. Thus, our results, which expand the spectrum of HDR-associated GATA3 mutations and report the first acceptor splice site mutation, help to elucidate the molecular mechanisms that alter the function of this zinc finger transcription factor and its role in causing this developmental anomaly. C1 Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Nuffield Dept Med,Acad Endocrine Unit, Oxford OX3 7LJ, England. NIH, Pediat & Reprod Endocrinol Branch, Bethesda, MD 20892 USA. Metrohlth Med Ctr, Dept Pediat, Div Genet, Cleveland, OH 44109 USA. Churchill Hosp, Dept Clin Genet, Oxford OX3 7L3, England. Guys Kings Coll &St Thomas Hosp Med & Dent Sch, Dept Chem Pathol, London SE1 7EH, England. Auckland Hosp, Dept Endocrinol, Auckland, New Zealand. Cleveland Clin, Childrens Hosp, Dept Pediat Oncol, Cleveland, OH 44195 USA. Mayo Clin & Mayo Fdn, Div Hematol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Div Oncol, Rochester, MN 55905 USA. Guys Hosp, Paediat Renal Unit, London SE1 9RT, England. Univ Wales Coll Med, Inst Med Genet, Cardiff CF14 4XN, S Glam, Wales. Morriston Hosp, Dept Nephrol, Swansea SA6 6NL, W Glam, Wales. RP Thakker, RV (reprint author), Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Nuffield Dept Med,Acad Endocrine Unit, Oxford OX3 7LJ, England. EM rajesh.thakker@ndm.ox.ac.uk OI Thakker, Rajesh/0000-0002-1438-3220; Levine, Michael/0000-0003-0036-7809 NR 63 TC 91 Z9 93 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 MAY 21 PY 2004 VL 279 IS 21 BP 22624 EP 22634 DI 10.1074/jbc.M401797200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 820VH UT WOS:000221417100114 PM 14985365 ER PT J AU Kalinin, AE Idler, WW Marekov, LN McPhie, P Bowers, B Steinert, PM Steven, AC AF Kalinin, AE Idler, WW Marekov, LN McPhie, P Bowers, B Steinert, PM Steven, AC TI Co-assembly of envoplakin and periplakin into oligomers and Ca-2 +-dependent vesicle binding - Implications for cornified cell envelope formation in stratified squamous epithelia SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYTOSKELETAL LINKER PROTEIN; LINKING FACTOR MACF; INTERMEDIATE-FILAMENTS; CROSS-LINKING; PLAKIN FAMILY; DESMOPLAKIN; PLECTIN; ACTIN; GENE; MICROTUBULES AB Plakin family members envoplakin and periplakin have been shown to be part of the cornified cell envelope in terminally differentiating stratified squamous epithelia. In the present study, purified recombinant human envoplakin and periplakin were used to investigate their properties and interactions. We found that envoplakin was insoluble at physiological conditions in vitro, and co- assembly with periplakin was required for its solubility. Envoplakin and periplakin formed soluble complexes with equimolar stoichiometry. Chemical cross- linking revealed that the major soluble form of all periplakin constructs and of envoplakin/ periplakin rod domains was a dimer, although co- assembly of the full-length proteins resulted in formation of higher order oligomers. Electron microscopy of rotary- shadowed periplakin demonstrated thin flexible molecules with an average contour length of 88 nm for the rod- plus- tail fragment, and immunolabeling EM confirmed the molecule as a parallel, in- register, dimer. Both periplakin and envoplakin/ periplakin oligomers were able to bind synthetic lipid vesicles whose composition mimicked the cytoplasmic side of the plasma membrane of eukaryotic cells. This binding was dependent on anionic phospholipids and Ca2+. These findings raise the possibility that envoplakin and periplakin bind to the plasma membrane upon elevation of intracellular [ Ca2+] in differentiating keratinocytes, where they serve as a scaffold for cornified cell envelope assembly. C1 NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. NIAMS, Struct Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kalinin, AE (reprint author), NIAMS, Skin Biol Lab, NIH, 9000 Rockville Pike,Bldg 50,Rm 1527, Bethesda, MD 20892 USA. EM kalinina@mail.nih.gov NR 41 TC 20 Z9 21 U1 2 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 21 PY 2004 VL 279 IS 21 BP 22773 EP 22780 DI 10.1074/jbc.M313660200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 820VH UT WOS:000221417100129 PM 15033990 ER PT J AU Miller, FG AF Miller, FG TI Painful deception SO SCIENCE LA English DT Letter C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 2 TC 1 Z9 1 U1 1 U2 1 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 MAY 21 PY 2004 VL 304 IS 5674 BP 1109 EP 1110 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822FP UT WOS:000221524500019 PM 15155932 ER PT J AU Valente, EM Abou-Sleiman, PM Caputo, V Muqit, MMK Harvey, K Gispert, S Ali, Z Del Turco, D Bentivoglio, AR Healy, DG Albanese, A Nussbaum, R Gonzalez-Maldonaldo, R Deller, T Salvi, S Cortelli, P Gilks, WP Latchman, DS Harvey, RJ Dallapiccola, B Auburger, G Wood, NW AF Valente, EM Abou-Sleiman, PM Caputo, V Muqit, MMK Harvey, K Gispert, S Ali, Z Del Turco, D Bentivoglio, AR Healy, DG Albanese, A Nussbaum, R Gonzalez-Maldonaldo, R Deller, T Salvi, S Cortelli, P Gilks, WP Latchman, DS Harvey, RJ Dallapiccola, B Auburger, G Wood, NW TI Hereditary early-onset Parkinson's disease caused by mutations in PINK1 SO SCIENCE LA English DT Article ID ALPHA-SYNUCLEIN; NEURODEGENERATION; APOPTOSIS; NEURONS AB Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly conserved amino acid. Cell culture studies suggest that PINK1 is mitochondrially located and may exert a protective effect on the cell that is abrogated by the mutations, resulting in increased susceptibility to cellular stress. These data provide a direct molecular link between mitochondria and the pathogenesis of PD. C1 IRCCS, CSS, Mendel Inst, I-00198 Rome, Italy. Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. Univ Roma La Sapienza, Dept Expt Med & Pathol, I-00187 Rome, Italy. Inst Child Hlth, Med Mol Biol Unit, London WC1N 1EH, England. Univ London, Sch Pharm, Dept Pharmacol, London WC1N 1AX, England. Univ Frankfurt, Inst Expt Neurobiol, D-60590 Frankfurt, Germany. Univ Frankfurt, Inst Clin Neuroanat, D-60590 Frankfurt, Germany. Univ Frankfurt, Sect Mol Neurogenet, Neurol Clin, D-60590 Frankfurt, Germany. Univ Sacred Heart, Inst Neurol, I-00168 Rome, Italy. Natl Neurol Inst Carlo Besta, I-20133 Milan, Italy. NHGRI, NIH, Bethesda, MD 20892 USA. Hosp Univ San Cecilio, Dept Neurol, Granada 18012, Spain. Univ Modena & Reggio Emilia, Dept Neurosci, I-41100 Modena, Italy. Univ London Birkbeck Coll, London WC1E 7HX, England. RP Valente, EM (reprint author), IRCCS, CSS, Mendel Inst, Viale Regina Margherita 261, I-00198 Rome, Italy. EM e.valente@css-mendel.it; auburger@em.uni-frankfurt.de; n.wood@ion.ucl.ac.uk RI Wood, Nicholas/C-2505-2009; Gilks, William/P-9137-2015; Dallapiccola, Bruno/K-8692-2016; OI Wood, Nicholas/0000-0002-9500-3348; Gilks, William/0000-0001-7814-3173; Muqit, Miratul/0000-0001-9733-2404; Dallapiccola, Bruno/0000-0002-5031-1013; Bentivoglio, Anna Rita/0000-0002-9663-095X; Cortelli, Pietro/0000-0002-3633-8818 FU Parkinson's UK [G-4029]; Telethon [GGP02089] NR 16 TC 1527 Z9 1595 U1 14 U2 123 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 MAY 21 PY 2004 VL 304 IS 5674 BP 1158 EP 1160 DI 10.1126/science.1096284 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822FP UT WOS:000221524500043 PM 15087508 ER PT J AU Cherstvy, AG Kornyshev, AA Leikin, S AF Cherstvy, AG Kornyshev, AA Leikin, S TI Torsional deformation of double helix in interaction and aggregation of DNA SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID BOND-ORIENTATIONAL ORDER; X-RAY-DIFFRACTION; ELECTROSTATIC INTERACTION; LIQUID-CRYSTALS; B-DNA; MACROMOLECULES; RECOMBINATION; CONDENSATION; MESOPHASES; ANGLES AB We incorporate sequence-dependent twisting between adjacent base pairs and torsional elasticity of double helix into the theory of DNA-DNA interaction. The results show that pairing and counterion-induced-aggregation of nonhomologous DNA are accompanied by considerable torsional deformation. The deformation tunes negatively charged phosphate strands and positively charged grooves on opposing molecules to stay "in register", substantially reducing nonideality of the helical structure of DNA. Its cost, however, makes interaction between nonhomologous DNA less energetically favorable. In particular, interaction between double helical DNA may result in sequence homology recognition and selective pairing of homologous fragments containing more than 100-200 base pairs. We also find a weak, but potentially measurable, increase in the expected counterion concentration required for aggregation of nonhomologous DNA and slightly higher solubility of such DNA above the critical concentration. C1 NICHHD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ London Imperial Coll Sci Technol & Med, Dept Chem, Fac Phys Sci, London SW7 2AY, England. Forschungszentrum Julich, Inst Festkorperforsch, D-52425 Julich, Germany. RP Leikin, S (reprint author), NICHHD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM leikins@mail.nih.gov RI Leikin, Sergey/A-5518-2008; Kornyshev, Alexei/C-3404-2008 OI Leikin, Sergey/0000-0001-7095-0739; NR 50 TC 56 Z9 56 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 20 PY 2004 VL 108 IS 20 BP 6508 EP 6518 DI 10.1021/jp0380475 PG 11 WC Chemistry, Physical SC Chemistry GA 821IZ UT WOS:000221455000051 PM 18950140 ER PT J AU Hirschberg, R La Montagne, J Fauci, AS AF Hirschberg, R La Montagne, J Fauci, AS TI Biomedical research - An integral component of national security . SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 NIAID, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Hirschberg, R (reprint author), NIAID, Dept Hlth & Human Serv, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 5 TC 8 Z9 9 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 20 PY 2004 VL 350 IS 21 BP 2119 EP 2121 DI 10.1056/NEJMp048123 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 821XM UT WOS:000221496700001 PM 15152055 ER PT J AU Mills, JL Signore, CC AF Mills, JL Signore, CC TI Folic acid and the prevention of neural-tube defects SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID FORTIFICATION C1 NICHHD, Bethesda, MD 20892 USA. RP Mills, JL (reprint author), NICHHD, Bethesda, MD 20892 USA. NR 5 TC 6 Z9 6 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 20 PY 2004 VL 350 IS 21 BP 2209 EP 2210 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 821XM UT WOS:000221496700029 PM 15152070 ER PT J AU Pavey, S Johansson, P Packer, L Taylor, J Stark, M Pollock, PM Walker, GJ Boyle, GM Harper, U Cozzi, SJ Hansen, K Yudt, L Schmidt, C Hersey, P Ellem, KAO O'Rourke, MGE Parsons, PG Meltzer, P Ringner, M Hayward, NK AF Pavey, S Johansson, P Packer, L Taylor, J Stark, M Pollock, PM Walker, GJ Boyle, GM Harper, U Cozzi, SJ Hansen, K Yudt, L Schmidt, C Hersey, P Ellem, KAO O'Rourke, MGE Parsons, PG Meltzer, P Ringner, M Hayward, NK TI Microarray expression profiling in melanoma reveals a BRAF mutation signature SO ONCOGENE LA English DT Article DE BRAF; melanoma; microarray; mitogenactivated protein kinase; mutation ID PROTEIN-TYROSINE-PHOSPHATASE; N-RAS; DIFFERENTIAL DISPLAY; ONCOGENIC PATHWAYS; KINASE ACTIVATION; GENE; CANCER; CLASSIFICATION; PROGRESSION; ADHESION AB We have used microarray gene expression pro. ling and machine learning to predict the presence of BRAF mutations in a panel of 61 melanoma cell lines. The BRAF gene was found to be mutated in 42 samples (69%) and intragenic mutations of the NRAS gene were detected in seven samples (11%). No cell line carried mutations of both genes. Using support vector machines, we have built a classifier that differentiates between melanoma cell lines based on BRAF mutation status. As few as 83 genes are able to discriminate between BRAF mutant and BRAF wild-type samples with clear separation observed using hierarchical clustering. Multidimensional scaling was used to visualize the relationship between a BRAF mutation signature and that of a generalized mitogen-activated protein kinase ( MAPK) activation ( either BRAF or NRAS mutation) in the context of the discriminating gene list. We observed that samples carrying NRAS mutations lie somewhere between those with or without BRAF mutations. These observations suggest that there are gene-specific mutation signals in addition to a common MAPK activation that result from the pleiotropic effects of either BRAF or NRAS on other signaling pathways, leading to measurably different transcriptional changes. C1 Queensland Inst Med Res, Herston, Qld 4006, Australia. Lund Univ, Dept Theoret Phys, Complex Syst Div, SE-22362 Lund, Sweden. Pk Ctr Mental Hlth, Queensland Ctr Schizophrenia Res, Wacol, Qld 4076, Australia. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. Univ Newcastle, Newcastle, NSW 2300, Australia. Mater Misericordiae Hosp, Brisbane, Qld 4101, Australia. RP Hayward, NK (reprint author), Queensland Inst Med Res, 300 Herston Rd, Herston, Qld 4006, Australia. EM nickH@qimr.edu.au RI Pavey, Sandra/B-3662-2011; Stark, Mitchell/E-3542-2010; Taylor, Jennifer/A-1686-2010; Schmidt, Christopher/A-4353-2009; Walker, Graeme/C-2548-2012; Boyle, Glen/G-1347-2013; Ringner, Markus/G-3641-2011; Johansson, Peter/K-1053-2014; hayward, nicholas/C-1367-2015; Parsons, Peter/J-4683-2013 OI Pavey, Sandra/0000-0003-4519-5932; Stark, Mitchell/0000-0002-4510-2161; Taylor, Jennifer/0000-0003-4231-0181; Schmidt, Christopher/0000-0002-3955-5076; Walker, Graeme/0000-0002-9392-8769; Boyle, Glen/0000-0002-1385-529X; Ringner, Markus/0000-0001-5469-8940; Johansson, Peter/0000-0001-7015-5452; hayward, nicholas/0000-0003-4760-1033; Parsons, Peter/0000-0002-0473-3346 NR 45 TC 123 Z9 125 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 20 PY 2004 VL 23 IS 23 BP 4060 EP 4067 DI 10.1038/sj.onc.1207563 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 822ER UT WOS:000221520200003 PM 15048078 ER PT J AU Olden, K AF Olden, K TI Genomics in environmental health research - opportunities and challenges SO TOXICOLOGY LA English DT Article; Proceedings Paper CT 5th Congress of Toxicology in Developing Countries CY OCT 10-13, 2003 CL GUILIN, PEOPLES R CHINA SP Chinese Soc Toxicol, Int Union Toxicol DE toxicogenomics; 'omics'; systems biology; gene-environment interactions; polymorphism; susceptibility ID POLYMORPHISMS; DISEASE; CANCER; TOXICOLOGY; MECHANISMS; TOXICITY; FINLAND; PROJECT; TWINS AB Environmental health research impacts both environmental health regulatory policy and the practice of medicine. However, this area of medical research has not garnered public support and attention of medical researchers because of its emphasis on prevention and public health. Also, the pervasiveness of a scientific culture wedded to old problems and outdated technologies and models systems has not been helpful in generating enthusiasm for the field. While the emphasis on prevention is both laudable and appropriate, the adoption of cutting-edge technologies to exploit the new scientific opportunities, made possible by the nation's investment in genomics, is essential if the discipline expects to be competitive with other highly deserving programs. The new 'omics' era of environmental health research, ushered in over the past decade, characterized by the linkage of genomics, proteomics and metabolomics to conventional toxicology and pathology databases, holds great promise for elucidating mechanisms of gene-environment interaction in human health and disease. These combined approaches will allow one to monitor multiple molecular events, pathways and interactive networks simultaneously-a requirement for elucidating toxic mechanisms. But, before embracing the 'omics' technologies as the 'be all-end all;' they need to be validated for their predictive capacities in large-scale multi-institutional studies, such as those described in this article. (C) 2004 Published by Elsevier Ireland Ltd. C1 NIEHS, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. NIH, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Olden, K (reprint author), NIEHS, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM olden@niehs.nih.gov NR 20 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD MAY 20 PY 2004 VL 198 IS 1-3 BP 19 EP 24 DI 10.1016/j.tox.2004.01.015 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 823OH UT WOS:000221622000004 PM 15138025 ER PT J AU Waalkes, MP Liu, J Ward, JM Diwan, LA AF Waalkes, MP Liu, J Ward, JM Diwan, LA TI Mechanisms underlying arsenic carcinogenesis: hypersensitivity of mice exposed to inorganic arsenic during gestation SO TOXICOLOGY LA English DT Article; Proceedings Paper CT 5th Congress of Toxicology in Developing Countries CY OCT 10-13, 2003 CL GUILIN, PEOPLES R CHINA SP Chinese Soc Toxicol, Int Union Toxicol DE arsenic; carcinogenesis; mice; gestational; liver ID DRINKING-WATER; TRANSPLACENTAL CARCINOGENICITY; DIAPLACENTAL INITIATION; CHRONIC STIMULATION; TUMOR-INCIDENCE; SKIN NEOPLASIA; GROWTH-FACTORS; F344/NCR RATS; ANIMAL-MODEL; NMRI MICE AB Inorganic arsenic is an important human carcinogen of unknown etiology. Defining carcinogenic mechanisms is critical to assessing the human health hazard of arsenic exposure but requires appropriate model systems. It has proven difficult to induced tumors in animals with inorganic arsenic alone. Several groups have studied the carcinogenic potential of inorganic arsenic in rodents, finding it to act as co-promoter or co-carcinogen, but not as a complete carcinogen. As gestation is a time of high sensitivity to chemical carcinogenesis, we performed two in utero exposure studies with inorganic arsenic. In the first study, pregnant mice received drinking water containing sodium arsenite at 0 (control), 42.5 and 85 ppm arsenic from gestation day 8 to 18, and the offspring were observed for up to 90 weeks. As adults, male offspring developed hepatocellular carcinoma (HCC) and adrenal tumors after in utero arsenite exposure. Although liver tumors were not induced by arsenic in female offspring, they did develop lung carcinoma, ovarian tumors, and uterine and oviduct preneoplasia. In a second study, the same doses of arsenic were used and the skin tumor promoting phorbol ester, TPA, was applied to the skin after birth in an effort to promote skin tumors potentially initiated by arsenic in utero. TPA did not promote dermal tumors after in utero arsenite exposure. Otherwise, results from the second chronic study largely duplicated the first and, irrespective of additional TPA exposure, arsenic exposure in utero induced HCC and adrenal tumors in males and ovarian tumors in females. In addition, combined arsenic and TPA induced a significant increase in hepatocellular tumors in female offspring, although arsenic alone was not effective. Thus, in utero inorganic arsenic exposure can act as a complete carcinogen in mice, with brief exposures consistently inducing tumors at several sites. In addition, it appears gestational arsenic can act as a tumor initiator in the female mouse liver, inducing liver lesions that can be promoted by TPA. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. NCI Frederick, Baic Res Program, SAIC Frederick, Ft Detrick, MD 21702 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, POB 12233,111 Alexander Dr,MD F0-09, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 30 TC 48 Z9 49 U1 0 U2 7 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD MAY 20 PY 2004 VL 198 IS 1-3 BP 31 EP 38 DI 10.1016/j.tox.2004.01.017 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 823OH UT WOS:000221622000006 PM 15138027 ER PT J AU Felton, JS Knize, MG Bennett, LM Malfatti, MA Colvin, ME Kulp, KS AF Felton, JS Knize, MG Bennett, LM Malfatti, MA Colvin, ME Kulp, KS TI Impact of environmental exposures on the mutagenicity/carcinogenicity of heterocyclic amines SO TOXICOLOGY LA English DT Article; Proceedings Paper CT 5th Congress of Toxicology in Developing Countries CY OCT 10-13, 2003 CL GUILIN, PEOPLES R CHINA SP Chinese Soc Toxicol, Int Union Toxicol DE mutagenicity; carcinogenicity; heterocyclic amines; PhIP ID DNA ADDUCT FORMATION; FRIED BEEF PATTIES; FEMALE F344 RATS; N-HYDROXY-PHIP; AROMATIC-AMINES; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE PHIP; NONHUMAN-PRIMATES; PAN RESIDUES; GREEN TEA; INHIBITION AB Carcinogenic heterocyclic amines are produced from overcooked foods and are highly mutagenic in most short-term test Systems. One of the most abundant of these amines, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), induces breast, colon and prostate tumors in rats. Human dietary epidemiology studies suggest a strong correlation between either meat consumption or well-done muscle meat consumption and cancers of the colon, breast, stomach, lung and esophagus. For over 20 years our laboratory has helped define the human exposure to these dietary carcinogens. In this report we describe how various environmental exposures may modulate the risk from exposure to heterocyclic amines, especially PhIR To assess the impact of foods on PhIP metabolism in humans, we developed an LC/MS/MS method to analyze the four major PhIP urinary metabolites following the consumption of a single portion of grilled chicken. Adding broccoli to the volunteers' diet altered the kinetics of PhIP metabolism. At the cellular level we have found that PhIP itself stimulates a significant estrogenic response in MCF-7 cells, but even more interestingly, co-incubation of the cells with herbal teas appear to enhance the response. Numerous environmental chemicals found in food or the atmosphere can impact the exposure, metabolism, and cell proliferation response of heterocyclic amines. (C) 2004 Published by Elsevier Ireland Ltd. C1 Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94551 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Felton, JS (reprint author), Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, L-452, Livermore, CA 94551 USA. EM feltonl@llnl.gov FU NCI NIH HHS [CA55861, CA94709] NR 61 TC 36 Z9 37 U1 2 U2 7 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD MAY 20 PY 2004 VL 198 IS 1-3 BP 135 EP 145 DI 10.1016/j.tox.2004.01.024 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 823OH UT WOS:000221622000016 PM 15138037 ER PT J AU Wexler, P AF Wexler, P TI The US National Library of Medicine's Toxicology and Environmental Health Information Program SO TOXICOLOGY LA English DT Article; Proceedings Paper CT 5th Congress of Toxicology in Developing Countries CY OCT 10-13, 2003 CL GUILIN, PEOPLES R CHINA SP Chinese Soc Toxicol, Int Union Toxicol DE information; databases; computerized access; world wide web; TOXNET; National Library of Medicine AB For nearly 40 years, the National Library of Medicine's (NLM) Toxicology and Environmental Health Information Program (TEHIP) has been a significant leader in organizing and providing public access to an extensive storehouse of toxicological information through its online databases. With the advent of the Internet, TEHIP has expanded its role to also serve as a pre-eminent portal to toxicological information worldwide. Its primary databases reside within the web-based TOXNET system, and include the scientifically peer-reviewed Hazardous Substances Data Bank (HSDB), the U.S. Environmental Protection Agency's Integrated Risk Information System (IRIS) and Toxics Release Inventory, the National Cancer Institute's Chemical Carcinogenesis Research Information System (CCRIS) and the TOXLINE file of over 3 million bibliographic references. TEHIP's ChemIDplus is an extensive chemical dictionary that extends beyond simple nomenclature to offer displays of molecular structures and links from particular chemicals to other databases containing more information. Specialty files in occupational safety and health, and household products have recently been added to TEHIP's suite of resources. Additional databases in risk assessment, drugs, toxicology education, and global resources, are under development. "Special Topics" pages lead users to structured summaries and links in areas such as arsenic, chemical warfare agents, biological warfare, and West Nile Virus. A database on alternatives to the use of live animals, a three-module toxicology tutor, and a glossary of terms in toxicology are among TEHIP's other information aids, as well an increasing commitment to serving consumers, as witnessed by the animated ToxTown program. Outside the sphere of TEHIP, NLM offers additional databases, such as PubMed, of significant value to toxicology researchers. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Natl Lib Med, Bethesda, MD 20892 USA. RP Wexler, P (reprint author), Natl Lib Med, 2 Democracy Plaza,Suite 510, Bethesda, MD 20892 USA. EM wexlerp@mail.nlm.nih.gov NR 0 TC 13 Z9 14 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD MAY 20 PY 2004 VL 198 IS 1-3 BP 161 EP 168 DI 10.1016/j.tox.2004.01.037 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 823OH UT WOS:000221622000018 PM 15138039 ER PT J AU Junghans, TB Sevin, IF Ionin, B Seifried, H AF Junghans, TB Sevin, IF Ionin, B Seifried, H TI Cancer information resources: digital and online sources SO TOXICOLOGY LA English DT Article; Proceedings Paper CT 5th Congress of Toxicology in Developing Countries CY OCT 10-13, 2003 CL GUILIN, PEOPLES R CHINA SP Chinese Soc Toxicol, Int Union Toxicol DE cancer; online; digital AB The Internet is becoming an increasingly important source of information on cancer. This article highlights major sites of credible information on cancer and describes the types of information each of these sites contains. Large directories that help point the visitor to additional cancer-related sites are described, as are searchable databases of information on cancer as a disease, its diagnosis and treatment. Sources of information on chemical carcinogens, mechanistic studies, and applied cancer toxicology are also described. These Internet sources of cancer information address the needs of toxicologists, environmental and occupational health scientists, cancer researchers and clinicians, government regulators, the public, and cancer survivors and their caregivers. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Tech Resources Int Inc, Bethesda, MD 20817 USA. Walter Reed Army Inst Res, Dept Bacterial Dis, Silver Spring, MD 20910 USA. NCI, Nutr Sci Res Grp, Rockville, MD 20852 USA. RP Junghans, TB (reprint author), Tech Resources Int Inc, 6500 Rock Spring Dr,Suite 650, Bethesda, MD 20817 USA. EM tjunghans@tech-res.com NR 0 TC 11 Z9 11 U1 0 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD MAY 20 PY 2004 VL 198 IS 1-3 BP 177 EP 193 DI 10.1016/j.tox.2004.02.021 PG 17 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 823OH UT WOS:000221622000020 PM 15138041 ER PT J AU Molia, S Chomel, BB Kasten, RW Leutenegger, CM Steele, BR Marker, L Martenson, JS Keet, DR Bengis, RG Peterson, RP Munson, L O'Brien, SJ AF Molia, S Chomel, BB Kasten, RW Leutenegger, CM Steele, BR Marker, L Martenson, JS Keet, DR Bengis, RG Peterson, RP Munson, L O'Brien, SJ TI Prevalence of Bartonella infection in wild African lions (Panthera leo) and cheetahs (Acinonyx jubatus) SO VETERINARY MICROBIOLOGY LA English DT Article DE Bartonella sp.; cheetah Acinonyx jubatus; lion Panthera leo; serosurvey ID CAT-SCRATCH DISEASE; ROCHALIMAEA-HENSELAE INFECTION; DOMESTIC CATS; SOUTH-AFRICA; SP-NOV; CLARRIDGEIAE; BACTEREMIA; ANTIBODY; TRANSMISSION; CALIFORNIA AB Bartonella species are emerging pathogens that have been isolated worldwide from humans and other mammals. Our objective was to estimate the prevalence of Bartonella infection in free-ranging African lions (Panthera leo) and cheetahs (Acinonyx jubatus). Blood and/or serum samples were collected from a convenience sample of 113 lions and 74 cheetahs captured in Africa between 1982 and 2002. Whole blood samples available from 58 of the lions and 17 of the cheetahs were cultured for evidence of Bartonella spp., and whole blood from 54 of the 58 lions and 73 of the 74 cheetahs tested for the presence of Bartonella DNA by TaqMan PCR. Serum samples from the 113 lions and 74 cheetahs were tested for the presence of antibodies against Bartonella henselae using an immunofluorescence assay. Three (5.2%) of the 58 lions and one (5.9%) of the 17 cheetahs were bacteremic. Two lions were infected with B. henselae, based on PCR/RFLP of the citrate synthase gene. The third lion and the cheetah were infected with previously unidentified Bartonella strains. Twenty-three percent of the 73 cheetahs and 3.7% of the 54 lions tested by TaqMan PCR were positive for Bartonella spp. B. henselae antibody prevalence was 17% (19/113) for the lions and 31% (23/74) for the cheetahs. The prevalence of seropositivity, bacteremia, and positive TaqMan PCR was not significantly different between sexes and age categories (juvenile versus adult) for both lions and cheetahs. Domestic cats are thus no longer the only known carriers of Bartonella spp. in Africa. Translocation of B. henselae seronegative and TaqMan PCR negative wild felids might be effective in limiting the spread of Bartonella infection. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. Univ Calif Davis, Sch Vet Med, Lucy Whittier Mol & Diagnost Core Facil, Dept Med & Epidemiol, Davis, CA 95616 USA. Cheetah Conservat Fund, Otjiwarongo, Namibia. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Kruger Natl Pk, ZA-1350 Skukuza, South Africa. Calif Dept Food & Agr, Anim Hlth Branch, Eureka, CA 95502 USA. Univ Calif Davis, Sch Vet Med, Dept Pathol Immunol & Microbiol, Davis, CA 95616 USA. RP Chomel, BB (reprint author), Univ Calif Davis, Sch Vet Med, Dept Populat Hlth & Reprod, Davis, CA 95616 USA. EM bbchomel@ucdavis.edu RI Molia, Sophie/E-7221-2011 NR 41 TC 38 Z9 40 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1135 J9 VET MICROBIOL JI Vet. Microbiol. PD MAY 20 PY 2004 VL 100 IS 1-2 BP 31 EP 41 DI 10.1016/j.vetmic.2004.01.007 PG 11 WC Microbiology; Veterinary Sciences SC Microbiology; Veterinary Sciences GA 823SY UT WOS:000221634700005 PM 15135511 ER PT J AU Liao, HJ Baker, CC Princler, GL Derse, D AF Liao, HJ Baker, CC Princler, GL Derse, D TI cis-acting and trans-acting modulation of equine infectious anemia virus alternative RNA splicing SO VIROLOGY LA English DT Article DE splicing; purine-rich element; EIAV ID PRE-MESSENGER-RNA; BRANCH SITE SELECTION; HNRNP A/B PROTEINS; TYPE-1 TAT EXON-2; SILENCER ELEMENT/; NUCLEAR EXPORT; BINDING-SITES; SR PROTEINS; REV PROTEIN; IN-VIVO AB Equine infectious anemia virus (EIAV), a lentivirus distantly related to HIV-1, encodes regulatory proteins, EIAV Tat (ETat) and Rev (ERev), from a four-exon mRNA. Exon 3 of the tat/rev mRNA contains a 30-nucleotide purine-rich element (PRE) which binds both ERev and SF2/ASF, a member of the SR family of RNA splicing factors. To better understand the role of this element in the regulation of EIAv pre-mRNA splicing, we quantified the effects of mutation or deletion of the PRE on exon 3 splicing in vitro and oil alternative splicing in vivo. We also determined the branch point elements upstream of exons 3 and 4. In vitro splicing of exon 3 to exon 4 was not affected by mutation of the PRE, and addition of purified SR proteins enhanced splicing independently of the PRE. In vitro splicing of exon 2 to exon 3 was dependent on the PRE; under conditions of excess SR proteins, either the PRE or the 5' splice site of exon 3 was sufficient to activate splicing. We applied isoform-specific primers in real-time RT-PCR reactions to quantitatively analyze alternative splicing in cells transfected with rev-minus EIAV provirus constructs. In the context of provirus with wild-type exon 3, greater than 80% of the viral mRNAs were multiply spliced, and of these, less than 1% excluded exon 3. Deletion of the PRE resulted in a decrease in the relative amount of multiply spliced mRNA to about 40% of the total and approximately 39% of the viral mRNA excluded exon 3. Ectopic expression of ERev caused a decrease in the relative amount of multiply spliced mRNA to approximately 50% of the total and increased mRNAs that excluded exert 3 to about 4%. Over-expression of SF2/ASF in cells transfected with wild-type provirus constructs inhibited splicing but did not significantly alter exon 3 skipping. Published by Elsevier Inc. C1 NCI Frederick, Ctr Canc Res, Basic Res Lab, Frederick, MD 21702 USA. SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Derse, D (reprint author), NCI Frederick, Ctr Canc Res, Basic Res Lab, Frederick, MD 21702 USA. EM derse@ncifcrf.gov FU NCI NIH HHS [N01-CO-56000] NR 43 TC 5 Z9 6 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 MAY 20 PY 2004 VL 323 IS 1 BP 131 EP 140 DI 10.1016/j.virol.2003.12.028 PG 10 WC Virology SC Virology GA 828VB UT WOS:000222000500012 PM 15165825 ER PT J AU Goley, EM Anderson, SJ Menard, C Chuang, E Lu, X Tofilon, PJ Camphausen, K AF Goley, EM Anderson, SJ Menard, C Chuang, E Lu, X Tofilon, PJ Camphausen, K TI Microarray analysis in clinical oncology: pre-clinical optimization using needle core biopsies from xenograft tumors SO BMC CANCER LA English DT Article ID MESSENGER-RNA AMPLIFICATION; GENE-EXPRESSION PROFILES; B-CELL LYMPHOMA; CDNA MICROARRAYS; BREAST-CANCER; LABELING METHODS; PREDICTION; CLASSIFICATION; SENSITIVITY; DISCOVERY AB Background: DNA microarray profiling performed on clinical tissue specimens can potentially provide significant information regarding human cancer biology. Biopsy cores, the typical source of human tumor tissue, however, generally provide very small amounts of RNA (0.3-15 mug). RNA amplification is a common method used to increase the amount of material available for hybridization experiments. Using human xenograft tissue, we sought to address the following three questions: 1) is amplified RNA representative of the original RNA profile? 2) what is the minimum amount of total RNA required to perform a representative amplification? 3) are the direct and indirect methods of labeling the hybridization probe equivalent? Methods: Total RNA was extracted from human xenograft tissue and amplified using a linear amplification process. RNA was labeled and hybridized, and the resulting images yielded data that was extracted into two categories using the mAdb system: "all genes" and "outliers". Scatter plots were generated for each slide and Pearson Coefficients of correlation were obtained. Results: Results show that the amplification of 5 mug of total RNA yields a Pearson Correlation Coefficient of 0.752 (N = 6,987 genes) between the amplified and total RNA samples. We subsequently determined that amplification of 0.5 mug of total RNA generated a similar Pearson Correlation Coefficient as compared to the corresponding original RNA sample. Similarly, sixty-nine percent of total RNA outliers were detected with 5 mug of amplified starting RNA, and 55% of outliers were detected with 0.5 mug of starting RNA. However, amplification of 0.05 mug of starting RNA resulted in a loss of fidelity ( Pearson Coefficient 0.669 between amplified and original samples, 44% outlier concordance). In these studies the direct or indirect methods of probe labeling yielded similar results. Finally, we examined whether RNA obtained from needle core biopsies of human tumor xenografts, amplified and indirectly labeled, would generate representative array profiles compared to larger excisional biopsy material. In this analysis correlation coefficients were obtained ranging from 0.750-0.834 between U251 biopsy cores and excised tumors, and 0.812-0.846 between DU145 biopsy cores and excised tumors. Conclusion: These data suggest that needle core biopsies can be used as reliable tissue samples for tumor microarray analysis after linear amplification and either indirect or direct labeling of the starting RNA. C1 NCI, Radiat Oncol Branch, NIH, DHHS, Bethesda, MD 20892 USA. NCI, Mol Radiat Therapeut Branch, NIH, DHHS, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, NIH, DHHS, Bldg 10, Bethesda, MD 20892 USA. EM goleye@mail.nih.gov; andersso@mail.nih.gov; menardc@mail.nih.gov; chuange@mail.nih.gov; lvxi@mail.nih.gov; tofilonp@mail.nih.gov; camphauk@mail.nih.gov NR 31 TC 12 Z9 12 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAY 19 PY 2004 VL 4 AR 20 DI 10.1186/1471-2407-4-20 PG 9 WC Oncology SC Oncology GA 833NI UT WOS:000222344000001 PM 15151703 ER PT J AU Jeong, SY Gaume, B Lee, YJ Hsu, YT Ryu, SW Yoon, SH Youle, RJ AF Jeong, SY Gaume, B Lee, YJ Hsu, YT Ryu, SW Yoon, SH Youle, RJ TI Bcl-x(L) sequesters its C-terminal membrane anchor in soluble, cytosolic homodimers SO EMBO JOURNAL LA English DT Article DE apoptosis; Bad; Bax; Bcl-2; Bcl-x(L); dimerization ID BCL-X-L; COMPLEX-FORMATION; BH3 DOMAIN; BAX; APOPTOSIS; LOCALIZATION; FAMILY; PROTEINS; DEATH; DIMERIZATION AB Bcl-x(L) is a potent inhibitor of apoptosis. While Bcl-x(L) can be bound to mitochondria, a substantial fraction, depending on the cell type or tissue, is found in the cytosol of healthy cells. Gel filtration and crosslinking experiments reveal that, unlike monomeric Bax, Bcl-x(L) migrates in a complex of approximately 50 kDa in the cytosol. Co-immunoprecipitation experiments indicate that Bcl-x(L) in the cytosol forms homodimers. The C-terminal hydrophobic tails of two Bcl-x(L) molecules are involved in homodimer formation, and analysis of mutants demonstrates that the C-terminal lysine residue and the G138 residue lining the BH3-binding pocket are required for homodimerization. The flexible loop preceding the C-terminal tail in Bcl-x(L) is longer than that of several monomeric Bcl-2 family members and is a requisite for the homodimer formation. Bad binding to Bcl-x(L) dissociates the homodimers and triggers Bcl-x(L) binding to mitochondrial membranes. The C-terminal tail of Bcl-x(L) is also required to mediate Bcl-x(L)/Bax heterodimer formation. Both mitochondrial import and antiapoptotic activity of different Bcl-x(L) mutants correlate with their ability to form homodimers. C1 NINCDS, Surg Neurol Branch, Biochem Sect, NIH, Bethesda, MD 20892 USA. Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. RP Youle, RJ (reprint author), NINCDS, Surg Neurol Branch, Biochem Sect, NIH, Bldg 10,Room 4N-258,MSC 1414,10 Ctr Dr, Bethesda, MD 20892 USA. EM youle@helix.nih.gov NR 34 TC 113 Z9 117 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 19 PY 2004 VL 23 IS 10 BP 2146 EP 2155 DI 10.1038/sj.emboj.7600225 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 821YR UT WOS:000221499800013 PM 15131699 ER PT J AU Dalakas, MC AF Dalakas, MC TI Intravenous immunoglobulin in autoimmune neuromuscular diseases SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Review ID GUILLAIN-BARRE-SYNDROME; MULTIFOCAL MOTOR NEUROPATHY; INCLUSION-BODY MYOSITIS; INFLAMMATORY DEMYELINATING POLYRADICULONEUROPATHY; RANDOMIZED CONTROLLED TRIAL; EATON MYASTHENIC SYNDROME; PLACEBO-CONTROLLED TRIAL; STIFF-PERSON SYNDROME; DOUBLE-BLIND; PLASMA-EXCHANGE AB Context Intravenous immunoglobulin (IVIG) enhances immune homeostasis by modulating expression and function of Fc receptors, interfering with activation of complement and production of cytokines, providing anti-idiotypic antibodies, and affecting the activation and effector functions of T and B cells. These mechanisms may explain the effectiveness of IVIG in autoimmune neuromuscular disorders. Objective To systematically review the current status of the treatment of autoimmune neuromuscular diseases with IVIG, with emphasis on controlled trials. Data Sources Peer-reviewed publications identified through MEDLINE (1966-2003), EMBASE (1974-2003), and references from bibliographies of pertinent articles. Each autoimmune neuromuscular disease term was searched in combination with the term intravenous immunoglobulin. Study Selection and Data Extraction Criteria for selection of studies included controlled study design, English language, and clinical pertinence. Data quality was based on venue of publication and relevance to clinical care. Data Synthesis Outcomes of controlled trials indicate that IVIG at a total dose of 2 g/kg is effective as first-line therapy in Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy and as second-line therapy in stiff-person syndrome, dermatomyositis, myasthenia gravis, and Lambert-Eaton myasthenic syndrome. in other controlled studies, IVIG produced a modest, variable, and transient but not statistically significant benefit in patients with inclusion body myositis and paraproteinemic anti-myelin-associated glycoprotein antibody demyelinating polyneuropathy. Intravenous immunoglobulin is not effective in patients with multiple sclerosis who have established weakness or optic neuritis. In myasthenia gravis, it should be reserved for difficult cases or before thymectomy in lieu of plasma exchange. Conclusion intravenous immunoglobulin is effective in many autoimmune neurologic diseases, but its spectrum of efficacy, especially as first-line therapy, and the appropriate dose for long-term maintenance therapy are not fully established. Further controlled studies of IVIG, combined with a dose-finding effect, pharmacoeconomics, and quality-of-life assessments, are warranted to improve the evidence base for clinical practice. C1 NINDS, NIH, Neuromuscular Dis Sect, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, NIH, Neuromuscular Dis Sect, Bldg 10,Room 4N248, Bethesda, MD 20892 USA. EM dalakasm@ninds.nih.gov NR 83 TC 163 Z9 177 U1 1 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 19 PY 2004 VL 291 IS 19 BP 2367 EP 2375 DI 10.1001/jama.291.19.2367 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 821JD UT WOS:000221455400025 PM 15150209 ER PT J AU Giacobini, P Kopin, AS Beart, PM Mercer, LD Fasolo, A Wray, S AF Giacobini, P Kopin, AS Beart, PM Mercer, LD Fasolo, A Wray, S TI Cholecystokinin modulates migration of gonadotropin-releasing hormone-1 neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE GnRH-1; CCK; CCK receptors; migration; olfactory system; development ID CENTRAL-NERVOUS-SYSTEM; MESSENGER-RNA; OLFACTORY PLACODE; LHRH NEURONS; RAT-BRAIN; IN-VITRO; EXPLANT CULTURES; EXPRESSION; RECEPTOR; CELLS AB Expression of the brain - gut peptide cholecystokinin (CCK) in the developing olfactory-gonadotropin-releasing hormone-1 (GnRH-1) neuroendocrine systems was characterized, and the function of CCK in these systems was analyzed both in vivo and in vitro. We present novel data demonstrating that CCK transcript and protein are expressed in sensory cells in the developing olfactory epithelium and vomeronasal organ, with both ligand and receptors (CCK-1R and CCK-2R) found on olfactory axons throughout prenatal development. In addition, migrating GnRH-1 neurons in nasal regions express CCK-1R but not CCK-2R receptors. The role of CCK in olfactory-GnRH-1 system development was evaluated using nasal explants, after assessing that the in vivo expression of both CCK and CCK receptors was mimicked in this in vitro model. Exogenous application of CCK (10(-7) M) reduced both olfactory axon outgrowth and migration of GnRH-1 cells. This inhibition was mediated by CCK-1R receptors. Moreover, CCK-1R but not CCK-2R antagonism caused a shift in the location of GnRH-1 neurons, increasing the distance that the cells migrated. GnRH-1 neuronal migration in mice carrying a genetic deletion of either CCK-1R or CCK-2R receptor genes was also analyzed. At embryonic day 14.5, the total number of GnRH-1 cells was identical in wild-type and mutant mice; however, the number of GnRH-1 neurons within forebrain was significantly greater in CCK-1R(-/-) embryos, consistent with an accelerated migratory process. These results indicate that CCK provides an inhibitory influence on GnRH-1 neuronal migration, contributing to the appropriate entrance of these neuroendocrine cells into the brain, and thus represent the first report of a developmental role for CCK. C1 NINDS, Cellular & Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Univ Turin, Dept Human & Anim Biol, Neurobiol Lab, I-10123 Turin, Italy. Tufts Univ New England Med Ctr, Dept Med, Boston, MA 02111 USA. Tufts Univ New England Med Ctr, Mol Pharmacol Res Ctr, Boston, MA 02111 USA. Monash Univ, Dept Pharmacol, Clayton, Vic 3800, Australia. Univ Melbourne, Howard Florey Inst Expt Physiol & Med, Parkville, Vic 3010, Australia. RP Wray, S (reprint author), NINDS, Cellular & Dev Neurobiol Sect, NIH, Bldg 36,Room 5A21,36 Convent Dr MSC 4156, Bethesda, MD 20892 USA. EM wrays@ninds.nih.gov RI Giacobini, Paolo/P-5451-2015; OI Giacobini, Paolo/0000-0002-3075-1441; wray, susan/0000-0001-7670-3915 FU NIDDK NIH HHS [DK46767] NR 76 TC 52 Z9 52 U1 0 U2 0 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 19 PY 2004 VL 24 IS 20 BP 4737 EP 4748 DI 10.1523/JNEUROSCI.0649-04.2004 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 823IQ UT WOS:000221604900005 PM 15152034 ER PT J AU Roper, P Callaway, J Armstrong, W AF Roper, P Callaway, J Armstrong, W TI Burst initiation and termination in phasic vasopressin cells of the rat supraoptic nucleus: A combined mathematical, electrical, and calcium fluorescence study SO JOURNAL OF NEUROSCIENCE LA English DT Article DE mathematical model; bursting; vasopressin; dynorphin; Hodgkin-Huxley; calcium imaging; neurosecretion ID DEPOLARIZING AFTER-POTENTIALS; OPIOID RECEPTOR ACTIVATION; NEURONS IN-VITRO; MAGNOCELLULAR NEUROENDOCRINE CELLS; NEUROSECRETORY-CELLS; PARAVENTRICULAR NEURONS; SECRETING NEURONS; OXYTOCIN; RELEASE; INVITRO AB Vasopressin secreting neurons of the rat hypothalamus discharge lengthy, repeating bursts of action potentials in response to physiological stress. Although many electrical currents and calcium-dependent processes have been isolated and analyzed in these cells, their interactions are less well fathomed. In particular, the mechanism of how each burst is triggered, sustained, and terminated is poorly understood. We present a mathematical model for the bursting mechanism, and we support our model with new simultaneous electrical recording and calcium imaging data. We show that bursts can be initiated by spike-dependent calcium influx, and we propose that the resulting elevation of bulk calcium inhibits a persistent potassium current. This inhibition depolarizes the cell above threshold and so triggers regenerative spiking and further calcium influx. We present imaging data to show that bulk calcium reaches a plateau within the first few seconds of the burst, and our model indicates that this plateau occurs when calcium influx is balanced by efflux and uptake into stores. We conjecture that the burst is terminated by a slow, progressive desensitization to calcium of the potassium leak current. Finally, we propose that the opioid dynorphin, which is known to be secreted from the somatodendritic region and has been shown previously to regulate burst length and phasic activity in these cells, is the autocrine messenger for this desensitization. C1 NIDDKD, Math Res Branch, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. Univ Tennessee, Coll Med, Dept Anat & Neurobiol, Memphis, TN 38163 USA. RP Roper, P (reprint author), NIDDKD, Math Res Branch, Lab Biol Modeling, NIH, 12A South Dr,Room 4007,MSC 5621, Bethesda, MD 20892 USA. EM pete.roper@nih.gov FU NINDS NIH HHS [NS23941, NS42276] NR 69 TC 43 Z9 44 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 19 PY 2004 VL 24 IS 20 BP 4818 EP 4831 DI 10.1523/JNEUROSCI.4203-03.2004 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 823IQ UT WOS:000221604900013 PM 15152042 ER PT J AU Colangelo, AM Mallei, A Johnson, PF Mocchetti, I AF Colangelo, AM Mallei, A Johnson, PF Mocchetti, I TI Synergistic effect of dexamethasone and beta-adrenergic receptor agonists on the nerve growth factor gene transcription SO MOLECULAR BRAIN RESEARCH LA English DT Article DE cAMP; clenbuterol; C6-2B glionia cells; CREB; C/EBP; GRE ID FACTOR MESSENGER-RNA; CCAAT/ENHANCER-BINDING PROTEIN; C6 GLIOMA-CELLS; RAT-BRAIN; GLUCOCORTICOID RESPONSE; BETA(2)-ADRENOCEPTOR AGONIST; FACTOR BIOSYNTHESIS; ASTROCYTOMA-CELLS; CEREBRAL-CORTEX; CYCLIC-AMP AB Activation of beta-adrenergic receptor (betaAR) increases the synthesis of nerve growth factor (NGF) in the brain and in C6-2B glioma cells. However, in the brain, the betaAR-mediated increase in NGF expression appears to require the presence of glucocorticoids, suggesting that NGF promoter may be sensitive to cAMP and glucocorticoid-dependent transcription factors. We tested this hypothesis by exposing C6-2B glioma cells to dexamethasone (DEX) in combination with agents that increase cAMP levels and examining the DNA binding activity of two cAMP-dependent transcription factors that regulate NGF expression: cAMP responsive element binding protein (CREB) and CCAAT/enhancer binding protein delta (C/EBPdelta). Electrophoretic mobility shift assays revealed that the beta(2)AR agonist clenbuterol (CLE) or high levels of cAMP elicited a time-dependent increase in C/EBPdelta binding activity as well as phosphorylated CREB (P-CREB). When DEX, which per se showed little effect on these transcription factors, was combined with CLE, dibutyryl cAMP or isoproterenol, enhanced induction of P-CREB and Cl EBPdelta binding activity as well as NGF mRNA was observed. Moreover, the increase in NGF mRNA in the presence of DEX was prolonged compared to that obtained by CLE or other cAMP inducing agents alone. In fact, NGF mRNA levels remained significantly elevated at least for 24 h. These studies suggest that the synergistic effect of DEX on the induction of NGF mRNA may include the ability of this glucocorticoid to potentiate the betaAR-mediated induction of transcription factors. (C) 2004 Elsevier B.V. All rights reserved. C1 Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20057 USA. NCI Frederick, Lab Prot Dynam & Signaling, Eukaryot Transcript Regulat Sect, Ft Detrick, MD 21702 USA. RP Mocchetti, I (reprint author), Georgetown Univ, Med Ctr, Dept Neurosci, Res Bldg,Box 571464, Washington, DC 20057 USA. EM Moccheti@georgetown.edu RI Johnson, Peter/A-1940-2012; OI Johnson, Peter/0000-0002-4145-4725; COLANGELO, ANNA MARIA/0000-0002-7971-4289 NR 40 TC 16 Z9 16 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD MAY 19 PY 2004 VL 124 IS 2 BP 97 EP 104 DI 10.1016/j.molbraines.2004.01.011 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 824LQ UT WOS:000221688500001 ER PT J AU Sabatinelli, D Flaisch, T Bradley, MM Fitzsimmons, JR Lang, PJ AF Sabatinelli, D Flaisch, T Bradley, MM Fitzsimmons, JR Lang, PJ TI Affective picture perception: gender differences in visual cortex? SO NEUROREPORT LA English DT Article DE attention; emotion; fMRI; gender differences; pictures; visual cortex ID SEX-DIFFERENCES; ACTIVATION; AROUSAL; EMOTION; STIMULI; FEAR AB Activity in extrastriate visual cortex is greater when people view emotional relative to neutral pictures. Prior brain imaging and psychophysiological work has further suggested a bias for men to react more strongly to pleasant pictures, and for women to react more strongly to unpleasant pictures. Here we investigated visual cortical activity using fMRI in 28 men and women during picture viewing. Men and women showed reliably greater visual cortical reactivity during both pleasant and unpleasant pictures, relative to neutral, consistent with the view that the motivational relevance of visual stimuli directs attention and enhances elaborative perceptual processing. However, men did show greater extrastriate activity than women specifically during erotic picture perception, possibly reflecting a gender-specific visual mechanism for sexual selection. C1 Univ Florida, NIMH Ctr Study Emot & Attent, Gainesville, FL 32610 USA. RP Sabatinelli, D (reprint author), Univ Florida, NIMH Ctr Study Emot & Attent, POB 100165 HSC, Gainesville, FL 32610 USA. EM sabat@ufl.edu RI Frank, David/E-8213-2012; OI sabatinelli, dean/0000-0001-7409-8504 FU NIMH NIH HHS [MH37757, P50-MH52384]; PHS HHS [P41-16105] NR 23 TC 122 Z9 122 U1 1 U2 19 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD MAY 19 PY 2004 VL 15 IS 7 BP 1109 EP 1112 DI 10.1097/01.wnr.0000126558.41468.3d PG 4 WC Neurosciences SC Neurosciences & Neurology GA 871NM UT WOS:000225140400005 PM 15129155 ER PT J AU Piontkivska, H Zhang, Y Green, ED Elnitski, L AF Piontkivska, H Zhang, Y Green, ED Elnitski, L CA NISC Comparative Sequencing Progra TI Multi-species sequence comparison reveals dynamic evolution of the elastin gene that has involved purifying selection and lineage-specific insertions/deletions SO BMC GENOMICS LA English DT Article ID SUPRAVALVULAR AORTIC-STENOSIS; TROPOELASTIN GENE; MESSENGER-RNA; REPEATED HEXAPEPTIDE; MONOCLONAL-ANTIBODY; WILLIAMS-SYNDROME; POINT MUTATIONS; CUTIS LAXA; DISEASE; BOVINE AB Background: The elastin gene (ELN) is implicated as a factor in both supravalvular aortic stenosis (SVAS) and Williams Beuren Syndrome (WBS), two diseases involving pronounced complications in mental or physical development. Although the complete spectrum of functional roles of the processed gene product remains to be established, these roles are inferred to be analogous in human and mouse. This view is supported by genomic sequence comparison, in which there are no large-scale differences in the similar to1.8 Mb sequence block encompassing the common region deleted in WBS, with the exception of an overall reversed physical orientation between human and mouse. Results: Conserved synteny around ELN does not translate to a high level of conservation in the gene itself. In fact, ELN orthologs in mammals show more sequence divergence than expected for a gene with a critical role in development. The pattern of divergence is non-conventional due to an unusually high ratio of gaps to substitutions. Specifically, multi-sequence alignments of eight mammalian sequences reveal numerous non-aligning regions caused by species-specific insertions and deletions, in spite of the fact that the vast majority of aligning sites appear to be conserved and undergoing purifying selection. Conclusions: The pattern of lineage-specific, in-frame insertions/deletions in the coding exons of ELN orthologous genes is unusual and has led to unique features of the gene in each lineage. These differences may indicate that the gene has a slightly different functional mechanism in mammalian lineages, or that the corresponding regions are functionally inert. Identified regions that undergo purifying selection reflect a functional importance associated with evolutionary pressure to retain those features. C1 Penn State Univ, Ctr Comparat Genom & Bioinformat, Dept Comp Sci & Engn, University Pk, PA 16802 USA. Penn State Univ, Dept Biol, University Pk, PA 16802 USA. Univ S Carolina, Dept Biol Sci, Columbia, SC 29208 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Elnitski, L (reprint author), Penn State Univ, Ctr Comparat Genom & Bioinformat, Dept Comp Sci & Engn, University Pk, PA 16802 USA. EM elena@biol.sc.edu; yuz10@psu.edu; egreen@nhgri.nih.gov; LLB111@psu.edu FU NHGRI NIH HHS [F32 HG002325, HG-02325]; NIGMS NIH HHS [GM066710, GM20293, R33 GM066710, R01 GM020293] NR 42 TC 17 Z9 18 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAY 18 PY 2004 VL 5 AR 31 DI 10.1186/1471-2164-5-31 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 832KP UT WOS:000222266700001 PM 15149554 ER PT J AU Srivastava, M Eidelman, O Zhang, J Paweletz, C Caohuy, H Yang, QF Jacobson, KA Heldman, E Huang, W Jozwik, C Pollard, BS Pollard, HB AF Srivastava, M Eidelman, O Zhang, J Paweletz, C Caohuy, H Yang, QF Jacobson, KA Heldman, E Huang, W Jozwik, C Pollard, BS Pollard, HB TI Digitoxin mimics gene therapy with CFTR and suppresses hypersecretion of IL-8 cyctic fibrosis lung epithelial cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSMEMBRANE CONDUCTANCE REGULATOR; NF-KAPPA-B; CYSTIC-FIBROSIS; CHLORIDE EFFLUX; PSEUDOMONAS-AERUGINOSA; WILD-TYPE; INTERLEUKIN-8; IDENTIFICATION; EXPRESSION; ACTIVATION AB Cystic fibrosis (CF) is a fatal, autosomal, recessive genetic disease that is characterized by profound lung inflammation. The inflammatory process is believed to be caused by massive overproduction of the proinflammatory protein IL-8, and the high levels of IL-8 in the CIF lung are therefore believed to be the central mechanism behind CF lung pathophysiology. We show here that digitoxin, at sub nM concentrations, can suppress hypersecretion of IL-8 from cultured CF lung epithelial cells. Certain other cardiac glycosides are also active but with much less potency. The specific mechanism of digitoxin action is to block phosphorylation of the inhibitor of NF-kappaB (IkappaBalpha). IkappaBalpha phosphorylation is a required step in the activation of the NF-kappaB signaling pathway and the subsequent expression of IL-8. Digitoxin also has effects on global gene expression in CF cells. of the informative genes expressed by the CF epithelial cell line IB-3, 58 are significantly (P < 0.05) affected by gene therapy with wild-type (CFTR CF transmembrane conductance regulator). Of these 58 genes, 36 (62%) are similarly affected by digitoxin and related active analogues. We interpret this result to suggest that digitoxin can also partially mimic the genomic consequences of gene therapy with CF transmembrane conductance regulator. We therefore suggest that digitoxin, with its lengthy history of human use, deserves consideration as a candidate drug for suppressing IL-8-dependent lung inflammation in CF. C1 Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Sch Med, Inst Mol Med, Bethesda, MD 20814 USA. NIDDKD, Mol Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. Ben Gurion Univ Negev, Dept Physiol, IL-84105 Beer Sheva, Israel. Equal Employment Opportun Commiss Headquarters, Off Informat Technol, Washington, DC 20507 USA. RP Pollard, HB (reprint author), Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. EM hpollard@usuh5.mil RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 49 TC 57 Z9 60 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 18 PY 2004 VL 101 IS 20 BP 7693 EP 7698 DI 10.1073/pnas.0402030101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822GW UT WOS:000221528100038 PM 15136726 ER PT J AU Yu, MYW Bartosch, B Zhang, P Guo, ZP Renzi, PM Shen, LM Granier, C Feinstone, SM Cosset, FL Purcell, RH AF Yu, MYW Bartosch, B Zhang, P Guo, ZP Renzi, PM Shen, LM Granier, C Feinstone, SM Cosset, FL Purcell, RH TI Neutralizing antibodies to hepatitis C virus (HCV) in immune globulins derived from anti-HCV-positive plasma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID POST-TRANSFUSION HEPATITIS; HYPERVARIABLE REGION 1; INTRAVENOUS IMMUNOGLOBULIN; HYPERIMMUNE SERUM; GAMMA-GLOBULIN; INFECTION; PREVENTION; CHIMPANZEES; FRACTIONATION; PARTICLES AB The role of humoral immunity in hepatitis C virus (HCV) infections is uncertain. Nevertheless, there is increasing evidence for neutralizing antibodies to HCV in the serum or plasma of chronically infected individuals. Immune globulins prepared by ethanol fractionation of plasma had long been considered safe until a commercial immune globulin product, Gammagard, prepared from plasma from which units containing anti-HCV had been excluded, transmitted HCV to recipients. Studies suggested that the exclusion might have removed neutralizing antibodies from the plasma and hence compromised the safety of the resulting immune globulins. In the present study, by using chimpanzees and a recently validated in vitro system based on neutralization of infectious HCV pseudoparticles, we found broadly reactive neutralizing and protective antibodies in experimental immune globulin preparations made from anti-HCV-positive donations. Neutralizing antibodies were also found in Gammagard lots made from unscreened plasma that did not transmit hepatitis C but not in Gammagard lots, which were prepared from anti-HCV-screened plasma, that did transmit hepatitis C. The results provide an explanation for the mechanism by which the safety of this product was compromised. Immune globulins made from anti-HCV-positive plasma and containing broadly reactive neutralizing antibodies may provide a method of preventing HCV infection. C1 US FDA, Ctr Biol Evaluat & Res, Div Hematol, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD 20892 USA. Ecole Normale Super Lyon, Lab Vectorol Retrovirale & Therapie Genique, Inst Natl Sante & Rech Med, U412, F-69364 Lyon, France. NIAID, Lab Infect Dis, NIH, Bethesda, MD 20892 USA. RP Purcell, RH (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Hematol, 29 Lincoln Dr, Bethesda, MD 20892 USA. EM rpurcell@niaid.nih.gov NR 35 TC 105 Z9 110 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 MAY 18 PY 2004 VL 101 IS 20 BP 7705 EP 7710 DI 10.1073/pnas.0402458101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822GW UT WOS:000221528100040 PM 15136748 ER PT J AU Honda, T Tamura, G Waki, T Kawata, S Nishizuka, S Motoyama, T AF Honda, T Tamura, G Waki, T Kawata, S Nishizuka, S Motoyama, T TI Promoter hypermethylation of the Chfr gene in neoplastic and non-neoplastic gastric epithelia SO BRITISH JOURNAL OF CANCER LA English DT Article DE Chfr; hypermethylation; gastric cancer ID MITOTIC STRESS CHECKPOINT; TUMOR-RELATED GENES; METHYLATION STATUS; FLOW-CYTOMETRY; LUNG-CANCER; CPG ISLAND; HSMAD2; INACTIVATION; INSTABILITY; SUPPRESSOR AB While chromosomal instability is a common feature of human solid tumours, no abnormalities in genes involved in the mitotic checkpoint have been identified. However, recently, Chfr (checkpoint with forkhead associated and ring finger), a mitotic stress checkpoint gene, has been reported to be inactivated due to promoter hypermethylation in several types of human malignancy. To clarify whether Chfr promoter hypermethylation is involved in gastric carcinogenesis, we investigated the promoter methylation status of the Chfr gene in gastric cancer cell lines and primary gastric cancers. Non-neoplastic gastric epithelia from cancer-bearing and noncancer-bearing stomachs were also examined for Chfr promoter hypermethylation to study its cancer specificity. Two of 10 gastric cancer cell lines (20%) showed Chfr promoter hypermethylation with resultant loss of expression, which could be restored by 5-aza-2' deoxycytidine treatment. Chfr promoter hypermethylation was present in 35% (25 of 71) of primary tumours and occurred at similar frequencies in early and advanced stages. As for non-neoplastic gastric epithelia, 1% (one of 91) from noncancer-bearing and 5% (four of 71) from cancer-bearing stomachs exhibited Chfr promoter hypermethylation. Thus, Chfr promoter hypermethylation is mostly cancer specific and frequently leads to chromosome instability in gastric cancer. (C) 2004 Cancer Research UK. C1 Yamagata Univ, Sch Med, Dept Pathol, Yamagata 9909585, Japan. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Tamura, G (reprint author), Yamagata Univ, Sch Med, Dept Pathol, 2-2-2 Iida Nishi, Yamagata 9909585, Japan. EM gtamura@med.id.yamagata-u.ac.jp NR 23 TC 28 Z9 30 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 17 PY 2004 VL 90 IS 10 BP 2013 EP 2016 DI 10.1038/sj.bjc.6601849 PG 4 WC Oncology SC Oncology GA 827BN UT WOS:000221873400024 PM 15138487 ER PT J AU Mandal, AK Zhang, ZJ Ray, R Choi, MS Chowdhury, B Pattabiraman, N Mukherjee, AB AF Mandal, AK Zhang, ZJ Ray, R Choi, MS Chowdhury, B Pattabiraman, N Mukherjee, AB TI Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE allergic airway inflammation; uteroglobin; Th2 cytokines; eosinophils; secretoglobin ID NF-KAPPA-B; CELL 10-KDA PROTEIN; PROGESTERONE-BINDING; PROSTAGLANDIN D-2; AIRWAY EPITHELIUM; ARACHIDONIC-ACID; COX-2 EXPRESSION; ASTHMA; MICE; RELEASE AB Uteroglobin (UG) is an antiinflammatory protein secreted by the epithelial lining of all organs communicating with the external environment. We reported previously that UG-knockout mice manifest exaggerated inflammatory response to allergen, characterized by increased eotaxin and Th2 cytokine gene expression, and eosinophil infiltration in the lungs. In this study, we uncovered that the air-way epithelia of these mice also express high levels of cyclooxygenase (COX)-2, a key enzyme for the production of proinflammatory lipid mediators, and the bronchoalveolar lavage fluid (BALF) contain elevated levels of prostaglandin D-2. These effects are abrogated by recombinant UG treatment. Although it has been reported that prostaglandin D-2 mediates allergic inflammation via its receptor, DP, neither the molecular mechanism(s) of DP signaling nor the mechanism by which UG suppresses DP-mediated inflammatory response are clearly understood. Here we report that DP signaling is mediated via p38 mitogen-activated protein kinase, p44/42 mitogen-activated protein kinase, and protein kinase C pathways in a cell type-specific manner leading to nuclear factor-kappaB activation stimulating COX-2 gene expression. Further, we found that recombinant UG blocks DP-mediated nuclear factor-kappaB activation and suppresses COX-2 gene expression. We propose that UG is an essential component of a novel innate homeostatic mechanism in the mammalian air-ways to repress allergen-induced inflammatory responses. C1 NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Oncol, Lombardi Canc Ctr, Washington, DC 20057 USA. RP Mukherjee, AB (reprint author), NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bldg 10,Rm 9S241,9000 Rockville Pike, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov NR 54 TC 67 Z9 69 U1 1 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 17 PY 2004 VL 199 IS 10 BP 1317 EP 1330 DI 10.1084/jem.20031666 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 822SL UT WOS:000221560300004 PM 15148333 ER PT J AU Yamano, Y Cohen, CJ Takenouchi, N Yao, K Tomaru, U Li, HC Reiter, Y Jacobson, S AF Yamano, Y Cohen, CJ Takenouchi, N Yao, K Tomaru, U Li, HC Reiter, Y Jacobson, S TI Increased expression of human T lymphocyte virus type I (HTLV-I) Tax11-19 peptide-human histocompatibility leukocyte antigen A*201 complexes on CD4(+) CD25(+) T cells detected by peptide-specific, major histocompatibility complex-restricted antibodies in patients with HTLV-I-associated neurologic disease SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE HAM/TSP; IL-2R alpha chain; regulatory T cell; tetramer; quantitative PCR ID TROPICAL SPASTIC PARAPARESIS; HUMAN RECOMBINANT ANTIBODIES; BLOOD MONONUCLEAR-CELLS; SPINAL-CORD LESIONS; PERIPHERAL-BLOOD; DIRECT VISUALIZATION; CEREBROSPINAL-FLUID; PHENOTYPIC ANALYSIS; PROVIRAL LOAD; MESSENGER-RNA AB Human T lymphocyte virus type I (HTLV-I)-associated chronic inflammatory neurological disease (HTLV-I-associated myelopathy/tropical spastic paraparesis [HAM/TSP]) is suggested to be an immunopathologically mediated disorder characterized by large numbers of HTLV-I Tax-specific CD8(+) T cells. The frequency of these cells in the peripheral blood and cerebrospinal fluid is proportional to the amount of HTLV-I proviral load and the levels of HTLV-I tax mRNA expression. As the stimulus for these virus-specific T cells are immunodominant peptide-human histocompatibility leukocyte antigen (HLA) complexes expressed on antigen-presenting cells, it was of interest to determine which cells express these complexes and at what frequency. However, until now, it has not been possible to identify and/or quantify these peptide-HLA complexes. Using a recently developed antibody that specifically recognizes Tax11-19 peptide-HLA-A(star)201 complexes, the level of Tax11-19-HLA-A(star)201 expression on T cells was demonstrated to be increased in HAM/TSP and correlated with HTLV-I proviral DNA load, HTLV-I tax mRNA load, and HTLV-I Tax-specific CD8(+) T cell frequencies. Furthermore, CD4(+) CD25(+) T cells were demonstrated to be the major reservoir of HTLV-I provirus as well as Tax11-19 peptide-HLA-A*201 complexes. These results indicate that the increased detection and visualization of peptide-HLA complexes in HAM/TSP CD4(+) CD25(+) T cell subsets that are shown to stimulate and expand HTLV-I Tax-specific CD8(+) T cells may play an important role in the pathogenesis of HTLV-I-associated neurological disease. C1 NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Technion Israel Inst Technol, Fac Biol, IL-32000 Haifa, Israel. Hokkaido Univ, Dept Pathol Pathophysiol, Grad Sch Med, Sapporo, Hokkaido 0608638, Japan. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bldg 10,Room 5B-16, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov NR 50 TC 60 Z9 62 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAY 17 PY 2004 VL 199 IS 10 BP 1367 EP 1377 DI 10.1084/jem.20032042 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 822SL UT WOS:000221560300008 PM 15136590 ER PT J AU Palacio, LG Sanchez, JL Jimenez, ME Rivera-Valencia, D Jimenez-Ramirez, R Arcos, OM AF Palacio, LG Sanchez, JL Jimenez, ME Rivera-Valencia, D Jimenez-Ramirez, R Arcos, OM TI Linkage analysis in an extended multigenerational family segregating for idiopathic epilepsy SO REVISTA DE NEUROLOGIA LA Spanish DT Article DE antioquia; chromosome 16; chromosome 21; chromosome 8; Colombia; epilepsy; generalised idiopathic epilepsy; genetics; linkage; microsatellites ID CHILDHOOD ABSENCE EPILEPSY; TONIC-CLONIC SEIZURES; GENERALIZED EPILEPSY; MYOCLONIC EPILEPSY; SUSCEPTIBILITY LOCUS; CHROMOSOME 8Q24; GENE; LOCALIZATION; ANTIOQUIA; COLOMBIA AB Introduction. Linkage analyses enable us to identify the loci that bestow susceptibility to certain diseases which are assumed to have a genetic aetiology by determining the cosegregation of alleles of specific markers within families. Aims. The aim of this study was to determine whether there is generalised idiopathic epilepsy (GIE) susceptibility in the 8q22.1-q24.23, 16p13.3 and 21q22.3 regions within an extended multigenerational family belonging to the Paisa community in Antioquia, a genetic isolate located in Colombia segregating for GIE with a strong capacity for detecting linkage. Patients and methods. A family with a number of individuals affected by idiopathic epilepsy who visited the Instituto Neurologico de Antioquia was selected for study. An affected individual was required to have been diagnosed by a neurologist as suffering from non-myoclonic idiopathic epilepsy or partial idiopathic epilepsy. All patients suspected of suffering from idiopathic epilepsy were submitted to video monitoring in order to characterise the seizures electroencephalographically. Results. Of the 106 individuals in this family that were included in the family tree, 76 were genotyped, 15 of whom were affected by generalised clonic tonic seizures and six were considered to be possibly affected. Results of the lod score were significantly negative for all the markers in relation to each model that was considered. Conclusions. The possibility of the genes located in the 8q22.1 -q24.23, 16p.13.3 and 21q22.3 regions being responsible for the familial aggregation of GIE in this family was ruled out, which is in accordance with claims made in previous studies conducted on other families. C1 Univ Antioquia, Inst Biol, Inst Neurol Antioquia, Medellin, Colombia. Univ Antioquia, Inst Biol, Grp Genet Poblaciones Mutacarchinogenesis & Epide, Medellin, Colombia. NHGRI, NIH, Bethesda, MD 20892 USA. RP Arcos, OM (reprint author), Calle 55,46-36, Medellin, Colombia. EM investigacion@neurologico.org.co NR 21 TC 0 Z9 0 U1 0 U2 0 PU REVISTA DE NEUROLOGIA PI BARCELONA PA C/O CESAR VIGUERA, EDITOR, APDO 94121, 08080 BARCELONA, SPAIN SN 0210-0010 J9 REV NEUROLOGIA JI Rev. Neurologia PD MAY 16 PY 2004 VL 38 IS 10 BP 916 EP 920 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 860XR UT WOS:000224378000004 PM 15175971 ER PT J AU Allen, LA O'Donnell, CJ Giugliano, RP Camargo, CA Lloyd-Jones, DM AF Allen, LA O'Donnell, CJ Giugliano, RP Camargo, CA Lloyd-Jones, DM TI Care concordant with guidelines predicts decreased long-term mortality in patients with unstable angina pectoris and non-ST-elevation myocardial infarction SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PLATELET GLYCOPROTEIN IIB/IIIA; ACUTE CORONARY SYNDROMES; PROPENSITY SCORES; MANAGEMENT; RISK; ASSOCIATION; INHIBITION; OUTCOMES; QUALITY AB Data are sparse regarding the long-term benefit of care concordant with clinical practice guidelines in patients presenting with unstable angina pectoris and non-ST-segment elevation myocardial infarction (UAP/NSTEMI), particularly in the general care setting. We extended follow-up in a preexisting cohort of 275 patients hospitalized with primary UAP/NSTEMI. Using Cox models, we compared long-term mortality between patients who received care concordant with 80% of 8 important guideline recommendations during the index hospitalization and patients who did not. Among all study patients, 68% received guideline-concordant care. During follow-up (median 9.4 years) 49% of patients died. Patients with UAP/NSTEMI who received guideline-concordant care had significantly decreased long-term mortality compared with those who received guideline-discordant care (hazards ratio [HR] 0.45, 95% confidence interval [CI] 0.32 to 0.64). Guideline-concordant care remained associated with decreased mortality after adjusting for other predictors of long-term mortality (HR 0.57, 95% CI 0.39 to 0.84) and after adjustment for the propensity to receive guideline-concordant care (HR 0.61, 95% CI 0.43 to 0.88). The benefit of guideline-concordant care relative to discordant care was preserved in high-risk populations shown to be less likely to receive guideline-concordant care, including patients with advanced age, congestive heart failure, elevated serum creatinine, and prior myocardial infarction. Care concordant with UAP/NSTEMI clinical practice guidelines is associated with substantially improved long-term survival. Our findings endorse the approach adopted by authors of clinical practice guidelines in generalizing evidence-based medicine to usual clinical care. In firmly establishing the benefit of consensus guidelines, the foundation is set for efforts to improve practitioner compliance with these standards. (C) 2004 by Excerpta Medical, Inc. C1 Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Emergency Med, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab,Dept Med, Boston, MA 02115 USA. RP Lloyd-Jones, DM (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Suite 1102, Chicago, IL 60611 USA. EM dlj@northwestern.edu RI Lloyd-Jones, Donald/C-5899-2009 FU NHLBI NIH HHS [K23 HL 04253] NR 20 TC 33 Z9 34 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 2004 VL 93 IS 10 BP 1218 EP 1222 DI 10.1016/j.amjcard.2004.01.063 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 822EZ UT WOS:000221521300004 PM 15135692 ER PT J AU Eaker, ED Sullivan, LM Kelly-Hayes, M D'Agostino, RB Benjamin, EJ AF Eaker, ED Sullivan, LM Kelly-Hayes, M D'Agostino, RB Benjamin, EJ TI Does job strain increase the risk for coronary heart disease or death in men and women? The Framingham Offspring Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; coronary disease; occupations; psychology; stress ID MYOCARDIAL-INFARCTION; DECISION LATITUDE; WHITEHALL-II; SOCIOECONOMIC-STATUS; WORK; MORTALITY; DEMANDS; HEALTH; SUPPORT; ANGINA AB Conflicting findings in the literature have made the relation between job strain and coronary heart disease (CHD) controversial. The effect of high job strain on the 10-year incidence of CHD and total mortality was examined in men and women participating in the Framingham Offspring Study; 3,039 participants, 1,711 men and 1,328 women, aged 18-77 years, were examined between 1984 and 1987 and followed for 10 years. Measures of job strain, occupational characteristics, and risk factors for CHD were collected at the baseline examination. Before and after controlling for systolic blood pressure, body mass index, cigarette smoking, diabetes, and the total/high density lipoprotein cholesterol ratio in Cox proportional hazards models, the authors found that high job strain was not associated with mortality or incident CHD in either men or women over the follow-up period. Contrary to expectation, women with active job strain (high demands-high control) had a 2.8-fold increased risk of CHD (95% confidence interval: 1.1, 7.2) compared with women with high job strain (high demands-low control). For men, higher education, personal income, and occupational prestige were related to decreased risk of total mortality and CHD. These findings do not support high job strain as a significant risk factor for CHD or death in men or women. C1 Eaker Epidemiol Enterprises LLC, Chili, WI 54420 USA. Boston Univ, Sch Publ Hlth, Dept Math & Stat, Boston, MA USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Cardiol, Boston, MA 02118 USA. RP Eaker, ED (reprint author), Eaker Epidemiol Enterprises LLC, 8975 Country Rd V, Chili, WI 54420 USA. EM eakerepi@tznet.com OI Sullivan, Lisa/0000-0003-0726-7149; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [N01-HC-25195, 1 R03 HL 67426-01] NR 31 TC 108 Z9 110 U1 0 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 MAY 15 PY 2004 VL 159 IS 10 BP 950 EP 958 DI 10.1093/aje/kwh127 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 819DU UT WOS:000221294600007 PM 15128607 ER PT J AU Laurin, D Masaki, KH Foley, DJ White, LR Launer, LJ AF Laurin, D Masaki, KH Foley, DJ White, LR Launer, LJ TI Midlife dietary intake of antioxidants and risk of late-life incident dementia - The Honolulu-Asia Aging Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Alzheimer disease; antioxidants; dementia; diet; dietary supplements ID CORONARY HEART-DISEASE; JAPANESE-AMERICAN MEN; C SUPPLEMENT USE; COGNITIVE FUNCTION; ALZHEIMER-DISEASE; VITAMIN-E; CONTROLLED TRIAL; BLOOD-PRESSURE; HAWAII; STROKE AB Antioxidants have been hypothesized to protect against Alzheimer's disease, but studies conducted in late life have been inconsistent. Risk factors measured in midlife may better predict dementia in late life because they are less affected by the disease process. The authors examined the association of midlife dietary intake of antioxidants to late-life dementia and its subtypes. Data were obtained from the Honolulu-Asia Aging Study, a prospective community-based study of Japanese-American men who were aged 45-68 years in 1965-1968, when a 24-hour dietary recall was administered. The analysis included 2,459 men with complete dietary data who were dementia-free at the first assessment in 1991-1993 and were examined up to two times for dementia between 1991 and 1999. The sample included 235 incident cases of dementia (102 cases of Alzheimer's disease, 38 cases of Alzheimer's disease with contributing cerebrovascular disease, and 44 cases of vascular dementia). Relative risks by quartile of intake were calculated using Cox proportional hazards models with age as the time scale, after adjustment for sociodemographic and lifestyle factors, cardiovascular risk factors, other dietary constituents, and apolipoprotein E e4. Intakes of beta-carotene, flavonoids, and vitamins E and C were not associated with the risk of dementia or its subtypes. This analysis suggests that midlife dietary intake of antioxidants does not modify the risk of late-life dementia or its most prevalent subtypes. C1 NIA, Neuroepidemiol Sect, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Pacific Hlth Res Inst, Honolulu, HI USA. RP Launer, LJ (reprint author), NIA, Neuroepidemiol Sect, Lab Epidemiol Demog & Biometry, Gateway Bldg,7201 Wisconsin Ave,Room 3C-309, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov FU NHLBI NIH HHS [N01-HC-05102]; NIA NIH HHS [N01-AG-4-2149]; PHS HHS [G3-0336] NR 43 TC 124 Z9 138 U1 5 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 15 PY 2004 VL 159 IS 10 BP 959 EP 967 DI 10.1093/aje/kwh124 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 819DU UT WOS:000221294600008 PM 15128608 ER PT J AU Venners, SA Wang, XB Chen, CZ Wang, LH Chen, DF Guang, WW Huang, AQ Ryan, L O'Connor, J Lasley, B Overstreet, J Wilcox, A Xu, XP AF Venners, SA Wang, XB Chen, CZ Wang, LH Chen, DF Guang, WW Huang, AQ Ryan, L O'Connor, J Lasley, B Overstreet, J Wilcox, A Xu, XP TI Paternal smoking and pregnancy loss: A prospective study using a biomarker of pregnancy SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE abortion, spontaneous; biological markers; chorionic gonadotropin; embryo loss; maternal exposure; prospective studies; smoking; tobacco smoke pollution ID TOBACCO-SMOKE; SPONTANEOUS-ABORTION; CIGARETTE-SMOKING; BIRTH-WEIGHT; EXPOSURE; RISK; REPRODUCTION; ESTROGENS; MODELS AB Results of studies on paternal smoking and spontaneous abortions have been inconsistent. The authors examined the effect of paternal smoking on the risk of pregnancy loss in a prospective cohort of 526 newly married, nonsmoking, female textile workers in China between 1996 and 1998. Upon stopping contraception, subjects provided daily urine specimens and records of vaginal bleeding for up to 1 year or until clinical pregnancy. Daily urinary human chorionic gonadotropin was assayed to detect conception and early pregnancy losses, and pregnancies were followed to detect clinical spontaneous abortions. Subjects were grouped by the number of cigarettes that husbands reported smoking daily: nonsmokers (group 1, n = 216), fewer than 20 cigarettes (group 2, n = 239), and 20 or more cigarettes (group 3, n = 71). Compared with that for group 1, the adjusted odds ratio of early pregnancy loss of any conception for group 2 was 1.04 (95% confidence interval (CI): 0.67, 1.63) and for group 3 was 1.81 (95% CI: 1.00, 3.29). The adjusted hazard ratio of conception for group 2 was 0.90 (95% CI: 0.70, 1.18) and for group 3 was 0.96 (95% CI: 0.66, 1.39), while the adjusted hazard ratio of clinical pregnancy for group 2 was 0.93 (95% CI: 0.72, 1.20) and for group 3 was 0.78 (95% CI: 0.55, 1.12). The authors conclude that heavy paternal smoking increased the risk of early pregnancy loss through maternal and/or paternal exposure. C1 Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. Boston Univ, Sch Med, Dept Pediat, Boston, MA 02118 USA. Boston Med Ctr, Boston, MA USA. Beijing Med Univ, Ctr Ecogenet & Reprod Hlth, Beijing 100083, Peoples R China. Anhui Med Univ, Inst Biomed, Anhui, Peoples R China. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. Columbia Univ, Coll Phys & Surg, Irving Ctr Clin Res, New York, NY USA. Univ Calif Davis, Sch Med, Dept Obstet & Gynecol, Davis, CA 95616 USA. Univ Calif Davis, Inst Toxicol & Environm Hlth, Davis, CA 95616 USA. NIEHS, Epidemiol Branch, NIH, Durham, NC USA. RP Xu, XP (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, 655 Huntington Ave,FXB-1, Boston, MA 02115 USA. EM xu@hsph.harvard.edu RI Ryan, Louise/A-4562-2009; OI Ryan, Louise/0000-0001-5957-2490; Wilcox, Allen/0000-0002-3376-1311 FU NICHD NIH HHS [HD32505]; NIEHS NIH HHS [ES-00002, ES06198, ES08957, ES11682, ES8337] NR 33 TC 60 Z9 62 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 15 PY 2004 VL 159 IS 10 BP 993 EP 1001 DI 10.1093/aje/kwh128 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 819DU UT WOS:000221294600012 PM 15128612 ER PT J AU Colfax, G Vittinghoff, E Husnik, MJ McKirnan, D Buchbinder, S Koblin, B Celum, C Chesney, M Huang, YJ Mayer, K Bozeman, S Judson, FN Bryant, KJ Coates, TJ AF Colfax, G Vittinghoff, E Husnik, MJ McKirnan, D Buchbinder, S Koblin, B Celum, C Chesney, M Huang, YJ Mayer, K Bozeman, S Judson, FN Bryant, KJ Coates, TJ CA EXPLORE Study Team TI Substance use and sexual risk: A participant- and episode-level analysis among a cohort of men who have sex with men SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; amphetamine; amyl nitrite; HIV; logistic models; risk factors; risk-taking; sexual behavior ID LONGITUDINAL DATA-ANALYSIS; HIV-POSITIVE MEN; DRUG-USE; BISEXUAL MEN; HOMOSEXUAL-MEN; SAN-FRANCISCO; YOUNG MEN; ABUSE TREATMENT; ALCOHOL-USE; GAY AB Prior reports associating substance use with sexual risk behavior have generally used summary measures and have not adjusted for participants' background levels of substance use. In this 1999-2001 US study (the EXPLORE study), the authors determined whether substance use during sex was independently associated with sexual risk during recent sexual episodes, as reported by 4,295 human immunodeficiency virus-negative men who have sex with men. The main outcome measure was serodiscordant unprotected anal sex (SDUA). The influence of participant-level characteristics was examined by using repeated-measures logistic models. In assessing the influence of episode-level predictors on SDUA, the influence of participant-level characteristics, including 6-month substance use, was removed by using conditional logistic regression, in effect making each participant his own control. The authors also adjusted for partner characteristics. Eleven percent of participants reported heavy alcohol use, 37% used poppers, 19% sniffed cocaine, and 13% used amphetamines. In the participant-level analysis, use of poppers, amphetamines, and sniffed cocaine as well as heavy alcohol use in the prior 6 months were independently associated with SDUA. In the conditional analysis, consumption of greater than or equal to6 alcoholic drinks or use of poppers, amphetamines, or sniffed cocaine just before or during sex was independently associated with SDUA. The authors concluded that programs aimed at preventing human immunodeficiency virus transmission should emphasize the influence of substance use during sex on increased risk behavior. C1 San Francisco Dept Publ Hlth, HIV Res Branch, San Francisco, CA 94102 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, Div Biostat, San Francisco, CA 94143 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Howard Brown Hlth Ctr, Chicago, IL USA. New York Blood Ctr, New York, NY 10021 USA. Univ Washington, Dept Med, Div Infect Dis, Seattle, WA USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. Fenway Community Hlth Ctr, Boston, MA USA. ABT Associates Inc, Cambridge, MA 02138 USA. Denver Publ Hlth Dept, Denver, CO USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. NIAAA, Bethesda, MD USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Infect Dis, Los Angeles, CA USA. RP Colfax, G (reprint author), San Francisco Dept Publ Hlth, HIV Res Branch, 25 Van Ness Ave,Suite 710, San Francisco, CA 94102 USA. EM Grant_Colfax@sfdph.org FU NIAID NIH HHS [U01 AI47995, 5 U01AI46749, N01 AI35176, N01 AI45200, U01 AI47981, U01 AI48016, U01 AI48040] NR 40 TC 207 Z9 208 U1 4 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAY 15 PY 2004 VL 159 IS 10 BP 1002 EP 1012 DI 10.1093/aje/kwh135 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 819DU UT WOS:000221294600013 PM 15128613 ER PT J AU Vourlekis, JS Schwarz, MI Cherniack, RM Curran-Everett, D Cool, CD Tuder, RM King, TE Brown, KK AF Vourlekis, JS Schwarz, MI Cherniack, RM Curran-Everett, D Cool, CD Tuder, RM King, TE Brown, KK TI The effect of pulmonary fibrosis on survival in patients with hypersensitivity pneumonitis SO AMERICAN JOURNAL OF MEDICINE LA English DT Article ID NONSPECIFIC INTERSTITIAL PNEUMONIA/FIBROSIS; EXTRINSIC ALLERGIC ALVEOLITIS; FARMERS LUNG; PROGNOSTIC-SIGNIFICANCE; PIGEON-BREEDERS; QUANTITATIVE ASSESSMENT; SCORING SYSTEM; FOLLOW-UP; DISEASE; PATHOLOGY AB PURPOSE: To determine the effect of pulmonary fibrosis on survival in an unselected group of patients with hypersensitivity pneumonitis. METHODS: We identified 72 patients with hypersensitivity pneumonitis confirmed by surgical lung biopsy in the database of the Clinical Interstitial Lung Disease Program at the National Jewish Medical and Research Center. All biopsy specimens were scored according to the presence or absence of fibrosis. Comparisons were made between patients with (fibrotic group) and without (nonfibrotic group) pathologic fibrosis. Vital status was ascertained and Kaplan-Meier curves were plotted. Cox regression analysis was used to determine predictors of survival. RESULTS: Forty-six patients were classified as fibrotic and 26 as nonfibrotic. Twenty-nine percent had exposure to a bird antigen, 33% had exposure to a microbial antigen, and 38% had unknown exposure. Patients with fibrosis were significantly older, showed greater restrictive lung physiology, and had greater all-cause and respiratory mortality. Median survival in fibrotic patients was 7.1 years, which was significantly less than survival in those without fibrosis. In an age-adjusted regression analysis, antigen class, symptom duration, and lung function had no effect on survival. Only the presence of pathologic fibrosis was predictive of increased mortality (hazard ratio = 6.01; 95% confidence interval: 1.68 to 21.45; P = 0.006). CONCLUSION: Pulmonary fibrosis is associated with diminished survival in patients with hypersensitivity pneumonitis. (C) 2004 by Excerpta Medica Inc. C1 Natl Jewish Med & Res Ctr, Dept Med, Denver, CO 80206 USA. NCI, Lung & Upper Aerodigest Canc Res Grp, Div Canc Prevent, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Div Pulm Sci & Crit Care Med, Denver, CO 80202 USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver, CO 80202 USA. Univ Colorado, Hlth Sci Ctr, Dept Physiol & Biophys, Denver, CO 80202 USA. Univ Colorado, Hlth Sci Ctr, Dept Pathol, Denver, CO 80202 USA. Natl Jewish Med & Res Ctr, Div Biostat, Denver, CO 80206 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21218 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. San Francisco Gen Hosp, San Francisco, CA 94110 USA. RP Brown, KK (reprint author), Natl Jewish Med & Res Ctr, Dept Med, 1400 Jackson St,F107, Denver, CO 80206 USA. EM brownk@njc.org NR 38 TC 89 Z9 91 U1 0 U2 1 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD MAY 15 PY 2004 VL 116 IS 10 BP 662 EP 668 DI 10.1016/j.amjmed.2003.12.030 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 817LG UT WOS:000221178400003 PM 15121492 ER PT J AU Addington, AM Gornick, M Sporn, AL Gogtay, N Greenstein, D Lenane, M Gochman, P Baker, N Balkissoon, R Vakkalanka, RK Weinberger, DR Straub, RE Rapoport, JL AF Addington, AM Gornick, M Sporn, AL Gogtay, N Greenstein, D Lenane, M Gochman, P Baker, N Balkissoon, R Vakkalanka, RK Weinberger, DR Straub, RE Rapoport, JL TI Polymorphisms in the 13q33.2 gene G72/G30 are associated with childhood-onset schizophrenia and psychosis not otherwise specified SO BIOLOGICAL PSYCHIATRY LA English DT Article DE candidate gene; genetic association; transmission disequilibrium test; quantitative transmission disequilibrium test; schizophrenia; children ID AFFECTIVE-DISORDERS; BIPOLAR DISORDER; K-SADS; AGE; DISEQUILIBRIUM; CHILDREN; LINKAGE; TRANSMISSION; SCHEDULE; VALIDITY AB Background: Childhood-onset schizophrenia (COS), defined as onset of psychotic symptoms by age 12 years, is a rare and severe form of the disorder that seems to be clinically and neurobiologically continuous with the adult disorder. Methods. We studied a rare cohort consisting of 98 probands; 71 of these probands received a DSM-defined diagnosis of schizophrenia, and the remaining 27 were diagnosed as psychosis not otherwise specified (NOS) (upon 2-6 year follow-up, 13 have subsequently developed bipolar disorder), Two overlapping genes, G72 and G30 on 13q33.2, were identified through linkage-disequilibrium-based positional cloning. Single nucleotide polymorphisms (SNPs) at the G72/G30 locus were independently associated with both bipolar illness and schizophrenia. We analyzed SNPs at this locus with a family-based transmission disequilibrium test (TDT) and haplotype analyses for the discrete trait, as well as quantitative TDT for intermediate phenotypes, using the 88 probands (including COS and pychosis-NOS) with parental participation. Results: We observed significant pairwise and haplotype associations between SNPs at the G72/G30 locus and psychotic illness. Furthermore, these markers showed associations with scores on a premorbid phenotype measured by the Autism Screening Questionnaire, and with age of onset. Conclusions. these findings, although limited by potential referral bias, confirm and strengthen previous reports that G72/G30 is a susceptibility locus both for schizophrenia and bipolar disorder. C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Addington, AM (reprint author), NIMH, Child Psychiat Branch, NIH, 10 Ctr Dr,Bldg 10,Room 3N202, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008 NR 26 TC 103 Z9 104 U1 1 U2 3 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 MAY 15 PY 2004 VL 55 IS 10 BP 976 EP 980 DI 10.1016/j.biopsych.2004.01.024 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 819UZ UT WOS:000221342700003 PM 15121480 ER PT J AU Sporn, AL Addington, AM Gogtay, N Ordonez, AE Gornick, M Clasen, L Greenstein, D Tossell, JW Gochman, P Lenane, M Sharp, WS Straub, RE Rapoport, JL AF Sporn, AL Addington, AM Gogtay, N Ordonez, AE Gornick, M Clasen, L Greenstein, D Tossell, JW Gochman, P Lenane, M Sharp, WS Straub, RE Rapoport, JL TI Pervasive developmental disorder and childhood-onset schizophrenia: Comorbid disorder or a phenotypic variant of a very early onset illness? SO BIOLOGICAL PSYCHIATRY LA English DT Article DE autism; child-onset schizophrenia; pervasive developmental disorder ID AUTISTIC DISORDER; PREMORBID ADJUSTMENT; DIAGNOSTIC INTERVIEW; K-SADS; GENE; ASSOCIATION; CHILDREN; MRI; LIFE; RELIABILITY AB Background: Childhood-onset schizophrenia (COS) is a severe form of the adult-onset disorder with a high rate of premorbid developmental abnormalities. Early symptoms of pervasive developmental disorder (PDD) have been reported in five independent studies of COS. In this study, we compared evidence for premorbid PDD as a nonspecific manifestation of impaired neurodevelopment seen in schizophrenia, or as an independent risk factor for COS. Methods. Diagnosis of past or current autism or PDD was made according to the DSM-IV criteria. COS patients with and without PDD were compared with respect to neuropsychological, clinical, and neurobiological measures. Several candidate genes for autism were examined in the entire COS sample and the subgroup with PDD using the Transmission Disequilibrium Test (TDT) and Quantitative TO T (QTDT). Results: Nineteen (25%) of COS probands bad a lifetime diagnosis of PDD: one met criteria for autism, two for Aspergers disorder, and 16 for PDD not otherwise specified. Premorbid social impairment was most common feature for COS-PDD subjects. The PDD group did not differ from the rest of the COS sample with respect to age of onset, IQ, response to medications, and rate of familial schizotypy. Unexpectedly, two siblings of COS-PDD probands met criteria for nuclear autism. There was no difference between PDD and non-PDD groups with respect to initial bra in magnetic resonance imaging (MRI) measures. However, rate of gray matter loss was greater for PDD (n = 12) than for the non-PDD (n = 2 7) subgroup (-19.5 +/- 11.3 mL/year vs. -9.6 +/- 15.3 mL/year; p = .05). None of eight candidate genes for autism were associated with COS or COS-PDD. Conclusions: Premorbid PDD in COS is more likely to be a nonspecific marker of severe early abnormal neurodevelopment. However, the occurrence of two siblings of COS-PDD probands (17016) with nuclear autism remains to be understood. C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. RP Sporn, AL (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Room 3N202, Bethesda, MD 20892 USA. RI Gogtay, Nitin/A-3035-2008 NR 49 TC 75 Z9 75 U1 2 U2 9 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 MAY 15 PY 2004 VL 55 IS 10 BP 989 EP 994 DI 10.1016/j.biopsych.2004.01.019 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 819UZ UT WOS:000221342700005 PM 15121482 ER PT J AU Mishara, AL Goldberg, TE AF Mishara, AL Goldberg, TE TI A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: Opening a closed book SO BIOLOGICAL PSYCHIATRY LA English DT Review DE antipsychotic; neuroleptic; neuropsychology; schizophrenia; meta-analysis ID CONTINUOUS PERFORMANCE TESTS; ANTIPSYCHOTIC-DRUGS; CLINICAL-TRIALS; ANTICHOLINERGIC MEDICATION; 1ST-EPISODE SCHIZOPHRENIA; NEUROCOGNITIVE DEFICITS; ATYPICAL ANTIPSYCHOTICS; PSYCHIATRIC-SYMPTOMS; PSYCHOTIC-PATIENTS; THOUGHT-DISORDER AB Background: In recent years, numerous studies have examined whether new-generation antipsychotic agents impact cognitive impairment in patients with schizophrenia when compared with conventional antipsychotic treatment. The working assumption of such studies, supported by narrative reviews, is that the conventional antipsychotic medications have little or no effect on cognition. The studies concerning the effects of conventional neuroleptics on cognition, however, have never been analyzed quantitatively. In this meta-analysis, we revisit the question of whether typical agents might have enhancing effects on cognition. Methods. The meta-analysis included studies that 1) compared the effects of typical neuroleptic agents with those of placebo or no medication on cognition; 2) examined adult patients identified as having schizophrenia; and 3) produced adequate data to estimate an effect size. Studies were identified by searches of computerized literature databases and by cross-referencing included studies. The effect size calculated was d, the difference between the means in cognitive measures of patients with schizophrenia taking and not taking conventional neuroleptic medication, divided by the pooled SD. Critically, when multiple measures were reported in a single article, effect sizes were combined so as to minimize the possibility that one study bad undue weight simply because of the number of cognitive outcome variables that it contained. These results were corrected for bias due to sample size, with each of the effect sizes weighted by the reciprocal of its variance. The final sample after exclusion of outliers comprised 208 effect sizes from 34 studies., Results: With a random-effects model, effect sizes from the primary studies were weighted according to sample size and averaged. The resulting mean effect size was .22 (95016 confidence interval = .10,.34). The result is positive, in that the range did not include zero and was of low moderate size. No moderating effects of study design or patient qualities were found to be significant. With the same procedures, effect sizes for individual neurocognitive domains were computed. Effect sizes were generally in the .13-.29 range for the majority of cognitive functions, whereas motor function was impacted negatively (-.11). Unexpectedly, medication dose did not correlate with effect size. Conclusions: Typical antipsychotic medication provides modest-to-moderate gains in multiple cognitive domains. Given unavoidable methodologic limitations of the primary studies, current findings suggest that the impact of conventional medication on cognitive function should be re-evaluated. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Goldberg, TE (reprint author), NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,MSC 1379, Bethesda, MD 20892 USA. NR 133 TC 174 Z9 181 U1 5 U2 24 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 MAY 15 PY 2004 VL 55 IS 10 BP 1013 EP 1022 DI 10.1016/j.biopsych.2004.01.027 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 819UZ UT WOS:000221342700009 PM 15121486 ER PT J AU Yoshida, S Rosen, TC Meyer, OGJ Sloan, MJ Ye, S Haufe, G Kirk, KL AF Yoshida, S Rosen, TC Meyer, OGJ Sloan, MJ Ye, S Haufe, G Kirk, KL TI Fluorinated phenylcyclopropylamines. Part 3: Inhibition of monoamine oxidase A and B SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE monoamine oxidase; fluorinated phenylcyclopropylamine; flavin; inhibitor ID IRREVERSIBLE INHIBITORS; MECHANISM; OXIDATION; ANALOGS AB Fluorinated phenylcyclopropylamines and alkylamines were examined as inhibitors of recombinant human liver monoamine oxidase A (MAO A) and B (MAO B). For a series of trans- and cis-2-fluoro-2-phenylcyclopropylamine analogues, the presence of fluorine attached to a cyclopropane ring was found to result in an increase in inhibitory activity towards both MAO A and B. In addition. p-substitution of electron-withdrawing groups such as Cl and F in the aromatic ring of the trans-isomers increased the inhibition of both enzymes. (1S,2S)-2-Fluoro-2-phenylcyclopropylamine was a more potent inhibitor of both MAO A and B than was the (1R,2R)-enantiomer, indicating that the presence of fluorine has no influence on the enantioselectivity of MAO inhibition. since a similar effect of stereochemistry has been reported for tranylcypromine. Interestingly, fluorination at the 2-position of 1-phenycyclopropylamine, which is known as a selective inhibitor of MAO 13 relative to MAO A, reversed the selectivity and resulted in a potent inhibitor selective for MAO A. All inhibitors showed time- and concentration-dependent inhibition for both enzymes. with the exception of trans-2-fluoro-2-phenylcyclopropyl ethylamine, which acts as a competitive and reversible MAO A selective inhibitor. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIDDKD, Bioorgan Chem Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Univ Munster, Inst Organ Chem, D-48149 Munster, Germany. RP Yoshida, S (reprint author), Ind Res Inst Tottori Prefecture, Ind Res Inst, Tottori, Japan. EM syoshida@pref.tottori.jp NR 33 TC 37 Z9 37 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAY 15 PY 2004 VL 12 IS 10 BP 2645 EP 2652 DI 10.1016/j.bmc.2004.03.010 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 820DC UT WOS:000221366000016 PM 15110846 ER PT J AU Neudorf, S Sanders, J Kobrinsky, N Alonzo, TA Buxton, AB Gold, S Barnard, DR Wallace, JD Kalousek, D Lange, BJ Woods, WG AF Neudorf, S Sanders, J Kobrinsky, N Alonzo, TA Buxton, AB Gold, S Barnard, DR Wallace, JD Kalousek, D Lange, BJ Woods, WG TI Allogeneic bone marrow transplantation for children with acute myelocytic leukemia in first remission demonstrates a role for graft versus leukemia in the maintenance of disease-free survival SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOBLASTIC-LEUKEMIA; HOST-DISEASE; CANCER GROUP; RISK-FACTORS; CHEMOTHERAPY; CHILDHOOD; PROPHYLAXIS; INDUCTION; DONORS AB in Children's Cancer Group (CCG) study 2891, patients who were recently diagnosed with acute myelocytic leukemia (AML) were assigned randomly to standard- or intensive-timing induction chemotherapy. Patients in first complete remission (CR1) and who had a human leukocyte antigen (HLA)-identical, related donor or a donor disparate at a single class 1 or 11 locus were nonrandomly assigned to receive a bone marrow transplant (BMT) by using oral busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg). Methotrexate only was given graft-versus-host disease (GVHD) prophylaxis. One hundred fifty patients received transplants. Grade 3 or 4 acute GVHD occurred in 9% of patients. Patients younger than 10 years had a lower incidence of grade 3 or 4 GVHD (4.6%) compared with patients 10 years or older (17.4%) (P =.044). Disease-free survival (DFS) at 6 years was 67% and 42% for recipients of intensive- and standard timing induction therapies, respectively. Multivariate analysis showed that receiving intensive-timing induction therapy (P =.027) and having no hepatomegaly diagnosis (P =.009) was associated with favorable DFS, and grades 3 and 4 acute GVHD were associated with inferior DFS. Multivariate analysis showed that grades 1 or 2 GVHD (P =.008) and no hepatomegaly at diagnosis (P =.014) were associated with improved relapse-free survival (RFS). Our results show that children older than 10 years are at higher risk for developing severe GVHD; acute GVHD is associated with favorable RFS. (C) 2004 by The American Society of Hematology. C1 Emory Univ, Childrens Healthcare, AFLAC Canc Ctr, Atlanta, GA 30322 USA. Izaak Walton Killam Hosp Children, Dept Pediat Hematol Oncol, Halifax, NS B3J 3G9, Canada. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. Roger Maris Canc Ctr, Dept Hematol Oncol, Fargo, ND USA. NCI, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Childrens Hosp Orange Cty, Dept Hematol Oncol, Orange, CA 92668 USA. Univ N Carolina, Dept Pediat Hematol Oncol, Chapel Hill, NC 27515 USA. Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. RP Childrens Canc Grp, POB 60012, Arcadia, CA 91066 USA. EM sneudorf@choc.org FU NCI NIH HHS [CA 07306, CA 10382, CA 11796, CA 26044, CA 27678, CA 69274, CA 79753, CA 02971, CA 03750, CA 17829, CA 26126, CA 29013, CA 29314, CA 36015, CA 42764, CA 61833, CA 79726] NR 26 TC 50 Z9 54 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD MAY 15 PY 2004 VL 103 IS 10 BP 3655 EP 3661 DI 10.1182/blood-2003-08-2705 PG 7 WC Hematology SC Hematology GA 823VW UT WOS:000221642800017 PM 14751924 ER PT J AU Gordeuk, VR Sergueeva, AI Miasnikova, GY Okhotin, D Voloshin, Y Choyke, PL Butman, JA Jedlickova, K Prchal, JT Polyakova, LA AF Gordeuk, VR Sergueeva, AI Miasnikova, GY Okhotin, D Voloshin, Y Choyke, PL Butman, JA Jedlickova, K Prchal, JT Polyakova, LA TI Congenital disorder of oxygen sensing: association of the homozygous Chuvash polycythemia VHL mutation with thrombosis and vascular abnormalities but not tumors SO BLOOD LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; HIPPEL-LINDAU-DISEASE; PLASMINOGEN-ACTIVATOR INHIBITOR-1; GENE-EXPRESSION; VEGF; VERA; HIF; HYDROXYLATION; ANGIOGENESIS; HOMEOSTASIS AB Adaptation to hypoxia is critical for survival and regulates multiple processes, including erythropoiesis and vasculogenesis. Chuvash polycythemia is a hypoxia-sensing disorder characterized by homozygous mutation (598C>T) of von Hippel-Lindau gene (VHL), a negative regulator of hypoxia sensing. Although endemic to the Chuvash population of Russia, this mutation occurs worldwide and originates from a single ancient event. That VHL 598C>T homozygosity causes elevated normoxic levels of the transcription factor hypoxia inducible factor-1alpha (HIF-1alpha), serum erythropoietin and hemoglobin is known, but the disease phenotype has not been documented in a controlled manner. In this matched cohort study, VHL 598C>T homozygosity was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum vascular endothelial growth factor (VEGF) concentrations (P <.0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classical VHL syndrome were not found, suggesting that overexpression of HIF-1alpha and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoletin concentrations were approximately 10-fold higher in VHL 598C>T homozygotes than in controls, erythropoietin response to hypoxia was identical. Thus, Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes. (C) 2004 by The American Society of Hematology. C1 Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. Howard Univ, Dept Med, Washington, DC 20059 USA. Cheboksary Childrens Hosp, Cheboksary, Russia. Chuvash Republ Clin Hosp 1, Cheboksary, Russia. Russian Res Serv, San Diego, CA USA. NIH, Dept Diagnost Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Baylor Univ, Dept Med, Houston, TX 77030 USA. RP Gordeuk, VR (reprint author), Howard Univ, Ctr Sickle Cell Dis, 2121 Georgia Ave NW, Washington, DC 20059 USA. EM vgordeuk@howard.edu RI Butman, John/A-2694-2008; OI Butman, John/0000-0002-1547-9195 FU NCRR NIH HHS [M01-RR10284]; NHLBI NIH HHS [R01HL5007-09, R01HL66333-01, UH1-HL03679-05] NR 43 TC 145 Z9 150 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 MAY 15 PY 2004 VL 103 IS 10 BP 3924 EP 3932 DI 10.1182/blood-2003-07-2535 PG 9 WC Hematology SC Hematology GA 823VW UT WOS:000221642800053 PM 14726398 ER PT J AU Yamashita, K Choi, U Woltz, PC Foster, SF Sneller, MC Hakim, F Fowler, DH Bishop, MR Pavletic, SZ Tamari, M Castro, K Barrett, AJ Childs, RW Illei, GG Leitman, SF Malech, HL Horwitz, ME AF Yamashita, K Choi, U Woltz, PC Foster, SF Sneller, MC Hakim, F Fowler, DH Bishop, MR Pavletic, SZ Tamari, M Castro, K Barrett, AJ Childs, RW Illei, GG Leitman, SF Malech, HL Horwitz, ME TI Severe chronic graft-versus-host disease is characterized by a preponderance of CD4(+) effector memory cells relative to central memory cells SO BLOOD LA English DT Article ID SYSTEMIC LUPUS-ERYTHEMATOSUS; T-CELLS; TRANSPLANTATION; CHEMOKINE; DYNAMICS; SUBSETS AB Donor alloreactive CD4(+) T cells are important to the pathogenesis of chronic graft-versus-host disease (cGVHD), but specific subsets of CD4(+) T cells responsible for GVHD have not been defined. We hypothesized that cGVHD might be associated with a preponderance of CD4+ effector memory cells (CCR7(-)/CD62L(low), CD4(EM)). We analyzed CCR7 and CD62L expression on CD4(+) T cells from stem cell transplantation patients, who did or did not develop cGVHD, and healthy donors. Patients with cGVHD had a higher percentage of CD4(EM) cells (35.5% +/- 2.9%) than healthy donors (113.8% +/- 0.7%; P <.0001) or patients without cGVHD that received a transplant (21.7% +/- 2.1%; P <.01). Using corticosteroid dose as a surrogate marker for cGVHD severity, severe cGVHD was associated with a higher percentage of CD4(EM) cells. The proportion of CD4(EM) cells in corticosteroid-dependent patients with systemic lupus erythematosis or Wegener granulomatosis did not differ from patients without cGVHD that received a transplant. This finding implies that overrepresentation of CD4(EM) cells is a unique feature of cGVHD. (C) 2004 by The American Society of Hematology. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NCI, Expt Transplantat Immunol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIAMSD, Arthrit & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Bone Marrow Transplant Program, Durham, NC 27706 USA. RP Yamashita, K (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Rm 11N113, Bethesda, MD 20892 USA. EM kyamashita@nlaid.nih.gov NR 13 TC 53 Z9 57 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 MAY 15 PY 2004 VL 103 IS 10 BP 3986 EP 3988 DI 10.1182/blood.2003-09-3286 PG 3 WC Hematology SC Hematology GA 823VW UT WOS:000221642800063 PM 14764530 ER PT J AU Al-Ubaydli, M AF Al-Ubaydli, M TI Handheld computers SO BRITISH MEDICAL JOURNAL LA English DT Review C1 NIH, Bethesda, MD 20814 USA. RP Al-Ubaydli, M (reprint author), NIH, Bethesda, MD 20814 USA. EM mo@mo.md NR 1 TC 20 Z9 20 U1 1 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD MAY 15 PY 2004 VL 328 IS 7449 BP 1181 EP 1184 DI 10.1136/bmj.328.7449.1181 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 821XU UT WOS:000221497500029 PM 15142928 ER PT J AU Seeff, LC Nadel, MR Klabunde, CN Thompson, T Shapiro, JA Vernon, SW Coates, RJ AF Seeff, LC Nadel, MR Klabunde, CN Thompson, T Shapiro, JA Vernon, SW Coates, RJ TI Patterns and predictors of colorectal cancer test use in the adult US population SO CANCER LA English DT Article DE colorectal cancer (CRC); mass screening; fetal occult blood test (FOBT); sigmoidoscopy; colonoscopy ID FECAL-OCCULT-BLOOD; HEALTH INTERVIEW SURVEY; SCREENING-TESTS; UNITED-STATES; MORTALITY; CARE; SIGMOIDOSCOPY; GUIDELINES; PROSTATE; PROGRESS AB BACKGROUND. Screening is effective in reducing the incidence and mortality of colorectal cancer. Rates of colorectal cancer test use continue to be low. METHODS. The authors analyzed data from the National Health Inter-view Survey concerning the use of the home-administered fecal occult blood test (FOBT) and sigmoidoscopy/colonoscopy/proctoscopy to estimate current rates of colorectal cancer test use and to identify factors associated with the use or nonuse of tests. RESULTS. In 2000, 17.1% of respondents reported undergoing a home FORT within the past year, 33.9% reported undergoing an endoscopy within the previous 10 years, and 42.5% reported undergoing either test within the recommended time intervals. The use of colorectal cancer tests varied by gender, race, ethnicity, age, education, income, health care coverage, and having a usual source of care. Having seen a physician within the past year had the strongest association with test use. Lack of awareness and lack of physician recommendation were the most commonly reported barriers to undergoing such tests. CONCLUSIONS. Less than half of the U.S. population age greater than or equal to 50 years underwent colorectal cancer tests within the recommended time intervals. Educational initiatives for patients and providers regarding the importance of colorectal cancer screening, efforts to reduce disparities in test use, and ensuring that all persons have access to routine primary care may help increase screening rates. (C) 2004 American Cancer Society. C1 Ctr Dis Control & Prevent, Div Canc Prevent & Control, Atlanta, GA 30341 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Texas, Sch Publ Hlth, Ctr Hlth Promot & Prevent Res, Houston, TX USA. RP Seeff, LC (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, 4770 Buford Highway NE,Mailstop K-55, Atlanta, GA 30341 USA. EM lvs3@cdc.gov NR 33 TC 363 Z9 367 U1 0 U2 12 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 15 PY 2004 VL 100 IS 10 BP 2093 EP 2103 DI 10.1002/cncr.20276 PG 11 WC Oncology SC Oncology GA 817DA UT WOS:000221157000006 PM 15139050 ER PT J AU Davidson, B Alejandro, E Florenes, VA Goderstad, JM Risberg, B Kristensen, GB Trope, CG Kohn, EC AF Davidson, B Alejandro, E Florenes, VA Goderstad, JM Risberg, B Kristensen, GB Trope, CG Kohn, EC TI Granulin-epithelin precursor is a novel prognostic marker in epithelial ovarian carcinoma SO CANCER LA English DT Article DE effusions; metastasis; prognosis; tumor microenvironment ID GROWTH-FACTOR; SEROUS EFFUSIONS; MESSENGER-RNA; CANCER-CELLS; EXPRESSION; PROGRANULIN; ACROGRANIN; TUMORIGENESIS; ACTIVATION; CYTOLOGY AB BACKGROUND. The granulin-epithelin precursor (GEP) was preferentially expressed in invasive ovarian tumor epithelium specimens compared with specimens of borderline ovarian tumors. The objective of the current study was to evaluate the anatomic site-related and cellular expression of GEP and its association with clinicopathologic parameters and survival in patients with advanced-stage ovarian carcinoma. METHODS. Effusions (n = 190), corresponding primary tumor specimens (n = 64), and specimens of metastatic lesions (n = 125) were analyzed using immunohistochemistry with a specific polyclonal antipeptide antibody. In addition, 36 effusions were analyzed using immunoblotting. RESULTS. GEP was detected in tumor cells in 171 of 190 (90%) effusions and demonstrated both focal membrane and cytoplasmic localization. Mesothelial cells were often GEP positive (81%). GEP was found in carcinoma cells in 180 of 189 (95%) tumor biopsy specimens, with stromal and endothelial cell expression in 93 of 180 (52%) and 124 of 185 (67%) specimens, respectively. Lower GEP expression in stromal cells was observed in metastases sampled during or after chemotherapy (P = 0.034). The presence of GEP-positive stromal cells in untreated primary tumor specimens correlated with worse overall survival (P = 0.014). Significantly more frequent GEP expression was observed in tumor cells of both primary (P = 0.002) and metastatic (P < 0.001) tissue specimens compared with malignant effusions. CONCLUSIONS. GEP expression was observed in primary and metastatic epithelial ovarian carcinoma specimens, with down-regulated expression in tumor cells of malignant effusions. The poor outcome associated with stromal GEP expression suggests a prognostic role for this growth factor in ovarian carcinoma. Published 2004 by the American Cancer Society.* C1 NCI, Mol Signaling Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Oslo, Norwegian Radium Hosp, Dept Pathol, Oslo, Norway. Univ Oslo, Norwegian Radium Hosp, Dept Gynecol Oncol, Oslo, Norway. RP Davidson, B (reprint author), NCI, Mol Signaling Sect, Pathol Lab, Ctr Canc Res, 10 Ctr Dr MSC-1500, Bethesda, MD 20892 USA. EM davidsob@mail.nih.gov RI Risberg, Bjorn/A-6447-2008 NR 32 TC 70 Z9 72 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 15 PY 2004 VL 100 IS 10 BP 2139 EP 2147 DI 10.1002/cncr.20219 PG 9 WC Oncology SC Oncology GA 817DA UT WOS:000221157000012 PM 15139056 ER PT J AU Widemann, BC Balis, FM Kempf-Bielack, B Bielack, S Pratt, CB Ferrari, S Bacci, G Craft, AW Adamson, PC AF Widemann, BC Balis, FM Kempf-Bielack, B Bielack, S Pratt, CB Ferrari, S Bacci, G Craft, AW Adamson, PC TI High-dose methotrexate-induced nephrotoxicity in patients with osteosarcoma - Incidence, treatment, and outcome SO CANCER LA English DT Review DE methotrexate toxicity; renal dysfunction; hemodialysis; hemoperfusion; carboxypeptidase-G(2); high-dose methotrexate ID ACUTE-RENAL-FAILURE; SCANDINAVIAN-SARCOMA-GROUP; HISTOLOGIC TUMOR RESPONSE; COOPERATIVE OSTEO-SARCOMA; HIGH-FLUX HEMODIALYSIS; NEOADJUVANT CHEMOTHERAPY; NONMETASTATIC OSTEOSARCOMA; ADJUVANT CHEMOTHERAPY; CHARCOAL HEMOPERFUSION; SERUM METHOTREXATE AB BACKGROUND. High-dose methotrexate (HDMTX)-induced renal dysfunction can be life threatening, because it delays methotrexate (MTX) excretion, thereby exacerbating the other toxicities of MTX HDMTX-induced nephrotoxicity has been managed with high-dose leucovorin, dialysis-based methods of MTX removal, thymidine, and with the recombinant enzyme, carboxypeptidase-G(2) (CPDG(2)), which cleaves MTX to inactive metabolites. The objectives of the current study were to estimate the current incidence of HDMTX-induced renal dysfunction in patients with osteosarcoma and to compare the efficacy and recovery of renal function for dialysis-based methods of MTX removal with treatment using CPDG(2). METHODS. The literature was reviewed for osteosarcoma trials, use of dialysis-based methods for MTX removal, and reports of MTX-induced nephrotoxicity, including information regarding recovery of renal function. Clinical trial databases of select osteosarcoma studies were reviewed. The efficacy of CPDG2 and renal recovery after CPDG2 rescue was obtained from the database of a compassionate-release trial. RESULTS. Approximately 1.8% of patients with osteosarcoma (68 of 3887 patients) who received HDMTX developed nephrotoxicity Grade greater than or equal to 2. The mortality rate among those patients was 4.4% (3 of 68 patients). Dialysis-based methods of MTX removal were used frequently but had limited effectiveness in removing MTX compared with the rapid reductions > 98% in plasma MTX concentrations achieved with CPDG(2). CPDG2 did not appear to increase the time to recovery of renal function compared with supportive treatment that included dialysis-based methods. CONCLUSIONS. HDMTX-induced renal dysfunction continues to occur in approximately 1.8% of patients with osteosarcoma who are treated on clinical protocols with optimal supportive care. For patients with delayed MTX excretion and high plasma MTX concentrations, CPDG2 should be considered over hemodialysis to lower plasma MTX concentrations rapidly and efficiently. Cancer 2004;100: 2222-32. (C) 2004 American Cancer Society. C1 NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Univ Childrens Hosp, Dept Pediat Hematol & Oncol, Munster, Germany. St Jude Childrens Res Hosp, Dept Hematol & Oncol, Memphis, TN USA. Ist Ortoped Rizzoli, Bologna, Italy. Royal Victoria Infirm, Dept Child Hlth, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England. Childrens Hosp Philadelphia, Div Clin Pharmacol & Therapeut, Philadelphia, PA USA. RP Widemann, BC (reprint author), NCI, Pediat Oncol Branch, 10 Ctr Dr,Bldg 10,Room 13C103, Bethesda, MD 20892 USA. EM bw42y@nih.gov NR 103 TC 96 Z9 105 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD MAY 15 PY 2004 VL 100 IS 10 BP 2222 EP 2232 DI 10.1002/cncr.20255 PG 11 WC Oncology SC Oncology GA 817DA UT WOS:000221157000024 PM 15139068 ER PT J AU Pompeia, C Hodge, DR Plass, C Wu, YZ Marquez, VE Kelley, JA Farrar, WL AF Pompeia, C Hodge, DR Plass, C Wu, YZ Marquez, VE Kelley, JA Farrar, WL TI Microarray analysis of epigenetic silencing of gene expression in the KAS-6/1 multiple myeloma cell line SO CANCER RESEARCH LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; TUMOR-SUPPRESSOR GENE; CPG ISLANDS; METHYLATION INHIBITOR; DNA METHYLATION; BREAST-CANCER; PROTEIN; CLONING; IDENTIFICATION; INTERLEUKIN-6 AB The epigenetic control of gene transcription in cancer has been the theme of many recent studies and therapeutic approaches. Carcinogenesis is frequently associated with hypermethylation and consequent down-regulation of genes that prevent cancer, e.g., those that control cell proliferation and apoptosis. We used the demethylating drug zebularine to induce changes in DNA methylation, then examined patterns of gene expression using cDNA array analysis and Restriction Landmark Genomic Scanning followed by RNase protection assay and reverse transcription-PCR to confirm the results. Microarray studies revealed that many genes were epigenetically regulated by methylation. We concluded that methylation decreased the expression of, or silenced, several genes, contributing to the growth and survival of multiple myeloma cells. For example, a number of genes (BAD, BAK, BIK, and BAX) involved in apoptosis were found to be suppressed by methylation. Sequenced methylation-regulated DNA fragments identified by Restriction Landmark Genomic Scanning were found to contain CpG islands, and some corresponded to promoters of genes that were regulated by methylation. We also observed that after the removal of the demethylating drug, the addition of interleukin 6 restored CpG methylation and re-established previously silenced gene patterns, thus implicating a novel role of interleukin 6 in processes regulating epigenetic gene repression and carcinogenesis. C1 NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Med Chem Lab, Frederick, MD 21702 USA. Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Div Human Canc Genet, Columbus, OH 43210 USA. RP Farrar, WL (reprint author), NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, 1050 Boyles St,Bldg 560,Room 31-68, Frederick, MD 21702 USA. EM farrar@mail.ncifcrf.gov RI Plass, Christoph/H-7192-2014 FU NCI NIH HHS [N01-CO-5600, CA93548] NR 54 TC 61 Z9 69 U1 1 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 MAY 15 PY 2004 VL 64 IS 10 BP 3465 EP 3473 DI 10.1158/0008-5472.CAN-03-3970 PG 9 WC Oncology SC Oncology GA 820WA UT WOS:000221419100016 PM 15150099 ER PT J AU Chen, SY Lin, JRV Darbha, R Lin, PP Liu, TY Chen, YMA AF Chen, SY Lin, JRV Darbha, R Lin, PP Liu, TY Chen, YMA TI Glycine N-methyltransferase tumor susceptibility gene in the benzo(a)pyrene-detoxification pathway SO CANCER RESEARCH LA English DT Article ID FOLATE-BINDING-PROTEIN; CRYSTAL-STRUCTURE; CELL-LINES; RAT-LIVER; S-ADENOSYLHOMOCYSTEINE; AUTOMATED DOCKING; AH RECEPTOR; DNA; EXPRESSION; MICE AB Glycine N-methyltransferase (GNMT) affects genetic stability by (a) regulating the ratio of S-adenosylmethionine to S-adenosylhomocystine and (b) binding to folate. Based on the identification of GNMT as a 4 S polyaromatic hydrocarbon-binding protein, we used liver cancer cell lines that expressed GNMT either transiently or stably in cDNA transfections to analyze the role of GNMT in the benzo(a)pyrene (BaP) detoxification pathway. Results from an indirect immunofluorescent antibody assay showed that GNMT was expressed in cell cytoplasm before BaP treatment and translocated to cell nuclei after BaP? treatment. Compared with cells transfected with the vector plasmid, the number of BaP-7,8-diol 9,10-epoxide-DNA adducts that formed in GNMT-expressing cells was significantly reduced. Furthermore, the dose-dependent inhibition of BaP-7,8-diol 9,10-epoxide-DNA adduct formation by GNMT was observed in HepG2 cells infected with different multiplicities of infection of recombinant adenoviruses carrying GNMT cDNA. According to an aryl hydrocarbon hydroxylase enzyme activity assay, GNMT inhibited BaP-induced cytochrome P450 1A1 enzyme activity. Automated BaP docking using a Lamarckian genetic algorithm with GNMT X-ray crystallography revealed a BaP? preference for the S-adenosylmethionine-binding domain of the dimeric form of GNMT, a novel finding of a cellular defense against potentially damaging exposures. In addition to GNMT, results from docking experiments showed that BaP binds readily with other DNA methyltransferases, including HhaI, HaeIII, PvuII methyltransferases and human DNA methyltransferase 2. We therefore hypothesized that BaP-DNA methyltransferase and BaP-GNMT interactions may contribute to carcinogenesis. C1 Natl Yang Ming Univ, Inst Publ Hlth, Div Prevent Med, Taipei 112, Taiwan. Natl Yang Ming Univ, AIDS Prevent & Res Ctr, Taipei 112, Taiwan. NCI, Macromol Crystallog Lab, Biomol Struct Sect, Frederick, MD 21701 USA. Chung Shan Med Univ, Inst Toxicol, Taichung, Taiwan. Taipei Vet Gen Hosp, Dept Med Res, Taipei, Taiwan. RP Chen, YMA (reprint author), Natl Yang Ming Univ, Inst Publ Hlth, Div Prevent Med, Taipei 112, Taiwan. EM arthur@ym.edu.tw RI Lin, Pinpin/B-2668-2010 NR 40 TC 37 Z9 38 U1 1 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 MAY 15 PY 2004 VL 64 IS 10 BP 3617 EP 3623 DI 10.1158/0008-5472.CAN-03-3726 PG 7 WC Oncology SC Oncology GA 820WA UT WOS:000221419100037 PM 15150120 ER PT J AU Facchinetti, MM De Siervi, A Toskos, D Senderowicz, AM AF Facchinetti, MM De Siervi, A Toskos, D Senderowicz, AM TI UCN-01-induced cell cycle arrest requires the transcriptional induction of p21(waf1/cip1) by activation of mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase pathway SO CANCER RESEARCH LA English DT Article ID HUMAN EPIDERMOID CARCINOMA; PROTEIN-KINASE; DEPENDENT KINASES; SELECTIVE INHIBITOR; ANTITUMOR-ACTIVITY; TRANSFORMED-CELLS; INDUCED APOPTOSIS; A431 CELLS; UCN-01; CANCER AB The small molecule UCN-01 is a cyclin-dependent kinase (CDK) modulator shown to have antiproliferative effects against several in vitro and in vivo cancer models currently being tested in human clinical trials. Although UCN-01 may inhibit several serine-threonine kinases, the exact mechanism by which it promotes cell cycle arrest is still unclear. We have reported previously that UCN-01 promotes G(1)-S cell cycle arrest in a battery of head and neck squamous cancer cell lines. The arrest is accompanied by an increase in both p21(waf1/cip1) and p27(kip1) CDK inhibitors leading to loss in G(1) CDK activity. In this report, we explore the role and the mechanism for the induction of these endogenous CDK inhibitors. We observed that p21 was required for the cell cycle effects of UCN-01, as HCT116 lacking p21 (HCT116 p21(-/-)) was refractory to the cell cycle effects of UCN-01. Moreover, UCN-01 promoted the accumulation of p21 at the mRNA level in the p53-deficient HaCaT cells without increase in the p21 mRNA half-life, suggesting that UCN-01 induced p21 at the transcriptional level. To study UCN-01 transcriptional activation of p21, we used several p21(waf1/cip1) promoter-driven luciferase reporter plasmids and observed that UCN-01 activated the full-length p21(waf1/cip1) promoter and a construct lacking p53 binding sites. The minimal promoter region required for UCN-01 (from - 110 bp to the transcription start site) was the same minimal p21(waf1/cip1) promoter region required for Ras enhancement of p21(waf1/cip1) transcription. Neither protein kinase C nor PDK1/AKT pathways were relevant for the induction of p21 by UCN-01. In contrast, the activation of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase mitogen-activated protein kinase pathways was required for p21 induction as UCN-01 activated this pathway, and genetic or chemical MEK inhibitors blunted p21 accumulation. These results demonstrated for the first time that p21 is required for UCN-01 cell cycle arrest. Moreover, we showed that the accumulation of p21 is transcriptional via activation of the MEK pathway. This novel mechanism, by which UCN-01 exerts its antiproliferative effect, represents a promising strategy to be exploited in future clinical trials. C1 NIDCR, Oral & Pharyngeal Canc Branch, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch,NIH, Bethesda, MD 20892 USA. RP Senderowicz, AM (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, Mol Therapeut Unit, Oral & Pharyngeal Canc Branch,NIH, 30 Convent Dr,Bldg 30,Room 212, Bethesda, MD 20892 USA. EM sendero@helix.nih.gov NR 64 TC 44 Z9 45 U1 1 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 MAY 15 PY 2004 VL 64 IS 10 BP 3629 EP 3637 DI 10.1158/0008-5472.CAN-03-3741 PG 9 WC Oncology SC Oncology GA 820WA UT WOS:000221419100039 PM 15150122 ER PT J AU Zeytin, HE Patel, AC Rogers, CJ Canter, D Hursting, SD Schlom, J Greiner, JW AF Zeytin, HE Patel, AC Rogers, CJ Canter, D Hursting, SD Schlom, J Greiner, JW TI Combination of a poxvirus-based vaccine with a cyclooxygenase-2 inhibitor (Celecoxib) elicits antitumor immunity and long-term survival in CEA.Tg/MIN mice SO CANCER RESEARCH LA English DT Article ID HUMAN CARCINOEMBRYONIC ANTIGEN; FAMILIAL ADENOMATOUS POLYPOSIS; CEA TRANSGENIC MICE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; MULTIPLE INTESTINAL NEOPLASIA; PREVENT COLORECTAL ADENOMAS; T-CELL-ACTIVATION; RANDOMIZED-TRIAL; CANCER-PATIENTS; KNOCKOUT MICE AB The present study was designed to determine whether: (a) chronic administration of dietary celecoxib (Celebrex), a potent nonsteroidal anti-inflammatory drug, which targets the cyclooxygenase-2 (COX-2) enzyme, negatively impacts host immunity; and (b) celecoxib can be coupled with a poxvirus-based vaccine to impact tumor burden in a murine tumor model of spontaneous adenomatous polyposis coli. Naive mice fed the celecoxib-supplemented diets developed eosinophilia with lowered plasma prostaglandin E-2 levels and reduced COX-2 mRNA expression levels in their splenic T cells. Responses of splenic T, B, and natural killer cells to broad-based and antigen-specific stimuli were, for the most part, unchanged in those mice as well as COX-2 knockout mice; exceptions included: (a) reduced IFN-gamma production by concanavalin A- or antigen-stimulated T cells; and (b) heightened lipopolysaccharide response of naive B cells from mice fed a diet supplemented with 1000 ppm of celecoxib. When transgenic mice that express the human carcinoembryonic antigen (CEA) gene (CEA transgenic) were bred with mice bearing a mutation in the Apc(Delta850) gene (multiple intestinal neoplasia mice), the progeny (CEA transgenic/multiple intestinal neoplasia) spontaneously develop multiple intestinal neoplasms that overexpress CEA and COX-2. Beginning at 30 days of age, the administration of a diversified prime/boost recombinant CEA-poxvirus-based vaccine regimen or celecoxib (1000 ppm)-supplemented diet reduced the number of intestinal neoplasms by 54% and 65%, respectively. Combining the CEA-based vaccine with the celecoxib-supplemented diet reduced tumor burden by 95% and significantly improved overall long-term survival. Both tumor reduction and improved overall survival were achieved without any evidence of autoimmunity directed at CEA-expressing or other normal tissues. Celecoxib is prescribed for the treatment of familial adenomatous polyposis in humans, and the CEA-based vaccines have been well tolerated and capable of eliciting anti-CEA host immune responses in early clinical studies. The results suggest that the administration of a recombinant poxvirus-based vaccine is compatible with celecoxib, and this combined chemoimmuno-based approach might lead to an additive therapeutic antitumor benefit not only in patients diagnosed with familial adenomatous polyposis but, perhaps, in other preventive settings in which COX-2 overexpression is associated with progression from premalignancy to neoplasia. C1 NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. NCI, Lab Biosyst & Canc, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Greiner, JW (reprint author), NCI, Lab Tumor Immunol & Biol, NIH, Bldg 10,Room 8B09,MSC 1750, Bethesda, MD 20892 USA. NR 63 TC 58 Z9 61 U1 1 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 MAY 15 PY 2004 VL 64 IS 10 BP 3668 EP 3678 DI 10.1158/0008-5472.CAN-03-3878 PG 11 WC Oncology SC Oncology GA 820WA UT WOS:000221419100044 PM 15150127 ER PT J AU Stemmer-Rachamimov, AO Louis, DN Nielsen, GP Antonescu, CR Borowsky, AD Bronson, RT Burns, DK Cervera, P McLaughlin, ME Reifenberger, G Schmale, MC MacCollin, M Chao, RC Cichowski, K Kalamarides, M Messerli, SM McClatchey, AI Niwa-Kawakita, M Ratner, N Reilly, KM Zhu, Y Giovannini, M AF Stemmer-Rachamimov, AO Louis, DN Nielsen, GP Antonescu, CR Borowsky, AD Bronson, RT Burns, DK Cervera, P McLaughlin, ME Reifenberger, G Schmale, MC MacCollin, M Chao, RC Cichowski, K Kalamarides, M Messerli, SM McClatchey, AI Niwa-Kawakita, M Ratner, N Reilly, KM Zhu, Y Giovannini, M TI Comparative pathology of nerve sheath tumors in mouse models and humans SO CANCER RESEARCH LA English DT Article ID NEUROFIBROMATOSIS TYPE-1; LEARNING-DEFICITS; MICE; NF1; MUTATION; PREDISPOSITION; INACTIVATION; MORTALITY; PROTEIN; DEVELOP AB Despite the progress made in our understanding of the biology of neurofibromatosis (NF), the long-term clinical outcome for affected patients has not changed significantly in the past decades, and both NF1 and NF2 are still associated with a significant morbidity and a decreased life span. A number of NF1 and NF2 murine models have been generated to aid in the study of NF tumor biology and in the development of targeted therapies for NF patients. A single, universal pathological classification of the lesions generated in these murine models is essential for the validation of the models, for their analysis and comparison with other models, and for their future effective use in preclinical treatment trials. For the formulation of a pathological classification of these lesions, the WHO classification of human tumors was used as a reference. However, it was not adopted for the classification of the GEM lesions because of some important differences between the human and murine lesions. A novel classification scheme for peripheral nerve sheath tumors in murine models was therefore devised. C1 CEPH, Fdn Jean Dausset, INSERM, U434, F-75010 Paris, France. Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Harvard Univ, Med Sch, Boston, MA 02114 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. Univ Calif Davis, Med Pathol Ctr Comparat Med, Davis, CA 95616 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX USA. Univ Texas, SW Med Ctr, Ctr Dev Biol, Dallas, TX USA. CEPH, Fdn Jean Dausset, INSERM, U434, Paris, France. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Univ Dusseldorf, Dept Neuropathol, Dusseldorf, Germany. Univ Miami, Rosenstiel Sch Marine & Atmospher Sci, Div Marine Biol & Fisheries, Miami, FL USA. Univ Calif San Francisco, Dept Med Vet Affairs, Ctr Med, Dept Med, San Francisco, CA 94143 USA. Harvard Univ, Sch Med, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Massachusetts Gen Hosp,Canc Ctr, Charlestown, MA USA. Univ Cincinnati, Coll Med, Dept Cell Biol Neurobiol & Anat, Cincinnati, OH USA. Mouse Canc Genet Program, Genet Modifiers Tumorigenesis Sect, NCI, Frederick, MD USA. Univ Michigan, Sch Med, Div Med & Mol Genet, Ann Arbor, MI USA. RP Giovannini, M (reprint author), CEPH, Fdn Jean Dausset, INSERM, U434, 27 Rue Juliette Dodu, F-75010 Paris, France. EM marco.giovannini@cephb.fr NR 30 TC 42 Z9 44 U1 1 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 MAY 15 PY 2004 VL 64 IS 10 BP 3718 EP 3724 DI 10.1158/0008-5472.CAN-03-4079 PG 7 WC Oncology SC Oncology GA 820WA UT WOS:000221419100050 PM 15150133 ER PT J AU Cortes, J Thomas, D Koller, C Giles, F Estey, E Faderl, S Garcia-Manero, G McConkey, D Patel, G Guerciolini, R Wright, J Kantarjian, H AF Cortes, J Thomas, D Koller, C Giles, F Estey, E Faderl, S Garcia-Manero, G McConkey, D Patel, G Guerciolini, R Wright, J Kantarjian, H TI Phase I study of bortezomib in refractory or relapsed acute leukemias SO CLINICAL CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; PROTEASOME INHIBITOR PS-341; TRANSCRIPTION FACTOR; CANCER-THERAPY; CELLS; ACTIVATION; APOPTOSIS; PROLIFERATION; MALIGNANCIES; DEGRADATION AB Bortezomib (Velcade, formerly PS-341) is proteasome inhibitor with documented antitumor activity in multiple myeloma and other lymphoid malignancies. We performed a Phase I study to investigate the maximum tolerated dose and dose-limiting toxicity of bortezomib in patients with acute leukemias refractory to or relapsing after prior therapy. Fifteen patients were treated with 0.75 (n = 3), 1.25 (n = 7), or 1.5 (n = 5) mg/m(2) bortezomib administered twice weekly for 4 weeks every 6 weeks. Dose-limiting toxicity included orthostatic hypotension (n = 2), nausea (n = 2), diarrhea (n = 1), and fluid retention (n = 1), all at 1.5 mg/m(2) bortezomib. Proteasome inhibition was dose dependent and reached 68% at 1.5 mg/m(2) bortezomib. Peak inhibition was observed 1 h after treatment and returned to near baseline levels by 72 It after treatment. Incubation of blast cells with bortezomib in vitro showed induction of apoptosis in three of five patients investigated. We conclude that the maximum tolerated dose of bortezomib in patients with acute leukemia is 1.25 mg/m(2), using a twice-weekly for 4 weeks every 6 weeks schedule. The in vitro evidence of antileukemia and transient hematological improvements observed in some patients warrants further investigation of bortezomib in acute leukemias, probably in combination with other agents. C1 Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. Millennium Pharmaceut Inc, Cambridge, MA USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Cortes, J (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, 1515 Holcombe Blvd,Box 428, Houston, TX 77030 USA. EM jcortes@mdanderson.org NR 36 TC 149 Z9 160 U1 1 U2 4 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 MAY 15 PY 2004 VL 10 IS 10 BP 3371 EP 3376 DI 10.1158/1078-0432.CCR-03-0508 PG 6 WC Oncology SC Oncology GA 823PY UT WOS:000221626600017 PM 15161691 ER PT J AU Goldman, M Zackin, R Fichtenbaum, CJ Skiest, DJ Koletar, SL Hafner, R Wheat, LJ Nyangweso, PM Yiannoutsos, CT Schnizlein-Bick, CT Owens, S Aberg, JA AF Goldman, M Zackin, R Fichtenbaum, CJ Skiest, DJ Koletar, SL Hafner, R Wheat, LJ Nyangweso, PM Yiannoutsos, CT Schnizlein-Bick, CT Owens, S Aberg, JA CA AIDS Clin Trials Grp A5038 Study Grp TI Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID MYCOBACTERIUM-AVIUM COMPLEX; HIV-INFECTED PATIENTS; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; SECONDARY PROPHYLAXIS; CRYPTOCOCCAL MENINGITIS; CAPSULATUM ANTIGEN; CELL COUNT; AIDS; DIAGNOSIS; RETINITIS AB We performed a prospective observational study to assess the safety of stopping maintenance therapy for disseminated histoplasmosis among human immunodeficiency virus - infected patients after response to antiretroviral therapy. All subjects received at least 12 months of antifungal therapy and 6 months of antiretroviral therapy before entry. Negative results of fungal blood cultures, urine and serum Histoplasma antigen level of <4.1 units, and CD4(+) T cell count of >150 cells/mm(3) were required for eligibility. Thirty-two subjects were enrolled; the median CD4(+) T cell count at study entry was 289 cells/mm(3). No relapses of histoplasmosis occurred after a median duration of follow-up of 24 months. This corresponded to an observed relapse rate of 0 cases per 65 person-years. The median CD4(+) T cell count at final study visit was 338 cells/mm(3). Discontinuation of antifungal maintenance therapy appears to be safe for patients with acquired immunodeficiency syndrome with previously treated disseminated histoplasmosis and sustained immunologic improvement in response to antiretroviral therapy. C1 Indiana Univ, Sch Med, Div Infect Dis, Indianapolis, IN USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. Univ Texas, SW Med Ctr, Div Infect Dis, Dallas, TX USA. Ohio State Univ, Div Infect Dis, Columbus, OH 43210 USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. Washington Univ, Sch Med, St Louis, MO USA. RP Goldman, M (reprint author), Indiana Univ, Sch Med, Wishard Mem Hosp, Div Infect Dis, Rm OPW-430,1001 W 10th St, Indianapolis, IN 46202 USA. EM mgoldman@iupui.edu NR 21 TC 6 Z9 6 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 MAY 15 PY 2004 VL 38 IS 10 BP 1490 EP 1494 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 817JH UT WOS:000221173300024 ER PT J AU Parada, LA Sotiriou, S Misteli, T AF Parada, LA Sotiriou, S Misteli, T TI Spatial genome organization SO EXPERIMENTAL CELL RESEARCH LA English DT Review DE chromatin; gene expression; nuclear compartments; protein dynamics ID DOUBLE-STRAND BREAKS; CHROMOSOME TERRITORIES; NUCLEAR ARCHITECTURE; CELL-CYCLE; TRANSCRIPTIONAL ACTIVITY; INTERPHASE NUCLEI; MAMMALIAN-CELLS; GENE-REGULATION; INACTIVE GENES; EARLY G1 AB The linear sequence of genomes exists within the three-dimensional space of the cell nucleus. The spatial arrangement of genes and chromosomes within the interphase nucleus is nonrandom and gives rise to specific patterns. While recent work has begun to describe some of the positioning patterns of chromosomes and gene loci, the structural constraints that are responsible for nonrandom positioning and the relevance of spatial genome organization for genome expression are unclear. Here we discuss potential functional consequences of spatial genome organization and we speculate on the possible molecular mechanisms of how genomes are organized within the space of the mammalian cell nucleus. Published by Elsevier Inc. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, 41 Lib Dr,Bldg 41,B610, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov NR 57 TC 62 Z9 65 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD MAY 15 PY 2004 VL 296 IS 1 BP 64 EP 70 DI 10.1016/j.yexcr.2004.03.013 PG 7 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 820FM UT WOS:000221372800010 PM 15120995 ER PT J AU Mason, RP AF Mason, RP TI Using anti-5,5-dimethyl-1-pyrroline N-oxide (anti-DMPO) to detect protein radicals in time and space with immuno-spin trapping SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE anti-5,5-dimethyl-1-pyrroline N-oxide; electron spin resonance; imuno-spin trapping; free radicals ID ELECTRON-PARAMAGNETIC-RESONANCE; HYDROGEN-PEROXIDE; CARBON-TETRACHLORIDE; ORGANIC RADICALS; PULSE-RADIOLYSIS; AQUEOUS-SOLUTION; KINETICS; OXIDATION; ADDUCTS; HEMOGLOBIN AB The detection of protein free radicals using the specific free radical reactivity of nitrone spin traps in conjunction with nitrone-antibody sensitivity and specificity greatly expands the utility of the spin trapping technique, which is no longer dependent on the quantum mechanical electron spin resonance (ESR). The specificity of the reactions of nitrone spin traps with free radicals has already made spin trapping with ESR detection the most universal, specific tool for the detection of free radicals in biological systems. Now the development of an immunoassay for the nitrone adducts of protein radicals brings the power of immunological techniques to bear on free radical biology. Polyclonal antibodies have now been developed that bind to protein adducts of the nitrone spin trap 5,5-dimethyl-l-pyrroline X-oxide (DMPO). In initial studies, anti-DMPO was used to detect DMPO protein adducts produced on myoglobin and hemoglobin resulting from self-peroxidation by H2O2. These investigations demonstrated that myoglobin forms the predominant detectable protein radical in rat heart supernatant, and hemoglobin radicals for, inside red blood cells. In time, all of the immunological techniques based on antibody-nitrone binding should become available for free radical detection in a wide variety of biological systems. Published by Elsevier Inc. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Mason, RP (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM mason4@niehs.nih.gov NR 52 TC 107 Z9 107 U1 3 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD MAY 15 PY 2004 VL 36 IS 10 BP 1214 EP 1223 DI 10.1016/j.freeradbiomed.2004.02.077 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 819DL UT WOS:000221293400004 PM 15110386 ER PT J AU Zhong, Z Connor, HD Froh, M Lind, H Bunzendahl, H Mason, RP Thurman, RG Lemasters, JJ AF Zhong, Z Connor, HD Froh, M Lind, H Bunzendahl, H Mason, RP Thurman, RG Lemasters, JJ TI Polyphenols from Camellia sinenesis prevent primary graft failure after transplantation of ethanol-induced fatty livers from rats SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE liver transplantation; steatosis; alcohol; polyphenols; free radical ID GREEN TEA POLYPHENOLS; NF-KAPPA-B; PRIMARY NONFUNCTION; REPERFUSION INJURY; FREE-RADICALS; LIPID-PEROXIDATION; ORGAN MANIPULATION; DONOR LIVERS; CELL INJURY; MECHANISMS AB Fatty liver caused by ethanol decreases survival after liver transplantation in rats. This study investigated if antioxidant polyphenols from Camellia sinenesis (green tea) prevent failure of fatty grafts from ethanol-treated rats. Donor rats were given ethanol intragastrically (6 g/kg). After 20 h, livers were explanted and stored in University of Wisconsin solution for 24 h. Prior to implantation, the explanted grafts were rinsed with lactated Ringer's solution containing 0 to 60 mug/ml polyphenols. Alanine aminotransferase (ALT) release after liver transplantation was 4.5-fold higher in recipients receiving ethanol-induced fatty grafts than in those receiving normal grafts. Liver grafts from ethanol-treated donors also developed severe focal necrosis. Graft survival Was 11% in the ethanol group versus 88% for normal grafts. Polyphenol treatment at 60 mug/ml blunted ALT release by 66%, decreased necrotic areas by 84%, and increased survival to 75%. Ethanol increased alpha-(4-pyridyl-1-oxide)-N-tert. -butylnitrone free radical adducts in bile by 2.5-fold, as measured by electron spin resonance spectroscopy, and caused accumulation of 4-hydroxynonenal in liver sections, effects blunted by polyphenols. Epicatechin gallate, a major potyphenol from C. sinenesis, also decreased enzyme release, minimized pathological changes, and decreased free radical adduct formation. In conclusion, polyphenols scavenged free radicals in ethanol-induced fatty livers and decreased injury after liver transplantation. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ N Carolina, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Surg, Chapel Hill, NC 27599 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. RP Zhong, Z (reprint author), Univ N Carolina, Dept Cell & Dev Biol, CB 7090, Chapel Hill, NC 27599 USA. EM zzhong@med.unc.edu FU NIAAA NIH HHS [AA09156]; NIDDK NIH HHS [K01 DK62089, P30 DK34987] NR 54 TC 26 Z9 28 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD MAY 15 PY 2004 VL 36 IS 10 BP 1248 EP 1258 DI 10.1016/j.freeradbiomed.2004.02.012 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 819DL UT WOS:000221293400008 PM 15110390 ER PT J AU Golden-Mason, L Douek, DC Koup, RA Kelly, J Hegarty, JE O'Farrelly, C AF Golden-Mason, L Douek, DC Koup, RA Kelly, J Hegarty, JE O'Farrelly, C TI Adult human liver contains CD8(pos) T cells with naive phenotype, but is not, a site for conventional alpha beta T cell development SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; THYMIC FUNCTION; EXPRESSION; INTERLEUKIN-7; LYMPHOCYTES AB Normal adult human liver (AHL) contains populations of unconventional lymphocytes that have been shown in the mouse to mature locally. The presence of lymphoid progenitors together with IL-7, recombinase-activating gene, and pre-TCR-alpha expression in AHL suggests similar local T cell development activity in humans. Flow cytometry was used to characterize potentially naive hepatic alphabeta-T cells. We looked for evidence of TCR-alphabeta cell development in AHL by quantifying delta deletion TCR excision circles (TRECs) in CD3(Pos) populations isolated from the liver and matched blood of eight individuals. Phenotypic analysis of hepatic T cells suggests the presence of Ag-inexperienced populations. TRECs were detected in all blood samples (mean, 164.10 TRECs/mug DNA), whereas only two hepatic samples were positive at low levels (59.40 and 1.92). The relatively high level of CD8P(os) T cells in these livers with a naive phenotype suggests that in addition to its role as a graveyard for Ag-specific activated CD8(pos) T cells, naive CD8(Pos) T cells may enter the liver without prior activation. The almost complete absence of TRECs suggests that normal AHL is not a site for the development of conventional alphabeta T cells. C1 St Vincents Univ Hosp, Educ & Res Ctr, Dublin 4, Ireland. St Vincents Univ Hosp, Natl Liver Transplant Unit, Dublin 4, Ireland. Univ Coll Dublin, Dublin Inst Technol, Dublin 2, Ireland. Univ Coll Dublin, Conway Inst, Dublin 2, Ireland. NIAID, Human Immunol Sect, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Golden-Mason, L (reprint author), St Vincents Univ Hosp, Educ & Res Ctr, Elm Pk, Dublin 4, Ireland. EM lucy.golden@ucd.ie NR 29 TC 8 Z9 8 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 MAY 15 PY 2004 VL 172 IS 10 BP 5980 EP 5985 PG 6 WC Immunology SC Immunology GA 818XD UT WOS:000221276900025 PM 15128780 ER PT J AU Huang, JP El-Gamil, M Dudley, ME Li, YF Rosenberg, SA Robbins, PF AF Huang, JP El-Gamil, M Dudley, ME Li, YF Rosenberg, SA Robbins, PF TI T cells associated with tumor regression recognize frameshifted products of the CDKN2A tumor suppressor gene locus and a mutated HLA class I gene product SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BETA-CATENIN; HUMAN CANCER; ANTIGEN; LYMPHOCYTES; MUTATIONS; DELETION; P53; IDENTIFICATION; P16(INK4A); CARCINOMA AB The dramatic tumor regression observed following adoptive T cell transfer in some patients has led to attempts to identify novel Ags to understand the nature of these responses. Nearly complete regression of multiple metastatic melanoma lesions was observed in patient 1913 following adoptive transfer of autologous tumor-infiltrating lymphocytes. The autologous 1913 melanoma cell line expressed a mutated HLA-A11 class I gene product that was recognized by the bulk tumor-infiltrating lymphocytes as well as a dominant T cell clone derived from this line. A second dominant T cell clone, T1D1, did not recognize the mutated HLA-A11 product, but recognized an allogeneic melanoma cell line that shared expression of HLA-A11 with the parental tumor cell line. Screening of an autologous melanoma cDNA library with clone T1D1 T cells in a cell line expressing the mutated HLA-A11 gene product resulted in the isolation of a p14ARF transcript containing a 2-bp deletion in exon 2. The T cell epitope recognized by T1D1, which was encoded within the frameshifted region of the deleted p14ARF transcript, was also generated from frameshifted p14ARF or p161NK4a transcripts that were isolated from two additional melanoma cell lines. The results of monitoring studies indicated that T cell clones reactive with the mutated HLA-A11 gene product and the mutated p14ARF product were highly represented in the peripheral blood of patient 1913 1 wk following adoptive transfer, indicating that they may have played a role in the nearly complete tumor regression that was observed following this treatment. C1 NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Robbins, PF (reprint author), NCI, Surg Branch, NIH, Bldg 10,Room 2B42, Bethesda, MD 20892 USA. EM Paul_Robbins@nih.gov FU Intramural NIH HHS [Z01 SC003811-32] NR 33 TC 45 Z9 48 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 MAY 15 PY 2004 VL 172 IS 10 BP 6057 EP 6064 PG 8 WC Immunology SC Immunology GA 818XD UT WOS:000221276900034 PM 15128789 ER PT J AU Sojka, DK Bruniquel, D Schwartz, RH Singh, NJ AF Sojka, DK Bruniquel, D Schwartz, RH Singh, NJ TI IL-2 secretion by CD4(+) T cells in vivo is rapid, transient, and influenced by TCR-specific competition SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INTERLEUKIN-2 EXPRESSION; ANTIGENIC-STIMULATION; ACTIVATION; MECHANISM; PROLIFERATION; COMPLEXES; ANERGY; NAIVE; TRANSCRIPTION; GENERATION AB The secretion of IL-2 is a critical and early landmark in the activation program of CD4(+) T cells in vitro, but the lack of sensitive assays has limited its application for studying T cell activation in vivo. Using a mouse cytokine capture assay we were able to detect the rapid secretion of IL-2 after an in vivo stimulus by 1-2 h in naive T cells and as early as 30 min in memory T cells. Maximal secretion was achieved within 1-2 h for memory cells or 6-8 h for naive T cells. Surprisingly IL-2 production terminated quickly in vivo and secretion was undetectable by 20-24 h in either cell type. We further demonstrated that this short duration of secretion can be influenced by cellular competition between Ag-specitic CD4(+) T cells. The consequences of competition were mimicked by reducing the strength of the antigenic stimulus. These data argue that early competition between T cells influences both the eventual frequency of IL-2 producers in the population and also the duration of their secretion, potentially by altering the strength or duration of the stimulus available to each T cell. C1 NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Singh, NJ (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, Bldg 4,Room 111,Mail Stop Code 0420,4 Ctr Dr, Bethesda, MD 20892 USA. EM nevil@helix.nih.gov NR 33 TC 73 Z9 74 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 MAY 15 PY 2004 VL 172 IS 10 BP 6136 EP 6143 PG 8 WC Immunology SC Immunology GA 818XD UT WOS:000221276900045 PM 15128800 ER PT J AU Semnani, RT Law, M Kubofcik, J Nutman, TB AF Semnani, RT Law, M Kubofcik, J Nutman, TB TI Filaria-induced immune evasion: Suppression by the infective stage of Brugia malayi at the earliest host-parasite interface SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LANGERHANS CELL-MIGRATION; HUMAN DENDRITIC CELLS; LEISHMANIA-MAJOR; INHIBITORY FACTOR; T-CELLS; MECHANISM; NEMATODE; MURINE; SKIN; KERATINOCYTES AB To assess the physiologic interactions between the infective stage of Brugia malayi-one of the extracellular parasites responsible for lymphatic filariasis in humans-and the APC with which they come in contact during their development and routes of travel, we have investigated the interaction between the infective stage (U) of B. malayi and human Langerhans cells (LC) in the skin. Our data indicate that live L3 result in increased migration of LC from the epidermis without affecting the viability of these cells and up-regulation of the IL-18 cytokine involved in LC migration. Live L3 also result in down-regulation of MHC class I and II on the LC cell surface. Additionally, microarray data indicate that live L3 significantly down-regulated expression of IL-8 as well as of multiple genes involved in Ag presentation, reducing the capacity of LC to induce CD4(+) T cells in allogeneic MLR, and thus resulting in a decreased ability of LC to promote CD4(+) T cell proliferation and production of IFN-gamma and IL-10. These data suggest that L3 exert a down-regulatory response in epidermal LC that leads to a diminished capacity of these cells to activate CD4(+) T cells. C1 NIAID, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA. RP Semnani, RT (reprint author), NIAID, Lab Parasit Dis, NIH, 4 Ctr Dr,Room 4-126, Bethesda, MD 20892 USA. EM rsemnani@niaid.nih.gov NR 44 TC 53 Z9 55 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2004 VL 172 IS 10 BP 6229 EP 6238 PG 10 WC Immunology SC Immunology GA 818XD UT WOS:000221276900056 PM 15128811 ER PT J AU Barouch, DH Pau, MG Custers, JHHV Koudstaal, W Kostense, S Havenga, MJE Truitt, DM Sumida, SM Kishko, MG Arthur, JC Korioth-Schmitz, B Newberg, MH Gorgone, DA Lifton, MA Panicali, DL Nabel, GJ Letvin, NL Goudsmit, J AF Barouch, DH Pau, MG Custers, JHHV Koudstaal, W Kostense, S Havenga, MJE Truitt, DM Sumida, SM Kishko, MG Arthur, JC Korioth-Schmitz, B Newberg, MH Gorgone, DA Lifton, MA Panicali, DL Nabel, GJ Letvin, NL Goudsmit, J TI Immunogenicity of recombinant adenovirus serotype 35 vaccine in the presence of pre-existing anti-Ad5 immunity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GENE-TRANSFER; FIBER PROTEINS; IN-VIVO; VECTORS; RECEPTOR; INFECTION; VIRUS; ANTIGEN; THERAPY; CELLS AB The high prevalence of pre-existing immunity to adenovirus serotype 5 (Ad5) in human populations may substantially limit the immunogenicity and clinical utility of recombinant Ad5 vector-based vaccines for HIV-1 and other pathogens. A potential solution to this problem is to use vaccine vectors derived from adenovirus (Ad) serotypes that are rare in humans, such as Ad35. However, cross-reactive immune responses between heterologous Ad serotypes have been described and could prove a major limitation of this strategy. In particular, the extent of immunologic cross-reactivity between Ad5 and Ad35 has not previously been determined. In this study we investigate the impact of pre-existing anti-Ad5 immunity on the immunogenicity of candidate rAd5 and rAd35 vaccines expressing SIV Gag in mice. Anti-Ad5 immunity at levels typically found in humans dramatically blunted the immunogenicity of rAd5-Gag. In contrast, even high levels of anti-Ad5 immunity did not substantially suppress Gag-specific cellular immune responses elicited by rAd35-Gag. Low levels of cross-reactive Ad5/Ad35-specific CD4(+) T lymphocyte responses were observed, but were insufficient to suppress vaccine immunogenicity. These data demonstrate the potential utility of Ad35 as a candidate vaccine vector that is minimally suppressed by anti-Ad5 immunity. Moreover, these studies suggest that using Ad vectors derived from immunologically distinct serotypes may be an effective and general strategy to overcome the suppressive effects of pre-existing anti-Ad immunity. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02215 USA. Crucell Holland, Leiden, Netherlands. Therion Biol, Cambridge, MA 02142 USA. Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Barouch, DH (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Res E Room 113,330 Brookline Ave, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu RI Korioth-Schmitz, Birgit/M-7816-2015 OI Korioth-Schmitz, Birgit/0000-0002-5271-9223 FU NIAID NIH HHS [AI60368, AI51223, AI58727, P30 AI28691] NR 33 TC 264 Z9 267 U1 2 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2004 VL 172 IS 10 BP 6290 EP 6297 PG 8 WC Immunology SC Immunology GA 818XD UT WOS:000221276900063 PM 15128818 ER PT J AU Wu, ZQ Roberts, M Porter, M Walker, F Wherry, EJ Kelly, J Gadina, M Silva, EM DosReis, GA Lopes, MF O'Shea, J Leonard, WJ Ahmed, R Siegel, RM AF Wu, ZQ Roberts, M Porter, M Walker, F Wherry, EJ Kelly, J Gadina, M Silva, EM DosReis, GA Lopes, MF O'Shea, J Leonard, WJ Ahmed, R Siegel, RM TI Viral FLIP impairs survival of activated T cells and generation of CD8+ T cell memory SO JOURNAL OF IMMUNOLOGY LA English DT Article ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; TRYPANOSOMA-CRUZI; TRANSGENIC MICE; HOMEOSTATIC PROLIFERATION; MEDIATED APOPTOSIS; INHIBITORY PROTEIN; CD8-T-CELL MEMORY; CD4-T-CELL HELP; DEATH; FAS AB Viral FLIPS (vFLIPs) interfere with apoptosis signaling by death-domain-containing receptors in the TNFR superfamily (death receptors). In this study, we show that T cell-specific transgenic expression of MC159-vFLIP from the human Molluscum contagiosum virus blocks CD95-induced apoptosis in thymocytes and peripheral T cells, but also impairs postactivation survival of in vitro activated primary T cells despite normal early activation parameters. MC159 vFLIP impairs T cell development to a lesser extent than does Fas-associated death domain protein deficiency or another viral FLIP, E8. In the periphery, vFLIP expression leads to a specific deficit of functional memory CD8(+) T cells. After immunization with a protein Ag, Ag-specific CD8(+) T cells initially proliferate, but quickly disappear and fail to produce Ag-specific memory CD8(+) T cells. Viral FLIP transgenic mice exhibit impaired CD8(+) T cell responses to lymphocytic choriomeningitis virus and Trypanosoma cruzi infections, and a specific defect in CD8(+) T cell recall responses to influenza virus was seen. These results suggest that vFLIP expression in T cells blocks signals necessary for the sustained survival of CD8(+) T cells and the generation of CD8(+) T cell memory. Through this mechanism, vFLIP proteins expressed by T cell tropic viruses may impair the CD8(+) T cell immune responses directed against them. C1 NIAMSD, Immunoregulat Unit, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. Emory Vaccine Ctr, Dept Microbiol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Atlanta, GA 30322 USA. NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, Ctr Ciencas Saude, Rio De Janeiro, Brazil. RP Siegel, RM (reprint author), NIAMSD, Immunoregulat Unit, Autoimmun Branch, NIH, Bldg 10,Room 9N238, Bethesda, MD 20892 USA. EM siegelr@mail.nih.gov RI Siegel, Richard/C-7592-2009; lopes, marcela/E-2201-2012 OI Siegel, Richard/0000-0001-5953-9893; lopes, marcela/0000-0002-4508-0505 NR 58 TC 36 Z9 36 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2004 VL 172 IS 10 BP 6313 EP 6323 PG 11 WC Immunology SC Immunology GA 818XD UT WOS:000221276900066 PM 15128821 ER PT J AU Kindzelskii, AL Ueki, T Michibata, H Chaiworapongsa, T Romero, R Petty, HR AF Kindzelskii, AL Ueki, T Michibata, H Chaiworapongsa, T Romero, R Petty, HR TI 6-phosphogluconate dehydrogenase and glucose-6-phosphate dehydrogenase form a supramolecular complex in human neutrophils that undergoes retrograde trafficking during pregnancy SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RAT PERITONEAL-MACROPHAGES; PHORBOL-MYRISTATE ACETATE; COLONY-STIMULATING FACTOR; SUPEROXIDE PRODUCTION; GLYCOLYTIC-ENZYMES; TETRAZOLIUM SALTS; OXIDANT RELEASE; METABOLISM; BINDING; TRANSPORT AB Neutrophils from pregnant women display reduced neutrophil-mediated effector functions, such as reactive oxygen metabolite (ROM) release. Because the NADPH oxidase and NO synthase produce ROMs and NO, the availability of their substrate NADPH is a potential regulatory factor. NADPH is produced by glucose-6-phosphate dehydrogenase (G-6-PDase) and 6-phosphogluconate dehydrogenase (6-PGDase), which are the first two steps of the hexose monophosphate shunt (HMS). Using immunofluorescence microscopy, we show that 6-PGDase, like G-6-PDase, undergoes retrograde transport to the microtubule-organizing centers in neutrophils from pregnant women. In contrast, 6-PGDase is found in an anterograde distribution in cells from nonpregnant women. However, lactate dehydrogenase distribution is unaffected by pregnancy. Cytochemical studies demonstrated that the distribution of 6-PGDase enzymatic activity is coincident with 6-PGDase Ag. The accumulation of 6-PGDase at the microtubule-organizing centers could be blocked by colchicine, suggesting that microtubules are important in this enzyme's intracellular distribution. In situ kinetic studies reveal that the rates of 6-gluconate turnover are indistinguishable in samples from nonpregnant and pregnant women, suggesting that the enzyme is functionally intact. Resonance energy transfer experiments showed that 6-PGDase and G-6-PDase are in close physical proximity within cells, suggesting the presence of supramolecular enzyme complexes. We suggest that the retrograde trafficking of HMS enzyme complexes during pregnancy influences the dynamics of NADPH production by separating HMS enzymes from glucose-6-phosphate generation at the plasma membrane and, in parallel, reducing ROM and NO production in comparison with fully activated neutrophils from nonpregnant women. C1 Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48105 USA. Hiroshima Univ, Grad Sch Sci, Marine Biol Lab, Hiroshima 730, Japan. Hutzel Hosp, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, Bethesda, MD 20892 USA. RP Petty, HR (reprint author), Univ Michigan, Sch Med, Dept Ophthalmol & Visual Sci, 1000 Wall St, Ann Arbor, MI 48105 USA. EM hpetty@umich.edu NR 47 TC 25 Z9 26 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2004 VL 172 IS 10 BP 6373 EP 6381 PG 9 WC Immunology SC Immunology GA 818XD UT WOS:000221276900073 PM 15128828 ER PT J AU Betts, MR Price, DA Brenchley, JM Lore, K Guenaga, FJ Smed-Sorensen, A Ambrozak, DR Migueles, SA Connors, M Roederer, M Douek, DC Koup, RA AF Betts, MR Price, DA Brenchley, JM Lore, K Guenaga, FJ Smed-Sorensen, A Ambrozak, DR Migueles, SA Connors, M Roederer, M Douek, DC Koup, RA TI The functional profile of primary human antiviral CD8(+) T cell effector activity is dictated by cognate peptide concentration SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEPATITIS-C VIRUS; EX-VIVO ANALYSIS; RECEPTOR REPERTOIRE; CYTOKINE PRODUCTION; IMMUNE-RESPONSES; VIRAL CLEARANCE; MHC COMPLEXES; LYMPHOCYTES; HIV AB Antiviral CD8(+) T cells can elaborate at least two effector functions, cytokine production and cytotoxicity. Which effector function is elaborated can determine whether the CD8(+) T cell response is primarily inflammatory (cytokine producing) or antiviral (cytotoxic). In this study we demonstrate that cytotoxicity can be triggered at peptide concentrations 10- to 100-fold less than those required for cytokine production in primary HIV- and CMV-specific human CD8(+) T cells. Cytolytic granule exocytosis occurs at peptide concentrations insufficient to cause substantial TCR down-regulation, providing a mechanism by which a CD8(+) T cell could engage and lyse multiple target cells. TCR sequence analysis of virus-specific cells shows that individual T cell clones can degranulate or degranulate and produce cytokine depending on the Ag concentration, indicating that response heterogeneity exists within individual CD8(+) T cell clonotypes. Thus, antiviral CD8(+) T cell effector function is determined primarily by Ag concentration and is not an inherent characteristic of a virus-specific CD8(+) T cell clonotype or the virus to which the response is generated. The inherent ability of viruses to induce high or low Ag states may be the primary determinant of the cytokine vs cytolytic nature of the virus-specific CD8(+) T cell response. C1 NIAID, Vaccine Res Ctr, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, Human Immunol Sect, NIH, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, Immunotechnol Sect, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Ctr Infect Med, S-10401 Stockholm, Sweden. RP Betts, MR (reprint author), NIAID, Vaccine Res Ctr, Immunol Lab, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM mbetts@mail.nih.gov RI Roederer, Mario/G-1887-2011; Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 NR 52 TC 104 Z9 105 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2004 VL 172 IS 10 BP 6407 EP 6417 PG 11 WC Immunology SC Immunology GA 818XD UT WOS:000221276900077 PM 15128832 ER PT J AU Skapenko, A Niedobitek, GU Kalden, JR Lipsky, PE Schulze-Koops, H AF Skapenko, A Niedobitek, GU Kalden, JR Lipsky, PE Schulze-Koops, H TI Generation and regulation of human Th1-biased immune responses in vivo: A critical role for IL-4 and IL-10 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLLAGEN-INDUCED ARTHRITIS; NONOBESE DIABETIC MICE; VERSUS-HOST-DISEASE; GROWTH-FACTOR-BETA; MEMORY T-CELLS; RHEUMATOID-ARTHRITIS; MESSENGER-RNA; PERIPHERAL-CIRCULATION; TRANSGENIC MICE; GENE-EXPRESSION AB Tissue damage in many human autoimmune diseases is mediated by activated autoantigen-specific Th1 cells. Delineation of the regulatory mechanisms controlling a Th1-biased human immune reaction and its pathologic potential is, therefore, a critical step in the understanding of autoimmune diseases. In this study, we introduce a novel means to investigate human Th1-biased immune responses in vivo. Intraperitoneal injection of human mononuclear cells into immunodeficient mice generates a xenogeneic Th1-biased human immune response characterized by systemic inflammation and leukocytic infiltrates with a granuloma-like architecture in the liver, and the perigastrointestinal and perirenal fatty tissue. Th1 cell activation was dependent on the presence of APCs and could be blocked by cyclosporine. Importantly, neutralization of endogenously produced IL-4 and IL-10 markedly exaggerated the immune response, whereas exogenous IL-4 and IL-10 inhibited systemic Th1 immunity. Thus, the model described in this paper presents a useful means to analyze the regulation of human immune reactions in an in vivo situation. The results suggest that both IL-4 and IL-10 contribute to controlling the development of a human Th1-biased immune reaction. C1 Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Clin Res Grp 3, Dept Internal Med 3, D-91054 Erlangen, Germany. Univ Erlangen Nurnberg, Inst Clin Immunol, D-91054 Erlangen, Germany. Univ Erlangen Nurnberg, Dept Pathol, D-91054 Erlangen, Germany. NIAMSD, Bethesda, MD 20892 USA. RP Schulze-Koops, H (reprint author), Univ Erlangen Nurnberg, Nikolaus Fiebiger Ctr Mol Med, Clin Res Grp 3, Dept Internal Med 3, Glueckstr 6, D-91054 Erlangen, Germany. EM Schulze-Koops@med3.imed.uni-erlangen.de NR 51 TC 28 Z9 31 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2004 VL 172 IS 10 BP 6427 EP 6434 PG 8 WC Immunology SC Immunology GA 818XD UT WOS:000221276900079 PM 15128834 ER PT J AU Blattner, WA Oursler, KA Cleghorn, F Charurat, M Sill, A Bartholomew, C Jack, N O'Brien, T Edwards, J Tomaras, G Weinhold, K Greenberg, M AF Blattner, WA Oursler, KA Cleghorn, F Charurat, M Sill, A Bartholomew, C Jack, N O'Brien, T Edwards, J Tomaras, G Weinhold, K Greenberg, M TI Rapid clearance of virus after acute HIV-1 infection: Correlates of risk of AIDS SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CYTOTOXIC T-LYMPHOCYTES; VIRAL LOAD; DISEASE PROGRESSION; TYPE-1 INFECTION; NATURAL-HISTORY; RNA LEVELS; HOMOSEXUAL-MEN; CD4(+) LYMPHOCYTES; IMMUNE ACTIVATION AB Objective. Our objective was to define early virologic and immunologic determinants of human immunodeficiency virus (HIV) type 1 disease progression among 22 case subjects with acute infection from the Trinidad Seroconvertor Cohort. Methods. A linear segmented regression model was fitted to sequential quantitative virus load measurements. Parameters of virus kinetics during different phases of primary infection were correlated with clinical and immunologic end points, by use of Kaplan-Meier estimates and Cox regression. Results. Ten individuals developed acquired immunodeficiency syndrome (AIDS) - defining events. In univariate analysis, progression to AIDS was associated with rate of initial HIV clearance (P = .002), virus load during set point (P = .008), and CD4(+) cell count during steady state (P = .04). In the multivariate analysis, a rapid rate of initial clearance was the sole independent predictor of subsequent progression to AIDS and was associated with a 92% reduction in the risk of AIDS. The rate of initial clearance is inversely correlated with the number of early symptoms (r = -0.66; P = .0008). However, symptoms did not predict subsequent risk of AIDS. Conclusion. Among a subset of patients, rapid clearance of plasma HIV-1 after peak viremia is associated with lower viral set point, prolonged virus suppression before loss of virologic control, and decreased risk of AIDS. These findings are consistent with the hypothesis that effective immune responses during the earliest phase of infection are important determinants of the subsequent natural history. C1 Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. Med Res Fdn Trinidad & Tobago, Port Of Spain, Trinid & Tobago. Duke Univ, Med Ctr, Cent Immunol Lab, Durham, NC USA. RP Blattner, WA (reprint author), Univ Maryland, Inst Human Virol, 725 W Lombard St,N449, Baltimore, MD 21201 USA. EM blattner@umbi.umd.edu RI Tomaras, Georgia/J-5041-2016 FU FIC NIH HHS [1D43TW007113-01]; PHS HHS [1P01 A140237-01] NR 55 TC 33 Z9 33 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 MAY 15 PY 2004 VL 189 IS 10 BP 1793 EP 1801 DI 10.1086/386306 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 823ZE UT WOS:000221652200002 PM 15122515 ER PT J AU Mildvan, D Bosch, RJ Kim, RS Spritzler, J Haas, DW Kuritzkes, D Kagan, J Nokta, M DeGruttola, V Moreno, M Landay, A AF Mildvan, D Bosch, RJ Kim, RS Spritzler, J Haas, DW Kuritzkes, D Kagan, J Nokta, M DeGruttola, V Moreno, M Landay, A TI Immunophenotypic markers and antiretroviral therapy (IMART): T cell activation and maturation help predict treatment response SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 9th Conference on Retroviruses and Opportunistic Infections CY FEB 24-28, 2002 CL Seattle, WA ID HUMAN-IMMUNODEFICIENCY-VIRUS; AIDS CLINICAL-TRIALS; PLASMA HIV RNA; SUSTAINED VIRAL SUPPRESSION; TOTAL LYMPHOCYTE COUNT; TRIPLE-DRUG THERAPY; IMMUNE ACTIVATION; HIV-1-INFECTED PATIENTS; INFECTED PATIENTS; TYPE-1 INFECTION AB To determine whether markers of T cell activation and maturation are independently predictive of the response to potent antiretroviral therapy, the Immunophenotypic Markers and Antiretroviral Therapy study applied a novel data-sharing strategy across 5 Adult AIDS Clinical Trial Group trials that counted naive and activated CD4(+) and CD8(+) T cells in 324 subjects. Regression models - adjustment for baseline CD4 cell count, human immunodeficiency virus (HIV) RNA, and study - revealed that high pretreatment CD8(+) T cell activation predicted virologic failure (P = .046). Additional models showed the greatest increase in CD4(+) T cell counts in subjects with highest pretreatment naive CD4(+) T cell counts (P < .0001), which was enhanced by high CD4(+) and low CD8(+) T cell activation. Total lymphocyte count also predicted a subsequent CD4(+) T cell change. These results document the utility of T cell markers in predicting treatment outcome and their potential value for the study and management of HIV-1 infection. C1 Beth Israel Med Ctr, Div Infect Dis, New York, NY 10003 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. Vanderbilt Univ, Nashville, TN USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. Social Sci Syst, Rockville, MD USA. Univ Texas, Galveston, TX 77555 USA. Rush Presbyterian Med Ctr, Chicago, IL USA. RP Mildvan, D (reprint author), Beth Israel Med Ctr, Div Infect Dis, 1st Ave & 16 St, New York, NY 10003 USA. EM mildvan@ix.netcom.com FU NCRR NIH HHS [RR16484]; NIAID NIH HHS [AI46339, AI-38855, AI-46370, AI27659] NR 78 TC 28 Z9 28 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 MAY 15 PY 2004 VL 189 IS 10 BP 1811 EP 1820 DI 10.1086/383277 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 823ZE UT WOS:000221652200004 PM 15122517 ER PT J AU Minkoff, H Feldman, JG Strickler, HD Watts, DH Bacon, MC Levine, A Palefsky, JM Burk, R Cohen, MH Anastos, K AF Minkoff, H Feldman, JG Strickler, HD Watts, DH Bacon, MC Levine, A Palefsky, JM Burk, R Cohen, MH Anastos, K TI Relationship between smoking and human papillomavirus infections in HIV-infected and -uninfected women SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CERVICAL-CANCER; CIGARETTE-SMOKE; IMMUNE-RESPONSE; YOUNG-WOMEN; RISK; PERSISTENCE; PREVALENCE; EXPRESSION; NEOPLASIA AB Background. Smoking may increase the risk of cervical cancer, a disease that is related to human papillomavirus (HPV) infection. However, the effects of smoking on the natural history of HPV are poorly understood, especially in women coinfected with human immunodeficiency virus (HIV). Methods. HIV-infected (n = 1797) and HIV-uninfected (n = 496) women were assessed every 6 months for type-specific HPV DNA. Smoking status was self-reported. Covariates included age, parity, sexual behavior, HIV load, CD4(+) T cell count, and antiretroviral therapy. Results. Smoking was positively associated with HPV prevalence at baseline in HIV-infected women (P = .002) and was significantly associated with type-specific HPV detection (e.g., type 18, odds ratio [OR], 2.45; 95% confidence interval [CI], 1.86 - 3.22). In Cox models, detection of HPV was significantly associated with smoking in HIV-infected women (relative hazard [RH], 1.33; 95% CI, 1.10 - 1.60; P = .003), but HPV persistence was not (RH, 0.97; 95% CI, 80 - 1.16;). The overall likelihood of acquiring persistent HPV was higher in smokers (OR, 1.39; 95% CI, 1.05 - 1.86; P = .023) because of greater incidence. Conclusions. Among HIV-infected women, smoking is associated with a significantly higher prevalence and incidence of HPV infection. Smoking during HIV infection may alter the natural history of HPV infection and increase the risk of cervical disease. C1 Maimonides Hosp, Dept Obstet, Brooklyn, NY 11219 USA. Maimonides Hosp, Dept Gynecol, Brooklyn, NY 11219 USA. SUNY Downstate, Brooklyn, NY USA. Montefiore Med Ctr, Dept Med, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, Rockville, MD USA. Georgetown Univ, Dept Med, Washington, DC USA. Univ So Calif, Sch Med, Dept Internal Med, Los Angeles, CA 90033 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA USA. Cook Cty Hosp, Dept Internal Med, Chicago, IL 60612 USA. RP Minkoff, H (reprint author), Maimonides Hosp, Dept Obstet, 967 48th St, Brooklyn, NY 11219 USA. EM hminkoff@maimonidesmed.org FU NCI NIH HHS [R01 CA85178-01]; NCRR NIH HHS [MO1 RR00079]; NIAID NIH HHS [N01-AI-35161, U01-AI-35004, U01-AI-34994, U01-AI-31834, U01-AI-42590, AI-34989, U01-AI-34993]; NICHD NIH HHS [U01-HD-32632] NR 30 TC 42 Z9 45 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 MAY 15 PY 2004 VL 189 IS 10 BP 1821 EP 1828 DI 10.1086/383479 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 823ZE UT WOS:000221652200005 PM 15122518 ER PT J AU Yuan, LJ Ishida, SI Honma, S Patton, JT Hodgins, DC Kapikian, AZ Hoshino, Y AF Yuan, LJ Ishida, SI Honma, S Patton, JT Hodgins, DC Kapikian, AZ Hoshino, Y TI Homotypic and heterotypic serum isotype-specific antibody responses to rotavirus nonstructural protein 4 and viral protein (VP) 4, VP6, and VP7 in infants who received selected live oral rotavirus vaccines SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID GNOTOBIOTIC PIG MODEL; IMMUNE-RESPONSES; BOVINE ROTAVIRUS; YOUNG-CHILDREN; SEQUENCE-ANALYSIS; NSP4 ENTEROTOXIN; GENETIC GROUPS; INFECTION; DISEASE; SAFETY AB Homotypic and heterotypic serum isotype-specific antibody responses to rotavirus enterotoxin nonstructural protein (NSP)-4, independent neutralization antigens viral protein (VP)-4 and VP7, and group A rotavirus common antigen VP6 were analyzed by an immunocytochemistry assay in infants who received 1 of several live oral rotavirus vaccines. Significant serum immunoglobulin (Ig) A and IgG antibody responses to homotypic and/or heterotypic NSP4s of genotype [ A], [ B], or [ C] were detected after vaccination. The magnitude of antibody responses to homotypic and heterotypic NSP4s was not significantly different, irrespective of the NSP4 genotype of the administered vaccine strain. In addition, there were no significant differences between IgA antibody responses to homotypic and heterotypic VP7s. In contrast, IgA antibody responses to VP4 were predominantly homotypic. IgA antibody responses to VP7 were lower in magnitude than those to VP4 but were comparable to those to NSP4. Antibody titers to homotypic and/or heterotypic NSP4s were positively correlated with those to VP6 before and after vaccination. C1 NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Guelph, Ontario Vet Coll, Dept Pathobiol, Guelph, ON N1G 2W1, Canada. RP Hoshino, Y (reprint author), NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bldg 50,Rm 6308,50 S Dr,MSC 8026, Bethesda, MD 20892 USA. EM thoshino@niaid.nih.gov RI Yuan, Lijuan/A-2468-2008 OI Yuan, Lijuan/0000-0003-0709-5228 NR 44 TC 22 Z9 24 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 MAY 15 PY 2004 VL 189 IS 10 BP 1833 EP 1845 DI 10.1086/383416 PG 13 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 823ZE UT WOS:000221652200007 PM 15122520 ER PT J AU Csernoch, L Zhou, J Stern, MD Brum, G Rios, E AF Csernoch, L Zhou, J Stern, MD Brum, G Rios, E TI The elementary events of Ca2+ release elicited by membrane depolarization in mammalian muscle SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID FROG SKELETAL-MUSCLE; RYANODINE RECEPTOR ISOFORMS; CALCIUM-RELEASE; SARCOPLASMIC-RETICULUM; CARDIAC MYOCYTES; TWITCH MUSCLE; TIME-COURSE; FIBERS; SPARKS; CHANNELS AB Cytosolic [Ca2+] transients elicited byvoltage clamp depolarization were examined by confocal line scanning of rat skeletal muscle fibres. Ca2+ sparks were observed in the fibres' membrane-permeabilized ends, but not in responses to voltage in the membrane-intact area. Elementary events of the depolarization-evoked response could be separated either at low voltages (near - 50 mV) or at - 20mV in partially inactivated cells. These were of lower amplitude, narrower and of much longer duration than sparks, similar to 'lone embers' observed in the permeabilized segments. Their average amplitude was 0.19 and spatial half-width 1.3 mum. Other parameters depended on voltage. At - 50 mV average duration was 111ms and latency 185 ms. At - 20 mV duration was 203 ms and latency 24 ms. Ca2+ release current, calculated on an average of events, was nearly steady at 0.5-0.6 pA. Accordingly, simulations of the fluorescence event elicited by a subresolution source of 0.5 pA open for 100 ms had morphology similar to the experimental average. Because 0.5 pA is approximately the current measured for single RyR channels in physiological conditions, the elementary fluorescence events in rat muscle probably reflect opening of a single RyR channel. A reconstruction of cell-averaged release flux at -20 mV based on the observed distribution of latencies and calculated elementary release had qualitatively correct but slower kinetics than the release flux in prior whole-cell measurements. The qualitative agreement indicates that global Ca2+ release flux results from summation of these discrete events. The quantitative discrepancies suggest that the partial inactivation strategy may lead to events of greater duration than those occurring physiologically in fully polarized cells. C1 Rush Univ, Sch Med, Dept Mol Biophys & Physiol, Sect Cell Signaling, Chicago, IL 60612 USA. Univ Republica, Fac Med, Dept Biofs, Montevideo, Uruguay. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Univ Debrecen, Dept Physiol, H-4012 Debrecen, Hungary. RP Rios, E (reprint author), Rush Univ, Sch Med, Dept Mol Biophys & Physiol, Sect Cell Signaling, 1750 W Harrison St,Suite 1279JS, Chicago, IL 60612 USA. EM erios@rush.edu OI Csernoch, Laszlo/0000-0002-2446-1456 FU NIAMS NIH HHS [R01 AR049184, R01 AR032808] NR 49 TC 30 Z9 30 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3751 EI 1469-7793 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAY 15 PY 2004 VL 557 IS 1 BP 43 EP 58 DI 10.1113/jphysiol.2003.059154 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 823XZ UT WOS:000221649000005 PM 14990680 ER PT J AU Koch-Paiz, CA Amundson, SA Bittner, ML Meltzer, PS Fornace, AJ AF Koch-Paiz, CA Amundson, SA Bittner, ML Meltzer, PS Fornace, AJ TI Functional genomics of UV radiation responses in human cells SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE UV irradiation; cDNA microarray hybridization; cell signaling; suramin ID GADD GENE RESPONSES; ULTRAVIOLET-LIGHT; GENOTOXIC STRESS; CDNA MICROARRAY; EXCISION-REPAIR; EXPRESSION; ACTIVATION; CANCER; IDENTIFICATION; TRANSCRIPTION AB The gene expression responses of MCF-7, a p53 wild-type (wt) human cell line, were monitored by cDNA microarray hybridization after exposure to different wavelengths of UV irradiation. Equitoxic doses of UVA, UVB, and UVC radiation were used to reduce survival to 37%. The effects of suramin, a signal pathway inhibitor, on the gene expression responses to the three UV wavelengths were also compared in this model system. UVB radiation triggered the broadest gene expression responses, and 172 genes were found to be consistently responsive in at least two-thirds of independent UVB experiments. These UVB radiation-responsive genes encode proteins with diverse cellular roles including cell cycle control, DNA repair, signaling. transcription, protein synthesis, protein degradation, and RNA metabolism. The set of UVB-responsive genes included most of the genes responding to an equitoxic dose of UVC radiation, plus additional genes that were not strongly triggered by UVC radiation. There was also some overlap with genes responding to an equitoxic dose of UVA radiation, although responses to this lower energy UV radiation were overall weaker. Signaling through growth factor receptors and other cytokine receptors was shown to have a major role in mediating UV radiation stress responses, as suramin, which inhibits such receptors, attenuated responses to UV radiation in nearly all the cases. Inhibition by suramin was greater for UVC than for UVB irradiation. This probably reflects the more prominent role in UVB damage response of signaling by reactive oxygen species, which would not be affected by suramin. Our results with suramin demonstrate the power of cDNA microarray hybridization to illuminate the global effects of a pharmacologic inhibitor on cell signaling. (C) 2004 Elsevier B.V. All rights reserved. C1 NCI, Gene Response Sect, Ctr Canc Res, Bethesda, MD 20892 USA. NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. RP Fornace, AJ (reprint author), NCI, Gene Response Sect, Ctr Canc Res, Bethesda, MD 20892 USA. EM fornace@nih.gov RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 41 TC 43 Z9 44 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD MAY 15 PY 2004 VL 549 IS 1-2 BP 65 EP 78 DI 10.1016/j.mrfmmm.2004.01.010 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 823BB UT WOS:000221583600005 PM 15120963 ER PT J AU Hamadeh, HK Jayadev, S Gaillard, ET Huang, QH Stoll, R Blanchard, K Chou, J Tucker, CJ Collins, J Maronpot, R Bushel, P Afshari, CA AF Hamadeh, HK Jayadev, S Gaillard, ET Huang, QH Stoll, R Blanchard, K Chou, J Tucker, CJ Collins, J Maronpot, R Bushel, P Afshari, CA TI Integration of clinical an gene expression endpoints to explore furan-mediated hepatotoxicity SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE toxicogenomics; data integration; furan; hepatotoxicity; rat; gene expression; liver; lobes ID HEPATIC STELLATE CELLS; RAT-LIVER FIBROGENESIS; PROCOLLAGEN TYPE-III; TISSUE INHIBITOR; FIBROSIS; ACTIVATION; TOXICITY; LOBES AB Molecular techniques, such as cDNA microarrays, are being used to aid in the elucidation of the mechanisms of toxicity of a variety of compounds. In this study, we evaluate the molecular effects of furan in the rat liver. Sprague-Dawley rats were exposed to 4 or 40 mg/kg furan for up to 14 days. Furan induced an initial degenerative and necrotic phenotype that was followed by inflammation and fibrosis, consistent with previous observations for this compound. RNA was harvested from each lobe of the liver at several time points to observe whether lobe-specific gene expression effects occurred. similar gene expression changes were observed in all lobes, however the magnitude of gene expression change was more pronounced in the right lobe. Finally, to help determine the correlation between gene expression changes and liver pathology, we applied traditional microarray visualization tools to the assessment of clinical chemistry and pathology parameters. (C) 2004 Elsevier B.V. All rights reserved. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. RP Hamadeh, HK (reprint author), Amgen Inc, 1 Amgen Ctr Dr, Thousand Oaks, CA 91360 USA. EM hhamadeh@amgen.com NR 22 TC 41 Z9 44 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD MAY 15 PY 2004 VL 549 IS 1-2 BP 169 EP 183 DI 10.1016/j.mrfmmm.2003.12.021 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 823BB UT WOS:000221583600011 PM 15120969 ER PT J AU Mannon, RB AF Mannon, RB TI Polyomavirus nephropathy: What have we learned? SO TRANSPLANTATION LA English DT Review ID BK-VIRUS NEPHROPATHY; RENAL-TRANSPLANT RECIPIENTS; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; BONE-MARROW-TRANSPLANTATION; ACUTE HEMORRHAGIC CYSTITIS; INTERSTITIAL NEPHRITIS; ALLOGRAFT RECIPIENTS; SUCCESSFUL RETRANSPLANTATION; INFECTION; DIAGNOSIS C1 NIDDKD, Transplantat & Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Mannon, RB (reprint author), NIDDKD, Transplantat & Autoimmun Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 11S224, Bethesda, MD 20892 USA. EM rozm@intra.niddk.nih.gov NR 57 TC 31 Z9 31 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAY 15 PY 2004 VL 77 IS 9 BP 1313 EP 1318 DI 10.1097/01.TP.0000107040.70217.B3 PG 6 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 822QX UT WOS:000221556000001 PM 15167583 ER PT J AU Yang, XL Jansson, PA Nagaev, I Jack, MM Carvalho, E Sunnerhagen, KS Cam, MC Cushman, SW Smith, U AF Yang, XL Jansson, PA Nagaev, I Jack, MM Carvalho, E Sunnerhagen, KS Cam, MC Cushman, SW Smith, U TI Evidence of impaired adipogenesis in insulin resistance SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE insulin resistance; adipogenesis; adipose cell recruitment; adipose cell size; Wnt signaling gene expression; microarray ID GENE-EXPRESSION; ADIPOSE-TISSUE; ADIPOCYTE DIFFERENTIATION; DIABETES-MELLITUS; PLASMA-PROTEIN; STEM-CELLS; ADIPONECTIN; SIZE; ATHEROSCLEROSIS; CLASSIFICATION AB To elucidate the roles of adipose tissue and skeletal muscle in the early development of insulin resistance, we characterized gene expression profiles of isolated adipose cells and skeletal muscle of non-diabetic insulin-resistant first-degree relatives of type 2 diabetic patients using oligonucleotide microarrays. About 600 genes and expressed sequence tags, which displayed a gene expression pattern of cell proliferation, were differentially expressed in the adipose cells. The differentially expressed genes in the skeletal muscle were mostly related to the cellular signal transduction and transcriptional regulation. To verify the microarray findings, we studied expression of genes participating in adipogenesis. The expression of Wnt signaling genes, WNT1, FZD1, DVL1, GSK3beta, beta-catenin, and TCF1, and adipogenic transcription factors, C/EBPalpha and beta and delta, PPARgamma, and SREBP-1, was reduced in the adipose tissue. The expression of adipose-specific proteins related to terminal differentiation, such as adiponectin and aP2, was reduced both in the adipose tissue and in the adipose cells isolated from portions of the biopsies. The adipose cells were enlarged in the insulin-resistant relatives and the cell size inversely correlated with the expression of the Wnt signaling genes, adiponectin, and aP2. Our findings suggest that insulin resistance is associated with an impaired adipogenesis. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med, Lundberg Lab Diabet Res, SE-41345 Gothenburg, Sweden. Univ Gothenburg, Sahlgrenska Acad, Dept Neurosci Rehabil Med, SE-41345 Gothenburg, Sweden. NIDDK, Expt Diabet Metab & Nutr Sect, NIH, Bethesda, MD 20892 USA. RP Smith, U (reprint author), Univ Gothenburg, Sahlgrenska Acad, Dept Internal Med, Lundberg Lab Diabet Res, SE-41345 Gothenburg, Sweden. EM ulf.smith@medic.gu.sc OI Carvalho, Eugenia/0000-0001-6264-3632; Stibrant Sunnerhagen, Katharina/0000-0002-5940-4400 NR 30 TC 106 Z9 109 U1 4 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAY 14 PY 2004 VL 317 IS 4 BP 1045 EP 1051 DI 10.1016/j.bbrc.2004.03.152 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 817JX UT WOS:000221174900012 PM 15094374 ER PT J AU Anantharaman, V Aravind, L AF Anantharaman, V Aravind, L TI Evolutionary analysis of domains involved in signal transduction SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C26 EP C26 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100118 ER PT J AU Andric, S Kostic, T Stojilkovic, S AF Andric, S Kostic, T Stojilkovic, S TI Role of cyclic nucleotide export pump (cNEP) on specificity in cyclic nucleotide signaling in anterior pituitary cells SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NICHD, ERRB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C156 EP C156 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100720 ER PT J AU Basu, NK Owens, IS AF Basu, NK Owens, IS TI Alteration of a PKC site of human UDP-glucuronosyltransferase (UGT)1A7 mimics the property of 1A10 due to a critical role of threonine and serine phosphorylation SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NICHD, HDB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C72 EP C72 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100330 ER PT J AU Brown, F Donaldson, J AF Brown, F Donaldson, J TI Phosphoinositide specificity of PH domains in ARNO and GRP1 regulates their ability to activate SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C260 EP C260 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101204 ER PT J AU Cao, HP Tuttle, J Blackshear, P AF Cao, HP Tuttle, J Blackshear, P TI Immunological characterization of tristetraprolin as a low abundance, inducible, stable cytosolic protein SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIEHS, Lab Signal Transduct, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C302 EP C302 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101393 ER PT J AU Chattopadhyay, MK Tabor, CW Tabor, H AF Chattopadhyay, MK Tabor, CW Tabor, H TI Microarray studies on possible functions of polyamines in S-cerevisiae SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIDDK, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C168 EP C168 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100774 ER PT J AU Clore, GM Williams, D AF Clore, GM Williams, D TI Molecular basis for synergistic transcriptional activation by Oct1 and Sox2 revealed from the solution structure of the 42 kDa Oct1-Sox2-Hoxb1-DNA ternary transcription factor complex SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C81 EP C81 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100368 ER PT J AU Demsey, A AF Demsey, A TI Preparing for a career future in research administration SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C316 EP C316 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101463 ER PT J AU Evans, C Belfer, I Buzas, B Hipp, H Phillips, G Taubman, J Lorincz, I Lipsky, RH Enoch, MA Max, MB Goldman, D AF Evans, C Belfer, I Buzas, B Hipp, H Phillips, G Taubman, J Lorincz, I Lipsky, RH Enoch, MA Max, MB Goldman, D TI Haplotype structure of the beta adrenergic genes in US Caucasians and African Americans SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIDCR, NIAAA, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C247 EP C247 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101141 ER PT J AU Flynn, E Trievel, R Dirk, L Beach, B Hurley, J Houtz, R AF Flynn, E Trievel, R Dirk, L Beach, B Hurley, J Houtz, R TI Analysis of a structurally unique C-terminal domain in the SET domain protein methyltransferase Rubisco LSMT SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 Univ Kentucky, Dept Hort, Program Mol Biol, Lexington, KY 40546 USA. Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA. NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C141 EP C141 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100651 ER PT J AU Gales, C Rebois, V Hogue, M Laperierre, A Bouvier, M AF Gales, C Rebois, V Hogue, M Laperierre, A Bouvier, M TI Real-time assessment of GPCRs activation-deactivation cycle in living cells using Bioluminescence Resonance Energy Transfer (BRET) SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 Univ Montreal, Dept Biochim, Montreal, PQ H3C 3J7, Canada. NIH, Bethesda, MD 20892 USA. RI Bouvier, Michel/H-2758-2014 OI Bouvier, Michel/0000-0003-1128-0100 NR 0 TC 0 Z9 0 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C125 EP C126 PG 2 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100580 ER PT J AU Gaussin, V Morley, GE Liu, J Cox, L Hong, C Depre, C Myers, D Mishina, Y Behringer, RR Hanks, MC Zwijsen, A Huylebroeck, D Fishman, GI Schneider, MD Burch, JB Vatner, SF AF Gaussin, V Morley, GE Liu, J Cox, L Hong, C Depre, C Myers, D Mishina, Y Behringer, RR Hanks, MC Zwijsen, A Huylebroeck, D Fishman, GI Schneider, MD Burch, JB Vatner, SF TI ALK3 is necessary for the development of atrioventricular valves and conduction system SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NYU, New York, NY USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. NIH, Res Triangle Pk, NC USA. Univ Leuven, Louvain, Belgium. UT MD Anderson, Houston, TX USA. Procter & Gamble Co, Mason, OH USA. Baylor Coll Med, Houston, TX 77030 USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. NR 0 TC 0 Z9 0 U1 0 U2 6 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C301 EP C301 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101389 ER PT J AU Gutkind, JS AF Gutkind, JS TI Cross talk between heterotrimeric G proteins and Rho GTPases SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIDCR, NIH, Bethesda, MD 20892 USA. RI Gutkind, J. Silvio/A-1053-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C308 EP C308 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101422 ER PT J AU Hipp, H Belfer, I Buzas, B Phillips, G Taubman, J Lorincz, I Evans, C Lipsky, RH Enoch, MA Max, MB Goldman, D AF Hipp, H Belfer, I Buzas, B Phillips, G Taubman, J Lorincz, I Evans, C Lipsky, RH Enoch, MA Max, MB Goldman, D TI Haplotype-based analysis of three alpha 2 adrenergic receptor genes captures information on known and unknown functional loci SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIDCR, NIAAA, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C247 EP C247 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101142 ER PT J AU Huang, FL Huang, KP AF Huang, FL Huang, KP TI Thionylation of protein by disulfide S-oxide and -dioxide generated from Fenton's reaction SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NICHD, ERRB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C277 EP C277 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101278 ER PT J AU Hunt, D Chen, XL Santos, M Neese, R Hellerstein, M Cushman, S AF Hunt, D Chen, XL Santos, M Neese, R Hellerstein, M Cushman, S TI The effects of rosiglitazone on adipose tissue dynamics in the fa/fa obese Zucker rat SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIH, Bethesda, MD 20892 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C118 EP C119 PG 2 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100545 ER PT J AU Hurley, JH Canagarajah, B Saidi, L Mischak, H Ho, JYS Leskow, FC Kazanietz, MG AF Hurley, JH Canagarajah, B Saidi, L Mischak, H Ho, JYS Leskow, FC Kazanietz, MG TI Structural mechanisms for signaling and sorting at membranes SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIDDKD, NIH, US Dept HHS, Bethesda, MD 20892 USA. Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA. RI Mischak, Harald/E-8685-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C221 EP C221 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101019 ER PT J AU Jang, MK Mochizuki, K Ozato, K AF Jang, MK Mochizuki, K Ozato, K TI Bromodomain protein Brd4 interacts with cyclin T1 SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C90 EP C90 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100414 ER PT J AU Jeong, J Rouault, TA Levine, RL AF Jeong, J Rouault, TA Levine, RL TI Iron regulatory protein 2 (IRP2) is a heme sensor SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RI Levine, Rodney/D-9885-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C131 EP C131 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100605 ER PT J AU Jeong, WJ Lee, DY Rhee, SG AF Jeong, WJ Lee, DY Rhee, SG TI Characterization of ERp16, a novel thioredoxin-like protein localized in the endoplasmic reticulum SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C75 EP C75 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100343 ER PT J AU Kashanchi, F Zhou, M Deng, L Brady, JN Shatkin, AJ Kumar, A AF Kashanchi, F Zhou, M Deng, L Brady, JN Shatkin, AJ Kumar, A TI Tat/TAR-dependent phosphorylation of RNA polymerase IIC-terminal domain stimulates cotranscriptional capping of HIV-1 mRNA SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 George Washington Univ, Washington, DC 20052 USA. NIH, Bethesda, MD 20892 USA. Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C284 EP C284 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101312 ER PT J AU Kim, WC Hong, SK Cha, MK Kim, IH AF Kim, WC Hong, SK Cha, MK Kim, IH TI Regulation of E. coli periplasmic thiol peroxidase (p20) gene & the antioxidative function SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 Paichai Univ, Dept Biochem, Taejon 302735, South Korea. NHLBI, Biochem Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C196 EP C196 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100903 ER PT J AU Klarmannn, G Eisenhauer, B Zhang, Y Sitaraman, K Chatterjee, D Hecht, S Le Grice, S AF Klarmannn, G Eisenhauer, B Zhang, Y Sitaraman, K Chatterjee, D Hecht, S Le Grice, S TI Using unnatural amino acids to probe the structure/function of HIV-1 reverse transcriptase SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NCI, Frederick, MD 21701 USA. Univ Virginia, Charlottesville, VA 22903 USA. SAIC, Frederick, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C147 EP C147 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100679 ER PT J AU Lebowitz, J Center, R Leapman, R Moss, B AF Lebowitz, J Center, R Leapman, R Moss, B TI Promoting the trimerization of soluble HIV-1 env through the use of HIV-1/SIV chimeras SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIH, Bethesda, MD 20892 USA. Univ Melbourne, Dept Microbiol & Immunol, Parkville, Vic 3010, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C82 EP C83 PG 2 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100377 ER PT J AU Lee, DY Jeong, W Chang, TS Rhee, SG AF Lee, DY Jeong, W Chang, TS Rhee, SG TI Champ (Calsequestrin homologous and multifunctional protein) is the regulator of Ca2+ in the ER SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C160 EP C161 PG 2 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100741 ER PT J AU Lee-Huang, S Huang, P Maiorov, V Huang, P Ng, A Chang, YT Kallenbach, N Chen, HC AF Lee-Huang, S Huang, P Maiorov, V Huang, P Ng, A Chang, YT Kallenbach, N Chen, HC TI Structure function mapping of anti-HIV activity of human lysozyme SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NYU, Sch Med, Dept Biochem, New York, NY 10016 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. NYU, Sch Med, Dept Biochem, New York, NY 10016 USA. Amer Biosci, Boston, MA 02114 USA. NYU, Dept Chem, New York, NY 10003 USA. NICHD, NIH, Bethesda, MD 20892 USA. RI Chang, Young-Tae/B-2780-2010 OI Chang, Young-Tae/0000-0002-1927-3688 NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C149 EP C149 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100687 ER PT J AU Liang, W Fishman, PH AF Liang, W Fishman, PH TI Evidence for proteasomal and lysosomal involvement in ubiquitination-independent degradation of the human beta(1)-adrenergic receptor (beta(1)AR) SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NINDS, Membrane Biochem Sect, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C130 EP C130 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100600 ER PT J AU Lin, Y Choksi, S Shen, HM Nedospasov, S Liu, ZG AF Lin, Y Choksi, S Shen, HM Nedospasov, S Liu, ZG TI TNF-induced necrotic cell death requires RIP mediated cellular reactive oxygen species accumulation SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NCI, Bethesda, MD 20892 USA. SAIC, Frederick, MD USA. RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Nedospasov, Sergei/Q-7319-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C97 EP C97 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100444 ER PT J AU Lippincott-Schwartz, J AF Lippincott-Schwartz, J TI Insights into molecular compartmentalization and membrane trafficking using GFP technology SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C229 EP C229 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101061 ER PT J AU Lippincott-Schwartz, J AF Lippincott-Schwartz, J TI Secretary membrane traffic and its regulation SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NICHD, Cell Biol & Metab Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C219 EP C219 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101012 ER PT J AU Liu, YS Zhao, Q Shepherd, E Chen, PL Kokkonen, G AF Liu, YS Zhao, Q Shepherd, E Chen, PL Kokkonen, G TI Regulation of proinflammatory cytokine production by MAP kinase phosphatase-1 in LPS-stimulated macrophages SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 Ohio State Univ, Childrens Hosp, Dept Pediat, Childrens Res Inst, Columbus, OH 43205 USA. NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C43 EP C43 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100195 ER PT J AU Loricz, I Buzas, B Belfer, I Hipp, H Evans, C Phillips, G Taubman, J Max, M Goldman, D AF Loricz, I Buzas, B Belfer, I Hipp, H Evans, C Phillips, G Taubman, J Max, M Goldman, D TI Haplotype structure of human alpha1-adrenergic receptor genes SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIAAA, Lab Neurogenet, Bethesda, MD USA. NIDCR, Pain & Neurosensory Mechanisms Branch, NIH, US Dept HHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C247 EP C247 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101143 ER PT J AU Misteli, T AF Misteli, T TI Nuclear architecture in health and disease SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C312 EP C312 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101444 ER PT J AU Mitra, PS Basu, NK Owens, IS AF Mitra, PS Basu, NK Owens, IS TI UGT2B7 requires phosphorylation for activity SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NICHD, HDB, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C73 EP C73 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100336 ER PT J AU Movsesian, M Krall, J Tikishvili, E Honeggar, M Manganiello, V AF Movsesian, M Krall, J Tikishvili, E Honeggar, M Manganiello, V TI Isoforms of PDE3 cyclic nucleotide phosphodiesterase in cardiac and vascular smooth muscle myocytes SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NHLBI, NIH, Bethesda, MD 20814 USA. Univ Utah, VA Salt Lake City Hlth Care Syst, Salt Lake City, UT 84148 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C258 EP C258 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101194 ER PT J AU Oubrahim, H Wang, J Stadtman, E Chock, PB AF Oubrahim, H Wang, J Stadtman, E Chock, PB TI Identification of caspase-12 promoter region SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NHLBI, NIH, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C203 EP C204 PG 2 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100937 ER PT J AU Padilla, PI Pacheco-Rodriguez, G Moss, J Vaughan, M AF Padilla, PI Pacheco-Rodriguez, G Moss, J Vaughan, M TI Nuclear localization and molecular partners of the brefeldin A-inhibited guanine nucleotide-exchange protein 1 (BIG1) for ADP-ribosylation factors SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NHLBI, PCCMB, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C233 EP C233 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101081 ER PT J AU Pellegrini, L Sik, A Passer, BJ Koonin, EV AF Pellegrini, L Sik, A Passer, BJ Koonin, EV TI P-beta, a nuclear-targeted peptide generated by self-regulated cleavage of the mitochondrial intramembrane-cleaving protease PARL, mediates a mammalian-specific signaling pathway that is likely implicated in neuronal development SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 Univ Laval, Quebec City, PQ G1K 7P4, Canada. Mol Engines Labs, Paris, France. NCBI, Natl Lib Med, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C287 EP C287 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101324 ER PT J AU Puertollano, R Janvier, K Bonifacino, JS AF Puertollano, R Janvier, K Bonifacino, JS TI Adaptor proteins involved in protein sorting to lysosomes SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NICHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C111 EP C111 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100506 ER PT J AU Rausch, J Qu, J Yi-Brunozzi, HY Kool, E Le Grice, S AF Rausch, J Qu, J Yi-Brunozzi, HY Kool, E Le Grice, S TI Hydrolysis of RNA/DNA hybrids containing non-polar pyrimidine isosteres defines regions essential for HIV-1 polypurine tract selection SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. Stanford Univ, Dept Chem, Stanford, CA 94305 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C135 EP C136 PG 2 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100624 ER PT J AU Smith, A Sanders, M Londos, C Bernlohr, D AF Smith, A Sanders, M Londos, C Bernlohr, D TI Co-localization of hormone-sensitive lipase and adipocyte fatty acid binding protein using fluorescence resonance energy transfer SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 Univ Minnesota, Minneapolis, MN 55455 USA. NIDDK, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C263 EP C263 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101215 ER PT J AU Su, D Sun, QA Novoselov, S Zhou, Y Oko, R Hatfield, D Gladyshev, V AF Su, D Sun, QA Novoselov, S Zhou, Y Oko, R Hatfield, D Gladyshev, V TI Disulfide bond isomerization by selenoprotein TGR during sperm maturation SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. Duke Univ, Med Ctr, Dept Med, HHMI, Durham, NC 27710 USA. Univ Nebraska, Ctr Biotechnol, Lincoln, NE 68588 USA. Queens Univ, Dept Anat & Cell Biol, Kingston, ON K7L 3N6, Canada. NCI, NIH, Bethesda, MD 20892 USA. RI Gladyshev, Vadim/A-9894-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C14 EP C14 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100064 ER PT J AU Tuymetova, G Balla, A Tsiomenko, A Balla, T AF Tuymetova, G Balla, A Tsiomenko, A Balla, T TI Identification of a novel family of proteins with six transmembrane domains as homologues of the yeast Sfk1 protein that regulates the yeast phosphatidylinositol 4-kinase, Stt4 SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NICHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C182 EP C182 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100841 ER PT J AU Ullah, H Storey, NM Gentile, S Erxleben, C Armstrong, DL AF Ullah, H Storey, NM Gentile, S Erxleben, C Armstrong, DL TI Non-genomic modulation of KCNH2 potassium channels by the nuclear receptor for thyroid hormone SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C260 EP C260 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639101203 ER PT J AU Voet, J Bell, JK AF Voet, J Bell, JK TI Emerging Areas in the Molecular Life Sciences I: Using the internet & II: Computational approaches in the future SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 Swarthmore Coll, Swarthmore, PA 19081 USA. NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C122 EP C123 PG 2 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100565 ER PT J AU Wang, J Oubrahim, H Boja, E Chock, B AF Wang, J Oubrahim, H Boja, E Chock, B TI TB-RBP/translin possesses both ssRNase and dsRNase activities SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NHLBI, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C18 EP C18 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100084 ER PT J AU Zhang, Y Fatima, N Dufau, M AF Zhang, Y Fatima, N Dufau, M TI Epigenetic regulation of the luteinizing hormone receptor gene transcription: Connection between histone modifications and DNA methylation SO FASEB JOURNAL LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Biochemistry-and-Molecular-Biology/8th Congress of the International-Union-for-Biochemistry-and-Molecular-Biology CY JUN 12-16, 2004 CL Boston, MA SP Amer Soc BioChem & Mol Biol, Int Union Biochem & Mol Biol C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY 14 PY 2004 VL 18 IS 8 SU S BP C201 EP C201 PG 1 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 823UP UT WOS:000221639100926 ER PT J AU Akiyama, TE Lambert, G Nicol, CJ Matsusue, K Peters, JM Brewer, HB Gonzalez, FJ AF Akiyama, TE Lambert, G Nicol, CJ Matsusue, K Peters, JM Brewer, HB Gonzalez, FJ TI Peroxisome proliferator-activated receptor beta/delta regulates very low density lipoprotein production and catabolism in mice on a Western diet SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ANGIOPOIETIN-LIKE PROTEIN-3; PPAR-GAMMA; GENE-EXPRESSION; LIPID-METABOLISM; FATTY-ACIDS; BETA-OXIDATION; DEFICIENT MICE; TARGETED DISRUPTION; INSULIN-RESISTANCE; ADIPOSE-TISSUE AB The results of recent studies using selective agonists for peroxisome proliferator-activated receptor beta (PPARbeta) suggest that this receptor may have a role in regulating levels of serum lipids in animal models of obesity and insulin resistance. To further examine this possibility, serum lipid profiles of mice lacking a functional PPARbeta receptor were determined. PPARbeta-null mice maintained on either normal chow or a 10-week high fat (HF) diet, a condition that has been shown to induce insulin resistance and obesity in mice, have elevated levels of serum triglycerides primarily associated with very low density lipoprotein (VLDL) with no difference in either total cholesterol or phospholipids. Consistent with this finding, PPARbeta-null mice on a HF-diet were shown to have an increased rate of hepatic VLDL production as well as lowered lipoprotein lipase activity in serum compared with wild-type controls. The latter parallels an increase in the hepatic expression of the genes encoding angiopoietin-like proteins 3 and 4 in PPARbeta-null mice on a HF diet, both proteins of which have recently been shown to inhibit lipoprotein lipase (LPL) activity in vivo. Consistent with elevated VLDL production, a marked increase in plasma VLDL apoB48, -E, -AI, and -AII, as well as a sharp depletion of the hepatic lipid stores was also found in PPARbeta-null mice. In addition, PPARbeta-null mice on a HF diet were shown to have increased adiposity, despite lower total body weight. Together, these results indicate a clear role for PPARbeta in regulating levels of serum triglycerides in mice on a high fat Western diet by modulating both VLDL production and LPL-mediated catabolism of VLDL-triglycerides and also suggest a potential therapeutic role for PPARbeta in the improvement of serum lipids in the setting of metabolic syndrome. C1 NCI, Lab Metab, Div Basic Sci, NIH, Bethesda, MD 20892 USA. NHLBI, Mol Dis Branch, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Vet Sci, University Pk, PA 16802 USA. Penn State Univ, Ctr Mol Toxicol, University Pk, PA 16802 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Div Basic Sci, NIH, Bldg 37,Rm 3106B, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov RI Peters, Jeffrey/D-8847-2011 NR 57 TC 69 Z9 74 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 14 PY 2004 VL 279 IS 20 BP 20874 EP 20881 DI 10.1074/jbc.M312802200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 818VY UT WOS:000221273800039 PM 15001574 ER PT J AU Cheng, WH von Kobbe, C Opresko, PL Arthur, LM Komatsu, K Seidman, MM Carney, JP Bohr, VA AF Cheng, WH von Kobbe, C Opresko, PL Arthur, LM Komatsu, K Seidman, MM Carney, JP Bohr, VA TI Linkage between Werner syndrome protein and the Mre11 complex via Nbs1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; HOMOLOGOUS RECOMBINATION; SACCHAROMYCES-CEREVISIAE; SYNDROME CELLS; REPAIR; HELICASE; KINASE; WRN; RAD50/MRE11/NBS1 AB The Werner syndrome and the Nijmegen breakage syndrome are recessive genetic disorders that show increased genomic instability, cancer predisposition, hypersensitivity to mitomycin C and gamma-irradiation, shortened telomeres, and cell cycle defects. The protein mutated in the premature aging disease known as the Werner syndrome is designated WRN and is a member of the RecQ helicase family. The Nbs1 protein is mutated in Nijmegen breakage syndrome individuals and is part of the mammalian Mre11 complex together with the Mre11 and Rad50 proteins. Here, we show that WRN associates with the Mre11 complex via binding to Nbs1 in vitro and in vivo. In response to gamma-irradiation or mitomycin C, WRN leaves the nucleoli and co-localizes with the Mre11 complex in the nucleoplasm. We detect an increased association between WRN and the Mre11 complex after cellular exposure to gamma-irradiation. Small interfering RNA and complementation experiments demonstrated convergence of WRN and Nbs1 in response to gamma-irradiation or mitomycin C. Nbs1 is required for the Mre11 complex promotion of WRN helicase activity. Taken together, these results demonstrate a functional link between the two genetic diseases with partially overlapping phenotypes in a pathway that responds to DNA double strand breaks and interstrand cross-links. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Univ Maryland, Sch Med, Radiat Oncol Lab, Baltimore, MD 21201 USA. Kyoto Univ, Dept Genome Repair Dynam, Radiat Biol Res Ctr, Kyoto 6068501, Japan. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov OI Opresko, Patricia/0000-0002-6470-2189 NR 36 TC 88 Z9 89 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 MAY 14 PY 2004 VL 279 IS 20 BP 21169 EP 21176 DI 10.1074/jbc.M312770200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 818VY UT WOS:000221273800075 PM 15026416 ER PT J AU Domenech, P Reed, MB Dowd, CS Manca, C Kaplan, G Barry, CE AF Domenech, P Reed, MB Dowd, CS Manca, C Kaplan, G Barry, CE TI The role of MmpL8 in sulfatide biogenesis and virulence of Mycobacterium tuberculosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SULFOLIPID-I; TRANSPOSON MUTAGENESIS; LIPIDS; MICE; GENE; DIFFERENTIATION; PURIFICATION; BIOSYNTHESIS; INHIBITION; COMPLEX AB To study the role of MmpL8-mediated lipid transport in sulfatide biogenesis, we insertionally inactivated the mmpL8 gene in Mycobacterium tuberculosis. Characterization of this strain showed that the synthesis of mature sulfolipid SL-1 was interrupted and that a more polar sulfated molecule, termed SL-N, accumulated within the cell. Purification of SL-N and structural analysis identified this molecule as a family of 2,3-diacyl-alpha,alpha'-D-trehalose-2'-sulfates. This structure suggests that transport and biogenesis of SL-1 are coupled and that the final step in sulfatide biosynthesis may be the extracellular esterification of two trehalose 6-positions with hydroxyphthioceranic acids. To assess the effect of the loss of this anionic surface lipid on virulence, we infected mice via aerosol with the MmpL8 mutant and found that, although initial replication rates and containment levels were identical, compared with the wild type, a significant attenuation of the MmpL8 mutant strain in time-to-death was observed. Early in infection, differential expression of cytokines and cytokine receptors revealed that the mutant strain less efficiently suppresses key indicators of a Th1-type immune response, suggesting an immunomodulatory role for sulfatides in the pathogenesis of tuberculosis. C1 NIAID, TB Res Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Publ Hlth Res Inst, Newark, NJ 07103 USA. RP Barry, CE (reprint author), NIAID, TB Res Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM cbarry@niaid.nih.gov RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11]; NIAID NIH HHS [AI 22616, AI 54361] NR 42 TC 100 Z9 103 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 14 PY 2004 VL 279 IS 20 BP 21257 EP 21265 DI 10.1074/jbc.M400324200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 818VY UT WOS:000221273800086 PM 15001577 ER PT J AU Cao, HP Tuttle, JS Blackshear, PJ AF Cao, HP Tuttle, JS Blackshear, PJ TI Immunological characterization of tristetraprolin as a low abundance, inducible, stable cytosolic protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FINGER TRANSCRIPTION FACTOR; PROLYL ISOMERASE PIN1; ALPHA MESSENGER-RNA; AU-RICH ELEMENTS; TNF-ALPHA; BINDING; CELLS; DEFICIENCY; PATHWAY; NUCLEAR AB Tristetraprolin (TTP) is a zinc finger protein that can bind to AU-rich elements within certain mRNAs, resulting in deadenylation and destabilization of those mRNAs. Its physiological targets include the mRNAs encoding the cytokines tumor necrosis factor alpha (TNF) and granulocyte-macrophage colony-stimulating factor. TTP was originally identified on the basis of its massive but transient increase in mRNA levels following mitogen stimulation of fibroblasts. It has been difficult to reconcile this transient mRNA profile with the presumed continuing "need" for TTP protein, for example, to reverse the effects of lipopolysaccharide (LPS)-stimulated TNF secretion. To investigate this and other questions concerning endogenous TTP protein in cells and tissues, we raised a high titer rabbit antiserum against full-length mouse TTP. TTP could be detected on immunoblots of mouse cytosolic tissue extracts; it was most highly expressed in spleen, but its concentration in that tissue was only about 1.5 nM. TTP could be detected readily in splenic macrophages and stromal cells from LPS-injected rats. In both LPS-treated RAW 264.7 macrophages and fetal calf serum-treated mouse embryonic fibroblasts, TTP protein was stable after induction, with minimal degradation occurring for several hours after treatment of the cells with cycloheximide. The biosynthesis of TTP was accompanied by large changes in electrophoretic mobility consistent with progressive phosphorylation. Confocal microscopy revealed that TTP accumulated in a vesicular pattern in the cytosol of the LPS-stimulated RAW 264.7 cells, and was occasionally seen in the cytosol of unstimulated dividing cells. Gel filtration of the endogenous protein suggested that its predominant structure was monomeric. TTP appears to be a low abundance, cytosolic protein in unstimulated cells and tissues, but once induced is relatively stable, in contrast to its very labile mRNA. C1 NIEHS, NIH, Dept Hlth & Human Serv, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. NIEHS, NIH, Dept Hlth & Human Serv, Off Clin Res, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP NIEHS, NIH, Dept Hlth & Human Serv, Lab Signal Transduct, A2-05,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov FU NIEHS NIH HHS [Z01 ES090080-08] NR 39 TC 71 Z9 74 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 14 PY 2004 VL 279 IS 20 BP 21489 EP 21499 DI 10.1074/jbc.M400900200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 818VY UT WOS:000221273800114 PM 15010466 ER PT J AU Wlodawer, A Li, M Gustchina, A Tsuruoka, N Ashida, M Minakata, H Oyama, H Oda, K Nishino, T Nakayama, T AF Wlodawer, A Li, M Gustchina, A Tsuruoka, N Ashida, M Minakata, H Oyama, H Oda, K Nishino, T Nakayama, T TI Crystallographic and biochemical investigations of kumamolisin-As, a serine-carboxyl peptidase with collagenase activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURE; MACROMOLECULAR STRUCTURES; STRAIN NTAP-1; PROTEINASE; KUMAMOLYSIN; PURIFICATION; SPECIFICITY; REFINEMENT; EXPRESSION; INHIBITOR AB Kumamolisin-As (previously called ScpA) is the first known example of a collagenase from the sedolisin family (MEROPS S53). This enzyme is active at low pH and in elevated temperatures. In this study that used x-ray crystallographic and biochemical methods, we investigated the structural basis of the preference of this enzyme for collagen and the importance of a glutamate residue in the unique catalytic triad (Ser(278)-Glu(78)-Asp(82)) for enzymatic activity. Crystal structures of the uninhibited enzyme and its complex with a covalently bound inhibitor, N-acetyl-isoleucyl-prolyl-phenylalaninal, showed the occurrence of a narrow S2 pocket and a groove that encompasses the active site and is rich in negative charges. Limited endoproteolysis studies of bovine type-I collagen as well as kinetic studies using peptide libraries randomized at P1 and P1', showed very strong preference for arginine at the P1 position, which correlated very well with the presence of a negatively charged residue in the S1 pocket of the enzyme. All of these features, together with those predicted through comparisons with fiddler crab collagenase, a serine peptidase, rationalize the enzyme's preference for collagen. A comparison of the Arrhenius plots of the activities of kumamolisin-As with either collagen or peptides as substrates suggests that collagen should be relaxed before proteolysis can occur. The E78H mutant, in which the catalytic triad was engineered to resemble that of subtilisin, showed only 0.01% activity of the wild-type enzyme, and its structure revealed that Ser(278), His(78), and Asp(82) do not interact with each other; thus, the canonical catalytic triad is disrupted. C1 NCI Frederick, NIH, Macromol Crystallog Lab, Prot Struct Sect, Frederick, MD 21702 USA. NCI Frederick, NIH, Sci Applicat Int Corp, Basic Res Program, Frederick, MD 21702 USA. Kanazawa Med Univ, Sch Med, Dept Biochem, Kanazawa, Ishikawa 9200293, Japan. Tohoku Univ, Grad Sch Engn, Dept Biomol Engn, Sendai, Miyagi 9808579, Japan. Suntory Inst Bioorgan Res, Osaka 6188503, Japan. Kyoto Inst Technol, Fac Text Sci, Dept Appl Biol, Sakyo Ku, Kyoto 6068585, Japan. RP Wlodawer, A (reprint author), NCI Frederick, NIH, Macromol Crystallog Lab, Prot Struct Sect, Frederick, MD 21702 USA. EM wlodawer@ncifcrf.gov FU NCI NIH HHS [N01 CO 12400] NR 35 TC 33 Z9 33 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 MAY 14 PY 2004 VL 279 IS 20 BP 21500 EP 21510 DI 10.1074/jbc.M401141200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 818VY UT WOS:000221273800115 PM 15014068 ER PT J AU Samet, JM DeMarini, DM Malling, HV AF Samet, JM DeMarini, DM Malling, HV TI Do airborne particles induce heritable mutations? SO SCIENCE LA English DT Editorial Material ID AIR-POLLUTION; DNA-DAMAGE; PATTERNS; EXPOSURE; REFLECT C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. US EPA, Res Triangle Pk, NC 27711 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Samet, JM (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. EM jsamet@jhsph.edu NR 13 TC 48 Z9 53 U1 1 U2 5 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 MAY 14 PY 2004 VL 304 IS 5673 BP 971 EP 972 DI 10.1126/science.1097441 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 820IV UT WOS:000221383300031 PM 15143266 ER PT J AU Ginis, I Luo, YQ Miura, T Thies, S Brandenberger, R Gerecht-Nir, S Amit, M Hoke, A Carpenter, MK Itskovitz-Eldor, J Rao, MS AF Ginis, I Luo, YQ Miura, T Thies, S Brandenberger, R Gerecht-Nir, S Amit, M Hoke, A Carpenter, MK Itskovitz-Eldor, J Rao, MS TI Differences between human and mouse embryonic stem cells SO DEVELOPMENTAL BIOLOGY LA English DT Review DE embryonic stem cells; human; mouse; markers; RT-PCR; cDNA microarray; leukemia inhibitory factor; apoptosis; cell cycle; cytokines ID RECEPTOR NUCLEAR TRANSLOCATOR; CILIARY NEUROTROPHIC FACTOR; INHIBITORY FACTOR-RECEPTOR; LONG-TERM CULTURE; GENE-EXPRESSION; IN-VITRO; TELOMERASE ACTIVITY; PROGENITOR CELLS; TRANSCRIPTION FACTOR; NEURAL STEM AB We compared gene expression profiles of mouse and human ES cells by immunocytochemistry, RT-PCR, and membrane-based focused cDNA array analysis. Several markers that in concert could distinguish undifferentiated ES cells from their differentiated progeny were identified. These included known markers such as SSEA antigens, OCT3/4, SOX-2, REX-1 and TERT, as well as additional markers such as UTF-1, TRF1, TRF2, connexin43, and connexin45, FGFR-4, ABCG-2, and Glut-1. A set of negative markers that confirm the absence of differentiation was also developed. These include genes characteristic of trophoectoderm, markers of germ layers, and of more specialized progenitor cells. While the expression of many of the markers was similar in mouse and human cells, significant differences were found in the expression of vimentin, beta-III tubulin, alpha-fetoprotein, eomesodermin, HEB, ARNT, and FoxD3 as well as in the expression of the LIF receptor complex LIFR/IL6ST (gp130). Profound differences in cell cycle regulation, control of apoptosis, and cytokine expression were uncovered using focused microarrays. The profile of gene expression observed in HI cells was similar to that of two other human ES cell lines tested (line 1-6 and clonal line-H9.2) and to feeder-free subclones of H1, H7, and H9, indicating that the observed differences between human and mouse ES cells were species-specific rather than arising from differences in culture conditions. (C) 2004 Elsevier Inc. All rights reserved. C1 NIA, Stem Cell Sect, GRC Lab Neurosci, NIH, Baltimore, MD 21224 USA. Geron Corp, Menlo Pk, CA 94025 USA. Technion Israel Inst Technol, Bruce Rappaport Fac Med, IL-31096 Haifa, Israel. Technion Israel Inst Technol, Rambam Med Ctr, Dept Obstet & Gynecol, Haifa, Israel. Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. Robarts Res Inst, London, ON N6A 5C1, Canada. RP Rao, MS (reprint author), NIA, Stem Cell Sect, GRC Lab Neurosci, NIH, Room 4E02,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM raomah@grc.nia.nih.gov RI Gerecht, Sharon/A-3388-2010; OI Hoke, Ahmet/0000-0003-1215-3373 NR 117 TC 427 Z9 451 U1 11 U2 57 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAY 13 PY 2004 VL 269 IS 2 BP 360 EP 380 DI 10.1016/j.ydbio.2003.12.034 PG 21 WC Developmental Biology SC Developmental Biology GA 817DN UT WOS:000221158300004 PM 15110706 ER PT J AU Nemoto, S Finkel, T AF Nemoto, S Finkel, T TI Ageing and the mystery at Arles SO NATURE LA English DT Article ID GENE-EXPRESSION PROFILE; CEREVISIAE LIFE-SPAN; OXIDATIVE STRESS; SACCHAROMYCES-CEREVISIAE; CAENORHABDITIS-ELEGANS; TRANSCRIPTION FACTORS; CALORIE RESTRICTION; SIGNALING PATHWAY; LONGEVITY; PROTEINS C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Nemoto, S (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10-6N-240,10 Ctr Dr, Bethesda, MD 20892 USA. EM finkelt@nhlbi.nih.gov NR 35 TC 45 Z9 46 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 13 PY 2004 VL 429 IS 6988 BP 149 EP 152 DI 10.1038/429149a PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 819ZU UT WOS:000221356300027 PM 15141200 ER PT J AU Nelson, H Sargent, D Wieand, HS Fleshman, J Anvari, M Stryker, SJ Beart, RW Hellinger, M Flanagan, R Peters, W Ota, D Hellinger, M AF Nelson, H Sargent, D Wieand, HS Fleshman, J Anvari, M Stryker, SJ Beart, RW Hellinger, M Flanagan, R Peters, W Ota, D Hellinger, M CA Clinical Outcomes Surg Therapy Stu TI A comparison of laparoscopically assisted and open colectomy for colon cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED TRIAL; CLASSIFICATION; SURGERY AB BACKGROUND: Minimally invasive, laparoscopically assisted surgery was first considered in 1990 for patients undergoing colectomy for cancer. Concern that this approach would compromise survival by failing to achieve a proper oncologic resection or adequate staging or by altering patterns of recurrence (based on frequent reports of tumor recurrences within surgical wounds) prompted a controlled trial evaluation. METHODS: We conducted a noninferiority trial at 48 institutions and randomly assigned 872 patients with adenocarcinoma of the colon to undergo open or laparoscopically assisted colectomy performed by credentialed surgeons. The median follow-up was 4.4 years. The primary end point was the time to tumor recurrence. RESULTS: At three years, the rates of recurrence were similar in the two groups -- 16 percent among patients in the group that underwent laparoscopically assisted surgery and 18 percent among patients in the open-colectomy group (two-sided P=0.32; hazard ratio for recurrence, 0.86; 95 percent confidence interval, 0.63 to 1.17). Recurrence rates in surgical wounds were less than 1 percent in both groups (P=0.50). The overall survival rate at three years was also very similar in the two groups (86 percent in the laparoscopic-surgery group and 85 percent in the open-colectomy group; P=0.51; hazard ratio for death in the laparoscopic-surgery group, 0.91; 95 percent confidence interval, 0.68 to 1.21), with no significant difference between groups in the time to recurrence or overall survival for patients with any stage of cancer. Perioperative recovery was faster in the laparoscopic-surgery group than in the open-colectomy group, as reflected by a shorter median hospital stay (five days vs. six days, P<0.001) and briefer use of parenteral narcotics (three days vs. four days, P<0.001) and oral analgesics (one day vs. two days, P=0.02). The rates of intraoperative complications, 30-day postoperative mortality, complications at discharge and 60 days, hospital readmission, and reoperation were very similar between groups. CONCLUSIONS: In this multi-institutional study, the rates of recurrent cancer were similar after laparoscopically assisted colectomy and open colectomy, suggesting that the laparoscopic approach is an acceptable alternative to open surgery for colon cancer. C1 Mayo Clin & Mayo Fdn, Div Colon & Rectal Surg, NCCTG, Rochester, MN 55905 USA. Washington Univ, Sch Med, RTOG, St Louis, MO USA. McMaster Univ, St Joseph Healthcare, NCIC, CTG, Hamilton, ON, Canada. Northwestern Univ, Feinberg Sch Med, ECOG, RTOG, Chicago, IL 60611 USA. Univ So Calif, Keck Sch Med, SWOG, Los Angeles, CA USA. Univ Miami, Jackson Mem Med Ctr, ECOG, Miami, FL USA. St Joseph Mercy Hosp, NCCTG, Ann Arbor, MI 48104 USA. Boone Hosp Ctr, CALGB, Columbia, MO USA. LDS Hosp, Intermt Hlth Care Canc Serv, RTOG, Salt Lake City, UT USA. Columbia Presbyterian Med Ctr, SWOG, New York, NY USA. Univ Missouri, CALGB, Columbia, MO USA. Midwest Surg PA, SWOG, Wichita, KS USA. Grp Hlth Cooperat Puget Sound, SWOG, Seattle, WA USA. Lahey Clin Fdn, CALGB, Burlington, MA USA. MD Anderson Orlando Canc Ctr, RTOG, Orlando, FL USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Univ Kentucky, SWOG, Lexington, KY USA. Kankenau Hosp, Inst Med Res, NSABP, Wynnewood, PA USA. Ottawa Reg Canc Ctr, NCIC, CTG, Ottawa, ON K1Y 4K7, Canada. Creighton Univ, NCCTG, Omaha, NE 68178 USA. Lehigh Valley Hosp, ECOG, Allentown, PA USA. Cleveland Clin Fdn, SWOG, Cleveland, OH 44195 USA. St Joseph Med Ctr, RTOG, Baltimore, MD USA. Eastern Virginia Med Sch, Norfolk Surg Grp, CALGB, Norfolk, VA 23501 USA. St Lukes Hosp, ECOG, Bethlehem, PA USA. Mercy Hlth Ctr, SWOG, Oklahoma City, OK USA. Mayo Clin, NCCTG, Scottsdale, AZ USA. Massachusetts Gen Hosp, CALGB, Boston, MA 02114 USA. Swedish Med Ctr, ECOG, Englewood, CO USA. Ctr Hosp Univ Quebec, NSABP, Quebec City, PQ, Canada. E Carolina Univ, Brody Sch Med, NSABP, Greenville, NC USA. Mt Sinai Hosp, CALGB, New York, NY 10029 USA. Jefferson Reg Med Ctr, ECOG, Pittsburgh, PA USA. St Joseph Mercy Hosp, NCCTG, Pontiac, MI USA. Abington Mem Hosp, ECOG, Abington, PA 19001 USA. Brigham & Womens Hosp, Boston Med Ctr, CALGB, Boston, MA 02115 USA. Dartmouth Hitchcock Med Ctr, CALGB, Lebanon, NH 03766 USA. Wilford Hall USAF Med Ctr, Wilford Hall, TX USA. Univ Virginia, ECOG, Charlottesville, VA USA. Legacy Hlth Syst, SWOG, Portland, OR USA. Allegheny Gen Hosp, NSABP, Pittsburgh, PA 15212 USA. John Muir Mt Diablo Hlth Syst, Mt Diablo Med Ctr, RTOG, Concord, CA USA. Huntington Mem Hosp, Beverly Hills, CA USA. Kaiser Permanente Med Ctr, NSABP, San Diego, CA USA. Univ Massachusetts, Mem Med Ctr, CALGB, Worcester, MA 01605 USA. Univ Texas, SW Med Ctr, NSABP, Dallas, TX USA. Dana Farber Canc Inst, CALGB, Boston, MA 02115 USA. Univ Pittsburgh, Pittsburgh, PA USA. RP Nelson, H (reprint author), Mayo Clin & Mayo Fdn, Div Colon & Rectal Surg, NCCTG, 200 1st St SW, Rochester, MN 55905 USA. NR 22 TC 1599 Z9 1638 U1 4 U2 44 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 13 PY 2004 VL 350 IS 20 BP 2050 EP 2059 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 819ZB UT WOS:000221354000006 ER PT J AU Harlan, DM Rother, KI AF Harlan, DM Rother, KI TI Islet transplantation as a treatment for diabetes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID PANCREAS TRANSPLANTATION; MORTALITY; NEUROPATHY C1 NIH, Bethesda, MD 20892 USA. RP Harlan, DM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM davidmh@intra.niddk.nih.gov FU Intramural NIH HHS [Z99 DK999999] NR 5 TC 10 Z9 10 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 13 PY 2004 VL 350 IS 20 BP 2104 EP 2104 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 819ZB UT WOS:000221354000031 PM 15141057 ER PT J AU Schreiber, K Cannon, RE Karrison, T Beck-Engeser, G Huo, DZ Tennant, RW Jensen, H Kast, WM Krausz, T Meredith, SC Chen, LP Schreiber, H AF Schreiber, K Cannon, RE Karrison, T Beck-Engeser, G Huo, DZ Tennant, RW Jensen, H Kast, WM Krausz, T Meredith, SC Chen, LP Schreiber, H TI Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors SO ONCOGENE LA English DT Article DE HPV 16; human papilloma virus 16; E6/E7; vHa ras; transgenic mice; synergy; primary tumors ID HUMAN-PAPILLOMAVIRUS TYPE-16; T-LYMPHOCYTE EPITOPE; TRANSGENIC MICE; HA-RAS; CERVICAL-CANCER; K-RAS; HIGH PREVALENCE; UTERINE CERVIX; HIGH-RISK; INTRAEPITHELIAL NEOPLASIA AB E6/E7 oncogenes of high-risk human papilloma virus (HPV) subtypes are essential for the development of certain types of cancers. However, these oncogenes are insufficient to transform normal cells into an immortalized or malignant state. Mutant Ha-ras cooperates with E6/E7 of HPV subtype 16 in transformation of cells in vitro and may contribute to some HPV-associated cancers in humans. This study investigates whether HPV16 E6/E7 and v-Ha-ras synergize in vivo. FVB/n mice transgenic for v-Ha-ras gene (R+) were crossed with transgenic C57BL/6 mice that harbor E6/E7 of HPV16 (E+). Beginning at about 3 months of age, the bitransgenic E+R+(C57BL/6 x FVB/n) F1 mice developed mouth, eye and ear tumors. By 6 months, the prevalence of these types of mouth, eye and ear tumors was 100, 71 and 79% respectively in the E+R+ mice. Most tumors grew progressively until the mice had to be killed. The median times for the appearance of the first mouth, eye and ear tumor were 3.6, 4.3 and 4.2 months, respectively. For the two singly transgenic groups of mice, the prevalence of mouth, eye and ear tumors was 0, 0 and 6% (E-R+) and 0, 0 and 0% (E+R-), respectively, and the median time to first tumor was greater than 12 months for singly transgenic mice (E-R+, E+R-). Thus, a remarkable synergy occurred between the v-Ha-ras and HPV16 E6/E7 oncogenes in the development of primary tumors in mice. C1 Univ Chicago, Dept Pathol, Chicago, IL 60637 USA. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. Mayo Clin, Dept Immunol, Rochester, MN 55905 USA. RP Schreiber, H (reprint author), Univ Chicago, Dept Pathol, 5841 S Maryland Ave,MC 3008, Chicago, IL 60637 USA. EM hszz@midway.uchicago.edu FU NCI NIH HHS [P01-CA97296, R01-CA37516, R01-CA22677] NR 58 TC 18 Z9 20 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 MAY 13 PY 2004 VL 23 IS 22 BP 3972 EP 3979 DI 10.1038/sj.onc.1207507 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 820IQ UT WOS:000221382000009 PM 15077191 ER PT J AU Han, SY Iliopoulos, D Druck, T Guler, G Grubbs, CJ Pereira, M Zhang, ZQ You, M Lubet, RA Fong, LYY Huebner, K AF Han, SY Iliopoulos, D Druck, T Guler, G Grubbs, CJ Pereira, M Zhang, ZQ You, M Lubet, RA Fong, LYY Huebner, K TI CpG methylation in the Fhit regulatory region: relation to Fhit expression in murine tumors SO ONCOGENE LA English DT Article DE CpG island methylation; Fhit promoter; epigenetics; tumor suppressor; gene inactivation; homozygous deletion ID DNA METHYLATION; DEFICIENT MICE; RENAL-CARCINOMA; URINARY-BLADDER; CELL CARCINOMAS; GENE-EXPRESSION; HUMAN CANCER; LUNG-CANCER; PROFILE; BREAST AB To determine if: (1) 5' CpG island methylation is related to Fhit inactivation; (2) there are tumor or carcinogen-specific methylation patterns, we examined 35 CpG sites in the promoter, exon and intron 1 of the mouse Fhit gene. In primary tumors of lung, urinary bladder and tongue, induced by different carcinogens, 15-35% of sites were methylated, with specific methylation patterns associated with each cancer type, suggesting cancer- or tissue-specific methylation patterns. The methylation patterns were associated with reduced Fhit expression, as determined by immunohistochemical analyses. Methylation of rat Fhit 5' CpGs in mammary adenocarcinomas, detected by methylation specific PCR amplification, also correlated with reduced gene expression. Thus, there was an overall association between promoter/exon 1 methylation and decreased Fhit expression. In contrast, in cancer- derived cell lines 70-95% of the CpG sites were methylated. This is the first detailed study of the relationship between Fhit 5' CpG island methylation and Fhit expression in murine tumors, our main models for preclinical cancer studies, and provides evidence that loss of Fhit expression and methylation are correlated in these mouse models and these models will be useful to examine the complex relationships among gene expression, methylation patterns and organ specific city. C1 Thomas Jefferson Univ, Kimmel Canc Ctr, BLSB 1008, Philadelphia, PA 19107 USA. Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. Med Coll Ohio, Dept Pathol, Toledo, OH 43699 USA. Washington Univ, Dept Surg, St Louis, MO USA. NCI, Div Canc Prevent & Control, DCPC, Rockville, MD 20852 USA. Univ Hacettepe, Dept Pathol, TR-06100 Ankara, Turkey. RP Huebner, K (reprint author), Thomas Jefferson Univ, Kimmel Canc Ctr, BLSB 1008, 233 S 10th St, Philadelphia, PA 19107 USA. EM K_Huebner@mail.jci.tju.edu FU NCI NIH HHS [N01-CN-25007, N01-CN-15128, CA56036, CA77738, N01-CN-15113] NR 33 TC 21 Z9 21 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 MAY 13 PY 2004 VL 23 IS 22 BP 3990 EP 3998 DI 10.1038/sj.onc.1207526 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 820IQ UT WOS:000221382000011 PM 15007387 ER PT J AU Miller, FG Emanuel, EJ Rosenstein, DL Straus, SF AF Miller, FG Emanuel, EJ Rosenstein, DL Straus, SF TI Ethical issues in research in complementary and alternative medicine - In reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. NIMH, Off Clin Director, Bethesda, MD 20892 USA. NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Bldg 10, Bethesda, MD 20892 USA. EM sstraus@nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 12 PY 2004 VL 291 IS 18 BP 2193 EP 2194 DI 10.1001/jama.291.18.2193-d PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 819GR UT WOS:000221303500018 ER PT J AU Lloyd-Jones, DM Nam, BH D'Agostino, RB Levy, D Murabito, JM Wang, TJ Wilson, PWF O'Donnell, CJ AF Lloyd-Jones, DM Nam, BH D'Agostino, RB Levy, D Murabito, JM Wang, TJ Wilson, PWF O'Donnell, CJ TI Parental cardiovascular disease as a risk factor for cardiovascular disease in middle-aged adults - A prospective study of parents and offspring SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; NEWCASTLE FAMILY-HISTORY; MYOCARDIAL-INFARCTION; ARTERY DISEASE; INDEPENDENT PREDICTOR; HIGH PREVALENCE; FRAMINGHAM; WOMEN; POPULATION AB Context Whether parental cardiovascular disease confers increased risk independent of other risk factors remains controversial. Prior studies relied on offspring report, without complete validation of parental events. Objective To determine whether parental cardiovascular disease predicts offspring events independent of traditional risk factors, using a prospective design for both parents and offspring, and uniform criteria to validate events. Design Inception cohort study. Setting Framingham Heart Study, a US population-based epidemiologic cohort begun in 1948 with the offspring cohort established in 1971. Participants All Framingham Offspring Study participants (aged greater than or equal to30 years) who were free of cardiovascular disease and both parents in the original Framingham cohort. Main Outcome Measures We examined the association of parental cardiovascular disease with 8-year risk of offspring cardiovascular disease, using pooled logistic regression. Results Among 2302 men and women (mean age, 44 years), 164 men and 79 women had cardiovascular events during follow-up. Compared with participants with no parental cardiovascular disease, those with at least 1 parent with premature cardiovascular disease (onset age <55 years in father, <65 years in mother) had greater risk for events, with age-adjusted odds ratios of 2.6 (95% confidence interval [CI], 1.7-4.1) for men and 2.3 (95% CI, 1.3-4.3) for women. Multivariable adjustment resulted in odds ratios of 2.0 (95% CI, 1.2-3.1) for men and 1.7 (95% CI, 0.9-3.1) for women. Nonpremature parental cardiovascular disease and parental coronary disease were weaker predictors. Addition of parental information aided in discriminating event rates, notably among offspring with intermediate levels of cholesterol and blood pressure, as well as intermediate predicted multivariable risk. Conclusions Using validated events, we found that parental cardiovascular disease independently predicted future offspring events in middle-aged adults. Addition of parental information may help clinicians and patients with primary prevention of cardiovascular disease, when treatment decisions may be difficult in patients at intermediate risk based on levels of single or multiple risk factors. These data also support further research into genetic determinants of cardiovascular risk. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Northwestern Univ, Feinberg Sch Med, Div Cardiol, Chicago, IL USA. Northwestern Univ, Dept Prevent Med, Chicago, IL USA. Boston Univ, Dept Epidemiol & Prevent Med, Stat & Consulting Unit, Boston, MA 02215 USA. Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. RP O'Donnell, CJ (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM codonnell@nih.gov RI Lloyd-Jones, Donald/C-5899-2009 FU NHLBI NIH HHS [N01-HC-25195, K23 HL04253] NR 51 TC 316 Z9 322 U1 1 U2 16 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 12 PY 2004 VL 291 IS 18 BP 2204 EP 2211 DI 10.1001/jama.291.18.2204 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 819GR UT WOS:000221303500022 PM 15138242 ER PT J AU Alkondon, M Pereira, EFR Yu, P Arruda, EZ Almeida, LEF Guidetti, P Fawcett, WP Sapko, MT Randall, WR Schwarcz, R Tagle, DA Albuquerque, EX AF Alkondon, M Pereira, EFR Yu, P Arruda, EZ Almeida, LEF Guidetti, P Fawcett, WP Sapko, MT Randall, WR Schwarcz, R Tagle, DA Albuquerque, EX TI Targeted deletion of the kynurenine aminotransferase II gene reveals a critical role of endogenous kynurenic acid in the regulation of synaptic transmission via alpha 7 nicotinic receptors in the hippocampus SO JOURNAL OF NEUROSCIENCE LA English DT Article DE nicotinic receptors; kynurenic acid; NMDA receptors; GABA; hippocampus; mice ID D-ASPARTATE RECEPTOR; ACETYLCHOLINE-RECEPTORS; HUNTINGTONS-DISEASE; CA1 INTERNEURONS; HUMAN ASTROCYTES; N-ACETYLASPARTYLGLUTAMATE; PATHWAY METABOLISM; MEDIATED RESPONSES; RAT HIPPOCAMPUS; TRANSGENIC MICE AB It has been postulated that endogenous kynurenic acid (KYNA) modulates alpha7(star) nicotinic acetylcholine receptor (nAChR) and NMDA receptor activities in the brain. a To test this hypothesis, alpha7(star) nAChR and NMDA receptor functions were studied in mice with a targeted null mutation in the gene encoding kynurenine aminotransferase II (mKat-2(-/-) mice), an enzyme responsible for brain KYNA synthesis. At 21 postnatal days, mKat-2(-/-) mice had lower hippocampal KYNA levels and higher spontaneous locomotor activity than wild-type (WT) mice. At this age, alpha7(star) nAChR activity induced by exogenous application of agonists to CA1 stratum radiatum interneurons was similar to65% higher in mKat-2(-/-) than WT mice. Binding studies indicated that the enhanced receptor activity may not have resulted from an increase in alpha7(star) nAChR number. In 21-d-old mKat-2(-/-) mice, endogenous alpha7(star) nAChR activity in the hippocampus was also increased, leading to an enhancement of GABAergic activity impinging onto CA1 pyramidal neurons that could be reduced significantly by acute exposure to KYNA (100 nM). The activities of GABA(A) and NMDA receptors in the interneurons and of alpha3beta4(star) nAChRs regulating glutamate release onto these neurons were comparable between mKat-2(-/-) and WT mice. By 60 d of age, KYNA levels and GABAergic transmission in the hippocampus and locomotor activity were similar between mKat-2(-/-) and WT mice. Our findings that alpha7(star) nAChRs are major targets for KYNA in the brain may provide insights into the pathophysiology of schizophrenia and Alzheimer's disease, disorders in which brain KYNA levels are increased and alpha7(star) nAChR functions are impaired. C1 Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Univ Fed Rio de Janeiro, Ctr Ciencias Saude, Inst Ciencias Biomed, Dept Farmacol Basica & Clin, BR-21944 Rio De Janeiro, Brazil. Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Catonsville, MD 21228 USA. RP Albuquerque, EX (reprint author), Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, 655 W Baltimore St, Baltimore, MD 21201 USA. EM ealbuque@umaryland.edu FU NINDS NIH HHS [NS25296, NS41671] NR 61 TC 96 Z9 98 U1 0 U2 2 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 MAY 12 PY 2004 VL 24 IS 19 BP 4635 EP 4648 DI 10.1523/JNEUROSCI.5631-03.2004 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 821QM UT WOS:000221477200017 PM 15140935 ER PT J AU Iwahara, J Schwieters, CD Clore, GM AF Iwahara, J Schwieters, CD Clore, GM TI Ensemble approach for NMR structure refinement against H-1 paramagnetic relaxation enhancement data arising from a flexible paramagnetic group attached to a macromolecule SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; PHOSPHORYL TRANSFER COMPLEX; COMPLETE CROSS-VALIDATION; GLOBAL FOLD DETERMINATION; SITE-DIRECTED SPIN; MOLECULAR-DYNAMICS; LARGE PROTEINS; ELECTRON-SPIN; DISTANCE RESTRAINTS; DIPOLE-DIPOLE AB Paramagnetic relaxation enhancement (PRE) measurements on H-1 nuclei have the potential to play an important role in NMR structure determination of macromolecules by providing unique long-range (10-35 Angstrom) distance information. Recent methodological advances for covalently attaching paramagnetic groups at specific sites on both proteins and nucleic acids have permitted the application of the PRE to various biological macromolecules. However, because artificially introduced paramagnetic groups are exposed to solvent and linked to the macromolecule by several freely rotatable bonds, they are intrinsically flexible. This renders conventional back-calculation of the H-1-PRE using a single-point representation inaccurate, thereby severely limiting the utility of the H-1-PRE as a tool for structure refinement. To circumvent these limitations, we have developed a theoretical framework and computational strategy with which to accurately back-calculate H-1-PREs arising from flexible paramagnetic groups attached to macromolecules. In this scheme, the H-1-PRE is calculated using a modified Solomon-Bloembergen equation incorporating a "model-free" formalism, based on a multiple-structure representation of the paramagnetic group in simulated annealing calculations. The ensemble approach for H-1-PRE back-calculation was examined using several SRY/DNA complexes incorporating dT-EDTA-Mn2+ at three distinct sites in the DNA, permitting a large data set comprising 435 experimental backbone and side-chain H-1-PREs to be obtained in a straightforward manner from 2D through-bond correlation experiments. Calculations employing complete cross-validation demonstrate that the ensemble representation provides a means to accurately utilize backbone and side-chain H-1-PRE data arising from a flexible paramagnetic group in structure refinement. The results of H-1-PRE based refinement, in conjunction with previously obtained NMR restraints, indicate that significant gains in accuracy can be readily obtained. This is particularly significant in the case of macromolecular complexes where intermolecular translational restraints derived from nuclear Overhauser enhancement data may be limited. C1 NIDDKD, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. Ctr Informat Technol, Div Computat Biosci, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008; OI Clore, G. Marius/0000-0003-3809-1027; Iwahara, Junji/0000-0003-4732-2173 NR 61 TC 184 Z9 188 U1 6 U2 45 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 MAY 12 PY 2004 VL 126 IS 18 BP 5879 EP 5896 DI 10.1021/ja031580d PG 18 WC Chemistry, Multidisciplinary SC Chemistry GA 818TW UT WOS:000221268400038 PM 15125681 ER PT J AU Fogli, A Schiffmann, R Bertini, E Ughetto, S Combes, P Eymard-Pierre, E Kaneski, CR Pineda, M Troncoso, M Uziel, G Surtees, R Pugin, D Chaunu, MP Rodriguez, D Boespflug-Tanguy, O AF Fogli, A Schiffmann, R Bertini, E Ughetto, S Combes, P Eymard-Pierre, E Kaneski, CR Pineda, M Troncoso, M Uziel, G Surtees, R Pugin, D Chaunu, MP Rodriguez, D Boespflug-Tanguy, O TI The effect of genotype on the natural history of eIF2B-related leukodystrophies SO NEUROLOGY LA English DT Article ID VANISHING WHITE-MATTER; NERVOUS-SYSTEM HYPOMYELINATION; INITIATION-FACTOR EIF2B; CHILDHOOD ATAXIA; OVARIAN DYSGENESIS; SEVERE VARIANT; LEUKOENCEPHALOPATHY; MUTATIONS; PHENOTYPE; SUBUNITS AB Background: Recessive mutations in the five eucaryotic initiation factor 2B (eIF2B) subunits have been found in leukodystrophies of variable age at onset and severity. Objectives: To evaluate the clinical spectrum of eIF2B-related disorders and search for a phenotype-genotype correlation. Methods: Ninety-three individuals ( 78 families) with an undetermined leukodystrophy were selected on MRI-based criteria of childhood ataxia with central hypomyelination/vanishing white matter (CACH/VWM) for EIF2B genes analysis. Results: Eighty-nine percent of individuals with MRI criteria of CACH/VWM have a mutation in one of the eIF2B beta to epsilon subunits. For 83 individuals (68 families), 46 distinct mutations (90% missense) in four of the five eIF2B subunits (beta, gamma, delta, epsilon) were identified. Sixty-four percent were in the epsilon subunit, a R113H substitution was found in 71% of eIF2B epsilon-mutated families. A large clinical spectrum was observed from rapidly fatal infantile to asymptomatic adult forms. Disease severity was correlated with age at onset (p < 0.0001) but not with the type of the mutated subunit nor with the position of the mutation within the protein. Mutations R113H in the epsilon subunit and E213G in the beta subunit were significantly associated with milder forms. Conclusions: The degree of eIF2B dysfunction, which is involved in the regulation of protein synthesis during cellular stress, may play a role in the clinical expression of eIF2B-related disorders. C1 Fac Med, INSERM, UMR 384, F-63001 Clermont Ferrand, France. Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, NIH, Bethesda, MD USA. Bambino Gesu Pediat Hosp, Mol Med Unit, Rome, Italy. Bambino Gesu Pediat Hosp, Div Metab Disorders, Rome, Italy. Ctr Hosp Univ Clermont, Serv Epidemiol, Clermont Ferrand, France. Hosp San Joan de Deu, Barcelona, Spain. Hosp San Borja Arriaran, Serv Neurol Infantil, Santiago, Chile. Carlo Basta Inst, Milan, Italy. UCL, Inst Child Hlth, London, England. Univ Hosp Geneva, Dept Neurol, Geneva, Switzerland. Ctr Hosp Univ Reims, Serv Neurol, Reims, France. Hop Trousseau, AP HP, INSERM, U546,Serv Neuropediat, F-75571 Paris, France. RP Boespflug-Tanguy, O (reprint author), Fac Med, INSERM, UMR 384, 28 Pl Henri Dunant BP 38, F-63001 Clermont Ferrand, France. EM Odile.Boespflug@inserm.u-clermont1.fr OI Kaneski, Christine/0000-0003-1453-2502 FU NIDDK NIH HHS [DK13499] NR 24 TC 83 Z9 88 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 11 PY 2004 VL 62 IS 9 BP 1509 EP 1517 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 819XU UT WOS:000221350400010 PM 15136673 ER PT J AU Liu, DL Umbach, DM Peddada, SD Li, LP Crockett, PW Weinberg, CR AF Liu, DL Umbach, DM Peddada, SD Li, LP Crockett, PW Weinberg, CR TI A random-periods model for expression of cell-cycle genes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bootstrap test; gene expression; microarray; nonlinear regression ID MICROARRAY DATA; TIME-COURSE; IDENTIFICATION; YEAST; PROFILES AB We propose a nonlinear regression model for quantitatively analyzing periodic gene expression in studies of experimentally synchronized cells. Our model accounts for the observed attenuation in cycle amplitude by a simple and biologically plausible mechanism. We represent the expression level for each gene as an average across a large number of cells. For a given cell-cycle gene, we model its expression in each cell in the culture as following the same sinusoidal function except that the period, which in any individual cell must be the same for all cell-cycle genes, varies randomly across cells. We model these random periods by using a lognormal distribution. The variability in period causes the measured amplitude of the cyclic expression trajectory to attenuate over time as cells fall increasingly out of synchrony. Gene-specific parameters include initial amplitude and phase angle. Applying the model to data from Whitfield et al. [Whitfield, M. L., Sherlock, G., Salclanha, A. J., Murray, J, I., Ball, C. A., et al. (2002) Mol. Biol. Cell 13, 1977-2000], we fit the trajectories of 18 well characterized phase-marker genes and find that the fit does not suffer when a common lognormal distribution is assumed for all 18 genes compared with a separate distribution for each. We then use the model to identify 337 periodically expressed transcripts, including the 18 phase-marker genes. The model permits estimation of and hypothesis testing about biologically meaningful parameters that characterize cycling genes. C1 NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. Constella Hlth Sci, Durham, NC 27713 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat Branch, NIH, POB 12233,Mail Drop A3-03, Res Triangle Pk, NC 27709 USA. EM weinberg@niehs.nih.gov RI Peddada, Shyamal/D-1278-2012 NR 22 TC 36 Z9 36 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 MAY 11 PY 2004 VL 101 IS 19 BP 7240 EP 7245 DI 10.1073/pnas.0402285101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822SA UT WOS:000221559100009 PM 15123814 ER PT J AU Grieshaber, NA Fischer, ER Mead, DJ Dooley, CA Hackstadt, T AF Grieshaber, NA Fischer, ER Mead, DJ Dooley, CA Hackstadt, T TI Chlamydial histone-DNA interactions are disrupted by a metabolite in the methylerythritol phosphate pathway of isoprenoid biosynthesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID H1-LIKE PROTEIN HC1; ESCHERICHIA-COLI; DEVELOPMENTAL CYCLE; GENE-EXPRESSION; TRACHOMATIS; SEQUENCE; 4-DIPHOSPHOCYTIDYL-2C-METHYL-D-ERYTHRITOL; PURIFICATION; TERPENOIDS; BACTERIA AB The chlamydial developmental cycle is characterized by an intracellular replicative form, termed the reticulate body, and an extracellular form called the elementary body. Elementary bodies are characterized by a condensed chromatin, which is maintained by a histone H1-like protein, Hc1. Differentiation of elementary bodies to reticulate bodies is accompanied by dispersal of the chromatin as chlamydiae become transcriptionally active, although the mechanisms of Hc1 release from DNA have remained unknown. Dissociation of the nucleoid requires chlamydial transcription and translation with negligible loss of Hc1. A genetic screen was therefore designed to identify chlamydial genes rescuing Escherichia coli from the lethal effects of Hc1 overexpression. CT804, a gene homologous to ispE, which encodes an intermediate enzyme of the non-mevalonate methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, was selected. E. coli coexpressing CT804 and Hc1 grew normally, although they expressed Hc1 to a level equivalent to that which condensed the chromatin of parent HO-expressing controls. Inhibition of the MEP pathway with fosmidomycin abolished IspE rescue of Hc1-expressing E. coli. Deproteinated extract from IspE-expressing bacteria caused dispersal of purified chlamydial nucleoids, suggesting that chlamydial histone-DNA interactions are disrupted by a small metabolite within the MEP pathway rather than by direct action of IspE. By partial reconstruction of the MEP pathway, we determined that 2-C-methylerythritol 2,4-cyclodiphosphate dissociated Hc1 from chlamydial chromatin. These results suggest that chlamydial histone-DNA interactions are disrupted upon germination by a small metabolite in the MEP pathway of isoprenoid biosynthesis. C1 NIAID, Lab Intracellular Parasites, Host Parasite Interact Sect, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Hackstadt, T (reprint author), NIAID, Lab Intracellular Parasites, Host Parasite Interact Sect, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM ted_hackstadt@nih.gov NR 35 TC 33 Z9 33 U1 2 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 MAY 11 PY 2004 VL 101 IS 19 BP 7451 EP 7456 DI 10.1073/pnas.0400754101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822SA UT WOS:000221559100045 PM 15123794 ER PT J AU Fenton, RA Chou, CL Stewart, GS Smith, CP Knepper, MA AF Fenton, RA Chou, CL Stewart, GS Smith, CP Knepper, MA TI Urinary concentrating defect in mice with selective deletion of phloretin-sensitive urea transporters in the renal collecting duct SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE UT-A; isolated perfused tubule; vasopressin; concentrating mechanism ID THICK ASCENDING LIMB; RAT-KIDNEY; UT-A; SODIUM-CHLORIDE; WATER TRANSPORT; HENLES LOOP; VASOPRESSIN; PERMEABILITY; EXPRESSION; CLONING AB To investigate the role of inner medullary collecting duct (IMCD) urea transporters in the renal concentrating mechanism, we deleted 3 kb of the UT-A urea transporter gene containing a single 140-bp exon (exon 10). Deletion of this segment selectively disrupted expression of the two known IMCD isoforms of UT-A, namely UT-A1 and UT-A3, producing UT-A1/3(-/-) mice. In isolated perfused IMCDs from UT-A1/3(-/-) mice, there was a complete absence of phloretin-sensitive or vasopressin-stimulated urea transport. On a normal protein intake (20% protein diet), UT-All 3(-/-) mice had significantly greater fluid consumption and urine flow and a reduced maximal urinary osmolality relative to wildtype controls. These differences in urinary concentrating capacity were nearly eliminated when urea excretion was decreased by dietary protein restriction (4% by weight), consistent with the 1958 Berliner hypothesis stating that the chief role of IMCD urea transport in the concentrating mechanism is the prevention of urea-induced osmotic diuresis. Analysis of inner medullary tissue after water restriction revealed marked depletion of urea in UT-A1/3(-1-) mice, confirming the concept that phloretin-sensitive IMCD urea transporters play a central role in medullary urea accumulation. However, there were no significant differences in mean inner medullary Na+ or Cl- concentrations between UT-A1/3(-/-) mice and wild-type controls, indicating that the processes that concentrate NaCl were intact. Thus, these results do not corroborate the predictions of passive medullary concentrating models stating that NaCl accumulation in the inner medulla depends on rapid vasopressin-regulated urea transport across the IMCD epithelium. C1 NHLBI, Lab Kidney & Electrolyte Metab, NIH, Bethesda, MD 20892 USA. Univ Manchester, Sch Biol Sci, Manchester M13 9PT, Lancs, England. RP Fenton, RA (reprint author), NHLBI, Lab Kidney & Electrolyte Metab, NIH, 10 Ctr Dr,Bldg 10,Room 6N260, Bethesda, MD 20892 USA. EM fentonr@nhlbi.nih.gov FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01 HL 01282 KE] NR 30 TC 156 Z9 159 U1 4 U2 24 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 11 PY 2004 VL 101 IS 19 BP 7469 EP 7474 DI 10.1073/pnas.0401704101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 822SA UT WOS:000221559100048 PM 15123796 ER PT J AU Rahman, M Brown, CD Coresh, J Davis, BR Eckfeldt, JH Kopyt, N Levey, AS Nwachuku, C Pressel, S Reisin, E Walworth, C AF Rahman, M Brown, CD Coresh, J Davis, BR Eckfeldt, JH Kopyt, N Levey, AS Nwachuku, C Pressel, S Reisin, E Walworth, C CA ALLHAT Collaborative Res Grp TI The prevalence of reduced glomerular filtration rate in older hypertensive patients and its association with cardiovascular disease - A report from the antihypertensive and lipid-lowering treatment to prevent heart attack trial SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 17th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 14-18, 2002 CL NEW YORK, NY SP Amer Soc Hypertens ID LEFT-VENTRICULAR HYPERTROPHY; NUTRITION EXAMINATION SURVEY; CHRONIC-RENAL-FAILURE; 3RD NATIONAL-HEALTH; SERUM CREATININE; PREDIALYSIS PATIENTS; BLOOD-PRESSURE; UNITED-STATES; INSUFFICIENCY; ALLHAT AB Background: The prevalence of reduced glomerular filtration rate (GFR) in older hypertensive patients and the relationship between level of GFR and cardiovascular disease (CVD) and its risk factors are not well known. Methods: We evaluated baseline renal function in 40 514 hypertensive patients 55 years or older who were enrolled in the Antilrypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). We used the simplified Modification of Diet in Renal Disease study equation to estimate GFR and examined the prevalence of CVD in patients with different levels of GFR. Results: Fifty-seven percent of patients had mild (60-89 mL/min per 1.73 m(2)), 17.2% had moderate (30-59 mL/ min per 1.73 m(2)), and 0.6% had severe (less than or equal to 29 mL/min per 1.73 m(2)) reductions in GFR. Compared with patients with normal or mildly reduced GFR, patients with moderate or severe reductions in GFR were more likely to have had a prior myocardial infarction or stroke (19.2% and 23.4% vs 28.7% and 26.9%, respectively), have ischemic changes on electrocardiography (ECG) (16.0% and 18.9% vs 24.6% and 34.1%, respectively) I and have left ventricular hypertrophy on ECG (ECG-LVH) (3.9% and 4.2% vs 6.0% and 11.2%, respectively). A decrease in GFR of 10 mL/min per 1.73 m(2) was independently associated with a 6% higher risk for CVD and 14% higher risk for ECG-LVH. The increase in risk was marked at a GFR of approximately 60 to 70 mL/min per 1.73 m(2). Conclusions: The prevalence of reduced GFR is high in older hypertensive patients. Patients with moderate or severe reduction in GFR are more likely to have a history of CVD and ECG-LVH. Even modest reductions in GFR are independently associated with a higher prevalence of CVD and ECG-LVH. C1 Univ Hosp Cleveland, Case Western Reserve Univ, Div Hypertens, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Case Western Reserve Univ, Div Nephrol, Cleveland, OH 44106 USA. Case Western Reserve Univ, Div Hypertens, Cleveland, OH 44106 USA. Case Western Reserve Univ, Div Hypertens, Cleveland, OH 44106 USA. Case Western Reserve Univ, Div Nephrol, Cleveland, OH 44106 USA. SUNY Hlth Sci Ctr, Div Nephrol, Brooklyn, NY USA. Lehigh Valley Hosp Ctr, Allentown, PA 18102 USA. Tufts Univ, Sch Med, New England Med Ctr, Dept Med, Boston, MA 02111 USA. Johns Hopkins Med Inst, Dept Epidemiol Biostat & Med, Baltimore, MD 21205 USA. Univ Texas, Hlth Sci Ctr, Sch Publ Hlth, Coordinating Ctr Clin Trials, Houston, TX USA. Univ Minnesota, Dept Pathol & Lab Med, Minneapolis, MN USA. NHLBI, NIH, Bethesda, MD 20892 USA. Louisiana State Univ, Sch Med, Nephrol Sect, New Orleans, LA 70112 USA. Androscoggin Clin Assoc, Lewiston, ME USA. RP Rahman, M (reprint author), Univ Hosp Cleveland, Case Western Reserve Univ, Div Hypertens, 11100 Euclid Ave, Cleveland, OH 44106 USA. EM mxr9@po.cwru.edu FU NIDDK NIH HHS [R01 DK 53869] NR 28 TC 40 Z9 45 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAY 10 PY 2004 VL 164 IS 9 BP 969 EP 976 DI 10.1001/archinte.164.9.969 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 818XF UT WOS:000221277100007 PM 15136305 ER PT J AU Matsumoto, RR Gilmore, DL Pouw, B Bowen, WD Williams, W Kausar, A Coop, A AF Matsumoto, RR Gilmore, DL Pouw, B Bowen, WD Williams, W Kausar, A Coop, A TI Novel analogs of the a receptor ligand BD1008 attenuate cocaine-induced toxicity in mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE cocaine; convulsion; lethality; sigma receptor; toxicity ID SIGMA-RECEPTOR; INDUCED CONVULSIONS; GUINEA-PIG; AUTORADIOGRAPHIC VISUALIZATION; BINDING-SITES; RAT-BRAIN; AFFINITY; DOPAMINE; PHARMACOTHERAPIES; TRANSPORTERS AB Previous studies have shown that BD1008 (N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamine) and related analogs attenuate the toxicity and stimulant effects of cocaine through antagonism of sigma receptors. In the present study, six analogs of BD1008 (UMB 98-103) were synthesized and evaluated in receptor binding and behavioral studies. Competition binding studies confirmed that all six compounds have high affinity for sigma(1) receptors, moderate affinity for sigma(2) receptors, and low to negligible affinity for monoamine transporters, opioid, N-methyl-D-aspartate, dopamine, and 5-HT receptors. In behavioral pharmacological studies, pretreatment of mice with UMB 100, UMB 101, or UMB 103 significantly attenuated cocaine-induced convulsions and lethality. Together with earlier studies, the data suggest that analogs of BD1008 are promising medication development leads for reducing the toxicity of cocaine. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, Oklahoma City, OK 73190 USA. NIDDK, Lab Med Chem, NIH, Bethesda, MD 20892 USA. Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. RP Matsumoto, RR (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharmaceut Sci, POB 26901,CPB 337, Oklahoma City, OK 73190 USA. EM rae-matsumoto@ouhsc.edu FU NIDA NIH HHS [DA13978, DA11979] NR 37 TC 21 Z9 22 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD MAY 10 PY 2004 VL 492 IS 1 BP 21 EP 26 DI 10.1016/j.ejphar.2004.03.037 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 825IF UT WOS:000221749100003 PM 15145701 ER PT J AU Candeil, L Gourdier, I Peyron, D Vezzio, N Copois, V Bibeau, F Orsetti, B Scheffer, GL Ychou, M Khan, QA Pommier, Y Pau, B Martineau, P Del Rio, M AF Candeil, L Gourdier, I Peyron, D Vezzio, N Copois, V Bibeau, F Orsetti, B Scheffer, GL Ychou, M Khan, QA Pommier, Y Pau, B Martineau, P Del Rio, M TI ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan-treated metastases SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE colorectal cancer; ABCG2; SN38; drug resistance ID ACUTE MYELOID-LEUKEMIA; DNA TOPOISOMERASE-I; BREAST-CANCER; MULTIDRUG-RESISTANCE; LUNG-CANCER; MONOCLONAL-ANTIBODY; HALF-TRANSPORTER; PROTEIN BCRP; EXPRESSION; GENE AB Overcoming drug resistance has become an important issue in cancer chemotherapy. Among all known mechanisms that confer resistance, active efflux of chemotherapeutic agents by proteins from the ATP-binding cassette family has been extensively reported. The aim of the present study was to determine the involvement of ABCG2 in resistance to SN38 (the active metabolite of irinotecan) in colorectal cancer. By progressive exposure to increasing concentrations of SN38, we isolated 2 resistant clones from the human colon carcinoma cell line HCT116. These clones were 6- and 53-fold more resistant to SN38 than the HCT116-derived sensitive clone. Topoisomerase I expression was unchanged in our resistant variants. The highest resistance level correlated with an ABCG2 amplification. This overexpression was associated with a marked decrease in the intracellular accumulation of SN38. The inhibition of ABCG2 function by Kol43 demonstrated that enhanced drug efflux from resistant cells was mediated by the activity of ABCG2 protein and confirmed that ABCG2 is directly involved in acquired resistance to SN38. Furthermore, we show, for the first time in clinical samples, that the ABCG2 mRNA content in hepatic metastases is higher after an irinotecan-based chemotherapy than in irinotecan-naive metastases. In conclusion, this study supports the potential involvement of ABCG2 in the development of irinotecan resistance in vivo. (C) 2004 Wiley-Liss, Inc. C1 CRLC Val dAurelle, Ctr Rech Cancerol, CNRS UMR 5160, F-34298 Montpellier 5, France. CRLC Val dAurelle, Serv Anatomopathol & Oncol Digest, F-34298 Montpellier, France. NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Free Univ Amsterdam Hosp, Dept Pathol, Amsterdam, Netherlands. CRLC Val dAurelle, Ctr Rech Cancerol, INSERM E229, F-34298 Montpellier 5, France. RP Del Rio, M (reprint author), CRLC Val dAurelle, Ctr Rech Cancerol, CNRS UMR 5160, Rue Croix Verte, F-34298 Montpellier 5, France. EM mdelrio@valdorel.fnclcc.fr OI Martineau, Pierre/0000-0002-7993-7183 NR 44 TC 83 Z9 85 U1 0 U2 13 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 MAY 10 PY 2004 VL 109 IS 6 BP 848 EP 854 DI 10.1002/ijc.20032 PG 7 WC Oncology SC Oncology GA 811NS UT WOS:000220779200007 PM 15027118 ER PT J AU Kohanoff, JJ Cachau, RE AF Kohanoff, JJ Cachau, RE TI Multiple proton translocation in biomolecular systems: concerted to stepwise transition in a simple model SO MOLECULAR PHYSICS LA English DT Article ID ALCOHOL-DEHYDROGENASE; HYDROGEN-BONDS; WATER TETRAMER; DYNAMICS; MOLECULES; COMPLEX; BATH AB In this paper we study a simple model potential energy surface (PES) useful for describing multiple proton translocation mechanisms. The approach presented is relevant to the study of more complex biomolecular systems like enzymes. In this model, at low temperatures, proton tunnelling favours a concerted proton transport mechanism, while at higher temperatures there is a crossover from concerted to stepwise mechanisms; the crossover temperature depends on the energetic features of the PES. We illustrate these ideas by calculating the crossover temperature using energies taken from ab initio calculations on specific systems. Interestingly, typical crossover temperatures lie around room temperature; thus both concerted and stepwise reaction mechanisms should play an important role in biological systems, and one can be easily turned into another by external means such as modifying the temperature or the pH, thus establishing a general mechanism for modulation of the biomolecular function by external effectors. C1 Queens Univ Belfast, Atomist Simulat Grp, Belfast BT7 1NN, Antrim, North Ireland. NCI, Adv Biomed Comp Ctr, SAIC, Frederick, MD 21702 USA. RP Kohanoff, JJ (reprint author), Queens Univ Belfast, Atomist Simulat Grp, Belfast BT7 1NN, Antrim, North Ireland. EM j.kohanoff@qub.ac.uk RI Kohanoff, Jorge/H-9874-2015 OI Kohanoff, Jorge/0000-0002-8237-7543 NR 29 TC 4 Z9 4 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0026-8976 J9 MOL PHYS JI Mol. Phys. PD MAY 10 PY 2004 VL 102 IS 9-10 BP 1007 EP 1014 DI 10.1080/00268970410001725738 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 853KM UT WOS:000223826500020 ER PT J AU Grant, DJ Hall, IJ Eastmond, DA Jones, IA Bell, DA AF Grant, DJ Hall, IJ Eastmond, DA Jones, IA Bell, DA TI Bilirubin UDP-glucuronosyltransferase 1A1 (UGT1A1) gene promoter polymorphisms and HPRT, glycophorin A, and micronuclei mutant frequencies in human blood SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE UGT1A1; genotypes; repeat polymorphisms; somatic mutation; HPRT; glycophorin A; micronuclei ID OXIDATIVE DNA-DAMAGE; UDP-GLUCURONOSYLTRANSFERASE; GILBERTS-SYNDROME; HUMAN-LYMPHOCYTES; NEGATIVE MICRONUCLEI; MISSENSE MUTATION; AFRICAN-AMERICANS; HUMAN FIBROBLASTS; CANCER-PATIENTS; ANTIOXIDANT AB A dinucleotide repeat polymorphism (5-, 6-, 7-, or 8-TA units) has been identified within the promoter region of UDP-glucuronosyltransferase 1A1 (UGT1A1) gene. The 7-TA repeat allele has been associated with elevated serum bilirubin levels that cause a mild hyperbilirubinemia (Gilbert's syndrome). Studies suggest that promoter transcriptional activity of UGT1A1 is inversely related to the number of TA repeats, and that unconjugated bilirubin concentration increases directly with the number of TA repeat elements. Because bilirubin is a known antioxidant, we hypothesized that UGT1A1 repeats associated with higher bilirubin may be protective against oxidative damage. We examined the effect of UGT1A1 genotype on somatic mutant frequency in the hypoxanthine-guanine phosphoribosyl-transferase (HPRT) gene in human lymphocytes and the glycophorin A (GPA) gene of red blood cells (both NO, NN mutants), and the frequency of lymphocyte micronuclei (both kinetochore (K)-positive or micronuclei K-negative) in 10 1 healthy smoking and nonsmoking individuals. As hypothesized, genotypes containing 7- and 8-TA displayed marginally lower GPA_NN mutant frequency relative to 5/5, 5/6, 6/6 genotypes (P < 0.05). In contrast, our analysis showed that lower expressing UGT1A1 alleles (7- and 8-TA) were associated with modestly increased HPRT mutation frequency (P < 0.05), while the same low-expression genotypes were not significantly associated with micronuclei frequencies (K-positive or K-negative) when compared to high-expression genotypes (5- and 6-TA). We found weak evidence that UGT1A1 genotypes containing 7- and 8-TA were associated with increased GPA_Ncircle divide mutant frequency relative to 515, 5/6, 6/6 genotypes (P < 0.05). These data suggest that UGT1A1 genotype may modulate somatic mutation of some types, in some cell lineages, by a mechanism not involving bilirubin antioxidant activity. More detailed studies examining UGT1A1 promoter variation, oxidant/antioxidant balance and genetic damage will be needed. (C) 2004 Elsevier B.V. All rights reserved. C1 NIEHS, Environm Genom Sect, Lab Computat Biol & Risk Assessment, Res Triangle Pk, NC 27709 USA. N Carolina Cent Univ, Canc Res Program, JLC Biomed Biotechnol Res Inst, Durham, NC USA. Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. Univ Calif Riverside, Environm Toxicol Grad Program, Riverside, CA 92521 USA. Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA USA. RP Bell, DA (reprint author), NIEHS, Environm Genom Sect, Lab Computat Biol & Risk Assessment, POB 12233,C3-03,POB 12233, Res Triangle Pk, NC 27709 USA. EM bell1@niehs.nih.gov NR 46 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD MAY 9 PY 2004 VL 560 IS 1 BP 1 EP 10 DI 10.1016/j.mrgentox.2004.01.010 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 818NM UT WOS:000221251800001 PM 15099818 ER PT J AU Yu, J Wang, J Cadet, JL Angulo, JA AF Yu, J Wang, J Cadet, JL Angulo, JA TI Histological evidence supporting a role for the striatal neurokinin-1 receptor in methamphetamine-induced neurotoxicity in the mouse brain SO BRAIN RESEARCH LA English DT Article DE methamphetamine; neurokinin-1receptor; degeneration; striatum; substance P; WIN-51,708 ID NITRIC-OXIDE SYNTHASE; TACHYKININ NK1 RECEPTOR; HUMAN ASTROCYTOMA-CELLS; SUBSTANCE-P; MESSENGER-RNA; DOPAMINERGIC NEUROTOXICITY; MICROGLIAL ACTIVATION; NEURONAL DEGENERATION; NUCLEUS-ACCUMBENS; GLUTAMATE RELEASE AB Several studies have documented the effect of methamphetamine (METH) on the toxicity of the dopamine (DA) terminals of the striatum but only a few studies have assessed the damaging effects of METH on striatal neurons postsynaptic to the nigrostriatal DA terminals. In the present study, we employed histological methods to study the effect of METH on DA terminals and striatal neurons. We also assessed the role of the striatal neurokinin-1 (NK-1) receptor on pre- and post-synaptic METH-induced damage. Male mice were treated with METH (10 mg/ kg) four times at 2-h intervals and were sacrificed 3 days after the treatment. A number of animals received the non-peptide NK-1 receptor antagonist WIN-51,708 (10 mg/kg) 30 min before the first and fourth injections of METH. Immunocytochemical staining for tyrosine hydroxylase (TH) showed significant deficits throughout all aspects of the caudate-putamen in animals exposed to METH. Pretreatment with WIN-51,708 prevented the METH-induced loss of TH immunostaining. Sections from a separate set of mice were stained with Fluoro-Jade B (FJB), a fluorochrome that binds specifically to degenerating fibers and cell bodies of neurons. Treatment with METH shows Fluoro-Jade B positive cell bodies in the striatum and pretreatment with WIN-51,708 abolished Fluoro-Jade B staining. Moreover, double labeling with Fluoro-Jade B and glial fibrillary acidic protein (GFAP) shows reactive astrocytosis in the area adjacent to the Fluoro-Jade B-positive cells but no Fluoro-Jade B staining of the astrocytes. This observation suggests that the degenerating cells must be striatal neurons and not astrocytes. The data demonstrate that METH induces pre- and post-synaptic damage in the striatum and the damage can be prevented with pharmacological blockade of the NK-1 receptor. These findings represent a new direction in the study of the mechanism of toxicity to METH and could be useful in the treatment of some neurological disorders. (C) 2004 Elsevier B.V. All rights reserved. C1 CUNY Hunter Coll, Dept Biol Sci, New York, NY 10021 USA. NIDA, Div Intramural Res, Mol Neuropsychiat Sect, NIH, Baltimore, MD 21224 USA. RP Angulo, JA (reprint author), CUNY Hunter Coll, Dept Biol Sci, 695 Pk Ave,Rm 927HN, New York, NY 10021 USA. EM angulo@genectr.hunter.cuny.edu RI Wang, Jing/E-6217-2012 FU NIDA NIH HHS [R01 DA020142-01A1, DA12136, R01 DA020142, R24 DA012136]; NINDS NIH HHS [NS41073, U54 NS041073] NR 64 TC 21 Z9 21 U1 3 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 8 PY 2004 VL 1007 IS 1-2 BP 124 EP 131 DI 10.1016/j.brainres.2004.01.077 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 815AV UT WOS:000221016100014 PM 15064143 ER PT J AU Chan, JCC Tycko, R AF Chan, JCC Tycko, R TI Broadband rotational resonance in solid state NMR spectroscopy SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID INTERNUCLEAR DISTANCES; MAGNETIC RESONANCE; SYSTEMS; BACTERIORHODOPSIN; CONFORMATION; SPECTRA AB A new technique for restoring nuclear magnetic dipole-dipole couplings under magic-angle spinning (MAS) in solid state nuclear magnetic resonance (NMR) spectroscopy is described and demonstrated. In this technique, called broadband rotational resonance (BroBaRR), the coupling between a pair of nuclear spins with NMR frequency difference close (but not necessarily equal) to the MAS frequency is restored by the application of a train of weak radio-frequency pulses at a carrier frequency close to the average of the two NMR frequencies. Phase or amplitude modulation of the pulse train at half the MAS frequency splits the carrier into sidebands close to the two NMR frequencies. The pulse train then removes offsets from the exact rotational resonance condition, leading to dipolar recoupling over a bandwidth controlled by the amplitude of the pulse train. C-13 NMR experiments on uniformly N-15, C-13-labeled L-valine.HCl.H2O powder validate the theoretical analysis. BroBaRR will be useful in studies of molecular structures by solid state NMR, for example in the detection of long-range couplings between carbons in uniformly labeled organic and biological materials. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertt@niddk.nih.gov RI Chan, Jerry/F-8075-2010 OI Chan, Jerry/0000-0002-5108-4166 NR 26 TC 15 Z9 15 U1 1 U2 6 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAY 8 PY 2004 VL 120 IS 18 BP 8349 EP 8352 DI 10.1063/1.1737369 PG 4 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 819EY UT WOS:000221298500002 PM 15267757 ER PT J AU Gillison, ML Lowy, DR AF Gillison, ML Lowy, DR TI A causal role for human papillomavirus in head and neck cancer SO LANCET LA English DT Editorial Material ID SQUAMOUS-CELL CARCINOMAS; ORAL-CANCER; INFECTION; RISK; P53; OVEREXPRESSION; P16(INK4A); CAVITY; SUBSET; DNA C1 Johns Hopkins Med Inst, Baltimore, MD 21231 USA. NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Gillison, ML (reprint author), Johns Hopkins Med Inst, Baltimore, MD 21231 USA. EM gillima@jhmi.edu NR 15 TC 138 Z9 141 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 8 PY 2004 VL 363 IS 9420 BP 1488 EP 1489 DI 10.1016/S0140-6736(04)16194-1 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 819GK UT WOS:000221302700004 PM 15135592 ER PT J AU Ye, N Park, G Przyborowska, AM Sloan, PE Clifford, T Bauer, CB Broker, GA Rogers, RD Ma, R Torti, SV Brechbiel, MW Planalp, RP AF Ye, N Park, G Przyborowska, AM Sloan, PE Clifford, T Bauer, CB Broker, GA Rogers, RD Ma, R Torti, SV Brechbiel, MW Planalp, RP TI Nickel(II), copper(II) and zinc(II) binding properties and cytotoxicity of tripodal, hexadentate tris(ethylenediamine) - analogue chelators SO DALTON TRANSACTIONS LA English DT Article ID EFFECTIVE IONIC-RADII; IRON CHELATOR; COMPLEXES; CIS,CIS-1,3,5-TRIAMINOCYCLOHEXANE; DERIVATIVES; N,N',N''-TRIS(2-PYRIDYLMETHYL)-CIS,CIS-1,3,5-TRIAMINOCYCLOHEXANE; RADIOPHARMACEUTICALS; APOPTOSIS; OXIDATION; CU(II) AB Three tripodal hexamine chelators based on cis,cis-1,3,5-triaminocyclohexane (tach) have been synthesized and their aqueous coordination chemistry with Ni(II), Cu(II) and Zn(II) is reported. The chelators have a 2-aminoethyl pendant arm attached to each nitrogen of tach, specifically 'tachen' (N, N', N"-tris(2-aminoethyl)cyclohexane-cis, cis-1, 3,5 triamine), and two with S,S,S-chiral pendant arms, 'tachpn' (N, N', N"-tris(2-aminopropyl)cyclohexane-cis, cis-1,3,5\-triamine) and 'tachbn'(N, N', N"- tris(2-amino-3-phenylpropyl)cyclohexane-cis, cis-1,3,5-triamine. These chelators complex Ni(II), Cu(II) and Zn(II) in aqueous or aqueous/methanolic medium. The crystalline products [(ML)-L-II](X)(2) are isolated, where M = Ni(II), Cu(II) or Zn(II), L = tachen, tachpn or tachbn, and X = ClO4-. Crystallographic study of selected tachpn and tachbn complexes shows the chelate arms are constrained in a Lambda(deltadeltadelta) configuration about M(II), which is attributed to their chirality Solution UV-vis spectroscopy of the Ni(II) and Cu(II) complexes indicates six-coordination and little effect of the pendant arm substitution on ligand-field strength. The single exception is [Cu(tachbn)]21, whose spectrum is consistent with five-coordination in solution. The cytotoxicities of tachen, tachpn and tachbn toward cultured cancer cells is in the order tachen < tachpn < tachbn < tachpyr, where tachpyr is the aminopyridyl chelator N,N', N"-tris(2-pyridylmethyl)cyclohexane- cis, cis-1,3,5-triamine. The cytotoxicity difference is attributed to an order of increasing lipophilicity, tachen < tachpn < tachbn. C1 Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. Wake Forest Univ Hlth Sci, Dept Biochem, Winston Salem, NC 27157 USA. Bruker AXS Inc, Madison, WI 53711 USA. Univ Alabama, Dept Chem, Tuscaloosa, AL 35487 USA. RP Planalp, RP (reprint author), Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. RI Rogers, Robin/C-8265-2013 OI Rogers, Robin/0000-0001-9843-7494 FU NIDDK NIH HHS [R01-DK57781] NR 28 TC 7 Z9 7 U1 0 U2 2 PU ROYAL SOC CHEMISTRY PI CAMBRIDGE PA THOMAS GRAHAM HOUSE, SCIENCE PARK, MILTON RD, CAMBRIDGE CB4 0WF, CAMBS, ENGLAND SN 1477-9226 J9 DALTON T JI Dalton Trans. PD MAY 7 PY 2004 IS 9 BP 1304 EP 1311 DI 10.1039/b403476g PG 8 WC Chemistry, Inorganic & Nuclear SC Chemistry GA 823WX UT WOS:000221645900005 PM 15252622 ER PT J AU Ouchi, M Fujiuchi, N Sasai, K Katayama, H Minamishima, YA Ongusaha, PP Deng, CX Sen, S Lee, SW Ouchi, T AF Ouchi, M Fujiuchi, N Sasai, K Katayama, H Minamishima, YA Ongusaha, PP Deng, CX Sen, S Lee, SW Ouchi, T TI BRCA1 phosphorylation by Aurora-A in the regulation of G(2) to M transition SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CANCER SUSCEPTIBILITY GENE; DNA-DAMAGE RESPONSE; BREAST-CANCER; CELL-CYCLE; SUBCELLULAR-LOCALIZATION; CENTROSOME AMPLIFICATION; TRANSCRIPTIONAL ACTIVATION; IONIZING IRRADIATION; S-PHASE; KINASE AB Aurora-A/BTAK/STK15 localizes to the centrosome in the G(2)-M phase, and its kinase activity regulates the G(2) to M transition of the cell cycle. Previous studies have shown that the BRCA1 breast cancer tumor suppressor also localizes to the centrosome and that BRCA1 inactivation results in loss of the G(2)-M checkpoint. We demonstrate here that Aurora-A physically binds to and phosphorylates BRCA1. Biochemical analysis showed that BRCA1 amino acids 1314 - 1863 binds to Aurora-A. Site-directed mutagenesis indicated that Ser(308) of BRCA1 is phosphorylated by Aurora-A in vitro. Anti-phospho-specific antibodies against Ser(308) of BRCA1 demonstrated that Ser(308) is phosphorylated in vivo. Phosphorylation of Ser(308) increased in the early M phase when Aurora-A activity also increases; these effects could be abolished by ionizing radiation. Consistent with these observations, acute loss of Aurora-A by small interfering RNA resulted in reduced phosphorylation of BRCA1 Ser(308), and transient infection of adenovirus Aurora-A increased Ser(308) phosphorylation. Mutation of a single phosphorylation site of BRCA1 (S308N), when expressed in BRCA1-deficient mouse embryo fibroblasts, decreased the number of cells in the M phase to a degree similar to that with wild type BRCA1-mediated G(2) arrest induced by DNA damage. We propose that BRCA1 phosphorylation by Aurora-A plays a role in G(2) to M transition of cell cycle. C1 NYU, Mt Sinai Sch Med, Derald H Ruttenberg Canc Ctr, New York, NY 10029 USA. Univ Texas, MD Anderson Canc Ctr, Div Pathol & Lab Med, Houston, TX 77030 USA. NIH, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Canc Biol Program, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. RP Ouchi, T (reprint author), NYU, Mt Sinai Sch Med, Derald H Ruttenberg Canc Ctr, Box 1130,1 Gustave L Levy Pl, New York, NY 10029 USA. EM Toru.Ouchi@mssm.edu RI deng, chuxia/N-6713-2016 FU NCI NIH HHS [CA 79892, CA 90631] NR 55 TC 154 Z9 165 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 7 PY 2004 VL 279 IS 19 BP 19643 EP 19648 DI 10.1074/jbc.M311780200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 817FX UT WOS:000221164500033 PM 14990569 ER PT J AU Xu, JK Liu, Y Yang, YY Bates, S Zhang, JT AF Xu, JK Liu, Y Yang, YY Bates, S Zhang, JT TI Characterization of oligomeric human half-ABC transporter ATP-binding cassette G2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CANCER RESISTANCE PROTEIN; TRANSMEMBRANE CONDUCTANCE REGULATOR; MINIMUM FUNCTIONAL UNIT; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; DROSOPHILA-MELANOGASTER; DRUG-TRANSPORT; CELLS; MEMBRANES; DIMERIZATION AB Human ATP-binding cassette G2 (ABCG2, also known as mitoxantrone resistance protein, breast cancer-resistance protein, ABC placenta) is a member of the superfamily of ATP-binding cassette ( ABC) transporters that have a wide variety of substrates. Overexpression of human ABCG2 in model cancer cell lines causes multidrug resistance by actively effluxing anticancer drugs. Unlike most of the other ABC transporters which usually have two nucleotide-binding domains and two transmembrane domains, ABCG2 consists of only one nucleotide-binding domain followed by one transmembrane domain. Thus, ABCG2 has been thought to be a half-transporter that may function as a homodimer. In this study, we characterized the oligomeric feature of human ABCG2 using non-denaturing detergent perfluorooctanoic acid and Triton X-100 in combination with gel filtration, sucrose density gradient sedimentation, and gel electrophoresis. Unexpectedly, we found that human ABCG2 exists mainly as a tetramer, with a possibility of a higher form of oligomerization. Monomeric and dimeric ABCG2 did not appear to be the major form of the protein. Further immunoprecipitation analysis showed that the oligomeric ABCG2 did not contain any other proteins. Taken together, we conclude that human ABCG2 likely exists and functions as a homotetramer. C1 Indiana Univ, Sch Med, Ctr Canc,Walther Canc Inst, Walther Oncol Ctr,Dept Pharmacol & Toxicol, Indianapolis, IN 46202 USA. NCI, Canc Therapeut Branch, Bethesda, MD 20892 USA. NIH, Pathol Lab, Bethesda, MD 20892 USA. RP Zhang, JT (reprint author), Indiana Univ, Sch Med, Ctr Canc,Walther Canc Inst, Walther Oncol Ctr,Dept Pharmacol & Toxicol, 1044 W Walnut St,R4-166, Indianapolis, IN 46202 USA. EM jianzhan@iupui.edu RI Zhang, Jian-Ting/L-8334-2015 FU NCI NIH HHS [CA 64539]; NIGMS NIH HHS [GM 59475] NR 36 TC 174 Z9 187 U1 0 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 7 PY 2004 VL 279 IS 19 BP 19781 EP 19789 DI 10.1074/jbc.M310785200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 817FX UT WOS:000221164500049 PM 15001581 ER PT J AU Gavva, NR Klionsky, L Qu, YS Shi, LC Tamir, R Edenson, S Zhang, TJ Viswanadhan, VN Toth, A Pearce, LV Vanderah, TW Porreca, F Blumberg, PM Lile, J Sun, Y Wildt, K Louis, JC Treanor, JJS AF Gavva, NR Klionsky, L Qu, YS Shi, LC Tamir, R Edenson, S Zhang, TJ Viswanadhan, VN Toth, A Pearce, LV Vanderah, TW Porreca, F Blumberg, PM Lile, J Sun, Y Wildt, K Louis, JC Treanor, JJS TI Molecular determinants of vanilloid sensitivity in TRPV1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ROOT GANGLION NEURONS; CAPSAICIN RECEPTOR VR1; ACTIVATED ION-CHANNEL; PROTEIN-KINASE-C; DIRECT PHOSPHORYLATION; ANALGESIC PROPERTIES; ANTAGONIST; BINDING; CELLS; PAIN AB Vanilloid receptor 1 (TRPV1), a membrane-associated cation channel, is activated by the pungent vanilloid from chili peppers, capsaicin, and the ultra potent vanilloid from Euphorbia resinifera, resiniferatoxin (RTX), as well as by physical stimuli (heat and protons) and proposed endogenous ligands (anandamide, N-arachidonyldopamine, N-oleoyldopamine, and products of lipoxygenase). Only limited information is available in TRPV1 on the residues that contribute to vanilloid activation. Interestingly, rabbits have been suggested to be insensitive to capsaicin and have been shown to lack detectable [H-3]RTX binding in membranes prepared from their dorsal root ganglia. We have cloned rabbit TRPV1 (oTRPV1) and report that it exhibits high homology to rat and human TRPV1. Like its mammalian orthologs, oTRPV1 is selectively expressed in sensory neurons and is sensitive to protons and heat activation but is 100-fold less sensitive to vanilloid activation than either rat or human. Here we identify key residues (Met(547) and Thr(550)) in transmembrane regions 3 and 4 (TM3/4) of rat and human TRPV1 that confer vanilloid sensitivity, [H-3]RTX binding and competitive antagonist binding to rabbit TRPV1. We also show that these residues differentially affect ligand recognition as well as the assays of functional response versus ligand binding. Furthermore, these residues account for the reported pharmacological differences of RTX, PPAHV (phorbol 12-phenyl-acetate 13-acetate 20-homovanillate) and capsazepine between human and rat TRPV1. Based on our data we propose a model of the TM3/4 region of TRPV1 bound to capsaicin or RTX that may aid in the development of potent TRPV1 antagonists with utility in the treatment of sensory disorders. C1 Amgen Inc, Dept Neurosci, Thousand Oaks, CA 91320 USA. Amgen Inc, Dept Mol Struct, Thousand Oaks, CA 91320 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, NIH, Bethesda, MD 20892 USA. Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA. RP Gavva, NR (reprint author), Amgen Inc, Dept Neurosci, MS 29-2-B,1 Amgen Ctr Dr, Thousand Oaks, CA 91320 USA. EM ngavva@amgen.com RI Toth, Attila/F-4859-2010 OI Toth, Attila/0000-0001-6503-3653 NR 39 TC 201 Z9 215 U1 0 U2 13 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 MAY 7 PY 2004 VL 279 IS 19 BP 20283 EP 20295 DI 10.1074/jbc.M312577200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 817FX UT WOS:000221164500106 PM 14996838 ER PT J AU Hess, S Gustafson, KR Milanowski, DJ Alvira, E Lipton, MA Pannell, LK AF Hess, S Gustafson, KR Milanowski, DJ Alvira, E Lipton, MA Pannell, LK TI Chirality determination of unusual amino acids using precolumn derivatization and liquid chromatography-electrospray ionization mass spectrometry SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE derivatization; LC; chirality; amino acids ID SPONGE CALLIPELTA SP; L-CYSTEINE REAGENTS; METHOXYETHYL ESTER; 1-FLUORO-2,4-DINITROPHENYL-5-L-ALANINE AMIDE; O-PHTHALDIALDEHYDE/3-MERCAPTOPROPIONIC ACID; ABSOLUTE-CONFIGURATION; CYCLIC DEPSIPEPTIDE; O-PHTHALDIALDEHYDE; STATIONARY PHASES; MARFEYS REAGENT AB Unusual amino acids such as beta-methoxytyrosine (beta-MeOTyr), allo-threonine (allo-Thr) and allo-isoleucine (allo-Ile) were derivatized with N-alpha-(2,4-dinitro-5-fluorophenyl)-L-alaninamide (FDAA), 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl isothiocyanate (GITC), (S)-N-(4-nitrophenoxycarbonyl)phenylalanine methoxyethyl ester (S-NIFE), or o-phthalaldehyde/isobutyryl-L-cysteine (OPA-ILBC), and then separated via reversed-phase high-performance chromatography followed by UV and electrospray ionization mass spectrometry detection. FDAA generally showed the highest enantioselectivity but the lowest sensitivity among the chiral derivatizing agents (CDAs) investigated. The detection limit of FDAA-dedvatized amino acids was in the low picomolar range. Although the enantioselectivity of FDAA derivatives was generally quite high, its selectivity among beta-MeOTyr isomers was poor. The best separation of beta-MeOTyr stereoisomers was achieved with S-NIFE. Due to the complex relationships between the investigated CDAs, stereochemical analyses using a combination of two or more of the CDAs gave the most reliable results for a given separation problem. In general, the methods described are selective and reliable, and are being applied to the analysis of unusual amino acids as they occur in marine peptides. (C) 2004 Elsevier B.V. All rights reserved. C1 NIDDKD, Struct Mass Spectrometry Facil, US Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NCI, CCR, Mol Targets Dev Program, Frederick, MD 21701 USA. Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. RP Hess, S (reprint author), NIDDKD, Struct Mass Spectrometry Facil, US Dept Hlth & Human Serv, NIH, Bldg 8,Room B24, Bethesda, MD 20892 USA. EM sonja_hess@nih.gov RI Hess, Sonja/K-4842-2013 OI Hess, Sonja/0000-0002-5904-9816 FU NIAID NIH HHS [R01 AI050888-03] NR 46 TC 40 Z9 44 U1 1 U2 18 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 MAY 7 PY 2004 VL 1035 IS 2 BP 211 EP 219 DI 10.1016/j.chroma.2004.02.068 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 811PF UT WOS:000220783100006 PM 15124814 ER PT J AU Gao, ZG Gross, AS Jacobson, KA AF Gao, ZG Gross, AS Jacobson, KA TI Effects of the allosteric modulator SCH-202676 on adenosine and P2Y receptors SO LIFE SCIENCES LA English DT Article DE adenosine receptor; P2Y receptor; allosteric modulator; 7TM receptor; SCH-202676 ID ANTAGONIST BINDING; AMILORIDE ANALOGS; AGONIST BINDING; 2-AMINO-3-BENZOYLTHIOPHENES; QUANTITATION; ENHANCEMENT; TARGETS; SERIES; A(1) AB The G protein-coupled receptor allosteric modulator SCH-202676 (N-(2,3-diphenyl-1,2,4-thiadiazol-5-(2H)ylidene)methanamine), which affects a wide range of structurally unrelated G protein-coupled receptors, has highly divergent effects on purine receptors. SCH-202676 inhibited radioligand binding to human adenosine A,, A(2A), and A(3) receptors (IC50 = 0.5-0.8 muM) and affected dissociation kinetics, but at the human P2Y(1) nucleotide receptor it had no effect. SCH-202676 (10 muM) selectively accelerated agonist dissociation at adenosine A3 receptors and either slowed (adenosine A(1) receptors) or accelerated (adenosine A(2A) receptors) antagonist dissociation. Thus, SCH-202676 differentially modulated A(1), A(2A), and A(3) receptors as well as agonist- and antagonist-occupied receptors. (C) 2004 Elsevier Inc. All rights reserved. C1 NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031116-20, Z01 DK031117-20, Z99 DK999999] NR 17 TC 19 Z9 19 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAY 7 PY 2004 VL 74 IS 25 BP 3173 EP 3180 DI 10.1016/j.lfs.2003.11.014 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 815CJ UT WOS:000221020100011 PM 15081581 ER PT J AU Berg, JM AF Berg, JM TI The problems of bonus pay SO SCIENCE LA English DT Letter C1 NIGMS, NIH, Bethesda, MD 20892 USA. RP Berg, JM (reprint author), NIGMS, NIH, 45 Ctr Dr,MSC 6200, Bethesda, MD 20892 USA. EM bergj@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 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 MAY 7 PY 2004 VL 304 IS 5672 BP 824 EP 824 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 818KC UT WOS:000221243000021 PM 15131290 ER PT J AU Nikolovska-Coleska, Z Xu, L Hu, ZJ Tomita, Y Li, P Roller, PP Wang, RX Fang, XL Guo, RB Zhang, MC Lippman, ME Yang, DJ Wang, SM AF Nikolovska-Coleska, Z Xu, L Hu, ZJ Tomita, Y Li, P Roller, PP Wang, RX Fang, XL Guo, RB Zhang, MC Lippman, ME Yang, DJ Wang, SM TI Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XLAP through structure-based computational screening of a traditional herbal medicine three-dimensional structure database SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID X-LINKED INHIBITOR; PROSTATE-CANCER CELLS; HUMAN OVARIAN-CANCER; APOPTOSIS PROTEIN XIAP; HUMAN LUNG-CANCER; IAP PROTEINS; MEDIATED APOPTOSIS; MALIGNANT GLIOMA; ESCHERICHIA-COLI; BIR DOMAIN AB The X-linked inhibitor of apoptosis (XIAP) is a promising new molecular target for the design of novel anticancer drugs aiming at overcoming apoptosis-resistance of cancer cells to chemotherapeutic agents and radiation therapy. Recent studies demonstrated that the BIR3 domain of XIAP where caspase-9 and Smac proteins bind is an attractive site for designing small-molecule inhibitors of XIAP. Through computational structure-based screening of an in-house traditional herbal medicine three-dimensional structure database of 8221 individual natural products, followed by biochemical testing of selected candidate compounds, we discovered embelin from the Japanese Ardisia herb as a small-molecular weight inhibitor that binds to the XIAP BIR3 domain. We showed that embelin binds to the XIAP BIR3 protein with an affinity similar to that of the natural Smac peptide using a fluorescence polarization-based binding assay. Our NMR analysis further conclusively confirmed that embelin interacts with several crucial residues in the XIAP BIR3 domain with which Smac and caspsase-9 bind. Embelin inhibits cell growth, induces apoptosis, and activates caspase-9 in prostate cancer cells with high levels of XIAP, but has a minimal effect on normal prostate epithelial and fibroblast cells with low levels of XIAP. In stably XIAP-transfected Jurkat cells, embelin effectively overcomes the protective effect of XIAP to apoptosis and enhances the etoposide-induced apoptosis and has a minimal effect in Jurkat cells transfected with vector control. Taken together, our results showed that embelin is a fairly potent, nonpeptidic, cell-permeable, small-molecule inhibitor of XIAP and represents a promising lead compound for designing an entirely new class of anticancer agents that target the BIR3 domain of XIAP. C1 Univ Michigan, Ctr Comprehens Canc, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Comprehens Canc, Dept Med Chem, Ann Arbor, MI 48109 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20057 USA. NCI, Med Chem Lab, FCRDC, Frederick, MD 21702 USA. RP Wang, SM (reprint author), Univ Michigan, Ctr Comprehens Canc, Dept Internal Med, CCGC 3316,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM shaomeng@umich.edu RI Wang, Shaomeng/E-9686-2010 NR 67 TC 217 Z9 227 U1 0 U2 19 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 MAY 6 PY 2004 VL 47 IS 10 BP 2430 EP 2440 DI 10.1021/jm030420+ PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 817NI UT WOS:000221183800009 PM 15115387 ER PT J AU Zhang, Y Pavlova, OA Chefer, SI Hall, AW Kurian, V Brown, LL Kimes, AS Mukhin, AG Horti, AG AF Zhang, Y Pavlova, OA Chefer, SI Hall, AW Kurian, V Brown, LL Kimes, AS Mukhin, AG Horti, AG TI 5-substituted derivatives of 6-halogeno-3-((2-(S)-azetidinyl)methoxy)pyridine and 6-halogeno-3-((2-(S)-pyrrolidinyl)methoxy)pyridine with low picomolar affinity for alpha 4 beta 2 nicotinic acetylcholine receptor and wide range of lipophilicity: Potential probes for imaging with positron emission tomography SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN-BRAIN; IN-VIVO; GRAPHICAL ANALYSIS; BINDING-SITES; PET; ANALOGS; RADIOLIGANDS; DOPAMINE; LIGAND; RADIOPHARMACEUTICALS AB Potential positron emission tomography (PET) ligands with low picomolar affinity at the nicotinic acetylcholine receptor (nAChR) and with lipophilicity (log D) ranging from -1.6 to +1.5 have been synthesized. Most members of the series, which are derivatives of 5-substituted-6-halogeno-A-85380, exhibited a higher binding affinity at alpha4beta2-nAChRs than epibatidine. An analysis, by molecular modeling, revealed an important role of the orientation of the additional heterocyclic ring on the binding affinity of the ligands with nAChRs. The existing nicotinic pharmacophore models do not accommodate this finding. Two compounds of the series, 6-[F-18]-fluoro-5-(pyridin-3-yl)-A-85380 ([F-18]31) and 6-chloro-3-((2-(S)-azetidinyl)methoxy)-5-(2- [F-18]-fluoropyridin-5-yl)pyridine) ([F-18]35), were radiolabeled with F-18. Comparison of PET data for [F-18]31 and 2-[F-18]FA shows the influence of lipophilicity on the binding potential. Our recent PET studies with [F-18]35 demonstrated that its binding potential values in Rhesus monkey brain were ca. 2.5 times those of 2-[F-18]FA. Therefore, [F-18]35 and several other members of the series, when radiolabeled, will be suitable for quantitative imaging of extrathalamic nAChRs. C1 NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Horti, AG (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ahorti@intra.nida.nih.gov NR 60 TC 41 Z9 41 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 6 PY 2004 VL 47 IS 10 BP 2453 EP 2465 DI 10.1021/jm030432v PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 817NI UT WOS:000221183800011 PM 15115389 ER PT J AU Das, K Clark, AD Lewi, PJ Heeres, J de Jonge, MR Koymans, LMH Vinkers, HM Daeyaert, F Ludovici, DW Kukla, MJ De Corte, B Kavash, RW Ho, CY Ye, H Lichtenstein, MA Andries, K Pauwels, R de Bethune, MP Boyer, PL Clark, P Hughes, SH Janssen, PAJ Arnold, E AF Das, K Clark, AD Lewi, PJ Heeres, J de Jonge, MR Koymans, LMH Vinkers, HM Daeyaert, F Ludovici, DW Kukla, MJ De Corte, B Kavash, RW Ho, CY Ye, H Lichtenstein, MA Andries, K Pauwels, R de Bethune, MP Boyer, PL Clark, P Hughes, SH Janssen, PAJ Arnold, E TI Roles of conformational and positional adaptability in structure-based design of TMC125-R165335 (etravirine) and related non-nucleoside reverse transcriptase inhibitors that are highly potent and effective against wild-type and drug-resistant HIV-1 variants SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; EFAVIRENZ DMP-266; K103N MUTANT; COMPLEX; BINDING; RT; MUTATIONS; DERIVATIVES AB Anti-AIDS drug candidate and non-nucleoside reverse transcriptase inhibitor (NNRTI) TMC125-R165335 (etravirine) caused an initial drop in viral load similar to that observed with a five-drug combination in naive patients and retains potency in patients infected with NNRTI-resistant HIV-1 variants. TMC125-R165335 and related anti-AIDS drug candidates can bind the enzyme RT in multiple conformations and thereby escape the effects of drug-resistance mutations. Structural studies showed that this inhibitor and other diarylpyrimidine (DAPY) analogues can adapt to changes in the NNRTI-binding pocket in several ways: (1) DAPY analogues can bind in at least two conformationally distinct modes; (2) within a given binding mode, torsional flexibility ("wiggling") of DAPY analogues permits access to numerous conformational variants; and (3) the compact design of the DAPY analogues permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for potency against wild-type and a wide range of drug-resistant mutant HIV-1 RTs. Exploitation of favorable components of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful drug design concept, especially for designing drugs that will be effective against rapidly mutating targets. C1 CABM, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. Janssen Pharmaceut, Ctr Mol Design, Vosselaar, Belgium. Janssen Res Fdn, B-2800 Mechelen, Belgium. NCI, HIV Drug Resistance Program, NIH, Ft Detrick, MD 21702 USA. RP Arnold, E (reprint author), CABM, 679 Hoes Ln, Piscataway, NJ 08854 USA. EM arnold@cabm.rutgers.edu RI de Jonge, Marc/B-3391-2010 OI de Jonge, Marc/0000-0003-3225-8172 FU NIAID NIH HHS [AI 27690]; NIGMS NIH HHS [P01 GM 56671] NR 52 TC 371 Z9 395 U1 6 U2 40 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 MAY 6 PY 2004 VL 47 IS 10 BP 2550 EP 2560 DI 10.1021/jm030558s PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 817NI UT WOS:000221183800019 PM 15115397 ER PT J AU Long, YQ Jiang, XH Dayam, R Sanchez, T Shoemaker, R Sei, S Neamati, N AF Long, YQ Jiang, XH Dayam, R Sanchez, T Shoemaker, R Sei, S Neamati, N TI Rational design and synthesis of novel dimeric diketoacid-containing inhibitors of HIV-1 integrase: Implication for binding to two metal ions on the active site of integrase SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CATALYTIC DOMAIN; MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; TERMINAL DOMAINS; STRAND TRANSFER; PRIMARY TARGET; DNA COMPLEX; MUTANT; CELLS AB Discovery of diketoacid-containing compounds as HIV-1 integrase (IN) inhibitors played a major role in validating this enzyme as an important target for the development of therapeutics against HIV infection. In fact, S-1360, the first clinically used IN inhibitor containing a triazole ring as a bioisostere of a carboxylic acid moiety belongs to this class of compounds. To understand the role of divalent metal-chelating in the inhibition of IN (J. Med. Chem. 2002, 45, 56615670), we designed and synthesized a series of novel dimeric diketo-containing compounds with the notion that such dimeric compounds may simultaneously bind to two divalent metal ions on the active site of IN. We rationalized that the two diketo subunits separated by uniquely designed linkers can potentially chelate two metal ions that are either provided from one IN active site or two active sites juxtaposed together in a higher order tetramer. Herein, we show that all the new compounds are highly potent against purified IN with varied selectivity for strand transfer, and that some of the analogues exert potent inhibition of the cytopathic effect of HIV-1 in infected CEM cells. This study represents the first attempt to rationally target two divalent metal ions on the active site of IN and may have potential implications for the design of second generation diketoacid-containing class of inhibitors. C1 CAS, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China. NCI, Lab Antiviral Drug Mech, Screening Technol Branch, DTP,DCTD, Frederick, MD 21702 USA. Univ So Calif, Sch Pharm, Dept Pharmaceut Sci, Los Angeles, CA 90089 USA. RP Long, YQ (reprint author), CAS, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China. EM yqlong@mail.shcnc.ac.cn; neamati@usc.edu FU PHS HHS [N01-C0-12400] NR 48 TC 154 Z9 161 U1 1 U2 18 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 MAY 6 PY 2004 VL 47 IS 10 BP 2561 EP 2573 DI 10.1021/jm030559k PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 817NI UT WOS:000221183800020 PM 15115398 ER PT J AU Jinsmaa, Y Miyazaki, A Fujita, Y Li, TY Fujisawa, Y Shiotani, K Tsuda, Y Yokoi, T Ambo, A Sasaki, Y Bryant, SD Lazarus, LH Okada, Y AF Jinsmaa, Y Miyazaki, A Fujita, Y Li, TY Fujisawa, Y Shiotani, K Tsuda, Y Yokoi, T Ambo, A Sasaki, Y Bryant, SD Lazarus, LH Okada, Y TI Oral bioavailability of a new class of mu-opioid receptor agonists containing 3,6-bis[Dmt-NH(CH2)(n)]2(1H)-pyrazinone with central-mediated analgesia SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID BLOOD-BRAIN-BARRIER; CENTRAL-NERVOUS-SYSTEM; ANALOGS PRODUCE ANALGESIA; DMT-TIC PHARMACOPHORE; DELTA-OPIATE RECEPTOR; LEU-OH DADLE; ANTINOCICEPTIVE ACTIVITY; ENKEPHALIN ANALOGS; AMINO-ACIDS; RAT-BRAIN AB The inability of opioid peptides to be transported through epithelial membranes in the gastrointestinal tract and pass the blood-brain barrier limits their effectiveness for oral application in an antinociceptive treatment regime. To overcome this limitation, we enhanced the hydrophobicity while maintaining the aqueous solubility properties in a class of opioidmimetic substances by inclusion of two identical N-termini consisting of Dmt (2',6'-dimethyl-L-tyrosine) coupled to a pyrazinone ring platform by means of alkyl chains to yield the class of 3,6-bis[Dmt-NH-(CH2)(n)],1-2(1H)-pyrazinones. These compounds displayed high mu-opioid receptor affinity (K(i)mu = 0.042-0.115 nM) and selectivity (K(i)delta/K(i)mu = 204-307) and functional p-opioid receptor agonism (guinea-pig ileum, IC50 = 1.3-1.9 nM) with little or undetectable bioactivity toward delta-opioid receptors (mouse vas deferens) and produced analgesia in mice in a naloxone reversible manner when administered centrally (intracerebroventricular, icv) or systemically (subcutaneously and orally). Furthermore, the most potent compound, 3,6-bis(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone (7') lacked functional delta-opioid receptor bioactivity and was 50-63-fold and 18-21-fold more active than morphine by icv administration as measured analgesia using tail-flick (spinal involvement) and hot-plate (supraspinal effect) tests, respectively; the compound ranged from 16 to 63% as potent upon systemic injection. These analgesic effects are many times greater than unmodified opioid peptides. The data open new possibilities for the rational design of potential opioid-mimetic drugs that pass through the epithelium of the gastrointestinal tract and the blood-brain barrier to target brain receptors. C1 NIEHS, LCBRA, Med Chem Grp, Res Triangle Pk, NC 27709 USA. Kobe Gakuin Univ, Fac Pharmaceut Sci, Dept Med Chem, Nishi Ku, Kobe, Hyogo 6512180, Japan. Kobe Gakuin Univ, High Technol Res Ctr, Nishi Ku, Kobe, Hyogo 6512180, Japan. Tohoku Pharmaceut Univ, Dept Biochem, Aoba Ku, Sendai, Miyagi 9818558, Japan. RP Lazarus, LH (reprint author), NIEHS, LCBRA, Med Chem Grp, POB 12233, Res Triangle Pk, NC 27709 USA. EM lazarus@niehs.nih.gov; okada@pharm.kobegakuin.ac.jp NR 58 TC 43 Z9 44 U1 0 U2 3 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 MAY 6 PY 2004 VL 47 IS 10 BP 2599 EP 2610 DI 10.1021/jm0304616 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 817NI UT WOS:000221183800023 PM 15115401 ER PT J AU Yu, H Kim, IJ Folk, JE Tian, XR Rothman, RB Baumann, MH Dersch, CM Flippen-Anderson, JL Parrish, D Jacobson, AE Rice, KC AF Yu, H Kim, IJ Folk, JE Tian, XR Rothman, RB Baumann, MH Dersch, CM Flippen-Anderson, JL Parrish, D Jacobson, AE Rice, KC TI Synthesis and pharmacological evaluation of 3-(3,4-dichlorophenyl)-1-indanamine derivatives as nonselective ligands for biogenic amine transporters SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID GBR12909 DECANOATE; COCAINE ABUSE; DOPAMINE; METHAMPHETAMINE; NOREPINEPHRINE; SEROTONIN; AGENT; IDENTIFICATION; INHIBITORS; REUPTAKE AB In our efforts toward developing a nonselective ligand that would block the effects of stimulants such as methamphetamine at dopamine (DA), serotonin (5-HT), and norepinephrine (NE) transporters, we synthesized a series of 3-(3,4-dichlorophenyl)-1-indanamine derivatives. Two of the examined higher affinity compounds had a phenolic hydroxyl group enabling preparation of a medium to long chain carboxylic acid ester that might eventually be useful for a long-acting depot formulation. The in vitro data indicated that (-)-(1R,3S)-trans-3-(3,4-dichlorophenyl)-6-hydroxy-N-methyl-1-indanamine ((-)-(1R,3S)-11) displays high-affinity binding and potent inhibition of uptake at all three biogenic amine transporters. In vivo microdialysis experiments demonstrated that intravenous administration of (-)-(1R,3S)-11 to rats elevated extracellular DA and 5-HT in the nucleus accumbens in a dose-dependent manner. Pretreating rats with 0.5 mg/kg (-)-(1R,3S)-11 elevated extracellular DA and 5-HT by approximately 150% and reduced methamphetamine-induced neurotransmitter release by about 50%. Ex vivo autoradiography, however, demonstrated that iv administration of (-)-(1R,3S)-11 produced a dose-dependent, persistent occupation of 5-HT transporter binding sites but not DA transporter sites. C1 NIDDKD, Med Chem Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NIDA, Clin Psychopharmacol Sect, Intramural Res Program, Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, Dept Hlth & Human Serv, NIH, Bldg 8,Room B1-23, Bethesda, MD 20892 USA. EM kr21f@nih.gov NR 27 TC 39 Z9 40 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 6 PY 2004 VL 47 IS 10 BP 2624 EP 2634 DI 10.1021/jm0305873 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 817NI UT WOS:000221183800025 PM 15115403 ER PT J AU Bhargava, R Levin, IW AF Bhargava, R Levin, IW TI Enhanced time-resolved Fourier transform infrared spectroscopic imaging for reversible dynamics SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID DISPERSED LIQUID-CRYSTALS; MOLECULAR-REORIENTATION; FILMS AB Time-resolved (TR) Fourier transform infrared (FTIR) spectroscopic imaging provides noninvasively spatial and spectral observations of molecular dynamic processes in heterogeneous environments. The technique, however, is limited by the readout time of the imaging focal plane array detector due to a tradeoff between the multichannel detection advantage and the achievable temporal resolution. We describe a generalized implementation of TR-FTIR spectroscopic imaging that, without affecting data quality, allows potential measurements of up to 2 orders of magnitude greater in time resolution than previously reported; that is, time resolutions of milliseconds to tenths of milliseconds are achievable for reversible dynamic processes. As an example, molecular rotations occurring in embedded liquid crystalline microdomains are monitored with a 2.5 ms time resolution allowing an accurate determination of events inherent in the reorientation and relaxation processes. C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Levin, IW (reprint author), NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. EM rohitb@niddk.nih.gov; iwl@helix.nih.gov OI Bhargava, Rohit/0000-0001-7360-994X NR 23 TC 8 Z9 8 U1 0 U2 1 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 MAY 6 PY 2004 VL 108 IS 18 BP 3896 EP 3901 DI 10.1021/jp037847c PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 816VO UT WOS:000221137600003 ER PT J AU Masison, DC AF Masison, DC TI Cell biology - Designer prions SO NATURE LA English DT Editorial Material ID CHAPERONE PROTEIN HSP104; OLIGOPEPTIDE REPEATS; YEAST; PROPAGATION; PSI(+) C1 NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM masisond@helix.nih.gov NR 9 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 6 PY 2004 VL 429 IS 6987 BP 37 EP 38 DI 10.1038/429037a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 818CB UT WOS:000221222100032 PM 15129269 ER PT J AU Cooper, JS Pajak, TF Forastiere, AA Jacobs, J Campbell, BH Saxman, SB Kish, JA Kim, HE Cmelak, AJ Rotman, M Machtay, M Ensley, JF Chao, KSC Schultz, CJ Lee, N Fu, KK AF Cooper, JS Pajak, TF Forastiere, AA Jacobs, J Campbell, BH Saxman, SB Kish, JA Kim, HE Cmelak, AJ Rotman, M Machtay, M Ensley, JF Chao, KSC Schultz, CJ Lee, N Fu, KK CA Rad Therapy Oncology Grp 9501 TI Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID ADVANCED LARYNGEAL-CANCER; LOCALLY ADVANCED HEAD; RADIATION-THERAPY; RANDOMIZED-TRIAL; CONCOMITANT CHEMOTHERAPY; EUROPEAN-ORGANIZATION; CHEMORADIOTHERAPY; RTOG; PRESERVATION; IRRADIATION AB BACKGROUND Despite the use of resection and postoperative radiotherapy, high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed. We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control. METHODS Between September 9, 1995, and April 28, 2000, 459 patients were enrolled. After undergoing total resection of all visible and palpable disease, 231 patients were randomly assigned to receive radiotherapy alone ( 60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks) and 228 patients to receive the identical treatment plus concurrent cisplatin (100 mg per square meter of body-surface area intravenously on days 1, 22, and 43). RESULTS After a median follow-up of 45.9 months, the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone ( hazard ratio for local or regional recurrence, 0.61; 95 percent confidence interval, 0.41 to 0.91; P = 0.01). The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group, as compared with 72 percent in the radiotherapy group. Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group ( hazard ratio for disease or death, 0.78; 95 percent confidence interval, 0.61 to 0.99; P= 0.04), but overall survival was not ( hazard ratio for death, 0.84; 95 percent confidence interval, 0.65 to 1.09; P= 0.19). The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group ( P< 0.001). Four patients who received combined therapy died as a direct result of the treatment. CONCLUSIONS Among high-risk patients with resected head and neck cancer, concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival. However, the combined treatment is associated with a substantial increase in adverse effects. C1 NYU Med Ctr, New York, NY 10016 USA. Radiat Therapy Oncol Grp Headquarters, Philadelphia, PA USA. Johns Hopkins Univ, Sch Med, Johns Hopkins Oncol Ctr, Baltimore, MD 21205 USA. Wayne State Univ, Sch Med, Detroit, MI USA. Med Coll Wisconsin, Milwaukee, WI 53226 USA. NCI, Bethesda, MD 20892 USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Vanderbilt Canc Ctr, Nashville, TN USA. SUNY Hlth Ctr Brooklyn, Brooklyn, NY USA. Univ Penn Hlth Syst, Philadelphia, PA USA. Washington Univ, Med Ctr, Mallinckrodt Inst Radiol, St Louis, MO 63110 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Cooper, JS (reprint author), NYU Med Ctr, New York, NY 10016 USA. OI Campbell, Bruce/0000-0001-9485-5728 FU NCI NIH HHS [CA21661, CA32115] NR 19 TC 1224 Z9 1261 U1 0 U2 26 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 MAY 6 PY 2004 VL 350 IS 19 BP 1937 EP 1944 DI 10.1056/NEJMoa032646 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 818AU UT WOS:000221218800005 PM 15128893 ER PT J AU Levine, RJ Karumanchi, SA AF Levine, RJ Karumanchi, SA TI Circulating angiogenic factors and preeclampsia - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NICHHD, Bethesda, MD 20892 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. RP Levine, RJ (reprint author), NICHHD, Bethesda, MD 20892 USA. EM levinerj@mail.nih.gov; sananth@bidmc.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 6 PY 2004 VL 350 IS 19 BP 2003 EP 2004 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 818AU UT WOS:000221218800022 ER PT J AU Young, NS Brown, KE AF Young, NS Brown, KE TI Parvovirus B19 - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID B19 INFECTION; GLOMERULONEPHRITIS C1 NHLBI, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, Bethesda, MD 20892 USA. EM youngn@nhlbi.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC/NEJM 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 MAY 6 PY 2004 VL 350 IS 19 BP 2007 EP 2007 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 818AU UT WOS:000221218800030 ER PT J AU Yang, O Zhang, R Wang, XW Linke, SP Sengupta, S Hickson, ID Pedrazzi, G Perrera, C Stagljar, I Littman, SJ Modrich, P Harris, CC AF Yang, O Zhang, R Wang, XW Linke, SP Sengupta, S Hickson, ID Pedrazzi, G Perrera, C Stagljar, I Littman, SJ Modrich, P Harris, CC TI The mismatch DNA repair heterodimer, hMSH2/6, regulates BLM helicase SO ONCOGENE LA English DT Article DE p53; Rad51; homologous recombination; DNA repair ID SYNDROME GENE-PRODUCT; MODULATES HOMOLOGOUS RECOMBINATION; DOUBLE-STRAND BREAKS; HOLLIDAY JUNCTIONS; MAMMALIAN-CELLS; REPLICATION FORKS; SYNDROME PROTEIN; BULGED BASES; TUMOR-CELLS; S-PHASE AB The human MSH2/6 complex is essential for mismatch recognition during the repair of replication errors. Although mismatch repair components have been implicated in DNA homologous recombination repair, the exact function of hMSH2/6 in this pathway is unclear. Here, we show that the recombinant hMSH2/6 protein complex stimulated the ability of the Bloom's syndrome gene product, BLM, to process Holliday junctions in vitro, an activity that could also be regulated by p53. Consistent with these observations, hMSH6 colocalized with BLM and phospho-ser15-p53 in hydroxyurea-induced RAD51 nuclear foci that may correspond to the sites of presumed stalled DNA replication forks and more likely the resultant DNA double-stranded breaks. In addition, we show that hMSH2 and hMSH6 coimmunoprecipitated with BLM, p53, and RAD51. Bot h the number of RAD51 foci and the amount of the BLM-p53-RAD51 complex are increased in hMSH2- or hMSH6-deficient cells. These data suggest that hMSH2/6 formed a complex with BLM-p53-RAD51 in response to the damaged DNA forks during double-stranded break repair. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. Univ Oxford, John Radcliffe Hosp, Canc Res UK, Weatherall Inst Mol Med, Oxford OX3 9DS, England. Univ Zurich Irchel, Inst Vet Biochem & Mol Biol, CH-8057 Zurich, Switzerland. Univ Zurich, Inst Mol Canc Res, CH-8006 Zurich, Switzerland. Duke Med Ctr, Dept Med, Durham, NC 27710 USA. Duke Med Ctr, Howard Hughes Med Inst, Dept Biochem, Durham, NC 27710 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Rm 3068,37 Convent Dr, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov RI Wang, Xin/B-6162-2009; OI Sengupta, Sagar/0000-0002-6365-1770 NR 58 TC 1 Z9 1 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 6 PY 2004 VL 23 IS 21 BP 3749 EP 3756 DI 10.1038/sj.onc.1207462 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 818JX UT WOS:000221242500002 ER PT J AU Guda, K Upender, MB Belinsky, G Flynn, C Nakanishi, M Marino, JN Ried, T Rosenberg, DW AF Guda, K Upender, MB Belinsky, G Flynn, C Nakanishi, M Marino, JN Ried, T Rosenberg, DW TI Carcinogen-induced colon tumors in mice are chromosomally stable and are characterized by low-level microsatellite instability SO ONCOGENE LA English DT Article DE azoxymethane; mice; colon tumorigenesis; chromosomal instability; spectral karyotyping; microsatellite instability ID COLORECTAL-CANCER; GENOMIC INSTABILITY; BETA-CATENIN; ALTERED EXPRESSION; HIGH-FREQUENCY; AZOXYMETHANE; MUTATIONS; PATHWAYS; DNA; TUMORIGENESIS AB The azoxymethane (AOM)-induced mouse colon tumor model recapitulates many of the histopathological features associated with the multistage progression of human sporadic colorectal cancers (CRCs). To better de. ne the genetic events associated with tumorigenesis in this murine model, we analysed tumors from A/J mice for chromosomal (CIN) and microsatellite (MSI) instabilities, two fundamental pathways of genomic instability that play a critical role in the pathogenesis of human CRCs. Male A/J mice, 6-week old, were injected with either AOM (n=5) (10 mg/kg b.w., i.p.) or vehicle (n=5) (0.9% NaCl solution) once a week for 6 weeks. At 32 weeks after the last dose, comparative genomic hybridization (CGH) was performed on 16 tumors harvested from five animals. Although 25% of the tumors displayed either a gain of chromosome 2 or loss of Y, the majority (75%) showed no genomic imbalances. Further analysis of chromosomal aberrations, using CGH and spectral karyotyping (SKY) was performed in our recently established A/J colon tumor-derived cell line, AJ02-NM0. Results showed a pseudotetraploid karyotype with loss of only the Y chromosome in these cultured cells, thereby providing additional evidence for the minimal role of CIN in the primary AOM-induced tumors. Interestingly, the majority (81%) of A/J tumors displayed low-level microsatellite instability (MSI-L) when analysed using mono- and dinucleotide repeat markers, and showed a significant expansion to high-level instability (MSI-H) in the AJ02-NM0 cells. This finding in cultured cells additionally provides evidence that a mild mutator pathway may contribute to the development of behaviorally benign carcinomas in situ in A/J mice. To better understand the tumorigenic process in the A/J colons, we screened for mutational alterations in key regions of the K-ras and Apc genes. Results showed a very low frequency (6%) of K-ras activating mutations, together with the absence of Apc truncation mutations in primary tumors and AJ02-NM0 cells. However, these tumors displayed intense nuclear accumulation of beta-catenin protein, indicating activation of the Wnt signaling pathway. Based on our molecular and cytogenetic findings, we propose that carcinogen-induced tumors may develop via mechanisms independent of the 'classical' CIN or MSI pathways. C1 NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Connecticut, Ctr Hlth, Ctr Mol Med, Farmington, CT 06030 USA. RP Ried, T (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, 50 South Dr,Room 1306, Bethesda, MD 20892 USA. EM riedt@mail.nih.gov RI guda, kishore/E-3389-2010 FU NCI NIH HHS [CA81428] NR 49 TC 36 Z9 36 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 6 PY 2004 VL 23 IS 21 BP 3813 EP 3821 DI 10.1038/sj.onc.1207489 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 818JX UT WOS:000221242500008 PM 15021908 ER PT J AU Zhang, ZQ Wang, Y Yao, RS Li, J Yan, Y La Regina, M Lemon, WL Grubbs, CL Lubet, RA You, M AF Zhang, ZQ Wang, Y Yao, RS Li, J Yan, Y La Regina, M Lemon, WL Grubbs, CL Lubet, RA You, M TI Cancer chemopreventive activity of a mixture of Chinese herbs (antitumor B) in mouse lung tumor models SO ONCOGENE LA English DT Article DE antitumor B; lung cancer; chemoprevention; A/J mice; transgenic mice; p53; Ink4a/Arf ID BREAST-CANCER CELLS; FEMALE A/J MICE; BETA-SITOSTEROL; ALPHA-SUBUNITS; G13 PROTEINS; GREEN TEA; TUMORIGENESIS; CARCINOGENESIS; PHYTOSTEROLS; INHIBITION AB Antitumor B (ATB), also known as Zeng Sheng Ping, is a Chinese herbal mixture composed of six plants. Previously, clinical studies have shown a significant chemopreventive efficacy of ATB against human esophageal and lung cancers. In the present study, A/J mice harboring a dominant-negative p53 and/or heterozygous deletion of Ink4a/Arf and treated with benzo[a] pyrene were used to investigate the chemopreventive effects of ATB on chemically induced lung tumorigenesis. Mice with various genotypes treated with ATB displayed a significant reduction in lung tumor multiplicity and tumor load. Treatment with ATB resulted in an approximately 40% decrease in tumor multiplicity and a 70% decrease in tumor load in both wild-type mice and in mice with a loss of the Ink4a/Arf tumor suppressor genes. Interestingly, ATB decreased tumor multiplicity and volume by 50 and 90%, respectively, in mice with a dominant-negative p53 and in mice with both a p53 mutation and deletion of Ink4a/Arf. Kras2 mutation analysis of the lung tumors revealed that tumors harbored mutations in the 12th codon of Kras2. There were no differences in either the incidence or types of mutations between tumors treated with or without ATB. Oligonucleotide array analysis revealed 284 genes that were differentially expressed in mouse lung tumors as compared to the normal lung, and it was found that 114 out of these 284 genes changed their expression toward the normal levels in tumors treated with ATB. Most of the genes modulated by ATB belong to several cellular signaling pathways, including Notch (Notch homolog 2, manic fringe homolog), growth factor (FGF intracellular-binding protein, PDGFalpha), G protein-Ras-MAPK (MAPK3, MAP3K4, rab3A, Rap1, RSG5, PKCh), ubiquitin- proteasome (CDC34, Cullin1, 26S proteasome), and apoptosis (BAD promoter, caspase 3). These results suggest that ATB is an effective chemopreventive against mouse lung tumorigenesis. Furthermore, ATB exhibited an enhanced inhibitory effect in animals harboring genetic alterations (Kras2, p53, and Ink4a/Arf), which are often seen in human lung adenocarcinomas. C1 Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. Washington Univ, Sch Med, Div Comparat Med, St Louis, MO 63110 USA. Univ Alabama, Chemoprevent Ctr, Dept Surg, Birmingham, AL 35295 USA. NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP You, M (reprint author), Washington Univ, Sch Med, Dept Surg, Campus Box 8109,660 S Euclid Ave, St Louis, MO 63110 USA. EM youm@msnotes.wustl.edu NR 29 TC 36 Z9 38 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 MAY 6 PY 2004 VL 23 IS 21 BP 3841 EP 3850 DI 10.1038/sj.onc.1207496 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 818JX UT WOS:000221242500011 PM 15021904 ER PT J AU Koshiji, M Kageyama, Y Pete, EA Horikawa, I Barrett, JC Huang, LE AF Koshiji, M Kageyama, Y Pete, EA Horikawa, I Barrett, JC Huang, LE TI HIF-1 alpha induces cell cycle arrest by functionally counteracting Myc SO EMBO JOURNAL LA English DT Article DE cell cycle; HIF-1 alpha; hypoxia; Myc; p21(cip1) ID HYPOXIA-INDUCIBLE FACTOR; TUMOR-SUPPRESSOR PROTEIN; UBIQUITIN-PROTEASOME PATHWAY; HIPPEL-LINDAU PROTEIN; C-MYC; FACTOR 1-ALPHA; TRANSCRIPTIONAL REPRESSION; GENE-EXPRESSION; DNA-DAMAGE; PROLYL HYDROXYLATION/ AB Hypoxia induces angiogenesis and glycolysis for cell growth and survival, and also leads to growth arrest and apoptosis. HIF-1alpha, a basic helix-loop-helix PAS transcription factor, acts as a master regulator of oxygen homeostasis by upregulating various genes under low oxygen tension. Although genetic studies have indicated the requirement of HIF-1alpha for hypoxia-induced growth arrest and activation of p21(cip1), a key cyclin-dependent kinase inhibitor controlling cell cycle checkpoint, the mechanism underlying p21(cip1) activation has been elusive. Here we demonstrate that HIF-1alpha, even in the absence of hypoxic signal, induces cell cycle arrest by functionally counteracting Myc, thereby derepressing p21(cip1). The HIF-1alpha antagonism is mediated by displacing Myc binding from p21(cip1) promoter. Neither HIF-1alpha transcriptional activity nor its DNA binding is essential for cell cycle arrest, indicating a divergent role for HIF-1alpha. In keeping with its antagonism of Myc, HIF-1alpha also downregulates Myc-activated genes such as hTERT and BRCA1. Hence, we propose that Myc is an integral part of a novel HIF-1alpha pathway, which regulates a distinct group of Myc target genes in response to hypoxia. C1 NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Biosyst & Canc, NIH, Bethesda, MD 20892 USA. RP Huang, LE (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37,Room 3044B,37 Convent Dr,MSC4255, Bethesda, MD 20892 USA. EM huange@mail.nih.gov NR 54 TC 344 Z9 361 U1 7 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD MAY 5 PY 2004 VL 23 IS 9 BP 1949 EP 1956 DI 10.1038/sj.emboj.7600196 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 821YP UT WOS:000221499600005 PM 15071503 ER PT J AU Kruit, MC Ferrari, MD Laurier, LJ AF Kruit, MC Ferrari, MD Laurier, LJ TI Migraine as a risk factor for subclinical brain lesions - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Kruit, MC (reprint author), Leiden Univ, Med Ctr, Dept Radiol, Leiden, Netherlands. EM m.c.kruit@lumc.nl RI Kruit, Mark/K-2431-2012 OI Kruit, Mark/0000-0002-4319-834X NR 4 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 5 PY 2004 VL 291 IS 17 BP 2072 EP 2073 DI 10.1001/jama.291.17.2072-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 817JR UT WOS:000221174300009 ER PT J AU Weed, DL Dores, GM AF Weed, DL Dores, GM TI Physicians as citizens SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NCI, Rockville, MD USA. RP Weed, DL (reprint author), NCI, Rockville, MD USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 5 PY 2004 VL 291 IS 17 BP 2076 EP 2076 DI 10.1001/jama.291.17.2076-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 817JR UT WOS:000221174300017 PM 15126431 ER PT J AU Muntner, P He, J Cutler, JA Wildman, RP Whelton, PK AF Muntner, P He, J Cutler, JA Wildman, RP Whelton, PK TI Trends in blood pressure among children and adolescents SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID NUTRITION EXAMINATION SURVEY; CORONARY RISK-FACTORS; NATIONAL-HEALTH; SECULAR TRENDS; UNITED-STATES; US CHILDREN; BODY-SIZE; HYPERTENSION; PREVALENCE; POPULATION AB Context The prevalence of overweight among children and adolescents increased between 1988 and 2000. The change in blood pressure among children and adolescents over that time and the role of overweight is unknown. Objective To examine trends in systolic and diastolic blood pressure among children and adolescents between 1988 and 2000. Design, Setting, and Population Two serially conducted cross-sectional studies using nationally representative samples of children and adolescents, aged 8 to 17 years, from the third National Health and Nutrition Examination Survey (NHANES 111) conducted in 1988-1994 (n=3496) and NHANES 1999-2000 (n=2086). Main Outcome Measures Systolic and diastolic blood pressure levels. Results In 1999-2000, the mean (SE) systolic blood pressure was 106.0 (0.3) mm Hg and diastolic blood pressure was 61.7 (0.5) mm Hg. After adjustment for age, mean systolic blood pressure was 1.6 mm Hg higher among non-Hispanic black girls (P=.11) and 2.9 mm Hg higher among non-Hispanic black boys (P<.001) compared with non-Hispanic whites. Among Mexican Americans, girls' systolic blood pressure was 1.0 mm Hg higher (P=.21) and boys' was 2.7 mm Hg higher (P<.001) compared with non-Hispanic whites (P<.001). With further adjustment for body mass index, these differences were attenuated. After age, race/ethnicity, and sex standardization, systolic blood pressure was 1.4 (95% confidence interval [CI], 0.6-2.2) mm Hg higher (P<.001) and diastolic blood pressure was 3.3 (95% Cl, 2.1-4.5) mm Hg higher in 1999-2000 (P<.001) compared with 1988-1994. With further adjustment for differences in the body mass index distribution in 1988-1994 and 1999-2000, the increase in systolic blood pressure was reduced by 29% and diastolic blood pressure was reduced by 12%. Conclusions Blood pressure has increased over the past decade among children and adolescents. This increase is partially attributable to an increased prevalence of overweight. C1 Tulane Univ, Sch Med, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. Tulane Univ, Sch Med, Sch Publ Hlth & Trop Med, Dept Med, New Orleans, LA 70112 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Muntner, P (reprint author), Tulane Univ, Sch Med, Sch Publ Hlth & Trop Med, Dept Epidemiol, 1430 Tulane Ave,SL-18, New Orleans, LA 70112 USA. EM pmuntner@tulane.edu FU NCRR NIH HHS [P2 0 RR017659]; NHLBI NIH HHS [R01 HL68057] NR 24 TC 396 Z9 413 U1 3 U2 16 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 5 PY 2004 VL 291 IS 17 BP 2107 EP 2113 DI 10.1001/jama.291.17.2107 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 817JR UT WOS:000221174300028 PM 15126439 ER PT J AU Compton, WM Grant, BF Colliver, JD Glantz, MD Stinson, FS AF Compton, WM Grant, BF Colliver, JD Glantz, MD Stinson, FS TI Prevalence of marijuana use disorders in the United States - 1991-1992 and 2001-2002 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ALCOHOL-USE DISORDER; INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; DSM-IV ALCOHOL; DRUG-USE; SUBSTANCE USE; PSYCHIATRIC-DISORDERS; EPIDEMIOLOGIC SURVEY; ICD-10 ALCOHOL; III-R AB Context Among illicit substance use disorders, marijuana use disorders are the most prevalent in the population. Yet, information about the prevalence of current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) marijuana use disorders and how prevalence has changed is lacking. Objective To examine changes in the prevalence of marijuana use, abuse, and dependence in the United States between 1991-1992 and 2001-2002. Design, Setting, and Participants Face-to-face interviews were conducted in 2 large national surveys conducted 10 years apart: the 1991-1992 National Longitudinal Alcohol Epidemiologic Survey ([NLAES] n=42862) and the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions ([NESARC] n =43 093). Main Outcome Measures Rates of past year marijuana use, abuse, and dependence. Results Among the adult US population, the prevalence of marijuana use remained stable at about 4.0% over the past decade. In contrast, the prevalence of DSM-IV marijuana abuse or dependence significantly (P=.01) increased between 1991-1992 (1.2%) and 2001-2002 (1.5%), with the greatest increases observed among young black men and women (P<.001) and young Hispanic men (P=.006). Further, marijuana use disorders among marijuana users significantly increased (P=.002) in the absence of increased frequency and quantity of marijuana use, suggesting that the concomitant increase in potency of delta-9-tetrahydrocannabinol (&UDelta;(9)-THC) may have contributed to the rising rates. Conclusions Despite the stability in the overall prevalence of marijuana use, more adults in the United States had a marijuana use disorder in 2001-2002 than in 1991-1992. Increases in the prevalence of marijuana use disorders were most notable among young black men and women and young Hispanic men. Although rates of marijuana abuse and dependence did not increase among young white men and women, their rates have remained high. The results of this study underscore the need to develop and implement new prevention and intervention programs targeted at youth, particularly minority youth. C1 NIDA, Div Epidemiol Serv & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. RP Compton, WM (reprint author), NIDA, Div Epidemiol Serv & Prevent Res, NIH, Dept Hlth & Human Serv, 6001 Execut Blvd,MSC 9589, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov NR 45 TC 364 Z9 368 U1 5 U2 27 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAY 5 PY 2004 VL 291 IS 17 BP 2114 EP 2121 DI 10.1001/jama.291.17.2114 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 817JR UT WOS:000221174300029 PM 15126440 ER PT J AU Kesavapany, S Amin, N Zheng, YL Nijhara, R Jaffe, H Sihag, R Gutkind, JS Takahashi, S Kulkarni, A Grant, P Pant, HC AF Kesavapany, S Amin, N Zheng, YL Nijhara, R Jaffe, H Sihag, R Gutkind, JS Takahashi, S Kulkarni, A Grant, P Pant, HC TI p35/Cyclin-dependent kinase 5 phosphorylation of ras guanine nucleotide releasing factor 2 (RasGRF2) mediates rac-dependent extracellular signal-regulated kinase 1/2 activity, altering RasGRF2 and microtubule-associated protein 1b distribution in neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE p35/Cdk5; RasGRF2; phosphorylation; rac; ERK1/2; MAP1b ID SITE-SPECIFIC PHOSPHORYLATION; EXCHANGE FACTOR RAS-GRF2; TAU-PHOSPHORYLATION; CDC2-LIKE KINASE; CEREBRAL-CORTEX; P35/CDK5 KINASE; CDK5 ACTIVATOR; P35; CALCIUM; EXPRESSION AB Cyclin-dependent kinase 5 (Cdk5) is a proline-directed kinase the activity of which is dependent on association with its neuron-specific activators, p35 and p39. Cdk5 activity is critical for the proper formation of cortical structures and lamination during development. In the adult nervous system, Cdk5 function is implicated in cellular adhesion, dopamine signaling, neurotransmitter release, and synaptic activity. In addition, Cdk5 is also involved in "cross-talk" with other signal transduction pathways. To further examine its involvement in cross-talk with other pathways, we identified proteins that interacted with p35 using the yeast two-hybrid system. We report here that p35 associates with Ras guanine nucleotide releasing factor 2 (RasGRF2) in coimmunoprecipitation and colocalization studies using transfected cell lines as well as primary cortical neurons. Additionally, Cdk5 phosphorylates RasGRF2 both in vitro and in vivo, leading to a decrease in Rac-guanidine exchange factor activity and a subsequent reduction in extracellular signal-regulated kinase 1/2 activity. We show that p35/Cdk5 phosphorylates RasGRF2 on serine(737), which leads to an accumulation of RasGRF2 in the neuronal cell bodies coinciding with an accumulation of microtubule-associated protein 1b. The membrane association of p35 and subsequent localization of Cdk5 activity toward RasGRF2 and Rac provide insights into important cellular signaling processes that occur at the membrane, resulting in downstream effects on signal transduction cascades. C1 Natl Inst Neurol Disorders & Stroke, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Prot & Peptide Facil, NIH, Bethesda, MD 20892 USA. NCI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Cranofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Cranofacial Res, Funct Genom Unit, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), Natl Inst Neurol Disorders & Stroke, Neurochem Lab, NIH, Bldg 36,Room 4D-28, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov RI Gutkind, J. Silvio/A-1053-2009 NR 56 TC 37 Z9 48 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 5 PY 2004 VL 24 IS 18 BP 4421 EP 4431 DI 10.1523/JNEUROSCI.0690-04.2004 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 819NS UT WOS:000221322400015 PM 15128856 ER PT J AU Greenspon, AJ Hart, RG Dawson, D Hellkamp, AS Silver, M Flaker, GC Schron, E Goldman, L Lee, KL Lamas, GA AF Greenspon, AJ Hart, RG Dawson, D Hellkamp, AS Silver, M Flaker, GC Schron, E Goldman, L Lee, KL Lamas, GA CA MOST Study Investigators TI Predictors of stroke in patients paced for sick sinus syndrome SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID ATRIAL-FIBRILLATION; ISCHEMIC STROKE; PERMANENT PACEMAKER; NODE DYSFUNCTION; SELECTION; DISEASE; PREVENTION; EMBOLISM; TRIAL; RISK AB OBJECTIVES This study was an analysis of factors associated with stroke in a population of patients paced for sinus node dysfunction in a large prospective clinical trial (Mode Selection Trial [MOST]). BACKGROUND The effects of dual-chamber versus single-chamber ventricular pacing on subsequent stroke in patients with sinus node dysfunction are not known. METHODS A total of 2,010 patients with sinus node dysfunction were randomized to ventricular or dual-chamber pacing and followed for a median of 33.1 months. RESULTS The median participant age was 74 years. During 5,664 patient-years of follow-up, 90 strokes (11 hemorrhagic) occurred. By life-table analysis, the rate of stroke was 2.2% (95% confidence interval [CI] 1.6 to 2.9) at one year and 5.8% (95% CI 4.5 to 7.1) at four years. The incidence of stroke was not significantly different in dual-chamber (4%) as compared with ventricular-paced patients (4.9%) (hazard ratio [HR] 0.82, 95% CI 0.54 to 1.25, p = 0.36). Multivariable analysis demonstrated that significant predictors of stroke included prior stroke or transient ischemic attack, Caucasian race, hypertension, prior systemic embolism, and New York Heart Association functional class III or IV (p < 0.05); pacing mode remained non-significant after adjustment for these factors (p = 0.37). Clinically reported atrial fibrillation after implantation was a risk factor for stroke in this cohort after adjustment for other predictors of stroke (p = 0.042, HR 1.68 [95% CI 1.02 to 2.76]). CONCLUSIONS Clinical characteristics, but not mode of pacing, were associated with subsequent stroke in patients paced for sinus node dysfunction. (J Am Coll Cardiol 2004;43:1617-22) (C) 2004 by the American College of Cardiology Foundation C1 Jefferson Med Coll, Jefferson Heart Inst, Div Cardiol, Philadelphia, PA 19107 USA. Thomas Jefferson Univ Hosp, Philadelphia, PA 19107 USA. Univ Texas San Antonio, San Antonio, TX 78285 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Duke Clin Res Inst, Durham, NC USA. Duke Univ, Durham, NC USA. Gastonia Mem Hosp, Gastonia, NC USA. Univ Missouri, Columbia, MO USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Mt Sinai Med Ctr, Miami Beach, FL 33140 USA. Univ Miami, Sch Med, Miami Beach, FL 33140 USA. RP Greenspon, AJ (reprint author), Jefferson Med Coll, Jefferson Heart Inst, Div Cardiol, 925 Chestnut St, Philadelphia, PA 19107 USA. EM arnold.greenspon@jefferson.edu FU NHLBI NIH HHS [U01 HL 55981, HL 53973, U01 HL 49804] NR 24 TC 25 Z9 25 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 5 PY 2004 VL 43 IS 9 BP 1617 EP 1622 DI 10.1016/j.jacc.2003.09.067 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 817CI UT WOS:000221155200020 PM 15120821 ER PT J AU Domanski, MJ AF Domanski, MJ TI Diuretic use, progressive heart failure, and death in patients in SOLVD - Reply SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter C1 NHLBI, Clin Trials Grp, Bethesda, MD 20892 USA. RP Domanski, MJ (reprint author), NHLBI, Clin Trials Grp, 6701 Rockledge Dr,Room 8146, Bethesda, MD 20892 USA. EM domanskm@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 5 PY 2004 VL 43 IS 9 BP 1723 EP 1723 DI 10.1016/j.jacc.2004.02.015 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 817CI UT WOS:000221155200037 ER PT J AU Taylor, PR Parnes, HL Lippman, SM AF Taylor, PR Parnes, HL Lippman, SM TI Science peels the onion of selenium effects on prostate carcinogenesis SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID CANCER PREVENTION TRIAL; VITAMIN-E; 3'-UNTRANSLATED REGION; INDUCED APOPTOSIS; SELENOPROTEIN-P; SUBSEQUENT RISK; LUNG-CANCER; CELL-CYCLE; GENE; SUPPLEMENTATION C1 Univ Texas, MD Anderson Canc Ctr, Dept Clin Canc Prevent, Div Canc Prevent, Houston, TX 77030 USA. NCI, Canc Prevent Studies Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Lippman, SM (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Clin Canc Prevent, Div Canc Prevent, 1515 Holcombe Blvd,Unit 236, Houston, TX 77030 USA. EM slippman@mdanderson.org FU NCI NIH HHS [CA16672] NR 51 TC 19 Z9 21 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 5 PY 2004 VL 96 IS 9 BP 645 EP 647 DI 10.1093/jnci/djh147 PG 3 WC Oncology SC Oncology GA 816ZQ UT WOS:000221148200003 PM 15126594 ER PT J AU Kobayashi, H Kawamoto, S Sakai, Y Choyke, PL Star, RA Brechbiel, MW Sato, N Tagaya, Y Morris, JC Waldmann, TA AF Kobayashi, H Kawamoto, S Sakai, Y Choyke, PL Star, RA Brechbiel, MW Sato, N Tagaya, Y Morris, JC Waldmann, TA TI Lymphatic drainage imaging of breast cancer in mice by micro-magnetic resonance lymphangiography using a nano-size paramagnetic contrast agent SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NODE BIOPSY; SENTINEL LYMPHADENECTOMY; POLYAMIDOAMINE DENDRIMER; MR LYMPHANGIOGRAPHY; TRANSGENIC MICE; LYMPHOSCINTIGRAPHY; LOCALIZATION; DISSECTION; CARCINOMA; CORE AB Background: The presence of lymph node metastases is an important factor in breast cancer patient prognosis. Therefore, the precise identification of sentinel lymph nodes in these patients is critical. Improving current magnetic resonance (MR) imaging methods using a newly synthesized nano-size paramagnetic molecule, G6, as a contrast agent, provides an attractive means toward attaining this goal. Methods: A four-dimensional method of micro-MR lymphangiography using G6 (9 nm/240 kd) was developed to visualize the lymphatic ducts and lymph nodes draining mouse mammary tumors over time. The ability of micro-MR lymphangiography with the G6 contrast agent to visualize lymphatic drainage of normal mouse mammary tissue was compared with that of the conventional MR contrast agent, Gd-[DTPA]-dimeglumine (<1 kd). Lymphatic drainage in spontaneous and xenografted breast tumor models was visualized using the G6 contrast agent. Results: Draining lymphatic ducts and lymph nodes were clearly visualized in the mammary tissue of normal mice and in spontaneous and xenografted breast tumor models after a direct mammary gland or peritumoral injection of G6. Gd-[DTPA]-dimeglumine, by contrast, failed to depict lymphatic flow from the mammary tissue in normal mice using the same method. Micro-MR lymphangiography using the G6 contrast agent revealed the absence of filling in the metastatic foci of affected lymph nodes. Conclusions: The superior temporal and spatial resolution of micro-MR lymphangiography using the contrast agent G6 may facilitate the study of tumor lymphatic drainage and lymphatic metastasis in both experimental animals and clinical medicine. In addition, this may be a powerful new method for sentinel lymph node localization in human breast cancer. C1 NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. NIDDKD, Dept Diagnost Radiol, Warren G Magnuson Clin Ctr, Renal Diagnost & Therapeut Unit,NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. RP Kobayashi, H (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10,Rm 4N109,10 Ctr Dr, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov NR 27 TC 108 Z9 115 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 5 PY 2004 VL 96 IS 9 BP 703 EP 708 DI 10.1093/jnci/djh124 PG 6 WC Oncology SC Oncology GA 816ZQ UT WOS:000221148200013 PM 15126607 ER PT J AU Krauss, J Arndt, MAE Zhu, Z Newton, DL Vu, BK Choudhry, V Darbha, R Ji, X Courtenay-Luck, NS Deonarain, MP Richards, J Rybak, SM AF Krauss, J Arndt, MAE Zhu, Z Newton, DL Vu, BK Choudhry, V Darbha, R Ji, X Courtenay-Luck, NS Deonarain, MP Richards, J Rybak, SM TI Impact of antibody framework residue V-H-71 on the stability of a humanised anti-MUC1 scFv and derived immunoenzyme SO BRITISH JOURNAL OF CANCER LA English DT Article DE scFv; stability; ribonuclease; MUC1; HMFG1; fusion protein ID SINGLE-CHAIN FV; POLYMORPHIC EPITHELIAL MUCIN; FAT GLOBULE-MEMBRANE; MONOCLONAL-ANTIBODY; HYPERVARIABLE LOOPS; CANCER; CONFORMATION; FRAGMENTS; AFFINITY; DOMAINS AB Anti-MUC1 single-chain Fv ( scFv) fragments generated from the humanised antibody huHMFG1 had adequate antigen-binding properties but very poor stability irrespective of the applied linker or domain orientation. Mutagenesis of heavy-chain framework residue V-H-71, previously described as a key residue for maintaining the CDR-H2 main-chain conformation and thus important for antigen binding, markedly stabilised the scFv while having only a minor effect on the binding affinity of the molecule. Because of its improved stability, the engineered fragment exhibited immunoreactivity with tumour cells even after 7 days of incubation in human serum at 37degreesC. It also showed, in contrast to the wild-type scFv, a concentration-dependent binding to the target antigen when displayed on phage. When fusing the scFv to the recombinant ribonuclease rapLRI, only the fusion protein generated with the stable mutant scFv was able to kill MUC1(+) tumour cells with an IC50 of 80 nM. We expect this novel immunoenzyme to become a promising tool for the treatment of MUC1(+) malignancies. C1 NCI, Dev Therapeut Program, Frederick, MD 21702 USA. NCI, SAIC, Frederick, MD 21702 USA. NCI, Lab Expt & Computat Biol, Frederick, MD 21702 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. Antisoma Res Ltd, Ealing W5 3QR, England. Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. NCI, Dev Therapeut Program, Frederick, MD 21702 USA. RP Rybak, SM (reprint author), NCI, Dev Therapeut Program, Frederick, MD 21702 USA. EM rybak@ncifcrf.gov RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU NCI NIH HHS [N01 CO 12400, N01CO12400] NR 49 TC 9 Z9 10 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 4 PY 2004 VL 90 IS 9 BP 1863 EP 1870 DI 10.1038/sj.bjc.6601759 PG 8 WC Oncology SC Oncology GA 816SJ UT WOS:000221129300032 PM 15150594 ER PT J AU Marenstein, DR Wilson, DM Teebor, GW AF Marenstein, DR Wilson, DM Teebor, GW TI Human AP endonuclease (APEI) demonstrates endonucleolytic activity against AP sites in single-stranded DNA SO DNA REPAIR LA English DT Article DE base excision repair; AP endonuclease; single-stranded; AP sites; oxidative damage ID BASE EXCISION-REPAIR; HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; HUMAN APURINIC ENDONUCLEASE; HUMAN ABASIC ENDONUCLEASE; PURIFIED HUMAN PROTEINS; ESCHERICHIA-COLI; GRANZYME-A; POLYMERASE-BETA; MAJOR HUMAN; LIGASE-III AB Human apurinic/apyrimidinic endonuclease (APE1) is an enzyme of DNA base excision repair (BER) which catalyzes endonucleolytic cleavage immediately 5' to abasic (AP) sites. APE I has long been thought to act on AP sites only in double stranded (ds) DNA, in order to generate the appropriate site for insertion of the correct nucleotide of DNA repair synthesis effected by DNA polymerase beta. We now present evidence that APE1 also acts on AP sites in single-stranded (ss) DNA. The catalytic efficiency of this activity (defined within as k(cat)/Km) is similar to20-fold less than the activity against AP sites in ds DNA, with the disparity stemming largely from a difference in Km. Similar to its action on AP sites in ds DNA, catalysis of endonucleolytic cleavage of ss DNA by APE] is Mg2+ dependent, DNA N-glycosylase independent, and requires an active site aspartate. In contrast to its activity against AP sites in ds DNA, APE1 does not display product inhibition when acting on an AP site in ss DNA. We suggest that this novel activity is related to the processing of DNA N-glycosylase initiated BER in ss DNA perhaps during replication and/or transcription. (C) 2004 Elsevier B.V. All rights reserved. C1 NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. NYU, Sch Med, Kaplan Comprehens Canc Ctr, New York, NY 10016 USA. NIA, Gerontol Res Ctr, Lab Mol Gerontol, IRP,NIH, Baltimore, MD 21224 USA. RP Teebor, GW (reprint author), NYU, Sch Med, Dept Pathol, 550 1st Ave, New York, NY 10016 USA. EM george.teebor@med.nyu.edu FU NCI NIH HHS [CA 16087, 5T32 CA-09161] NR 57 TC 35 Z9 39 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAY 4 PY 2004 VL 3 IS 5 BP 527 EP 533 DI 10.1016/j.dnarep.2004.01.010 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 817CU UT WOS:000221156400009 PM 15084314 ER PT J AU Shkriabai, N Patil, SS Hess, S Budihas, SR Craigie, R Burke, TR Le Grice, SFJ Kvaratskhelia, M AF Shkriabai, N Patil, SS Hess, S Budihas, SR Craigie, R Burke, TR Le Grice, SFJ Kvaratskhelia, M TI Identification of an inhibitor-binding site to HIV-1 integrase with affinity acetylation and mass spectrometry SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; DNA-BINDING; IN-VITRO; CATALYTIC DOMAIN; CHICORIC ACID; NUCLEOCAPSID PROTEIN; PEPTIDE INHIBITORS; CRYSTAL-STRUCTURE; TERMINAL DOMAINS; STRAND TRANSFER AB We report a methodology that combines affinity acetylation with MS analysis for accurate mapping of an inhibitor-binding site to a target protein. For this purpose, we used a known HIV-1 integrase inhibitor containing aryl di-O-acetyl groups (Acetylated-inhibitor). In addition, we designed a control compound (Acetylated-Control) that also contained an aryl di-O-acetyl group but did not inhibit HIV-1 integrase. Examination of the reactivity of these compounds with a model peptide library, which collectively contained all 20 natural amino acids, revealed that aryl di-O-acetyl compounds effectively acetylate Cys, Lys, and Tyr residues. Acetylated-inhibitor and Acetylated-Control exhibited comparable chemical reactivity with respect to these small peptides. However, these two compounds differed markedly in their interactions with HIV-1 integrase. In particular, Acetylated-Inhibitor specifically acetylated K173 at its inhibitory concentration (3 muM) whereas this site remained unrecognized by Acetylated-Control. Our data enabled creation of a detailed model for the integrase:Acetylated-inhibitor complex, which indicated that the inhibitor selectively binds at an architecturally critical region of the protein. The methodology reported herein has a generic application for systems involving a variety of ligand-protein interactions. C1 Ohio State Univ, Hlth Sci Ctr, Coll Pharm, Ctr Retrovirus Res, Columbus, OH 43210 USA. Ohio State Univ, Hlth Sci Ctr, Coll Pharm, Ctr Comprehens Canc, Columbus, OH 43210 USA. NCI, Med Chem Lab, Frederick, MD 21702 USA. NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Kvaratskhelia, M (reprint author), Ohio State Univ, Hlth Sci Ctr, Coll Pharm, Ctr Retrovirus Res, 500 W 12th Ave,238 LM Pk Hall, Columbus, OH 43210 USA. EM kvaratskhelia.1@osu.edu RI Hess, Sonja/K-4842-2013; Burke, Terrence/N-2601-2014 OI Hess, Sonja/0000-0002-5904-9816; NR 40 TC 35 Z9 35 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 4 PY 2004 VL 101 IS 18 BP 6894 EP 6899 DI 10.1073/pnas.0400873101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 818SO UT WOS:000221265000013 PM 15118107 ER PT J AU Liu, MF Tolstorukov, M Zhurkin, V Garges, S Adhya, S AF Liu, MF Tolstorukov, M Zhurkin, V Garges, S Adhya, S TI A mutant spacer sequence between-35 and-10 elements makes the P-lac promoter hyperactive and cAMP receptor protein-independent SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID COLI RNA-POLYMERASE; OPEN COMPLEX-FORMATION; AROMATIC-AMINO-ACIDS; ESCHERICHIA-COLI; TRANSCRIPTION INITIATION; BACTERIAL PROMOTERS; BACILLUS-SUBTILIS; DNA-SEQUENCE; SIGMA-70 SUBUNIT; BINDING-SITE AB To determine whether the spacer region between the -35 and -10 elements plays any sequence-specific role, we randomized the GC-rich sequence ((-20)CCGGCTCG(-13)) within the spacer region of the cAMP-dependent lac promoter and selected an activator-independent mutant, which showed extraordinarily high intrinsic activity. The hyperactive promoter is obtained by incorporation of a specific 10-bp-long AT-rich DNA sequence within the spacer, referred to as the -15 sequence, which must be juxtaposed to the upstream end of the -10 sequence for the hyperactivity. The transcription enhancement functions only in the presence of a -35 element. The spacer sequence enhanced both RNA polymerase binding and open complex formation. Isolated in the lac promoter, it also enhanced transcription when placed at two other unrelated promoters. Sequence analysis shows a low GC content and an abundance of stereochemically flexible TG:CA and TA:TA dimeric steps in the -18/-9 region and a strong correlation between the presence of flexible dimeric steps in this region and the intrinsic strength of the promoter. C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Adhya, S (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM sadhya@helix.nih.gov NR 49 TC 41 Z9 43 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 MAY 4 PY 2004 VL 101 IS 18 BP 6911 EP 6916 DI 10.1073/pnas.0401929101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 818SO UT WOS:000221265000016 PM 15118087 ER PT J AU Kim, A Dean, A AF Kim, A Dean, A TI Developmental stage differences in chromatin subdomains of the beta-globin locus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RNA-POLYMERASE-II; HISTONE ACETYLATION PATTERN; CONTROL REGION; TRANSCRIPTIONAL ACTIVATION; INTERGENIC TRANSCRIPTION; HYPERSENSITIVE SITES; GENE ACTIVATION; ACTIVE GENES; IN-VIVO; METHYLATION AB The mammalian beta-globin loci each contain a family of developmentally expressed genes, and a far upstream regulatory element, the locus control region (LCR). In adult murine erythroid cells, the LCR and the transcribed beta-globin genes exist within domains of histone acetylation and RNA polymerase II (pol II) is associated with them. In contrast, the silent embryonic genes lie between these domains within hypoacetylated chromatin, and pol 11 is not found there. We used chromatin immunoprecipitation and real-time PCR to analyze histone modification and pol 11 recruitment to the globin locus in human erythroid K562 cells that express the embryonic E-globin gene but not the adult beta-globin gene. H3 and H4 acetylation and H3 K4 methylation were continuous over a 17-kb region including the LCR and the active E-globin gene. The level of modification varied directly with the transcription of the E-globin gene. In contrast, this region in nonerythroid HeLa cells lacked these modifications and displayed instead widespread H3 K9 methylation. pol 11 was also detected continuously from the LCR to the e-globin gene. These studies reveal several aspects of chromatin structure and pol 11 distribution that distinguish the globin locus at embryonic and adult stages and suggest that both enhancer looping and tracking mechanisms may contribute to LCR-promoter communication at different developmental stages. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dean, A (reprint author), Bldg 50,Room 3154,50 S Dr,MSC 8028, Bethesda, MD 20892 USA. EM anndean@helix.nih.gov NR 56 TC 52 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 MAY 4 PY 2004 VL 101 IS 18 BP 7028 EP 7033 DI 10.1073/pnas.0307985101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 818SO UT WOS:000221265000036 PM 15105444 ER PT J AU Jansen, MS Nagel, SC Miranda, PJ Lobenhofer, EK Afshari, CA McDonnell, DP AF Jansen, MS Nagel, SC Miranda, PJ Lobenhofer, EK Afshari, CA McDonnell, DP TI Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ESTROGEN PLUS PROGESTIN; POSTMENOPAUSAL WOMEN; VALPROIC ACID; GROWTH-FACTOR; CANCER CELLS; PHOSPHORYLATION; IDENTIFICATION; EXPOSURE; DISEASE; RISKS AB In this study, we demonstrate that the pervasive xenobiotic methoxyacetic acid and the commonly prescribed anticonvulsant valproic acid, both short-chain fatty acids (SCFAs), dramatically increase cellular sensitivity to estrogens, progestins, and other nuclear hormone receptor ligands. These compounds do not mimic endogenous hormones but rather act to enhance the transcriptional efficacy of ligand activated nuclear hormone receptors by up to 8-fold in vitro and in vivo. Detailed characterization of their mode of action revealed that these SCFAs function as both activators of p42/p44 mitogen-activated protein kinase and as inhibitors of histone deacetylases at doses that parallel known exposure levels. Our results define a class of compounds that possess a dual mechanism of action and function as hormone sensitizers. These findings prompt an evaluation of previously unrecognized drug-drug interactions in women who are administered exogenous hormones while exposed to certain xenobiotic SCFAs. Furthermore, our study highlights the need to structure future screening programs to identify additional hormone sensitizers. C1 Duke Univ, Ctr Med, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. NIEHS, Natl Ctr Toxicogenom, Res Triangle Pk, NC 27709 USA. RP McDonnell, DP (reprint author), Duke Univ, Ctr Med, Dept Pharmacol & Canc Biol, Box 3813, Durham, NC 27710 USA. EM donald.mcdonnell@duke.edu OI Nagel, Susan C./0000-0003-4703-7604 FU NCI NIH HHS [F32 CA092984, R01 CA090645, CA90645, CA92984]; NIDDK NIH HHS [R01 DK048807, DK48807, R37 DK048807] NR 35 TC 60 Z9 64 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 MAY 4 PY 2004 VL 101 IS 18 BP 7199 EP 7204 DI 10.1073/pnas.0402014101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 818SO UT WOS:000221265000065 PM 15103026 ER PT J AU Peddi, S Roth, BL Glennon, RA Westkaemper, RB AF Peddi, S Roth, BL Glennon, RA Westkaemper, RB TI Structural determinants for high 5-HT2A receptor affinity of spiro[9,10-dihydroanthracenel-9,3'-pyrrolidine (SpAMDA) SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID SEROTONIN RECEPTOR; 9-(AMINOMETHYL)-9,10-DIHYDROANTHRACENE; SPIRO; ANTAGONIST; ALKYLATION; UNIQUE AB The synthesis and 5-HT2A receptor affinities of ring altered derivatives of spiro[9,10-dihydroanthracene]-9,3'-pyrrolidine (4), a structurally unique tetracyclic 5-HT2A receptor antagonist, are described. The characteristics of the parent compound prove to be necessary for optimal 5-HT2A receptor affinity. However, expansion of the size of the pyrrolidine and central rings produce compounds with reasonably high 5-HT2A receptor affinities. In addition, the parent compound is shown to have high 5-HT2 receptor selectivity. (C) 2004 Elsevier Ltd. All rights reserved. C1 Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, Richmond, VA 23298 USA. Case Western Reserve Univ, NIMH Psychoact Drug Screening Program, Sch Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Biochem, Sch Med, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Psychiat, Sch Med, Cleveland, OH 44106 USA. RP Westkaemper, RB (reprint author), Virginia Commonwealth Univ, Sch Pharm, Dept Med Chem, POB 980540, Richmond, VA 23298 USA. EM richard.westkaemper@vcu.edu RI Roth, Bryan/F-3928-2010 FU NIMH NIH HHS [MH57969]; PHS HHS [N0280005] NR 14 TC 8 Z9 8 U1 0 U2 0 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 MAY 3 PY 2004 VL 14 IS 9 BP 2279 EP 2283 DI 10.1016/j.bmcl.2004.02.014 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 817EG UT WOS:000221160200054 PM 15081025 ER PT J AU Lee, J Kang, SU Choi, HK Lee, J Lim, JO Kil, MJ Jin, MK Kim, KP Sung, JH Chung, SJ Ha, HJ Kim, YH Pearce, LV Tran, R Lundberg, DJ Wang, Y Toth, A Blumberg, PM AF Lee, J Kang, SU Choi, HK Lee, J Lim, JO Kil, MJ Jin, MK Kim, KP Sung, JH Chung, SJ Ha, HJ Kim, YH Pearce, LV Tran, R Lundberg, DJ Wang, Y Toth, A Blumberg, PM TI Analysis of structure-activity relationships for the 'B-region' of N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea analogues as vanilloid receptor antagonists: discovery of an N-hydroxythiourea analogue with potent analgesic activity SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE vanilloid receptor 1; TRPV1; antagonist; analgesic ID HIGH-AFFINITY ANTAGONISTS; CAPSAICIN RECEPTOR; IODO-RESINIFERATOXIN; THIOUREA DERIVATIVES; PAIN; TETRAHYDROPYRAZINE-1(2H)-CARBOX-AMIDE(BCTC); NOCICEPTION; ACTIVATION; AGONISTS; CHANNELS AB The structural modifications on the B-region of the potent and high affinity vanilloid receptor (VR1) lead ligand N-(3-acyloxy-2-benzylpropyl)-N'-[4-(methylsulfonylamino)benzyl]thiourea were investigated by the replacement of the thiourea with diverse isosteric functional groups. Structure-activity analysis indicated that the A-region in this series was the primary factor in determining the agonistic/antagonistic activities regardless of the B-region. The N-C-hydroxy thiourea analogues (12, 13) showed excellent analgesic activities in the acetic acid writhing assay compared to the parent thiourea analogues. (C) 2004 Elsevier Ltd. All rights reserved. C1 Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Seoul 151742, South Korea. Digital Biotech, Ansan 425839, Kyounggi Do, South Korea. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), Seoul Natl Univ, Coll Pharm, Pharmaceut Sci Res Inst, Shinlim Dong, Seoul 151742, South Korea. EM jeewoo@snu.ac.kr RI Toth, Attila/F-4859-2010; OI Toth, Attila/0000-0001-6503-3653; Lee, Jiyoun/0000-0003-3819-5889 NR 38 TC 10 Z9 10 U1 1 U2 3 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 MAY 3 PY 2004 VL 14 IS 9 BP 2291 EP 2297 DI 10.1016/j.bmcl.2004.02.002 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 817EG UT WOS:000221160200056 PM 15081027 ER PT J AU Madhavarao, CN Moffett, JR Moore, RA Viola, RE Namboodiri, MAA Jacobowitz, DM AF Madhavarao, CN Moffett, JR Moore, RA Viola, RE Namboodiri, MAA Jacobowitz, DM TI Immunohistochemical localization of asparoacylase in the rat central nervous system SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE ASPA; deacetylase; N-acetylaspartate; oligodendrocytes; Canavan disease; myelin deficiency; microglia; acetate ID L-ASPARTIC ACID; N-ACETYLASPARTATE; CANAVAN-DISEASE; ASPARTOACYLASE ACTIVITY; LIPID-SYNTHESIS; ACETYL GROUPS; BRAIN; OLIGODENDROCYTES; CELLS; BIOSYNTHESIS AB Aspartoacylase (ASPA; EC 3.5.1.15) catalyzes deacetylation of N-acetylaspartate (NAA) to generate free acetate in the central nervous system (CNS). Mutations in the gene coding ASPA cause Canavan disease (CD), an autosomal recessive neurodegenerative disease that results in death before 10 years of age. The pathogenesis of CD remains unclear. Our working hypothesis is that deficiency in the supply of the NAA-derived acetate leads to inadequate lipid/myelin synthesis during development, resulting in CD. To explore the localization of ASPA in the CNS, we used double-label immunohistochemistry for ASPA and several cell-specific markers. A polyclonal antibody was generated in rabbit against mouse recombinant ASPA, which reacted with a single band (similar to37 kD) on Western blots of rat brain homogenate. ASPA colocalized throughout the brain with CC1 , a marker for oligodendrocytes, with 92-98% of CC1-positive cells also reactive with the ASPA antibody. Many cells were labeled with ASPA antibodies in white matter, including cells in the corpus callosum and cerebellar white matter. Relatively fewer cells were labeled in gray matter, including cerebral cortex. No astrocytes were labeled for ASPA. Neurons were unstained in the forebrain, although small numbers of large reticular and motor neurons were faintly to moderately stained in the brainstem and spinal cord. Many ascending and descending neuronal fibers were moderately stained for ASPA in the medulla and spinal cord. Microglial-like cells showed faint to moderate staining with the ASPA antibodies throughout the brain by the avidin/biotin-peroxidase detection method, and colocalization studies with labeled lectins confirmed their identity as microglia. The predominant immunoreactivity in oligodendrocytes is consistent with the proposed role of ASPA in myelination, supporting the case for acetate supplementation as an immediate and inexpensive therapy for infants diagnosed with CD. Published 2004 Wiley-Liss, Inc. C1 USUHS, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. Univ Toledo, Dept Chem, Toledo, OH 43606 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Namboodiri, MAA (reprint author), USUHS, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM anamboodiri@usuhs.mil RI Viola, Ronald/C-5904-2011 FU NINDS NIH HHS [R01 NS39387] NR 27 TC 80 Z9 81 U1 0 U2 2 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD MAY 3 PY 2004 VL 472 IS 3 BP 318 EP 329 DI 10.1002/cne.20080 PG 12 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 809HC UT WOS:000220626800005 PM 15065127 ER PT J AU Diallo, DA Doumbo, OK Dicko, A Guindo, A Coulibaly, D Kayentao, K Djimde, AA Thera, MA Fairhurst, RA Plowe, CV Wellems, TE AF Diallo, DA Doumbo, OK Dicko, A Guindo, A Coulibaly, D Kayentao, K Djimde, AA Thera, MA Fairhurst, RA Plowe, CV Wellems, TE TI A comparison of anemia in hemoglobin C and normal hemoglobin A children with Plasmodium falciparum malaria SO ACTA TROPICA LA English DT Article DE erythrocyte senescence; malaria-protective polymorphism; mean corpuscular hemoglobin concentration; hematocrit ID DOGON AB Plasmodium falciparum infection accelerates the senescence of erythrocytes. Senescence in hemoglobin C (HbC) erythrocytes relative to normal hemoglobin A (HbA) erythrocytes is also increased, presumably because of the sensitivity of HbC to oxidative damage and denaturation. To test for a possible increased rate of anemia in HbC individuals with malaria, we evaluated children with uncomplicated P.falciparum malaria in Bandiagara, Mali, a village with a high prevalence of HbC. The average hematocrit was significantly lower in AC children (heterozygous for HbC) than in AA children (homozygous for normal HbA). Calculated blood hemoglobin concentrations from these groups, however, showed no significant differences because of the increased mean corpuscular hemoglobin concentration (MCHC) and decreased mean corpuscular volume (MCV) of AC relative to AA erythrocytes. Average hemoglobin concentration is a better measure of oxygen delivery capacity and anemia than hematocrit value. By this measure, HbC, a malaria-protective polymorphism with few deleterious consequences, does not appear to be associated with more frequent anemia than normal HbA in episodes of uncomplicated P.falciparum malaria. (C) 2004 Elsevier B.V. All rights reserved. C1 NIAID, Bethesda, MD 20892 USA. Univ Bamako, Fac Med Pharm & Odontostomatol, Bamako, Mali. Univ Maryland, Ctr Vaccine Dev, Baltimore, MD 21201 USA. RP Wellems, TE (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twellems@niaid.nih.gov FU PHS HHS [N01-85346] NR 18 TC 7 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0001-706X J9 ACTA TROP JI Acta Trop. PD MAY PY 2004 VL 90 IS 3 BP 295 EP 299 DI 10.1016/j.actatropica.2004.02.005 PG 5 WC Parasitology; Tropical Medicine SC Parasitology; Tropical Medicine GA 818YT UT WOS:000221281100009 PM 15099817 ER PT J AU Kulkosky, J Sullivan, J Xu, Y Souder, E Hamer, DH Pomerantz, RJ AF Kulkosky, J Sullivan, J Xu, Y Souder, E Hamer, DH Pomerantz, RJ TI Expression of latent HAART-persistent HIV type 1 induced by novel cellular activating agents SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; REPLICATION-COMPETENT HIV-1; IN-VIVO; IMMUNE-ACTIVATION; VIRUS; RESERVOIR; INFECTION; COMBINATION; RECOVERY AB The novel antitumor-promoting phorbol ester, prostratin, was evaluated for its ability to induce the expression of latent, highly active antiretroviral therapy (HAART)-persistent human immunodeficiency virus type I (HIV-1) from specific subsets of patients' peripheral blood cells. This evaluation was performed relative to the use of other cellular activating agents, such as OKT3, a monoclonal antibody against the human T cell receptor, interleukin-2 (IL-2), phytohemagglutinin (PHA), p24 antigen (HIV-1-speciric capsid protein), and a molecular relative of prostratin, 12-deoxyphorbol 13-phenylacetate (DPP). Prostratin performed as efficiently as the other cellular activators at inducing the expression of latent HIV-1 from cells of patients on virally suppressive HAART. Of interest was the induction of a novel species of latent virus from the cells of an individual after exposure to the HIV-1-specific capsid protein, p24, relative to virus expression induced by several other cell activators. This suggests that a variety of agents may be available for animal model studies of lentiviral latency and clinical use to broadly induce the expression of latent, HAART-persistent HIV-1 in vivo with the goal of potential HIV-1 reservoir depletion or eradication. C1 Thomas Jefferson Univ, Jefferson Med Coll, Dorrance H Hamilton Labs,Dept Med, Ctr Human Virol & Biodefense,Div Infect Dis & Env, Philadelphia, PA 19107 USA. Chestnut Hill Coll, Dept Biol, Philadelphia, PA 19118 USA. NCI, Biochem Lab, Bethesda, MD 20892 USA. RP Pomerantz, RJ (reprint author), Thomas Jefferson Univ, Jefferson Med Coll, Dorrance H Hamilton Labs,Dept Med, Ctr Human Virol & Biodefense,Div Infect Dis & Env, 1020 Locust St,Suite 329, Philadelphia, PA 19107 USA. EM Joseph.Kulkosky@che.edu; Roger.J.Pomerantz@jefferson.edu FU NIAID NIH HHS [AI3289] NR 41 TC 35 Z9 37 U1 1 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAY PY 2004 VL 20 IS 5 BP 497 EP 505 DI 10.1089/088922204323087741 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 825MV UT WOS:000221763500006 PM 15186524 ER PT J AU Yu, XG Addo, MM Perkins, BA Wej, FL Rathod, A Geer, SC Parta, M Cohen, D Stone, DR Russell, CJ Tanzi, G Mei, S Wurcel, AG Frahm, N Lichterfeld, M Heath, L Mullins, JI Marincola, F Goulder, PJR Brander, C Allen, T Cao, YZ Walker, BD Altfeld, M AF Yu, XG Addo, MM Perkins, BA Wej, FL Rathod, A Geer, SC Parta, M Cohen, D Stone, DR Russell, CJ Tanzi, G Mei, S Wurcel, AG Frahm, N Lichterfeld, M Heath, L Mullins, JI Marincola, F Goulder, PJR Brander, C Allen, T Cao, YZ Walker, BD Altfeld, M TI Differences in the expressed HLA class I alleles effect the differential clustering of HIV type 1-specific T cell responses in infected Chinese and Caucasians SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID LYMPHOCYTE RESPONSES; VIRAL LOAD; SUBTYPE-C; IMMUNE-RESPONSES; VACCINE DESIGN; CTL RESPONSES; DRUG-USERS; VIREMIA; AIDS; IDENTIFICATION AB China is a region of the world with a rapidly spreading HIV-1 epidemic. Studies providing insights into HIV-1 pathogenesis in infected Chinese are urgently needed to support the design and testing of an effective HIV-1 vaccine for this population. HIV-1-specific T cell responses were characterized in 32 HIV-1-infected individuals of Chinese origin and compared to 34 infected caucasians using 410 overlapping peptides spanning the entire HIV-1 clade B consensus sequence in an IFN-gamma ELISpot assay. All HIV-1 proteins were targeted with similar frequency in both populations and all study subjects recognized at least one overlapping peptide. HIV-1-specific T cell responses clustered in seven different regions of the HIV-1 genome in the Chinese cohort and in nine different regions in the caucasian cohort. The dominant HLA class I alleles expressed in the two populations differed significantly, and differences in epitope clustering pattern were shown to be influenced by differences in class I alleles that restrict immunodominant epitopes. These studies demonstrate that the clustering of HIV-1-specific T cell responses is influenced by the genetic HLA class I background in the study populations. The design and testing of candidate vaccines to fight the rapidly growing HIV-1 epidemic must therefore take the HLA genetics of the population into account as specific regions of the virus can be expected to be differentially targeted in ethnically diverse populations. C1 Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Div Infect Dis, Charlestown, MA 02129 USA. Harvard Univ, Sch Med, Div Aids, Boston, MA 02129 USA. CAPM, Dept Clin Virol, Natl Ctr HIV AIDS Prevent & Control, Beijing, Peoples R China. Bellevue Hosp Ctr, AIDS Program, New York, NY 10016 USA. Fenway Community Hlth Ctr, Boston, MA 02115 USA. Lemuel Shattuck Hosp, Boston, MA 02108 USA. Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. John Radcliffe Hosp, Dept Med, Oxford OX3 9DU, England. RP Altfeld, M (reprint author), Massachusetts Gen Hosp, Partners AIDS Res Ctr, 149 13th St,Room 5212D, Charlestown, MA 02129 USA. EM maltfeld@partners.org RI Allen, Todd/F-5473-2011 FU NIAID NIH HHS [N01 AI-15442] NR 40 TC 13 Z9 14 U1 2 U2 3 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAY PY 2004 VL 20 IS 5 BP 557 EP 564 DI 10.1089/088922204323087813 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 825MV UT WOS:000221763500013 PM 15186531 ER PT J AU Conner, KR Chiapella, P AF Conner, KR Chiapella, P TI Alcohol and suicidal behavior: Overview of a research workshop SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article; Proceedings Paper CT Research Workshop on Alcohol and Suicidal Behavior CY MAR 21-22, 2002 CL Bethesda, MD SP NIAAA C1 Univ Rochester, Sch Med & Dent, Dept Psychiat, Ctr Study & Prevent Suicide, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, Dept Psychiat, Lab Personal & Dev, Rochester, NY 14642 USA. NIAAA, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. RP Conner, KR (reprint author), Univ Rochester, Sch Med & Dent, Dept Psychiat, Ctr Study & Prevent Suicide, 300 Crittenden Blvd, Rochester, NY 14642 USA. EM Kenneth_conner@urmc.rochester.edu NR 6 TC 5 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU 1 BP 2S EP 5S DI 10.1097/01.ALC.0000127409.84505.FC PG 4 WC Substance Abuse SC Substance Abuse GA 839YM UT WOS:000222820900002 PM 15166631 ER PT J AU Sun, H Moradel, EM Weight, FF Zhang, L AF Sun, H Moradel, EM Weight, FF Zhang, L TI Ethanol and phorbol esters potentiate 5-HT3A receptor function through independent mechanisms. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 12A EP 12A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300032 ER PT J AU Schwandt, ML Shannon, C Lindell, SG Becker, ML Suomi, SJ Higley, JD AF Schwandt, ML Shannon, C Lindell, SG Becker, ML Suomi, SJ Higley, JD TI Effects of age at first exposure to alcohol and rearing condition on alcohol consumption in rhesus macaques (Macaca mulatta) SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, NIH, Clin Studies Lab, Primate Unit,Anim Ctr, Poolesville, MD 20837 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 13A EP 13A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300042 ER PT J AU Enoch, MA White, KV Harris, CR Goldman, D AF Enoch, MA White, KV Harris, CR Goldman, D TI Independent and interactive effects of alcoholism and mood disorders on P300 ERP amplitude in women SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 21A EP 21A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300090 ER PT J AU Hommer, DW Bjork, JM Knutson, B Caggiano, D Fong, G Danube, C AF Hommer, DW Bjork, JM Knutson, B Caggiano, D Fong, G Danube, C TI Motivation in children of alcoholics: An fMRI study SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, NIH, Bethesda, MD USA. Stanford Univ, Stanford, CA 94305 USA. NR 0 TC 10 Z9 10 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 22A EP 22A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300096 ER PT J AU Salloum, JB Hommer, D Maldonado, L Momenan, R Bodurka, J George, DT AF Salloum, JB Hommer, D Maldonado, L Momenan, R Bodurka, J George, DT TI Differential neural responses during decoding of emotional facial expressions in alcoholics SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. NIMH, Tesla Funct Neuroimaging Facil, NIH, Bethesda, MD 20892 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 22A EP 22A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300094 ER PT J AU Yoon, YH Dufour, MC Yi, HY AF Yoon, YH Dufour, MC Yi, HY TI Drinking, other drug use, and hepatitis C infection in the United States: Findings from the NHANES III SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Alcohol Epidemiol Data Syst, NIH, CSR Inc, Arlington, VA 22201 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 34A EP 34A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300167 ER PT J AU Ramchandani, VA Li, TK Plawecki, M O'Connor, S AF Ramchandani, VA Li, TK Plawecki, M O'Connor, S TI Drinks can be standardized, drinkers can't: An examination of variability in breath alcohol concentrations (BrACs) following oral alcohol administration. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Bethesda, MD USA. Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. Richard L Roudebush Vet Affairs Med Ctr, Indianapolis, IN 46202 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 39A EP 39A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300199 ER PT J AU Herman, AI Danube, CL Philbeck, JW DePetrillo, PB AF Herman, AI Danube, CL Philbeck, JW DePetrillo, PB TI The serotonin transporter promoter polymorphism, neuroticism and tension-reduction drinking in college students. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Unit Clin & Biochem Pharmacol, Clin Studies Lab, Intramural Res Program,NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Psychol, Washington, DC 20052 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 48A EP 48A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300250 ER PT J AU Hu, X Zhu, G Akhtar, L Taubman, J Goldmam, D AF Hu, X Zhu, G Akhtar, L Taubman, J Goldmam, D TI Reanalysis of HTTLPR effects using a new functional allele and genotype expression SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 48A EP 48A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300251 ER PT J AU Xu, K Westly, E Taubman, J Astor, W Lipsky, RH Goldman, D AF Xu, K Westly, E Taubman, J Astor, W Lipsky, RH Goldman, D TI Linkage disequilibrium relationships among GABRA cluster genes located on chromosome 4 with alcohol dependence in two populations SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 0 TC 7 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 48A EP 48A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300252 ER PT J AU Zhou, Z Lipsky, R Kuchipudi, K Zhu, G Taubman, J Enoch, M Virkkunen, M Roy, A Goldman, D AF Zhou, Z Lipsky, R Kuchipudi, K Zhu, G Taubman, J Enoch, M Virkkunen, M Roy, A Goldman, D TI Haplotype based linkage of TPH2 with major depression and suicide in three case-control populations SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 50A EP 50A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300260 ER PT J AU Zhu, GS Zhou, ZF Hu, XZ Walker, AC Taubman, J Mash, DC Virkkunen, M Lipsky, RH Goldman, D AF Zhu, GS Zhou, ZF Hu, XZ Walker, AC Taubman, J Mash, DC Virkkunen, M Lipsky, RH Goldman, D TI Functionality of a polymorphism in the NPY 5' UTR and a linkage to anxiety and alcohol dependence to Finnish men SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Changhai Hosp, Shanghai 200433, Peoples R China. Univ Miami, Dept Neurol, Miami, FL 33136 USA. Univ Helsinki, Helsinki, Finland. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 50A EP 50A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300261 ER PT J AU Enoch, MA Waheed, J Harris, CR Goldman, D AF Enoch, MA Waheed, J Harris, CR Goldman, D TI Alcoholism, smoking and anxiety in an American Indian tribe is influenced by COMT VAL158MET genotype SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 51A EP 51A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300266 ER PT J AU Enoch, MA Xu, K Waheed, J Harris, CR Lipsky, RH AF Enoch, MA Xu, K Waheed, J Harris, CR Lipsky, RH TI A functional promoter polymorphism of the brain-derived neurotrophic factor gene is associated with lower harm avoidance in a predominantly US Caucasian population SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 51A EP 51A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300265 ER PT J AU Honse, Y Lovinger, DM AF Honse, Y Lovinger, DM TI Ethanol inhibition of synaptic and extrasynaptic NMDA receptors in autaptic hippocampal neurons. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, NIH, Bethesda, MD 20892 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 57A EP 57A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300306 ER PT J AU Zhu, PJ Lovinger, DM AF Zhu, PJ Lovinger, DM TI Ethanol increases GABA release onto basolateral amygdala neurons freshly isolated using an enzyme-free procedure. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 58A EP 58A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300312 ER PT J AU Hu, XQ Machu, T Lovinger, D AF Hu, XQ Machu, T Lovinger, D TI Role of leucine 293 in alcohol modulatory actions on 5-HT3A receptors. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, NIH, Bethesda, MD 20892 USA. Univ N Texas, Hlth Sci Ctr, Ft Worth, TX 76107 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 60A EP 60A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300320 ER PT J AU Xiong, KM Li, C Stewart, RR Weight, FF AF Xiong, KM Li, C Stewart, RR Weight, FF TI Mutation of cysteines in the rat P2X(4) receptor alters the mechanism by which ethanol inhibits receptor function. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 60A EP 60A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300322 ER PT J AU Harris, CR Goldman, D Enoch, MA AF Harris, CR Goldman, D Enoch, MA TI Severe consequences of childhood sexual abuse for plains American Indian women SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 66A EP 66A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300355 ER PT J AU Williams, MB Dufour, MC AF Williams, MB Dufour, MC TI Is the beneficial effect of alcohol consumption on glycemia in women moderated by estrogen? SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Alcohol Epidemiol Data Syst, NIH, CSR Inc, Arlington, VA 22201 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 73A EP 73A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300402 ER PT J AU Yi, H Chen, CM Faden, VB AF Yi, H Chen, CM Faden, VB TI Alcohol consumption among adolescents ages 12-17 in the United States SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, NIH, Bethesda, MD 20892 USA. CSR Inc, Alcohol Epidemiol Data Syst, Arlington, VA 22201 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 79A EP 79A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300434 ER PT J AU Harford, TC Yi, H Hilton, ME AF Harford, TC Yi, H Hilton, ME TI Alcohol use during young adulthood and long-term risk for alcohol abuse and dependence: Ten-year prospective follow-up in a national survey SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 CSR Inc, Alcohol Epidemiol Data Syst, Arlington, VA 22201 USA. NIAAA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 81A EP 81A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300447 ER PT J AU Harford, TC Yi, H Hough, JF AF Harford, TC Yi, H Hough, JF TI Alcohol use disorders and alcohol treatment utilization among adolescents ages 12-17 SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, NIH, Bethesda, MD 20892 USA. CSR Inc, Alcohol Epidemiol Data Syst, Arlington, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 81A EP 81A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300446 ER PT J AU Barr, CS Newman, TK Dvoskin, RL Goldman, D Higley, JD AF Barr, CS Newman, TK Dvoskin, RL Goldman, D Higley, JD TI CRH gene promoter variation is associated with increased LHPA-axis response to alcohol in rhesus macaques SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, NIH, Poolesville, MD 20837 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 87A EP 87A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300482 ER PT J AU Newman, TK Barr, CS Syagailo, Y Champoux, M Suomi, SJ Higley, JD Lesch, KP AF Newman, TK Barr, CS Syagailo, Y Champoux, M Suomi, SJ Higley, JD Lesch, KP TI MAOA gene promoter polymorphism interacts with infant rearing condition to influence aggression and ethanol consumption in rhesus macaques (Macaca mulatta) SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, NIH, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 90A EP 90A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300499 ER PT J AU Jaruga, B Hong, F Kim, WH Sun, R Fan, SJ Gao, B AF Jaruga, B Hong, F Kim, WH Sun, R Fan, SJ Gao, B TI Chronic alcohol consumption accelerates liver injury in T cell-mediated hepatitis: Alcohol disregulation of NF-kappa B and STAT3 signaling pathways SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 121A EP 121A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300689 ER PT J AU Theruvathu, JA Brooks, PJ AF Theruvathu, JA Brooks, PJ TI Development of a new isotope dilution GC-MS assay for N2-ethyl 2 ' deoxyguanosine, an acetaldehyde-derived DNA SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 123A EP 123A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300696 ER PT J AU Jiang, XY Marini, AM Lipsky, RH AF Jiang, XY Marini, AM Lipsky, RH TI Upstream stimulatory factor 1 (USF1) suppresses basal expression of promoter III of the brain-derived neurotrophic factor gene in hippocampal rat SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 Uniformed Serv Univ Hlth Sci, Dept Neurol & Neurosci, Bethesda, MD 20814 USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 130A EP 130A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300738 ER PT J AU Ramchandani, VA Morzorati, S Flury, L Blekher, T Foroud, T Li, TK O'Connor, S AF Ramchandani, VA Morzorati, S Flury, L Blekher, T Foroud, T Li, TK O'Connor, S TI Comparison of subjective responses to alcohol administered by different routes of administration that result in similar breath alcohol levels. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. RL Roudebush VA Med Ctr, Indianapolis, IN 46202 USA. NIAAA, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 147A EP 147A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300844 ER PT J AU Hilton, ME AF Hilton, ME TI Barriers to alcoholism treatment self-reports from NESARC SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 163A EP 163A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549300937 ER PT J AU Goldman, D Radel, M Westly, E Finch, T Xu, K AF Goldman, D Radel, M Westly, E Finch, T Xu, K TI Chromosome four and chromosome five GABAA gene clusters and alcoholism SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 185A EP 185A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549301069 ER PT J AU Lakshman, MR Marmillot, P Ghosh, P AF Lakshman, MR Marmillot, P Ghosh, P TI Sialic acid index of plasma apolipoprotein J (SIJ) as a viable marker for chronic alcohol consumption SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 DVA Med Ctr, Lipid Res Lab, Washington, DC USA. George Washington Univ, Dept Biochem Mol Biol & Med, Washington, DC USA. NIH, Bethesda, MD 20892 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 189A EP 189A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549301090 ER PT J AU Bryant, KJ AF Bryant, KJ TI Does change in alcohol-use behavior mediate the effectiveness of interventions for HIV-risk among men who have sex with men? SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Bethesda, MD 20892 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 197A EP 197A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549301137 ER PT J AU Dawson, DA Grant, BF Stinson, FS Chou, PS AF Dawson, DA Grant, BF Stinson, FS Chou, PS TI Psychopathology associated with drinking and alcohol use disorders in the college and general adult populations SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Lab Epidemiol & Biometry, NIH, Bethesda, MD 20082 USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 198A EP 198A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549301142 ER PT J AU Grant, BF Chou, PS Anderson, K Dawson, DA AF Grant, BF Chou, PS Anderson, K Dawson, DA TI Nicotine dependence and alcohol and drug use disorders in the United States SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Lab Epidemiol & Biometry, NIH, Bethesda, MD 20082 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 198A EP 198A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549301144 ER PT J AU Grant, BF Stinson, FS Dawson, DA Chou, PS AF Grant, BF Stinson, FS Dawson, DA Chou, PS TI Acculturation and lifetime prevalence of DSM-VI psychiatric disorders among Mexican Americans and non-Hispanic Whites in the US: Results from the National Epidemiologic Survey an Alcohol and Related Conditions SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism C1 NIAAA, Lab Epidemiol & Biometry, NIH, Bethesda, MD 20082 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 SU S BP 198A EP 198A PG 1 WC Substance Abuse SC Substance Abuse GA 822OK UT WOS:000221549301143 ER PT J AU Thanos, PK Taintor, NB Rivera, SN Umegaki, H Ikari, H Roth, G Ingram, DK Hitzemann, R Fowler, JS Gatley, SJ Wang, GJ Volkow, ND AF Thanos, PK Taintor, NB Rivera, SN Umegaki, H Ikari, H Roth, G Ingram, DK Hitzemann, R Fowler, JS Gatley, SJ Wang, GJ Volkow, ND TI DRD2 gene transfer into the nucleus accumbens core of the alcohol preferring and nonpreferring rats attenuates alcohol drinking SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcoholism adenovirus addiction positron emission tomography (PET) gene therapy ID DOPAMINE D-2 RECEPTOR; POSITRON-EMISSION-TOMOGRAPHY; REWARD DEFICIENCY SYNDROME; FREELY MOVING RATS; P-RATS; EXTRACELLULAR DOPAMINE; REINFORCED BEHAVIOR; PREFRONTAL CORTEX; BRAIN DOPAMINE; D-AMPHETAMINE AB Background: Transient overexpression of the dopamine D2 receptor (DRD2) gene in the nucleus accumbens (NAc) using an adenoviral vector has been associated with a significant decrease in alcohol intake in Sprague Dawley rats. This overexpression of DRD2 reduced alcohol consumption in a two-bottle-choice paradigm and supported the view that high levels of DRD2 may be protective against alcohol abuse. Methods: Using a limited access (1 hr) two-bottle-choice (water versus 10% ethanol) drinking paradigm, we examined the effects of the DRD2 vector in alcohol intake in the genetically inbred alcohol-preferring (P) and -nonpreferring (NP) rats. In addition, micro-positron emission tomography imaging was used at the completion of the study to assess in vivo the chronic (7 weeks) effects of ethanol exposure on DRD2 levels between the two groups. Results: P rats that were treated with the DRD2 vector (in the NAc) significantly attenuated their alcohol preference (37% decrease) and intake (48% decrease), and these measures returned to pretreatment levels by day 20. A similar pattern of behavior (attenuation of ethanol drinking) was observed in NP rats. Analysis of the [C-11]raclopride micro-positron emission tomography data after chronic (7 weeks) exposure to ethanol revealed clear DRD2 binding differences between the 11 and NP rats. P rats showed 16% lower [C-11]raclopride specific binding in striatum than the NP rats. Conclusions: These findings further support our hypothesis that high levels of DRD2 are causally associated with a reduction in alcohol consumption and may serve as a protective factor against alcoholism. That this effect was seen in P rats, which are predisposed to alcohol intake, suggests that they are protective even in those who are genetically predisposed to high alcohol intake. It is noteworthy that increasing DRD2 significantly decreased alcohol intake but did not abolish it, suggesting that high DRD2 levels may specifically interfere with the administration of large quantities of alcohol. The significantly higher DRD2 concentration in NP than P rats after 7 weeks of ethanol therefore could account for low alcohol intake. C1 Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA. Nagoya Univ, Sch Med, Dept Geriatr, Aichi, Japan. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Oregon Hlth Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA. NIAAA, Lab Neuroimaging, Bethesda, MD USA. RP Thanos, PK (reprint author), Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. EM thanos@bnl.gov FU NIAAA NIH HHS [AA07611, AA 07574, AA 11034] NR 74 TC 68 Z9 68 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAY PY 2004 VL 28 IS 5 BP 720 EP 728 DI 10.1097/01.ALC.0000125270.30501.08 PG 9 WC Substance Abuse SC Substance Abuse GA 822OH UT WOS:000221549000006 PM 15166646 ER PT J AU Stone, PH Lloyd-Jones, DM Johnstone, M Carlson, W Rubenstein, J Creager, M Frei, B Sopko, G Clark, ME MacCallum, G Kinlay, S Orav, J Selwyn, AP AF Stone, PH Lloyd-Jones, DM Johnstone, M Carlson, W Rubenstein, J Creager, M Frei, B Sopko, G Clark, ME MacCallum, G Kinlay, S Orav, J Selwyn, AP TI Vascular basis for the treatment of myocardial ischemia study: Trial design and baseline characteristics SO AMERICAN HEART JOURNAL LA English DT Article ID VITAMIN-E SUPPLEMENTATION; CORONARY-ARTERY DISEASE; VASODILATOR FUNCTION; VASOMOTOR RESPONSE; ANGINA-PECTORIS; STABLE ANGINA; CHOLESTEROL; REDUCTION; EXERCISE; ATHEROSCLEROSIS AB Background Increased low-density lipoprotein (LDL) and oxidized LDL cholesterol levels adversely affect endothelial function in patients with stable coronary artery disease (CAD). Statin drugs are efficacious in primary and secondary prevention of clinical CAD events, but they have not been extensively studied as a treatment for ischemia during routine daily activities or during exercise, indicators of high-risk in patients with stable CAD. The purpose of the Vascular Basis for the Treatment of Myocardial Ischemia study is to determine whether aggressive lowering of LDL cholesterol level with atorvastatin, with or without supplemental antioxidant vitamins C and E, can improve endothelial function and ischemia during ambulatory electrocardiogram (AECG) monitoring and exercise treadmill testing (ETT). Methods Patients are eligible when they have ischemia during an ETT and AECG monitoring and when their fasting total cholesterol level is less than or equal to250 mg/dL. Eligible patients are randomized to receive 1 of 3 treatments: intensive atorvastatin to reduce LDL cholesterol level to less than or equal to80 mg/dL, intensive atorvastatin to reduce LDL cholesterol level to less than or equal to80 mg/dL plus antioxidant vitamins C and E, and control of diet and low-dose lovastatin, when needed, to reduce LDL cholesterol level less than or equal to to 130 mg/dL. Patients undergo endothelial function testing, 48-hour AECG monitoring, and ETT at randomization and at 6 and 12 months. Results A total of 300 patients have been randomized: 101 to receive atorvastatin alone, 103 to receive atorvastatin plus antioxidant vitamins, and 96 to receive placebo. Baseline characteristics are similar across treatment groups. Conclusions The Vascular Basis study will provide important insight on the effects of aggressive management of dyslipidemia with statin drugs and antioxidant vitamins in patients with stable but high-risk CAD. C1 Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Harvard Vanguard Med Associates, Boston, MA USA. Newton Wellesley Hosp, Newton, MA USA. Oregon State Univ, Corvallis, OR 97331 USA. NIH, Cardiac Dis Branch, Bethesda, MD 20892 USA. RP Stone, PH (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM pstone@partners.org RI Lloyd-Jones, Donald/C-5899-2009 FU NHLBI NIH HHS [R0-1 HL 38780] NR 24 TC 4 Z9 4 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD MAY PY 2004 VL 147 IS 5 BP 875 EP 882 DI 10.1016/j.ahj.2003.10.046 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 821RB UT WOS:000221479100028 PM 15131545 ER PT J AU Stark, KD Holub, BJ AF Stark, KD Holub, BJ TI Differential eicosapentaenoic acid elevations and altered cardiovascular disease risk factor responses after supplementation with docosahexaenoic acid in postmenopausal women receiving and not receiving hormone replacement therapy SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE fish oil; n-3 fatty acids; docosahexaenoic acid; DHA; total cholesterol; LDL cholesterol; HDL cholesterol; triacylglycerol; postmenopausal women; hormone replacement therapy; cardiovascular disease; retroconversion; heart rate; C-reactive protein ID CORONARY-HEART-DISEASE; ESTROGEN PLUS PROGESTIN; C-REACTIVE PROTEIN; DIETARY FISH-OIL; FATTY-ACID; DENSITY-LIPOPROTEIN; MYOCARDIAL-INFARCTION; DEFICIENT MICE; BLOOD-PRESSURE; SERUM-LIPIDS AB Background: Dietary docosahexaenoic acid (DHA) has triacylglycerol-lowering potential and undergoes in vivo retrocon-version to eicosapentaenoic acid (EPA) in humans. Hormone replacement therapy (HRT) influences circulating lipid concentrations and fatty acid metabolism. DHA supplementation has not been studied in postmenopausal women. Objective: We studied the effects of supplementation with DHA (free of EPA) on the resulting elevation in EPA and on selected cardiovascular disease risk factors in postmenopausal women. Design: Women receiving (n = 18) and not receiving (n = 14) HRT completed a randomized, double-blind, placebo-controlled crossover trial with a DHA supplement (2.8 g DHA/d). A washout period of : 6 wk divided the two 28-d intervention periods. Fasting blood samples were collected for analysis. Results: In all women, DHA supplementation was associated with significant changes (P < 0.05), including 20% lower serum triacylglycerol concentrations, 8% higher HDL-cholesterol concentrations, a 28% lower overall ratio of serum triacylglycerol to HDL cholesterol, and a 7% decrease in resting heart rate. DHA supplementation resulted in a 45% lower net increase (P = 0.02) in EPA and a 42% lower (P = 0.0028) estimated percentage retroconversion of DHA to EPA [&UDelta;EPA/(&UDelta;EPA + &UDelta;DHA) x 100] in women re-ceiving than in those not receiving HRT. Conclusion: With DHA supplementation, the accumulation of EPA in serum phospholipids is significantly attenuated in postmenopausal women receiving HRT compared with that in women not receiving HRT. DHA supplementation can also favorably influence selected cardiovascular disease risk factors in postmenopausal women. C1 Univ Guelph, Dept Human Biol & Nutr Sci, Guelph, ON N1G 2W1, Canada. NIAAA, Div Intramural Clin & Biol Res, Lab Membrane Biochem & Biophys, Sect Nutr Neurosci,NIH, Rockville, MD 20852 USA. RP Holub, BJ (reprint author), Univ Guelph, Dept Human Biol & Nutr Sci, Guelph, ON N1G 2W1, Canada. EM bholub@uoguelph.ca RI Stark, Ken/I-1347-2016 OI Stark, Ken/0000-0001-7828-4072 NR 56 TC 99 Z9 101 U1 1 U2 2 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 MAY PY 2004 VL 79 IS 5 BP 765 EP 773 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 815LU UT WOS:000221044600008 PM 15113713 ER PT J AU Tooze, JA Subar, AF Thompson, FE Troiano, R Schatzkin, A Kipnis, V AF Tooze, JA Subar, AF Thompson, FE Troiano, R Schatzkin, A Kipnis, V TI Psychosocial predictors of energy underreporting in a large doubly labeled water study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE dietary assessment methods; epidemiologic methods; diet; nutrition surveys; biological markers; energy expenditure; doubly labeled water ID NUTRITION EXAMINATION SURVEY; SOCIAL DESIRABILITY SCALE; 3RD NATIONAL-HEALTH; BODY-MASS INDEX; EATING BEHAVIOR; DIETARY-INTAKE; FOOD-INTAKE; LIFE-STYLE; OLDER MEN; WOMEN AB Background: Underreporting of energy intake is associated with self-reported diet measures and appears to be selective according to personal characteristics. Doubly labeled water is an unbiased reference biomarker for energy intake that may be used to assess under-reporting. Objective: Our objective was to determine which factors are associated with underreporting of energy intake on food-frequency questionnaires (FFQs) and 24-h dietary recalls (24HRs). Design: The study participants were 484 men and women aged 40 - 69 y who resided in Montgomery County, MD. Using the doubly labeled water method to measure total energy expenditure, we considered numerous psychosocial, lifestyle, and sociodemographic factors in multiple logistic regression models for prediction of the probability of underreporting on the FFQ and 24HR. Results: In the FFQ models, fear of negative evaluation, weight-loss history, and percentage of energy from fat were the best predictors of underreporting in women (R-2 = 0.09); body mass index, comparison of activity level with that of others of the same sex and age, and eating 2 frequency were the best predictors in men (R-2 = 0.10). In the 24HR models, social desirability, fear of negative evaluation, body mass index, percentage of energy from fat, usual activity, and variability in number of meals per day were the best predictors of underreporting in women (R-2 = 0.22); social desirability, dietary restraint, body mass index, eating frequency, dieting history, and education were the best predictors in men (R-2 = 0.25). Conclusion: Although the final models were significantly related to underreporting on both the FFQ and the 24HR, the amount of variation explained by these models was relatively low, especially for the FFQ. C1 NCI, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Tooze, JA (reprint author), NCI, Canc Prevent Fellowship Program, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM toozej@mail.nih.gov OI Troiano, Richard/0000-0002-6807-989X NR 49 TC 156 Z9 161 U1 3 U2 13 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 MAY PY 2004 VL 79 IS 5 BP 795 EP 804 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 815LU UT WOS:000221044600012 PM 15113717 ER PT J AU Travis, LA Lyness, JM Shields, CG King, DA Cox, C AF Travis, LA Lyness, JM Shields, CG King, DA Cox, C TI Social support, depression, and functional disability in older adult primary-care patients SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article; Proceedings Paper CT 54th Annual Meeting of the Gerontological-Society-of-America CY NOV 15-18, 2001 CL CHICAGO, IL SP Gerontol Soc Amer ID CORONARY-ARTERY-DISEASE; RISK-FACTORS; RATING-SCALE; LATE-LIFE; HEALTH; SYMPTOMS; OUTCOMES; NETWORKS; INTEGRATION; DISORDERS AB Objective: The authors asked whether social support and depression are independently associated with functional disability and examined the potential role of social support as a moderator in the depression-junctional disability association. Methods: Subjects were 305 patients age 60 years and over Predictor variables were social support, depressive symptoms, and depression diagnosis. Dependent variables were the Instrumental Activities of Daily Living Scale, the Physical Self-Maintenance Scale, and the Physical Functioning subscale of the Medical Outcomes Study 36-Item Short-Form Health Survey Authors used multiple-regression analyses. Results: Depressive symptoms and all dimensions of social support were independently associated with junctional disability the specifics of these relationships varied among types of social support and functional disability Depression diagnosis was not independently associated with any functional disability measure. Social support (more instrumental help, more perceived satisfaction) moderated some depression diagnosis-functional disability associations, and one depressive symptom-functional disability association. Conclusions: The study hypotheses were partially confirmed. Different dimensions of social support have important and varied roles in the depression-functional disability dynamic. Future research is needed to further specify the complex relationships among depression, social support, and functional disability. C1 Univ Rochester, Ctr Med, Dept Psychiat & Med Comorbid, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Dept Psychiat, Lab Depress, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Dept Psychiat, Program Geriatr & Neuropsychiat, Rochester, NY 14642 USA. Univ Rochester, Ctr Med, Wynne Ctr Family Res, Rochester, NY 14627 USA. Univ Rochester, Ctr Med, Dept Family Med, Rochester, NY 14627 USA. Univ Rochester, Ctr Med, Dept Biostat & Computat Biol, Rochester, NY 14627 USA. NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lyness, JM (reprint author), Univ Rochester, Ctr Med, Dept Psychiat & Med Comorbid, 300 Crittenden Blvd, Rochester, NY 14642 USA. EM Jeffrey_Lyness@URMC.Rochester.edu OI Shields, Cleveland/0000-0003-3709-6969 FU NIMH NIH HHS [T32 MH18911, K07-MH01113] NR 43 TC 55 Z9 55 U1 0 U2 9 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAY-JUN PY 2004 VL 12 IS 3 BP 265 EP 271 DI 10.1176/appi.ajgp.12.3.265 PG 7 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 816TT UT WOS:000221132900005 PM 15126227 ER PT J AU Li, AR Jiao, XD Munier, FL Schorderet, DF Yao, WL Iwata, F Hayakawa, M Kanai, A Chen, MS Lewis, RA Heckenlively, J Weleber, RG Traboulsi, EI Zhang, QJ Xiao, XS Kaiser-Kupfer, M Sergeev, YV Hejtmancik, JF AF Li, AR Jiao, XD Munier, FL Schorderet, DF Yao, WL Iwata, F Hayakawa, M Kanai, A Chen, MS Lewis, RA Heckenlively, J Weleber, RG Traboulsi, EI Zhang, QJ Xiao, XS Kaiser-Kupfer, M Sergeev, YV Hejtmancik, JF TI Bietti crystalline corneoretinal dystrophy is caused by mutations in the novel gene CYP4V2 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID IDENTIFICATION; OPTIMIZATION; CONFORMATION; SEQUENCE; LINKAGE; CHINA AB Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive retinal dystrophy characterized by multiple glistening intraretinal crystals scattered over the fundus, a characteristic degeneration of the retina, and sclerosis of the choroidal vessels, ultimately resulting in progressive night blindness and constriction of the visual field. The BCD region of chromosome 4q35.1 was refined to an interval flanked centromerically by D4S2924 by linkage and haplotype analysis; mutations were found in the novel CYP450 family member CYP4V2 in 23 of 25 unrelated patients with BCD tested. The CYP4V2 gene, transcribed from 11 exons spanning 19 kb, is expressed widely. Homology to other CYP450 proteins suggests that CYP4V2 may have a role in fatty acid and steroid metabolism, consistent with biochemical studies of patients with BCD. C1 NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. Jules Gonin Eye Hosp, Oculgenet Unit, Lausanne, Switzerland. Inst Rech Ophtalmol, Sion, Switzerland. Juntendo Univ, Sch Med, Dept Ophthalmol, Tokyo 113, Japan. Natl Taiwan Univ Hosp, Dept Ophthalmol, Taipei, Taiwan. Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA. Baylor Coll Med, Dept Human & Mol Genet, Houston, TX 77030 USA. Univ Michigan, Jules Kellogg Eye Ctr, Ann Arbor, MI 48109 USA. Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Sun Yat Sen Univ, Zhongshan Ophthalm Ctr, Guangzhou, Peoples R China. RP Hejtmancik, JF (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bldg 10,Room 10B10,10 Ctr Dr,MSC 1860, Bethesda, MD 20892 USA. EM f3h@helix.nih.gov NR 24 TC 91 Z9 101 U1 1 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 MAY PY 2004 VL 74 IS 5 BP 817 EP 826 DI 10.1086/383228 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 813SF UT WOS:000220926100004 PM 15042513 ER PT J AU Patterson, N Hattangadi, N Lane, B Lohmueller, KE Hafler, DA Oksenberg, JR Hauser, SL Smith, MW O'Brien, SJ Altshuler, D Daly, MJ Reich, D AF Patterson, N Hattangadi, N Lane, B Lohmueller, KE Hafler, DA Oksenberg, JR Hauser, SL Smith, MW O'Brien, SJ Altshuler, D Daly, MJ Reich, D TI Methods for high-density admixture mapping of disease genes SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID AFRICAN-AMERICAN POPULATION; FACTOR-V-LEIDEN; LINKAGE-DISEQUILIBRIUM; ADMIXED POPULATIONS; MULTIPLE-SCLEROSIS; ADMIRED POPULATIONS; HAPLOTYPE STRUCTURE; ALLELE FREQUENCIES; ETHNIC-DIFFERENCES; ASSOCIATION AB Admixture mapping (also known as "mapping by admixture linkage disequilibrium," or MALD) has been proposed as an efficient approach to localizing disease-causing variants that differ in frequency ( because of either drift or selection) between two historically separated populations. Near a disease gene, patient populations descended from the recent mixing of two or more ethnic groups should have an increased probability of inheriting the alleles derived from the ethnic group that carries more disease-susceptibility alleles. The central attraction of admixture mapping is that, since gene flow has occurred recently in modern populations ( e. g., in African and Hispanic Americans in the past 20 generations), it is expected that admixture-generated linkage disequilibrium should extend for many centimorgans. High-resolution marker sets are now becoming available to test this approach, but progress will require ( a) computational methods to infer ancestral origin at each point in the genome and (b) empirical characterization of the general properties of linkage disequilibrium due to admixture. Here we describe statistical methods to estimate the ancestral origin of a locus on the basis of the composite genotypes of linked markers, and we show that this approach accurately estimates states of ancestral origin along the genome. We apply this approach to show that strong admixture linkage disequilibrium extends, on average, for 17 cM in African Americans. Finally, we present power calculations under varying models of disease risk, sample size, and proportions of ancestry. Studying similar to2,500 markers in similar to2,500 patients should provide power to detect many regions contributing to common disease. A particularly important result is that the power of an admixture mapping study to detect a locus will be nearly the same for a wide range of mixture scenarios: the mixture proportion should be 10%-90% from both ancestral populations. C1 Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. Harvard Univ, Sch Med, Lab Mol Immunol, Boston, MA USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. Georgetown Univ, Washington, DC USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. NCI, Lab Genom Divers, Frederick, MD 21701 USA. Sci Applicat Int Corp, Basic Res Program, Frederick, MD USA. RP Reich, D (reprint author), Harvard Univ, Sch Med, Dept Genet, New Res Bldg,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM reich@receptor.med.harvard.edu RI Altshuler, David/A-4476-2009; Smith, Michael/B-5341-2012; Hauser, Stephen/J-2978-2016 OI Altshuler, David/0000-0002-7250-4107; FU NHGRI NIH HHS [K-01 HG002758-01, K01 HG002758]; NIAID NIH HHS [U19 AI050864, U19 AI50864] NR 69 TC 306 Z9 322 U1 0 U2 9 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 MAY PY 2004 VL 74 IS 5 BP 979 EP 1000 DI 10.1086/420871 PG 22 WC Genetics & Heredity SC Genetics & Heredity GA 813SF UT WOS:000220926100017 PM 15088269 ER PT J AU Smith, MW Patterson, N Lautenberger, JA Truelove, AL McDonald, GJ Waliszewska, A Kessing, BD Malasky, MJ Scafe, C Le, E De Jager, PL Mignault, AA Yi, Z de The, G Essex, M Sankale, JL Moore, JH Poku, K Phair, JP Goedert, JJ Vlahov, D Williams, SM Tishkoff, SA Winkler, CA De La Vega, FM Woodage, T Sninsky, JJ Hafler, DA Altshuler, D Gilbert, DA O'Brien, SJ Reich, D AF Smith, MW Patterson, N Lautenberger, JA Truelove, AL McDonald, GJ Waliszewska, A Kessing, BD Malasky, MJ Scafe, C Le, E De Jager, PL Mignault, AA Yi, Z de The, G Essex, M Sankale, JL Moore, JH Poku, K Phair, JP Goedert, JJ Vlahov, D Williams, SM Tishkoff, SA Winkler, CA De La Vega, FM Woodage, T Sninsky, JJ Hafler, DA Altshuler, D Gilbert, DA O'Brien, SJ Reich, D TI A high-density admixture map for disease gene discovery in African Americans SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MULTILOCUS GENOTYPE DATA; LINKAGE-DISEQUILIBRIUM; POPULATION-STRUCTURE; ADMIXED POPULATIONS; ADMIRED POPULATIONS; ETHNIC-DIFFERENCES; MAPPING GENES; HUMAN GENOME; ASSOCIATION; MARKERS AB Admixture mapping ( also known as "mapping by admixture linkage disequilibrium," or MALD) provides a way of localizing genes that cause disease, in admixed ethnic groups such as African Americans, with similar to100 times fewer markers than are required for whole-genome haplotype scans. However, it has not been possible to perform powerful scans with admixture mapping because the method requires a dense map of validated markers known to have large frequency differences between Europeans and Africans. To create such a map, we screened through databases containing similar to450,000 single-nucleotide polymorphisms (SNPs) for which frequencies had been estimated in African and European population samples. We experimentally confirmed the frequencies of the most promising SNPs in a multiethnic panel of unrelated samples and identified 3,011 as a MALD map (1.2 cM average spacing). We estimate that this map is similar to70% informative in differentiating African versus European origins of chromosomal segments. This map provides a practical and powerful tool, which is freely available without restriction, for screening for disease genes in African American patient cohorts. The map is especially appropriate for those diseases that differ in incidence between the parental African and European populations. C1 Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. NCI, Lab Genom Divers, Frederick, MD 21701 USA. NCI, Basic Res Program, Sci Applicat Int Corp, Frederick, MD 21701 USA. Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. Harvard Univ, Sch Med, Lab Mol Immunol, Boston, MA USA. Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Harvard AIDS Inst, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. Appl Biosyst Inc, Foster City, CA 94404 USA. Chinese Acad Prevent Med, Inst Virol, Beijing 100052, Peoples R China. Inst Pasteur, CNRS, Dept Viral Oncol Epidemiol, Paris, France. Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN USA. Vanderbilt Univ, Dept Med, Div Cardiovasc Med, Nashville, TN USA. Vanderbilt Univ, Dept Physiol & Mol Biophys, Nashville, TN USA. Univ Ghana, Sch Adm, Legon, Ghana. Northwestern Univ, Howard Brown Hlth Ctr, Chicago, IL 60611 USA. Northwestern Univ, Dept Med, Chicago, IL 60611 USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. New York Acad Med, Ctr Urban Epidemiol Studies, New York, NY USA. Univ Maryland, Dept Biol, College Pk, MD 20742 USA. Celera Diagnost, Alameda, CA USA. RP Reich, D (reprint author), Harvard Univ, Sch Med, Dept Genet, New Res Bldg,77 Ave Louis Pasteur, Boston, MA 02115 USA. EM reich@receptor.med.harvard.edu RI Altshuler, David/A-4476-2009; Smith, Michael/B-5341-2012; Williams, Scott/B-9491-2012 OI Altshuler, David/0000-0002-7250-4107; FU NCI NIH HHS [N01CO12400]; NHGRI NIH HHS [K-01 HG002758-01, K01 HG002758]; NHLBI NIH HHS [HL-65234, R01 HL065234]; NIAID NIH HHS [U19 AI050864, U19-AI50864]; NINDS NIH HHS [K08 NS046341]; PHS HHS [N01-C0-12400] NR 52 TC 330 Z9 335 U1 1 U2 9 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 MAY PY 2004 VL 74 IS 5 BP 1001 EP 1013 DI 10.1086/420856 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 813SF UT WOS:000220926100018 PM 15088270 ER PT J AU Barzilay, JI Pressel, S Davis, BR Margolis, KL Cutler, J Ong, STG Basile, J Sadler, LS Summerson, J Whelton, PK AF Barzilay, JI Pressel, S Davis, BR Margolis, KL Cutler, J Ong, STG Basile, J Sadler, LS Summerson, J Whelton, PK CA ALLHAT Collaborat Res Grp TI Risk and impact of incident glucose disorders in hypertensive older adults treated with an ace inhibitor, a diuretic, or a calcium channel blocker: A report from the ALLHAT trial SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 18-22, 2004 CL New York, NY SP Amer Soc Hyperters DE diabetes; fasting glucose; CVD risk C1 Kaiser Permanente Georgia, Tucker, GA USA. Univ Texas, Hlth Sci Ctr, Sch Publ Hlth, Coordinating Ctr Clin Trials, Houston, TX USA. Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Ong Med Ctr, Oxon Hill, MD USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. St Vincent Char Hosp & Hlth Ctr, Lipid Res Ctr, Cleveland, OH USA. Wake Forest Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. Tulane Univ, Hlth Sci Ctr, New Orleans, LA 70118 USA. NR 0 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 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2004 VL 17 IS 5 MA OR2 BP 1A EP 1A PN 2 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818YW UT WOS:000221281400003 ER PT J AU Yang, ZW Yu, PY Asicol, LD Wang, Z Jones, JE Sibley, DR Jose, PA AF Yang, ZW Yu, PY Asicol, LD Wang, Z Jones, JE Sibley, DR Jose, PA TI D-5 dopamine receptor regulation of reactive oxygen species production and blood pressure in mice SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 18-22, 2004 CL New York, NY SP Amer Soc Hyperters DE D5 receptor; reactive oxygen species; hypertension C1 Georgetown Univ, Med Ctr, Dept Pediat Physiol & Biophys, Washington, DC 20007 USA. NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2004 VL 17 IS 5 MA OR45 BP 20A EP 20A PN 2 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818YW UT WOS:000221281400046 ER PT J AU Ilic, V Peterson, G Vagaonescu, T Gabriel, A Kendrick, C Phillips, RA AF Ilic, V Peterson, G Vagaonescu, T Gabriel, A Kendrick, C Phillips, RA CA AASK Investigators TI Baseline echocardiographic characteristics and the predictors of LV mass in the African American study of kidney disease (AASK) SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 18-22, 2004 CL New York, NY SP Amer Soc Hyperters DE left ventricular hypertrophy; kidney disease; diastolic dysfunction C1 Lenox Hill Hosp, New York, NY 10021 USA. NYU, Sch Med, New York, NY USA. Cardiovasc Res Fdn, New York, NY USA. Univ Texas, Dallas, TX 75230 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2004 VL 17 IS 5 MA OR63 BP 27A EP 28A PN 2 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818YW UT WOS:000221281400064 ER PT J AU Wright, MBL Devereux, RB Roman, MJ Chinali, M Best, LG Galloway, JM Fabsitz, RR Zhang, Y Lee, ET Howard, BV AF Wright, MBL Devereux, RB Roman, MJ Chinali, M Best, LG Galloway, JM Fabsitz, RR Zhang, Y Lee, ET Howard, BV TI Left ventricular structure and function predict clinical cardiovascular risk in prehypertension: The Strong Heart Study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 18-22, 2004 CL New York, NY SP Amer Soc Hyperters DE prehypertension; cardiac structure and function; cardiovascular morbidity and mortality C1 Weill Cornell Med Ctr, New York, NY USA. Missouri Breaks Ind Res Inc, Timber Lake, SD USA. Univ Arizona, Flagstaff, AZ USA. NHLBI, Bethesda, MD 20892 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. MedStar Res Inst, Hyattsville, MD USA. RI Chinali, Marcello/H-5794-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2004 VL 17 IS 5 MA OR68 BP 29A EP 29A PN 2 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818YW UT WOS:000221281400069 ER PT J AU Cushman, WC Ford, CE Einhorn, P Wright, JT Preston, RA Davis, BR Basile, JN AF Cushman, WC Ford, CE Einhorn, P Wright, JT Preston, RA Davis, BR Basile, JN TI Blood pressure control by randomized drug group in ALLHAT SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 18-22, 2004 CL New York, NY SP Amer Soc Hyperters DE blood pressure control; antihypertensive agents; randomized controlled trial C1 Vet Affairs Med Ctr, Med Res Serv, Memphis, TN USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. NHLBI, Bethesda, MD 20892 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Miami, Miami, FL 33152 USA. Vet Affairs Med Ctr, Charleston, SC 29403 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2004 VL 17 IS 5 MA OR70 BP 30A EP 30A PN 2 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818YW UT WOS:000221281400071 ER PT J AU Cutler, JA Piller, LB Pressel, S Graumlich, JF Hamilton, BP Parish, DC Qureshi, N Randall, OS Davis, BR AF Cutler, JA Piller, LB Pressel, S Graumlich, JF Hamilton, BP Parish, DC Qureshi, N Randall, OS Davis, BR CA ALLHAT Collaborat Res Grp TI Results of monotherapy in ALLHAT: On-treatment analyses SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 18-22, 2004 CL New York, NY SP Amer Soc Hyperters DE antihypertensive monotherapy; cardiovascular events; ALLHAT C1 NHLBI, ALLHAT Collaborat Res Grp, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2004 VL 17 IS 5 MA OR71 BP 30A EP 31A PN 2 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818YW UT WOS:000221281400072 ER PT J AU Wright, MBL Devereux, RB Roman, MJ Liu, JE Best, LG Galloway, JM Fabsitz, RR Lee, ET Howard, BV AF Wright, MBL Devereux, RB Roman, MJ Liu, JE Best, LG Galloway, JM Fabsitz, RR Lee, ET Howard, BV TI The association between isolated systolic hypertension and aortic regurgitation is not independent of age: The strong heart study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 18-22, 2004 CL New York, NY SP Amer Soc Hyperters DE isolated systolic hypertension; aortic regurgitation; left ventricular hypertrophy C1 Weil Cornell Med Ctr, New York, NY USA. Missouri Breaks Ind Res Inc, Timber Lake, SD USA. Univ Arizona, Flagstaff, AZ USA. NHLBI, Bethesda, MD 20892 USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK 73104 USA. Medstar Res Inst, Hyattsville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2004 VL 17 IS 5 MA P363 BP 166A EP 167A PN 2 PG 2 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818YW UT WOS:000221281400440 ER PT J AU Lloyd-Jones, DM Evans, JC Levy, D AF Lloyd-Jones, DM Evans, JC Levy, D TI Epidemiology of hypertension in the old old: Data from the community in the 1990s SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 18-22, 2004 CL New York, NY SP Amer Soc Hyperters DE hypertension; treatment and control; cardiovascular disease C1 NHLBI, Framingham Heart Study, Framingham, MA USA. RI Lloyd-Jones, Donald/C-5899-2009 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2004 VL 17 IS 5 MA P457 BP 200A EP 200A PN 2 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818YW UT WOS:000221281400533 ER PT J AU Wyatt, SB Walker, ER Connor, MH Heard, S King, DS Howard, T Knight, J Magers, W AF Wyatt, SB Walker, ER Connor, MH Heard, S King, DS Howard, T Knight, J Magers, W TI A statewide plan for reducing cardiovascular disease and stroke SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 18-22, 2004 CL New York, NY SP Amer Soc Hyperters DE high risk groups; risk factors; statewide registry C1 Univ Mississippi, Med Ctr, Div Hypertens, Jackson, MS 39216 USA. Univ Mississippi, Med Ctr, Sch Nursing, Jackson, MS 39216 USA. Univ Mississippi, Med Ctr, Sch Pharm Hlth Practice, Jackson, MS 39216 USA. NHLBI, Jackson Heart Study Field Ctr, Jackson, MS USA. Amer Heart Assoc, Jackson, MS USA. Informat & Qual Hlth Care, Jackson, MS USA. Mississippi Dept Hlth, Jackson, MS USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2004 VL 17 IS 5 MA P477 BP 207A EP 207A PN 2 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818YW UT WOS:000221281400553 ER PT J AU Sharabi, Y Goldstein, DS Holmes, C Pechnik, S Grossman, E Eisenhofer, G AF Sharabi, Y Goldstein, DS Holmes, C Pechnik, S Grossman, E Eisenhofer, G TI Divergent relationship of body mass index with plasma norepinephrine and epinephrine SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Meeting Abstract CT 19th Annual Scientific Meeting of the American-Society-of-Hypertension CY MAY 18-22, 2004 CL New York, NY SP Amer Soc Hyperters DE obesity; catecholamines; metanephrines C1 NINDS, NIH, Bethesda, MD 20892 USA. Chaim Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2004 VL 17 IS 5 MA P482 BP 209A EP 209A PN 2 PG 1 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818YW UT WOS:000221281400558 ER PT J AU Sharabi, Y Grotto, I Huerta, M Grossman, E AF Sharabi, Y Grotto, I Huerta, M Grossman, E TI Susceptibility of the influence of weight on blood pressure in men versus women - Lessons from a large-scale study of young adults SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE hypertension; obesity; gender; population study ID BODY-MASS INDEX; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; US ADULTS; CARDIOVASCULAR RISK; ABDOMINAL ADIPOSITY; UNITED-STATES; OBESITY; HYPERTENSION; PREVALENCE AB Background: Weight and blood pressure (BP) are closely related. The aim of this study was to quantify this relationship and compare it to other factors in a population of relatively young adults, with particular focus on the possible role of gender. Methods: We conducted a cross-sectional analysis of the Young Adult Periodic Examinations in Israel (YAPEIS) database of healthy people aged 25 to 45 years undergoing routine periodic examinations. Between 1991 and 1999, 38,558 subjects (88.1% men, mean age 36 +/- 8 years) were examined. The correlation between BP and weight was evaluated with adjustments for age, sex, physical activity, cigarette smoking, and fasting blood glucose levels. Results: Blood pressure correlated positively with body mass index (BMI), spanning the spectrum of BMI values. Weight accounted for 8% to 10% of BP variance. The odds ratio for hypertension increased by 16% for each additional unit of BMI, compared to 6% for each year increase in age. The relative propensity of men toward hypertension, typical of this age group, was less pronounced at higher BMI values (male:female ratio = 2.2 at BMI <25 kg/m(2), and 1.28 at BMI greater than or equal to35 kg/m(2)). Conclusions: The association between BP and body weight is at least as strong as that between BP and age and is especially prominent in women. (C) 2004 American Journal of Hypertension, Ltd. C1 Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. Chaim Sheba Med Ctr, Israeli Def Force Med Corps, Period Examinat Ctr, Tel Hashomer, Israel. RP Sharabi, Y (reprint author), Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, 10 Ctr Dr,MSC-1620,Bldg 10,Room 6N252, Bethesda, MD 20892 USA. EM sharabiy@ninds.nih.gov RI Grotto, Itamar/F-2028-2012; OI Grossman, Ehud/0000-0001-8353-0661 NR 25 TC 20 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 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD MAY PY 2004 VL 17 IS 5 BP 404 EP 408 DI 10.1016/j.amjhyper.2003.12.012 PN 1 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 818TB UT WOS:000221266300004 PM 15110898 ER PT J AU Rajaraman, P De Roos, AJ Stewart, PA Linet, MS Fine, HA Shapiro, WR Selker, RG Black, PM Inskip, PD AF Rajaraman, P De Roos, AJ Stewart, PA Linet, MS Fine, HA Shapiro, WR Selker, RG Black, PM Inskip, PD TI Occupation and risk of meningioma and acoustic neuroma in the United States SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE brain; tumor; case-control; occupation ID LOS-ANGELES COUNTY; INTERNATIONAL CASE-CONTROL; BRAIN-TUMORS; INTRACRANIAL TUMORS; ADULT GLIOMA; ETIOLOGY; SYSTEM; TRAUMA; CANCER; WOMEN AB Background Workplace exposures may be related to the development of brain tumors. In this case-control study, we examine occupation as a risk factor for meningioma and acoustic neuroma. Methods A lifetime work history was obtained for 197 incident cases of meningioma, 96 cases of acoustic neuroma and 799 controls with non-malignant diseases enrolled from three hospitals in the United States between 1994 and 1998. Jobs considered to have similar tasks and chemical exposures were assigned to an occupational group. Logistic regression was used to estimate odds ratios (OR) adjusted for study matching factors (hospital, age, sex, race/ethnicity, and proximity of residence to the hospital) and education. Results Elevated risk of meningioma was observed for individuals who had ever worked in the following occupational groups: auto body painters, designers and decorators, military occupations, industrial production supervisors, teachers, and managers. For acoustic neuroma, increased risk was noted for having worked as an athlete, gas station attendant, purchasing agent, sales representative, or teacher. Conclusions Although limited by multiple comparisons and the relatively small number of cases and controls in many occupational groups, these results nevertheless provide clues that deserve additional study in future epidentiologic studies. Am. J. Ind. Med. 45:395407, 2004. published 2004 Wiley-Liss, Inc.(dagger). C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NCI, Neurooncol Branch, Bethesda, MD 20892 USA. St Josephs Hosp, Barrow Neurol Inst, Phoenix, AZ 85013 USA. St Josephs Med Ctr, Phoenix, AZ USA. Western Penn Hosp, Pittsburgh, PA 15224 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Rajaraman, P (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS Room 7045, Bethesda, MD 20892 USA. EM rajarama@mail.nih.gov NR 27 TC 18 Z9 19 U1 2 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD MAY PY 2004 VL 45 IS 5 BP 395 EP 407 DI 10.1002/ajim.10363 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 818KY UT WOS:000221245200001 PM 15095422 ER PT J AU Massad, LS Silverberg, MJ Springer, G Minkoff, H Hessol, N Palefsky, JM Strickler, HD Levine, AM Sacks, HS Moxley, M Watts, H AF Massad, LS Silverberg, MJ Springer, G Minkoff, H Hessol, N Palefsky, JM Strickler, HD Levine, AM Sacks, HS Moxley, M Watts, H TI Effect of antiretroviral therapy on the incidence of genital warts and vulvar neoplasia among women with the human immunodeficiency virus SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE genital warts; vulvar neoplasia; vulvar cancer; human papillomavirus; human immunodeficiency virus ID HUMAN-PAPILLOMAVIRUS INFECTION; INTERAGENCY HIV; HIGH-RISK; INTRAEPITHELIAL NEOPLASIA; CONDYLOMATA ACUMINATA; UNINFECTED WOMEN AB Objective: The purpose of this study was to determine the incidence and predictors of genital warts and vulvar intraepithelial neoplasia among women with the human immunodeficiency virus. Study design: This was a multicenter prospective cohort study comprised of women without warts or vulvar intraepithelial neoplasia at baseline who underwent CD4 count, human immunodeficiency virus RNA measurement, examination, Papanicolaou test, and biopsy, as indicated, every 6 months. Human papillomavirus DNA typing was examined at baseline. Results: The incidence of warts among women who were human immunodeficiency virus seronegative was 1.31 versus 5.01 per 100 person-years among women who were seropositive (P < .001). Incidence of vulvar intraepithelial neoplasia among women who were seronegative was 1.31 versus 4.67 per 100 person-years among women who were seropositive (P < .001). In multivariable analysis, warts were associated with highly active antiretroviral therapy (relative hazard, 0.76), CD4 count (relative hazard, 0.91/100 cell/cm(2) increase), acquired immunodeficiency syndrome (relative hazard, 1.25), abnormal Papanicolaou test results (relative hazard, 2.18), high- or medium-risk human papillornavirus types (relative hazard, 1.91), low-risk human papillornavirus types (relative hazard, 1.48), smoking (relative hazard, 1.43), having 1 child (relative hazard, 1.54), and age (relative hazard, 0.74/10 years). Vulvar intraepithelial neoplasia was linked to highly active antiretroviral therapy (relative hazard, 0.65), CD4 count (relative hazard, 0.92), abnormal Papanicolaou test results (relative hazard, 16.03), high- or medium-risk human papillomavirus types (relative hazard, 1.37), and age (relative hazard, 0.85/10 years). Conclusion: Warts and vulvar intraepithelial neoplasia are common among women with human immunodeficiency virus. Highly active antiretroviral therapy decreases their incidence. (C) 2004 Elsevier Inc. All rights reserved. C1 So Illinois Univ, Sch Med, Dept Obstet & Gynecol, Springfield, IL 62794 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. SUNY Brooklyn, Maimonides Med Ctr, Brooklyn, NY USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. Mt Sinai Sch Med, New York, NY USA. Georgetown Univ Hosp, Washington, DC 20007 USA. Natl Inst Child Hlth, Bethesda, MD USA. RP Massad, LS (reprint author), So Illinois Univ, Sch Med, Dept Obstet & Gynecol, POB 19640, Springfield, IL 62794 USA. EM LSMASSAD@ameritech.net FU NCI NIH HHS [R01-CA85178-01]; NCRR NIH HHS [M01-RR00083, M01-RR00079]; NIAID NIH HHS [U01-AI-42590, U01-AI-31834, UO1-AI-34994, U01-AI35004, U01-AI-34993, UO1-AI-34989]; NICHD NIH HHS [U01-HD-32632] NR 16 TC 28 Z9 32 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAY PY 2004 VL 190 IS 5 BP 1241 EP 1248 DI 10.1016/j.ajog.2003.12.037 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 826JJ UT WOS:000221825100014 PM 15167825 ER PT J AU Newman, TK Jolly, CJ Rogers, J AF Newman, TK Jolly, CJ Rogers, J TI Mitochondrial phylogeny and systematics of baboons (Papio) SO AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY LA English DT Article DE taxonomy; primate; cercopithecine; mtDNA; ND4; ND5 ID NUCLEOTIDE-SEQUENCES; DNA; EVOLUTION; CYNOCEPHALUS; ORGANIZATION; DIVERGENCE; MACAQUES; MONKEYS AB Baboons (Papio, s.s.) comprise a series of parapatric allotaxa (subspecies or closely related species) widely distributed in sub-Saharan Africa. Despite extensive studies of their ecology, morphology, and behavior, disagreement about their phylogenetic relationships continues, as expressed in the current coexistence of at least three major, competing taxonomic treatments. To help resolve this situation, we sequenced similar to900 bases of mitochondrial DNA of 40 individuals from five of the widely recognized "major" allotaxa. Total sequence diversity (>5%) is high compared to most primate species. Major mitochondrial. clades correspond to recognized allotaxa, with the important exception that haplotypes from yellow and olive baboons form a single, monophyletic clade within which the two allotaxa do not comprise mutually exclusive clusters. The major clades fall unambiguously into the pattern: (chacma (Guinea (hamadryas (yellow + olive)))). This phylogeny does not support taxonomies that oppose hamadryas to all other baboons ("desert" vs. "savanna"), but is compatible with the view that all definable allotaxa should be recognized as coordinates, either as "phylogenetic" species or "biological" subspecies. The close relationship and unsegregated distribution of haplotypes from Kenyan and Tanzanian yellow and olive baboons are unexplained, but may reflect introgression across the documented hybrid zone. The overall phylogeny, when combined with paleontological data, suggests a southern African origin for extant Papio baboons, with all extant lineages sharing a common mitochondrial ancestor at approximately 1.8 Ma. (C) 2004 Wiley-Liss, Inc. C1 SW Fdn Biomed Res, Dept Genet, San Antonio, TX 78227 USA. NYU, Dept Anthropol, New York, NY 10003 USA. SW Natl Primate Ctr, San Antonio, TX 78227 USA. RP Newman, TK (reprint author), NIAAA, Neurogenet Lab, NIH, 12420 Parklawn Dr,Pk 5 Bldg,Room 451, Rockville, MD 20852 USA. EM tknewman@mail.nih.gov FU NCRR NIH HHS [RR13986]; NHLBI NIH HHS [HL28972] NR 56 TC 68 Z9 74 U1 5 U2 30 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0002-9483 J9 AM J PHYS ANTHROPOL JI Am. J. Phys. Anthropol. PD MAY PY 2004 VL 124 IS 1 BP 17 EP 27 DI 10.1002/ajpa.10340 PG 11 WC Anthropology; Evolutionary Biology SC Anthropology; Evolutionary Biology GA 816LS UT WOS:000221112000002 PM 15085544 ER PT J AU Fryer, AD Lein, PJ Howard, AS Yost, BL Beckles, RA Jett, DA AF Fryer, AD Lein, PJ Howard, AS Yost, BL Beckles, RA Jett, DA TI Mechanisms of organophosphate insecticide-induced airway hyperreactivity SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE asthma; pesticide; muscarinic receptor; cholinesterase ID PULMONARY PARASYMPATHETIC NERVES; MUSCARINIC RECEPTOR SUBTYPES; PESTICIDE EXPOSURE; GUINEA-PIG; RAT-BRAIN; CHOLINESTERASE INHIBITION; ACETYLCHOLINE-RECEPTOR; OCCUPATIONAL ASTHMA; CHILDRENS EXPOSURE; UNITED-STATES AB It has been suggested that pesticide exposure may be a contributing factor underlying the increased incidence of asthma in the United States and other industrialized nations. To test this hypothesis, airway hyperreactivity was measured in guinea pigs exposed to chlorpyrifos, a widely used organophosphate pesticide. Electrical stimulation of the vagus nerves caused frequency-dependent bronchoconstriction that was significantly potentiated in animals 24 h or 7 days after a single subcutaneous injection of either 390 mg/kg or 70 mg/kg of chlorpyrifos, respectively. Mechanisms by which chlorpyrifos may cause airway hyperreactivity include inhibition of acetylcholinesterase (AChE) or dysfunction of M3 muscarinic receptors on airway smooth muscle or of autoinhibitory M2 muscarinic receptors on parasympathetic nerves in the lung. AChE activity in the lung was significantly inhibited 24 h after treatment with 390 mg/kg of chlorpyrifos, but not 7 days after injection of 70 mg/kg of chlorpyrifos. Acute exposure to eserine ( 250 mug/ml) also significantly inhibited lung AChE but did not potentiate vagally induced bronchoconstriction. Neuronal M2 receptor function was tested using the M2 agonist pilocarpine, which inhibits vagally induced bronchoconstriction in control animals. In chlorpyrifostreated animals, pilocarpine dose-response curves were shifted significantly to the right, demonstrating decreased responsiveness of neuronal M2 receptors. In contrast, chlorpyrifos treatment did not alter methacholine-induced bronchoconstriction, suggesting that chlorpyrifos does not alter M3 muscarinic receptor function on airway smooth muscle. These data demonstrate that organophosphate insecticides can cause airway hyperreactivity in the absence of AChE inhibition by decreasing neuronal M2 receptor function. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. RP Jett, DA (reprint author), NINDS, NIH, 6001 Execut Blvd,NSC,Suite 3149,MSC 9535, Bethesda, MD 20892 USA. EM dj140o@nih.gov RI Fryer, Allison/F-2420-2014 OI Fryer, Allison/0000-0003-1712-9831 FU NIEHS NIH HHS [1-R21-ES-11771, R21 ES011771, T32-ES-07141] NR 76 TC 29 Z9 32 U1 1 U2 5 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 MAY 1 PY 2004 VL 286 IS 5 BP L963 EP L969 DI 10.1152/ajplung.00343.2003 PG 7 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 808SD UT WOS:000220587900012 PM 14704222 ER PT J AU Castrop, H Schweda, F Mizel, D Huang, YN Briggs, J Kurtz, A Schnermann, J AF Castrop, H Schweda, F Mizel, D Huang, YN Briggs, J Kurtz, A Schnermann, J TI Permissive role of nitric oxide in macula densa control of renin secretion SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE plasma renin; isolated; perfused kidney; neuronal nitric oxide synthase knockout; endothelial nitric oxide synthase knockout; furosemide; bumetanide ID SYNTHASE KNOCKOUT MICE; JUXTAGLOMERULAR CELLS; GENE-EXPRESSION; RELAXING FACTOR; ANGIOTENSIN-II; BLOOD-PRESSURE; RELEASE; FUROSEMIDE; INHIBITION; KIDNEY AB Experiments were performed in neuronal (nNOS)- and endothelial nitric oxide synthase ( eNOS)- deficient mice to study the role of nitric oxide ( NO) in macula densa control of renin secretion in vivo and in the isolated, perfused mouse kidney. Acute and chronic administration of loop diuretics was used as a method to stimulate macula densa-mediated renin secretion. Increases in plasma renin concentration (PRC) in response to a 3-day infusion of bumetanide (50 mg . kg(-1) . day(-1)) or an acute injection of furosemide (50 mg/kg ip) were not markedly altered in nNOS-/- mice. Responses to furosemide were also maintained in eNOS-/- mice, but the administration of N(omega)-nitro-L-arginine methyl ester (L-NAME) markedly attenuated the PRC response to furosemide in these mice. In the isolated kidney preparation, bumetanide caused similar relative increases in renin secretion in kidneys of wild-type, nNOS-/-, and eNOS-/- mice. Bumetanide only marginally increased renin secretion in L-NAME-treated kidneys, but the bumetanide effect was normalized by S-nitroso-N-acetyl-penicillamine. Basal PRC was significantly reduced in male nNOS -/- mice compared with nNOS +/+ (189 +/- 28 vs. 355 +/- 57 ng ANG I . ml(-1) . h(-1); P = 0.017). There was no significant difference in PRC between eNOS -/-, and eNOS -/- mice. Basal renin secretion rates in perfused kidneys isolated from nNOS -/- or eNOS -/- mice were markedly reduced compared with wild-type controls. Our data suggest that NO generated by macula densa nNOS does not play a specific mediator role in macula densa-dependent renin secretion. However, NO independent of its exact source permits the macula densa pathway of renin secretion to function normally. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. Univ Regensburg, Inst Physiol, D-93040 Regensburg, Germany. RP Schnermann, J (reprint author), NIDDK, NIH, Bldg 10,Rm 4 D51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov NR 54 TC 38 Z9 38 U1 0 U2 0 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 MAY 1 PY 2004 VL 286 IS 5 BP F848 EP F857 DI 10.1152/ajprenal.00272.2003 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 808HU UT WOS:000220561000004 PM 15075180 ER PT J AU Kim, SW Wang, WD Nielsen, J Praetorius, J Kwon, TH Knepper, MA Frokiaer, J Nielsen, S AF Kim, SW Wang, WD Nielsen, J Praetorius, J Kwon, TH Knepper, MA Frokiaer, J Nielsen, S TI Increased expression and apical targeting of renal ENaC subunits in puromycin aminonucleoside-induced nephrotic syndrome in rats SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE collecting duct; edema; proteinuria; sodium transport; water retention ID EPITHELIAL SODIUM-CHANNEL; CORTICAL COLLECTING TUBULE; LUNG LIQUID CLEARANCE; NA-CL COTRANSPORTER; ARGININE-VASOPRESSIN; GAMMA-SUBUNITS; ANGIOTENSIN-II; BETA-SUBUNIT; ALPHA-ENAC; A6 CELLS AB Nephrotic syndrome is often accompanied by sodium retention and generalized edema. However, the molecular basis for the decreased renal sodium excretion remains undefined. We hypothesized that epithelial Na channel (ENaC) subunit dysregulation may be responsible for the increased sodium retention. An experimental group of rats was treated with puromycin aminonucleoside (PAN; 180 mg/kg iv), whereas the control group received only vehicle. After 7 days, PAN treatment induced significant proteinuria, hypoalbuminemia, decreased urinary sodium excretion, and extensive ascites. The protein abundance of alpha-ENaC and beta-ENaC was increased in the inner stripe of the outer medulla (ISOM) and in the inner medulla (IM) but was not altered in the cortex. gamma-ENaC abundance was increased in the cortex, ISOM, and IM. Immunoperoxidase brightfield- and laser-scanning confocal fluorescence microscopy demonstrated increased targeting of alpha-ENaC, beta-ENaC, and gamma-ENaC subunits to the apical plasma membrane in the distal convoluted tubule (DCT2), connecting tubule, and cortical and medullary collecting duct segments. Immunoelectron microscopy further revealed an increased labeling of alpha-ENaC in the apical plasma membrane of cortical collecting duct principal cells of PAN-treated rats, indicating enhanced apical targeting of alpha-ENaC subunits. In contrast, the protein abundances of Na(+)/ H(+) exchanger type 3 (NHE3), Na(+)-K(+)-2Cl(-) cotransporter (BSC-1), and thiazide-sensitive Na(+)- Cl(-) cotransporter (TSC) were decreased. Moreover, the abundance of the alpha(1)-subunit of the Na-K-ATPase was decreased in the cortex and ISOM, but it remained unchanged in the IM. In conclusion, the increased or sustained expression of ENaC subunits combined with increased apical targeting in the DCT2, connecting tubule, and collecting duct are likely to play a role in the sodium retention associated with PAN-induced nephrotic syndrome. The decreased abundance of NHE3, BSC-1, TSC, and Na-K-ATPase may play a compensatory role to promote sodium excretion. C1 Univ Aarhus, Water & Salt Res Ctr, DK-8000 Aarhus C, Denmark. Kyungpook Natl Univ, Sch Med, Dept Biochem, Taegu 700422, South Korea. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Nielsen, S (reprint author), Univ Aarhus, Water & Salt Res Ctr, Bldg 233-234, DK-8000 Aarhus C, Denmark. EM sn@ana.au.dk OI Frokiaer, Jorgen/0000-0002-6206-8065 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 51 TC 60 Z9 61 U1 0 U2 0 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 MAY 1 PY 2004 VL 286 IS 5 BP F922 EP F935 DI 10.1152/ajprenal.00277.2003 PG 14 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 808HU UT WOS:000220561000012 PM 15075188 ER PT J AU Stewart, GS Fenton, RA Wang, WD Kwon, TH White, SJ Collins, VM Cooper, G Nielsen, S Smith, CP AF Stewart, GS Fenton, RA Wang, WD Kwon, TH White, SJ Collins, VM Cooper, G Nielsen, S Smith, CP TI The basolateral expression of mUT-A3 in the mouse kidney SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE inner medullary collecting duct cells; fluid homeostasis ID REGULATED UREA TRANSPORTER; MEDULLARY COLLECTING DUCT; COUNTERCURRENT MULTIPLICATION SYSTEM; RAT-KIDNEY; UT-A; MOLECULAR CHARACTERIZATION; CLONING; VASOPRESSIN; LOCALIZATION; UT-A1 AB Facilitative UT-A urea transporters play a central role in the urinary concentrating mechanism. There are three major UT-A isoforms found in the mouse kidney: mUT-A1, mUT-A2, and mUT-A3. The major aim of this study was to identify the location and function of mUT-A3. UT-A proteins were investigated using three novel mouse UT-A-targeted antibodies: ML446, MQ2, and ML194. ML446 detected mUT-A1 and mUT-A3. ML194 detected mUT-A1 and mUT-A2. Importantly, MQ2 was found to be selective for mUT-A3. MQ2 detected a 45- to 65-kDa signal in the mouse kidney inner medulla, which was deglycosylated to a 40-kDa protein band. Immunolocalization studies showed that mUT-A3 was strongly detected in the papillary tip, mainly in the basolateral regions of inner medullary collecting duct (IMCD) cells. Immunoblotting of subcellular fractions of inner medullary protein suggested that in mouse kidney mUT-A3 was present in plasma membranes. Consistent with this, immunoelectron microscopy demonstrated that mUT-A3 was predominantly localized at the basal plasma membrane domains of the IMCD cells in mouse kidney. Heterologous expression of mUT-A3-enhanced green fluorescent protein in Madin-Darby canine kidney cells showed that the protein localized to the basolateral membrane. In conclusion, our study indicates that mUT-A3 is a basolateral membrane transporter expressed in IMCD cells. C1 Univ Manchester, Sch Biol Sci, Manchester M13 9PT, Lancs, England. Univ Leeds, Sch Biomed Sci, Leeds LS2 9JT, W Yorkshire, England. Univ Sheffield, Dept Biomed Sci, Sheffield S10 2TN, S Yorkshire, England. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Univ Aarhus, Water & Salt Res Ctr, DK-8000 Aarhus C, Denmark. RP Smith, CP (reprint author), Univ Manchester, Sch Biol Sci, G-38 Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. EM cpsmith@man.ac.uk NR 32 TC 42 Z9 44 U1 0 U2 7 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 MAY 1 PY 2004 VL 286 IS 5 BP F979 EP F987 DI 10.1152/ajprenal.00334.2003 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 808HU UT WOS:000220561000018 PM 15075194 ER PT J AU Sykes, D Sweet, DH Lowes, S Nigam, SK Pritchard, JB Miller, DS AF Sykes, D Sweet, DH Lowes, S Nigam, SK Pritchard, JB Miller, DS TI Organic anion transport in choroid plexus from wild-type and organic anion transporter 3 (Slc22a8)-null mice SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE blood-cerebrospinal fluid barrier; confocal microscopy; sodium-dependent transport ID RAT-BRAIN; EXPRESSION; KIDNEY; IDENTIFICATION; EPITHELIUM; LIVER; OATP2; LOCALIZATION; INVOLVEMENT; SUBSTRATE AB The choroid plexus actively transports endogenous, xenobiotic, and therapeutic compounds from cerebrospinal fluid to blood, thereby limiting their exposure to the central nervous system (CNS). Establishing the mechanisms responsible for this transport is critical to our understanding of basic choroid plexus physiology and will likely impact drug targeting to the CNS. We recently generated an organic anion transporter 3-(Oat3)-null mouse, which exhibited loss of PAH, estrone sulfate, and taurocholate transport in kidney and of fluorescein (FL) transport in choroid plexus. Here, we measured the uptake of four Oat3 substrates by choroid plexus from wild-type and Oat3-null mice to establish 1) the contribution of Oat3 to the apical uptake of each substrate and 2) the Na dependence of transport by Oat3 in the intact tissue. Mediated transport of PAH and FL was essentially abolished in tissue from Oat3-null mice. In contrast, only a 33% reduction in estrone sulfate uptake was observed in tissue from Oat3-null mice and, surprisingly, no reduction in taurocholate uptake could be detected. For PAH, FL, and estrone sulfate, all Oat3-mediated transport was Na dependent. However, estrone sulfate and taurocholate also exhibited additional mediated and Na-dependent components of uptake that were not attributed to Oat3, demonstrating the complexity of organic anion transport in this tissue and the need for further examination of expressed transporters and their energetics. C1 NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Med Univ S Carolina, Dept Pharmaceut Sci, Charleston, SC 29425 USA. Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Med, Div Nephrol Hypertens, La Jolla, CA 92093 USA. RP Miller, DS (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM miller@niehs.nih.gov RI Sweet, Douglas/H-7914-2013 OI Sweet, Douglas/0000-0002-8911-9184 FU NICHD NIH HHS [R01-HD-40011] NR 25 TC 43 Z9 44 U1 0 U2 0 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 MAY 1 PY 2004 VL 286 IS 5 BP F972 EP F978 DI 10.1152/ajprenal.00356.2003 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 808HU UT WOS:000220561000017 PM 15075193 ER PT J AU Miller, KE Laszlo, K Suomi, SJ AF Miller, K. E. Laszlo, K. Suomi, S. J. TI The relationship between social rank and food consumption, relative to food accessibility in captive tufted capuchins (Cebus apella) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Miller, K. E.; Laszlo, K.; Suomi, S. J.] NIH Anim Ctr, NIH, LCE NICHD, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 16 BP 40 EP 41 PG 2 WC Zoology SC Zoology GA V44HI UT WOS:000202993400017 ER PT J AU Howell, S Westergaard, G Cleveland, A Higley, JD AF Howell, S. Westergaard, G. Cleveland, A. Higley, J. D. TI Physiological correlates of maternal style in free-ranging rhesus macaques (Macaca mulatta) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Howell, S.; Westergaard, G.; Cleveland, A.] Carolina Res, Yemassee, SC 29945 USA. [Higley, J. D.] NIAAA, NIH, LCS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 34 BP 50 EP 51 PG 2 WC Zoology SC Zoology GA V44HI UT WOS:000202993400035 ER PT J AU Schwandt, ML Lindell, S Shannon, C Suomi, S Higley, JD AF Schwandt, M. L. Lindell, S. Shannon, C. Suomi, S. Higley, J. D. TI Physiological correlates of behavior in macaque (Macaca mulatta) mothers during the first month postpartum and during the early weaning period: Does maternal experience influence the interaction between physiology and behavior? SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Schwandt, M. L.; Lindell, S.; Higley, J. D.] NIAAA, NIH, Clin Studies Lab, Primate Unit, Poolesville, MD 20837 USA. [Shannon, C.; Suomi, S.] NICHD, NIH, Comparat Ethol Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 49 BP 59 EP 59 PG 1 WC Zoology SC Zoology GA V44HI UT WOS:000202993400050 ER PT J AU Becker, ML Bernhards, DE Chisholm, KL Maimon, G Champoux, M Higley, JD Suomi, SJ Newman, JD AF Becker, M. L. Bernhards, D. E. Chisholm, K. L. Maimon, G. Champoux, M. Higley, J. D. Suomi, S. J. Newman, J. D. TI Calling rate as a measure of stress reactivity in mother- and nursery-reared rhesus infants (Macaca mulatta) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Becker, M. L.; Bernhards, D. E.; Maimon, G.; Champoux, M.; Suomi, S. J.; Newman, J. D.] NICHD, NIH, Anim Ctr, LCE, Poolesville, MD 20837 USA. [Chisholm, K. L.; Higley, J. D.] NIAAA, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 2 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 50 BP 60 EP 60 PG 1 WC Zoology SC Zoology GA V44HI UT WOS:000202993400051 ER PT J AU Rakhovskaya, MV Soltis, J Bernhards, D Becker, ML Sander, K Newman, JD AF Rakhovskaya, M. V. Soltis, J. Bernhards, D. Becker, M. L. Sander, K. Newman, J. D. TI Captive squirrel monkey groups respond to isolation call playbacks with separation calls SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Rakhovskaya, M. V.; Soltis, J.; Bernhards, D.; Becker, M. L.; Sander, K.; Newman, J. D.] Natl Inst Child & Human Dev, Comparat Ethol Lab, NIH, DHHS, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 54 BP 62 EP 62 PG 1 WC Zoology SC Zoology GA V44HI UT WOS:000202993400055 ER PT J AU Chisholm, KL Becker, ML Schivandt, ML Suomi, SJ Higley, JD AF Chisholm, K. L. Becker, M. L. Schivandt, M. L. Suomi, S. J. Higley, J. D. TI Risk-taking and its relationship to alcohol consumption in rhesus macaques (Macaca mulatta) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Chisholm, K. L.; Schivandt, M. L.; Higley, J. D.] NIAAA, NIH, Clin Studies Lab, Primate Unit,Anim Ctr, Poolesville, MD 20837 USA. [Becker, M. L.; Suomi, S. J.] NICHD, NIH, Comparat Ethol Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 59 BP 65 EP 65 PG 1 WC Zoology SC Zoology GA V44HI UT WOS:000202993400060 ER PT J AU Laszlo, K Miller, KE Suomi, SJ AF Laszlo, K. Miller, K. E. Suomi, S. J. TI Urine washing in captive tufted capuchin monkeys (Cebus apella) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Laszlo, K.; Miller, K. E.; Suomi, S. J.] NICHHD, NIH, Comparat Ethol Lab, Anim Ctr, Poolesville, MD 20837 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 65 BP 68 EP 69 PG 2 WC Zoology SC Zoology GA V44HI UT WOS:000202993400066 ER PT J AU Gerald, MS Lyons, H Treier, KM Robbins, KLR AF Gerald, M. S. Lyons, H. Treier, K. M. Robbins, K. L. Rasmussen TI Face and sex skin colors variably correlate with age, body and fat measures in free-ranging adult female rhesus macaques (Macaca mulatta) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Gerald, M. S.; Lyons, H.] Caribbean Primate Res Ctr, Punta Santiago, PR 00741 USA. [Gerald, M. S.; Lyons, H.] Univ Puerto Rico, Dept Med, San Juan, PR 00936 USA. [Treier, K. M.; Robbins, K. L. Rasmussen] NICHD, NIH, Comparat Ethol Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 89 BP 81 EP 82 PG 2 WC Zoology SC Zoology GA V44HI UT WOS:000202993400090 ER PT J AU Kramer, PA Newell-Morris, LL Simkin, PA Ingram, D AF Kramer, P. A. Newell-Morris, L. L. Simkin, P. A. Ingram, D. TI Does caloric restriction effect the progression of spinal osteoarthritis in rhesus macaques (Macaca mulatta) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Kramer, P. A.; Newell-Morris, L. L.; Simkin, P. A.] Univ Washington, Seattle, WA 98195 USA. [Ingram, D.] NIA, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 107 BP 91 EP 92 PG 2 WC Zoology SC Zoology GA V44HI UT WOS:000202993400108 ER PT J AU Sheldon, EL Barr, CS Newman, TK Novak, MS Shannon-Lindell, C Champoux, M Schwandt, M Higley, JD Soumi, SJ AF Sheldon, E. L. Barr, C. S. Newman, T. K. Novak, M. S. Shannon-Lindell, C. Champoux, M. Schwandt, M. Higley, J. D. Soumi, S. J. TI The effects of parental serotonin transporter gene alleles (5HTTLPR) on birthweight in a captive colony of rhesus macaques (Macaca mulatta) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Sheldon, E. L.; Novak, M. S.; Shannon-Lindell, C.; Champoux, M.; Soumi, S. J.] NICHHD, Comparat Ethol Lab, NIH, Anim Ctr, Poolesville, MD 20837 USA. [Barr, C. S.; Newman, T. K.; Schwandt, M.; Higley, J. D.] NIAAA, Clin Studies Lab, NIH, Anim Ctr, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 106 BP 91 EP 91 PG 1 WC Zoology SC Zoology GA V44HI UT WOS:000202993400107 ER PT J AU Hamby, SM Pierre, PJ Becker, M DePetrillo, PB Higley, JD Suomi, SJ Bennett, AJ AF Hamby, S. M. Pierre, P. J. Becker, M. DePetrillo, P. B. Higley, J. D. Suomi, S. J. Bennett, A. J. TI The effects of acute ketamine anesthesia on monoamine metabolites in ketamine-nafve versus ketamine-experienced infant rhesus monkeys (Macaca mulatta) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Hamby, S. M.; Pierre, P. J.; Bennett, A. J.] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC 27157 USA. [Becker, M.; DePetrillo, P. B.; Higley, J. D.] NIAAA, Clin Studies Lab, Bethesda, MD USA. [Suomi, S. J.] NICHD, Comparat Ethol Lab, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 108 BP 92 EP 92 PG 1 WC Zoology SC Zoology GA V44HI UT WOS:000202993400109 ER PT J AU O'Neill-Wagner, P AF O'Neill-Wagner, P. TI Fostering infants into a semi-freeranging group of rhesus monkeys (Macaca mulatta) for genetic diversity SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [O'Neill-Wagner, P.] NICHD, Comparat Ethol Lab, NIH, Anim Ctr, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 111 BP 94 EP 94 PG 1 WC Zoology SC Zoology GA V44HI UT WOS:000202993400112 ER PT J AU Barr, CS Dvoskin, RL Newman, TK Goldman, D Suomi, SJ Higley, JD AF Barr, C. S. Dvoskin, R. L. Newman, T. K. Goldman, D. Suomi, S. J. Higley, J. D. TI CRH gene promoter variation influences LHPA-axis activity in infant rhesus macaques (Macaca mulatta) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Barr, C. S.; Dvoskin, R. L.; Newman, T. K.; Goldman, D.; Suomi, S. J.; Higley, J. D.] NIH, Anim Ctr, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 122 BP 100 EP 100 PG 1 WC Zoology SC Zoology GA V44HI UT WOS:000202993400122 ER PT J AU Bennett, AJ Kaiss, KM Laudenslager, M Kaplan, JR Robbins, KL Ma, R Suomi, SJ DePetrillo, PB AF Bennett, A. J. Kaiss, K. M. Laudenslager, M. Kaplan, J. R. Robbins, K. L. Ma, R. Suomi, S. J. DePetrillo, P. B. TI Comparison of allele frequencies in Macaca fascicularis, M-mulatta, M-nemestrina, and M-radiata using an enhanced method for detecting the short and long promoter alleles of the Macaca SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Bennett, A. J.] Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27157 USA. [Bennett, A. J.] Wake Forest Univ, Bowman Gray Sch Med, Dept Pediat, Winston Salem, NC 27157 USA. [Kaiss, K. M.; Ma, R.; DePetrillo, P. B.] NIAAA, Clin Studies Lab, DICBR, NIH, Bethesda, MD USA. [Laudenslager, M.] Univ Colorado, Hlth Sci Ctr, Dept Psychiat, Boulder, CO 80309 USA. [Kaplan, J. R.] Wake Forest Univ, Bowman Gray Sch Med, Dept Comparat Med, Winston Salem, NC 27109 USA. [Robbins, K. L.; Suomi, S. J.] NICHD, Comparat Ethol Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 123 BP 100 EP 101 PG 2 WC Zoology SC Zoology GA V44HI UT WOS:000202993400123 ER PT J AU Newman, TK Barr, CS Babb, P Becker, M Suomi, SJ Lesch, K Higley, JD AF Newman, T. K. Barr, C. S. Babb, P. Becker, M. Suomi, S. J. Lesch, K. Higley, J. D. TI Social impulsivity in captive rhesus monkeys (Macaca mulatta) is influenced by variation in a functional MAOA gene promoter polymorphism SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Newman, T. K.; Barr, C. S.; Babb, P.; Higley, J. D.] NIAAA, NIH, Rockville, MD 20852 USA. [Becker, M.; Suomi, S. J.] NICHD, NIH, Bethesda, MD USA. [Lesch, K.] Univ Wurtzburg, Wurzburg, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 126 BP 102 EP 103 PG 2 WC Zoology SC Zoology GA V44HI UT WOS:000202993400126 ER PT J AU Freeman, H Cantalupo, C Weiss, A King, J Hopkins, W AF Freeman, H. Cantalupo, C. Weiss, A. King, J. Hopkins, W. TI Assocation between personality and brain asymmetries in the limbic system of chimpanzees SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Freeman, H.; Cantalupo, C.; Hopkins, W.] Yerkes Reg Primate Res Ctr, Div Psychobiol, Atlanta, GA 30322 USA. [Cantalupo, C.] Georgia State Univ, Language Res Ctr, Atlanta, GA 30303 USA. [Weiss, A.] NIA, Bethesda, MD 20892 USA. [King, J.] Univ Arizona, Dept Psychol, Tucson, AZ 85721 USA. [Hopkins, W.] Berry Coll, Dept Psychol, Mt Berry, GA 30419 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 131 BP 105 EP 106 PG 2 WC Zoology SC Zoology GA V44HI UT WOS:000202993400131 ER PT J AU Newman, JD Becker, ML AF Newman, J. D. Becker, M. L. TI Vocal sequences as markers of developmental milestones, neurological maturation and individual experience SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Newman, J. D.; Becker, M. L.] NICHD, LCE, NIH, Anim Ctr, Poolesville, MD 20837 USA. [Newman, J. D.; Becker, M. L.] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 164 BP 123 EP 124 PG 2 WC Zoology SC Zoology GA V44HI UT WOS:000202993400164 ER PT J AU Weed, JL AF Weed, J. L. TI Owl monkeys (Aotus spp.) in the laboratory: Thinking outside the nest box SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Meeting Abstract C1 [Weed, J. L.] NIH, Div Vet Resources, Off Res Serv, DHHS, Poolesville, MD 20837 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2004 VL 62 IS 1 SU 1 MA 172 BP 128 EP 128 PG 1 WC Zoology SC Zoology GA V44HI UT WOS:000202993400172 ER PT J AU Fee, E Brown, TM AF Fee, E Brown, TM TI Popularizing the toothbrush SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 NIH, Div Med, Natl Lib Med, Bethesda, MD USA. Univ Rochester, Dept Hist, Rochester, NY 14627 USA. Univ Rochester, Dept Community & Prevent Med, Rochester, NY 14627 USA. RP Fee, E (reprint author), Bldg 38,Room 1E21,8600 Rockville Pike, Bethesda, MD 20892 USA. EM elizabeth_fee@nlm.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2004 VL 94 IS 5 BP 721 EP 721 DI 10.2105/AJPH.94.5.721 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 816LM UT WOS:000221111400008 PM 15117686 ER PT J AU Brown, TM Fee, E AF Brown, TM Fee, E TI Sir James Crichton-Browne - Victorian psychiatrist and public health reformer SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 Univ Rochester, Dept Hist, Rochester, NY 14627 USA. Univ Rochester, Dept Commun & Prevent Med, Rochester, NY 14627 USA. NIH, Natl Lib Med, Hist Med Div, Bethesda, MD USA. RP Brown, TM (reprint author), Univ Rochester, Dept Hist, Rochester, NY 14627 USA. EM theodore_brown@urmc.rochester.edu NR 4 TC 2 Z9 2 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2004 VL 94 IS 5 BP 724 EP 724 DI 10.2105/AJPH.94.5.724 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 816LM UT WOS:000221111400037 PM 15117688 ER PT J AU Bonham, VL Sellers, SL Neighbors, HW AF Bonham, VL Sellers, SL Neighbors, HW TI John Henryism and self-reported physical health among high-socioeconomic status African American men SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID BLOOD-PRESSURE DIFFERENCES; JOHN-HENRYISM; BLACK-MEN AB We performed a cross-sectional survey of high-socioeconomic status (SES) African American men and their health to examine the relationship between John Henryism (the strong behavioral predisposition to directly confront barriers to upward social mobility) and self-reported physical health status. We found a positive association between John Henryism and better physical health among high-SES African American men. The study of social and behavioral implications of health of men of differing SES is required to develop strategies to improve the health of African American men. C1 Michigan State Univ, E Lansing, MI 48824 USA. Univ Wisconsin, Madison, WI 53706 USA. Univ Michigan, Ann Arbor, MI 48109 USA. RP Bonham, VL (reprint author), NHGRI, NIH, 31 Ctr Dr,Bldg 31,Room 4B09, Bethesda, MD 20892 USA. EM bonhamv@mail.nih.gov FU BHP HRSA HHS [D34 MB 04036-06] NR 12 TC 29 Z9 29 U1 0 U2 4 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAY PY 2004 VL 94 IS 5 BP 737 EP 738 DI 10.2105/AJPH.94.5.737 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 816LM UT WOS:000221111400011 PM 15117690 ER PT J AU Boyd, SJ Thomas-Gosain, NF Umbricht, A Tucker, MJ Leslie, JM Chaisson, RE Preston, KL AF Boyd, SJ Thomas-Gosain, NF Umbricht, A Tucker, MJ Leslie, JM Chaisson, RE Preston, KL TI Gender differences in indices of opioid dependency and medical comorbidity in a population of hospitalized HIV-infected African-Americans SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID IMMUNODEFICIENCY-VIRUS DISEASE; DRUG-USERS; CLINICAL-MANIFESTATIONS; NATURAL-HISTORY; SEX-DIFFERENCES; ADDICT CAREERS; PROGRESSION; ZIDOVUDINE AB We examined gender differences in drug use patterns and in medical presentation among 520 hospitalized, HIV-infected African-Americans Substance abuse history was self-reported, and medical data were obtained by chart review. Overall, 321 (65%) reported ever having used heroin, with equivalent rates in men and women. Women were more likely to report current use, to have sought treatment, and tended to feel more dependent on heroin than men. Among heroin users, women were more likely to be admitted for conditions related to drug use, rather than AIDS, and to have CD4 counts >200/mm(3). These gender differences in opioid dependency and medical comorbidity may indicate a need for alternative treatment approaches for men and women. C1 NIDA, IRP, Baltimore, MD 21224 USA. Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Preston, KL (reprint author), NIDA, IRP, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM kpreston@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 NR 21 TC 2 Z9 2 U1 0 U2 0 PU BRUNNER-ROUTLEDGE PI PHILADELPHIA PA 325 CHESTNUT ST, 8TH FL, PHILADELPHIA, PA 19106 USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD MAY-JUN PY 2004 VL 13 IS 3 BP 281 EP 291 DI 10.1080/10550490490459960 PG 11 WC Substance Abuse SC Substance Abuse GA 836XT UT WOS:000222590200007 PM 15370947 ER PT J AU Womack, S Compton, WM Dennis, M McCormick, S Fraser, J Horton, JC Spitznagel, EL Cottler, LB AF Womack, S Compton, WM Dennis, M McCormick, S Fraser, J Horton, JC Spitznagel, EL Cottler, LB TI Improving treatment services for substance abusers with comorbid depression SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article; Proceedings Paper CT 63rd Annual Scientific Meeting of the CPDD CY JUN, 2001 CL Scottsdale, AZ SP CPDD ID PSYCHIATRIC-DISORDERS; MAINTENANCE PATIENTS; MAJOR DEPRESSION; COCAINE ABUSERS; MALE VETERANS; PRIMARY-CARE; DEPENDENCE; ALCOHOLISM; MANAGEMENT; METHADONE AB Early identification of patients with comorbid depression and their subsequent enrollment in an enhanced psychiatric case management (PCM) intervention were examined as an effective way to engage depressed substance abuse patients into psychiatric treatment. Depression was screened using the Global Appraisal of Individual Needs (GAIN) and a DMS-IV checklist. Patients positive on both evaluations were assigned to PCM (n = 10) or to no case management,or treatment as usual (TAU) (n = 10). An examination of outcomes at six weeks indicated that PCM services are feasible and appear to be effective in encouraging use of psychiatric referral buy depressed substance abusers. C1 Washington Univ, Dept Psychiat, St Louis, MO USA. Washington Univ, Dept Math, St Louis, MO 63130 USA. Chestnut Hlth Syst, Granite City, IL USA. Chestnut Hlth Syst, Bloomington, IL USA. RP Compton, WM (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,Room 5153,MSC 9589, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov FU NIDA NIH HHS [DA00488, DA07313]; PHS HHS [T112541] NR 49 TC 4 Z9 4 U1 2 U2 3 PU BRUNNER-ROUTLEDGE PI PHILADELPHIA PA 325 CHESTNUT ST, 8TH FL, PHILADELPHIA, PA 19106 USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD MAY-JUN PY 2004 VL 13 IS 3 BP 295 EP 304 DI 10.1080/10550490490460102 PG 10 WC Substance Abuse SC Substance Abuse GA 836XT UT WOS:000222590200009 PM 15370949 ER PT J AU Miao, WW Gastwirth, JL AF Miao, WW Gastwirth, JL TI The effect of dependence on confidence intervals for a population proportion SO AMERICAN STATISTICIAN LA English DT Article DE coverage probability; dependent observations; expected length of confidence interval; jury discrimination ID BINOMIAL PROPORTION; MARKOV-CHAIN; APPROXIMATE; TRIALS; PARAMETER AB The binomial model is widely used in statistical applications. Usually, the success probability, p, and its associated confidence interval are estimated from a random sample. Thus, the observations are independent and identically distributed. Motivated by a legal case where some grand jurors could serve a second year, this article shows that when the observations are dependent, even slightly, the coverage probabilities of the usual confidence intervals can deviate noticeably from their nominal level. Several modified confidence intervals that incorporate the dependence structure are proposed and examined. Our results show that the modified Wilson, Agresti-Coull, and Jeffreys confidence intervals perform well and can be recommended for general use. C1 Macalester Coll, Dept Math & Comp Sci, St Paul, MN 55105 USA. George Washington Univ, Dept Stat, Washington, DC 20052 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Miao, WW (reprint author), Macalester Coll, Dept Math & Comp Sci, St Paul, MN 55105 USA. EM miao@macalester.edu; jigast@gwu.edu NR 30 TC 12 Z9 12 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0003-1305 J9 AM STAT JI Am. Stat. PD MAY PY 2004 VL 58 IS 2 BP 124 EP 130 DI 10.1198/0003130043303 PG 7 WC Statistics & Probability SC Mathematics GA 816UU UT WOS:000221135600005 ER PT J AU Vila, C Leonard, JA Iriarte, A O'Brien, SJ Johnson, WE Wayne, RK AF Vila, C Leonard, JA Iriarte, A O'Brien, SJ Johnson, WE Wayne, RK TI Detecting the vanishing populations of the highly endangered Darwin's fox, Pseudalopex fulvipes SO ANIMAL CONSERVATION LA English DT Article ID GENETIC-ANALYSIS; FECES; CONSERVATION; HABITAT; CHILE AB Darwin's fox (Pseudalopex fulvipes) is known to survive only on Chiloe Island off the coast of southern Chile and in Nahuelbuta National Park, 600 kin to the north in mainland Chile. The Valdivian coastal forest, in which the Darwin's fox lives, historically spanned from Nahuelbuta National Park southward past Chiloe Island on the mainland. Furthermore, the forest on Chiloe Island was connected to the mainland forest by a land bridge for much of the Pleistocene. Thus, the distribution of Valdivian forest suggests that the historic range of Darwin's fox may have been much larger. We searched the remnant pockets of coastal forest on mainland Chile using live traps, non-invasive techniques and interviews to look for new populations of the critically endangered Darwin's fox. Although no Darwin's fox was captured, evidence of a new population near Punta Chanchan was found. C1 NCI, Lab Genom Divers, FCRDC, Frederick, MD 21702 USA. Univ Calif Los Angeles, Dept Organism Biol Ecol & Evolut, Los Angeles, CA 90095 USA. Serv Agricola & Ganadero, Santiago, Chile. RP Johnson, WE (reprint author), NCI, Lab Genom Divers, FCRDC, Frederick, MD 21702 USA. EM johnsonw@ncifcrf.gov RI Johnson, Warren/D-4149-2016; Vila, Carles/H-4893-2013; Leonard, Jennifer/A-7894-2010 OI Johnson, Warren/0000-0002-5954-186X; Vila, Carles/0000-0002-4206-5246; Leonard, Jennifer/0000-0003-0291-7819 NR 27 TC 10 Z9 11 U1 2 U2 18 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 1367-9430 J9 ANIM CONSERV JI Anim. Conserv. PD MAY PY 2004 VL 7 BP 147 EP 153 DI 10.1017/s1367943004001271 PN 2 PG 7 WC Biodiversity Conservation; Ecology SC Biodiversity & Conservation; Environmental Sciences & Ecology GA 828JR UT WOS:000221970100005 ER PT J AU Manolio, TA Cushman, M Gottdiener, JS Dobs, A Kuller, LH Kronmal, RA AF Manolio, TA Cushman, M Gottdiener, JS Dobs, A Kuller, LH Kronmal, RA CA CHS Coll Research Grp TI Predictors of falling cholesterol levels in older adults: The cardiovascular health study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE aged; cholesterol; epidemiology; risk factors ID DENSITY-LIPOPROTEIN CHOLESTEROL; CORONARY HEART-DISEASE; SERUM-CHOLESTEROL; LONGITUDINAL CHANGES; BLOOD CHOLESTEROL; MEASUREMENT ERROR; MORTALITY; MEN; ASSOCIATION; HYPOCHOLESTEROLEMIA AB PURPOSE: To estimate 4-year change in serum total cholesterol levels in a population-based sample of older adults and identify independent predictors of cholesterol decline. METHODS: Prospective study of 2837 adults aged 65 years and older with serum cholesterol measured in 1992-1993 and 1996-1997. RESULTS: Mean serum cholesterol levels declined 6.3 mg/dl between the two examinations. Declines were greater in white (- 7.3 mg/dl) than black (- 1.4 mg/dl) participants and in those in good/excellent health (-0.9 mg/dl) vs. fair/poor health (-3.1 mg/dl; both p < 0.01). Factors associated with greater decline on multivariate analysis included age, male gender, and higher white cell count, albumin, and baseline cholesterol. Cholesterol levels declined 2.0 mg/dl per 6 year increment in baseline age and 6.8 mg/dl more in men than women after adjustment for other factors. C-reactive protein levels were unrelated to cholesterol change. CONCLUSION: Declining cholesterol levels were associated with male gender, advanced age, weight loss, and white blood cell count but not with C-reactive protein levels. The role of declining cholesterol synthesis, due to as yet undefined age-related changes or to cytokine-mediated reductions related to illness, should be examined to help clarify the mechanisms of the sometimes marked declines in cholesterol levels observed at advanced ages. (C) 2004 Elsevier Inc. All rights reserved. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Vermont, Dept Med, Burlington, VT USA. St Francis Hosp, Div Cardiol, Roslyn, NY USA. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. RP Manolio, TA (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr,Room 8160, Bethesda, MD 20892 USA. EM manolio@nih.gov FU NHLBI NIH HHS [N01 HC-15103, N01-HC-85086, N01-HC-35129, N01-HC-85079] NR 40 TC 10 Z9 11 U1 1 U2 1 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 MAY PY 2004 VL 14 IS 5 BP 325 EP 331 DI 10.1016/j.annepidem.2003.09.006 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 829MW UT WOS:000222053800003 PM 15177271 ER PT J AU Seggewiss, R Ho, AD Kraemer, A AF Seggewiss, R Ho, AD Kraemer, A TI Remarkable response to rituximab in a patient with atypical CD20(++) mantle cell lymphoma of the bone marrow leading to severe pancytopenia SO ANNALS OF HEMATOLOGY LA English DT Article DE rituximab; CD20; mantle cell lymphoma; pancytopenia ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ANTI-CD20 MONOCLONAL-ANTIBODY; THERAPY; MECHANISMS AB Rituximab, a chimeric monoclonal antibody which binds to the CD20 antigen, has been reported in several studies to induce remissions in low- and high-grade non-Hodgkin's lymphoma without causing myelosuppression. We report here a case of a 68-year-old female patient with an atypical mantle cell lymphoma infiltrating only the bone marrow without leukemic involvement or any other nodal or extranodal manifestations. Progressive severe pancytopenia due to the diffuse bone marrow infiltration led to life-threatening infections following oral chlorambucil treatment. No response to chlorambucil was noted. The patient attained a complete remission after salvage therapy with four weekly infusions of single-agent rituximab at a standard dose of 375 mg/m(2). Thus, anti-CD20 antibody may be the treatment of choice for patients with CD20(+) B-non-Hodgkin's lymphoma who cannot tolerate chemotherapy due to high risk of infectious complications as a result of severe pancytopenia. C1 Univ Heidelberg, Dept Internal Med 5, D-69115 Heidelberg, Germany. RP Seggewiss, R (reprint author), NHLBI, NIH, DHHS, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM seggewir@nhlbi.nih.gov NR 22 TC 2 Z9 2 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0939-5555 J9 ANN HEMATOL JI Ann. Hematol. PD MAY PY 2004 VL 83 IS 5 BP 316 EP 318 DI 10.1007/s00277-003-0793-z PG 3 WC Hematology SC Hematology GA 815JI UT WOS:000221038200012 PM 15064861 ER PT J AU Weitz, CA Garruto, RM Chin, CT Liu, JC AF Weitz, CA Garruto, RM Chin, CT Liu, JC TI Morphological growth and thorax dimensions among Tibetan compared to Han children, adolescents and young adults born and raised at high altitude SO ANNALS OF HUMAN BIOLOGY LA English DT Article ID PHYSICAL GROWTH; EUROPEAN ANCESTRY; CHEST MORPHOLOGY; ANDEAN POPULATIONS; BODY PROPORTIONS; CHINESE CHILDREN; AYMARA CHILDREN; LUNG; HEALTH; NUTRITION AB Background: Studies comparing the growth of indigenous high-altitude Aymara children and children of low-altitude European descent who have been born and raised at high altitude in the Andes have provided evidence for genetically-determined differences in thorax growth, as well as for population differences in height, weight and other measures of overall size. Comparable studies now can be undertaken in Asia because of the growing number of Han Chinese who have been born and raised at high altitude on the Qinghai-Tibetan Plateau. Aim: The study compares the growth of indigenous Tibetan children and children of Han descent who have been born and raised at the same high altitudes, and under similar socio-economic conditions. Subjects and methods: Measurements of stature, sitting height, weight, triceps and subscapular skinfolds, upper arm muscle area, transverse chest diameter, anterio-posterior chest diameter, and chest circumference were taken on 1439 Tibetan and Han males and females between the ages of 6 and 29 years who were born and raised 3200 m, 3800 m or at 4300 m in the high altitude province of Qinghai in western China. Results: Han-Tibetan differences in body size do not occur systematically for any measurement, for any age group, or for either gender; nor is there a systematic pattern of body size differences between 3200 m and 4300 m. This indicates that there are no differences in general growth between the two groups at high altitude in Qinghai, although both groups grow more slowly than urban children at low altitude in China. On the other hand, Tibetan males possess significantly deeper chests than Han males, and Tibetan females possess significantly wider chests than Han females. Tibetans of both sexes possess significantly larger chest circumferences than Han males and females. Conclusions: Although genetic similarities cannot be ruled out, comparable dietary stress is a likely explanation for the similar and slow morphological growth of Han and Tibetans at high altitude. However, Han-Tibetan differences in thorax dimensions are likely a consequence of population (genetic) differences in the response to hypoxia during growth. C1 Temple Univ, Dept Anthropol, Philadelphia, PA 19122 USA. SUNY Binghamton, Binghamton, NY 13902 USA. NIH, Bethesda, MD 20891 USA. Beijing Med Univ, Maternal & Childrens Hosp, Beijing 100083, Peoples R China. RP Weitz, CA (reprint author), Temple Univ, Dept Anthropol, 214 Gladfelter Hall, Philadelphia, PA 19122 USA. EM WEITZ@TEMPLE.EDU NR 46 TC 24 Z9 29 U1 3 U2 4 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0301-4460 J9 ANN HUM BIOL JI Ann. Hum. Biol. PD MAY-JUN PY 2004 VL 31 IS 3 BP 292 EP 310 DI 10.1080/0301446042000196316 PG 19 WC Anthropology; Biology; Public, Environmental & Occupational Health SC Anthropology; Life Sciences & Biomedicine - Other Topics; Public, Environmental & Occupational Health GA 828UY UT WOS:000222000100003 PM 15204346 ER PT J AU Anderson, SA Shukaliak-Quandt, J Jordan, EK Arbab, AS Martin, R McFarland, H Frank, JA AF Anderson, SA Shukaliak-Quandt, J Jordan, EK Arbab, AS Martin, R McFarland, H Frank, JA TI Magnetic resonance imaging of labeled T-Cells in a mouse model of multiple sclerosis SO ANNALS OF NEUROLOGY LA English DT Article ID IN-VIVO TRACKING; TRANSFECTION AGENTS; STEM-CELLS; CONTRAST AGENTS; ENCEPHALOMYELITIS; NANOPARTICLES; MIGRATION AB Multiple sclerosis (MS) is a T cell-mediated autoimmune disease with early lesions characterized by mononuclcear cellular infiltrate, edema, demyelination, and axonal loss that contribute to the clinical course of the disease. Experimental autoimmune encephalomyelitis (EAE) in the mouse is a valuable model with a similar disease course to relapsing-remitting MS. The ability to detect the migration of encephalitogenic T cells into the central nervous system in EAE and MS would provide key information on these cells role in the development of lesions observed on magnetic resonance imaging (MRI). T cells were labeled for detection by magnetic resonance imaging using Food and Drug Administration-approved, superparamagnetic iron oxide nanoparticles (Ferumoxides) complexed to poly-L-Lysine (FE-PLL). EAE was induced by adoptive transfer of either labeled or unlabeled T cells. After disease onset, FE-PLL-labeled T cells were detected in the mouse spinal cord using in vivo and ex vivo cellular MRI. Excellent correlation was seen between MRI-visible lesions in the spinal cord and histopathology. The results demonstrate that T cells labeled with FE-PLL can induce EAE disease and can be detected in vivo in the mouse model. The magnetic labeling of cells opens the possibility of monitoring specific cellular phenotypes or pharmacologically or genetically engineered cells by MRI. C1 NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. NIH, Lab Diagnost Radiol Res, Expt Neuroimaging Sect, Bethesda, MD 20892 USA. RP Anderson, SA (reprint author), NINDS, Neuroimmunol Branch, NIH, 10 Ctr Dr,Bldg 10,Room B1N256,MSC 1074, Bethesda, MD 20892 USA. EM sanderso@helix.nih.gov NR 17 TC 104 Z9 112 U1 2 U2 7 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAY PY 2004 VL 55 IS 5 BP 654 EP 659 DI 10.1002/ana.20066 PG 6 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 816NE UT WOS:000221115800008 PM 15122705 ER PT J AU Vortmeyer, AO Yuan, QY Lee, YS Zhuang, ZP Oldfield, EH AF Vortmeyer, AO Yuan, QY Lee, YS Zhuang, ZP Oldfield, EH TI Developmental effects of von Hippel-Lindau gene deficiency SO ANNALS OF NEUROLOGY LA English DT Article ID NATURAL-HISTORY; DISEASE; HEMANGIOBLASTOMAS; HISTOGENESIS; LESIONS; CANCER; INSIGHTS AB The histogenetic origin and the basis of the distribution of central nervous system (CNS) hemangioblastomas in the von Hippel-Lindau (VHL) tumor suppressor gene syndrome, VHL disease, are unknown. To better understand hemangio-blastoma histogenesis, we analyzed postmortem CNS tissues from four patients with well-established diagnosis of VHL disease including development of characteristic tumors and positive family history. Numerous angiomesenchymal tumor-lets, which resembled hemangioblastoma, but which also consistently showed distinct histological features, were distributed in the nerve roots, spinal cord, and cerebellum. Genetic analysis consistently showed deletion of the wild-type VHL allele in these tumorlets. Most angiomesenchymal tumorlets were in the dorsal nerve roots; the anterior roots and cerebellum were less frequently affected. Tumorlet distribution was highly consistent in the four cases. In analogy to the wide morphological spectrum of lesions known to exist in VHL kidneys, nerve roots appear to harbor more wide-spread and morphologically heterogeneous changes than previously appreciated. The abundance of tumorlets, associated with highly consistent morphology and topography, suggests a developmental origin of hemangioblastoma. Therefore, in VHL disease, inactivation of the VHL wild-type allele appears necessary, but not sufficient, for the formation of tumor that produces symptoms and neurological disability. C1 NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. RP Vortmeyer, AO (reprint author), NINDS, Surg Neurol Branch, Bldg 10,Room 5037,10 Ctr Dr, Bethesda, MD 20892 USA. EM aov@helix.nih.gov NR 17 TC 31 Z9 33 U1 0 U2 0 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAY PY 2004 VL 55 IS 5 BP 721 EP 728 DI 10.1002/ana.20090 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 816NE UT WOS:000221115800016 PM 15122713 ER PT J AU Garraux, G Bauer, A Hanakawa, T Wu, T Kansaku, K Hallett, M AF Garraux, G Bauer, A Hanakawa, T Wu, T Kansaku, K Hallett, M TI Changes in brain anatomy in focal hand dystonia SO ANNALS OF NEUROLOGY LA English DT Article ID AREA AB No consistent cerebral anatomical abnormality has ever been reported in primary focal hand dystonia (FHD). The present voxel-based morphometry study showed a significant bilateral increase in gray matter in the hand representation area of primary somatosensory and, to a lesser extent, primary motor cortices in 36 patients with unilateral FHD compared with 36 controls. The presence of anatomical changes in the perirolandic cortex for the unaffected hand as well as that for the affected hand suggests that these disturbances may be, at least in part, primary. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Liege, Cyclotron Res Ctr, Liege, Belgium. Univ Liege, Dept Neurol, Liege, Belgium. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov RI Garraux, Gaetan/G-9050-2011 NR 18 TC 91 Z9 94 U1 1 U2 4 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAY PY 2004 VL 55 IS 5 BP 736 EP 739 DI 10.1002/ana.20113 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 816NE UT WOS:000221115800019 PM 15122716 ER PT J AU Isenberg, JS AF Isenberg, JS TI Hematopoietic stem cells mobilization and immune response in tumor-bearing mice SO ANNALS OF PLASTIC SURGERY LA English DT Article; Proceedings Paper CT 20th Annual Meeting of the Northeastern-Society-of-Plastic-Surgeons CY OCT 02-05, 2003 CL Baltimore, MD SP NE Soc Plast Surg ID COLONY-STIMULATING FACTOR; BLOOD MONONUCLEAR-CELLS; T-CELL; PERIPHERAL-BLOOD; IN-VITRO; ANTIGEN PRESENTATION; DOWN-REGULATION; BREAST-CANCER; AGING HUMANS; MURINE MODEL AB Introduction: Malignant diseases are known to modulate the number and function of myeloid, erythroid, and lymphoid cells. Since these cells are derived from hematopoietic stem cells (HSC), it is not clear if the observed effects of cancer on such cells are direct or indirect via stem cells. The purpose of this study was to evaluate the effect of breast cancer upon the levels and activity of peripheral blood hematopoietic stem cells. Materials and Methods: Four weeks following the establishment of 4T1 breast cancers in BALB/c mice, the animals were killed, blood and spleen harvested, and processed for light density mononuclear cells. Colony forming unit in culture assay was used to determine the activity of HSCs. Flow cytometry was used to determine the levels of lineage negative HSCs expressing c-kit and Sca-1 antigen (Lin(-) c-kit(+)Sca-1(+)). Mitogenic, cytotoxic and ELISPOT assays were used to evaluate functional properties of cells. Plasma cytokine levels were determined with ELISA assay. Results: In tumor-bearing mice, there was a 2- and 4-fold increase in the levels and proliferative capacity of HSCs, respectively, compared with controls. Contemporaneously, there was a 13-fold increase in plasma G-CSF in tumor-bearing animals compared with controls (0.225 ng/ml versus 3.0 ng/ml). Furthermore, the number of interferon gamma-secreting cells was significantly increased in tumor-bearing animals. Concurrently, cytotoxic activity of NK cells was significantly increased in tumor-bearing animals as compared with controls (22.4 +/- 10.6 versus 10.3 +/- 2.95; P < 0.05). Summary: These results suggest that (1) breast cancer mobilizes hematopoietic stem cells in mice presumably through G-CSF production, and (2) that such cancer-mobilized stem cells give rise to immune cell lineages which are functionally hyperactive in their cytotoxic activities. Such cells could be expected to have appreciable therapeutic benefit in terms of cancer cell cytotoxic activity when used as part of stein cell transplantation therapy in cancer patients. C1 Georgetown Univ, Ctr Med, Vincent T Lombardi Canc Res Ctr, Dept Oncol, Washington, DC USA. RP Isenberg, JS (reprint author), NCI, NIH, Bldg 10,Room 2A 27,10 Ctr Dr, Bethesda, MD 20892 USA. FU NCI NIH HHS [5 P30 CA 51008-15, 5 R01 CA 93495, 5 K01 CA 085502] NR 41 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-7043 J9 ANN PLAS SURG JI Ann. Plast. Surg. PD MAY PY 2004 VL 52 IS 5 BP 523 EP 531 DI 10.1097/01.sap.0000123355.38162.d3 PG 9 WC Surgery SC Surgery GA 818ZS UT WOS:000221283600016 PM 15096946 ER PT J AU Norton, JA Alexander, HR Fraker, DL Venzon, DJ Gibril, F Jensen, RT AF Norton, JA Alexander, HR Fraker, DL Venzon, DJ Gibril, F Jensen, RT TI Does the use of routine duodenotomy (DUODX) affect rate of cure, development of liver metastases, or survival in patients with Zollinger-Ellison syndrome? SO ANNALS OF SURGERY LA English DT Article; Proceedings Paper CT 115th Annual Session of the Southern-Surgical-Association CY NOV 30-DEC 03, 2003 CL Hot Springs, VA SP SO Surg Assoc ID SOMATOSTATIN RECEPTOR SCINTIGRAPHY; ENDOCRINE NEOPLASIA TYPE-1; ISLET CELL TUMORS; DUODENAL GASTRINOMAS; SURGICAL-MANAGEMENT; NATURAL-HISTORY; LONG-TERM; RESECTION; LOCALIZATION; SURGERY AB Objective: To determine whether routine use of duodenotomy (DUODX) alters cure rate, survival, or development of liver metas-tases in 143 patients (162 operations) with Zollinger-Ellison syn-drome (ZES) without MENI. Summary Background Data: DUODX has been shown to increase the detection of duodenal gastrinomas, but it is unknown if it alters rate of cure. liver metastases. or survival. Data from our prospective studies of surgery in ZES allow us to address this issue because DUODX was not performed before 1987, whereas it was routinely done after 1987. Methods: All patients with sporadic ZES (non-MEN1) undergoing surgery for possible cure without a prior DUODX front November 1980 to June 2003 were included. Patients had preoperative com-puted tomography (CT), magnetic resonance imaging (MRI), or ultrasound: if unclear. angiography and somatostatin receptor scin-tigraphy since 1994. At surgery. all had the same standard ZES operation and were assessed immediately postoperatively, at 3 to 6 months, and yearly for cure (fasting gastrin, secretin test. and imaging studies). Results: A DUODX was performed in 79 patients (94 operations), and no DUODX was performed in 64 patients (68 operations), with 10 patients having both (no DUODX, then a DUODX later). Gastrinoma was found in 98% with DUODX compared with 76% with no DUODX (P < 0.00001). Duodenal gastrinomas were found more frequently with DUODX (62% vs. 18%; P < 0.00001), whereas pancreatic, lymph node, and other primary gastrinomas occurred similarly. Six of the 10 patients with 2 operations had a duodenal tumor found with DUODX during a second operation that was missed in the first operation without DUODX. Both the immediate postoperative cure rate (65% vs. 44%; P = 0.010) and long-term cure rate at last follow-up (8.8 +/- 0.4 years; range, 0.1 to 21.5) (52% vs. 26%; P = 0.0012) were significantly greater with a DUODX than without. In patients without pancreatic tumors or liver metas-tases at surgery, both the rate of developing liver metastases (6% vs. 9.5%) and the disease-related death rate (0% vs. 2%) were low and not significantly different in patients with or Without a DUODX. Conclusions: These results demonstrate that routine use of DUODX increases the short-term and long-term cure rate due to the detection of more duodenal gastrinomas. The rate of development of hepatic metastases and/or disease-related mortality in patients without pan-these parameters was seen. Duodenotomy (DUODX) should be routinely performed during all operations for cure of sporadic ZES. C1 Stanford Univ, Dept Surg, Palo Alto, CA 94304 USA. NCI, Surg Metab Sect, Surg Branch, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Hosp Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. RP Norton, JA (reprint author), Stanford Univ, Ctr Med, Dept Surg, Room H-3591,300 Pasteur Dr, Stanford, CA 94305 USA. EM janorton@stanford.edu RI Venzon, David/B-3078-2008 NR 59 TC 79 Z9 83 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD MAY PY 2004 VL 239 IS 5 BP 617 EP 625 DI 10.1097/01.sla.0000124290.05524.5e PG 9 WC Surgery SC Surgery GA 815DS UT WOS:000221023600008 PM 15082965 ER PT J AU Li, Q Verschraegen, CF Mendoza, J Hassan, R AF Li, Q Verschraegen, CF Mendoza, J Hassan, R TI Cytotoxic activity of the recombinant anti-mesothelin immunotoxin, SS1(dsFv)PE38, towards tumor cell lines established from ascites of patients with peritoneal mesotheliomas SO ANTICANCER RESEARCH LA English DT Article DE peritoneal mesothelioma; SS1(dsFv)PE38; mesothelin; immunotoxin ID MONOCLONAL-ANTIBODY; ANTITUMOR-ACTIVITY; MALIGNANT MESOTHELIOMA; CANCER-INSTITUTE; OVARIAN CANCERS; NUDE-MICE; IN-VITRO; DIAGNOSIS; CARCINOMA; AFFINITY AB Background: Mesothelin, a cell surface glycoprotein, is an attractive candidate for targeted therapy given its overexpression, as detected by immunohistochemistry, in mesotheliomas. The goal of this study was to evaluate mesothelin expression in fresh tumor cells obtained from ascites of patients with peritoneal mesothelioma, as well as to determine the sensitivity of these cells to an immunotoxin targeting mesothelin. Materials and Methods: Tumor cells were evaluated for mesothelin expression by flow cytometry using the marine anti-mesothelin monoclonal antibody K1. The sensitivity of these tumor cells to SS1(dsFv)PE38, an immunotoxin consisting of the anti-mesothelin Fv linked to a mutated Pseudomonas exotoxin, was evaluated using a cell proliferation assay. Results: Of the 7 tumor cell lilies established from ascites of 12 patients with peritoneal mesothelioma, 6 expressed mesothelin while one cell line did not. Cell lilies that expressed mesothelin were very sensitive to SS1(dsFv)PE38 with IC(50)s ranging between 0.08-3.9 ng/ml, while the cell line that was mesothelin-negative was resistant to SS1(dsFv)PE38. Conclusion: High expression of mesothelin is seen on tumor cells of patients with peritoneal mesothelioma and correlates with sensitivity to SS1(dsFv)PE38. Clinical studies of SS1(dsFv)PE38 in patients with peritoneal mesotheliomas are ongoing. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA. Univ New Mexico, Hlth Sci Ctr, Canc Res & Treatment Ctr, Albuquerque, NM 87131 USA. Stehlin Fdn, Houston, TX USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,Rm 5116, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov NR 29 TC 36 Z9 36 U1 0 U2 1 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD MAY-JUN PY 2004 VL 24 IS 3A BP 1327 EP 1335 PG 9 WC Oncology SC Oncology GA 839AW UT WOS:000222756700001 PM 15274292 ER PT J AU Krieg, RC Fogt, F Braunschweig, T Herrmann, PC Wollscheidt, V Wellmann, A AF Krieg, RC Fogt, F Braunschweig, T Herrmann, PC Wollscheidt, V Wellmann, A TI ProteinChip((R)) array analysis of microdissected colorectal carcinoma and associated tumor stroma shows specific protein bands in the 3.4 to 3.6 kDa range SO ANTICANCER RESEARCH LA English DT Article DE SELDI; ProteinChip; proteome; protein; array; colorectal cancer; carcinoma ID AFFINITY MASS-SPECTROMETRY; PROTEOMIC ANALYSIS; PROSTATE-CANCER; IDENTIFICATION; BIOCHIP AB Multiple pathways of carcinogenesis have been associated with colorectal carcinomas, including the adenoma-carcinoma sequence. The non polyposis coli gene has also been implicated in the pathogenesis of these tumors. Identification of the epithelial- mesenchymal interaction may help in understanding the pathways of invasion and may lead to the development of new, non-invasive tools for the diagnosis and prognosis of colon carcinomas. A ProteinChip(R) Array technology (SELDI=Surface Enhanced Laser Desoiption Ionization) has been developed enabling analysis and profiling of complex protein mixtures from a few cells. This study describes the protein analysis of approximately 500-1000 freshly obtained cells from normal and malignant colonic epithelium and its associated stroma by SELDI-TOF-MS (Surface Enhanced Laser Desorption Ionization Time-of-Flight Mass Spectrometry). Pure cell populations of normal and malignant epithelium as well as stroma (without tumor cells) were selected by microdissection from 9 patients. A pattern of 3 peptides of 3.48, 3.55 and 3.6 kDa, which were increased in the colon tumor epithelium and stroma compared to associated normal colon and stroma in all 9 patients, was observed. Coupling microdissection with SELDI represents a powetful tool to identify cell and tumor specific proteins and to understand molecular events underlying the invasive event in colorectal carcinomas. The presence of certain proteins in invasive carcinomas may lead to the development of non invasive biomarkers for the identification or detection of recurrence of colorectal malignancies. C1 Univ Bonn, Inst Pathol, D-53127 Bonn, Germany. Rhein Westfal TH Aachen, UK Aachen, D-52074 Aachen, Germany. Univ Penn, Presbyterian Med Ctr, Philadelphia, PA 19104 USA. PALM Microlaser Technol AG, D-82347 Bernried, Germany. NCI, US FDA, Clin Proteom Program, Bethesda, MD 20892 USA. RP Wellmann, A (reprint author), Univ Bonn, Inst Pathol, Siegmund Freud Str 25, D-53127 Bonn, Germany. EM axel_wellmann@yahoo.com NR 14 TC 23 Z9 25 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD MAY-JUN PY 2004 VL 24 IS 3A BP 1791 EP 1796 PG 6 WC Oncology SC Oncology GA 839AW UT WOS:000222756700066 PM 15274357 ER PT J AU Dadachova, E Burns, T Bryan, RA Apostolidis, C Brechbiel, MW Nosanchuk, JD Casadevall, A Pirofski, L AF Dadachova, E Burns, T Bryan, RA Apostolidis, C Brechbiel, MW Nosanchuk, JD Casadevall, A Pirofski, L TI Feasibility of radioimmunotherapy of experimental pneumococcal infection SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID MONOCLONAL-ANTIBODY; CAPSULAR POLYSACCHARIDE; STREPTOCOCCUS-PNEUMONIAE; CRYPTOCOCCUS-NEOFORMANS; SOLID TUMORS; ALPHA; CANCER; BI-213; MODEL; THERAPY AB Streptococcus pneumoniae is an important cause of community-acquired pneumonia, meningitis, and bacteremia. The problem of pneumococcal disease is exacerbated by increasing drug resistance. Furthermore, patients with impaired immunity are at high risk for invasive pneumococcal infections. Thus, there is an urgent need for new approaches to antimicrobial therapy. Antibody therapies take advantage of the specificity and high affinity of the antigen-antibody interaction to deliver antibacterial compounds to a site of infection in the form of naked or conjugated antibodies. We have recently established that radioimmunotherapy (RIT) can be used to treat experimental fungal infections in mice. In the present study, we investigated the feasibility of applying a RIT approach to the treatment of S. pneumoniae infection by evaluating the susceptibility of S. pneumoniae to radiolabeled antibody in vitro and in an animal infection model. For the specific antibody carrier, we used human monoclonal antibody D11, which binds to pneumococcal capsular polysaccharide 8. We have selected the alpha particle emitter Bi-213 as the radionuclide for conjugation to the antibody. Incubation of serotype 8 S.pneumoniae with Bi-213-D11 resulted in dose-dependent killing of bacteria. RIT of S.pneumoniae infection in C57BL/6 mice showed that 60% more mice survived in the Bi-213-D11-treated group (80 muCi) than in the untreated group (P < 0.01). The treatment did not cause hematological toxicity, as demonstrated by platelet counts. This feasibility study establishes that RIT can be applied to the treatment of bacterial infections. C1 Albert Einstein Coll Med, Dept Nucl Med, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10461 USA. Albert Einstein Coll Med, Dept Med, Bronx, NY 10461 USA. Inst Transuranium Elements, Heidelberg, Germany. NCI, NIH, Bethesda, MD 20892 USA. RP Dadachova, E (reprint author), Albert Einstein Coll Med, Dept Nucl Med, 1695A Eastchester Rd, Bronx, NY 10461 USA. EM edadacho@aecom.yu.edu RI Dadachova, Ekaterina/I-7838-2013 FU NIAID NIH HHS [AI035370, AI033774, AI52042, AI52733, R01 AI033774, R01 AI035370, R01 AI052733, R21 AI052042] NR 29 TC 28 Z9 30 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAY PY 2004 VL 48 IS 5 BP 1624 EP 1629 DI 10.1128/AAC.48.5.1624-1629.2004 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 818EH UT WOS:000221227900023 PM 15105113 ER PT J AU Bennett, JE Izumikawa, K Marr, KA AF Bennett, JE Izumikawa, K Marr, KA TI Mechanism of increased fluconazole resistance in Candida glabrata during prophylaxis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID AZOLE ANTIFUNGAL AGENTS; TRANSPORTER GENE; DRUG EFFLUX; ELECTROPHORETIC KARYOTYPES; TORULOPSIS-GLABRATA; ALBICANS; SUSCEPTIBILITY; PDH1 AB Candida glabrata can become resistant to fluconazole, causing persistent colonization and invasive infection during prolonged exposure to the drug. To determine the mechanism of resistance in this setting, weekly oropharyngeal cultures for C. glabrata were obtained over a 2-year period from hematopoietic stem cell transplant recipients who were receiving fluconazole prophylaxis. In 20 patients from whom at least two isolates of the same karyotype were obtained more than two weeks apart, fluconazole MICs doubled every 31 days on average. The mechanism of fluconazole resistance in isolates from the 14 of the 20 patients studied in whom MICs changed at least fourfold was studied. Cellular resistance was accompanied by increased drug efflux as measured by decreased accumulation of fluconazole and rhodamine 6G and increased abundance of transcripts from two drug transporters, CgCDR1 and PDH1. The rapidity and regularity of the rising resistance indicated that C. glabrata is able to upregulate drug efflux without losing the ability to maintain colonization. C1 NIAID, Clin Mycol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Univ Washington, Sch Med, Fred Hutchinson Canc Res Ctr, Seattle, WA USA. RP Bennett, JE (reprint author), NIAID, Clin Mycol Sect, Clin Invest Lab, NIH, Clin Ctr Room 11C304, Bethesda, MD 20892 USA. EM jbennett@niaid.nih.gov FU NIAID NIH HHS [AI01571] NR 21 TC 130 Z9 141 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAY PY 2004 VL 48 IS 5 BP 1773 EP 1777 DI 10.1128/AAC.48.5.1773-1777.2004 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 818EH UT WOS:000221227900044 PM 15105134 ER PT J AU Buckheit, RW Russell, J Hartman, TL Imnan, JK Schito, M Goel, A Appella, E Turpin, JA AF Buckheit, RW Russell, J Hartman, TL Imnan, JK Schito, M Goel, A Appella, E Turpin, JA TI Synergistic anti-HIV activity of zinc-finger inhibitory molecules used in combination with a variety of other anti-HIV agents SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract CT 17th International Conference on Antiviral Resarch CY MAY 02-06, 2004 CL Tucson, AZ SP Int Soc Antiviral Res, Hilton El Conquistador Hotel C1 So Res Inst, Frederick, MD USA. GeneLog Inc, Gaithersburg, MD USA. NCI, Bethesda, MD 20892 USA. Henry M Jackson Fdn, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAY PY 2004 VL 62 IS 2 MA 3 BP A27 EP A28 PG 2 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 816XO UT WOS:000221142800004 ER PT J AU Hartman, TL Buckheit, RW Turpin, JA Inman, JK Srivastava, P Hara, T Fattah, R Schito, M Appella, E AF Hartman, TL Buckheit, RW Turpin, JA Inman, JK Srivastava, P Hara, T Fattah, R Schito, M Appella, E TI Optimization of unique thioesters as antiviral agents that target HIV-1 nucleocapsid protein (NCp7) SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract CT 17th International Conference on Antiviral Resarch CY MAY 02-06, 2004 CL Tucson, AZ SP Int Soc Antiviral Res, Hilton El Conquistador Hotel C1 GeneLog Inc, Gaithersburg, MD USA. Henry M Jackson Fdn, Rockville, MD USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAY PY 2004 VL 62 IS 2 MA 24 BP A37 EP A37 PG 1 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 816XO UT WOS:000221142800025 ER PT J AU Serbin, AV Timofeyev, IV Alikhanova, OL Perminova, NG Semerikov, VN Karpyshev, NN Ermakov, IV Timofeyev, DI Grebinic, TS Bakulina, AY Margolis, L Kiseleva, YY AF Serbin, AV Timofeyev, IV Alikhanova, OL Perminova, NG Semerikov, VN Karpyshev, NN Ermakov, IV Timofeyev, DI Grebinic, TS Bakulina, AY Margolis, L Kiseleva, YY TI Synthetic polymeric antagonists for receptors of HIV-1 entry into human cells SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract CT 17th International Conference on Antiviral Resarch CY MAY 02-06, 2004 CL Tucson, AZ SP Int Soc Antiviral Res, Hilton El Conquistador Hotel C1 RAS, Topchiev Inst Petrochem, Moscow, Russia. Hlth RDF, Moscow, Russia. SRC VB Vector, Koltsov, Russia. NICHHD, NIH, Bethesda, MD 20892 USA. EM heal@aha.ru NR 0 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAY PY 2004 VL 62 IS 2 MA 18 BP A35 EP A35 PG 1 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 816XO UT WOS:000221142800019 ER PT J AU Yang, Q Roberts, P Zhu, W Stephen, A Adelsberger, J Currens, M Feng, Y Fisher, R Rein, A Shoemaker, R Sei, S AF Yang, Q Roberts, P Zhu, W Stephen, A Adelsberger, J Currens, M Feng, Y Fisher, R Rein, A Shoemaker, R Sei, S TI Discovery of a novel class of small-molecule HIV entry inhibitors that target the gp120-binding domain of CD4 SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract CT 17th International Conference on Antiviral Resarch CY MAY 02-06, 2004 CL Tucson, AZ SP Int Soc Antiviral Res, Hilton El Conquistador Hotel C1 Lab Antiviral Drug Mech, Frederick, MD USA. Prot Chem Lab, Frederick, MD USA. SAIC Frederick, Clin Serv Program, Frederick, MD USA. Screening Technol Branch, Frederick, MD USA. NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAY PY 2004 VL 62 IS 2 MA 4 BP A28 EP A28 PG 1 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 816XO UT WOS:000221142800005 ER PT J AU Zemlicka, J Zhou, S Kern, ER Cheng, YC Drach, JC Mitsuya, H AF Zemlicka, J Zhou, S Kern, ER Cheng, YC Drach, JC Mitsuya, H TI New class of fluoro, substituted methylenecyclopropane analogues of nucleosides as antiviral agents: Synthesis and antiviral activity SO ANTIVIRAL RESEARCH LA English DT Meeting Abstract CT 17th International Conference on Antiviral Resarch CY MAY 02-06, 2004 CL Tucson, AZ SP Int Soc Antiviral Res, Hilton El Conquistador Hotel C1 Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI 48201 USA. Univ Alabama, Sch Med, Birmingham, AL USA. Yale Univ, Sch Med, New Haven, CT USA. Univ Michigan, Sch Dent, Ann Arbor, MI 48109 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD MAY PY 2004 VL 62 IS 2 MA 100 BP A67 EP A68 PG 2 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 816XO UT WOS:000221142800101 ER PT J AU Clemons, TE Kurinij, N Sperduto, RD Bressler, SB Kassoff, A Kassoff, J Buehler, J Eglow, M Silverman, S Mehu, M Kieval, S Kaufman, F Mairs, M Graig, B Quattrocchi, A Jones, D Locatelli, J Ruby, A Capone, A Garretson, B Hassan, T Trese, MT Williams, GA Regan, V Manatrey, P Streasick, P Szydlowski, L McIver, F Bridges, C Stanley, C Cumming, K Mitchell, B Holloway, J Lewis, B Zajechowski, M Margherio, RR Cox, MS Werner, JC Falk, R Siedlak, P Neubert, C Klein, ML Stout, JT Lauer, AK Beardsley, C Anderson, H Wallace, P Smith, G Howard, S Dreyer, RF Ma, C Chenoweth, RG Zilis, JD O'Malley, A Robertson, JE Wilson, DJ Johnson, M Rice, P Daniel, H Crider, H Parker, S Sherman, K Martin, DF Aaberg, TM Hubbard, GB Garcia, E Curtis, LT DeLeon, A Myles, B Capone, A Lambert, M Meredith, T Aaberg, TM Sternberg, P Saperstein, D Lim, JI Stribling, B Ju, B Armiger, D Gilman, J Jordan, D Strittman, S Swords, R Orth, DH Flood, TP Civantos, J deBustros, S Packo, KH Merrill, PT Cohen, JA Chow, D Figliulo, C Morrison, C Bryant, DA Doherty, D McVicker, M Drefcinski, T Seddon, JM Pinnolis, MK Sachdeva, M Taytsel, T Burton, I Walsh, D Callahan, C Evans, C Snow, KK Jones-Devonish, DA Crouse, VD Rosenberg, J Davis, N Dubois-Moran, J Chew, EY Csaky, K Ferris, FL Shimel, KH Woods, MA Cunningham, D Kuehl, EM Palmer, M Babilonia-Ayukawa, G Foster, GE Kim, YJ Kivitz, IJ Koutsandreas, D LaReau, A Mercer, RF Nashwinter, R Rowan, J Short, G McCarthy, SA Ciatto, PF Ayres, LM Goodman, L Lopez, P Perry, C Randalls, A Friberg, TR Eller, AW Gorin, MB Mack, B Curtin, DY Ostroska, PP Fijewski, E Alexander, J Nixon, S Paine, MK Corbin, PS Warnicki, J Bressler, SB Bressler, NM Cassel, G Finkelstein, D Goldberg, M Haller, JA Ratner, L Schachat, AP Sherman, SH Sunness, JS Schenning, S Sackett, C Cain, D Emmert, D Herring, M McDonald, J Falk, R Wheeler, S Mcmillan, M George, T Elman, MJ Ballinger, R Betancourt, A Herr, M Lammlein, J Raden, RZ Seff, R Shuman, M Starr, J Firestone, D Sloan, M Sotirakos, P Cain, T Mathews, T Glasser, D Hirsch, D Killingsworth, D Kohlhepp, P Ringrose, C Carrigan, A Chandra, SR Gottlieb, JL Ip, MS Klein, R Nork, M Stevens, TS Blodi, BA Altaweel, M Klein, BEK Davis, MD Olson, M Skoldberg, A Christianson, E Solerling, B Perry-Raymond, JR Burke, K Knutson, G Peterson, J Krolnik, D Harrison, R Somers, G Myers, FL Wallow, I Olsen, TW Bresnik, G De Venecia, G Perkins, T Walker, W Miller, JL Blatz, M Neider, M Wabers, HD Weber, G Amspaugh, B Buechner, J Myers, HEL Davis, MD Klein, BEK Klein, R Blodi, B Danis, R Hubbard, L Neider, M Vargo, P Wabers, HD Armstrong, J Benz, W Dohm, KL Fink, C Harding, T Hurtenbach, C Lang, K Reed, S Fisher, MR Gangnon, R Lee, LY Carr, A Baliker, J Kastorff, L Robinson, N Glander, KE Surfus, J Ansay, S Magli, YL Badal, D Craanen, S Elledge, J Esser, B Geithman, PL Miner, KD Reimers, J Webster, M Gai, CY King, W Osterby, K Onofrey, J Brickbauer, J Schleicher, RL Miller, DT Sowell, AL Gunter, EW Bowman, BA Lindblad, AS Milton, RC Clemons, TE Gensler, G Rankin, M Henning, A Entler, G McBee, W Watson, V Davis, C Stine, E Berlin, SH Thotapally, K Jackson, M Tomlin, K Pallas, S Scholl, PR Mengers, SA Ederer, F Anand, R Roberts, K Ferris, FL Sperduto, RD Kurinij, N Chew, EY SanGiovanni, JP AF Clemons, TE Kurinij, N Sperduto, RD Bressler, SB Kassoff, A Kassoff, J Buehler, J Eglow, M Silverman, S Mehu, M Kieval, S Kaufman, F Mairs, M Graig, B Quattrocchi, A Jones, D Locatelli, J Ruby, A Capone, A Garretson, B Hassan, T Trese, MT Williams, GA Regan, V Manatrey, P Streasick, P Szydlowski, L McIver, F Bridges, C Stanley, C Cumming, K Mitchell, B Holloway, J Lewis, B Zajechowski, M Margherio, RR Cox, MS Werner, JC Falk, R Siedlak, P Neubert, C Klein, ML Stout, JT Lauer, AK Beardsley, C Anderson, H Wallace, P Smith, G Howard, S Dreyer, RF Ma, C Chenoweth, RG Zilis, JD O'Malley, A Robertson, JE Wilson, DJ Johnson, M Rice, P Daniel, H Crider, H Parker, S Sherman, K Martin, DF Aaberg, TM Hubbard, GB Garcia, E Curtis, LT DeLeon, A Myles, B Capone, A Lambert, M Meredith, T Aaberg, TM Sternberg, P Saperstein, D Lim, JI Stribling, B Ju, B Armiger, D Gilman, J Jordan, D Strittman, S Swords, R Orth, DH Flood, TP Civantos, J deBustros, S Packo, KH Merrill, PT Cohen, JA Chow, D Figliulo, C Morrison, C Bryant, DA Doherty, D McVicker, M Drefcinski, T Seddon, JM Pinnolis, MK Sachdeva, M Taytsel, T Burton, I Walsh, D Callahan, C Evans, C Snow, KK Jones-Devonish, DA Crouse, VD Rosenberg, J Davis, N Dubois-Moran, J Chew, EY Csaky, K Ferris, FL Shimel, KH Woods, MA Cunningham, D Kuehl, EM Palmer, M Babilonia-Ayukawa, G Foster, GE Kim, YJ Kivitz, IJ Koutsandreas, D LaReau, A Mercer, RF Nashwinter, R Rowan, J Short, G McCarthy, SA Ciatto, PF Ayres, LM Goodman, L Lopez, P Perry, C Randalls, A Friberg, TR Eller, AW Gorin, MB Mack, B Curtin, DY Ostroska, PP Fijewski, E Alexander, J Nixon, S Paine, MK Corbin, PS Warnicki, J Bressler, SB Bressler, NM Cassel, G Finkelstein, D Goldberg, M Haller, JA Ratner, L Schachat, AP Sherman, SH Sunness, JS Schenning, S Sackett, C Cain, D Emmert, D Herring, M McDonald, J Falk, R Wheeler, S Mcmillan, M George, T Elman, MJ Ballinger, R Betancourt, A Herr, M Lammlein, J Raden, RZ Seff, R Shuman, M Starr, J Firestone, D Sloan, M Sotirakos, P Cain, T Mathews, T Glasser, D Hirsch, D Killingsworth, D Kohlhepp, P Ringrose, C Carrigan, A Chandra, SR Gottlieb, JL Ip, MS Klein, R Nork, M Stevens, TS Blodi, BA Altaweel, M Klein, BEK Davis, MD Olson, M Skoldberg, A Christianson, E Solerling, B Perry-Raymond, JR Burke, K Knutson, G Peterson, J Krolnik, D Harrison, R Somers, G Myers, FL Wallow, I Olsen, TW Bresnik, G De Venecia, G Perkins, T Walker, W Miller, JL Blatz, M Neider, M Wabers, HD Weber, G Amspaugh, B Buechner, J Myers, HEL Davis, MD Klein, BEK Klein, R Blodi, B Danis, R Hubbard, L Neider, M Vargo, P Wabers, HD Armstrong, J Benz, W Dohm, KL Fink, C Harding, T Hurtenbach, C Lang, K Reed, S Fisher, MR Gangnon, R Lee, LY Carr, A Baliker, J Kastorff, L Robinson, N Glander, KE Surfus, J Ansay, S Magli, YL Badal, D Craanen, S Elledge, J Esser, B Geithman, PL Miner, KD Reimers, J Webster, M Gai, CY King, W Osterby, K Onofrey, J Brickbauer, J Schleicher, RL Miller, DT Sowell, AL Gunter, EW Bowman, BA Lindblad, AS Milton, RC Clemons, TE Gensler, G Rankin, M Henning, A Entler, G McBee, W Watson, V Davis, C Stine, E Berlin, SH Thotapally, K Jackson, M Tomlin, K Pallas, S Scholl, PR Mengers, SA Ederer, F Anand, R Roberts, K Ferris, FL Sperduto, RD Kurinij, N Chew, EY SanGiovanni, JP CA AREDS Res Grp TI Associations of mortality with ocular disorders and an intervention of high-dose antioxidants and zinc in the age-related eye disease study - AREDS report no. 13 SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; MACULAR DEGENERATION; CATARACT-EXTRACTION; DEPRESSIVE SYMPTOMS; ELDERLY-PATIENTS; LENS OPACITIES; POPULATION; SURVIVAL; SUPPLEMENTATION; HYPERTENSION AB Objective: To assess the association of ocular disorders and high doses of antioxidants or zinc with mortality in the Age-Related Eye Disease Study (AREDS). Methods: Baseline fundus and lens photographs were used to grade the macular and lens status of AREDS participants. Participants were randomly assigned to receive oral supplements of high-dose antioxidants, zinc, antioxidants plus zinc, or placebo. Risk of all-cause and cause-specific mortality was assessed using adjusted Cox proportional hazards models. Results: During median follow-up of 6.5 years, 534 (11%) of 4753 AREDS participants died. In fully adjusted models, participants with advanced age-related macular degeneration (AMD) compared with participants with few, if any, drusen had increased mortality (relative risk [RR], 1.41; 95% confidence interval [CI], 1.08-1.86). Advanced AMD was associated with cardiovascular deaths. Compared with participants having good acuity in both eyes, those with visual acuity worse than 20/40 in 1 eye had increased mortality (RR, 1.36; 95% CI, 1.12-1.65). Nuclear opacity (RR, 1.40; 95% CI, 1.12-1.75) and cataract surgery (RR, 1.55; 95% CI, 1.18-2.05) were associated with increased all-cause mortality and with cancer deaths. Participants randomly assigned to receive zinc had lower mortality than those not taking zinc (RR, 0.73; 95% CI, 0.61-0.89). Conclusions: The decreased survival of AREDS participants with AMD and cataract suggests that these conditions may reflect systemic rather than only local processes. The improved survival in individuals randomly assigned to receive zinc requires further study. C1 EMMES Corp, Rockville, MD 20850 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. NEI, Bethesda, MD 20892 USA. RP Clemons, TE (reprint author), EMMES Corp, 401 N Washington St,Suite 700, Rockville, MD 20850 USA. EM aredspub@emmes.com; aredspub@emmes.com RI SanGiovanni, John Paul/A-7605-2008 FU NEI NIH HHS [Z01 EY000394-03] NR 31 TC 121 Z9 123 U1 2 U2 20 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD MAY PY 2004 VL 122 IS 5 BP 716 EP 726 PG 11 WC Ophthalmology SC Ophthalmology GA 819TU UT WOS:000221339400006 PM 15136320 ER PT J AU Mofenson, LM AF Mofenson, LM TI Successes and challenges in the perinatal HIV-1 epidemic in the United States as illustrated by the HIV-1 serosurvey of childbearing women SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; SUB-SAHARAN AFRICA; PREGNANT-WOMEN; VERTICAL TRANSMISSION; MISSED OPPORTUNITIES; INFECTED WOMEN; CLINICAL-TRIAL; PREVENTION; POPULATION; ZIDOVUDINE C1 NICHHD, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Childrens, NIH, Rockville, MD 20852 USA. RP Mofenson, LM (reprint author), NICHHD, Pediat Adolescent & Maternal AIDS Branch, Ctr Res Mothers & Childrens, NIH, 6100 Execut Blvd,Room 4B11, Rockville, MD 20852 USA. EM LM65D@nih.gov OI Mofenson, Lynne/0000-0002-2818-9808 NR 43 TC 27 Z9 28 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD MAY PY 2004 VL 158 IS 5 BP 422 EP 425 DI 10.1001/archpedi.158.5.422 PG 4 WC Pediatrics SC Pediatrics GA 818VI UT WOS:000221272200005 PM 15123471 ER PT J AU Siegel, KL Hicks, JE Koziol, DE Gerber, LH Rider, LG AF Siegel, KL Hicks, JE Koziol, DE Gerber, LH Rider, LG TI Walking ability and its relationship to lower-extremity muscle strength in children with idiopathic inflammatory myopathies SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article DE gait; muscle weakness; myositis; rehabilitation ID JUVENILE DERMATOMYOSITIS; GAIT; DISEASE; PARAMETERS; FORCE AB Objective: To describe gait deficits and their association with lower-extremity muscle strength in children with juvenile idiopathic inflammatory myopathies (IIM). Design: Cross-sectional, descriptive study. Setting: Clinical research center. Participants: Consecutive sample of 25 ambulatory children diagnosed with juvenile IIM. Interventions: Not applicable. Main Outcome Measures: Manual muscle test (MMT) of bilateral hip flexor, extensor, and abductor; knee extensor; and ankle plantarflexor strength, all measured on a 0- to 10-point scale and summary strength measures. Video-based movement analysis to determine walking speed; gait cycle time; right and left step time; stride length; right and left step length; and stance, swing, and double-limb support phase durations. Results: Walking speed (1.03+/-0.27m/s) was reduced because of shortened stride lengths (1.03+/-0.21m) more than prolonged gait cycle times (1.05+/-0.22s). Walking speed highly correlated with the number of muscle groups weaker than grade 7 out of 10 (r=-.89) and the strength of the hip flexors (r=.85). Conclusions: Lower-extremity strength measures, including MMT scores of individual muscle groups and the number of weak muscle groups, were predictive of gait limitations in children with juvenile IIM. C1 NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. Warren G Magnuson Clin Ctr, NIH, Biostat & Clin Epidemiol Serv, Bethesda, MD 20892 USA. Natl Inst Hlth, Natl Inst Environm Hlth Sci, Environm Autoimmun Grp, Office Clin Res,Dept Hlth & Human Serv, Bethesda, MD USA. RP NIH, Phys Disabil Branch, Bldg 10,Rm 6S235,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM karen_siegel@nih.gov RI Siegel, Karen Lohmann/B-5898-2008; OI Siegel, Karen Lohmann/0000-0002-0788-6612; Rider, Lisa/0000-0002-6912-2458 NR 20 TC 13 Z9 13 U1 0 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 0003-9993 EI 1532-821X J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD MAY PY 2004 VL 85 IS 5 BP 767 EP 771 DI 10.1016/j.apmr.2003.07.005 PG 5 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 818XC UT WOS:000221276800011 ER PT J AU Ballantyne, CM Hoogeveen, RC Bang, H Coresh, J Folsom, AR Sharrett, AR Wu, KK Myerson, M Chambless, LE Boerwinkle, E AF Ballantyne, CM Hoogeveen, RC Bang, H Coresh, J Folsom, AR Sharrett, AR Wu, KK Myerson, M Chambless, LE Boerwinkle, E TI The relation of lipoprotein-associated phospholipase A(2) and C-reactive protein to incident stroke in middle-aged men and women: The Atherosclerosis Risk in Communities study SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Meeting Abstract CT 5th Annual Conference on Arteriosclerosis, Thrombosis, and Vascular Biology CY MAY 06-08, 2004 CL San Francisco, CA C1 Baylor Coll Med, Houston, TX 77030 USA. Univ N Carolina, Chapel Hill, NC USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Minnesota, Minneapolis, MN USA. Univ Texas, Hlth Sci Ctr, Houston, TX USA. NHLBI, Bethesda, MD 20892 USA. RI Ballantyne, Christie/A-6599-2008 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 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD MAY PY 2004 VL 24 IS 5 MA P441 BP E77 EP E78 PG 2 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 818VN UT WOS:000221272700444 ER PT J AU Wang, MY Zhang, J Spinetti, G Monticone, R Zhang, D Cheng, L Krawczyk, M Talan, M Lakatta, EG AF Wang, MY Zhang, J Spinetti, G Monticone, R Zhang, D Cheng, L Krawczyk, M Talan, M Lakatta, EG TI Chronic angiotensin II administration to young rodents upregulates MMP-2 activation and mimics age-associated arterial remodeling SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Meeting Abstract CT 5th Annual Conference on Arteriosclerosis, Thrombosis, and Vascular Biology CY MAY 06-08, 2004 CL San Francisco, CA C1 NIA, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 MAY PY 2004 VL 24 IS 5 MA P403 BP E71 EP E71 PG 1 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 818VN UT WOS:000221272700411 ER PT J AU Huber, AM Feldman, BM Rennebohm, RM Hicks, JE Lindsley, CB Perez, MD Zemel, LS Wallace, CA Ballinger, SH Passo, MH Reed, AM Summers, RM White, PH Katona, IM Miller, FW Lachenbruch, PA Rider, LG AF Huber, AM Feldman, BM Rennebohm, RM Hicks, JE Lindsley, CB Perez, MD Zemel, LS Wallace, CA Ballinger, SH Passo, MH Reed, AM Summers, RM White, PH Katona, IM Miller, FW Lachenbruch, PA Rider, LG TI Validation and clinical significance of the childhood myositis assessment scale for assessment of muscle function in the juvenile idiopathic inflammatory myopathies SO ARTHRITIS AND RHEUMATISM LA English DT Article ID DISEASE-ACTIVITY; DAMAGE INDEXES; HEALTH-STATUS; CHILDREN; DERMATOMYOSITIS; RESPONSIVENESS; RELIABILITY AB Objective. To examine the measurement characteristics of the Childhood Myositis Assessment Scale (CMAS) in children with juvenile idiopathic inflammatory myopathy (juvenile IIM), and to obtain preliminary data on the clinical significance of CMAS scores. Methods. One hundred eight children with juvenile IIM were evaluated on 2 occasions, 7-9 months apart, using various measures of physical function, strength, and disease activity. Interrater reliability, construct validity, and responsiveness of the CMAS were examined. The minimum clinically important difference (MID) and CMAS scores corresponding to various degrees of physical disability were estimated. Results. The intraclass correlation coefficient for 26 patients assessed by 2 examiners was 0.89, indicating very good interrater reliability. The CMAS score correlated highly with the Childhood Health Assessment Questionnaire (C-HAQ) score and with findings on manual muscle testing (MMT) (r(s) = -0.73 and 0.73, respectively) and moderately with physician-assessed global disease activity and skin activity, parent-assessed global disease severity, and muscle magnetic resonance imaging (rs = -0.44 to -0.61), thereby demonstrating good construct validity. The standardized response mean was 0.81 (95% confidence interval 0.53, 1.09) in patients with at least 0.8 cm improvement on a 10-cm visual analog scale for physician-assessed global disease activity, indicating strong responsiveness. In bivariate regression models predicting physician-assessed global disease activity, MMT remained significant in models containing the CMAS (P = 0.03) while the C-HAQ did not (P = 0.4). Estimates of the MID ranged from 1.5 to 3.0 points on a 0-52-point scale. CMAS scores corresponding to no, mild, mild-to-moderate, and moderate physical disability, respectively, were 48, 45, 39, and 30. Conclusion. The CMAS exhibits good reliability, construct validity, and responsiveness, and is therefore a valid instrument for the assessment of physical function, muscle strength, and endurance in children with juvenile IIM. Preliminary data on MID and corresponding levels of disability should aid in the clinical interpretation of CMAS scores when assessing patients with juvenile IIM. C1 IWK Hlth Ctr, Halifax, NS B3J 3G9, Canada. Dalhousie Univ, Halifax, NS, Canada. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Univ Toronto, Toronto, ON, Canada. Ohio State Univ, Columbus, OH 43210 USA. Columbus Childrens Hosp, Columbus, OH USA. NIH, Ctr Clin, Bethesda, MD USA. Univ Kansas, Kansas City, KS USA. Baylor Coll Med, Houston, TX 77030 USA. Texas Childrens Hosp, Houston, TX 77030 USA. Univ Connecticut, Hartford, CT 06112 USA. Connecticut Childrens Med Ctr, Hartford, CT USA. Childrens Hosp, Seattle, WA USA. Univ Washington, Seattle, WA 98195 USA. James Whitcomb Riley Hosp Children, Indianapolis, IN 46202 USA. Indiana Univ, Indianapolis, IN 46204 USA. Childrens Hosp, Cincinnati, OH 45229 USA. Univ Cincinnati, Cincinnati, OH USA. Mayo Clin, Rochester, MN USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Natl Inst Environm Hlth Sci, NIH, Bethesda, MD USA. US FDA, Ctr Biol Evaluat & Res, Rockville, MD USA. RP Huber, AM (reprint author), IWK Hlth Ctr, 5850 Univ Ave, Halifax, NS B3J 3G9, Canada. EM adam.huber@iwk.nshealth.ca RI Feldman, Brian/A-8586-2011; OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 NR 21 TC 83 Z9 86 U1 2 U2 3 PU WILEY-LISS PI NEW YORK PA DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD MAY PY 2004 VL 50 IS 5 BP 1595 EP 1603 DI 10.1002/art.20179 PG 9 WC Rheumatology SC Rheumatology GA 819UI UT WOS:000221340900028 PM 15146430 ER PT J AU Phillips, SJ AF Phillips, SJ TI The role of federal programs in the transfer of biomedical technology SO ARTIFICIAL ORGANS LA English DT Editorial Material C1 ASAIO, Urbandale, IA 50322 USA. Natl Lib Med, Urbandale, IA 50322 USA. NIH, Urbandale, IA 50322 USA. RP Phillips, SJ (reprint author), ASAIO, 8081 Cobblestone Rd, Urbandale, IA 50322 USA. EM SP226@aol.com NR 0 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0160-564X J9 ARTIF ORGANS JI Artif. Organs PD MAY PY 2004 VL 28 IS 5 BP 432 EP 436 DI 10.1111/j.1525-1594.2004.01031.x PG 5 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA 821II UT WOS:000221453200003 PM 15113335 ER PT J AU Berzofsky, JA AF Berzofsky, JA TI New strategies for designing and optimizing vaccines SO ASM NEWS LA English DT Article ID AIDS VACCINE; HIV VACCINE; T-CELLS; IMMUNITY AB Traditional vaccines largely depend on eliciting neutralizing antibodies to prevent infections. However, viruses that cause chronic infections, such as Hepatitis C virus and Human immunodeficiency virus, make poor targets for neutralizing antibodies. An alternative immunizing strategy revolves around CD8-positive cytotoxic T lymphocytes (CTL). Although CTL typically do not provide sterilizing immunity, they can effectively control chronic viral infections and also some tumors. The key point with CTL is that they are not limited to detecting cell surface proteins, CTL recognize protein fragments presented by class II or class I products of the major histocompatibility complex (MHC). A number of issues need to be addressed to develop effective CTL-based vaccines such as the affinity of the peptide to the MHC molecule, whether the vaccine evokes a Th1 or a Th2 T cell response and also the avidity of the vaccine. C1 NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Berzofsky, JA (reprint author), NCI, Vaccine Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 12 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0044-7897 J9 ASM NEWS JI ASM News PD MAY PY 2004 VL 70 IS 5 BP 219 EP 223 PG 5 WC Microbiology SC Microbiology GA 004EI UT WOS:000234734400016 ER PT J AU DuPree, MG Mustanski, BS Bocklandt, S Nievergelt, C Hamer, DH AF DuPree, MG Mustanski, BS Bocklandt, S Nievergelt, C Hamer, DH TI A candidate gene study of CYP19 (aromatase) and male sexual orientation SO BEHAVIOR GENETICS LA English DT Article DE homosexuality; sexual orientation; aromatase; CYP19; linkage, expression ID HOMOSEXUAL-MEN; SUPRACHIASMATIC NUCLEUS; ANTERIOR COMMISSURE; PARTNER PREFERENCE; COMPLEX TRAITS; RECEPTOR GENE; HUMAN BRAIN; MALE-MICE; LINKAGE; BEHAVIOR AB Aromatase cytochrome P450 (CYP19), which is necessary for the conversion of androgens to estrogens, plays an important role in the sexual differentiation of the brain. To investigate whether differences in the gene encoding the aromatase enzyme influence sexual orientation in men, we conducted linkage, association, and expression analyses in a large sample of homosexual brothers using microsatellite markers in and around CYP19. No linkage was detected, and a gene-specific relative risk of 1.5-fold could be excluded at a lod score of -2. Results of the TDT demonstrated no preferential transmission of any of the CYP19 alleles in this sample. Expression of aromatase mRNA by microarray analysis was not significantly different between heterosexual and homosexual men. These results suggest that variation in the gene for this subunit of the aromatase enzyme complex is not likely to be a major factor in the development of individual differences in male sexual orientation. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Penn State Univ, Dept Anthropol, University Pk, PA 16802 USA. Univ Calif Los Angeles, Ctr Neurobehav Genet, Los Angeles, CA 90095 USA. Indiana Univ, Dept Psychol, Bloomington, IN 47405 USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. RP DuPree, MG (reprint author), Univ Calif Los Angeles, Ctr Neurobehav Genet, Gonda Ctr 3554-B,695 Charles Young Dr S, Los Angeles, CA 90095 USA. EM mdupree@mednet.ucla.edu OI Nievergelt, Caroline/0000-0001-5766-8923 NR 65 TC 25 Z9 27 U1 3 U2 20 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD MAY PY 2004 VL 34 IS 3 BP 243 EP 250 DI 10.1023/B:BEGE.0000017870.77610.52 PG 8 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 778WD UT WOS:000189263600003 PM 14990865 ER PT J AU Zhao, R Planalp, RP Ma, R Greene, BT Jones, BT Brechbiel, MW Torti, FM Torti, SV AF Zhao, R Planalp, RP Ma, R Greene, BT Jones, BT Brechbiel, MW Torti, FM Torti, SV TI Role of zinc and iron chelation in apoptosis mediated by tachpyridine, an anti-cancer iron chelator SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE chelator; zinc; iron; caspase; apoptosis; chemotherapeutic agent ID PERFORMANCE LIQUID-CHROMATOGRAPHY; CELLULAR ZINC; CELLS; NEUROBLASTOMA; DEFEROXAMINE; METABOLITE; GROWTH; PLASMA; CIS,CIS-1,3,5-TRIAMINOCYCLOHEXANE; ACTIVATION AB Tachpyridine (N,N',N"-tris(2-pyridylmethyl)-cis,cis-1,3,5-triaminocyclohexane; tachpyr) is a potent hexadentate iron chelator under preclinical investigation as a potential anti-cancer agent. Tachpyridine induces apoptosis in cultured cancer cells by triggering a mitochondrial pathway of cell death that is p53-independent. To explore the relationship between the chelation chemistry of tachpyridine and its biological activity, a sensitive and specific reversed-phase high-performance liquid chromatography (R-P-HPLC) method was devised and used to measure tachpyr and its metal complexes in cells and tissue culture media. Major species identified in cells treated with tachpyr were tachpyr itself, [Zn(tachpyr)](2+), and iron coordinated to two partially oxidized species of tachpyridine, [Fe(tachpyr-ox-2)](2+), and [Fe(tachpyr-ox-4)](2+). The kinetics of intracellular accumulation of [Zn(tachpyr)](2+) and [Fe(tachpyr-ox-2)](2+) were markedly different: [Zn(tachpyr)](2+) rapidly reached plateau levels, whereas intracellular levels of [Fe(tachpyr-ox-2)]2+ and free tachpyr rose steadily. At the last timepoint measured, 9% of total cellular iron and 13% of total cellular zinc were bound by tachpyridine. Taken together, [Zn(tachpyr)](2+), [Fe(tachpyr-ox-2)](2+), and free tachpyr accounted for virtually all of the tachpyr added, indicating that iron and zinc are the principal metals targeted by tachpyridine in cells. Consistent with these findings, activation of the apoptotic caspases 9 and 3 was blocked in cells pre-treated with either iron or zinc. Pretreatment with either of these metals also completely protected cells from the cytotoxic effects of tachpyridine. These results demonstrate a link between metal depletion and chelator cytotoxicity, and suggest that intracellular chelation of zinc as well as iron may play a role in the cytotoxicity of tachpyridine. (C) 2004 Elsevier Inc. All rights reserved. C1 Wake Forest Univ Hlth Sci, Ctr Comprehens Canc, Winston Salem, NC 27109 USA. Wake Forest Univ Hlth Sci, Dept Canc Biol, Winston Salem, NC USA. Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. Wake Forest Univ Hlth Sci, Dept Biochem, Winston Salem, NC USA. Wake Forest Univ, Dept Chem, Winston Salem, NC 27109 USA. NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Torti, SV (reprint author), Wake Forest Univ Hlth Sci, Ctr Comprehens Canc, Winston Salem, NC 27109 USA. EM storti@wfubmc.edu RI Jones, Bradley/G-7925-2012 FU NIDDK NIH HHS [DK 57781] NR 45 TC 38 Z9 39 U1 5 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 1 PY 2004 VL 67 IS 9 BP 1677 EP 1688 DI 10.1016/j.bcp.2003.12.036 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 815YX UT WOS:000221078700006 PM 15081867 ER PT J AU Mamedova, LK Joshi, BV Gao, ZG von Kugelgen, I Jacobson, KA AF Mamedova, LK Joshi, BV Gao, ZG von Kugelgen, I Jacobson, KA TI Diisothiocyanate derivatives as potent, insurmountable antagonists of P2y(6) nucleotide receptors SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE P2Y(6) nucleotide receptor; GPCR; pyrimidines; purines; isothiocyanate; apoptosis ID PHOSPHOLIPASE-C; INDUCED APOPTOSIS; ADENYLYL-CYCLASE; CELLS; ATP; IDENTIFICATION; QUANTITATION; EXPRESSION; FAMILIES; DISEASE AB The physiological role of the P2Y(6) nucleotide receptor may involve cardiovascular, immune and digestive functions based on the receptor tissue distribution, and selective antagonists for this receptor are lacking. We have synthesized a series of symmetric aryl diisothiocyanate derivatives and examined their ability to inhibit phospholipase C (PLC) activity induced by activation of five subtypes of recombinant P2Y receptors. Several derivatives were more potent at inhibiting action of UDP at both human and rat P2Y(6) receptors expressed in 1321N1 human astrocytes than activation of human P2Y(1), P2Y(2), P2Y(4) and P2Y(11) receptors. The inhibition by diisothiocyanate derivatives of 1,2-diphenylethane (MRS2567) and 1,4-di-(phenylthioureido) butane (MRS2578) was concentration-dependent and insurmountable, with IC50 values of 126 +/- 15 nM and 37 +/- 16 nM (human) and 101 +/- 27 nM and 98 +/- 11 nM (rat), respectively. A derivative of 1,4-phenylendiisothiocyanate (MRS2575) inhibited only human but not rat P2Y6 receptor activity. MRS2567 and MRS2578 at 10 muM did not affect the UTP (100 nM)-induced responses of cells expressing P2Y(2) and P2Y(4) receptors, nor did they affect the 2-methylthio-ADP (30 nM)-induced responses at the P2Y(1) receptor or the ATP (10 muM)-induced responses at the P2Y(11) receptor. Other antagonists displayed mixed selectivities. The selective antagonists MRS2567, MRS2575 and MRS2578 (1 muM) completely blocked the protection by UDP of cells undergoing TNFalpha-induced apoptosis. Thus, we have identified potent, insurmountable antagonists of P2Y(6) receptors that are selective within the family of PLC-coupled P2Y receptors. (C) 2004 Elsevier Inc. All rights reserved. C1 NIDDKD, Lab Bioorgan Chem, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. Univ Bonn, Dept Pharmacol, D-53113 Bonn, Germany. RP Jacobson, KA (reprint author), NIDDKD, Lab Bioorgan Chem, Mol Recognit Sect, NIH, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031116-20] NR 23 TC 83 Z9 84 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD MAY 1 PY 2004 VL 67 IS 9 BP 1763 EP 1770 DI 10.1016/j.bcp.2004.01.011 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 815YX UT WOS:000221078700014 PM 15081875 ER PT J AU Oliver, B Parisi, M AF Oliver, B Parisi, M TI Battle of the Xs SO BIOESSAYS LA English DT Article ID GENE-EXPRESSION; DROSOPHILA-MELANOGASTER; C-ELEGANS; ONTOGENIC CONFLICT; Y-CHROMOSOME; SEX; EVOLUTION; GENOME; FITNESS; TRANSCRIPTION AB Females and males often exhibit conspicuous morphological, physiological and behavioral differences. Similarly, gene expression profiles indicate that a large portion of the genome is sex-differentially deployed, particularly in the germ line. Because males and females are so fundamentally different, each sex is likely to have a different optimal gene expression profile that is never fully achieved in either sex because of antagonistic selection in females versus males. Males are hemizygous for the X chromosome, which means that recessive male-favorable de novo mutations on the X chromosome are subject to immediate selection. In females, a recessive female-favorable mutation on one of two X chromosomes is not available for selection until it becomes frequent enough in the local population to result in homozygous individuals. Given that most mutations are recessive, one would expect that genes or alleles favoring males should accumulate on the X chromosome. Recent microarray work in Drosophila and C. elegans clearly shows the opposite. Why is the X chromosome a highly disfavored location for genes with male-biased expression in these animals? Published 2004 Wiley Periodicals, Inc. C1 NIDDKD, Cellular & Dev Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Oliver, B (reprint author), NIDDKD, Cellular & Dev Biol Lab, NIH, Dept Hlth & Human Serv, 50 S Dr, Bethesda, MD 20892 USA. EM oliver@helix.nih.gov NR 35 TC 35 Z9 35 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0265-9247 J9 BIOESSAYS JI Bioessays PD MAY PY 2004 VL 26 IS 5 BP 543 EP 548 DI 10.1002/bies.20034 PG 6 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 817JU UT WOS:000221174600010 PM 15112234 ER PT J AU Clifford, RJ Edmonson, MN Nguyen, C Buetow, KH AF Clifford, RJ Edmonson, MN Nguyen, C Buetow, KH TI Large-scale analysis of non-synonymous coding region single nucleotide polymorphisms SO BIOINFORMATICS LA English DT Article ID 41 CANDIDATE GENES; JAPANESE POPULATION; SEQUENCE; IDENTIFICATION; COLLECTION; ALIGNMENT; DATABASE; GENOME AB Motivation: Single nucleotide polymorphisms (SNPs) are the most common form of genetic variant in humans. SNPs causing amino acid substitutions are of particular interest as candidates for loci affecting susceptibility to complex diseases, such as diabetes and hypertension. To efficiently screen SNPs for disease association, it is important to distinguish neutral variants from deleterious ones. Results: We describe the use of Pfam protein motif models and the HMMER program to predict whether amino acid changes in conserved domains are likely to affect protein function. We find that the magnitude of the change in the HMMER E-value caused by an amino acid substitution is a good predictor of whether it is deleterious. We provide internet-accessible display tools for a genomewide collection of SNPs, including 7391 distinct non-synonymous coding region SNPs in 2683 genes. C1 NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. RP Buetow, KH (reprint author), NCI, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. EM buetowk@nih.gov NR 34 TC 50 Z9 54 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAY 1 PY 2004 VL 20 IS 7 BP 1006 EP 1014 DI 10.1093/bioinformatics/bth029 PG 9 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 816WJ UT WOS:000221139700002 PM 14751981 ER PT J AU Kirby, NI DeRose, EF London, RE Mueller, GA AF Kirby, NI DeRose, EF London, RE Mueller, GA TI NvAssign: Protein NMR spectral assignment with NMRView SO BIOINFORMATICS LA English DT Article ID AUTOMATED-ANALYSIS AB Motivation: Nuclear magnetic resonance (NMR) protein studies rely on the accurate assignment of resonances. The general procedure is to (1) pick peaks, (2) cluster data from various experiments or spectra, (3) assign peaks to the sequence and (4) verify the assignments with the spectra. Many algorithms already exist for automating the assignment process (step 3). What is lacking is a flexible interface to help a spectroscopist easily move from clustering (step 2) to assignment algorithms (step 3) and back to verification of the algorithm output with spectral analysis (step 4). Results: A software module, NvAssign, was written for use with NMRView. It is a significant extension of the previous CBCA module. The module provides a flexible interface to cluster data and interact with the existing assignment algorithms. Further, the software module is able to read the results of other algorithms so that the data can be easily verified by spectral analysis. The generalized interface is demonstrated by connecting the clustered data with the assignment algorithms PACES and MONTE using previously assigned data for the lyase domain of DNA polymerase lambda. The spectral analysis program NMRView is now able to read the output of these programs for simplified analysis and verification. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Mueller, GA (reprint author), NIEHS, Struct Biol Lab, NIH, MR-01,Box 12233, Res Triangle Pk, NC 27709 USA. EM mueller3@niehs.nih.gov NR 7 TC 11 Z9 11 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAY 1 PY 2004 VL 20 IS 7 BP 1201 EP 1203 DI 10.1093/bioinformatics/bth064 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 816WJ UT WOS:000221139700026 PM 14871875 ER PT J AU Shaywitz, BA Shaywitz, SE Blachman, BA Pugh, KR Fulbright, RK Skudlarski, P Mencl, WE Constable, RT Holahan, JM Marchione, KE Fletcher, JM Lyon, GR Gore, JC AF Shaywitz, BA Shaywitz, SE Blachman, BA Pugh, KR Fulbright, RK Skudlarski, P Mencl, WE Constable, RT Holahan, JM Marchione, KE Fletcher, JM Lyon, GR Gore, JC TI Development of left occipitotemporal systems for skilled reading in children after a phonologically-based intervention SO BIOLOGICAL PSYCHIATRY LA English DT Article DE reading; dyslexia; fluency; functional magnetic resonance imaging; plasticity; intervention ID WORD FORM AREA; FUNCTIONAL MRI; CEREBRAL MECHANISMS; BRAIN ACTIVATION; DYSLEXIC ADULTS; FMRI; DISRUPTION; LANGUAGE; CORTEX; ORGANIZATION AB Background. A range of neurobiological investigations shows a failure of left hemisphere posterior brain systems to function properly during reading in children and adults with reading disabilities. Such evidence of a disruption in the normal reading pathways provides a neurobiological target for reading interventions. In this study, we hypothesized that the provision of an evidence-based, phonologically mediated reading intervention would improve reading fluency and the development of the fast-paced occipitotemporal systems serving skilled reading. Methods. Functional magnetic resonance imaging was used to study the effects of a phonologically based reading intervention on brain organization and reading fluency in 77 children aged 6.1-9.4 years (49 with reading disability and 28 control subjects). Children comprised three experimental groups: experimental intervention (n = 37), community intervention (n = 12), and community control subjects (n = 28). Results. Immediately after the year-long intervention, children taught with the experimental intervention had made significant gains in reading fluency and demonstrated increased activation in left hemisphere regions, including the inferior frontal gyrus and the middle temporal gyrus; 1 year after the experimental intervention bad ended these children were activating bilateral inferior frontal gyri and left superior temporal and occipitotemporal regions. Conclusions. These data indicate that the nature of the remedial educational intervention is critical to successful outcomes in children with reading disabilities and that the use of an evidence-based phonologic reading intervention facilitates the development of those fast-paced neural systems that underlie skilled reading. C1 Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06510 USA. Haskins Labs Inc, New Haven, CT 06511 USA. Yale Univ, Dept Appl Phys, New Haven, CT 06520 USA. Syracuse Univ, Dept Psychol, Syracuse, NY USA. Syracuse Univ, Sch Educ, Syracuse, NY USA. Univ Texas, Hlth Sci Ctr, Dept Pediat, Houston, TX USA. NICHHD, Child Dev & Behav Branch, NIH, Bethesda, MD 20892 USA. Vanderbilt Univ, Inst Imaging Sci, Nashville, TN USA. Vanderbilt Univ, Dept Radiol & Radiol Sci, Nashville, TN USA. RP Shaywitz, BA (reprint author), Yale Univ, Sch Med, Dept Pediat, POB 3333, New Haven, CT 06510 USA. FU NICHD NIH HHS [P01 HD 21888, P50 HD25802] NR 56 TC 283 Z9 286 U1 6 U2 31 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 MAY 1 PY 2004 VL 55 IS 9 BP 926 EP 933 DI 10.1016/j.biopsych.2003.12.019 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 813QR UT WOS:000220922100007 PM 15110736 ER PT J AU Szabo, ST Gold, MS Goldberger, BA Blier, P AF Szabo, ST Gold, MS Goldberger, BA Blier, P TI Effects of sustained gamma-hydroxybutyrate treatments on spontaneous and evoked firing activity of locus coeruleus norepinephrine neurons SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT Annual Convention of the Society-of-Biological-Psychiatry CY MAY 17, 2003 CL San Francisco, CA SP Soc Biolog Psychiatry DE anxiety disorders; withdrawal; addiction; sleep; drug abuse ID EXCITATORY AMINO-ACID; SEMIALDEHYDE DEHYDROGENASE-DEFICIENCY; GABA(B) RECEPTORS; OPIATE WITHDRAWAL; RAT-BRAIN; PANIC DISORDER; BINDING-SITES; QUANTITATIVE AUTORADIOGRAPHY; POSTSYNAPTIC POTENTIALS; NORADRENERGIC FUNCTION AB Background: Gamma-hydroxybutyrate is currently used to promote nighttime sleep in the treatment of narcolepsy; however, it is also a drug of abuse ("Liquid Ecstacy") associated with a withdrawal syndrome with anxiety features, Of interest, the activity of locus coeruleus neurons is a reflective index of these above mentioned behavioral states. Methods: Using in vivo extracellular unitary recordings, sustained administration of gamma-hydroxybutyrate (40 mg/kg/day via minipump implanted subcutaneously) on the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons was assessed in rats. Results. A 2-day and 10-day gamma-hydroxybutyrate administration decreased the spontaneous firing activity of locus coeruleus neurons by 52% and 54%, respectively, when compared with controls. A similar degree of attenuation on evoked burst firing of norepinephrine neurons also occurred in these rats (2-day gamma-hydroxybutyrate: 47% and 10-day gamma-hydroxybutyrate: 58%), when compared with controls. In contrast, rats treated with gamma-hydroxybutyrate for 10 days followed by removal of the minipump for 36 hours resulted in a 33% augmentation in spontaneous locus coeruleus activity as compared with controls. Furthermore, a robust 79% increase in burst firing in response to paw-pinch was exhibited in theses rats. Conclusions. Chronic gamma-hydroxybutyrate treatment inhibits the spontaneous and sensory-evoked burst firing of locus coeruleus norepinephrine neurons, whereas these indices are enhanced during drug withdrawal. The alteration in norepinephrine activity during chronic gamma-hydroxybutyrate administration may contribute to the ability of this agent to induce sleep and regulate narcoleptic episodes. Enhanced norepinephrine activity during withdrawal may be related to symptoms of anxiety on rapid termination of this drug in abusers. C1 NIMH, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. Univ Florida, Dept Psychiat & Neurosci, Gainesville, FL USA. Univ Florida, McKnight Brain Inst, Gainesville, FL USA. Univ Florida, Dept Pathol Immunol & Lab Med, Gainesville, FL USA. RP Szabo, ST (reprint author), NIMH, Mol Pathophysiol Lab, NIH, 49 Convent Dr,Bldg 49,Room B1EE16, Bethesda, MD 20892 USA. FU Intramural NIH HHS NR 62 TC 19 Z9 22 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 1 PY 2004 VL 55 IS 9 BP 934 EP 939 DI 10.1016/j.biopsych.2003.12.013 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 813QR UT WOS:000220922100008 PM 15110737 ER PT J AU Liu, Y Rao, MS AF Liu, Y Rao, MS TI Glial progenitors in the CNS and possible lineage relationships among them SO BIOLOGY OF THE CELL LA English DT Review DE oligodendrocyte; astrocyte; differentiation; CNS injury; radial glia ID CENTRAL-NERVOUS-SYSTEM; NEURAL STEM-CELLS; RAT SPINAL-CORD; SUBCORTICAL WHITE-MATTER; ADULT-MOUSE BRAIN; PRECURSOR CELLS; RESTRICTED PRECURSORS; SUBVENTRICULAR ZONE; DENTATE GYRUS; OLIGODENDROGLIAL PROGENITORS AB Glial cells are derived from stem cells that mature through specific stages of development to generate fully differentiated astrocytes and oligodendrocytes. Several types of intermediate precursors have been described and in some cases lineage relationships identified although this remains a subject of controversy. We review recent findings and discuss some possibilities. Motoneuron-oligodendrocyte precursors (MNOPs), white matter progenitor cells (WMPCs), polydendrocytes, glial restricted precursors (GRPs), astrocyte precursor cells (APCs), and oligodendroblasts are likely all derived from earlier appearing stem cells but segregate at different stages in development. Some of these precursors persist in the adult, and it is these glial progenitors rather than stem cells that respond after injury and participate in the repair process. Although which specific glial progenitor responds remains unclear, the availability of new markers will likely resolve this issue. We believe that the development of consensus sets of markers and an improvement in our ability to define stages of glial maturation will lead to a clearer appreciation of the importance of glia in the etiopathology of disease. (C) 2004 Elsevier SAS. All rights reserved. C1 NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Rao, MS (reprint author), NIA, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM raomah@grc.nia.nih.gov NR 103 TC 57 Z9 57 U1 0 U2 4 PU EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0248-4900 J9 BIOL CELL JI Biol. Cell PD MAY PY 2004 VL 96 IS 4 BP 279 EP 290 DI 10.1016/j.biolcel.2004.02.001 PG 12 WC Cell Biology SC Cell Biology GA 825RM UT WOS:000221776000005 PM 15145532 ER PT J AU Tchilibon, S Kim, SK Gao, ZG Harris, BA Blaustein, JB Gross, AS Duong, HT Melman, N Jacobson, KA AF Tchilibon, S Kim, SK Gao, ZG Harris, BA Blaustein, JB Gross, AS Duong, HT Melman, N Jacobson, KA TI Exploring distal regions of the A(3) adenosine receptor binding site: sterically constrained N-6-(2-phenylethyl)adenosine derivatives as potent ligands SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE nucleoside; agonist; molecular modeling; GPCR; purine receptor ID STRUCTURAL DETERMINANTS; ANALYSIS COMSIA; AGONISTS; CELLS; PHARMACOLOGY; MOLECULES; PROTEINS; EFFICACY; SUBTYPES; ISCHEMIA AB We synthesized phenyl ring-substituted analogues of N-6-(1S,2R)-(2-phenyl-l-cyclopropyl)adenosine, which is highly potent in binding to the human A(3)AR with a K-i value of 0.63 nM. The effects of these structural changes on affinity at human and rat adenosine receptors and on intrinsic efficacy at the hA(3)AR were measured. A 3-nitrophenyl analogue was resolved chromatographically into pure diastereomers, which displayed 10-fold stereoselectivity in A(3)AR binding in favor of the 1S,2R isomer. A molecular model defined a hydrophobic region (Phel68) in the putative A(3)AR binding site around the phenyl moiety. A hetero-aromatic group (3-thienyl) could substitute for the phenyl moiety with retention of high affinity of A(3)AR binding. Other related N-6-substituted adenosine derivatives were included for comparison. Although the N-6-(2-phenyl-l-cyclopropyl) derivatives were full A(3)AR agonists, several other derivatives had greatly reduced efficacy. N-6-Cyclopropyladenosine was an A(3)AR antagonist, and adding either one or two phenyl rings at the 2-position of the cyclopropyl moiety restored efficacy. N-6-(2,2-Diphenylethyl)adenosine was an A(3)AR antagonist, and either adding a bond between the two phenyl rings (N-6-9-fluorenylmethyl) or shortening the ethyl moiety (N-6-diphenylmethyl) restored efficacy. A QSAR study of the N-6 region provided a model that was complementary to the putative A(3)AR binding site in a rhodopsin-based homology model. Thus, a new series of high-affinity A(3)AR agonists and related nucleoside antagonists was explored through both empirical and theoretical approaches. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH,DHHS, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH,DHHS, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031117-20] NR 38 TC 48 Z9 50 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAY 1 PY 2004 VL 12 IS 9 BP 2021 EP 2034 DI 10.1016/j.bmc.2004.02.037 PG 14 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 817EC UT WOS:000221159800006 PM 15080906 ER PT J AU Matveev, V Zucker, RS Sherman, A AF Matveev, V Zucker, RS Sherman, A TI Facilitation through buffer saturation: Constraints on endogenous buffering properties SO BIOPHYSICAL JOURNAL LA English DT Article ID TRANSMITTER RELEASE MODULATION; PRESYNAPTIC CALCIUM DYNAMICS; TERM SYNAPTIC ENHANCEMENT; ADRENAL CHROMAFFIN CELLS; SACCULAR HAIR-CELLS; NEUROMUSCULAR FACILITATION; NERVE-TERMINALS; MOBILE BUFFERS; NEUROTRANSMITTER RELEASE; RESIDUAL CALCIUM AB Synaptic facilitation (SF) is a ubiquitous form of short-term plasticity, regulating synaptic dynamics on fast timescales. Although SF is known to depend on the presynaptic accumulation of Ca2+, its precise mechanism is still under debate. Recently it has been shown that at certain central synapses SF results at least in part from the progressive saturation of an endogenous Ca2+ buffer (Blatow et al., 2003), as proposed by Klingauf and Neher (1997). Using computer simulations, we study the magnitude of SF that can be achieved by a buffer saturation mechanism (BSM), and explore its dependence on the endogenous buffering properties. We find that a high SF magnitude can be obtained either by a global saturation of a highly mobile buffer in the entire presynaptic terminal, or a local saturation of a completely immobilized buffer. A characteristic feature of BSM in both cases is that SF magnitude depends nonmonotonically on the buffer concentration. In agreement with results of Blatow et al. (2003), we find that SF grows with increasing distance from the Ca2+ channel cluster, and increases with increasing external Ca2+, [Ca2+](text), for small levels of [Ca2+](text). We compare our modeling results with the experimental properties of SF at the crayfish neuromuscular junction, and find that the saturation of an endogenous mobile buffer can explain the observed SF magnitude and its supralinear accumulation time course. However, we show that the BSM predicts slowing of the SF decay rate in the presence of exogenous Ca2+ buffers, contrary to experimental observations at the crayfish neuromuscular junction. Further modeling and data are required to resolve this aspect of the BSM. C1 NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. New Jersey Inst Technol, Dept Math Sci, Newark, NJ 07102 USA. Univ Calif Berkeley, Dept Mol & Cell Biol, Div Neurobiol, Berkeley, CA 94720 USA. RP Sherman, A (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM asherman@nih.gov RI Zucker, Robert/J-9995-2012 NR 80 TC 61 Z9 62 U1 0 U2 3 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY PY 2004 VL 86 IS 5 BP 2691 EP 2709 DI 10.1016/S0006-3495(04)74324-6 PG 19 WC Biophysics SC Biophysics GA 816HW UT WOS:000221102000006 PM 15111389 ER PT J AU Veatch, SL Polozov, IV Gawrisch, K Keller, SL AF Veatch, SL Polozov, IV Gawrisch, K Keller, SL TI Liquid domains in vesicles investigated by NMR and fluorescence microscopy SO BIOPHYSICAL JOURNAL LA English DT Article ID DIFFERENTIAL SCANNING CALORIMETRY; NUCLEAR MAGNETIC-RESONANCE; DETERGENT-SOLUBLE BILAYERS; LIPID RAFTS; MICRODOMAIN FORMATION; PLASMA-MEMBRANES; MODEL MEMBRANES; RESISTANT RAFTS; CHOLESTEROL; MIXTURES AB We use H-2-NMR, H-1-MAS NMR, and fluorescence microscopy to detect immiscibility in three particular phospholipid ratios mixed with 30% cholesterol: 2:1 DOPC/DPPC, 1:1 DOPC/DPPC, and 1:2 DOPC/DPPC. Large-scale (much greater than160 nm) phase separation into liquid-ordered (L-o) and liquid-crystalline (L-alpha) phases is observed by both NMR and fluorescence microscopy. By fitting superimposed H-2-NMR spectra, we quantitatively determine that the L-o phase is strongly enriched in DPPC and moderately enriched in cholesterol. Tie-lines estimated at different temperatures and membrane compositions are based on both H-2-NMR observations and a previously published ternary phase diagram. H-2- and H-1-MAS NMR techniques probe significantly smaller length scales than microscopy experiments (submicron versus micron-scalp), and complex behavior is observed near the miscibility transition. Fluorescence microscopy of giant unilamellar vesicles shows micrometer- scale domains below the miscibility transition. In contrast, NMR of multilamellar vesicles gives evidence for smaller (similar to80 nm) domains just below the miscibility transition, whereas large-scale demixing occurs at a lower temperature, T-low. A transition at T-low is also evident in fluorescence microscopy measurements of the surface area fraction of ordered phase in giant unilamellar vesicles. Our results reemphasize the complex phase behavior of cholesterol-containing membranes and provide a framework for interpreting H-2-NMR experiments in similar membranes. C1 Univ Washington, Dept Chem, Seattle, WA 98195 USA. Univ Washington, Dept Phys, Seattle, WA 98195 USA. NIAAA, Lab Membrane Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Keller, SL (reprint author), Univ Washington, Dept Chem, Seattle, WA 98195 USA. EM slkeller@chem.washington.edu RI Wunder, Stephanie/B-5066-2012; Zdilla, Michael/B-4145-2011; Veatch, Sarah/G-9512-2016 OI Veatch, Sarah/0000-0002-9317-2308 FU NIGMS NIH HHS [5T32-GM08268-14, T32 GM008268] NR 40 TC 285 Z9 292 U1 10 U2 79 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY PY 2004 VL 86 IS 5 BP 2910 EP 2922 DI 10.1016/S0006-3495(04)74342-8 PG 13 WC Biophysics SC Biophysics GA 816HW UT WOS:000221102000024 PM 15111407 ER PT J AU Shah, SB Davis, J Weisleder, N Kostavassili, I McCulloch, AD Ralston, E Capetanaki, Y Lieber, RL AF Shah, SB Davis, J Weisleder, N Kostavassili, I McCulloch, AD Ralston, E Capetanaki, Y Lieber, RL TI Structural and functional roles of desmin in mouse skeletal muscle during passive deformation SO BIOPHYSICAL JOURNAL LA English DT Article ID NUCLEAR LAMIN-B; INTERMEDIATE-FILAMENTS; MECHANICAL-PROPERTIES; PROTEIN-COMPOSITION; ATTACHMENT SITE; CELL PERIPHERY; CARDIAC-MUSCLE; LACKING DESMIN; ADULT-RAT; ORGANIZATION AB Mechanical interactions between desmin and Z-disks, costameres, and nuclei were measured during passive deformation of single muscle cells. Image processing and continuum kinematics were used to quantify the structural connectivity among these structures. Analysis of both wild-type and desmin-null fibers revealed that the costamere protein talin colocalized with the Z-disk protein alpha-actinin, even at very high strains and stresses. These data indicate that desmin is not essential for mechanical coupling of the costamere complex and the sarcomere lattice. Within the sarcomere lattice, significant differences in myofibrillar connectivity were revealed between passively deformed wild-type and desmin-null fibers. Connectivity in wild-type fibers was significantly greater compared to desmin-null fibers, demonstrating a significant functional connection between myofibrils that requires desmin. Passive mechanical analysis revealed that desmin may be partially responsible for regulating fiber volume, and consequently, fiber mechanical properties. Kinematic analysis of alpha-actinin strain fields revealed that knockout fibers transmitted less shear strain compared to wild-type fibers and experienced a slight increase in fiber volume. Finally, linkage of desmin intermediate filaments to muscle nuclei was strongly suggested based on extensive loss of nuclei positioning in the absence of desmin during passive fiber loading. C1 Vet Adm Med Ctr, Dept Orthopaed 9151, San Diego, CA 92161 USA. Univ Calif San Diego, Dept Bioengn, Biomed Sci Grad Grp, San Diego, CA 92161 USA. Univ Calif San Diego, Dept Orthopaed, Biomed Sci Grad Grp, San Diego, CA 92161 USA. Baylor Coll Med, Dept Cell Biol, Houston, TX 77030 USA. NIH, Bethesda, MD 20892 USA. Acad Athens, Fdn Biomed Res, Ctr Basic Res, Athens, Greece. Univ Patras, Dept Biol, GR-26110 Patras, Greece. RP Lieber, RL (reprint author), Vet Adm Med Ctr, Dept Orthopaed 9151, 3350 La Jolla Village Dr, San Diego, CA 92161 USA. EM rlieber@ucsd.edu RI Shah, Sameer/A-6899-2008; Weisleder, Noah/A-7098-2013 OI Weisleder, Noah/0000-0002-2619-8022 FU NHLBI NIH HHS [T32 HL007089, T32HL07089]; NIAMS NIH HHS [AR40050, R01 AR040050] NR 64 TC 65 Z9 67 U1 0 U2 5 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY PY 2004 VL 86 IS 5 BP 2993 EP 3008 DI 10.1016/S0006-3495(04)74349-0 PG 16 WC Biophysics SC Biophysics GA 816HW UT WOS:000221102000031 PM 15111414 ER PT J AU Yarchoan, R AF Yarchoan, R TI KSHV induces heme ozygenase: another trick by a wily virus SO BLOOD LA English DT Editorial Material ID KAPOSIS-SARCOMA; IDENTIFICATION; EXPRESSION; HYPOXIA C1 NCI, Bethesda, MD 20892 USA. RP Yarchoan, R (reprint author), NCI, Bethesda, MD 20892 USA. NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 2004 VL 103 IS 9 BP 3252 EP 3253 DI 10.1182/blood-2004-02-0689 PG 2 WC Hematology SC Hematology GA 822UJ UT WOS:000221565600008 ER PT J AU Alsina, M Fonseca, R Wilson, EF Belle, AN Gerbino, E Price-Troska, T Overton, RM Ahmann, G Bruzek, LM Adjei, AA Kaufmann, SH Wright, JJ Sullivan, D Djulbegovic, B Cantor, AB Greipp, PR Dalton, WS Sebti, SM AF Alsina, M Fonseca, R Wilson, EF Belle, AN Gerbino, E Price-Troska, T Overton, RM Ahmann, G Bruzek, LM Adjei, AA Kaufmann, SH Wright, JJ Sullivan, D Djulbegovic, B Cantor, AB Greipp, PR Dalton, WS Sebti, SM TI Farnesyltransferase inhibitor tipifarnib is well tolerated, induces stabilization of disease, and inhibits farnesylation and oncogenic/tumor survival pathways in patients with advanced multiple myeloma SO BLOOD LA English DT Article ID GERANYLGERANYLTRANSFERASE-I INHIBITORS; MEDIATED DRUG-RESISTANCE; MARROW STROMAL CELLS; N-RAS; TRANSFERASE INHIBITORS; CANCER-THERAPY; K-RAS; PRENYLATION; TRANSFORMATION; APOPTOSIS AB Patients with multiple myeloma (MM) with mutated RAS are less likely to respond to chemotherapy and have a shortened survival. Therefore, targeting RAS farnesylation may be a novel approach to treatment of MM. We evaluated the activity and tolerability of the farnesyltransferase (FTase) inhibitor tipifarnib (Zarnestra) in a phase 2 trial as well as its ability to inhibit protein farnesylation and oncogenic pathways in patients with relapsed MM. Forty-three patients (median age, 62 years [range, 33-82 years]) with a median of 4 (range, 1-6) chemotherapy regimens entered the study. Tipifarnib, 300 mg orally twice daily, was administered for 3 weeks every 4 weeks. The most common toxicity was fatigue occurring in 66% of patients. Other toxicities included diarrhea, nausea, neuropathy, anemia, and thrombocytopenia. Sixty-four percent of the patients had disease stabilization. Treatment with tipifarnib suppressed FTase (but not geranylgeranyltransferase 1) in bone marrow and peripheral blood mononuclear cells and also inhibited the farnesylation of HDJ-2 in unfractionated mononuclear cells and purified myeloma cells. Inhibition of farnesylation did not correlate with disease stabilization. Finally, tipifarnib decreased the levels of phosphorylated Akt and STAT3 (signal transducer and activator of transcription 3) but not Erk1/2 (extracellular signal regulated kinase 1 and 2) in bone marrow cells. We conclude that tipifarnib is tolerable, can induce disease stabilization, and can inhibit farnesylation and oncogenic/turnor survival pathways. (C) 2004 by The American Society of Hematology. C1 Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, MRCDRDIS,Drug Discovery Program, Tampa, FL 33612 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Expt Therapeut Program, Tampa, FL 33612 USA. Univ S Florida, Dept Oncol, Tampa, FL 33612 USA. Mayo Clin & Mayo Fdn, Div Hematol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Oncol, Rochester, MN 55905 USA. NCI, Bethesda, MD 20892 USA. RP Sebti, SM (reprint author), Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, MRCDRDIS,Drug Discovery Program, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM sebti@moffitt.usf.edu RI Djulbegovic, Benjamin/I-3661-2012; OI Djulbegovic, Benjamin/0000-0003-0671-1447; Fonseca, Rafael/0000-0002-5938-3769 FU NCI NIH HHS [CA21115-25C, R01 CA83724, R01 CA83978]; NCRR NIH HHS [M01-RR00585] NR 33 TC 120 Z9 130 U1 1 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 MAY 1 PY 2004 VL 103 IS 9 BP 3271 EP 3277 DI 10.1182/blood-2003-08-2764 PG 7 WC Hematology SC Hematology GA 822UJ UT WOS:000221565600015 PM 14726402 ER PT J AU Farel, CE Chaitt, DG Hahn, BK Tavel, JA Kovacs, JA Polis, MA Masur, H Follmann, DA Lane, HC Davey, RT AF Farel, CE Chaitt, DG Hahn, BK Tavel, JA Kovacs, JA Polis, MA Masur, H Follmann, DA Lane, HC Davey, RT TI Induction and maintenance therapy with intermittent interleukin-2 in HIV-1 infection SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; SUBCUTANEOUS INTERLEUKIN-2; COMBINATION; LYMPHOCYTES; BLOOD AB Studies establishing that intermittent subcutaneous interleukin-2 (IL-2) therapy can lead to substantial CD4 cell increases in many HIV-infected patients have generally been of limited duration. We studied 77 patients participating in active longitudinal studies of subcutaneous IL-2 therapy at our center in order to determine the long-term feasibility of this approach. Following initial induction, patients in each trial were eligible to receive intermittent 5-day cycles of subcutaneous IL-2 treatment at individualized doses and frequencies capable of maintaining CD4 counts at postinduction levels. The mean duration of study participation to date is 5.9 years (range, 1.0-9.3 years). Mean baseline CD4 cell count and CD4 percent values of 0.521 x 10(9)/L (521 cells/ muL) and 27% have risen to 1.005 x 10(9)/L (1005 cells/muL) and 38%, respectively, at 90 months. The mean number of subcutaneous IL-2 cycles required to achieve and maintain these increases was 10 cycles (range, 3-29 cycles), and the current mean interval of cycling required to maintain these elevations is 39 months (median, 35 months; range, 2-91 months). We conclude that subcutaneous IL-2 therapy is capable of maintaining CD4 cell increases for an extended period using a remarkably low frequency of intermittent cycling. These observations may contribute to patients' acceptance of subcutaneous IL-2 as a favorable long-term treatment strategy. (C) 2004 by The American Society of Hematology. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. US Dept HHS, NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Davey, RT (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10 Rm 11C-103, Bethesda, MD 20892 USA. EM rdavey@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268 NR 20 TC 32 Z9 33 U1 1 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 MAY 1 PY 2004 VL 103 IS 9 BP 3282 EP 3286 DI 10.1182/blood-2003-09-3283 PG 5 WC Hematology SC Hematology GA 822UJ UT WOS:000221565600017 PM 14726376 ER PT J AU Bauer, TR Creevy, KE Gu, YC Tuschong, LM Donahue, RE Metzger, ME Embree, LJ Burkholder, T Bacher, JD Romines, C Thomas, ML Colenda, L Hickstein, DD AF Bauer, TR Creevy, KE Gu, YC Tuschong, LM Donahue, RE Metzger, ME Embree, LJ Burkholder, T Bacher, JD Romines, C Thomas, ML Colenda, L Hickstein, DD TI Very low levels of donor CD18(+) neutrophils following allogeneic hematopoietic stem cell transplantation reverse the disease phenotype in canine leukocyte adhesion deficiency SO BLOOD LA English DT Article; Proceedings Paper CT 45th Annual Meeting of the American-Society-of-Hematology CY DEC 06-09, 2003 CL SAN DIEGO, CA SP Amer Soc Hematol ID GRANULOCYTOPATHY SYNDROME; MARROW TRANSPLANTATION; MONOCLONAL-ANTIBODIES; PROTEIN-DEFICIENCY; PERIPHERAL-BLOOD; DOG; LFA-1; DYSFUNCTION; NEUTROPENIA; INFECTIONS AB Children with the severe phenotype of the genetic immunodeficiency disease leukocyte adhesion deficiency or LAD experience life-threatening bacterial infections because of molecular defects in the leukocyte integrin CD18 molecule and the resultant failure to express the CD11/CD18 adhesion molecules on the leukocyte surface. Hematopoietic stem cell transplantation remains the only definitive therapy for LAD; however, the degree of donor chimerism and particularly the number of CD18(+) donor-derived neutrophils required to reverse the disease phenotype are not known. We performed nonmyeloablative hematopoletic stem cell transplantations from healthy matched littermates in 9 dogs with the canine form of LAD known as CLAD and demonstrate that in the 3 dogs with the lowest level of donor chimerism, less than 500 CD18+ donor-derived neutrophils/muL in the peripheral blood of the CLAD recipients resulted in reversal of the CLAD disease phenotype. These results demonstrate the value of a disease-specific, large-animal model for identifying the lowest therapeutic level required for successful cellular and gene therapy. (C) 2004 by The American Society of Hematology. C1 NIH, Ctr Canc Res, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD USA. NHLBI, Hematol Branch, Off Res Serv, Vet Resource Program,NIH, Rockville, MD USA. RP Bauer, TR (reprint author), NIH, Ctr Canc Res, Expt Transplantat & Immunol Branch, Bldg 10,Rm 12C-116,10 Ctr Dr,MSC1907, Bethesda, MD 20892 USA. EM bauert@mail.nih.gov NR 28 TC 21 Z9 21 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 1 PY 2004 VL 103 IS 9 BP 3582 EP 3589 DI 10.1182/blood-2003-11-4008 PG 8 WC Hematology SC Hematology GA 822UJ UT WOS:000221565600062 PM 14715622 ER PT J AU Miller, JL AF Miller, JL TI A genome-based approach for the study of erythroid biology and disease SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article; Proceedings Paper CT Red Cell Club Meeting CY OCT 24, 2003 CL Yale Univ, Sch Med, New Haven, CT HO Yale Univ, Sch Med DE erythroid; genome-based approach; disease ID BLOOD; ERYTHROPOIESIS; EXPRESSION; FETAL; DIFFERENTIATION; IDENTIFICATION; PROLIFERATION; MODULATION; CELLS AB The human genome contains all elements of the erythroid transcriptome with the exception of those genes encoded in mitochondrial DNA. The concept of a "genome-based" approach for the study of erythroid biology and disease was envisioned in the mid-1990s as a logical offshoot of efforts to map the human genome. Although a completed human genome map was not expected until 2005 [Science 279 (1998) 23], the idea of creating a robust and retrievable description of erythroid gene activity was both encouraged and supported on the NIDDK Bethesda campus of the National Institutes of Health. The 5-10-year goals were organized into three parts. The initial project goal involved the collection of sequence data derived from mRNA expressed in developmentally staged erythroblasts. Those cells were isolated prospectively by flow cytometry monitoring of CD71 and glycophorin A expression patterns. Next, the sequence data was organized into a database and integrated with related information available in the public domain. The paramount goal of the project continues to be clinical application. As discussed in this paper, progress already made in each of these areas suggests that genome-based approaches will greatly facilitate future studies of erythroid biology and disease. Published by Elsevier Inc. C1 NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDKD, Biol Chem Lab, NIH, Room 9B17,Bldg 10,9000 Rockville Pike,MSC 1822, Bethesda, MD 20892 USA. EM jm7f@nih.gov NR 17 TC 5 Z9 5 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAY-JUN PY 2004 VL 32 IS 3 BP 341 EP 343 DI 10.1016/h,bcmd.2004.01.003 PG 3 WC Hematology SC Hematology GA 825DY UT WOS:000221737400002 PM 15121088 ER PT J AU Dejam, A Hunter, CJ Schechter, AN Gladwin, MT AF Dejam, A Hunter, CJ Schechter, AN Gladwin, MT TI Emerging role of nitrite in human biology SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article; Proceedings Paper CT Red Cell Club Meeting CY OCT 24, 2003 CL Yale Univ, Sch Med, New Haven, CT HO Yale Univ, Sch Med DE nitric oxide; vasodilation; endothelial function; nitrite; nitric oxide stores ID RED-BLOOD-CELLS; DIRECTLY ACTING VASODILATOR; HUMAN FOREARM VASCULATURE; OXIDE SYNTHASE ACTIVITY; NO IN-VIVO; S-NITROSOHEMOGLOBIN; CIRCULATING NITRITE; PLASMA NITRITE; CAPILLARY ELECTROPHORESIS; ENDOTHELIAL FUNCTION AB Nitric oxide (NO) plays a fundamental role in maintaining normal vascular function. NO is produced by endothelial cells and diffuses both into smooth muscle causing vasodilation and into the vessel lumen where the majority of this highly potent gas is rapidly inactivated by dioxygenation reaction with oxyhemoglobin to form nitrate. Diffusional barriers for NO around the erythrocyte and along the endothelium in laminar flowing blood reduce the inactivation reaction of NO by hemoglobin, allowing sufficient NO to escape for vasodilation and also to react in plasma and tissues to form nitrite anions (NO2-) and NO-modified peptides and proteins (RX-NO). Several recent studies have highlighted the importance of the nitrite anion in human biology. These studies have shown that measurement of plasma nitrite is a sensitive index of constitutive NO synthesis, suggesting that it may be useful as a marker of endothelial function. Additionally, recent evidence suggests that nitrite represents a circulating storage pool of NO and may selectively donate NO to hypoxic vascular beds. The conversion of nitrite to NO requires a reaction with a deoxygenated heme protein, suggesting a novel function of hemoglobin as a deoxygenation-dependent nitrite reductase. This review focuses on the role of nitrite as a circulating NO donor, its potential as an index of NO synthase (NOS) activity and endothelial function, and discusses potential diagnostic and therapeutic applications. Published by Elsevier Inc. C1 NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NIH, Dept Crit Care Med, Warren G Magnuson Clin Ctr, Room 7D43,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM mgladwin@cc.nih.gov RI Hunter, Christian/G-4344-2010; OI Schechter, Alan N/0000-0002-5235-9408 FU NIGMS NIH HHS [T32 GM 08361] NR 79 TC 118 Z9 122 U1 1 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAY-JUN PY 2004 VL 32 IS 3 BP 423 EP 429 DI 10.1016/j.bcmd.2004.02.002 PG 7 WC Hematology SC Hematology GA 825DY UT WOS:000221737400016 PM 15121102 ER PT J AU Robinson, MR Lee, SS Rubin, BI Wayne, AS Pavletic, SZ Bishop, MR Childs, R Barrett, AJ Csaky, KG AF Robinson, MR Lee, SS Rubin, BI Wayne, AS Pavletic, SZ Bishop, MR Childs, R Barrett, AJ Csaky, KG TI Topical corticosteroid therapy for cicatricial conjunctivitis associated with chronic graft-versus-host disease SO BONE MARROW TRANSPLANTATION LA English DT Article DE conjunctiva; corticosteroid therapy; stem cell transplantation; graft-versus-host disease ID BONE-MARROW TRANSPLANTATION; STEM-CELL TRANSPLANTATION; OCULAR MANIFESTATIONS; LACRIMAL GLAND; EYE; COMPLICATIONS; FK506 AB A retrospective chart review was performed on seven patients treated with topical ocular corticosteroid therapy for progressive cicatricial conjunctivitis associated with chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. A clinical grading criteria for conjunctival GVHD based on the degree of cicatrization was developed and patients graded prior to therapy. During the treatment course, the dose and frequency of topical corticosteroids and clinical outcomes were recorded. A complete response was defined as a complete resolution of the conjunctival hyperemia with either total resolution of the conjunctival fibrovascularization or presence of inactive conjunctival scarring. Prednisolone acetate 1% eye drops were used in a total of eight courses of therapy in seven patients. A complete response was documented in all seven patients with a total treatment duration of 7 weeks (median, range: 3-16 weeks). Additional studies are required to determine the long-term safety and efficacy of topical corticosteroids for cicatricial conjunctivitis associated with ocular GVHD in the context of a randomized, prospective clinical trial. C1 NEI, NIH, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Graft Versus Host Dis & Autoimmun Unit, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Stem Cell Allotransplantat Sect, NIH, Bethesda, MD 20892 USA. RP Robinson, MR (reprint author), NEI, NIH, 10-10S229,10 Ctr Dr MSC 1863, Bethesda, MD 20892 USA. EM robinsonm@nei.nih.gov NR 31 TC 49 Z9 50 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAY PY 2004 VL 33 IS 10 BP 1031 EP 1035 DI 10.1038/sj.bmt.1704453 PG 5 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 818JY UT WOS:000221242600009 PM 15048138 ER PT J AU Valle, M Price, RW Nilsson, A Heyes, M Verotta, D AF Valle, M Price, RW Nilsson, A Heyes, M Verotta, D TI CSF quinolinic acid levels are determined by local HIV infection: cross-sectional analysis and modelling of dynamics following antiretroviral therapy SO BRAIN LA English DT Article DE AIDS; CSF; HIV; treatment; quinolinic acid ID AIDS DEMENTIA COMPLEX; HUMAN-IMMUNODEFICIENCY-VIRUS; RETROVIRUS-INDUCED IMMUNODEFICIENCY; PLATELET-ACTIVATING-FACTOR; PLACEBO-CONTROLLED TRIAL; CENTRAL-NERVOUS-SYSTEM; CEREBROSPINAL-FLUID; COGNITIVE IMPAIRMENT; CLINICAL-TRIALS; NEUROPSYCHIATRIC ASPECTS AB Quinolinic acid (QUIN) is a product of tryptophan metabolism that can act as an endogenous brain excitotoxin when released by activated macrophages. Previous studies have shown correlations between increased CSF QUIN levels and the presence of the AIDS dementia complex (ADC), a neurodegenerative condition complicating late-stage human immunodeficiency virus type 1 (HIV) infection in some patients. CSF QUIN is putatively one of the important molecular mediators of the brain injury in this clinical setting and, more generally, serves as a marker of local macrophage activation. This study was undertaken to examine the relationship of CSF QUIN concentrations to local HIV infection and to define the effects of antiretroviral drug treatment on CSF QUIN using two complementary approaches. The first was an exploratory cross-sectional analysis of a clinically heterogeneous sample of 62 HIV-infected subjects, examining correlations of CSF QUIN levels with CSF and plasma HIV RNA levels and other salient parameters of infection. The second involved longitudinal observations of a subset of 20 of these subjects who initiated new antiretroviral therapy regimens. In addition to descriptive analysis, we used kinetic modelling of QUIN decay in relation to that of HIV RNA to assess further the relationship between CSF QUIN and infection in the dynamic setting of treatment. The cross-sectional studies showed strong correlations of CSF QUIN with both CSF HIV RNA and blood QUIN levels, as well as with elevations in CSF white blood cells, CSF total protein and CSF:blood albumin ratio. In this group of subjects with a low incidence of active, untreated ADC, CSF QUIN did not correlate with ADC stage or measures of quantitative neurological performance. Antiviral treatment reduced the CSF QUIN levels in all the longitudinally followed, treated subjects. Kinetic modelling of CSF QUIN decay indicated that CSF QUIN levels were driven primarily by CSF HIV infection with a lesser contribution from blood QUIN levels. In three subjects with new-onset, untreated ADC, CSF QUIN decay paralleled both CSF HIV decrement and improvement in neurological performance. These studies show that CSF QUIN concentrations relate primarily to active CSF HIV infection and to a lesser extent to plasma QUIN. CSF QUIN serves as a marker of local infection with a wide dynamic range. The time course of therapy-induced changes links CSF QUIN to local infection and supports the action of antiviral therapy in ameliorating immunopathological brain injury and ADC. C1 Univ Calif San Francisco, Dept Biopharmaceut Sci, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. NIMH, Bethesda, MD 20892 USA. RP Price, RW (reprint author), San Francisco Gen Hosp, Room 4M62,1001 Potrero Ave, San Francisco, CA 94110 USA. EM price@itsa.ucsf.edu OI valle, marta/0000-0002-3515-251X FU NCRR NIH HHS [5-M01-RR-00083-36]; NIAID NIH HHS [R01 AI 050587]; NIMH NIH HHS [R01 MH62701]; NINDS NIH HHS [R01 NS37660] NR 59 TC 26 Z9 30 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 2004 VL 127 BP 1047 EP 1060 DI 10.1093/brain/awh130 PN 5 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 816XE UT WOS:000221141800010 PM 15013955 ER PT J AU Schmidt, J Rakocevic, G Raju, R Dalakas, MC AF Schmidt, J Rakocevic, G Raju, R Dalakas, MC TI Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body myositis muscle: significance for CD8(+) T cell cytotoxicity SO BRAIN LA English DT Article DE inclusion body myositis; co-stimulation; autoimmunity; muscle inflammation; perforin ID INFLAMMATORY MYOPATHIES; IN-VIVO; CUTTING EDGE; TNF-ALPHA; EXPRESSION; MOLECULE; RECEPTOR; POLYMYOSITIS; RESPONSES; DERMATOMYOSITIS AB Interactions between inducible co-stimulatory molecule (ICOS) and ICOS-ligand (ICOS-L) are crucial for T-cell co-stimulation, effector cell differentiation and memory CD8(+) T-cell activation. Because in the muscle of patients with sporadic inclusion body myositis (sIBM) clonally expanded CD8(+) T cells invade major histocompatibility complex (MHC) class I-expressing muscle fibres, we investigated ICOS.ICOS-L interactions and correlated their expression with perforin, a marker for cytotoxic effector function by autoinvasive CD8(+) T cells. The mRNA from 20 muscle biopsies of sIBM, 20 non-inflammatory or dystrophic controls, two dermatomyositis (DM) and two polymyositis (PM) patients was reverse transcribed and reamplified by semi-quantitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR), using primers for ICOS, ICOS-L and perforin. The glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-normalized ratio of ICOS, ICOS-L and perforin expression was compared with the degree of endomysial inflammation. Protein expression of ICOS, ICOS-L and perforin was confirmed by immunohistochemistry. We demonstrate that ICOS-L mRNA was upregulated in sIBM (arbitrary units, median +/- SEM: 48.6 +/- 14.9) compared with controls (6.2 +/- 17.8, P < 0.05) and significantly correlated with the expression of ICOS (53.9 +/- 16.6 versus 6.7 +/- 8.9 in controls, P < 0.001). By triple labelling immunohistochemistry, the CD8(+) T cells in sIBM and PM were found to invade ICOS-L- and MHC class I-co-expressing muscle fibres. Among the autoinvasive CD8(+) T cells, however, only a subset of similar to5-10% were ICOS positive, and thereby perceptive for ICOS.ICOS-L signalling at the immunological synapse. In contrast, in Duchenne muscular dystrophy and DM, although ICOS and ICOS-L mRNA expression was also increased, the majority of ICOS-L- and ICOS-positive cells were in the perimysial regions and connective tissue. The mRNA for perforin was increased in sIBM (28.1 +/- 8.7) compared with controls (4.3 +/- 11.2, P = 0.18), and significantly correlated with mRNA of ICOS, ICOS-L and the degree of endomysial inflammation as assessed in coded haematoxylin/eosin tissue sections. By triple immunohistochemical staining and cell counting, perforin granules were found in 71% of the autoinvasive CD8(+) T cells that were also ICOS positive. Our data indicate that in sIBM there is upregulation of ICOS.ICOS-L co-stimulatory signalling in association with enhanced perforin expression by the autoinvasive CD8(+) T cells. The findings support previous suggestions that in IBM, the muscle fibres have the capacity for antigen presentation, thereby activating a specific subset among the autoinvasive CD8(+) T cells to exert a cytotoxic effect. The observations strengthen the immunopathogenesis of sIBM, and offer the basis for future therapeutic interventions targeting ICOS.ICOS-L co-stimulatory interactions. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N 250,10 Ctr Dr MSC 1382, Bethesda, MD 20892 USA. EM j.schmidt@gmx.org; DalakasM@ninds.nih.gov RI Schmidt, Jens/B-5791-2013 NR 37 TC 50 Z9 50 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAY PY 2004 VL 127 BP 1182 EP 1190 DI 10.1093/brain/awh148 PN 5 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 816XE UT WOS:000221141800020 PM 15047591 ER PT J AU Horwitz, B Braun, AR AF Horwitz, B Braun, AR TI Brain network interactions in auditory, visual and linguistic processing SO BRAIN AND LANGUAGE LA English DT Article ID PREFRONTAL CORTEX; WORKING-MEMORY; TEMPORAL-LOBE; MODEL; FMRI; PET; CONNECTIVITY; RECOGNITION; COGNITION; ATTENTION AB In the paper, we discuss the importance of network interactions between brain regions in mediating performance of sensorimotor and cognitive tasks, including those associated with language processing. Functional neuroimaging, especially PET and fMRI, provide data that are obtained essentially simultaneously from much of' the brain, and thus are ideal for enabling one to assess interregional functional interactions. Two ways to use these types of data to assess network interactions are presented. First, using PET, we demonstrate that anterior and posterior perisylvian language areas have stronger functional connectivity during spontaneous narrative production than during other less linguistically demanding production tasks. Second, we show how one can use large-scale neural network modeling to relate neural activity to the hemodynamically-based data generated by fMRI and PET. We review two versions of a model of object processing - one for visual and one for auditory objects. The regions comprising the models include primary and secondary sensory cortex, association cortex in the temporal lobe, and prefrontal cortex. Each model incorporates specific assumptions about how neurons in each of these areas function, and how neurons in the different areas are interconnected with each other. Each model is able to perform a delayed match-to-sample task for simple objects (simple shapes for the Visual model; tonal contours for the auditory model). We find that the simulated electrical activities in each region are similar to those observed in nonhuman primates performing analogous tasks, and the absolute values of the simulated integrated synaptic activity in each brain region match human fMRI/PET data. Thus, this type of' modeling provides a way to understand the neural bases for the sensorimotor and cognitive tasks of interest. Published by Elsevier Inc. C1 Natl Inst Deafness & Other Commun Disorders, Language Branch, NIH, Bethesda, MD 20892 USA. RP Horwitz, B (reprint author), Natl Inst Deafness & Other Commun Disorders, Language Branch, NIH, 9000 Rockville Pike,Bldg 10,Rm 6C420,MSC 1591, Bethesda, MD 20892 USA. EM horwitz@helix.nih.gov NR 31 TC 44 Z9 45 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD MAY PY 2004 VL 89 IS 2 BP 377 EP 384 DI 10.1016/S0093-934X(03)00349-3 PG 8 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 813ZK UT WOS:000220944800013 PM 15068921 ER PT J AU Kopnisky, KL Stoff, DM Rausch, DM AF Kopnisky, KL Stoff, DM Rausch, DM TI Workshop report: the effects of psychological variables on the progression of HIV-1 disease SO BRAIN BEHAVIOR AND IMMUNITY LA English DT Review DE psychoneuroimmunology; HIV; behavior; infection; neuroendocrine; neuroimmune; stress; disease progression ID STRESSFUL LIFE EVENTS; IMMUNODEFICIENCY-VIRUS TYPE-1; DEXAMETHASONE SUPPRESSION TEST; CELL-SURFACE EXPRESSION; CHEMOKINE RECEPTOR GENE; TO-BRAIN COMMUNICATION; CENTRAL-NERVOUS-SYSTEM; NATURAL-KILLER-CELLS; DEPRESSIVE SYMPTOMS; IMMUNE-RESPONSE AB The reciprocal interactions between the neuroendocrine, immune, and autonomic nervous systems are complicated, yet worthy of examination. A body of literature suggests that psychological factors such as stress, or psychiatric conditions such as major depression, may influence the immune system thereby altering host susceptibility to viral, or other types of infection. Alternately, in an attempt to limit infection and replication, the anti-viral host response, via innate and acquired immunity and subsequent release of pro-inflammatory cytokines and additional anti-viral mediators, may affect mood, cognition emotion, and possibly precipitate a psychiatric disorder. In order to address what is known regarding neuroendocrine-immune interactions in the context of HIV infection, the Center for Mental Health Research on AIDS convened a panel of scientists from diverse areas of expertise. Their primary charge was to examine whether stress-induced activation of the neuroendocrine system affects the immune system in a manner that negatively influences HIV disease progression, and whether HIV infection influences the central nervous system and behavior. The ensuing report summarizes their deliberations as they discussed the current body of information and identified outstanding critical questions in the areas of research. The group consensus was that the biological mediators of psychological status can play an important role in mediating HIV disease progression, particularly in subgroups of vulnerable patients; furthermore, they identified candidate biological mediators and mechanisms of disease progression. The Workgroup outlined the inherent challenges and limitations of such research and provided recommendations as to the future directions of research utilizing human, animal, and in vitro models of HIV-1 infection and stress. (C) 2004 Elsevier Inc. All rights reserved. C1 NIMH, Ctr Mental Hlth Res AIDS, Bethesda, MD 20892 USA. RP Kopnisky, KL (reprint author), NIMH, Ctr Mental Hlth Res AIDS, 6001 Execut Blvd,MSC 9619, Bethesda, MD 20892 USA. EM kkopnisk@mail.nih.gov NR 119 TC 29 Z9 31 U1 5 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0889-1591 J9 BRAIN BEHAV IMMUN JI Brain Behav. Immun. PD MAY PY 2004 VL 18 IS 3 BP 246 EP 261 DI 10.1016/j.bbi.2003.08.003 PG 16 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 812AU UT WOS:000220813200007 PM 15050652 ER PT J AU Yan, X Shen, H Zaharia, M Wang, J Wolf, D Li, F Lee, GD Cao, W AF Yan, X Shen, H Zaharia, M Wang, J Wolf, D Li, F Lee, GD Cao, W TI Involvement of phosphatidylinositol 3-kinase and insulin-like growth factor-I in YXLST-mediated neuroprotection SO BRAIN RESEARCH LA English DT Article DE neuroprotection; insulin-like growth factor-I; phosphatidylinositol 3-kinase; Yan Xin Life Sciences Technology; external Qi ID PHOSPHOINOSITIDE 3-KINASE; CELL-DEATH; SURVIVAL; KINASE; PATHWAYS; TRANSFORMATION; ACTIVATION; NEURONS; BRAIN AB In the present study, we examine the neuroprotective role of the external Qi of YXLST in cultured retinal neurons. Primary retinal neuronal cultures were grown from retinas of 0-2-day-old Sprague-Dawley rats. Cultures were treated directly with external Qi of YXLST 30 min prior to H2O2 exposure in most experiments. Cell viability was measured by 3,(4,5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide (MTT) assay. Apoptotic cell death was evaluated by the TdT-mediated digoxigenin-dUTP nick-end labeling TUNEL assay, and by DNA laddering analysis. Northern blot analysis was performed to examine the level of insulin-like growth factor-I (IGF-1) gene expression. Phosphatidylinositol 3-kinase (PI3K) assay was performed to study the PI3K activity. The results showed that treatment of external Qi of YXLST significantly attenuated neuronal death that was induced by 24-h exposure to hydrogen peroxide, and greatly inhibited hydrogen peroxide-induced apoptosis. External Qi of YXLST also upregulated IGF-I gene expression and increased PI3K activity. These observations indicate that external Qi-mediated IGF-I expression and PI3K signaling could be one of the mechanisms in neuroprotection by YXLST. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Oklahoma, Dept Ophthalmol, Dean A McGee Eye Inst, Oklahoma City, OK 73104 USA. Amer New Med Inst, New York, NY 10107 USA. Univ Sherbrooke, Sherbrooke, PQ J1K 2R1, Canada. Harvard Univ, Sch Med, Boston, MA 02115 USA. NIA, NIH, Baltimore, MD 21224 USA. Inst Chongqing Tradit Chinese Med, Chongqing, Peoples R China. RP Cao, W (reprint author), Univ Oklahoma, Dept Ophthalmol, Dean A McGee Eye Inst, 608 Stanton L Young Blvd, Oklahoma City, OK 73104 USA. EM wei-cao@ouhsc.edu FU NEI NIH HHS [EYEY12190, EY014427] NR 48 TC 12 Z9 12 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 1 PY 2004 VL 1006 IS 2 BP 198 EP 206 DI 10.1016/j.brainres.2004.01.068 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 812EK UT WOS:000220822600007 PM 15051523 ER PT J AU Santini, G De Souza, C Aversa, S Patti, C Tedeschi, L Candela, M Olivieri, A Chisesi, T Rubagotti, A Centurioni, R Nardi, V Congiu, M Gennaro, M Truini, M AF Santini, G De Souza, C Aversa, S Patti, C Tedeschi, L Candela, M Olivieri, A Chisesi, T Rubagotti, A Centurioni, R Nardi, V Congiu, M Gennaro, M Truini, M TI A third generation regimen VACOP-B with or without adjuvant radiotherapy for aggressive localized non-Hodgkin's lymphoma - Report from the Italian Non-Hodgkin's Lymphoma Co-operative Study Group SO BRAZILIAN JOURNAL OF MEDICAL AND BIOLOGICAL RESEARCH LA English DT Article DE localized aggressive non-Hodgkin's lymphoma; VACOP-B; radiotherapy; toxicity ID PROSPECTIVE RANDOMIZED-TRIAL; LARGE-CELL LYMPHOMA; MACOP-B; STAGE INTERMEDIATE; BRIEF CHEMOTHERAPY; RADIATION-THERAPY; RESPONSE CRITERIA; ELDERLY-PATIENTS; BONE-MARROW; GRADE AB The objective of this multicenter prospective study was to determine the clinical efficacy and toxicity of a polychemotherapeutic third generation regimen, VACOP-B, with or without radiotherapy as frontline therapy in aggressive localized non-Hodgkin's lymphoma. Ninety-three adult patients (47 males and 46 females, median age 45 years) with aggressive localized non-Hodgkin's lymphoma, 43 in stage I and 50 in stage II (non-bulky), were included in the study. Stage I patients received VACOP-B for 6 weeks plus involved field radiotherapy and stage II patients received 12 weeks VACOP-B plus involved field radiotherapy on residual masses. Eighty-six (92.5%) achieved complete remission and 4 (4.3%) partial remission. Three patients (3.2%) were primarily resistant. Ten-year probability of survival, progression-free survival and disease-free survival were 87.3, 79.9 and 83.9%, respectively. Eighty-four patients are surviving at a median observation time of 57 months (range: 6-126). Statistical analysis showed no difference between stages I and II in terms of response, ten-year probability of survival, progression-free survival or disease-free survival. Side effects and toxicity were negligible and were similar in the two patient groups. The results of this prospective study suggest that 6 weeks of VACOP-B treatment plus radiotherapy may be the therapy of choice in stage I aggressive non-Hodgkin's lymphoma. Twelve weeks of VACOP-B treatment with or without radiotherapy was shown to be effective and feasible for stage II. These observations need to be confirmed by a phase III study comparing first and third generation protocols in stage I-II aggressive non-Hodgkin's lymphoma. C1 Osped San Martino Genova, Dipartimento Ematol, I-16132 Genoa, Italy. Univ Estadual Campinas, Ctr Hematol & Transfusao Sangue, Campinas, SP, Brazil. Padua Hosp, Div Oncol, Padua, Italy. Cervello Hosp, Dept Hematol, Palermo, Italy. San Carlo Borromeo Hosp, Div Oncol, Milan, Italy. Univ Ancona, Dept Med, Ancona, Italy. Univ Ancona, Dept Hematol, Ancona, Italy. SS Giovanni & Paolo Hosp, Dept Hematol, Venice, Italy. Natl Canc Inst, Dept Biostat, Genoa, Italy. Univ Genoa, Genoa, Italy. Civitanova Marche Hosp, Dept Med, Civita, Italy. San Martino Hosp, Dept Pathol, Genoa, Italy. RP Santini, G (reprint author), Osped San Martino Genova, Dipartimento Ematol, Largo Rosanna Benzi 10, I-16132 Genoa, Italy. EM gino.santini@hsanmartino.liguria.it NR 28 TC 1 Z9 1 U1 0 U2 1 PU ASSOC BRAS DIVULG CIENTIFICA PI SAO PAULO PA FACULDADE MEDICINA, SALA 21, 14049 RIBEIRAO PRETO, SAO PAULO, BRAZIL SN 0100-879X J9 BRAZ J MED BIOL RES JI Brazilian J. Med. Biol. Res. PD MAY PY 2004 VL 37 IS 5 BP 719 EP 728 DI 10.1590/S0100-879X2004000500014 PG 10 WC Biology; Medicine, Research & Experimental SC Life Sciences & Biomedicine - Other Topics; Research & Experimental Medicine GA 820EK UT WOS:000221369800014 PM 15107935 ER PT J AU Chen, GB Zeng, WH Green, S Young, NS AF Chen, GB Zeng, WH Green, S Young, NS TI Frequent HPRT mutations in paroxysmal nocturnal haemoglobinuria reflect T cell clonal expansion, not genomic instability SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE paroxysmal nocturnal haemoglobinuria; hypoxanthine-guanine phosphoribosyltransferase gene; GPI-anchored protein; mutant frequency ID DECAY-ACCELERATING FACTOR; MARROW FAILURE SYNDROMES; MYELIN BASIC-PROTEIN; CLASS-II HAPLOTYPE; PIG-A GENE; APLASTIC-ANEMIA; MULTIPLE-SCLEROSIS; NORMAL INDIVIDUALS; PERIPHERAL-BLOOD; MYELODYSPLASTIC SYNDROME AB Paroxysmal nocturnal haemoglobinuria (PNH) results from acquired mutations in the PIG-A gene of an haematopoietic stem cell, leading to defective biosynthesis of glycosylphosphatidylinositol (GPI) anchors and deficient expression of GPI-anchored proteins on the surface of the cell's progeny. Some laboratory and clinical findings have suggested genomic instability to be intrinsic in PNH; this possibility has been supported by mutation analysis of hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene abnormalities. However, the HPRT assay examines lymphocytes in peripheral blood (PB), and T cells may be related to the pathophysiology of PNH. We analysed the molecular and functional features of HPRT mutants in PB mononuclear cells from eleven PNH patients. CD8 T cells predominated in these samples; approximately half of the CD8 cells lacked GPI-anchored protein expression, while only a small proportion of CD4 cells appeared to derive from the PNH clone. The HPRT mutant frequency (Mf) in T lymphocytes from PNH patients was significantly higher than in healthy controls. The majority of the mutant T lymphocyte clones were of CD4 phenotype, and they had phenotypically normal GPI-anchored protein expression. In PNH patients, the majority of HPRT mutant clones were contained within the Vbeta2 T cell receptor (TCR) subfamily, which was oligoclonal by complementarity-determining region three (CDR3) size analysis. Our results are more consistent with detection of uniform populations of expanded T cell clones, which presumably acquired HPRT mutations during antigen-driven cell proliferation, and not due to an increased Mf in PNH. HPRT mutant analysis does not support underlying genomic instability in PNH. C1 NHLBI, Haematol Branch, NIH, Bethesda, MD 20892 USA. RP Young, NS (reprint author), NHLBI, Haematol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM youngn@nhlbi.nih.gov NR 54 TC 6 Z9 8 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAY PY 2004 VL 125 IS 3 BP 383 EP 391 DI 10.1111/j.1365-2141.2004.04912.x PG 9 WC Hematology SC Hematology GA 812RS UT WOS:000220857200013 PM 15086421 ER PT J AU Hasler, G Moergeli, H Bachmann, R Lambreva, E Buddeberg, C Schnyder, U AF Hasler, G Moergeli, H Bachmann, R Lambreva, E Buddeberg, C Schnyder, U TI Patient satisfaction with outpatient psychiatric treatment: The role of diagnosis, pharmacotherapy, and perceived therapeutic change SO CANADIAN JOURNAL OF PSYCHIATRY-REVUE CANADIENNE DE PSYCHIATRIE LA English DT Article DE consumer satisfaction; outcome assessment; drug therapy; psychotherapy ID CARE; GENDER; SERVICES AB Objective: To investigate the influence of diagnosis, type of treatment, and perceived therapeutic change on patient satisfaction following psychiatric treatment for nonpsychotic, nonsubstance-related disorders. Method: We mailed questionnaires, including Larsen's Client Satisfaction Questionnaire and Grawe's Bern Inventory of Treatment Goals, to outpatients who had undergone 8 or more therapy sessions I year following treatment. Results: Patients with somatoform, eating, and personality disorders were less satisfied than patients with affective, anxiety, and adjustment disorders. Symptom reduction and changes in the interpersonal domain were important outcomes associated with patient satisfaction. Although pharmacotherapy itself was not related to patient satisfaction, patients who perceived improvements in pharmacotherapy as one of the most important treatment outcomes were less satisfied than others. Preliminary evidence shows that coping with specific problems and symptoms is associated with satisfaction among male patients, whereas changes in the interpersonal domain seem to produce satisfaction among female patients. Conclusion: Patient-reported change and diagnostic category appear to play a relevant role in generating patient satisfaction. Further research is needed to clarify the interactions between sex, perceived outcome, and satisfaction. C1 Univ Zurich Hosp, Dept Psychiat, Zurich, Switzerland. Univ Zurich Hosp, Div Psychosocial Med, Zurich, Switzerland. RP Hasler, G (reprint author), NIMH, NIH, Mood & Anxiety Disorders Program, 15K North Dr,Room 300C,MSC 2670, Bethesda, MD 20892 USA. EM g.hasler@bluewin.ch RI Hasler, Gregor/E-4845-2012 OI Hasler, Gregor/0000-0002-8311-0138 NR 27 TC 23 Z9 30 U1 0 U2 3 PU CANADIAN PSYCHIATRIC ASSOC PI OTTAWA PA 141 LAURIER AVENUE WEST, STE 701, OTTAWA, ONTARIO K1P 5J3, CANADA SN 0706-7437 J9 CAN J PSYCHIAT JI Can. J. Psychiat.-Rev. Can. Psychiat. PD MAY PY 2004 VL 49 IS 5 BP 315 EP 321 PG 7 WC Psychiatry SC Psychiatry GA 003UN UT WOS:000234707200007 PM 15198468 ER PT J AU Flegal, KM Williamson, DF Graubard, BI AF Flegal, KM Williamson, DF Graubard, BI TI Letters to the editor SO CANADIAN JOURNAL OF PUBLIC HEALTH-REVUE CANADIENNE DE SANTE PUBLIQUE LA English DT Letter C1 Ctr Dis Control & Prevent, Hyattsville, MD 20782 USA. Univ Calif Berkeley, Ctr Weight & Hlth, Berkeley, CA 94720 USA. NCI, Bethesda, MD 20892 USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Hyattsville, MD 20782 USA. RI Flegal, Katherine/A-4608-2013 NR 3 TC 1 Z9 1 U1 0 U2 0 PU CANADIAN PUBLIC HEALTH ASSOC PI OTTAWA PA 1565 CARLING AVE, SUITE 400, OTTAWA, ONTARIO K1Z 8R1, CANADA SN 0008-4263 J9 CAN J PUBLIC HEALTH JI Can. J. Public Health-Rev. Can. Sante Publ. PD MAY-JUN PY 2004 VL 95 IS 3 BP 235 EP 235 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 825AW UT WOS:000221729400027 PM 15191140 ER PT J AU Singh, GK Miller, BA AF Singh, GK Miller, BA TI Health, life expectancy, and mortality patterns among immigrant populations in the United States SO CANADIAN JOURNAL OF PUBLIC HEALTH-REVUE CANADIENNE DE SANTE PUBLIQUE LA English DT Article; Proceedings Paper CT National Symposium on Immigrant Health in Canada CY MAR 25, 2003 CL Ottawa, CANADA ID CANCER MORTALITY; NATIVITY; US; ACCULTURATION; CANADA; BORN; RACE/ETHNICITY; BEHAVIORS; IMPACT; WOMEN AB Background: The US immigrant population has grown considerably in the last three decades, from 9.6 million in 1970 to 32.5 million in 2002. However, this unprecedented population rise has not been accompanied by increased immigrant health monitoring. In this study, we examined the extent to which US- and foreign-born blacks, whites, Asians, and Hispanics differ in their health, life expectancy, and mortality patterns across the life course. Methods: We used National Vital Statistics System (1986-2000) and National Health Interview Survey (1992-1995) data to examine nativity differentials in health outcomes. Logistic regression and age-adjusted death rates were used to examine differentials. Results: Male and female immigrants had, respectively, 3.4 and 2.5 years longer life expectancy than the US-born. Compared to their US-born counterparts, black immigrant men and women had, respectively, 9.4 and 7.8 years longer life expectancy, but Chinese, Japanese, and Filipino immigrants had lower life expectancy. Most immigrant groups had lower risks of infant mortality and low birthweight than the US-born. Consistent with the acculturation hypothesis, immigrants' risks of disability and chronic disease morbidity increased with increasing length of residence. Cancer and other chronic disease mortality patterns for immigrants and natives varied considerably, with Asian Immigrants experiencing substantially higher stomach, liver and cervical cancer mortality than the US-born. Immigrants, however, had significantly lower mortality from lung, colorectal, breast, prostate and esophageal cancer, cardiovascular disease, cirrhosis, diabetes, respiratory diseases, HIV/AIDS, and suicide. Interpretation: Migration selectivity, social support, socio-economic, and behavioural characteristics may account for health differentials between immigrants and the US-born. C1 NCI, Surveillance Res Program, NIH, Bethesda, MD 20892 USA. RP Singh, GK (reprint author), NCI, Div Canc Control & Populat Sci, 6116 Execut Blvd,Suite 504,MSC 8316, Bethesda, MD 20892 USA. EM gopal_singh@nih.gov NR 50 TC 65 Z9 66 U1 4 U2 20 PU CANADIAN PUBLIC HEALTH ASSOC PI OTTAWA PA 1565 CARLING AVE, SUITE 400, OTTAWA, ONTARIO K1Z 8R1, CANADA SN 0008-4263 J9 CAN J PUBLIC HEALTH JI Can. J. Public Health-Rev. Can. Sante Publ. PD MAY-JUN PY 2004 VL 95 IS 3 BP I14 EP I21 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 825AW UT WOS:000221729400013 PM 15191127 ER PT J AU Goldin, LR Pfeiffer, RM Gridley, G Gail, MH Li, XJ Mellemkjaer, L Olsen, JH Hemminki, K Linet, MS AF Goldin, LR Pfeiffer, RM Gridley, G Gail, MH Li, XJ Mellemkjaer, L Olsen, JH Hemminki, K Linet, MS TI Familial aggregation of Hodgkin lymphoma and related tumors SO CANCER LA English DT Article DE Hodgkin lymphoma; lymphoproliferative tumors; familial aggregation; case-control study; linked registries ID LONG-TERM SURVIVORS; CANCER DATABASE; DISEASE; RELATIVES; RISK; PROBANDS; SIBLINGS; CHILDREN AB BACKGROUND. The importance of genetic factors in the etiology of Hodgkin lymphoma (HL) has been suggested by family and population studies. However, the spectrum of malignancies associated with common genetic etiology and the effects of gender and age on familial risk have not been established. METHODS. Diagnoses of lymphoproliferative malignancies were compared in 15,799 first-degree relatives of 5047 patients with HL versus 32,117 first-degree relatives of 10,078 control probands from Sweden and in 7185 first-degree relatives of 2429 patients with HL versus 27,434 first-degree relatives of 8,495 control probands from Denmark using marginal survival models. RESULTS. The risk of HL in relatives of patients with HL was increased significantly in both populations, with relative risks of 3.47 (95% confidence interval [95% CI], 1.77-6.80) in Sweden and 2.55 (95% CI, 1.01-6.45) in Denmark and a pooled estimate of 3.11 (95%CI, 1.82-5.29). In Sweden, risks for relatives of patients also were increased significantly for chronic lymphocytic leukemia and non-Hodgkin lymphoma (in males). Relative risks were higher in males compared with females and in siblings of patients compared with parents and offspring of patients. Relatives of patients with earlier-onset disease were at higher risk for HL. CONCLUSIONS. HL has an important familial component, which is stronger in families of affected individuals age < 40 years, in males, and in siblings, and it is shared with some (but not other) lymphoproliferative malignancies. The cumulative lifetime risks are very small, however, for the development of HL de novo or in first-degree relatives of affected patients. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Karolinska Inst, Novum, Dept Biosci, Stockholm, Sweden. Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. German Canc Res Ctr, Div Mol Genet Epidemiol, D-6900 Heidelberg, Germany. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Goldin, LR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7236, Bethesda, MD 20892 USA. EM goldinl@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; OI Olsen, Jorgen Helge/0000-0001-9633-5662 NR 26 TC 103 Z9 106 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAY 1 PY 2004 VL 100 IS 9 BP 1902 EP 1908 DI 10.1002/cncr.20189 PG 7 WC Oncology SC Oncology GA 813TI UT WOS:000220929000017 PM 15112271 ER PT J AU Price, DK Figg, WD AF Price, DK Figg, WD TI Intations in the EGFR the importance of genotyping SO CANCER BIOLOGY & THERAPY LA English DT Article DE gefitinib; EGFR; mutation; lung cancer; genotype ID RECEPTOR TYROSINE KINASE; CELL LUNG-CANCER; TRIAL; INHIBITOR; GEFITINIB; ZD1839 AB Gefitinib reached the clinic with anticipation, but initial clinical trials were disappointing with only a small number of patients showing response to treatment. In two recent articles published simultaneously, Lynch et al., and Paez et al. help to explain those initial clinical findings. Both groups report that somatic mutations found within the coding region of the EGFR may predict the sensitivity to gefitinib treatment. C1 NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Canc Res Ctr, Bethesda, MD 20892 USA. RP Price, DK (reprint author), NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Canc Res Ctr, 10 Ctr Dr, Bethesda, MD 20892 USA. EM dkprice@mail.nih.gov RI Figg Sr, William/M-2411-2016 NR 7 TC 6 Z9 8 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 MAY PY 2004 VL 3 IS 5 BP 434 EP 435 PG 2 WC Oncology SC Oncology GA 898RO UT WOS:000227094100006 PM 15254431 ER PT J AU Coyne, RS McDonald, HB Edgemon, K Brody, LC AF Coyne, RS McDonald, HB Edgemon, K Brody, LC TI Functional characterization of BRCA1 sequence variants using a yeast small colony phenotype assay SO CANCER BIOLOGY & THERAPY LA English DT Article DE BRCA1 protein; breast neoplasms; Saccharomyces cerevisiae ID HEREDITARY BREAST-CANCER; OVARIAN-CANCER; TRANSCRIPTIONAL ACTIVATION; FAMILIAL BREAST; TERMINAL REGION; GENE; MUTATIONS; CARRIERS; DOMAINS; LINKAGE AB Germline mutations that inactivate the tumor suppressor gene BRCA1 are associated with an increased risk of cancers of the breast and other tissues, but the functional consequence of many missense variants found in the human population is uncertain. Several predictive methods have been proposed to distinguish cancer-predisposing missense mutations from harmless polymorphisms, including a small colony phenotype (SCP) assay performed in the model organism, yeast (Saccharomyces cerevisiae). The goal of this study was to further evaluate this colony size assay. We constructed 28 missense mutations throughout the C-terminal 305 amino acid residues of BRCA1. Mutated proteins were expressed in yeast and evaluated using the SCP assay. We conclude there is as yet no evidence the assay can identify inactivating mutations upstream of the BRCT repeats. However, within and between the BRCT repeats, results of the assay are in general agreement with predictions based on structural modeling, other in vitro and in vivo assays, and cross-species sequence conservation. Thus, the yeast assay appears to provide confirmatory in vivo evidence to aid in characterizing some BRCA1 missense variants. C1 Univ Virginia, Hlth Sci Ctr, Dept Biochem & Mol Genet, Charlottesville, VA USA. Colgate Univ, Dept Biol, Hamilton, NY 13346 USA. NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bethesda, MD 20892 USA. RP Coyne, RS (reprint author), Natl Sci Fdn, 4201 Wilson Blvd, Arlington, VA 22230 USA. EM rcoyne@nsf.gov NR 50 TC 24 Z9 24 U1 1 U2 13 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 MAY PY 2004 VL 3 IS 5 BP 453 EP 457 PG 5 WC Oncology SC Oncology GA 898RO UT WOS:000227094100010 PM 15004537 ER PT J AU Zhang, YW Holford, TR Leaderer, B Zahm, SH Boyle, P Morton, LM Zhang, B Zou, KY Flynn, S Tallini, G Owens, PH Zheng, TZ AF Zhang, YW Holford, TR Leaderer, B Zahm, SH Boyle, P Morton, LM Zhang, B Zou, KY Flynn, S Tallini, G Owens, PH Zheng, TZ TI Prior medical conditions and medication use and risk of non-Hodgkin lymphoma in connecticut United States women SO CANCER CAUSES & CONTROL LA English DT Article DE case-control studies; medical condition; medication; non-Hodgkin's lymphoma ID T-CELL LYMPHOMA; RHEUMATOID-ARTHRITIS; MALIGNANT-LYMPHOMA; INTERLEUKIN-6 PRODUCTION; ANTICONVULSANT DRUGS; REPRODUCTIVE FACTORS; MULTIPLE-MYELOMA; STROMAL CELLS; BONE-MARROW; CANCER-RISK AB Objective: To further investigate the role of prior medical conditions and medication use in the etiology of non-Hodgkin lymphoma (NHL), we analyzed the data from a population-based case-control study of NHL in Connecticut women. Methods: A total of 601 histologically confirmed incident cases of NHL and 717 population-based controls were included in this study. In-person interviews were administered using standardized, structured questionnaires to collect information on medical conditions and medication use. Results: An increased risk was found among women who had a history of autoimmune disorders (such as rheumatoid arthritis, lupus erythematosus, Sjogren's syndrome, and multiple sclerosis), anemia, eczema, or psoriasis. An increased risk was also observed among women who had used steroidal anti-inflammatory drugs and tranquilizers. A reduced risk was found for women who had scarlet fever or who had used estrogen replacement therapy, aspirin, medications for non-insulin dependent diabetes, HMG-CoA reductase inhibitors, or beta-adrenergic blocking agents. Risk associated with past medical history appeared to vary based on NHL subtypes, but the results were based on small number of exposed subjects. Conclusion: A relationship between certain prior medical conditions and medication use and risk of NHL was observed in this study. Further studies are warranted to confirm our findings. C1 Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. European Inst Oncol, Dept Biostat & Epidemiol, I-20141 Milan, Italy. McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ H3A 1A2, Canada. Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. RP Zheng, TZ (reprint author), 129 Church St,Suite 700, New Haven, CT 06510 USA. EM tongzhang.zheng@yale.edu RI Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015; Morton, Lindsay/B-5234-2015; OI Boyle, Peter/0000-0001-6251-0610; Morton, Lindsay/0000-0001-9767-2310; Tallini, Giovanni/0000-0003-0113-6682 FU NCI NIH HHS [CA62006] NR 55 TC 114 Z9 116 U1 0 U2 3 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAY PY 2004 VL 15 IS 4 BP 419 EP 428 DI 10.1023/B:CACO.0000027506.55846.5d PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 820BB UT WOS:000221360300008 PM 15141141 ER PT J AU Dancey, JE AF Dancey, JE TI Predictive factors for epidermal growth factor receptor inhibitors - The bull's-eye hits the arrow SO CANCER CELL LA English DT Editorial Material ID CELL LUNG-CANCER; TYROSINE KINASE INHIBITOR; CIGARETTE-SMOKING; UNITED-STATES; EGF RECEPTOR; FACTOR-ALPHA; GEFITINIB; TRIAL; EXPRESSION; ZD1839 AB Studies have shown that epidermal growth factor receptor (EGFR) signaling is important to normal development and neoplastic transformation, and that EGFR inhibition reduces cancer cell proliferation. The promising response rates of the EGFR inhibitor gefitinib in patients with chemotherapy-refractory non-small cell lung cancer (NSCLC) led to its approval for clinical use. However, there was little understanding of why gefitinib was effective in only some NSCLC patients. Two recent studies have identified somatic mutations in EGFR that confer its sensitivity to gefitinib in vitro and correlate strongly with patients' clinical response to the inhibitor. C1 NCI, Canc Therapy Evaluat Program, Invest Drug Branch, Rockville, MD 20852 USA. RP Dancey, JE (reprint author), NCI, Canc Therapy Evaluat Program, Invest Drug Branch, 6130 Executive Blvd,Room 7131, Rockville, MD 20852 USA. EM danceyj@ctep.nci.nih.gov NR 30 TC 61 Z9 62 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD MAY PY 2004 VL 5 IS 5 BP 411 EP 415 DI 10.1016/S1535-6108(04)00122-9 PG 5 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 829AX UT WOS:000222016300004 PM 15144948 ER PT J AU Dabydeen, DA Florence, GJ Paterson, I Hamel, E AF Dabydeen, DA Florence, GJ Paterson, I Hamel, E TI A quantitative evaluation of the effects of inhibitors of tubulin assembly on polymerization induced by discodermolide, epothilone B, and paclitaxel SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE discodermolide; epothilone B; paclitaxel; tubulin assembly ID MICROTUBULE-ASSOCIATED PROTEINS; RAT-BRAIN TUBULIN; PURIFIED TUBULIN; STABILIZING AGENTS; VINCA DOMAIN; BINDING; TAXOL; MECHANISM; COLCHICINE; DOLASTATIN-15 AB Purpose: To determine whether inhibitors of microtubule assembly inhibit polymerization induced by discodermolide and epothilone B, as well as paclitaxel, and to quantitatively measure such effects. Methods: Inhibition was quantitated by measuring polymer formation either by turbidimetry or by centrifugation, and the amount of inhibitor required to inhibit 50% relative to an appropriate control reaction was determined. Results: The inhibitory drugs evaluated were four colchicine site agents (combretastatin A-4, podophyllotoxin, nocodazole, and N-acetylcolchinol-O-methyl ether), maytansine, which competitively inhibits the binding of Catharanthus alkaloids to tubulin, halichondrin B and phomopsin A, which noncompetitively inhibit the binding of Catharanthus alkaloids to tubulin, and the depsipeptide dolastatin 15. While relative inhibitory effects were highly variable, a few broad generalizations can be made. First, assembly reactions that were either enhanced or dependent upon all three stimulatory drugs were subject to inhibition by all inhibitors. Second, the more readily the tubulin assembled, the greater the concentration of inhibitor required to inhibit polymerization. Drug IC50 values were generally lowest with no stimulatory drug and highest when discodermolide was present; IC50 values were higher as reaction temperature increased; and IC50 values were higher as the tubulin concentration increased. Third, inhibition of assembly by inhibitors of Catharanthus alkaloid binding to tubulin changed much less as a function of changes in reaction conditions than inhibition by inhibitors of colchicine binding. Conclusions: Since there was no apparent quantitative predictability of combined drug interactions with tubulin, any combination of interest must be studied in detail. C1 NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. RP Hamel, E (reprint author), NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. EM hamele@mail.nih.gov OI Florence, Gordon/0000-0001-9921-4399 NR 27 TC 18 Z9 20 U1 0 U2 5 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD MAY PY 2004 VL 53 IS 5 BP 397 EP 403 DI 10.1007/s00280-003-0755-0 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 817SI UT WOS:000221196800006 PM 15060743 ER PT J AU Yabroff, KR Breen, N Vernon, SW Meissner, HI Freedman, AN Ballard-Barbash, R AF Yabroff, KR Breen, N Vernon, SW Meissner, HI Freedman, AN Ballard-Barbash, R TI What factors are associated with diagnostic follow-up after abnormal mammograms? Findings from a US national survey SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID FECAL OCCULT BLOOD; INCOME MINORITY WOMEN; STAGE BREAST-CANCER; COLORECTAL-CANCER; CERVICAL-CANCER; PAPANICOLAOU SMEARS; PAP SMEARS; SCREENING-PROGRAM; UNITED-STATES; MEDICAL-CARE AB The purpose of this study was to identify factors associated with diagnostic follow-up after an abnormal mammogram in a national sample of women in the U.S. The sample was selected from the year 2000 National Health Interview Survey and included 1901 women aged 30 and above who reported ever having an abnormal mammogram. The outcome measure was receipt of at least some diagnostic follow-up after an abnormal mammogram. Bivariate and multivariate logistic regression analyses were used to explore the associations between sociodemographic characteristics, general health and health behaviors, cancer risk and risk perceptions, and health care utilization characteristics and follow-up. Approximately 9% of women who reported ever having abnormal mammograms reported not completing any additional diagnostic follow-up. Controlling for all other factors, women with less than a high school education were less likely to report follow-up after an abnormal mammogram than were women who had at least completed college (odds ratio = 0.56; 95% confidence interval: 0.32, 0.98). Younger women and women in poorer health were also less likely to report follow-up. Women who perceived a high versus low level of cancer in their family were more likely to report follow-up (odds ratio = 1.65; 95% confidence interval: 1.04, 2.62), controlling for all other factors. In a national sample of women with abnormal mammograms, a substantial number did not complete any diagnostic follow-up, potentially reducing the effectiveness of mammography screening programs in the U.S. Additional research on subsequent screening behaviors for women with incomplete follow-up and in-depth exploration of the roles of patient-provider interactions and health care system factors related to the index abnormal mammogram is warranted. C1 NCI, Div Canc Control & Populat Sci, Appl Res Program, Hlth Serv & Econ Branch, Bethesda, MD 20892 USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. RP Yabroff, KR (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Hlth Serv & Econ Branch, Executive Pl N,Room 4005,6130 Executive Blvd,MSC, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 NR 92 TC 60 Z9 60 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAY PY 2004 VL 13 IS 5 BP 723 EP 732 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 822XF UT WOS:000221573300005 PM 15159302 ER PT J AU Smith, KR Ellington, L Chan, AY Croyle, RT Botkin, JR AF Smith, KR Ellington, L Chan, AY Croyle, RT Botkin, JR TI Fertility intentions following testing for a BRCA1 gene mutation SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HUNTINGTONS-DISEASE; OVARIAN-CANCER; EVENT SCALE; BREAST; CARRIERS; IMPACT; SUSCEPTIBILITY; DISCLOSURE; RISKS; ATTITUDES AB Objective: To test whether fertility intentions differed among persons who tested positive, tested negative, or did not know their genetic status for a mutation of the BRCA1 gene. Method: Participants were members of a large Utah-based kindred with an identified mutation at the BRCA1 locus. Participants received genetic counseling prior to testing and were interviewed at baseline before testing and at three points after receiving test results from a genetic counselor. The sample included men and women who completed all interviews, were between ages 18 and 45, and were fertile, resulting in a sample of 101 respondents. The primary dependent variable measured whether a subject indicated that they were moderately or very sure at all three post-testing interviews that they intended to have additional children. Effects of BRCA1 mutation status on fertility intentions were estimated using multivariate logistic regressions where we controlled for gender, age, marital status, and baseline fertility intentions. Results: Female carriers were less likely to want additional children in relation to female non-carriers (odds ratio 0.12, 95% confidence interval 0.01-1.23; P = 0.074). No differences were found among men. There was a significant difference in the effect of mutation status on fertility intentions between males and females (Gender x Carrier status interaction; P = 0.009). Persons who did not know their mutation status were less likely to want more children than non-carriers (odds ratio 0.09, 95% confidence interval 0.01-0.75; P = 0.027). Conclusion: Predictive genetic testing for late-onset cancer susceptibility affects family planning decision-making. Persons contemplating predictive testing should be informed about possible effects such testing may have on their plans for future fertility. C1 Univ Utah, Salt Lake City, UT 84112 USA. US Bur Census, Washington, DC USA. NCI, Bethesda, MD 20892 USA. RP Smith, KR (reprint author), Univ Utah, 225 S 1400 E, Salt Lake City, UT 84112 USA. EM Ken.smith@fcs.utah.edu FU NCRR NIH HHS [M01-RR00064]; NHGRI NIH HHS [HG00199] NR 36 TC 32 Z9 33 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 MAY PY 2004 VL 13 IS 5 BP 733 EP 740 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 822XF UT WOS:000221573300006 PM 15159303 ER PT J AU Hannan, LM Leitzmann, MF Lacey, JV Colbert, LH Albanes, D Schatzkin, A Schairer, C AF Hannan, LM Leitzmann, MF Lacey, JV Colbert, LH Albanes, D Schatzkin, A Schairer, C TI Physical activity and risk of ovarian cancer: A prospective cohort study in the United States SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID C-REACTIVE PROTEIN; REPLACEMENT THERAPY; BREAST; INFLAMMATION; EXERCISE; ESTROGEN; WOMEN AB Increased physical activity may lower the risk of ovarian cancer by reducing the frequency of ovulation, decreasing body fat, or diminishing chronic inflammation. Previous epidemiological studies examining the association between physical activity and risk of ovarian cancer have been inconsistent. We investigated the association of physical activity with ovarian cancer in a prospective cohort of 27,365 individuals from the Breast Cancer Detection Demonstration Project. During 227,045 person-years of follow-up, 121 cases of ovarian cancer were ascertained. Usual physical activity during the past year was assessed by a self-administered questionnaire. After adjusting for potential risk factors for ovarian cancer, the relative risks (95% confidence intervals) across increasing quintiles of total physical activity were 1.0, 0.73 (0.43-1.25),0.84 (0.50-1.40),0.56 (0.31-1.00), and 0.70 (0.41-1.21), respectively (P for trend = 0.13). In this prospective cohort study among U.S. women, we found no overall significant association between physical activity and risk of ovarian cancer, although the results are suggestive of an inverse association. C1 NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Dept HHS,NIH, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA USA. Univ Wisconsin, Dept Kinesiol, Madison, WI USA. RP Leitzmann, MF (reprint author), NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Dept HHS,NIH, 6120 Executive Blvd,EPS MSC 7232, Bethesda, MD 20892 USA. RI Albanes, Demetrius/B-9749-2015 NR 24 TC 30 Z9 31 U1 0 U2 1 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 MAY PY 2004 VL 13 IS 5 BP 765 EP 770 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 822XF UT WOS:000221573300011 PM 15159308 ER PT J AU Gustin, DM Rodvold, KA Sosman, JA Diwadkar-Navsariwala, V Stacewicz-Sapuntzakis, M Viana, M Crowell, JA Murray, J Tiller, P Bowen, PE AF Gustin, DM Rodvold, KA Sosman, JA Diwadkar-Navsariwala, V Stacewicz-Sapuntzakis, M Viana, M Crowell, JA Murray, J Tiller, P Bowen, PE TI Single-dose pharmacokinetic study of lycopene delivered in a well-defined food-based lycopene delivery system (tomato paste-oil mixture) in healthy adult male subjects SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID RICH LIPOPROTEIN FRACTION; CAROTENOID-BINDING-PROTEIN; BETA-CAROTENE; CARDIOVASCULAR-DISEASE; INTESTINAL-ABSORPTION; PROSTATE-CANCER; PLASMA; MEN; SUPPLEMENTATION; BIOAVAILABILITY AB This report details the findings of a single-dose Phase I pharmacokinetic and toxicity study of a food-based formulation of lycopene in healthy adult male subjects. Five dosing groups (n = 5 per group) were sequentially treated with increasing doses of lycopene ranging from 10 to 120 mg. Blood samples were collected for a total of 28 days (672 h) after administration of single doses of lycopene. The mean time (t(max)) to reach maximum total lycopene concentration (C-max) ranged from 15.6 to 32.6 h. The Cmax for total lycopene ranged between 4.03 and 11.27 mug/dl (0.075-0.210 mum). Mean AUC(0-96) and elimination half-life for total lycopene ranged from 214 to 655 mug h/dl (3.986-12.201 mumol h/l) and 28.1 and 61.6 h, respectively. The changes observed in lycopene exposure parameters (e.g., C-max and AUC(0-96)) were not proportional to increments in dose, with larger increases observed at the lowest end of the dosing range (10-30 mg). Chylomicron lycopene was measured during the first 12 h with the differences observed among the dosing groups not reaching statistical significance. These findings may reflect a process of absorption that is saturable at very low dosing levels or may be explained by the large interindividual variability in attained lycopene concentrations that were observed within each dosing group. Pharmacokinetic parameters for trans- and cis-lycopene isomers were calculated and are reported here. The formulation was well tolerated with minimal side effects, which were mainly of gastrointestinal nature and of very low grade. C1 Univ Illinois, Coll Pharm, Dept Pharm Practice, Chicago, IL 60612 USA. Univ Illinois, Div Hematol Oncol, Dept Med, Chicago, IL 60612 USA. Univ Illinois, Dept Human Nutr, Chicago, IL 60612 USA. Univ Illinois, Dept Ophthalmol, Chicago, IL 60612 USA. Univ Illinois, Dept Visual Sci, Chicago, IL 60612 USA. Vanderbilt Univ, Dept Med, Div Hematol Oncol, Nashville, TN USA. Natl Canc Inst, Div Canc Prevent, Rockville, MD USA. RP Rodvold, KA (reprint author), Univ Illinois, Coll Pharm, Dept Pharm Practice, 833 S Wood St,Room 164, Chicago, IL 60612 USA. EM kar@uic.edu FU NCI NIH HHS [N01-CN-85081-70]; NCRR NIH HHS [M01-RR-13987] NR 53 TC 39 Z9 39 U1 0 U2 11 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 MAY PY 2004 VL 13 IS 5 BP 850 EP 860 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 822XF UT WOS:000221573300022 PM 15159319 ER PT J AU Yao, ZS Dai, WL Perry, J Brechbiel, MW Sung, C AF Yao, ZS Dai, WL Perry, J Brechbiel, MW Sung, C TI Effect of albumin fusion on the biodistribution of interleukin-2 SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE albuleukin; interleukin-2; biodistribution; whole-body autoradiography; In-111-radiolabeling; mice ID RECOMBINANT INTERLEUKIN-2; MONOCLONAL-ANTIBODIES; I-125 INTERLEUKIN-2; MICE; PHARMACOKINETICS; IMMUNOTHERAPY; KIDNEY; RAT AB Purpose We investigated and compared the biodistribution of Albuleukin, a human serum albumin (HSA)-interleukin-2 (IL-2) fusion protein., with those of IL-2 and HSA. The objective was to determine whether Albuleukin distributes differently to normal organs and lymphoid tissues than IL-2 by virtue of its genetic fusion with HSA. Methods The chelating agent 2-(13-isothiocyanatobenzyl)-cyclohexyl-diethylenetriaminepentaacetic acid (CHX-A(II) was selected for radiolabeling with In-111, and conjugation with CHX-A(II) did not alter bioactivities of IL-2 and Albuleukin on proliferation of CTLL-2 cells. The radiolabeled proteins were injected intravenously into mice, uptake in organs was measured, and whole-body autoradiography was performed. Results Striking differences in the biodistribution of IL-2 and Albuleukin were noted. In-111-IL-2 cleared from blood rapidly, with less than 1% ID/g (percentage of injected dose per gram of tissue) at 20 min after injection. At this time, the kidneys showed more than 120% ID/g uptake, and these high levels persisted through 6 h. In-111-Albuleukin, by contrast, showed significantly longer circulation (14% ID/g at 6 h), lower kidney uptake (<6% ID/g), and higher localization in liver, spleen, and lymph nodes (maximal uptake &SIM;22% ID/g for all three organs). Uptake in liver, spleen, and lymph nodes appears to be mediated in part by the IL-2 component of Albuleukin because In-111-HSA showed significantly lower accumulation in those tissues despite more prolonged circulation in blood. Conclusion These data support the hypothesis that Albuleukin targets tissues where lymphocytes reside to a much greater extent than does IL-2, and suggest that Albuleukin may exhibit improved efficacy and reduced toxicity in the treatment of solid tumors. Clinical trials underway will determine whether the improved targeting in the mice translates into a better therapeutic index in humans. C1 Human Genome Sci, Rockville, MD 20850 USA. NCI, Dept Radiat Oncol, Bethesda, MD 20892 USA. RP Sung, C (reprint author), Human Genome Sci, 14200 Shady Grove Rd, Rockville, MD 20850 USA. EM cynthia_sung@hgsi.com NR 26 TC 25 Z9 25 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAY PY 2004 VL 53 IS 5 BP 404 EP 410 DI 10.1007/s00262-003-0454-z PG 7 WC Oncology; Immunology SC Oncology; Immunology GA 814RP UT WOS:000220992100004 PM 14624312 ER PT J AU Li, CQ Robles, AI Hanigan, CL Hofseth, LJ Trudel, LJ Harris, CC Wogan, GN AF Li, CQ Robles, AI Hanigan, CL Hofseth, LJ Trudel, LJ Harris, CC Wogan, GN TI Apoptotic signaling pathways induced by nitric oxide in human lymphoblastoid cells expressing wild-type or mutant p53 SO CANCER RESEARCH LA English DT Article ID COLORECTAL-CANCER CELLS; X-LINKED INHIBITOR; CYTOCHROME-C; TRANSCRIPTIONAL TARGET; P53-INDUCED APOPTOSIS; MITOCHONDRIAL DAMAGE; GENOTOXIC STRESS; TUMOR-SUPPRESSOR; DOWN-REGULATION; BCL-2 FAMILY AB Loss of p53 function by inactivating mutations results in abrogation of NO.-induced apoptosis in human lymphoblastoid cells. Here we report characterization of apoptotic signaling pathways activated by NO. in these cells by cDNA microarray expression and immunoblotting. A p53-mediated transcriptional response to NO. was observed in p53-wild-type TK6, but not in closely related p53-mutant WTK1, cells. Several previously characterized p53 target genes were up-regulated transcriptionally in TK6 cells, including phosphatase PPM1D (WIP1), oxidoreductase homolog PIG3, death receptor TNFRSF6 (Fas/CD95). and BH3-only proteins BBC3 (PUMA) and PMAIP1 (NOXA). NO. also modulated levels of several gene products in the mitochondria-dependent and death-receptor-mediated apoptotic pathways. Inhibitors of apoptosis proteins X-chromosome-linked inhibitor of apoptosis, cellular inhibitor of apoptosis protein-1, and survivin were significantly down-regulated in TK6 cells, but not in WTK1 cells. Smac release from mitochondria was induced in both cell types, but release of apoptosis-inducing factor and endonuclease G was detected only in TK6 cells. Fas/CD95 was increased, and levels of the antiapoptotic proteins Bcl-2 and Bcl-x/L were reduced in TK6 cells. Activation of procaspases 3, 8, 9, and 10, as well as Bid and poly(ADPribose) polymerase cleavage, were observed only in TK6 cells. NO. treatment did not alter levels of death receptors 4 and 5, Fas-associated death domain or proapoptotic Bax and Bak proteins in either cell line. Collectively, these data show that NO. exposure activated a complex network of responses leading to p53-dependent apoptosis via both mitochondrial and Fas receptor pathways, which were abrogated in the presence of mutant p53. C1 MIT, Biol Engn Div, Cambridge, MA 02139 USA. MIT, Dept Chem, Cambridge, MA 02139 USA. NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Wogan, GN (reprint author), MIT, Biol Engn Div, 77 Massachusetts Ave, Cambridge, MA 02139 USA. EM wogan@mit.edu FU NCI NIH HHS [5 P01 CA26731] NR 51 TC 53 Z9 55 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 MAY 1 PY 2004 VL 64 IS 9 BP 3022 EP 3029 DI 10.1158/0008-5472.CAN-03-1880 PG 8 WC Oncology SC Oncology GA 817AN UT WOS:000221150500014 PM 15126337 ER PT J AU Kedei, N Lundberg, DJ Toth, A Welburn, P Garfield, SH Blumberg, PM AF Kedei, N Lundberg, DJ Toth, A Welburn, P Garfield, SH Blumberg, PM TI Characterization of the interaction of ingenol 3-angelate with protein kinase C SO CANCER RESEARCH LA English DT Article ID ESTER-INDUCED DIFFERENTIATION; GREEN FLUORESCENT PROTEIN; SELECTIVE DOWN-REGULATION; SKIN TUMOR PROMOTION; PHORBOL ESTER; BRYOSTATIN 1; PKC-ALPHA; OSTEOBLASTIC CELLS; HUMAN-FIBROBLASTS; GENE-EXPRESSION AB Ingenol 3-angelate (I3A) is one of the active ingredients in Euphorbia peplus. which has been used in traditional medicine. Here, we report the initial characterization of I3A as a protein kinase C (PKC) ligand. I3A bound to PKC-alpha in the presence of phosphatidylserine with high affinity; however, under these assay conditions, little PKC isoform selectivity was observed. PKC isoforms did show different sensitivity and selectivity for down-regulation by. I3A and phorbol 12-myristate 13-acetate (PMA) in WEHI-231, HOP-92, and Colo-205 cells. In all of the three cell types, I3A inhibited cell proliferation with somewhat lower potency than did PMA. In intact CHO-K1 cells, I3A was able to translocate different green fluorescent protein-tagged PKC isoforms, visualized by confocal microscopy, with equal or higher potency than PMA. PKC-delta in particular showed a different pattern of translocation in response to I3A and PMA. I3A induced a higher level of secretion of the inflammatory cytokine interleukin 6 compared with PMA in the WEHI-231 cells and displayed a marked biphasic dose-response curve for the induction. I3A was unable to cause the same extent of association of the C1b domain of PKC-delta with lipids, compared with PMA or the physiological regulator diacylglycerol, and was able to partially block the association induced by these agents, measured by surface plasmon resonance. The in vitro kinase activity of PKC-a induced by I3A was lower than that induced by PMA. The novel pattern of behavior of I3A makes it of great interest for further evaluation. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. Peplin Biotech, Fortitude Valley, Qld, Australia. RP Blumberg, PM (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Bldg 37,Room 4048B,37 Convent Dr,MSC 4255, Bethesda, MD 20892 USA. EM blumberp@dc37a.nci.nih.gov RI Toth, Attila/F-4859-2010 OI Toth, Attila/0000-0001-6503-3653 NR 78 TC 97 Z9 98 U1 2 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 1 PY 2004 VL 64 IS 9 BP 3243 EP 3255 DI 10.1158/0008-5472.CAN-03-3403 PG 13 WC Oncology SC Oncology GA 817AN UT WOS:000221150500043 PM 15126366 ER PT J AU Gaudet, MM Olshan, AF Poole, C Weissler, MC Watson, M Bell, DA AF Gaudet, MM Olshan, AF Poole, C Weissler, MC Watson, M Bell, DA TI Diet, GSTM1 and GSTT1 and head and neck cancer SO CARCINOGENESIS LA English DT Article ID GLUTATHIONE-S-TRANSFERASE; PHARYNGEAL CANCER; ESOPHAGEAL CANCER; ORAL-CAVITY; FOOD GROUPS; RISK; POLYMORPHISMS; ISOTHIOCYANATES; WOMEN; MEN AB A decreased incidence of squamous cell carcinoma of the head and neck (SCCHN) associated with fruit and vegetable intake may act through chemopreventive compounds, which may be more available to persons homozygous for the deletion genotypes of the glutathione S-transferase (GST). We evaluated interactions between fruits and vegetables and GSTM1 and GSTT1 on incidence of SCCHN using data from a case-control study of 149 cases and 180 age- and gender-matched controls. After adjustment for age, gender, race, tobacco and alcohol use, weekly consumption of four or more servings of raw vegetables was inversely associated with SCCHN [odds ratio (OR) = 0.66, 95% confidence intervals (CI) 0.30-1.3]. Contrary to expectation, relatively high intake of cooked vegetables (14 or more weekly servings) and legumes (two or more weekly servings) were associated with increased incidence (OR = 2.5, 95% CI 1.1-6.0; OR = 2.5, 95% CI 1.2-5.2, respectively). In general, our results did not suggest a clear or consistent pattern of modification by GST genotypes of the association between foods and SCCHN. For example, eating cruciferous vegetables, foods of a priori interest, and having the GSTM1-deletion genotype was not associated with the expected reduction in incidence compared with abstaining from cruciferous vegetable intake and having the GSTM1-present genotype. Among non-consumers of cruciferous vegetables, the GSTM1-deletion genotype was inversely associated with SCCHN (OR = 0.55, 95% CI 0.07-4.2). Raw vegetables were associated with a reduction in incidence only among persons with the GSTM1-deletion genotype (OR = 0.69, 95% CI 0.29-1.6), whereas either factor alone had a null association. Future research of GST-diet interactions and SCCHN would benefit from larger, population-based studies. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. NIEHS, Lab Computat Biol & Risk Assessment, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Med, Dept Otolaryngol Head & Neck Surg, Chapel Hill, NC 27599 USA. RP Gaudet, MM (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA. EM gaudet@email.unc.edu FU NCI NIH HHS [CA 61188]; NIEHS NIH HHS [P30 ES 10126] NR 30 TC 19 Z9 23 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 MAY PY 2004 VL 25 IS 5 BP 735 EP 740 DI 10.1093/carcin/bgh054 PG 6 WC Oncology SC Oncology GA 814WH UT WOS:000221004300010 PM 14688020 ER PT J AU Almahmeed, T Boyle, JO Cohen, EG Carew, JF Du, BH Altorki, NK Kopelovich, L Fang, JL Lazarus, P Subbaramaiah, K Dannenberg, AJ AF Almahmeed, T Boyle, JO Cohen, EG Carew, JF Du, BH Altorki, NK Kopelovich, L Fang, JL Lazarus, P Subbaramaiah, K Dannenberg, AJ TI Benzo[a]pyrene phenols are more potent inducers of CYP1A1, CYP1B1 and COX-2 than benzo[a]pyrene glucuronides in cell lines derived from the human aerodigestive tract SO CARCINOGENESIS LA English DT Article ID COLON-CANCER CELLS; UDP-GLUCURONOSYLTRANSFERASES; PROSTAGLANDIN E-2; EPITHELIAL-CELLS; EXPRESSION; HEAD; NECK; CYCLOOXYGENASE-2; BENZOPYRENE; CARCINOMA C1 Cornell Univ, Dept Med, Weill Med Coll, New York, NY 10021 USA. Strang Canc Prevent Ctr, New York, NY 10021 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Canc Control, Tampa, FL 33612 USA. Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Div Mol Oncol, Tampa, FL 33612 USA. NCI, CADRG, DCP, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Dept Cardiothorac Surg, New York, NY 10021 USA. Cornell Univ, Weill Med Coll, Dept Otorhinolaryngol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Head & Neck Serv, Dept Surg, New York, NY 10021 USA. RP Dannenberg, AJ (reprint author), Cornell Univ, Dept Med, Weill Med Coll, New York, NY 10021 USA. EM ajdannen@med.cornell.edu FU NCI NIH HHS [R01 CA 82578, T32 CA 09685, P01 CA 68384, N01 CN 35107]; NIDCR NIH HHS [R01 DE 13158] NR 45 TC 9 Z9 9 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 MAY PY 2004 VL 25 IS 5 BP 793 EP 799 DI 10.1093/carcin/bgh078 PG 7 WC Oncology SC Oncology GA 814WH UT WOS:000221004300018 PM 14729581 ER PT J AU Dmitrieva, NI Burg, MB AF Dmitrieva, NI Burg, MB TI Living with DNA breaks is an everyday reality for cells adapted to high NaCl SO CELL CYCLE LA English DT Article DE DNA damage; DNA repair; osmotic stress; NaCl; renal cells; H2AX; Mre11; Chk1; cell cycle ID DOUBLE-STRAND BREAKS; MURINE KIDNEY-CELLS; HISTONE H2AX; ORGANIC OSMOLYTES; MEDULLARY CELLS; MRE11 PROTEIN; IN-VIVO; REPAIR; DAMAGE; STRESS AB A rapid, coordinated response to DNA breaks, including activation of cell cycle checkpoints and initiation of accurate DNA repair is believed to be necessary to maintain genomic integrity and prevent accumulation of mutations. That is why it was so unexpected to discover recently that in the mouse renal inner medulla the otherwise healthy cells contain numerous DNA breaks, yet they survive and function adequately. The DNA breaks in the renal inner medulla are caused by the high NaCl concentrations to which the cells are constantly exposed as a consequence of the urinary concentrating mechanism. Cells adapted to high NaCl in cell culture also contain many DNA breaks. The DNA breaks do not trigger cell cycle arrest or cause apoptosis, and the cells safely proliferate rapidly despite their presence. Further, high NaCl inhibits the activity of key components of the classical DNA damage response such as Mre11, chk1 and H2AX. In order to explain why the DNA breaks do not cause disabling mutations, oncogenic transformations and/or apoptosis we speculate that in the presence of high NaCl there might be alternative DNA damage response pathways or special ways of coping with DNA damage. C1 NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Dmitrieva, NI (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, 10 Ctr Dr,MSC 1603,Bldg 10,Room 6N260, Bethesda, MD 20892 USA. EM dmitrien@nhlbi.nih.gov RI Dmitrieva, Natalia/A-2924-2013 OI Dmitrieva, Natalia/0000-0001-8074-6950 NR 31 TC 13 Z9 13 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY PY 2004 VL 3 IS 5 BP 561 EP 563 PG 3 WC Cell Biology SC Cell Biology GA 833TJ UT WOS:000222361900012 PM 15107607 ER PT J AU McCulloch, SD Kokoska, RJ Kunkel, RA AF McCulloch, SD Kokoska, RJ Kunkel, RA TI Efficiency, fidelity and enzymatic switching during translesion DNA synthesis SO CELL CYCLE LA English DT Article DE translesion synthesis; thymine-thymine dimer; polymerase h; polymerase switching; Sso; Dpo4; UV mutagenesis ID SYN THYMINE DIMER; DAMAGE-INDUCED MUTAGENESIS; POLYMERASE-ETA; CIS-SYN; ERROR-PRONE; CRYSTAL-STRUCTURE; Y-FAMILY; BYPASS; REPLICATION; PCNA AB More than half of the 16 human DNA polymerases may have some role in DNA replication and potentially modulate the biological effects of DNA template lesions that impede replication fork progression. As one approach to understand how multiple polymerases are coordinated at the fork, we recently quantified the efficiency and fidelity with which one particular translesion synthesis enzyme, human DNA polymerase h, copies templates containing cis-syn thymine dimers. Several observations from that study were unanticipated. Here we discuss the structural and biological implications of those results in light of earlier studies of translesion synthesis. C1 NIEHS, Genet Mol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Kunkel, RA (reprint author), NIEHS, Genet Mol Lab, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov NR 24 TC 16 Z9 16 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY PY 2004 VL 3 IS 5 BP 580 EP 583 PG 4 WC Cell Biology SC Cell Biology GA 833TJ UT WOS:000222361900018 PM 15118407 ER PT J AU Cuello, M Coats, AO Darko, I Ettenberg, SA Gardner, GJ Nau, MM Liu, JR Birrer, MJ Lipkowitz, S AF Cuello, M Coats, AO Darko, I Ettenberg, SA Gardner, GJ Nau, MM Liu, JR Birrer, MJ Lipkowitz, S TI N-(4-hydroxyphenyl) retinamide (4HPR) enhances TRAIL-mediated apoptosis through enhancement of a mitochondrial-dependent amplification loop in ovarian cancer cell lines SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE apoptosis; death receptors; fenretinide (4HPR); ovarian cancer; TRAIL ID ANTI-FAS ANTIBODY; SYNTHETIC RETINOID CD437; DRUG-INDUCED APOPTOSIS; CYTOCHROME-C RELEASE; NF-KAPPA-B; CARCINOMA-CELLS; TUMOR-CELLS; DIAZEPINYLBENZOIC ACIDS; CHEMOTHERAPEUTIC-AGENTS; SYNERGISTIC INDUCTION AB The majority of ovarian cancer cells are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Subtoxic concentrations of the semisynthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) enhanced TRAIL-mediated apoptosis in ovarian cancer cell lines but not in immortalized nontumorigenic ovarian epithelial cells. The enhancement of TRAIL-mediated apoptosis by 4HPR was not due to changes in the levels of proteins known to modulate TRAIL sensitivity. The combination of 4HPR and TRAIL enhanced cleavage of multiple caspases in the death receptor pathway (including the two initiator caspases, caspase-8 and caspase-9). The 4HPR and TRAIL combination leads to mitochondrial permeability transition, significant increase in cytochrome c release, and increased caspase-9 activation. Caspase-9 may further activate caspase-8, generating an amplification loop. Stable overexpression of Bcl-xL abrogates the interaction between 4HPR and TRAIL at the mitochondrial level by blocking cytochrome c release. As a consequence, a decrease in activation of caspase-9, caspase-8, and TRAIL-mediated apoptosis occurs. These results indicate that the enhancement in TRAIL-mediated apoptosis induced by 4HPR is due to the increase in activation of multiple caspases involving an amplification loop via the mitochondrial-death pathway. These findings offer a promising and novel strategy for the treatment of ovarian cancer. C1 NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Pontificia Univ Catolica Chile, Fac Med, Dept Obstet & Gynecol, Santiago, Chile. NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Michigan, Dept Obstet & Gynecol, Div Gynecol Oncol, Ann Arbor, MI 48109 USA. RP Lipkowitz, S (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bldg 37,Rm 1E24,37 Convent Dr MSC 4255, Bethesda, MD 20892 USA. EM Stan_Lipkowitz@nih.gov NR 71 TC 32 Z9 35 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD MAY PY 2004 VL 11 IS 5 BP 527 EP 541 DI 10.1038/sj.cdd.4401387 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 813AD UT WOS:000220879100005 PM 14765134 ER PT J AU Meetei, AR de Winter, J Medhurst, A Wallisch, M Waisfisz, Q van de Vrugt, H Oostra, A Yan, Z Ling, C Bishop, C Hoatlin, M Joenje, H Wang, O AF Meetei, Amom Ruhikanta de Winter, Johan Medhurst, Annette Wallisch, Michael Waisfisz, Quinten van de Vrugt, Henri Oostra, Anneke Yan, Zhijiang Ling, Chen Bishop, Colin Hoatlin, Maureen Joenje, Hans Wang, OWeidona TI A Fanconi anemia core complex contains a ubiquitin ligase and is required for monoubiquitination of FANCD2 SO CELL STRUCTURE AND FUNCTION LA English DT Meeting Abstract C1 [Meetei, Amom Ruhikanta; Yan, Zhijiang; Ling, Chen; Wang, OWeidona] NIA, NIH, Genet Lab, Baltimore, MD 21224 USA. [de Winter, Johan; Medhurst, Annette; Waisfisz, Quinten; van de Vrugt, Henri; Oostra, Anneke; Joenje, Hans] Free Univ Med Ctr, Dept Clin Genet & Human Genet, Amsterdam, Netherlands. [Wallisch, Michael; Hoatlin, Maureen] Oregon Hlth & Sci Univ, Div Mol Med, Portland, OR 97239 USA. [Bishop, Colin] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN SOC CELL BIOLOGY PI KYOTO PA C/O NAKANISHI PRINTING SHIMODACHIURI OGAWA HIGASHI, KAMIGYO-KU, KYOTO, 602-8048, JAPAN SN 0386-7196 EI 1347-3700 J9 CELL STRUCT FUNCT JI Cell Struct. Funct. PD MAY PY 2004 VL 29 SU S BP 11 EP 11 PG 1 WC Cell Biology SC Cell Biology GA V44IL UT WOS:000202996300027 ER PT J AU Puertollano, R Bonifacino, J AF Puertollano, Rosa Bonifacino, Juan TI Function of GGA3 in endosomes through interactions with the ubiquitin sorting machinery SO CELL STRUCTURE AND FUNCTION LA English DT Meeting Abstract DE GGAs; sorting; ubiquitin C1 [Puertollano, Rosa; Bonifacino, Juan] NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN SOC CELL BIOLOGY PI KYOTO PA C/O NAKANISHI PRINTING SHIMODACHIURI OGAWA HIGASHI, KAMIGYO-KU, KYOTO, 602-8048, JAPAN SN 0386-7196 EI 1347-3700 J9 CELL STRUCT FUNCT JI Cell Struct. Funct. PD MAY PY 2004 VL 29 SU S BP 111 EP 111 PG 1 WC Cell Biology SC Cell Biology GA V44IL UT WOS:000202996300396 ER PT J AU Roblick, UJ Hirschberg, D Habermann, JK Palmberg, C Becker, S Kruger, S Gustafsson, M Bruch, HP Franzen, B Ried, T Bergmann, T Auer, G Jornvall, H AF Roblick, UJ Hirschberg, D Habermann, JK Palmberg, C Becker, S Kruger, S Gustafsson, M Bruch, HP Franzen, B Ried, T Bergmann, T Auer, G Jornvall, H TI Sequential proteome alterations during genesis and progression of colon cancer SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE proteomics; 2-D gel electrophoresis; mass spectrometry; tumor marker; colon cancer ID POLYACRYLAMIDE-GEL ELECTROPHORESIS; HUMAN-BREAST; PROTEINS; EXPRESSION; CARCINOMA; IDENTIFICATION; OVARIAN; CELLS AB Changes in the proteome of colon mucosal cells accompany the transition from normal mucosa via adenoma and invasive cancer to metastatic disease. Samples from 15 patients with sporadic sigmoid cancers were analyzed. Proteins were separated by two-dimensional gel electrophoresis. Relative differences in expression levels between normal tissue, adenoma, carcinoma and metastasis were evaluated in both intra- and inter-patient comparisons. Up- and down-regulated proteins (24 h, therefore limiting the use of short-lived alpha emitters. This study investigated the biodistribution of bismuth-labeled biotin in A431 tumor-bearing mice pretar-geted with antibody B3-streptavidin (B3-SA) and examined the therapeutic efficacy of the alpha emitter, Bi-213-labeled biotin. Experimental Design: Biotinidase-resistant 7,10-tetra-azacyclododecane-N,N',N",N'"-tetraacetic acid (DOTA)-bio-tin was radiolabeled with (205,206) Bi or (213) Bi. Treatment of tumor-bearing mice began by administration of B3-SA (400 mug) to target the tumor sites for 24 h. Then, an agent containing biotin and galactose groups was used to clear the conjugate from the circulation. Four h later, bismuth-radiolabeled DOTA-biotin was given, and biodistribution or therapy was evaluated. Dose escalation treatment from 3.7-74 MBq was performed, and the effects on tumors of different sizes were investigated. Tumor growth, complete blood cell counts, toxicity, and survival were monitored. Results: Radiolabeled biotin cleared rapidly. Rapid tumor uptake resulted in much higher tumor:nontumor targeting ratios than achieved with the directly labeled monoclonal antibody. Dose escalation revealed that 74 MBq caused acute death of mice, whereas 0.37-37 MBq doses inhibited tumor growth and prolonged survival significantly. Evidence of mild hematological toxicity was noted. At therapeutically effective doses renal toxicity was observed. Conclusions: Bi-213-DOTA-biotin, directed by the Pre-target method to tumor-targeted B3-SA, showed a therapeutic effect, although the therapeutic index was low. The source of the toxicity was most likely related to the renal toxicity. C1 NCI, NIH, Dept Nucl Med, Bethesda, MD 20892 USA. NCI, NIH, Dept Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NCI, NIH, Metab Branch, Bethesda, MD 20892 USA. NCI, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. NCI, NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. NeoRx Corp, Seattle, WA USA. RP Carrasquillo, JA (reprint author), NCI, NIH, Dept Nucl Med, 10 Ctr Dr MSC-1180, Bethesda, MD 20892 USA. EM jcarrasquillo@cc.NIH.gov RI Carrasquillo, Jorge/E-7120-2010 NR 50 TC 28 Z9 28 U1 0 U2 3 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 MAY 1 PY 2004 VL 10 IS 9 BP 3137 EP 3146 DI 10.1158/1078-0432.CCR-03-0171 PG 10 WC Oncology SC Oncology GA 818UN UT WOS:000221270100033 PM 15131055 ER PT J AU Penzak, SR Acosta, EP Turner, M Tavel, JA Masur, H AF Penzak, SR Acosta, EP Turner, M Tavel, JA Masur, H TI Antiretroviral drug content in products from developing countries SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material AB Generic and brand name antiretroviral drugs are becoming increasingly available in developing countries. We analyzed 6 antiretroviral medications from 4 international sources for drug content. The active ingredient in tested drug products was within 15% of the labeled amount (range, - 12% to + 15%) for drugs that were properly stored. C1 NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. Univ Alabama, Div Clin Pharmacol, Birmingham, AL 35294 USA. RP Penzak, SR (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Pharm, Ctr Clin, Bldg 10,1N 257, Bethesda, MD 20892 USA. EM spenzak@mail.cc.nih.gov FU NIAID NIH HHS [UO1 AI32775] NR 11 TC 8 Z9 8 U1 0 U2 0 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 MAY 1 PY 2004 VL 38 IS 9 BP 1317 EP 1319 DI 10.1086/383575 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 813SG UT WOS:000220926200020 PM 15127347 ER PT J AU Fox, CS Longenecker, JC Powe, NR Klag, MJ Fink, NE Parekh, R Coresh, J AF Fox, CS Longenecker, JC Powe, NR Klag, MJ Fink, NE Parekh, R Coresh, J CA CHOICE Study TI Undertreatment of hyperlipidemia in a cohort of United States kidney dialysis patients SO CLINICAL NEPHROLOGY LA English DT Article DE ESRD; dialysis; HD; PD; epidemiology; treatment; control; hyperlipidemia ID CHRONIC-RENAL-FAILURE; LOW-DENSITY-LIPOPROTEIN; INITIAL MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; HEMODIALYSIS-PATIENTS; RISK-FACTORS; CLINICAL EPIDEMIOLOGY; LDL-CHOLESTEROL; HEART-DISEASE; DYSLIPIDEMIA AB Background: Application of national guidelines regarding cardiovascular disease risk reduction to kidney dialysis patients is complicated by the conflicting observations that dialysis patients have a high risk of atherosclerotic cardiovascular disease (ASCVD), but dialysis patients with higher serum cholesterol have lower mortality rates. Actual treatment patterns of hyperlipidemia are not well studied. Methods: We assessed the prevalence, treatment and control of hyperlipidemia in this high-risk patient population from 1995-1998. We measured low-density lipoprotein cholesterol, treatment with a lipid-lowering agent, and prevalence of hyperlipidernia as defined by the National Cholesterol Education Program (NCEP), Adult Treatment Panel (ATP) II guidelines in 812 incident hemodialysis (HD), and peritoneal dialysis (PD) patients from dialysis clinics in 19 states throughout the United States. Results: Hyperlipidemia was present in 40% of HD and 62% of PD patients. Among subjects with hyperlipidemia, 67% of HD and 63% of PD patients were untreated and only 22% of HD and 14% of PD patients were treated and controlled. Those who entered the study in 1997 or 1998, those with diabetes, males and Caucasians were more likely to be treated and controlled, whereas subjects on PD and those with ASCVD were less likely to be treated and controlled. Conclusion: These data suggest that high rates of undertreatment exist in the United States ESRD dialysis population. Whether improved rates of treatment will result in decreased cardiovascular disease events needs to be tested in randomized clinical trials. C1 Johns Hopkins Univ, Welch ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. NHLBI, Framingham Heart Study, Bethesda, MD 20892 USA. Johns Hopkins Sch Hyg & Publ Hlth, Dept Biostat, Baltimore, MD USA. Johns Hopkins Sch Hyg & Publ Hlth, Brigham & Womens Hosp, Dept Med, Baltimore, MD USA. Johns Hopkins Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Sch Hyg & Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. Kuwait Univ, Fac Med, Kuwait, Kuwait. RP Coresh, J (reprint author), Johns Hopkins Univ, Welch ctr Prevent Epidemiol & Clin Res, 2024 E Monument,Suite 2-600, Baltimore, MD 21205 USA. EM coresh@jhu.edu FU AHRQ HHS [R01-HS-08365]; NCRR NIH HHS [M01-RR00052]; NHLBI NIH HHS [K08-HL-03896, R01-HL-62985]; NICHD NIH HHS [P30-HD-27799]; NIDDK NIH HHS [K24-DK-02856, K24-DK-02643] NR 46 TC 13 Z9 13 U1 0 U2 0 PU DUSTRI-VERLAG DR KARL FEISTLE PI OBERHACHING PA BAJUWARENRING 4, D-82041 OBERHACHING, GERMANY SN 0301-0430 J9 CLIN NEPHROL JI Clin. Nephrol. PD MAY PY 2004 VL 61 IS 5 BP 299 EP 307 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 817HU UT WOS:000221169400001 PM 15182124 ER PT J AU Lane, RM Kivipelto, M Greig, NH AF Lane, RM Kivipelto, M Greig, NH TI Acetylcholinesterase and its inhibition in Alzheimer disease SO CLINICAL NEUROPHARMACOLOGY LA English DT Review DE acetylcholinesterase; Alzheimer disease; cholinesterase inhibitors ID AMYLOID-BETA-PEPTIDE; CEREBRAL BLOOD-FLOW; CEREBROSPINAL-FLUID-ACETYLCHOLINESTERASE; CHOLINESTERASE-INHIBITORS; PRECURSOR PROTEIN; BRAIN ACETYLCHOLINESTERASE; TRANSGENIC MICE; AD PATIENTS; READTHROUGH ACETYLCHOLINESTERASE; COGNITIVE DETERIORATION AB Until recently, the only established function of acetylcholinesterase (AChE) was the termination of cholinergic neurotransmission. Therefore, the use of AChE inhibitors to treat symptoms caused by cholinergic imbalances in Alzheimer disease (AD) represented a rational approach. However, it is now clear that AChE and the cholinergic system may have broader effects in AD. Of particular interest may be signal transduction pathways mediated through cholinergic receptors that promote nonamyloidogenic amyloid precursor protein processing and decrease tau phosphorylation, and the role of AChE in the aggregation of beta-amyloid (Abeta) peptide. In addition, the neuronal and nonneuronal cholinergic systems have important roles in the modulation of regional cerebral blood flow. These findings may modify the overly simplistic cholinergic hypothesis in AD that is limited to symptomatic treatment and ignores the potential of cholinergic therapies as disease-modifying agents. Chronic increases in AChE activity may exacerbate neurodegenerative processes, make clinically relevant levels of AChE inhibition more difficult to achieve, and cause the therapeutic value of cholinesterase inhibitors (ChE-Is) to be limited and temporary. Rapidly reversible ChE-Is appear to increase AChE activity over the longer term whereas, remarkably, irreversible or very slowly reversible ChE-Is do not seem to have this effect. If such differences between ChE-Is are shown to have clinical correlates, this may prompt reconsideration of the rationale and expectations of some agents in the long-term management of AD. C1 Novartis Pharmaceut Corp, Novartis Neurosci, E Hanover, NJ 07936 USA. Karolinska Inst, NEUROTEC, Aging Res Ctr, Stockholm, Sweden. NIA, Bethesda, MD 20892 USA. RP Lane, RM (reprint author), Novartis Pharmaceut Corp, Novartis Neurosci, 59 Route 10, E Hanover, NJ 07936 USA. EM roger.lane@pharma.novartis.com NR 102 TC 58 Z9 62 U1 9 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0362-5664 J9 CLIN NEUROPHARMACOL JI Clin. Neuropharmacol. PD MAY-JUN PY 2004 VL 27 IS 3 BP 141 EP 149 DI 10.1097/00002826-200405000-00011 PG 9 WC Clinical Neurology; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 830CM UT WOS:000222099200011 PM 15190239 ER PT J AU Cizza, G Mistry, S Phillips, T AF Cizza, G Mistry, S Phillips, T TI Serum markers of bone metabolism show bone loss in hibernating bears SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Letter ID LEPTIN; WOMEN; MASS C1 NIDDK, Clin Endocrinol Branch, Bethesda, MD 20892 USA. NIH, Ultramicro Analyt Immunochem Resource Div Bioengn, Bethesda, MD 20892 USA. RP Cizza, G (reprint author), NIDDK, Clin Endocrinol Branch, Bethesda, MD 20892 USA. NR 8 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD MAY PY 2004 IS 422 BP 281 EP 283 DI 10.1097/01.blo.0000129556.26221.c0 PG 3 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 824XW UT WOS:000221721500057 PM 15187881 ER PT J AU Engels, FK ten Tije, AJ Baker, SD Lee, CKK Loos, WJ Vulto, AG Verweij, J Sparreboom, A AF Engels, FK ten Tije, AJ Baker, SD Lee, CKK Loos, WJ Vulto, AG Verweij, J Sparreboom, A TI Effect of cytochrome P450 3A4 inhibition on the pharmacokinetics of docetaxel SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID CLINICAL PHARMACOKINETICS; CYP3A5 EXPRESSION; IN-VITRO; PHASE-I; METABOLISM; KETOCONAZOLE; CLEARANCE; TAXOTERE; CANCER; LIVER AB Objective: In vitro studies indicate that the anticancer drug docetaxel is primarily eliminated by cytochrome P450 (CYP) 3A4-mediated metabolism. Coadministration of drugs that modulate the activity of CYP3A4 is, therefore, likely to have undesirable clinical consequences. We investigated the effects of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of docetaxel in patients with cancer. Methods: Seven patients were treated in a randomized crossover design with docetaxel (100 mg/m(2)), followed 3 weeks later by docetaxel (10 mg/m2) given in combination with orally administered ketoconazole (200 mg once daily for 3 days), or the reverse sequence. Plasma concentration-time data were analyzed by noncom-partmental analysis. Results: Ketoconazole coadministration resulted in a 49% decrease in clearance of docetaxel (P=.018). The mean ( +/-SD) clearance values were 35.0 +/- 11.8 L/h (95% confidence interval, 24.1-45.9 L/h) for docetaxel alone and 18.2 L/h (95% confidence interval, 9.22-27.1 L/h) in the presence of ketoconazole, respectively. The docetaxel clearance ratio in the presence and absence of ketoconazole was weakly related to the area under the curve of ketoconazole (R-2 = 0.529, P =.064). Conclusion: Inhibition of CYP3A4 by ketoconazole in vivo results in docetaxel clearance values that have previously been shown to be associated with a several-fold increase in the odds for febrile neutropenia at standard doses. Caution should be taken and substantial dose reductions are required if docetaxel has to be administered together with potent inhibitors of CYP3A4. C1 NCI, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. Erasmus Univ, Med Ctr, Dept Med Oncol, Dr Daniel Denhoed Canc Ctr, Rotterdam, Netherlands. Erasmus Univ, Med Ctr, Dept Clin Pharm, Rotterdam, Netherlands. Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Div Expt Therapeut, Baltimore, MD USA. RP Sparreboom, A (reprint author), NCI, Med Oncol Clin Res Unit, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM SparrebA@mail.nih.gov RI Sparreboom, Alex/B-3247-2008 NR 29 TC 78 Z9 79 U1 0 U2 5 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAY PY 2004 VL 75 IS 5 BP 448 EP 454 DI 10.1016/j.clpt.2004.01.001 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 818VD UT WOS:000221271700010 PM 15116057 ER PT J AU Simon, A Drewe, E van der Meer, JWM Powell, RJ Kelley, RI Stalenhoef, AFH Drenth, JPH AF Simon, A Drewe, E van der Meer, JWM Powell, RJ Kelley, RI Stalenhoef, AFH Drenth, JPH TI Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ENCODING MEVALONATE KINASE; HYPER-IGD; BIOSYNTHESIS; MUTATIONS; STATINS AB Hyperimmunoglobulinemia D (hyper-IgD) and periodic fever syndrome, a hereditary autoinflammatory syndrome, is characterized by lifelong recurrent episodes of fever and inflammation. No effective treatment is known. It is caused by a defect of mevalonate kinase, an enzyme that follows 3'-hydroxy-3'-methylglutarylcoenzyme A (HMG-CoA) reductase in the isoprenoid pathway. We wanted to test the hypothesis that inhibition of HMG-CoA reductase would ameliorate the inflammatory attacks. Six patients with hyper-IgD syndrome and proven mevalonate kinase deficiency were followed up for 2 treatment periods with either simvastatin, 80 mg/d, or placebo for 24 weeks, separated by a 4-week washout period in a double-blind fashion. Simvastatin resulted in a drop in urinary mevalonic acid concentration in all patients and decreased the number of febrile days in 5 of 6 patients. No side effects were observed. These data offer preliminary evidence for the hypothesis that simvastatin may improve inflammatory attacks in the hyper-IgD syndrome. This highlights the anti-inflammatory properties of HMG-CoA reductase inhibition. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. Univ St Radboud, Med Ctr, Dept Gen Internal Med, Nijmegen, Netherlands. Univ St Radboud, Med Ctr, Dept Gastroenterol, Nijmegen, Netherlands. Queens Med Ctr, Clin Immunol Unit, Nottingham NG7 2UH, England. Kennedy Krieger Inst, Bethesda, MD 20892 USA. RP Drenth, JPH (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101, Bethesda, MD 20892 USA. EM JoosrPHDrenth@CS.com RI Simon, Anna/D-3757-2009; Stalenhoef, A.F.H./H-8094-2014; Drenth, J.P.H./H-8025-2014; van der Meer, Jos/C-8521-2013 OI Simon, Anna/0000-0002-6141-7921; van der Meer, Jos/0000-0001-5120-3690 NR 17 TC 108 Z9 114 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAY PY 2004 VL 75 IS 5 BP 476 EP 483 DI 10.1016/j.clpt.2004.01.012 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 818VD UT WOS:000221271700013 PM 15116060 ER PT J AU Hasler, G Moergeli, H Schnyder, U AF Hasler, G Moergeli, H Schnyder, U TI Outcome of psychiatric treatment: What is relevant for our patients? SO COMPREHENSIVE PSYCHIATRY LA English DT Article ID CLINICAL-SIGNIFICANCE; PANIC DISORDER; PSYCHOTHERAPY; DEPRESSION; PHARMACOTHERAPY; SATISFACTION; ADJUSTMENT; GOALS AB This study investigated relevant outcome domains in the patient's perspective following psychiatric outpatient treatment for non-psychotic, non-substance-related disorders. Questionnaires, including the Client Satisfaction Questionnaire (CSQ) and the Bern Inventory of Treatment Goals (BIT-C) applied as a broad typology of outcome domains, were mailed 1 year after treatment to outpatients who had undergone eight or more therapy sessions. Patients reported a wide range of relevant outcomes, including changes with respect to the interpersonal domain, their self-concept, and existential issues. Changes in depressive and anxiety symptoms were rated as particularly important; the reports of both symptomatic and more integral changes were related to treatment characteristics, patient's diagnostic category, and patient's employment status. Patient satisfaction was particularly related to reported changes in the interpersonal domain. This exploratory study provides evidence that traditional outcome measures that include mood, anxiety, and fear symptoms continue to assess the most important areas for change in patients' views. However, they might miss relevant therapeutic achievements in some of our patients, particularly in those suffering from adjustment and personality disorders. The use of measures that include dimensions such as personal growth, purpose of life, and positive relations with others may record important changes in these patients. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Zurich Hosp, Dept Psychiat, Zurich, Switzerland. RP Hasler, G (reprint author), NIMN, Mood & Anxiety Disorders Program, NIH, 15K N Dr,Room 300C,MSC 2670, Bethesda, MD 20892 USA. EM g.hasler@bluewin.ch RI Hasler, Gregor/E-4845-2012 OI Hasler, Gregor/0000-0002-8311-0138 NR 20 TC 17 Z9 20 U1 0 U2 4 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0010-440X J9 COMPR PSYCHIAT JI Compr. Psychiat. PD MAY-JUN PY 2004 VL 45 IS 3 BP 199 EP 205 DI 10.1016/j.comppsych.2004.02.001 PG 7 WC Psychiatry SC Psychiatry GA 820VE UT WOS:000221416800006 PM 15124150 ER PT J AU Clarke, CL Perdue, KA AF Clarke, CL Perdue, KA TI Detection and clearance of Syphacia obvelata infection in Swiss Webster and athymic nude mice SO CONTEMPORARY TOPICS IN LABORATORY ANIMAL SCIENCE LA English DT Article ID INBRED STRAINS; MOUSE STRAIN; INDUCTION; RESISTANCE; LYMPHOMA AB Our routine health-surveillance program is based on use of the Swiss Webster mouse, with sentinels submitted for testing every 7 weeks. Athymic nude (nu(+)/nu(+)) mice are used as an adjunct method to detect pinworm infections. The premise for the use of the nude mouse was based on research that revealed the thymus as necessary to confer resistance to pinworm infections. In light of this finding, it was inferred that an athymic mouse would be more susceptible to pinworm infections than a euthymic mouse, and hence a better sentinel animal for pinworm detection. To test the validity of this assumption, the Syphacia obvelata detection ability of the athymic nude mouse was compared to that of the Swiss Webster. Our results indicate no significant temporal difference in the detection ability of the two genotypes of mice. A clearance study for the parasite was also performed, in which the majority of Swiss Webster mice cleared the infection whereas athymic nude mice did not. In light of our results, we conclude that use of the athymic nude mouse for Syphacia obvelata detection offered no significant advantage over the euthymic Swiss Webster mouse for our program. C1 NIAID, Comparat Med Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. Biocon Inc, Rockville, MD USA. NIH, Div Vet Resources, Off Res Serv, Off Director, Bethesda, MD 20892 USA. RP Clarke, CL (reprint author), NIAID, Comparat Med Branch, Div Intramural Res, NIH, 9000 Rockville Pike Bldg 14BS Room 28, Bethesda, MD 20892 USA. NR 19 TC 8 Z9 8 U1 1 U2 2 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1060-0558 J9 CONTEMP TOP LAB ANIM JI Contemp. Top. Lab. Anim. Sci. PD MAY PY 2004 VL 43 IS 3 BP 9 EP 13 PG 5 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 824CU UT WOS:000221662500004 PM 15174810 ER PT J AU Strom, BL Berlin, JA Weber, AL Norman, SA Bernstein, L Burkman, RT Daling, JR Deapen, D Folger, SG Malone, KE Marchbanks, PA Simon, MS Ursin, G Weiss, LK Spirtas, R AF Strom, BL Berlin, JA Weber, AL Norman, SA Bernstein, L Burkman, RT Daling, JR Deapen, D Folger, SG Malone, KE Marchbanks, PA Simon, MS Ursin, G Weiss, LK Spirtas, R TI Absence of an effect of injectable and implantable progestin-only contraceptives on subsequent risk of breast cancer SO CONTRACEPTION LA English DT Article DE breast cancer; progestin; contraceptive patch; contraceptives; implantable contraceptives; injectable contraceptives; medroxyprogesterone acetate ID HORMONE REPLACEMENT THERAPY; DEPOT-MEDROXYPROGESTERONE ACETATE; MAMMARY-GLAND; PROLIFERATION; REGIMENS; MACAQUES; ESTROGEN; WOMEN AB Animal data indicate that both estrogens and progestins could be carcinogenic and that progestins could serve as tumor promoters. Human studies have not confirmed an increased risk of breast cancer from long-term use of oral contraceptives, but have shown an increased risk from hormone replacement therapy including progestins. The present study analyzed the relationship between breast cancer and use of injectable and implantable progestin-only contraceptives. Analyses were performed on data collected in a population-based, multicenter, case-control study, the Women's Contraceptive and Reproductive Experiences Study of the National Institute of Child Health and Human Development. The study involved 4575 randomly sampled cases with invasive breast cancer diagnosed between 1994 and 1998, and 4682 controls, identified using random digit dialing. We assessed the association between exposure to injectable contraceptives and risk of breast cancer. The use of injectable contraceptives was not associated with an increased risk of breast cancer [odds ratio (OR) = 0.9, 95% confidence interval (CI): 0.7, 1.2]. Risk was not increased among current users, defined as women who used injectable contraceptives within 1 year of the reference date (OR = 0.7, 95% CI: 0.4, 1.3) or those who initiated use in the 5 years immediately preceding the reference date (OR = 0.9, 95% CI: 0.5, 1.4), or with use beginning before age 35 (OR = 0.9, 95% CI: 0.6, 1.3). Among users, risk increased with increasing duration of use (p = 0.03). However, short-term users (<6 months duration) were at decreased risk relative to never users (OR = 0.6, 95% CI: 0.4, 1.0). When the short-term users were then excluded from the duration-response analysis, the slope of the duration-response became slightly (and nonsignificantly) negative. Risk was not increased among women with 24 or more months of use relative to never users (OR = 1.4, 95% CI: 0.8, 2.5). No increased risk was seen from implantable contraceptives either, although the sample sizes were small. This study does not support an increased risk of breast cancer associated with the use of injectable or implantable progestin-only contraceptives in women aged 35 to 64. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. Henry Ford Hlth Syst, Dept Obstet & Gynecol, Detroit, MI USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. Wayne State Univ, Karmanos Canc Inst, Dept Internal Med, Detroit, MI USA. NICHHD, Populat Res Ctr, Contracept & Reprod Hlth Branch, Bethesda, MD 20892 USA. RP Strom, BL (reprint author), Univ Penn, Ctr Clin Epidemiol & Biostat, 824 Blockley Hall,423 Guardian Dr, Philadelphia, PA 19104 USA. EM bstrom@cceb.med.upenn.edu FU NCI NIH HHS [N01-PC-67010, N01-CN-0532, N01-CN-65064, N01-PC-67006]; NICHD NIH HHS [N01-HD-3-3175, N01-HD-3-3176, Y01-HD-7022, N01-HD-2-3166, N01-HD-3-3168, N01-HD-3-3174] NR 21 TC 26 Z9 26 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 J9 CONTRACEPTION JI Contraception PD MAY PY 2004 VL 69 IS 5 BP 353 EP 360 DI 10.1016/j.contraception.2003.12.015 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 817KI UT WOS:000221176000003 PM 15105056 ER PT J AU Stein, WD Bates, SE Fojo, T AF Stein, WD Bates, SE Fojo, T TI Intractable cancers: The many faces of multidrug resistance and the many targets it presents for therapeutic attack SO CURRENT DRUG TARGETS LA English DT Review DE drug resistance; intractable tumors; ABC transporters; apoptosis; DNA repair; drug distribution; anoikis; cell adhesion ID FIBROBLAST-GROWTH-FACTOR; RENAL-CELL CARCINOMA; HUMAN SOLID TUMORS; CONFLUENCE-DEPENDENT RESISTANCE; TERMINAL PROLIFERATION ARREST; CHRONIC MYELOGENOUS LEUKEMIA; GENE-EXPRESSION SIGNATURES; NUCLEOTIDE EXCISION-REPAIR; P-GLYCOPROTEIN EXPRESSION; PRIMARY BREAST-CANCER AB Some types of cancer respond far less favorably to treatment than do others. A quantitative estimate of this intuition can be obtained from the SEER (Surveillance, Epidemiology and End-Results) Cancer Statistics Review. Of particular interest, from a drug resistance perspective, are the five-year survival data for patients presenting with tumors that were diagnosed as "distant". A good correlation can be found between those numbers and an estimate of treatment successes obtained from a survey of current literature on chemotherapy applied to cancers originating from these various tissues. These two measures, considered together, define "the axis of intractability", a parameter that characterizes the (possibly) inherent, physiological basis of the tissue-by-tissue intractability of cancers. Exploring the basis of this intractability, it appears that factors other than the classical ABC transporter-based, multidrug resistance systems probably play a major role. An ineffective DNA repair system, coupled to reduced apoptosis, is the basis for the inherent tractability of testicular cancer. For other tissues, important contributions to resistance arise from cell adhesion-mediated drug resistance, which is overcome when cells are released from tissues during anoikis. Making a direct comparison between gene expression in solid tumors and their corresponding cell lines, genes controlling the extracellular matrix and cell-cell communication appear among the genes that are over-expressed in the solid tumors, while genes coding for the protein biosynthesis system are over-expressed in the cell lines. The more tractable cancers are closer to the cell lines in their expression profiles of these sets of genes. C1 Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. NCI, Med Branch, Bethesda, MD 20892 USA. RP Stein, WD (reprint author), Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. EM wdstein@vms.huji.ac.il NR 131 TC 39 Z9 45 U1 1 U2 9 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1389-4501 J9 CURR DRUG TARGETS JI Curr. Drug Targets PD MAY PY 2004 VL 5 IS 4 BP 333 EP 346 DI 10.2174/1389450043345489 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 816FS UT WOS:000221096400002 PM 15134216 ER PT J AU Stadtman, ER AF Stadtman, ER TI Role of oxidant species in aging SO CURRENT MEDICINAL CHEMISTRY LA English DT Review ID METHIONINE SULFOXIDE REDUCTASE; OXIDATIVELY DENATURED PROTEINS; METAL-CATALYZED OXIDATION; PEROXYNITRITE-MEDIATED NITRATION; BUTYL-ALPHA-PHENYLNITRONE; MIXED-FUNCTION OXIDATION; RED-BLOOD-CELLS; NITRIC-OXIDE; CARBON-DIOXIDE; ESCHERICHIA-COLI AB Organisms are constantly exposed to many different forms of reactive oxygen species and reactive nitrogen species that damage proteins, nucleic acids, and lipids, leading to loss of biological function. The possibility that reactive oxygen/nitrogen-mediated protein damage contributes to the aging process is supported by results of many studies showing that aging is associated with the accumulation of such protein damage. Summarized here are results of studies, showing that the accumulation of protein damage is a complex function of a multiplicity of factors that govern the intracellular levels of reactive oxygen/nitrogen species, on the one hand, and a multiplicity of factors that govern the degradation and/or repair of damaged proteins, on the other. Basic mechanisms involved in the modification of proteins by various forms of reactive oxygen/nitrogen species are also discussed. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, ER (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2140,50 South Dr,MSC-8012, Bethesda, MD 20892 USA. EM erstadtman@nih.gov NR 127 TC 173 Z9 179 U1 4 U2 18 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD MAY PY 2004 VL 11 IS 9 BP 1105 EP 1112 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 818FA UT WOS:000221229800004 PM 15134509 ER PT J AU Bird, GS Aziz, O Lievremont, JP Wedel, BJ Trebak, M Vazquez, G Putney, JW AF Bird, GS Aziz, O Lievremont, JP Wedel, BJ Trebak, M Vazquez, G Putney, JW TI Mechanisms of phospholipase C-regulated calcium entry SO CURRENT MOLECULAR MEDICINE LA English DT Review ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; CAPACITATIVE CA2+ ENTRY; SMOOTH-MUSCLE-CELLS; CA2+-PERMEABLE CATION CHANNEL; STORE-OPERATED CHANNEL; HUMAN EMBRYONIC KIDNEY; RAT OLFACTORY NEURONS; PLASMA-MEMBRANE; TRANSIENT RECEPTOR; ARACHIDONIC-ACID AB In a variety of cell types, activation of phospholipase C-linked receptors results in the generation of intracellular Ca2+ signals comprised of components of both intracellular Ca2+ release, and enhanced entry of Ca2+ across the plasma membrane. This entry of Ca2+ occurs by either of two general mechanisms: the release of stored Ca2+ can activate, by an unknown mechanism, storeoperated channels in the plasma membrane, a process known as capacitative calcium entry. Alternatively, second messengers generated at the plasma membrane can activate Ca2+ channels more directly, a non-capacitative calcium entry process. This review summarizes current knowledge of the underlying signaling mechanisms and the nature of the channel molecules responsible for these two general categories of regulated Ca2+ entry. C1 NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM Putney@niehs.nih.gov RI Trebak, Mohamed/E-7405-2014 NR 126 TC 64 Z9 68 U1 1 U2 10 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD MAY PY 2004 VL 4 IS 3 BP 291 EP 301 DI 10.2174/1566524043360681 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 811ZT UT WOS:000220810500007 PM 15101686 ER PT J AU Sharabi, Y Dagan, Y Grossman, E AF Sharabi, Y Dagan, Y Grossman, E TI Sleep apnea as a risk factor for hypertension SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE antihypertensive medication; continuous positive airway pressure; hypertension mechanism; obstructive sleep apnea epidemiology; weight reduction ID POSITIVE AIRWAY PRESSURE; BLOOD-PRESSURE; ADHESION MOLECULES; HEART HEALTH; PREVALENCE; ASSOCIATION; OBESITY; TRIAL; PROTEINURIA; RESISTANCE AB Purpose of review High blood pressure and obstructive sleep apnea are closely related, and the latter is considered to induce hypertension. The primary underlying mechanism is sympathetic activation triggered by apneic episodes. This type of hypertension is difficult to treat. The purpose of this review is (1) to evaluate the epidemiological data in view of the current focus on preclinical sleep apnea and prehypertension, (2) to examine additional factors that might contribute to high blood pressure, and (3) to indicate the best therapeutic strategy for treatment of hypertension in these patients. Recent findings Cardiovascular effects of sleep apnea can be detected early in the course of the disease, and young subjects are particularly susceptible to its deleterious effect. Blood pressure profiles in these patients show higher diastolic blood pressure and no nocturnal dipping. The renin-angiotensin axis in conjunction with other vasoactive hormones add to the sympathetic activation in elevating blood pressure in sleep apnea. Proinflammatory cytokines further contribute to the atherosclerotic consequences that primarily affect the heart and brain, and spare the kidneys. Mounting evidence indicates that treatment of sleep apnea using positive airway pressure, palato-nasal surgery and weight reduction correct the associated hypertension. Conversely, antihypertensive therapy is less effective. Summary Even the early stages of sleep apnea are associated with high blood pressure and cardiovascular consequences. Despite our knowledge of the role of the sympathetic activation and vasoactive hormones, no specific anti hypertensive therapy is superior, and the optimal way of controlling hypertension is to treat sleep apnea and associated obesity. C1 Tel Aviv Univ, Tel Hashomer Sch Med, Chaim Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. Tel Aviv Univ, Tel Hashomer Sch Med, Chaim Sheba Med Ctr, Inst Fatigue & Sleep Med, IL-52621 Tel Hashomer, Israel. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Sharabi, Y (reprint author), Tel Aviv Univ, Tel Hashomer Sch Med, Chaim Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. EM sharabiy@ninds.nih.gov NR 46 TC 11 Z9 15 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD MAY PY 2004 VL 13 IS 3 BP 359 EP 364 DI 10.1097/01.mnh.0000126796.23841.89 PG 6 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 818GA UT WOS:000221232400013 PM 15073496 ER PT J AU Barteneva, N Kim, M Luther, E Luo, K Chang, DC Carman, C Brochu, M Sumen, C Ketman, K Telford, WG AF Barteneva, N Kim, M Luther, E Luo, K Chang, DC Carman, C Brochu, M Sumen, C Ketman, K Telford, WG TI A novel approach to fluorescence resonance energy transfer (FRET)-analysis using biosensors and cytometers equipped with mercury ARC lamp or violet diode lasers SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA USA. CompuCyte, Cambridge, MA USA. Hong Kong Univ Sci & Technol, Hong Kong, Hong Kong, Peoples R China. NPE Syst, Pembroke Pines, FL USA. NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 30 EP 31 PG 2 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900023 ER PT J AU Schleinitz, TA Telford, WG Perfetto, SP Caporaso, NE Stetler-Stevenson, M Abbasi, F Zenger, VE Marti, GE AF Schleinitz, TA Telford, WG Perfetto, SP Caporaso, NE Stetler-Stevenson, M Abbasi, F Zenger, VE Marti, GE TI Multicolor flow cytometry (MCFCM) analysis of precursor states in chronic lymphocytic leukemia (CLL) SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 Inst J Paoli I Calmettes, CBER FDA, F-13009 Marseille, France. NCI, Flow Core Facil, Bethesda, MD 20892 USA. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. US FDA, CBER, Bethesda, MD 20014 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 39 EP 39 PG 1 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900045 ER PT J AU Telford, WG AF Telford, WG TI Analysis of UV-excited fluorochromes by flow cytometry using near-ultraviolet laser diodes SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd International Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 41 EP 41 PG 1 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900052 ER PT J AU Telford, WG AF Telford, WG TI Yellow helium neon lasers in flow and image cytometry SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd International Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4922 EI 1552-4930 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 41 EP 41 PG 1 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900051 ER PT J AU Baerlocher, GM Vulto, IM Alter, BP Wagner, JE Sloand, EM Young, NS Lansdorp, PM AF Baerlocher, GM Vulto, IM Alter, BP Wagner, JE Sloand, EM Young, NS Lansdorp, PM TI Automated multicolor flow-fish for telomere length: A sensitive and rapid technique to identify individuals with primary defects in telomere maintenance SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 Univ Bern, Bern, Switzerland. BC Canc Agcy, Terry Fox Lab Hematol Oncol, Vancouver, BC, Canada. NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Rockville, MA USA. NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 46 EP 46 PG 1 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900065 ER PT J AU Murphy, RF Novo, D Roederer, M Sudar, D Treister, A Wood, JCS AF Murphy, RF Novo, D Roederer, M Sudar, D Treister, A Wood, JCS TI The common cytometry dictionary SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. Univ Calif Los Angeles, Los Angeles, CA USA. NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Univ Calif Berkeley, Lawrence Berkeley Lab, Berkeley, CA 94720 USA. Tree Star Inc, San Carlos, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 51 EP 51 PG 1 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900080 ER PT J AU Bortner, CD Cidlowski, JA AF Bortner, CD Cidlowski, JA TI Defining primary and secondary cell shrinkage during the apoptotic volume decrease response of Jurkat cells by flow cytometry and confocal microscopy SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 NIEHS, NIH, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 67 EP 67 PG 1 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900128 ER PT J AU Khan, SS Smith, M Suffredini, AF McCoy, JP AF Khan, SS Smith, M Suffredini, AF McCoy, JP TI Multiplex bead array assays and ELISAs for detection of soluble cytokines: Comparisons of sensitivity and quantitative values among kits from multiple manufacturers SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 NHLBI, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 75 EP 75 PG 1 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900150 ER PT J AU Parks, D Roederer, M Moore, WA AF Parks, D Roederer, M Moore, WA TI "Logicle" functions provide improved displays of FACS data and avoid the deceptive effects of log scaling for low signals SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 Herzenberg Lab, Stanford, CA USA. NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Stanford Univ, Stanford, CA 94305 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 87 EP 87 PG 1 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900185 ER PT J AU Fischer, RT Slota, R Longo, NS Sohn, HW Yarboro, C Illei, GG Pierce, S Lipsky, PE Grammer, AC AF Fischer, RT Slota, R Longo, NS Sohn, HW Yarboro, C Illei, GG Pierce, S Lipsky, PE Grammer, AC TI Functional and phenotypic characterization of anergic B cells circulating in the periphery of active SLE patients SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 Natl Inst Arthrit & Musculoskeletal & Skin, NIH, Bethesda, MD USA. NAIAD, NIH, Rockville, MD USA. NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 88 EP 89 PG 2 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900189 ER PT J AU Perfetto, SP Roederer, M AF Perfetto, SP Roederer, M TI New advances in flow cytometry: How to do successful polychromatic flow cytometry SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 98 EP 99 PG 2 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900219 ER PT J AU Lamoreaux, L Fischer, J Bailer, R Roederer, M Koup, R AF Lamoreaux, L Fischer, J Bailer, R Roederer, M Koup, R TI Low frequency measurement and validation of CD4+ and CD8+ IFN-7 and IL2 producing cells in vaccine trials SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 133 EP 133 PG 1 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900321 ER PT J AU Telford, WG Frolova, EG AF Telford, WG Frolova, EG TI Discrimination of the Hoechst side population in mouse bone marrow with violet and near-UV laser diodes SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NICHD, NIH, Lab Mammalian Genes & Dev, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 146 EP 146 PG 1 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900363 ER PT J AU Roederer, M Perfetto, SP Harper, T Bruchez, M AF Roederer, M Perfetto, SP Harper, T Bruchez, M TI Quantum dots in flow cytometry SO CYTOMETRY PART A LA English DT Meeting Abstract CT 22nd Congress of the International-Society-for-Analytical-Cytology CY MAY 22-27, 2004 CL Montpellier, FRANCE SP Ins Soc Analyt Cytol C1 NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Quantum Dot Corp, Hayward, CA USA. RI Bruchez, Marcel/C-2271-2009 OI Bruchez, Marcel/0000-0002-7370-4848 NR 0 TC 2 Z9 2 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0196-4763 J9 CYTOM PART A JI Cytom. Part A PD MAY PY 2004 VL 59A IS 1 BP 148 EP 148 PG 1 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 819MV UT WOS:000221319900370 ER PT J AU Neimeyer, RA Wittkowski, J Moser, RP AF Neimeyer, RA Wittkowski, J Moser, RP TI Psychological research on death attitudes: An overview and evaluation SO DEATH STUDIES LA English DT Review ID SITUATIONS INVOLVING DEATH; TERROR MANAGEMENT THEORY; NURSING-HOME PERSONNEL; ANXIETY SCALE; BEGINNING COUNSELORS; MORTALITY SALIENCE; LIFE SATISFACTION; MEDICAL-STUDENTS; ELDERLY PERSONS; CANCER-PATIENTS AB One of the most substantial legacies of Herman Feifel was his pioneering research on attitudes toward death and dying in a variety of populations. The authors review the large and multifaceted literature on death anxiety, fear, threat and acceptance focusing on The attitudes toward death and dying of relevant professional and patient groups, and the relationship of death concern to aging, physical and mental health, religiosity, and terror management strategies. We conclude with several recommendations fir improving the conceptual and practical yield of future work in this area. C1 Univ Memphis, Dept Psychol, Memphis, TN 38152 USA. Univ Wurzburg, D-97070 Wurzburg, Germany. NCI, Bethesda, MD 20892 USA. RP Neimeyer, RA (reprint author), Univ Memphis, Dept Psychol, Memphis, TN 38152 USA. EM neimeyer@memphis.edu NR 128 TC 105 Z9 106 U1 7 U2 50 PU BRUNNER/MAZEL INC PI BRISTOL PA 1900 FROST RD, STE 101, BRISTOL, PA 19007-1598 USA SN 0748-1187 J9 DEATH STUD JI Death Stud. PD MAY PY 2004 VL 28 IS 4 BP 309 EP 340 DI 10.1080/07481180490432324 PG 32 WC Psychology, Multidisciplinary; Social Issues; Social Sciences, Biomedical SC Psychology; Social Issues; Biomedical Social Sciences GA 816AZ UT WOS:000221084100004 PM 15129688 ER PT J AU Stottmann, RW Choi, M Mishina, Y Meyers, EN Klingensmith, J AF Stottmann, RW Choi, M Mishina, Y Meyers, EN Klingensmith, J TI BMP receptor IA is required in mammalian neural crest cells for development of the cardiac outflow tract and ventricular myocardium SO DEVELOPMENT LA English DT Article DE BMPRIA; neural crest; heart; outflow tract; myocardium; epicardium ID MORPHOGENETIC PROTEIN-RECEPTOR; SMOOTH-MUSCLE-CELLS; MOUSE EMBRYO; CARDIOVASCULAR DEVELOPMENT; CRANIOFACIAL DEVELOPMENT; HEART MORPHOGENESIS; RETINOIC ACID; RXR-ALPHA; MICE; EPICARDIUM AB The neural crest is a multipoteut, migratory cell population arising from the border of the neural and surface ectoderm. In mouse, the initial migratory neural crest cells occur at the five-somite stage. Bone morphogenetic proteins (BMPs), particularly BMP2 and BMP4, have been implicated as regulators of neural crest cell induction, maintenance, migration, differentiation and survival. Mouse has three known BMP2/4 type I receptors, of which Bmprla is expressed in the neural tube sufficiently early to be involved in neural crest development from the outset; however, earlier roles in other domains obscure its requirement in the neural crest. We have ablated Bmprla specifically in the neural crest, beginning at the five-somite stage. We find that most aspects of neural crest development occur normally; suggesting that BMPRIA is unnecessary for many aspects of early neural crest biology. However, mutant embryos display a shortened cardiac outflow tract with defective septation, a process known to require neural crest cells and to be essential for perinatal viability. Surprisingly, these embryos die in mid-gestation from acute heart failure, with reduced proliferation of ventricular myocardium. The myocardial defect may involve reduced BMP signaling in a novel, minor population of neural crest derivatives in the epicardium, a known source of ventricular myocardial proliferation signals. These results demonstrate that BMP2/4 signaling in mammalian neural crest derivatives is essential for outflow tract development and may regulate a crucial proliferation signal for the ventricular myocardium. C1 Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA. RP Klingensmith, J (reprint author), Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. EM kling@cellbio.duke.edu FU NICHD NIH HHS [HD39948, P01 HD039948]; NIDCR NIH HHS [R56 DE013674, DE13674, R01 DE013674]; NINDS NIH HHS [F31 NS042486-01, NS42486, F31 NS042486, F31 NS042486-03, F31 NS042486-02] NR 84 TC 122 Z9 126 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAY PY 2004 VL 131 IS 9 BP 2205 EP 2218 DI 10.1242/dev.01086 PG 14 WC Developmental Biology SC Developmental Biology GA 824DE UT WOS:000221663600028 PM 15073157 ER PT J AU Andl, T Ahn, K Kairo, A Chu, EY Wine-Lee, L Reddy, ST Croft, NJ Cebra-Thomas, JA Metzger, D Chambon, P Lyons, KM Mishina, Y Seykora, JT Crenshaw, EB Millar, SE AF Andl, T Ahn, K Kairo, A Chu, EY Wine-Lee, L Reddy, ST Croft, NJ Cebra-Thomas, JA Metzger, D Chambon, P Lyons, KM Mishina, Y Seykora, JT Crenshaw, EB Millar, SE TI Epithelial Bmpr1a regulates differentiation and proliferation in postnatal hair follicles and is essential for tooth development SO DEVELOPMENT LA English DT Article DE hair follicle; skin; tooth; BMP; BMPR1a; BMPR1B; beta-catenin; gata3; MSX; Foxn1 ID MULTIPOTENT STEM-CELLS; IBMP RECEPTOR BMPRIB; GENE-EXPRESSION; SONIC-HEDGEHOG; TRANSGENIC MICE; SKIN TUMOR; MORPHOGENESIS; GROWTH; INDUCTION; NOGGIN AB Bone morphogenetic protein (BMP) signaling is thought to perform multiple functions in the regulation of skin appendage morphogenesis and the postnatal growth of hair follicles. However, definitive genetic evidence for these roles has been lacking. Here, we show that Cre-mediated mutation of the gene encoding BMP receptor 1A in the surface epithelium and its derivatives causes arrest of tooth morphogenesis and lack of external hair. The hair shaft and hair follicle inner root sheath (IRS) fail to differentiate, and expression of the known transcriptional regulators of follicular differentiation Msx1, Msx2, Foxn1 and Gata3 is markedly downregulated or absent in mutant follicles. Lef1 expression is maintained, but nuclear beta-catenin is absent from the epithelium of severely affected mutant follicles, indicating that activation of the WNT pathway lies downstream of BMPR1A signaling in postnatal follicles. Mutant hair follicles fail to undergo programmed regression, and instead continue to proliferate, producing follicular cysts and matricomas. These results provide definitive genetic evidence that epithelial Bmpr1a is required for completion of tooth morphogenesis, and regulates terminal differentiation and proliferation in postnatal hair follicles. C1 Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Chilhood Commun, Philadelphia, PA 19104 USA. ULP, Coll France, INSERM, CNRS,Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France. Univ Calif Los Angeles, David Geffen Sch Med, Dept Cell Mol & Dev Biol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Orthopaed Surg, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Biol Chem, Los Angeles, CA 90095 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Millar, SE (reprint author), Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. EM millars@mail.med.upenn.edu RI Lyons, Karen/P-1843-2014 OI Lyons, Karen/0000-0001-9420-5813 FU NIAMS NIH HHS [AR47709, R01 AR044528, T32 AR007465]; NIDCD NIH HHS [DC03917]; NINDS NIH HHS [NS39159] NR 61 TC 225 Z9 238 U1 1 U2 16 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAY PY 2004 VL 131 IS 10 BP 2257 EP 2268 DI 10.1242/dev.01125 PG 12 WC Developmental Biology SC Developmental Biology GA 830MY UT WOS:000222127700005 PM 15102710 ER PT J AU Chen, YT Knezevic, V Ervin, V Hutson, R Ward, Y Mackem, S AF Chen, YT Knezevic, V Ervin, V Hutson, R Ward, Y Mackem, S TI Direct interaction with Hoxd proteins reverses Gli3-repressor function to promote digit formation downstream of Shh SO DEVELOPMENT LA English DT Article DE AP pattern; digit formation; limb development; hoxd genes; Gli3; sonic hedgehog; mouse ID CHICK LIMB BUD; SONIC-HEDGEHOG; GENE-EXPRESSION; GLI PROTEINS; IDENTITY; MICE; MISEXPRESSION; MUTATIONS; SKELETON; PATTERN AB Sonic hedgehog (Shh) signaling regulates both digit number and identity, but how different distinct digit types (identities) are specified remains unclear. Shh regulates digit formation largely by preventing cleavage of the GO transcription factor to a repressor form that shuts off expression of Shh target genes. The functionally redundant 5'Hoxd genes regulate digit pattern downstream of Shh and GO, through as yet unknown targets. Enforced expression of any of several 5'Hoxd genes causes polydactyly of different distinct digit types with posterior transformations in a Gli3(+) background, whereas, in GO null limbs, polydactylous digits are all similar, short and dysmorphic, even though endogenous 5'Hoxd genes are broadly misexpressed. We show that Hoxd12 interacts genetically and physically with Gli3, and can convert the GO repressor into an activator of Shh target genes. Several 5'Hoxd genes, expressed differentially across the limb bud, interact physically with GO. We propose that a varying [Gli3]:[total Hoxd] ratio across the limb bud leads to differential activation of GO target genes and contributes to the regulation of digit pattern. The resulting altered balance between 'effective' GO activating and repressing functions may also serve to extend the Shh activity gradient spatially or temporally. C1 NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Mackem, S (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10, Bethesda, MD 20892 USA. EM smack@helix.nih.gov NR 37 TC 82 Z9 85 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAY PY 2004 VL 131 IS 10 BP 2339 EP 2347 DI 10.1242/dev.01115 PG 9 WC Developmental Biology SC Developmental Biology GA 830MY UT WOS:000222127700012 PM 15102708 ER PT J AU Iezzi, S Di Padova, M Serra, C Caretti, G Simone, C Maklan, E Minetti, G Zhao, P Hoffman, EP Puri, PL Sartorelli, V AF Iezzi, S Di Padova, M Serra, C Caretti, G Simone, C Maklan, E Minetti, G Zhao, P Hoffman, EP Puri, PL Sartorelli, V TI Deacetylase inhibitors increase muscle cell size by promoting myoblast recruitment and fusion through induction of follistatin SO DEVELOPMENTAL CELL LA English DT Article ID SATELLITE CELLS; IN-VIVO; DIFFERENTIATION; EXPRESSION; MYOSTATIN; GROWTH; MICE; GENE; REGENERATION; MYOGENESIS AB Fusion of undifferentiated myoblasts into multinucleated myotubes is a prerequisite for developmental myogenesis and postnatal muscle growth. We report that deacetylase inhibitors favor the recruitment and fusion of myoblasts into preformed myotubes. Muscle-restricted expression of follistatin is induced by deacetylase inhibitors and mediates myoblast recruitment and fusion into myotubes through a pathway distinct from those utilized by either IGF-1 or IL-4. Blockade of follistatin expression by RNAi-mediated knockdown, functional inactivation with either neutralizing antibodies or the antagonist protein myostatin, render myoblasts refractory to HDAC inhibitors. Muscles from animals treated with the HDAC inhibitor trichostatin A display increased production of follistatin and enhanced expression of markers of regeneration following muscle injury. These data identify follistatin as a central mediator of the fusigenic effects exerted by deacetylase inhibitors on skeletal muscles and establish a rationale for their use to manipulate skeletal myogenesis and promote muscle regeneration. C1 NIAMS, Muscle Gene Express Grp, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. Fdn A Cesalpino Inst Cell Biol & Tissue Engn, Dulbecco Telethon Inst, Gene Express Lab, I-00128 Rome, Italy. Salk Inst Biol Studies, Peptide Biol Lab, La Jolla, CA 92093 USA. Childrens Natl Med Ctr, Res Ctr Genet Med, Washington, DC 20010 USA. RP Sartorelli, V (reprint author), NIAMS, Muscle Gene Express Grp, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. EM sartorev@mail.nih.gov OI DI PADOVA, Monica/0000-0003-3808-7159; SIMONE, Cristiano/0000-0002-2628-7658 FU Telethon [GFP01009] NR 40 TC 114 Z9 123 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD MAY PY 2004 VL 6 IS 5 BP 673 EP 684 DI 10.1016/S1534-5807(04)00107-8 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 834XB UT WOS:000222443100011 PM 15130492 ER PT J AU Ross, KE Cohen-Fix, O AF Ross, KE Cohen-Fix, O TI A role for the FEAR pathway in nuclear positioning during anaphase SO DEVELOPMENTAL CELL LA English DT Article ID SISTER-CHROMATID SEPARATION; SACCHAROMYCES-CEREVISIAE; BUDDING YEAST; MITOTIC EXIT; CELL-CYCLE; CDC14; MITOSIS; COMPLEX; PHOSPHATASE; CLEAVAGE AB In budding yeast, cells lacking separase function exit mitosis with an undivided nucleus localized to the daughter cell. Here we show that the inability to separate sister chromatids per se is not sufficient to cause the daughter preference. Rather, separase affects nuclear positioning as part of the Cdc14 early anaphase release (FEAR) pathway. The role of the FEAR pathway in nuclear positioning is exerted during anaphase and is not shared by the mitotic exit network. We find that the nuclear segregation defect in FEAR mutants does not stem from nonfunctional spindle poles or the absence of cytoplasmic microtubules. Instead, the concomitant inactivation of sister chromatid separation and the FEAR pathway uncovered a mother-directed force in anaphase that was previously masked by the elongating spindle. We propose that at anaphase onset, the FEAR pathway activates cytoplasmic microtubule-associated forces that facilitate chromosome segregation to the mother cell. C1 NIDDKD, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cohen-Fix, O (reprint author), NIDDKD, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. EM ornacf@helix.nih.gov NR 32 TC 48 Z9 49 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD MAY PY 2004 VL 6 IS 5 BP 729 EP 735 DI 10.1016/S1534-5807(04)00128-5 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 834XB UT WOS:000222443100016 PM 15130497 ER PT J AU Baier, LJ Hanson, RL AF Baier, LJ Hanson, RL TI Genetic studies of the etiology of type 2 diabetes in Pima Indians - Hunting for pieces to a complicated puzzle SO DIABETES LA English DT Article ID BODY-MASS INDEX; RECEPTOR SUBSTRATE-1 GENE; AUTOSOMAL GENOMIC SCAN; ACID-BINDING PROTEIN; SEGREGATION ANALYSIS; INSULIN-SECRETION; MAJOR-GENE; MEXICAN-AMERICANS; CROHNS-DISEASE; MELLITUS C1 NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. RP Baier, LJ (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. EM lbaier@phx.niddk.nih.gov RI Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 NR 54 TC 52 Z9 56 U1 2 U2 6 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2004 VL 53 IS 5 BP 1181 EP 1186 DI 10.2337/diabetes.53.5.1181 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817DD UT WOS:000221157300001 PM 15111484 ER PT J AU de Courten, BV Degawa-Yamauchi, M Considine, RV Tataranni, PA AF de Courten, BV Degawa-Yamauchi, M Considine, RV Tataranni, PA TI High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians SO DIABETES LA English DT Article ID GLUCOSE-METABOLISM; DIABETES-MELLITUS; SKELETAL-MUSCLE; EXPRESSION; OBESITY; TISSUE; ADIPONECTIN; RECEPTOR; PROTEIN; HUMANS AB Resistin is an adipokine with putative prodiabetogenic properties. Like other hormones secreted by adipose tissue, resistin is being investigated as a possible etiologic link between excessive adiposity and insulin resistance. Although there is growing evidence that circulating levels of this adipokine are proportional to the degree of adiposity, an effect on insulin resistance in humans remains unproven. To evaluate the relations among resistin, obesity, and insulin resistance, we measured fasting serum resistin levels in 113 nondiabetic (75-g oral glucose tolerance test) Pima Indians (ages 29 +/- 7 years, body fat 31 +/- 8%, resistin 3.7 +/- 1.1 ng/ml [means +/- SDI), who were characterized for body composition (assessed by hydrodensitometry or dual-energy X-ray absorptiometry), whole-body insulin sensitivity (M; assessed by hyperinsulinemic clamp), basal hepatic glucose output (BHGO) and hepatic glucose output during low-dosage insulin infusion of a hyperinsulinemic clamp (HGO; a measure of hepatic insulin resistance), and acute insulin secretory response (AIR; assessed by 25-g intravenous glucose tolerance test). Follow-up measurements of M, BHGO, HGO, and AIR were available for 34 subjects who had normal glucose tolerance at baseline and remained nondiabetic at follow-up. The average time to follow-up was 4.5 +/- 2.7 years. In cross-sectional analyses, serum resistin levels were positively associated with percent body fat (r = 0.37, P = 0.0001) and 2-h glucose (r = 0.19, P = 0.04), respectively. Serum resistin levels were not associated with fasting glucose and insulin levels, M, BHGO, HGO, or AIR (r = 0.17, 0.12, -0.13, -0.06, -0.03, and -0.04, respectively; all P > 0.05). After adjusting for percent body fat, there was no association between serum resistin levels and 2-h glucose (r = 0.06, P = 0.6). In prospective analyses, high serum resistin levels at baseline were not associated with a decline in M (r = -0.1, P > 0.5). Resistin levels were, however, associated with increases in percent body fat, fasting plasma insulin, and HGO (r = 0.34, 0.36, and 0.37; all P < 0.05) after adjusting for sex, age, and time to follow-up. After additional adjustment for the change in percent body fat, there was no association between baseline serum resistin levels and changes in plasma insulin or HGO (r = 0.26 and 0.23; both P > 0.1). We conclude that in Pima Indians, like other human populations, circulating resistin levels are proportional to the degree of adiposity, but not the degree of insulin resistance. We unexpectedly found that high serum resistin levels do predict future increases in percent body fat. Our data suggest that resistin promotes obesity but not obesity-associated insulin resistance in humans. C1 NIDDKD, Clin Diabet & Nutr Sect, NIH, DHHS, Phoenix, AZ 85016 USA. Indiana Univ, Sch Med, Dept Med, Div Endocrinol & Metab, Indianapolis, IN 46204 USA. RP Tataranni, PA (reprint author), NIDDKD, Clin Diabet & Nutr Sect, NIH, DHHS, 4212 N 16Th St,Rm 541, Phoenix, AZ 85016 USA. EM antoniot@mail.nih.gov NR 29 TC 96 Z9 99 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2004 VL 53 IS 5 BP 1279 EP 1284 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817DD UT WOS:000221157300014 PM 15111497 ER PT J AU Fox, CS Heard-Costa, NL Wilson, PWF Levy, D D'Agostino, RB Atwood, LD AF Fox, CS Heard-Costa, NL Wilson, PWF Levy, D D'Agostino, RB Atwood, LD TI Genome-wide linkage to chromosome 6 for waist circumference in the Framingham Heart Study SO DIABETES LA English DT Article ID BODY-MASS INDEX; DEPENDENT DIABETES-MELLITUS; TO-HIP RATIO; FAT DISTRIBUTION; METABOLIC SYNDROME; OBESITY; FAMILY; HEALTH; RISK; SCAN AB While several loci for BMI have been identified, it is not known whether genes underlie the process of regional fat deposition. We sought to test whether waist circumference, a measure of central adiposity, contains a genetic component. Variance components linkage analysis was performed on 330 families from the Framingham Heart Study original and offspring cohorts, using a 10-cM genome-wide linkage analysis. Overall, 2,086 subjects (51% women), mean age 48 years, were available for analysis. The overall heritability of waist circumference was 0.41. The maximum logarithm of odds (LOD) score in the full dataset was 3.3 on chromosome 6 at marker D6S1009; when subjects were limited to those aged < 60 years, the peak LOD score was 3.7 at the same location. Substantial evidence exists for linkage to waist circumference, a measure of central adiposity. Potential candidate genes include ESR1, OPRM1, and NMBR. Further research is necessary to understand the genes involved in central adiposity. C1 NHLBI, Framingham Heart Study, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02215 USA. Boston Univ, Stat & Consulting Unit, Boston, MA 02215 USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov FU NHLBI NIH HHS [N01 HC 25195] NR 25 TC 32 Z9 34 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAY PY 2004 VL 53 IS 5 BP 1399 EP 1402 DI 10.2337/diabetes.53.5.1399 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817DD UT WOS:000221157300029 PM 15111512 ER PT J AU Pavkov, ME Sievers, ML Knowler, WC Bennett, PH Nelson, RG AF Pavkov, ME Sievers, ML Knowler, WC Bennett, PH Nelson, RG TI An explanation for the increase in heart disease mortality rates in diabetic Pima Indians - Effect of renal replacement therapy SO DIABETES CARE LA English DT Article ID AMERICAN-INDIANS; MELLITUS; PROTEINURIA; EPIDEMIC; TRENDS; DEATH AB OBJECTIVE - Diabetic nephropathy (DN) became the leading cause of death in diabetic Pima Indians in the 1970s, but was superseded by ischemic heart disease (IHD) in the 1980s. This study tests the hypothesis that the rise in the IHD death rate between 1965 and 1998 is attributable to access to renal replacement therapy (RRT). RESEARCH DESIGN AND METHODS - Underlying causes of death were determined among 2,095 diabetic Pima Indians greater than or equal to35 years old during four 8.5-year time intervals. To assess the effect of access to RRT on IHD death rates, trends were reexamined after Subjects receiving RRT were classified Lis if they had cited of DN. RESULTS - During a median follow-up of 11.1 years (range 0.01-34), 818 subjects died, The age- and sex-adjusted DN death rate decreased over the 34-year study (P = 0.05), whereas the IHD death rate increased from 3.3 deaths/1,000 person-years (05% CI 1.4-5.2) to 6.3 deaths/1,000 person-years (95% CI 4.5-8.0; P = 0.03). After 151 subjects on RRT were reclassified as if they had died of DN, the death rate for DN increased from 4.8 deaths/1,000 person-years (95% CI 2.6-7) to 11.3 deaths/1,000 person-years (95% CI 9-13.6: P = 0.0007), whereas the increase in the IHD death rate disappeared (P = 0.57). CONCLUSIONS - The incidence rate of renal failure attributable to diabetes has increased rapidly over the past 34 years in Pima Indians. IHD has emerged as the leading cause of death due largely to the availability of RRT and to changes in the pattern of death among those with DN. C1 NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85014 USA. RP Pavkov, ME (reprint author), NIDDKD, Phoenix Epidemiol & Clin Res Branch, NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM mpavkov@phx.niddk.nih.gov RI Nelson, Robert/B-1470-2012 NR 25 TC 15 Z9 16 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2004 VL 27 IS 5 BP 1132 EP 1136 DI 10.2337/diacare.27.5.1132 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817DB UT WOS:000221157100020 PM 15111533 ER PT J AU Franks, PW Ekelund, U Brage, S Wong, MY Wareham, NJ AF Franks, PW Ekelund, U Brage, S Wong, MY Wareham, NJ TI Does the association of habitual physical activity with the metabolic syndrome differ by level of cardiorespiratory fitness? SO DIABETES CARE LA English DT Article ID MIDDLE-AGED MEN; ENERGY-EXPENDITURE; DIABETES-MELLITUS; LEISURE-TIME; HERITAGE FAMILY; EUROPEAN-UNION; HUMAN GENE; WEIGHT; PERFORMANCE; CALORIMETRY AB OBJECTIVE - Cardiovascular fitness (VO2max) and physical activity arc both related to risk of Metabolic disease. It is unclear, however, whether the metabolic effects of sedentary living are the same in fit and unfit individuals. The purpose of this study was, therefore, to describe the association between physical activity and the metabolic syndrome and to test whether fitness level modifies this relationship. RESEARCH DESIGN AND METHODS - physical activity Was measured objectively using individually calibrated heart rate against energy expenditure. VO2max was predicted front a submaximal exercise stress test. Fat mass and fat-free mass (FFM) were calculated using impedance biometry. A metabolic syndrome score was computed by summing the standardized values for obesity, hypertension, hyperglycemia, insulin resistance, hypertriglyceridemia, and the inverse level of HDL cholesterol and was expressed as a continuously distributed Outcome. To correct for exposure measurement cri-or, a random subsample (22% of cohort) re-attended for three repeat measurements in the year following the first assessment. RESULTS - The relationship of VO2max (ml O-2 (.) kg(FFM)(-1) (.) min(-1)) and the metabolic syndrome score was of borderline significance after adjusting for age, sex, physical activity, and measurement error (beta = -0.58, P = 0.06). The magnitude of the association between physical activity (kJ (.) d(-1) (.) kg(FFM)(-1)) and the metabolic syndrome was more than three tunes greater than for VO(2ma)x (standardized beta = - 1,83, P = 0.0042). VO2max however, modified the relationship between physical activity energy expenditure and metabolic syndrome (P = 0 036). CONCLUSIONS - This study demonstrates a Strong inverse association between physical activity and metabolic syndrome, an association that is much steeper in unfit individuals. Thus, prevention of metabolic disease may be most effective In the subset of unfit inactive people. C1 MRC, Epidemiol Unit, Cambridge, England. Hong Kong Univ Sci & Technol, Dept Math, Hong Kong, Hong Kong, Peoples R China. RP Franks, PW (reprint author), NIDDK, Diabet & Arthrit Epidemiol Sect, NIH, 4881 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM pfranks@niddk.nih.gov RI Ekelund, Ulf/A-1046-2008; Brage, Soren/C-6415-2013; Loureiro, Nuno/I-6400-2012 OI Brage, Soren/0000-0002-1265-7355; Loureiro, Nuno/0000-0002-1166-3219 NR 48 TC 110 Z9 115 U1 1 U2 8 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2004 VL 27 IS 5 BP 1187 EP 1193 DI 10.2337/diacare.27.5.1187 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817DB UT WOS:000221157100030 PM 15111543 ER PT J AU Karne, RJ Chen, H Quon, MJ AF Karne, RJ Chen, H Quon, MJ TI Diagnosing insulin resistance by simple quantitative methods in subjects with normal glucose metabolism SO DIABETES CARE LA English DT Letter ID SENSITIVITY CHECK INDEX; HOMEOSTASIS MODEL ASSESSMENT; MINIMAL-MODEL; HUMANS; QUICKI C1 Natl Ctr Complementary & Alternat Med, Diabet Unit, NIH, Bethesda, MD 20892 USA. RP Quon, MJ (reprint author), Natl Ctr Complementary & Alternat Med, 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 NR 17 TC 2 Z9 2 U1 0 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2004 VL 27 IS 5 BP 1247 EP 1248 DI 10.2337/diacare.27.5.1247-a PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817DB UT WOS:000221157100059 PM 15111572 ER PT J AU Hirshberg, B Rother, KI Digon, BJ Harlan, DM AF Hirshberg, B Rother, KI Digon, BJ Harlan, DM TI Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression SO DIABETES CARE LA English DT Letter C1 NIDDKD, Islet & Autoimmun Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Harlan, DM (reprint author), NIDDKD, Islet & Autoimmun Branch, Dept Hlth & Human Serv, NIH, Bldg 10,Room 8N307, Bethesda, MD 20892 USA. EM davidmh@intra.niddk.nih.gov NR 5 TC 2 Z9 2 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAY PY 2004 VL 27 IS 5 BP 1250 EP 1251 DI 10.2337/diacare.27.5.1250 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817DB UT WOS:000221157100062 ER PT J AU Paciotti, GF Myer, L Weinreich, D Goia, D Pavel, N McLaughlin, RE Tamarkin, L AF Paciotti, GF Myer, L Weinreich, D Goia, D Pavel, N McLaughlin, RE Tamarkin, L TI Colloidal gold: A novel nanoparticle vector for tumor directed drug delivery SO DRUG DELIVERY LA English DT Article DE colloidal gold; drug delivery; tumor necrosis factor ID INTERSTITIAL FLUID PRESSURE; NECROSIS-FACTOR-ALPHA; I CLINICAL-TRIAL; PHASE-I; SOLID TUMORS; PERFUSION; LIPOSOMES; RAT; MELPHALAN; MELANOMA AB Colloidal gold, a sol comprised of nanoparticles of Au-0, has been used as a therapeutic for the treatment of cancer as well as an indicator for immunodiagnostics. However, the use of these gold nanoparticles for in vivo drug delivery has never been described. This communication outlines the development of a colloidal gold (cAu) nanoparticle vector that targets the delivery of tumor necrosis factor (TNF) to a solid tumor growing in mice. The optimal vector, designated PT-cAu-TNF, consists of molecules of thiol-derivatized PEG ( PT) and recombinant human TNF that are directly bound onto the surface of the gold nanoparticles. Following intravenous administration, PT-cAu-TNF rapidly accumulates in MC-38 colon carcinoma tumors and shows little to no accumulation in the livers, spleens (i.e., the RES) or other healthy organs of the animals. The tumor accumulation was evidenced by a marked change in the color of the tumor as it acquired the bright red/purple color of the colloidal gold sol and was coincident with the active and tumor-specific sequestration of TNF. Finally, PT-cAu-TNF was less toxic and more effective in reducing tumor burden than native TNF since maximal antitumor responses were achieved at lower doses of drug. C1 CytImmune Sci Inc, College Pk, MD 20740 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. OMG dmc2 LP, S Plainfield, NJ USA. Ferro Corp, S Plainfield, NJ USA. RP Paciotti, GF (reprint author), CytImmune Sci Inc, 8075 Greenmead Dr, College Pk, MD 20740 USA. EM gpaciotti@cytommune.com NR 42 TC 642 Z9 660 U1 27 U2 266 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1071-7544 J9 DRUG DELIV JI Drug Deliv. PD MAY-JUN PY 2004 VL 11 IS 3 BP 169 EP 183 DI 10.1080/10717540490433895 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 826AR UT WOS:000221801700002 PM 15204636 ER PT J AU Lukashey, D Ohta, A Sitkovsky, M AF Lukashey, D Ohta, A Sitkovsky, M TI Targeting hypoxia-A(2A) adenosine receptor-mediated mechanisms of tissue protection SO DRUG DISCOVERY TODAY LA English DT Review ID FUNCTION IN-VITRO; PROTEIN-KINASE; A(2A) RECEPTOR; LYMPHOCYTE DEVELOPMENT; DEAMINASE DEFICIENCY; PURINERGIC RECEPTOR; HISTAMINE-RELEASE; EXTRACELLULAR ATP; T-LYMPHOCYTES; CYCLIC-AMP AB Despite inflammation having beneficial effects, the action of toxic proinflammatory molecules can result in excessive tissue damage that subsequently contributes to the pathogenesis of many major diseases. The development of novel drugs and therapeutic strategies for the treatment of inflammation requires an improved understanding of the molecular mechanisms that terminate inflammation. The physiological hypothesis proposes that excessive levels of inflammatory tissue damage result in local hypoxia and accumulation of extracellular adenosine. The A(2A) adenosine receptor and hypoxia-inducible factor play important roles in the attenuation of proinflammatory processes in a delayed, negative-feedback manner and thus protect organs from excessive damage. Targeting individual stages of the hypoxia-A(2A) receptor signaling pathway represents an attractive strategy for the modulation of inflammation. C1 NIAID, Biochem & Immunopharmacol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Lukashey, D (reprint author), NIAID, Biochem & Immunopharmacol Sect, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mvsitkov@helix.nih.gov NR 71 TC 17 Z9 17 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD MAY 1 PY 2004 VL 9 IS 9 BP 403 EP 409 AR PII S1359-6446(04)03044-2 DI 10.1016/S1359-6446(04)03044-2 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 816IQ UT WOS:000221104000009 PM 15081957 ER PT J AU Holleran, JL Fourcade, J Egorin, MJ Eiseman, JL Parise, RA Musser, SM White, KD Covey, JM Forrest, GL Pan, SS AF Holleran, JL Fourcade, J Egorin, MJ Eiseman, JL Parise, RA Musser, SM White, KD Covey, JM Forrest, GL Pan, SS TI In vitro metabolism of the phosphatidylinositol 3-kinase inhibitor, wortmannin, by carbonyl reductase SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID PHOSPHOINOSITIDE 3-KINASE; ANTICANCER AGENTS; KINASE INHIBITORS; LIQUID-CHROMATOGRAPHY; SIGNAL-TRANSDUCTION; BINDING PROTEIN; CANCER; TARGETS; LIPIDS AB The phosphatidylinositol 3-kinase inhibitor, wortmannin, is extensively used in molecular signaling studies and has been proposed as a potential antineoplastic agent. The failure to detect wortmannin in mouse plasma after i.v. administration prompted in vitro studies of wortmannin metabolism. Wortmannin was incubated with mouse tissue homogenates, homogenate fractions, or purified, recombinant human carbonyl reductase in the presence of specified cofactors and inhibitors. Reaction products were characterized and quantified with liquid chromatography (LC)/mass spectrometry. Reaction rates were characterized using Michaelis-Menten kinetics. Wortmannin was metabolized to a material 2 atomic mass units greater than wortmannin. Liver homogenate had the highest metabolic activity. Some metabolism occurred in kidney and lung homogenates. Very little metabolism occurred in brain or red blood cell homogenates. Liver S9 fraction and cytosol metabolized wortmannin in the presence of NADPH and, to a much lesser extent, in the presence of NADH. Microsomal metabolism of wortmannin was minimal. Purified, recombinant human carbonyl reductase metabolized wortmannin. Quercetin, a carbonyl reductase inhibitor, greatly decreased wortmannin metabolism by S9, cytosol, and carbonyl reductase. The K-M for wortmannin metabolism by purified, recombinant human carbonyl reductase was 119+/-9 muM, and the V-max was 58+/-9 nmol/min/mg of protein. LC-tandem mass spectrometry spectra indicated that carbonyl reductase metabolized wortmannin to 17-OH-wortmannin. Wortmannin reduction by carbonyl reductase may partly explain why wortmannin is not detected in plasma after being administered to mice. Metabolism of wortmannin to 17-OH-wortmannin has mechanistic, and possibly toxicologic, implications because 17-OH-wortmannin is 10-fold more potent an inhibitor of phosphatidylinositol 3-kinase than is wortmannin. C1 Univ Pittsburgh, Inst Canc, Mol Therapeut Drug Discovery Program, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. US FDA, Instrumentat & Biophys Branch, Ctr Food Safety & Appl Nutr, College Pk, MD USA. NCI, Toxicol & Pharmacol Branch, DTP, Bethesda, MD 20892 USA. City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. RP Egorin, MJ (reprint author), Univ Pittsburgh, Inst Canc, Mol Therapeut Drug Discovery Program, Room G27E,Hillman Res Pavil,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM egorinmj@msx.upmc.edu FU NCI NIH HHS [2P30 CA 47904, N01 CM 07106] NR 38 TC 11 Z9 11 U1 2 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD MAY 1 PY 2004 VL 32 IS 5 BP 490 EP 496 DI 10.1124/dmd.32.5.490 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 814BZ UT WOS:000220951500004 PM 15100170 ER PT J AU Yu, AM Idle, JR Gonzalez, FJ AF Yu, AM Idle, JR Gonzalez, FJ TI Polymorphic cytochrome p450 2D6: Humanized mouse model and endogenous substrates SO DRUG METABOLISM REVIEWS LA English DT Article; Proceedings Paper CT 12th North American ISSX Meeting CY OCT 12-16, 2003 CL Providence, RI DE cytochrome p450; CYP2D6; polymorphism; humanized mice; drug metabolism; pharmacokinetics; debrisoquine; dextromethorphan; sparteine; Tryptamines; beta-carbolines; genotype; phenotype; Parkinson's disease ID DEXTROMETHORPHAN O-DEMETHYLATION; HUMAN-LIVER-MICROSOMES; VARIANT CYP2D6 ALLELE; CATALYZING DEBRISOQUINE 4-HYDROXYLATION; POOR METABOLIZER PHENOTYPE; N-DEALKYLATION REACTIONS; COMMON GENETIC-DEFECT; HUMAN PINEAL-GLAND; GUINEA-PIG ILEUM; HUMAN CELL-LINE AB Cytochrome P450 2D6 (CYP2D6) is the first well-characterized polymorphic phase I drug-metabolizing enzyme, and more than 80 allelic variants have been identified for the CYP2D6 gene, located on human chromosome 22q13.1. Human debrisoquine and sparteine metabolism is subdivided into two principal phenotypes-extensive metabolizer and poor metabolizer-that arise from variant CYP2D6 genotypes. It has been estimated that CYP2D6 is involved in the metabolism and disposition of more than 20% of prescribed drugs, and most of them act in the central nervous system or on the heart. These drug substrates are characterized as organic bases containing one nitrogen atom with a distance about 5, 7, or 10 Angstrom from the oxidation site. Aspartic acid 301 and glutamic acid 216 were determined as the key acidic residues for substrate-enzyme binding through electrostatic interactions. CYP2D6 transgenic mice, generated using a lambda phage clone containing the complete wildtype CYP2D6 gene, exhibits enhanced metabolism and disposition of debrisoquine. This transgenic mouse line and its wild-type control are models for human extensive metabolizers and poor metabolizers, respectively, and would have broad application in the study of CYP2D6 polymorphism in drug discovery and development, and in clinical practice toward individualized drug therapy. Endogenous 5-methoxyindole-thylamines derived from 5-hydroxytryptamine were identified as high-affinity substrates of CYP2D6 that catalyzes their O-demethylations with high enzymatic capacity and specificity. Thus, polymorphic CYP2D6 may play an important role in the interconversions of these psychoactive tryptamines, including a crucial step in a serotonin-melatonin cycle. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Bern, Inst Clin Pharmacol, Bern, Switzerland. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 3106,37 Convent Dr, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov NR 212 TC 83 Z9 85 U1 2 U2 7 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 0360-2532 J9 DRUG METAB REV JI Drug Metab. Rev. PD MAY PY 2004 VL 36 IS 2 SI SI BP 243 EP 277 DI 10.1081/DMR-120034000 PG 35 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 832BE UT WOS:000222241400005 PM 15237854 ER PT J AU Ma, W Li, BS Zhang, L Pant, HC AF Ma, W Li, BS Zhang, L Pant, HC TI Signaling cascades implicated in muscarinic regulation of proliferation of neural stem and progenitor cells SO DRUG NEWS & PERSPECTIVES LA English DT Article ID PROTEIN-KINASE-C; RECEPTOR-INDUCED PROLIFERATION; GLYCOGEN-SYNTHASE KINASE-3; INTEGRIN-LINKED KINASE; CENTRAL-NERVOUS-SYSTEM; MEDIATED DNA-SYNTHESIS; BETA-GAMMA-SUBUNITS; GROWTH-FACTOR; COUPLED RECEPTORS; ASTROGLIAL CELLS AB Muscarinic acetylcholine receptors (mAChRs) belong to the G-protein-coupled receptor superfamily that transduces signals through multiple intracellular signaling cascades to regulate a wide variety of physiological responses. Recently, it has been discovered that subtypes of mAChRs are expressed in proliferative neuroepithelial cells of the ventricular zone and in basic fibroblast growth factor-expanded neural stem and progenitor cell cultures. Activation of the mAChRs by ACh or its analogue carbachol leads to increased DNA synthesis and neurogenesis. The mitogenic effects of muscarinic agonists are likely mediated via mAChR-activated multisignaling pathways. The exact intracellular mechanisms underlying mAChR-modulated DNA synthesis and neurogenesis are not fully understood. However, several pathways through Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C, c-Src and Ca2+ signaling have been shown to play roles in this dynamic process. These novel signaling cascades may improve our understanding of the intracellular mechanisms underlying mAChR-stimulated neural progenitor proliferation and provide insights for therapeutic drug development. (C) 2004 Prous Science. All rights reserved. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. NIMH, Lab Behav & Endocrinol, NIH, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bldg 36,Room 4D20,900 Rockville Pike, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov NR 68 TC 23 Z9 25 U1 0 U2 1 PU PROUS SCIENCE, SA PI BARCELONA PA PO BOX 540, PROVENZA 388, 08025 BARCELONA, SPAIN SN 0214-0934 J9 DRUG NEWS PERSPECT JI Drug News Perspect. PD MAY PY 2004 VL 17 IS 4 BP 258 EP 266 DI 10.1358/dnp.2004.17.4.829053 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 837RB UT WOS:000222652100009 PM 15334175 ER PT J AU Veenstra, TD Conrads, TP Issaq, HJ AF Veenstra, TD Conrads, TP Issaq, HJ TI Commentary: What to do with "one-hit wonders"? SO ELECTROPHORESIS LA English DT Editorial Material ID MASS-SPECTROMETRY; PROTEOME C1 Natl Canc Inst, Lab Proteom & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), Natl Canc Inst, Lab Proteom & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 5 TC 60 Z9 60 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD MAY PY 2004 VL 25 IS 9 SI SI BP 1278 EP 1279 DI 10.1002/elps.200490007 PG 2 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 825DB UT WOS:000221735100014 PM 15174049 ER PT J AU Zhou, M Lucas, DA Chan, KC Issaq, HJ Petricoin, EF Liotta, LA Veenstra, TD Conrads, TR AF Zhou, M Lucas, DA Chan, KC Issaq, HJ Petricoin, EF Liotta, LA Veenstra, TD Conrads, TR TI An investigation into the human serum "interactome" SO ELECTROPHORESIS LA English DT Article; Proceedings Paper CT 14th Annual Frederick Conference on Capillary Electrophoresis/Proteomics CY NOV 03-04, 2003 CL NCI, Frederick, MD HO NCI DE albumin; biomarker; human serum; proteome; surface-enhanced laser desorption/ionization ID PROSTATE-SPECIFIC ANTIGEN; HUMAN PLASMA PROTEOME; PANCREATIC-CANCER; OVARIAN-CANCER; DOWN-SYNDROME; EXPRESSION; IDENTIFICATION; PATTERNS; PROTEINS; BINDING AB The protein content of human serum is composed of a millieu of proteins from almost every type of cell and tissue within the body. The serum proteome has been shown to contain information that directly reflects pathophysiological states and represents an invaluable source of diagnostic information for a variety of different diseases. Unfortunately, the dynamic range of protein abundance, ranging from much greater than mg/mL level to much less than pg/mL level, renders complete characterization of this proteome nearly impossible with current analytical methods. To study low-abundance proteins, which have potential value for clinical diagnosis, the high-abundant species, such as immunoglobulins and albumin, are generally eliminated as the first step in many analytical protocols. This step, however, is hypothesized to concomitantly remove proteins/peptides associated with the high-abundant proteins targeted for depletion. In this study, immunoprecipitation was combined with microcapillary reversed-phase liquid chromatography (muRPLC) coupled on-line with tandem mass spectrometry (MS/MS) to investigate the low-molecular-weight proteins/peptides that associate with the most abundant species in serum. By this targeted isolation of select highly abundant serum proteins, the associated proteins/peptides can be enriched and effectively identified by muRPLC-MS/MS. Among the 210 proteins identified, 73% and 67% were not found in previous studies of the low-molecular-weight or whole-serum proteome, respectively. C1 SAIC Frederick Inc, Natl Canc Inst, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. US FDA, Ctr Biol Evaluat & Res, Natl Canc Inst, Clin Proteom Program, Bethesda, MD 20014 USA. NCI, Ctr Canc Res, Pathol Lab, Bethesda, MD 20892 USA. RP Conrads, TR (reprint author), SAIC Frederick Inc, Natl Canc Inst, Lab Proteom & Analyt Technol, POB B, Frederick, MD 21702 USA. EM Conrads@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 48 TC 222 Z9 229 U1 2 U2 17 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD MAY PY 2004 VL 25 IS 9 SI SI BP 1289 EP 1298 DI 10.1002/elps.200405866 PG 10 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 825DB UT WOS:000221735100016 PM 15174051 ER PT J AU Blonder, J Hale, ML Lucas, DA Schaefer, CF Yu, LR Conrads, TR Issaq, HJ Stiles, BG Veenstra, TD AF Blonder, J Hale, ML Lucas, DA Schaefer, CF Yu, LR Conrads, TR Issaq, HJ Stiles, BG Veenstra, TD TI Proteomic analysis of detergent-resistant membrane rafts SO ELECTROPHORESIS LA English DT Article; Proceedings Paper CT 14th Annual Frederick Conference on Capillary Electrophoresis/Proteomics CY NOV 03-04, 2003 CL NCI, Frederick, MD HO NCI DE detergent-resistant membrane rafts; gas-phase fractionation; membrane proteomics; reversed-phase liquid chromatography; vero cells ID B-CELL RECEPTOR; LIPID RAFTS; MASS-SPECTROMETRY; GLUCOSE-TRANSPORTER; TARGETING PROTEINS; CAVEOLAE MEMBRANE; STOMATIN; DOMAINS; IDENTIFICATION; PALMITOYLATION AB A combined, detergent- and organic solvent-based proteomic method for the analysis of detergent-resistant membrane rafts (DRMR) is described. These specialized domains of the plasma membrane contain a distinctive and dynamic protein and/or lipid complement, which can be isolated from most mammalian cells. Lipid rafts are predominantly involved in signal transduction and adapted to mediate and produce different cellular responses. To facilitate a better understanding of their biology and role, DRMR were isolated from Vero cells as a Triton X-100 insoluble fraction. After detergent removal, sonication in 60% buffered methanol was used to extract, solubilize and tryptically digest the resulting protein complement. The peptide digestate was analyzed by microcapillary reversed-phase liquid chromatography-tandem mass spectrometry. Gas-phase fractionation in the mass-to-charge range was employed to broaden the selection of precursor ions and increase the number of identifications in an effort to detect less abundant proteins. A total of 380 proteins were identified including all known lipid raft markers. A total of 91 (24%) proteins were classified as integral alpha-helical membrane proteins, of which 51 (56%) were predicted to have multiple transmembrane domains. C1 NCI, SAIC Frederick, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. USA, Med Res Inst Infect Dis, Dept Immunol & Mol Biol, Toxinol Div, Frederick, MD USA. NCI, Ctr Bioinformat, Bethesda, MD 20892 USA. RP Veenstra, TD (reprint author), NCI, SAIC Frederick, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-2400] NR 48 TC 69 Z9 76 U1 1 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD MAY PY 2004 VL 25 IS 9 SI SI BP 1307 EP 1318 DI 10.1002/elps.200405891 PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 825DB UT WOS:000221735100018 PM 15174053 ER PT J AU Conrads, KA Yu, LR Lucas, DA Zhou, M Chan, KC Simpson, KA Schaefer, CF Issaq, HJ Veenstra, TD Beck, GR Conrads, TP AF Conrads, KA Yu, LR Lucas, DA Zhou, M Chan, KC Simpson, KA Schaefer, CF Issaq, HJ Veenstra, TD Beck, GR Conrads, TP TI Quantitative proteomic analysis of inorganic phosphate-induced murine MC3T3-E1 osteoblast cells SO ELECTROPHORESIS LA English DT Article; Proceedings Paper CT 14th Annual Frederick Conference on Capillary Electrophoresis/Proteomics CY NOV 03-04, 2003 CL NCI, Frederick, MD HO NCI DE cleavable isotope-coded affinity tag; inorganic phosphate; MC3T3-E1 cells; osteoblast; proteomics ID CODED AFFINITY TAGS; BETA-GLYCEROPHOSPHATE; PROTEIN; IDENTIFICATION; MINERALIZATION; EXPRESSION; INVITRO; DIFFERENTIATION; CALCIFICATION; ENRICHMENT AB Cleavable isotope-coded affinity tag (cICAT) reagents were utilized to identify and. quantitate protein expression differences in control and inorganic phosphate-treated murine MC3T3-E1 osteoblast cells. Proteins extracted from control and treated cells were labeled with the light and heavy isotopic versions of cICAT reagents, respectively. The cICAT-labeled samples were combined, proteolytically digested, and the cICAT-derivatized peptides isolated using immobilized avidin chromatography. The cICAT-labeled peptides were resolved into 96 fractions by strong cation-exchange (SCX) liquid chromatography (LC). Analysis of the SCX-LC cICAT peptide fractions by microcapillary reversed-phase LC-tandem mass spectrometry resulted in the identification and quantitation of 7227 unique peptides corresponding to 2501 proteins, or roughly 9% of the proteins currently predicted to be encoded by the mouse genome. A false positive analysis indicated a 98% confidence in the peptide identifications. To corroborate changes in abundance measured by cICAT with those detectable in traditionally prepared cell lysate, we chose to analyze cyclin D1. Cyclin D1 has been previously identified as a phosphate-responsive gene and was likewise identified as a phosphate-responsive protein in the current analysis. The 1.76-fold increase in abundance in cyclin D1 determined from cICAT corresponds well with the 2.41 -fold increase as determined by Western blotting. These results demonstrate that quantitative proteomics is capable of providing a quantitative view of thousands of proteins in mammalian cells within a defined set of experiments. C1 NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD 21701 USA. NCI, Ctr Canc Res, Lab Canc Prevent, Frederick, MD 21701 USA. NCI, Ctr Bioinformat, Bethesda, MD 20892 USA. RP Conrads, TP (reprint author), NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, POB B, Frederick, MD 21701 USA. EM gbeck@ncifcrf.gov; conrads@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400, CA84573] NR 29 TC 27 Z9 29 U1 0 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD MAY PY 2004 VL 25 IS 9 SI SI BP 1342 EP 1352 DI 10.1002/elps.200405892 PG 11 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 825DB UT WOS:000221735100022 PM 15174057 ER PT J AU McDuffie, JR Yanovski, JA AF McDuffie, JR Yanovski, JA TI Treatment of childhood and adolescent obesity SO ENDOCRINOLOGIST LA English DT Article DE obesity; weight loss; adolescence; childhood; treatment ID GASTRIC BYPASS-SURGERY; MORBID-OBESITY; PEDIATRIC OBESITY; FOLLOW-UP; CHILDREN; METFORMIN; ORLISTAT; EFFICACY; PROGRAM; GLUCOSE AB Early intervention is crucial in the treatment of childhood and adolescent obesity. The most effective first intervention is referral to a comprehensive conventional treatment program. If conventional treatment fails, then aggressive treatments could be considered. There is no conclusive evidence that protein-sparing modified fasts (PSMFs) produce significant, long-term weight loss, but selected patients requiring short-term, rapid weight loss could benefit from a PSMF. Although a few published trials on pharmaceutical agents are promising, only cautious optimism is warranted as a result of the lack of long-term, randomized, double-blind, placebo-controlled trials and the significant side effects that accompany each of the available agents. Bariatric surgery is the only treatment of which there is any evidence of significant, long-lasting weight loss in severely overweight adolescents. However, such surgery can cause substantial morbidity. Promotion of physical activity and of appropriate portion sizes can help contain the pediatric obesity epidemic while we await the development of new therapeutic approaches. C1 NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. US PHS, Washington, DC USA. RP McDuffie, JR (reprint author), Sch Publ Hlth, Dept Nutr, 800 Eastowne Dr,Suite 100, Chapel Hill, NC 27514 USA. EM mcduffj@unc.edu OI Yanovski, Jack/0000-0001-8542-1637 NR 27 TC 2 Z9 2 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-2144 J9 ENDOCRINOLOGIST JI Endocrinologist PD MAY-JUN PY 2004 VL 14 IS 3 BP 138 EP 143 DI 10.1097/01.ten.0000127925.63097.f7 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 823CK UT WOS:000221587100007 ER PT J AU Leschek, EW AF Leschek, EW TI Familial male-limited precocious puberty SO ENDOCRINOLOGIST LA English DT Article DE precocious puberty; testotoxicosis; FMPP ID LUTEINIZING-HORMONE RECEPTOR; SPIRONOLACTONE; KETOCONAZOLE; TESTOLACTONE; TESTOTOXICOSIS; DESLORELIN; THERAPY AB Familial male-limited precocious puberty (FMPP) is an autosomal-dominant form of gonadotropin-independent precocious puberty resulting from a heterozygous activating mutation in the gene encoding the luteinizing hormone (LH) receptor. Affected males usually show evidence of virilization and accelerated linear growth by 1 to 3 years of age. Untreated, affected males experience premature epiphyseal fusion and compromised adult height. Establishing the diagnosis of FMPP is straightforward when a positive family history is present. In the absence of a positive family history, mutation analysis of the LH receptor can be performed once other etiologies of precocious puberty have been excluded. There are 2 primary treatment approaches to FMPP. The first is oral administration of ketoconazole to block sex steroid synthesis. This approach suppresses puberty until the addition of GnRH analog is necessary for suppression of secondary GnRH-dependent precocious puberty. Occasionally, serious close-independent hepatotoxicity results from ketoconazole therapy. The second treatment approach involves a combination of spironolactone and testolactone to block androgen effect and estrogen synthesis. Again, addition of GnRH analog is necessary once secondary GnRH-dependent puberty is present. Long-term treatment with spironolactone, testolactone, and GnRH analog normalizes rate of growth and bone maturation and improves adult height in boys with FMPP. C1 NIDDKD, Type 1 Diabet TrialNet, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. RP Leschek, EW (reprint author), NIDDKD, Type 1 Diabet TrialNet, Div Diabet Endocrinol & Metab Dis, NIH, 6707 Democracy Blvd,Room 603,MSC 5460, Bethesda, MD 20892 USA. EM LeschekE@extra.niddk.nih.gov NR 10 TC 10 Z9 11 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-2144 J9 ENDOCRINOLOGIST JI Endocrinologist PD MAY-JUN PY 2004 VL 14 IS 3 BP 148 EP 151 DI 10.1097/01.ten.0000127927.01216.90 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 823CK UT WOS:000221587100009 ER PT J AU Angeloni, SV Glynn, N Ambrosini, G Garant, MJ Higley, JD Suomi, S Hansen, BC AF Angeloni, SV Glynn, N Ambrosini, G Garant, MJ Higley, JD Suomi, S Hansen, BC TI Characterization of the rhesus monkey ghrelin gene and factors influencing ghrelin gene expression and fasting plasma levels SO ENDOCRINOLOGY LA English DT Article ID GASTRIC BYPASS-SURGERY; AGING-RELATED CHANGES; GROWTH-HORMONE; FOOD-INTAKE; BODY-WEIGHT; CIRCULATING GHRELIN; HUMAN OBESITY; DIABETES-MELLITUS; ACYLATED PEPTIDE; MESSENGER-RNA AB Ghrelin stimulates release of GH from the pituitary, stimulates appetite, and may influence metabolic processes in other tissues expressing the GH secretagogue receptor. Ghrelin can thus influence behaviors and endocrine pathways contributing to weight gain. In this study we characterized the ghrelin gene from the rhesus monkey and analyzed the association of plasma ghrelin levels with metabolic and endocrine markers. Rhesus ghrelin is 97, 91, and 96% homologous to the human cDNA, gene, and peptide, respectively. Ghrelin expression was highest in the stomach with lower levels found in muscle and duodenum. In these tissues, ghrelin expression in calorie-restricted and obese animals was about 40-99% lower than in lean animals. In addition, ghrelin expression in muscle was fairly high and may allow this tissue to contribute significantly to plasma levels. Fasting plasma ghrelin concentrations were also inversely correlated with body mass index and exhibited a nonlinear association with age with increased levels in younger and older monkeys and lower levels in middle-aged monkeys. Although a significant inverse correlation between fasting plasma ghrelin and fasting insulin levels were found, iv glucose and insulin administration did not significantly alter ghrelin levels. These studies demonstrate that ghrelin levels are influenced by age-related factors and adiposity in the rhesus monkey. These similarities between the rhesus monkey and human ghrelin genes and plasma ghrelin responses suggest a unique opportunity to study the mechanisms regulating ghrelin secretion and gene expression in different tissues in normal and disease states using this model system. C1 Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Obes & Diabet Res Ctr, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. NIAAA, Clin Studies Lab, Primate Sect Unit, NIH, Poolesville, MD 20837 USA. NICHHD, Comparat Ethol Lab, NIH, Poolesville, MD 20837 USA. RP Angeloni, SV (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, 685 W Baltimore St,Room 480, Baltimore, MD 21201 USA. EM sangelon@medicine.umaryland.edu RI Hansen, Barbara/J-8723-2012 OI Hansen, Barbara/0000-0001-9646-3525 FU NIA NIH HHS [N01-AG-0-2100] NR 65 TC 18 Z9 19 U1 0 U2 0 PU ENDOCRINE SOC PI BETHESDA PA 4350 EAST WEST HIGHWAY SUITE 500, BETHESDA, MD 20814-4110 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAY PY 2004 VL 145 IS 5 BP 2197 EP 2205 DI 10.1210/en.2003-1103 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 816HV UT WOS:000221101900011 PM 14736731 ER PT J AU Schecter, A Lucier, GW Cunningham, ML Abdo, KM Blumenthal, G Silver, AG Melnick, R Portier, C Barr, DB Barr, JR Stanfill, SB Patterson, DG Needham, LL Stopford, W Masten, S Mignogna, J Tung, KC AF Schecter, A Lucier, GW Cunningham, ML Abdo, KM Blumenthal, G Silver, AG Melnick, R Portier, C Barr, DB Barr, JR Stanfill, SB Patterson, DG Needham, LL Stopford, W Masten, S Mignogna, J Tung, KC TI Human consumption of methyleugenol and its elimination from serum SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE 4-allyl-1,2-dimethoxybenzene; carcinogen; dose; food; human; ingestion; kinetics; methyleugenol; serum levels; urine ID RAT AB Under a mandate from the U.S. Congress, the National Toxicology Program (NTP) of the U.S. Department of Health and Human Services conducts animal bioassays for carcinogenicity of potentially toxic chemicals to which the U.S. population might be exposed. Methyleugenol, a natural as well as synthesized substance, was nominated for study because it is structurally similar to safrole, a known animal carcinogen. Methyleugenol was found to be a very potent multisite carcinogen in male and female F344/N rats and B6C3F(1) mice at all doses tested in 2-year NTP bioassays using gavage dosing. For this reason, human toxicokinetic studies were added to the traditional NTP protocol. A commercial brand of gingersnaps was found by chemists at the Centers for Disease Control and Prevention to contain a relatively high concentration of methyleugenol. After thorough scientific and clinical review, and approval by a National Institutes of Health institutional review board for the protection of human subjects, a study was conducted with nine healthy adult male and female human volunteers. The volunteers were given 12 gingersnaps for breakfast. Blood was drawn immediately before the meal and at 15, 30, 60, and 120 min afterward. The mean +/- SD fasting level of methyleugenol in serum was 16.2 +/- 4.0 pg/g wet weight. Peak blood levels were found at 15 min (mean +/- SD, 53.9 +/- 7.3 pg/g wet weight), followed by a rapid decline; the half-life of elimination was about 90 min. The peak levels were within the range of methyleugenol blood levels in the U.S. population, as measured concurrently in a subset of nonfasting participants in the Third National Health and Nutrition Examination Survey (NHANES III). C1 Univ Texas, Sch Publ Hlth, Dallas, TX 75390 USA. NIEHS, Natl Toxicol Program, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Dept Hlth & Human Serv, Atlanta, GA 30341 USA. Duke Univ, Med Ctr, Div Occupat Med, Durham, NC USA. RP Schecter, A (reprint author), Univ Texas, Sch Publ Hlth, 5323 Harry Hines Blvd,V8 112, Dallas, TX 75390 USA. EM arnold.schecter@utsouthwestern.edu RI Portier, Christopher/A-3160-2010; Needham, Larry/E-4930-2011; Barr, Dana/E-6369-2011; Barr, Dana/E-2276-2013; masten, scott/R-1403-2016 OI Portier, Christopher/0000-0002-0954-0279; masten, scott/0000-0002-7847-181X NR 11 TC 9 Z9 10 U1 0 U2 4 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAY PY 2004 VL 112 IS 6 BP 678 EP 680 DI 10.1289/ehp.6766 PG 3 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 822DD UT WOS:000221514400033 PM 15121510 ER PT J AU McNeill, DR Narayana, A Wong, HK Wilson, DM AF McNeill, DR Narayana, A Wong, HK Wilson, DM TI Inhibition of Ape1 nuclease activity by lead, iron, and cadmium SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE Ape1 AP endonuclease; base excision DNA repair; environmental heavy metal toxicity; lead; mutagenesis/carcinogenesis ID HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; HUMAN APURINIC ENDONUCLEASE; ABASIC SITE RECOGNITION; BASE EXCISION-REPAIR; DNA-REPAIR; MAJOR HUMAN; EXONUCLEASE-III; METAL-COMPOUNDS; PROTEIN; DAMAGE C1 NIA, Lab Mol Gerontol, Gerontol Res Ctr, Intramural Res Program,Natl Inst Hlth,Dept Hlth &, Baltimore, MD 21224 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, Gerontol Res Ctr, Intramural Res Program,Natl Inst Hlth,Dept Hlth &, Baltimore, MD 21224 USA. EM wilsonda@grc.nia.nih.gov NR 45 TC 72 Z9 75 U1 0 U2 8 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAY PY 2004 VL 112 IS 7 BP 799 EP 804 DI 10.1289/txg.7038 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 823ZS UT WOS:000221653700013 PM 15159209 ER PT J AU Galperin, MY AF Galperin, MY TI All bugs, big and small SO ENVIRONMENTAL MICROBIOLOGY LA English DT Editorial Material ID COMPLETE GENOME SEQUENCE C1 Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 8 TC 3 Z9 3 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-2912 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD MAY PY 2004 VL 6 IS 5 BP 435 EP 437 DI 10.1111/j.1462-2920.2004.00629.x PG 3 WC Microbiology SC Microbiology GA 806WR UT WOS:000220464500001 PM 15049916 ER PT J AU Villanueva, CM Cantor, KP Cordier, S Jaakkola, JJK King, WD Lynch, CF Porru, S Kogevinas, M AF Villanueva, CM Cantor, KP Cordier, S Jaakkola, JJK King, WD Lynch, CF Porru, S Kogevinas, M TI Disinfection byproducts and bladder cancer - A pooled analysis SO EPIDEMIOLOGY LA English DT Article ID GLUTATHIONE-S-TRANSFERASE; DRINKING-WATER SOURCE; GENDER-RELATED DIFFERENCES; MULTICENTER CASE-CONTROL; WASHINGTON COUNTY; RISK; CHLORINATION; CONSUMPTION; POPULATION; MORTALITY AB Background: Exposure to disinfection byproducts in drinking water has been associated with an increased risk of bladder cancer. We pooled the primary data from 6 case-control studies of bladder cancer that used trihalomethanes as a marker of disinfection byproducts. Methods: Two studies were included from the United States and one each from Canada, France, Italy, and Finland. Inclusion criteria were availability of detailed data on trihalomethane exposure and individual water consumption. The analysis included 2806 cases and 5254 controls, all of whom had measures of known exposure for at least 70% of the exposure window of 40 years before the interview. Cumulative exposure to trihalomethanes was estimated by combining individual year-by-year average trihalomethane level and daily tap water consumption. Results: There was an adjusted odds ratio (OR) of 1.24 in men exposed to an average of more than 1 mug/L (ppb) trihalomethanes compared with those who had lower or no exposure (95% confidence interval [CI] = 1.09-1.41). Estimated relative risks increased with increasing exposure, with an OR of 1.44 (1.20-1.73) for exposure higher than 50 mug/L (ppb). Similar results were found with other indices of trihalomethane exposure. Among women, trihalomethane exposure was not associated with bladder cancer risk (0.95; 0.76-1.20). Conclusions: These findings strengthen the hypothesis that the risk of bladder cancer is increased with long-term exposure to disinfection byproducts at levels currently observed in many industrialized countries. C1 Municipal Inst Med Res, Resp & Environm Hlth Res Unit, Barcelona 08003, Spain. Univ Autonoma Barcelona, Dept Genet & Microbiol, Barcelona, Spain. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Rennes 1, INSERM, U435, F-35014 Rennes, France. Univ Helsinki, Dept Publ Hlth, FIN-00014 Helsinki, Finland. Univ Birmingham, Inst Occupat Hlth, Birmingham B15 2TT, W Midlands, England. Queens Univ, Dept Community Hlth & Epidemiol, Kingston, ON K7L 3N6, Canada. Univ Iowa, Dept Epidemiol, Iowa City, IA USA. Univ Brescia, Inst Occupat Hlth, Brescia, Italy. RP Kogevinas, M (reprint author), Municipal Inst Med Res, Resp & Environm Hlth Res Unit, 80 Dr Aiguader Rd, Barcelona 08003, Spain. EM kogevinas@imim.es RI Jaakkola, Jouni/G-4314-2012; Villanueva, Cristina/N-1942-2014; Cordier, Sylvaine/F-7919-2013; Kogevinas, Manolis/C-3918-2017 OI Villanueva, Cristina/0000-0002-0783-1259; FU NIEHS NIH HHS [P30 ES05605] NR 51 TC 203 Z9 207 U1 8 U2 49 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAY PY 2004 VL 15 IS 3 BP 357 EP 367 DI 10.1097/01.ede.0000121380.02594.fc PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 815UO UT WOS:000221067400020 PM 15097021 ER PT J AU De Roos, AJ Ward, MH AF De Roos, AJ Ward, MH TI Drinking water and cancer - To the editor SO EPIDEMIOLOGY LA English DT Letter ID NITRATE; RISK; TRIHALOMETHANES; EXPOSURE; SUPPLIES; COUNTY; WOMEN C1 Univ Washington, Dept Epidemiol, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS, Rockville, MD USA. RP De Roos, AJ (reprint author), Univ Washington, Dept Epidemiol, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. EM aderoos@fhcrc.org NR 17 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAY PY 2004 VL 15 IS 3 BP 378 EP 380 DI 10.1097/01.ede.0000122631.63762.b2 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 815UO UT WOS:000221067400027 PM 15097029 ER PT J AU Bai, YW Feng, HQ AF Bai, YW Feng, HQ TI Selection of stably folded proteins by phage-display with proteolysis SO EUROPEAN JOURNAL OF BIOCHEMISTRY LA English DT Review DE hydrophobic repacking; phage-display; protein design; proteolysis ID DE-NOVO DESIGN; 4-HELIX BUNDLE PROTEIN; STRUCTURAL-CHARACTERIZATION; BACKBONE FLEXIBILITY; SEQUENCE SELECTION; NATIVE-LIKE; SIDE-CHAIN; CORE; STABILITY; UBIQUITIN AB To facilitate the process of protein design and learn the basic rules that control the structure and stability of proteins, combinatorial methods have been developed to select or screen proteins with desired properties from libraries of mutants. One such method uses phage-display and proteolysis to select stably folded proteins. This method does not rely on specific properties of proteins for selection. Therefore, in principle it can be applied to any protein. Since its first demonstration in 1998, the method has been used to create hyperthermophilic proteins, to evolve novel folded domains from a library generated by combinatorial shuffling of polypeptide segments and to convert a partially unfolded structure to a fully folded protein. C1 NCI, Biochem Lab, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, Bldg 37,Room 6114E, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov NR 35 TC 21 Z9 22 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2956 J9 EUR J BIOCHEM JI Eur. J. Biochem. PD MAY PY 2004 VL 271 IS 9 BP 1609 EP 1614 DI 10.1111/j.1432-1033.2004.04074.x PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 813CV UT WOS:000220886100003 PM 15096199 ER PT J AU Bartak, V Vybiral, S Papezova, H Dostalova, I Pacak, K Nedvidkova, J AF Bartak, V Vybiral, S Papezova, H Dostalova, I Pacak, K Nedvidkova, J TI Basal and exercise-induced sympathetic nervous activity and lipolysis in adipose tissue of patients with anorexia nervosa SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Article DE adipose tissue; anorexia nervosa; catecholamines; exercise; lipolysis; microdialysis ID MICRODIALYSIS; RESPONSES; PLASMA; CATECHOLAMINES; RELEASE; LACTATE; GLUCOSE; SYSTEM; STRESS; MUSCLE AB Background The sympathetic nervous system plays an important role in the regulation of adipose tissue (AT) lipolysis, which is a key step in the metabolic processes leading to the decrease of fat mass. The present study was designed to determine in vivo basal and exercise-stimulated lipolysis and concentrations of catecholamines, the major hormones controlling lipolysis, in subcutaneous abdominal AT in patients with anorexia nervosa (AN), characterized by self-induced starvation and excessive exercises resulting in severe malnutrition and fat store loss. The results of local catecholamines and glycerol levels were compared with those in plasma in both experimental groups. Material and methods An in vivo microdialysis technique was used for the assessment of norepinephrine, dihydroxyphenylalanine, dihydroxyphenylacetic acid and glycerol concentrations in subcutaneous AT of 10 women with AN (body mass index: 15.57 +/- 0.55 kg m(-2)) and 10 age-matched controls (body mass index: 21.56 +/- 0.41 kg m(-2)). Both the AN patients and the control subjects underwent a 1.5 W kg(-1) exercise test. Results Basal AT norepinephrine concentrations were increased in the AN patients in comparison with the controls. Basal AT glycerol concentrations were similar in both groups. During exercise, a local increase in the AT norepinephrine and glycerol concentrations was observed in the AN patients only. In contrast to the controls, the basal AT dihydroxyphenylalanine and dihydroxyphenylacetic acid levels in the AN patients were high and remained unchanged during exercise. Basal and exercise-stimulated plasma norepinephrine, dihydroxyphenylalanine, dihydroxyphenylacetic acid and glycerol levels were not different in the AN patients and healthy controls. Conclusion Our study provides evidence of elevated baseline and exercise-induced sympathetic nervous activity and exercise-induced lipolysis in abdominal AT of AN patients. C1 Inst Endocrinol, Prague 11694 1, Czech Republic. Charles Univ, Fac Sci, Dept Physiol Dev Biol, Prague, Czech Republic. Charles Univ, Dept Psychiat, Prague, Czech Republic. NICHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD USA. RP Nedvidkova, J (reprint author), Inst Endocrinol, Narodni 8, Prague 11694 1, Czech Republic. EM jara.nedvidkova@tiscali.cz NR 26 TC 21 Z9 21 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD MAY PY 2004 VL 34 IS 5 BP 371 EP 377 DI 10.1111/j.1365-2362.2004.01344.x PG 7 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 821VI UT WOS:000221490700008 PM 15147335 ER PT J AU Ufer, M Svensson, JO Krausz, KW Gelboin, HV Rane, A Tybring, G AF Ufer, M Svensson, JO Krausz, KW Gelboin, HV Rane, A Tybring, G TI Identification of cytochromes P-450 2C9 and 3A4 as the major catalysts of phenprocoumon hydroxylation in vitro SO EUROPEAN JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article; Proceedings Paper CT 6th Congress of the European Association for Clinical Pharmacology and Therapeutics CY JUN, 2003 CL Istanbul, TURKEY DE cytochrome P(450)2C9; cytochrome P-450 3A4; phenprocoumon ID HUMAN LIVER-MICROSOMES; PERFORMANCE LIQUID-CHROMATOGRAPHY; DRUG-INTERACTIONS; WARFARIN; ACENOCOUMAROL; METABOLISM; CYP2C9; PHARMACOKINETICS; ANTICOAGULANTS; P450 AB Objective. This in-vitro study aimed at an identification of cytochrome P-450 (CYP) enzymes catalysing the (S)- and (R)-hydroxylation of the widely used anticoagulant phenprocoumon (PPC) to its major, inactive metabolites. Methods. Relevant catalysts were identified by kinetic, correlation and inhibition experiments using human liver microsomes and recombinant enzymes. Results. Kinetics revealed (S)-7-hydroxylation as quantitatively most important. Biphasic Eadie-Hofstee plots indicated more than one catalyst for the 4'-, 6- and 7-hydroxylation of both enantiomers with mean K-m1 and K-m2 of 144.5+/-34.9 and 10.0+/-6.49 muM, respectively. PPC hydroxylation rates were significantly correlated with CYP2C9 and CYP3A4 activity and expression analysing 11 different CYP-specific probes. Complete inhibition of PPC hydroxylation was achieved by combined addition of the CYP3A4-specific inhibitor triacetyloleandomycin (TAO) and a monoclonal, inhibitory antibody (mAb) directed against CYP2C8, 9, 18 and 19, except for the (R)-4'-hydroxylation that was, however, inhibited by similar to80% using TAO alone. (S)-PPC hydroxylation was reduced by similar to2/3 and similar to1/3 using mAb2C8-9-18-19 and TAO, respectively, but (R)-6- and 7-hydroxylation by similar to50% each. Experiments with mAbs directed against single CYP2C enzymes clearly indicated CYP2C9 as a major catalyst of the 6- and 7-hydroxylation for both enantiomers. However, CYP2C8 was equally important regarding the (S)-4'-hydroxylation. Recombinant CYP2C8 and CYP2C9 were high-affinity catalysts (K-m <5 muM), whereas CYP3A4 operated with low affinity (K-m >100 muM). Conclusion. CYP2C9 and CYP3A4 are major catalysts of (S)- and (R)-PPC hydroxylation, while CYP2C8 partly catalysed the (S)-4'-hydroxylation. Increased vigilance is warranted when PPC treatment is combined with substrates, inhibitors, or inducers of these enzymes. C1 Huddinge Univ Hosp, Karolinska Inst, Dept Lab Med, Div Clin Pharmacol, S-14186 Stockholm, Sweden. Univ Tubingen Hosp, Inst Pharmacol & Toxicol, Div Clin Pharmacol, Tubingen, Germany. NCI, Lab Mol Carcinogenesis & Metab, NIH, Bethesda, MD USA. RP Ufer, M (reprint author), Huddinge Univ Hosp, Karolinska Inst, Dept Lab Med, Div Clin Pharmacol, S-14186 Stockholm, Sweden. EM mikeufer@gmx.de NR 44 TC 52 Z9 52 U1 0 U2 2 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0031-6970 J9 EUR J CLIN PHARMACOL JI Eur. J. Clin. Pharmacol. PD MAY PY 2004 VL 60 IS 3 BP 173 EP 182 DI 10.1007/s00228-004-0740-5 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 821FQ UT WOS:000221446200006 PM 15054565 ER PT J AU Jacob, AC Zmuda, JM Cauley, JA Metter, EJ Hurley, BF Ferrell, RE Roth, SM AF Jacob, AC Zmuda, JM Cauley, JA Metter, EJ Hurley, BF Ferrell, RE Roth, SM TI Ciliary neurotrophic factor (CNTF) genotype and body composition SO EUROPEAN JOURNAL OF HUMAN GENETICS LA English DT Article DE CNTF null allele; genetics; genotype; weight; body mass index; fat mass ID NULL MUTATION; GENE; AGE; MEN; OBESITY; WOMEN; SCLEROSIS; STRENGTH; QUALITY; INDEX AB Exogenous ciliary neurotrophic factor ( CNTF) administration causes significant weight loss in both humans and animal models, but the effects of endogenous CNTF and the CNTF null allele on body composition are not fully understood. A recent study in a European cohort demonstrated a significantly higher body weight and body mass index (BMI) in older males homozygous for the CNTF null allele (A/A genotype). We sought to replicate these findings in three cohorts: the Baltimore Longitudinal Study on Aging (BLSA) consisting of 422 adult men and women ( 19 - 90 years); the Study of Osteoporotic Risk in Men ( STORM) consisting of 333 older men ( 50 - 84 years); and a third sample obtained by combining older males aged 59 - 73 years from the BLSA and STORM cohorts (n = 286). In contrast to the European study, we were unable to detect a significant association between CNTF genotype and body weight in the BLSA ( P = 0.49), the STORM ( P = 0.28), or the combined samples ( P = 0.72). There was also no significant association observed between CNTF genotype and BMI in the BLSA ( P = 0.59), the STORM ( P = 0.34) or the combined ( P = 0.56) samples. In addition, we were unable to detect a significant association between CNTF genotype and total body fat ( P = 0.95) or fat-free mass ( P = 0.86) in the BLSA cohort. Our results do not support an effect of the CNTF null allele on body composition, contrary to previous findings. C1 Univ Maryland, Coll Hlth & Human Performance, Dept Kinesiol, College Pk, MD 20742 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Harbor Hosp, NIA, Clin Res Branch, Baltimore, MD 21225 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15261 USA. RP Roth, SM (reprint author), Univ Maryland, Coll Hlth & Human Performance, Dept Kinesiol, College Pk, MD 20742 USA. EM sroth1@umd.edu RI Cauley, Jane/N-4836-2015; OI Cauley, Jane/0000-0003-0752-4408; Roth, Stephen/0000-0002-7841-3695 FU NIA NIH HHS [AG22791]; NIAMS NIH HHS [AR35582, P60-AR44811]; NIDDK NIH HHS [DK46204] NR 27 TC 7 Z9 7 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1018-4813 J9 EUR J HUM GENET JI Eur. J. Hum. Genet. PD MAY PY 2004 VL 12 IS 5 BP 372 EP 376 DI 10.1038/sj.ejhg.5201159 PG 5 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 813AI UT WOS:000220879600007 PM 14747836 ER PT J AU Fujita, M Varrone, A Kim, KM Watabe, H Zoghbi, SS Seneca, N Tipre, D Seibyl, JP Innis, RB Iida, H AF Fujita, M Varrone, A Kim, KM Watabe, H Zoghbi, SS Seneca, N Tipre, D Seibyl, JP Innis, RB Iida, H TI Effect of scatter correction on the compartmental measurement of striatal and extrastriatal dopamine D-2 receptors using [I-123]epidepride SPET SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE nonlinear least-squares analysis; ordered subsets expectation maximization putamen; thalamus; temporal cortex ID NONUNIFORM ATTENUATION CORRECTION; PHOTON-EMISSION-TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; D-2/D-3 RECEPTORS; BRAIN; QUANTIFICATION; BINDING; RECONSTRUCTION; COMPENSATION; ACCURACY AB Prior studies with anthropomorphic phantoms and single, static in vivo brain images have demonstrated that scatter correction significantly improves the accuracy of regional quantitation of single-photon emission tomography (SPET) brain images. Since the regional distribution of activity changes following a bolus injection of a typical neuroreceptor ligand, we examined the effect of scatter correction on the compartmental modeling of serial dynamic images of striatal and extrastriatal dopamine D-2 receptors using [I-123]epidepride. Eight healthy human subjects [age 30+/-8 (range 22-46) years] participated in a study with a bolus injection of 373+/-12 (354-389) MBq [I-123]epidepride and data acquisition over a period of 14 h. A transmission scan was obtained in each study for attenuation and scatter correction. Distribution volumes were calculated by means of compartmental nonlinear least-squares analysis using metabolite-corrected arterial input function and brain data processed with scatter correction using narrow-beam geometry mu (SC) and without scatter correction using broad-beam mu (NoSC). Effects of SC were markedly different among brain regions. SC increased activities in the putamen and thalamus after 1-1.5 h while it decreased activity during the entire experiment in the temporal cortex and cerebellum. Compared with NoSC, SC significantly increased specific distribution volume in the putamen (58%, P=0.0001) and thalamus (23%, P=0.0297). Compared with NoSC, SC made regional distribution of the specific distribution volume closer to that of [F-18]fallypride. It is concluded that SC is required for accurate quantification of distribution volumes of receptor ligands in SPET studies. C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Psychiat, West Haven, CT 06516 USA. VA Connecticut Healthcare Syst, West Haven, CT USA. CNR, Biostruct & Bioimaging Inst, Naples, Italy. Natl Cardiovasc Ctr, Res Inst, Dept Invest Radiol, Osaka, Japan. Yale Univ, Sch Med, Dept Radiol, West Haven, CT 06516 USA. Inst Neurodegenerat Disorders, New Haven, CT USA. RP Fujita, M (reprint author), NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. EM FujitaM@intra.nimh.nih.gov RI Iida, Hidehiro/D-4582-2011 NR 28 TC 7 Z9 8 U1 0 U2 0 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD MAY PY 2004 VL 31 IS 5 BP 644 EP 654 DI 10.1007/s00259-003-1431-7 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 813AN UT WOS:000220880100005 PM 14730406 ER PT J AU Shoptaw, S Majewska, MD Wilkins, J Twitchell, G Yang, XW AF Shoptaw, S Majewska, MD Wilkins, J Twitchell, G Yang, XW TI Participants receiving dehydroepiandrosterone during treatment for cocaine dependence show high rates of cocaine use in a placebo-controlled pilot study SO EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID GABA-A RECEPTOR; CONTROLLED TRIAL; STRESS; PSYCHOSTIMULANTS; NEUROSTEROIDS; PROLACTIN; CORTISOL; MULTIPLE; DOPAMINE; RELEASE AB Twenty-three cocaine-dependent participants were randomly assigned to receive either dehydroepiandrosterone (DHEA; n = 11; 100 mg/day) or placebo (n = 12) in the context of 12 weeks of thrice weekly cognitive-behavioral group counseling. Outcomes were retention, urine drug screening, cocaine craving, adverse experiences, and medication compliance. DHEA-treated participants averaged 45.8 (SD = 28.8) days in treatment, compared with 70.7 (SD = 20.6) days for placebo, t(21) = -2.4, p = .03, and provided 26.8% (SD = 29.3) of urine samples free of cocaine metabolite compared with 70.6% (SD = 39.9) for the placebo condition, t(21) = -3.0, p = .01. No differences were detected between conditions for cocaine craving or adverse experiences. High levels of medication compliance were documented. Results argue against using high doses of DHEA as a pharmacotherapy for cocaine dependence. C1 UCLA Integrated Substance Abuse Program, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90025 USA. Friends Res Inst, Los Angeles, CA USA. Natl Inst Hlth, Natl Inst Drug Abuse, Bethesda, MD USA. RP Shoptaw, S (reprint author), UCLA Integrated Substance Abuse Program, Dept Psychiat & Biobehav Sci, 11075 Santa Monica Blvd,Suite 200, Los Angeles, CA 90025 USA. EM shoptaw@friendsresearch.org FU NIDA NIH HHS [Y01 DA 50038] NR 39 TC 19 Z9 19 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 1064-1297 J9 EXP CLIN PSYCHOPHARM JI Exp. Clin. Psychopharmacol. PD MAY PY 2004 VL 12 IS 2 BP 126 EP 135 DI 10.1037/1064-1297.12.2.126 PG 10 WC Psychology, Biological; Psychology, Clinical; Pharmacology & Pharmacy; Psychiatry SC Psychology; Pharmacology & Pharmacy; Psychiatry GA 817GF UT WOS:000221165300005 PM 15122957 ER PT J AU Liu, J AF Liu, J TI Fas-mediated signaling pathway in ethanol-induced liver apoptosis: Inhibition by zinc SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Editorial Material ID OXIDATIVE STRESS; ACTIVATION C1 NIEHS, NCI, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Liu, J (reprint author), NIEHS, NCI, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM Liu6@niehs.nih.gov NR 6 TC 2 Z9 4 U1 0 U2 0 PU SOC EXPERIMENTAL BIOLOGY MEDICINE PI MAYWOOD PA 195 WEST SPRING VALLEY AVE, MAYWOOD, NJ 07607-1727 USA SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD MAY PY 2004 VL 229 IS 5 BP 365 EP 366 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 833FO UT WOS:000222322100001 PM 15096646 ER PT J AU Kunieda, T Ikeda, A Ohara, S Matsumoto, R Taki, W Hashimoto, N Baba, K Ioue, Y Mihara, T Yagi, K Shibasaki, H AF Kunieda, T Ikeda, A Ohara, S Matsumoto, R Taki, W Hashimoto, N Baba, K Ioue, Y Mihara, T Yagi, K Shibasaki, H TI Role of lateral non-primary motor cortex in humans as revealed by epicortical recording of Bereitschaftspotentials SO EXPERIMENTAL BRAIN RESEARCH LA English DT Article DE lateral non-primary motor area; primary negative motor area; movement-related cortical potentials; subdural recording; somatotopic organization ID POSITRON-EMISSION-TOMOGRAPHY; MOVEMENT-RELATED POTENTIALS; PACED HAND MOVEMENTS; SLOW CORTICAL POTENTIALS; MACAQUE MONKEY; INFERIOR AREA-6; SPINAL-CORD; FUNCTIONAL-ORGANIZATION; ELECTRICAL-STIMULATION; CORTICOSPINAL NEURONS AB In order to clarify the role of the lateral non-primary motor area in the control of voluntary movements, we studied movement-related cortical potentials (MRCPs) by direct epicortical recording from the lateral frontal lobe in nine patients with intractable partial epilepsy as a part of presurgical evaluation. We adopted movement tasks involving different body sites: eye closing, lip pursing, shoulder abduction, middle finger extension, thumb abduction, and foot dorsiflexion. We found that one or two small areas on the caudal lateral convexity of the frontal lobe generated pre-movement potential shifts regardless of the sites of movement (omni-Bereitschaftspotential; "omni-BP"). Such regions were located at or just rostral to the primary motor face area in six subjects, and at or rostral to the primary motor upper extremity area in three. Moreover, half of those areas were identified just adjacent (either rostral or caudal) to the primary negative motor area (PNMA), a cortical area of the lateral frontal lobe where negative motor responses were elicited by electric cortical stimulation. In conclusion, it is suggested that the lateral non-primary motor area plays a significant role, and has a close and direct relationship with other cortical areas in the frontal lobe, just like its counterpart on the mesial frontal cortex (supplementary negative motor area, SNMA). C1 Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Kyoto, Japan. Kyoto Univ, Grad Sch Med, Dept Neurosurg, Kyoto, Japan. Kyoto Univ, Grad Sch Med, Dept Neurol, Sakyo Ku, Kyoto 6068507, Japan. Shizuoka Med Inst Neurol Disorder, Natl Epilepsy Ctr, Shizuoka, Japan. Mie Univ, Sch Med, Dept Neurosurg, Tsu, Mie 514, Japan. RP Shibasaki, H (reprint author), NINDS, POB 5801, Bethesda, MD 20824 USA. EM shib@kuhp.kyoto-u.ac.jp RI Matsumoto, Riki/I-8397-2016; OI Matsumoto, Riki/0000-0003-3985-9210; Ikeda, Akio/0000-0002-0790-2598 NR 68 TC 13 Z9 13 U1 0 U2 1 PU SPRINGER-VERLAG PI NEW YORK PA 175 FIFTH AVE, NEW YORK, NY 10010 USA SN 0014-4819 J9 EXP BRAIN RES JI Exp. Brain Res. PD MAY PY 2004 VL 156 IS 2 BP 135 EP 148 DI 10.1007/s00221-003-1769-x PG 14 WC Neurosciences SC Neurosciences & Neurology GA 813KN UT WOS:000220906100002 PM 15344849 ER PT J AU Hakansson, P Segal, D Lassen, C Gullberg, U Morse, HC Fioretos, T Meltzer, PS AF Hakansson, P Segal, D Lassen, C Gullberg, U Morse, HC Fioretos, T Meltzer, PS TI Identification of genes differentially regulated by the P210BCR/ABL1 fusion oncogene using cDNA microarrays SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; BCR-ABL; INTERFERON-ALPHA; MEDIATED TRANSFORMATION; TRANSCRIPTION FACTORS; STAT PROTEINS; EXPRESSION; CELLS; BCR/ABL AB Objective. The t(9;22) translocation is associated with more than 95% of cases of chronic myeloid leukemia. The resulting fusion of the BCR and ABL1 loci produces the constitutively active BCR/ABL1 tyrosine kinase. A wide range of signal transduction molecules are activated by BCR/ABL1, including MYC, PI-3 kinase, and different STAT molecules. In contrast, relatively few genes are known to be regulated by BCR/ABL1 at the level of transcription. Materials and Methods. In an effort to better understand the transcriptional program activated by BCR/ABL1, we used cDNA microarrays to evaluate the relative expression of approximately 6450 human genes in U937 myelomonocytic cells expressing P210 BCR/ABL1 via a tetracycline-inducible promoter. Results. We confirmed the previously reported up-regulation of the PIM1 and JUN oncogenes by BCR/ABL1. In addition, we identified 59 more genes up-regulated by BCR/ABLI. Interestingly, roughly one third of these were genes previously reported to be interferon (IFN)-responsive, including the OAS1, IFIT1, IFI16, ISGF3G, and STAT1 genes. An additional seven BCR/ABL1-regulated genes were found to be IFN-responsive in U937 cells. The expression profile also included genes encoding transcription factors, kinases, and signal transduction molecules, as well as genes regulating cell growth, differentiation, apoptosis, and cell adhesion, features previously suggested to be affected by BCR/ABLI. Conclusion. These observations shed novel insight into the mechanism of BCR/ABL1 action and provide a range of targets for further investigation. (C) 2004 International Society for Experimental Hematology. Published by Elsevier Inc. C1 Univ Lund Hosp, Dept Clin Genet, SE-22185 Lund, Sweden. NIAID, Immunopathol Lab, NIH, Bethesda, MD USA. Lund Univ, Dept Hematol, Ctr Biomed, Lund, Sweden. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Segal, D (reprint author), Univ Lund Hosp, Dept Clin Genet, SE-22185 Lund, Sweden. EM Thoas.Fioretos@klingen.lu.se OI Fioretos, Thoas/0000-0002-3235-6154; Morse, Herbert/0000-0002-9331-3705 NR 37 TC 27 Z9 30 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD MAY PY 2004 VL 32 IS 5 BP 476 EP 482 DI 10.1016/j.exphem.2004.02.012 PG 7 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 825CR UT WOS:000221734100011 PM 15145216 ER PT J AU Boger, HA Middaugh, LD Zaman, V Gerhardt, GA Hoffer, BJ Granholm, AC AF Boger, HA Middaugh, LD Zaman, V Gerhardt, GA Hoffer, BJ Granholm, AC TI A slow progressive model for motor dysfunction. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 11th Annual Conference of the American-Society-for-Neural-Transplantation-and-Repair CY MAY 06-09, 2004 CL Clearwater, FL SP Amer Soc Neural Transplantat & Repair C1 Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. Univ Kentucky, Dept Anat & Neurobiol, Albert B Chandler Med Ctr, Lexington, KY 40506 USA. NIDA, Intramural Res Program, Baltimore, MD USA. NR 0 TC 0 Z9 0 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 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2004 VL 187 IS 1 BP 204 EP 204 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 813FE UT WOS:000220892200027 ER PT J AU Fotter, EL Zeng, X Rao, MS Freed, WJ AF Fotter, EL Zeng, X Rao, MS Freed, WJ TI Neural differentiation of human embryonic stem cells. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 11th Annual Conference of the American-Society-for-Neural-Transplantation-and-Repair CY MAY 06-09, 2004 CL Clearwater, FL SP Amer Soc Neural Transplantat & Repair C1 NIDA, Cellular Neurobiol Res Branch, DHHS, Baltimore, MD 21224 USA. NIA, Neurosci Lab, DHHS, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2004 VL 187 IS 1 BP 208 EP 208 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 813FE UT WOS:000220892200039 ER PT J AU Granholm, L Zaman, V Boger, HA Moore, A Hoffer, BJ Gerhardt, GA McGinty, JF Middaugh, L Bhat, NR Nelson, M AF Granholm, L Zaman, V Boger, HA Moore, A Hoffer, BJ Gerhardt, GA McGinty, JF Middaugh, L Bhat, NR Nelson, M TI The dual-hit hypothesis of age-related dopaminergic degeneration. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 11th Annual Conference of the American-Society-for-Neural-Transplantation-and-Repair CY MAY 06-09, 2004 CL Clearwater, FL SP Amer Soc Neural Transplantat & Repair C1 MUSC, Ctr Aging, Charleston, SC USA. MUSC, Dept Physiol, Charleston, SC USA. MUSC, Dept Neurosci, Charleston, SC USA. MUSC, Dept Neurol, Charleston, SC USA. NIDA, Intramural Res Program, Baltimore, MD USA. Univ Kentucky, Albert B Chandler Med Ctr, Dept Anat & Neurobiol, Lexington, KY 40506 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2004 VL 187 IS 1 BP 209 EP 209 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 813FE UT WOS:000220892200043 ER PT J AU Harvey, BK Shen, H Bickford, PC Hoffer, BJ Chiang, YH Wang, Y AF Harvey, BK Shen, H Bickford, PC Hoffer, BJ Chiang, YH Wang, Y TI Inosine reduces cerebral infarction induced by middle cerebral arterial ligation in rats. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 11th Annual Conference of the American-Society-for-Neural-Transplantation-and-Repair CY MAY 06-09, 2004 CL Clearwater, FL SP Amer Soc Neural Transplantat & Repair C1 NIDA, Neural Protect & Regenerat Sect, Mol Neuropsychiat Branch, Baltimore, MD USA. Tri Serv Gen Hosp, Natl Def Med Ctr, Taipei, Taiwan. Univ S Florida, Dept Neurosurg, Tampa, FL 33620 USA. RI Harvey, Brandon/A-5559-2010; Bickford, Paula/J-5970-2012 OI Bickford, Paula/0000-0001-9657-7725 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2004 VL 187 IS 1 BP 209 EP 210 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 813FE UT WOS:000220892200046 ER PT J AU Li, QY Cao, CH Chackerian, B Schiller, J Gordon, M Ugen, K Morgan, D AF Li, QY Cao, CH Chackerian, B Schiller, J Gordon, M Ugen, K Morgan, D TI Antigen masking of anti-A beta antibodies in A beta immunized amyloid precursor protein transgenic mice. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 11th Annual Conference of the American-Society-for-Neural-Transplantation-and-Repair CY MAY 06-09, 2004 CL Clearwater, FL SP Amer Soc Neural Transplantat & Repair C1 Univ S Florida, Dept Pharmacol, Alzheimers Res Lab, Tampa, FL 33612 USA. Univ S Florida, Dept Med Microbiol & Immunol, Tampa, FL 33612 USA. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2004 VL 187 IS 1 BP 212 EP 213 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 813FE UT WOS:000220892200057 ER PT J AU Marchionini, DM Lehrmann, E Becker, KG Sortwell, CE Freed, WJ Collier, TJ AF Marchionini, DM Lehrmann, E Becker, KG Sortwell, CE Freed, WJ Collier, TJ TI Survey of genes upregulated in nigrostriatal development: Identification of the trophic factor pleiotrophin as a candidate to restore striatal dopamine in Parkinson's disease. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 11th Annual Conference of the American-Society-for-Neural-Transplantation-and-Repair CY MAY 06-09, 2004 CL Clearwater, FL SP Amer Soc Neural Transplantat & Repair C1 Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. NIDA, DHHS, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2004 VL 187 IS 1 BP 214 EP 214 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 813FE UT WOS:000220892200062 ER PT J AU Wang, Y Chang, CF Chen, GJ Chou, J Shen, H Harvey, BK Hoffer, BJ AF Wang, Y Chang, CF Chen, GJ Chou, J Shen, H Harvey, BK Hoffer, BJ TI BMP-7 induces neuroregeneration in rodents after stroke. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 11th Annual Conference of the American-Society-for-Neural-Transplantation-and-Repair CY MAY 06-09, 2004 CL Clearwater, FL SP Amer Soc Neural Transplantat & Repair C1 NIDA, NPR Sect, Baltimore, MD USA. Natl Def Med Ctr, Tri Serv Hosp, Taipei, Taiwan. RI Harvey, Brandon/A-5559-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2004 VL 187 IS 1 BP 223 EP 223 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 813FE UT WOS:000220892200097 ER PT J AU Whittemore, SR Cao, QL Talbott, JF Tsoulfas, P Bunge, NB Xu, XM Qiu, MS Liu, Y Rao, MS AF Whittemore, SR Cao, QL Talbott, JF Tsoulfas, P Bunge, NB Xu, XM Qiu, MS Liu, Y Rao, MS TI Functional remyelination of the injured adult rat spinal cord. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 11th Annual Conference of the American-Society-for-Neural-Transplantation-and-Repair CY MAY 06-09, 2004 CL Clearwater, FL SP Amer Soc Neural Transplantat & Repair C1 Univ Louisville, Louisville, KY 40292 USA. Kentucky Spinal Cord Injury Res Ctr, Louisville, KY USA. Univ Miami, Miami, FL 33152 USA. Miami Project Cure Paralysis, Miami, FL USA. NIA, Neurosci Lab, NIH, Baltimore, MD 21224 USA. Univ Utah, Salt Lake City, UT 84112 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2004 VL 187 IS 1 BP 223 EP 223 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 813FE UT WOS:000220892200098 ER PT J AU Zaman, V Boger, H Gerhardt, GA Moore, A Nelson, M Middaugh, L Hoffer, BJ Granholm, ACH AF Zaman, V Boger, H Gerhardt, GA Moore, A Nelson, M Middaugh, L Hoffer, BJ Granholm, ACH TI Pre-natal lipopolysaccharide exposure induces cell loss of dopaminergic neurons in substantia nigra of GDNF heterozygous mice. SO EXPERIMENTAL NEUROLOGY LA English DT Meeting Abstract CT 11th Annual Conference of the American-Society-for-Neural-Transplantation-and-Repair CY MAY 06-09, 2004 CL Clearwater, FL SP Amer Soc Neural Transplantat & Repair C1 Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. Univ Kentucky, Dept Anat & Neurobiol, Albert B Chandler Med Ctr, Lexington, KY USA. NIDA, Intramural Res Program, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD MAY PY 2004 VL 187 IS 1 BP 224 EP 224 PG 1 WC Neurosciences SC Neurosciences & Neurology GA 813FE UT WOS:000220892200102 ER PT J AU Panelli, MC Wang, E Monsurro, V Jin, P Zavaglia, K Smith, K Ngalame, Y Marincola, FM AF Panelli, MC Wang, E Monsurro, V Jin, P Zavaglia, K Smith, K Ngalame, Y Marincola, FM TI Vaccination with T cell-defined antigens SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Review DE IL-2; immunisation; immunotherapy; melanoma ID CUTANEOUS MALIGNANT-MELANOMA; TUMOR-ANTIGEN; METASTATIC MELANOMA; GENE-EXPRESSION; IN-VIVO; CANCER REGRESSION; DENDRITIC CELLS; CLINICAL-TRIALS; PEPTIDE VACCINE; IMMUNOTHERAPY AB Tumour immunology encompasses a broad array of biological phenomena including interactions between neoplastic cells and the innate and adaptive immune response. Among immune cells, T cells have taken the centre stage because they can be easily demonstrated to specifically recognise autologous cancer cells. As most tumour-associated antigens are intracellular proteins, T cells appear to be the most suitable tool for cancer-specific attack, as antibodies do not cross the cell membrane and the innate immune response lacks the same level of specificity. Finally, the relative ease in which T cells can be educated through antigen-specific immunisation to recognise cancer cells has elevated them to an even higher stature. In this review, it will be argued that T cells represent a unique anticancer agent, characterised by absolute specificity. Although other therapeutic modalities (antibody-based) have been effectively implemented, a comparison of T cell-based approaches with other modalities goes beyond the purposes of this review and will not be included in the discussion. However, it is obvious that the role of the T cell is limited and other components of the immune response (effector mononuclear phagocytes, natural killer cells, cytokines, chemokines, soluble factors), genetic background and tumour heterogeneity are likely to be necessary for the completion of cancer rejection. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM FMarincola@cc.nih.gov NR 88 TC 3 Z9 3 U1 0 U2 0 PU ASHLEY PUBLICATIONS LTD PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD MAY PY 2004 VL 4 IS 5 BP 697 EP 707 PG 11 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 821MS UT WOS:000221465600009 PM 15155161 ER PT J AU Ingram, JL Rice, AB Geisenhoffer, K Madtes, DK Bonner, JC AF Ingram, JL Rice, AB Geisenhoffer, K Madtes, DK Bonner, JC TI IL-13 and IL-1 beta promote lung fibroblast growth through coordinated up-regulation of PDGF-AA and PDGF-R alpha SO FASEB JOURNAL LA English DT Article DE stromal cells; cytokines; cytokine receptors; cellular proliferation; lung ID RAT PULMONARY MYOFIBROBLASTS; ACTIVATED PROTEIN-KINASE; SMOOTH-MUSCLE CELLS; RECEPTOR-ALPHA; IN-VITRO; TRANSFORMING GROWTH-FACTOR-BETA-1; AIRWAYS HYPERREACTIVITY; ALVEOLAR MACROPHAGES; INTERLEUKIN-13; PROLIFERATION AB Peribronchiolar fibrosis is a prominent feature of airway remodeling in asthma and involves fibroblast growth and collagen deposition. Interleukin-13 (IL-13), a T-helper 2 cytokine, is a key mediator of airway remodeling in asthma, yet the mechanism through which IL-13 promotes fibroblast growth has not been investigated. In this study, we show that IL-13 stimulates the mitogenesis of mouse, rat, and human lung fibroblasts through release of a soluble mitogen that we identified as PDGF-AA. The IL-13-induced growth of human lung fibroblasts was attenuated by an anti-PDGF-AA neutralizing antibody, and IL-13 stimulated human lung fibroblasts to secrete PDGF-AA. Fibroblasts derived from mouse embryos possessing the lethal Patch mutation, which lack the PDGF-Ralpha, showed no mitogenic response to IL-13. However, Patch cells did exhibit IL-13-induced STAT-6 phosphorylation. Stable transfection of the PDGF-Ralpha into Patch cells restored the growth response to PDGF-AA and IL-13. Through the use of lung fibroblasts from STAT-6-deficient mice, we showed that IL-13-induced PDGF-AA release is STAT-6 dependent, but PDGF-AA-induced growth is STAT-6 independent. Finally, we showed that IL-1beta enhanced IL-13-induced mitogenesis of rat lung fibroblasts through up-regulation of the PDGF-Ralpha. Our findings indicate that IL-13 acts in synergy with IL-1beta to stimulate growth by coordinately up-regulating PDGF-AA and the PDGF-Ralpha, respectively. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. RP Bonner, JC (reprint author), CIIT Ctr Hlth Res, POB 12137, Res Triangle Pk, NC 27709 USA. EM jbonner@ciit.org NR 39 TC 51 Z9 51 U1 1 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY PY 2004 VL 18 IS 7 BP 1132 EP + DI 10.1096/fj.03-1492fje PG 21 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 827EZ UT WOS:000221883200002 PM 15155567 ER PT J AU Nemes, Z Devreese, B Steinert, PM Van Beeumen, J Fesus, L AF Nemes, Z Devreese, B Steinert, PM Van Beeumen, J Fesus, L TI Cross-linking of ubiquitin, HSP27, parkin and alpha-synuclein by gamma-glutamyl-epsilon-lysine bonds in Alzheimer's neurofibrillary tangles SO FASEB JOURNAL LA English DT Article DE transglutaminase; neurodegeneration; proteasome; neurofibrillary tangles ID PAIRED HELICAL FILAMENTS; SODIUM DODECYL-SULFATE; HEAT-SHOCK-PROTEIN; LEWY BODIES; HUNTINGTONS-DISEASE; NEURODEGENERATIVE DISORDERS; PROTEASOME INHIBITION; CEREBROSPINAL-FLUID; TAU-PROTEIN; CELL-DEATH AB The accumulation of misfolded proteins in intracellular inclusions is a generic feature of neurodegenerative disorders. Although heavily ubiquitylated, the aggregated proteins are not degraded by the proteasomes. A possible reason for this phenomenon may be a modification of deposited proteins by transglutaminases forming gamma-glutamyl-epsilon-lysine (GGEL) cross-links between distinct proteins. Here, we show that the frequency of GGEL cross-links is an order of magnitude higher in Alzheimer's brain cortex than in age-matched or younger controls. This difference is due to the accumulation of GGEL cross-links in ubiquitin-immunopositive protein particles present in both Alzheimer's brains and those from aged individuals. The highly crosslinked protein aggregates show immunoreactivity to antibodies against tau and neurofilament proteins, and partially also to alpha-synuclein, indicating that these structures are inherent in Alzheimer's neurofibrillary tangles and Lewy bodies. Using mass sequence analysis, we identified the same six pairs of peptide sequences cross-linked in both senile and Alzheimer's specimens: Gln(31) and Gln(190) of HSP27 protein are cross-linked with Lys(29) and Lys(48) of ubiquitin and HSP27 therefore may cross-link two (poly) ubiquitin chains. One lysine residue of parkin and one of alpha-synuclein were also found to be cross-linked. The data suggest that cross-linking of (poly) ubiquitin moieties via HSP27 may have a role in the stabilization of the intraneuronal protein aggregates by interference with the proteasomal elimination of unfolded proteins. C1 Univ Debrecen, Res Ctr Mol Med, Hungarian Acad Sci, Dept Psychiat, H-4012 Debrecen, Hungary. Univ Debrecen, Res Ctr Mol Med, Hungarian Acad Sci, Dept Biochem & Mol Biol, H-4012 Debrecen, Hungary. Univ Debrecen, Res Ctr Mol Med, Hungarian Acad Sci, Signaling & Apoptosis Res Grp, H-4012 Debrecen, Hungary. Univ Ghent, Lab Prot Biochem & Prot Engn, B-9000 Ghent, Belgium. NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Nemes, Z (reprint author), Univ Debrecen, Med & Hlth Sci Ctr, Dept Psychiat, Nagyerdei Krt 98, H-4012 Debrecen, Hungary. EM znemes@dote.hu RI Devreese, Bart/B-2011-2009 OI Devreese, Bart/0000-0002-9764-2581 NR 63 TC 68 Z9 68 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 EI 1530-6860 J9 FASEB J JI Faseb J. PD MAY PY 2004 VL 18 IS 7 BP 1135 EP + DI 10.1096/fj.04-1493fje PG 25 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 827EZ UT WOS:000221883200019 PM 15132984 ER PT J AU Chen, G Bower, KA Ma, CL Fang, SY Thiele, CJ Luo, J AF Chen, G Bower, KA Ma, CL Fang, SY Thiele, CJ Luo, J TI Glycogen synthase kinase 3 beta (GSK3 beta) mediates 6-hydroxydopamine-induced neuronal death SO FASEB JOURNAL LA English DT Article DE apoptosis; caspases; endoplasmic reticulum stress; neurodegeneration; neurotrophins ID ENDOPLASMIC-RETICULUM STRESS; CEREBELLAR GRANULE NEURONS; UNFOLDED PROTEIN RESPONSE; NERVE GROWTH-FACTOR; PARKINSONS-DISEASE; CELL-DEATH; NEUROTROPHIC FACTOR; DOPAMINERGIC-NEURONS; ALZHEIMERS-DISEASE; INDUCED APOPTOSIS AB The causes of sporadic Parkinson's disease (PD) are poorly understood. 6-Hydroxydopamine (6-OHDA), a PD mimetic, is widely used to model this neurodegenerative disorder in vitro and in vivo; however, the underlying mechanisms remain incompletely elucidated. We demonstrate here that 6-OHDA evoked endoplasmic reticulum ( ER) stress, which was characterized by an up-regulation in the expression of GRP78 and GADD153 (Chop), cleavage of procaspase-12, and phosphorylation of eukaryotic initiation factor-2 alpha in a human dopaminergic neuronal cell line (SH-SY5Y) and cultured rat cerebellar granule neurons (CGNs). Glycogen synthase kinase-3 beta (GSK3beta) responds to ER stress, and its activity is regulated by phosphorylation. 6-OHDA significantly inhibited phosphorylation of GSK3beta at Ser9, whereas it induced hyperphosphorylation of Tyr216 with little effect on GSK3beta expression in SH-SY5Y cells and PC12 cells (a rat dopamine cell line), as well as CGNs. Furthermore, 6-OHDA decreased the expression of cyclin D1, a substrate of GSK3beta, and dephosphorylated Akt, the upstream signaling component of GSK3beta. Protein phosphatase 2A (PP2A), an ER stress-responsive phosphatase, was involved in 6-OHDA-induced GSK3beta dephosphorylation (Ser9). Blocking GSK3beta activity by selective inhibitors ( lithium, TDZD-8, and L803-mts) prevented 6-OHDA-induced cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), DNA fragmentations and cell death. With a tetracycline (Tet)-controlled TrkB inducible system, we demonstrated that activation of TrkB in SH-SY5Y cells alleviated 6-OHDA-induced GSK3beta dephosphorylation (Ser9) and ameliorated 6-OHDA neurotoxicity. TrkB activation also protected CGNs against 6-OHDA-induced damage. Although antioxidants also offered neuroprotection, they had little effect on 6-OHDA-induced GSK3beta activation. These results suggest that GSK3beta is a critical intermediate in pro-apoptotic signaling cascades that are associated with neurodegenerative diseases, thus providing a potential target site amenable to pharmacological intervention. C1 W Virginia Univ, Sch Med, Robert C Byrd Hlth Sci Ctr, Dept Microbiol Immunol & Cell Biol, Morgantown, WV 26506 USA. Univ Maryland, Inst Biotechnol, Ctr Med Biotechnol, Baltimore, MD 21201 USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Chinese Acad Sci, SIBS, Inst Nutr Sci, Shanghai, Peoples R China. RP Luo, J (reprint author), W Virginia Univ, Sch Med, Robert C Byrd Hlth Sci Ctr, Dept Microbiol Immunol & Cell Biol, Morgantown, WV 26506 USA. EM jluo@hsc.wvu.edu RI Fang, Shengyun/H-3802-2011; Luo, Jia/E-4674-2012 FU NCI NIH HHS [CA90385]; NIAAA NIH HHS [AA12968] NR 85 TC 195 Z9 205 U1 1 U2 14 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAY PY 2004 VL 18 IS 7 BP 1162 EP + DI 10.1096/fj.04-1551fje PG 26 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 827EZ UT WOS:000221883200022 PM 15132987 ER PT J AU Bhagwat, AA Bhagwat, M AF Bhagwat, AA Bhagwat, M TI Comparative analysis of transcriptional regulatory elements of glutamate-dependent acid-resistance systems of Shigella flexneri and Escherichia coli O157 : H7 SO FEMS MICROBIOLOGY LETTERS LA English DT Article DE microbial food safety; enteropathogens; glutamate decarboxylase ID ENTERIC BACTERIA; SALMONELLA-TYPHIMURIUM; PATHOGENICITY ISLAND; DECARBOXYLASE GENES; GADE YHIE; COLI; PH; EXPRESSION; TOLERANCE; SURVIVAL AB The ability to withstand an acid-challenge of pH 2.5 or less by Shigella flexneri is a necessary trait for virulence and is generally believed to be restricted to the stationary-phase of growth. Earlier reports indicated the glutamate-dependent acid-resistance (GDAR) system of S. flexneri is under the regulation of rpoS, the gene encoding alternative sigma factor that is induced in the stationary-growth phase. The present study reports that unlike Escherichia coli O157:H7, S. flexneri cells when grown in minimal medium, require acid-induction in the stationary-growth phase for a functional GDAR. When grown on complex medium at pH 5.5, GDAR of S. flexneri was vigorous compared to the cells grown at pH 7.5. No acid-induction was required for the stationary phase E coli cells grown on either minimal or complex growth media. Distinct differences in the gadA, gadBC, gadE, and hdeA (but not in rpoS) transcript levels were observed in the stationary-growth phase cells between the two pathogens grown oil minimal medium. Additionally, rpoS-independent acid-induction of GDAR in the logarithmic growth phase that has been recently observed in E. coli strains [FEMS Microbiol. Lett. 227 (2003) 39-45] was not detected in the S. flexneri rpoS mutant. Although some differences in the DNA sequence at the upstream regulatory elements of gadBC were noticed, they do not appear to be significant and involvement of additional regulators in S. flexneri is anticipated, which also may explain the observed differences in the GDAR of two enteric pathogens. (C) 2004 Federation of European Microbiological Societies. Published by Elsevier B.V. All rights reserved. C1 USDA, Agr Res Serv, Henry A Wallace Beltsville Agr Res Ctr, Produce Qual & Safety Lab, Beltsville, MD 20705 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Bhagwat, AA (reprint author), USDA, Agr Res Serv, Henry A Wallace Beltsville Agr Res Ctr, Produce Qual & Safety Lab, Bldg 002,10300 Baltimore Ave, Beltsville, MD 20705 USA. EM bhagwata@ba.ars.usda.gov NR 41 TC 24 Z9 24 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1097 J9 FEMS MICROBIOL LETT JI FEMS Microbiol. Lett. PD MAY 1 PY 2004 VL 234 IS 1 BP 139 EP 147 DI 10.1016/j.femsle.2004.03.020 PG 9 WC Microbiology SC Microbiology GA 818AP UT WOS:000221218300020 PM 15109732 ER PT J AU Calvisi, DF Factor, VM Ladu, S Conner, EA Thorgeirsson, SS AF Calvisi, DF Factor, VM Ladu, S Conner, EA Thorgeirsson, SS TI Disruption of beta-catenin pathway or genomic instability define two distinct categories of liver cancer in transgenic mice SO GASTROENTEROLOGY LA English DT Article ID HUMAN HEPATOCELLULAR CARCINOMAS; GROWTH-FACTOR-ALPHA; C-MYC OVEREXPRESSION; MOUSE MODEL; ACCELERATED HEPATOCARCINOGENESIS; PROGNOSTIC-SIGNIFICANCE; ALLELIC DELETIONS; DNA-REPLICATION; GENE-EXPRESSION; B6C3F1 MICE AB Background & Aims: Human liver cancer can be divided into 2 categories that are characterized by activation of P-catenin and genomic instability. Here we investigate whether similar categories exist among 5 transgenic models of liver cancer, including c-myc, transforming growth factor-alpha, E2F-1, c-myc/transforming growth factor-et, and c-myc/E2F-1 mice. Methods: The random amplified polymorphic DNA method was used to assess the overall genomic instability, and chromosomal loci affected by genomic alterations were determined by microsatellite analysis. beta-Catenin mutations and deletions were analyzed by polymerase chain reaction and sequencing screening. Cellular localization of beta-catenin and expression of alpha-fetoprotein, a prognostic marker of hepatocellular carcinoma, were investigated by immunohistochemistry. Results: Liver tumors from the transgenic mice could be divided into 2 broad categories characterized by extensive genomic instability (exemplified by the c-myc/transforming growth factor-alpha mouse) and activation of beta-catenin (exemplified by the c-myc/E2F-1 mouse). The c-myc/transforming growth factor-alpha tumors displayed extensive genomic instability with recurrent loss of heterozygosity at chromosomes 1, 2, 4, 6, 7, 9, 12, 14, and X and a low rate of beta-catenin activation. The genomic instability was evident from the early dysplastic stage and occurred concomitantly with increased expression of alpha-fetoprotein. The c-myc/E2F-1 tumors were characterized by a high frequency of beta-catenin activation in the presence of a relatively stable genome and low alpha-fetoprotein levels. Conclusions: We have identified 2 prototype experimental models, i.e., c-myc/transforming growth factor-alpha and c-myc/E2F-1 mice, for the 2 categories of human hepatocellular carcinoma characterized by genomic instability and beta-catenin activation, respectively. These mouse models will assist in the elucidation of the molecular basis of human hepatocellular carcinoma. C1 NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37,Room 4146A,37 Convent Dr MSC 4262, Bethesda, MD 20892 USA. EM snorri_thorgeirsson@nih.gov NR 78 TC 65 Z9 66 U1 1 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2004 VL 126 IS 5 BP 1374 EP 1386 DI 10.1053/j.gastro.2004.02.014 PG 13 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 818AD UT WOS:000221217100019 PM 15131798 ER PT J AU Hawk, ET Umar, A Viner, JL AF Hawk, ET Umar, A Viner, JL TI Colorectal cancer chemoprevention - An overview of the science SO GASTROENTEROLOGY LA English DT Review ID FAMILIAL ADENOMATOUS POLYPOSIS; ABERRANT CRYPT FOCI; FECAL-OCCULT-BLOOD; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; RANDOMIZED CONTROLLED TRIAL; ELEVATED CYCLOOXYGENASE-2 EXPRESSION; INDUCED COLON CARCINOGENESIS; BOWMAN-BIRK INHIBITOR; ORNITHINE DECARBOXYLASE INHIBITOR; PRIMARY SCLEROSING CHOLANGITIS AB The development and dissemination of sophisticated detection technologies have recently exposed the high prevalence of preinvasive colorectal neoplasia in the adult U.S. population. Although cancer screening and surveillance provide opportunities for risk stratification, they achieve risk reduction only when coupled with effective interventions. This review surveys the lead compounds for colorectal cancer prevention and the measures by which they may be prioritized for clinical testing. Clinical trials remain the rate-limiting step in agent development, and novel trial designs are needed to hasten agent identification and testing for cancer prevention. Innovative research models include the nesting of prevention end points within cancer treatment trials and within trials testing promising preventive compounds intended for nononcologic indications. C1 NCI, Gastrointestinal & Other Canc Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. RP Hawk, ET (reprint author), NCI, Gastrointestinal & Other Canc Res Grp, Div Canc Prevent, EBN,Suite 2141,6130 Execut Blvd, Bethesda, MD 20892 USA. EM eh51p@nih.gov NR 287 TC 54 Z9 60 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAY PY 2004 VL 126 IS 5 BP 1423 EP 1447 DI 10.1053/j.gastro.2004.03.002 PG 25 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 818AD UT WOS:000221217100024 PM 15131803 ER PT J AU Woodside, KJ Shen, H Muntzel, C Daller, JA Sommers, CL Love, PE AF Woodside, KJ Shen, H Muntzel, C Daller, JA Sommers, CL Love, PE TI Expression of Dlx and Lhx family homeobox genes in fetal thymus and thymocytes SO GENE EXPRESSION PATTERNS LA English DT Article DE fetal thymocytes; homeobox gene; Dlx; Lhx; Lim; thymus development; thymus ID T-CELL RECEPTOR; LYMPHOCYTES; FOREBRAIN; DIFFERENTIATION; MORPHOGENESIS; TISSUES; SUBSETS; CORTEX; STEPS AB Homeobox genes comprise a nearly ubiquitous and highly conserved superfamily of developmental regulatory genes that encode transcription factors involved in the determination of axis and tissue identity. While homeobox gene expression has been well characterized in a variety of embryonic tissues. their expression has not been extensively studied in lymphoid progenitor cells or in sites of lymphogenesis. To examine homeobox gene expression in the developing thymus, we screened an embryonic day 13.5 thymus cDNA library by polymerase chain reaction (PCR) using degenerate oligonucleotides within the highly conserved homeodomain region of eight homeobox gene families. The resulting PCR products were then cloned and sequenced. Transcripts for multiple Dlx family members and Lhx2 were repeatedly detected in this screen. Screening of embryonic day 16.5 and adult murine thymus and Thy1(+) thymocytes was performed for selected members of these homeobox gene families. Transcripts encoding Lhx2. Lhx3, and Lhx9, as well as Dlx1 and Dlx2 were detected in both thymus and purified thymocytes. Dlx1 is a member of the distal-less homeobox gene family that has been shown to regulate embryonic craniofacial development. Significantly, Dlx1 is expressed in the third branchial arch, which contributes to the thymus. Although Dlx1 knockout mice did not display any obvious developmental defects in thymus or thymocyte development, the expression of these homeobox,genes in neural crest derivatives suggests a possible role in cell migration and development that may overlap with other homeobox genes. (C) 2003 Elsevier B.V. All rights reserved. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Dept Surg, Galveston, TX 77555 USA. RP Love, PE (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bldg 6B,Room 2B-210,9000 Rockville Pike, Bethesda, MD 20892 USA. EM lovep@mail.nih.gov OI Woodside, Kenneth/0000-0002-7495-3758 NR 26 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-133X J9 GENE EXPR PATTERNS JI Gene Expr. Patterns PD MAY PY 2004 VL 4 IS 3 BP 315 EP 320 DI 10.1016/j.modgep.2003.10.003 PG 6 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 813RF UT WOS:000220923500011 PM 15053981 ER PT J AU Buchholz, DR Ishizuya-Oka, A Shi, YB AF Buchholz, DR Ishizuya-Oka, A Shi, YB TI Spatial and temporal expression pattern of a novel gene in the frog Xenopus laevis: correlations with adult intestinal epithelial differentiation during metamorphosis SO GENE EXPRESSION PATTERNS LA English DT Article DE Xenopus laevis; tadpole; metamorphosis; intestine; tectorin; nidogen ID THYROID-HORMONE REGULATION; AMPHIBIAN METAMORPHOSIS; ALPHA-TECTORIN; SMART AB We report the cloning of a novel gene (ID14) and its expression pattern in tadpoles and adults of Xenopus laevis. ID14 encodes a 315-amino acid protein that has a signal peptide and a nidogen domain. Even though several genes have a nidogen domain, ID14 is not the homolog of any known gene. ID14 is a late thyroid hormone (TH)-regulated gene in the tadpole intestine, and its expression in the intestine does not begin until the climax of metamorphosis, correlating with adult intestinal epithelial differentiation. In contrast, ID14 is expressed in tadpole skin and tail and is not regulated by TH. In situ hybridization revealed that this Putative extracellular matrix protein is expressed in the epithelia of the tadpole skin and tail and in the intestinal epithelium after metamorphosis. In the adult, ID14 is found predominantly in the intestine with weak expression in the stomach, lung. and testis. Its exclusive expression in the adult intestinal epithelial cells makes it a useful marker for developmental studies and may give insights into cell/cell interactions in intestinal metamorphosis and adult intestinal stein cell maintenance. (C) 2004 Elsevier B.V. All rights reserved. C1 NICHHD, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Dokkyo Univ, Sch Med, Dept Histol & Neurobiol, Mibu, Tochigi 3210293, Japan. RP Shi, YB (reprint author), NICHHD, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. EM shi@helix.nih.gov NR 18 TC 11 Z9 13 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-133X J9 GENE EXPR PATTERNS JI Gene Expr. Patterns PD MAY PY 2004 VL 4 IS 3 BP 321 EP 328 DI 10.1016/j.modgep.2003.10.005 PG 8 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 813RF UT WOS:000220923500012 PM 15053982 ER PT J AU Toyama, R Gomez, DM Mana, MD Dawid, IB AF Toyama, R Gomez, DM Mana, MD Dawid, IB TI Sequence relationships and expression patterns of zebrafish zic2 and zic5 genes SO GENE EXPRESSION PATTERNS LA English DT Article DE zinc finger gene; zic2; zic5; zebrafish; central nervous system; eye; somite ID NEURAL CREST DEVELOPMENT; PRESUMPTIVE NEURECTODERM; XENOPUS; FAMILY; INDUCTION; LIM1 AB The zinc finger motif forms a DNA binding domain that is found in a wide variety of proteins. Among, them, the members of the zic gene family are highly conserved throughout metazoans. We report here the isolation of two new members of this gene family in zebrafish, zic2.2 and Zic5, isolated during random screening for tissue-specific genes. Zic2.2 is closely related to the previously reported zic2 gene, which we propose to rename zic2.1: these two genes form a subfamily with other vertebrate zic2 genes. We compare here the expression patterns of zic2.1. zic2.2. and zic5. All three genes showed dynamic expression patterns starting after the initiation of zygotic transcription, predominantly in the developing neural tube. Compared to zic2.1. zic2.2 was expressed in a similar but distinct manner during early development. particularly in the retina and the forming somites. A zic2.2 ortholog has not been identified in other vertebrate species, suggesting that the zic2.1/zic2.2 pair resulted from a genome duplication event during the evolution of the zebrafish lineage. (C) 2003 Elsevier B.V. All rights reserved. C1 NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), NICHHD, Mol Genet Lab, NIH, Bldg 6B,Room 413,9000 Rockville Pike, Bethesda, MD 20892 USA. EM idawid@nih.gov NR 20 TC 19 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-133X J9 GENE EXPR PATTERNS JI Gene Expr. Patterns PD MAY PY 2004 VL 4 IS 3 BP 345 EP 350 DI 10.1016/j.modgep.2003.09.011 PG 6 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 813RF UT WOS:000220923500016 PM 15053986 ER PT J AU Shi, Q Ando, H Coon, SL Sato, S Ban, M Urano, A AF Shi, Q Ando, H Coon, SL Sato, S Ban, M Urano, A TI Embryonic and post-embryonic expression of arylalkylamine N-acetyltransferase and melatonin receptor genes in the eye and brain of chum salmon (Oncorhynchus keta) SO GENERAL AND COMPARATIVE ENDOCRINOLOGY LA English DT Article DE AANAT; melatonin receptor; real-time PCR; retina; brain; development; salmonid ID BINDING-SITES; RAINBOW-TROUT; PINEAL ORGAN; CIRCADIAN VARIATIONS; GOLDFISH BRAIN; MESSENGER-RNA; RAT-BRAIN; RHYTHM; RETINA; LIGHT AB Melatonin and arylalkylamine N-acetyltransferase (AANAT), the rate-limiting enzyme in melatonin synthesis, have taken on special importance in vertebrate circadian biology. Recent identification of genes encoding two AANAT (AANAT(1) and AANAT(2)) and two subtypes of melatonin receptor (Mel-R; Mel(1a) and Mel(1b)) in several fish species has led to rapid advances in characterizing the physiological roles of melatonin. In the present study, partial cDNAs encoding these four genes were cloned from the eye and brain of chum salmon (Oncorhynchus keta). Based on the nucleotide sequences, we developed highly sensitive real-time PCR systems for these four mRNAs. The development of daily rhythmicity in AANAT(1), AANAT(2), Mel(1a), and Mel(1b) transcript levels was examined in the eye and brain of chum salmon during embryonic and post-embryonic stages (from day -9 to day +180). In a parallel experiment, ocular and brain melatonin levels were measured by radioimmunoassay. Parallelism in developmental changes and in circadian rhythms of AANAT mRNAs and melatonin levels in the eye and the brain supports a hypothesis that the developmental increases of nocturnal melatonin levels results partly from the elevated transcription of AANAT genes. Moreover, abundant expression of AANAT and Mel-R mRNAs in the optic tectum, thalamus, hypothalamus, cerebellum, and eye indicates possible roles of melatonin in visual processing and neuroendocrine regulation, through which melatonin might be involved in migratory behavior of chum salmon. (C) 2004 Elsevier Inc. All rights reserved. C1 Hokkaido Univ, Grad Sch Sci, Div Biol Sci, Sapporo, Hokkaido 0600810, Japan. NICHHD, Dev Neurobiol Lab, NIH, Bethesda, MD 20892 USA. Natl Salmon Resource Ctr, Sapporo, Hokkaido 0620922, Japan. RP Ando, H (reprint author), Hokkaido Univ, Grad Sch Sci, Div Biol Sci, Sapporo, Hokkaido 0600810, Japan. EM hando@sci.hokudai.ac.jp NR 50 TC 28 Z9 30 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0016-6480 J9 GEN COMP ENDOCR JI Gen. Comp. Endocrinol. PD MAY 1 PY 2004 VL 136 IS 3 BP 311 EP 321 DI 10.1016/j.ygcen.2004.01.004 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 817MR UT WOS:000221182100001 PM 15081830 ER EF