FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Grimm, D Eggers, CH Caimano, MJ Tilly, K Stewart, PE Elias, AF Radolf, JD Rosa, PA AF Grimm, D Eggers, CH Caimano, MJ Tilly, K Stewart, PE Elias, AF Radolf, JD Rosa, PA TI Experimental assessment of the roles of linear plasmids 1p25 and 1p28-1 of Borrelia burgdorferi throughout the infectious cycle SO INFECTION AND IMMUNITY LA English DT Article ID LYME-DISEASE SPIROCHETE; EXTRACHROMOSOMAL DNAS; ANTIGENIC VARIATION; CLONAL POPULATIONS; CIRCULAR PLASMIDS; GENE-EXPRESSION; MAMMALIAN HOST; IN-VITRO; SEQUENCE; VLSE AB Borrelia burgdorferi, which causes Lyme disease in humans, has an unusual genome composed of a linear chromosome and up to 21 extrachromosomal elements. Experimental data suggest that two of these elements, linear plasmids lp25 and lp28-1, play essential roles for infectivity in mice. In this study, we prove the essential natures of these two plasmids by selectively displacing lp25 or lp28-1 in an infectious wild-type clone with incompatible shuttle vectors derived from the native plasmids, rendering the respective transformants noninfectious to mice. Conversely, restoration of plasmid lp25 or lp28-1 in noninfectious clones that naturally lack the corresponding plasmid reestablished infectivity in mice. This approach establishes the ability to manipulate the plasmid content of strains by eliminating or introducing entire plasmids in B. burgdorferi and will be valuable in assessing the roles of plasmids even in unsequenced B. burgdorferi strains. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Connecticut, Ctr Hlth, Dept Pathol, Farmington, CT USA. Univ Connecticut, Ctr Hlth, Ctr Microbial Pathogenesis, Farmington, CT USA. Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT USA. RP Rosa, PA (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM prosa@niaid.nih.gov FU NIAID NIH HHS [AI-29735, R01 AI029735, R56 AI029735] NR 52 TC 68 Z9 70 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD OCT PY 2004 VL 72 IS 10 BP 5938 EP 5946 DI 10.1128/IAI.72.10.5939-5946.2004 PG 9 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 857QS UT WOS:000224134000048 PM 15385497 ER PT J AU Ribeiro, JMC Topalis, P Louis, C AF Ribeiro, JMC Topalis, P Louis, C TI AnoXcel: an Anopheles gambiae protein database SO INSECT MOLECULAR BIOLOGY LA English DT Article DE spreadsheet; annotation; proteome; mosquito; genomics ID SEQUENCE AB The proteome of the mosquito Anopheles gambiae was organized on a hyperlinked spreadsheet format containing one protein per row and several pieces of information in each column. The information for each protein ranges from the presence or absence of signal peptide indicative of secretion, presence of transmembrane domains, similarities to several databases, chromosomal location, and relatedness to other An. gambiae proteins, etc. Hosted by ANOBASE (http://www.anobase. org/), the whole spreadsheet or segments of it can be downloaded or searched from www.anobase.org/ AnoBase/Genes/Ano-Xcel by the scientist dealing with the annotation of proteome subsets such as those deriving from transcriptomes, nucleotide microarrays or high throughput mass spectrometry data. C1 NIAID, LMVR, Bethesda, MD 20892 USA. Fdn Res & Technol Hellas, Inst Mol Biol & Biotechnol, Iraklion, Greece. Univ Crete, Dept Biol, Iraklion, Greece. RP Ribeiro, JMC (reprint author), NIAID, LMVR, 12735 Twinbrook Pkwy,Room 2E32D, Bethesda, MD 20892 USA. EM jribeiro@niaid.nih.gov OI Ribeiro, Jose/0000-0002-9107-0818 NR 13 TC 28 Z9 28 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0962-1075 J9 INSECT MOL BIOL JI Insect Mol. Biol. PD OCT PY 2004 VL 13 IS 5 BP 449 EP 457 DI 10.1111/j.0962-1075.2004.00503.x PG 9 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 855ED UT WOS:000223955000001 PM 15373803 ER PT J AU Tarnay, JN Szeri, F Ilias, A Annilo, T Sung, C Le Saux, O Varadi, A Dean, M Boyd, CD Robinow, S AF Tarnay, JN Szeri, F Ilias, A Annilo, T Sung, C Le Saux, O Varadi, A Dean, M Boyd, CD Robinow, S TI The dMRP/CG6214 gene of Drosophila is evolutionarily and functionally related to the human multidrug resistance-associated protein family SO INSECT MOLECULAR BIOLOGY LA English DT Article DE ATP-binding cassette transporters; membrane transporters; ABCC subfamily; MRP ID GLUTATHIONE-S-TRANSFERASE; CASSETTE ABC TRANSPORTER; PERSISTENT HYPERINSULINEMIC HYPOGLYCEMIA; CAUSE PSEUDOXANTHOMA ELASTICUM; DUBIN-JOHNSON-SYNDROME; MEMBRANE TOPOLOGY; ORGANIC-ANIONS; MRP2 GENE; CALLIPHORA-ERYTHROCEPHALA; TRANSMEMBRANE DOMAIN AB ATP-binding cassette (ABC) transporters are involved in the transport of substrates across biological membranes and are essential for many cellular processes. Of the fifty-six Drosophila ABC transporter genes only white, brown, scarlet, E23 and Atet have been studied in detail. Phylogenetic analyses identify the Drosophila gene dMRP/CG6214 as an orthologue to the human multidrug-resistance associated proteins MRP1, MRP2, MRP3 and MRP6. To study evolutionarily conserved roles of MRPs we have initiated a characterization of dMRP. In situ hybridization and Northern analysis indicate that dMRP is expressed throughout development and appears to be head enriched in adults. Functional studies indicate that DMRP is capable of transporting a known MRP1 substrate and establishes DMRP as a high capacity ATP-dependent, vanadate-sensitive organic anion transporter. C1 Univ Hawaii, Dept Zool, Honolulu, HI 96822 USA. Hungarian Acad Sci, Inst Enzymol, Budapest, Hungary. NCI, Human Genet Sect, Lab Genom Divers, Frederick, MD 21701 USA. Univ Hawaii Manoa, Dept Zool, Honolulu, HI 96822 USA. Univ Hawaii Manoa, Pacific Biomed Res Ctr, Honolulu, HI 96822 USA. RP Robinow, S (reprint author), Univ Hawaii, Dept Zool, 2538 McCarthy Mall, Honolulu, HI 96822 USA. EM robinow@hawaii.edu RI Varadi, Andras/A-2055-2012; Dean, Michael/G-8172-2012; Annilo, Tarmo/J-2900-2013; OI Dean, Michael/0000-0003-2234-0631; Annilo, Tarmo/0000-0002-9588-3058; Ilias, Attila/0000-0003-3196-0795 FU NCRR NIH HHS [P20 RR016453, RR416453]; NIGMS NIH HHS [5R25GM56930-06] NR 79 TC 23 Z9 23 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0962-1075 J9 INSECT MOL BIOL JI Insect Mol. Biol. PD OCT PY 2004 VL 13 IS 5 BP 539 EP 548 DI 10.1111/j.0962-1075.2004.00512.x PG 10 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 855ED UT WOS:000223955000008 PM 15373810 ER PT J AU Vitale, M Carlomagno, S Falco, M Pende, D Romeo, E Rivera, P Della Chiesa, M Mavilio, D Moretta, A AF Vitale, M Carlomagno, S Falco, M Pende, D Romeo, E Rivera, P Della Chiesa, M Mavilio, D Moretta, A TI Isolation of a novel KIR2DL3-specific mAb: comparative analysis of the surface distribution and function of KIR2DL2, KIR2DL3 and KIR2DS2 SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE HLA-specific receptors; immunoglobulin superfamily; KIR; NK cells ID CLASS-I MOLECULES; NATURAL-KILLER-CELLS; HUMAN NK CELLS; INHIBITORY RECEPTORS; ACTIVATING RECEPTORS; RECOGNITION; CLONES; IDENTIFICATION; CYTOTOXICITY; LYSIS AB In recent years an increasing number of sequences coding for new KIRs have been described. However, the limited availability of mAbs with unique KIR specificities has hindered an exhaustive assessment of their actual function, HLA-specificity, expression at the cell surface and distribution in different cell populations. In this study we report the generation of a novel mAb (ECM41) specific for KIR2DL3 molecules. By the use of cell transfectants expressing one or other KIR we show that this reagent allows discrimination of KIR2DL3 from other GL183 mAb-reactive molecules such as KIR2DL2 and KIR2DS2. Moreover we show that this novel mAb can be used to assess the surface expression and distribution of KIR2DL3 in different polyclonal NK populations and in NK cell clones. Along this line, we were able to analyze the HLA class I specificity of NK clones expressing either KIR2DL3 or KIR2DL2, two inhibitory receptors that were so far serologically undistinguishable. Finally, the combined use of GL183 and ECM41 mAbs in redirected killing assays allowed us to investigate the functional outcome of the simultaneous engagement of KIR2DL3 and KIR2DS2 in NK cell clones co-expressing KIRs that display opposite (inhibitory vs activating) function. C1 Univ Genoa, Dipartimento Med Sperimentale, I-16132 Genoa, Italy. Ist Nazl Ric Canc, I-16132 Genoa, Italy. Ist Giannina Gaslini, I-16148 Genoa, Italy. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Univ Genoa, Ctr Eccellenza Ric Biomed, I-16132 Genoa, Italy. RP Moretta, A (reprint author), Univ Genoa, Dipartimento Med Sperimentale, Via LB Alberti 2, I-16132 Genoa, Italy. EM alemoret@unige.it RI Vitale, Massimo/G-5135-2016; Pende, Daniela/J-7429-2016; Falco, Michela/K-1574-2016; OI Vitale, Massimo/0000-0001-5372-7885; Pende, Daniela/0000-0003-1565-451X; Mavilio, Domenico/0000-0001-6147-0952 NR 43 TC 12 Z9 13 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD OCT PY 2004 VL 16 IS 10 BP 1459 EP 1466 DI 10.1093/intimm/dxh147 PG 8 WC Immunology SC Immunology GA 856XQ UT WOS:000224079800011 PM 15314042 ER PT J AU Stefanek, M AF Stefanek, M TI Commentary on "Group interventions for patients with cancer and HIV disease" SO INTERNATIONAL JOURNAL OF GROUP PSYCHOTHERAPY LA English DT Editorial Material ID DIFFERENT PHASES; OUTCOMES; ILLNESS C1 NCI, Div Canc Control & Populat Sci, Basic Biobehav Res Branch, Behav Res Program, Bethesda, MD 20892 USA. RP Stefanek, M (reprint author), NCI, Div Canc Control & Populat Sci, Basic Biobehav Res Branch, Behav Res Program, 6130 Execut Blvd,EPN 4066, Bethesda, MD 20892 USA. EM stefanem@mail.nih.gov NR 8 TC 1 Z9 1 U1 1 U2 1 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0020-7284 J9 INT J GROUP PSYCHOTH JI Int. J. Group Psychother. PD OCT PY 2004 VL 54 IS 4 BP 569 EP 574 DI 10.1521/ijgp.54.4.569.42767 PG 6 WC Psychology, Clinical SC Psychology GA 858SW UT WOS:000224213100010 ER PT J AU Santos, CL Torres, J Sanchez, J Dasgupta, A Jeronimo, J AF Santos, CL Torres, J Sanchez, J Dasgupta, A Jeronimo, J TI Lack of effectiveness of CO2 cryotherapy for treatment of CIN SO INTERNATIONAL JOURNAL OF GYNECOLOGY & OBSTETRICS LA English DT Editorial Material DE cryotherapy; CO2; cervical intraepithelial neoplasia; cervical cancer ID INTRA-EPITHELIAL NEOPLASIA; UTERINE CERVIX C1 Inst Enfermedades Neoplasicas Eduardo Caceres Gra, Dept Gynecol, Lima, Peru. Inst Enfermedades Neoplasicas Eduardo Caceres Gra, Dept Pathol, Lima, Peru. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. RP Jeronimo, J (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,MSC 7234, Bethesda, MD 20892 USA. EM guibovij@mail.nih.gov NR 4 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0020-7292 J9 INT J GYNECOL OBSTET JI Int. J. Gynecol. Obstet. PD OCT PY 2004 VL 87 IS 1 BP 44 EP 45 DI 10.1016/j.ijgo.2004.06.014 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 864VT UT WOS:000224661800013 PM 15464779 ER PT J AU Normanno, N De Luca, A Maiello, MR Bianco, C Mancino, M Strizzi, L Arra, C Ciardiello, F Agrawal, S Salomon, DS AF Normanno, N De Luca, A Maiello, MR Bianco, C Mancino, M Strizzi, L Arra, C Ciardiello, F Agrawal, S Salomon, DS TI CRIPTO-1: A novel target for therapeutic intervention in human carcinoma SO INTERNATIONAL JOURNAL OF ONCOLOGY LA English DT Article DE CRIPTO-1; antisense; therapy; carcinoma ID GROWTH-FACTOR-ALPHA; BREAST-CANCER CELLS; DIFFERENTIAL IMMUNOHISTOCHEMICAL DETECTION; MAMMARY EPITHELIAL-CELLS; EGF-RELATED PEPTIDES; ANTISENSE OLIGONUCLEOTIDES; MESSENGER-RNA; TUMOR-CELLS; AMPHIREGULIN; EXPRESSION AB Evidence suggests that CRIPTO-1 (CR-1) might be involved in the pathogenesis of human carcinoma. In the present study, we have screened the expression of CR-1 mRNA and protein in a wide panel of human cancer cell lines by using reverse transcriptase (RT)-PCR, real-time PCR and immunocytochemistry. Results of these experiments demonstrate that CR-1 is expressed in several, different carcinoma types. The anchorage-independent growth of colon, ovarian, lung and breast carcinoma cells was significantly inhibited by treatment with anti-CR-1 second generation antisense oligonucleotides. Similar results were obtained with anti-transforming growth factor a (TGF-alpha) and anti-amphiregulin (AR) antisense oligonucleotides. Treatment of carcinoma cells with CR-1 antisense oligonucleotides resulted in a significant reduction in the levels of expression of CR-1 mRNA and protein, and in the levels of activation of Akt. Finally, oral administration of either CR-1, AR or TGF-alpha antisense oligonucleotides produced a significant reduction in the growth of GEO colon carcinoma xenografts in nude mice that was associated with a reduction in the levels of expression of the target proteins. Taken together, these data strongly suggest that CR-1 might represent a novel target for therapeutic intervention in different carcinoma types. C1 Fdn Pascale, INT, Dept Expt Oncol & Haematol Oncol, I-80131 Naples, Italy. Fdn Pascale, INT, Anim Facil, I-80131 Naples, Italy. NCI, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. SUN, Dipartimento Med Chirurg Internist Clin & Sperime, Naples, Italy. Hybridon Inc, Cambridge, MA 02139 USA. RP Normanno, N (reprint author), Fdn Pascale, INT, Dept Expt Oncol & Haematol Oncol, Via Mariano Semmola, I-80131 Naples, Italy. EM nicnorm@yahoo.com RI De Luca, Antonella/J-8737-2016; OI De Luca, Antonella/0000-0001-5762-447X; Ciardiello, Fortunato/0000-0002-3369-4841; Arra, Claudio/0000-0003-3162-2091; Normanno, Nicola/0000-0002-7158-2605 NR 33 TC 23 Z9 24 U1 0 U2 0 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1019-6439 J9 INT J ONCOL JI Int. J. Oncol. PD OCT PY 2004 VL 25 IS 4 BP 1013 EP 1020 PG 8 WC Oncology SC Oncology GA 856VP UT WOS:000224073700025 PM 15375551 ER PT J AU Pipe, ME Orbach, Y Lamb, M AF Pipe, ME Orbach, Y Lamb, M TI Autobiographical memory and children's testimony: A crosscultural perspective SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 NICHHD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD OCT-DEC PY 2004 VL 39 IS 5-6 SU S BP 7 EP 7 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 884WS UT WOS:000226118000056 ER PT J AU Fernandez-Santaella, MD Rodriguez, S Guerra, P Munoz, MA Viedma, M AF Fernandez-Santaella, MD Rodriguez, S Guerra, P Munoz, MA Viedma, M TI Food craving and heart rate variability (HRV) SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 Univ Granada, E-18071 Granada, Spain. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD OCT-DEC PY 2004 VL 39 IS 5-6 SU S BP 135 EP 135 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 884WS UT WOS:000226118001227 ER PT J AU Zhao, L Jiang, Y Wei, JH AF Zhao, L Jiang, Y Wei, JH TI The changes of EEG synchronization index spectrum related to visual selective mental arithmetic SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD OCT-DEC PY 2004 VL 39 IS 5-6 SU S BP 189 EP 189 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 884WS UT WOS:000226118001715 ER PT J AU Bornstein, M AF Bornstein, M TI Cross-cultural views of parenting SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD OCT-DEC PY 2004 VL 39 IS 5-6 SU S BP 222 EP 222 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 884WS UT WOS:000226118002028 ER PT J AU Ando, M Asakura, T Simons-Morton, B AF Ando, M Asakura, T Simons-Morton, B TI Psychosocial influences on physical, verbal, and indirect bullying among Japanese junior high school students SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 Tokyo Gakugei Univ, Tokyo, Japan. NIH, Bethesda, MD USA. RI ANDO, Mikayo/B-1378-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD OCT-DEC PY 2004 VL 39 IS 5-6 SU S BP 409 EP 410 PG 2 WC Psychology, Multidisciplinary SC Psychology GA 884WS UT WOS:000226118003728 ER PT J AU Desimone, R AF Desimone, R TI Synchronized neural activity and selective attention in visual cortex SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 NIMH, Neuropsychol Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD OCT-DEC PY 2004 VL 39 IS 5-6 SU S BP 474 EP 474 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 884WS UT WOS:000226118004290 ER PT J AU Hu, XZ AF Hu, XZ TI HTTLPR is triallelic and the high expression allele is linked to obsessive-compulsive disorder SO INTERNATIONAL JOURNAL OF PSYCHOLOGY LA English DT Meeting Abstract C1 NIAAA, LNG, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0020-7594 J9 INT J PSYCHOL JI Int. J. Psychol. PD OCT-DEC PY 2004 VL 39 IS 5-6 SU S BP 528 EP 528 PG 1 WC Psychology, Multidisciplinary SC Psychology GA 884WS UT WOS:000226118004777 ER PT J AU Franklin, AJ Jetton, TL Kuchemann, CL Russell, SR Kohn, EC AF Franklin, AJ Jetton, TL Kuchemann, CL Russell, SR Kohn, EC TI CAI is a potent inhibitor of neovascularization and imparts neuroprotection in a mouse model of ischemic retinopathy SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; SUBFOVEAL CHOROIDAL NEOVASCULARIZATION; OXYGEN-INDUCED RETINOPATHY; EPITHELIUM-DERIVED FACTOR; RANDOMIZED CLINICAL-TRIALS; IMPROVES RETINAL NEOVASCULARIZATION; SIGNAL-TRANSDUCTION INHIBITOR; ARGON-LASER PHOTOCOAGULATION; CALCIUM INFLUX INHIBITOR; CANCER CELL-LINES AB PURPOSE. This study was performed to characterize the effects of an antimetastatic and antiangiogenic molecule, carboxyamidotriazole (CAI), on retinal neovascularization in a mouse model. METHODS. Neonatal mice were subjected to 75% to 85% oxygen from postnatal day (PND)-7 to -12 and then were abruptly placed in room air. CAI ( 100 mg/kg) or vehicle control polyethylene glycol-400 (PEG-400) was given daily from PND-14 to - 16, and mice were killed on PND-17 to form group A. In group B, CAI ( 100 mg/kg) or PEG-400 was given daily from PND-17 to - 19, and mice were killed on PND-20. RESULTS. A 92% inhibition of neovascular cell nuclei on light microscopy was observed in mice treated with CAI in group A ( P < 0.0001). Fluorescein-perfusion demonstrated a similar profound inhibition of neovascular frond formation in CAI-treated mice in group A. In group B, after neovascular fronds had already formed, CAI administration reduced neovascular cell nuclei by 72% ( P < 0.001). Fluorescein perfusion studies confirmed that CAI induced regression of neovascular fronds. Similar amounts of posterior retinal ischemia were observed in all mice at both PND-17 and - 20. In group A and B animals, CAI increased immunoreactivity of a cellular survival factor, Bcl-2, decreased TUNEL-positive cells, and after CAI treatment the normal morphology of the inner retina remained intact. CONCLUSIONS. CAI almost completely abolished retinal neovascularization in group A, and neovascular fronds involuted after treatment with CAI in group B. Thus, CAI is a potent inhibitor of ischemia-induced neovascularization and also imparts retinal neuroprotection after ischemic injury. C1 Univ Iowa Hosp & Clin, Dept Ophthalmol, Iowa City, IA 52242 USA. Univ Iowa Hosp & Clin, Dept Anim Care, Iowa City, IA 52242 USA. Univ Vermont, Dept Endocrinol, Burlington, VT USA. NCI, Pathol Lab, Mol Signaling Sect, Bethesda, MD 20892 USA. RP Franklin, AJ (reprint author), Coll Med, Chattanooga Unit, Hlth Sci Ctr, 979 E 3rd St,Suite C235, Chattanooga, TN 37403 USA. EM alfranklin@aol.com NR 124 TC 5 Z9 6 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2004 VL 45 IS 10 BP 3756 EP 3766 DI 10.1167/iovs.03-1126 PG 11 WC Ophthalmology SC Ophthalmology GA 857YB UT WOS:000224154800051 PM 15452087 ER PT J AU Strunnikova, N Zhang, C Teichberg, D Cousins, SW Baffi, J Becker, KG Csaky, KG AF Strunnikova, N Zhang, C Teichberg, D Cousins, SW Baffi, J Becker, KG Csaky, KG TI Survival of retinal pigment epithelium after exposure to prolonged oxidative injury: A detailed gene expression and cellular analysis SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 04-09, 2003 CL FT LAUDERDALE, FL SP Assoc Res Vis & Ophthalmol ID MATRIX-METALLOPROTEINASE ACTIVITY; STRESS-INDUCED APOPTOSIS; MACULAR DEGENERATION; MICROARRAY ANALYSIS; CONFERRING PROTECTION; EXTRACELLULAR-MATRIX; ALZHEIMERS-DISEASE; DNA MICROARRAY; BLEB FORMATION; GROWTH-FACTOR AB PURPOSE. To detail, by DNA microarrays and cellular structure labeling, the in vitro responses of retinal pigment epithelial (RPE) cells to a nonlethal dose of the oxidant agent hydroquinone (HQ). METHODS. The viability of growth-quiescent ARPE-19 cells after treatment with HQ was measured by XTT conversion, H-3-leucine incorporation, trypan blue exclusion, and the presence of DNA laddering. The effect of a nonlethal dose of HQ on the localization of apoptosis-induced factor (AIF) and phosphorylation of stress-activated kinase-2/p38 (SAPK2/p38) was detected by immunocytochemistry. Actin structures were visualized by phalloidin staining. Cell membrane blebbing was detected using GFP-membrane-labeled RPE cells (ARPE-GFP-c'-rRas). Changes in gene expression patterns of RPE cells within 48 hours of prolonged treatment with a nonlethal dose of HQ were evaluated by microarray analysis and confirmed by Northern blotting. RESULTS. The viability of RPE after a prolonged sublethal injury dose of HQ was determined by multiple assays and confirmed by the absence of AIF translocation or DNA laddering. Prolonged exposure ( 16 hours) of RPE cells to a nonlethal dose of HQ resulted in actin rearrangement into globular aggregates and cell membrane blebbing. Kinetic microarray analysis at several time points over a 48-hour recovery period revealed significant upregulation of genes involved in ameliorating the oxidative stress, chaperone proteins, anti-apoptotic factors, and DNA repair factors, and downregulation of pro-apoptotic genes. Genes involved in extracellular matrix functions were also dysregulated. Recovery of RPE cells after the injury was confirmed by the normalization of gene expression dysregulation back to baseline levels within 48 hours. CONCLUSIONS. RPE cells avoided cell death and recovered from prolonged oxidative injury by activating a host of defense mechanisms while simultaneously triggering genes and cellular responses that may be involved in RPE disease development. C1 NEI, NIH, Bethesda, MD 20892 USA. NIA, DNA Array Unit, Res Resources Branch, NIH, Baltimore, MD 21224 USA. Univ Miami, Dept Ophthalmol, Miami, FL 33152 USA. RP Csaky, KG (reprint author), NEI, NIH, Bldg 10-10B11,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kcsaky@helix.nih.gov OI Becker, Kevin/0000-0002-6794-6656 NR 83 TC 47 Z9 49 U1 0 U2 1 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD OCT PY 2004 VL 45 IS 10 BP 3767 EP 3777 DI 10.1167/iovs.04-0311 PG 11 WC Ophthalmology SC Ophthalmology GA 857YB UT WOS:000224154800052 PM 15452088 ER PT J AU Berhane, K Karim, R Cohen, MH Masri-Lavine, L Young, M Anastos, K Augenbraun, M Watts, DH Levine, AM AF Berhane, K Karim, R Cohen, MH Masri-Lavine, L Young, M Anastos, K Augenbraun, M Watts, DH Levine, AM TI Impact of highly active antiretroviral therapy on anemia and relationship between anemia and survival in a large cohort of HIV-infected women - Women's interagency HIV study SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE HIV; AIDS; anemia; women; survival ID HUMAN-IMMUNODEFICIENCY-VIRUS; CELL LUNG-CANCER; QUALITY-OF-LIFE; BONE-MARROW; EPOETIN-ALPHA; AIDS; ERYTHROPOIETIN; PREVALENCE; DISEASE; TYPE-1 AB Background: Anemia is common in HIV-infected individuals and may be associated with decreased survival. Objective: To ascertain the impact of highly active antiretroviral therapy (HAART) on anemia and the relationship between anemia and overall survival in HIV-infected women. Methods: A prospective multicenter study of HIV-1 infection in women. Visits occurred every 6 months, including a standardized history, physical examination, and comprehensive laboratory evaluation. The setting was a university-affiliated clinic at 6 sites in the United States. Participants were 2056 HIV-infected women from the Women's Interagency HIV Study (WIHS). The Outcome measure was anemia, defined as hemoglobin (Hb) < 12 g/dL. Survival analysis was based on overall mortality during the follow-up period. Results: Among HIV-infected women who were notaneirtic at baseline, 47% became anemic by 3.5 years of follow-up. On multivariate analysis, the use of HAART was associated with resolution of anemia even when used for only 6 months (odds ratio [OR] = 1.45; P < 0.05). In the multivariate model, a CD4 cell count <200 cells/muL (OR = 0.56; P < 0.00 1); HIV-1 RNA level greater than or equal to 50,000 copies/mL (OR = 0.65; P < 0.001), and mean corpuscular volume (MCV) value <80 fL (OR 0.40; P < 0.001) were also associated with an inability to Correct anemia. Similarly, use of HAART for 12 months or more was associated with a protective effect against development of anemia (OR = 0.71; P < 0.001). Among HIV-infected women, anemia was independently associated with decreased survival (hazard ratio [HR] = 2.58; P < 0.001). Other factors associated with decreased Survival included a CD4 cell Count <200 cells/pL (HR = 5.83; P < 0.001), HIV-1 RNA level greater than or equal to 50,000 copies/ml- (HR = 2.12; P < 0.001), and clinical diagnosis of AIDS (HR = 2.83-1 P < 0.001). Conclusions: Anemia is an independent risk factor for decreased Survival among HIV-infected women. HAART therapy for as little as 6 months is associated with resolution of anernia. C1 Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. Cook Cty Hosp, Chicago, IL 60612 USA. Georgetown Univ, Washington, DC USA. Montefiore Med Ctr, Bronx, NY 10467 USA. Maimonides Hosp, Brooklyn, NY 11219 USA. Natl Inst Hlth, Rockville, MD USA. RP Berhane, K (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, 1540 Alcazar St,CHP-220, Los Angeles, CA 90089 USA. EM kiros@usc.edu FU NIAID NIH HHS [N01-AI-35161, U01-AI-31834, U01-AI-34989, U01-AI-34994, U01-AI-35004, U01-AI-42590]; NICHD NIH HHS [U01-HD-32632] NR 42 TC 65 Z9 69 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2004 VL 37 IS 2 BP 1245 EP 1252 DI 10.1097/01.qai.0000134759.01684.27 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 857ZJ UT WOS:000224159300004 PM 15385731 ER PT J AU Atkinson, JO Biggar, RJ Goedert, JJ Engels, EA AF Atkinson, JO Biggar, RJ Goedert, JJ Engels, EA TI The incidence of Kaposi sarcoma among injection drug users with AIDS in the United States SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE Kaposi sarcoma; human herpesvirus 8 (Kaposi sarcoma-associated; herpesvirus); AIDS; cancer; epidemiology; injection drug use ID IMMUNODEFICIENCY-VIRUS-INFECTION; HUMAN-HERPESVIRUS-8 INFECTION; RISK-FACTORS; SEXUAL TRANSMISSION; HIV-INFECTION; HERPESVIRUS; COHORT; WOMEN; MEN; SEROEPIDEMIOLOGY AB Some studies report increased prevalence of human herpesvirus 8 (HHV-8), the causative agent of Kaposi sarcoma (KS), among injection drug users (IDUs), suggesting that HHV-8 may be transmitted through blood-borne or other exposures common in this population. Since an elevated HHV-8 prevalence in IDUs would likely lead to increased KS incidence, KS incidence was studied in IDUs and non-IDU's with AIDS. AIDS-related KS cases were identified using linked US AIDS and cancer registry data for 25,891 women, 47,782 heterosexual men, and 90,616 men who have sex with men (MSM). KS arose in 7099 persons with AIDS. KS incidence was highest for MSM (5.7 per 100 person-years), substantially lower for heterosexual men (0.7 per 100 person-years), and lowest for women (0.4 per 100 person-years). After adjustment for age, race, registry location, and year of AIDS onset, relative risks for KS associated with injection drug use were 1.3 (95% CI, 0.9-1.8) among women, 1.1 (0.7-1.6) among heterosexual men, and 0.9 (0.8-0.9) among MSM. It is concluded that injection drug use was not associated with an increased risk of AIDS-related KS. Thus, these data suggest that IDUs' risk of acquiring HHV-8, through needle sharing or other behaviors related to injection drug use, is low. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD 20892 USA. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 6120 Executive Blvd,EPS 8010, Rockville, MD 20892 USA. EM engelse@exchange.nih.gov NR 26 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2004 VL 37 IS 2 BP 1282 EP 1287 DI 10.1097/01.qai.0000120807.43677.b6 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 857ZJ UT WOS:000224159300009 PM 15385736 ER PT J AU Liu, CL Carrington, M Kaslow, RA Gao, XJ Rinaldo, CR Jacobson, LP Margolick, JB Phair, J Obrien, SJ Detels, R AF Liu, CL Carrington, M Kaslow, RA Gao, XJ Rinaldo, CR Jacobson, LP Margolick, JB Phair, J Obrien, SJ Detels, R TI Lack of associations between HLA class II alleles and resistance to HIV-1 infection among white, non-hispanic homosexual men SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE resistance to HIV-1 infection; HLA; class II ID IMMUNODEFICIENCY-VIRUS TYPE-1; MULTICENTER AIDS COHORT; DR ALLELES; DISEASE ASSOCIATION; AFRICAN-AMERICANS; SERONEGATIVE MEN; SUSCEPTIBILITY; TRANSMISSION; PROTECTION; ANTIBODIES AB HLA class II alleles were molecularly typed for 100 high-risk seronegative men and 184 low-risk seroconverters from file Multicenter AIDS Cohort Study (MACS). Seven resistant individuals homozygous for CCR5 Delta32 deletions were excluded from analysis. In the Univariate analysis, no significant HLA class II associations with resistance/susceptibility to HIV type 1 infection were identified. However, the transporter associated with antigen presentation 2 (TAP2) Ala 665 variant associated with resistance in earlier analyses in the MACS was in linkage disequilibrium With some HLA class II alleles. After adjusting for the established associations with HLAA*0205 subgroup and TAP2 Ala 665 variant, no HLA class II alleles were independently associated with resistance/susceptibility to HIV-1 infection. Other genetic factors in the HLA class II-TAP region of the major histocorripatibility complex might be involved. C1 Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. SAIC Frederick Inc, Basic Res Program, NCI, Frederick, MD USA. Univ Alabama, Sch Publ Hlth, Birmingham, AL 35294 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. Northwestern Univ, Feinberg Sch Med, Howard Brown Hlth Ctr, Evanston, IL 60208 USA. NCI, Lab Genom Divers, Frederick, MD 21701 USA. RP Detels, R (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, 71-269 CHS,Box 951772, Los Angeles, CA 90095 USA. EM detels@ucla.edu FU NCI NIH HHS [N01-CO-12400]; NCRR NIH HHS [5-M01-RR-00722]; NIAID NIH HHS [UO1-AI-35039, UO1-AI-37984, UO1-AI-35042, UO1-AI-37613, UO1-AI-35043, R01-AI41951, UO1-AI-35041, UO1-AI-35040] NR 27 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2004 VL 37 IS 2 BP 1313 EP 1317 DI 10.1097/01.qai.0000127026.47429.5c PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 857ZJ UT WOS:000224159300013 PM 15385740 ER PT J AU Gordon, CM Stall, R Cheever, LW AF Gordon, CM Stall, R Cheever, LW TI Prevention interventions with persons living with HIV/AIDS - Challenges, progress, and research priorities SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Editorial Material ID SAFER-SEX; HIV; MEN C1 NIMH, Ctr Mental Hlth Res AIDS, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Prevent Res Branch, Atlanta, GA USA. US Hlth Resources & Serv Adm, HIV AIDS Bur, Rockville, MD 20857 USA. RP Gordon, CM (reprint author), NIMH, Ctr Mental Hlth Res AIDS, 6001 Execut Blvd,Room 6204, Bethesda, MD 20892 USA. EM cgordon1@mail.nih.gov NR 8 TC 20 Z9 20 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2004 VL 37 SU 2 BP S53 EP S57 DI 10.1097/01.qai.0000142321.27136.8b PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 859EC UT WOS:000224244500001 PM 15385900 ER PT J AU Mayer, KH Safren, SA Gordon, CM AF Mayer, KH Safren, SA Gordon, CM TI HIV care providers and prevention - Opportunities and challenges SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; SEXUALLY-TRANSMITTED DISEASE; SEROPOSITIVE GAY; BISEXUAL MEN; SEX; TRANSMISSION; INTERVENTION; INDIVIDUALS; PREVALENCE; INFECTION C1 Brown Univ, Miriam Hosp, Dept Med, Div Infect Dis, Providence, RI 02906 USA. Fenway Communit Hlth, Res Dept, Boston, MA USA. Fenway Communit Hlth, Fenway Inst, Boston, MA USA. Harvard Univ, Sch Med, Dept Psychol, Boston, MA USA. NIMH, Ctr Mental Hlth Res AIDS, Bethesda, MD 20892 USA. RP Mayer, KH (reprint author), Brown Univ, Miriam Hosp, Dept Med, Div Infect Dis, 164 Summit Ave, Providence, RI 02906 USA. EM Kenneth-Mayer@brown.edu NR 24 TC 19 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD OCT 1 PY 2004 VL 37 SU 2 BP S130 EP S132 DI 10.1097/01.qai.0000140613.66887.0c PG 3 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 859EC UT WOS:000224244500012 PM 15385911 ER PT J AU Malech, HL Choi, U Brenner, S AF Malech, HL Choi, U Brenner, S TI Progress toward effective gene therapy for chronic granulomatous disease SO JAPANESE JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 4th International Peroxidase Meeting CY OCT 27-30, 2004 CL Kyoto, JAPAN ID DEFECTS AB Previous clinical studies of ex vivo gene therapy for chronic granulomatous disease (CGD) without marrow conditioning have resulting in transient correction of the oxidase defect in over 0.1% of circulation neutrophils. Use of improved RD114 envelope pseudotyped vectors capable of transducing >95% of CD34(+) stem cells ex vivo, together with non-ablative marrow conditioning will be incorporated into the next generation of clinical trials of ex vivo gene therapy for CGD. These maneuvers might result in clinical benefit to CGD patients from gene therapy. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Malech, HL (reprint author), NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. EM hmalech@nih.gov RI Brenner, Sebastian/D-7456-2013 NR 7 TC 25 Z9 25 U1 0 U2 0 PU NATL INST INFECTIOUS DISEASES PI TOKYO PA JPN J INFECT DIS ED OFF NATL INST INFECTIOUS DISEASES TOYAMA 1-23-1, SHINJUKU-KU, TOKYO, 162-8640, JAPAN SN 1344-6304 EI 1884-2836 J9 JPN J INFECT DIS JI Jpn. J. Infect. Dis. PD OCT PY 2004 VL 57 IS 5 BP S27 EP S28 PG 2 WC Infectious Diseases SC Infectious Diseases GA 867WE UT WOS:000224872600030 PM 15507764 ER PT J AU Mizuno, K Kunii, M Seita, T Ono, S Komada, Y Shirakawa, S AF Mizuno, K Kunii, M Seita, T Ono, S Komada, Y Shirakawa, S TI Effects of habitual exercise on sleep habits and sleep health in middle-aged and older Japanese women SO JAPANESE JOURNAL OF PHYSICAL FITNESS AND SPORTS MEDICINE LA Japanese DT Article DE sleep health; exercise habit; middle-aged and older Japanese women ID GENERAL-POPULATION; CIRCADIAN-RHYTHMS; QUALITY INDEX; LIFE-STYLE; MORTALITY; DURATION; INSOMNIA; BRAIN AB The present study performed a cross-sectional survey to investigate sleep habits And sleep health in Japanese women aged 40 to 69 years with and without a habit of exercise. A standardized questionnaire evaluating sleep was administered to two subject groups. One was the "exercise group" who habitually performed aerobic exercise at mild to moderate intensity with a frequency of 2 times/week and duration of greater than or equal to30 minutes/one session (n=207). The other was the age-matched "non-exercise group" who had no exercise habit (n=567). Two-way ANOVA was employed for comparing the two subject groups and examining the effects of exercise on aging. Regarding sleep habits, as bed time significantly advanced with advancing age, sleep habits (bed time, waking time and sleep duration) were significantly more regular in the exercise group than in the non-exercise group. Concerning independent sleep health risk factors consisting of sleep initiation, sleep maintenance, sleep apnea, parasomnia, and waking-up, the factor score for sleep maintenance significantly deteriorated with advancing age; and was significantly better in the exercise group than in the non-exercise group. These results suggest that an exercise habit may improve sleep health in middle-aged and older Japanese women among which a higher prevalence of sleep problems has been reported. C1 NIMH, Bethesda, MD 20892 USA. Kao Tokyo Inst, Tokyo, Japan. RP Mizuno, K (reprint author), NIMH, Bethesda, MD 20892 USA. NR 22 TC 3 Z9 3 U1 1 U2 2 PU JAPANESE SOC PHYSICAL FITNESS SPORTS MEDICINE PI TOKYO PA C/O BUSINESS CENTER ACAD SOC JAPAN, 5-16-9 HONKOMAGOME, BUNKYO-KU, TOKYO, 113, JAPAN SN 0039-906X J9 JPN J PHYS FIT SPORT JI Jpn. J. Phys. Fit. Sports Med. PD OCT PY 2004 VL 53 IS 5 BP 527 EP 536 PG 10 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 896ZP UT WOS:000226973600006 ER PT J AU Ernst, M Dickstein, DP Munson, S Eshel, N Pradella, A Jazbec, S Pine, DS Leibenluft, E AF Ernst, M Dickstein, DP Munson, S Eshel, N Pradella, A Jazbec, S Pine, DS Leibenluft, E TI Reward-related processes in pediatric bipolar disorder: a pilot study SO JOURNAL OF AFFECTIVE DISORDERS LA English DT Article; Proceedings Paper CT 2nd International Conference on Pediatric Bipolar Disorder CY MAR 21, 2003 CL Washington, DC SP NIMH DE pediatric bipolar disorder; reward; punishment; decision-making; risk; motivation ID DEFICIT-HYPERACTIVITY DISORDER; DECISION-MAKING; PREFRONTAL CORTEX; JUVENILE MANIA; RESPONSE COST; RISK-TAKING; CHILDREN; PERFORMANCE; ATTENTION; DEPRESSION AB Background: Neuropsychological research on children with bipolar disorder (BPD) is scarce. Here, we examine reward-related behaviors in children with BPD using a Wheel of Fortune task in which subjects could win or lose money depending on their decisions. The intent of this work was to investigate performance differences between BPD and healthy children on a task that could be used in an fMRI environment to inform the neural substrates of reward processes in BPD. This study has no direct clinical implications. We hypothesized that relative to healthy children, children with BPD would select risky options more frequently, be less confident in a favorable outcome, and report stronger emotional responses to outcomes. Methods: Forty-four children (22 BPD; 22 control) were compared on (i) decision-making with varying levels of risk, (ii) level of confidence in favorable outcomes, and (iii) responses to feedback. The task included a win-no win version and a lose-no lose version. Results: Patterns of selection did not differ between groups. In the lose-no lose task, BPD patients were less confident than controls in favorable outcomes. BPD patients expressed greater dissatisfaction than controls at not winning in win-no win, and greater satisfaction than controls at not losing in lose-no lose. Limitations: Limitations of this study included that the children with BPD were mostly in a depressed state, were medicated, and had co-morbid disorders. Conclusions: This is the first experimental study to examine associations between pediatric BPD and reward-related behaviors. Although we failed to detect abnormalities in risky decision-making in children with BPD, we found significant differences between groups in both confidence ratings and response to feedback, consistent with our predictions. Our ultimate goal is to use this task in the fMRI environment to gain a better understanding of the neural correlates of reward-related processes in pediatric BPD. Published by Elsevier B.V. C1 NIMH, Mood & Anxiety Disorders Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Ernst, M (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, US Dept HHS, 15K N Dr,Room 118, Bethesda, MD 20892 USA. EM emstm@intra.nimh.nih.gov RI Dickstein, Daniel/L-3210-2016; OI Dickstein, Daniel/0000-0003-1647-5329; Eshel, Neir/0000-0002-5976-2013 NR 28 TC 35 Z9 35 U1 6 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0327 J9 J AFFECT DISORDERS JI J. Affect. Disord. PD OCT PY 2004 VL 82 SU 1 BP S89 EP S101 DI 10.1016/j.jad.2004.05.022 PG 13 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 884WO UT WOS:000226117600010 PM 15571794 ER PT J AU Silverman, ES Breault, DT Vallone, J Subramanian, S Yilmaz, AD Mathew, S Subramaniam, V Tantisira, K Pacak, K Weiss, ST Majzoub, JA AF Silverman, ES Breault, DT Vallone, J Subramanian, S Yilmaz, AD Mathew, S Subramaniam, V Tantisira, K Pacak, K Weiss, ST Majzoub, JA TI Corticotropin-releasing hormone deficiency increases allergen-induced airway inflammation in a mouse model of asthma SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE corticotropin-releasing hormone; asthma; airway responsiveness; glucocorticoids; rodent; eosinophils; knockout; lung; ovalbumin; catecholamines ID IMPAIRED STRESS-RESPONSE; PITUITARY-ADRENAL AXIS; PERIPHERAL INFLAMMATION; RECEPTOR ANTAGONIST; IMMUNOGLOBULIN-E; MURINE MODEL; IN-VIVO; MICE; CRH; GLUCOCORTICOIDS AB Background: Corticotropin-releasing hormone (CRH) is a major regulator of adrenocorticotropic hormone and the production of glucocorticoids by the adrenal gland. Abnormal regulation of CRH and endogenous glucocorticoids has been implicated in the pathogenesis of asthma. Objective: We postulated that CRH deficiency could increase asthma severity by disrupting hypothalamus-pituitary-adrenal axis function and the induction of glucocorticoids through inflammatory and physiologic stress. However, CRH is expressed by several types of immune cells and might be induced at sites of inflammation, where it has local immunostimulatory actions. Thus CRH deficiency could decrease asthma severity. Methods: To test these possibilities, we subjected CRH-knockout mice to an ovalbumin-induced airway inflammation protocol that mimics many features of asthma. Results: CRH-knockout mice had an increase in airway inflammation of approximately 80% to 300% and an increase in goblet cell hyperplasia of approximately 70% compared with wild-type mice. In contrast, IgE induction was unaffected by CRH deficiency. The increased inflammation in knockout mice was associated with increased tissue resistance, elastance, and hysteresivity. Levels of IL-4, IL-5, IL-13, RANTES, IFN-gamma, and eotaxin were all increased in knockout mice. Serum corticosterone levels were decreased in knockout mice and might account for some of the differences between knockout and wild-type mice. Conclusion: We conclude that CRH deficiency disrupts endogenous glucocorticoid production and enhances allergen-induced airway inflammation and lung mechanical dysfunction in mice. Thus inherited or acquired CRH deficiency could increase asthma severity in human subjects. C1 Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Physiol Program, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. Harvard Univ, Sch Med, Childrens Hosp, Div Endocrinol, Boston, MA USA. Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Silverman, ES (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Physiol Program, 665 Huntington Ave, Boston, MA 02115 USA. EM esilverm@HSPH.harvard.edu FU NHLBI NIH HHS [HL70573, HL03827, HL65899, U01 HL065899] NR 33 TC 42 Z9 46 U1 0 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2004 VL 114 IS 4 BP 747 EP 754 DI 10.1016/j.jaci.2004.06..055 PG 8 WC Allergy; Immunology SC Allergy; Immunology GA 861SO UT WOS:000224439100005 PM 15480311 ER PT J AU Chinen, J Shearer, WT AF Chinen, J Shearer, WT TI Subcutaneous immunoglobulins: Alternative for the hypogammaglobulinemic patient? SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Editorial Material DE subcutaneous immunoglobulins; IVIG; primary immunodeficiencies; quality of life; hypogammaglobulinemia ID INTRAVENOUS IMMUNOGLOBULIN; HOME TREATMENT; REPLACEMENT; INFUSION; IMMUNODEFICIENCIES; THERAPY; SAFETY C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Pediat, Allergy & Immunol Sect, Houston, TX 77030 USA. RP Chinen, J (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, 49 Convent Dr,Bldg 49,Room 4A18, Bethesda, MD 20892 USA. EM jchinen@nhgri.nih.gov NR 12 TC 6 Z9 6 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD OCT PY 2004 VL 114 IS 4 BP 934 EP 935 DI 10.1016/j.jaci.2004.07.045 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 861SO UT WOS:000224439100032 PM 15480338 ER PT J AU Cui, XZ Parent, C Macarthur, H Ochs, SD Gerstenberg, E Solomon, S Fitz, Y Danner, RL Banks, SM Natanson, C Salvemini, D Eichacker, PQ AF Cui, XZ Parent, C Macarthur, H Ochs, SD Gerstenberg, E Solomon, S Fitz, Y Danner, RL Banks, SM Natanson, C Salvemini, D Eichacker, PQ TI Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE septic shock; treatments; superoxide dismutase mimetic; M40401 ID REACTIVE OXYGEN METABOLITES; ENDOGENOUS NITRIC-OXIDE; SURVIVAL RATE; SEPTIC SHOCK; LIPID-PEROXIDATION; PLATELET-ADHESION; OXIDATIVE STRESS; ENDOTOXEMIC RATS; RELAXING FACTOR; PORCINE MODEL AB Previous analysis showed that selective inhibitors of five different host inflammatory mediators administered for sepsis, although beneficial with severe sepsis and high-control mortality rates, were ineffective or harmful with less severe sepsis. We hypothesized that severity of sepsis would also influence inhibition of superoxide anion, another inflammatory mediator. To test this, 6-h infusions of M40401, a selective SOD mimetic, or placebo were given to antibiotic-treated rats (n=547) starting 3 h after challenge with differing doses of intravenous Escherichia coli designed to produce low- or high-control mortality rates. There was a positive and significant (P=0.0008) relationship between the efficacy of M40401 on survival rate and control mortality rates. M40401 increased or decreased the log (odds ratio Of Survival) (means+/-SE), dependent on whether control mortality rates were greater or less than the median (66%) (+0.19+/-0.12 vs. -0.25+/-0.10, P=0.01). In a subset of animals examined (n=152) at 9 h after E. coli challenge, M40401 increased (mean effect+/-SE compared with control) mean arterial blood pressure (8+/-5 mmHg) and decreased platelets (-37+/-22 cells x 10(2)/ml) with high-control mortality rates but had opposing effects on each parameter (-3+/-3 mmHg and 28+/-19 cells x 10(3)/ml, respectively) with low rates (Pless than or equal to0.05 for the differing effects of M40401 on each parameter with high- vs. low-control mortality rates). A metaregression analysis of published preclinical sepsis studies testing SOD preparations and SOD mimetics showed that most (16 of 18) had control mortality rates >66%. However, across experiments from published studies, these agents were less beneficial as control mortality rate decreased (P=0.03) in a relationship not altered (P=not significant) by other variables associated with septic challenge or regimen of treatment and which was similar, compared with experiments with M40401 (P=not significant). Thus, in these preclinical sepsis models, possibly related to divergent effects on vascular function, inhibition of superoxide anion improved survival with more severe sepsis and high-control mortality rates but was less effective or harmful with less severe sepsis. Extrapolated clinically, inhibition of superoxide anion may be most efficacious in septic patients with severe sepsis and a high risk of death. C1 NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. Metaphore Pharmaceut, St Louis, MO 63114 USA. RP Cui, XZ (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Rm 7D43, Bethesda, MD 20892 USA. EM cxizhong@mail.cc.nih.gov NR 50 TC 14 Z9 15 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD OCT PY 2004 VL 97 IS 4 BP 1349 EP 1357 DI 10.1152/japplphysiol.01161.2003 PG 9 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 859FB UT WOS:000224247700024 PM 15169752 ER PT J AU Novichkov, PS Omelchenko, MV Gelfand, MS Mironov, AA Wolf, YI Koonin, EV AF Novichkov, PS Omelchenko, MV Gelfand, MS Mironov, AA Wolf, YI Koonin, EV TI Genome-wide molecular clock and horizontal gene transfer in bacterial evolution SO JOURNAL OF BACTERIOLOGY LA English DT Article ID TRANSFER-RNA SYNTHETASES; PHYLOGENETIC ANALYSIS; MAXIMUM-LIKELIHOOD; SEQUENCE ALIGNMENT; COG DATABASE; PROTEINS; CLASSIFICATION; TREES; HISTORY; PROKARYOTES AB We describe a simple theoretical framework for identifying orthologous sets of genes that deviate from a clock-like model of evolution. The approach used is based on comparing the evolutionary distances within a set of orthologs to a standard intergenomic distance, which was defined as the median of the distribution of the distances between all one-to-one orthologs. Under the clock-like model, the points on a plot of intergenic distances versus intergenomic distances are expected to fit a straight line. A statistical technique to identify significant deviations from the clock-like behavior is described. For several hundred analyzed orthologous sets representing three well-defined bacterial lineages, the alpha-Proteobacteria, the gamma-Proteobacteria, and the Bacillus-Clostridium group, the clock-like null hypothesis could not be rejected for similar to70% of the sets, whereas the rest showed substantial anomalies. Subsequent detailed phylogenetic analysis of the genes with the strongest deviations indicated that over one-half of these genes probably underwent a distinct form of horizontal gene transfer, xenologous gene displacement, in which a gene is displaced by an ortholog from a different lineage. The remaining deviations from the clock-like model could be explained by lineage-specific acceleration of evolution. The results indicate that although xenologous gene displacement is a major force in bacterial evolution, a significant majority of orthologous gene sets in three major bacterial lineages evolved in accordance with the clock-like model. The approach described here allows rapid detection of deviations from this mode of evolution on the genome scale. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Uniformed Serv Univ Hlth Sci, FE Hebert Sch Med, Dept Pathol, Bethesda, MD 20814 USA. Moscow MV Lomonosov State Univ, Dept Bioengn & Bioinformat, Moscow, Russia. Russian Acad Sci, Inst Problems Informat Transmiss, Moscow, Russia. State Sci Ctr GosNIIGenet, Moscow, Russia. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI Mironov, Andrey/C-8024-2012; Gelfand, Mikhail/F-3425-2012 NR 57 TC 51 Z9 59 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2004 VL 186 IS 19 BP 6575 EP 6585 DI 10.1128/JB.186.19.6575-6585.2004 PG 11 WC Microbiology SC Microbiology GA 855QL UT WOS:000223988700027 PM 15375139 ER PT J AU Chen, S Zhang, AX Blyn, LB Storz, G AF Chen, S Zhang, AX Blyn, LB Storz, G TI MicC, a second small-RNA regulator of Omp protein expression in Escherichia coli SO JOURNAL OF BACTERIOLOGY LA English DT Article ID OUTER-MEMBRANE PROTEINS; MESSENGER-RNA; GENE-EXPRESSION; COMPARATIVE GENOMICS; NONCODING RNAS; ANTISENSE RNA; PORIN GENES; BACTERIA; HFQ; IDENTIFICATION AB In a previous bioinformatics-based search for novel small-RNA genes encoded by the Escherichia coli genome, we identified a region, IS063, located between the ompN and ydbK genes, that encodes an similar to100-nucleotide small-RNA transcript. Here we show that the expression of this small RNA is increased at a low temperature and in minimal medium. Twenty-two nucleotides at the 5' end of this transcript have the potential to form base pairs with the leader sequence of the mRNA encoding the outer membrane protein OmpC. The deletion of IS063 increased the expression of an ompC-luc translational fusion 1.5- to 2-fold, and a 10-fold overexpression of the small RNA led to a 2- to 3-fold repression of the fusion. Deletion and overexpression of the IS063 RNA also resulted in increases and decreases, respectively, in OmpC protein levels. Taken together, these results suggest that IS063 is a regulator of OmpC expression; thus, the small RNA has been renamed MicC. The antisense regulation was further demonstrated by the finding that micC mutations were suppressed by compensatory mutations in the ompC mRNA. MicC was also shown to inhibit ribosome binding to the ompC mRNA leader in vitro and to require the Hfq RNA chaperone for its function. We suggest that the MicF and MicC RNAs act in conjunction with the EnvZ-OmpR two-component system to control the OmpF/OmpC protein ratio in response to a variety of environmental stimuli. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. ISIS Pharmaceut Inc, IBIS Therapeut, Carlsbad, CA USA. RP Storz, G (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bldg 18T,Room 101,18 Lib Dr,MSC 5430, Bethesda, MD 20892 USA. EM storz@helix.nih.gov RI Chen, Shawn/K-3585-2012; OI Storz, Gisela/0000-0001-6698-1241 NR 36 TC 149 Z9 153 U1 2 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2004 VL 186 IS 20 BP 6689 EP 6697 DI 10.1128/JB.186.20.6689-6697.2004 PG 9 WC Microbiology SC Microbiology GA 860SW UT WOS:000224364500003 PM 15466019 ER PT J AU Opdyke, JA Kang, JG Storz, G AF Opdyke, JA Kang, JG Storz, G TI GadY, a small-RNA regulator of acid response genes in Escherichia coli SO JOURNAL OF BACTERIOLOGY LA English DT Article ID GLUTAMATE-DECARBOXYLASE; OXYS RNA; TRANSLATION; RESISTANCE; RPOS; EXPRESSION; ACTIVATOR; SYSTEM; HFQ; DEGRADATION AB A previous bioinformatics-based search for small RNAs in Escherichia coli identified a novel RNA named IS183. The gene encoding this small RNA is located between and on the opposite strand of genes encoding two transcriptional regulators of the acid response, gadX (yhiX) and gadW (yhiW). Given that IS183 is encoded in the gad gene cluster and because of its role in regulating acid response genes reported here, this RNA has been renamed GadY. We show that GadY exists in three forms, a long form consisting of 105 nucleotides and two processed forms, consisting of 90 and 59 nucleotides. The expression of this small RNA is highly induced during stationary phase in a manner that is dependent on the alternative sigma factor sigmas. Overexpression of the three GadY RNA forms resulted in increased levels of the mRNA encoding the GadX transcriptional activator, which in turn caused increased levels of the GadA and GadB glutamate decarboxylases. A promoter mutation which abolished gadY expression resulted in a reduction in the amount of gadX mRNA during stationary phase. The gadY gene was shown to overlap the 3' end of the gadX gene, and this overlap region was found to be necessary for the GadY-dependent accumulation of gadY mRNA. We suggest that during stationary phase, GadY forms base pairs with the 3'-untranslated region of the gadY mRNA and confers increased stability, allowing for gadX mRNA accumulation and the increased expression of downstream acid resistance genes. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Storz, G (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Room 101,18 Lib Dr,MSC 5430, Bethesda, MD 20892 USA. EM storz@helix.nih.gov RI Luan, Gan/B-3211-2015; OI Storz, Gisela/0000-0001-6698-1241 NR 30 TC 190 Z9 198 U1 1 U2 11 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2004 VL 186 IS 20 BP 6698 EP 6705 DI 10.1128/JB.186.20.6698-6705.2004 PG 8 WC Microbiology SC Microbiology GA 860SW UT WOS:000224364500004 PM 15466020 ER PT J AU Kubler-Kielb, J Coxon, B Schneerson, R AF Kubler-Kielb, J Coxon, B Schneerson, R TI Chemical structure, conjugation, and cross-reactivity of Bacillus pumilus Sh18 cell wall polysaccharide SO JOURNAL OF BACTERIOLOGY LA English DT Article ID HEMOPHILUS-INFLUENZAE TYPE; CAPSULAR POLYSACCHARIDE; STAPHYLOCOCCUS-AUREUS; BACTERIAL POLYSACCHARIDES; PSEUDOMONAS-AERUGINOSA; ACID-HYDROLYSIS; TEICHOIC-ACIDS; DEFINED MEDIUM; EXOTOXIN-A; PEPTIDOGLYCAN AB Bacillus pumilus strain Sh18 cell wall polysaccharide (CWP), cross-reactive with the capsular polysaccharide of Haemophilus influenzae type b, was purified and its chemical structure was elucidated using fast atom bombardment mass spectrometry, nuclear magnetic resonance techniques, and sugar-specific degradation procedures. Two major structures, 1,5-poly(ribitol phosphate) and 1,3-poly(glycerol phosphate), with the latter partially substituted by 2-acetamido-2-deoxy-alpha-galactopyranose (13%) and 2-acetamido-2-deoxy-alpha-glucopyranose (6%) on position O-2, were found. A minor component was established to be a polymer of -->3-O-(2-acetamido-2-deoxy-beta-glucopyranosyl)-1-->4-ribitol-1-OPO3-->. The ratios of the three components were 56, 34, and 10 mol%, respectively. The Sh18 CWP was covalently bound to carrier proteins, and the immunogenicity of the resulting conjugates was evaluated in mice. Two methods of conjugation were compared: (i) binding of 1-cyano-4-dimethylaminopyridinium tetrafluoroborate-activated hydroxyl groups of the CWP to adipic acid dihydrazide (ADH)-derivatized protein, and (ii) binding of the carbodiimide-activated terminal phosphate group of the CWP to ADH-derivatized protein. The conjugate-induced antibodies reacted in an enzyme-linked immunosorbent assay with the homologous polysaccharide and with a number of other bacterial polysaccharides containing ribitol and glycerol phosphates, including H. influenzae types a and b and strains of Staphylococcus aureus and Staphylococcus epidermidis. C1 NICHHD, Dev & Mol Immun Lab, NIH, Bethesda, MD 20892 USA. RP Kubler-Kielb, J (reprint author), NICHD, NIH, 9000 Rockville Pike,Bldg 6,Rm 1A05, Bethesda, MD 20892 USA. EM kielbj@mail.nih.gov NR 40 TC 11 Z9 12 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD OCT PY 2004 VL 186 IS 20 BP 6891 EP 6901 DI 10.1128/JB.186.20.6891-6901.2004 PG 11 WC Microbiology SC Microbiology GA 860SW UT WOS:000224364500027 PM 15466043 ER PT J AU Conti, MA Even-Ram, S Liu, CY Yamada, KM Adelstein, RS AF Conti, MA Even-Ram, S Liu, CY Yamada, KM Adelstein, RS TI Defects in cell adhesion and the visceral endoderm following ablation of nonmuscle myosin heavy chain II-A in mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GASTRULATION; MIGRATION; MUTATION; DOMAIN AB Previous work has shown that ablation or mutation of nonmuscle myosin heavy chain II-B (NMHC II-B) in mice results in defects in the heart and brain with death occurring between embryonic day 14.5 (E14.5) and birth (Tullio, A.N., Accili, D., Ferrans, V.J., Yu, Z.X., Takeda, K., Grinberg, A., Westphal, H., Preston, Y.A., and Adelstein, R. S. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 12407-12412). Here we show that mice ablated for NMHC II-A fail to develop a normal patterned embryo with a polarized visceral endoderm by E6.5 and die by E7.5. Moreover, A(-)/A(-) embryoid bodies grown in suspension culture constantly shed cells. These defects in cell adhesion and tissue organization are explained by loss of E-cadherin and beta-catenin localization to cell adhesion sites in both cell culture and in the intact embryos. The defects can be reproduced by introducing siRNA directed against NMHC II-A into wild-type embryonic stem cells. Our results suggest an essential role for a single, specific nonmuscle myosin isoform in maintaining cell-cell adhesions in the early mammalian embryo. C1 NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Transgen Core Facil, NIH, Bethesda, MD 20892 USA. RP Conti, MA (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bldg 10,Rm 8N202,10 Ctr Dr,MSC 1762, Bethesda, MD 20892 USA. EM contim@nhlbi.nih.gov OI Even-Ram, Sharona/0000-0002-5540-3822; Yamada, Kenneth/0000-0003-1512-6805; Adelstein, Robert/0000-0002-8683-2144 NR 16 TC 198 Z9 206 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 1 PY 2004 VL 279 IS 40 BP 41263 EP 41266 DI 10.1074/jbc.C400352200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 856WG UT WOS:000224075500002 PM 15292239 ER PT J AU Calzada, MJ Annis, DS Zeng, BX Marcinkiewicz, C Banas, B Lawler, J Mosher, DF Roberts, DD AF Calzada, MJ Annis, DS Zeng, BX Marcinkiewicz, C Banas, B Lawler, J Mosher, DF Roberts, DD TI Identification of novel beta(1) integrin binding sites in the type 1 and type 2 repeats of thrombospondin-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMINO-ACID SUBSTITUTIONS; ARG-GLY-ASP; CELL ATTACHMENT; ALPHA-3-BETA-1 INTEGRIN; T-CELL; ALPHA(3)BETA(1) INTEGRIN; ALPHA-4-BETA-1 INTEGRIN; NEURITE OUTGROWTH; MESANGIAL CELLS; I REPEATS AB In addition to the three known beta(1) integrin recognition sites in the N-module of thrombospondin-1 (TSP1), we found that beta(1) integrins mediate cell adhesion to the type 1 and type 2 repeats. The type 1 repeats of TSP1 differ from typical integrin ligands in that recognition is pan-beta(1)-specific. Adhesion of cells that express one dominant beta(1) integrin on immobilized type 1 repeats is specifically inhibited by antagonists of that integrin, whereas adhesion of cells that express several beta(1) integrins is partially inhibited by each alpha-subunit-specific antagonist and completely inhibited by combining the antagonists. beta(1) integrins recognize both the second and third type 1 repeats, and each type 1 repeat shows pan-beta(1) specificity and divalent cation dependence for promoting cell adhesion. Adhesion to the type 2 repeats is less sensitive to alpha-subunit antagonists, but a beta(1) blocking antibody and two disintegrins inhibit adhesion to immobilized type 2 repeats. beta(1) integrin expression is necessary for cell adhesion to the type 1 or type 2 repeats, and beta(1) integrins bind in a divalent cation-dependent manner to a type 1 repeat affinity column. The widely used TSP1 function blocking antibody A4.1 binds to a site in the third type 2 repeat. A4.1 proximally inhibits beta(1) integrin-dependent adhesion to the type 2 repeats and indirectly inhibits integrin-dependent adhesion mediated by the TSP1 type 1 repeats. Although antibody A4.1 is also an antagonist of CD36 binding to TSP1, these data suggest that some biological activities of A4.1 result from antagonism of these novel beta(1) integrin binding sites. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Med, Madison, WI 53706 USA. Temple Univ, Dept Biol, Coll Sci & Technol, Philadelphia, PA 19122 USA. Univ Regensburg, Med Klin 2, D-93053 Regensburg, Germany. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Rm 2A33,10 Ctr Dr,MSC 1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 NR 63 TC 47 Z9 47 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 OCT 1 PY 2004 VL 279 IS 40 BP 41734 EP 41743 DI 10.1074/jbc.M406267200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 856WG UT WOS:000224075500061 PM 15292271 ER PT J AU Buckley, CT Sekiya, F Kim, YJ Rhee, SG Caldwell, KK AF Buckley, CT Sekiya, F Kim, YJ Rhee, SG Caldwell, KK TI Identification of phospholipase C-gamma 1 as a mitogen-activated protein kinase substrate SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID D-ASPARTATE RECEPTOR; C-GAMMA; GROWTH-FACTOR; DOCKING SITES; MAP KINASE; TRANSCRIPTION FACTORS; SH3 DOMAIN; C-GAMMA-1; PHOSPHORYLATION; EXPRESSION AB The discovery of sequence motifs that mediate protein-protein interactions, coupled with the availability of protein amino acid sequence data, allows for the identification of putative protein binding pairs. The present studies were based on our identification of an amino acid sequence in phosphatidylinositol-specific phospholipase C-gamma1 (PLC-gamma1) that fits the consensus sequence for a mitogen-activated protein kinase (MAPK) binding site, termed the D-domain. Extracellular signal-regulated kinase 2 (ERK2), an MAPK, and phospho-ERK2 were bound by an immobilized peptide sequence containing the identified PLC-gamma1 D-domain. Furthermore, a peptide containing the PLC-gamma1 D-domain was able to competitively inhibit the in vitro phosphorylation of recombinant PLC-gamma1 by recombinant phospho-ERK2, whereas a control peptide derived from a distant region of PLC-gamma1 was ineffective. Similarly, the peptide containing the PLC-gamma1 D-domain, but not the control peptide, competitively inhibited the in vitro phosphorylation of Elk-1 and c-Jun catalyzed by recombinant phospho-ERK2 and phospho-c-Jun N-terminal kinase 3 (phospho-JNK3), another type of MAPK, respectively. Incubation of anti-PLC-gamma1 immunocomplexes isolated from rat brain with recombinant phospho-ERK2 opposed the increase in PLC-gamma1-catalyzed hydrolysis of phosphatidylinositol 4,5-P-2 (PtdIns(4,5)P-2), which was produced by a tyrosine kinase associated with the immunocomplexes, whereas in vitro phosphorylation of recombinant PLC-gamma1 by recombinant phospho-ERK2 did not alter PLC-gamma1-catalyzed PtdIns(4,5)P-2 hydrolysis. These studies have uncovered a previously unidentified mechanism for the integration of PLC-gamma1- and ERK2-dependent signaling. C1 Univ New Mexico, Hlth Sci Ctr, Dept Neurosci, Albuquerque, NM 87131 USA. NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Caldwell, KK (reprint author), Univ New Mexico, Hlth Sci Ctr, Dept Neurosci, MSC08 4740, Albuquerque, NM 87131 USA. EM kcaldwell@salud.unm.edu NR 51 TC 12 Z9 13 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 OCT 1 PY 2004 VL 279 IS 40 BP 41807 EP 41814 DI 10.1074/jbc.M407851200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 856WG UT WOS:000224075500070 PM 15258148 ER PT J AU Chang, TS Cho, CS Park, S Yu, SQ Kang, SW Rhee, SG AF Chang, TS Cho, CS Park, S Yu, SQ Kang, SW Rhee, SG TI Peroxiredoxin III, a mitochondrion-specific peroxidase, regulates apoptotic signaling by mitochondria SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-NECROSIS-FACTOR; PROGRAMMED CELL-DEATH; MANGANESE SUPEROXIDE-DISMUTASE; PERMEABILITY TRANSITION PORE; CYTOCHROME-C RELEASE; REACTIVE OXYGEN; HYDROGEN-PEROXIDE; GLUTATHIONE-PEROXIDASE; OXIDATIVE STRESS; MAMMALIAN PEROXIREDOXIN AB Various proapoptotic stimuli increase the production of superoxide and H2O2 by mitochondria. Whereas superoxide impairs mitochondrial function and is removed by Mn2+-dependent superoxide dismutase, the role and metabolism of mitochondrial H2O2 during apoptosis have remained unclear. The effects on apoptotic signaling of depletion of peroxiredoxin (Prx) III, a mitochondrion-specific H2O2-scavenging enzyme, have now been investigated by RNA interference in HeLa cells. Depletion of Prx III resulted in increased intracellular levels of H2O2 and sensitized cells to induction of apoptosis by staurosporine or TNF-alpha. The rates of mitochondrial membrane potential collapse, cytochrome c release, and caspase activation were increased in Prx III-depleted cells, and these effects were reversed by ectopic expression of Prx III or mitochondrion-targeted catalase. Depletion of Prx III also exacerbated damage to mitochondrial macromolecules induced by the proapoptotic stimuli. Our results suggest that Prx III is a critical regulator of the abundance of mitochondrial H2O2, which itself promotes apoptosis in cooperation with other mediators of apoptotic signaling. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. Ewha Womans Univ, Ctr Cell Signaling Res, Div Mol Life Sci, Seoul 120750, South Korea. RP Rhee, SG (reprint author), Bldg 50,Room 3523,S Dr,MSC 8015, Bethesda, MD 20892 USA. EM sgrhee@nih.gov NR 86 TC 241 Z9 252 U1 1 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 1 PY 2004 VL 279 IS 40 BP 41975 EP 41984 DI 10.1074/jbc.M407707200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 856WG UT WOS:000224075500090 PM 15280382 ER PT J AU Goto, M Eddy, EM AF Goto, M Eddy, EM TI Speriolin is a novel spermatogenic cell-specific centrosomal protein associated with the seventh WD motif of Cdc20 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ANAPHASE-PROMOTING COMPLEX; MAD2-DEPENDENT SPINDLE CHECKPOINT; MOUSE SPERMATOCYTES; MITOTIC REGULATOR; CRYSTAL-STRUCTURE; UBIQUITIN LIGASE; GENE-EXPRESSION; FISSION YEAST; MEIOSIS; IDENTIFICATION AB The fundamental mechanisms of mitosis are conserved throughout evolution in eukaryotes, including ubiquitin-mediated proteolysis of cell cycle regulators by the anaphase-promoting complex/cyclosome. The spindle checkpoint protein Cdc20 activates the anaphase-promoting complex/cyclosome in a substrate-specific manner. It is present in the cytoplasm and concentrated in the centrosomes throughout the cell cycle, accumulates at the kinetochores in metaphase, and is no longer detected following anaphase. However, it is unknown whether Cdc20 has the same activities and distribution during meiosis in male germ cells. We found that in mice, Cdc20 accumulates in the cytoplasm of pachytene spermatocytes during meiosis I, is distributed throughout spermatocytes undergoing meiotic division, and is present in the cytoplasm of postmeiotic spermatids. Several proteins bind to and regulate the function of Cdc20 during mitosis. We identified speriolin and determined that it is a novel spermatogenic cell-specific Cdc20-binding protein, is present in the cytoplasm, and is concentrated at the centrosomes of spermatocytes and spermatids and that a leucine zipper domain is required to target speriolin to the centrosome. The seven tandem WD motifs of Cdc20 probably fold into a seven-blade beta-propeller structure, and we determined that they are required for speriolin binding and for localization of Cdc20 to the centrosomes and nucleus, suggesting that speriolin might regulate or stabilize the folding of Cdc20 during meiosis in spermatogenic cells. C1 NIEHS, LRDT, NIH, Gamete Biol Sect,Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. RP Eddy, EM (reprint author), NIEHS, LRDT, NIH, Gamete Biol Sect,Lab Reprod & Dev Toxicol, C4-01,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eddy@niehs.nih.gov NR 51 TC 23 Z9 26 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 1 PY 2004 VL 279 IS 40 BP 42128 EP 42138 DI 10.1074/jbc.M403190200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 856WG UT WOS:000224075500105 PM 15280373 ER PT J AU Dong, JS Lai, R Nielsen, K Fekete, CA Qiu, HF Hinnebusch, AG AF Dong, JS Lai, R Nielsen, K Fekete, CA Qiu, HF Hinnebusch, AG TI The essential ATP-binding cassette protein RLI1 functions in translation by promoting preinitiation complex assembly SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE; KINASE GCN2; IN-VIVO; ABC TRANSPORTER; MULTIFACTOR COMPLEX; MEDIATE BINDING; SHUTTLE VECTORS; GENE DELETION; INITIATION; YEAST AB RLI1 is an essential yeast protein closely related in sequence to two soluble members of the ATP-binding cassette family of proteins that interact with ribosomes and function in translation elongation (YEF3) or translational control (GCN20). We show that affinity-tagged RLI1 co-purifies with eukaryotic translation initiation factor 3 (eIF3), eIF5, and eIF2, but not with other translation initiation factors or with translation elongation or termination factors. RLI1 is associated with 40 S ribosomal subunits in vivo, but it can interact with eIF3 and -5 independently of ribosomes. Depletion of RLI1 in vivo leads to cessation of growth, a lower polysome content, and decreased average polysome size. There was also a marked reduction in 40 S-bound eIF2 and eIF1, consistent with an important role for RLI1 in assembly of 43 S preinitiation complexes in vivo. Mutations of conserved residues in RLI1 expected to function in ATP hydrolysis were lethal. A mutation in the second ATP-binding cassette domain of RLI1 had a dominant negative phenotype, decreasing the rate of translation initiation in vivo, and the mutant protein inhibited translation of a luciferase mRNA reporter in wild-type cell extracts. These findings are consistent with a direct role for the ATP-binding cassettes of RLI1 in translation initiation. RLI1-depleted cells exhibit a deficit in free 60 S ribosomal subunits, and RLI1-green fluorescent protein was found in both the nucleus and cytoplasm of living cells. Thus, RLI1 may have dual functions in translation initiation and ribosome biogenesis. C1 NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHD, Lab Gene Regulat & Dev, NIH, Bldg 6A,Rm B1A13, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov NR 49 TC 102 Z9 107 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 1 PY 2004 VL 279 IS 40 BP 42157 EP 42168 DI 10.1074/jbc.M404502200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 856WG UT WOS:000224075500108 PM 15277527 ER PT J AU Papaiahgari, S Kleeberger, SR Cho, HY Kalvakolanu, DV Reddy, SP AF Papaiahgari, S Kleeberger, SR Cho, HY Kalvakolanu, DV Reddy, SP TI NADPH oxidase and ERK signaling regulates hyperoxia-induced Nrf2-ARE transcriptional response in pulmonary epithelial cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INDUCED LUNG INJURY; PROTEIN-KINASE-C; HUMAN NEUROBLASTOMA-CELLS; OXIDATIVE STRESS; GENE-EXPRESSION; NF-E2-RELATED FACTOR-2; SUPEROXIDE-DISMUTASE; MOLECULAR MECHANISMS; CELLULAR-RESPONSE; HEME OXYGENASE-1 AB Oxidative stress plays a major role in hyperoxia-induced acute lung injury. We have shown previously that mice lacking the Nrf2 are more susceptible to hyperoxia than are wild-type mice. Nrf2 activates antioxidant response element (ARE)-mediated gene expression involved in cellular protection against toxic insults. The present study was designed to investigate the mechanisms that control the activation of Nrf2 by hyperoxia using a non-malignant murine alveolar epithelial cell line, C10. No significant alteration in the levels of Nrf2 mRNA and protein was found following exposure to hyperoxia. In contrast, hyperoxia caused the translocation of Nrf2 from the cytoplasm to the nucleus within 30-60 min of exposure. Consistent with these observations, gel shift and reporter analyses demonstrated a correlation between the hyperoxia-enhanced ARE DNA-binding activity of Nrf2 and an up-regulation of ARE-driven transcription. Inhibition of NADPH oxidase with diphenyleneiodonium (DPI) blocked both Nrf2 translocation and ARE-mediated transcription. Inhibition of the MEK/ERK pathway caused a similar effect. Consistent with this finding, hyperoxia stimulated ERK-1 and ERK-2 phosphorylation, whereas DPI or N-acetyl-L-cysteine blocked such activation. Hyperoxia stimulated the phosphorylation of endogenous Nrf2, but not in the presence of U0126, suggesting a critical role for ERK signaling in the activation of Nrf2. Consistent with this notion, hyperoxia did not stimulate the phosphorylation of Nrf2 in fibroblasts lacking the ERK-1. Collectively, our findings suggest that hyperoxia-induced, ARE-driven, Nrf2-dependent transcription is controlled by NADPH oxidase and ERK-1 signaling. C1 Johns Hopkins Univ, Dept Environm Hlth Sci, Div Physiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Univ Maryland, Maryland Greenbaum Canc Ctr, Baltimore, MD 21201 USA. RP Reddy, SP (reprint author), Johns Hopkins Univ, Dept Environm Hlth Sci, Div Physiol, Bloomberg Sch Publ Hlth, Rm W7006,615 N Wolfe St, Baltimore, MD 21205 USA. EM sreddy@jhsph.edu FU NCI NIH HHS [CA105005, CA78282]; NHLBI NIH HHS [HL66109, P50 HL073996]; NIEHS NIH HHS [ES30819] NR 62 TC 112 Z9 115 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 1 PY 2004 VL 279 IS 40 BP 42302 EP 42312 DI 10.1074/jbc.M408275200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 856WG UT WOS:000224075500122 PM 15292179 ER PT J AU Jaroniec, CP Ulmer, TS Bax, A AF Jaroniec, CP Ulmer, TS Bax, A TI Quantitative J correlation methods for the accurate measurement of 13C'-13C alpha dipolar couplings in proteins SO JOURNAL OF BIOMOLECULAR NMR LA English DT Article DE alpha-synuclein; dipolar coupling; GB3; HNCO; HN(CO)CA; quantitative J correlation; TROSY ID NMR EXPERIMENTS; BIOLOGICAL MACROMOLECULES; ORIENTED MACROMOLECULES; POLYACRYLAMIDE GELS; ALIGNMENT TENSOR; ALPHA-SYNUCLEIN; C-13; SPECTROSCOPY; SENSITIVITY; TROSY AB Methods are described for the precise and accurate measurement of one-bond dipolar 13C'-13-alpha couplings in weakly aligned proteins. The experiments are based on the principle of quantitative J correlation, where 1JC'C-alpha (or JC'C-alpha+1DC'C-alpha) is measured from the relative intensity of two interleaved 3D TROSY-HN(CO)CA or 3D TROSY-HNCO spectra recorded with dephasing intervals of zero (reference spectrum) and approximate 3/(21JC'C-alpha) (attenuated spectrum). In analogy to other quantitative J correlation techniques, the random error in the measured 1JC'C-alpha value is inversely proportional to the signal-to-noise ratio in the reference spectrum. It is shown that for weakly aligned proteins, with the magnitude of the alignment tensor of D-a-NH less-than-or-equal-to 10-15 Hz, the systematic errors are typically negligible. The methods are demonstrated for the third IgG-binding domain of protein G (GB3) and alpha-synuclein in complex with a detergent micelle, where errors in 1DC'C-alpha of less than 0.1 Hz and ca 0.2 Hz, respectively, are estimated. Remarkably, the dipolar couplings determined for GB3 are in even better agreement with the recently refined 1.1-A X-ray structure than the input 13C'-13C-alpha couplings used for the refinement. C1 NIDDKD, Lab Chem Phys, Bethesda, MD 20892 USA. RP Jaroniec, CP (reprint author), NIDDKD, Lab Chem Phys, Bethesda, MD 20892 USA. RI Jaroniec, Christopher/A-4948-2008; OI Jaroniec, Christopher/0000-0003-0364-2888 NR 41 TC 24 Z9 24 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0925-2738 J9 J BIOMOL NMR JI J. Biomol. NMR PD OCT PY 2004 VL 30 IS 2 BP 181 EP 194 DI 10.1023/B:JNMR.0000048946.71249.2f PG 14 WC Biochemistry & Molecular Biology; Spectroscopy SC Biochemistry & Molecular Biology; Spectroscopy GA 872PJ UT WOS:000225219400010 PM 15666562 ER PT J AU Katz, SI AF Katz, SI TI Boning up for health: The national bone and joint decade SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Editorial Material C1 NIAMSD, Off Commun & Publ Liaison, Bethesda, MD 20892 USA. RP Katz, SI (reprint author), NIAMSD, Off Commun & Publ Liaison, Bldg 31,Room 4C02,31 Ctr Dr,MSC 2350, Bethesda, MD 20892 USA. EM flemingr@mail.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 IS 10 BP 1605 EP 1606 DI 10.1359/JBMR.040810 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 856YS UT WOS:000224082600001 PM 15355553 ER PT J AU Barzel, US Aragaki, A Ritenbaugh, C Wylie-Rosett, J LeBoff, MS McGowan, JA AF Barzel, US Aragaki, A Ritenbaugh, C Wylie-Rosett, J LeBoff, MS McGowan, JA TI Increased risk of fractures is associated with acidogenic food intake among post-menopausal women enrolled in the observational study of the women's health initiative. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Montefiore Med Ctr, Bronx, NY 10467 USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Womens Hlth Initiat, Seattle, WA USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. NIAMS, Musculoskeletal Dis Branch, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S160 EP S161 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800633 ER PT J AU Bi, Y Kilts, T Young, MF AF Bi, Y Kilts, T Young, MF TI Biglycan and fibromodulin potentially inhibit ectopic ossification in tendon by inhibiting the differentiation of osteogenic stem cells. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S221 EP S221 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326801236 ER PT J AU Black, DM Rosen, CJ Palermo, L Hue, T Ensrud, KE Greenspan, SL Lang, TF McGowan, JA Bilezikian, JP AF Black, DM Rosen, CJ Palermo, L Hue, T Ensrud, KE Greenspan, SL Lang, TF McGowan, JA Bilezikian, JP TI The effect of 1 year of alendronate following 1 year of PTH 1-84: Second year results from the PTH and alendronate (PaTH) trial. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. ME Ctr Osteo Res, Bangor, ME USA. Univ Minnesota, Minneapolis, MN USA. MVAMC, Minneapolis, MN USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NIAMS, NIH, Bethesda, MD USA. Columbia Univ, New York, NY 10027 USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S26 EP S26 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800099 ER PT J AU Cauley, JA Kanaya, A Harris, F Strotmeyer, E Lee, J Zmuda, JM Rauer, D Cummings, S Tylavsky, F Harris, T Ensrud, K Newman, A AF Cauley, JA Kanaya, A Harris, F Strotmeyer, E Lee, J Zmuda, JM Rauer, D Cummings, S Tylavsky, F Harris, T Ensrud, K Newman, A TI Adipocyte hormones and fracture risk in older men and women. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Calif Pacific Med Ctr, Res Inst, San Francisco, CA 94115 USA. Univ Memphis, Memphis, TN 38152 USA. NIA, Bethesda, MD 20892 USA. Univ Minnesota, Minneapolis, MN USA. RI Strotmeyer, Elsa/F-3015-2014; Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S7 EP S7 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800022 ER PT J AU Farhat, GN Strotmeyer, ES Newman, AB Sutton-Tyrrell, K Bauer, DC Harris, T Johnson, KC Taaffe, D Cauley, JA AF Farhat, GN Strotmeyer, ES Newman, AB Sutton-Tyrrell, K Bauer, DC Harris, T Johnson, KC Taaffe, D Cauley, JA TI Volumetric and areal bone mineral density measures are associated with cardiovascular disease in older men and women: The health aging and body composition study (Health ABC) SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Bethesda, MD 20892 USA. Univ Tennessee, Memphis, TN USA. Univ Queensland, St Lucia, Qld 4067, Australia. RI Strotmeyer, Elsa/F-3015-2014; Newman, Anne/C-6408-2013; Cauley, Jane/N-4836-2015 OI Newman, Anne/0000-0002-0106-1150; Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S49 EP S49 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800190 ER PT J AU Han, F Tao, Z Williams, CJ Zaka, R Tuan, RS Norton, PA Hickok, NJ AF Han, F Tao, Z Williams, CJ Zaka, R Tuan, RS Norton, PA Hickok, NJ TI TGF-beta 1 regulates ATDC5 differentiation, and fibronectin isoform and SRp40 expression. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Thomas Jefferson Univ, Dept Med, Div Rheumatol, Philadelphia, PA 19107 USA. NIAMS, Cartilage Biol Orthop Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S117 EP S117 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800457 ER PT J AU Hannan, T Broe, KE Rivinus, M Hogan, M Murabito, J AF Hannan, T Broe, KE Rivinus, M Hogan, M Murabito, J TI Prior foot fracture, current foot pain and physical function in men and women of the Framingham Foot Study SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Hebrew Rehabil Ctr Aged, Boston, MA 02131 USA. NHLBI, Framingham Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 MA M342 BP S425 EP S425 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326802414 ER PT J AU Harada, S Kasparcova, V Kamiya, N Starbuck, MW Gentile, MA Fukuda, T Behringer, RR Mishina, Y AF Harada, S Kasparcova, V Kamiya, N Starbuck, MW Gentile, MA Fukuda, T Behringer, RR Mishina, Y TI BMP type IA receptor signaling in osteoblasts regulates bone resorption and osteoclast functions. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Merck Res Labs, W Point, PA USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S11 EP S11 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800040 ER PT J AU Hassan, MQ Javed, A Morasso, MI Karlin, J Montecino, M van Wijnen, AJ Stein, GS Stein, JL Lian, JB AF Hassan, MQ Javed, A Morasso, MI Karlin, J Montecino, M van Wijnen, AJ Stein, GS Stein, JL Lian, JB TI Dlx3 is a transcriptional regulator of osteoblast differentiation and increases expression and promoter activity of Runx2. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01605 USA. Univ Massachusetts, Sch Med, Ctr Canc, Worcester, MA 01605 USA. NIAMS, Dev Skin Biol Unit, NIH, Bethesda, MD USA. Univ Concepcion, Dept Mol Biol, Concepcion, Chile. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S37 EP S37 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800145 ER PT J AU Horlick, M Lappe, JM Gilsanz, V Kalkwarf, HJ Zemel, BS Mahboubi, S Shepherd, JA Frederick, MM Winer, K AF Horlick, M Lappe, JM Gilsanz, V Kalkwarf, HJ Zemel, BS Mahboubi, S Shepherd, JA Frederick, MM Winer, K TI The bone mineral density in childhood study (BMDCS): Baseline results for 1554 healthy pediatric volunteers. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Columbia Univ, New York, NY USA. Creighton Univ, Omaha, NE 68178 USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. CTASC, Baltimore, MD USA. NICHD, Rockville, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S14 EP S14 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800049 ER PT J AU Karasik, D Kiely, DK Cupples, LA Wilson, PWF O'Donnell, CJ Kiel, DP Felson, DT AF Karasik, D Kiely, DK Cupples, LA Wilson, PWF O'Donnell, CJ Kiel, DP Felson, DT TI Association between hand and lumbar exostoses and abdominal aortic calcification: The Framingham study. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Hebrew Rehabil Ctr Aged, Boston, MA USA. BU, Sch Pub Hlth, Boston, MA USA. Med Univ S Carolina, Charleston, SC 29425 USA. NHLBI, Farmington, MA USA. BU, Sch Med, Clin Epid, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S115 EP S115 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800449 ER PT J AU Kozloff, KM Bergwitz, C Uveges, TE Chen, T Morris, MD Gronowicz, G Ledgard, F Goldstein, SA Marini, JC AF Kozloff, KM Bergwitz, C Uveges, TE Chen, T Morris, MD Gronowicz, G Ledgard, F Goldstein, SA Marini, JC TI Homozygosity for a dominant mutation in col1a1 restores pup survival, bone mechanics and histology and collagen fibril diameter to near-WT values, in comparison to the moderately severe bone disease (Type IV OI) present in heterozygous Brtl mice. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Univ Michigan, Ortho Res Labs, Ann Arbor, MI 48109 USA. NICHD, NIH, Bethesda, MD USA. Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. Univ Connecticut, Ctr Hlth, Farmington, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S54 EP S54 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800206 ER PT J AU Lang, TF Sigurdsson, G Jonsdottir, B Siggeirsdottir, K Eiriksdottir, G Sigurdsson, S Garcia, M Meta, M Harris, T AF Lang, TF Sigurdsson, G Jonsdottir, B Siggeirsdottir, K Eiriksdottir, G Sigurdsson, S Garcia, M Meta, M Harris, T TI The muscle-bone relationship in the lower skeleton is gender-specific: The age, gene/environment susceptibility study. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Iceland Heart Assoc, Reykjavik, Iceland. NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S244 EP S244 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326801328 ER PT J AU Lee, SK Govoni, K Chung, Y Kesavan, C Baylink, DJ LeRoith, D Clemens, T Mohan, S AF Lee, SK Govoni, K Chung, Y Kesavan, C Baylink, DJ LeRoith, D Clemens, T Mohan, S TI Targeted disruption of IGF-I gene in mature osteoblasts using human osteocalcin promoter driven Cre in mice. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 LLU, JLP VAMC, Loma Linda, CA USA. Univ Alabama, Birmingham, AL USA. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S136 EP S136 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800532 ER PT J AU Mishina, Y Zhang, J Zhang, S Xie, Y Kamiya, N Dusevich, V Li, L Eick, D Bonewald, L Feng, JQ AF Mishina, Y Zhang, J Zhang, S Xie, Y Kamiya, N Dusevich, V Li, L Eick, D Bonewald, L Feng, JQ TI Ectopic bone formation in tooth pulp, absence of cementum, hyperplastic periodontal ligament and reduced or no dentin in mice lacking bone morphogenetic protein receptor type 1A (BMPR1A) SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Univ Missouri, Sch Dent, Kansas City, MO 64110 USA. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Stowers Inst, Kansas City, MO USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S46 EP S46 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800178 ER PT J AU Mohammad, KS Wang, Z Martinez, A Corey, E Vessella, RL Guise, TA Chirgwin, JM AF Mohammad, KS Wang, Z Martinez, A Corey, E Vessella, RL Guise, TA Chirgwin, JM TI Adrenomedullin is made by prostate cancers and increases both osteolytic and osteoblastic bone metastases. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Univ Virginia, Charlottesville, VA 22903 USA. Northwestern Univ, Chicago, IL 60611 USA. NCI, Bethesda, MD 20892 USA. Univ Washington, Seattle, WA 98195 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S25 EP S25 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800094 ER PT J AU Pidasheva, S Simonds, WF Marx, SJ Hendy, GN AF Pidasheva, S Simonds, WF Marx, SJ Hendy, GN TI Impaired translocation of calcium-sensing receptor nascent chains into endoplasmic reticulum due to signal peptide missense mutations in familial hypocalciuric hypercalcemia. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 McGill Univ, Montreal, PQ, Canada. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S195 EP S195 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326801127 ER PT J AU Riminucci, M Cherman, N Holmbeck, K Michienzi, S Travaglini, L Bianco, P Robey, RG AF Riminucci, M Cherman, N Holmbeck, K Michienzi, S Travaglini, L Bianco, P Robey, RG TI Gs-alpha expression is biallelic in normal and fibrous dysplastic bone. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 NIDCR, NIH, DHHS, Bethesda, MD USA. Univ Roma La Sapienza, Rome, Italy. Univ Aquila, I-67100 Laquila, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S41 EP S41 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800158 ER PT J AU Schwartz, AV Vittinghoff, E Sellmeyer, DE De Rekeneire, N Feingold, KR Nevitt, MC Strotmeyer, ES Resnick, HE Shorr, RI Cauley, JA Cummings, SR Harris, TB AF Schwartz, AV Vittinghoff, E Sellmeyer, DE De Rekeneire, N Feingold, KR Nevitt, MC Strotmeyer, ES Resnick, HE Shorr, RI Cauley, JA Cummings, SR Harris, TB TI Falls and physical performance changes in older adults with diabetes and pre-diabetes. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. Medstar Res Inst, Hyattsville, MD USA. Univ Tennessee, Memphis, TN USA. Calif Pacific Med Ctr, San Francisco, CA USA. RI Strotmeyer, Elsa/F-3015-2014; Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 1 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S29 EP S29 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800111 ER PT J AU Shepherd, JA Fan, B Sherman, M Gilsanz, V Horlick, M Kalkwarf, H Lappe, J Mahboubi, S Zemel, B Fredrick, M Winer, K AF Shepherd, JA Fan, B Sherman, M Gilsanz, V Horlick, M Kalkwarf, H Lappe, J Mahboubi, S Zemel, B Fredrick, M Winer, K TI Pediatric DXA precision varies with age. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Columbia Univ, New York, NY USA. Creighton Univ, Omaha, NE 68178 USA. Clin Trials & Surveys Corp, Baltimore, MD USA. NICHHD, Ctr Res Mothers & Children, Bethesda, MD 20892 USA. RI Zemel, Babette/D-1117-2009 NR 0 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S234 EP S234 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326801290 ER PT J AU Sigurdsson, G Aspelund, T Jonsdottir, B Gudmundsson, A Harris, TB Gudnason, V Lang, TF AF Sigurdsson, G Aspelund, T Jonsdottir, B Gudmundsson, A Harris, TB Gudnason, V Lang, TF TI The age-related increase in bone area assessed by QCT is site- but not sex-specific: Age, Gene/Environment Susceptibility-Reykjavik Study. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Iceland Heart Assoc, Kopavogur, Iceland. NIA, San Francisco, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RI Aspelund, Thor/C-5983-2008; Aspelund, Thor/F-4826-2011; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S33 EP S33 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800125 ER PT J AU Strotmeyer, ES Cauley, JA Schwartz, AV de Rekeneire, N Resnick, HE Goodpaster, B Short, R Tylaysky, FA Vinik, AI Harris, TB Newman, AB AF Strotmeyer, ES Cauley, JA Schwartz, AV de Rekeneire, N Resnick, HE Goodpaster, B Short, R Tylaysky, FA Vinik, AI Harris, TB Newman, AB TI Reduced nerve function is related to lower hip BMD and heel QUS in older white and black adults. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Univ Pittsburgh, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Bethesda, MD 20892 USA. Med Star Res Inst, Hyattsville, MD USA. Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. Eastern Virginia Med Sch, Norfolk, VA 23501 USA. RI Strotmeyer, Elsa/F-3015-2014; Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S7 EP S7 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800023 ER PT J AU Wadhwa, S Embree, M Bi, Y Young, M AF Wadhwa, S Embree, M Bi, Y Young, M TI Biglycan and decorin are essential for post-natal Fronto-Nasal craniofacial growth and development. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 NIDCR, Csdb, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S21 EP S21 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800079 ER PT J AU Woodard, GE Lin, L Agarwal, SK Marx, SJ Simonds, WF AF Woodard, GE Lin, L Agarwal, SK Marx, SJ Simonds, WF TI Parafibromin, product of the hyperparathyroidism-jaw tumor gene HRPT2, is a nucleocytoplasmic protein that regulates cyclin D1 expression. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 NIH, Metab Dis Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S102 EP S102 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800399 ER PT J AU Wren, TAL Gilsanz, V Pitukcheewanont, P Liu, X Horlick, M Lappe, JM Kalkwarf, H Zemel, BS Mahboubi, S Shepherd, JA Frederick, MM Winer, K AF Wren, TAL Gilsanz, V Pitukcheewanont, P Liu, X Horlick, M Lappe, JM Kalkwarf, H Zemel, BS Mahboubi, S Shepherd, JA Frederick, MM Winer, K TI The bone mineral density in childhood study (BMDCS): Substudy comparing DXA and CT vertebral bone measurements in healthy children and adolescents SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. St Lukes Roosevelt Hosp, New York, NY 10025 USA. Creighton Univ, Omaha, NE 68178 USA. Childrens Hosp Med Ctr, Cincinnati, OH USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Clin Trials & Surveys Corp, Baltimore, MD USA. NICHD, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S67 EP S67 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800259 ER PT J AU Yakar, S Beamer, WG Delahunty, KM Rosen, CJ LeRoith, D AF Yakar, S Beamer, WG Delahunty, KM Rosen, CJ LeRoith, D TI Possible pathogenic mechanisms in a mouse model of type II diabetes mellitus with severe osteopenia. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Diabet Branch, NIH, Bethesda, MD USA. Jackson Lab, Bar Harbor, ME 04609 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S307 EP S307 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326801595 ER PT J AU Yin, J Oberst, MD Chock, MK Ward, Y Kelly, K AF Yin, J Oberst, MD Chock, MK Ward, Y Kelly, K TI The RalGEF pathway promotes prostate cancer metastasis to bone SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S362 EP S363 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326802158 ER PT J AU Yin, L Wang, J Du, X Zhao, L Su, N Chen, L Li, C Deng, C AF Yin, L Wang, J Du, X Zhao, L Su, N Chen, L Li, C Deng, C TI A Pro253Arg mutation in mouse FGFR2 causes craniosynostosis. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 26th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY OCT 01-05, 2004 CL Seattle, WA SP Amer Soc Bone & Mineral Res C1 Daping Hosp, Chongqing, Peoples R China. NIH, Bethesda, MD 20892 USA. RI deng, chuxia/N-6713-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD OCT PY 2004 VL 19 SU 1 BP S35 EP S35 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860FB UT WOS:000224326800135 ER PT J AU Zeng, XC Bhasin, S Wu, XF Lee, JG Maffi, S Nichols, CJ Lee, KJ Taylor, JP Greene, LE Eisenberg, E AF Zeng, XC Bhasin, S Wu, XF Lee, JG Maffi, S Nichols, CJ Lee, KJ Taylor, JP Greene, LE Eisenberg, E TI Hsp70 dynamics in vivo: effect of heat shock and protein aggregation SO JOURNAL OF CELL SCIENCE LA English DT Article DE Hsp70; mobility; heat shock; huntingtin ID CREB-BINDING PROTEIN; NUCLEAR ACCUMULATION; EXPANDED POLYGLUTAMINE; MOLECULAR CHAPERONES; AGGRESOME FORMATION; MISFOLDED PROTEINS; PARKINSONS-DISEASE; DROSOPHILA MODEL; MAMMALIAN-CELLS; STRESS AB The molecular chaperone Hsp70 interacts with misfolded proteins and also accumulates in the nucleus during heat shock. Using GFP-Hsp70 and fluorescence recovery after photobleaching, we show that Hsp70 accumulates in the nucleus during heat shock not only because its inflow rate increases but also because of a marked decrease in its outflow rate. Dynamic imaging also shows that GFP-Hsp70 has greatly reduced mobility when it interacts with organelles such as nucleoli in heat-shocked cells or the large inclusions formed from fragments of mutant huntingtin protein. In heat-shocked cells, nucleoplasmic Hsp70 has reduced mobility relative to the cytoplasm, whereas the ATPase-deficient mutant of Hsp70, Hsp70(K71E), is almost completely immobilized both in the nucleoplasm and the cytoplasm. Moreover, the Hsp70 mutant shows reduced mobility in the presence of diffusive huntingtin fragments with expanded polyglutamine repeats. This provides strong evidence that Hsp70 interacts not only with organelles but also with diffusive proteins in the nucleoplasm and cytoplasm during heat shock as well as with diffusive huntingtin fragments. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Neurogenet Branch, NIH, Bethesda, MD 20893 USA. RP Eisenberg, E (reprint author), NHLBI, Cell Biol Lab, NIH, 50 South Dr,MSC 8017, Bethesda, MD 20892 USA. EM eisenbee@nhlbi.nih.gov NR 47 TC 40 Z9 44 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD OCT 1 PY 2004 VL 117 IS 21 BP 4991 EP 5000 DI 10.1242/jcs.01373 PG 10 WC Cell Biology SC Cell Biology GA 871QY UT WOS:000225149600013 PM 15367583 ER PT J AU Pine, DS Lissek, S Klein, RG Mannuzza, S Moulton, JL Guardino, M Woldehawariat, G AF Pine, DS Lissek, S Klein, RG Mannuzza, S Moulton, JL Guardino, M Woldehawariat, G TI Face-memory and emotion: associations with major depression in children and adolescents SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE face processing; adolescence; depression; cognitive neuroscience ID MOOD DISORDERS; FACIAL EXPRESSIONS; PANIC DISORDER; AMYGDALA RESPONSE; ANXIETY DISORDERS; NEURAL SYSTEMS; RECOGNITION; BRAIN; PARENTS; ENGAGEMENT AB Background: Studies in adults with major depressive disorder (MDD) document abnormalities in both memory and face-cmotion processing. The current study used a novel face-memory task to test the hypothesis that adolescent MDD is associated with a deficit in memory for face-emotions. The study also examines the relationship between parental MDD and memory performance in offspring. Methods: Subjects were 152 offspring (ages 9-19) of adults with either MDD, anxiety disorders, both MDD and anxiety, or no disorder. Parents and offspring were assessed for mental disorders. Collection of face-memory data was blind to offspring and parent diagnosis. A computerized task was developed that required rating of facial photographs depicting 'happy,' Tearful,' or,angry' emotions followed by a memory recall test. Recall accuracy was examined as a function of face-emotion type. Results: Age and gender independently predicted memory, with better recall in older and female subjects. Controlling for age and gender, offspring with a history of MDD (n = 19) demonstrated significant deficits in memory selectively for fearful faces, but not happy or angry faces. Parental MDD was not associated with face-memory accuracy. Discussion: This study found an association between MDD in childhood or adolescence and perturbed encoding of fearful faces. MDD in young individuals may predispose to subtle anomalies in a neural circuit encompassing the amygdala, a brain region implicated in the processing of fearful facial expressions. These findings suggest that brain imaging studies using similar face-emotion paradigms should test whether deficits in processing of fearful faces relate to amygdala dysfunction in children and adolescents with MDD. C1 NIMH, Sect Dev & Affect Neurosci, Mood & Anxiety Disorders Program, Intramural Res Program, Bethesda, MD 20817 USA. NYU, Ctr Child Study, New York, NY USA. Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. Freedom Fear, Staten Isl, NY USA. RP Pine, DS (reprint author), NIMH, Sect Dev & Affect Neurosci, Mood & Anxiety Disorders Program, Intramural Res Program, Bldg 15-K,Room 110,MSC-2670, Bethesda, MD 20817 USA. EM daniel.pine@nih.gov RI Lissek, Shmuel/B-6577-2008 FU NIMH NIH HHS [R01 MH-59171] NR 52 TC 47 Z9 48 U1 0 U2 10 PU BLACKWELL PUBL LTD PI OXFORD PA 108 COWLEY RD, OXFORD OX4 1JF, OXON, ENGLAND SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD OCT PY 2004 VL 45 IS 7 BP 1199 EP 1208 DI 10.1111/j.1469-7610.2004.00311.x PG 10 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 854YQ UT WOS:000223940300003 PM 15335340 ER PT J AU Ross, JL Sandberg, DE Rose, SR Leschek, EW Baron, J Chipman, JJ Cassorla, FG Quigley, CA Crowe, BJ Roberts, K Cutler, GB AF Ross, JL Sandberg, DE Rose, SR Leschek, EW Baron, J Chipman, JJ Cassorla, FG Quigley, CA Crowe, BJ Roberts, K Cutler, GB TI Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID QUALITY-OF-LIFE; PERCEIVED COMPETENCE; ADULT HEIGHT; SELF-ESTEEM; ADOLESCENTS; THERAPY; DISADVANTAGE; ADJUSTMENT; AMERICAN; PARENTS AB The influence of short stature on psychological adaptation in childhood and adolescence is controversial. GH is currently used to treat children with idiopathic short stature (ISS, also known as non-GH-deficient short stature). This study represents the first double-blind, placebo-controlled trial of the effects of GH on the psychological adaptation of children and adolescents with ISS, treated with GH until adult height was attained. Sixty-eight children (53 males, 15 females), 9-16 yr old, with marked ISS (measured height or predicted adult height -2.5 SD or less) received either GH 0.074 mg/kg or placebo sc three times per week until height velocity decreased to less than 1.5 cm/yr. Parents completed the Child Behavior Checklist (CBCL) and children the Self-Perception Profile (SPP) and Silhouette Apperception Technique at baseline and annually thereafter. Baseline behavioral/emotional adjustment (CBCL) and self-concept (SPP) scores for children with ISS were within the normative range. The two study groups exhibited similar behavioral and self-concept profiles (CBCL) during the first 2 yr of the study. However, CBCL behavior problems (internalizing, externalizing, and total problems) appeared to decline, in yr 3 and 4, in the GH-treated group relative to the placebo-treated group. Group differences in CBCL competency domains and the SPP were not observed at any point during the study. Short stature among children with ISS enrolled in this long-term, placebo-controlled study was not associated with problems in psychological adaptation or self-concept with the psychological instruments employed. GH treatment was associated with a trend toward improvement in problem behaviors, as measured by questionnaires ( CBCL) completed by study participants' parents. It remains to be determined whether GH treatment significantly impacts adaptation, psychosocial function, or quality of life in children with ISS. C1 Thomas Jefferson Univ, Dept Pediat, Philadelphia, PA 19107 USA. Alfred I DuPont Hosp Children, Wilmington, DE 19899 USA. SUNY Coll Buffalo, Dept Psychiat, Buffalo, NY 14222 USA. SUNY Coll Buffalo, Dept Pediat, Buffalo, NY 14222 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Childrens Hosp, Med Ctr, Dept Endocrinol, Cincinnati, OH 45229 USA. Univ Cincinnati, Cincinnati, OH 45229 USA. Univ Chile, Inst Invest Materno Infantil, Santiago, Chile. Eli Lilly & Co, Indianapolis, IN 46285 USA. RP Thomas Jefferson Univ, Dept Pediat, 1025 Walnut St, Philadelphia, PA 19107 USA. EM judith.ross@mail.tju.edu OI Sandberg, David E./0000-0002-7389-8283 NR 37 TC 64 Z9 67 U1 1 U2 5 PU ENDOCRINE SOC PI WASHINGTON PA 2055 L ST NW, SUITE 600, WASHINGTON, DC 20036 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2004 VL 89 IS 10 BP 4873 EP 4878 DI 10.1210/jc.2004-0791 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860EW UT WOS:000224326300015 PM 15472178 ER PT J AU Bakalov, VK Van, PL Baron, J Reynolds, JC Bondy, CA AF Bakalov, VK Van, PL Baron, J Reynolds, JC Bondy, CA TI Growth hormone therapy and bone mineral density in Turner syndrome SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID FINAL HEIGHT; GIRLS; TERM; MASS AB In a previous report, preliminary data showed a significant reduction in cortical bone mineral density (BMD) in women with Turner syndrome that had been treated with GH compared with women with Turner syndrome that had not been treated. To clarify this point, we have investigated the effects of GH treatment at multiple sites in this case-control, cross-sectional study. There were 23 women per group, who were similar in age, height, body mass index, estrogen use, and ethnic makeup. Median age ( range) at start and duration of GH treatment was 9 (3-17) and 5 (2-9) yr, respectively. GH-treated women had a slightly greater (similar to8%, P = 0.03) width of the radial shaft, but otherwise there were no significant differences between groups in bone dimensions or BMD at the distal radius, lumbar spine, or femoral neck. Furthermore, regression analysis in a linear model including independent variables of age, age at diagnosis, body mass index, presence of spontaneous puberty, and GH use confirmed that GH use did not contribute to variation in BMD. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Radiol, Bethesda, MD 20892 USA. RP Bakalov, VK (reprint author), NICHHD, Dev Endocrinol Branch, NIH, 10 Ctr Dr,Bldg 10-10N262, Bethesda, MD 20892 USA. EM bakalov@mail.nih.gov NR 13 TC 17 Z9 17 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD OCT PY 2004 VL 89 IS 10 BP 4886 EP 4889 DI 10.1210/jc.2004-0481 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 860EW UT WOS:000224326300017 PM 15472180 ER PT J AU Rother, KI Harlan, DM AF Rother, KI Harlan, DM TI Challenges facing islet transplantation for the treatment of type 1 diabetes mellitus SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID PANCREATIC BETA-CELLS; PIG ENDOGENOUS RETROVIRUSES; EMBRYONIC STEM-CELLS; BLOOD-PRESSURE; MICROVASCULAR COMPLICATIONS; INSULIN REQUIREMENT; ENDOTHELIAL-CELLS; GENE-THERAPY; RISK; DISEASE AB Islet transplantation represents a most impressive recent advance in the search for a type 1 diabetes mellitus cure. While several hundred patients have achieved at least temporary insulin independence after receiving the islet "mini-organs" (containing insulin-producing P cells), very few patients remain insulin independent beyond 4 years after transplantation. In this review, we describe historic as well as technical details about the procedure and provide insight into clinical and basic research efforts to overcome existing hurdles for this promising therapy. C1 Natl Inst Diabet, Islet & Autoimmun Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Digest & Kidney Dis, Islet & Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Harlan, DM (reprint author), Natl Inst Diabet, Islet & Autoimmun Branch, NIH, Bldg 10,Room 8N307, Bethesda, MD 20892 USA. EM davidmh@intra.niddk.nih.gov FU Intramural NIH HHS [Z99 DK999999] NR 87 TC 110 Z9 118 U1 0 U2 10 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD OCT PY 2004 VL 114 IS 7 BP 877 EP 883 DI 10.1172/JC1200423235 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 858WT UT WOS:000224223800004 PM 15467822 ER PT J AU Walsh, TJ Shoham, S Petraitiene, R Sein, T Schaufele, R Kelaher, A Murray, H Mya-San, C Bacher, J Petraitis, V AF Walsh, TJ Shoham, S Petraitiene, R Sein, T Schaufele, R Kelaher, A Murray, H Mya-San, C Bacher, J Petraitis, V TI Detection of galactomannan antigenemia in patients receiving piperacillin-tazobactam and correlations between in vitro, in vivo, and clinical properties of the drug-antigen interaction SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID INVASIVE ASPERGILLOSIS; PULMONARY ASPERGILLOSIS; ENZYME-IMMUNOASSAY; AMPHOTERICIN-B; DIAGNOSIS; EFFICACY; RABBITS AB Recent case reports describe patients receiving piperacillin-tazobactam who were found to have circulating galactomannan detected by the double sandwich enzyme-linked immunosorbent assay (ELISA) system, leading to the false presumption of invasive aspergillosis. Since this property of piperacillin-tazobactam and galactomannan ELISA is not well understood, we investigated the in vitro, in vivo, and clinical properties of this interaction. Among the 12 reconstituted antibiotics representing four classes of antibacterial compounds that are commonly used in immunocompromised patients, piperacillin-tazobactam expressed a distinctively high level of galactomannan antigen in vitro (P = 0.001). After intravenous infusion of piperacillin-tazobactam into rabbits, the serum galactomannan index (GMI) in vivo changed significantly (P = 0.0007) from a preinfusion mean baseline value of 0.27 to a mean GMI of 0.83 by 30 min to slowly decline to a mean GMI of 0.44 24 h later. Repeated administration of piperacillin-tazobactam over 7 days resulted in accumulation of circulating galactomannan to a mean peak GMI of 1.31 and a nadir of 0.53. Further studies revealed that the antigen reached a steady state by the third day of administration of piperacillin-tazobactam. Twenty-six hospitalized patients with no evidence of invasive aspergillosis who were receiving antibiotics and ten healthy blood bank donors were studied for expression of circulating galactomannan. Patients (n = 13) receiving piperacillin-tazobactam had significantly greater mean serum GMI values (0.74 +/- 0.14) compared to patients (n = 13) receiving other antibiotics (0.14 +/- 0.08) and compared to healthy blood bank donors (0.14 +/- 0.06) (P<0.001). Five (38.5%) of thirteen patients receiving piperacillin-tazobactam had serum GMI values >0.5 compared to none of thirteen subjects receiving other antibiotics (P = 0.039) and to none of ten healthy blood bank donors (P = 0.046). These data demonstrate that among antibiotics that are commonly used in immunocompromised patients, only piperacillin-tazobactam contains significant amounts of galactomannan antigen in vitro, that in animals receiving piperacillin-tazobactam circulating galactomannan antigen accumulates in vivo to significantly increased and sustained levels, and that some but not all patients receiving this antibiotic will demonstrate circulating galactomannan above the threshold considered positive for invasive aspergillosis by the recently licensed double sandwich ELISA. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. NIH, Surg Serv, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. Washington Hosp Ctr, Div Infect Dis, Washington, DC 20010 USA. SAIC, Frederick, MD USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bldg 10,Rm 13N-240,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov NR 18 TC 96 Z9 114 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD OCT PY 2004 VL 42 IS 10 BP 4744 EP 4748 DI 10.1128/JCM.42.10.4744-4748.2004 PG 5 WC Microbiology SC Microbiology GA 862EM UT WOS:000224473000048 PM 15472335 ER PT J AU Martin, DH Nsuami, M Schachter, J Hook, EW Ferrero, D Quinn, TC Gaydos, C AF Martin, DH Nsuami, M Schachter, J Hook, EW Ferrero, D Quinn, TC Gaydos, C TI Use of multiple nucleic acid amplification tests to define the infected-patient "gold standard" in clinical trials of new diagnostic tests for Chlamydia trachomatis infections SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID DISCREPANT ANALYSIS; NEISSERIA-GONORRHOEAE; EDITORIAL RESPONSE; ASYMPTOMATIC MEN; URINE SPECIMENS; CHAIN-REACTION; ASSAY; BIAS AB Nucleic acid amplification tests (NAATs) can be used to define the infected-patient "gold standard" for the purpose of designing studies of the performance of Chlamydia trachomatis diagnostic tests. It is unclear how many test results run by different NAATs and what combinations of specimens comprise the best infected-patient gold standard. We approached this question with data from a large study of the performance of a new NAAT. Data were available from three endocervical swabs and a urine specimen collected from each of 1,412 women and tested by three different NAATs. Results from all three assays were used equally in a rotating fashion to define the infected-patient gold standard. Multiple different infected-patient gold standards for estimating swab and urine specimen sensitivity and specificity for one NAAT method were created by varying the number and combinations of swab and urine comparator results with two different NAATs, The effect of changing the infected-patient gold standard definition was determined by constructing receiver-operator-like curves with calculated sensitivities and specificities for each test. The one-positive-of-two-results or two-positive-of-two-results (same or two different assays) infected-patient gold standard definitions produced low sensitivity and low specificity estimates, respectively. If four comparator NAAT results were used, the any-three-positive-of-four-results definition or the at-least-one-specimen-positive-by-each-of-two-comparator-assays definition appeared to provide better combinations of sensitivity and specificity estimates. The any-two-positive-out-of-three-results definition resulted in estimates that were as good as produced with the former two definitions. This analytic approach provides a means of clearly visualizing the effects of changing NAAT-based infected-patient gold standards and should be helpful in designing future studies of new C. trachomatis diagnostic tests. C1 Louisiana State Univ, Hlth Sci Ctr, Dept Med, Infect Dis Sect, New Orleans, LA 70112 USA. Univ San Francisco, San Francisco, CA 94117 USA. San Joaquin Cty Publ Hlth Dept, San Joaquin, CA USA. Univ Alabama, Birmingham, AL USA. Johns Hopkins Univ, Baltimore, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Martin, DH (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Med, Infect Dis Sect, 1542 Tulane Ave, New Orleans, LA 70112 USA. EM dhmartin@lsuhsc.edu RI Gaydos, Charlotte/E-9937-2010 NR 14 TC 48 Z9 51 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD OCT PY 2004 VL 42 IS 10 BP 4749 EP 4758 DI 10.1128/JCM.42.10.4749-4758.2004 PG 10 WC Microbiology SC Microbiology GA 862EM UT WOS:000224473000049 PM 15472336 ER PT J AU Lippman, SM Levin, B Brenner, DE Gordon, GB Aldige, CR Kramer, BS Garber, JE Hawk, E Ganz, PA Somerfield, MR AF Lippman, SM Levin, B Brenner, DE Gordon, GB Aldige, CR Kramer, BS Garber, JE Hawk, E Ganz, PA Somerfield, MR CA ASCO Canc Prevention Comm TI Cancer prevention and the American Society of Clinical Oncology SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material C1 Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Abbott Labs, Abbott Pk, IL 60064 USA. Canc Prevent & Res Fdn, Alexandria, VA USA. NIH, Dept Hlth & Human Serv, Bethesda, MD USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Dept Hlth & Human Serv, Bethesda, MD USA. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA USA. RP Lippman, SM (reprint author), Univ Texas, MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. NR 0 TC 12 Z9 12 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 1 PY 2004 VL 22 IS 19 BP 3848 EP 3851 DI 10.1200/JCO.2004.07.139 PG 4 WC Oncology SC Oncology GA 859PY UT WOS:000224281600004 PM 15353541 ER PT J AU Bishop, MR Fowler, DH Marchigiani, D Castro, K Kasten-Sportes, C Steinberg, SM Gea-Banacloche, JC Dean, R Chow, CK Carter, C Read, EJ Leitman, S Gress, R AF Bishop, MR Fowler, DH Marchigiani, D Castro, K Kasten-Sportes, C Steinberg, SM Gea-Banacloche, JC Dean, R Chow, CK Carter, C Read, EJ Leitman, S Gress, R TI Allogeneic lymphocytes induce tumor regression of advanced metastatic breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 31-JUN 03, 2003 CL CHICAGO, IL SP Amer Soc Clin Oncol ID BONE-MARROW-TRANSPLANTATION; GRAFT-VERSUS-TUMOR; MAMMARY ADENOCARCINOMA; CELL TRANSPLANTATION; HOST DISEASE; T-CELL; CHEMOTHERAPY; IMMUNITY; CYCLOPHOSPHAMIDE; IMMUNOTHERAPY AB Purpose Allogeneic T lymphocytes can induce regression of metastatic breast cancer through an immune-mediated graft-versus-tumor (GVT) effect in murine models. To determine if a clinical GVT effect exists against metastatic breast cancer, allogeneic lymphocytes were used as adoptive cellular therapy after a reduced-intensity chemotherapy conditioning regimen and allogeneic hematopoietic stem-cell transplantation (HSCT) from human leukocyte antigen-matched siblings. Patients and Methods Sixteen patients with metastatic breast cancer that had progressed after treatment with anthracyclines, taxanes, hormonal agents, and trastuzumab, received allogeneic HSCT. The reduced-intensity transplant conditioning regimen consisted of cyclophosphamide and fludarabine. To distinguish an immunological GVT effect from any antitumor effect of cytotoxic chemotherapy in the transplant-conditioning regimen, allogeneic T lymphocytes were removed from the stem-cell graft and were subsequently administered late postallogeneic HSCT. Allogeneic lymphocytes containing 1 X 10(6), 5 X 10(6), and 10 X 10(6) CD3(+) cells/kg were infused on days +42, +70, and +98 post-allogeneic HSCT, respectively. Results Objective tumor regressions occurred after day +28 post-allogeneic HSCT in six patients and were attributed to allogeneic lymphocyte infusions. Two of these responding patients had disease progression post-allogeneic HSCT before subsequent tumor regression. Tumor regressions occurred concomitantly with the establishment of complete donor T-lymphoid engraftment, were associated with the development of graft-versus-host disease (GVHD), and were abrogated by subsequent systemic immunosuppression for GVHD. Conclusion Allogeneic lymphocytes can induce regression of advanced metastatic breast cancer. These results indicate that an immunological GVT effect from allogeneic lymphocytes exists against metastatic breast cancer and provide rationale for further development of allogeneic cellular therapy for this largely incurable disease. C1 NCI, Ctr Canc Res, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Biostat & Data Management Sect, NIH, Bethesda, MD 20892 USA. RP Bishop, MR (reprint author), NCI, Ctr Canc Res, Expt Transplantat & Immunol Branch, NIH, Bldg 10,Room 12N226, Bethesda, MD 20892 USA. EM mbishop@mail.nih.gov RI Ain, Kenneth/A-5179-2012 OI Ain, Kenneth/0000-0002-2668-934X NR 30 TC 71 Z9 74 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 1 PY 2004 VL 22 IS 19 BP 3886 EP 3892 DI 10.1200/JCO.2004.01.127 PG 7 WC Oncology SC Oncology GA 859PY UT WOS:000224281600009 PM 15314059 ER PT J AU Kammula, US Ghossein, R Bhattacharya, S Coit, DG AF Kammula, US Ghossein, R Bhattacharya, S Coit, DG TI Serial follow-up and the prognostic significance of reverse transcriptase-polymerase chain reaction-staged sentinel lymph nodes from melanoma patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PRIMARY CUTANEOUS MELANOMA; TYROSINASE MESSENGER-RNA; MALIGNANT-MELANOMA; RT-PCR; PERIPHERAL-BLOOD; II MELANOMA; RECURRENCE; LYMPHADENECTOMY; METASTASES; BIOPSY AB Purpose Reverse transcriptase-polymerase chain reaction (RT-PCR) may provide an extremely sensitive method for detection of occult nodal disease. We evaluated the role of a single-marker RT-PCR assay for tyrosinase mRNA in the detection of melanoma sentinel lymph node (SLN) metastases and correlated the results with long-term clinical outcome. Patients and Methods One hundred twelve patients who underwent SLN biopsy for melanoma were prospectively analyzed. SLNs were bivalved, with half of each specimen evaluated by histologic methods and the other half evaluated by nested RT-PCR for tyrosinase. Results Fifteen patients (13%) had histologically positive SLNs, all of whom were also positive by RT-PCR (HISTO+/PCR+). Thirty-nine patients (35%) had SLNs that were negative by both histology and RT-PCR (HISTO-/PCR-). Fifty-eight patients (52%) were histologically negative but upstaged with a positive RT-PCR result (HISTO-/PCR+). Initially, at a median follow-up of 42 months, recurrence rates among the three cohorts were statistically different (HISTO+/PCR+, 53%,; HISTO-/PCR+, 14%;- and HISTO-/PCR-, 0%). However, at a longer median follow-up (67 months), recurrence rates for the HISTO-/PCR+ (24%) and HISTO-/PCR- (15%) groups were no longer statistically different (P = .25). The median time to relapse between the HISTO-/PCR+ and HISTO-/PCR- groups differed by 10 months (31 v 41 months, respectively). Conclusion With extended follow-up of patients with histologically negative SLNs, detection of submicroscopic disease by tyrosinase RT-PCR does not define a subgroup that is at higher recurrence risk when compared with patients with RT-PCR-negative SLNs. Future studies evaluating molecular staging will require approximately 5 years of median follow-up to accurately define outcome for patients with occult melanoma metastases. C1 Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Kammula, US (reprint author), NCI, Surg Branch, Bldg 10,Room 2B04,10 Ctr Dr MSC 1502, Bethesda, MD 20892 USA. EM udai_kammula@nih.gov NR 27 TC 46 Z9 46 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 1 PY 2004 VL 22 IS 19 BP 3989 EP 3996 DI 10.1200/JCO.2004.03.052 PG 8 WC Oncology SC Oncology GA 859PY UT WOS:000224281600022 PM 15459222 ER PT J AU Figueiredo, ML Cullen, J Hwang, YT Rowland, JH Mandelblatt, JS AF Figueiredo, ML Cullen, J Hwang, YT Rowland, JH Mandelblatt, JS TI Breast cancer treatment in older women: Does getting what you want improve your long-term body image and mental health? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 23rd Annual Meeting of the Society-of-Behavioral-Medicine CY APR 03-06, 2002 CL WASHINGTON, D.C. SP Soc Behav Med ID QUALITY-OF-LIFE; COMPARING TOTAL MASTECTOMY; PSYCHOLOGICAL ADJUSTMENT; OUTCOMES; SURGERY; LUMPECTOMY; SURVIVORS; SATISFACTION; ATTITUDES; PATTERNS AB Purpose Little is known about the impact of surgical treatment on body image and health outcomes in older breast cancer patients. The purpose of this article is to evaluate whether concordance between treatment received and treatment preferences predicts posttreatment body image and whether body image, in turn, affects mental health in older women with breast cancer 2 years after treatment. Patients and Methods A longitudinal cohort of 563 women who were 67 years old or older and who had stages I and II breast cancer were surveyed by telephone at 3, 12, and 24 months after surgery. All women were clinically eligible for breast conservation. Body image was measured using questions adapted from the Cancer Rehabilitation Evaluation System-Short Form, and mental health was evaluated using a Medical Outcomes Study subscale. Results Body image was an important factor in treatment decisions for 31% of women. Women who received breast conservation had better body image 2 years after treatment than women who had mastectomies (P < .0001). Women who preferred breast conservation but received mastectomy had the poorest body image. Using generalized estimating equations, we found that body image, in turn, predicted 2-year mental health. Conclusion Body image is important for many older women, and receiving treatment consistent with preferences about appearance was important in long-term mental health outcomes. Health professionals should elicit preferences about appearance from women and provide treatment choices in concordance with these preferences. Enhancing shared decision making has the potential to improve mental health in older breast cancer survivors. C1 Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Dept Oncol,Canc Control Program, Washington, DC 20007 USA. Natl Canc Inst, Off Canc Survivorship, Rockville, MD USA. RP Mandelblatt, JS (reprint author), Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Dept Oncol,Canc Control Program, 2233 Wisconsin Ave,Ste 317, Washington, DC 20007 USA. EM mandelbj@georgetown.edu FU AHRQ HHS [R01 HS 08395]; NCI NIH HHS [1U10 CA 84131, K05 CA 96940] NR 39 TC 71 Z9 73 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD OCT 1 PY 2004 VL 22 IS 19 BP 4002 EP 4009 DI 10.1200/JCO.2004.07.030 PG 8 WC Oncology SC Oncology GA 859PY UT WOS:000224281600024 PM 15459224 ER PT J AU Best, B Capparelli, EV Stek, A Burchett, S Read, J Smith, E Hu, C Gardella, J Elgie, C Schiffhauer, J Mirochnick, M AF Best, B Capparelli, EV Stek, A Burchett, S Read, J Smith, E Hu, C Gardella, J Elgie, C Schiffhauer, J Mirochnick, M CA PACTG 1026s Study Team TI Abacavir pharmacokinetics during pregnancy SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-College-of-Clinical-Pharmacology CY OCT 03-05, 2004 CL Phoenix, AZ SP Amer Coll Clin Pharmacol C1 Univ Calif San Diego, San Diego, CA 92103 USA. Univ So Calif, Los Angeles, CA 90089 USA. Childrens Hosp, Boston, MA 02115 USA. NICHD, Bethesda, MD USA. NIAID, Bethesda, MD 20892 USA. Harvard Univ, Boston, MA 02115 USA. Boston Univ, Boston, MA 02215 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. PACTG, Silver Spring, MD USA. RI Hu, Chengcheng/A-8391-2017 NR 0 TC 0 Z9 0 U1 0 U2 6 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2004 VL 44 IS 10 MA 59 BP 1199 EP 1199 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 852JF UT WOS:000223750900064 ER PT J AU Gupta, M Zhang, L Tolley, E Li, R Bauer, D Ding, J Harris, T Newman, A Kritchevsky, S Meibohm, B AF Gupta, M Zhang, L Tolley, E Li, R Bauer, D Ding, J Harris, T Newman, A Kritchevsky, S Meibohm, B TI Racial differences in the association of beta 2-AR polymorphisms with prevalence and severity of COPD SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Meeting Abstract CT 33rd Annual Meeting of the American-College-of-Clinical-Pharmacology CY OCT 03-05, 2004 CL Phoenix, AZ SP Amer Coll Clin Pharmacol C1 Univ Tennessee, Memphis, TN USA. Univ Memphis, Memphis, TN 38152 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD OCT PY 2004 VL 44 IS 10 MA 82 BP 1204 EP 1204 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 852JF UT WOS:000223750900082 ER PT J AU Umbricht, A Huestis, MA Cone, EJ Preston, KL AF Umbricht, A Huestis, MA Cone, EJ Preston, KL TI Effects of high-dose intravenous buprenorphine in experienced opioid abusers SO JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article ID BENZODIAZEPINES; DEPENDENCE; HUMANS; METHADONE; AGONIST; PHARMACOLOGY; MAINTENANCE; DEATHS; AGENT; COMBINATION AB Sublingual buprenorphine, a long-acting, partial muopioid agonist, is as effective as methadone in the treatment of heroin dependence, with a better safety profile due to its antagonist activity. However, the safety of therapeutic doses (8 to 16 mg) that might be diverted for intravenous (IV) use has not been demonstrated. To evaluate the safety and possible ceiling effects of buprenorphine administered IV to experienced opioid users, buprenorphine was administered to 6 nondependent opioid abusers residing on a research unit; the doses tested, in separate sessions, were 12 mg buprenorphine sublingual, IV/sublingual placebo, and escalating IV buprenorphine (2, 4, 8, 12, and 16 mg). Physiologic and subjective measures were collected for 72 hours post-drug administration. Buprenorphine minimally but significantly increased systolic blood pressure. Changes in heart rate or oxygen saturation among the 7 drug conditions were not statistically significant. The mean maximum decrease in oxygen saturation from baseline was greatest for the 8-mg IV dose. Buprenorphine produced positive mood effects, although with substantial variability among participants. Onset and peak effects occurred earlier following IV administration: peak IV effects occurred between 0.25 and 3 hours; peak sublingual effects occurred at 3 to 7 hours. Duration of effects varied among the outcome measures. The dose-response curves were flat for most parameters, particularly subjective measures. Side effects were mild except in one participant who experienced severe nausea and vomiting after the 12-mg IV dose. Buprenorphine appears to have a ceiling for cardiorespiratory and subjective effects and a high safety margin even when taken by the IV route. C1 NIDA, Intramural Res Program, Baltimore, MD 21224 USA. RP Preston, KL (reprint author), NIDA, Intramural Res Program, 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 45 TC 21 Z9 22 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0271-0749 J9 J CLIN PSYCHOPHARM JI J. Clin. Psychopharmacol. PD OCT PY 2004 VL 24 IS 5 BP 479 EP 487 DI 10.1097/01.jcp.0000138766.15858.c6 PG 9 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 856UD UT WOS:000224069600002 PM 15349002 ER PT J AU Kim, BS Lee, JB Jang, HS Kwon, YW Kwon, KS Oh, CK AF Kim, BS Lee, JB Jang, HS Kwon, YW Kwon, KS Oh, CK TI Multiple basal cell carcinomas arising in a port-wine stain with a remote history of therapeutic irradiation SO JOURNAL OF DERMATOLOGY LA English DT Article DE port-wine stain; basal cell carcinoma; tholium X; argon laser ID NEVUS-FLAMMEUS; THORIUM-X AB The coexistence of a basal cell carcinoma and a port-wine stain is a very rare condition that may be associated with previous treatments. We present a case of multiple basal cell carcinomas developing within the boundaries of a port-wine stain, which had been treated with a tholium X and argon laser. Our case suggests that port-wine stains which were previously treated with irradiation or argon laser should be examined carefully and regularly by both physician and patient, because they may hide basal cell carcinomas. C1 Pusan Natl Univ, Dept Dermatol, Coll Med, Pusan 602739, South Korea. NIAID, NIH, Immunopathol Lab, Bethesda, MD 20892 USA. RP Oh, CK (reprint author), Pusan Natl Univ, Dept Dermatol, Coll Med, 1-10 Ami Dong, Pusan 602739, South Korea. NR 12 TC 3 Z9 7 U1 1 U2 1 PU JAPANESE DERMATOLGICAL ASSOC PI TOKYO PA TAISEI-BLDG., 14-10 HONGO 3-CHOME, BUNKYO-KU, TOKYO, 113-0033, JAPAN SN 0385-2407 J9 J DERMATOL JI J. Dermatol. PD OCT PY 2004 VL 31 IS 10 BP 820 EP 823 PG 4 WC Dermatology SC Dermatology GA 866LG UT WOS:000224774400008 PM 15672711 ER PT J AU Kwon, KS Jang, HS Son, HS Oh, CK Kwon, YW Kim, KH Suh, SB AF Kwon, KS Jang, HS Son, HS Oh, CK Kwon, YW Kim, KH Suh, SB TI Widespread and invasive Trichophyton rubrum infection mimicking Kaposi's sarcoma in a patient with AIDS SO JOURNAL OF DERMATOLOGY LA English DT Article DE dermatophyte infection; trichophyton rubrum; AIDS ID IMMUNOCOMPROMISED HOST; DERMATOPHYTOSIS; MENTAGROPHYTES; DISEASE AB Opportunistic fungal infections are commonly encountered in AIDS patients. Candidiasis, tinea pedis, onychomycosis, and deep mycotic infections have been the fungal infections most frequently reported in these patients. Dermatophyte infections can appear to be atypical and aggressive in these patients and may lead to a misdiagnosis. We report a Trichophyton rubrum infection in a 44-year-old man with AIDS that presented as a widespread and multiple tumor-like appearance. After the patient was treated with terbinafine for 21 weeks, the lesions cleared completely. We think that this type of dermatophyte infection is very unusual in patients with AIDS and could lead to inappropriate diagnostic processes and treatments. C1 Pusan Natl Univ, Dept Dermatol, Coll Med, Pusan 602739, South Korea. NIAID, Mol Pathol Sect, Immunopathol Lab, NIH, Rockville, MD USA. Yeungnam Univ, Taegu, South Korea. Catholic Skin Dis Clin, Taegu, South Korea. RP Kwon, KS (reprint author), Pusan Natl Univ, Dept Dermatol, Coll Med, 1-10 Ami Dong, Pusan 602739, South Korea. NR 11 TC 10 Z9 11 U1 0 U2 0 PU JAPANESE DERMATOLGICAL ASSOC PI TOKYO PA TAISEI-BLDG., 14-10 HONGO 3-CHOME, BUNKYO-KU, TOKYO, 113-0033, JAPAN SN 0385-2407 J9 J DERMATOL JI J. Dermatol. PD OCT PY 2004 VL 31 IS 10 BP 839 EP 843 PG 5 WC Dermatology SC Dermatology GA 866LG UT WOS:000224774400013 PM 15672716 ER PT J AU Hart, TC Pihlstrom, BL Tabak, LA AF Hart, TC Pihlstrom, BL Tabak, LA TI Oral health research at the crossroads: Translate we must! SO JOURNAL OF ENDODONTICS LA English DT Review ID CLINICAL-RESEARCH; HUMAN-GENOME; MEDICAL-RESEARCH; BIOLOGY; DISEASE; FUTURE C1 NIDCR, Bethesda, MD 20892 USA. RP Tabak, LA (reprint author), NIDCR, 31 Ctr Dr,MSC 2290,Bldg 31,Room 2C39, Bethesda, MD 20892 USA. EM lawrence.tabak@nih.gov NR 40 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0099-2399 J9 J ENDODONT JI J. Endod. PD OCT PY 2004 VL 30 IS 10 BP 684 EP 688 DI 10.1097/00004770-200410000-00002 PG 5 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 857JY UT WOS:000224113700002 PM 15448459 ER PT J AU Valenzuela, JG Garfield, M Rowton, ED Pham, VM AF Valenzuela, JG Garfield, M Rowton, ED Pham, VM TI Identification of the most abundant secreted proteins from the salivary glands of the sand fly Lutzomyia longipalpis, vector of Leishmania chagasi SO JOURNAL OF EXPERIMENTAL BIOLOGY LA English DT Article DE salivary gland transcript; salivary protein; New World sand fly; Lutzomyia longipalpis; saliva ID TICK IXODES-SCAPULARIS; VASODILATORY PEPTIDE; BORRELIA-BURGDORFERI; HOST-RESISTANCE; TRANSMISSION; MAXADILAN; MOSQUITO; SIALOME; DATABASE; BINDING AB Using massive cDNA sequencing, proteomics and customized computational biology approaches, we have isolated and identified the most abundant secreted proteins from the salivary glands of the sand fly Lutzomyia longipalpis. Out of 550 randomly isolated clones from a full-length salivary gland cDNA library, we found 143 clusters or families of related proteins. Out of these 143 families, 35 were predicted to be secreted proteins. We confirmed, by Edman degradation of Lu. longipalpis salivary proteins, the presence of 17 proteins from this group. Full-length sequence for 35 cDNA messages for secretory proteins is reported, including an RGD-containing peptide, three members of the yellow-related family of proteins, maxadilan, a PpSP15-related protein, six members of a family of putative anticoagulants, an antigen 5-related protein, a D7-related protein, a cDNA belonging to the Cimex apyrase family of proteins, a protein homologous to a silk protein with amino acid repeats resembling extracellular matrix proteins, a 5'-nucleotidase, a peptidase, a palmitoyl-hydrolase, an endonuclease, nine novel peptides and four different groups of proteins with no homologies to any protein deposited in accessible databases. Sixteen of these proteins appear to be unique to sand flies. With this approach, we have tripled the number of isolated secretory proteins from this sand fly. Because of the relationship between the vertebrate host immune response to salivary proteins and protection to parasite infection, these proteins are promising markers for vector exposure and attractive targets for vaccine development to control Leishmania chagasi infection. C1 NIAID, Lab Malaria & Vector Res, Vector Mol Biol Unit, NIH, Rockville, MD 20852 USA. NIAID, Struct Biol Unit, Rockville, MD 20852 USA. Walter Reed Army Med Ctr, Walter Reed Army Inst Res, Dept Entomol, Washington, DC 20307 USA. RP Valenzuela, JG (reprint author), NIAID, Lab Malaria & Vector Res, Vector Mol Biol Unit, NIH, 12735Twinbrook Pkwy,Room 2E-22C, Rockville, MD 20852 USA. EM jvalenzuela@niaid.nih.gov RI Rowton, Edgar/A-4474-2012; Rowton, Edgar/A-1975-2011 OI Rowton, Edgar/0000-0002-1979-1485 NR 46 TC 79 Z9 84 U1 2 U2 8 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0022-0949 J9 J EXP BIOL JI J. Exp. Biol. PD OCT PY 2004 VL 207 IS 21 BP 3717 EP 3729 DI 10.1242/jeb.01185 PG 13 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 870XW UT WOS:000225093200018 PM 15371479 ER PT J AU Kitaguchi, T Sukhareva, M Swartz, KJ AF Kitaguchi, T Sukhareva, M Swartz, KJ TI Stabilizing the closed S6 gate in the Shaker K-v channel through modification of a hydrophobic seal SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article DE voltage-dependent gating; closed gate; Agitoxin; mutagenesis; potassium channel ID POTASSIUM CHANNEL; ACTIVATION GATE; GATING CHARGE; ION CHANNELS; CRYSTAL-STRUCTURE; MOLECULAR-BASIS; VOLTAGE SENSOR; MOVING PARTS; OPEN STATE; PORE AB The primary activation gate in K+ channels is thought to reside near the intracellular entrance to the ion conduction pore. In a previous study of the S6 activation gate in Shaker (Hackos et al., 2002), we found that mutation of V478 to W results in a channel that cannot conduct ions even though the voltage sensors are competent to translocate gating charge in response to membrane depolarization. In the present study we explore the mechanism underlying the nonconducting phenotype in V478W and compare it to that of W434F, a mutation located in ail extracellular region of the pore that is nonconducting because the channel is predominant]), found in an inactivated state. We began by examining whether the intracellular gate moves using probes that interact with the intracellular pore and by studying the inactivation properties of heterodimeric channels that are competent to conduct ions. The results of these experiments support distinct mechanisms underlying nonconduction in W434F and V478W, suggesting that the gate in V478W either remains closed, or that the Mutation has created a large barrier to ion permeation in the open state. Single channel recordings for heterodimeric and double mutant constructs in which ion conduction is rescued suggest that the V478W mutation does not dramatically alter unitary conductance. Taken together, our results suggest that the V478W mutation causes a profound shift of the closed to open equilibrium toward the closed state. This mechanism is discussed in the context of the structure of this critical region in K+ channels. C1 NINDS, Mol Physiol & Biophys Sect, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Swartz, KJ (reprint author), NINDS, Mol Physiol & Biophys Sect, NIH, Porter Neurosci Res Ctr, 3B-215,35 Convent Dr,MSC 3701, Bethesda, MD 20892 USA. EM swartzk@ninds.nih.gov RI Kitaguchi, Tetsuya/F-5260-2017 FU Intramural NIH HHS [ZIA NS002945-13] NR 54 TC 42 Z9 43 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD OCT PY 2004 VL 124 IS 4 BP 319 EP 332 DI 10.1085/jgp.200409098 PG 14 WC Physiology SC Physiology GA 860YL UT WOS:000224380500003 PM 15365093 ER PT J AU Tsina, E Chen, CH Koutalos, Y Ala-Laurila, P Tsacopoulos, M Wiggert, B Crouch, RK Cornwall, MC AF Tsina, E Chen, CH Koutalos, Y Ala-Laurila, P Tsacopoulos, M Wiggert, B Crouch, RK Cornwall, MC TI Physiological and microfluorometric studies of reduction and clearance of retinal in bleached rod photoreceptors SO JOURNAL OF GENERAL PHYSIOLOGY LA English DT Article DE retinol; vitamin A; photoreceptor; visual cycle; IRBP ID BINDING PROTEIN IRBP; ALL-TRANS-RETINOL; OUTER SEGMENTS; DARK-ADAPTATION; VISUAL-PIGMENT; RHODOPSIN; PHOTOTRANSDUCTION; GLUCOSE; CYCLE; DEHYDROGENASE AB The visual cycle comprises a sequence of reactions that regenerate the visual pigment in photoreceptors during dark adaptation, starting with the reduction of all-trans retinal to all-trans retinol and its clearance from photoreceptors. We have followed the reduction of retinal and clearance of retinol within bleached outer segments of red rods isolated from salamander retina by measuring its intrinsic fluorescence. Following exposure to a bright light (bleach), increasing fluorescence intensity was observed to propagate along the outer segments in a direction from the proximal region adjacent to the inner segment toward the distal tip. Peak retinol fluorescence was achieved after similar to30 min, after which it declined very slowly. Clearance of retinol fluorescence is considerably accelerated by the presence of the exogenous lipophilic substances IRBP (interphotoreceptor retinoid binding protein) and serum albumin. We have used simultaneous fluorometric and electrophysiological measurements to compare the rate of reduction of all-trans retinal to all-trans retinol to the rate of recovery of flash response amplitude in these cells in the presence and absence of IRBP We rind that flash response recovery in rods is modestly accelerated in the presence of extracellular IRBP. These results suggest such substances may participate in the clearance of retinoids from rod photoreceptors, and that this clearance, at least in rods, may facilitate dark adaptation by accelerating the clearance of photoproducts of bleaching. C1 Boston Univ, Sch Med, Dept Physiol & Biophys, Boston, MA 02118 USA. Univ Colorado, Sch Med, Dept Physiol & Biophys, Denver, CO 80262 USA. Univ Athens, Dept Expt Physiol, Athens, Greece. NEI, NIH, Bethesda, MD 20892 USA. Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29425 USA. RP Cornwall, MC (reprint author), Boston Univ, Sch Med, Dept Physiol & Biophys, 715 Albany St, Boston, MA 02118 USA. EM cornwall@bu.edu OI Cornwall, M./0000-0002-0847-939X; Ala-Laurila, Petri/0000-0002-6139-6825 FU NEI NIH HHS [EY01157, EY014793, EY11351, R01 EY001157, R01 EY004939, R24 EY014793] NR 44 TC 35 Z9 37 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1295 J9 J GEN PHYSIOL JI J. Gen. Physiol. PD OCT PY 2004 VL 124 IS 4 BP 429 EP 443 DI 10.1085/jgp.200409078 PG 15 WC Physiology SC Physiology GA 860YL UT WOS:000224380500011 PM 15452202 ER PT J AU Gearhart, PJ AF Gearhart, PJ TI The birth of molecular immunology SO JOURNAL OF IMMUNOLOGY LA English DT Editorial Material ID ANTIBODY C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Gearhart, PJ (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM gearhartp@grc.nia.nih.gov NR 5 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2004 VL 173 IS 7 BP 4259 EP 4259 PG 1 WC Immunology SC Immunology GA 856VF UT WOS:000224072600001 PM 15383552 ER PT J AU Nelson, GW Martin, MP Gladman, D Wade, J Trowsdale, J Carrington, M AF Nelson, GW Martin, MP Gladman, D Wade, J Trowsdale, J Carrington, M TI Cutting edge: Heterozygote advantage in autoimmune disease: Hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CELL RECEPTORS; NK CELLS; GENES AB Functionally relevant combinations of HLA and killer Ig-like receptor (KIR) genotypes influence resistance to, several diseases in humans. Analysis of genetic data from such studies is challenging because it involves multiple linked and unlinked loci that exert their influence in an epistatic manner. We previously reported that subjects with certain activating receptors were susceptible to developing psoriatic arthritis (PSA), an effect that was strongest when HLA ligands for corresponding homologous inhibitory receptors were missing. In this study, we present a novel model in which susceptibility to PsA is determined by the overall balance of activating and inhibitory composite KIR-HLA genotypes. This model fits our knowledge of clonal NK cell expression of KIR and regulation of NK cell activity better than does the previous model, as reflected in a robust trend for increasing susceptibility to PsA with more activating genotypes. These data emphasize the remarkable influence of KIR/HLA combinations on this, disease. C1 NCI Frederick, Basic Res Program, Sci Applicat Int Corp, Ft Detrick, MD 21702 USA. Toronto Western Res Inst, Toronto, ON, Canada. Toronto Western Hosp, Ctr Prognosis Studies Rheumat Dis, Toronto, ON, Canada. Univ Hlth Network, Reg HLA Lab, Toronto, ON, Canada. Univ Cambridge, Dept Pathol, Div Immunol, Cambridge, England. RP Carrington, M (reprint author), NCI Frederick, Basic Res Program, Sci Applicat Int Corp, POB B, Ft Detrick, MD 21702 USA. EM carringt@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 10 TC 181 Z9 187 U1 1 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2004 VL 173 IS 7 BP 4273 EP 4276 PG 4 WC Immunology SC Immunology GA 856VF UT WOS:000224072600004 PM 15383555 ER PT J AU Abrahams, VM Bole-Aldo, P Kim, YM Straszewski-Chavez, SL Chaiworapongsa, T Romero, R Mor, G AF Abrahams, VM Bole-Aldo, P Kim, YM Straszewski-Chavez, SL Chaiworapongsa, T Romero, R Mor, G TI Divergent trophoblast responses to bacterial products mediated by TLRs SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTOR-2; NF-KAPPA-B; INNATE IMMUNE-SYSTEM; INTRAUTERINE GROWTH RESTRICTION; CUTTING EDGE; PATTERN-RECOGNITION; INDUCED APOPTOSIS; PRETERM DELIVERY; FAS LIGAND; DIFFERENTIAL REGULATION AB Intrauterine infections have been associated with pregnancy complications that are also linked with increased trophoblast apoptosis. TLRs are key components of the innate immune system which recognize conserved sequences on the surface of pathogens and trigger effector cell functions. We hypothesize that intrauterine infections may cause the excessive trophoblast cell apoptosis observed in abnormal pregnancies and that TLR may provide a mechanism of pathogenesis. In this study we describe the expression and function of TLR-2 and TLR-4 in first trimester trophoblast cells. Although ligation of TLR4 induced cytokine production by trophoblast cells, TLR-2 activation induced apoptosis. TLR-2 mediated apoptosis was dependent upon the Fas-associated death domain, the inactivation of the X-finked inhibitor of apoptosis, and the activation of caspases 8, 9, and 3. These results suggest that certain intrauterine infections may directly induce trophoblast cell death through TLR-2. Our findings provide a novel mechanism of pathogenesis for certain pregnancy complications in which there is engagement of the innate immune system. C1 Yale Univ, Sch Med, Reprod Immunol Unit, Dept Obstet & Gynecol, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA. Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Mor, G (reprint author), Yale Univ, Sch Med, Reprod Immunol Unit, Dept Obstet & Gynecol, 333 Cedar St,FMB 301, New Haven, CT 06520 USA. EM Gil.Mor@yale.edu NR 80 TC 151 Z9 160 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2004 VL 173 IS 7 BP 4286 EP 4296 PG 11 WC Immunology SC Immunology GA 856VF UT WOS:000224072600006 PM 15383557 ER PT J AU Hon, H Rucker, EB Hennighausen, L Jacob, J AF Hon, H Rucker, EB Hennighausen, L Jacob, J TI bcl-X-L is critical for dendritic cell survival in vivo SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; TUMOR-NECROSIS-FACTOR; EPIDERMAL LANGERHANS CELLS; INDUCED APOPTOSIS; ANTIGENIC-STIMULATION; HEMATOPOIETIC-CELLS; INTERFERING RNAS; MAMMALIAN-CELLS; GENE-EXPRESSION; FAMILY-MEMBER AB Dendritic cells (DC) are important regulators of immune function, transporting Ags from the periphery to draining lymph nodes (dLN) where they prime Ag-specific T lymphocytes. The magnitude of the immune response generated depends upon the longevity of the Ag-bearing DC in lymphoid tissues. We hypothesized that the control of DC survival is regulated by the antiapoptotic factor bcl-x(L). Gene gun immunization of dual-expression DNA vaccines into a bcl-x(fl/fl) mouse resulted in the delivery of Ag, as well as selective deletion of the bcl-x gene in directly transfected, skin-residing DC. bcl-x-deficient DC failed to mount effective immune responses, and this corresponded to their rapid disappearance from the dLN due to apoptosis. We confirmed these results using RNA interference to specifically silence the antiapoptotic bcl-x, isoform in targeted skin-residing DC of C57BL/6 mice. In addition, delivery of bcl-x(L) in trans complemented the bcl-x deficiency in DC of bcl-x(fl/fl) mice, resulting in the maintenance of normal levels of Ag-bearing DC in the dLN. Taken together, our work demonstrates that the bcl-x(L) isoform is critical for survival of skin-derived, Ag-bearing DC in vivo. C1 Emory Univ, Vaccine Ctr, Dept Microbiol & Immunol, Atlanta, GA 30329 USA. Univ Missouri, Dept Anim Sci, Columbia, MO 65211 USA. NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Jacob, J (reprint author), Emory Univ, Vaccine Ctr, Dept Microbiol & Immunol, 954 Gatewood Rd NE, Atlanta, GA 30329 USA. EM jjacob3@emory.edu NR 40 TC 39 Z9 40 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2004 VL 173 IS 7 BP 4425 EP 4432 PG 8 WC Immunology SC Immunology GA 856VF UT WOS:000224072600022 PM 15383573 ER PT J AU Fear, DJ McCloskey, N O'Connor, B Felsenfeld, G Gould, HJ AF Fear, DJ McCloskey, N O'Connor, B Felsenfeld, G Gould, HJ TI Transcription of Ig germline genes in single human B cells and the role of cytokines in isotype determination SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CLASS-SWITCH RECOMBINATION; HEAVY-CHAIN TRANSCRIPTS; CYTIDINE DEAMINASE AID; EPSILON-TRANSCRIPTS; DNA RECOMBINATION; PLASMA-CELLS; REGION GENE; EXPRESSION; DIFFERENTIATION; INTERLEUKIN-4 AB We have developed a critical test of the chromatin accessibility model of Ig isotype determination in which local unfolding of chromatin higher order structure (chromatin accessibility) in the region of specific germline genes in the H chain locus determines the Ab class to be expressed in the B cell. We show that multiple germline genes are constitutively transcribed in the majority of naive human B eel Is in a population. Thus, because chromatin in its higher order structure cannot be transcribed, the entire Ig H chain locus must be unfolded in naive B cells. We have also established that IL-4 and anti-CD40 act by enhancing transcription in the majority of cells, rather than by activating transcription in more of the cells. Transcriptional activity in the human H chain locus rules out the perturbation of chromatin higher order structure as a factor in isotype determination. We have also found that the levels of germline gene transcription cannot fully account for the levels of secretion of the different Ig isotypes, and that secretion of IgE, in particular, is suppressed relative to that of IgG. C1 Kings Coll London, Randall Ctr, London SE1 1UL, England. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Guys Kings & St Thomas Sch Med, Dept Resp Med & Allergy, London, England. RP Gould, HJ (reprint author), Kings Coll London, Randall Ctr, New Hunts House, London SE1 1UL, England. EM hannah.gould@kcl.ac.uk NR 58 TC 31 Z9 32 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2004 VL 173 IS 7 BP 4529 EP 4538 PG 10 WC Immunology SC Immunology GA 856VF UT WOS:000224072600034 PM 15383585 ER PT J AU Poloso, NJ Muntasell, A Roche, PA AF Poloso, NJ Muntasell, A Roche, PA TI MHC class II molecules traffic into lipid rafts during intracellular transport SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTIGEN-PROCESSING COMPARTMENTS; INVARIANT CHAIN COMPLEXES; GPI-ANCHORED PROTEINS; DENDRITIC CELLS; PEPTIDE COMPLEXES; HLA-DM; ENDOCYTIC PATHWAY; PLASMA-MEMBRANE; DR MOLECULES; DOMAINS AB There have been many studies demonstrating that a portion of MHC class II molecules reside in detergent-insoluble membrane domains (commonly referred to as lipid rafts). We have proposed that the function of raft association is to concentrate specific MHC class II-peptide complexes in plasma membrane microdomains that can facilitate efficient T cell activation. We now show that MHC class II becomes lipid raft associated before binding antigenic peptides. Using pulse-chase radiolabeling techniques, we find that newly synthesized MHC class II and MHC class II-invariant chain complexes initially reside in a detergent-soluble membrane fraction and acquire detergent insolubility as they traffic to lysosomal Ag processing compartments. Monensin, an inhibitor of protein transport through the Golgi apparatus, blocks association of newly synthesized MHC class-II with lipid rafts. Treatment of cells with leupeptin, which inhibits invariant chain degradation, leads to the accumulation of MHC class II in lipid rafts within the lysosome-like Ag-processing compartments. Raft fractionation of lysosomal membranes confirmed the presence of MHC class II in detergent-insoluble microdomains in Ag-processing compartments. These findings indicate that newly synthesized MHC class II complexes are directed to detergent-insoluble lipid raft microdomains before peptide loading, a process that may facilitate the loading of similar peptides on MHC class II complexes in these microdomains. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Roche, PA (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. EM paul.roche@nih.gov RI Muntasell, Aura/F-7869-2014 OI Muntasell, Aura/0000-0003-2894-0486 NR 39 TC 28 Z9 29 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2004 VL 173 IS 7 BP 4539 EP 4546 PG 8 WC Immunology SC Immunology GA 856VF UT WOS:000224072600035 PM 15383586 ER PT J AU Lee, SJ Garza, L Yao, J Notkins, AL Zhou, P AF Lee, SJ Garza, L Yao, J Notkins, AL Zhou, P TI A nonneutralizing anti-HIV-1 antibody turns into a neutralizing antibody when expressed on the surface of HIV-1-susceptible cells: A new way to fight HIV SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODY; ENVELOPE GLYCOPROTEINS; CONFORMATIONAL-CHANGES; GENE-TRANSFER; HTLV-III; TYPE-1; GP41; INFECTION; EPITOPE AB During HIV-1 infection or vaccination, HIV-1 envelope spikes elicit Ab responses. Neutralizing Abs block viral entry by recognizing epitopes on spikes critical for their interaction with receptor, coreceptors or fusion. In contrast, nonneutralizing Abs fail to do so because they recognize epitopes either buried or exposed but not critical for viral entry. Previously, we produced a high-affinity human mAb against the cluster II determinant of gp41. This Ab or its recombinant Fab and single-chain Fv have been repeatedly shown to bind to HIV-1 gp160 or gp41, but fail to block viral entry. We report that, surprisingly, expression of this nonneutralizing anti-HIV-1 gp41 single-chain Fv on the surface of human CD4 T cells markedly inhibits HIV-1 replication and cell-cell fusion. The inhibition targets the HIV-1 envelope at the level of viral entry, regardless of HIV-1 tropism. Although this bona fide nonneutralizing Ab does not neutralize HIV-1 entry when produced as a soluble protein, it acts as a neutralizing Ab when expressed on the cell surface. Expressing Abs on the surface of HIV-1-susceptible cells can be anew way to fight HIV-1. C1 SW Fdn Biomed Res, Dept Virol & Immunol, San Antonio, TX 78245 USA. Natl Inst Dent & Craniofacial Res, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Zhou, P (reprint author), SW Fdn Biomed Res, Dept Virol & Immunol, POB 760549, San Antonio, TX 78245 USA. EM pzhou@sfbr.org FU NIAID NIH HHS [AI47682, AI054254] NR 40 TC 11 Z9 16 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 1 PY 2004 VL 173 IS 7 BP 4618 EP 4626 PG 9 WC Immunology SC Immunology GA 856VF UT WOS:000224072600045 PM 15383596 ER PT J AU Li, HC Biggar, RJ Miley, WJ Maloney, EM Cranston, B Hanchard, B Hisada, M AF Li, HC Biggar, RJ Miley, WJ Maloney, EM Cranston, B Hanchard, B Hisada, M TI Provirus load in breast milk and risk of mother-to-child transmission of human T lymphotropic virus type I SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CELL LEUKEMIA-VIRUS; HTLV-I; SEROCONVERSION; TRANSFUSION; BLOOD; JAPAN; DNA AB In a prospective study of 101 mother-child pairs in Jamaica, we examined the association of provirus load in breast milk and the risk of mother-to-child transmission of human T lymphotropic virus type I. The provirus load in breast milk was a strong predictor of risk of transmission to children ( relative risk, 2.34/quartile), after adjustment for other known risk factors. The risk of transmission increased from 4.7/1000 person-months when the provirus load in breast milk was <0.18% to 28.7/1000 person-months when it was >1.5%. Provirus detection in maternal breast milk predicted transmission months before infection in children was detected by serologic testing. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Sci Applicat Int Corp, AIDS Vaccine Program, Viral Epidemiol Sect, Frederick, MD USA. Univ W Indies, Kingston 7, Jamaica. RP Hisada, M (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8008, Rockville, MD 20852 USA. EM hisadam@exchange.nih.gov FU NCI NIH HHS [N01-CP-40548] NR 15 TC 48 Z9 49 U1 0 U2 2 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 OCT 1 PY 2004 VL 190 IS 7 BP 1275 EP 1278 DI 10.1086/423941 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 855JC UT WOS:000223968400010 PM 15346338 ER PT J AU Cooper, PJ Chico, ME Sandoval, C Nutman, TB AF Cooper, PJ Chico, ME Sandoval, C Nutman, TB TI Atopic phenotype is an important determinant of immunoglobulin E-mediated inflammation and expression of T helper cell type 2 cytokines to Ascaris antigens in children exposed to ascariasis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID INTESTINAL HELMINTH INFECTION; SCHISTOSOMA-HAEMATOBIUM; ALLERGIC REACTIVITY; NEMATODE INFECTIONS; IMMUNE-RESPONSES; SLUM CHILDREN; SKIN-TEST; IGE; REINFECTION; RESISTANCE AB Studies have shown a strong inverse relationship between atopy and geohelminth infection, indicating that atopy may protect against geohelminth infection. Resistance to ascariasis in atopic individuals may occur through greater immunoglobulin E-mediated responses and expression of T helper cell type 2 (Th2) cytokines to parasite antigens. To investigate the effect that atopy has on the immune response to Ascaris antigens, school-age children were recruited from rural schools in Ecuador. Immunologic variables were compared between children stratified by atopic and/or A. lumbricoides-infection status; the variables included cytokine expression by peripheral-blood mononuclear cells (PBMCs) and histamine release in response to Ascaris antigens. Atopic children had both greater frequencies of PBMCs expressing interleukin (IL)-4 and IL-5 and enhanced histamine release, compared with those in nonatopic children. Stratification by atopic and A. lumbricoides-infection status revealed the greatest histamine and Th2 cytokine responses in the stratum of atopic, noninfected children. Multivariate regression analyses showed significant effects for atopic status but not for infection status on Th2 cytokine expression and histamine release. C1 Hosp Pedro Vicente Maldonado, Lab Invest, Quito, Pichincha Prov, Ecuador. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Univ London St Georges Hosp, Sch Med, Dept Infect Dis, London SW17 0RE, England. RP Cooper, PJ (reprint author), Hosp Pedro Vicente Maldonado, Lab Invest, Casilla 17-14-30, Quito, Pichincha Prov, Ecuador. EM pcooper@ecnet.ec NR 40 TC 31 Z9 34 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 OCT 1 PY 2004 VL 190 IS 7 BP 1338 EP 1346 DI 10.1086/423944 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 855JC UT WOS:000223968400019 PM 15346347 ER PT J AU Liang, XJ Shen, DW Gottesman, MM AF Liang, XJ Shen, DW Gottesman, MM TI A pleiotropic defect reducing drug accumulation in cisplatin-resistant cells SO JOURNAL OF INORGANIC BIOCHEMISTRY LA English DT Article; Proceedings Paper CT 9th International Symposium on Platinum Compounds in Cancer Chemotherapy CY OCT, 2003 CL New York Univ, New York, NY HO New York Univ DE cisplatin resistance; dominant gene(s); membrane protein mislocalization; defective endocytosis; reduced in vivo tumorigenicity ID ADENOSINE-TRIPHOSPHATASE ATP7B; OVARIAN-CARCINOMA CELLS; MULTIDRUG-RESISTANCE; CROSS-RESISTANCE; CELLULAR PHARMACOLOGY; ADENOCARCINOMA CELLS; GENE-EXPRESSION; CANCER-CELLS; LINES; PROTEINS AB The resistance of tumors to cisplatin remains a major cause of treatment failure in cancer patients. Multiple, simultaneous alterations are frequently encountered in cancer cells selected for cisplatin resistance. To determine whether the complex phenotype results from many different cellular alterations, single-step variants were isolated based on one-step selection in cisplatin. Reduced drug accumulation is a common feature of cisplatin-resistant (CP-r) cancer cells, which is probably caused by one or more dominant genes. Pulse-chase labeling and pulse-chase biotinylation of cell surface proteins suggest that membrane protein mislocalization occurs in CP-r cells, caused mainly by a defect in plasma membrane protein recycling, manifested also as a defect in acidification of lysosomes. This membrane protein mislocalization is presumed to reduce cell surface expression of a putative cisplatin carrier or carriers. In cells selected in several steps, decreased expression of folate-binding protein and arsenic-binding proteins, and reduced endocytosis were detected in CP-r cells, contributing to the reduced uptake of cisplatin, methotrexate and other related compounds. Multiple mechanisms in CP-r cells keep cytotoxic platinum compounds out of cells through defective expression of cell surface proteins such as transporters and carriers, and decreased expression of proteins involved in endocytosis. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, Cell Biol Lab, Canc Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Canc Res Ctr, Natl Inst Hlth, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov NR 37 TC 26 Z9 27 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0162-0134 J9 J INORG BIOCHEM JI J. Inorg. Biochem. PD OCT PY 2004 VL 98 IS 10 BP 1599 EP 1606 DI 10.1016/j.jinorgbio.2004.05.015 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Inorganic & Nuclear SC Biochemistry & Molecular Biology; Chemistry GA 863YI UT WOS:000224599100008 PM 15458822 ER PT J AU Blonder, J Terunuma, A Conrads, TR Chan, KC Yee, C Lucas, DA Schaefer, CF Yu, LR Issaq, HJ Veenstra, TD Vogel, JC AF Blonder, J Terunuma, A Conrads, TR Chan, KC Yee, C Lucas, DA Schaefer, CF Yu, LR Issaq, HJ Veenstra, TD Vogel, JC TI A proteomic characterization of the plasma membrane of human epidermis by high-throughput mass spectrometry SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article DE keratinocytes; epidermis; proteomics; mass spectrometry; membrane proteins ID PROTEINS; CELL; EXPRESSION; RAFTS; TRAFFICKING; COMPONENTS; JUNCTIONS; ADHESION; PATHWAYS; BARRIER AB Membrane proteins are responsible for many critical cellular functions and identifying cell surface proteins on different keratinocyte populations by proteomic approaches would improve our understanding of their biological function. The ability to characterize membrane proteins, however, has lagged behind that of soluble proteins both in terms of throughput and protein coverage. In this study, a membrane proteomic investigation of keratinocytes using a two-dimensional liquid chromatography (LC) tandem-mass spectrometry (MS/MS) approach that relies on a buffered methanol-based solubilization, and tryptic digestion of purified plasma membrane is described. A highly enriched plasma membrane fraction was prepared from newborn foreskins using sucrose gradient centrifugation, followed by a single-tube solubilization and tryptic digestion of membrane proteins. This digestate was fractionated by strong cation-exchange chromatography and analyzed using microcapillary reversed-phase LC-MS/MS. In a set of 1306 identified proteins, 866 had a gene ontology (GO) annotation for cellular component, and 496 of these annotated proteins (57.3%) were assigned as known integral membrane proteins or membrane-associated proteins. Included in the identification of a large number of aqueous insoluble integral membrane proteins were many known intercellular adhesion proteins and gap junction proteins. Furthermore, 121 proteins from cholesterol-rich plasma membrane domains (caveolar and lipid rafts) were identified. C1 NCI, Dermatol Branch, NIH, Ctr Bioinformat, Bethesda, MD 20892 USA. SAIC Frederick Inc, Lab Proteom & Anal Technol, Frederick, MD USA. Natl Canc Inst, Frederick, MD USA. Natl Canc Inst, Ctr Bioinformat, Bethesda, MD USA. RP Vogel, JC (reprint author), NCI, Dermatol Branch, NIH, Ctr Bioinformat, Bldg 10,Room 12N238,10 Ctr dr,MSC 1908, Bethesda, MD 20892 USA. EM jonvogel@mail.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 31 TC 54 Z9 59 U1 1 U2 3 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD OCT PY 2004 VL 123 IS 4 BP 691 EP 699 DI 10.1111/j.0022-202X.2004.23421.x PG 9 WC Dermatology SC Dermatology GA 855OF UT WOS:000223982900019 PM 15373774 ER PT J AU Swartz, JM Bystrom, J Dyer, KD Nitto, T Wynn, TA Rosenberg, HF AF Swartz, JM Bystrom, J Dyer, KD Nitto, T Wynn, TA Rosenberg, HF TI Plasminogen activator inhibitor-2 (PAI-2) in eosinophilic leukocytes SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE eosinophils; proteases; protease inhibitor; secretory proteins; serpin ID TISSUE EOSINOPHILIA; HELMINTH-PARASITES; TUMOR-GROWTH; HOST-DEFENSE; ASTHMA; EXPRESSION; TYPE-2; METASTASIS; SYSTEM; CANCER AB Plasminogen activator inhibitor-2 (PAI-2) as a potential eosinophil protein was inferred from our gene microarray study of mouse eosinophilopoiesis. Here, we detect 47 kDa intracellular and similar to60 kDa secretory forms of PAI-2 in purified human eosinophil extracts. PAI-2 is present at variable concentrations in eosinophil lysates, ranging from 30 to 444 ng/10(6) Cells, with a mean of 182 ng/10(6) cells from 10 normal donors, which is the highest per-cell concentration among all leukocyte subtypes evaluated. Enzymatic assay confirmed that eosinophil-derived PAI-2 is biologically active and inhibits activation of its preferred substrate, urokinase. Immunohistochemical and immunogold staining demonstrated PAI-2 localization in eosinophil-specific granules. Immunoreactive PAI-2 was detected in extracellular deposits in and around the eosinophil-enriched granuloma tissue encapsulating the parasitic egg in livers of wildtype mice infected with the helminthic parasite Schistosoma mansoni. Among the possibilities, we consider a role for eosinophil-derived PAI-2 in inflammation and remodeling associated with parasitic infection as well as allergic airways disease, respiratory virus infection, and host responses to tumors and metastasis in vivo. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike,Bldg 10,Room 11N104, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 NR 61 TC 21 Z9 22 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD OCT PY 2004 VL 76 IS 4 BP 812 EP 819 DI 10.1189/jlb.0304182 PG 8 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 858HO UT WOS:000224183100007 PM 15277569 ER PT J AU Vikramadithyan, RK Kako, Y Chen, GP Hu, YY Arikawa-Hirasawa, E Yamada, Y Goldberg, IJ AF Vikramadithyan, RK Kako, Y Chen, GP Hu, YY Arikawa-Hirasawa, E Yamada, Y Goldberg, IJ TI Atherosclerosis in perlecan heterozygous mice SO JOURNAL OF LIPID RESEARCH LA English DT Article DE heparan; low density lipoprotein receptor; apolipoprotein E; proteoglycans; lipoproteins ID LOW-DENSITY LIPOPROTEINS; SMOOTH-MUSCLE-CELLS; ARTERIAL PROTEOGLYCANS; SULFATE PROTEOGLYCAN; RECEPTOR-DEFICIENT; APOLIPOPROTEIN-E; MURINE MODELS; LESIONS; GLYCOSAMINOGLYCANS; BINDING AB The hypothesis that lipoprotein association with perlecan is atherogenic was tested by studying atherosclerosis in mice that had a heterozygous deletion of perlecan, the primary extracellular heparan sulfate proteoglycan in arteries. We first studied the expression of perlecan in mouse lesions and noted that this proteoglycan in aorta was found in the subendothelial matrix. Perlecan was also a major component of the lesional extracellular matrix. Mice with a heterozygous deletion had a reduction in arterial wall perlecan expression. Atherosclerosis in these mice was studied after crossing the defect into the apolipoprotein E (apoE) and LDL receptor knockout backgrounds. At 12 weeks, chow-fed apoE null mice with a heterozygous deletion had less atherosclerosis. However, at 24 weeks and in the LDL receptor heterozygous background, the presence of a perlecan knockout allele did not significantly alter lesion size. jlr Thus, it appears that loss of perlecan leads to less atherosclerosis in early lesions. Although this might be attributable to a decrease in lipoprotein retention, it should be noted that perlecan might mediate multiple other processes that could, in sum, accelerate atherosclerosis. -Vikramadithyan, R. K., Y. Kako, G. Chen, Y. Hu, E. Arikawa-Hirasawa, Y. Yamada, and I. J. Goldberg. Atherosclerosis in perlecan heterozygous mice. C1 Columbia Univ, Dept Med, New York, NY 10032 USA. Natl Dent & Craniofacial Res, Bethesda, MD 20892 USA. RP Goldberg, IJ (reprint author), Columbia Univ, Dept Med, New York, NY 10032 USA. EM ijg3@columbia.edu FU NHLBI NIH HHS [HL 56984, HL 62301] NR 30 TC 28 Z9 28 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2004 VL 45 IS 10 BP 1806 EP 1812 DI 10.1194/jlr.M400019-JLR200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 859ZR UT WOS:000224307400002 PM 15258195 ER PT J AU Elosua, R Ordovas, JM Cupples, LA Fox, CS Polak, JF Wolf, PA D'Agostino, RA O'Donnell, CJ AF Elosua, R Ordovas, JM Cupples, LA Fox, CS Polak, JF Wolf, PA D'Agostino, RA O'Donnell, CJ TI Association of APOE genotype with carotid atherosclerosis in men and women: the Framingham Heart Study SO JOURNAL OF LIPID RESEARCH LA English DT Article DE genetics; atherosclerosis; carotid artery; lipoprotein; apolipoprotein E genotype ID APOLIPOPROTEIN-E POLYMORPHISM; INTIMA-MEDIA THICKNESS; ARTERIAL-WALL THICKNESS; CARDIOVASCULAR-DISEASE; MYOCARDIAL-INFARCTION; ASYMPTOMATIC ADULTS; TRIGLYCERIDE LEVELS; RISK-FACTORS; E ALLELES; E GENE AB The aim of this study was to determine the association between APOE genotype and carotid atherosclerosis, defined as intimal-medial thickness (IMT) and stenosis, and to assess if other cardiovascular risk factors modify this association. A total of 1,315 men and 1,408 women from the Framingham Offspring Study underwent carotid ultrasound during examination cycle 6 and had complete data on APOE genotype. Three APOE genotype groups were defined: APOE2 (including E2/E2, E3/E2 genotypes), APOE3 (010), and APOE4 (including E4/E3, E4/E4 genotypes). Carotid IMT and the presence of carotid stenosis > 25% were determined by ultrasonography. In women, the APOE2 group was associated with lower carotid IMT (0.67 vs. 0.73 mm) and lower prevalence of stenosis (odds ratio = 0.49; 95% confidence interval = 0.30-0.81) compared with the APOE3 group. In men, APOE genotype was not associated with carotid IMT or stenosis in the whole group; however, diabetes modified the association between APOE genotype and carotid IMT (P for interaction = 0.044). Among men with diabetes, the APOE4 group was associated with a higher internal carotid artery IMT (1.22 mm) than the APOE3 group (0.90 mm) or the APOE2 group (0.84 mm). jlr The E2 allele was associated with lower carotid atherosclerosis in women, and the E4 allele was associated with higher internal carotid IMT in diabetic men. -Elosua, R., J. M. Ordovas, L. A. Cupples, C. S. Fox, J. F. Polak, P. A. Wolf, R. A. D'Agostino, Sr., and C. J. O'Donnell. Association of APOE genotype with carotid atherosclerosis in men and women. The Framingham Heart Study. C1 NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Cardiol Div, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Boston Univ, Dept Neurol & Prevent Med, Boston, MA 02215 USA. Boston Univ, Dept Epidemiol, Boston, MA 02215 USA. Boston Univ, Dept Biostat, Boston, MA 02215 USA. Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP O'Donnell, CJ (reprint author), NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. EM codonnell@partners.org OI ELOSUA, ROBERTO/0000-0001-8235-0095; Ordovas, Jose/0000-0002-7581-5680 FU NHLBI NIH HHS [HL 54776, N01 HC 25195]; NINDS NIH HHS [5R01 NS 17950-22] NR 46 TC 51 Z9 52 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD OCT PY 2004 VL 45 IS 10 BP 1868 EP 1875 DI 10.1194/jlr.M4000114-JLR200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 859ZR UT WOS:000224307400009 PM 15258198 ER PT J AU Shen, J Yang, JH Choi, IY Li, SZS Chen, ZG AF Shen, J Yang, JH Choi, IY Li, SZS Chen, ZG TI A new strategy for in vivo spectral editing. Application to GABA editing using selective homonuclear polarization transfer spectroscopy SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE GABA; vigabatrin; spectral editing; polarization transfer; quantification ID GAMMA-AMINOBUTYRIC-ACID; DOUBLE-QUANTUM FILTER; HUMAN CEREBRAL GABA; HUMAN BRAIN; RAT-BRAIN; COHERENCE TRANSFER; H-1-NMR SPECTRA; VINYL GABA; METABOLITES; VIGABATRIN AB A novel single-shot in vivo spectral editing method is proposed in which the signal to be detected, is regenerated anew from the thermal equilibrium magnetization of a source to which it is J-coupled. The thermal equilibrium magnetization of the signal to be detected together with those of overlapping signals are suppressed by single-shot gradient dephasing prior to the signal regeneration process. Application of this new strategy to in vivo GABA editing using selective homonuclear polarization transfer allows complete suppression of overlapping creatine and glutathione while detecting the GABA-4 methylene resonance at 3.02ppm with an editing yield similar to that of conventional editing methods. The NAA methyl group at 2.02 ppm was simultaneously detected and can be used as an internal navigator echo for correcting the zero order phase and frequency shifts and as an internal reference for concentration. This new method has been demonstrated for robust in vivo GABA editing in the rat brain and for study of GABA synthesis after acute vigabatrin administration. (C) 2004 Elsevier Inc. All rights reserved. C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NIMH, Spectroscopy Core Facil, Bethesda, MD 20892 USA. Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. RP Shen, J (reprint author), NIMH, Mol Imaging Branch, Bldg 10,Room 2D51A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM shenj@intra.nimh.nih.gov FU NIA NIH HHS [R03AG022193]; NIBIB NIH HHS [8R01EB00315] NR 36 TC 23 Z9 25 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 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD OCT PY 2004 VL 170 IS 2 BP 290 EP 298 DI 10.1016/j.jmr.2004.05.022 PG 9 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 858WW UT WOS:000224224200016 PM 15388093 ER PT J AU Moore, DF Ye, F Brennan, ML Gupta, S Barshop, BA Steiner, RD Rhead, WJ Brady, RO Hazen, SL Schiffmann, R AF Moore, DF Ye, F Brennan, ML Gupta, S Barshop, BA Steiner, RD Rhead, WJ Brady, RO Hazen, SL Schiffmann, R TI Ascorbate decreases Fabry cerebral hyperperfusion suggesting a reactive oxygen species abnormality: An arterial spin tagging study SO JOURNAL OF MAGNETIC RESONANCE IMAGING LA English DT Article DE Fabry disease; ascorbate; cerebral blood flow; stroke; reactive oxygen species ID BLOOD-FLOW; HYPERPOLARIZING FACTOR; ENZYME REPLACEMENT; IN-VIVO; DISEASE; BRAIN; MYELOPEROXIDASE; DYSFUNCTION; INCREASES; RADICALS AB Purpose: To test the hypothesis that reactive oxygen species contribute to the cerebral hyperperfusion in Fabry disease. Material and Methods: We examined the effect of intravenous injection of ascorbate on cerebral blood flow (CBF) using magnetic resonance arterial spin tagging. Nineteen patients with Fabry disease and 15 control subjects were studied as part of a randomized double-blind placebo-controlled trial of enzyme replacement therapy (ERT). Results: Vertebro-basilar hyperperfusion was observed in patients with Fabry disease. A decrease in systemic ascorbate levels relative to healthy controls was found in the patients. CBF decreased after ascorbate infusion in both control subjects and patients treated with ERT. The placebo group had a significantly delayed decrease in the CBF response after ascorbate infusion. Myeloperoxidase levels were elevated in Fabry patients, consistent with ongoing inflammatory processes in these patients. Conclusion: Increased CBF in Fabry disease may be related to increased production of reactive oxygen species, while low plasma ascorbate levels suggests a global redox imbalance. These abnormalities were improved by ERT. These observations have implications regarding oxidative processes contributing to accelerated atherosclerosis in Fabry disease. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Manitoba, Dept Internal Med, Neurol Sect, Winnipeg, MB R3T 2N2, Canada. NIMH, Funct MRI Facil, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Cleveland Clin Fdn, Ctr Cardiovasc Diagnost & Prevent, Dept Cell Biol & Cardiovasc Med, Cleveland, OH 44195 USA. Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. Univ Calif San Diego, Inst Mol Genet, San Diego, CA 92103 USA. Oregon Hlth & Sci Univ, Portland, OR USA. Childrens Hosp Wisconsin, Dept Pediat, Genet Sect, Milwaukee, WI 53201 USA. RP Schiffmann, R (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D03,9000 Rockville Pike, Bethesda, MD 20892 USA. EM RS4e@nih.gov OI Steiner, Robert/0000-0003-4177-4590 FU NCRR NIH HHS [M01 RR018390]; NHLBI NIH HHS [HL62526, HL70621]; NINDS NIH HHS [NS002984-05] NR 34 TC 40 Z9 41 U1 1 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1053-1807 J9 J MAGN RESON IMAGING JI J. Magn. Reson. Imaging PD OCT PY 2004 VL 20 IS 4 BP 674 EP 683 DI 10.1002/imri.20162 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 858VA UT WOS:000224219000016 PM 15390234 ER PT J AU Lockett, S de Solorzano, CO Baggett, D Chin, K AF Lockett, S de Solorzano, CO Baggett, D Chin, K TI Quantitative three-dimensional microscopy approaches with applications in breast cancer biology including measurement of genomic instability SO JOURNAL OF MAMMARY GLAND BIOLOGY AND NEOPLASIA LA English DT Article DE fluorescence microscopy; quantitative 3D imaging; mammary gland; genomic instability ID CELLS; NUCLEI; SPECTROSCOPY; SEGMENTATION; MORPHOLOGY; IMAGES AB Understanding tissue development, tissue homeostasis and what goes wrong in these processes during tumorigenesis, requires knowledge of the kinetics of multiple, molecular pathways in individual cells while cells are in their tissue context. This review outlines progress and future directions necessary in quantitative microscopy for gaining this knowledge, using the mammary gland as a model system. C1 NCI, Frederick Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. Lawrence Berkeley Lab, Div Life Sci, Berkeley, CA USA. Worcester Polytech Inst, Worcester, MA 01609 USA. Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Comprehens Canc, San Francisco, CA 94143 USA. RP Lockett, S (reprint author), NCI, Frederick Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. EM slockett@ncifcrf.gov RI Ortiz de Solorzano, Carlos/G-3278-2010 OI Ortiz de Solorzano, Carlos/0000-0001-8720-0205 FU NCI NIH HHS [N01-CO56000] NR 25 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1083-3021 J9 J MAMMARY GLAND BIOL JI J. Mammary Gland Biol. Neoplasia PD OCT PY 2004 VL 9 IS 4 BP 383 EP 391 DI 10.1007/x10911-004-1408-6 PG 9 WC Oncology; Endocrinology & Metabolism; Physiology SC Oncology; Endocrinology & Metabolism; Physiology GA 918ER UT WOS:000228525600007 PM 15838607 ER PT J AU [Anonymous] AF [Anonymous] TI Increased pathogenicity and neurovirulence in rhesus macaques of an SIV isolate from a rapid progressor macaque SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract RP NIAID, LMM, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2004 VL 33 IS 5-6 BP 284 EP 284 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 858GC UT WOS:000224179300016 ER PT J AU [Anonymous] AF [Anonymous] TI Selective depletion of naive CD4(+) T cell during the acute phase of highly pathogenic SHIV infections SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract RP NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2004 VL 33 IS 5-6 BP 291 EP 291 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 858GC UT WOS:000224179300035 ER PT J AU [Anonymous] AF [Anonymous] TI A novel microbicide to prevent intravaginal transmission of SIV in rhesus macaques SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract RP NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2004 VL 33 IS 5-6 BP 292 EP 292 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 858GC UT WOS:000224179300039 ER PT J AU [Anonymous] AF [Anonymous] TI Polarized outcome following SIVmac251 challenge of macaques vaccinated with a polypeptide mimicking the envelope CD4 binding site: Complete protection vs. high viremia and decreased CD4 dependence SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract RP NCI, NIH, Basic Res Lab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2004 VL 33 IS 5-6 BP 298 EP 298 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 858GC UT WOS:000224179300058 ER PT J AU [Anonymous] AF [Anonymous] TI Natural killer activity of rhesus macaque PBMC against a rhesus macaque-derived target cell line is mediated largely by CD3-CD8(lo) CD16(+) CD11b(+) lymphocytes SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract RP NCI, SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2004 VL 33 IS 5-6 BP 300 EP 301 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 858GC UT WOS:000224179300065 ER PT J AU [Anonymous] AF [Anonymous] TI SHIV-specific cellular responses in SHIV-infected long-term non-progressor pig-tailed macaques SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract RP NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2004 VL 33 IS 5-6 BP 303 EP 304 PG 2 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 858GC UT WOS:000224179300073 ER PT J AU [Anonymous] AF [Anonymous] TI Therapeutic immunization of rhesus macaques chronically infected with SIVmac239, using chemically inactivated SIV virions with functionally intact envelope glycoproteins SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract RP NCI, SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2004 VL 33 IS 5-6 BP 304 EP 304 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 858GC UT WOS:000224179300074 ER PT J AU [Anonymous] AF [Anonymous] TI Novel forms of DNA vaccines decrease viremia in juvenile and neonate macaques upon SIVmac251 challenge SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract RP NCI, Human Retrovirus Sect, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2004 VL 33 IS 5-6 BP 308 EP 308 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 858GC UT WOS:000224179300085 ER PT J AU [Anonymous] AF [Anonymous] TI A novel RT-SHIV to study HIV-1NNRTI activity in pigtailed macaques SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract RP NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2004 VL 33 IS 5-6 BP 310 EP 310 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 858GC UT WOS:000224179300092 ER PT J AU [Anonymous] AF [Anonymous] TI An unusual case of severe SIV encephalitis in a MVA-SIV-immunized slow progressor macaque SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract RP NIH, LMM, 12441 Parklawn Dr, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2004 VL 33 IS 5-6 BP 311 EP 311 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 858GC UT WOS:000224179300096 ER PT J AU [Anonymous] AF [Anonymous] TI Real-time QRT-PCR assays to monitor the emergence of genotypic changes in SIV genomes associated with phenotypic drug resistance SO JOURNAL OF MEDICAL PRIMATOLOGY LA English DT Meeting Abstract RP NCI, SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0047-2565 J9 J MED PRIMATOL JI J. Med. Primatol. PD OCT PY 2004 VL 33 IS 5-6 BP 321 EP 321 PG 1 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 858GC UT WOS:000224179300126 ER PT J AU Gokhale, AM Evans, RA Mackes, JL Mouton, PR AF Gokhale, AM Evans, RA Mackes, JL Mouton, PR TI Design-based estimation of surface area in thick tissue sections of arbitrary orientation using virtual cycloids SO JOURNAL OF MICROSCOPY-OXFORD LA English DT Article DE cycloids; first-order stereology; surface area; unbiased stereology; vertical sections; virtual probes ID VERTICAL SECTIONS; STEREOLOGICAL ESTIMATION; LENGTH; NUMBER; VOLUME; DENSITY; PROBES AB Surface area is a first-order stereological parameter with important biological applications, particularly at the intersection of biological phases. To deal with the inherent anisotropy of biological surfaces, state-of-the-art design-based methods require tissue rotation around at least one axis prior to sectioning. This paper describes the use of virtual cycloids for surface area estimation of objects and regions in thick, transparent tissue sections cut at any arbitrary (convenient) orientation. Based on the vertical section approach of Baddeley et al., the present approach specifies the vertical axis as the direction of sectioning (i.e. the direction perpendicular to the tissue section), and applies computer-generated cycloids (virtual cycloids) with their minor axis parallel to the vertical axis. The number of surface-cycloid intersections counted on focal planes scanned through the z-axis is proportional to the surface area of interest in the tissue, with no further assumptions about size, shape or orientation. Optimal efficiency at each x-y location can be achieved by three virtual cycloids orientated with their major axes (which are parallel to the observation planes) mutually at an angle of 120degrees. The major practical advantage of the present approach is that estimates of total surface area (S) and surface density (S-V) can be obtained in tissue sections cut at any convenient orientation through the reference space. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Georgia Inst Technol, Sch Mat Sci & Engn, Atlanta, GA 30332 USA. Syst Planning & Anal Inc, Alexandria, VA USA. Stereol Resource Ctr, Baltimore, MD USA. RP Mouton, PR (reprint author), NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. EM src@disector.com FU NIBIB NIH HHS [1R43EB001605-01] NR 26 TC 11 Z9 11 U1 1 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-2720 J9 J MICROSC-OXFORD JI J. Microsc.-Oxf. PD OCT PY 2004 VL 216 BP 25 EP 31 DI 10.1111/j.0022-2720.2004.01392.x PN 1 PG 7 WC Microscopy SC Microscopy GA 854BP UT WOS:000223875400004 PM 15369480 ER PT J AU Zhang, P Bos, E Heymann, J Gnaegi, H Kessel, M Peters, PJ Subramaniam, S AF Zhang, P Bos, E Heymann, J Gnaegi, H Kessel, M Peters, PJ Subramaniam, S TI Direct visualization of receptor arrays in frozen-hydrated sections and plunge-frozen specimens of E-coli engineered to overproduce the chemotaxis receptor Tsr SO JOURNAL OF MICROSCOPY-OXFORD LA English DT Article DE chemotaxis receptor; cryoelectron microscopy; diamond knife; frozen-hydrated section; high-pressure freezing; signal transduction ID BACTERIAL CHEMOTAXIS; ELECTRON-MICROSCOPY; BIOLOGICAL SAMPLES; MEMBRANE; CRYOSECTIONS; SENSITIVITY; TOMOGRAPHY; ARTIFACTS; COMPLEXES; SYSTEM AB We have recently reported electron tomographic studies of sections obtained from chemically fixed E. coli cells overproducing the 60-kDa chemotaxis receptor Tsr. Membrane extracts from these cells prepared in the presence of Tween-80 display hexagonally close-packed microcrystalline assemblies of Tsr, with a repeating unit large enough to accommodate six Tsr molecules arranged as trimers of receptor dimers. Here, we report the direct visualization of the Tsr receptor clusters in (i) vitrified cell suspensions of cells overproducing Tsr, prepared by rapid plunge-freezing, and (ii) frozen-hydrated sections obtained from cells frozen under high pressure. The frozen-hydrated sections were generated by sectioning at -150 degreesC using a diamond knife with a 25degrees knife angle, with nominal thicknesses ranging from 20 to 60 nm. There is excellent correspondence between the spatial arrangement of receptors in thin frozen-hydrated sections and the arrangements found in negatively stained membrane extracts and plunge-frozen cells, highlighting the potential of using frozen-hydrated sections for the study of macromolecular assemblies within cells under near-native conditions. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20817 USA. Diatome SA, CH-2500 Biel, Switzerland. Netherlands Canc Inst, Div Tumor Biol, Amsterdam, Netherlands. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20817 USA. EM p.peters@nki.nl; ss1@nih.gov NR 30 TC 62 Z9 62 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-2720 J9 J MICROSC-OXFORD JI J. Microsc.-Oxf. PD OCT PY 2004 VL 216 BP 76 EP 83 DI 10.1111/j.0022-2720.2004.01395.x PN 1 PG 8 WC Microscopy SC Microscopy GA 854BP UT WOS:000223875400011 PM 15369487 ER PT J AU Moroz, OV Harkiolaki, M Galperin, MY Vagin, AA Gonzalez-Pacanowska, D Wilson, KS AF Moroz, OV Harkiolaki, M Galperin, MY Vagin, AA Gonzalez-Pacanowska, D Wilson, KS TI The crystal structure of a complex of Campylobacter jejuni dUTPase with substrate analogue sheds light on the mechanism and suggests the "basic module" for dimeric d(C/U)TPases SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE dUTPase; dCTPase; bacteriophage; enzyme specificity; ligand complex ID BIFUNCTIONAL DCTP DEAMINASE; ESCHERICHIA-COLI; LEISHMANIA-MAJOR; TRIPHOSPHATE NUCLEOTIDOHYDROLASE; METHANOCALDOCOCCUS-JANNASCHII; METHANOCOCCUS-JANNASCHII; HOMOTRIMERIC DUTPASES; LIGAND INTERACTIONS; HORIZONTAL TRANSFER; DNA-POLYMERASES AB The crystal structure of the dUTPase from the important gastric pathogen Campylobacter jejuni has been solved at 1.65 Angstrom spacing. This essential bacterial enzyme is the second representative of the new family of dimeric dUTPases to be structurally characterised. Members of this family have a novel all-alpha fold and are unrelated to the all-beta dUTPases of the majority of organisms including eukaryotes such as humans, bacteria such as Escherichia coli, archaea like Methanococcus jannaschii and animal viruses. Therefore, dimeric dUTPases can be considered as candidate drug targets. The X-ray structure of the C. jejuni dUTPase in complex with the nonhydrolysable substrate analogue dUpNHp allows us to define the positions of three catalytically significant phosphate-binding magnesium ions and provides a starting point for a detailed understanding of the mechanism of dUTP/dUDP hydrolysis by dimeric dUTPases. Indeed, a water molecule present in the structure is ideally situated to act as the attacking nucleophile during hydrolysis. A comparison of the dUTPases from C. jejuni and Trypanosoma cruzi reveals a common fold with certain distinct features, both in the rigid and mobile domains as defined in the T. cruzi structure. Homologues of the C. jejuni dUTPase have been identified in several other bacteria and bacteriophages, including the dCTPase of phage T4. Sequence comparisons of these proteins define a new superfamily of d(C/U)TPases that includes three distinct enzyme families: (1) dUTPases in trypanosomatides, C. jejuni and several other Gram-negative bacteria, (2) predicted dUTPases in various Gram-positive bacteria and their phages, and (3) dCTP/dUTPases in enterobacterial T4-like phages. All these enzymes share a basic module that consists of two alpha-helices from the rigid domain, two helices from the mobile domain and connecting loops. These results in concert with a number of conserved residues responsible for interdomain cross-talk provide valuable insight towards rational drug design. (C) 2004 Published by Elsevier Ltd. C1 Univ York, Dept Chem, Struct Biol Lab, Heslington YO10 5YW, Yorks, England. Canc Res UK Cell Signalling Grp, Oxford OX3 9DS, England. Weatherall Inst Mol Med, Oxford OX3 9DS, England. Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. Inst Parasitol & Biomed Lopez Neyra, Granada 18001, Spain. RP Wilson, KS (reprint author), Univ York, Dept Chem, Struct Biol Lab, Heslington YO10 5YW, Yorks, England. EM keith@ysbl.york.ac.uk RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 NR 62 TC 41 Z9 44 U1 2 U2 2 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 OCT 1 PY 2004 VL 342 IS 5 BP 1583 EP 1597 DI 10.1016/j.jmb.2004.07.050 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 857RH UT WOS:000224135500020 PM 15364583 ER PT J AU Stokes, K Alston-Mills, B Teng, C AF Stokes, K Alston-Mills, B Teng, C TI Estrogen response element and the promoter context of the human and mouse lactoferrin genes influence estrogen receptor alpha-mediated transactivation activity in mammary gland cells SO JOURNAL OF MOLECULAR ENDOCRINOLOGY LA English DT Article ID BREAST-CANCER CELLS; NUCLEAR RECEPTOR; TRANSCRIPTIONAL SYNERGY; ER-ALPHA; COACTIVATOR RECRUITMENT; ALLOSTERIC MODULATION; REPRODUCTIVE FUNCTION; MOLECULAR-MECHANISMS; HALF-SITE; BETA AB A critical step in estrogen action is the recognition of estrogen responsive elements (EREs) by liganded estrogen receptor. Our current studies were designed to determine whether an extended estrogen response element half-site (ERRE) contributes to the differential estrogen responses of the human and mouse lactoferrin overlapping chicken ovalbumin upstream promoter/ERE sequences (estrogen response modules, ERMs) in the context of their natural promoters. Transient transfections of MCF-7 cells show that liganded estrogen receptor alpha (ERalpha) activates transcription of the human lactoferrin ERM fourfold higher than the mouse lactoferrin ERM in the context of their natural promoters. Since the ERRE of the human lactoferrin gene naturally occurs 18 bp upstream from the ERM and is absent in the mouse lactoferrin gene promoter, we created a chimeric mouse lactoferrin CAT reporter, which now encodes the ERRE in tie identical location as in the human lactoferrin gene. The addition of the ERRE in the mouse lactoferrin gene rendered this reporter extremely responsive to estrogen stimulation. Using limited protease digestions and electrophoretic mobility shift assays, we showed that the binding and protease sensitivity of ERalpha bound to the mouse ERM with or without the ERRE, differed. Importantly, occupancy of additional nuclear receptors at the ERRE may contribute to ERalpha binding and activation. Furthermore, the presence of ERRE influences the selectivity of coactivators in liganded ERalpha-mediated transcriptional activity. When the receptor is bound to human and mouse plus genes, which contain the ERRE, steroid receptor coactivator (SRC)-2 was preferred, while SRC-1 and SRC-3 coactivators selectively enhanced the mouse lactoferrin gene activity. Moreover, peroxisome proliferator activated receptor-gamma coactivator-1 (PGC-1alpha) and PGC-1-related estrogen receptor coactivator (PERC) robustly increase the transcriptional function of ERalpha in the presence of the ERRE. In conclusion, these data show that the context of the lactoferrin gene influences the ERalpha-mediated transcriptional activity. C1 NIEHS, Gene Regulat Sect, Reprod & Dev Toxicol Lab, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Coll Agr & Life Sci, Dept Anim Sci, Raleigh, NC 27695 USA. RP Teng, C (reprint author), NIEHS, Gene Regulat Sect, Reprod & Dev Toxicol Lab, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. EM Teng@niehs.nih.gov NR 86 TC 16 Z9 16 U1 0 U2 1 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0952-5041 J9 J MOL ENDOCRINOL JI J. Mol. Endocrinol. PD OCT PY 2004 VL 33 IS 2 BP 315 EP 334 DI 10.1677/jme.101456 PG 20 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 864MZ UT WOS:000224638900001 PM 15525592 ER PT J AU Satta, Y Hickerson, M Watanabe, H O'hUigin, C Klein, J AF Satta, Y Hickerson, M Watanabe, H O'hUigin, C Klein, J TI Ancestral population sizes and species divergence times in the primate lineage on the basis of intron and BAC end sequences SO JOURNAL OF MOLECULAR EVOLUTION LA English DT Article DE ancestral population size; nucleotide substitution rate heterogeneity; primate phylogeny; species divergence time ID DNA-SEQUENCES; MODERN HUMANS; BAYES ESTIMATION; COMMON ANCESTOR; MULTIPLE LOCI; EVOLUTION; HOMINOIDS; DIVERSITY; POLYMORPHISMS; CHIMPANZEES AB The effective sizes of ancestral populations and species divergence times of six primate species (humans, chimpanzees, gorillas, orangutans, and representatives of Old World monkeys and New World monkeys) are estimated by applying the two-species maximum likelihood (ML) method to intron sequences of 20 different loci. Examination of rate heterogeneity of nucleotide substitutions and intragenic recombination identifies five outrageous loci (ODC1, GHR, HBE, INS, and HBG). The estimated ancestral polymorphism ranges from 0.21 to 0.96% at major divergences in primate evolution. One exceptionally low polymorphism occurs when African and Asian apes diverged. However, taking into consideration the possible short generation times in primate ancestors, it is concluded that the ancestral population size in the primate lineage was no smaller than that of extant humans. Furthermore, under the assumption of 6 million years (myr) divergence between humans and chimpanzees, the divergence time of humans from gorillas, orangutans, Old World monkeys, and New World monkeys is estimated as 7.2, 18, 34, and 65 myr ago, respectively, which are generally older than traditional estimates. Beside the intron sequences, three other data sets of orthologous sequences are used between the human and the these data sets including 58,156 random BAC end sequences (BES) shows that the nucleotide substitution rate is as low as 0.6-0.8 x 10(-9) per site per year and the extent of ancestral polymorphism is 0.33-0.51%. With such a low substitution rate and short generation time, the relatively high extent of polymorphism suggests a fairly large effective population size in the ancestral lineage common to humans and chimpanzees. C1 Grad Univ Adv Studies, Dept Biosyst Sci, Kanagawa 2400193, Japan. Duke Univ, Dept Biol, Durham, NC USA. Nara Inst Sci & Technol, Dept Bioinformat & Genom, Nara 6300101, Japan. NCI, NIH, Bethesda, MD USA. Max Planck Inst Biol, Immungenet Abt, D-72076 Tubingen, Germany. RP Satta, Y (reprint author), Grad Univ Adv Studies, Dept Biosyst Sci, Kanagawa 2400193, Japan. EM satta@soken.ac.jp NR 40 TC 24 Z9 24 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0022-2844 J9 J MOL EVOL JI J. Mol. Evol. PD OCT PY 2004 VL 59 IS 4 BP 478 EP 487 DI 10.1007/s00239-004-2639-2 PG 10 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 859XK UT WOS:000224301500006 PM 15638459 ER PT J AU Klausmeyer, P Chmurny, GN McCloud, TG Tucker, KD Shoemaker, RH AF Klausmeyer, P Chmurny, GN McCloud, TG Tucker, KD Shoemaker, RH TI A novel antimicrobial indolizinium alkaloid from Aniba panurensis SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID BRAZILIAN LAURACEAE; PROSOPIS-JULIFLORA; STYRYLPYRONES; NEOLIGNANS; CHEMISTRY AB Activity-guided fractionation of an Aniba panurensis organic solvent extract has led to the isolation of the novel alkaloid 6,8-didec-(1Z)-enyl-5,7-dimethyl-2,3-dihydro-1H-indolizinium, as the trifluoroacetic acid salt (1). Its structure was determined by NMR and mass spectrometry. Bioassays performed in vitro demonstrated toxicity of compound 1 to a drug-resistant strain of Candida albicans. C1 SAIC Frederick Inc, Nat Prod Support Grp, Frederick, MD 21702 USA. SAIC Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. SAIC Frederick Inc, Antimicrobial Res Support Grp, Frederick, MD 21702 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21702 USA. RP McCloud, TG (reprint author), SAIC Frederick Inc, Nat Prod Support Grp, Frederick, MD 21702 USA. EM mccloud@dtpax2.ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 13 TC 28 Z9 32 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD OCT PY 2004 VL 67 IS 10 BP 1732 EP 1735 DI 10.1021/np040114e PG 4 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 865MR UT WOS:000224707700020 PM 15497951 ER PT J AU Bremner, JD Vermetten, E Afzal, N Vythilingam, M AF Bremner, JD Vermetten, E Afzal, N Vythilingam, M TI Deficits in verbal declarative memory function in women with childhood sexual abuse-related posttraumatic stress disorder SO JOURNAL OF NERVOUS AND MENTAL DISEASE LA English DT Article DE PTSD; memory; hippocampus; childhood abuse ID VIETNAM COMBAT VETERANS; SHORT-TERM-MEMORY; HIPPOCAMPAL VOLUME; RAPE VICTIMS; DENTATE GYRUS; PTSD SCALE; INFORMATION; ATTENTION; PERFORMANCE; TRAUMA AB Several studies have shown deficits in verbal declarative memory function in posttraumatic stress disorder (PTSD). Most of these studies have been performed in men with combat-related PTSD compared with healthy subjects; relatively little is known about memory function in women with abuse-related PTSD, or whether these effects are specific to PTSD or are a nonspecific outcome of exposure to early abuse. The purpose of this study was to assess declarative memory function in women with and without a history of early childhood sexual abuse and PTSD. Forty-three women with and without a history of early childhood sexual abuse and PTSD underwent neuropsychological testing with subtests of the Wechsler Memory Scale-Revised for measurement of verbal and visual memory and subtests of the Wechsler Adult Intelligence Scale for measurement of IQ, and behavioral ratings of PTSD and other psychiatric symptoms. Abused women with PTSD had deficits in verbal declarative memory as measured with the subtests of the Wechsler Memory Scale-Revised compared with women with early abuse without PTSD and nonabused women without PTSD. There were no significant differences in IQ. These findings suggest that early abuse with PTSD is associated with deficits in verbal declarative memory, and that these effects are not related to the nonspecific effects of childhood abuse. C1 Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Emory Ctr Positron Emiss Tomog, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Radiol, Emory Ctr Positron Emiss Tomog, Atlanta, GA 30322 USA. Atlanta VAMC, Decatur, GA USA. NIMH, Program Mood & Anxiety Disorders, Bethesda, MD 20892 USA. RP Bremner, JD (reprint author), Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Emory Ctr Positron Emiss Tomog, 1256 Briarcliff Rd, Atlanta, GA 30322 USA. RI Bremner, James/B-1632-2013; OI Vermetten, Eric/0000-0003-0579-4404 FU NIMH NIH HHS [1P50 MH58922, 1R01MH56120-02] NR 69 TC 92 Z9 96 U1 6 U2 21 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-3018 J9 J NERV MENT DIS JI J. Nerv. Ment. Dis. PD OCT PY 2004 VL 192 IS 10 BP 643 EP 649 DI 10.1097/01.nmd.0000142027.52893.c8 PG 7 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 862RL UT WOS:000224508500001 PM 15457106 ER PT J AU Kansy, JW Daubner, SC Nishi, A Sotogaku, N Lloyd, MD Nguyen, C Lu, L Haycock, JW Hope, BT Fitzpatrick, PF Bibb, JA AF Kansy, JW Daubner, SC Nishi, A Sotogaku, N Lloyd, MD Nguyen, C Lu, L Haycock, JW Hope, BT Fitzpatrick, PF Bibb, JA TI Identification of tyrosine hydroxylase as a physiological substrate for Cdk5 SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE Cdk5; cocaine; dopamine; MAPK; phosphorylation; tyrosine hydroxylase ID CYCLIN-DEPENDENT KINASE-5; SITE-DIRECTED MUTAGENESIS; VENTRAL TEGMENTAL AREA; PROTEIN-KINASE; RAT-BRAIN; PHOSPHORYLATION SITES; DOPAMINE SYNTHESIS; NUCLEUS-ACCUMBENS; REPEATED COCAINE; ENZYME-ACTIVITY AB Cyclin-dependent kinase 5 (Cdk5) is emerging as a neuronal protein kinase involved in multiple aspects of neurotransmission in both post- and presynaptic compartments. Within the reward/motor circuitry of the basal ganglia, Cdk5 regulates dopamine neurotransmission via phosphorylation of the postsynaptic signal transduction pathway integrator, DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein, M-r 32 000). Cdk5 has also been implicated in regulating various steps in the presynaptic vesicle cycle. Here we report that Cdk5 phosphorylates tyrosine hydroxylase (TH), the key enzyme for synthesis of dopamine. Using phosphopeptide mapping, site-directed mutagenesis, and phosphorylation state-specific antibodies, the site was identified as Ser31, a previously defined extracellular signal-regulated kinases 1/2 (ERK1/2) site. The phosphorylation of Ser31 by Cdk5 versus ERK1/2 was investigated in intact mouse striatal tissue using a pharmacological approach. The results indicated that Cdk5 phosphorylates TH directly and also regulates ERK1/2-dependent phosphorylation of TH through the phosphorylation of mitogen-activated protein kinase kinase 1 (MEK1). Finally, phospho-Ser31 TH levels were increased in dopaminergic neurons of rats trained to chronically self-administer cocaine. These results demonstrate direct and indirect regulation of the phosphorylation state of a Cdk5/ERK1/2 site on TH and suggest a role for these pathways in the neuroadaptive changes associated with chronic cocaine exposure. C1 Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75390 USA. Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. Kurume Univ, Sch Med, Dept Pharmacol, Fukuoka, Japan. NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, New Orleans, LA USA. RP Bibb, JA (reprint author), Univ Texas, SW Med Ctr, Dept Psychiat, 5323 Harry Hines Blvd,NC5-410, Dallas, TX 75390 USA. EM james.bibb@utsouthwestern.edu RI Hope, Bruce/A-9223-2010 OI Hope, Bruce/0000-0001-5804-7061 FU NIGMS NIH HHS [GM 47291, R01 GM047291]; NINDS NIH HHS [NS25134] NR 50 TC 33 Z9 35 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD OCT PY 2004 VL 91 IS 2 BP 374 EP 384 DI 10.1111/j.1471-4159.2004.02723.x PG 11 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 856UH UT WOS:000224070100012 PM 15447670 ER PT J AU Takikawa, Y Kawagoe, R Hikosaka, O AF Takikawa, Y Kawagoe, R Hikosaka, O TI A possible role of midbrain dopamine neurons in short- and long-term adaptation of saccades to position-reward mapping SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID PRIMATE SUBSTANTIA-NIGRA; BASAL GANGLIA; PARS RETICULATA; EYE-MOVEMENTS; OCULOMOTOR FUNCTIONS; MOTIVATIONAL CONTROL; RESPONSES; MONKEY; PREDICTION; INHIBITION AB Dopamine (DA) neurons respond to sensory stimuli that predict reward. To understand how DA neurons acquire such ability, we trained monkeys on a one-direction-rewarded version of memory-guided saccade task (1DR) only when we recorded from single DA neurons. In 1DR, position-reward mapping was changed across blocks of trials. In the early stage of training of 1DR, DA neurons responded to reward delivery; in the later stages, they responded predominantly to the visual cue that predicted reward or no reward ( reward predictor) differentially. We found that such a shift of activity from reward to reward predictor also occurred within a block of trials after position-reward mapping was altered. A main effect of long-term training was to accelerate the within-block reward-to-predictor shift of DA neuronal responses. The within-block shift appeared first in the intermediate stage, but was slow, and DA neurons often responded to the cue that indicated reward in the preceding block. In the advanced stage, the reward-to-predictor shift occurred quickly such that the DA neurons' responses to visual cues faithfully matched the current position-reward mapping. Changes in the DA neuronal responses co-varied with the reward-predictive differentiation of saccade latency both in short-term (within-block) and long-term adaptation. DA neurons' response to the fixation point also underwent long-term changes until it occurred predominantly in the first trial within a block. This might trigger a switch between the learned sets. These results suggest that midbrain DA neurons play an essential role in adapting oculomotor behavior to frequent switches in position-reward mapping. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Juntendo Univ, Sch Med, Dept Physiol, Tokyo 1138421, Japan. RP Hikosaka, O (reprint author), NEI, Sensorimotor Res Lab, NIH, 49 Convent Dr,Bldg 49,Rm 2A50, Bethesda, MD 20892 USA. EM oh@lsr.nei.nih.gov NR 33 TC 52 Z9 52 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD OCT PY 2004 VL 92 IS 4 BP 2520 EP 2529 DI 10.1152/jn.00238.2004 PG 10 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 855DY UT WOS:000223954500051 PM 15163669 ER PT J AU Rubin, SA Liu, D Pletnikov, M McCullers, JA Ye, ZP Levandowski, RA Johannessen, J Carbone, KM AF Rubin, SA Liu, D Pletnikov, M McCullers, JA Ye, ZP Levandowski, RA Johannessen, J Carbone, KM TI Wild-type and attenuated influenza virus infection of the neonatal rat brain SO JOURNAL OF NEUROVIROLOGY LA English DT Article DE influenza virus; neurotropism; neurovirulence; rat; vaccine ID SYMMETRICAL THALAMIC LESIONS; A VIRUS; ACUTE ENCEPHALOPATHY; INFANT RAT; MENTAL-RETARDATION; NERVOUS-SYSTEM; ENCEPHALITIS; DISORDERS; SCHIZOPHRENIA; EPIDEMICS AB Although influenza virus infection of humans has been associated with a wide spectrum of clinical neurological syndromes, the pathogenesis of influenza virus associated central nervous system (CNS) disease in humans remains controversial. To better study influenza virus neuropathogenesis, an animal model of influenza-associated CNS disease using human virus isolates without adaptation to an animal host was developed. This neonatal rat model of influenza virus CNS infection was developed using low-passage human isolates and shows outcomes in specific brain regions, cell types infected, and neuropathological outcomes that parallel the available literature on cases of human CNS infection. The degree of virus replication and spread in the rat brain correlated with the strains' neurotoxicity potential for humans. In addition, using sensitive neurobehavioral test paradigms, changes in brain function were found to be associated with areas of virus replication in neurons. These data suggest that further evaluation of this pathogenesis model may provide important information regarding influenza virus neuropathogenesis, and that this model may have possible utility as a preclinical assay for evaluating the neurological safety of new live attenuated influenza virus vaccine strains. C1 CBER, DVP, OVRR, US FDA, Bethesda, MD 20892 USA. NIA, Neurosci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. US FDA, OS, OC, Rockville, MD 20857 USA. CBER, OD, US FDA, Bethesda, MD USA. RP Rubin, SA (reprint author), CBER, DVP, OVRR, US FDA, Bldg 29A,Room 1A-21,8800 Rockville Pike, Bethesda, MD 20892 USA. EM rubins@cber.fda.gov NR 56 TC 7 Z9 9 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1355-0284 J9 J NEUROVIROL JI J. Neurovirol. PD OCT PY 2004 VL 10 IS 5 BP 305 EP 314 DI 10.1080/13550280490499579 PG 10 WC Neurosciences; Virology SC Neurosciences & Neurology; Virology GA 854ET UT WOS:000223884600005 PM 15385253 ER PT J AU Ali, AA Velasquez, MT Hansen, CT Mohamed, AI Bhathena, SJ AF Ali, AA Velasquez, MT Hansen, CT Mohamed, AI Bhathena, SJ TI Effects of soybean isoflavones, probiotics, and their interactions on lipid metabolism and endocrine system in an animal model of obesity and diabetes SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Article DE soy isoflavones; probiotics; plasma cholesterol; steroid hormones; thyroid hormones ID OVARIECTOMIZED CYNOMOLGUS MONKEYS; CARDIOVASCULAR RISK-FACTORS; SOY PROTEIN-CONCENTRATE; POSTMENOPAUSAL WOMEN; LACTOBACILLUS-ACIDOPHILUS; DIETARY PHYTOESTROGENS; PLASMA-CHOLESTEROL; BLOOD-LIPIDS; HYPERCHOLESTEROLEMIC MEN; BIFIDOBACTERIUM-LONGUM AB The effects of soybean isoflavones with or without probiotics on tissue fat deposition, plasma cholesterol, and steroid and thyroid hormones were studied in SHR/N-cp rats, an animal model of obesity, and were compared to lean phenotype. We tested the hypothesis that probiotics by promoting the conversion of isoflavone glycosides to their metabolically active aglycone form will have a synergistic effect on body fat, cholesterol metabolism, and the endocrine system. Obese and lean SHR/N-cp rats were fed AIN-93 diets containing 0.1% soy isoflavone mixture, 0.1% probiotic mixture, or both together. Different fat tissues were teased and weighed. Plasma was analyzed for cholesterol and steroid and thyroid hormones. In both phenotypes, isoflavones lowered fat deposition in several fat depots. Probiotics alone had no significant effect on fat depots. Isoflavones lowered total, LDL, and HDL cholesterol in lean rats, but in obese rats isoflavones lowered only total and LDL cholesterol. Isoflavones also lowered many of the steroid hormones involved in lipid metabolism but had no significant effect on thyroid hormones. Probiotics had no significant effect on cholesterol or hormones. Thus, our data show that soy isoflavones also lower plasma cholesterol and that this hypocholesterolemic effect appears to be due in part to the modulation of steroid hormones. Probiotics do not seem to enhance the effect of isoflavones. Published by Elsevier Inc. All rights reserved. C1 USDA ARS, Phytonutrients Lab, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. George Washington Univ, Med Ctr, Dept Med, Washington, DC 20037 USA. NIH, Bethesda, MD 20892 USA. Virginia State Univ, Petersburg, VA USA. RP Bhathena, SJ (reprint author), USDA ARS, Phytonutrients Lab, Beltsville Human Nutr Res Ctr, Bldg 307,Room 315, Beltsville, MD 20705 USA. EM bhathens@ba.ars.usda.gov NR 70 TC 62 Z9 69 U1 2 U2 21 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD OCT PY 2004 VL 15 IS 10 BP 583 EP 590 DI 10.1016/j.jnutbio.2004.04.005 PG 8 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 877WM UT WOS:000225605600003 PM 15542349 ER PT J AU Prescilla, RP Frattarelli, DAC Haritos, D Aranda, JV Edwards, DJ AF Prescilla, RP Frattarelli, DAC Haritos, D Aranda, JV Edwards, DJ TI Pharmacokinetics of rofecoxib in children with sickle cell hemoglobinopathy SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Article DE nonsteroidal anti-inflammatory drugs (NSAIDs); cyclooxygenase-2 (COX-2); sickle cell; pain; inflammation ID COX-2; CYCLOOXYGENASE-2; INHIBITORS; HUMANS; SINGLE AB Rofecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor approved for the treatment of pain and arthritis in adults. It is available as a suspension, but there are no published pediatric pharmacokinetic data. This study characterized the disposition of rofecoxib in children with sickle cell hemoglobinopathy in a single-oraldose, intensive pharmacokinetic study. Eight subjects aged 3 to 14 years (mean 8.9 years, 5 boys and 3 girls) received a single oral dose of rofecoxib (1 mg/kg, maximum 50 mg) as a suspension. Blood samples were collected over 72 hours following drug administration and plasma was assayed for rofecoxib using high-performance liquid chromatography (HPLC). Pharmacokinetic parameters (peak concentration [C-max], time to reach peak concentration It [t(max)], area under the curve [AUC], oral clearance [Cl/F], elimination half-life [t(1/2)]) were calculated using standard noncompartmental methods. The mean dose was 35.6 mg (range 15-50 mg). C-max, averaged 582 129 ng/mL, with a median t(max) of 4.0 hours. Secondary peaks were observed in two Subjects. Two subjects were discharged at 12 hours, preventing characterization of elimination. fit the remaining six subjects, Cl/F averaged 1.34 +/- 0.32 mL/rnin/kg, with a t(1/2) of 14.8 +/- 4.5 hours. No significant adverse events were observed. The disposition of rofecoxib in children appears to be similar to that in adults, with comparable values for C-max, t(max), t(1/2), and Cl/F. C1 Wayne State Univ, Childrens Hosp, Sch Med, Dept Pediat,Div Clin Pharmacol & Toxicol, Detroit, MI USA. NICHD, Pediat Pharmacol Res Unit, Detroit, MI USA. Wayne State Univ, Sch Med, Dept Emergency Med, Detroit, MI 48202 USA. Wayne State Univ, Eugene Applebaum Coll Pharm & Hlth Sci, Dept Pharm Practice, Detroit, MI 48202 USA. RP Prescilla, RP (reprint author), 3901 Beaubien, Detroit, MI 48201 USA. EM rprescil@bmed.wayne.edu NR 18 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD OCT PY 2004 VL 26 IS 10 BP 661 EP 664 DI 10.1097/01.mph.0000142491.79664.16 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 860AF UT WOS:000224308800009 PM 15454838 ER PT J AU Hunt, CE AF Hunt, CE TI Neurocognitive outcomes in sleep-disordered breathing SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID SNORING CHILDREN; DEFICITS; APNEA C1 NHLBI, Natl Ctr Sleep Disorders Res, NIH, Bethesda, MD 20892 USA. RP Hunt, CE (reprint author), NHLBI, Natl Ctr Sleep Disorders Res, NIH, 1 Rockledge Ctr,Room 6022,6705 Rockledge Dr,MSC 7, Bethesda, MD 20892 USA. NR 14 TC 9 Z9 10 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD OCT PY 2004 VL 145 IS 4 BP 430 EP 432 DI 10.1016/j.jpeds.2004.07.026 PG 3 WC Pediatrics SC Pediatrics GA 861LH UT WOS:000224417500003 PM 15480358 ER PT J AU Hunt, CE Corwin, M Baird, T Tinsley, LR Palmer, P Ramanathan, R Crowell, DH Schafer, S Martin, RJ Hufford, D Peucker, M Weese Mayer, DE Silvestri, JM Neuman, MR Cantey-Kiser, J AF Hunt, CE Corwin, M Baird, T Tinsley, LR Palmer, P Ramanathan, R Crowell, DH Schafer, S Martin, RJ Hufford, D Peucker, M Weese Mayer, DE Silvestri, JM Neuman, MR Cantey-Kiser, J CA Collaborative Home Infant Monito TI Cardiorespiratory events detected by home memory monitoring and one-year neurodevelopmental outcome SO JOURNAL OF PEDIATRICS LA English DT Article ID BIRTH-WEIGHT INFANTS; OBSTRUCTIVE SLEEP-APNEA; CHILDREN; PERFORMANCE; DEFICITS; THERAPY AB Objective To determine if infants with cardiorespiratory events detected by home memory monitoring during early infancy have decreased neurodevelopmental performance. Study design Infants (n = 256) enrolled in the Collaborative Home Infant Monitoring Evaluation also completed the Bayley Scales of Infant Development II at 92 weeks' postconceptional age. Infants were classified as having 0, 1 to 4, or 5+ cardiorespiratory events. Events were defined as apnea greater than or equal to20 seconds or heart rate <60 to 80 bpm or <50 to 60 bpm, for greater than or equal to5 to 15 seconds, depending on age. Results For term infants, having 0, 1 to 4, and 5+ cardiorespiratory events was associated with unadjusted mean Mental Developmental Index (MDI) values (+/-SD) of 103.6 (10.6), 104.2 (10.7), and 97.7 (10.9), respectively, and mean Psychomotor Developmental Index (PDI) values of 109.5 (16.6), 105.8 (16.5), and 100.2 (17.4). For preterm infants, having 0, 1 to 4, and 5+ cardiorespiratory events was associated with unadjusted mean MDI values of 100.4 (10.3), 96.8 (11.5), and 95.8 (10.6), respectively, and mean PDI values of 91.7 (19.2), 93.8 (15.5), and 94.4 (17.7). The adjusted difference in mean MDI scores with 5+ events compared with 0 events was 5.6 points lower in term infants (P = .03) and 4.9 points lower in preterm infants (P = .04). Conclusions Having 5+ conventional events is associated with lower adjusted mean differences in MDI in term and preterm infants. C1 NHLBI, Natl Ctr Sleep Disorders Res, Bethesda, MD 20892 USA. RP Hunt, CE (reprint author), NHLBI, Natl Ctr Sleep Disorders Res, 6705 Rockledge Dr,Ste 6022, Bethesda, MD 20892 USA. OI Corwin, Michael/0000-0002-6591-209X FU NICHD NIH HHS [HD 28971, HD 20056, HD 29060, HD 29067, HD 29071, HD 29073, HD 34625] NR 21 TC 39 Z9 40 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD OCT PY 2004 VL 145 IS 4 BP 465 EP 471 DI 10.1016/j.jpeds.2004.05.045 PG 7 WC Pediatrics SC Pediatrics GA 861LH UT WOS:000224417500011 PM 15480368 ER PT J AU Peerzada, JM Richardson, DK Burns, JP AF Peerzada, JM Richardson, DK Burns, JP TI Delivery room decision-making at the threshold of viability SO JOURNAL OF PEDIATRICS LA English DT Article ID NEONATAL INTENSIVE-CARE; EXTREMELY PREMATURE NEWBORNS; EXTREMELY PRETERM INFANTS; BIRTH-WEIGHT INFANTS; OF-LIFE DECISIONS; BABY-DOE; RESUSCITATION; ATTITUDES; PHYSICIANS; LIMITS AB Objectives To assess attitudes of neonatologists toward parental wishes in delivery room resuscitation decisions at the threshold of viability. Study design Cross-sectional survey of the 175 practicing level II/III neonatologists in six New England states. Results Response rate was 85% (149/175). At 24 1/7-6/7 weeks' gestation, 41% of neonatologists considered treatment clearly beneficial, and at 25 1/7-6/7 weeks' gestation, 84% considered treatment clearly beneficial. When respondents consider treatment clearly beneficial, 91% reported that they would resuscitate in the delivery room despite parental requests to withhold. At or below 23 0/7 weeks gestation, 93% of neonatologists considered treatment futile. Thirty-three percent reported that they would provide what they consider futile treatment at parental request. When respondents consider treatment to be of uncertain benefit, all reported that they would resuscitate when parents request it, 98% reported that they would resuscitate when parents are unsure, and 76% reported that they would follow parental requests to withhold. Conclusions Variation in neonatologists' beliefs about the gestational age bounds of clearly beneficial treatment and attitudes toward parental wishes in the context of uncertainty is likely to impact the manner in which they discuss options with parents before delivery. This supports the importance of transparency in neonatal decision-making. C1 Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Harvard Univ, Sch Med, Dept Anaesthesia, Boston, MA 02115 USA. Childrens Hosp, Boston, MA 02115 USA. Beth Israel Deaconess Hosp, Dept Neonatol, Boston, MA USA. Harvard Univ, Sch Med, Div Newborn Med, Boston, MA USA. NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Peerzada, JM (reprint author), 10 Ctr Dr,MSC 1156, Bethesda, MD 20892 USA. EM jpeerzada@cc.nih.gov FU BHP HRSA HHS [T32 PE 10018] NR 45 TC 64 Z9 64 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD OCT PY 2004 VL 145 IS 4 BP 492 EP 498 DI 10.1016/j.jpeds.2004.06.018 PG 7 WC Pediatrics SC Pediatrics GA 861LH UT WOS:000224417500015 PM 15480373 ER PT J AU Kleta, R Bernardini, I Ueda, M Varade, WS Phornphutkul, C Krasnewich, D Gahl, WA AF Kleta, R Bernardini, I Ueda, M Varade, WS Phornphutkul, C Krasnewich, D Gahl, WA TI Long-term follow-up of well-treated nephropathic cystinosis patients SO JOURNAL OF PEDIATRICS LA English DT Article ID CTNS MUTATIONS; CYSTEAMINE THERAPY; CORNEAL CRYSTALS; RENAL-FUNCTION; GENE CTNS; IDENTIFICATION; INSUFFICIENCY; COMPLICATIONS; DYSFUNCTION; LYSOSOMES AB We report the excellent clinical outcomes of siblings with nephropathic cystinosis treated diligently with cysteamine starting 2 at 20 months and 2 months of age. Now 15 and 8 years old, they have glomerular filtration rates of 78 and 105 mL/min/1.73m(2) respectively. These cases illustrate the critical importance of early diagnosis and treatment. C1 NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Off Rare Dis, Intramural Program, NIH, Bethesda, MD USA. Univ Rochester, Med Ctr, Golisano Childrens Hosp Strong, Dept Pediat, Rochester, NY USA. RP Kleta, R (reprint author), NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, 10 Ctr Dr,MSC 1851,Bldg 10,Room 10C-107, Bethesda, MD 20892 USA. EM kletar@mail.nih.gov NR 42 TC 52 Z9 55 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD OCT PY 2004 VL 145 IS 4 BP 555 EP 560 DI 10.1016/j.jpeds.2004.03.056 PG 6 WC Pediatrics SC Pediatrics GA 861LH UT WOS:000224417500027 PM 15480385 ER PT J AU De Dios, AC Sears, DN Tycko, R AF De Dios, AC Sears, DN Tycko, R TI NMR studies of peptide T, an inhibitor of HIV infectivity, in an aqueous environment SO JOURNAL OF PEPTIDE SCIENCE LA English DT Article DE peptide T; DAPTA; gp120; CCR5; NMR; ROESY; chemokine receptor ID SOLID-STATE NMR; RECEPTOR-BINDING; CHEMICAL-SHIFTS; CONFORMATION; ENTRY; SPECTROSCOPY; CHEMOTAXIS; PROTEINS; GP120; H-1 AB The synthetic octapeptide peptide T (ASTTTNYT) has been shown to interfere with binding of the HIV-1 envelope glycoprotein gp 120 to the chemokine receptor R5, thus preventing viral infection. This study investigated the degree of conformational order of two analogs of peptide T, one biologically active (D-Ala peptide T amide) and one inactive (D-Ala, D-Tyr peptide T amide) using nuclear magnetic resonance (NMR) spectroscopy in an aqueous environment, both in solution and in the frozen solid state. Standard solution NMR techniques such as DQFCOSY, HMQC, ROESY and inversion recovery measurements have been utilized to characterize these peptides. Solid state NMR experiments were likewise employed to study the peptides in a frozen glycerol:water mixture. The NMR results indicate that the monomeric form of both peptide T analogs have considerable conformational heterogeneity. Solid state NMR studies indicate aggregation of D-Ala peptide T, possibly into a P-sheet structure, at concentrations higher than 10 mm. Copyright (C) 2004 European Peptide Society and John Wiley Sons, Ltd. C1 Georgetown Univ, Dept Chem, Washington, DC 20057 USA. NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP De Dios, AC (reprint author), Georgetown Univ, Dept Chem, 37th & O St, Washington, DC 20057 USA. EM dediosa@georgetown.edu RI de Dios, Angel/H-4034-2011 NR 26 TC 6 Z9 6 U1 0 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1075-2617 J9 J PEPT SCI JI J. Pept. Sci. PD OCT PY 2004 VL 10 IS 10 BP 622 EP 630 DI 10.1002/psc.571 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 864TN UT WOS:000224655900004 PM 15526711 ER PT J AU Podgornik, R AF Podgornik, R TI Polyelectrolyte-mediated bridging interactions SO JOURNAL OF POLYMER SCIENCE PART B-POLYMER PHYSICS LA English DT Article DE bridging interactions; polyelectrolyte chains ID DEBYE-HUCKEL APPROXIMATION; CHARGED SURFACES; POISSON-BOLTZMANN; POLYMER-CHAINS; COUNTER-IONS; FIELD-THEORY; MONTE-CARLO; ADSORPTION; FORCES; PARTICLES AB Polyelectrolyte chains confined by macroions bearing electrostatic charges of opposite sign can mediate an effective attraction between the macroions. This polyelectrolyte-mediated attraction is usually referred to as the bridging interaction. I review the theories of polyelectrolyte-mediated interactions based on analytic mean-field and variational approaches. I will describe the origin and the salient properties of this interaction in the context of planar and point macroions with special emphasis on the connection between the polymer chain conformations and the ensuing polymer mediated interactions. (C) 2004 Wiley Periodicals, Inc. C1 NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Univ Ljubljana, Dept Phys, Ljubljana 1000, Slovenia. J Stefan Inst, Dept Theoret Phys, SI-1000 Ljubljana, Slovenia. RP Podgornik, R (reprint author), NICHD, Lab Phys & Struct Biol, NIH, Bld 9,Rm 1E116, Bethesda, MD 20892 USA. EM rudi@helix.nih.gov RI Podgornik, Rudolf/C-6209-2008 OI Podgornik, Rudolf/0000-0002-3855-4637 NR 59 TC 38 Z9 38 U1 2 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-6266 J9 J POLYM SCI POL PHYS JI J. Polym. Sci. Pt. B-Polym. Phys. PD OCT 1 PY 2004 VL 42 IS 19 BP 3539 EP 3556 DI 10.1002/polb.20205 PG 18 WC Polymer Science SC Polymer Science GA 854SH UT WOS:000223923100003 ER PT J AU Glass, JM Lyden, AK Petzke, F Stein, P Whalen, G Ambrose, K Chrousos, G Clauw, DJ AF Glass, JM Lyden, AK Petzke, F Stein, P Whalen, G Ambrose, K Chrousos, G Clauw, DJ TI The effect of brief exercise cessation on pain, fatigue, and mood symptom development in healthy, fit individuals SO JOURNAL OF PSYCHOSOMATIC RESEARCH LA English DT Article DE fibromyalgia; chronic fatigue syndrome; exercise; human stress response; autonomic function; pain; fatigue ID PITUITARY-ADRENAL AXIS; HEART-RATE-VARIABILITY; IMMUNOLOGICAL ABNORMALITIES; FIBROMYALGIA SYNDROME; AUTONOMIC FUNCTION; DYSFUNCTION; ACTIVATION; STRESS; PERTURBATIONS; INFLAMMATION AB Objective: Abnormalities of the biological stress response (hypothalamic-pituitary-adrenal axis and the autonomic nervous system) have been identified in both fibromyalgia (FM) and chronic fatigue syndrome (CFS). Although these changes have been considered to be partly responsible for symptom expression, we examine an alternative hypothesis that these HPA and autonomic changes can be found in subsets of healthy individuals in the general population who may be at risk of developing these conditions. Exposure to "stressors" (e.g., infections, trauma, etc.) may lead to symptom expression (pain, fatigue, and other somatic symptoms) in part by precipitating lifestyle changes. In particular, we focus on the effect of deprivation of routine aerobic exercise on the development of somatic symptoms. Methods: Eighteen regularly exercising ( greater than or equal to 4 h/week) asymptomatic, healthy adults refrained from physical activity for I week. We predicted that a subset of these individuals would develop symptoms of FM/CFS with exercise deprivation, and this manuscript focuses on the baseline HPA axis, immune, and autonomic function measures that may predict the development of symptoms. Results: Eight of the subjects reported a 10% increase in one or more symptoms (pain, fatigue, mood) after I week of exercise deprivation. These symptomatic subjects had lower HPA axis (baseline cortisol prior to VO2max testing), immune (NK cell responsiveness to venipuncture), and autonomic function (measured by heart rate variability) at baseline (prior to cessation of exercise) when compared to the subjects who did not develop symptoms. Conclusions: A subset of subjects developed symptoms of pain, fatigue, or mood changes after exercise deprivation. This cohort was different from the individuals who did not develop symptoms in baseline measures of HPA axis, immune, and autonomic function. We speculate that a subset of healthy individuals who have hypoactive function of the biological stress response systems unknowingly exercise regularly to augment the function of these systems and thus suppress symptoms. These individuals may be at risk for developing chronic multisymptom illnesses (CMIs) (e.g., FM or CFS among others) when a "stressor" leads to lifestyle changes that disrupt regular exercise. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Michigan, Inst Social Res, Ann Arbor, MI 48106 USA. Univ Michigan, Dept Psychiat, Ann Arbor, MI 48106 USA. Univ Michigan, Dept Med, Div Rheumatol, Ann Arbor, MI 48106 USA. Univ Cologne, Dept Anesthesiol, D-5000 Cologne 41, Germany. Washington Univ, Div Cardiovasc, St Louis, MO 63130 USA. Georgetown Univ, Div Rheumatol Allergy & Immunol, Washington, DC 20057 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Glass, JM (reprint author), Univ Michigan, Inst Social Res, Room 5256,426 Thompson St, Ann Arbor, MI 48106 USA. EM jglass@umich.edu NR 62 TC 73 Z9 79 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-3999 J9 J PSYCHOSOM RES JI J. Psychosomat. Res. PD OCT PY 2004 VL 57 IS 4 BP 391 EP 398 DI 10.1016/j.jpsychores.2004.04.002 PG 8 WC Psychiatry SC Psychiatry GA 873XF UT WOS:000225314100010 PM 15518675 ER PT J AU Woodburn, J Nelson, KM Siegel, KL Kepple, TM Gerber, LH AF Woodburn, J Nelson, KM Siegel, KL Kepple, TM Gerber, LH TI Multisegment foot motion during gait: Proof of concept in rheumatoid arthritis SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE multisegment foot kinematics; rheumatoid arthritis; footimpairments ID STANCE PHASE; MIDTARSAL JOINTS; KINEMATICS; SUBTALAR; WALKING; FOREFOOT; DEFORMITY; REARFOOT; POSITION; ANKLE AB Objective. To test a multisegment foot model for kinematic analysis during barefoot walking in patients with well established rheumatoid arthritis (RA) and foot impairments. Methods. Five healthy adult subjects and 11 RA patients with advanced disease were studied. Foot impairments were assessed using standardized outcomes and clinical examination techniques. A 6-camera 60 Hz video-based motion- analysis system was used to measure motion of the shank, rear-foot, forefoot, and hallux segments and the vertical displacement of the navicular. Face validity and estimates of repeatability were determined. Motion patterns were calculated and comparisons were made between healthy subjects and patients with RA. Relationships between clinical impairment and abnormal motion were determined through inspection of individual RA cases. Results. Across the motion variables, the within-day and between-day coefficient of multiple correlation, values ranged from 0.677 to 0.982 for the healthy subjects and 0.830 to 0.981 for RA patients. Based on previous studies, motion parameters for the healthy subjects showed excellent face validity. In RA patients, there was reduced range of motion across all segments and all planes of motion, which was consistent with joint stiffness. In the RA patients, rearfoot motion was shifted towards eversion and external rotation and peak values for these variables were increased, on average, by 7degrees and 11degrees, respectively. Forefoot range of motion was reduced in all 3 planes (between 31% and 53%), but the maximum and minimum angles were comparable to normal. The navicular height, during full foot contact, was on average 3 mm lower in the RA patients in comparison to normal. The hallux was less extended in the RA subjects in comparison to normal (21degrees vs 33degrees) during the terminal stance phase. Individual cases showed abnormal patterns of motion consistent with their clinical impairments, especially those with predominant forefoot pain or pes planovalgus. Conclusion. In RA, multisegment foot models may provide a more complete description of foot motion abnormalities where pathology presents at multiple joints, leading to complex and varied patterns of impairment. This technique may be useful to evaluate functional changes in the foot and to help plan and assess logical, structurally based corrective interventions. C1 Univ Leeds, Acad Unit Musculoskeletal Dis, Leeds LS2 9NZ, W Yorkshire, England. NIH, Dept Rehabil Med, Phys Disabil Branch, Warren Grant Magnuson Clin Ctr,Dept Hlth & Human, Bethesda, MD 20892 USA. RP Woodburn, J (reprint author), Univ Leeds, Acad Unit Musculoskeletal Dis, 36 Clarendon Rd, Leeds LS2 9NZ, W Yorkshire, England. EM j.woodburn@leeds.ac.uk RI Siegel, Karen Lohmann/B-5898-2008; OI Siegel, Karen Lohmann/0000-0002-0788-6612 NR 20 TC 55 Z9 56 U1 0 U2 7 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD OCT PY 2004 VL 31 IS 10 BP 1918 EP 1927 PG 10 WC Rheumatology SC Rheumatology GA 860FC UT WOS:000224326900010 PM 15468354 ER PT J AU Cooper, GS Parks, CG Treadwell, EL Clair, EWS Gilkeson, GS Dooley, MA AF Cooper, GS Parks, CG Treadwell, EL Clair, EWS Gilkeson, GS Dooley, MA TI Occupational risk factors for the development of systemic lupus erythematosus SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE systemic lupus erythematosus; autoimmune disease; occupation; mercury; solvents; pesticides ID DENTAL LABORATORY TECHNICIANS; SOUTHEASTERN UNITED-STATES; MRL-+/+ MICE; AUTOIMMUNE-RESPONSE; SOLVENT EXPOSURE; MERCURY; DISEASE; MELATONIN; CONCORDANCE; SCLERODERMA AB Objective. There have been few studies of occupational exposures and systemic lupus erythematosus (SLE). We examined the association between the risk of SLE and occupational exposures (mercury, solvents, and pesticides), specific jobs (ever worked in teaching, healthcare, and cosmetology), and working night or rotating shifts. Methods. Patients with recently diagnosed SLE (n = 265) were recruited through 4 university based and 30 community based rheumatology practices in North Carolina and South Carolina, USA. Controls (n = 355) were identified through driver's license records and were frequency matched to patients by age, sex, and state. Data collection included ail in-person interview with detailed farming and work histories. Results. Associations were seen with self-reported occupational exposure to mercury (OR 3.6, 95% CI 1.3, 10.0), mixing pesticides for agricultural work (OR 7.4, 95% CI 1.4, 40.0), and among dental workers (OR 7.1, 95% CI 2.2, 23.4). Although these associations were fairly strong and statistically significant, the prevalence of these exposures was very low and thus these estimates are based on a small number of exposed cases and controls. Weaker associations were seen between SLE and shift work (OR 1.6, 95% CI 0.99, 2.7) and among healthcare workers with patient contact (OR 1.7, 95% CI 0.99, 2.9). There was no association of SLE with use of solvents or among teachers or cosmetologists. Conclusion. This study reveals the potential contribution of occupational exposures to the development of SLE, and highlights some exposures and experiences that should be examined in other studies using more extensive exposure assessment techniques and in experimental studies of autoimmunity. C1 NIEHS, Epidemiol Branch, Durham, NC 27709 USA. E Carolina Univ, Sch Med, Div Rheumatol, Greenville, NC USA. Duke Univ, Med Ctr, Div Rheumatol, Durham, NC USA. Ralph H Johnson Vet Adm Med Ctr, Med Res Serv, Charleston, SC USA. Med Univ S Carolina, Charleston, SC 29425 USA. Univ N Carolina, Div Rheumatol, Chapel Hill, NC USA. RP Cooper, GS (reprint author), NIEHS, Epidemiol Branch, A3-05,POB 12233, Durham, NC 27709 USA. EM cooper1@niehs.nih.gov OI Parks, Christine/0000-0002-5734-3456 NR 32 TC 81 Z9 83 U1 0 U2 3 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD OCT PY 2004 VL 31 IS 10 BP 1928 EP 1933 PG 6 WC Rheumatology SC Rheumatology GA 860FC UT WOS:000224326900011 PM 15468355 ER PT J AU Blanco, I Canto, H de Serres, FJ Fernandez-Bustillo, E Rodriguez, MC AF Blanco, I Canto, H de Serres, FJ Fernandez-Bustillo, E Rodriguez, MC TI Alpha(1)-antitrypsin replacement therapy controls fibromyalgia symptoms in 2 patients with PI ZZ alpha(1)-antitrypsin deficiency SO JOURNAL OF RHEUMATOLOGY LA English DT Article DE alpha(1)-antitrypsin; fibromyalgia ID ALPHA-1-ANTITRYPSIN; CYTOKINES; EUROPE; EPIDEMIOLOGY; PREVALENCE; DISEASES; SPAIN AB Two Spanish sisters with alpha(1)-antitrypsin (AAT) deficiency and fibromyalgia (FM) started AAT replacement therapy with commercial alpha(1)-antitrypsin infusions in 1992. They both experienced a rapid, progressive, and constant control of their FM symptoms during the next 6 years (1992-98). However, in 1998, treatment of both patients was affected by the worldwide commercial shortage of AAT replacement therapy; replacement therapy infusions were halted for about 4-6 consecutive months every year for 5 years. As a result, we observed a striking recurrence of FM symptoms. Equally striking was the total disappearance of these symptoms when AAT replacement therapy infusions were resumed. C1 Hosp Valle Nalon, Resp Dis Branch, Dept Internal Med, Sama De Langreo 33920, Asturias, Spain. NIEHS, Environm Toxicol Program, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. Hosp Univ Cent Asturias, Biostat Unit, Asturias, Spain. Hosp Univ Cent Asturias, Inst Nacl Silicosis, Biochem Lab, Asturias, Spain. RP Blanco, I (reprint author), Hosp Valle Nalon, Resp Dis Branch, Dept Internal Med, Sama De Langreo 33920, Asturias, Spain. EM ignacio.blanco@sespa.princast.es NR 15 TC 19 Z9 20 U1 0 U2 1 PU J RHEUMATOL PUBL CO PI TORONTO PA 920 YONGE ST, SUITE 115, TORONTO, ONTARIO M4W 3C7, CANADA SN 0315-162X J9 J RHEUMATOL JI J. Rheumatol. PD OCT PY 2004 VL 31 IS 10 BP 2082 EP 2085 PG 4 WC Rheumatology SC Rheumatology GA 860FC UT WOS:000224326900036 PM 15468381 ER PT J AU Compton, WM Pringle, B AF Compton, WM Pringle, B TI Services research on adolescent drug treatment. Commentary on "The Cannabis Youth Treatment (CYT) Study: Main findings from two randomized trials" SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Editorial Material C1 NIDA, Div Epidemiol, Serv & Prevent Res, Bethesda, MD 20892 USA. RP Compton, WM (reprint author), NIDA, Div Epidemiol, Serv & Prevent Res, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov NR 6 TC 13 Z9 13 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD OCT PY 2004 VL 27 IS 3 BP 195 EP 196 DI 10.1016/j.jsat.2004.07.003 PG 2 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 869TU UT WOS:000225008000003 PM 15501372 ER PT J AU Wayne, SJ Lopez, ST Butler, LM Baumgartner, KB Baumgartner, RN Ballard-Barbash, R AF Wayne, SJ Lopez, ST Butler, LM Baumgartner, KB Baumgartner, RN Ballard-Barbash, R TI Changes in dietary intake after diagnosis of breast cancer SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; PHYSICAL-ACTIVITY; ENERGY-INTAKE; WEIGHT-GAIN; VEGETABLES; NUTRITION; HEALTH; WOMEN; INTERVENTION; PREDICTORS AB Objective To quantify change in intake of kilocalories macronutrients, and fruit and vegetable servings after diagnosis of breast cancer, and to correlate these changes with subject characteristics and with self-reported global change in dietary patterns. Design Food frequency questionnaires were completed by women newly diagnosed with breast cancer shortly after diagnosis. They were asked to recall intake 1 year before diagnosis. Two years after the initial interview another food frequency questionnaire was completed recalling intake during the previous year. At the 2-year follow-up interview women were also asked if they had changed their intake of fruit, vegetables, and fat since diagnosis. Subjects/Setting Two hundred sixty New Mexico women with newly diagnosed breast cancer between July 1997 and March 1999. Analysis Two-year change scores for kilocalories, macronutrients, and fruit and vegetable servings were calculated and tested for difference from zero using paired t tests or Wilcoxon signed rank tests. Subjects' characteristics were related to change in kilocalories and linear regression was used to determine the relative importance of these characteristics. Amount of change in fruit and vegetable servings and fat intake were calculated using food frequency data for women who reported increasing their intake of fruits and vegetables or decreasing their intake of fat after diagnosis. Results Small but significant decreases in intake of total energy and macronutrients were found 2 years post-diagnosis, with younger women reporting the greatest decreases. Fat as a percentage of diet increased over this period. There was no change in mean intake of fruit and vegetable servings. There is agreement between change as measured by food frequency questionnaire and change reported by more global questions on dietary habits; however, the amount of change measured was small. Women reporting an increase in fruit and vegetable intake postdiagnosis described an increase of one-quarter serving of fruit and one-third serving of vegetables per day. Conclusions Breast cancer diagnosis results in modest dietary changes. Small changes in fruit and vegetable consumption suggest that efforts are needed to encourage increased consumption of these foods. C1 Univ New Mexico, Aging & Genet Epidemiol Program, Sch Med, Dept Internal Med, Albuquerque, NM 87131 USA. Univ New Mexico, Canc Res Treatment Ctr, Sch Med, Dept Internal Med, Albuquerque, NM 87131 USA. Univ New Mexico, Div Epidemiol & Prevent Med, Sch Med, Dept Internal Med, Albuquerque, NM 87131 USA. NCI, Appl Res Program, Bethesda, MD 20892 USA. RP Wayne, SJ (reprint author), Univ New Mexico, Aging & Genet Epidemiol Program, Sch Med, Dept Internal Med, 2701 Frontier Pl,NE,Surge Bldg,Room 215, Albuquerque, NM 87131 USA. EM swayne@salud.unm.edu NR 33 TC 42 Z9 44 U1 0 U2 4 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD OCT PY 2004 VL 104 IS 10 BP 1561 EP 1568 DI 10.1016/j.jada.2004.07.028 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 858WP UT WOS:000224223300014 PM 15389414 ER PT J AU Blanc, P Corsi, AM Gabbuti, A Peduzzi, C Meacci, F Olivieri, F Lauretani, F Francesco, M Ferrucci, L AF Blanc, P Corsi, AM Gabbuti, A Peduzzi, C Meacci, F Olivieri, F Lauretani, F Francesco, M Ferrucci, L TI Chlamydia pneumoniae seropositivity and cardiovascular risk factors: The InCHIANTI study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE Chlamydia pneumoniae; elderly; inflammation; cytokines ID CORONARY-HEART-DISEASE; SOLUBLE INTERLEUKIN-6 RECEPTOR; BLOOD MONONUCLEAR-CELLS; NECROSIS-FACTOR-ALPHA; MYOCARDIAL-INFARCTION; ENDOTHELIAL-CELLS; HIGH PREVALENCE; FINNISH MEN; ANTIBODIES; ASSOCIATION AB Objectives: To assess the prevalence of Chlamydia pneumoniae (CP) seropositivity and test the hypothesis that CP infection (CPI) is associated with cardiovascular (CV) risk factors and levels of inflammatory biomarkers. Design: Cross-sectional survey. Setting: Representative sample of the residents of Greve in Chianti and Bagno a Ripoli, two small towns located in the Chianti geographic area (Tuscany, Italy). Participants: A total of 1,304 (age-range: 20-103, 79% agedgreater than or equal to65) participants of the InCHIANTI study. Measurements: CP seropositivity was assessed using immunofluorescence. Previous CPI was defined as immunoglobulin (Ig) G greater than or equal to1/16 and <1/256, and recent CPI was defined as IgG greater than or equal to1/512 or IgM greater than or equal to1/16. Inflammatory markers included interleukin (IL)-6, soluble IL-6 receptor (sIL-6r), tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-1 receptor antagonist (IL-1ra), iron, ferritin, and C-reactive protein (CRP). CV risk factors included smoking, body mass index (BMI), lipid profile, and hypertension. Results: The prevalence of CP seropositivity was 75%, increased with age, and was higher in men than in women (P<.01). CPI was not associated with IL-1beta, IL-1ra, iron, ferritin, CRP, BMI, lipids, and smoking. After adjusting for age and sex, previous or recent CPI was associated with higher TNF-alpha (P<.01), IL-6 (P<.03), sIL-6R (P<.01), and hypertension (P<.02). In additional age and sex-adjusted models, the associations between CPI and TNF-alpha, IL-6, sIL-6r, and hypertension appeared to be mutually independent. Conclusion: CP seropositivity is highly prevalent in the older population and is a significant, independent correlate of hypertension and circulating levels of TNF-alpha, IL-6, and sIL-6r. C1 Hosp SS Annunziata, Infect Dis Sect, Florence, Italy. INRCA, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. INRCA, Lab Mol Biol & Genet, Ancona, Italy. NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, Harper Hosp, 3001 Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov RI Olivieri, Fabiola/K-6465-2016; Lauretani, Fulvio/K-5115-2016 OI Olivieri, Fabiola/0000-0002-9606-1144; Lauretani, Fulvio/0000-0002-5287-9972 NR 50 TC 12 Z9 12 U1 1 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2004 VL 52 IS 10 BP 1626 EP 1631 DI 10.1111/j.1532-5415.2004.52453.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 855TU UT WOS:000223998300004 PM 15450037 ER PT J AU Bryson, CL Smith, NL Kuller, LH Chaves, PHM Manolio, TA Lewis, W Boyko, EJ Furberg, CD Psaty, BM AF Bryson, CL Smith, NL Kuller, LH Chaves, PHM Manolio, TA Lewis, W Boyko, EJ Furberg, CD Psaty, BM TI Risk of congestive heart failure in an elderly population treated with peripheral alpha-1 antagonists SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE hypertension treatment; heart failure; alpha-1 antagonist; thiazide ID LIPID-LOWERING TREATMENT; ATTACK TRIAL ALLHAT; SYSTEMIC HYPERTENSION; CARDIOVASCULAR EVENTS; BLOOD-PRESSURE; OLDER PERSONS; DOXAZOSIN; HEALTH; CHLORTHALIDONE; ATENOLOL AB Objectives: To compare the risk of congestive heart failure (CHF) in elderly individuals treated with any peripheral alpha-1 antagonist for hypertension with any thiazide, test whether the risk persists in subjects without cardiovascular disease (CVD) at baseline, and examine CHF risk in normotensive men with prostatism treated with alpha antagonists. Design: Prospective cohort study. Setting: Four U.S. sites: Washington County, Maryland; Allegheny County, Pennsylvania; Sacramento County, California; and Forsyth County, North Carolina. Participants: A total of 5,888 community-dwelling subjects aged 65 and older. Measurements: Adjudicated incident CHF. Results: The 3,105 participants with treated hypertension were at risk for CHF; 22% of men and 8% of women took alpha antagonists during follow-up. The age-adjusted risk of CHF in those receiving monotherapy treated with alpha antagonists was 1.90 (95% confidence interval=1.03-3.50) compared with thiazides. In subjects without CVD at baseline receiving monotherapy, women taking an alpha antagonist had a 3.6 times greater age-adjusted risk of CHF, whereas men had no difference in risk. Adjustment for systolic blood pressure attenuated statistical differences in risk. There were 930 men without hypertension at risk for CHF; 5% used alpha antagonists during follow-up, with no observed increase in CHF risk. Conclusion: Subjects receiving alpha antagonist monotherapy for hypertension had a two to three times greater risk of incident CHF, also seen in lower-risk subjects, but differences in blood pressure control partly explained this. C1 VA Puget Sound HSR&D, Seattle VAMC, Seattle, WA 98108 USA. VA Puget Sound Healthcare Syst, Epidemiol Res & Informat Ctr, VAMC, Seattle, WA USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. Univ Washington, Dept Epidemiol & Hlth Serv, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Calif Davis, Dept Internal Med, Sacramento, CA 95817 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. RP Bryson, CL (reprint author), VA Puget Sound HSR&D, Seattle VAMC, MS 152,1660 S Columbian Way, Seattle, WA 98108 USA. EM cbryson@u.washington.edu FU NHLBI NIH HHS [N01-HC-85081, N01-HC-85086, N01-HC-85082, N01-HC-35129, N01-HC-85085, N01-HC-85079, N01-HC-85083, N01-HC-15103, N01-HC-85084, N01-HC-85080] NR 21 TC 10 Z9 10 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2004 VL 52 IS 10 BP 1648 EP 1654 DI 10.1111/j.1532-5415.2004.52456.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 855TU UT WOS:000223998300007 PM 15450040 ER PT J AU Abbatecola, AM Paolisso, G Lamponi, M Bandinelli, S Lauretani, F Launer, L Ferrucci, L AF Abbatecola, AM Paolisso, G Lamponi, M Bandinelli, S Lauretani, F Launer, L Ferrucci, L TI Insulin resistance and executive dysfunction in older persons SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; executive dysfunction; insulin resistance; Trail Making Test; InCHIANTI ID COGNITIVE FUNCTION; ELDERLY POPULATION; ALZHEIMERS-DISEASE; GLUCOSE-TOLERANCE; BRAIN INSULIN; HYPERINSULINEMIA; ROTTERDAM AB Objectives: To evaluate the association between insulin resistance (IR) and executive dysfunction in a large, population-based study of older persons without diabetes mellitus (DM) or dementia. Design: Cross-sectional study. Setting: Outpatient clinic in Greve in Chianti and Bagno a Ripoli, Italy. Participants: A total of 597 subjects aged 65 to 93 without DM or dementia. Measurements: Anthropometric measurements; plasma fasting levels of glucose, insulin, cholesterol (total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol), and insulin-like growth factor-1 (IGF-1); homeostasis model assessment (HOMA) to estimate degree of IR; Trail Making Test (TMT) A; TMT-B; TMT-B minus TMT-A (DIFF B-A); and Mini-Mental State Examination (MMSE). Results: IR (HOMA) was associated with longer TMT-B (correlation coefficient (r)=0.11; P=.006) and DIFF B-A times (r=0.10; P=.022). Subjects in the upper tertile of IR were older and had longer TMT-B and DIFF B-A than participants in the lowest tertile. After adjusting for age, sex, and years of formal education, IR was significantly correlated with TMT-A, TMT-B, and DIFF B-A. After adjusting for age, sex, education, body mass index, waist:hip girth ratio, HDL-C, triglycerides, IGF-1, hypertension, drug intake, and physical activity, the results did not significantly change. After introducing MMSE score into the model, IR continued to be an independent determinant of TMT-A (beta=11.005; P=.021), TMT-B (beta=28.379; P<.001), and DIFF B-A (beta=17.374; P=.011). Conclusion: IR is independently associated with frontal cortex function evidenced by poor TMT times in older persons without DM or dementia. C1 Univ Naples 2, Dept Geriatr Med & Metab Dis, Naples, Italy. INRCA, Dept Geriatr, Lab Clin Epidemiol, Florence, Italy. NIA, Lab Epidemiol Biometry & Demog, Bethesda, MD 20892 USA. NIA, Longitudinal Studies Sect, Baltimore, MD 21224 USA. RP Ferrucci, L (reprint author), Harefield Hosp, ASTRA Unit, Clin Res Branch, Longitudinal Studies Sect, 5th Floor,3001 Hanover St, Baltimore, MD 21225 USA. EM FerrucciLu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016 OI Paolisso, Giuseppe/0000-0002-2137-455X; Lauretani, Fulvio/0000-0002-5287-9972 NR 30 TC 60 Z9 61 U1 1 U2 7 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2004 VL 52 IS 10 BP 1713 EP 1718 DI 10.1111/j.1532-5415.2004.52466.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 855TU UT WOS:000223998300017 PM 15450050 ER PT J AU Mazza, C Benvenuti, F Bimbi, C Stanhope, SJ AF Mazza, C Benvenuti, F Bimbi, C Stanhope, SJ TI Association between subject functional status, seat height, and movement strategy in sit-to-stand performance SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE sit-to-stand; functional evaluation; compensatory movement strategy; chair height; seat height ID LOWER-EXTREMITY FUNCTION; CHAIR HEIGHT; YOUNG-WOMEN; SPEED; TASK; BIOMECHANICS; DISABILITY; BATTERY; ADULTS; BODY AB Objectives: To explore the association between an individual's functional status, movement task difficulty, and effectiveness of compensatory movement strategies within a sit-to-stand (STS) paradigm. Design: Cross-sectional study. Settings: Rehabilitation unit of the Istituto Nazionale Riposo e Cura Anziani Geriatric Hospital of Florence, Italy. Participants: A convenience sample (131 subjects) of the outpatient clinic and day-hospital population. Measurements: A performance-based test (repeated chair standing) was used to divide the subjects into five functional groups. Subjects performed a series of single STS tasks across a range of five descending seat heights. They were instructed to stand without using arms or compensatory strategies. If unable, swinging the arms was allowed, and if the inability persisted, subjects could push with their arms during subsequent attempts. The strategy or inability to stand formed the dependent measures. Results: Subjects within the two highest functional groups could complete the single STS task at all seat heights, with a slight increased use of compensatory strategies at the lowest seat height. The effectiveness of the compensatory strategies decreased rapidly as a function of seat height and functional status. One-third (35.5%) of the subjects in the middle functional group swung their arms at the lower seat heights. Across the three least functional groups, 11.8%, 30.6%, and 83.3% of the subjects, respectively, were unable to stand at the lowest seat height. Conclusion: The individual's functional status and difficulty of the task influenced the effectiveness of a compensatory strategy to maintain the ability to stand, supporting the idea that disability depends on the interplay between environmental demands and physical ability. C1 Ist Univ Sci Motorie, Dept Human Movement & Sport Sci, Rome, Italy. Ist Nazl Riposa & Cura Anziani, Dept Geriatr, Lab Physiopathol & Rehabil Movement, Florence, Italy. NIH, Phys Disabil Branch, Bethesda, MD 20892 USA. RP Benvenuti, F (reprint author), Osped Infermi, Dipartimento Riabilitaz, AUSL11,Reg Toscana,Piazza XX Settembre 10, I-56028 Pisa, Italy. EM f.benvenuti@usl11.tos.it RI mazza, claudia/G-3906-2011; OI Mazza, Claudia/0000-0002-5215-1746 NR 22 TC 19 Z9 20 U1 1 U2 5 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD OCT PY 2004 VL 52 IS 10 BP 1750 EP 1754 DI 10.1111/j.1532-5415.2004.52472.x PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 855TU UT WOS:000223998300023 PM 15450056 ER PT J AU Jo, SK Hu, XZ Yuen, PST Aslamkhan, AG Pritchard, JB Dear, JW Star, RA AF Jo, SK Hu, XZ Yuen, PST Aslamkhan, AG Pritchard, JB Dear, JW Star, RA TI Delayed DMSO administration protects the kidney from mercuric chloride-induced injury SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID ACUTE-RENAL-FAILURE; ACUTE TUBULAR-NECROSIS; INORGANIC MERCURY; DIMETHYL-SULFOXIDE; LIPID-PEROXIDATION; N-ACETYLCYSTEINE; MICE; RAT; GLUTATHIONE; TOXICITY AB Reactive oxygen species are implicated as mediators of tissue damage in ischemic and toxic acute renal failure. Whereas many agents can inhibit renal ischemic injury, only hepatocyte growth factor, melatonin, N-acetylcysteine, and DMSO inhibit injury after mercuric chloride administration. Although it has been suggested that DMSO may chelate the mercuric ion, more recent studies suggest that it has antiinflammatory and antioxidant effects. Acute renal failure was induced by 5 mg/kg subcutaneous injection of mercuric chloride in BALB/c mice. DMSO (3.8 ml/kg, 40% in PBS) or vehicle (PBS) was injected intraperitoneally at 0 and 24 h after mercuric chloride injection, or DMSO treatment was delayed 3 or 5 h. DMSO prevented increases in serum creatinine and tubular damage at 24 and 48 h. When DMSO treatment was delayed by 3 h, it was still beneficial; however, with a 5-h delay, the histology score and serum creatinine were not significantly decreased. DMSO partially prevented a mercuric chloride-induced decrease in glutathione peroxidase activity and completely prevented the transient decrease in superoxide dismutase activity. Neither mercuric chloride nor DMSO affected catalase activity significantly. For investigating possible effects of DMSO on cellular mercuric ion uptake, MDCK cells that were transfected with human organic anion transporter-1 were used. Hg-203 uptake was inhibited 90% by N-acetyleysteine but only 5% by DMSO, indicating that the effect of DMSO is not related to chelating mercuric ion or inhibiting its uptake. It is concluded that DMSO acts in part as an antioxidant to inhibit mercuric chloride-induced acute renal injury. C1 NIDDK, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. NIEHS, Lab Pharmacol & Chem, NIH, Bethesda, MD USA. RP Star, RA (reprint author), NIDDK, Renal Diagnost & Therapeut Unit, NIH, 10 Ctr Dr,Room 3N108, Bethesda, MD 20892 USA. EM Robert_Star@nih.gov RI Yuen, Peter/B-1954-2008 OI Yuen, Peter/0000-0001-9557-3909 NR 33 TC 14 Z9 15 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD OCT PY 2004 VL 15 IS 10 BP 2648 EP + DI 10.1097/01.ASN.0000139933.20109.CB PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 857SJ UT WOS:000224138300016 PM 15466269 ER PT J AU Gorbach, AM AF Gorbach, AM TI Local alternated temperature gradients as footprints of cortical functional activation SO JOURNAL OF THERMAL BIOLOGY LA English DT Article; Proceedings Paper CT International Thermal Physiology Symposium CY OCT 10-15, 2004 CL Rhodes, GREECE DE infrared imaging; functional activation; cortical local blood flow; brain temperature gradients ID BRAIN TEMPERATURE; INTRACEREBRAL TEMPERATURE; NEUROSURGICAL PATIENTS; MONKEY; BLOOD AB Heat liberation in the brain was utilized as a direct signature of functional activation. We hypothesize that both temporal and spatial uncoupling between local cerebral blood flow (ICBF) and metabolic temperature components can be explored through the imaging of brain thermal gradients evoked by functional stimulation. Surface cortical infrared (IR) images were obtained from 34 patients undergoing surgery for brain lesions under baseline conditions following peripheral nerve stimulation and, in some patients, during active behavioral tasks such as finger apposition and repetitive hand movements. An IR camera (0.02 degreesC sensitivity, 3-5 mum wavelength) was used to image local thermal gradients across the cerebral cortex by passively detecting IR emission. Neural activation elicited reproducible temperature changes (0.04-0.09 degreesC) within the primary somatosensory cortex during median nerve stimulation and in the sensorimotor cortex during repetitive hand movements and finger tapping. The initial temperature responses were detected as early as 100-200 ms, the peak IR response occurred 5-7 s after stimulus onset. Models of the relationship between evoked thermal gradients, ICBF and metabolic heat are proposed. Since the latencies of local metabolic and ICBF responses to stimulation vary by more than an order of magnitude, we are able to separate vascular-dependent and metabolic-dependent temperature components and thus create two discrete brain images, each reflecting distinct physiological mechanisms of functional activation. The resultant temperature profile reflects the balance between metabolism and ICBF, and therefore the degree of their functional uncoupling for the exposed and (possibly) for the intact normal human brain. Published by Elsevier Ltd. C1 NIH, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Gorbach, AM (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Bldg 13,Room 3N-15, Bethesda, MD 20892 USA. EM gorbach@helix.nih.gov NR 18 TC 2 Z9 2 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4565 J9 J THERM BIOL JI J. Therm. Biol. PD OCT-DEC PY 2004 VL 29 IS 7-8 BP 589 EP 598 DI 10.1016/j.jtherbio.2004.08.072 PG 10 WC Biology; Zoology SC Life Sciences & Biomedicine - Other Topics; Zoology GA 861VJ UT WOS:000224446400036 ER PT J AU Collogan, LK Tuma, F Dolan-Sewell, R Borja, S Fleischman, AR AF Collogan, LK Tuma, F Dolan-Sewell, R Borja, S Fleischman, AR TI Ethical issues pertaining to research in the aftermath of disaster SO JOURNAL OF TRAUMATIC STRESS LA English DT Article DE IRB; disaster; research ethics; human subjects; research protections ID VICTIMS; CONSENT; TRAUMA AB In January 2003, The New York Academy of Medicine and the National Institute of Mental Health sponsored a meeting entitled "Ethical Issues Pertaining to Research in the Aftermath of Disaster." The purpose of the meeting was to bring together various experts to examine evidence concerning the impact of research on trauma-exposed participants, review the applicable ethical principles and policies concerning protection of human subjects, and offer guidance to investigators, IRBs, public health and local officials, and others interested in assuring that research in the aftermath of a disaster is conducted in a safe and ethical manner. This article summarizes the group's key findings and outlines potential considerations for those working in this field. C1 New York Acad Med, Ctr Urban Bioeth, New York, NY 10029 USA. NIMH, Div Mental Disorders Behav Res & AIDS, Bethesda, MD 20892 USA. RP Fleischman, AR (reprint author), New York Acad Med, Ctr Urban Bioeth, 1216 5th Ave, New York, NY 10029 USA. EM afleischman@nyam.org NR 27 TC 41 Z9 43 U1 2 U2 9 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD OCT PY 2004 VL 17 IS 5 BP 363 EP 372 DI 10.1023/B:JOTS.0000048949.43570.6a PG 10 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 881BI UT WOS:000225838000002 PM 15633915 ER PT J AU Rosenstein, DL AF Rosenstein, DL TI Decision-making capacity and disaster research SO JOURNAL OF TRAUMATIC STRESS LA English DT Article; Proceedings Paper CT Meeting on Ethical Issues Pertaining to Research in the Aftermath of Disaster CY JAN 13-14, 2003 CL New York, NY SP New York Acad Med, Nat Inst Mental Hlth DE decision-making capacity; disaster; research; ethics; trauma ID INFORMED-CONSENT; PSYCHIATRIC RESEARCH; ALZHEIMERS-DISEASE; DEPRESSED-PATIENTS; CLINICAL-RESEARCH; TRAUMA SURVIVORS; MEDICAL-RESEARCH; COMPETENCE; STRESS; ADULTS AB The extent to which victims of a disaster are able to make capacitated and voluntary decisions to enroll in research is an important and virtually unexplored question. Although there are no compelling data to suggest that experiencing a severe trauma, in and of itself, renders all or even most individuals incapable of making autonomous decisions, the assessment of decision-making capacity (DMC) for research participation warrants serious consideration. This paper provides a framework for and procedural approach to the assessment of DMC in research with individuals exposed to disaster. Particular attention is paid to the implementation of additional safeguards to protect subjects who are vulnerable by virtue of impaired DMC. Recommendations are offered to clinical investigators, ethical review boards, and policymakers with regard to the design, review, and conduct of research in the aftermath of disaster. C1 NIMH, Bethesda, MD 20892 USA. RP Rosenstein, DL (reprint author), NIMH, Bldg 10,Room 3N 242,10 Ctr Dr MSC 1277, Bethesda, MD 20892 USA. EM donaldrosenstein@nih.gov NR 43 TC 17 Z9 19 U1 0 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0894-9867 J9 J TRAUMA STRESS JI J. Trauma Stress PD OCT PY 2004 VL 17 IS 5 BP 373 EP 381 DI 10.1023/B:JOTS.0000048950.36359.a2 PG 9 WC Psychology, Clinical; Psychiatry SC Psychology; Psychiatry GA 881BI UT WOS:000225838000003 PM 15633916 ER PT J AU Espinoza, J Goncalves, LF Lee, W Chaiworapongsa, T Treadwell, MC Stites, S Schoen, ML Mazor, M Romero, R AF Espinoza, J Goncalves, LF Lee, W Chaiworapongsa, T Treadwell, MC Stites, S Schoen, ML Mazor, M Romero, R TI The use of the minimum projection mode in 4-dimensional examination of the fetal heart with spatiotemporal image correlation SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE congenital heart; disease; fetal echocardiography; 4-dimensional ultrasonography; rendering algorithms; spatiotemporal image correlation; 3-dimensional ultrasonography ID PRENATAL-DIAGNOSIS; CONOTRUNCAL ANOMALIES; GREAT-ARTERIES; POWER DOPPLER; DISEASE; ULTRASOUND; ULTRASONOGRAPHY; DEFECTS; POPULATION; ACCURACY AB Objective. The minimum projection mode (MPM) is a rendering algorithm available in some 3- and 4-dimensional ultrasonography systems that, in I image, allows the visualization of vessels and cystic anatomic structures located in different scanning planes. The objective of this study was to compare the information displayed in images obtained with the MPM with their corresponding 2-dimensional ultrasonographic images from fetuses with and without structural heart defects. Methods. Thirty-two volume data sets acquired with the spatiotemporal image correlation technique from fetuses with (n = 15) and without (n = 17) structural heart defects were analyzed. Rendered images of the upper abdomen, 4-chamber view, and 3-vessel view were compared with the corresponding 2-dimensional images. Two independent observers with experience in fetal echocardiography reviewed these volume data sets using the MPM. The visualization rate of specific anatomic structures seen from a transverse sweep of the heart was recorded for each observer, and the interobserver agreement was assessed by statistical indices of agreement (K statistic). Results. Images obtained by the MPM displayed more vascular structures than those of corresponding 2-dimensional images at the level of the 3-vessel view. For conotruncal anomalies, the minimum mode projected the aorta and pulmonary arteries in 1 single plane, facilitating the understanding of their spatial relationships. The interobserver agreement score was moderate to "almost perfect" for assessment of most anatomic structures in the upper abdomen, 4-chamber view, and 3-vessel view sections. However interobserver agreement ranged from fair to poor for visualization of the left outflow tract, atrial septum, and flap of the foramen ovale. Conclusions. The MPM is an alternative rendering modality that facilitates visualization of normal and abnormal vascular connections to the fetal heart at the level of the 3-vessel view. This technique may be useful in prenatal diagnosis of conotruncal anomalies and in assessment of the spatial relationships of abnormal vascular connections in the upper mediastinum. C1 Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. William Beaumont Hosp, Div Fetal Imaging, Royal Oak, MI 48072 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Hosp, Dept Obstet Gynecol, Perinatol Res Branch,NICHHD, 4707 St Antoine Blvd, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov NR 44 TC 25 Z9 29 U1 0 U2 2 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD OCT PY 2004 VL 23 IS 10 BP 1337 EP 1348 PG 12 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 857TD UT WOS:000224140300011 PM 15448324 ER PT J AU Schmidt, LS Nickerson, ML Angeloni, D Glenn, GM Walther, MM Albert, PS Warren, MB Choyke, PL Torres-Cabala, CA Merino, MJ Brunet, J Berez, V Borras, J Sesia, G Middelton, L Phillips, JL Stolle, C Zbar, B Pautler, SE Linehan, WM AF Schmidt, LS Nickerson, ML Angeloni, D Glenn, GM Walther, MM Albert, PS Warren, MB Choyke, PL Torres-Cabala, CA Merino, MJ Brunet, J Berez, V Borras, J Sesia, G Middelton, L Phillips, JL Stolle, C Zbar, B Pautler, SE Linehan, WM TI Early onset hereditary papillary renal carcinoma: Germline missense mutations in the tyrosine kinase domain of the met proto-oncogene SO JOURNAL OF UROLOGY LA English DT Article DE kidney; carcinoma; renal cell; neoplastic syndromes; hereditary; proto-oncogene protein c-met; mutation ID CELL CARCINOMA; RECEPTOR; CYTOGENETICS; FAMILIES; TUMORS; GROWTH; CANCER AB Purpose: Hereditary papillary renal carcinoma (HPRC) is characterized by a predisposition to multiple, bilateral papillary type 1 renal tumors caused by inherited activating missense mutations in the tyrosine kinase domain of the MET proto-oncogene. In the current study we evaluated the clinical phenotype and germline MET mutation of 3 new HPRC families. We describe the early onset clinical features of HPRC. Materials and Methods: We identified new HPRC families of Italian (family 177), Spanish (family 223) and Cuban (family 268) descent. We evaluated their clinical features, performed MET mutation analysis by denaturing high performance liquid chromatography and DNA sequencing, and estimated age dependent penetrance and survival using Kaplan-Meier analysis. We characterized renal tumors by histology and fluorescence in situ hybridization. Results: Identical germline MET c.3522G-->A mutations (V11101) were identified in families 177 and 268 but no evidence of a founder effect was found. Affected members of family 223 carried a germline c.3906G-->C.3522G-->A MET mutation (V12381). Age dependent penetrance but not survival was significantly earlier for the c.3522G-->A mutation than for the c.3906G-->A mutation in these HPRC families. Trisomy of chromosome 7 and papillary renal carcinoma type 1 histology were detected in papillary renal tumors. Conclusions: HPRC can occur in an early onset form. The median age for renal tumor development in these 3 HPRC families was 46 to 63 years. HPRC associated papillary renal tumors may be aggressive and metastasize, leading to mortality. Median survival age was 60 to 70 years. Families with identical germline mutations in MET do not always share a common ancestor. HPRC is characterized by germline mutations in MET and papillary type 1 renal tumor histology. C1 NCI, Immunobiol Lab, Canc Res Ctr, Frederick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. NCI, Urol Oncol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, Rockville, MD USA. Scuola Super SantAnna, Pisa, Italy. CNR, Inst Clin Physiol, Pisa, Italy. Josep Trueta Hosp, Catalan Inst Oncol, Canc Risk Evaluat Unit, Girona, Spain. Univ Rovira & Virgili, Hosp Sant Joan, E-43201 Reus, Spain. Childrens Hosp Philadelphia, Mol Genet Lab, Dept Clin Labs & Pathol, Philadelphia, PA 19104 USA. RP Schmidt, LS (reprint author), NCI, Immunobiol Lab, Canc Res Ctr, Bldg 560,Room 12-69, Frederick, MD 21702 USA. EM schmidtl@mail.ncifcrf.gov OI Brunet, Joan/0000-0003-1945-3512 FU PHS HHS [N01-C0-12400] NR 21 TC 52 Z9 53 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD OCT PY 2004 VL 172 IS 4 BP 1256 EP 1261 DI 10.1097/01.ju.0000139583.63354.e0 PN 1 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 854JN UT WOS:000223899000007 PM 15371818 ER PT J AU Ornstein, DK Rayford, W Fusaro, VA Conrads, TP Ross, SJ Hitt, BA Wiggins, WW Veenstra, TD Liotta, LA Petricoin, EF AF Ornstein, DK Rayford, W Fusaro, VA Conrads, TP Ross, SJ Hitt, BA Wiggins, WW Veenstra, TD Liotta, LA Petricoin, EF TI Serum proteomic profiling can discriminate prostate cancer from benign prostates in men with total prostate specific antigen levels between 2.5 and 15.0 ng/ml SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; prostate-specific antigen; computational biology; spectrum analysis; mass ID MASS-SPECTROMETRY; BREAST-CANCER; SELDI-TOF; PATTERNS; BIOMARKERS; DIAGNOSIS; DISEASE AB Purpose: Artificial intelligence based pattern recognition algorithms have been developed and successfully used to analyze complex serum proteomic data streams generated by surface enhanced, laser desorption ionization time-of-flight mass spectroscopy. In the current study we used a high performance, hybrid quadrupole time-of-flight mass spectrometer to generate discriminatory serum proteomic profiles to determine if this technology could be used to determine the need for prostate biopsy in men with elevated prostate specific antigen (PSA). Materials and Methods: Serum samples were collected from 154 men with serum PSA 2.5 to 15.0 ng/ml and/or abnormal digital rectal examination prior to transrectal ultrasound guided biopsy. Serum samples were applied to WCX2 (weak cation exchange protein chip) Protein Arrays (Ciphergen Biosystems, Fremont, California) by a Biomek 2000 robotic liquid handler (Beckman-Coulter, Chaska, Minnesota) and low molecular weight (less than 20 kDa) protemic patterns were generated with an API QSTAR Pulsar i LC/MS/MS System (Applied Biosystems, Framingham, Massachusetts). High resolution mass spectra were analyzed with a pattern recognition bioinformatics tool, that is Proteome Quest beta version 1.0 (Correlogic Systems, Inc., Bethesda, Maryland), in an attempt to identify and discover key discriminating ion signatures. Serum samples from 63 men (2 or more negative prostate biopsies in 23, 1 negative biopsy in 10 and biopsy detected prostate cancer [CaP] in 30) were used to train the diagnostic algorithm. The remaining 91 samples, including 28 of prostate cancer and 63 of 1 or more negative biopsies, were analyzed in blinded fashion. Results: The most discriminatory model was found using the WCX2 chip. Testing the remaining 91 men with this model yielded 100% sensitivity and 67% specificity. In other words, if the proteomic pattern had been used to determine the need for prostate biopsy in this cohort of men with PSA between 2.5 and 15.0 ng/ml, 67% (42 of 63) with negative biopsies would have avoided unnecessary biopsy, while no cancers would have been missed. Conclusions: Our data demonstrate that high resolution mass spectroscopy can generate serum proteomic patterns that discriminate men with elevated PSA due to benign processes from men with CaP even when PSA is within the diagnostic gray zone. We are currently expanding the testing set to determine the reliability of this new technology to decrease unnecessary prostate biopsies without compromising the detection of curable CaP. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA. Louisiana State Univ, Dept Urol, New Orleans, LA USA. NIH, Clin Prote Program, US FDA, Bethesda, MD 20892 USA. Correl Syst, Bethesda, MD USA. RP Ornstein, DK (reprint author), Univ Calif Irvine, Irvine Med Ctr, Dept Urol, 101 City Dr S,Bldg 55,Room 300, Orange, CA 92868 USA. EM dornstei@uci.edu NR 20 TC 82 Z9 90 U1 3 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD OCT PY 2004 VL 172 IS 4 BP 1302 EP 1305 DI 10.1097/01.ju.0000139572.88463.39 PN 1 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 854JN UT WOS:000223899000017 PM 15371828 ER PT J AU Darnell, MER Subbarao, K Feinstone, SM Taylor, DR AF Darnell, MER Subbarao, K Feinstone, SM Taylor, DR TI Inactivation of the coronavirus that induces severe acute respiratory syndrome, SARS-CoV SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE SARS; coronavirus; virus inactivation; tissue culture ID GAMMA-IRRADIATION; VIRUS; GLYCOPROTEIN; VACCINE AB Severe acute respiratory syndrome (SARS) is a life-threatening disease caused by a novel coronavirus termed SARS-CoV. Due to the severity of this disease, the World Health Organization (WHO) recommends that manipulation of active viral cultures of SARS-CoV be performed in containment laboratories at biosafety level 3 (BSL3). The virus was inactivated by ultraviolet light (UV) at 254 nm, heat treatment of 65 degreesC or greater, alkaline (pH > 12) or acidic (pH < 3) conditions, formalin and glutaraldehyde treatments. We describe the kinetics of these efficient viral inactivation methods, which will allow research with SARS-CoV containing materials, that are rendered non-infectious, to be conducted at reduced safety levels. (C) 2004 Elsevier B.V. All rights reserved. C1 US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Taylor, DR (reprint author), US FDA, Ctr Biol Evaluat & Res, 8800 Rockville Pike,HFM448, Bethesda, MD 20892 USA. EM taylord@cber.fda.gov NR 23 TC 27 Z9 29 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD OCT PY 2004 VL 121 IS 1 BP 85 EP 91 DI 10.1016/j.jviromet.2004.06.006 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 856JY UT WOS:000224042700012 PM 15350737 ER PT J AU Fogg, C Lustig, S Whitbeck, JC Eisenberg, RJ Cohen, GH Moss, B AF Fogg, C Lustig, S Whitbeck, JC Eisenberg, RJ Cohen, GH Moss, B TI Protective immunity to vaccinia virus induced by vaccination with multiple recombinant outer membrane proteins of intracellular and extracellular virions SO JOURNAL OF VIROLOGY LA English DT Article ID NEUTRALIZING MONOCLONAL-ANTIBODIES; SURFACE HEPARAN-SULFATE; SMALLPOX VACCINE; ENVELOPED VIRUS; NONHUMAN-PRIMATES; SAPONIN ADJUVANT; IN-VIVO; CELLS; INFECTION; IMMUNOGENICITY AB Infectious intracellular and extracellular forms of vaccinia virus have different outer membrane proteins, presenting multiple targets to the immune system. We investigated the immunogenicity of soluble forms of L1, an outer membrane protein of the intracellular mature virus, and of A33 and B5, outer membrane proteins of the extracellular enveloped virus. The recombinant proteins, in 10-mug amounts mixed with a Ribi- or saponin-type adjuvant, were administered subcutaneously to mice. Antibody titers to each protein rose sharply after the first and second boosts, reaching levels that surpassed those induced by percutaneous immunization with live vaccinia virus. Immunoglobulin G1 (IgG1) antibody predominated after the protein immunizations, indicative of a T-helper cell type 2 response, whereas live vaccinia virus induced mainly IgG2a, indicative of a T-helper cell type I response. Mice immunized with any one of the recombinant proteins survived an intranasal challenge with 5 times the 50% lethal dose of the pathogenic WR strain of vaccinia virus. Measurements of weight loss indicated that the A33 immunization most effectively prevented disease. The superiority of protein combinations was demonstrated when the challenge virus dose was increased 20-fold. The best protection was obtained with a vaccine made by combining recombinant proteins of the outer membranes of intracellular and extracellular virus. Indeed, mice immunized with A33 plus B5 plus L1 or with A33 plus L1 were better protected than mice immunized with live vaccinia virus. Three immunizations with the three-protein combination were necessary and sufficient for complete protection. These studies suggest the feasibility of a multiprotein smallpox vaccine. C1 NIH, Viral Dis Lab, NIAID, Bethesda, MD 20892 USA. Univ Penn, Sch Dent Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Vet Med, Philadelphia, PA 19104 USA. RP Moss, B (reprint author), NIH, Viral Dis Lab, NIAID, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU CCR NIH HHS [RCE-U54-AI57168]; NIAID NIH HHS [AI53404, U54 AI057168] NR 40 TC 135 Z9 140 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2004 VL 78 IS 19 BP 10230 EP 10237 DI 10.1128/JVI.78.19.10230-10237.2004 PG 8 WC Virology SC Virology GA 855HP UT WOS:000223964300003 PM 15367588 ER PT J AU da Fonseca, FG Weisberg, AS Caeiro, MF Moss, B AF da Fonseca, FG Weisberg, AS Caeiro, MF Moss, B TI Vaccinia virus mutants with alanine substitutions in the conserved G5R gene fail to initiate morphogenesis at the nonpermissive temperature SO JOURNAL OF VIROLOGY LA English DT Article ID GOLGI INTERMEDIATE COMPARTMENT; THREONINE PROTEIN-KINASE; DISULFIDE BOND FORMATION; FORM IMMATURE VIRIONS; SENSITIVE MUTANTS; ENDOPLASMIC-RETICULUM; VIRAL MEMBRANES; DNA-REPLICATION; ESSENTIAL COMPONENT; A14 PHOSPHOPROTEIN AB The initial characterization of the product of the vaccinia virus G5R gene, which is conserved in all poxviruses sequenced to date, is described. The G5 protein was detected in the core fraction of purified virions, and transcription and translation of the G5R open reading frame occurred early in infection, independently of DNA replication. Attempts to delete the G5R gene and isolate a replication-competent virus were unsuccessful, suggesting that G5R encodes an essential function. We engineered vaccinia virus mutants with clusters of charged amino acids changed to alanines and determined that several were unable to replicate at 40degreesC but grew well at 37degreesC. At the nonpermissive temperature, viral gene expression and DNA replication and processing were unperturbed. However, tyrosine phosphorylation and proteolytic cleavage of the A17 membrane protein and proteolytic cleavage of core proteins were inhibited at 40degreesC, suggesting an assembly defect. The cytoplasm of cells that had been infected at the nonpermissive temperature contained large granular areas devoid of cellular organelles or virus structures except for occasional short crescent-shaped membranes and electron-dense lacy structures. The temperature-sensitive phenotype of the G5R mutants closely resembled the phenotypes of vaccinia virus mutants carrying conditionally lethal F10R protein kinase and H5R mutations. F10, although required for phosphorylation of A17 and viral membrane formation, was synthesized by the G5R mutants under nonpermissive conditions. An intriguing possibility is that G5 participates in the formation of viral membranes, a poorly understood event in poxvirus assembly. C1 NIH, Viral Dis Lab, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIH, Viral Dis Lab, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov RI Caeiro, Maria/C-1200-2014 OI Caeiro, Maria/0000-0003-0559-6344 NR 60 TC 24 Z9 26 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2004 VL 78 IS 19 BP 10238 EP 10248 DI 10.1128/JVI.78.19.10238-10248.2004 PG 11 WC Virology SC Virology GA 855HP UT WOS:000223964300004 PM 15367589 ER PT J AU Hashimoto, K Graham, BS Geraci, MW Fitzgerald, GA Egan, K Zhou, WS Goleniewska, K O'Neal, JF Morrow, JD Durbin, RK Wright, PF Collins, RD Suzutani, T Peebles, RS AF Hashimoto, K Graham, BS Geraci, MW Fitzgerald, GA Egan, K Zhou, WS Goleniewska, K O'Neal, JF Morrow, JD Durbin, RK Wright, PF Collins, RD Suzutani, T Peebles, RS TI Signaling through the prostaglandin I-2 receptor IP protects against respiratory syncytial virus-induced illness SO JOURNAL OF VIROLOGY LA English DT Article ID PULMONARY-HYPERTENSION; PROSTANOID RECEPTORS; DEFICIENT MICE; INFECTION; PROSTACYCLIN; PATHOGENESIS AB The role of prostanoids in modulating respiratory syncytial virus (RSV) infection is unknown. We found that RSV infection in mice increases production of prostaglandin I-2 (PGI(2)). Mice that overexpress PGI(2) synthase selectively in bronchial epithelium are protected against RSV-induced weight loss and have decreased peak viral replication and gamma interferon levels in the lung compared to nontransgenic littermates. In contrast, mice deficient in the PGI(2) receptor IP have exacerbated RSV-induced weight loss with delayed viral clearance and increased levels of gamma interferon in the lung compared to wild-type mice. These results suggest that signaling through IP has antiviral effects while protecting against RSV-induced illness and that PGI(2) is a potential therapeutic target in the treatment of RSV. C1 Vanderbilt Univ, Sch Med, Ctr Lung Res, Med Ctr,Dept Med, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Pediat, Nashville, TN 37232 USA. Vanderbilt Univ, Sch Med, Dept Pathol, Nashville, TN 37232 USA. Fukushima Med Univ, Dept Microbiol, Fukushima, Japan. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 USA. Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA. RP Peebles, RS (reprint author), Vanderbilt Univ, Sch Med, Ctr Lung Res, Med Ctr,Dept Med, T-1217 MCN,221 Kirkland Hall, Nashville, TN 37232 USA. EM stokes.peebles@vanderbilt.edu RI FitzGerald, Garret/A-4222-2010 FU NCI NIH HHS [CA 77839, P01 CA077839]; NIAID NIH HHS [R01 AI045512, R01 AI054660, R01-AI 045512, R01-AI 054660]; NIDDK NIH HHS [DK 26657, P30 DK026657, R01 DK048831]; NIGMS NIH HHS [GM 15431, P01 GM015431, P50 GM015431] NR 26 TC 27 Z9 28 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2004 VL 78 IS 19 BP 10303 EP 10309 DI 10.1128/JVI.78.19.10303.10309.2004 PG 7 WC Virology SC Virology GA 855HP UT WOS:000223964300011 PM 15367596 ER PT J AU Biancotto, A Grivel, JC Gondois-Rey, F Bettendroffer, L Vigne, R Brown, S Margolis, LB Hirsch, I AF Biancotto, A Grivel, JC Gondois-Rey, F Bettendroffer, L Vigne, R Brown, S Margolis, LB Hirsch, I TI Dual role of prostratin in inhibition of infection and reactivation of human immunodeficiency virus from latency in primary blood lymphocytes and lymphoid tissue SO JOURNAL OF VIROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; CD-1 MOUSE SKIN; NONPROMOTING 12-DEOXYPHORBOL 13-ESTERS; PHORBOL 12-MYRISTATE 13-ACETATE; HIV-1 INFECTION; IN-VIVO; MOLECULAR CHARACTERIZATION; ACQUIRED-IMMUNODEFICIENCY; MONONUCLEAR-CELLS AB To design strategies to purge latent reservoirs of human immunodeficiency virus type 1 (HrV-1), we investigated mechanisms by which a non-tumor-promoting phorbol ester, prostratin, inhibits infection of CD4(+) T lymphocytes and at the same time reactivates virus from latency. CD4(+) T lymphocytes from primary blood mononuclear cells (PBMC) and in blocks of human lymphoid tissue were stimulated with prostratin and infected with HIV-1 to investigate the effects of prostratin on cellular susceptibility to the virus. The capacity of prostratin to reactivate HIV from latency was tested in CD4(+) T cells harboring preintegrated and integrated latent provirus. Prostratin stimulated CD4(+) T cells in an aberrant way. It induced expression of the activation markers CD25 and CD69 but inhibited cell cycling. HIV-1 uptake was reduced in prostratin-stimulated CD4(+) T PBMC and tissues in a manner consistent with a downregulation of CD4 and CXCR4 receptors in these systems. At the postentry level, prostratin inhibited completion of reverse transcription of the viral genome in lymphoid tissue. However, prostratin facilitated integration of the reverse-transcribed HIV-1 genome in nondividing CD4(+) T cells and facilitated expression of already integrated HIV-1, including latent forms. Thus, while stimulation with prostratin restricts susceptibility of primary resting CD4(+) T cells to HIV infection at the virus cell-entry level and at the reverse transcription level, it efficiently reactivates HIV-1 from pre- and postintegration latency in resting CD4(+) T cells. C1 INSERM, U372, Lab Pathogenie Infect Lentivirus, F-13276 Marseille 9, France. NICHHD, Lab Mol & Cellular Biophys, Bethesda, MD 20892 USA. AIDS ReSearch Alliance, W Hollywood, CA USA. RP Hirsch, I (reprint author), INSERM, U372, Lab Pathogenie Infect Lentivirus, 163 Ave Luminy,BP 178,Parc Sci & Technol Luminy, F-13276 Marseille 9, France. EM ihirsch@marseille.insermfr RI Hirsch, Ivan/J-7726-2015; OI Hirsch, Ivan/0000-0003-1701-1438 NR 52 TC 63 Z9 67 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2004 VL 78 IS 19 BP 10507 EP 10515 DI 10.1128/JVI.78.19.10507-10515.2004 PG 9 WC Virology SC Virology GA 855HP UT WOS:000223964300032 PM 15367617 ER PT J AU Di Mascio, M Markowitz, M Louie, M Hurley, A Hogan, C Simon, V Follmann, D Ho, DD Perelson, AS AF Di Mascio, M Markowitz, M Louie, M Hurley, A Hogan, C Simon, V Follmann, D Ho, DD Perelson, AS TI Dynamics of intermittent viremia during highly active antiretroviral therapy in patients who initiate therapy during chronic versus acute and early human immunodeficiency virus type 1 infection SO JOURNAL OF VIROLOGY LA English DT Article ID RESIDUAL VIRAL REPLICATION; ACUTE HIV-1 INFECTION; IN-VIVO; COMBINATION THERAPY; ANTIVIRAL THERAPY; LATENT RESERVOIR; PLASMA; RNA; DECAY; CELL AB The meaning of viral blips in human immunodeficiency virus type 1 (HIV-1)-infected patients treated with seemingly effective highly active antiretroviral therapy (HAART) is still controversial and under investigation. Blips might represent low-level ongoing viral replication in the presence of drug or simply release of virions from the latent reservoir. Patients treated early during HIV-1 infection are more likely to have a lower total body viral burden, a homogenous viral population, and preserved HIV-1-specific immune responses. Consequently, viral blips may be less frequent in them than in patients treated during chronic infection. To test this hypothesis, we compared the occurrence of viral blips in 76 acutely infected patients (primary HIV infection [PHI] group) who started therapy within 6 months of the onset of symptoms with that in 47 patients who started HAART therapy during chronic infection (chronic HIV infection [CHI] group). Viral blip frequency was approximately twofold higher in CHI patients (0.122 +/- 0.12/viral load [VL] sample, mean standard deviation) than in PHI patients (0.066 +/- 0.09/VL sample). However, in both groups, viral blip frequency did not increase with longer periods of observation. Also, no difference in viral blip frequency was observed between treatment subgroups, and the occurrence of a blip was not associated with a recent change in CD4(+) T-cell count. Finally, in PHI patients the VL set point was a significant predictor of blip frequency during treatment. C1 NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. Los Alamos Natl Lab, Div Theoret, Los Alamos, NM USA. Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. RP Di Mascio, M (reprint author), NIAID, Biostat Res Branch, NIH, MS 7609,6700B Rockledge Dr, Bethesda, MD 20892 USA. EM mdimascio@niaid.nih.gov FU NCRR NIH HHS [M01-RR00102, R01 RR006555, RR06555, M01 RR000102]; NIAID NIH HHS [AI28433, R01 AI047033, R37 AI028433, U01 AI041534, R01 AI028433, AI47033, AI41534] NR 39 TC 32 Z9 33 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2004 VL 78 IS 19 BP 10566 EP 10573 DI 10.1128/JVI.78.19.10566-10573.2004 PG 8 WC Virology SC Virology GA 855HP UT WOS:000223964300038 PM 15367623 ER PT J AU Ofek, G Tang, M Sambor, A Katinger, H Mascola, JR Wyatt, R Kwong, PD AF Ofek, G Tang, M Sambor, A Katinger, H Mascola, JR Wyatt, R Kwong, PD TI Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; HIV-1 GP41; NEUTRALIZING EPITOPE; ENVELOPE GLYCOPROTEIN; ELECTRON-DENSITY; VACCINE DESIGN; ELDKWA-EPITOPE; BINDING-SITE; PROTEIN; FUSION AB The membrane-proximal region of the ectodomain of the gp41 envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) is the target of three of the five broadly neutralizing anti-HIV-1 antibodies thus far isolated. We have determined crystal structures of the antigen-binding fragment for one of these antibodies, 2F5, in complex with 7-mer, 11-mer, and 17-mer peptides of the gp41 membrane-proximal region, at 2.0-, 2.1-, and 2.24 resolutions, respectively. The structures reveal an extended gp41 conformation, which stretches over 30 Angstrom in length. Contacts are made with five complementarity-determining regions of the antibody as well as with nonpolymorphic regions. Only one exclusive charged face of the gp41 epitope is bound by 2F5, while the nonbound face, which is hydrophobic, may be hidden due to occlusion by other portions of the ectodomain. The structures reveal that the 2F5 antibody is uniquely built to bind to an epitope that is proximal to a membrane surface and in a manner mostly unaffected by large-scale steric hindrance. Biochemical studies with proteoliposomes confirm the importance of lipid membrane and hydrophobic context in the binding of 2F5 as well as in the binding of 4E10, another broadly neutralizing antibody that recognizes the membrane-proximal region of gp41. Based on these structural and biochemical results, immunization strategies for eliciting 2F5- and 4E10-like broadly neutralizing anti-HIV-1 antibodies are proposed. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Agr Sci, Inst Appl Microbiol, Vienna, Austria. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Room 4508, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Ofek, Gilad/A-6965-2010 NR 68 TC 351 Z9 358 U1 3 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2004 VL 78 IS 19 BP 10724 EP 10737 DI 10.1128/JVI.78.19.10724-10737.2004 PG 14 WC Virology SC Virology GA 855HP UT WOS:000223964300054 PM 15367639 ER PT J AU Vashisht, K Faaberg, KS Aber, AL Brown, KE O'Sullivan, MG AF Vashisht, K Faaberg, KS Aber, AL Brown, KE O'Sullivan, MG TI Splice junction map of simian Parvovirus transcripts SO JOURNAL OF VIROLOGY LA English DT Article ID MINUTE VIRUS; AUTONOMOUS PARVOVIRUS; CYNOMOLGUS MONKEYS; MESSENGER-RNAS; SEVERE ANEMIA; B19; GENOME; INFECTION; PROMOTER; MICE AB The transcription map of simian parvovirus (SPV), an Erythrovirus similar to Parvovirus B19, was investigated. RNA was extracted from tissues of experimentally infected cynomolgus macaques and subjected to reverse transcription-PCR with SPV-specific primers. The PCR products were cloned and sequenced to identify splice junctions. A total of 14 distinct sequences were identified as putative partial transcripts. Of these, 13 were spliced; a single unspliced transcript putatively encoded NS1. Sequence analysis revealed that spliced partial transcripts may encode portions of open reading frames for the major capsid proteins VP1 and VP2 and smaller, unknown proteins. These unspliced and spliced transcripts and putative proteins encoded by SPV were similar to those of B19. Initial splice junctions at nucleotides 279 and 333 were analogous to those at nucleotides 406 and 441, respectively, in B19. Seven of the 10 splices identified had typical GT/AG donor/acceptor junctions. The splice sites were confirmed by Northern blotting and autoradiography. In contrast to B19, which has a maximum of two splices per transcript, up to three splices were observed in SPV transcripts. A spliced transcript putatively encoding a truncated version of NS1, as seen with minute virus of mice and adeno-associated virus 2, was also observed. The findings indicate that that the splicing pattern of transcripts of SPV and B19 is similar, but SPV also has coding strategies in common with other parvoviruses. C1 Univ Minnesota, Dept Vet Pathobiol, St Paul, MN USA. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Vashisht, K (reprint author), 2617 VMBSB,2001 S Lincoln Ave, Urbana, IL 61802 USA. EM vashisht@uiuc.edu FU NCRR NIH HHS [RR 14098]; NICHD NIH HHS [HD 34364] NR 27 TC 9 Z9 9 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2004 VL 78 IS 20 BP 10911 EP 10919 DI 10.1128/JVI.78.20.10911-10919.2004 PG 9 WC Virology SC Virology GA 858YO UT WOS:000224229000008 PM 15452211 ER PT J AU Hibbert, CS Mirro, J Rein, A AF Hibbert, CS Mirro, J Rein, A TI MRNA molecules containing murine leukemia virus packaging signals are encapsidated as dimers SO JOURNAL OF VIROLOGY LA English DT Article ID DIMERIZATION INITIATION SITE; MOMULV GENOMIC RNA; SARCOMA-VIRUS; NUCLEOCAPSID PROTEIN; RETROVIRAL RNA; IN-VITRO; CIS ELEMENTS; STEM-LOOPS; VIRAL-RNA; SEQUENCES AB Prior work by others has shown that insertion of psi (i.e., leader) sequences from the Moloney murine leukemia virus (MLV) genome into the 3' untranslated region of a nonviral mRNA leads to the specific encapsidation of this RNA in MLV particles. We now report that these RNAs are, like genomic RNAs, encapsidated as dimers. These dimers have the same thermostability as MLV genomic RNA dimers; like them, these dimers are more stable if isolated from mature virions than from immature virions. We characterized encapsidated mRNAs containing deletions or truncations of MLV psi or with psi sequences from MLV-related acute transforming viruses. The results indicate that the dimeric linkage in genomic RNA can be completely attributed to the psi region of the genome. While this conclusion agrees with earlier electron microscopic studies on mature MLV dimers, it is the first evidence as to the site of the linkage in immature dimers for any retrovirus. Since the Psi(+) mRNA is not encapsidated as well as genomic RNA, it is only present in a minority of virions. The fact that it is nevertheless dimeric argues strongly that two of these molecules are packaged into particles together. We also found that the kissing loop is unnecessary for this coencapsidation or for the stability of mature dimers but makes a major contribution to the stability of immature dimers. Our results are consistent with the hypothesis that the packaging signal involves a dimeric structure in which the RNAs are joined by intermolecular interactions between GACG loops. C1 NCI, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. RP Rein, A (reprint author), NCI, HIV Drug Resistance Program, POB B, Ft Detrick, MD 21702 USA. EM rein@ncifcrf.gov NR 67 TC 47 Z9 47 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2004 VL 78 IS 20 BP 10927 EP 10938 DI 10.1128/JVI.78.20.10927-10938.2004 PG 12 WC Virology SC Virology GA 858YO UT WOS:000224229000010 PM 15452213 ER PT J AU An, P Bleiber, G Duggal, P Nelson, G May, M Mangeat, B Alobwede, I Trono, D Vlahov, D Donfield, S Goedert, JJ Phair, J Buchbinder, S O'Brien, SJ Telenti, A Winkler, CA AF An, P Bleiber, G Duggal, P Nelson, G May, M Mangeat, B Alobwede, I Trono, D Vlahov, D Donfield, S Goedert, JJ Phair, J Buchbinder, S O'Brien, SJ Telenti, A Winkler, CA TI APOBEC3G genetic variants and their influence on the progression to AIDS SO JOURNAL OF VIROLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 INFECTION; VIF PROTEIN; PROMOTER VARIANT; ENZYME APOBEC3G; EDITING ENZYME; DNA; HYPERMUTATION; HEMOPHILIA; DEAMINASE AB The cytosine deaminase APOBEC3G, in the absence of the human immunodeficiency virus type 1 (HIV-1) accessory gene HIV-1 viral infectivity factor (vif), inhibits viral replication by introducing G-->A hypermutation in the newly synthesized HIV-1 DNA negative strand. We tested the hypothesis that genetic variants of APOBEC3G may modify HIV-1 transmission and disease progression. Single nucleotide polymorphisms were identified in the promoter region (three), introns (two), and exons (two). Genotypes were determined for 3,073 study participants enrolled in six HIV-AIDS prospective cohorts. One codon-changing variant, H186R in exon 4, was polymorphic in African Americans (AA) (f = 37%) and rare in European Americans (f < 3%) or Europeans (f = 5%). For AA, the variant allele 186R was strongly associated with decline in CD4 T cells (CD4 slope on square root scale: -1.86, P = 0.009), The 186R allele was also associated with accelerated progression to AIDS-defining conditions in AA. The in vitro antiviral activity of the 186R enzyme was not inferior to that of the common H186 variant. These studies suggest that there may be a modifying role of variants of APOBEC3G on HIV-1 disease progression that warrants further investigation. C1 NCI, Basic Res Program, SAIC Frederick, Canc Res & Dev Ctr, Frederick, MD 21702 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. NHGRI, Inherited Dis Res Branch, Baltimore, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. Rho Inc, Chapel Hill, NC USA. Northwestern Univ, Fineberg Sch Med, Comprehens AIDS Ctr, Chicago, IL 60611 USA. San Francisco Dept Publ Hlth, San Francisco, CA USA. Univ Lausanne, Inst Microbiol, CH-1015 Lausanne, Switzerland. Univ Geneva, Dept Genet & Microbiol, CH-1211 Geneva 4, Switzerland. Univ Hosp Geneva, Div Infect Dis, Geneva, Switzerland. Univ Bristol, Bristol BS8 1TH, Avon, England. RP Winkler, CA (reprint author), NCI, Basic Res Program, SAIC Frederick, Canc Res & Dev Ctr, Frederick, MD 21702 USA. EM winkler@mail.ncifcrf.gov RI May, Margaret/E-8099-2013; SHCS, all/G-4072-2011; SHCS, int. coll. A/G-4083-2011 OI May, Margaret/0000-0002-9733-1003; FU NCI NIH HHS [N01 CO 124000]; NIDA NIH HHS [DA 04334, R01 DA004334, R37 DA004334, R56 DA004334] NR 33 TC 131 Z9 141 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2004 VL 78 IS 20 BP 11070 EP 11076 DI 10.1128/JVI.78.20.11070-11076.2004 PG 7 WC Virology SC Virology GA 858YO UT WOS:000224229000024 PM 15452227 ER PT J AU Younis, I Khair, L Dundr, M Lairmore, MD Franchini, G Green, PL AF Younis, I Khair, L Dundr, M Lairmore, MD Franchini, G Green, PL TI Repression of human T-cell leukemia virus type 1 and type 2 replication by a viral mRNA-encoded posttranscriptional regulator SO JOURNAL OF VIROLOGY LA English DT Article ID TROPICAL SPASTIC PARAPARESIS; I-ASSOCIATED MYELOPATHY; OPEN READING FRAMES; HTLV-I; FUNCTIONAL DOMAIN; PX REGION; EXPRESSION; REX; TAX; PROTEINS AB Human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2 are complex retroviruses that persist in the host, eventually causing leukemia and neurological disease in a small percentage of infected individuals. In addition to structural and enzymatic proteins, HTLV encodes regulatory (Tax and Rex) and accessory (open reading frame I and II) proteins. The viral Tax and Rex proteins positively regulate virus production. Tax activates viral and cellular transcription to promote T-cell growth and, ultimately, malignant transformation. Rex acts posttranscriptionally to facilitate cytoplasmic expression of viral mRNAs that encode the structural and enzymatic gene products, thus positively controlling virion expression. Here, we report that both HTLV-1 and HTLV-2 have evolved accessory genes to encode proteins that act as negative regulators of both Tax and Rex. HTLV-1 p30(II) and the related HTLV-2 p28(II) inhibit virion production by binding to and retaining tax/rex mRNA in the nucleus. Reduction of viral replication in a cell carrying the provirus may allow escape from immune recognition in an infected individual. These data are consistent with the critical role of these proteins in viral persistence and pathogenesis in animal models of HTLV-1 and HTLV-2 infection. C1 Ohio State Univ, Dept Vet Biosci, Columbus, OH 43210 USA. Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. Ohio State Univ, Ctr Retrovirus Res, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Ohio State Univ, Mol Cellular & Dev Biol Grad Program, Columbus, OH 43210 USA. NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. RP Green, PL (reprint author), Ohio State Univ, Dept Vet Biosci, 1925 Coffey Rd, Columbus, OH 43210 USA. EM green.466@osu.edu FU NCI NIH HHS [P01 CA100730-01, R01 CA077556, R01 CA092009, CA 77556, CA 92009] NR 47 TC 53 Z9 54 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2004 VL 78 IS 20 BP 11077 EP 11083 DI 10.1128/JVI.78.20.11077-11083.2004 PG 7 WC Virology SC Virology GA 858YO UT WOS:000224229000025 PM 15452228 ER PT J AU Thio, CL Mosbruger, TL Kaslow, RA Karp, CL Strathdee, SA Vlahov, D O'Brien, SJ Astemborski, J Thomas, DL AF Thio, CL Mosbruger, TL Kaslow, RA Karp, CL Strathdee, SA Vlahov, D O'Brien, SJ Astemborski, J Thomas, DL TI Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MULTICENTER AIDS COHORT; CTLA-4 BLOCKADE; JAPANESE POPULATION; AUTOIMMUNE-DISEASE; VIRAL-HEPATITIS; HOMOSEXUAL-MEN; DRUG-USERS; CELLS; POLYMORPHISMS AB Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an inhibitory T-cell receptor expressed by activated and regulatory T cells. We hypothesized that single-nucleotide polymorphisms (SNPs) in the gene encoding CTLA-4 may affect the vigor of the T-cell response to hepatitis B virus (HBV) infection, thus influencing viral persistence. To test this hypothesis, we genotyped six CTLA4 SNPs, from which all frequent haplotypes can be determined, using a large, matched panel of subjects with known HBV outcomes. Haplotypes with these SNPs were constructed for each subject using PHASE software. The haplotype distribution differed between those with viral persistence and those with clearance. Two haplotypes were associated with clearance of HBV infection, which was most likely due to associations with the SNPs - 1722C (odds ratio [OR] = 0.60, P = 0.06) and +49G (OR = 0.73, P = 0.02). The wild-type haplotype, which contains an SNP leading to a decreased T-cell response (+6230A), was associated with viral persistence (OR = 1.32, P = 0.04). These data suggest that CTLA4 influences recovery from HBV infection, which is consistent with the emerging role of T regulatory cells in the pathogenesis of disease. C1 Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Epidemiol, Baltimore, MD 21205 USA. NCI, Lab Genomic Divers, Frederick, MD 21701 USA. Univ Alabama, Dept Epidemiol, Birmingham, AL USA. Cincinnati Childrens Hosp, Med Ctr, Div Mol Immunol, Cincinnati, OH USA. New York Acad Med, New York, NY USA. RP Thio, CL (reprint author), 1503 E Jefferson St, Baltimore, MD 21231 USA. EM cthio@jhmi.edu RI Strathdee, Steffanie/B-9042-2009; OI Karp, Christopher/0000-0002-0832-2659 FU NCI NIH HHS [N01 CO 12400, N01CO12400]; NCRR NIH HHS [5M01 RR 00722, M01 RR000722]; NIAID NIH HHS [U01 AI 35039, U01 AI 35040, U01 AI 35041, U01 AI 35042, U01 AI 35043, U01 AI 37613, U01 AI 37984, U01 AI035039, U01 AI035040, U01 AI035041, U01 AI035042, U01 AI035043, U01 AI037613, U01 AI037984]; NIDA NIH HHS [DA 12568, DA 00441, DA 04334-17, DA 13324, K08 DA000441, R01 DA004334, R01 DA012568, R01 DA013324, R37 DA004334, R56 DA004334, R56 DA012568]; NIDDK NIH HHS [DK 56415, R01 DK056415] NR 36 TC 72 Z9 78 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD OCT PY 2004 VL 78 IS 20 BP 11258 EP 11262 DI 10.1128/JVI.78.20.11258-11262.2004 PG 5 WC Virology SC Virology GA 858YO UT WOS:000224229000041 PM 15452244 ER PT J AU Oberdorfer, MD AF Oberdorfer, MD TI Research opportunities in low vision and blindness rehabilitation SO JOURNAL OF VISUAL IMPAIRMENT & BLINDNESS LA English DT Editorial Material C1 NEI, Bethesda, MD 20892 USA. RP Oberdorfer, MD (reprint author), NEI, 5635 Fishers Lane,Suite 1300, Bethesda, MD 20892 USA. EM oberdorfer@nei.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER FOUNDATION BLIND PI NEW YORK PA J VISUAL IMPAIRMENT BLINDNESS 11 PENN PLAZA SUITE 300, NEW YORK, NY 10001 USA SN 0145-482X J9 J VISUAL IMPAIR BLIN JI J. Vis. Impair. Blind. PD OCT PY 2004 VL 98 IS 10 BP 583 EP 584 PG 2 WC Rehabilitation SC Rehabilitation GA 922IH UT WOS:000228830100003 ER PT J AU Johnson, BD Merz, CNB Braunstein, GD Berga, SL Bittner, V Hodgson, TK Gierach, GL Reis, SE Vido, DA Sharaf, BL Smith, KM Sopko, G Kelsey, SF AF Johnson, BD Merz, CNB Braunstein, GD Berga, SL Bittner, V Hodgson, TK Gierach, GL Reis, SE Vido, DA Sharaf, BL Smith, KM Sopko, G Kelsey, SF TI Determination of menopausal status in women: The NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) study SO JOURNAL OF WOMENS HEALTH LA English DT Article ID CORONARY-HEART-DISEASE; FOLLICLE-STIMULATING-HORMONE; ENDOGENOUS SEX-HORMONES; POPULATION-BASED SAMPLE; POSTMENOPAUSAL WOMEN; RISK-FACTORS; CARDIOVASCULAR-DISEASE; ATHEROSCLEROSIS RISK; LUTEINIZING-HORMONE; MENSTRUAL CYCLES AB Purpose: Accurate classification of menopausal status is important to epidemiological research evaluating the role of reproductive hormones in disease processes. Algorithms relying on repeat hormone assays are unfeasible in large epidemiological studies. This paper summarizes the development of the Women's Ischemia Syndrome Evaluation ( WISE) Hormonal menopausal status algorithm for determining premenopausal, perimenopausal, and postmenopausal status using menstrual and reproductive history and reproductive hormone levels obtained at a single clinic visit. Methods: The authors compared the accuracy of this algorithm with two currently used self-report algorithms: Menstrual, based only on months since last menstrual period, and Historical, which adds age and surgical history. Results: The study population consisted of 515 women ( 329 clearly postmenopausal) enrolled in the WISE study who were undergoing coronary angiography for suspected ischemia. A subgroup of 186, not clearly postmenopausal, was classified by these three algorithms. Results were evaluated against individualized expert consensus classification. The Menstrual and Historical classifications differed significantly ( p < 0.0001) from expert consensus, with 32% - 26% discordant classifications, respectively. For the WISE Hormonal classification, discordance was 4%. Conclusions: The authors conclude that inaccurate classifications of menopausal status occur frequently in self-report algorithms. Use of the relatively simple WISE algorithm can improve the accuracy of menopausal status classification for epidemiological research. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA USA. Univ Alabama, Birmingham, AL USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Allegheny Univ Hlth Sci, Dept Med, Div Cardiol, Pittsburgh, PA USA. Rhode Isl Hosp, Div Cardiol, Providence, RI USA. Univ Florida, Dept Med, Div Cardiol, Gainesville, FL USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Johnson, BD (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Parran 127,130 DeSoto St, Pittsburgh, PA 15261 USA. EM djohnson@edc.pitt.edu RI Reis, Steven/J-3957-2014; Gierach, Gretchen/E-1817-2016 OI Gierach, Gretchen/0000-0002-0165-5522 FU NCRR NIH HHS [M01-RR00425]; NHLBI NIH HHS [N01-HV-68161, N01-HV-68162, N01-HV-68163] NR 77 TC 44 Z9 44 U1 1 U2 3 PU MARY ANN LIEBERT INC PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD OCT PY 2004 VL 13 IS 8 BP 872 EP 887 PG 16 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 875CA UT WOS:000225396100003 PM 15671703 ER PT J AU Reuben, DB Seeman, TE Keeler, E Hayes, RP Bowman, L Sewall, A Hirsch, SH Wallace, RB Guralnik, JM AF Reuben, DB Seeman, TE Keeler, E Hayes, RP Bowman, L Sewall, A Hirsch, SH Wallace, RB Guralnik, JM TI Refining the categorization of physical functional status: The added value of combining self-reported and performance-based measures SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID LOWER-EXTREMITY FUNCTION; OLDER PERSONS; SUBSEQUENT DISABILITY; DEPENDENCE; MORTALITY; ADULTS; RISK; PREDICTOR; LEVEL AB Background. When considered individually, self-reported functional status and performance-based functional status predict functional status decline and mortality. However, what additional prognostic information is gained by combining these approaches remains unknown. Methods. The authors used three waves of three sites (5138 participants) of the Established Populations for Epidemiologic Studies of the Elderly to determine the prognostic value of individual and combined approaches. Baseline self-reported (mobility and activities of daily living [ADL] items) and performance-based (Physical Performance Score) functional status information was classified into three and four hierarchical categories. respectively. Results. Based on self-reported information alone, at 1 year, 73% participants had not changed, 15% declined, 6% improved, and 6% died. At 4 years, 53% had not changed, 24% declined, 2% improved, and 22% died. Based on performance-based assessment alone, at 4 years, 33% of the sample remained stable, 37% declined, 6% improved, and 24% died. In the top two self-reported categories, functioning on the performance-based assessment varied widely. Among those who were independent in all self-reported functioning, approximately 40% scored in each of the top two performance-based categories. Among persons in the top two self-reported categories, poorer performance was associated with progressively higher 1-year and 4-year mortality rates. Among persons with impaired mobility and at least 1 ADL dependency, the mortality rate was high and was not influenced by performance-based score. Conclusions. Combining self-reported and performance-based measurements can refine prognostic information, particularly among older persons with high self-reported functioning. However, if ADL dependency is present, performance-based measures do not add prognostic value regarding mortality. C1 Univ Calif Los Angeles, David Geffen Sch Med, Multicampus Program Geriatr Med & Gerontol, Los Angeles, CA 90095 USA. RAND Corp, Santa Monica, CA 90406 USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Sewall Inc, Bethesda, MD USA. Univ Iowa, Dept Epidemiol, Iowa City, IA 52242 USA. NIA, Bethesda, MD 20892 USA. RP Reuben, DB (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Multicampus Program Geriatr Med & Gerontol, 10945 Le Conte Ave,Suite 2339, Los Angeles, CA 90095 USA. EM dreuben@mednet.ucla.edu FU NIA NIH HHS [AG16677, P60AG10415] NR 25 TC 67 Z9 67 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2004 VL 59 IS 10 BP 1056 EP 1061 PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 868IQ UT WOS:000224907700011 PM 15528778 ER PT J AU Leveille, SG Fried, LP Guralnik, JM AF Leveille, SG Fried, LP Guralnik, JM TI Advancing in the analysis of disability in cognitively impaired older adults - Authors' reponse SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Letter C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Publ Hlth, Baltimore, MD 21218 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Leveille, SG (reprint author), 330 Brookline Ave,RD-103, Boston, MA 02215 USA. EM sleveill@bidnic.harvard.edu NR 2 TC 0 Z9 0 U1 0 U2 0 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD OCT PY 2004 VL 59 IS 10 BP 1078 EP 1078 PG 1 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 868IQ UT WOS:000224907700016 ER PT J AU Leypoldt, JK Cheung, AK Deeter, RB Goldfarb-Rumyantzev, A Greene, T Depner, TA Kusek, J AF Leypoldt, JK Cheung, AK Deeter, RB Goldfarb-Rumyantzev, A Greene, T Depner, TA Kusek, J TI Kinetics of urea and beta(2)-microglobulin during and after short hemodialysis treatments SO KIDNEY INTERNATIONAL LA English DT Article; Proceedings Paper CT 35th Annual Meeting of the American-Society-of-Nephrology CY NOV 01-06, 2002 CL PHILADELPHIA, PA SP Amer Soc Nephrol DE adequacy; clearance; dose; middle molecule; postdialysis rebound ID KT/V; HEMO; VALIDATION; DIALYSIS; REMOVAL; MODELS AB Background. Daily short hemodialysis (HD) is often prescribed by simply doubling treatment frequency and halving treatment time; however, the effect of this prescription approach on the equilibrated HD dose (urea eKt/V) and whole body clearance for beta(2)-microglobulin has not been established. Methods. We compared urea and beta(2)-microglobulin kinetics during and 60 minutes after a short HD treatment and a conventional HD treatment in a crossover study on 22 maintenance HD patients: 16 male and 6 female, 61 +/- 18 (mean +/- standard deviation) years of age. One patient in each treatment modality was excluded from certain analyses because of missing data. Short and conventional HD treatments were essentially identical, except for treatment times, which were 116 +/- 14 and 241 +/- 27 minutes, respectively. Blood samples were collected at regular intervals during and after treatments, and additional blood and dialysate samples were collected at 60 minutes of treatment to evaluate dialyzer clearances. Results. Plasma water urea clearances measured directly across the dialyzer during short and conventional HD treatments were not different (255 +/- 23 mL/min and 255 +/- 28 mL/min, respectively). The 60-minute postdialysis blood urea nitrogen concentration rebounded more (P < 0.01) after short HD than conventional HD (5.9 +/- 3.1 vs. 4.0 +/- 1.5 mg/dL, respectively). Calculated urea eKt/V values using the Daugirdas-Schneditz rate equation were not different from those measured during conventional HD using the 60-minute postdialysis concentration but significantly overestimated measured urea eKt/V values during short HD. Postdialysis rebound of β(2)-microglobulin concentrations was variable but similar after short and conventional HD treatments (0.1 +/- 3.4 vs. 0.7 +/- 1.8 mg/L, respectively). Whole body clearances of β(2)-microglobulin calculated from predialysis and immediate (10-second) postdialysis serum concentrations during short and conventional HD treatments were not different from each other (42.9 +/- 24.1 vs. 41.9 +/- 22.4 mL/min, respectively). Conclusion. These observations show that the Daugirdas-Schneditz rate equation is accurate in predicting urea eKt/V during conventional, but not during short, HD. In contrast, whole body clearances of β(2)-microglobulin during short and conventional HD treatments were similar. We conclude that calculation of accurate estimates of urea eKt/V, but not clearances of β(2)-microglobulin, differ during short and conventional HD treatments. C1 Univ Utah, Dialysis Program, Salt Lake City, UT 84112 USA. VA Salt Lake City Hlth Care Syst, Salt Lake City, UT USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Calif Davis, Sacramento, CA 95817 USA. NIDDK, NIH, Bethesda, MD USA. RP Leypoldt, JK (reprint author), Univ Utah, Dialysis Program, 85 N Med Dr E Room 201, Salt Lake City, UT 84112 USA. EM Ken.Leypoldt@hsc.utah.edu NR 26 TC 15 Z9 15 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD OCT PY 2004 VL 66 IS 4 BP 1669 EP 1676 DI 10.1111/j.1523-1755.2004.00934.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 853IR UT WOS:000223821000043 PM 15458465 ER PT J AU Hoffmann, S Park, J Jacobson, LM Muehrer, RJ Lorentzen, D Kleiner, D Becker, YT Hullett, DA Mannon, R Kirk, AD Becker, BN AF Hoffmann, S Park, J Jacobson, LM Muehrer, RJ Lorentzen, D Kleiner, D Becker, YT Hullett, DA Mannon, R Kirk, AD Becker, BN TI Donor genomics influence graft events: The effect of donor polymorphisms on acute rejection and chronic allograft nephropathy SO KIDNEY INTERNATIONAL LA English DT Article DE gene polymorphisms; donor populations; kidney transplantation ID CYTOKINE GENE POLYMORPHISMS; TUBULAR EPITHELIAL-CELLS; RENAL-TRANSPLANTATION; INTERFERON-GAMMA; TNF-ALPHA; KIDNEY-TRANSPLANTATION; CHEMOKINE RECEPTORS; BRAIN-DEATH; IFN-GAMMA; EXPRESSION AB Background. Organs procured from deceased donors emanate from individuals with diverse genetic backgrounds. Donor organs, therefore, may vary in their response to injury and immune stimuli in a genetically determined manner. We assessed polymorphisms from 244 renal allograft donors to better understand the impact of donor polymorphisms on selected transplant outcomes. Methods. Donor genomic DNA restriction fragment length polymorphisms were assayed for evidence of common cytokine [interleukin (IL)-2, IL-6, IL-10, tumor necrosis factor (TNF)-alpha, TGF-beta, interferon (IFN)-gamma] and chemokine (CCR2, CCR5) polymorphisms. Associations between donor polymorphisms and graft events were determined using chi-square, linear regression, and Kaplan-Meier analyses. Results. Several genotypic polymorphisms demonstrated a modest association with acute rejection, including the transforming growth factor (TGF)-beta T/C codon 10 (P = 0.027) and the CCR5 G/A 59029 (P = 0.039) genes by chi-square analysis. Notably, the presence of the T allele in the IFN-gamma gene ( + 874) demonstrated a highly significant association with biopsy-proven chronic allograft nephropathy (P < 0.008). This association remained highly significant in a multiple linear regression model that incorporated biopsy-proven acute rejection as a covariate. Conclusion. These data suggest that many of the donor polymorphisms studied in this analysis may influence a recipient's immune response to a renal allograft. However, their greatest impact may be demonstrated in long-term outcomes. C1 NIDDKD, Transplantat Branch, Bethesda, MD 20892 USA. Henry Jackson Fdn, Rockville, MD USA. Univ Wisconsin, Dept Surg, Madison, WI USA. Univ Wisconsin, Dept Med, Madison, WI USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. RP Becker, BN (reprint author), 3034 Fish Hatchery Rd,UW Nephrol,Suite B, Madison, WI 53717 USA. EM bnb@medicine.wisc.edu RI Kirk, Allan/B-6905-2012; OI Kleiner, David/0000-0003-3442-4453 FU NIAID NIH HHS [1R01 AI-45925-04]; NIDDK NIH HHS [5K24 DK616962-02] NR 37 TC 49 Z9 54 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0085-2538 J9 KIDNEY INT JI Kidney Int. PD OCT PY 2004 VL 66 IS 4 BP 1686 EP 1693 DI 10.1111/j.1523-1755.2004.00936.x PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 853IR UT WOS:000223821000045 PM 15458467 ER PT J AU Saika, S Kono-Saika, S Tanaka, T Yamanaka, O Ohnishi, Y Sato, M Muragaki, Y Ooshima, A Yoo, J Flanders, KC Roberts, AB AF Saika, S Kono-Saika, S Tanaka, T Yamanaka, O Ohnishi, Y Sato, M Muragaki, Y Ooshima, A Yoo, J Flanders, KC Roberts, AB TI Smad3 is required for dedifferentiation of retinal pigment epithelium following retinal detachment in mice SO LABORATORY INVESTIGATION LA English DT Article DE retinal pigment epithelial cell; epithelial-mesenchymal transition; transforming growth factor-beta; Smad; proliferative vitreoretinopathy; mouse ID GROWTH-FACTOR-BETA; EXPERIMENTAL PROLIFERATIVE VITREORETINOPATHY; MUSCLE ACTIN EXPRESSION; TGF-BETA; MESENCHYMAL TRANSITION; TRANSFORMING GROWTH-FACTOR-BETA-2; TARGETED DISRUPTION; SIGNALING PATHWAYS; CELL-LINE; IN-VIVO AB Retinal pigment epithelial (RPE) cells dedifferentiate and undergo epithelial-mesenchymal transition (EMT) following retinal detachment, playing a central role in formation of fibrous tissue on the detached retina and vitreous retraction (proliferative vitreoretinopathy (PVR)). We have developed a mouse model of subretinal fibrosis with implications for PVR in which retinal detachment is induced without direct damage to the RPE cells. Transforming growth factor-beta (TGF-beta) has long been implicated both in EMT of RPEs and the development of PVR. Using mice null for Smad3, a key signaling intermediate downstream of TGF-beta and activin receptors, we show that Smad3 is essential for EMT of RPE cells induced by retinal detachment. De novo accumulation of fibrous tissue derived from multilayered RPE cells was seen following experimental retinal detachment in eyes of wild type, but not Smad3-null mice. Expression of alpha-smooth muscle actin, a hallmark of EMT in this cell type, and extracellular matrix components, lumican and collagen VI, were also not observed in eyes of Smad3-null mice. Our data show that induction of PDGF-BB by Smad3-dependent TGF-beta signaling is likely an important secondary proliferative component of the disease process. The results suggest that blocking the Smad3 pathway might be beneficial in prevention/treatment of PVR. C1 Wakayama Med Univ, Dept Ophthalmol, Wakayama 6410012, Japan. Wakayama Med Univ, Dept Pathol, Wakayama 6410012, Japan. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Saika, S (reprint author), Wakayama Med Univ, Dept Ophthalmol, 811-1 Kimiidera, Wakayama 6410012, Japan. EM shizuya@wakayama-med.ac.jp NR 56 TC 80 Z9 92 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD OCT PY 2004 VL 84 IS 10 BP 1245 EP 1258 DI 10.1038/labinvest.3700156 PG 14 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 855EZ UT WOS:000223957300004 PM 15273699 ER PT J AU Saika, S Ikeda, K Yamanaka, O Sato, M Muragaki, Y Ohnishi, Y Ooshima, A Nakajima, Y Namikawa, K Kiyama, H Flanders, KC Roberts, AB AF Saika, S Ikeda, K Yamanaka, O Sato, M Muragaki, Y Ohnishi, Y Ooshima, A Nakajima, Y Namikawa, K Kiyama, H Flanders, KC Roberts, AB TI Transient adenoviral gene transfer of Smad7 prevents injury-induced epithelial-mesenchymal transition of lens epithelium in mice SO LABORATORY INVESTIGATION LA English DT Article DE lens epithelial cell; epithelial-mesenchymal transition; transforming growth factor beta; Smad; mouse ID GROWTH-FACTOR-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; LACKING SMAD3; EXPRESSION; FIBROSIS; CELLS; TRANSDIFFERENTIATION; MECHANISMS; ACTIVATION; PROTEINS AB We examined the effect of adenovirus-mediated transient expression of Smad7, an inhibitory Smad in TGFbeta/activin signaling, on injury-induced epithelial-mesenchymal transition (EMT) of lens epithelium in mice. A volume of 3 mul of adenoviral solution was injected into the right lens of adult male C57BL/6 mice (n = 56) at the time of capsular injury made using a hypodermic needle under general anesthesia. A mixture of recombinant adenovirus carrying CAG promoter-driven Cre (Cre adv) and mouse Smad7 complementary DNA (Smad7 adv) was administered to induce Smad7 expression, while control lenses were treated with Cre adv alone. After healing intervals of 2, 3, 5, and 10 days, animals were killed 2 h after labeling with bromodeoxyuridine (BrdU) and eyes were processed for histology. During healing, marked expression of Smad7 was observed in lens epithelial cells in the Smad7 adv group with loss of nuclear translocation of Smads2/3, while little Smad7 and abundant nuclear Smads2/3 were seen in cells in the Cre adv group. Lens epithelial cells in the Cre adv control group exhibited a fibroblastic appearance at days 5 and 10 and the capsular break was sealed with fibrous tissue, while Smad7 adv-treated cells around the capsular break retained their epithelial morphology and the break was not sealed. Expression of snail mRNA, and a-smooth muscle actin, lumican, and collagen VI proteins, markers of EMT, was observed in control-treated eyes, but not in cells of the Smad7 adv group at day 5 with minimal expression at day 10. Additionally, cell proliferation increased in epithelium infected with Smad7 adv consistent with suppression of injury-induced upregulation of TGFbeta1 in epithelium. We conclude that gene transfer of Smad7 in mice prevents injury-induced EMT of lens epithelial cells and sealing of the capsular break with fibrous tissue. C1 Wakayama Med Univ, Dept Ophthalmol, Wakayama 6410012, Japan. Osaka City Univ, Grad Sch Med, Dept Anat, Osaka, Japan. Wakayama Med Univ, Dept Pathol, Wakayama, Japan. Osaka City Univ, Grad Sch Med, Dept Anat Neurobiol, Osaka, Japan. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Saika, S (reprint author), Wakayama Med Univ, Dept Ophthalmol, 811-1 Kimiidera, Wakayama 6410012, Japan. EM shizuya@wakayama-med.ac.jp RI Kiyama, Hiroshi/M-8867-2014 OI Kiyama, Hiroshi/0000-0001-5963-046X NR 48 TC 57 Z9 67 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD OCT PY 2004 VL 84 IS 10 BP 1259 EP 1270 DI 10.1038/labinvest.3700151 PG 12 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 855EZ UT WOS:000223957300005 PM 15258599 ER PT J AU Hassan, R Gupta, M Kern, W Ozer, H AF Hassan, R Gupta, M Kern, W Ozer, H TI Acute myeloid leukemia following treatment with cladribine for hairy cell leukemia: A case report and review of the literature SO LEUKEMIA & LYMPHOMA LA English DT Article DE hairy cell leukemia; acute myeloid leukemia; cladribine ID 2ND MALIGNANCIES; RELAPSE; THERAPY AB The overall survival of patients with hairy cell leukemia (HCL) has significantly increased in recent years because of the development of effective treatments such as interferon alpha and purine analogs. Several reports have described an increased risk of secondary cancers, particularly solid tumors, in patients with HCL. We describe a case of a patient with HCL, who had prolonged pancytopenia after a single course of cladribine. Fifteen months after the diagnosis of HCL the patient developed acute myeloid leukemia (AML) and died shortly afterwards. Review of the literature shows few reports of acute leukemia in HCL patients. All of the 11 reported cases of leukemia in patients with HCL have been in patients who have been treated with either interferon alpha or purine analogs, and developed several years (mean 4.3 years; range 1.6 - 6.4 years) after the diagnosis of HCL. Our case is unusual in that the patient developed AML shortly (1.2 years) after the diagnosis and treatment of HCL. Further studies are needed to clarify whether leukemias seen in patients following the treatment of their HCL are incidental findings or related to HCL and its treatments. C1 Univ Oklahoma, Hlth Sci Ctr, Dept Med, Hematol Oncol Sect, Oklahoma City, OK USA. Univ Oklahoma, Hlth Sci Ctr, OU Canc Ctr, Dept Pathol, Oklahoma City, OK USA. RP Hassan, R (reprint author), NCI, Mol Biol Lab, NIH, 37 Convent Dr,Room 5116, Bethesda, MD 20892 USA. EM hassanr@mail.nih.gov NR 17 TC 7 Z9 7 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1042-8194 J9 LEUKEMIA LYMPHOMA JI Leuk. Lymphoma PD OCT PY 2004 VL 45 IS 10 BP 2149 EP 2152 DI 10.1080/10428190410001714070 PG 4 WC Oncology; Hematology SC Oncology; Hematology GA 849FH UT WOS:000223523600025 PM 15370263 ER PT J AU Matsumoto, K English, S Yoo, J Yamada, K Devasahayam, N Cook, JA Mitchell, JB Subramanian, S Krishna, MC AF Matsumoto, K English, S Yoo, J Yamada, K Devasahayam, N Cook, JA Mitchell, JB Subramanian, S Krishna, MC TI Pharmacokinetics of a triarylmethyl-type paramagnetic spin probe used in EPR oximetry SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE concentration; spin probe; continuous wave EPR; imaging; time-domain EPR imaging; overhauser-enhanced MRI; mouse ID CEREBRAL BLOOD-FLOW; CENTRAL-NERVOUS-SYSTEM; POSITRON-EMISSION-TOMOGRAPHY; TISSUE OXYGEN CONCENTRATION; MAGNETIC-RESONANCE; IN-VIVO; TECHNETIUM-99M L,L-ECD; COMPUTED-TOMOGRAPHY; FREE-RADICALS; HYPOXIA AB The paramagnetic spin probe Oxo63 is used in oximetric imaging studies based on electron paramagnetic resonance (EPR) methods by monitoring the oxygen-dependent linewidth while minimizing the contributions from self-broadening seen at high probe concentrations. Therefore, it is necessary to determine a suitable dose of Oxo63 for EPR-based oxygen mapping where the self-broadening effects are minimized while signal intensity adequate for imaging can be realized. A constant tissue concentration of spin probe would be useful to image a subject and assess changes in pO(2) over time; accumulation or elimination of the compound in specific anatomical regions could translate to and be mistaken for changes in local pO(2), especially in OMRI-based oximetry. The in vivo pharmacokinetics of the spin probe, Oxo63, after bolus and/or continuous intravenous infusion was investigated in mice using a novel approach with X-band EPR spectroscopy. The results show that the half-life in blood was 17-21 min and the clearance by excretion was 0.033-0.040 min(-1). Continuous infusion following a bolus injection of the probe was found to be effective to obtain stable plasma concentration as well as image intensity to permit reliable pO(2) estimates. Published 2004 Wiley-Liss, lnc.(dagger) C1 NCI, Radiat Biol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NIH, Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM murali@helix.nih.gov RI Yamada, Ken-ichi/E-6318-2012 NR 46 TC 25 Z9 25 U1 1 U2 4 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD OCT PY 2004 VL 52 IS 4 BP 885 EP 892 DI 10.1002/mrm.20222 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 859CB UT WOS:000224238600024 PM 15389949 ER PT J AU Bektas, A Schurman, SH Sharov, AA Carter, MG Dietz, HC Francomano, CA AF Bektas, A Schurman, SH Sharov, AA Carter, MG Dietz, HC Francomano, CA TI Klotho gene variation and expression in 20 inbred mouse strains SO MAMMALIAN GENOME LA English DT Article ID TRANSCRIPTS ENCODING MEMBRANE; HUMAN FIBROBLASTS; BETA-GLUCOSIDASE; TELOMERE LENGTH; PROTEIN; MICE; HYDROLASE; STRESS AB A defect in klotho gene expression in the mouse results in a syndrome that resembles human aging, with greatly shortened lifespan, arteriosclerosis, and defective hearing. In an effort to find functional murine variants of klotho, we sequenced the gene and examined renal expression of the secreted and membrane-bound Klotho isoforms from 16 laboratory-derived and 4 wild-derived inbred strains. Among the laboratory-derived strains, no sequence variation was found in any of the exons or intron-exon boundaries. Among the wild-derived strains, we found 45 sequence variants with six resulting in amino acid substitutions. One wild-derived strain, SPRET/Ei, had four amino acid substitutions and higher levels of the membrane form and total klotho mRNA. In addition, the membrane to secreted klotho expression ratio was elevated in three wild-derived strains with amino acid substitutions. Interestingly, SPRET/Ei mice have longer lifespans, decreased atherosclerosis risk factors, and better hearing than almost all other mouse strains. C1 NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. Howard Hughes Med Inst, Baltimore, MD 21205 USA. RP Bektas, A (reprint author), NIA, Genet Lab, NIH, 333 Cassell Dr,Suite 3000, Baltimore, MD 21224 USA. EM bektasar@grc.nia.nih.gov RI Carter, Mark/B-5089-2010; OI Schurman, Shepherd/0000-0002-9133-7906 NR 34 TC 10 Z9 10 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0938-8990 J9 MAMM GENOME JI Mamm. Genome PD OCT PY 2004 VL 15 IS 10 BP 759 EP 767 DI 10.1007/s00335-004-2375-3 PG 9 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 856OH UT WOS:000224054000002 PM 15520879 ER PT J AU Smoak, KA Cidlowski, JA AF Smoak, KA Cidlowski, JA TI Mechanisms of glucocorticoid receptor signaling during inflammation SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Review DE glucocorticoids; glucocorticoid receptor (GR); NF-kappa B; AP-1 ID NF-KAPPA-B; NUCLEAR HORMONE-RECEPTORS; CREB-BINDING-PROTEIN; MOLECULAR-MECHANISMS; DNA-BINDING; TRANSCRIPTIONAL ACTIVATION; COACTIVATOR INTERACTIONS; INCREASED EXPRESSION; INDUCED APOPTOSIS; MULTIPLE-MYELOMA AB Glucocorticoids are among the most widely prescribed anti-inflammatory drugs. They act by binding to the glucocorticoid receptor (GR) that, upon activation, translocates to the nucleus and either stimulates or inhibits gene expression. GR inhibition of many proinflammatory response genes occurs through induction of the synthesis of anti-inflammatory proteins as well as through repression of proinflammatory transcription factors, such as nuclear factor-kappaB (NF-kappaB) or activator protein-1 (AP-1). In this review, we discuss the molecular mechanisms underlying GR inhibition of inflammatory responses, with an emphasis on repression of NF-kappaB and AP-1 and their respective signaling pathways. Published by Elsevier Ireland Ltd. C1 NIEHS, Dept Hlth & Human Serv, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Dept Hlth & Human Serv, Lab Signal Transduct, NIH, Bldg 101, Res Triangle Pk, NC 27709 USA. EM cidlowski@niehs.nih.gov NR 75 TC 197 Z9 218 U1 1 U2 22 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD OCT-NOV PY 2004 VL 125 IS 10-11 BP 697 EP 706 DI 10.1016/j.mad.2004.06.010 PG 10 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 877ZM UT WOS:000225614800006 PM 15541765 ER PT J AU Iordanescu, G Summers, RM AF Iordanescu, G Summers, RM TI Reduction of false positives on the rectal tube in computer-aided detection for CT colonography SO MEDICAL PHYSICS LA English DT Article; Proceedings Paper CT 89th Scientific Assembly and Annual Meeting of the Radiological-Society-of-North-America (RSNA) CY NOV 30-DEC 05, 2003 CL CHICAGO, IL SP Radiol Soc N Amer DE CT; rectal tube segmentation; colon; CTC; colon cancer; image processing ID POLYP DETECTION; FEASIBILITY; DIAGNOSIS AB Purpose: To eliminate false-positive (FP) polyp detections on the rectal tube (RT) in CT colonography (CTC) computer-aided detection (CAD). Methods: We use a three-stage approach to detect the RT: detect the RT shaft, track the tube to the tip and label all the voxels that belong to the RT. We applied our RT detection algorithm on a CTC dataset consisting of 80 datasets (40 patients scanned in both prone and supine positions). Two different types of RTs were present, characterized by differences in shaft/bulb diameters, wall intensities, and shape of tip. Results: The algorithm detected 90% of RT shafts and completely tracked 72% of them. We labeled all the voxels belonging to the completely tracked RTs (72%) and in 11 out of 80 (14%) cases the RT voxels were partially labeled. We obtained a 9.2% reduction of the FPs in the initial polyp candidates' population, and a 7.9% reduction of the FPs generated by our CAD system. None of the true-positive detections were mislabeled. Conclusions: The algorithm detects the RTs with good accuracy, is robust with respect to the two different types of RT used in our study, and is effective at reducing the number of RT FPs reported by our CAD system. C 2004 American Association of Physicists in Medicine. C1 NIH, Dept Radiol, Bethesda, MD 20892 USA. RP Summers, RM (reprint author), NIH, Dept Radiol, Bldg 10,Room 1C660,10 Ctr Dr MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov NR 16 TC 17 Z9 17 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD OCT PY 2004 VL 31 IS 10 BP 2855 EP 2862 DI 10.1118/1.1790131 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 865ZR UT WOS:000224743200020 ER PT J AU Jeong, S Han, M Lee, H Kim, M Kim, J Nicol, CJ Kim, BH Choi, JH Nam, KH Oh, GT Yoon, M AF Jeong, S Han, M Lee, H Kim, M Kim, J Nicol, CJ Kim, BH Choi, JH Nam, KH Oh, GT Yoon, M TI Effects of fenofibrate on high-fat diet-induced body weight gain and adiposity in female C57BL/6J mice SO METABOLISM-CLINICAL AND EXPERIMENTAL LA English DT Article ID ACTIVATED RECEPTOR-ALPHA; PPAR-GAMMA ACTIVATORS; RETINOID-X-RECEPTOR; ESTROGEN-RECEPTOR; RESPONSE ELEMENT; GENE-EXPRESSION; FOOD-INTAKE; RATS; METABOLISM; OBESITY AB Our previous study suggested that fenofibrate affects obesity and lipid metabolism in a sexually dimorphic manner in part through the differential activation of hepatic peroxisome proliferator-activated receptor alpha (PPARalpha) in male and female C57BL/6J mice. To determine whether fenofibrate reduces body weight gain and adiposity in female sham-operated (Sham) and ovariectomized (OVX) C57BL/6J mice, the effects of fenofibrate on not only body weight, white adipose tissue (WAT) mass, and food intake, but also the expression of both leptin and PPARa target genes were measured. Compared to their respective low-fat diet-fed controls, both Sham and OVX mice exhibited increases in body weight and WAT mass when fed a high-fat diet. Fenofibrate treatment decreased body weight gain and WAT mass in OVX, but not in Sham mice. Furthermore, fenofibrate increased the mRNA levels of PPARalpha target genes encoding peroxisomal enzymes involved in fatty acid beta-oxidation, and reduced apolipoprotein C-III (apo C-III) mRNA, all of which were expressed at higher levels in OVX compared to Sham mice. However, leptin mRNA levels were found to positively correlate with WAT mass, and food intake was not changed in either OVX or Sham mice following fenofibrate treatment. These results suggest that fenofibrate differentially regulates body weight and adiposity due in part to differences in PPARalpha activation, but not to differences in leptin production, between female OVX and Sham mice. (C) 2004 Elsevier Inc. All rights reserved. C1 Mokwon Univ, Dept Life Sci, Taejon 302729, South Korea. Korea Res Inst Biosci & Biotechnol, Genet Resouces Ctr, Taejon, South Korea. Natl Inst Hlth, Lab Metab, Canc Res Ctr, Bethesda, MD USA. RP Yoon, M (reprint author), Mokwon Univ, Dept Life Sci, Taejon 302729, South Korea. NR 33 TC 35 Z9 35 U1 0 U2 5 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0026-0495 J9 METABOLISM JI Metab.-Clin. Exp. PD OCT PY 2004 VL 53 IS 10 BP 1284 EP 1289 DI 10.1016/j.metabol.2004.05.003 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 861MT UT WOS:000224421500006 PM 15375783 ER PT J AU von Stebut, E Udey, MC AF von Stebut, E Udey, MC TI Requirements for Th1-dependent immunity against infection with Leishmania major SO MICROBES AND INFECTION LA English DT Review DE Leishmania; dendritic cells; Th1; IL-12; macrophages ID EXPERIMENTAL CUTANEOUS LEISHMANIASIS; DENDRITIC CELLS; T-CELL; RESISTANT MICE; SUSCEPTIBLE MICE; TH1 RESPONSES; C57BL/6 MICE; IFN-GAMMA; INTERLEUKIN-12; IL-12 AB Protective immunity against cutaneous leishmaniasis is dependent on the induction of Thl/Tcl immune responses resulting in efficient parasite elimination. In this review, the mechanisms leading to protection are discussed with special focus on the role of Leishmania major-infected dendritic cells (DC) in induction of Thl-dependent immunity. Murine strain-dependent differences between DC derived from Leishmania-susceptible as compared to resistant mice are highlighted. (c) 2004 Elsevier SAS. All rights reserved. C1 Univ Mainz, Dept Dermatol, D-55101 Mainz, Germany. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP von Stebut, E (reprint author), Univ Mainz, Dept Dermatol, Langenbeckstr 1, D-55101 Mainz, Germany. EM vonstebu@mail.uni-mainz.de NR 45 TC 52 Z9 52 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD OCT PY 2004 VL 6 IS 12 BP 1102 EP 1109 DI 10.1016/j.micinf.2004.05.024 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 017NL UT WOS:000235700200008 PM 15380780 ER PT J AU Voyich, JM Musser, JM DeLeo, FR AF Voyich, JM Musser, JM DeLeo, FR TI Streptococcus pyogenes and human neutrophils: a paradigm for evasion of innate host defense by bacterial pathogens SO MICROBES AND INFECTION LA English DT Review DE polymorphonuclear leukocytes; neutrophils; Streptococcus pyogenes; phagocytosis; apoptosis; innate immunity ID GROUP-A STREPTOCOCCI; EXTRACELLULAR CYSTEINE PROTEASE; POLYMORPHONUCLEAR LEUKOCYTES; SURFACE-PROTEINS; IMMUNOGLOBULIN-G; VIRULENCE FACTOR; MOLECULAR-BASIS; OPSONOPHAGOCYTOSIS; SPEB; PHAGOCYTOSIS AB Human polymorphonuclear leukocytes (PMNs) are the first line of defense against invading microorganisms. Although most invading bacteria are eliminated by PMNs, some have evolved complex strategies to prevent normal PMN function. This review focuses on the interaction of human PMNs with Streptococcus pyogenes as a paradigm for successful pathogen evasion mechanisms. (c) 2004 Published by Elsevier SAS. C1 NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Baylor Coll Med, Dept Pathol, Ctr Human Bacterial Pathogenesis Res, Houston, TX USA. RP DeLeo, FR (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 NR 31 TC 42 Z9 44 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD OCT PY 2004 VL 6 IS 12 BP 1117 EP 1123 DI 10.1016/j.micinf.2004.05.022 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 017NL UT WOS:000235700200010 PM 15380782 ER PT J AU Mattu, R Sorbara, L Filie, AC Little, R Wilson, W Raffeld, M Abati, A AF Mattu, R Sorbara, L Filie, AC Little, R Wilson, W Raffeld, M Abati, A TI Utilization of polymerase chain reaction on archival cytologic material: a comparison with fresh material with special emphasis on cerebrospinal fluids SO MODERN PATHOLOGY LA English DT Article DE cytology; slide scrape lysates; polymerase chain reaction ID FINE-NEEDLE-ASPIRATION; EPSTEIN-BARR-VIRUS; LYMPHOPROLIFERATIVE DISORDERS; LEPTOMENINGEAL INVOLVEMENT; SMEARS; CLONALITY; DIAGNOSIS; MICRODISSECTION; LYMPHOMA; LEUKEMIA AB Use of the polymerase chain reaction (PCR) for the detection of B- and T-cell clonality, Epstein-Barr virus (EBV) and Human Herpes Virus 8 (HHV 8) infection is gaining increasing importance as a diagnostic modality. These tests are usually performed on fresh specimens. There are instances when fresh material is not available and there is a clinical utility for the performance of PCR on archival material via slide scrape lysates (SSL). However, the suitability of archival material may be questioned. Records were searched for all archival cytology cases submitted for SSL molecular diagnostics tests since 1998. Results for each case were analyzed for PCR amplification status and individual test results. A randomly chosen control group of equivalent cytologic samples submitted fresh was evaluated for comparison of amplification status. In all, 241 PCR runs were performed on SSL of archival material from 112 cytologic samples (89 cerebrospinal fluids (CSFs), 13 fine-needle aspirates (FNAs), 10 effusions). Out of these samples, 95 (85%) had amplifiable DNA, as assessed by a positive reaction for glyceraldehyde phosphate dehydrogenase (GAPDH). For the control group, 320 PCR runs were performed on 112 fresh cytologic samples (89 CSFs, 13 FNAs, 10 effusions). In total, 102 samples (91%) had amplifiable DNA. There was no statistical difference in the amplification yield between the two groups (P=0.2177). A morphologic review of 16 of the 17 SSL archival cytologic cases that did not show amplification revealed 11/16 to be of sparse cellularity. Molecular diagnostic tests are performed routinely on fresh cytologic samples with excellent results. At times critical decisions on patient care may need to be made when fresh tissue is not available for molecular diagnostic tests. SSL of archival cytologic material can be used with excellent results for molecular diagnostic tests when fresh material is not available or when the cytologic diagnosis needs further clarification. C1 NCI, Cytopathol Sect, Pathol Lab, Bethesda, MD 20892 USA. HIV & AIDS Malignancy Branch, Bethesda, MD USA. NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Abati, A (reprint author), NCI, Cytopathol Sect, Pathol Lab, Bldg 10,Rm 2A 19,10 Ctr Dr, Bethesda, MD 20892 USA. EM abatia@mail.nih.gov NR 24 TC 8 Z9 8 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0893-3952 J9 MODERN PATHOL JI Mod. Pathol. PD OCT PY 2004 VL 17 IS 10 BP 1295 EP 1301 DI 10.1038/modpathol.3800185 PG 7 WC Pathology SC Pathology GA 857CU UT WOS:000224094600016 PM 15195110 ER PT J AU Urtz, N Olivera, A Bofill-Cardona, E Csonga, R Billich, A Mechtcheriakova, D Bornancin, F Woisetschlager, M Rivera, J Baumruker, T AF Urtz, N Olivera, A Bofill-Cardona, E Csonga, R Billich, A Mechtcheriakova, D Bornancin, F Woisetschlager, M Rivera, J Baumruker, T TI Early activation of sphingosine kinase in mast cells and recruitment to Fc epsilon RI are mediated by its interaction with Lyn kinase SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID AFFINITY IGE RECEPTOR; CALCIUM MOBILIZATION; MOLECULAR-CLONING; MEMBRANE DOMAINS; TYROSINE KINASES; SPHINGOSINE-1-PHOSPHATE; PROTEIN; GROWTH; DEGRANULATION; 1-PHOSPHATE AB Sphingosine kinase has been recognized as an essential signaling molecule that mediates the intracellular conversion of sphingosine to sphingosine-1-phosphate. In mast cells, induction of sphingosine kinase and generation of sphingosine-1-phosphate have been linked to the initial rise in Ca2+, released from internal stores, and to degranulation. These events either precede or are concomitant with the activation of phospholipase C-gamma and the generation of inositol trisphosphate. Here we show that sphingosine kinase type 1 (SPHK1) interacts directly with the tyrosine kinase Lyn and that this interaction leads to the recruitment of this lipid kinase to the high-affinity receptor for immunoglobulin E (FcepsilonRI). The interaction of SPHK1 with Lyn caused enhanced lipid and tyrosine kinase activity. After FcepsilonRI triggering, enhanced sphingosine kinase activity was associated with FcepsilonRI in sphingolipid-enriched rafts of mast cells. Bone marrow-derived mast cells from Lyn(-/-) mice, compared to syngeneic wild-type cells, were defective in the initial induction of SPHK1 activity, and the defect was overcome by retroviral Lyn expression. These findings position the activation of SPHK1 as an FcepsilonRI proximal event. C1 Novartis Inst Biomed Res, A-1235 Vienna, Austria. NIH, Mol Immunol & Inflammat Branch, Bethesda, MD USA. RP Baumruker, T (reprint author), Novartis Inst Biomed Res, Brunner Str 59, A-1235 Vienna, Austria. EM thomas.baumruker@pharma.novartis.com NR 51 TC 54 Z9 55 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2004 VL 24 IS 19 BP 8765 EP 8777 DI 10.1128/MCB.24.19.8765-8777.2004 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 855QZ UT WOS:000223990100040 PM 15367693 ER PT J AU Gould, DB Miceli-Libby, L Savinova, OV Torrado, M Tomarev, SI Smith, RS John, SWM AF Gould, DB Miceli-Libby, L Savinova, OV Torrado, M Tomarev, SI Smith, RS John, SWM TI Genetically increasing Myoc expression supports a necessary pathologic role of abnormal proteins in glaucoma SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID OPEN-ANGLE GLAUCOMA; TRABECULAR MESHWORK CELLS; GLUCOCORTICOID RESPONSE PROTEIN; INDUCED OCULAR HYPERTENSION; BALTIMORE EYE SURVEY; INTRAOCULAR-PRESSURE; OPTIC-NERVE; MYOC/TIGR GENE; LOCALIZATION; TIGR/MYOC AB Despite the importance of MYOC for glaucoma, the protein's normal function(s) and the pathogenic mechanism(s) of MYOC mutations are not clear. Elevated intraocular pressure (IOP) and glaucoma are sometimes induced by corticosteroids, and corticosteroid use can result in substantially increased MYOC expression. It has been suggested, therefore, that steroid-induced MYOC protein levels cause steroid-induced glaucoma and that protein level-increasing mutations in MYOC contribute to glaucoma not associated with steroid use. A causative role of elevated MYOC levels in steroid-induced glaucoma is controversial, however, and it is not clear if elevated MYOC levels can result in IOP elevation. To directly test if increased levels of MYOC can cause IOP elevation and glaucoma, we generated bacterial artificial chromosome transgenic mice that overexpress Myoc at a level similar to that induced by corticosteroid use. These mice do not develop elevated IOP or glaucoma. Our present findings, along with the absence of glaucoma in mice completely lacking MYOC, show that changing the level of MYOC is not pathogenic (from absent to approximately 15 times normal). These findings suggest that noncoding sequence variants are unlikely to influence glaucoma and that disease pathogenesis in primary open-angle glaucoma patients is dependent upon the expression of abnormal mutant proteins. This work does not support a causative role for increased MYOC levels or the MYOC gene in steroid-induced glaucoma. C1 Howard Hughes Med Inst, Bar Harbor, ME USA. Jackson Lab, Bar Harbor, ME USA. NEI, Sect Mol Mech Glaucoma, Lab Mol & Dev Biol, NIH, Bethesda, MD 20892 USA. Tufts Univ, Sch Med, Dept Ophthalmol, Boston, MA 02111 USA. RP John, SWM (reprint author), Howard Hughes Med Inst, 600 Main St, Bar Harbor, ME USA. EM swmj@jax.org RI Torrado, Mario/A-4889-2010 OI Torrado, Mario/0000-0001-9762-7018 FU NCI NIH HHS [CA34196, P30 CA034196]; NEI NIH HHS [EY11721, R01 EY011721, R29 EY011721] NR 53 TC 68 Z9 73 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2004 VL 24 IS 20 BP 9019 EP 9025 DI 10.1128/MCB.24.20.9019-9025.2004 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 859CG UT WOS:000224239100020 PM 15456875 ER PT J AU Buchholz, DR Tomita, A Fu, LZ Paul, BD Shi, YB AF Buchholz, DR Tomita, A Fu, LZ Paul, BD Shi, YB TI Transgenic analysis reveals that thyroid hormone receptor is sufficient to mediate the thyroid hormone signal in frog metamorphosis SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID XENOPUS-LAEVIS METAMORPHOSIS; ACID-BINDING PROTEIN; IN-VIVO ANALYSIS; COREPRESSOR COMPLEX; TRANSCRIPTIONAL REGULATION; POSTNATAL-DEVELOPMENT; BETA-RECEPTOR; TR-BETA; POSTEMBRYONIC DEVELOPMENT; AMPHIBIAN METAMORPHOSIS AB Thyroid hormone (T3) has long been known to be important for vertebrate development and adult organ function. Whereas thyroid hormone receptor (TR) knockout and transgenic studies of mice have implicated TR involvement in mammalian development, the underlying molecular bases for the resulting phenotypes remain to be determined in vivo, especially considering that T3 is known to have both genomic, i.e., through TRs, and nongenomic effects on cells. Amphibian metamorphosis is an excellent model for studying the role of TR in vertebrate development because of its total dependence on T3. Here we investigated the role of TR in metamorphosis by developing a dominant positive mutant thyroid hormone receptor (dpTR). In the frog oocyte transcription system, dpTR bound a T3-responsive promoter and activated the promoter independently of T3. Transgenic expression of dpTR under the control of a heat shock-inducible promoter in premetamorphic tadpoles led to precocious metamorphic transformations. Molecular analyses showed that dpTR induced metamorphosis by specifically binding to known T3 target genes, leading to increased local histone acetylation and gene activation, similar to T3-bound TR during natural metamorphosis. Our experiments indicated that the metamorphic role of T3 is through genomic action of the hormone, at least on the developmental parameters tested. They further provide the first example where TR is shown to mediate directly and sufficiently these developmental effects of T3 in individual organs by regulating target gene expression in these organs. C1 NICHD, LGRD, Sect Mol Morphogenesis, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHD, LGRD, Sect Mol Morphogenesis, NIH, Bldg 18T,Rm 106, Bethesda, MD 20892 USA. EM shi@helix.nih.gov NR 65 TC 80 Z9 81 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2004 VL 24 IS 20 BP 9026 EP 9037 DI 10.1128/MCB.24.20.9026-9037.2004 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 859CG UT WOS:000224239100021 PM 15456876 ER PT J AU Farina, A Hattori, M Qin, J Nakatani, Y Minato, N Ozato, K AF Farina, A Hattori, M Qin, J Nakatani, Y Minato, N Ozato, K TI Bromodomain protein Brd4 binds to GTPase-activating SPA-1, modulating its activity and subcellular localization SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID EFFECT HOMEOTIC GENE; FAMILY PROTEINS; LIVING CELLS; RAP1; RAS; CAMP; CHROMATIN; COMPLEX; TRANSLOCATION; ASSOCIATION AB Brd4 is a mammalian protein that contains a double bromodomain. It binds to chromatin and regulates cell cycle progression at multiple stages. By immunopurification and mass spectrometry, we identified a Rap GTPase-activating protein (GAP), signal-induced proliferation-associated protein 1 (SPA-1), as a factor that interacts with Brd4. SPA-1 localizes to the cytoplasm and to a lesser degree in the nucleus, while Brd4 resides in the nucleus. Bifluorescence complementation revealed that Brd4 and SPA-1 interact with each other in the nucleus of living cells. Supporting the functional importance of the interaction, Brd4 enhanced Rap GAP activity of SPA-1. Furthermore ectopic expression of SPA-1 and Brd4 redirected subcellular localization of the partner and disrupted normal cell cycle progression. These effects were, however, reversed by coexpression of the two proteins, indicating that a proper balance between Brd4 and SPA-1 in G, is required for cell division. This work reveals a novel link between Brd4 and a GTPase-dependent mitogenic signaling pathway. C1 NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. Kyoto Univ, Grad Sch Med, Dept Immunol & Cell Biol, Kyoto, Japan. Baylor Coll Med, Dept Biochem & Cell Biol, Houston, TX 77030 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. EM ozatok@nih.gov NR 42 TC 41 Z9 42 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2004 VL 24 IS 20 BP 9059 EP 9069 DI 10.1128/MCB.24.20.9059-9069.2004 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 859CG UT WOS:000224239100024 PM 15456879 ER PT J AU Hassan, MQ Javed, A Morasso, MI Karlin, J Montecino, M van Wijnen, AJ Stein, GS Stein, JL Lian, JB AF Hassan, MQ Javed, A Morasso, MI Karlin, J Montecino, M van Wijnen, AJ Stein, GS Stein, JL Lian, JB TI Dlx3 transcriptional regulation of osteoblast differentiation: Temporal recruitment of Msx2 Dlx3 an Dlx5 homeodomain proteins to chromatin of the osteocalcin gene SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID TISSUE-SPECIFIC TRANSCRIPTION; RNA-POLYMERASE-II; BONE SIALOPROTEIN; HOMEOBOX GENE; TRICHODENTOOSSEOUS SYNDROME; CRANIOFACIAL DEVELOPMENT; PROGRESSIVE DEVELOPMENT; FUNCTIONAL ANTAGONISM; MOUSE KERATINOCYTES; RETROVIRUS VECTOR AB Genetic studies show that Msx2 and Dlx5 homeodomain (HD) proteins support skeletal development, but null mutation of the closely related Dlx3 gene results in early embryonic lethality. Here we find that expression of Dlx3 in the mouse embryo is associated with new bone formation and regulation of osteoblast differentiation. Dlx3 is expressed in osteoblasts, and overexpression of Dlx3 in osteoprogenitor cells promotes, while specific knock-down of Dlx3 by RNA interference inhibits, induction of osteogenic markers. We characterized gene regulation by Dlx3 in relation to that of Msx2 and Dlx5 during osteoblast differentiation. Chromatin immunoprecipitation assays revealed a molecular switch in HD protein association with the bone-specific osteocalcin (OC) gene. The transcriptionally repressed OC gene was occupied by Msx2 in proliferating osteoblasts, while Dlx3, Dlx5, and Runx2 were recruited postproliferatively to initiate transcription. Dlx5 occupancy increased over Dlx3 in mature osteoblasts at the mineralization stage of differentiation, coincident with increased RNA polymerase II occupancy. Dlx3 protein-DNA interactions stimulated OC promoter activity, while Dlx3-Runx2 protein-protein interaction reduced Runx2-mediated transcription. Deletion analysis showed that the Dlx3 interacting domain of Runx2 is from amino acids 376 to 432, which also include the transcriptionally active subnuclear targeting sequence (376 to 432). Thus, we provide cellular and molecular evidence for Dlx3 in regulating osteoprogenitor cell differentiation and for both positive and negative regulation of gene transcription. We propose that multiple HD proteins in osteoblasts constitute a regulatory network that mediates development of the bone phenotype through the sequential association of distinct HD proteins with promoter regulatory elements. C1 Univ Massachusetts, Sch Med, Dept Cell Biol, Worcester, MA 01655 USA. Univ Massachusetts, Sch Med, Ctr Canc, Worcester, MA USA. NIAMSD, Dev Skin Biol Unit, NIH, Bethesda, MD USA. Univ Concepcion, Dept Mol Biol, Concepcion, Chile. RP Lian, JB (reprint author), Univ Massachusetts, Sch Med, Dept Cell Biol, 55 Lake Ave,N, Worcester, MA 01655 USA. EM jane.lian@umassmed.edu OI Javed, Amjad/0000-0002-0847-8266 FU NIAMS NIH HHS [AR39588, P01 AR048818, P01 AR48818, R01 AR039588, R01 AR049069]; NIDCR NIH HHS [DE12528, R01 DE012528, R37 DE012528] NR 91 TC 173 Z9 179 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD OCT PY 2004 VL 24 IS 20 BP 9248 EP 9261 DI 10.1128/MCB.24.20.9248-9261.2004 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 859CG UT WOS:000224239100039 PM 15456894 ER PT J AU Achaz, G Palmer, S Kearney, M Maldarelli, F Mellors, JW Coffin, JM Wakeley, J AF Achaz, G Palmer, S Kearney, M Maldarelli, F Mellors, JW Coffin, JM Wakeley, J TI A robust measure of HIV-1 population turnover within chronically infected individuals SO MOLECULAR BIOLOGY AND EVOLUTION LA English DT Article DE intra-host HIV evolution; effective population size; chronically infected individual ID IMMUNODEFICIENCY-VIRUS TYPE-1; IN-VIVO; GENETIC DRIFT; METAPOPULATION MODELS; SEQUENCE ALIGNMENT; GENERATION TIME; EFFECTIVE SIZE; DNA-SEQUENCES; MUTATION-RATE; EVOLUTION AB A simple nonparameteric test for population structure was applied to temporally spaced samples of HIV-1 sequences from the gag-pol region within two chronically infected individuals. The results show that temporal structure can be detected for samples separated by about 22 months or more. The performance of the method, which was originally proposed to detect geographic structure, was tested for temporally spaced samples using neutral coalescent simulations. Simulations showed that the method is robust to variation in samples sizes and mutation rates, to the presence/absence of recombination, and that the power to detect temporal structure is high. By comparing levels of temporal structure in simulations to the levels observed in real data, we estimate the effective intra-individual population size of HIV-1 to be between 10(3) and 10(4) viruses, which is in agreement with some previous estimates. Using this estimate and a simple measure of sequence diversity, we estimate an effective neutral mutation rate of about 5 x 10(-6) per site per generation in the gag-pol region. The definition and interpretation of estimates of such "effective" population parameters are discussed. C1 Harvard Univ, Dept Organ & Evolutionary Biol, Cambridge, MA 02138 USA. NIH, HIV Drug Resistance Program, NCI, Frederick, MD USA. Univ Pittsburgh, Dept Infect Dis, Pittsburgh, PA 15260 USA. RP Achaz, G (reprint author), Harvard Univ, Dept Organ & Evolutionary Biol, Cambridge, MA 02138 USA. EM gachaz@oeb.harvard.edu FU NCI NIH HHS [R01-CA089441] NR 55 TC 75 Z9 75 U1 3 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0737-4038 J9 MOL BIOL EVOL JI Mol. Biol. Evol. PD OCT PY 2004 VL 21 IS 10 BP 1902 EP 1912 DI 10.1093/molbev/msh196 PG 11 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 855ZJ UT WOS:000224013100009 PM 15215321 ER PT J AU Snapp, EL Iida, T Frescas, D Lippincott-Schwartz, J Lilly, MA AF Snapp, EL Iida, T Frescas, D Lippincott-Schwartz, J Lilly, MA TI The fusome mediates intercellular endoplasmic reticulum connectivity in Drosophila ovarian cysts SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID LIVING CELLS; OOCYTE DIFFERENTIATION; PROTEIN; OOGENESIS; GERMLINE; TRANSPORT; SPECTRIN; SPECIFICATION; MELANOGASTER; DIFFUSION AB Drosophila ovarian cysts arise through a series of four synchronous incomplete mitotic divisions. After each round of mitosis, a membranous organelle, the fusome, grows along the cleavage furrow and the remnants of the mitotic spindle to connect all cystocytes in a cyst. The fusome is essential for the pattern and synchrony of the mitotic cyst divisions as well as oocyte differentiation. Using live cell imaging, greenfluorescent protein-tagged proteins, and photobleaching techniques, we demonstrate that fusomal endomembranes are part of a single continuous endoplasmic reticulum (ER) that is shared by all cystocytes in dividing ovarian cysts. Membrane and lumenal proteins of the common ER freely and rapidly diffuse between cystocytes. The fusomal ER mediates intercellular ER connectivity by linking the cytoplasmic ER membranes of all cystocytes within a cyst. Before entry into meiosis and onset of oocyte differentiation (between region 1 and region 2A), ER continuity between cystocytes is lost. Furthermore, analyses of hts and Dhc64c mutants indicate that intercellular ER continuity within dividing ovarian cysts requires the fusome cytoskeletal component and suggest a possible role for the common ER in synchronizing mitotic cyst divisions. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Lilly, MA (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM mlilly@helix.nih.gov OI Lilly, Mary/0000-0003-1564-619X NR 47 TC 61 Z9 64 U1 0 U2 4 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD OCT PY 2004 VL 15 IS 10 BP 4512 EP 4521 DI 10.1091/mbc.E04-06-0475 PG 10 WC Cell Biology SC Cell Biology GA 858AJ UT WOS:000224162200015 PM 15292454 ER PT J AU Soriano, JV Liu, NF Gao, Y Yao, ZJ Ishibashi, T Underhill, C Burke, TR Bottaro, DP AF Soriano, JV Liu, NF Gao, Y Yao, ZJ Ishibashi, T Underhill, C Burke, TR Bottaro, DP TI Inhibition of angiogenesis by growth factor receptor bound protein 2-Src homology 2 domain binding antagonists SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAYS; GRB2 SH2 DOMAIN; PHOSPHATE-CONTAINING LIGANDS; ALDRICH-SYNDROME PROTEIN; ACTIN-BASED MOTILITY; ENDOTHELIAL-CELLS; TYROSINE KINASE; ADAPTER PROTEINS; TUBE FORMATION; POTENT AB Growth factor receptor bound protein 2 (Grb2) is an intracellular adaptor protein that participates in the signal transduction cascades of several angiogenic factors, including hepatocyte growth factor, basic fibroblast growth factor, and vascular endothelial growth factor. We described previously the potent blockade of hepatocyte growth factor-stimulated cell motility, matrix invasion, and epithelial tubulogenesis by synthetic Grb2-Src homology 2 (SH2) domain binding antagonists. Here, we show that these binding antagonists block basic morphogenetic events required for angiogenesis, including hepatocyte growth factor-, vascular endothelial growth factor-, and basic fibroblast growth factor-stimulated endothelial cell proliferation and migration, as well as phorbol 12-myristate 13-acetate-stimulated endothelial cell migration and matrix invasion. The Grb2-SH2 domain binding antagonists also impair angiogenesis in vitro, as shown by the inhibition of cord formation by macrovascular endothelial cells on Matrigel. We further show that a representative compound inhibits angiogenesis in vivo as measured using a chick chorioallantoic membrane assay. These results suggest that Grb2 is an important mediator of key proangiogenic events, with potential application to pathologic conditions where neovascularization contributes to disease progression. In particular, the well-characterized role of Grb2 in signaling cell cycle progression together with our present findings suggests that Grb2-SH2 domain binding antagonists have the potential to act as anticancer drugs that target both tumor and vascular cell compartments. C1 NCI, Canc Res Ctr, Urol Oncol Branch, Lab Cellular & Mol Biol,NIH, Bethesda, MD 20892 USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Social Insurance Cent Gen Hosp, Dept Otolaryngol, Tokyo, Japan. Georgetown Univ, Dept Cell Biol, Washington, DC USA. RP Bottaro, DP (reprint author), NCI, Canc Res Ctr, Urol Oncol Branch, Lab Cellular & Mol Biol,NIH, Bldg 10,Room 2B47,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dbottaro@helix.nih.gov RI Bottaro, Donald/F-8550-2010; Burke, Terrence/N-2601-2014; Yao, Zhu-Jun/E-7635-2015 OI Bottaro, Donald/0000-0002-5057-5334; NR 69 TC 25 Z9 26 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD OCT PY 2004 VL 3 IS 10 BP 1289 EP 1299 PG 11 WC Oncology SC Oncology GA 862KB UT WOS:000224488400013 PM 15486196 ER PT J AU Loganzo, F Hari, M Annable, T Tan, XZ Morilla, DB Musto, S Zask, A Kaplan, J Minnick, AA May, MK Ayral-Kaloustian, S Poruchynsky, MS Fojo, T Greenberger, LM AF Loganzo, F Hari, M Annable, T Tan, XZ Morilla, DB Musto, S Zask, A Kaplan, J Minnick, AA May, MK Ayral-Kaloustian, S Poruchynsky, MS Fojo, T Greenberger, LM TI Cells resistant to HTI-286 do not overexpress P-glycoprotein but have reduced drug accumulation and a point mutation in alpha-tubulin SO MOLECULAR CANCER THERAPEUTICS LA English DT Article; Proceedings Paper CT 94th Annual Meeting of the American-Association-for-Cancer-Research CY JUL 11-14, 2003 CL WASHINGTON, DC SP Amer Assoc Canc Res ID HAMSTER OVARY CELLS; BETA-TUBULIN; MULTIDRUG-RESISTANCE; IN-VITRO; TRIPEPTIDE HEMIASTERLIN; SYNTHETIC ANALOG; CANCER; MECHANISMS; MICROTUBULES; PACLITAXEL AB HTI-286, a synthetic analogue of hemiasterlin, depolymerizes microtubules and is proposed to bind at the Vinca peptide site in tubulin. It has excellent in vivo antitumor activity in human xenograft models, including tumors that express P-glycoprotein, and is in phase 11 clinical evaluation. To identify potential mechanisms of resistance induced by HTI-286, KB-3-1 epidermoid carcinoma cells were exposed to increasing drug concentrations. When maintained in 4.0 nmol/L HTI-286, cells had 12-fold resistance to HTI-286. Cross-resistance was observed to other Vinca peptide-binding agents, including hemiasterlin A, dolastatin-10, and vinblastine (7- to 28-fold), and DNA-damaging drugs, including Adriamycin and mitoxantrone (16- to 57-fold), but minimal resistance was seen to taxanes, epothilones, or colchicine (1- to 4-fold). Resistance to HTI-286 was retained when KB-HTI-resistant cells were grown in athymic mice. Accumulation of [H-3]HTI-286 was lower in cells selected in intermediate (2.5 nmol/L) and high (4.0 nmol/L) concentrations of HTI286 compared with parental cells, whereas accumulation of [C-14) paclitaxel was unchanged. Sodium azide treatment partially reversed low HTI-286 accumulation, suggesting involvement of an ATP-dependent drug pump. KB-HTI-resistant cells did not overexpress P-glycoprotein, breast cancer resistance protein (BCRP/ABCG2/MXR), MRP1, or MRP3. No mutations were found in the major beta-tubulin isoform. However, 4.0 nmol/L HTI-286-selected cells had a point mutation in a-tubulin that substitutes Ser for Ala(12) near the nonexchangeable GTP-binding site of alpha-tubulin. KB-HTI-resistant cells removed from drug became less resistant to HTI-286, no longer had low HTI-286 accumulation, and retained the Ala(12) mutation. These data suggest that HTI-286 resistance may be partially mediated by mutation of a-tubulin and by an ATP-binding cassette drug pump distinct from P-glycoprotein, ABCG2, MRP1, or MRP3. C1 Wyeth Res, Oncol Res, Pearl River, NY 10965 USA. Wyeth Res, Chem & Screening Sci, Pearl River, NY 10965 USA. Wyeth Res, Radiosynth Grp, Pearl River, NY 10965 USA. NCI, Canc Res Ctr, Bethesda, MD 20892 USA. RP Loganzo, F (reprint author), Wyeth Res, Oncol Res, 401 N Middletown Rd,200-4709, Pearl River, NY 10965 USA. EM loganzf@wyeth.com NR 38 TC 32 Z9 36 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD OCT PY 2004 VL 3 IS 10 BP 1319 EP 1327 PG 9 WC Oncology SC Oncology GA 862KB UT WOS:000224488400016 PM 15486199 ER PT J AU Takahashi, Y Lavigne, JA Hursting, SD Chandramouli, GVR Perkins, SN Barrett, JC Wang, TTY AF Takahashi, Y Lavigne, JA Hursting, SD Chandramouli, GVR Perkins, SN Barrett, JC Wang, TTY TI Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: Identification of novel targets SO MOLECULAR CARCINOGENESIS LA English DT Article DE genistein; isoflavone; microarray; phytochemical; prostate cancer ID ACTIVATED RECEPTOR-ALPHA; IN-VITRO; STE20/SPS1-RELATED KINASE; SOY ISOFLAVONE; GROWTH-FACTORS; EXPRESSION; GENE; APOPTOSIS; PLASMA; LNCAP AB Many studies have correlated the consumption of soy-rich diets with a decreased risk of developing hormone-dependent cancers, including prostate cancer. Genistein is a candidate prostate cancer preventive phytochemical found at high levels in soybean and soy foods. To better understand the, molecular mechanisms underlying the beneficial effects of genistein on prostate cancer prevention, we used a DNA microarray approach to examine the effects of genistein at concentrations in the physiologic range on global gene expression patterns in and rogen-responsive cancer cells. Microarray analyses were performed on androgen-responsive LNCaP human prostate cancer cells exposed to 0, 1, 5, or 25 muM genistein. We found a concentration-dependent modulation of multiple cellular pathways that are important in prostate carcinogenesis. Interestingly, the androgen receptor (AR)-mediated pathways, in particular, appeared to be modulated by genistein at the lowest concentrations. Based on these results, we propose that the regulation of AR-mediated pathways is potentially the most relevant chemopreventive mechanism for genistein administered at physiologic levels. Published 2004 Wiley-Liss, Inc.(dagger). C1 USDA, ARS, Phytonutrients Lab, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. Natl Food Res Inst, Tsukuba, Ibaraki 305, Japan. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. RP Wang, TTY (reprint author), USDA, ARS, Phytonutrients Lab, Beltsville Human Nutr Res Ctr, Bldg 307C,Room 132, Beltsville, MD 20705 USA. NR 52 TC 35 Z9 36 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD OCT PY 2004 VL 41 IS 2 BP 108 EP 119 DI 10.1002/mc.20045 PG 12 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 859MC UT WOS:000224266800004 PM 15378649 ER PT J AU Ali, IU Chelius, D Umar, A Zhang, T Lynch, PM Phillips, RKS Hawk, ET Luke, BT Greenwald, P AF Ali, Iqbal U. Chelius, Dirk Umar, Asad Zhang, Terry Lynch, Patrick M. Phillips, Robin K. S. Hawk, Ernest T. Luke, Brian T. Greenwald, Peter TI Search for celecoxib-modulated proteomic markers: Use of two-dimensional liquid chromatography and tandem mass spectrometry SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Ali, Iqbal U.; Umar, Asad; Hawk, Ernest T.; Greenwald, Peter] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Chelius, Dirk; Zhang, Terry] Thermo Finnigan, San Jose, CA USA. [Lynch, Patrick M.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Phillips, Robin K. S.] St Marks Hosp, Imperial Canc Res Fund, London EC1V 2PS, England. [Luke, Brian T.] SAIC Frederick Inc, NCI, Frederick, MD USA. RI Ali, Imran/F-7710-2010 OI Ali, Imran/0000-0001-6511-8374 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2004 VL 3 IS 10 SU S BP S17 EP S17 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IA UT WOS:000202995200046 ER PT J AU Cao, H Lai, WS Deterding, LJ Venable, J Kennington, EA Haystead, TAJ Yates, JR Tomer, KB Blackshear, PJ AF Cao, Heping Lai, Wi S. Deterding, Leesa J. Venable, John Kennington, Elizabeth A. Haystead, Timothy A. J. Yates, John R., III Tomer, Kenneth B. Blackshear, Perry J. TI Identification of phosphorylation sites in human tristetraprolin that affect its electrophoretic mobility SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 NIEHS, NIH, Dept Hlth & Human Serv, Off Clin Res, Res Triangle Pk, NC 27709 USA. NIEHS, NIH, Dept Hlth & Human Serv, Labs Signal Transduct & Neurobiol, Res Triangle Pk, NC 27709 USA. [Deterding, Leesa J.; Tomer, Kenneth B.] NIEHS, NIH, Dept Hlth & Human Serv, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2004 VL 3 IS 10 SU S BP S66 EP S66 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IA UT WOS:000202995200168 ER PT J AU Deterding, LJ Bunger, MK Archer, TK Merrick, BA Bruno, ME Madenspacher, JE Dubin, JR Tomer, KB AF Deterding, L. J. Bunger, M. K. Archer, T. K. Merrick, B. A. Bruno, M. E. Madenspacher, J. E. Dubin, J. R. Tomer, K. B. TI Mass spectrometry in targeted and differential proteomics SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Deterding, L. J.; Bunger, M. K.; Archer, T. K.; Merrick, B. A.; Bruno, M. E.; Madenspacher, J. E.; Dubin, J. R.; Tomer, K. B.] Natl Inst Environm Hlth Sci, NIH, DHHS, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2004 VL 3 IS 10 SU S BP S124 EP S124 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IA UT WOS:000202995200313 ER PT J AU Fann, YC Yavatkar, A Campbell, C AF Fann, Yang C. Yavatkar, Amar Campbell, Catherine TI Mats-Pro: An intearated proteomics data management system for neuroscience research SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Fann, Yang C.; Yavatkar, Amar; Campbell, Catherine] NINDS, Intramural IT Program, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2004 VL 3 IS 10 SU S BP S193 EP S193 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IA UT WOS:000202995200471 ER PT J AU Kagan, J AF Kagan, Jacob TI The mitochondria and cancer detection SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2004 VL 3 IS 10 SU S BP S193 EP S193 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IA UT WOS:000202995200472 ER PT J AU Schmidt, MW Wolf, DA Ivanov, AR AF Schmidt, Michael W. Wolf, Dieter A. Ivanov, Alexander R. TI Polymeric monolithic capillary columns in on-line 2D-LC ESI-MS/MS proteomic analysis SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Schmidt, Michael W.; Wolf, Dieter A.; Ivanov, Alexander R.] Harvard Univ, Sch Publ Hlth, Harvard Niehs Ctr Proteom Facil, Dept Genet & Complex Dis, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2004 VL 3 IS 10 SU S BP S287 EP S287 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IA UT WOS:000202995200692 ER PT J AU Srivastava, S AF Srivastava, Sudhir TI Proteomics biomarkers for cancer diagnosis: Promises and challenges SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Srivastava, Sudhir] NCI, Canc Biomarkers Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2004 VL 3 IS 10 SU S BP S274 EP S274 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IA UT WOS:000202995200657 ER PT J AU Wang, DX Xu, WP Neckers, L Cotter, RJ AF Wang, Dongxia Xu, Wanping Neckers, Len Cotter, Robert J. TI Novel strategy for determining protein ubiquitination by mass Spectrometry SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Meeting Abstract C1 [Wang, Dongxia; Cotter, Robert J.] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Xu, Wanping; Neckers, Len] NCI, Ctr Canc Res, NIH, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD OCT PY 2004 VL 3 IS 10 SU S BP S142 EP S142 PG 1 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA V44IA UT WOS:000202995200354 ER PT J AU Huang, WD Zhang, J Wei, P Schrader, WT Moore, DD AF Huang, WD Zhang, J Wei, P Schrader, WT Moore, DD TI Meclizine is an agonist ligand for mouse constitutive androstane receptor (CAR) and an inverse agonist for human CAR SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PREGNANE-X RECEPTOR; NUCLEAR RECEPTORS; DRUG-METABOLISM; XENOBIOTIC RESPONSE; BILIRUBIN CLEARANCE; PXR; DETOXIFICATION; GENES; INDUCTION; TOXICITY AB The constitutive androstane receptor (CAR, NR1I3) is a key regulator of xenobiotic and endobiotic metabolism. The ligand-binding domains of murine ( m) and human ( h) CAR are divergent relative to other nuclear hormone receptors, resulting in species-specific differences in xenobiotic responses. Here we identify the widely used antiemetic meclizine (Antivert; Bonine) as both an agonist ligand for mCAR and an inverse agonist for hCAR. Meclizine increases mCAR transactivation in a dose-dependent manner. Like the mCAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene, meclizine stimulates binding of steroid receptor coactivator 1 to the murine receptor in vitro. Meclizine administration to mice increases expression of CAR target genes in a CAR-dependent manner. In contrast, meclizine suppresses hCAR transactivation and inhibits the phenobarbital-induced expression of the CAR target genes, cytochrome p450 monooxygenase (CYP) 2B10, CYP3A11, and CYP1A2, in primary hepatocytes derived from mice expressing hCAR, but not mCAR. The inhibitory effect of meclizine also suppresses acetaminophen-induced liver toxicity in humanized CAR mice. These results demonstrate that a single compound can induce opposite xenobiotic responses via orthologous receptors in rodents and humans. C1 Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. X Ceptor Therapeut Inc, San Diego, CA 92121 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Moore, DD (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, 1 Baylor Plaza, Houston, TX 77030 USA. EM moore@bcm.tmc.edu FU NIDDK NIH HHS [R01DK46546, U19 DK62434] NR 32 TC 68 Z9 74 U1 1 U2 4 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD OCT PY 2004 VL 18 IS 10 BP 2402 EP 2408 DI 10.1210/me.2004-0046 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 856DW UT WOS:000224025200004 PM 15272053 ER PT J AU Sullivan, DC Ferrari, M AF Sullivan, Daniel C. Ferrari, Mauro TI Nanotechnology and Tumor Imaging: Seizing an Opportunity SO MOLECULAR IMAGING LA English DT Review DE Molecular imaging; cancer; nanotechnology; noninvasive; early detection AB Nanoparticles, labeled with a signaling moiety for in vivo imaging, and one or more ligands for molecularly targeted specificity, hold considerable promise in oncology. Nanoparticles can serve as modular platforms, from which a wide variety of highly sensitive and specific imaging agents can be created. For example, many hundreds or thousands of atoms that provide imaging signals, such as radioisotopes, lanthanides, or fluorophores, can be attached to each nanoparticle, to form imaging agents that would provide higher sensitivity that can be obtained from agents based on small molecules. Similarly, many copies of targeted ligands can be attached to nanoparticles to markedly inrease specific binding. Drugs or therapeutic isotopes can be added to create multifunctional nanoparticles. Appropriately labeled and targeted nanoparticles could lead to a paradigm change in which cancer detection, diagnosis, and therapy are combined in a single molecular complex. Mol Imaging (2004) 3, 364-369. C1 [Sullivan, Daniel C.] NCI, Div Canc Treatment & Diag, EPN, Rockville, MD 20892 USA. [Ferrari, Mauro] Ohio State Univ, Columbus, OH 43210 USA. RP Sullivan, DC (reprint author), NCI, Div Canc Treatment & Diag, EPN, Room 6052,6130 Execut Blvd, Rockville, MD 20892 USA. EM ds274k@nih.gov NR 25 TC 34 Z9 36 U1 2 U2 13 PU B C DECKER INC PI HAMILTON PA 69 JOHN STREET SOUTH, STE 310, HAMILTON, ONTARIO L8N 2B9, CANADA SN 1535-3508 J9 MOL IMAGING JI Mol. Imaging PD OCT PY 2004 VL 3 IS 4 BP 364 EP 369 DI 10.1162/1535350042973526 PG 6 WC Biochemical Research Methods; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Radiology, Nuclear Medicine & Medical Imaging GA V22QO UT WOS:000208289900009 PM 15802054 ER PT J AU Kino, T Chrousos, GP AF Kino, T Chrousos, GP TI Combating atherosclerosis with LXR alpha and PPAR alpha agonists: Is rational multitargeted polypharmacy the future of therapeutics in complex diseases? SO MOLECULAR INTERVENTIONS LA English DT Editorial Material ID ACTIVATED RECEPTOR-ALPHA; HIGH-DENSITY-LIPOPROTEIN; FATTY-ACID-METABOLISM; LIVER-X-RECEPTORS; CROSS-TALK; NUTRITIONAL REGULATION; GENE; PEROXISOME-PROLIFERATOR-ACTIVATED-RECEPTOR-(PPAR)-ALPHA; TRANSCRIPTION; INHIBITION AB The development of atherosclerosis can, in the absence of intervention, lead to cardiovascular disease, which is responsible for the demise of more Americans per year than any other disease. Beyer and colleagues report, in the Journal of Pharmacology and Experimental Therapeutics, that treating mice with a liver X receptor (LXR) agonist increases not only the concentration of circulating high-density lipoprotein (HDL) but also, unfortunately, that of circulating triglycerides. When doubly treated with LXR agonists together with peroxisome proliferator-activated receptor alpha (PPARalpha) agonists, mice exhibited reduced concentrations of circulating triglycerides (but interestingly, triglyceride concentrations in the liver were not reduced) while their HDL concentrations remained elevated. The authors suggest that activation of both receptors, through the development and use of LXRalpha-PPARalpha dual agonists, might become a useful therapy to bolster HDL levels while simultaneously suppressing circulating triglycerides in patients. C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20205 USA. RP Kino, T (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20205 USA. EM chrousog@mail.nih.gov NR 24 TC 3 Z9 4 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD OCT PY 2004 VL 4 IS 5 BP 254 EP + DI 10.1124/mi.4.5.5 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863BM UT WOS:000224535200005 PM 15471908 ER PT J AU Quiroz, JA Gould, TD Manji, HK AF Quiroz, JA Gould, TD Manji, HK TI Molecular effects of lithium SO MOLECULAR INTERVENTIONS LA English DT Review ID PROTEIN-KINASE-C; GLYCOGEN-SYNTHASE KINASE-3; HIPPOCAMPAL-KINDLED RAT; INOSITOL-POLYPHOSPHATE 1-PHOSPHATASE; EMERGING EXPERIMENTAL THERAPEUTICS; MANIC-DEPRESSIVE ILLNESS; NERVE GROWTH-FACTOR; N-ACETYL-ASPARTATE; IN-VIVO EVIDENCE; BIPOLAR DISORDER AB Bipolar affective disorder is a common, severe, chronic, and often life-threatening illness, associated with other medical and psychiatric conditions (i.e., co-morbidity). The treatment of this devastating disorder was revolutionized by the discovery of lithium's antimanic effects over fifty years ago. Recent molecular and cellular biological studies have identified a number of unexpected targets for this monovalent cation, notably glycogen synthase kinase-3 and neurotrophic signaling cascades. These findings are leading to a reconceptualization of the biological underpinnings of bipolar disorder and are resulting in considerable interest in utilizing lithium for the treatment of certain neurodegenerative disorders. We review recent insights into lithium's actions including its direct inhibitory actions on inositol monophosphatase, inositol polyphosphate 1-phosphatase, glycogen synthase kinase-3, fructose 1,6-bisphospatase, bisphosphate nucleotidase, and phosphoglucomutase enzymes. We also discuss lithium's intracellular downstream targets including adenylate cyclase, the phosphoinositol cascade (and its effect on protein kinase C), arachidonic acid metabolism, and effects on neurotrophic cascades. Many of the new insights of lithium's actions may lead to the strategic development of improved therapeutics for the treatment of bipolar disorder. C1 NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Quiroz, JA (reprint author), NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. EM manji@nih.gov FU Intramural NIH HHS NR 154 TC 131 Z9 137 U1 0 U2 9 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 1534-0384 J9 MOL INTERV JI Mol. Interv. PD OCT PY 2004 VL 4 IS 5 BP 259 EP 272 DI 10.1124/mi.4.5.6 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 863BM UT WOS:000224535200006 PM 15471909 ER PT J AU Schalk, IJ Yue, WW Buchanan, SK AF Schalk, IJ Yue, WW Buchanan, SK TI Recognition of iron-free siderophores by TonB-dependent iron transporters SO MOLECULAR MICROBIOLOGY LA English DT Review ID OUTER-MEMBRANE RECEPTOR; BACTERIAL-CELL ENVELOPE; PSEUDOMONAS-AERUGINOSA; ESCHERICHIA-COLI; TRANSCRIPTION INITIATION; PATHOGENIC NEISSERIA; SIGNAL-TRANSDUCTION; SERRATIA-MARCESCENS; CRYSTAL-STRUCTURE; SIGMA-FACTOR AB TonB-dependent iron transporters reside in the outer membranes of Gram-negative bacteria, transporting ferric-complexes into the periplasm by a mechanism requiring proton motive force and an integral inner membrane complex, TonB-ExbB-ExbD. Certain TonB-dependent transporters contain an additional domain at the N-terminus, which interacts with an inner membrane regulatory protein and a cytoplasmic sigma factor to induce transcription of iron transport genes when a ferric-ligand is bound at the extracellular surface of the transporter. Transport of the ferric-ligand is apparently not necessary for transcription induction. Recent biophysical and crystallographic experiments have shown that this subclass of TonB-dependent iron transporters can bind iron-free ligands, whereas only the ferric-ligands are transported into the periplasm. This review focuses on the ligand binding properties of these transporters and includes a discussion of the biological function of the additional domain, the mechanism of transcription induction and the mechanism of ferric-ligand transport. C1 ESBS, Dept Recepteurs & Proteines Membranaires, UPR 9050, CNRS, F-67400 Strasbourg, France. NIDDKD, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ London Birkbeck Coll, Dept Crystallog, London WC1E 7HX, England. RP Buchanan, SK (reprint author), ESBS, Dept Recepteurs & Proteines Membranaires, UPR 9050, CNRS, Bld Sebastien Brant, F-67400 Strasbourg, France. EM skbuchan@helix.nih.gov NR 52 TC 66 Z9 69 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2004 VL 54 IS 1 BP 14 EP 22 DI 10.1111/j.1365-2958.2004.04241.x PG 9 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 858FY UT WOS:000224178900002 PM 15458401 ER PT J AU Dangi, B Gronenborn, AM Rosner, JL Martin, RG AF Dangi, B Gronenborn, AM Rosner, JL Martin, RG TI Versatility of the carboxy-terminal domain of the alpha subunit of RNA polymerase in transcriptional activation: use of the DNA contact site as a protein contact site for MarA SO MOLECULAR MICROBIOLOGY LA English DT Article ID MULTIPLE ANTIBIOTIC-RESISTANCE; ALANINE-SCANNING MUTAGENESIS; SOXS BINDING-SITES; ESCHERICHIA-COLI; INDUCIBLE PROMOTERS; DEPENDENT PROMOTERS; SUPEROXIDE STRESS; ROB; REGULON; IDENTIFICATION AB The transcriptional activator, MarA, interacts with RNA polymerase (RNAP) to activate promoters of the mar regulon. Here, we identify the interacting surfaces of MarA and of the carboxy-terminal domain of the alpha subunit of RNAP (alpha-CTD) by NMR-based chemical shift mapping. Spectral changes were monitored for a MarA-DNA complex upon titration with alpha-CTD, and for alpha-CTD upon titration with MarA-DNA. The mapping results were confirmed by mutational studies and retention chromatography. A model of the ternary complex shows that alpha-CTD uses a '265-like determinant' to contact MarA at a surface distant from the DNA. This is unlike the interaction of alpha-CTD with the CRP or Fis activators where the '265 determinant' contacts DNA while another surface of the same alpha-CTD molecule contacts the activator. These results reveal a new versatility for alpha-CTD in transcriptional activation. C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Martek Biosci, Columbia, MD 21045 USA. RP Martin, RG (reprint author), NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. EM rgmartin@helix.nih.gov OI Gronenborn, Angela M/0000-0001-9072-3525 NR 57 TC 21 Z9 21 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD OCT PY 2004 VL 54 IS 1 BP 45 EP 59 DI 10.1111/j.1365-2958.2004.04250.x PG 15 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 858FY UT WOS:000224178900005 PM 15458404 ER PT J AU Shen, DW Liang, XJ Gawinowicz, MA Gottesman, MM AF Shen, DW Liang, XJ Gawinowicz, MA Gottesman, MM TI Identification of cytoskeletal [C-14]carboplatin-binding proteins reveals reduced expression and disorganization of actin and filamin in cisplatin-resistant cell lines SO MOLECULAR PHARMACOLOGY LA English DT Article ID MULTIDRUG-RESISTANCE; ENDOCYTOSIS; CANCER; MECHANISMS AB Cisplatin resistant (CP-r) cells often show decreased uptake of cisplatin in association with reduced cell surface proteins and decreased endocytosis. In this report, two major [C-14] carboplatin-binding proteins were identified as filamin and actin by photoaffinity labeling and mass spectrometry. Decreased expression of these two proteins was found in two different human CP-r cell lines (KB-CP20 and 7404-CP20), in comparison with their parental cell lines (KB-3-1 and BEL-7404), respectively. Disorganization of beta-actin and filamin 250 and 90 was also detected in these CP-r cells by confocal microscopy. Transfection of a wild-type actin-enhanced green fluorescent protein (EGFP) expression vector into 7404-CP20 cells resulted in a nonfilamentous actin-EGFP distribution compared with a normal distribution in the cisplatin-sensitive BEL-7404 cells, suggesting that cytoskeletal organization is disturbed in the CP-r cells. The identification of actin and filamin as [C-14] carboplatin-binding proteins and decreased expression and disorganization of several cytoskeletal proteins in CP-r cells provide a molecular and cellular basis for the known defect in endocytosis in these cells. C1 NCI, Cell Biol Lab, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. Columbia Univ, Protein Core Facil, New York, NY USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, Ctr Canc Res, 37 Convent Dr,Room 1A09, Bethesda, MD 20892 USA. EM mgottesman@nih.gov NR 14 TC 23 Z9 24 U1 0 U2 4 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 2004 VL 66 IS 4 BP 789 EP 793 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 855TN UT WOS:000223997400004 PM 15385639 ER PT J AU Le, YY Iribarren, P Zhou, Y Gong, WH Hu, JY Zhang, X Wang, JM AF Le, YY Iribarren, P Zhou, Y Gong, WH Hu, JY Zhang, X Wang, JM TI Silencing the formylpeptide receptor FPR by short-interfering RNA SO MOLECULAR PHARMACOLOGY LA English DT Article ID FORMYL-PEPTIDE RECEPTORS; DOUBLE-STRANDED-RNA; MAMMALIAN-CELLS; ESCHERICHIA-COLI; N-FORMYLPEPTIDE; GENE-EXPRESSION; HAIRPIN RNAS; SUPPRESSION; REPLICATION; INHIBITION AB A double-stranded short-interfering RNA ( siRNA) was designed to attenuate the expression and function of the formylpeptide receptor FPR, a G protein-coupled receptor mediating migration and activation of phagocytic leukocytes in response to bacterial chemotactic formylpeptides. Retrovirus-based constructs were generated to introduce FPR-siRNA into a rat leukemia cell line transfected to overexpress FPR. Cells infected with FPR-siRNAT28, which targets the nucleotides 926 to 944 of FPR mRNA corresponding to the third extracellular loop of the putative receptor protein, showed significantly reduced expression of FPR mRNA and protein, in association with impaired calcium mobilization and chemotactic responses to peptide agonists. Direct transduction of synthetic FPR-siRNAT28 into human macrophages also inhibited the expression of FPR and abrogated cell chemotaxis and the release of superoxide anions induced by the bacterial formylpeptide. FPR-siRNA additionally abrogated the expression and function of FPR in a human malignant glioma cell line. Our study demonstrates successful application of siRNA to silence a G protein-coupled chemoattractant receptor involved in inflammation and suggests the potential to use this approach in studies of receptor regulation and prevention of undesirable side effects associated with FPR activation. C1 NCI, Ctr Canc Res, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Expt Immunol Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Nutr Sci, Shanghai, Peoples R China. Cent So Univ, Xiang Ya Med Sch, Inst Canc Res, Changsha, Peoples R China. RP Wang, JM (reprint author), NCI, Ctr Canc Res, Mol Immunoregulat Lab, Bldg 560,Room 31-40, Frederick, MD 21702 USA. EM wangji@mail.ncifcrf.gov RI Zhang, Xia/B-8152-2008 OI Zhang, Xia/0000-0002-9040-1486 FU PHS HHS [N01-C0-12400] NR 31 TC 13 Z9 15 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD OCT PY 2004 VL 66 IS 4 BP 1022 EP 1028 DI 10.1124/mol.104.001982 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 855TN UT WOS:000223997400029 PM 15258259 ER PT J AU Snider, LA Swedo, SE AF Snider, LA Swedo, SE TI PANDAS: current status and directions for research SO MOLECULAR PSYCHIATRY LA English DT Review DE obsessive-compulsive disorder; autoimmune; streptococcal infection ID OBSESSIVE-COMPULSIVE DISORDER; AUTOIMMUNE NEUROPSYCHIATRIC DISORDERS; STREPTOCOCCAL INFECTION PANDAS; BASAL GANGLIA ANTIBODIES; 7-YEAR FOLLOW-UP; SYDENHAMS CHOREA; TOURETTES-SYNDROME; RHEUMATIC-FEVER; TIC DISORDERS; PSYCHIATRIC-DISORDERS AB The recognition of the five criteria for PANDAS ( pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections) by Swedo et al established a homogenous subgroup of children with childhood onset obsessive - compulsive disorder (OCD) and/or tic disorders. The five clinical characteristics that define the PANDAS subgroup are the presence of OCD and/or tic disorder, prepubertal age of onset, abrupt onset and relapsing - remitting symptom course, association with neurological abnormalities during exacerbations ( adventitious movements or motoric hyperactivity), and a temporal association between symptom exacerbations and a Group-A beta-hemolytic streptococcal ( GAS) infection. These five criteria have been used for the purpose of systematic research on the phenomenology and unique therapies for the PANDAS subgroup as well as studies of the pathophysiology of post-streptococcal OCD and tic disorders. The etiology of OCD and tics in the PANDAS subgroup is unknown, but is theorized to occur as a result of post-streptococcal autoimmunity in a manner similar to that of Sydenham's chorea. The working hypothesis for the pathophysiology begins with a GAS infection in a susceptible host that incites the production of antibodies to GAS that crossreact with the cellular components of the basal ganglia, particularly in the caudate nucleus and putamen. The obsessions, compulsions, tics, and other neuropsychiatric symptoms seen in these children are postulated to arise from an interaction of these antibodies with neurons of the basal ganglia. C1 NIMH, Pediat & Dev Neuropsychiat Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Snider, LA (reprint author), NIMH, Pediat & Dev Neuropsychiat Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM SniderL@intra.nimh.nih.gov NR 85 TC 101 Z9 105 U1 5 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD OCT PY 2004 VL 9 IS 10 BP 900 EP 907 DI 10.1038/sj.mp.4001542 PG 8 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 857CB UT WOS:000224092100004 PM 15241433 ER PT J AU Zhang, PW Ishiguro, H Ohtsuki, T Hess, J Carillo, F Walther, D Onaivi, ES Arinami, T Uhl, GR AF Zhang, PW Ishiguro, H Ohtsuki, T Hess, J Carillo, F Walther, D Onaivi, ES Arinami, T Uhl, GR TI Human cannabinoid receptor 1: 5 ' exons, candidate regulatory regions, polymorphisms, haplotypes and association with polysubstance abuse SO MOLECULAR PSYCHIATRY LA English DT Article DE cannabinoid receptor 1; isoform; expression; association; addiction; haplotype ID GENE CNR1 POLYMORPHISM; CENTRAL-NERVOUS-SYSTEM; KNOCKOUT MICE; MESSENGER-RNA; SUSCEPTIBILITY LOCUS; SUBSTANCE-ABUSE; CB1 RECEPTORS; CHROMOSOME 6Q; CODING EXON; RAT-BRAIN AB A number of lines of evidence make the gene that encodes the G-protein-coupled CB1/Cnr1 receptor a strong candidate to harbor variants that might contribute to individual differences in human addiction vulnerability. The CB1/Cnr1 receptor is the major brain site at which cannabinoid marijuana constituents are psychoactive as well as the principal brain receptor for endogenous anandamide ligands. It is densely expressed in brain circuits likely to be important for both the reward and mnemonic processes important for addiction. Altered drug effects in CB1/Cnr1 knockout mice and initial association studies also make variants at the CB1/Cnr1 locus candidates for roles in human vulnerabilities to addictions. However, many features of this gene's structure, regulation and variation remain poorly defined. This poor definition has limited the ability of previous association studies to adequately sample variation at this locus. We now report improved definition of the human CB1/Cnr1 locus and its variants. Novel exons 1 - 3, splice variant and candidate promoter region sequences add to the richness of the CB1/Cnr1 locus. Candidate promoter region sequences confer reporter gene expression in cells that express CB1/Cnr1. Common polymorphisms reveal patterns of linkage disequilibrium in European- and in African-American individuals. A 5' CB1/Cnr1 'TAG' haplotype displays significant allelic frequency differences between substance abusers and controls in European- American, African-American and Japanese samples. Post-mortem brain samples of heterozygous individuals contain less mRNA transcribed from the TAG alleles than from other CB1/Cnr1 haplotypes. CB1/Cnr1 genomic variation thus appears to play roles in human addiction vulnerability. C1 NIDA, Mol Neurobiol Branch, IRP, NIH,DHSS, Baltimore, MD USA. Univ Tsukuba, Inst Basic Med, Dept Human Genet, Ibaraki, Japan. William Paterson Univ, Dept Biol, Wayne, NJ USA. RP Uhl, GR (reprint author), Box 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov NR 49 TC 148 Z9 158 U1 3 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD OCT PY 2004 VL 9 IS 10 BP 916 EP 931 DI 10.1038/sj.mp.4001560 PG 16 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 857CB UT WOS:000224092100006 PM 15289816 ER PT J AU Bara-Jimenez, W Dimitrova, T Sherzai, A Favit, A Mouradian, MM Chase, TN AF Bara-Jimenez, W Dimitrova, T Sherzai, A Favit, A Mouradian, MM Chase, TN TI Effect of monoamine reuptake inhibitor NS 2330 in advanced Parkinson's disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; dyskinesia; dopamine; levodopa; striatum; uptake; transporter; clinical trial ID DOPAMINE TRANSPORTER; NONHUMAN PRIMATE; STRIATUM; NEURONS AB Dopamine reuptake blockers, by enhancing and stabilizing intrasynaptic transmitter levels, could help palliate motor dysfunction in Parkinson's disease. This randomized, double-blind, placebo-controlled study compared the acute effects of the monoamine uptake inhibitor NS 2330 to those of placebo in 9 relatively advanced parkinsonian patients. At the dose administered, no change in parkinsonian scores was found when NS 2330 was given alone or with levodopa. Moreover, NS 2330 coadministration did not appear to alter dyskinesia severity or the duration of the antiparkinsonian response to levodopa. The drug was well tolerated. Under the conditions of this study, the present results failed to support the usefulness of dopamine reuptake inhibition in the treatment of advanced Parkinson's disease. C1 NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Chase, TN (reprint author), NINDS, Expt Therapeut Branch, NIH, Bldg 10,Room 5C103, Bethesda, MD 20892 USA. EM chaset@ninds.nih.gov OI Mouradian, M. Maral/0000-0002-9937-412X NR 16 TC 30 Z9 30 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD OCT PY 2004 VL 19 IS 10 BP 1183 EP 1186 DI 10.1002/mds.20124 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 861MY UT WOS:000224422000007 PM 15390018 ER PT J AU Resnik, DB AF Resnik, DB TI The need for international stem cell agreements SO NATURE BIOTECHNOLOGY LA English DT Letter C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, POB 12233,Mail Drop NH-06, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov NR 4 TC 2 Z9 3 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD OCT PY 2004 VL 22 IS 10 BP 1207 EP 1207 DI 10.1038/nbt1004-1207a PG 1 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 860EU UT WOS:000224326100010 PM 15470449 ER PT J AU Dauter, Z AF Dauter, Z TI Phasing in iodine for structure determination SO NATURE BIOTECHNOLOGY LA English DT Editorial Material ID GENETIC-CODE C1 NCI, Synchrotron Radiat Res Sect, Brookhaven Natl Lab, Upton, NY 11973 USA. RP Dauter, Z (reprint author), NCI, Synchrotron Radiat Res Sect, Brookhaven Natl Lab, Bldg 725A, Upton, NY 11973 USA. EM dauter@bnl.gov NR 10 TC 1 Z9 2 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1087-0156 J9 NAT BIOTECHNOL JI Nat. Biotechnol. PD OCT PY 2004 VL 22 IS 10 BP 1239 EP 1240 DI 10.1038/nbt1004-1239 PG 2 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 860EU UT WOS:000224326100021 PM 15470459 ER PT J AU Su, QN Cai, Q Gerwin, C Smith, CL Sheng, ZH AF Su, QN Cai, Q Gerwin, C Smith, CL Sheng, ZH TI Syntabulin is a microtubule-associated protein implicated in syntaxin transport in neurons SO NATURE CELL BIOLOGY LA English DT Article ID PRESYNAPTIC ACTIVE ZONES; KINESIN LIGHT-CHAIN; SYNAPTIC VESICLE; MEMBRANE-PROTEINS; AXONAL-TRANSPORT; PLASMA-MEMBRANE; MOTOR; COMPLEX; TRAFFICKING; RECEPTOR AB Different types of cargo vesicles containing presynaptic proteins are transported from the nerve cell body to the nerve terminal, and participate in the formation of active zones. However, the identity of the membranous cargoes and the nature of the motor-cargo interactions remain unsolved. Here, we report the identification of a syntaxin-1-binding protein named syntabulin. Syntabulin attaches syntaxin-containing vesicles to microtubules and migrates with syntaxin within the processes of hippocampal neurons. Knock-down of syntabulin expression with targeted small interfering RNAs (siRNAs) or interference with the syntabulin-syntaxin interaction inhibit attachment of syntaxin-cargo vesicles to microtubules and reduce syntaxin-1 distribution in neuronal processes. Furthermore, conventional kinesin I heavy chain binds to syntabulin and associates with syntabulin-linked syntaxin vesicles in vivo. These findings suggest that syntabulin functions as a linker molecule that attaches syntaxin-cargo vesicles to kinesin I, enabling the transport of syntaxin-1 to neuronal processes. C1 NINDS, Synapt Funct Unit, NIH, Bethesda, MD 20892 USA. NINDS, Light Imaging Facil, NIH, Bethesda, MD 20892 USA. Shanghai Med Univ 2, Neurobiol Lab, Shanghai 200025, Peoples R China. RP Sheng, ZH (reprint author), NINDS, Synapt Funct Unit, NIH, Bldg 35,Room 3B203,MSC 3701,35 Convent Dr, Bethesda, MD 20892 USA. EM shengz@ninds.nih.gov NR 48 TC 91 Z9 97 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD OCT PY 2004 VL 6 IS 10 BP 941 EP + DI 10.1038/ncb1169 PG 17 WC Cell Biology SC Cell Biology GA 859FY UT WOS:000224250000009 PM 15459722 ER PT J AU Jeong, S Pfeifer, K AF Jeong, S Pfeifer, K TI Shifting insulator boundaries SO NATURE GENETICS LA English DT Editorial Material ID TRANSCRIPTION; PARP; CTCF; EPIGENETICS C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Jeong, S (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bldg 6B-206, Bethesda, MD 20892 USA. EM pfeiferk@mail.nih.gov OI Pfeifer, Karl/0000-0002-0254-682X NR 14 TC 11 Z9 11 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2004 VL 36 IS 10 BP 1036 EP 1037 DI 10.1038/ng1004-1036 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 857YN UT WOS:000224156500007 PM 15454938 ER PT J AU Yu, WQ Ginjala, V Pant, V Chernukhin, I Whitehead, J Docquier, F Farrar, D Tavoosidana, G Mukhopadhyay, R Kanduri, C Oshimura, M Feinberg, AP Lobanenkov, V Klenova, E Ohlsson, R AF Yu, WQ Ginjala, V Pant, V Chernukhin, I Whitehead, J Docquier, F Farrar, D Tavoosidana, G Mukhopadhyay, R Kanduri, C Oshimura, M Feinberg, AP Lobanenkov, V Klenova, E Ohlsson, R TI Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation SO NATURE GENETICS LA English DT Article ID IMPRINTING CONTROL REGION; METHYLATION-FREE DOMAINS; PROTEIN CTCF; GENE; H19; EXPRESSION; TRANSCRIPTION; BINDING; PARP; ASSOCIATION AB Chromatin insulators demarcate expression domains by blocking the cis effects of enhancers or silencers in a position-dependent manner(1,2). We show that the chromatin insulator protein CTCF carries a post-translational modification: poly(ADP-ribosyl)ation. Chromatin immunoprecipitation analysis showed that a poly(ADP-ribosyl)ation mark, which exclusively segregates with the maternal allele of the insulator domain in the H19 imprinting control region, requires the bases that are essential for interaction with CTCF3. Chromatin immunoprecipitation-on-chip analysis documented that the link between CTCF and poly(ADP-ribosyl)ation extended to more than 140 mouse CTCF target sites. An insulator trap assay showed that the insulator function of most of these CTCF target sites is sensitive to 3-aminobenzamide, an inhibitor of poly(ADP-ribose) polymerase activity. We suggest that poly(ADP-ribosyl)ation imparts chromatin insulator properties to CTCF at both imprinted and nonimprinted loci, which has implications for the regulation of expression domains and their demise in pathological lesions. C1 Uppsala Univ, Evolut Biol Ctr, Dept Genet & Dev, S-75236 Uppsala, Sweden. Univ Essex, Dept Biol Sci, Colchester CO4 3SQ, Essex, England. Tottori Univ, Dept Mol & Cellular Biol, Tottori, Japan. Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. NIAID, Mol PAthol Sect, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. RP Ohlsson, R (reprint author), Uppsala Univ, Evolut Biol Ctr, Dept Genet & Dev, Norbyvagen 18A, S-75236 Uppsala, Sweden. EM Rolf.Ohlsson@ebc.uu.se RI Whitehead, Joanne/A-8597-2008; OI Whitehead, Joanne/0000-0002-9602-2081; Lobanenkov, Victor/0000-0001-6665-3635 FU NCI NIH HHS [R37 CA054358, R37 CA054358-14]; Worldwide Cancer Research [99-0514] NR 30 TC 164 Z9 166 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2004 VL 36 IS 10 BP 1105 EP 1110 DI 10.1038/ng1426 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 857YN UT WOS:000224156500020 PM 15361875 ER PT J AU Ding, H Wu, XL Bostrom, H Kim, I Wong, N Tsoi, B O'Rourke, M Koh, GY Soriano, P Betsholtz, C Hart, TC Marazita, ML Field, LL Tam, PPL Nagy, A AF Ding, H Wu, XL Bostrom, H Kim, I Wong, N Tsoi, B O'Rourke, M Koh, GY Soriano, P Betsholtz, C Hart, TC Marazita, ML Field, LL Tam, PPL Nagy, A TI A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling SO NATURE GENETICS LA English DT Article ID CELL-CELL ADHESION; CLEFT-PALATE; KNOCKOUT MICE; BETA-RECEPTOR; EXPRESSION; ROLES; DEFICIENT; MUTATIONS; TISSUES; FUSION AB PDGF-C is a member of the platelet-derived growth factor (PDGF) family, which signals through PDGF receptor (PDGFR) alphaalpha and alphabeta dimers(1,2). Here we show that Pdgfc(-/-) mice die in the perinatal period owing to feeding and respiratory difficulties associated with a complete cleft of the secondary palate. This phenotype was less severe than that of Pdgfra(-/-) embryos. Pdgfc(-/-) Pdgfa(-/-) embryos developed a cleft face, subepidermal blistering, deficiency of renal cortex mesenchyme, spina bifida and skeletal and vascular defects. Complete loss of function of both ligands, therefore, phenocopied the loss of PDGFR-alpha function, suggesting that both PDGF-A and PDGF-C signal through PDGFR-alpha to regulate the development of craniofacial structures, the neural tube and mesodermal organs. Our results also show that PDGF-C signaling is a new pathway in palatogenesis, different from, and independent of, those previously implicated. C1 Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. Gothenburg Univ, Dept Biochem Med, S-41124 Gothenburg, Sweden. Korea Adv Inst Sci & Technol, Biomed Res Ctr, Taejon 305701, South Korea. Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. Univ Sydney, Sydney, NSW 2006, Australia. Childrens Med Res Inst, Embryol Unit, Sydney, NSW, Australia. Fred Hutchinson Canc Res Ctr, Div Basic Sci, Program Dev Biol, Seattle, WA 98104 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Ctr Craniofacial & Dent Genet, Pittsburgh, PA 15260 USA. Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 1M9, Canada. BC Res Inst Childrens & Womens Hlth, Vancouver, BC, Canada. Univ Toronto, Dept Med Genet & Microbiol, Toronto, ON, Canada. RP Nagy, A (reprint author), Mt Sinai Hosp, Samuel Lunenfeld Res Inst, 600 Univ Ave, Toronto, ON M5G 1X5, Canada. EM nagy@mshri.on.ca RI Kim, Injune/C-1710-2011; Koh, Gou Young /C-1615-2011; Nagy, Andras/G-6465-2013; Ehrencrona, Hans/M-5619-2014; Soriano, Philippe/E-5797-2015 OI Kim, Injune/0000-0001-9244-815X; Ehrencrona, Hans/0000-0002-5589-3622; Soriano, Philippe/0000-0002-0427-926X NR 30 TC 119 Z9 124 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2004 VL 36 IS 10 BP 1111 EP 1116 DI 10.1038/ng1415 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 857YN UT WOS:000224156500021 PM 15361870 ER PT J AU He, XC Zhang, JW Tong, WG Tawfik, O Ross, J Scoville, DH Tian, Q Zeng, X He, X Wiedemann, LM Mishina, Y Li, LH AF He, XC Zhang, JW Tong, WG Tawfik, O Ross, J Scoville, DH Tian, Q Zeng, X He, X Wiedemann, LM Mishina, Y Li, LH TI BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling SO NATURE GENETICS LA English DT Article ID MORPHOGENETIC PROTEIN-RECEPTOR; TUMOR-SUPPRESSOR; JUVENILE POLYPOSIS; TRANSCRIPTIONAL ACTIVATION; NEGATIVE REGULATION; GERMLINE MUTATIONS; PTEN; GENE; TRANSDUCTION; GROWTH AB In humans, mutations in BMPR1A, SMAD4 and PTEN are responsible for juvenile polyposis syndrome(1), juvenile intestinal polyposis(2) and Cowden disease(3), respectively. The development of polyposis is a common feature of these diseases, suggesting that there is an association between BMP and PTEN pathways(4,5). The mechanistic link between BMP and PTEN pathways and the related etiology of juvenile polyposis is unresolved. Here we show that conditional inactivation of Bmpr1a in mice disturbs homeostasis of intestinal epithelial regeneration with an expansion of the stem and progenitor cell populations, eventually leading to intestinal polyposis resembling human juvenile polyposis syndrome. We show that BMP signaling suppresses Wnt signaling to ensure a balanced control of stem cell self-renewal. Mechanistically, PTEN, through phosphatidylinosital-3 kinase-Akt, mediates the convergence of the BMP and Wnt pathways on control of beta-catenin. Thus, BMP signaling may control the duplication of intestinal stem cells, thereby preventing crypt fission and the subsequent increase in crypt number. C1 Stowers Inst Med Res, Kansas City, MO 64110 USA. Univ Kansas, Med Ctr, Dept Pathol & Lab Med, Kansas City, KS 66160 USA. Inst Systemsbiol, Seattle, WA 98103 USA. Childrens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Li, LH (reprint author), Stowers Inst Med Res, 1000 E 50th St, Kansas City, MO 64110 USA. EM lil@stowers-institute.org RI Wiedemann, Leanne/E-3316-2010 NR 30 TC 555 Z9 578 U1 4 U2 29 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD OCT PY 2004 VL 36 IS 10 BP 1117 EP 1121 DI 10.1038/ng1430 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 857YN UT WOS:000224156500022 PM 15378062 ER PT J AU Xue, HH Bollenbacher, J Rovella, V Tripuraneni, R Du, YB Liu, CY Williams, A McCoy, JP Leonard, WJ AF Xue, HH Bollenbacher, J Rovella, V Tripuraneni, R Du, YB Liu, CY Williams, A McCoy, JP Leonard, WJ TI GA binding protein regulates interleukin 7 receptor alpha-chain gene expression in T cells SO NATURE IMMUNOLOGY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; THYMIC STROMAL LYMPHOPOIETIN; TRANSCRIPTION FACTOR; UTROPHIN PROMOTER; MEMORY CELLS; ETS FAMILY; COMPLEX; PU.1; DNA; DOMAIN AB The interleukin 7 receptor alpha-chain (IL-7Ralpha) is essential for T cell development in both humans and mice and for B cell development in mice. Whereas the transcription factor PU. 1 regulates IL-7Ra expression in mouse pro-B cells via a GGAA motif, we demonstrate here that GA binding protein (GABP) bound to this site and was essential in the regulation of IL-7Ralpha expression in T cells, where PU. 1 is not expressed. Moreover, IL-7Ralpha expression was diminished substantially in thymocytes but was normal on B220(+) fetal liver cells from mouse embryos with diminished expression of GABPalpha. Thus, GABP is essential for the regulation of IL-7Ralpha expression in T cells, and the differential regulation of IL-7Ralpha in distinct lymphoid lineages is achieved at least in part by differential recruitment of factors to the same GGAA motif. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NHLBI, Transgenic Facil, NIH, Bethesda, MD 20892 USA. NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Room 7N252, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov NR 47 TC 99 Z9 101 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD OCT PY 2004 VL 5 IS 10 BP 1036 EP 1044 DI 10.1038/ni1117 PG 9 WC Immunology SC Immunology GA 857YO UT WOS:000224156600027 PM 15361867 ER PT J AU Seder, RA Sacks, DL AF Seder, RA Sacks, DL TI Memory may not need reminding SO NATURE MEDICINE LA English DT Editorial Material ID LEISHMANIA-MAJOR; CELL GENERATION; EFFECTOR; PERSISTENCE; IMMUNITY; SUBSETS AB After primary Leishmania major infection, two populations of CD4(+) T cells, termed 'effector' and 'central memory' T cells, are generated. Work in mice shows that both populations can mediate protection against subsequent infection, and that persistent infection keeps the effector response robust (pages 1104-1110). C1 NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Seder, RA (reprint author), NIAID, Cellular Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM rseder@mail.nih.gov NR 10 TC 5 Z9 5 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2004 VL 10 IS 10 BP 1045 EP 1047 DI 10.1038/nm1004-1045 PG 4 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 859EM UT WOS:000224245800021 PM 15459703 ER PT J AU Hunter, CJ Dejam, A Blood, AB Shields, H Kim-Shapiro, D Machado, RF Tarekegn, S Mulla, N Hopper, AO Schechter, AN Power, GG Gladwin, MT AF Hunter, CJ Dejam, A Blood, AB Shields, H Kim-Shapiro, D Machado, RF Tarekegn, S Mulla, N Hopper, AO Schechter, AN Power, GG Gladwin, MT TI Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator SO NATURE MEDICINE LA English DT Article ID RESPIRATORY-FAILURE; S-NITROSOHEMOGLOBIN; OXIDE THERAPY; NEWBORN; DEOXYHEMOGLOBIN; HYPERTENSION; VASOCONSTRICTION; NITROSOTHIOLS; MECHANISM; REDUCTION AB The blood anion nitrite contributes to hypoxic vasodilation through a heme-based, nitric oxide (NO)-generating reaction with deoxyhemoglobin and potentially other heme proteins(1). We hypothesized that this biochemical reaction could be harnessed for the treatment of neonatal pulmonary hypertension, an NO-deficient state characterized by pulmonary vasoconstriction, right-to-left shunt pathophysiology and systemic hypoxemia(2). To test this, we delivered inhaled sodium nitrite by aerosol to newborn lambs with hypoxic and normoxic pulmonary hypertension. Inhaled nitrite elicited a rapid and sustained reduction (similar to 65%) in hypoxia-induced pulmonary hypertension, with a magnitude approaching that of the effects of 20 p. p. m. NO gas inhalation. This reduction was associated with the immediate appearance of NO in expiratory gas. Pulmonary vasodilation elicited by aerosolized nitrite was deoxyhemoglobin- and pH-dependent and was associated with increased blood levels of iron-nitrosyl-hemoglobin. Notably, from a therapeutic standpoint, short-term delivery of nitrite dissolved in saline through nebulization produced selective, sustained pulmonary vasodilation with no clinically significant increase in blood methemoglobin levels. These data support the concept that nitrite is a vasodilator acting through conversion to NO, a process coupled to hemoglobin deoxygenation and protonation, and evince a new, simple and inexpensive potential therapy for neonatal pulmonary hypertension. C1 NHLBI, Dept Crit Care Med, Ctr Clin, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Loma Linda Univ, Sch Med, Dept Physiol, Ctr Perinatal Biol, Loma Linda, CA 92350 USA. Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. Loma Linda Univ, Sch Med, Dept Pediat, Loma Linda, CA 92350 USA. RP Gladwin, MT (reprint author), NHLBI, Dept Crit Care Med, Ctr Clin, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM gpower@som.llu.edu; mgladwin@nih.gov RI Hunter, Christian/G-4344-2010; OI Schechter, Alan N/0000-0002-5235-9408 FU NHLBI NIH HHS [HL654941, HL58091, R01 HL058091] NR 30 TC 176 Z9 181 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD OCT PY 2004 VL 10 IS 10 BP 1122 EP 1127 DI 10.1038/nm1109 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 859EM UT WOS:000224245800044 PM 15361865 ER PT J AU Mattson, MP Taub, DD AF Mattson, MP Taub, DD TI Ancient viral protein enrages astrocytes in multiple sclerosis SO NATURE NEUROSCIENCE LA English DT Editorial Material ID SYNCYTIN; PATHOGENESIS; OSTEOPONTIN; THERAPY AB Syncytin is a viral envelope protein encoded in the human genome. New work in this issue indicates that it is activated in multiple sclerosis astrocytes and microglia, contributing to the inflammation-induced myelin destruction that causes disease symptoms. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. NIA, Immunol Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 15 TC 9 Z9 10 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD OCT PY 2004 VL 7 IS 10 BP 1021 EP 1023 DI 10.1038/nn1004-1021 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 857YQ UT WOS:000224156900004 PM 15452568 ER PT J AU von Eschenbach, AC AF von Eschenbach, AC TI A vision for the National Cancer Program in the United States SO NATURE REVIEWS CANCER LA English DT Article ID PROGRESSION; INTERFERENCE; EXPRESSION; INHIBITOR; MUTATIONS; DIAGNOSIS; PROSTATE; THERAPY; RNAS; RAS AB The intersection of two noble endeavors - the scientists' quest to understand life itself and the physicians' dedication to relieve suffering and prolong life - came into sharp focus in 1971 with the United States National Cancer Act. This focus has led to an exponential expansion of our understanding of cancer at the genetic, molecular and cellular levels, and concomitant advances in our ability to disrupt the disease process through prevention, early detection and successful treatment. At the National Cancer Institute we are committed to capitalize on these achievements. A new era is now within our grasp, a time when no one suffers or dies as a result of cancer. C1 NCI, NIH, Bethesda, MD 20892 USA. RP von Eschenbach, AC (reprint author), NCI, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM avonesch@mail.nih.gov NR 37 TC 28 Z9 28 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD OCT PY 2004 VL 4 IS 10 BP 820 EP 828 DI 10.1038/nrc1458 PG 9 WC Oncology SC Oncology GA 859EL UT WOS:000224245700018 PM 15510163 ER PT J AU Cashman, NR Caughey, B AF Cashman, NR Caughey, B TI Prion diseases - Close to effective therapy? SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID CREUTZFELDT-JAKOB-DISEASE; TRANSMISSIBLE SPONGIFORM ENCEPHALOPATHY; FOLLICULAR DENDRITIC CELLS; INFECTED NEUROBLASTOMA-CELLS; PROTEASE-RESISTANT STATE; SCRAPIE-ASSOCIATED FORM; DEXTRAN SULFATE 500; CONGO RED; CULTURED-CELLS; IN-VITRO AB The transmissible spongiform encephalopathies could represent a new mode of transmission for infectious diseases-a process more akin to crystallization than to microbial replication. The prion hypothesis proposes that the normal isoform of the prion protein is converted to a disease-specific species by template-directed misfolding. Therapeutic and prophylactic strategies to combat these diseases have emerged from immunological and chemotherapeutic approaches. The lessons learned in treating prion disease will almost certainly have an impact on other diseases that are characterized by the pathological accumulation of misfolded proteins. C1 Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON M55 3H2, Canada. NIH, Rocky Mt Labs, Hamilton, MT USA. RP Cashman, NR (reprint author), Univ Toronto, Ctr Res Neurodegenerat Dis, 6 Queens Pk Crescent, Toronto, ON M55 3H2, Canada. EM neil.cashman@utoronto.ca; bcaughey@niaid.nih.gov NR 160 TC 80 Z9 85 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD OCT PY 2004 VL 3 IS 10 BP 874 EP 884 DI 10.1038/nrd1525 PG 11 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 859EO UT WOS:000224246000021 PM 15459678 ER PT J AU Bhalla, T Rosenthal, JJC Holmgren, M Reenan, R AF Bhalla, T Rosenthal, JJC Holmgren, M Reenan, R TI Control of human potassium channel inactivation by editing of a small mRNA hairpin SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID SHAKER K-CHANNELS; ADENOSINE-DEAMINASE; BETA-SUBUNIT; SITE; PHOSPHORYLATION; PROPAGATION; PREDICTION; DROSOPHILA; MECHANISMS; FREQUENCY AB Genomic recoding by A-->I RNA editing plays an important role in diversifying the proteins involved in electrical excitability. Here, we describe editing of an intronless potassium channel gene. A small region of human K(V)1.1 mRNA sequence directs efficient modification of one adenosine by human adenosine deaminase acting on RNA 2 (hADAR2). Mutational analysis shows that this region adopts a hairpin structure. Electrophysiological characterization reveals that the editing event (I/V) profoundly affects channel inactivation conferred by accessory beta subunits. Drosophila melanogaster Shaker channels, mimicking this editing event through mutation, exhibit a similar effect. In addition, we demonstrate that mRNAs for the paralogous D. melanogaster Shab potassium channel are edited at the same position by fly ADAR-a clear example of convergent evolution driven by adenosine deamination. These results suggest an ancient and key regulatory role for this residue in K-V channels. C1 Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT 06030 USA. Univ Puerto Rico, Inst Neurobiol, San Juan, PR 00901 USA. NINDS, Mol Neurophysiol Unit, NIH, Bethesda, MD 20892 USA. RP Reenan, R (reprint author), Univ Connecticut, Ctr Hlth, Dept Genet & Dev Biol, Farmington, CT 06030 USA. EM holmgren@ninds.nih.gov; rreenan@neuron.uchc.edu NR 41 TC 138 Z9 147 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD OCT PY 2004 VL 11 IS 10 BP 950 EP 956 DI 10.1038/nsmb825 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 857NM UT WOS:000224124200015 PM 15361858 ER PT J AU Jinek, M Rehwinkel, J Lazarus, BD Izaurralde, E Hanover, JA Conti, E AF Jinek, M Rehwinkel, J Lazarus, BD Izaurralde, E Hanover, JA Conti, E TI The superhelical TPR-repeat domain of O-linked GlcNAc transferase exhibits structural similarities to importin alpha SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID TETRATRICOPEPTIDE REPEATS; NUCLEAR-PORE; CRYSTALLOGRAPHIC ANALYSIS; SUBSTRATE-SPECIFICITY; N-ACETYLGLUCOSAMINE; KARYOPHERIN ALPHA; PROTEIN; RECOGNITION; GLYCOSYLATION; GLYCOPROTEINS AB Addition of N-acetylglucosamine (GlcNAc) is a ubiquitous form of intracellular glycosylation catalyzed by the conserved O-linked GlcNAc transferase (OGT). OGT contains an N-terminal domain of tetratricopeptide (TPR) repeats that mediates the recognition of a broad range of target proteins. Components of the nuclear pore complex are major OGT targets, as OGT depletion by RNA interference (RNAi) results in the loss of GlcNAc modification at the nuclear envelope. To gain insight into the mechanism of target recognition, we solved the crystal structure of the homodimeric TPR domain of human OGT, which contains 11.5 TPR repeats. The repeats form an elongated superhelix. The concave surface of the superhelix is lined by absolutely conserved asparagines, in a manner reminiscent of the peptide-binding site of importin alpha. Based on this structural similarity, we propose that OGT uses an analogous molecular mechanism to recognize its targets. C1 European Mol Biol Lab, Struct & Computat Biol Programme, D-69117 Heidelberg, Germany. European Mol Biol Lab, Gene Express Programme, D-69117 Heidelberg, Germany. NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Conti, E (reprint author), European Mol Biol Lab, Struct & Computat Biol Programme, Meyerhofstr 1, D-69117 Heidelberg, Germany. EM conti@embl-heidelberg.de RI Jinek, Martin/E-6621-2011; Izaurralde, Elisa/G-3239-2012; OI Jinek, Martin/0000-0002-7601-210X NR 42 TC 146 Z9 148 U1 4 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD OCT PY 2004 VL 11 IS 10 BP 1001 EP 1007 DI 10.1038/nsmb833 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 857NM UT WOS:000224124200022 PM 15361863 ER PT J AU Read, JCA Cumming, BG AF Read, JCA Cumming, BG TI Understanding the cortical specialization for horizontal disparity SO NEURAL COMPUTATION LA English DT Article ID CAT STRIATE CORTEX; PRIMARY VISUAL-CORTEX; BINOCULAR DEPTH DISCRIMINATION; CLASSICAL RECEPTIVE-FIELD; MACAQUE V1 NEURONS; SIMPLE CELLS; NEURAL MECHANISMS; STEREO DISPARITY; COMPLEX CELLS; LISTINGS LAW AB Because the eyes are displaced horizontally, binocular vision is inherently anisotropic. Recent experimental work has uncovered evidence of this anisotropy in primary visual cortex (V1): neurons respond over a wider range of horizontal than vertical disparity, regardless of their orientation tuning. This probably reflects the horizontally elongated distribution of two-dimensional disparity experienced by the visual system, but it conflicts with all existing models of disparity selectivity, in which the relative response range to vertical and horizontal disparities is determined by the preferred orientation. Potentially, this discrepancy could require us to abandon the widely held view that processing in V1 neurons is initially linear. Here, we show that these new experimental data can be reconciled with an initial linear stage; we present two physiologically plausible ways of extending existing models to achieve this. First, we allow neurons to receive input from multiple binocular subunits with different position disparities (previous models have assumed all subunits have identical position and phase disparity). Then we incorporate a form of divisive normalization, which has successfully explained many response properties of VI neurons but has not previously been incorporated into a model of disparity selectivity. We show that either of these mechanisms decouples disparity tuning from orientation tuning and discuss how the models could be tested experimentally. This represents the first explanation of how the cortical specialization for horizontal disparity may be achieved. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. RP Read, JCA (reprint author), NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. EM jcr@lsr.nei.nih.gov; bgc@lsr.nei.nih.gov RI Read, Jenny/A-7493-2013 OI Read, Jenny/0000-0002-9029-5185 FU NEI NIH HHS [Z01 EY000404-04] NR 66 TC 28 Z9 28 U1 1 U2 3 PU M I T PRESS PI CAMBRIDGE PA FIVE CAMBRIDGE CENTER, CAMBRIDGE, MA 02142 USA SN 0899-7667 J9 NEURAL COMPUT JI Neural Comput. PD OCT PY 2004 VL 16 IS 10 BP 1983 EP 2020 DI 10.1162/0899766041732440 PG 38 WC Computer Science, Artificial Intelligence SC Computer Science GA 847NE UT WOS:000223401400001 PM 15333204 ER PT J AU Hill, DA Linet, MS Black, PM Fine, HA Selker, RG Shapiro, WR Inskip, PD AF Hill, DA Linet, MS Black, PM Fine, HA Selker, RG Shapiro, WR Inskip, PD TI Meningioma and schwannoma risk in adults in relation to family history of cancer SO NEURO-ONCOLOGY LA English DT Article ID LOS-ANGELES-COUNTY; CENTRAL NERVOUS-SYSTEM; BRAIN-TUMORS; ANAPLASTIC MENINGIOMAS; 1ST-DEGREE RELATIVES; NATIONWIDE COHORT; BREAST-CANCER; GLIOMA; ASSOCIATION; MELANOMA AB Relatively little is known about factors that contribute to the development of meningloma and vestibular schwannoma, two intracranial nervous system tumors. We evaluated the risk of these tumors in relation to family history of malignant or benign tumors. Incident cases of meningioma (n = 197) or schwannoma (n = 96) were identified at three U.S. referral hospitals between June 1994 and August 1998. Controls (n = 799) admitted to the same hospitals for nonmalignant conditions were matched to cases on age, sex, race/ethm city, hospital, and proximity of residence to hospital. We found that risk of meningioma was increased among persons reporting a family history of a benign brain tumor (odds ratio [OR], 4.5; 95% confidence interval [CI], 1.0-21.0; n = 5) or melanoma (OR, 4.2; 95% CI, 1.2-15.0; n = 5). A family history of breast cancer was associated with an elevated meningioma risk among participants aged 18 to 49 years (OR, 3.9; 95% CI, 1.4-11.0; n = 8) but a reduced risk among older respondents (OR, 0.2; 95% CI, 0. 1-0.7; n = 3). Family history of cancer did not differ between schwannoma cases and controls, although the statistical power to detect associations was limited. Some relative risk estimates were based on a small number of observations and may have arisen by chance. Inheritance of predisposing genes, shared environmental factors, or both within families with a history of benign brain tumors, melanoma, or possibly breast cancer may be related to altered meningioma risk. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Neuro Oncol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. Western Penn Hosp, Div Neurosurg, Pittsburgh, PA 15224 USA. St Josephs Hosp, Barrow Neurol Inst, Dept Neurol, Phoenix, AZ 85013 USA. Med Ctr, Phoenix, AZ 85013 USA. RP Hill, DA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,MSC 7238N, Bethesda, MD 20892 USA. EM dhill@mail.nih.gov NR 36 TC 8 Z9 10 U1 0 U2 1 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2004 VL 6 IS 4 BP 274 EP 280 DI 10.1215/S1152851704 PG 7 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 860HF UT WOS:000224332400002 PM 15494094 ER PT J AU Lavoie, JF LeSauteur, L Wong, J Thiele, CJ Kaplan, DR AF Lavoie, JF LeSauteur, L Wong, J Thiele, CJ Kaplan, DR TI TrkA induces the death of neuroblastoma cells, and does so via a p53-dependent mechanism SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 9th Annual Meeting of the Society-for-Neuro-Oncology CY NOV 18-21, 2004 CL Toronto, CANADA SP Soc Neuro Oncol C1 Univ Toronto, Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Montreal Neurol Inst, Montreal, PQ, Canada. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2004 VL 6 IS 4 BP 318 EP 318 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 860HF UT WOS:000224332400051 ER PT J AU Blumenthal, DT Quezado, M Santi, M Rapkiewicz, A Ronchetti, R Rushing, EJ AF Blumenthal, DT Quezado, M Santi, M Rapkiewicz, A Ronchetti, R Rushing, EJ TI Prognostic value of epidermal growth factor receptor expression and small-cell phenotype in patients with glioblastoma treated with induction chemotherapy, radiotherapy, O-6 benzylguanine SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 9th Annual Meeting of the Society-for-Neuro-Oncology CY NOV 18-21, 2004 CL Toronto, CANADA SP Soc Neuro Oncol C1 Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. Childrens Hosp, Natl Med Ctr, Dept Pathol, Washington, DC 20010 USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. SWOG, Brain Comm, San Antonio, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2004 VL 6 IS 4 BP 350 EP 350 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 860HF UT WOS:000224332400176 ER PT J AU Cairncross, G Seiferheld, W Shaw, E Jenkins, R Scheithauer, B Brachman, D Buckner, J Fink, K Souhami, L Curran, W AF Cairncross, G Seiferheld, W Shaw, E Jenkins, R Scheithauer, B Brachman, D Buckner, J Fink, K Souhami, L Curran, W TI An intergroup randomized controlled clinical trial (RCT) of chemotherapy plus radiotherapy (RT) versus RT alone for pure and mixed anaplastic oligodendroglioma: Initial report of RTOG 94-02 SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 9th Annual Meeting of the Society-for-Neuro-Oncology CY NOV 18-21, 2004 CL Toronto, CANADA SP Soc Neuro Oncol C1 Radiat Therapy Oncol Grp, Philadelphia, PA USA. SW Oncol Grp, San Antonio, TX USA. N Cent Canc Treatment Grp, Rochester, MN USA. Eastern Cooperat Oncol Grp, Philadelphia, PA USA. NCI, Canadas Clin Trails Grp, Toronto, ON, Canada. NR 0 TC 3 Z9 3 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2004 VL 6 IS 4 BP 371 EP 371 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 860HF UT WOS:000224332400261 ER PT J AU Wen, PY Yung, WKA Lamborn, K Peng, B Dahia, P Abrey, L Raiser, J Cloughesy, T Fink, K Gilbert, M Chang, S Junck, L Schiff, D Lieberman, F Fine, H Mehta, M Robins, HI DeAngelis, LM Hess, K Groves, M Puduvalli, VK Levin, V Conrad, C Kuhn, J Maher, E Hayes, M Silberman, S Letvak, L Capdeville, R Kaplan, R Murgo, A Stiles, C Prados, MD AF Wen, PY Yung, WKA Lamborn, K Peng, B Dahia, P Abrey, L Raiser, J Cloughesy, T Fink, K Gilbert, M Chang, S Junck, L Schiff, D Lieberman, F Fine, H Mehta, M Robins, HI DeAngelis, LM Hess, K Groves, M Puduvalli, VK Levin, V Conrad, C Kuhn, J Maher, E Hayes, M Silberman, S Letvak, L Capdeville, R Kaplan, R Murgo, A Stiles, C Prados, MD TI Phase I/II study of imatinib mesylate (STI571) for patients with recurrent malignant gliomas (NABTC 99-08) SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 9th Annual Meeting of the Society-for-Neuro-Oncology CY NOV 18-21, 2004 CL Toronto, CANADA SP Soc Neuro Oncol C1 Univ Texas, MD Anderson Canc Ctr, N Amer Brain Tumor Consortium, Houston, TX 77030 USA. Novartis, E Hanover, NJ USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RI Kesari, Santosh/E-8461-2013 NR 0 TC 11 Z9 11 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2004 VL 6 IS 4 BP 385 EP 385 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 860HF UT WOS:000224332400315 ER PT J AU Shimoda, KC Wolters, P Warren, K AF Shimoda, KC Wolters, P Warren, K TI A pilot study of proton magnetic resonance spectroscopic imaging in the evaluation of neurotoxicity in Cancer patients: Neuropsychological functioning SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 11th International Symposium on Pediatric Neuro-Oncology CY JUN 13-16, 2004 CL Boston, MA C1 NCI, Neurooncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2004 VL 6 IS 4 BP 434 EP 434 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 860HF UT WOS:000224332400460 ER PT J AU Warren, K Hill, R Black, J Aikin, A Wolters, P Shimoda, K Balis, F AF Warren, K Hill, R Black, J Aikin, A Wolters, P Shimoda, K Balis, F TI Evaluating neurotoxicity in Cancer patients SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 11th International Symposium on Pediatric Neuro-Oncology CY JUN 13-16, 2004 CL Boston, MA C1 NCI, Neurooncol Branch, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2004 VL 6 IS 4 BP 435 EP 435 PG 1 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 860HF UT WOS:000224332400464 ER PT J AU Wolters, P Martin, S Tamula, MA Wiener, L Perez, L Aikin, A Balis, F Shimoda, K Warren, K AF Wolters, P Martin, S Tamula, MA Wiener, L Perez, L Aikin, A Balis, F Shimoda, K Warren, K TI Development of a quality of life scale for children with chronic illness with CNS involvement: Preliminary data SO NEURO-ONCOLOGY LA English DT Meeting Abstract CT 11th International Symposium on Pediatric Neuro-Oncology CY JUN 13-16, 2004 CL Boston, MA C1 NCI, Med Illness Counseling Ctr, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. NR 0 TC 3 Z9 3 U1 0 U2 0 PU DUKE UNIV PRESS PI DURHAM PA 905 W MAIN ST, STE 18-B, DURHAM, NC 27701 USA SN 1522-8517 J9 NEURO-ONCOLOGY JI Neuro-Oncology PD OCT PY 2004 VL 6 IS 4 BP 448 EP 449 PG 2 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 860HF UT WOS:000224332400523 ER PT J AU Shen, DG Liu, DF Liu, H Clasen, L Giedd, J Davatzikos, C AF Shen, DG Liu, DF Liu, H Clasen, L Giedd, J Davatzikos, C TI Automated morphometric study of brain variation in XXY males SO NEUROIMAGE LA English DT Article DE XXY brain; 47,XXY brain; sex chromosome aneuploidy; Klinefelter's syndrome; morphometric study; volumetric analysis ID KLINEFELTERS-SYNDROME; CHROMOSOME; ADOLESCENTS; IMAGES AB This paper studies brain morphometry variation associated with XXY males (Klinefelter's syndrome) by using an automated whole-brain volumetric analysis method. The application to 34 XXY males and 62 normal male controls reveals pronounced volume reduction in the brains of XXY males, relative to the brains of normal controls, localized at the insula, temporal gyri, amygdala, hippocampus, cingulate, and occipital gyri. Most of these statistically significant regions are in the gray matter structures, with the exception of one cluster of atrophy involved in white matter structure, i.e., right parietal lobe white matter. Compared to previous findings documented in the literature, our findings provide a better spatial localization of the affected regions. In addition to the reduction of local volume, overall enlargement of ventricles and overall volume reduction of both white matter and gray matter are also found in XXY males. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Penn, Dept Radiol, Sect Biomed Image Anal, Philadelphia, PA 19104 USA. NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Shen, DG (reprint author), Univ Penn, Dept Radiol, Sect Biomed Image Anal, 3600 Mk St,Suite 380, Philadelphia, PA 19104 USA. RI 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 NR 20 TC 55 Z9 55 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD OCT PY 2004 VL 23 IS 2 BP 648 EP 653 DI 10.1016/j.neuroimage.2004.08.018 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 867BM UT WOS:000224817100021 PM 15488414 ER PT J AU Hasler, G Drevets, WC Manji, HK Charney, DS AF Hasler, G Drevets, WC Manji, HK Charney, DS TI Discovering endophenotypes for major depression SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE depression; phenotype; genetics; classification; biological psychiatry; epidemiology ID CORTICOTROPIN-RELEASING HORMONE; POSITRON-EMISSION-TOMOGRAPHY; CEREBRAL-BLOOD-FLOW; SUBGENUAL PREFRONTAL CORTEX; SEROTONIN TRANSPORTER GENE; NEO PERSONALITY-INVENTORY; SUBSTANCE USE DISORDERS; DEXAMETHASONE-CRH TEST; CONGRUENT MEMORY BIAS; HIGH FAMILIAL RISK AB The limited success of genetic studies of major depression has raised questions concerning the definition of genetically relevant phenotypes. This paper presents strategies to improve the phenotypic definition of major depression by proposing endophenotypes at two levels: First, dissecting the depressive phenotype into key components results in narrow definitions of putative psychopathological endophenotypes: mood bias toward negative emotions, impaired reward function, impaired learning and memory, neurovegetative signs, impaired diurnal variation, impaired executive cognitive function, psychomotor change, and increased stress sensitivity. A review of the recent literature on neurobiological and genetic findings associated with these components is given. Second, the most consistent heritable biological markers of major depression are proposed as biological endophenotypes for genetic studies: REM sleep abnormalities, functional and structural brain abnormalities, dysfunctions in serotonergic, catecholaminergic, hypothalamic-pituitary-adrenocortical axis, and CRH systems, and intracellular signal transduction endophenotypes. The associations among the psychopathological and biological endophenotypes are discussed with respect to specificity, temporal stability, heritability, familiality, and clinical and biological plausibility. Finally, the case is made for the development of a new classification system in order to reduce the heterogeneity of depression representing a major impediment to elucidating the genetic and neurobiological basis of this common, severe, and often life-threatening illness. C1 NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Hasler, G (reprint author), NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, NIH, 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 195 TC 580 Z9 601 U1 8 U2 97 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2004 VL 29 IS 10 BP 1765 EP 1781 DI 10.1038/sj.npp.1300506 PG 17 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 855TY UT WOS:000223998700001 PM 15213704 ER PT J AU Shen, HW Hagino, Y Kobayashi, H Shinohara-Tanaka, K Ikeda, K Yamamoto, H Yamamoto, T Lesch, KP Murphy, DL Hall, FS Uhl, GR Sora, I AF Shen, HW Hagino, Y Kobayashi, H Shinohara-Tanaka, K Ikeda, K Yamamoto, H Yamamoto, T Lesch, KP Murphy, DL Hall, FS Uhl, GR Sora, I TI Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE dopamine; serotonin; monoamine transporter; cocaine reward; knockout mice; in vivo microdialysis ID VENTRAL TEGMENTAL AREA; CONDITIONED PLACE PREFERENCE; CHRONIC FLUOXETINE TREATMENT; RAT PREFRONTAL CORTEX; MONOAMINE REUPTAKE; COCAINE REWARD; KNOCKOUT MICE; NOREPINEPHRINE TRANSPORTER; NUCLEUS-ACCUMBENS; BRAIN AB Cocaine conditioned place preference (CPP) is intact in dopamine transporter (DAT) knockout ( KO) mice and enhanced in serotonin transporter (SERT) KO mice. However, cocaine CPP is eliminated in double-KO mice with no DAT and either no or one SERT gene copy. To help determine mechanisms underlying these effects, we now report examination of baselines and drug-induced changes of extracellular dopamine (DA(ex)) and serotonin (5-HTex) levels in microdialysates from nucleus accumbens (NAc), caudate putamen (CPu), and prefrontal cortex (PFc) of wild-type, homozygous DAT- or SERT-KO and heterozygous or homozygous DAT/SERT double-KO mice, which are differentially rewarded by cocaine. Cocaine fails to increase DAex in NAc of DAT- KO mice. By contrast, systemic cocaine enhances DAex in both CPu and PFc of DAT- KO mice though local cocaine fails to affect DAex in CPu. Adding SERT to DAT deletion attenuates the cocaine-induced DAex increases found in CPu, but not those found in PFc. The selective SERT blocker fluoxetine increases DAex in CPu of DAT- KO mice, while cocaine and the selective DAT blocker GBR12909 increase 5-HTex in CPu of SERT-KO mice. These data provide evidence that ( a) cocaine increases DA(ex) in PFc independently of DAT and that (b), in the absence of SERT, CPu levels of 5-HTex can be increased by blocking DAT. Cocaine-induced alterations in CPu DA levels in DAT-, SERT-, and DAT/SERT double-KO mice appear to provide better correlations with cocaine CPP than cocaine-induced DA level alterations in NAc or PFc. C1 Tohoku Univ, Grad Sch Med, Dept Neurosci, Div Psychobiol, Sendai, Miyagi 9808574, Japan. Tokyo Inst Psychiat, Dept Mol Psychiat, Tokyo, Japan. Yokohama City Univ, Grad Sch Integrated Sci, Lab Mol Recognit, Yokohama, Kanagawa, Japan. Univ Wurzburg, Dept Psychiat & Psychotherapy, D-97070 Wurzburg, Germany. NIMH, Intramural Res Program, Clin Sci Lab, Bethesda, MD 20892 USA. NIDA, Mol Neurobiol Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Sora, I (reprint author), Tohoku Univ, Grad Sch Med, Dept Neurosci, Div Psychobiol, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan. EM isora@mail.cc.tohoku.ac.jp RI Kobayashi, Hideaki/C-8617-2009; Ikeda, Kazutaka/I-4694-2013; Hall, Frank/C-3036-2013; Lesch, Klaus-Peter/J-4906-2013; OI Kobayashi, Hideaki/0000-0003-3599-0465; Ikeda, Kazutaka/0000-0001-8342-0278; Hall, Frank/0000-0002-0822-4063; Lesch, Klaus-Peter/0000-0001-8348-153X; Shen, Hao-wei/0000-0002-2766-5139 NR 48 TC 109 Z9 117 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2004 VL 29 IS 10 BP 1790 EP 1799 DI 10.1038/sj.npp.1300476 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 855TY UT WOS:000223998700003 PM 15226739 ER PT J AU Culm, KE Lugo-Escobar, N Hope, BT Hammer, RP AF Culm, KE Lugo-Escobar, N Hope, BT Hammer, RP TI Repeated quinpirole treatment increases cAMP-dependent protein kinase activity and CREB phosphorylation in nucleus accumbens and reverses quinpirole-induced sensorimotor gating deficits in rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE prepulse inhibition; schizophrenia; D-2-like receptors; PKA; phospho-CREB; nucleus accumbens ID ELEMENT-BINDING PROTEIN; D-2 DOPAMINE-RECEPTORS; ADENYLATE-CYCLASE; PREPULSE INHIBITION; COCAINE; SCHIZOPHRENIA; AGONISTS; STRIATUM; SENSITIZATION; LOCALIZATION AB Sensorimotor gating, which is severely disrupted in schizophrenic patients, can be measured by assessing prepulse inhibition of the acoustic startle response (PPI). Acute administration of D-2-like receptor agonists such as quinpirole reduces PPI, but tolerance occurs upon repeated administration. In the present study, PPI in rats was reduced by acute quinpirole (0.1 mg/kg, s.c.), but not following repeated quinpirole treatment once daily for 28 days. Repeated quinpirole treatment did not alter the levels of basal-, forskolin- (5 muM), or SKF 82958- (10 muM) stimulated adenylate cyclase activity in the nucleus accumbens (NAc), but significantly increased cAMP-dependent protein kinase (PKA) activity. Phosphorylation of cAMP response element-binding protein ( CREB) was significantly greater in the NAc after repeated quinpirole treatment than after repeated saline treatment with or without acute quinpirole challenge. Activation of PKA by intra-accumbens infusion of the cAMP analog, Sp-cAMPS, prevented acute quinpirole-induced PPI disruption, similar to the behavioral effect observed following repeated quinpirole treatment. Thus, repeated quinpirole treatment increases NAc PKA activity and CREB phosphorylation, and this neuroadaptive response might facilitate the recovery of sensorimotor gating in schizophrenia. C1 Tufts Univ, Sch Med, Dept Pharmacol, Boston, MA 02111 USA. Tufts Univ, Sch Med, Dept Expt Therapeut, Boston, MA 02111 USA. Tufts Univ, Sch Med, Dept Neurosci Anat & Psychiat, Boston, MA 02111 USA. NIDA, Behav Neurosci Branch, Intramural Res Program, Baltimore, MD USA. RP Hammer, RP (reprint author), Tufts New England Med Ctr, Dept Psychiat, Box 1007,750 Washington St, Boston, MA 02111 USA. EM Ron.Hammer@tufts.edu RI Hope, Bruce/A-9223-2010 OI Hope, Bruce/0000-0001-5804-7061 FU NHLBI NIH HHS [T35 HL007785]; NIMH NIH HHS [R01 MH60251, MH66954, R01 MH060251] NR 34 TC 24 Z9 24 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2004 VL 29 IS 10 BP 1823 EP 1830 DI 10.1038/sj.npp.1300483 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 855TY UT WOS:000223998700007 PM 15138441 ER PT J AU Petrie, KA Bubser, M Casey, CD Davis, MD Roth, BL Deutch, AY AF Petrie, KA Bubser, M Casey, CD Davis, MD Roth, BL Deutch, AY TI The neurotensin agonist PD149163 increases Fos expression in the prefrontal cortex of the rat SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE dopamine; GABA; interneuron; neurotensin receptor; PD149163; SR48692 ID CORTICAL PROJECTION PATTERNS; BASAL FOREBRAIN NEURONS; LOCAL-CIRCUIT NEURONS; PREPULSE INHIBITION; CEREBRAL-CORTEX; MESSENGER-RNA; CHEMICAL CHARACTERISTICS; SCHIZOPHRENIC-PATIENTS; FUNCTIONAL EXPRESSION; DOPAMINERGIC-NEURONS AB Dopaminergic axons innervating the prefrontal cortex (PFC) target both pyramidal cells and GABAergic interneurons. Many of these dopamine (DA) axons in the rat coexpress the peptide neurotransmitter neurotensin. Previous electrophysiological data have suggested that neurotensin activates GABAergic interneurons in the PFC. Activation of D2-like DA receptors increases extracellular GABA levels in the PFC, as opposed to the striatum, where D2 receptor activation inhibits GABAergic neurons. Because activation of presynaptic D2 release-modulating autoreceptors in the PFC suppresses DA release but increases release of the cotransmitter neurotensin, D2 agonists may enhance the activity of GABAergic interneurons via release of neurotensin. In order to determine if neurotensin can activate GABAergic interneurons, we treated rats with the peptide neurotensin agonist, PD149163, and examined Fos expression in PFC neurons. Systemic administration of PD149163 increased overall Fos expression in the PFC, but not in the dorsal striatum. PD149163 induced Fos in PFC interneurons, as defined by the presence of calcium-binding proteins, and in pyramidal cells. Pretreatment with the high-affinity neurotensin antagonist, SR48692, blocked neurotensin agonist-induced Fos expression. These data suggest that neurotensin activates interneurons in the PFC of the rat. C1 Vanderbilt Univ, Med Ctr, Ctr Mol Neurosci, Dept Psychiat, Nashville, TN USA. Vanderbilt Univ, Med Ctr, Ctr Mol Neurosci, Dept Pharmacol, Nashville, TN USA. Pfizer Inc, CNS Pharmacol, Ann Arbor, MI USA. Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, NIMH, Psychoact Drug Screening Program, Cleveland, OH 44106 USA. RP Deutch, AY (reprint author), Psychiat Hosp Vanderbilt, Suite 313,1601 23rd Ave S, Nashville, TN 37212 USA. EM ariel.deutch@vanderbilt.edu RI Roth, Bryan/F-3928-2010; Davis, Michael/F-7931-2010; OI Bubser, Michael/0000-0002-0583-5248 FU NIMH NIH HHS [KO2MH01366, MH-12972, MH-45124, MH-57995] NR 77 TC 28 Z9 28 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD OCT PY 2004 VL 29 IS 10 BP 1878 EP 1888 DI 10.1038/sj.npp.1300494 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 855TY UT WOS:000223998700012 PM 15150532 ER PT J AU Eckelman, WC AF Eckelman, WC TI Obituary - Joseph Steigman SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Biographical-Item C1 NIH, Bethesda, MD 20892 USA. RP Eckelman, WC (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 1 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 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD OCT PY 2004 VL 31 IS 7 BP 971 EP 972 DI 10.1016/j.nucmedbio.2004.05.006 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 862UM UT WOS:000224516600017 ER PT J AU Zhang, J Hatch, M Zhang, D Shulman, J Harville, E Thomas, AG AF Zhang, J Hatch, M Zhang, D Shulman, J Harville, E Thomas, AG TI Frequency of douching and risk of bacterial vaginosis in African-American women SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID VAGINAL MICROFLORA; GENITAL-TRACT; HEALTH; LACTOBACILLI; INFECTION AB OBJECTIVE: Frequent vaginal douching has been associated with bacterial vaginosis. We investigated whether infrequent douching is also a risk factor for bacterial vaginosis. METHODS: In this cross-sectional study, we recruited 411 African-American women of reproductive age who were visiting gynecologic or family planning clinics of 2 hospitals in New York City from 1999 to 2001. Detailed information on demographic characteristics, feminine hygiene practice, contraceptive use, and reproductive and medical history was collected through in-person interview. Pelvic examinations and laboratory tests on vaginal secretions were performed. Bacterial vaginosis was defined as Gram stain score of 7 or greater. RESULTS: The overall prevalence of bacterial vaginosis in this population was 27%, similar to the national average. Water-vinegar solution was the most common douche. Although one half of the subjects reported douching regularly, only 2% douched frequently (once per week or more). Frequent douching in the past 3 months had a prevalence ratio of bacterial vaginosis of 2.35 (95% confidence interval 0.98-5.63). However, douching less than once per week was not associated with bacterial vaginosis. CONCLUSION: Douching less than once per week, particularly with a water-vinegar douche, is not associated with bacterial vaginosis in this African-American population. (C) 2004 by The American College of Obstetricians and Gynecologists. C1 Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. Mt Sinai Sch Med, Dept Pathol, New York, NY USA. Mt Sinai Sch Med, Dept Gynecol & Reprod Sci, New York, NY USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Zhang, J (reprint author), NICHHD, Epidemiol Branch, NIH, Bldg 6100,Room 7B03, Bethesda, MD 20892 USA. EM zhangj@mail.nih.gov NR 21 TC 20 Z9 22 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD OCT PY 2004 VL 104 IS 4 BP 756 EP 760 DI 10.1097/01.AOG.0000139947.90826.98 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 875JF UT WOS:000225415600019 PM 15458898 ER PT J AU Nygaard, IE McCreery, R Brubaker, L Connolly, AM Cundiff, G Weber, AM Zyczynski, H AF Nygaard, IE McCreery, R Brubaker, L Connolly, AM Cundiff, G Weber, AM Zyczynski, H CA Pelvic Floor Disorders Networks TI Abdominal sacrocolpopexy: A comprehensive review SO OBSTETRICS AND GYNECOLOGY LA English DT Review ID VAGINAL-VAULT PROLAPSE; PELVIC ORGAN PROLAPSE; TERM-FOLLOW-UP; LAPAROSCOPIC SACRAL COLPOPEXY; URINARY STRESS-INCONTINENCE; GENITOURINARY PROLAPSE; UTEROVAGINAL PROLAPSE; MESH EROSION; POSTERIOR COMPARTMENT; SURGICAL-MANAGEMENT AB OBJECTIVE: To summarize published data about abdominal sacrocolpopexy and to highlight areas about which data are lacking. DATA SOURCES: We conducted a literature search on MEDLINE using Ovid and PubMed, from January, 1966 to january, 2004, using search terms "sacropexy," "sacrocolpope," "sacral colpopexy," "colpopexy," "sacropexy," "colposacropexy," "abdominal sacrocolpopexy" "pelvic organ prolapse and surgery," and "vaginal vault prolapse or surgery" and included articles with English-language abstracts. We examined reference lists of published articles to identify other articles not found on the electronic search. METHODS OF STUDY SELECTION: We examined all studies identified in our search that provided any outcome data on sacrocolpopexy. Because of the substantial heterogeneity of outcome measures and follow-up intervals in case studies, we did not apply meta-analytic techniques to the data. TABULATION, INTEGRATION, AND RESULTS: Follow-up duration for most studies ranged from 6 months to 3 years. The success rate, when defined as lack of apical prolapse post-operatively, ranged from 78-100% and when defined as no postoperative prolapse, from 58-100%. The median reoperation rates for pelvic organ prolapse and for stress urinary incontinence in the studies that reported these outcomes were 4.4% (range 0-18.2%) and 4.9% (range 1.2% to 30.90%) respectively. The overall rate of mesh erosion was 3.4% (70 of 2,178). Some reports found more mesh erosions when concomitant total hysterectomy was done, whereas other reports did not. There were no data to either support or refute the contentions that concomitant culdoplasty or paravaginal repair decreased the risk of failure. Most authors recommended burying the graft under the peritoneum to attempt to decrease the risk of bowel obstruction; despite this, the median rate (when reported) of small bowel obstruction requiring surgery was 1.1% (range 0.6% to 8.6%). Few studies rigorously assessed pelvic symptoms, bowel function, or sexual function. CONCLUSION: Sacrocolpopexy is a reliable procedure that effectively and consistently resolves vaginal vault prolapse. Patients should be counseled about the low, but present risk, of reoperation for prolapse, stress incontinence, and complications. Prospective trials are needed to understand the effect of sacrocolpopexy on functional outcomes. (C) 2004 by The American College of Obstetricians and Gynecologists. C1 Univ Iowa, Dept Obstet & Gynecol, Carver Coll Med, Iowa City, IA 52242 USA. Baylor Coll Med, Houston, TX USA. Loyola Univ, Chicago, IL 60611 USA. Univ N Carolina, Chapel Hill, NC USA. Johns Hopkins Sch Med, Baltimore, MD USA. NICHHD, Bethesda, MD 20892 USA. Magee Womens Hosp, Pittsburgh, PA USA. RP Nygaard, IE (reprint author), Univ Iowa, Dept Obstet & Gynecol, Carver Coll Med, 200 Hawkins Dr,2BT, Iowa City, IA 52242 USA. EM ingrid-nygaard@uiowa.edu FU NICHD NIH HHS [U10 HD 41268, U01 HD 41249, U01 HD 41267, U10 HD 41248, U10 HD 41263, U10 HD 41250, U10 HD 41261, U10 HD 41269, U10 HD041263] NR 99 TC 391 Z9 408 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD OCT PY 2004 VL 104 IS 4 BP 805 EP 823 DI 10.1097/01.AOG.0000139514.90897.07 PG 19 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 875JF UT WOS:000225415600027 PM 15458906 ER PT J AU Mooney, MM Schoenfeldt, M AF Mooney, MM Schoenfeldt, M CA EMMES Corp TI Current phase II and phase III clinical trials in the treatment of colorectal cancer SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID COLON-CANCER; PLUS IRINOTECAN; FLUOROURACIL; LEUCOVORIN; OXALIPLATIN C1 NCI, Bethesda, MD 20892 USA. Emmes Corp, Rockville, MD USA. RP Mooney, MM (reprint author), NCI, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD OCT PY 2004 VL 18 IS 11 BP 1396 EP + PG 5 WC Oncology SC Oncology GA 052DS UT WOS:000238212000011 PM 15609469 ER PT J AU Rosenberg, SA AF Rosenberg, SA TI The Buzaid article reviewed SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID METASTATIC CANCER; INTERLEUKIN-2; LYMPHOCYTES; ANTIGENS C1 NCI, Div Clin Sci, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Div Clin Sci, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD OCT PY 2004 VL 18 IS 11 BP 1457 EP 1457 PG 1 WC Oncology SC Oncology GA 052DS UT WOS:000238212000019 ER PT J AU Evidente, VGH Esteban, RP Hernandez, JL Natividad, FF Advincula, J Gwinn-Hardy, K Hardy, J Singleton, A Singleton, A AF Evidente, VGH Esteban, RP Hernandez, JL Natividad, FF Advincula, J Gwinn-Hardy, K Hardy, J Singleton, A Singleton, A TI Smell testing is abnormal in 'lubag' or X-linked dystonia-parkinsonism: a pilot study SO PARKINSONISM & RELATED DISORDERS LA English DT Article DE olfaction; X-linked dystonia parkinsonism; XDP; Lubag ID OLFACTORY DYSFUNCTION; DISEASE; DYT3; LOCUS AB We administered a culturally corrected University of Pennsylvania Smell Identification Test (ccUPSIT) consisting of 25 odor items to 20 patients with 'Lubag' or X-linked dystonia-parkinsonism and 20 control subjects matched by sex, age, educational background, smoking history, and geographical origin. The mean ccUPSIT score of Lubag patients (18 +/- 3.19) was statistically lower (P = 0.003) than controls (20.5 +/- 3.02). The smell scores did not correlate with phenotype, severity of dystonia, or duration of disease. Nine of 20 Lubag patients (45%) had ccUPSIT scores below the mean, with the lowest score being 11. This pilot study suggests that olfactory dysfunction may occur in Lubag patients. (C) 2004 Elsevier Ltd. All rights reserved. C1 Mayo Clin Scottsdale, Dept Neurol, Scottsdale, AZ 85259 USA. St Lukes Hosp, Dept Neurosci, Quezon City, Philippines. Mayo Clin Scottsdale, Dept Neurosci, Scottsdale, AZ 85259 USA. Western Visayas State Univ, Med Ctr, Iloilo, Philippines. NINDS, NIH, Bethesda, MD 20892 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Evidente, VGH (reprint author), Mayo Clin Scottsdale, Dept Neurol, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM evidente.virgilio@mayo.edu RI Gwinn, Katrina/C-2508-2009; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; OI Gwinn, Katrina/0000-0002-8277-651X NR 21 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1353-8020 J9 PARKINSONISM RELAT D JI Parkinsonism Relat. Disord. PD OCT PY 2004 VL 10 IS 7 BP 407 EP 410 DI 10.1016/j.parkreldis.2004.04.011 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 864BN UT WOS:000224607900003 PM 15465396 ER PT J AU Alter, BP AF Alter, BP TI Commentary - Growth hormone and the risk of malignancy SO PEDIATRIC BLOOD & CANCER LA English DT Editorial Material ID PITUITARY-STALK INTERRUPTION; FANCONI-ANEMIA; ADULT HEIGHT; LEUKEMIA; DEFICIENCY; CANCER; CHILDREN; SAFETY C1 NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Alter, BP (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, 6120 Execut Blvd,Execut Plaza S,Room 7020, Rockville, MD 20852 USA. EM alterb@mail.nih.gov NR 25 TC 3 Z9 3 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT PY 2004 VL 43 IS 5 BP 534 EP 535 DI 10.1002/phc.20110 PG 2 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 858KS UT WOS:000224191300002 PM 15382267 ER PT J AU Bell, MJ Hallenbeck, JM Gallo, V AF Bell, MJ Hallenbeck, JM Gallo, V TI Determining the fetal inflammatory response in an experimental model of intrauterine inflammation in rats SO PEDIATRIC RESEARCH LA English DT Article ID TUMOR-NECROSIS-FACTOR; WHITE-MATTER LESIONS; FACTOR-ALPHA; INTERFERON-GAMMA; CEREBRAL-PALSY; BRAIN-INJURY; NERVOUS-SYSTEM; PERIVENTRICULAR LEUKOMALACIA; INTERLEUKIN-6 IL-6; NITRIC-OXIDE AB Intrauterine infection is a risk factor for developmental brain injuries in childhood. A variety of cytokines known to be toxic to developing brain cells have been isolated from mothers or children at risk for developmental disabilities, and these cytokines have been proposed as mediators of these injuries. We have developed a model of intrauterine inflammation that damages the developing white matter and we now hypothesize that selected cytokines are increased after our experimental inflammatory stimulus. Timed-pregnant Fischer 344 and Lewis rats were injected with 0.1 mg/kg of lipopolysaccharide (LPS) into the cervix at E15. Tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-6, and IL-10 were measured in homogenates of fetal brain and placenta at serial time periods within the first 24 h after the inflammatory stimulus. TNF-a was increased 20-fold in the placenta and more than 5-fold in the fetal brain after the stimulus. IFN-gamma was only increased within the fetal brain (20-fold) and IL-6 was only increased in the placenta (10-fold). IL-10 was mildly increased in the placenta and was decreased slightly in the fetal brain. Our observations show that an intrauterine inflammatory stimulus can cause large increases in Th1 cytokines within the fetal brain. The placenta can produce selected cytokines but fails to produce IFN-gamma, suggesting that the fetal immune system produces this cytokine in response to our stimulus. By studying placental and brain cytokine responses in models such as ours, the mechanisms responsible for the damage to developing white matter can be determined. C1 Childrens Natl Med Ctr, Dept Crit Care Med, Childrens Res Inst, Ctr Neurosci Res, Washington, DC 20010 USA. NINDS, Stroke Branch, Bethesda, MD 20892 USA. RP Bell, MJ (reprint author), Childrens Natl Med Ctr, Dept Crit Care Med, Childrens Res Inst, Ctr Neurosci Res, 111 Michigan Ave NW, Washington, DC 20010 USA. EM mbell@cnmc.org FU NICHD NIH HHS [K08 HD044716, K12 HD01399] NR 42 TC 79 Z9 85 U1 0 U2 2 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD OCT PY 2004 VL 56 IS 4 BP 541 EP 546 DI 10.1203/01.PDR.0000139407.89883.6B PG 6 WC Pediatrics SC Pediatrics GA 855WG UT WOS:000224005000005 PM 15295096 ER PT J AU Blair, RJR Mitchell, DGV Peschardt, KS Colledge, E Leonard, RA Shine, JH Murray, LK Perrett, DI AF Blair, RJR Mitchell, DGV Peschardt, KS Colledge, E Leonard, RA Shine, JH Murray, LK Perrett, DI TI Reduced sensitivity to others' fearful expressions in psychopathic individuals SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article DE facial expressions; fear; amygdala; orbital frontal cortex; violence inhibition mechanism ID BILATERAL AMYGDALA DAMAGE; FACIAL EXPRESSIONS; RESPONSE REVERSAL; NEURAL RESPONSES; STARTLE REFLEX; DISTRESS CUES; EMOTION; RECOGNITION; IMPAIRMENT; PERSONALITY AB This study investigates the ability of psychopathic individuals to process facial emotional expressions. Psychopathic and comparison individuals, as defined by the Hare Psychopathy Checklist Revised (PCL-R), were presented with a standardized set of facial expressions depicting six emotions: happy, surprised, disgusted, angry, sad and fearful. Participants observed as these facial expressions slowly evolved through 20 successive frames of increasing intensity. The dependent variables were latency in responding as measured by frame and number of errors. The psychopathic individuals showed selective impairment for the recognition of fearful expressions. The results are interpreted with reference to the Violence Inhibition Mechanism model of psychopathy and the suggestion that psychopathic individuals present with amygdala dysfunction. Published by Elsevier Ltd. C1 NIMH, Mood & Anxiety Disorders Program, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. UCL, Inst Cognit Neurosci, Dept Psychol, London WC1E 6BT, England. Kings Coll London, Inst Psychiat, SGDP Res Ctr, London WC2R 2LS, England. Univ St Andrews, Sch Psychol, St Andrews KY16 9AJ, Fife, Scotland. RP Blair, RJR (reprint author), NIMH, Mood & Anxiety Disorders Program, Dept Hlth & Human Serv, NIH, 15K N Dr,Room 206,MSC 2760, Bethesda, MD 20892 USA. EM blairj@intra.nimh.nih.gov NR 52 TC 137 Z9 141 U1 11 U2 51 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD OCT PY 2004 VL 37 IS 6 BP 1111 EP 1122 DI 10.1016/j.paid.2003.10.008 PG 12 WC Psychology, Social SC Psychology GA 860TN UT WOS:000224366300001 ER PT J AU Blair, RJR Mitchell, DGV Leonard, A Budhani, S Peschardt, KS Newman, C AF Blair, RJR Mitchell, DGV Leonard, A Budhani, S Peschardt, KS Newman, C TI Passive avoidance learning in individuals with psychopathy: modulation by reward but not by punishment SO PERSONALITY AND INDIVIDUAL DIFFERENCES LA English DT Article DE passive avoidance; psychopathy; amygdala; reward; punishment ID PERSONALITY; DISINHIBITION; DISORDERS; OFFENDERS; AMYGDALA; EVENTS AB This study investigates the ability of individuals with psychopathy to perform passive avoidance learning and whether this ability is modulated by level of reinforcement/punishment. Nineteen psychopathic and 21 comparison individuals, as defined by the Hare Psychopathy Checklist Revised (Hare, 1991), were given a passive avoidance task with a graded reinforcement schedule. Response to each rewarding number gained a point reward specific to that number (i.e., 1, 700, 1400 or 2000 points). Response to each punishing number lost a point punishment specific to that number (i.e., the loss of 1, 700, 1400 or 2000 points). In line with predictions, individuals with psychopathy made more passive avoidance errors than the comparison individuals. In addition, while the performance of both groups was modulated by level of reward, only the performance of the comparison population was modulated by level of punishment. The results are interpreted with reference to a computational account of the emotional learning impairment in individuals with psychopathy. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIMH, Mood & Anxiety Disorders Program, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. UCL, Inst Cognit Neurosci, London WC1E 6BT, England. UCL, Dept Psychol, London WC1E 6BT, England. HMP Wormwood Scrubs, Dept Psychol, London, England. RP Blair, RJR (reprint author), NIMH, Mood & Anxiety Disorders Program, Dept Hlth & Human Serv, NIH, 15K N Dr,Room 206,MSC 2670, Bethesda, MD 20892 USA. EM blairj@intra.nimh.nih.gov NR 34 TC 57 Z9 57 U1 4 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0191-8869 J9 PERS INDIV DIFFER JI Pers. Individ. Differ. PD OCT PY 2004 VL 37 IS 6 BP 1179 EP 1192 DI 10.1016/j.paid.2003.12.001 PG 14 WC Psychology, Social SC Psychology GA 860TN UT WOS:000224366300006 ER PT J AU Guerra, L Favia, M Fanelli, T Calamita, G Svelto, M Bagorda, A Jacobson, KA Reshkin, SJ Casavola, V AF Guerra, L Favia, M Fanelli, T Calamita, G Svelto, M Bagorda, A Jacobson, KA Reshkin, SJ Casavola, V TI Stimulation of Xenopus P2Y1 receptor activates CFTR in A6 cells SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE Xenopus P2Y1; CFTR; NHERF-2; A6 ID TRANSMEMBRANE CONDUCTANCE REGULATOR; PROTEIN-KINASE-A; MEMBRANE CHLORIDE PERMEABILITY; RENAL EPITHELIAL-CELLS; CYSTIC-FIBROSIS; EXTRACELLULAR ATP; ADENYLYL-CYCLASE; APICAL MEMBRANE; PURINERGIC RECEPTORS; ADENINE-NUCLEOTIDES AB Nucleotide binding to purinergic P2Y receptors contributes to the regulation of a variety of physiological functions in renal epithelial cells. Here, we investigate the regulatory mechanism of the P2Y1 receptor agonist 2-methylthioadenosine diphosphate (2-MeSADP) on Cl- transport in A6 cells, a commonly used model of the distal section of the Xenopus laevis nephron. Protein and mRNA expression analysis together with functional measurements demonstrated the basolateral location of the Xenopus P2Y1 receptor. 2-MeSADP increased intracellular [Ca2+] and cAMP and Cl- efflux, responses that were all inhibited by the specific P2Y1 receptor antagonist MRS 2179. Cl- efflux was also inhibited by the cystic fibrosis transmembrane conductance regulator (CFTR) blocker glibenclamide. Inhibition of either protein kinase A (PKA) or the binding between A-kinase-anchoring proteins (AKAPs) and the regulatory PKA RII subunit blocked the 2-MeSADP-induced activation of CFTR, suggesting that PKA mediates P2Y1 receptor regulation of CFTR through one or more AKAPs. Further, the truncation of the PDZ1 domain of the scaffolding protein Na+/H+ exchanger regulatory factor-2 (NHERF-2) inhibited 2-MeSADP-dependent stimulation of Cl- efflux, suggesting the involvement of this scaffolding protein. Activation or inhibition of PKC had no effect per se on basal Cl- efflux but potentiated or reduced the 2-MeSADP-dependent stimulation of Cl- efflux, respectively. These data suggest that the X. laevis P2Y1 receptor in A6 cells can increase both cAMP/PKA and Ca2+/PKC intracellular levels and that the PKC pathway is involved in CFTR activation via potentiation of the PKA pathway. C1 Univ Bari, Dept Gen & Environm Physiol, I-70126 Bari, Italy. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD USA. RP Casavola, V (reprint author), Univ Bari, Dept Gen & Environm Physiol, Via Amendola 165-A, I-70126 Bari, Italy. EM casavola@biologia.uniba.it RI Jacobson, Kenneth/A-1530-2009; OI Jacobson, Kenneth/0000-0001-8104-1493; CASAVOLA, Valeria/0000-0003-4471-4948; Calamita, Giuseppe/0000-0003-4666-9546; Reshkin, Stephan/0000-0001-9757-5908; Svelto, Maria/0000-0002-5584-9541; GUERRA, Lorenzo/0000-0003-3950-9405 FU Intramural NIH HHS [Z01 DK031116-20]; Telethon [E.1125] NR 52 TC 13 Z9 13 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0031-6768 J9 PFLUG ARCH EUR J PHY JI Pflugers Arch. PD OCT PY 2004 VL 449 IS 1 BP 66 EP 75 DI 10.1007/s00424-004-1293-2 PG 10 WC Physiology SC Physiology GA 863SX UT WOS:000224583900007 PM 15235914 ER PT J AU Dominick, KL Bosworth, HB Jeffreys, AS Grambow, SC Oddone, EZ Horner, RD AF Dominick, KL Bosworth, HB Jeffreys, AS Grambow, SC Oddone, EZ Horner, RD TI Racial/ethnic variations in non-steroidal anti-inflammatory drug (NSAID) use among patients with osteoarthritis SO PHARMACOEPIDEMIOLOGY AND DRUG SAFETY LA English DT Article DE osteoarthritis; ethnic groups; non-steroidal anti-inflammatory drugs; pharmacoepidemiology; health services research; physician's practice patterns ID TOTAL HIP-ARTHROPLASTY; CYCLOOXYGENASE-2 SELECTIVITY; ETHNIC-DIFFERENCES; CARE; ARTHRITIS; PAIN; COMPLICATIONS; DISPARITIES; MANAGEMENT; POPULATION AB Purpose Non-steroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed drugs for the treatment of osteoarthritis (OA). While there are documented racial differences in the use of opioid analgesics, little is known about racial differences in the use of NSAIDs. Methods This was a retrospective cohort study among a national sample of 6038 veterans with OA. Patients were new NSAID users, followed for approximately 6 months. Primary outcomes included: type of NSAID prescribed (COX-2 selective or preferentially COX-2 selective NSAIDs vs other NSAIDs), days' supply of initial prescription and time to discontinuation of the index NSAID. Results In an analysis adjusted for demographic and gastrointestinal (GI) bleeding risk factors (age, sex, geographic region, history of GI bleeding, comorbid illnesses, use of anti-coagulants and glucocorticoids), Hispanics were less likely than whites to be prescribed an NSAID with some degree of COX-2 selectivity (odds ratio (OR): 0.47, p < 0.01). The days' supply of the initial prescription was lower for both blacks and Hispanics compared to whites (mean: 38, 31 and 43 days respectively, p < 0.01). In an analysis adjusted for demographics, GI bleeding risk factors and type of NSAID prescribed, blacks discontinued use of the index NSAID earlier than whites (hazard ratio = 1.19, p < 0.001) and there was a similar trend for Hispanics. Conclusion Minorities with OA were prescribed NSAIDs with less COX-2 selectivity and lower days' supply than whites. Further research should address underlying reasons and whether these differences impact outcomes such as pain control, side effects and cost-effectiveness of care. Published in 2003 by John Wiley Sons, Ltd. C1 Ctr Hlth Serv Res Primary Care, Durham Vet Affairs Med Ctr, Durham, NC 27705 USA. Duke Univ, Med Ctr, Div Gen Internal Med, Dept Med, Durham, NC 27706 USA. Duke Univ, Ctr Aging & Human Dev, Durham, NC 27706 USA. Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27706 USA. Duke Univ, Med Ctr, Dept Biostat & Bioinformat, Durham, NC 27706 USA. NINDS, Off Minor Hlth & Res, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Dominick, KL (reprint author), Ctr Hlth Serv Res Primary Care, Durham Vet Affairs Med Ctr, 508 Fulton St, Durham, NC 27705 USA. EM domin004@mc.duke.edu RI Grambow, Steven/E-1422-2015 OI Grambow, Steven/0000-0001-6037-3253 NR 45 TC 19 Z9 19 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1053-8569 J9 PHARMACOEPIDEM DR S JI Pharmacoepidemiol. Drug Saf. PD OCT PY 2004 VL 13 IS 10 BP 683 EP 694 DI 10.1002/pds.904 PG 12 WC Public, Environmental & Occupational Health; Pharmacology & Pharmacy SC Public, Environmental & Occupational Health; Pharmacology & Pharmacy GA 862GO UT WOS:000224478800003 PM 15386734 ER PT J AU Wojnowski, L Turner, PC Pedersen, B Hustert, E Brockmoller, J Mendy, M Whittle, HC Kirk, G Wild, CP AF Wojnowski, L Turner, PC Pedersen, B Hustert, E Brockmoller, J Mendy, M Whittle, HC Kirk, G Wild, CP TI Increased levels of aflatoxin-albumin adducts are associated with CYP3A5 polymorphisms in The Gambia, West Africa SO PHARMACOGENETICS LA English DT Article DE aflatoxins; hepatocellular carcinoma; CYP3A5; genetic polymorphism ID CARCINOGEN METABOLIZING ENZYMES; HUMAN LIVER; GENETIC-DETERMINANTS; EPOXIDE HYDROLASE; DRUG-METABOLISM; PUBLIC-HEALTH; EXPRESSION; B-1; HEPATITIS; ACTIVATION AB Objectives Major risk factors for hepatocellular carcinoma (HCC) are hepatitis viruses and exposure to aflatoxins, including aflatoxin B1 (AFB1). The mutagenic effect of AFB1 results from hepatic bioactivation to AFB1 -exo-8,9-epoxide. This is in part catalysed by CYP3A5, an enzyme expressed polymorphically. We investigated the role of CYP3A5 polymorphisms in the formation of AFB1 -exo-8,9-epoxide in The Gambia, a population exposed to high aflatoxin levels. Methods Common CYP3A5 polymorphisms were identified in an African-American population. Subsequently, 288 Gambian subjects were genotyped and CYP3A5 activity predicted using haplotypes of the three variant loci (CYP3A5*3, *6 and *7) associated with decreases in protein expression. CYP3A5 expression was then compared to aflatoxin-albumin (AF-alb) adduct, a biomarker of AFB1 bioactivation; data were also analysed in relation to expression of other aflatoxin-metabolizing enzymes. Results CYP3A5 haplotypes reflecting high CYP3A5 protein expression were associated with increased AF-alb. Compared to individuals with predicted low expression those predicted to express CYP3A5 from one allele displayed 16.1% higher AF-alb (95% CI: -2.5,38.2, P = 0.093) and homozygous expressers displayed 23.2% higher AF-alb levels (95% CI: -0.01, 52.0, P = 0.051). The effect of the CYP3A5 polymorphism was strongest in individuals with low CYP3A4 activity with a 70.1% increase in AF-alb (95% CI: 11.8,158.7, P < 0.05) in high compared to low expressers. A similar effect was observed for individuals with null alleles of GSTM1, which conjugates the AFB1 -exo-8,9-epoxide to reduced glutathione. Conclusions The CYP3A5 polymorphism is associated with increased levels of the mutagenic AFB1 -exo-8,9-epoxide, particularly in individuals with low CYP3A4, and this may modulate individual risk of HCC. (C) 2004 Lippincott Williams Wilkins. C1 Univ Leeds, Ctr Biostat & Epidemiol, Mol Epidemiol Unit, Leeds Inst Genet Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England. Johannes Gutenberg Univ Mainz, Dept Pharmacol, D-55101 Mainz, Germany. US Dept HHS, NCI, Viral Epidemiol Branch, NIH, Bethesda, MD USA. Epidauros Biotechnol AG, D-82347 Bernried, Germany. MRC Labs, Fajara, Gambia. Univ Gottingen, Dept Clin Pharmacol, D-37075 Gottingen, Germany. RP Wild, CP (reprint author), Univ Leeds, Ctr Biostat & Epidemiol, Mol Epidemiol Unit, Leeds Inst Genet Hlth & Therapeut, Leeds LS2 9JT, W Yorkshire, England. EM c.p.wild@leeds.co.uk RI Turner, Paul/A-6152-2011; Turner, Paul/B-8131-2013 NR 23 TC 39 Z9 44 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0960-314X J9 PHARMACOGENETICS JI Pharmacogenetics PD OCT PY 2004 VL 14 IS 10 BP 691 EP 700 DI 10.1097/00008571-200410000-00007 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 865FK UT WOS:000224687700007 PM 15454734 ER PT J AU Ganesh, SK Skelding, KA Mehta, L O'Neill, K Joo, J Zheng, G Goldstein, J Simari, R Billings, E Geller, NL Holmes, D O'Neill, WW Nabel, EG AF Ganesh, SK Skelding, KA Mehta, L O'Neill, K Joo, J Zheng, G Goldstein, J Simari, R Billings, E Geller, NL Holmes, D O'Neill, WW Nabel, EG TI Rationale and study design of the CardioGene Study: genomics of in-stent restenosis SO PHARMACOGENOMICS LA English DT Article DE cardiovascular disease; genetic susceptibility; genomics; genotyping; proteomics ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; RAT CAROTID ARTERIES; SMOOTH-MUSCLE-CELLS; CORONARY ANGIOPLASTY; NEOINTIMAL FORMATION; BALLOON ANGIOPLASTY; INTIMAL HYPERPLASIA; BONE-MARROW; P-SELECTIN; HYPERCHOLESTEROLEMIC RABBITS C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. Mayo Clin, Div Cardiovasc Dis, Rochester, MN USA. William Beaumont Hosp, Div Cardiol, Royal Oak, MI 48072 USA. RP Nabel, EG (reprint author), NHLBI, Cardiovasc Branch, NIH, 50 S Dr,Bldg 50,Rm 4523, Bethesda, MD 20892 USA. EM enabel@nih.gov RI Mehta, Laxmi/E-3654-2011 NR 83 TC 3 Z9 3 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD OCT PY 2004 VL 5 IS 7 BP 949 EP + DI 10.1517/14622416.5.7.949 PG 56 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 864CU UT WOS:000224611500017 ER PT J AU Goldspiel, BR AF Goldspiel, BR TI Chemotherapy dose density in early-stage breast cancer and non-Hodgkin's lymphoma SO PHARMACOTHERAPY LA English DT Review DE standard-dose chemotherapy; dose-dense chemotherapy; early-stage breast cancer; non-Hodgkin's lymphoma; hematologic toxicity; neutropenia; colony-stimulating factor ID COLONY-STIMULATING FACTOR; LARGE-CELL LYMPHOMA; BONE-MARROW-TRANSPLANTATION; 3-WEEKLY CHOP CHEMOTHERAPY; SURGICAL ADJUVANT BREAST; ELDERLY-PATIENTS; PHASE-II; RANDOMIZED-TRIAL; AGGRESSIVE LYMPHOMAS; PROGNOSTIC-SIGNIFICANCE AB Delivering standard-dose chemotherapy on schedule is important for survival in early-stage breast cancer and non-Hodgkin's lymphoma. Trials of dose-escalated regimens, in which higher-than-standard doses of chemotherapy are used, have produced equivocal results. In contrast, dose-dense regimens, in which standard doses are given with shorter (usually 14-day) intervals between cycles, have been more efficacious than standard 21-day regimens in trials in both early-stage breast cancer and non-Hodgkin's lymphoma. Furthermore, a shorter course of chemotherapy is likely to cause less disruption in patients' lives. Despite the evidence of the importance of maintaining chemotherapy dose intensity (the amount of drug administered/unit of time), undertreatment of patients with early-stage breast cancer and non-Hodgkin's lymphoma is common. Neutropenia is the primary dose-limiting toxicity of many chemotherapy regimens, and it is frequently managed by dose reductions and delays that decrease dose intensity. Colony-stimulating factors reduce the prevalence and severity of neutropenia and its complications, and their proactive use can improve adherence to the planned schedule of both standard-dose and dose-dense chemotherapy. The promising results with dose-dense chemotherapy in early-stage breast cancer and non-Hodgkin's lymphoma indicate that it should be tested in patients with other chemosensitive tumors. C1 NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. RP Goldspiel, BR (reprint author), NIH, Ctr Clin, Dept Pharm, Bldg 10,Room 1N-257, Bethesda, MD 20892 USA. EM bgoldspiel@nih.gov NR 76 TC 5 Z9 5 U1 0 U2 1 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD OCT PY 2004 VL 24 IS 10 BP 1347 EP 1357 DI 10.1592/phco.24.14.1347.43154 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 858HG UT WOS:000224182300007 PM 15628832 ER PT J AU Lee, CR Pieper, JA Hawke, RL Hinderliter, AL Blaisdell, JA Goldstein, JA AF Lee, CR Pieper, JA Hawke, RL Hinderliter, AL Blaisdell, JA Goldstein, JA TI Twenty-four hour tolbutamide plasma concentration as a phenotypic measure of CYP2C9 activity in humans SO PHARMACOTHERAPY LA English DT Meeting Abstract CT Annual Meeting of the American-College-of-Clinical-Pharmacy CY OCT 24-27, 2004 CL Dallas, TX SP Amer Coll Clin Pharm C1 UNC, Chapel Hill, NC USA. Univ New Mexico, Albuquerque, NM 87131 USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD OCT PY 2004 VL 24 IS 10 MA 261 BP 1459 EP 1459 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 858HG UT WOS:000224182300204 ER PT J AU Westbroek, W Lambert, J De Schepper, S Kleta, R Van den Bossche, K Seabra, MC Huizing, M Mommaas, M Naeyaert, JM AF Westbroek, W Lambert, J De Schepper, S Kleta, R Van den Bossche, K Seabra, MC Huizing, M Mommaas, M Naeyaert, JM TI Rab27b is up-regulated in human Griscelli syndrome type II melanocytes and linked to the actin cytoskeleton via exon F-myosin va transcripts SO PIGMENT CELL RESEARCH LA English DT Article DE Griscelli syndrome; RAB27A; RAB27B; melanophilin; myosin Va; melanosome; melanocyte ID NEUROLOGICAL INVOLVEMENT; MELANOSOME TRANSPORT; MUTATIONS; GENE; PROTEINS; DISEASE; GTPASES; TYROSINASE; MOVEMENT; RECEPTOR AB Patients with the autosomal recessive Griscelli-Prunieras syndrome type II are immunologically impaired and have an unusual silvery-grey hypopigmented colour of scalp hair, eyelashes and eyebrows but no noteworthy pigmentary abnormalities of the skin. In most Griscelli patients, the RAB27A gene, which encodes a small GTPase that is associated with the melanosome membrane in melanocytes, is mutated. Here we discuss a genomic RAB27A deletion found in a 21-month-old Moroccan Griscelli patient. Additionally, we provide evidence that the loss of functional Rab27a in melanocytes of this Griscelli patient is partially compensated by the up-regulation of Rab27b, a homologue of Rab27a. By real-time quantitative PCR and western blot analysis, we found that Rab27b mRNA and protein, expressed at low levels in normal human melanocytes, is significantly up-regulated in melanocytes derived from this patient. Our immunofluorescence and yeast two-hybrid screening studies reveal that Rab27b can form a tripartite complex on the melanosome membrane with Melanophilin, a Rab27a effector, and protein products of Myosin Va transcripts that contain exon F. Our data suggest that up-regulated Rab27b in melanocytes of the Griscelli patient can partially take over the function of Rab27a, which could explain the fact that this patient had an evenly pigmented skin and was able to tan. C1 Ghent Univ Hosp, Dept Dermatol, B-9000 Ghent, Belgium. NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Univ London Imperial Coll Sci Technol & Med, Fac Med, Div Biomed Sci, Sect Cell & Mol Biol, London, England. Leiden Univ, Med Ctr, Dept Mol Cell Biol, Leiden, Netherlands. RP Naeyaert, JM (reprint author), Ghent Univ Hosp, Dept Dermatol, De Pintelaan 185, B-9000 Ghent, Belgium. EM jeanmarie.naeyaert@ugent.be OI Seabra, Miguel/0000-0002-6404-4892 NR 36 TC 28 Z9 29 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD OCT PY 2004 VL 17 IS 5 BP 498 EP 505 DI 10.1111/j.1600-0749.2004.00173.x PG 8 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 852IF UT WOS:000223748300006 PM 15357836 ER PT J AU Stennett, LS Riker, AI Kroll, TM Chamberlin, J Miki, T Nickoloff, BJ Le Poole, IC AF Stennett, LS Riker, AI Kroll, TM Chamberlin, J Miki, T Nickoloff, BJ Le Poole, IC TI Expression of gp100 and CDK2 in melanoma cells is not co-regulated by a shared promoter region SO PIGMENT CELL RESEARCH LA English DT Article DE gp100; cyclin dependent kinase 2; promoter; transcription factor; gene expression; tumor associated antigen; melanoma ID SILVER LOCUS PROTEIN; CD8(+) T-CELLS; ANTIGEN GP100; GENOMIC ORGANIZATION; HUMAN MELANOCYTES; PMEL 17; MITF; LYMPHOCYTES; INHIBITION; VITILIGO AB Expression of the pigmentation-associated gene PMel17 is regulated by a 1 kB promoter region shared between the PMel17 and CDK2 genes. The encoded melanosomal glycoprotein gp100 and the cell cycle regulatory protein CDK2 are transcribed in opposite directions. Luciferase reporter constructs were generated for subregions of the promoter containing 0, 1, 2 or 3 putative binding sites for transcription factors with basic helix-loop-helix (bHLH) motifs. The potential contribution of bHLH transcription factor microphthalmia transcription factor (MITF) to promoter activity was investigated by re-introducing microphthalmia into melanoma cells lacking expression. A bi-directional reporter construct was generated to investigate potential co-regulation of gp100 and CDK2 transcription. Promoter activity was assessed in presence and absence of phorbol ester tetradecanoyl phorbol 13-acetate (TPA). FACS analysis and immunohistology served to evaluate co-regulation of gp100 and CDK2 expression at the protein level. The full-length promoter, including a consensus binding site for MITF was found to contain sequences that suppressed gp100 expression. Introduction of MITF into non-expressing 1123 melanoma cells did not restore gp100 expression levels. A lack of coregulation for gp100 and CDK2 as suggested by immunostaining was supported by findings of dissimilar expression regulation by TPA for either gene. The current study provides insight into transcriptional regulation of the PMel17 and CDK2 genes, important to identify strategies for modulating expression of gp100 and CDK2 proteins by melanoma cells. C1 Loyola Univ Chicago, Med Ctr, Cardinal Bernardin Canc Ctr, Maywood, IL 60153 USA. H Lee Moffit Canc Ctr & Res Inst, Tampa, FL USA. NCI, Mol Tumor Biol Sect, Basic Res Lab, Bethesda, MD 20892 USA. RP Le Poole, IC (reprint author), Loyola Univ Chicago, Med Ctr, Cardinal Bernardin Canc Ctr, Oncol Inst Bldg 112 Rm 203,2160 S 1st Ave, Maywood, IL 60153 USA. EM ilepool@lumc.edu RI Riker, Adam/A-6065-2011 NR 34 TC 7 Z9 7 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD OCT PY 2004 VL 17 IS 5 BP 525 EP 532 DI 10.1111/j.1600-0749.2004.00180.x PG 8 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 852IF UT WOS:000223748300010 PM 15357840 ER PT J AU Ward, N Larsen, O Sakwa, J Bruseth, L Khouri, H Durkin, AS Dimitrov, G Jiang, LX Scanlan, D Kang, KH Lewis, M Nelson, KE Methe, B Wu, M Heidelberg, JF Paulsen, IT Fouts, D Ravel, J Tettelin, H Ren, QH Read, T DeBoy, RT Seshadri, R Salzberg, SL Jensen, HB Birkeland, NK Nelson, WC Dodson, RJ Grindhaug, SH Holt, I Eidhammer, I Jonasen, I Vanaken, S Utterback, T Feldblyum, TV Fraser, CM Lillehaug, JR Eisen, JA AF Ward, N Larsen, O Sakwa, J Bruseth, L Khouri, H Durkin, AS Dimitrov, G Jiang, LX Scanlan, D Kang, KH Lewis, M Nelson, KE Methe, B Wu, M Heidelberg, JF Paulsen, IT Fouts, D Ravel, J Tettelin, H Ren, QH Read, T DeBoy, RT Seshadri, R Salzberg, SL Jensen, HB Birkeland, NK Nelson, WC Dodson, RJ Grindhaug, SH Holt, I Eidhammer, I Jonasen, I Vanaken, S Utterback, T Feldblyum, TV Fraser, CM Lillehaug, JR Eisen, JA TI Genomic insights into methanotrophy: The complete genome sequence of Methylococcus capsulatus (Bath) SO PLOS BIOLOGY LA English DT Review ID SOLUBLE METHANE MONOOXYGENASE; METHYLOSINUS-TRICHOSPORIUM OB3B; METHYLOBACTERIUM-EXTORQUENS AM1; P-TYPE ATPASE; ESCHERICHIA-COLI; FORMALDEHYDE DEHYDROGENASE; METHYLOTROPHIC BACTERIA; OXIDIZING BACTERIUM; MOLECULAR-BIOLOGY; ASP-TRNA(ASN) AMIDOTRANSFERASE AB Methanotrophs are ubiquitous bacteria that can use the greenhouse gas methane as a sole carbon and energy source for growth, thus playing major roles in global carbon cycles, and in particular, substantially reducing emissions of biologically generated methane to the atmosphere. Despite their importance, and in contrast to organisms that play roles in other major parts of the carbon cycle such as photosynthesis, no genome-level studies have been published on the biology of methanotrophs. We report the first complete genome sequence to our knowledge from an obligate methanotroph, Methylococcus capsulatus (Bath), obtained by the shotgun sequencing approach. Analysis revealed a 3.3-Mb genome highly specialized for a methanotrophic lifestyle, including redundant pathways predicted to be involved in methanotrophy and duplicated genes for essential enzymes such as the methane monooxygenases. We used phylogenomic analysis, gene order information, and comparative analysis with the partially sequenced methylotroph Methylobacterium extorquens to detect genes of unknown function likely to be involved in methanotrophy and methylotrophy. Genome analysis suggests the ability of M. capsulatus to scavenge copper (including a previously unreported nonribosomal peptide synthetase) and to use copper in regulation of methanotrophy, but the exact regulatory mechanisms remain unclear. One of the most surprising outcomes of the project is evidence suggesting the existence of previously unsuspected metabolic flexibility in M. capsulatus, including an ability to grow on sugars, oxidize chemolithotrophic hydrogen and sulfur, and live under reduced oxygen tension, all of which have implications for methanotroph ecology. The availability of the complete genome of M. capsulatus (Bath) deepens our understanding of methanotroph biology and its relationship to global carbon cycles. We have gained evidence for greater metabolic flexibility than was previously known, and for genetic components that may have biotechnological potential. C1 Inst Genom Res, Rockville, MD USA. Ctr Marine Biotechnol, Baltimore, MD USA. Univ Bergen, Dept Biol, Bergen, Norway. Univ Bergen, Dept Mol Biol, Bergen, Norway. Johns Hopkins Univ, Dept Biol, Baltimore, MD USA. Natl Human Genet Res Inst, NIH, Bethesda, MD USA. Univ Bergen, Dept Informat, N-5008 Bergen, Norway. George Washington Univ, Ctr Med, Washington, DC USA. Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD USA. RP Ward, N (reprint author), Inst Genom Res, Rockville, MD USA. EM nward@tigr.org RI Ravel, Jacques/D-2530-2009; Read, Timothy/E-6240-2011; Paulsen, Ian/K-3832-2012; Nelson, William/E-9263-2016; Salzberg, Steven/F-6162-2011; OI Fraser, Claire/0000-0003-1462-2428; Eisen, Jonathan A./0000-0002-0159-2197; Paulsen, Ian/0000-0001-9015-9418; Nelson, William/0000-0002-1873-3929; Salzberg, Steven/0000-0002-8859-7432; Ravel, Jacques/0000-0002-0851-2233; Heidelberg, John/0000-0003-0673-3224 NR 110 TC 188 Z9 654 U1 3 U2 56 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD OCT PY 2004 VL 2 IS 10 BP 1616 EP 1628 AR e303 DI 10.1371/journal.pbio.0020303 PG 13 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 865XI UT WOS:000224737100018 PM 15383840 ER PT J AU Korde, LA Calzone, KA Zujewski, J AF Korde, LA Calzone, KA Zujewski, J TI Assessing breast cancer risk - Genetic factors are not the whole story SO POSTGRADUATE MEDICINE LA English DT Article ID POSTMENOPAUSAL WOMEN; COLLABORATIVE REANALYSIS; MUTATION CARRIERS; INDIVIDUAL DATA; BRCA2 MUTATION; OVARIAN-CANCER; DISEASE; TRIAL; CONTRACEPTIVES; OOPHORECTOMY AB Genetic syndromes that convey a significant risk of breast cancer are responsible for a small but significant percentage of these cancers. However, the;vast majority of breast cancers occur in women with no family history of the disease. Nongenetic risk factors include age, previous breast disease, breast tissue density, radiation exposure, and lifestyle factors, such as weight, exercise, and alcohol consumption. In this article, the authors outline. genetic and other risk factors for breast cancer, explore risk-reduction strategies, and encourage primary care physicians to assess breast cancer risk in all their patients. C1 NCI, Canc Res Ctr, Genet Branch, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Breast Canc Sect, Med Oncol Clin Res Unit, Bethesda, MD 20892 USA. EM kordel@mail.nih.gov NR 38 TC 8 Z9 8 U1 0 U2 0 PU MCGRAW HILL HEALTHCARE PUBLICATIONS PI MINNEAPOLIS PA 4530 WEST 77TH ST, MINNEAPOLIS, MN 55435-5000 USA SN 0032-5481 J9 POSTGRAD MED JI Postgrad. Med. PD OCT PY 2004 VL 116 IS 4 BP 6 EP + PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 864IC UT WOS:000224626200001 PM 15510590 ER PT J AU Lee, WC Chen, JJ Hunt, DD Hou, CW Lai, YC Lin, FC Chen, CY Lin, CH Liao, YH Kuo, CH AF Lee, WC Chen, JJ Hunt, DD Hou, CW Lai, YC Lin, FC Chen, CY Lin, CH Liao, YH Kuo, CH TI Effects of hiking at altitude on body composition and insulin sensitivity in recovering drug addicts SO PREVENTIVE MEDICINE LA English DT Article DE insulin resistance; hypoxia; addiction; stress hormones; obesity ID MUSCLE LIPOPROTEIN-LIPASE; 24-H ENERGY-EXPENDITURE; FAT DISTRIBUTION; ADIPOSE-TISSUE; GROWTH-HORMONE; EXERCISE INTENSITY; SKELETAL-MUSCLE; FOLLOW-UP; SEA-LEVEL; TESTOSTERONE AB In the current study individuals with a history of drug abuse (users of heroin, cocaine, or amphetamine) displayed a 13-100% increase in body weight (self-reported) and exhibited a trend toward insulin resistance. Therefore, we investigated the effects of long-term altitude hiking on insulin sensitivity in this special population. Nine males recovering from drug addiction (ex-addicts) (age 28.7 +/- 1.3 years) and 17 control subjects (age 29 +/- 1.1 years) voluntarily participated in a 25-day hiking activity (altitude 2200-3800 M). On the 25th day of hiking, oral glucose tolerance test (OGTT), insulin response, lean body mass, fat mass, and waist-to-hip ratio (WHR) were measured in all subjects. After the altitude expedition, insulin levels during the OGTT in ex-addicts were similar to controls, suggesting that insulin sensitivity in this special population was normalized by long-term altitude activity. Along with improvements in insulin sensitivity, a significant reduction in WHR, but small increase in lean body mass, was observed. Twenty-five days of altitude activity significantly reverses hyperinsulinemia in the ex-addicts and this improvement appears to be partially associated with the reduction in central fatness. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 Taipei Phys Educ Coll, Lab Exercise Biochem, Taipei, Taiwan. Shih Hsin Univ, Comm Gen Studies, Taipei, Taiwan. Natl Yang Ming Univ, Inst Phys Therapy, Taipei 112, Taiwan. Natl Yang Ming Univ, Fac Phys Therapy, Taipei 112, Taiwan. NIDDK, NIH, Bethesda, MD USA. Yuan Ze Univ, Dept Phys Educ, Taoyuan, Taiwan. RP Kuo, CH (reprint author), Taipei Phys Educ Coll, Lab Exercise Biochem, 5 Dun Hua N Rd, Taipei, Taiwan. EM kch@tpec.edu.tw NR 37 TC 9 Z9 11 U1 3 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD OCT PY 2004 VL 39 IS 4 BP 681 EP 688 DI 10.1016/j.ypmed.2004.02.035 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 856OC UT WOS:000224053500006 PM 15351533 ER PT J AU Romanko, MJ Rola, R Fike, JR Szele, FG Dizon, MLV Felling, RJ Brazel, CY Levison, SW AF Romanko, MJ Rola, R Fike, JR Szele, FG Dizon, MLV Felling, RJ Brazel, CY Levison, SW TI Roles of the mammalian subventricular zone in cell replacement after brain injury SO PROGRESS IN NEUROBIOLOGY LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; NEURAL STEM-CELLS; FOCAL CEREBRAL-ISCHEMIA; EPIDERMAL-GROWTH-FACTOR; INVITRO CLONOGENIC-ASSAY; ROSTRAL MIGRATORY STREAM; ADULT-MOUSE BRAIN; GLIAL PROGENITOR CELLS; RAT SUBEPENDYMAL PLATE; PSA-NCAM EXPRESSION AB The subventricular zones (SVZs) are essential sources of new cells in the developing brain and remnants of these germinal zones persist into adulthood. As these cells have the capacity to replenish neurons and glia that are turning over, many investigators have assessed the SVZ's role in replacing neural cells eliminated by brain injuries. A review of the literature reveals that the progenitors within the SVZs are vulnerable to chemical, radiation and ischemia-induced damage, whereas the neural stem cells are resilient. With moderate insults, the SVZ can recover, but it cannot recover after more severe injury. Thus, the vulnerability of these cells has important ramifications when considering therapeutic interventions for the treatment of brain tumors and for the prospect of recovery after ischemia. The cells of the perinatal and adult SVZ not only have the capacity to replenish their own numbers, but they also have the capacity to replace neurons and glia after ischemic and traumatic brain injuries. Moreover, the mechanisms underlying these regenerative responses are beginning to be revealed. By reviewing, comparing and contrasting the responses of the SVZs to different injuries, our goal is to provide a foundation from which current and future studies on the potential of the SVZs for cell replacement can be evaluated. (C) 2004 Elsevier Ltd. All rights reserved. C1 UMDNJ, New Jersey Med Sch, Dept Neurol & Neurosci, Newark, NJ 07101 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Neural & Behav Sci, Hershey, PA 17033 USA. Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA. Northwestern Univ, Childrens Mem Hosp, Feinberg Sch Med, Dept Pediat, Chicago, IL 60614 USA. NIA, Stem Cell Biol Unit, Neurosci Lab, Ctr Gerontol Res, Baltimore, MD 21224 USA. RP Levison, SW (reprint author), UMDNJ, New Jersey Med Sch, Dept Neurol & Neurosci, 185 S Orange Ave,H-506, Newark, NJ 07101 USA. EM levisosw@undnj.edu OI Levison, Steven/0000-0002-1264-7309 FU NCI NIH HHS [R01 CA76141]; NIMH NIH HHS [MH 30705, MH 59950, R01 MH059950]; NINDS NIH HHS [R21 NS40088, R01 NS/AG42253-01] NR 154 TC 82 Z9 90 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD OCT PY 2004 VL 74 IS 2 BP 77 EP 99 DI 10.1016/j.pneurobio.2004.07.001 PG 23 WC Neurosciences SC Neurosciences & Neurology GA 872TJ UT WOS:000225231100001 PM 15518954 ER PT J AU Harris, JI Hibbeln, JR Mackey, RH Muldoon, MF AF Harris, JI Hibbeln, JR Mackey, RH Muldoon, MF TI Statin treatment alters serum n-3 and n-6 fatty acids in hypercholesterolemic patients SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article ID COA REDUCTASE INHIBITORS; ARACHIDONIC-ACID; OMEGA-3-FATTY-ACID LEVELS; ALZHEIMERS-DISEASE; COGNITIVE FUNCTION; LEARNING-ABILITY; MAJOR DEPRESSION; GENE-EXPRESSION; RAT-BRAIN; CHOLESTEROL AB Statins are highly effective cholesterol-lowering drugs but may have broader effects on metabolism. This investigation examined effects of simvastatin on serum levels of n-6 and n-3 polyunsaturated fatty acids (PUFAs). Subjects were 106 healthy adults with hypercholesterolemia randomly assigned to receive placebo or 40 mg simvastatin daily for 24 weeks. Serum fatty acids were analyzed by gas chromatography. Total fatty acid concentration fell 22% in subjects receiving simvastatin (P<.001), with similar declines across most fatty acids. However, concentrations of arachidonic acid (AA, 20:4n-6), eicosapentanoic acid (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3) were unchanged. Relative percentages of linoleic acid (LA, 18:2n-6) and alpha-linolenic acid (LNA, 18:3n-3), decreased while AA and DHA increased (P's less than or equal to.007). In addition, simvastatin increased the AA:EPA ratio from 15.5 to 18.8 (P<.01), and tended to increase the AA:DHA ratio (P=.053). Thus, simvastatin lowered serum fatty acid concentrations while also altering the relative percentages of important PUFAs. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Pittsburgh, Sch Med, Dept Med, Ctr Clin Pharmacol, Pittsburgh, PA 15260 USA. NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, Bethesda, MD USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Muldoon, MF (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Ctr Clin Pharmacol, Old Engn Hall,Room 506, Pittsburgh, PA 15260 USA. EM mfm10@pitt.edu OI Mackey, Rachel/0000-0001-6088-2664 FU NHLBI NIH HHS [HL-46328] NR 54 TC 46 Z9 50 U1 0 U2 1 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD OCT PY 2004 VL 71 IS 4 BP 263 EP 269 DI 10.1016/j.plefa.2004.06.001 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 848QL UT WOS:000223482100010 PM 15310527 ER PT J AU Zou, ZC Sun, PD AF Zou, ZC Sun, PD TI Overexpression of human transforming growth factor-beta 1 using a recombinant CHO cell expression system SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE TGF-beta 1; LAP; LTBP; Chinese hamster ovary cell expression; protein purification ID GROWTH-FACTOR-BETA; HAMSTER OVARY CELLS; TGF-BETA; PROTEIN; PRECURSOR; LATENCY; ACTIVATION; MECHANISMS; SECRETION; SEQUENCE AB Transforming growth factor-beta1 (TGF-beta1) is secreted by most cells as a high molecular weight latent complex, which consists of latent TGF-beta1 disulfide bonded to latent TGF-beta1-binding protein (LTBP). Current recombinant expression systems yield less than 1-2 mg of the mature TGF-beta1 per liter of cell culture medium. In an effort to produce large quantities of the recombinant cytokine for structural studies, we have constructed a mammalian expression system based on a modified pcDNA3.1(+) vector with a glutamine synthetase gene inserted for gene amplification. The leader peptide of TGF-beta1 was replaced with that of rat serum albumin, and an eight-histidine tag was inserted immediately after the leader sequence to facilitate protein purification. In addition, Cys 33 of TGF-beta1, which forms a disulfide bond with LTBP, was replaced by a serine residue. The resulting expression construct produced a stable clone expressing 30 mg of mature TGF-beta1 per liter of spent medium. Purified TGF-beta1 bound with high affinity to its type 11 receptor with a solution dissociation constant of similar to70 nM, and was fully active in both a Mv1Lu cell growth inhibition assay and in a PAI-1 luciferase reporter assay. Owing to similarities in the synthesis, secretion, and structure of TGF-beta family members, this recombinant expression system may also be applied to the overexpression of other TGF-beta isomers and even to members of the TGF-beta superfamily to facilitate their preparation. (C) 2004 Elsevier Inc. All rights reserved. C1 NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Sun, PD (reprint author), NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM psun@nih.gov NR 25 TC 17 Z9 20 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD OCT PY 2004 VL 37 IS 2 BP 265 EP 272 DI 10.1016/j.pep.2003.06.001 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 858BY UT WOS:000224166400001 PM 15358346 ER PT J AU Tsai, HH Tsai, CJ Ma, BY Nussinov, R AF Tsai, HH Tsai, CJ Ma, BY Nussinov, R TI In silico protein design by combinatorial assembly of protein building blocks SO PROTEIN SCIENCE LA English DT Article DE protein building block; computational protein design; combinatorial assembly; protein G; ubiquitin; molecular dynamics simulation ID AUTOMATED SEQUENCE SELECTION; COMPUTATIONAL DESIGN; GLOBULAR-PROTEINS; FOLDING MODEL; PATHWAYS; RECOMBINATION; PROTEOLYSIS; PERSPECTIVE; FRAGMENTS; STABILITY AB Utilizing concepts of protein building blocks, we propose a de novo computational algorithm that is similar to combinatorial shuffling experiments. Our goal is to engineer new naturally occurring folds with low homology to existing proteins. A selected protein is first partitioned into its building blocks based on their compactness, degree of isolation from the rest of the structure, and hydrophobicity. Next, the protein building blocks are substituted by fragments taken from other proteins with overall low sequence identity, but with a similar hydrophobic/hydrophilic pattern and a high structural similarity. These criteria ensure that the designed protein has a similar fold, low sequence identity, and a good hydrophobic core compared with its native counterpart. Here, we have selected two proteins for engineering, protein G 131 domain and ubiquitin. The two engineered proteins share similar to20% and similar to25% amino acid sequence identities with their native counterparts, respectively. The stabilities of the engineered proteins are tested by explicit water molecular dynamics simulations. The algorithm implements a strategy of designing a protein using relatively stable fragments, with a high population time. Here, we have selected the fragments by searching for local minima along the polypeptide chain using the protein building block model. Such an approach provides a new method for engineering new proteins with similar folds and low homology. C1 NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Lab Expt & Computat Biol, Bldg 469,Room 145, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 37 TC 25 Z9 25 U1 1 U2 5 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2004 VL 13 IS 10 BP 2753 EP 2765 DI 10.1110/ps.04774004 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 855XH UT WOS:000224007700020 PM 15388863 ER PT J AU Xi, ZX Gilbert, J Campos, AC Kline, N Ashby, CR Hagan, JJ Heidbreder, CA Gardner, EL AF Xi, ZX Gilbert, J Campos, AC Kline, N Ashby, CR Hagan, JJ Heidbreder, CA Gardner, EL TI Blockade of mesolimbic dopamine D-3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE accumbens; addiction; cocaine; dopamine; D-3 antagonist; reinstatement; relapse; SB-277011A; self-administration; stress ID INSITU HYBRIDIZATION HISTOCHEMISTRY; CORTICOTROPIN-RELEASING FACTOR; PREFRONTAL CORTEX; AGONIST 7-OH-DPAT; INDUCED RELAPSE; HEROIN-SEEKING; D3 RECEPTOR; MEDICATION DEVELOPMENT; NUCLEUS-ACCUMBENS; RHESUS-MONKEYS AB Rationale: The dopamine (DA) D-3 receptor is preferentially expressed in the mesolimbic system. We have previously shown that selective D-3 receptor blockade by the novel D-3 antagonist SB-277011A inhibits cocaine's reinforcing action and cocaine-induced reinstatement of cocaine-seeking behavior. Objective: In the present study, we investigated whether SB-277011A similarly inhibits stress-induced reinstatement of cocaine-seeking behavior. Methods: Rats were allowed to self-administer cocaine (0.5 mg/kg per infusion, 3h per session) for 10-14 days, followed by a once-daily extinction session for 7-14 days during which saline was substituted for cocaine. Extinction criteria were fewer than ten lever-presses per 3-h session for at least 3 consecutive days. After cocaine-seeking behavior was extinguished, each animal was tested twice for footshock-stress-induced reinstatement, once with vehicle (25% hydroxypropyl-beta-cyclodextrin) and once with one of three doses of SB-277011A in counterbalanced fashion. Results: During the last 3 days of cocaine self-administration (SA), active lever-presses were approximately 100 per session under fixed-ratio 2 reinforcement (similar to25 mg/kg cocaine per session). After extinction, intermittent footshock (10 min, 0.5 mA, 0.5 s on with a mean inter-shock interval of 40 s) robustly reinstated the cocaine-seeking behavior (8.4+/-3.6 active lever-presses in last extinction session to 35.3+/-5.2 in animals after footshock stress). Intraperitoneal (IP) injections of SB-277011A (3, 6, and 12 mg/kg) dose-dependently blocked stress-induced reinstatement of cocaine-seeking. Reinstatement was also blocked by microinjections of SB-277011A (1.5 mug/0.5 mul per side) bilaterally into the nucleus accumbens, but not into the dorsal striatum. Conclusions: The mesolimic DA D-3 receptor plays an important role in mediating stress-induced reinstatement. C1 NIDA, Neuropsychopharmacol Sect, Intramural Res Program, US Dept HHS,NIH, Baltimore, MD 21224 USA. St Johns Univ, Coll Pharm & Allied Hlth Profess, Dept Pharmaceut Sci, Jamaica, NY 11439 USA. GlaxoSmithKline Pharmaceut, Psychiat Ctr Excellence Drug Discovery, Harlow CM19 5AW, Essex, England. GlaxoSmithKline Pharmaceut, Psychiat Ctr Excellence Drug Discovery, I-37135 Verona, Italy. RP Xi, ZX (reprint author), NIDA, Neuropsychopharmacol Sect, Intramural Res Program, US Dept HHS,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM zxi@intra.nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 57 TC 108 Z9 109 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2004 VL 176 IS 1 BP 57 EP 65 DI 10.1007/s00213-004-1858-y PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864AM UT WOS:000224605000005 PM 15083257 ER PT J AU Lu, L Grimm, JW Dempsey, J Shaham, Y AF Lu, L Grimm, JW Dempsey, J Shaham, Y TI Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months SO PSYCHOPHARMACOLOGY LA English DT Article DE craving; cocaine cues; extinction; priming; reinstatement; relapse; self-administration; withdrawal ID VENTRAL TEGMENTAL AREA; CORTICOTROPIN-RELEASING FACTOR; DRUG-SEEKING; INDUCED REINSTATEMENT; BEHAVIORAL SENSITIZATION; NEUROTROPHIC FACTOR; 2ND-ORDER SCHEDULE; DEPENDENT CHANGES; ANIMAL-MODEL; RELAPSE AB Rationale and objectives: We previously found time dependent increases, or incubation, of cocaine seeking induced by re-exposure to cocaine cues over withdrawal periods of up to 3 months. Here, we studied cocaine seeking induced by re-exposure to cocaine cues or cocaine itself over an extended withdrawal period of 6 months. Methods: Rats were trained to self-administer intravenous cocaine for 6 h/day for 10 days. Cocaine seeking induced by re-exposure to cocaine cues or cocaine itself, as measured in extinction or drug-induced reinstatement tests, respectively, was then assessed 1 day, or 1, 3 or 6 months after withdrawal. Rats were first given six 1-h extinction sessions wherein lever presses resulted in contingent presentations of cues previously paired with cocaine infusions. Subsequently, reinstatement of drug seeking induced by cocaine injections (expt 1: 0, 5, and 15 mg/kg, IP; expt 2: 0, 2.5, and 5 mg/kg) was assessed during three 1-h sessions. Results: Profound time dependent changes in responsiveness to cocaine cues in the extinction tests were observed, with low responding after 1 day, high responding after 1 and 3 months, and intermediate responding after 6 months of withdrawal. In contrast, no significant time dependent changes in cocaine-induced drug seeking were found; acute re-exposure to cocaine effectively reinstated responding at all withdrawal periods. Conclusions: Results indicate that the withdrawal period is a critical modulator of drug seeking provoked by re-exposure to cocaine cues, but not cocaine itself. Results also indicate that while the incubation of responsiveness to cocaine cues is a long lasting phenomenon, it is not permanent. C1 NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014 NR 50 TC 91 Z9 91 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2004 VL 176 IS 1 BP 101 EP 108 DI 10.1007/s00213-004-1860-4 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864AM UT WOS:000224605000011 PM 15071719 ER PT J AU Lu, L Dempsey, J AF Lu, L Dempsey, J TI Cocaine seeking over extended withdrawal periods in rats: time dependent increases of responding induced by heroin priming over the first 3 months SO PSYCHOPHARMACOLOGY LA English DT Article DE craving; cross-reinstatement; extinction; priming; relapse; self-administration; withdrawal ID VENTRAL TEGMENTAL AREA; STRESS-INDUCED RELAPSE; SELF-ADMINISTRATION BEHAVIOR; MESSENGER-RNA LEVELS; NUCLEUS-ACCUMBENS; INDUCED REINSTATEMENT; MORPHINE; DRUG; DOPAMINE; SENSITIZATION AB Rationale: Using a rat relapse model, recent studies reported time dependent increases in cocaine seeking induced by re-exposure to cocaine cues, but not cocaine itself, over withdrawal periods of up to 3 months. Objectives: In the present study, we explored the time course of cocaine seeking induced by priming injections of heroin over the first 3 months of withdrawal from cocaine. Methods: Rats were trained to self-administer intravenous cocaine for 6 h/day over a period of 10 days. Cocaine seeking induced by heroin priming was then assessed in different groups of rats after 1 day, and 1 and 3 months of withdrawal from cocaine. During the test day, rats were first given six 1-h extinction sessions. Subsequently, reinstatement of cocaine seeking induced by non-contingent saline and heroin injections (0.125 and 0.25 mg/kg, SC) was assessed during three 1-h sessions. Results: As in previous studies, extinction responding was substantially greater after 1 and 3 months of withdrawal than after 1 day. More importantly, we also found that the effect of heroin priming on reinstatement of cocaine seeking is time dependent, with higher responding occurring after 1 and 3 months than after 1 day. Conclusion: The present results replicate previous findings on the time dependent increases in resistance to extinction after withdrawal from cocaine, and further indicate that the duration of the drug withdrawal period is a critical modulator of the effect of heroin priming on cocaine seeking. These data may have implications for the treatment of cocaine relapse induced by other drugs. C1 NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. RP Lu, L (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM llu@intra.nida.nih.gov NR 48 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2004 VL 176 IS 1 BP 109 EP 114 DI 10.1007/s00213-004-1861-3 PG 6 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 864AM UT WOS:000224605000012 PM 15071720 ER PT J AU Hutchison, KE Rutter, MC Niaura, R Swift, RM Pickworth, WB Sobik, L AF Hutchison, KE Rutter, MC Niaura, R Swift, RM Pickworth, WB Sobik, L TI Olanzapine attenuates cue-elicited craving for tobacco SO PSYCHOPHARMACOLOGY LA English DT Article DE smoking; nicotine; craving; olanzapine ID DRD4 VNTR POLYMORPHISM; SMOKING CUES; PREPULSE INHIBITION; SUBSTANCE USE; SCHIZOPHRENIA; SMOKERS; CLOZAPINE; ALCOHOL; REACTIVITY; HALOPERIDOL AB Rationale: Recent biological conceptualizations of craving and addiction have implicated mesolimbic dopamine activity as a central feature of the process of addiction. Imaging, and pharmacological studies have supported a role for dopaminergic structures in cue-elicited craving for tobacco. Objective: If mesolimbic dopamine activity is associated with cue-elicited craving for tobacco, a dopamine antagonist should attenuate cue-elicited craving for tobacco. Thus, the aim of the present study was to determine whether an atypical antipsychotic (olanzapine, 5 mg) decreased cue-elicited craving for tobacco. Method: Participants were randomly assigned to 5 days of pretreatment with olanzapine (5 mg; n=31) or were randomly assigned to 5 days of a matching placebo (n=28). Approximately 8 h after the last dose, participants were exposed to a control cue (pencil) followed by exposure to smoking cues. Participants subsequently smoked either nicotine cigarettes or de-nicotinized cigarettes. Results: Olanzapine attenuated cue-elicited craving for tobacco but did not moderate the subjective effects of smoking. Discussion: This study represents one of the first investigations of the effect of atypical antipsychotics on cue-elicited craving for tobacco. The results suggest that medications with similar profiles may reduce cue-elicited craving, which in turn, may partially explain recent observations that atypical antipsychotics may reduce substance use. C1 Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. Ctr Behav Med, Providence, RI USA. Brown Univ, Providence Vet Affairs Med Ctr, Providence, RI 02912 USA. Brown Univ, Ctr Alcohol & Addict Studies, Providence, RI 02912 USA. Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD USA. RP Hutchison, KE (reprint author), Univ Colorado, Dept Psychol, Campus Box 345, Boulder, CO 80309 USA. EM kenth@psych.colorado.edu FU NCI NIH HHS [1 R21 CA 81637]; NCRR NIH HHS [2 M01-RR00051] NR 45 TC 30 Z9 30 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2004 VL 175 IS 4 BP 407 EP 413 DI 10.1007/s00213-004-1837-3 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 863SW UT WOS:000224583800003 PM 15042276 ER PT J AU Oberlies, NH Kim, NC Brine, DR Collins, BJ Handy, RW Sparacino, CM Wani, MC Wall, ME AF Oberlies, NH Kim, NC Brine, DR Collins, BJ Handy, RW Sparacino, CM Wani, MC Wall, ME TI Analysis of herbal teas made from the leaves of comfrey (Symphytum officinale): reduction of N-oxides results in order of magnitude increases in the measurable concentration of pyrrolizidine alkaloids SO PUBLIC HEALTH NUTRITION LA English DT Article DE comfrey; pyrrolizidine; N-oxide; Symphytum officinale; symphytine; echimidine ID VENO-OCCLUSIVE DISEASE; HEPATIC VENOOCCLUSIVE DISEASE; LIQUID-CHROMATOGRAPHY; SENECIO-RIDDELLII; RAT-LIVER; PLANTS; HEPATOTOXICITY; METABOLITES; INGESTION; TOXICITY AB Objectives: To determine the relative quantities of two hepatotoxic pyrrolizidine alkaloids, symphytine and echimidine, in teas prepared from comfrey leaves (Symphytum officinale), and to determine the potential contribution of the N-oxide forms of these alkaloids to levels of the parent alkaloids. Design: Comfrey leaves were purchased from three commercial sources and used to prepare tea in a manner consistent with the methods used by consumers. An extraction scheme was devised for extraction of the alkaloids, and a gas chromatographic method was developed to quantify the two major alkaloids, symphytine and echimidine. Recognising that the N-oxide derivatives of these alkaloids have also been identified in comfrey preparations, chemical reduction was applied to determine the total quantities of the alkaloids as free bases and as N-oxide derivatives. Results: The concentration of symphytine and echimidine varied considerably between teas prepared from leaves purchased from the different vendors of plant material. Moreover, a much higher concentration of symphytine was found in the tea when steps were included to reduce N-oxides prior to analysis. The treatment of pure symphytine with hot water did not generate the N-oxide derivative de novo. Conclusions: Since the pyrrolizidine alkaloids are known to be hepatotoxic, consumption of herbal teas made from comfrey leaves may be ill-advised. The concentration of pyrrolizidine alkaloids in such teas may be underestimated substantially unless the concentration of N-oxides is taken into consideration. C1 RTI Int, Nat Prod Lab, Res Triangle Pk, NC 27709 USA. RTI Int, Hlth Sci Unit, Res Triangle Pk, NC 27709 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Oberlies, NH (reprint author), RTI Int, Nat Prod Lab, POB 12194, Res Triangle Pk, NC 27709 USA. EM oberlies@rti.org OI Oberlies, Nicholas/0000-0002-0354-8464 FU NIEHS NIH HHS [N01-ES-55386] NR 41 TC 20 Z9 20 U1 1 U2 16 PU C A B I PUBLISHING PI WALLINGFORD PA C/O PUBLISHING DIVISION, WALLINGFORD OX10 8DE, OXON, ENGLAND SN 1368-9800 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD OCT PY 2004 VL 7 IS 7 BP 919 EP 924 DI 10.1079/PHN2004624 PG 6 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 861VS UT WOS:000224447300015 PM 15482618 ER PT J AU Panza, F Solfrizzi, V Colacicco, AM D'Introno, A Capurso, C Torres, F Del Parigi, A Capurso, S Capurso, A AF Panza, F Solfrizzi, V Colacicco, AM D'Introno, A Capurso, C Torres, F Del Parigi, A Capurso, S Capurso, A TI Mediterranean diet and cognitive decline SO PUBLIC HEALTH NUTRITION LA English DT Article DE age-related cognitive decline; Alzheimer's disease; vascular dementia; Mediterranean diet ID FATTY-ACIDS; ALZHEIMERS-DISEASE; NUTRITIONAL-STATUS; ELDERLY PEOPLE; VASCULAR DEMENTIA; POPULATION; STROKE; ASSOCIATION; PREVALENCE; ROTTERDAM AB Objective: To investigate the possible role of diet in age-related cognitive decline (ARCD) and cognitive impairment of both degenerative (Alzheimer's disease, AD) and vascular (vascular dementia, VaD) origin. Design: Literature review. Results: In an elderly population of southern Italy with a typical Mediterranean diet, high energy intake of monounsaturated fatty acids (MUFA) appeared to be associated with a high level of protection against ARCD. In addition, dietary fat and energy in the elderly seem to be risk factors, while fish consumption and cereals are found to reduce the prevalence of AD in European and North American countries. Finally, the relative risk of dementia (AD and VaD) was lower in the subjects of a French cohort who drank three or four glasses of red wine each day compared with total abstainers. Conclusion: Essential components of the Mediterranean diet - MUFA, cereals and wine - seem to be protective against cognitive decline. As such, dietary antioxidants and supplements, specific macronutrients of the Mediterranean diet, oestrogens and anti-inflammatory drugs may act synergistically with other protective factors, opening up new therapeutic interventions for cognitive decline. C1 Univ Bari, Policlin, Ctr Aging Brain, Dept Geriatr, I-70124 Bari, Italy. NIDDKD, NIH, Phoenix, AZ USA. RP Capurso, A (reprint author), Univ Bari, Policlin, Ctr Aging Brain, Dept Geriatr, Piazza Giulio Cesare 11, I-70124 Bari, Italy. EM geriat.dot@geriatria.uniba.it OI Capurso, Cristiano/0000-0002-1152-3371; Panza, Francesco/0000-0002-7220-0656 NR 57 TC 102 Z9 103 U1 3 U2 20 PU C A B I PUBLISHING PI WALLINGFORD PA C/O PUBLISHING DIVISION, WALLINGFORD OX10 8DE, OXON, ENGLAND SN 1368-9800 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD OCT PY 2004 VL 7 IS 7 BP 959 EP 963 DI 10.1079/PHN2004561 PG 5 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 861VS UT WOS:000224447300022 PM 15482625 ER PT J AU Hartman, DS Choyke, PL Hartman, MS AF Hartman, DS Choyke, PL Hartman, MS TI From the RSNA refresher courses - A practical approach to the cystic renal mass SO RADIOGRAPHICS LA English DT Article DE kidney, cysts; kidney neoplasms, CT; kidney neoplasms, diagnosis; kidney neoplasms, MR; kidney neoplasms, US ID BOSNIAK CATEGORY-III; CELL CARCINOMA; CT; DIAGNOSIS; KIDNEY; LESIONS; CLASSIFICATION; ENHANCEMENT; NEOPLASMS; NEPHROMA AB The pathologic and imaging features of the renal cyst have been well described. A fluid-filled lesion is considered a cystic mass (ie, not a simple cyst) when it has any of the following features: calcification, high attenuation (>20 HU) at computed tomography, signal intensity not typical of water at magnetic resonance imaging, septations, multiple locules, enhancement, wall thickening, or nodularity. There are two important causes of a cystic renal mass: a complicated simple cyst (eg, one with hemorrhage, infection, or ischemia) and cystic renal cell carcinoma. At radiologic evaluation of such masses, it is imperative that optimal imaging techniques be used. Masses with calcification, high attenuation or high signal intensity, or septations can be categorized as benign (no further evaluation required), as requiring follow-up (probably benign) or as requiring surgery Lesions requiring surgery,. can be benign or malignant at microscopic examination. Lesions that are multiloculated or demonstrate enhancement, wall thickening, or nodularity usually require surgery. When multiple features are present (eg, calcification and enhancement), the mass should be managed according to its most aggressive feature. Likewise when there are con, flicting findings at evaluation with different imaging modalities, the mass should be managed according to the most aggressive finding. C1 Penn State Univ, Milton S Hershey Med Ctr, Sch Med, Dept Radiol, Hershey, PA 17033 USA. NIH, Ctr Clin, Dept Radiol, Bethesda, MD USA. Emory Univ, Sch Med, Dept Radiol, Atlanta, GA 30322 USA. RP Hartman, DS (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Sch Med, Dept Radiol, HO66,500 Univ Dr, Hershey, PA 17033 USA. EM dhartman@psu.edu NR 35 TC 39 Z9 41 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0271-5333 J9 RADIOGRAPHICS JI Radiographics PD OCT PY 2004 VL 24 SI SI BP S101 EP S115 DI 10.1148/rg.24si045515 PG 15 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 861NR UT WOS:000224424100012 PM 15486234 ER PT J AU Summers, RM Yao, JH Johnson, CD AF Summers, RM Yao, JH Johnson, CD TI CT colonography with computer-aided detection: Automated recognition of ileocecal valve to reduce number of false-positive detections SO RADIOLOGY LA English DT Article DE colon, CT; colon neoplasms; colon neoplasms; computers, diagnostic aid ID VIRTUAL BRONCHOSCOPY; MICROSATELLITE INSTABILITY; COLONIC POLYPS; FEASIBILITY; DIAGNOSIS; DISPLAY AB The ileocecal valve (ICV) is a common cause of false-positive detections of polyps at computed tomographic (CT) colonography with computer-aided detection (CAD). The authors developed a CAD algorithm for differentiating, the' ICV from a true polyp and evaluated this algorithm by using two colonoscopy-confirm ed CF colonography data sets. Data sets 1 and 2 consisted of the data obtained at CT colonographic examinations performed in 20 -and 40 patients, respectively. Forty of these patients had at least one polyp 1 cm or larger. For data set 1, the proposed ICV recognition algorithm eliminated three of nine (33%; 95% confidence interval [CI]: 8%, 70%) false-positive CAD detections that were attributable to the ICV and none of the true-positive polyp detections. For data set 2, with use of identical parameters, the algorithm eliminated 11 of 18 (610/6; 95% CI: 36%, 83%) falsepositive detections that were attributable to the ICV and none of the truepositive detections. The thresholds used -to recognize the lCV were a mean internal Uattenuation of less than - 124 HU and a volume of greater than 1.5 cm(2). The proposed algorithm successfully recognized the lCV and eliminated it in some cases. This result is clinically important because, by reducing the frequency of a common cause of false-positive'detections, this algorithm may improve the efficiency of physicians who use CAD. (C) RSNA, 2004. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, NIH, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Dept Radiol, Rochester, MN 55905 USA. RP Summers, RM (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, NIH, Bldg 10,Rm 1C660,10 Ctr Dr,MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov FU NCI NIH HHS [R01 CA75333] NR 19 TC 28 Z9 29 U1 0 U2 0 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD OCT PY 2004 VL 233 IS 1 BP 266 EP 272 DI 10.1148/radiol.2331031326 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 856WC UT WOS:000224075000034 PM 15454623 ER PT J AU Rancati, T Fiorino, C Gagliardi, G Cattaneo, GM Sanguineti, G Borca, VC Cozzarini, C Fellin, G Foppiano, F Girelli, G Menegotti, L Piazzolla, A Vavassori, V Valdagni, R AF Rancati, T Fiorino, C Gagliardi, G Cattaneo, GM Sanguineti, G Borca, VC Cozzarini, C Fellin, G Foppiano, F Girelli, G Menegotti, L Piazzolla, A Vavassori, V Valdagni, R TI Fitting late rectal bleeding data using different NTCP models: results from an Italian multi-centric study (AIROPROS0101) SO RADIOTHERAPY AND ONCOLOGY LA English DT Article DE NTCP; dose-volume effects; prostate radiotherapy; rectal toxicity ID DOSE-VOLUME HISTOGRAMS; TISSUE COMPLICATION PROBABILITIES; PROSTATE CONFORMAL RADIOTHERAPY; RELATIVE SERIALITY MODEL; SURFACE HISTOGRAMS; RADIATION-THERAPY; WALL HISTOGRAMS; BREAST-CANCER; GY; IRRADIATION AB Background and purpose: Recent investigations demonstrated a significant correlation between rectal dose-volume patterns and late rectal toxicity. The reduction of the DVH to a value expressing the probability of complication would be suitable. To fit different normal tissue complication probability (NTCP) models to clinical outcome on late rectal bleeding after external beam radiotherapy (RT) for prostate cancer. Patients and methods: Rectal dose-volume histograms of the rectum (DVH) and clinical records of 547 prostate cancer patients (pts) pooled from five institutions previously collected and analyzed were considered. All patients were treated in supine position with 3 or 4-field techniques: 123 patients received an ICRU dose between 64 and 70 Gy, 255 patients between 70 and 74 Gy and 169 patients between 74 and 79.2 Gy; 457/547 patients were treated with conformal RT and 203/547 underwent radical prostatectomy before RT. Minimum follow-up was 18 months. Patients were considered as bleeders if showing grade 2/3 late bleeding (slightly modified RTOG/EORTC scoring system) within 18 months after the end of RT. Four NTCP models were considered: (a) the Lyman model with DVH reduced to the equivalent uniform dose (LEUD, coincident with the classical Lyman-Kutcher-Burman, LKB, model), (b) logistic with DVH reduced to EUD (LOGEUD), (c) Poisson coupled to EUD reduction scheme and (d) relative seriality (RS). The parameters for the different models were fit to the patient data using a maximum likelihood analysis. The 68% confidence intervals (CI) of each parameter were also derived. Results: Forty six out of five hundred and forty seven patients experienced grade 2/3 late bleeding: 38/46 developed rectal bleeding within 18 months and were then considered as bleeders The risk of rectal bleeding can be well calculated with a 'smooth' function of EUD (with a seriality parameter n equal to 0.23 (CI 0.05), best fit result). Using LEUD the relationship between EUD and NTCP can be described with a TD50 of 81.9 Gy (CI 1.8 Gy) and a steepness parameter m of 0.19 (CI 0.01); when using LOGEUD, TD50 is 82.2 Gy and k is 7.85. Best fit parameters for RS are s = 0.49, gamma = 1.69, TD50 = 83.1 Gy. Qualitative as well as quantitative comparisons (chi-squared statistics, P=0.005) show that the models fit the observed complication rates very well. The results found in the overall population were substantially confirmed in the subgroup of radically treated patients (LEUD: n=0.24 m=0.14 TD50=75.8Gy). If considering just the grade 3 bleeders (n = 9) the best fit is found in correspondence of a n-value around 0.06, suggesting that for severe bleeding the rectum is more serial. Conclusions: Different NTCP models fit quite accurately the considered clinical data. The results are consistent with a rectum 'less serial' than previously reported investigations when considering grade 2 bleeding while a more serial behaviour was found for severe bleeding. EUD may be considered as a robust and simple parameter correlated with the risk of late rectal bleeding. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 HS Raffaele, Med Phys & Radiotherapy, Milan, Italy. Univ Milan, Dept Phys, I-20122 Milan, Italy. Karolinska Hosp, Hosp Phys, S-10401 Stockholm, Sweden. UTMB, Radiotherapy, Galveston, TX USA. Azienda Osped ASL 9, Ivrea, Italy. Osped S Chiara, Trento, Italy. Natl Canc Inst, Genoa, Italy. Osped Circolo Varese, Varese, Italy. Natl Canc Inst, Sci Directors Off, AIRO Prostate Working Grp, I-20133 Milan, Italy. RP Gagliardi, G (reprint author), HS Raffaele, Med Phys & Radiotherapy, Milan, Italy. RI Valdagni, Riccardo/K-1361-2016; Rancati, Tiziana/K-7921-2016; OI Valdagni, Riccardo/0000-0001-5140-9728; Rancati, Tiziana/0000-0002-7849-603X; Cozzarini, Cesare/0000-0002-7006-8196 NR 50 TC 122 Z9 126 U1 0 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD OCT PY 2004 VL 73 IS 1 BP 21 EP 32 DI 10.1016/j.radonc.2004.08.013 PG 12 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 865NM UT WOS:000224709800003 PM 15465142 ER PT J AU Gius, D AF Gius, D TI Increased radiosensitization in cervical tumor cells following HSP90 inhibition with geldanamycin SO RADIOTHERAPY AND ONCOLOGY LA English DT Meeting Abstract CT 23rd Annual Meeting of the European-Society-for-Therapeutic-Radiology-and-Oncology (ESTRO 23) CY OCT 24-28, 2004 CL Amsterdam, NETHERLANDS SP European Soc Therapeut Radiol Oncol C1 NCI, Radiat Oncol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD OCT PY 2004 VL 73 SU 1 BP S106 EP S106 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 886OH UT WOS:000226237700231 ER PT J AU Karimpour, S Kheem, B Bradbury, M Gius, D AF Karimpour, S Kheem, B Bradbury, M Gius, D TI GA and 17-AAG function as cytotoxic and radiosensitizing agents in vivo and in vitro SO RADIOTHERAPY AND ONCOLOGY LA English DT Meeting Abstract CT 23rd Annual Meeting of the European-Society-for-Therapeutic-Radiology-and-Oncology (ESTRO 23) CY OCT 24-28, 2004 CL Amsterdam, NETHERLANDS SP European Soc Therapeut Radiol Oncol C1 NCI, Radiat Oncol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD OCT PY 2004 VL 73 SU 1 BP S106 EP S107 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 886OH UT WOS:000226237700232 ER PT J AU Parliament, M Damaraju, S Murray, D Dufour, J Myrehaug, S Greiner, W Fallone, G Field, C Menard, C Hanson, J AF Parliament, M Damaraju, S Murray, D Dufour, J Myrehaug, S Greiner, W Fallone, G Field, C Menard, C Hanson, J TI Single nucleotide polymorphisms in radiation response genes correlate with clinical late toxicity in patients treated with three-dimensional conformal radiotherapy (3DCRT) for adenocarcinoma of the prostate SO RADIOTHERAPY AND ONCOLOGY LA English DT Meeting Abstract CT 23rd Annual Meeting of the European-Society-for-Therapeutic-Radiology-and-Oncology (ESTRO 23) CY OCT 24-28, 2004 CL Amsterdam, NETHERLANDS SP European Soc Therapeut Radiol Oncol C1 Cross Canc Inst, PolyomX Program, Edmonton, AB T6G 1Z2, Canada. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD OCT PY 2004 VL 73 SU 1 BP S23 EP S23 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 886OH UT WOS:000226237700050 ER PT J AU Wong, RKS Paul, N Ding, K Fyles, A Wilke, D Nabid, A Fortin, A Wilson, D McKkenzie, M Pater, J AF Wong, RKS Paul, N Ding, K Fyles, A Wilke, D Nabid, A Fortin, A Wilson, D McKkenzie, M Pater, J TI A phase III double blind randomized trial comparing ondansetron (OND) plus dexamethasone (DEX) vs. ond alone in the prophylaxis against radiation-induced emesis. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Study SO RADIOTHERAPY AND ONCOLOGY LA English DT Meeting Abstract CT 23rd Annual Meeting of the European-Society-for-Therapeutic-Radiology-and-Oncology (ESTRO 23) CY OCT 24-28, 2004 CL Amsterdam, NETHERLANDS SP European Soc Therapeut Radiol & Oncol C1 Princess Margaret Hosp, Radiat Med Program, Toronto, ON, Canada. NCI, Canada Clin Trials Grp, Kingston, ON, Canada. Nova Scotia Canc Ctr, Halifax, NS, Canada. CHUS Hop Fleurimont, Sherbrooke, PQ, Canada. CHUQ, Pavillon Hotel Dieu Quebec, Quebec City, PQ, Canada. BC Canc Agcy, Fraser Valley Ctr, Surrey, BC, Canada. BCCA, Vancouver Canc Ctr, Vancouver, BC, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD OCT PY 2004 VL 73 SU 1 BP S387 EP S388 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 886OH UT WOS:000226237701419 ER PT J AU Payne, SG Milstien, S Barbour, SE Spiegel, S AF Payne, SG Milstien, S Barbour, SE Spiegel, S TI Modulation of adpative immune responses by sphingosine-1-phosphate SO SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY LA English DT Review DE cytokines; chemokines; GPCR; FFY720; sphingosine-1-phosphate ID SPHINGOSINE 1-PHOSPHATE RECEPTORS; BRONCHIAL EPITHELIAL-CELLS; PROTEIN-COUPLED RECEPTORS; LYSOPHOSPHATIDIC ACID; DENDRITIC CELLS; SIGNAL-TRANSDUCTION; CUTTING EDGE; TNF-ALPHA; INTERLEUKIN-8 SECRETION; LYSOPHOSPHOLIPASE-D AB Sphingosine-1-phosphate (S1P) has long been recognized as a mediator of a variety of cell functions. A growing body of evidence has accumulated demonstrating its role in cell migration and as a mediator of growth factor-induced events. In recent years, it has become apparent that S1P also mediates many cytokine and chemokine functions. Cells of the immune system function and migrate in response to a complex network of cytokines and chemokines, and the outcome is determined by the interplay of the effects of these molecules on the target cell. S1P may be a bona fide component of these networks and influence the responses of cells to these immune modulators. (C) 2004 Elsevier Ltd. All rights reserved. C1 Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM sspiegel@vcu.edu NR 56 TC 12 Z9 13 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1084-9521 J9 SEMIN CELL DEV BIOL JI Semin. Cell Dev. Biol. PD OCT PY 2004 VL 15 IS 5 BP 521 EP 527 DI 10.1016/j.semcdb.2004.05.008 PG 7 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 856NH UT WOS:000224051400008 PM 15271297 ER PT J AU Dunbar, CE AF Dunbar, CE TI Introduction - Gene therapy for hematologic disease: Don't throw the baby out with the bathwater! SO SEMINARS IN HEMATOLOGY LA English DT Editorial Material C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2004 VL 41 IS 4 BP 255 EP 256 DI 10.1053/j.seminhematol.2004.07.001 PG 2 WC Hematology SC Hematology GA 870JA UT WOS:000225052200001 ER PT J AU Larochelle, A Dunbar, CE AF Larochelle, A Dunbar, CE TI Genetic manipulation of hematopoietic stem cells SO SEMINARS IN HEMATOLOGY LA English DT Review ID IN-VIVO SELECTION; BLOOD CD34(+) CELLS; BONE-MARROW-CELLS; SEVERE COMBINED IMMUNODEFICIENCY; PSEUDOTYPED RETROVIRAL VECTORS; NOD/SCID-REPOPULATING CELLS; IMMUNE-DEFICIENT MICE; MURINE LEUKEMIA-VIRUS; LONG-TERM HEMATOPOIESIS; RHESUS PERIPHERAL-BLOOD C1 NIH, NHLBI, Hematol Branch, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NIH, NHLBI, Hematol Branch, Bldg 10,Room 7C-103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov NR 122 TC 20 Z9 21 U1 0 U2 0 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2004 VL 41 IS 4 BP 257 EP 271 DI 10.1053/j.seminhematol.2004.07.002 PG 15 WC Hematology SC Hematology GA 870JA UT WOS:000225052200002 PM 15508111 ER PT J AU Persons, DA Tisdale, JF AF Persons, DA Tisdale, JF TI Gene therapy for the hemoglobin disorders SO SEMINARS IN HEMATOLOGY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; HUMAN BETA-GLOBIN; IN-VIVO SELECTION; BONE-MARROW-TRANSPLANTATION; LONG-TERM ENGRAFTMENT; LOCUS-CONTROL REGION; LOW-DOSE IRRADIATION; REPOPULATING CELLS; LENTIVIRAL VECTORS; PROGENITOR CELLS C1 St Jude Childrens Res Hosp, Dept Hematol Oncol, Div Expt Hematol, Memphis, TN 38105 USA. NIH, Mol & Clin Hematol Branch, NIDDK, Bethesda, MD USA. RP Persons, DA (reprint author), St Jude Childrens Res Hosp, Dept Hematol Oncol, Div Expt Hematol, 332 N Lauderdale St Dr, Memphis, TN 38105 USA. EM Derek.persons@stjude.org FU NCI NIH HHS [CA-21765]; NHLBI NIH HHS [P01 HL53749, R01 HL70705, U54 HL70590, KO8 HL04205] NR 83 TC 18 Z9 19 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2004 VL 41 IS 4 BP 279 EP 286 DI 10.1053/j.seminhematol.2004.07.004 PG 8 WC Hematology SC Hematology GA 870JA UT WOS:000225052200004 PM 15508113 ER PT J AU Gunay-Aygun, M Huizing, M Gahl, WA AF Gunay-Aygun, M Huizing, M Gahl, WA TI Molecular defects that affect platelet dense granules SO SEMINARS IN THROMBOSIS AND HEMOSTASIS LA English DT Article DE platelet dense granules; storage pool deficiency; Hermansky-Pudlak syndrome; lysosome-related organelles; intracellular vesicle formation ID HERMANSKY-PUDLAK-SYNDROME; STORAGE-POOL DEFICIENCY; CHEDIAK-HIGASHI-SYNDROME; WISKOTT-ALDRICH-SYNDROME; GENOTYPE-PHENOTYPE CORRELATION; X-LINKED THROMBOCYTOPENIA; PULMONARY-FIBROSIS; ALPHA-GRANULES; MULTIVESICULAR BODIES; SECRETORY GRANULES AB Platelet dense granules form using mechanisms shared by melanosomes in melanocytes and by subsets of lysosomes in more generalized cells. Consequently, disorders of platelet dense granules can reveal how organelles form and move within cells. Models for the study of new vesicle formation include isolated delta-storage pool deficiency, combined alphadelta-storage pool deficiency, Hermansky-Pudlak syndrome (HPS), Chediak-Higashi syndrome, Griscelli syndrome, thrombocytopenia absent radii syndrome, and Wiskott-Aldrich syndrome. The molecular bases of dense granule deficiency are known for the seven subtypes of HPS, as well as for Chediak-Higashi syndrome, Griscelli syndrome, and Wiskott-Aldrich syndrome. The gene products involved in these disorders help elucidate the generalized process of the formation of vesicles from extant membranes such as the Golgi. C1 NHGRI, NIH, Sect Human Biochem Genet, Med Genet Branch, Bethesda, MD 20892 USA. RP Gahl, WA (reprint author), NHGRI, NIH, Sect Human Biochem Genet, Med Genet Branch, 10 Ctr Dr,MSC 1851,Bldg 10,Room 10C-103, Bethesda, MD 20892 USA. EM bgahl@helix.nih.gov NR 84 TC 69 Z9 71 U1 0 U2 6 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0094-6176 J9 SEMIN THROMB HEMOST JI Semin. Thromb. Hemost. PD OCT PY 2004 VL 30 IS 5 BP 537 EP 547 DI 10.1055/s-2004-835674 PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 866XI UT WOS:000224806300005 PM 15497096 ER PT J AU Zheng, G Freidlin, B Gastwirth, JL AF Zheng, G Freidlin, B Gastwirth, JL TI Using Kullback-Leibler information for model selection when the data-generating model is unknown: Applications to genetic testing problems SO STATISTICA SINICA LA English DT Article DE admissible genetic model; association and linkage; Kullback-Leibler information; maximin; minimax; robustness ID ROBUST LINKAGE TESTS; AFFECTED SIBS; ASSOCIATION; POWER; LOCI AB In genetic studies of complex diseases the underlying genetic model is usually unknown. Thus, a family of locally optimal statistics is obtained for testing association or linkage. Utilizing two new measures based on Kullback-Leibler information, we are able to define a family of admissible genetic models and obtain the corresponding two optimality criteria to select robust models. The model selection procedures described in this paper are valid regardless of sample size. The results are applied to genetic linkage analysis using affected sibs and candidate-gene association tests using the case-parents design. Our results provide insight into some commonly used statistics in the genetic linkage analysis of affected sib-pairs. C1 NHLBI, Off Biostat Res, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. George Washington Univ, Dept Stat, Washington, DC 20052 USA. NCI, Biostat Branch, Div Epidemiol & Genet, Bethesda, MD 20892 USA. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr,Room 8223,MSC 7938, Bethesda, MD 20892 USA. EM zhengg@nhlbi.nih.gov; freidlinb@ctep.nci.nih.gov; jlgast@gwu.edu NR 23 TC 3 Z9 3 U1 0 U2 1 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 J9 STAT SINICA JI Stat. Sin. PD OCT PY 2004 VL 14 IS 4 BP 1021 EP 1036 PG 16 WC Statistics & Probability SC Mathematics GA 870YJ UT WOS:000225094500001 ER PT J AU Rao, MS AF Rao, MS TI Stem sense: A proposal for the classification of stem cells SO STEM CELLS AND DEVELOPMENT LA English DT Article ID PROGENITOR CELLS; DIFFERENTIATION AB Stem cells, while difficult to define, hold great promise as tools for understanding development and as therapy. However, this difficulty in defining stem cells has led to a multiplicity of stem cells that may or may not be distinct. The lack of common standards or definitions, the absence of a common forum for discussion, and the range in the ability to manipulate his/her favorite system of stem cells has led to further fragmentation of a field bedeviled by controversy. I suggest that stratification and classification of stem cells on the basis of their function, characteristics, and capabilities would be of enormous benefit to the community. This absence of uniform nomenclature and classification has led to many contradictory claims as to the abilities of stem cells and has made it very difficult to generalize across systems and cell types. I illustrate the problem by providing two examples of how the lack of uniform definitions has slowed progress. I suggest that the effort to establish a consensus on what constitutes a tissue-specific stem cell ( definition) and how one would stratify cells ( classification) would greatly facilitate progress and perhaps help resolve some of the outstanding controversies. C1 NIA, Stem Cell Sect, Neurosci Lab, NIH, Baltimore, MD 21224 USA. RP Rao, MS (reprint author), NIA, LNS, GRC, TIAD Technol Ctr, 333 Cassell Dr, Baltimore, MD 21224 USA. EM raomah@grc.nia.nih.gov NR 13 TC 14 Z9 15 U1 0 U2 4 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 EI 1557-8534 J9 STEM CELLS DEV JI Stem Cells Dev. PD OCT PY 2004 VL 13 IS 5 BP 452 EP 455 DI 10.1089/1547328042417327 PG 4 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 869QW UT WOS:000225000100002 PM 15588501 ER PT J AU Posner, GH Jeon, HB Sarjeant, A Riccio, ES Doppalapudi, RS Kapetanovic, IM Saha, U Dolan, P Kensler, TW AF Posner, GH Jeon, HB Sarjeant, A Riccio, ES Doppalapudi, RS Kapetanovic, IM Saha, U Dolan, P Kensler, TW TI Low-calcemic, efficacious, 1 alpha,25-dihydroxyvitamin D-3 analog QW-1624F(2)-2: calcemic dose-response determination, preclinical genotoxicity testing, and revision of A-ring stereochemistry SO STEROIDS LA English DT Article DE calcitriol hybrid analog; low-calcemic analog ID PRELIMINARY BIOLOGICAL EVALUATION; HYBRID ANALOGS; 1-ALPHA,25-DIHYDROXY-19-NORVITAMIN D-3; SIDE-CHAIN; DIFFERENTIATION; CALCITRIOL; DESIGN; CELLS; ASSAY AB Based on an X-ray crystal structure determination, the A-ring stereochemistry of hybrid analog QW-1624F(2)-2 (1alpha-hydroxymethyl-16-ene-24,24-difluoro-25-hydroxy-26,27-bis-homovitamin D-3) is revised to be 1alpha-CH2OH-3beta-OH. This analog is shown to be approximately 80-100 times less calciuric than the natural hormone 1alpha,25-dihydoxyvitamin D-3. This analog is shown also to be non-genotoxic in three different standard assays. (C) 2004 Elsevier Inc. All rights reserved. C1 Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. SRI Int, Toxicol & Pharmacol Lab, Menlo Pk, CA 94025 USA. NCI, NIH, Div Canc Prevent, Bethesda, MD 20892 USA. Cytochroma Inc, Markham, ON L3R 8E4, Canada. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Div Environm Hlth Sci, Baltimore, MD 21205 USA. RP Posner, GH (reprint author), Johns Hopkins Univ, Dept Chem, 3400 N Charles St, Baltimore, MD 21218 USA. EM ghp@jhu.edu RI Kensler, Thomas/D-8686-2014 OI Kensler, Thomas/0000-0002-6676-261X FU NCI NIH HHS [CA88843, CA93547] NR 18 TC 29 Z9 30 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X J9 STEROIDS JI Steroids PD OCT-NOV PY 2004 VL 69 IS 11-12 BP 757 EP 762 DI 10.1016/j.steroids.2004.09.004 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 885XE UT WOS:000226189800006 PM 15579327 ER PT J AU Barrientos, LG Lasala, F Delgado, R Sanchez, A Gronenborn, AM AF Barrientos, LG Lasala, F Delgado, R Sanchez, A Gronenborn, AM TI Flipping the switch from monomeric to dimeric CV-N has little effect on antiviral activity SO STRUCTURE LA English DT Article ID DOMAIN-SWAPPED DIMER; IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-INACTIVATING PROTEIN; CYANOVIRIN-N; EBOLA-VIRUS; GLYCOPROTEINS; DISCOVERY; BINDING; MUTANT AB Cyanovirin-N can exist in solution in monomeric and domain-swapped dimeric forms, with HIV-antiviral activity being reported for both. Here we present results for CN-N variants that form stable solution dimers: the obligate dimer [DeltaQ50]CV-N and the preferential dimer [S52P]CV-N. These variants exhibit comparable DeltaG values (10.6 +/- 0.5 and 9.4 +/- 0.5 kcal.mol(-1), respectively), similar to that of stabilized, monomeric [P51G]CV-N (9.8 +/- 0.5 kcal.mol(-1)), but significantly higher than wild-type CV-N (4.1 +/- 0.2 kcal.mol(-1)). During folding/ unfolding, no stably folded monomer was observed under any condition for the obligate dimer [AQ50] CV-N, whereas two monomeric, metastable species were detected for [S52P]CV-N at low concentrations. This is in contrast to our previous results for [P51G] CV-N and wild-type CV-N, for which the dimeric forms were found to be the metastable species. The dimeric mutants exhibit comparable antiviral activity against HIV and Ebola, similar to that of wild-type CV-N and the stabilized [P51G]CV-N variant. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Special Pathogens Branch, DVRD, NCID, Atlanta, GA 30333 USA. Hosp 12 Octubre, Mol Biol Lab, Madrid 28041, Spain. RP Gronenborn, AM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM lbarrientos1@cdc.gov; gronenborn@nih.gov RI Delgado, Rafael/C-4910-2016; OI Delgado, Rafael/0000-0002-6912-4736; Gronenborn, Angela M/0000-0001-9072-3525 NR 22 TC 28 Z9 28 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT PY 2004 VL 12 IS 10 BP 1799 EP 1807 DI 10.1016/j.str.2004.07.019 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 863DL UT WOS:000224540800007 PM 15458629 ER PT J AU Krahn, JM Beard, WA Wilson, SH AF Krahn, JM Beard, WA Wilson, SH TI Structural insights into DNA polymerase beta deterrents for misincorporation support an induced-fit mechanism for fidelity SO STRUCTURE LA English DT Article ID K-RAS GENE; ACTIVE-SITE; NUCLEOTIDE INCORPORATION; CRYSTAL-STRUCTURE; ANGSTROM RESOLUTION; CATALYTIC MECHANISM; MOLECULAR-DYNAMICS; KINETIC MECHANISM; TEMPLATE-PRIMER; BASE-PAIRS AB DNA polymerases generally select the correct nucleotide from a pool of structurally similar molecules to preserve Watson-Crick base-pairing rules. We report the structure of DNA polymerase beta with DNA mismatches situated in the polymerase active site. This was achieved by using nicked product DNA that traps the mispair (template-primer, A-C or T-C) in the nascent base pair binding pocket. The structure of each mispair complex indicates that the bases do not form hydrogen bonds with one another, but form a staggered arrangement where the bases of the mispair partially overlap. This prevents closure/opening of the N subdomain that is believed to be required for catalytic cycling. The partially open conformation of the N subdomain results in distinct hydrogen bonding networks that are unique for each mispair. These structures define diverse molecular aspects of misinsertion that are consistent with the induced-fit model for substrate specificity. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 58 TC 60 Z9 62 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD OCT PY 2004 VL 12 IS 10 BP 1823 EP 1832 DI 10.1016/j.str.2004.08.001 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 863DL UT WOS:000224540800009 PM 15458631 ER PT J AU Janda, I Devedjiev, Y Derewenda, U Dauter, Z Bielnicki, J Cooper, DR Graf, PCF Joachimiak, A Jakob, U Derewenda, ZS AF Janda, I Devedjiev, Y Derewenda, U Dauter, Z Bielnicki, J Cooper, DR Graf, PCF Joachimiak, A Jakob, U Derewenda, ZS TI The crystal structure of the reduced, Zn2+-bound form of the B. subtilis Hsp33 chaperone and its implications for the activation mechanism SO STRUCTURE LA English DT Article ID HEAT-SHOCK-PROTEIN; MOLECULAR CHAPERONE; ANGSTROM RESOLUTION; REDOX SWITCH; CRYSTALLIZATION; DOMAIN; REFINEMENT AB The bacterial heat shock protein Hsp33 is a redox-regulated chaperone activated by oxidative stress. In response to oxidation, four cysteines within a Zn2+ binding C-terminal domain form two disulfide bonds with concomitant release of the metal. This leads to the formation of the biologically active Hsp33 dimer. The crystal structure of the N-terminal domain of the E. coli protein has been reported, but neither the structure of the Zn2+ binding motif nor the nature of its regulatory interaction with the rest of the protein are known. Here we report the crystal structure of the full-length B. subtilis Hsp33 in the reduced form. The structure of the N-terminal, dimerization domain is similar to that of the E. coli protein, although there is no domain swapping. The Zn2+ binding domain is clearly resolved showing the details of the tetrahedral coordination of Zn2+ by four thiolates. We propose a structure-based activation pathway for Hsp33. C1 Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. Brookhaven Natl Lab, NCI, Macromol Crystallog Lab, Synchrotron Radiat Res Sect, Upton, NY 11973 USA. Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. Argonne Natl Lab, Biosci Div, Argonne, IL 60439 USA. Argonne Natl Lab, Struct Biol Ctr, Argonne, IL 60439 USA. RP Derewenda, ZS (reprint author), Univ Virginia, Dept Mol Physiol & Biol Phys, Charlottesville, VA 22908 USA. EM zsd4n@virginia.edu OI Graf, Paul/0000-0002-1094-7498 FU NIGMS NIH HHS [GM065318, GM62615, P50 GM062414, R01 GM062615, R01 GM065318] NR 29 TC 48 Z9 49 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 EI 1878-4186 J9 STRUCTURE JI Structure PD OCT PY 2004 VL 12 IS 10 BP 1901 EP 1907 DI 10.1016/j.str.2004.08.003 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 863DL UT WOS:000224540800016 PM 15458638 ER PT J AU Hassan, M Little, RF Vogel, A Aleman, K Wyvill, K Yarchoan, R Gandjbakhche, AH AF Hassan, M Little, RF Vogel, A Aleman, K Wyvill, K Yarchoan, R Gandjbakhche, AH TI Quantitative assessment of tumor vasculature and response to therapy in Kaposi's sarcoma using functional noninvasive imaging SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Article DE Kaposi's sarcoma; angiogenesis; anti-KS therapy; thermal imaging; laser doppler imaging ID SKIN BLOOD-FLOW; PROTEIN-COUPLED RECEPTOR; LASER-DOPPLER FLOWMETRY; ANGIOGENESIS; AIDS; PERFUSION; TEMPERATURE; GROWTH; MICROCIRCULATION; THERMOGRAPHY AB Two noninvasive methods, thermography and laser Doppler imaging (LDI), were assessed for their ability to quantitatively assess parameters of vascularity in lesions of HIV-associated Kaposi's sarcoma (KS). Thermography and LDI images of a representative KS lesion were recorded in 16 patients and compared to normal skin either adjacent to the lesion or on the contralateral side. Eleven of the 16 patients had greater than 0.5 degreesC increased temperature and 12 of the 16 patients had increased flux (measured by LDI) as compared to normal skin. There was a strong correlation between these two parameters (R = 0.81, p < 0.001). In ten patients, measurements were obtained prior to therapy and after receiving a regimen of liposomal doxorubicin and interleukin-12. After 18 weeks of therapy, temperature and blood flow of the lesions were significantly reduced from the baseline (p = 0.004 and 0.002 respectively). These techniques hold promise to assess physiologic parameters in KS lesions and their changes with therapy. C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. NCI, HIV & AIDS Malignancy Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Hassan, M (reprint author), NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. EM hassanm@mail.nih.gov NR 38 TC 23 Z9 24 U1 0 U2 1 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 1533-0346 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD OCT PY 2004 VL 3 IS 5 BP 451 EP 457 PG 7 WC Oncology SC Oncology GA 864ZM UT WOS:000224671900006 PM 15453810 ER PT J AU Verma, M AF Verma, M TI Biomarkers for risk assessment in molecular epidemiology of cancer SO TECHNOLOGY IN CANCER RESEARCH & TREATMENT LA English DT Article ID CERVICAL-CANCER; LUNG-CANCER; BREAST-CANCER; COLORECTAL-CANCER; DNA METHYLATION; GENE-EXPRESSION; CELL; TUMORS; CARCINOMA; LYMPHOMA AB one out of four deaths in the USA is due to cancer. Identification of populations at risk of developing cancer is important as it provides opportunities for prevention and treatment of cancer. Biomarkers are measurable indicators of exposure effects and susceptibility or disease state, and are used to understand the mechanisms of cancer progression. In recent molecular epidemiology studies genomic, proteomic, and epigenomic markers have been utilized which exhibit high sensitivity and specificity for different tumor types and can be assayed in biofluids and other specimens collected by non-invasive technologies. The current challenges and future directions in the field are discussed in this article. C1 NCI, Analyt Epidemiol Res Branch, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Verma, M (reprint author), NCI, Analyt Epidemiol Res Branch, Epidemiol & Genet Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM vermam@mail.nih.gov NR 65 TC 8 Z9 8 U1 0 U2 0 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 1533-0346 J9 TECHNOL CANCER RES T JI Technol. Cancer Res. Treat. PD OCT PY 2004 VL 3 IS 5 BP 505 EP 514 PG 10 WC Oncology SC Oncology GA 864ZM UT WOS:000224671900012 PM 15453816 ER PT J AU Dimitrova, MN Piszczek, G Ginsburg, A AF Dimitrova, MN Piszczek, G Ginsburg, A TI On the conformational stability and dimerization of phosphotransferase enzyme I from Escherichia coli SO THERMOCHIMICA ACTA LA English DT Article; Proceedings Paper CT 6th Mediterranean Conference on Calorimetry and Thermal Analysis CY JUL 27-29, 2003 CL Univ Porto, Dept Chem, Fac Sci, Oporto, PORTUGAL SP Assoc Italiana Calorimetria & Analisi Termica, Gruppo Interdivis Calorimetria & Analisi Termica, SCI, GECAT, Hellin Soc Thermal Anal, Israeli Grp Thremal Anal & Calorimetry, CATPOR HO Univ Porto, Dept Chem, Fac Sci DE enzyme I; E. coli phosphoenolpyruvate; sugar phosphotransferase system; active-site mutant [EI(H 189A)]; phosphoenolpyruvate; pyruvate; Mg2+; differential scanning calorimetry; Trp fluorescence; sedimentation equilibrium; dimerization; isothermal titration calorimetry ID DIFFERENTIAL SCANNING CALORIMETRY; AMINO-TERMINAL DOMAIN; BACTERIAL PHOSPHOENOLPYRUVATE; SYSTEM; PHOSPHORYLATION; PROTEIN; PYRUVATE; VITRO; DIMER AB The activity of enzyme I (EI), the first protein in the bacterial PEP:sugar phosphotransferase system, is regulated by a monomer-dimer equilibrium where a Mg2+-dependent autophosphorylation by PEP requires the homodimer. Using inactive EI(H189A), in which alanine is substituted for the active-site His 189, substrate binding effects can be separated from those of phosphorylation. Whereas 1 mM PEP (with 2 MM Mg2+) strongly promotes dimerization of EI(H189A) at pH 7.5 and 20degreesC, 5 mM pyruvate (with 2 mM Mg2+) has the opposite effect. A correlation between the coupling of N- and C-terminal domain unfolding, measured by differential scanning calorimetry, and the dimerization constant for EI, determined by sedimentation equilibrium, is observed. That is, when the coupling between N- and C-terminal domain unfolding produced by 0.2 or 1.0 mM PEP and 2 mM Mg2+ is inhibited by 5 mM pyruvate, the dimerization constant for EI(H189A) decreases from > 10(8) to <5 x 10(5) or 3 x 10(7) M-1, respectively. With 2 mM Mg2+ at 15-25degreesC and pH 7.5, PEP has been found to bind to one site/monomer of EI(H189A) with K'(A) congruent to 10(6) M-1 (DeltaG' = -33.7 +/- 0.2 kJ mol(-1) and DeltaH = +16.3 kJ mol(-1) at 20degreesC with DeltaC(p) = 1.4 kJ K-1 mol(-1)). The bindine of PEP to EI(H189A) is synergistic with that of Mg2+. Thus, physiological concentrations of PEP and Mg2+ increase, whereas pyruvate and Mg2+ decrease the amount of dimeric, active, dephospho-enzyme 1. (C) 2004 Elsevier B.V. All rights reserved. C1 Natl Heart Lung & Blood Inst, Sect Prot Chem, Lab Biochem, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Ginsburg, A (reprint author), Natl Heart Lung & Blood Inst, Sect Prot Chem, Lab Biochem, Dept Hlth & Human Serv,NIH, 50 S Dr,Room 2339, Bethesda, MD 20892 USA. EM marianad@amgen.eom; ginsbura@nhlbi.nih.gov NR 27 TC 1 Z9 1 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0040-6031 J9 THERMOCHIM ACTA JI Thermochim. Acta PD OCT 1 PY 2004 VL 420 IS 1-2 SI SI BP 37 EP 43 DI 10.1016/j.tca.2003.10.028 PG 7 WC Thermodynamics; Chemistry, Analytical; Chemistry, Physical SC Thermodynamics; Chemistry GA 860VM UT WOS:000224371800008 ER PT J AU Jin, P Provenzano, M Panelli, MC Ngalame, Y Marincola, FM Wang, E AF Jin, P Provenzano, M Panelli, MC Ngalame, Y Marincola, FM Wang, E TI Integromics approaches to dissect genetic and functional heterogeneities between Caucasian and Asian immune responses SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 1st International Conference on Basic and Clinical Immunogenomics (BCI 2004) CY OCT 03-07, 2004 CL Budapest, HUNGARY SP Agilent Technologies, Beckman Coulter, Bio Rad, IBM, Appl Biosyst, Promega, Kromat, Pfizer, Qiagen, Biomed Hungaria, Intercell, ComGenex, Gedeon Richter Pharmaceut, Astra Zeneca, Bio Sci, Csertex, Abbott Labs Hungary, Biotest, Johnson & Johnson, Aventis, Genodia C1 NIH, Immunogenet Lab, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD OCT PY 2004 VL 64 IS 4 BP 322 EP 322 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 854BY UT WOS:000223876400007 ER PT J AU Wang, E Panelli, MC Monsurro, V Ping, J Zavaglia, K Marincola, FM AF Wang, E Panelli, MC Monsurro, V Ping, J Zavaglia, K Marincola, FM TI The enigma of tumor immune responsiveness: A high-throughput genomics question? SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 1st International Conference on Basic and Clinical Immunogenomics (BCI 2004) CY OCT 03-07, 2004 CL Budapest, HUNGARY SP Agilent Technologies, Beckman Coulter, Bio Rad, IBM, Appl Biosyst, Promega, Kromat, Pfizer, Qiagen, Biomed Hungaria, Intercell, ComGenex, Gedeon Richter Pharmaceut, Astra Zeneca, Bio Sci, Csertex, Abbott Labs Hungary, Biotest, Johnson & Johnson, Aventis, Genodia C1 Ctr Clin, Dept Transfus Med, Immunogenet Lab, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD OCT PY 2004 VL 64 IS 4 BP 340 EP 340 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 854BY UT WOS:000223876400049 ER PT J AU Becker, KG AF Becker, KG TI Comparative immunogenomics of autoimmune and inflammatory disorders SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 1st International Conference on Basic and Clinical Immunogenomics (BCI 2004) CY OCT 03-07, 2004 CL Budapest, HUNGARY SP Agilent Technologies, Beckman Coulter, Bio Rad, IBM, Appl Biosyst, Promega, Kromat, Pfizer, Qiagen, Biomed Hungaria, Intercell, ComGenex, Gedeon Richter Pharmaceut, Astra Zeneca, Bio Sci, Csertex, Abbott Labs Hungary, Biotest, Johnson & Johnson, Aventis, Genodia C1 NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD OCT PY 2004 VL 64 IS 4 BP 343 EP 343 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 854BY UT WOS:000223876400057 ER PT J AU Wynn, TA Mentink-Kane, MM Sandler, NG Hari, D Thompson, RW Cheever, AW AF Wynn, TA Mentink-Kane, MM Sandler, NG Hari, D Thompson, RW Cheever, AW TI Gene expression profiling in diseased tissues reveals divergent roles for Th1 and Th2 responses in tissue repair SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 1st International Conference on Basic and Clinical Immunogenomics (BCI 2004) CY OCT 03-07, 2004 CL Budapest, HUNGARY SP Agilent Technologies, Beckman Coulter, Bio Rad, IBM, Appl Biosyst, Promega, Kromat, Pfizer, Qiagen, Biomed Hungaria, Intercell, ComGenex, Gedeon Richter Pharmaceut, Astra Zeneca, Bio Sci, Csertex, Abbott Labs Hungary, Biotest, Johnson & Johnson, Aventis, Genodia C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RI Wynn, Thomas/C-2797-2011 NR 5 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD OCT PY 2004 VL 64 IS 4 BP 345 EP 345 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 854BY UT WOS:000223876400062 ER PT J AU Kashmiri, S Gonzales, NR Padlan, EA De Pascalis, R Schuck, P Schlom, J AF Kashmiri, S Gonzales, NR Padlan, EA De Pascalis, R Schuck, P Schlom, J TI SDR grafting of a murine antibody using multiple human germline templates to minimize its immunogenicity SO TISSUE ANTIGENS LA English DT Meeting Abstract CT 1st International Conference on Basic and Clinical Immunogenomics (BCI 2004) CY OCT 03-07, 2004 CL Budapest, HUNGARY SP Agilent Technologies, Beckman Coulter, Bio Rad, IBM, Appl Biosyst, Promega, Kromat, Pfizer, Qiagen, Biomed Hungaria, Intercell, ComGenex, Gedeon Richter Pharmaceut, Astra Zeneca, Bio Sci, Csertex, Abbott Labs Hungary, Biotest, Johnson & Johnson, Aventis, Genodia C1 NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD OCT PY 2004 VL 64 IS 4 BP 429 EP 429 PG 1 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 854BY UT WOS:000223876400258 ER PT J AU Marroni, F Curcio, M Fornaciari, S Lapi, S Mariotti, ML Scatena, F Presciuttini, S AF Marroni, F Curcio, M Fornaciari, S Lapi, S Mariotti, ML Scatena, F Presciuttini, S TI Microgeographic variation of HLA-A, -B, and -DR haplotype frequencies in Tuscany, Italy: implications for recruitment of bone marrow donors SO TISSUE ANTIGENS LA English DT Article DE bone marrow donors; haplotype frequency; HLA; Tuscany ID POPULATION; DIFFERENTIATION; REGISTRIES; SURNAMES; ALLELES; GENES AB HLA-A/B haplotype frequencies were estimated in a sample of 2355 bone marrow donors born in a subregion of Tuscany (Italy), and the HLA-A, -B, -DR haplotype frequencies were estimated in a subset of 809 individuals. This area was divided in 10 subsamples (two-locus haplotypes), or six subsamples (three-locus haplotypes), all with sample size >50, based on administrative boundaries. A considerable level of heterogeneity of haplotype frequency was present among subsamples; this heterogeneity was associated to a large variation (up to 4-fold) of the number of new donors that must be typed in order to reach 50% chance of finding an HLA-A, -B phenotype of intermediate frequency. Knowledge of the genetic structure of the population at a microgeographic level may be useful in directing the search of specific bone marrow donors. C1 Univ Pisa, Ctr Stat Genet, I-56127 Pisa, Italy. Univ Pisa, Sect Pathol, Dept Oncol Transplants & New Technol Med, Pisa, Italy. Azienda Osped Pisana, UO Immunoematol 2, Pisa, Italy. NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. RP Presciuttini, S (reprint author), Univ Pisa, Ctr Stat Genet, SS Abetone & Brennero 2, I-56127 Pisa, Italy. EM sprex@biomed.unipi.it OI Marroni, Fabio/0000-0002-1556-5907 NR 23 TC 6 Z9 6 U1 0 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD OCT PY 2004 VL 64 IS 4 BP 478 EP 485 DI 10.1111/j.1399-0039.2004.00292.x PG 8 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 854BY UT WOS:000223876400281 PM 15361126 ER PT J AU Martin, KR Jokinen, MP Honeycutt, HP Quinn, A Kari, FW Barrett, JC French, JE AF Martin, KR Jokinen, MP Honeycutt, HP Quinn, A Kari, FW Barrett, JC French, JE TI Tumor profile of novel p53 heterozygous Tg.AC (v-Ha-ras) bitransgenic mice treated with benzo(a)pyrene and fed dietary N-acetyl-L-cysteine (NAC) SO TOXICOLOGICAL SCIENCES LA English DT Article DE p53; Tg; AC; v-Ha-ras; antioxidant; NAC ID TRANSGENIC MOUSE; P53-DEFICIENT MICE; CANCER PREVENTION; TUMORIGENESIS; ACETYLCYSTEINE; CARCINOGENICITY; MUTATIONS; LESIONS AB We designed a novel short-term bitransgenic model to better characterize the effects of benzo(a)pyrene (BP) exposure on multi-organ carcinogenesis and to evaluate the effects of a well-recognized antioxidant, N-acetyl-L-cysteine (NAC), on neoplasia. We selected the p53 heterozygous Tg.AC (v-Ha-ras) mouse model for our studies because these mice possess a carcinogen-inducible ras oncogene and one functional p53 tumor suppressor allele. Both mutations occur frequently in human cancers. In a 2 x 2 experimental design, both female and male mice were fed basal diet alone or containing 3% NAC and administered by gavage corn oil vehicle alone or containing 20 mg BP/kg body weight given twice weekly for 10 weeks. Mice (n = 15 for each grouping and sex) were subsequently observed an additional 18 weeks followed by tissue collection for evaluation of multi-organ pathology. Benzo(a)pyrene increased neoplasia in the thymus, spleen, stomach, and hematopoietic system after 28 weeks. We observed modest NAC-associated decreases in BP-induced pathology of the liver, papilloma formation and hyperplasia in the forestomach, and the occurrence of malignant lymphoma. Benzo(a)pyrene exposure reduced survival to similar to40% in male mice, suggesting toxicity; however, survival in control groups was similar to60%. Survival decreased to similar to30% for females in all groups. We noted a clear, but nonsignificant, 15% decline in body weights of male, but not female, mice fed NAC, although food intake did not differ. Collectively, the data suggested carcinogen and antioxidant-associated effects on neoplasia that appeared sex-dependent. Thus, this novel short-term bitransgenic model may potentially be useful for testing dietary modulation of carcinogenesis. C1 Penn State Univ, Nutr & Canc Lab, University Pk, PA 16802 USA. Pathol Associates Int, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Martin, KR (reprint author), Penn State Univ, Nutr & Canc Lab, 126 Henderson Bldg S, University Pk, PA 16802 USA. EM krm12@psu.edu NR 40 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 EI 1096-0929 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2004 VL 81 IS 2 BP 293 EP 301 DI 10.1093/toxsci/kfh226 PG 9 WC Toxicology SC Toxicology GA 855BW UT WOS:000223948900006 PM 15254344 ER PT J AU Scallet, AC Schmued, LC Slikker, W Grunberg, N Faustino, PJ Davis, H Lester, D Pine, PS Sistare, F Hanig, JP AF Scallet, AC Schmued, LC Slikker, W Grunberg, N Faustino, PJ Davis, H Lester, D Pine, PS Sistare, F Hanig, JP TI Developmental neurotoxicity of ketamine: Morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons SO TOXICOLOGICAL SCIENCES LA English DT Article DE neurodegeneration; apoptosis; blood levels; anesthesia; NMDA; caspase-3 ID PERFORMANCE LIQUID-CHROMATOGRAPHY; DEPARTMENT SAFETY PROFILE; DEVELOPING BRAIN; INTRAMUSCULAR KETAMINE; PEDIATRIC SEDATION; MOUSE-BRAIN; FLUORO-JADE; CELL-DEATH; NEURODEGENERATION; CHILDREN AB Ketamine is a widely used pediatric anesthetic recently reported (C. Ikonomidou et al., 1999, Science 283, 70-74) to enhance neuronal death in neonatal rats. To confirm and extend these results, we treated four groups of PND 7 rats with seven sc doses, one every 90 min, of either saline, 10 mg/kg ketamine, 20 mg/kg ketamine, or a single dose of 20 mg/kg ketamine. The repeated doses of 20 mg/kg ketamine increased the number of silver-positive (degenerating) neurons in the dorsolateral thalamus to a degree comparable to previous results (Ikonomidou et al., 1999, Science 283, 70-74), i.e., 28-fold vs. 31-fold respectively. However, blood levels of ketamine immediately after the repeated 20 mg/kg doses were about 14 mug/ml, about seven-fold greater than anesthetic blood levels in humans (J. M. Malinovsky et al., 1996, Br. J. Anaesth. 77, 203-207; R. A. Mueller and R. Hunt, 1998, Pharmacol. Biochem. Behav. 60, 15-22). Levels of ketamine in blood following exposure to the multiple 10 mg/kg doses of ketamine or to a single 20 mg/kg dose ranged around 2-5 mug/ml; although these blood levels are close to an anesthetic level in humans, they failed to produce neurodegeneration. To investigate the mode of ketamine-induced neuronal death, coronal sections were stained with both Fluoro-Jade B (a green fluorescent stain selective for neurodegeneration) and DAPI (a blue DNA stain), as well as for caspase-3 (using an antisera labeled red with rhodamine). These histochemical results confirmed the developmental neurotoxicity of ketamine, demonstrated that Fluoro-Jade B (FJ-B), like silver methods, successfully stained degenerating neurons in neonatal rats, and indicated that ketamine acts by increasing the rate of neuronal apoptosis. C1 US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. USUHS, Bethesda, MD 20892 USA. US FDA, CDER, Silver Spring, MD 20993 USA. NIDA, NIH, Bethesda, MD 20892 USA. RP Scallet, AC (reprint author), US FDA, Div Neurotoxicol, Natl Ctr Toxicol Res, 3900 NCTR Dr, Jefferson, AR 72079 USA. EM AScallet@nctr.fda.gov NR 45 TC 154 Z9 168 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2004 VL 81 IS 2 BP 364 EP 370 DI 10.1093/toxsci/kfh224 PG 7 WC Toxicology SC Toxicology GA 855BW UT WOS:000223948900014 PM 15254342 ER PT J AU Bishop, JB Tani, Y Witt, K Johnson, JA Peddada, S Dunnick, J Nyska, A AF Bishop, JB Tani, Y Witt, K Johnson, JA Peddada, S Dunnick, J Nyska, A TI Mitochondrial damage revealed by morphometric and semiquantitative analysis of mouse pup cardiomyocytes following in utero and postnatal exposure to zidovudine and lamivudine SO TOXICOLOGICAL SCIENCES LA English DT Article DE mitochondria; heart; AIDS drugs; transplacental exposure; mice; electron microscopy; morphometry ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED WOMEN; ANTIRETROVIRAL THERAPY; UNINFECTED INFANTS; PATAS MONKEYS; TOXICITY; DYSFUNCTION; TRANSMISSION; MYOPATHY; CHILDREN AB Zidovudine (ZDV), an antiretroviral drug used alone or in combination with other antiretroviral agents to treat HIV-infected pregnant women and their newborn infants, effectively reduces mother-to-child transmission of the virus. That myopathy and cardiomyopathy, related to mitochondrial damage, develop in some adults chronically treated with ZDV has long been known; recently, reports have suggested that similar adverse effects may occur in some infants exposed perinatally. Using a mouse model of human neonatal exposure, we treated pregnant CD-1 mice twice daily with doses of 75 mg/kg ZDV plus 37.5 mg/kg lamivudine throughout gestation and lactation; pups were exposed by direct gavage beginning postnatal day (PND) 4 and sacrificed on PND 28. Hearts were removed rapidly, and ventricles were processed for electron microscopy. Morphometric and semiquantitative morphological analyses were performed on three micrographs from each of three blocks from each of three females and three males from the control and treated groups. Treated mice showed significant increases in the mean area and decreases in the mean number of cardiomyocytic mitochondria compared to controls. We observed clusters of damaged mitochondria more frequently in treated animals than in controls; damage included fragmentation and loss of cristae. These results, demonstrating alterations in cardiomyocytic mitochondria of mice exposed in utero and postnatally, may model cardiac damage reported in human infants similarly exposed to ZDV. Critical insights derived from animal-model data like these may be used to mitigate risks to thousands of human infants receiving essential lifesaving therapy with antiretroviral drugs. C1 NIEHS, Mol Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Toxicol Operat Branch, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Bishop, JB (reprint author), NIEHS, Mol Toxicol Lab, NIH, MD EC-01,POB 12233,79 TW Alexander Dr,Bldg 4401,S, Res Triangle Pk, NC 27709 USA. EM bishop@niehs.nih.gov RI Peddada, Shyamal/D-1278-2012 NR 33 TC 20 Z9 20 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2004 VL 81 IS 2 BP 512 EP 517 DI 10.1093/toxsci/kfh208 PG 6 WC Toxicology SC Toxicology GA 855BW UT WOS:000223948900028 PM 15229369 ER PT J AU Wormser, U Langenbach, R Peddada, S Sintov, A Brodsky, B Nyska, A AF Wormser, U Langenbach, R Peddada, S Sintov, A Brodsky, B Nyska, A TI Reduced sulfur mustard-induced skin toxicity in cyclooxygenase-2 knockout and celecoxib-treated mice SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE sulfur mustard; skin; COX-2; knockout mice ID EAR VESICANT MODEL; HISTOPATHOLOGIC FEATURES; HUMAN KERATINOCYTES; CUTANEOUS INJURY; GENE DISRUPTION; GUINEA-PIGS; MOUSE SKIN; EXPRESSION; LESIONS; INFLAMMATION AB Sulfur mustard (SM), a potent vesicant and chemical warfare agent, induces tissue damage involving an inflammatory response, including vasodilatation, polymorphonuclear infiltration, production of inflammatory mediators, and cyclooxygenase activity. To evaluate the role of cyclooxygenase-1 and -2 (COX-1, COX-2) in sulfur mustard-induced skin toxicity, we applied the agent to the cars of wildtype (WT) and COX-1- and COX-2-deficient mice. In the latter, ear swelling 24 and 48 h after exposure was significantly reduced (P < 0.05) by 55% and 30%, respectively, compared to WT. Quantitative histopathology revealed no epidermal ulceration in COX-2-deficient mice but some degree of severity in WT. COX-2-deficient mice showed significant reductions (P < 0.05) in severity of epidermal necrosis (29%), acute inflammation (42%), and hemorrhage (25%), compared to the WT mice. COX-1 deficiency resulted in significant exacerbation (P < 0.05) in severity of some parameters, including increases of 4.6- and 1.2-fold in epidermal ulceration and epidermal necrosis, respectively, compared to WT. Postexposure treatment of normal male ICR mice with the selective COX-2 inhibitor celecoxib resulted in significant reductions of 27% (P < 0.05) and 28% (P < 0.01) in ear swelling at intervals of 40 and 60 min between exposure and treatment, respectively. Histopathological evaluation revealed significant reductions (P < 0.05) in subepidermal microblister formation (73%) and dermal necrosis (32%), compared to the control group. These findings may indicate that COX-2 participates in the early stages of sulfur mustard-induced acute skin toxicity and that COX-1 might exert some protective function against this chemical insult. (C) 2004 Published by Elsevier Inc. C1 Hebrew Univ Jerusalem, Inst Life Sci, Fac Med, Dept Pharmacol, IL-91904 Jerusalem, Israel. NIEHS, Lab Mol Carcinogensis, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. Ben Gurion Univ Negev, Inst Appl Res, Beer Sheva, Israel. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Wormser, U (reprint author), Hebrew Univ Jerusalem, Inst Life Sci, Fac Med, Dept Pharmacol, Berman Bldg, IL-91904 Jerusalem, Israel. EM wormser@cc.huji.ac.il RI Peddada, Shyamal/D-1278-2012 NR 42 TC 26 Z9 28 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD OCT 1 PY 2004 VL 200 IS 1 BP 40 EP 47 DI 10.1016/j.taap.2004.03.013 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 861WC UT WOS:000224448300005 PM 15451306 ER PT J AU Reeves, R Thiruchelvam, M Richfield, EK Cory-Slechta, DA AF Reeves, R Thiruchelvam, M Richfield, EK Cory-Slechta, DA TI The effect of developmental exposure to the fungicide triadimefon on behavioral sensitization to triadimefon during adulthood SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE triadimefon; developmental neurotoxicity; pesticides; behavioral sensitization; dopamine ID EXPLORATORY-BEHAVIOR; REPEATED COCAINE; D-AMPHETAMINE; DOPAMINE; RATS; RECEPTORS; SCHEDULE; PARAQUAT; RELEASE; ANIMALS AB Triadimefon (TDF) is a triazole fungicide that acts as an indirect dopamine (DA) agonist by binding to the dopamine transporter (DAT) and increasing levels of synaptic DA. Studies in this laboratory have found that repeated dosing with TDF in adult mice leads to the development and robust expression of behavioral sensitization, a response mediated by dopaminergic and glutamatergic neurotransmitter systems, and causing long-term changes in dopaminergic function. Few studies have focused on the potential for TDF to be a developmental neurotoxicant. As such, the objective of the present study was to determine whether postnatal exposure to TDF would permanently alter DA systems and thereby influence TDF-induced expression of behavioral sensitization during adulthood. Male C57BL/6 mice were dosed intraperitoneally (i.p.) with 25 mg/kg TDF (TDF25), or oil (veh) from postnatal day (PND) 8 to 21. At 8-9 weeks of age, mice were split into four groups and treated with 75 mg/kg TDF (TDF75) or vehicle twice a week for a total of seven injections, with locomotor activity measured immediately after each injection. After a 2-week withdrawal period, mice were further split into eight groups, and challenged with TDF75 or vehicle to test for the expression of behavioral sensitization. Postnatal TDF exposure attenuated both the induction and expression of TDF-induced vertical but not horizontal sensitization in adults. Postnatal TDF exposure also produced long-term decreases in basal striatal dihydroxyphenylacetic acid (DOPAC) levels and nucleus accumbens shell DAT binding. These results indicate for the first time that TDF may be considered an environmental risk factor for developmental dopaminergic neurotoxicity. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Rochester, Sch Med & Dent, Dept Environm Med, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, NIEHS Environm Hlth Sci Ctr, Rochester, NY 14642 USA. Univ Rochester, Sch Med & Dent, Dept Pathol & Lab Med, Rochester, NY 14642 USA. RP Cory-Slechta, DA (reprint author), Rutgers State Univ, Robert Wood Johnson Med Sch, Environm & Occupat Hlth Sci Inst, 70 Frelinghuysen Rd, Piscataway, NJ 08854 USA. EM dcs@eohsi.rutgers.edu NR 29 TC 4 Z9 4 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD OCT 1 PY 2004 VL 200 IS 1 BP 54 EP 63 DI 10.1016/j.taap.2004.03.020 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 861WC UT WOS:000224448300007 PM 15451308 ER PT J AU Buehler, PW Alayash, AI AF Buehler, PW Alayash, AI TI Toxicities of hemoglobin solutions: in search of in-vitro and in-vivo model systems SO TRANSFUSION LA English DT Review ID CROSS-LINKED HEMOGLOBIN; CELL-FREE HEMOGLOBIN; SUPEROXIDE DISMUTASE-CATALASE; POLYMERIZED PYRIDOXYLATED HEMOGLOBIN; ISCHEMIA-REPERFUSION INJURY; REGIONAL BLOOD-CIRCULATION; NITRIC-OXIDE SCAVENGER; STROMA-FREE HEMOGLOBIN; POLYOXYETHYLENE CONJUGATE; HEMORRHAGIC-SHOCK AB Several hemoglobin-based oxygen carriers (HBOCs) have been developed with a rationale focused on exploiting one or more physicochemical properties (e.g., oxygen affinity, molecular weight, viscosity, and colloid osmotic pressure) resulting from the chemical or recombinant modification of hemoglobin (Hb). Several chemically modified Hbs have reached late stages of clinical evaluation in the United States and Canada. These Hbs, in general, demonstrated mixed preclinical safety and efficacy, and reasonable safety in Phase I trials. However, as clinical development shifted into later stages, an undesirable safety and efficacy profile became clear in patient populations studied, and as a result some products were withdrawn from further clinical pursuit. Several questions still remain unanswered regarding the safety of Hb products for their proposed clinical indication(s). For example, 1) were preclinical studies predictive of clinical outcome? And, 2) were the most appropriate preclinical studies performed to predict clinical outcome? The primary objectives of this analysis are to explore prelinical safety issues associated with HBOCs and provide an overview of the in-vitro and in-vivo models employed. The methods for obtaining data to serve as a basis for discussion are compiled from a literature-based survey of safety and efficacy derived from biochemical, cellular, and whole animal assessment of HBOCs. Results from this overview of a vast body of published data may provide a means for identifying critical preclinical safety issues, which may ultimately lead to identification of potential limitations in the effective clinical use of certain HBOCs. C1 USDA, ARS, Lab Biochem & Vasc Biol, Div Hematol, Bethesda, MD USA. USDA, ARS, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Alayash, AI (reprint author), NIH, Bldg 29,Room 112,8800 Rockville Pike, Bethesda, MD 20892 USA. EM alayash@cber.fda.gov NR 154 TC 61 Z9 63 U1 1 U2 7 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2004 VL 44 IS 10 BP 1516 EP 1530 DI 10.1111/j.1537-2995.2004.04081.x PG 15 WC Hematology SC Hematology GA 858DX UT WOS:000224171600019 PM 15383027 ER PT J AU Leitman, SF Bolan, CD Klein, HG AF Leitman, SF Bolan, CD Klein, HG TI Hemochromatosis blood donor programs: marginal for the red blood cell supply but potentially good for patient care - Reply SO TRANSFUSION LA English DT Letter C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Leitman, SF (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD OCT PY 2004 VL 44 IS 10 BP 1537 EP 1538 DI 10.1111/j.0041-1132.2004.00420_2.x PG 2 WC Hematology SC Hematology GA 858DX UT WOS:000224171600025 ER PT J AU Nilsson, O Baron, J AF Nilsson, O Baron, J TI Fundamental limits on longitudinal bone growth: growth plate senescence and epiphyseal fusion SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID CATCH-UP GROWTH; ESTROGEN-RECEPTOR-ALPHA; CELL-CYCLE WITHDRAWAL; PRECOCIOUS PUBERTY; AROMATASE DEFICIENCY; POSTNATAL-GROWTH; HORMONE AGONIST; THYROID-HORMONE; RAT TIBIA; DIFFERENTIATION AB Longitudinal bone growth occurs rapidly in early life but then slows and, eventually, ceases. The decline in growth rate is caused primarily by a decrease in the rate of chondrocyte proliferation and is accompanied by structural changes in growth plate cartilage. This programmed senescence does not appear to be caused by hormonal or other systemic mechanisms but is intrinsic to the growth plate itself. In particular, recent evidence indicates that senescence might occur because stem-like cells in the resting zone have a finite proliferative capacity, which is exhausted gradually. In some mammals, including humans, proliferative exhaustion is followed by epiphyseal fusion, an abrupt event in which the growth plate cartilage is replaced completely by bone. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Baron, J (reprint author), NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. EM baronj@cc1.nichd.nih.gov OI Nilsson, Ola/0000-0002-9986-8138 NR 58 TC 55 Z9 57 U1 2 U2 6 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD OCT PY 2004 VL 15 IS 8 BP 370 EP 374 DI 10.1016/j.tem.2004.08.004 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 865IN UT WOS:000224696000005 PM 15380808 ER PT J AU Verkhratsky, A Mattson, MP Toescu, EC AF Verkhratsky, A Mattson, MP Toescu, EC TI Aging in the mind SO TRENDS IN NEUROSCIENCES LA English DT Editorial Material ID ALZHEIMERS-DISEASE; SENILE DEMENTIA; TANGLES C1 Univ Manchester, Sch Biol Sci, Manchester M13 9PT, Lancs, England. NIA, Gerontol Res Ctr, Neurosci Lab, Baltimore, MD 21224 USA. Univ Birmingham, Dept Physiol, Div Med Sci, Birmingham B15 2TT, W Midlands, England. RP Verkhratsky, A (reprint author), Univ Manchester, Sch Biol Sci, G-38 Stopford Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. EM alexej.verkhratsky@man.ac.uk RI Mattson, Mark/F-6038-2012; Verkhratsky, Alexei/J-4527-2013 OI Verkhratsky, Alexei/0000-0003-2592-9898 NR 9 TC 9 Z9 9 U1 0 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD OCT PY 2004 VL 27 IS 10 BP 577 EP 578 DI 10.1016/j.tins.2004.07.008 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 862RQ UT WOS:000224509000001 PM 15374665 ER PT J AU Mattson, MP Maudsley, S Martin, B AF Mattson, MP Maudsley, S Martin, B TI BDNF and 5-HT: a dynamic duo in age-related neuronal plasticity and neurodegenerative disorders SO TRENDS IN NEUROSCIENCES LA English DT Editorial Material ID ELEMENT-BINDING PROTEIN; SPATIAL MEMORY FORMATION; HUNTINGTIN MUTANT MICE; TRAUMATIC BRAIN-INJURY; NEUROTROPHIC FACTOR; RAT-BRAIN; DIETARY RESTRICTION; GLUCOSE-METABOLISM; ALZHEIMERS-DISEASE; MESSENGER-RNA AB Brain-derived neurotrophic factor (BDNF) and serotonin (5-hydroxytryptamine, 5-HT) are known to regulate synaptic plasticity, neurogenesis and neuronal survival in the adult brain. These two signals co-regulate one another such that 5-HT stimulates the expression of BDNF, and BDNF enhances the growth and survival of 5-HT neurons. Impaired 5-HT and BDNF signaling is central to depression and anxiety disorders, but could also play important roles in the pathogenesis of several age-related disorders, including insulin resistance syndrome, Alzheimer's disease and Huntington's disease. Enhancement of BDNF signaling may be a key mechanism whereby cognitive stimulation, exercise, dietary restriction and antidepressant drugs preserve brain function during aging. Behavioral and pharmacological manipulations that enhance 5-HT and BDNF signaling could help promote healthy brain aging. C1 NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 NR 70 TC 434 Z9 463 U1 8 U2 41 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD OCT PY 2004 VL 27 IS 10 BP 589 EP 594 DI 10.1016/j.tins.2004.08.001 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 862RQ UT WOS:000224509000005 PM 15374669 ER PT J AU Fotheringham, J Mayne, M Holden, C Nath, A Geiger, JD AF Fotheringham, J Mayne, M Holden, C Nath, A Geiger, JD TI Adenosine receptors control HIV-1 Tat-induced inflammatory responses through protein phosphatase SO VIROLOGY LA English DT Article DE monocytes/macrophages; immunodeficiency diseases; cytokines; cellular activation; signal transduction ID IMMUNODEFICIENCY-VIRUS TYPE-1; NECROSIS-FACTOR-ALPHA; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; RAT NEOSTRIATAL NEURONS; A(2A) RECEPTOR; TNF-ALPHA; HUMAN MONOCYTES; INHIBITS IL-12; CYCLIC-AMP; IN-VITRO AB Recently, adenosine has been proposed to be a "metabolic" switch that may sense and direct immune and inflammatory responses. Inflammation and pro-inflammatory cytokine production are important in development of HIV-1 associated dementia, a devastating consequence of HIV-1 infection of the CNS. The HIV-1 protein Tat induces cell death in the CNS and activates local inflammatory responses partially by inducing calcium release from the endoplasmic reticulum. Because activation of adenosine receptors decreases production of the pro-inflammatory cytokine TNF-alpha in several experimental paradigms both in vitro and in vivo, we hypothesized that adenosine receptor activation would control both increased intracellular calcium and TNF-alpha production induced by Tat. Treatment of primary monocytes with Tat significantly increased the levels of intracellular calcium released from IP3 stores. Activation of adenosine receptors with CGS 21680 inhibited Tat-induced increases of intracellular calcium by 90 +/- 8% and was dependent on protein phosphatase activity because okadaic acid blocked the actions of CGS 21680. Tat-induced TNF-alpha production was inhibited 90 +/- 6% by CGS 21680 and concurrent treatment with okadaic acid blocked the inhibitory actions of CGS 21680. Using a model monocytic cell line, CGS 21680 treatment increased cytosolic serine/threonine phosphatase. Together, these data indicate that A(2A) receptor activation increases protein phosphatase activity, which blocks IP3 receptor-regulated calcium release and reduction of intracellular calcium inhibits TNF-alpha production in monocytes. (C) 2004 Elsevier Inc. All rights reserved. C1 Natl Res Council Canada, Inst Nutrisci & Hlth, Charlottetown, PE C1A 4P3, Canada. Univ Manitoba, Dept Pharmacol & Therapeut, Winnipeg, MB, Canada. Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bethesda, MD USA. Johns Hopkins Univ, Dept Neurol, Baltimore, MD USA. Univ N Dakota, Sch Med, Dept Pharmacol Physiol & Therapeut, Grand Forks, ND USA. RP Mayne, M (reprint author), Natl Res Council Canada, Inst Nutrisci & Hlth, 106C Classroom Ctr,550 Univ Ave, Charlottetown, PE C1A 4P3, Canada. EM michael.mayne@nrc.gc.ca NR 49 TC 21 Z9 21 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT 1 PY 2004 VL 327 IS 2 BP 186 EP 195 DI 10.1016/j.virol.2004.07.007 PG 10 WC Virology SC Virology GA 855KA UT WOS:000223970900005 PM 15351206 ER PT J AU Sepehr, A Kamangar, F Abnet, CC Fahimi, S Pourshams, A Poustchi, H Zeinali, S Sotoudeh, M Islami, F Nasrollahzadeh, D Malekzadeh, R Taylor, PR Dawsey, SM AF Sepehr, A Kamangar, F Abnet, CC Fahimi, S Pourshams, A Poustchi, H Zeinali, S Sotoudeh, M Islami, F Nasrollahzadeh, D Malekzadeh, R Taylor, PR Dawsey, SM TI Genetic polymorphisms in three Iranian populations with different risks of esophageal cancer, an ecologic comparison SO CANCER LETTERS LA English DT Article DE genetic polymorphisms; esophageal cancer; Iran ID SQUAMOUS-CELL CARCINOMA; S-TRANSFERASES M1; ALDEHYDE DEHYDROGENASE-2; JAPANESE ALCOHOLICS; STOMACH CANCERS; CYP2A6 GENE; SUSCEPTIBILITY; SMOKING; CHINA; GSTM1 AB The age-standardized incidence of esophageal cancer (EC) varies from 3 to >100/100,000 per year in different provinces of Iran. This striking variation of incidence is associated with differences in ethnic backgrounds, raising the possibility that genetic factors are involved in the pathogenesis of EC. We compared the frequencies of polymorphisms in ten genes that have been hypothesized to have a role in risk of EC (CYP1A1, CYP2A6, CYP2E1, GSTM1, GSTP1, GS771, ADH2, ADH3, ALDH2, and O(6)-MGMT) among three Iranian ethnic groups with highly varying rates of EC. These three groups included high-risk Turkomans, medium-risk Turks, and low-risk Zoroastrian Persians. Compared to Zoroastrians, Turkomans had higher frequency of four alleles that are speculated to favor carcinogenesis (CYP1A1 m1, CYP1A1 m2, CYP2A6*9, and ADH2*1); these results are consistent with an influence of these allele variants on the population risk of EC. However, none of these four alleles had a high enough prevalence in Turkomans to explain the high rates of EC in this group. Three of these four alleles (CYP1A1 m1, CYP1A1 m2, CYP2A6*9) were less frequent among Turkomans than in some Asian populations with lower risks of EC. We conclude that it is unlikely that variations in these polymorphic genes are major contributors to the high incidence of EC among Turkomans in Iran. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NCI, CCR, Canc Prevent Studies Branch, Bethesda, MD 20892 USA. Int Agcy Res Canc, F-69372 Lyon, France. Univ Tehran Med Sci, Digest Dis Res Ctr, Tehran, Iran. RP Dawsey, SM (reprint author), NCI, CCR, Canc Prevent Studies Branch, 6116 Execut Blvd,Suite 705, Bethesda, MD 20892 USA. EM dawseys@mail.nih.gov RI Abnet, Christian/C-4111-2015; OI Abnet, Christian/0000-0002-3008-7843; Malekzadeh, Reza/0000-0003-1043-3814 NR 37 TC 20 Z9 22 U1 0 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD SEP 30 PY 2004 VL 213 IS 2 BP 195 EP 202 DI 10.1016/j.canlet.2004.05.017 PG 8 WC Oncology SC Oncology GA 858DQ UT WOS:000224170900009 PM 15327835 ER PT J AU Haoudi, A Semmes, OJ Mason, JM Cannon, RE AF Haoudi, A Semmes, OJ Mason, JM Cannon, RE TI Retrotransposition-competent human LINE-1 induces apoptosis in cancer cells with intact p53 SO JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY LA English DT Article ID HUMAN L1 ELEMENT; REVERSE TRANSCRIPTION; TRANSPOSABLE ELEMENT; FAS COUNTERATTACK; DNA METHYLATION; COLON-CANCER; IN-VIVO; SEQUENCES; INSERTION; EXPRESSION AB Retrotransposition of human LINE-I (D) element, a major representative non-LTR retrotransposon in the human genome, is known to be a source of insertional mutagenesis. However, nothing is known about effects of L1 retrotransposition on cell growth and differentiation. To investigate the potential for such biological effects and the impact that human L1 retrotransposition has upon cancer cell growth, we examined a panel of human L1 transformed cell lines following a complete retrotransposition process. The results demonstrated that transposition of L1 leads to the activation of the p53-mediated apoptotic pathway in human cancer cells that possess a wild-type p53. In addition, we found that inactivation of p53 in cells, where L1 was undergoing retrotransposition, inhibited the induction of apoptosis. This suggests an association between active retrotransposition and a competent p53 response in which induction of apoptosis is a major outcome. These data are consistent with a model in which human retrotransposition is sensed by the cell as a "genetic damaging event" and that massive retrotransposition triggers signaling pathways resulting in apoptosis. C1 Eastern Virginia Med Sch, Dept Microbiol & Mol Cell Biol, Norfolk, VA 23501 USA. Eastern Virginia Med Sch, Virginia Prostate Ctr, Norfolk, VA 23501 USA. NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Environm Carcinogenesis & Mutagenesis, NIH, Res Triangle Pk, NC 27709 USA. RP Haoudi, A (reprint author), Eastern Virginia Med Sch, Dept Microbiol & Mol Cell Biol, Lewis Hall 3011,700 W Olney Rd, Norfolk, VA 23501 USA. EM haoudia@evms.edu NR 43 TC 36 Z9 38 U1 1 U2 3 PU HINDAWI PUBLISHING CORPORATION PI NEW YORK PA 410 PARK AVENUE, 15TH FLOOR, #287 PMB, NEW YORK, NY 10022 USA SN 1110-7243 J9 J BIOMED BIOTECHNOL JI J. Biomed. Biotechnol. PD SEP 30 PY 2004 IS 4 BP 185 EP 194 AR PII S111072430443131 PG 10 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 943JS UT WOS:000230350300003 ER PT J AU Sanabia, JE Goldner, LS Lacaze, PA Hawkins, ME AF Sanabia, JE Goldner, LS Lacaze, PA Hawkins, ME TI On the feasibility of single-molecule detection of the guanosine-analogue 3-MI SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; PTERIDINE NUCLEOSIDE ANALOGS; 2-PHOTON EXCITATION; HIV-1 INTEGRASE; ONE-PHOTON; OLIGONUCLEOTIDES; 2-AMINOPURINE; MICROSCOPY; OPTICS AB We present UV fluorescence fluctuation correlation spectroscopy (FCS) measurements on the guanosine-analogue 3-MI [3-methyl-8-(2-deoxy-beta-D-ribofuranosyl)isoxanthopterin], a pteridine widely used in studies of DNA binding and dynamics. We measure the photon count rate and signal-to-background ratio per molecule, for both monomeric 3-MI and a 3-MI-containing oligonucleotide. For the monomer, we find a maximum photon count rate per molecule above 4 kHz and a maximum signal-to-background ratio of 5. For incorporated 3-MI, both parameters are a factor of 4 smaller. We discuss the triplet and photobleaching behavior of 3-MI and the possibilities of using this analogue in single-molecule studies of DNA dynamics. Comparisons are made to the behavior of stilbene 3, a brilliant laser dye with a similar fluorescence spectrum. C1 Natl Inst Stand & Technol, Opt Technol Div, Gaithersburg, MD 20899 USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Goldner, LS (reprint author), Natl Inst Stand & Technol, Opt Technol Div, Gaithersburg, MD 20899 USA. EM lori.goldner@nist.gov NR 27 TC 12 Z9 12 U1 1 U2 3 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 SEP 30 PY 2004 VL 108 IS 39 BP 15293 EP 15300 DI 10.1021/jp049901a PG 8 WC Chemistry, Physical SC Chemistry GA 856UI UT WOS:000224070200071 ER PT J AU Puck, JM Straus, SE AF Puck, JM Straus, SE TI Somatic mutations - Not just for cancer anymore SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; APOPTOSIS C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Puck, JM (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NR 5 TC 19 Z9 19 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 30 PY 2004 VL 351 IS 14 BP 1388 EP 1390 DI 10.1056/NEJMp048116 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 857XT UT WOS:000224153900006 PM 15459299 ER PT J AU Walsh, TJ Teppler, H Donowitz, GR Maertens, JA Baden, LR Dmoszynska, A Cornely, OA Bourque, MR Lupinacci, RJ Sable, CA dePauw, BE AF Walsh, TJ Teppler, H Donowitz, GR Maertens, JA Baden, LR Dmoszynska, A Cornely, OA Bourque, MR Lupinacci, RJ Sable, CA dePauw, BE TI Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID DOUBLE-BLIND; IN-VITRO; IMMUNOCOMPROMISED PATIENTS; MK-0991 L-743,872; CANCER; CANDIDIASIS; ASPERGILLOSIS; MULTICENTER; FLUCONAZOLE; INFECTIONS AB BACKGROUND: Patients with persistent fever and neutropenia often receive empirical therapy with conventional or liposomal amphotericin B for the prevention and early treatment of invasive fungal infections. Caspofungin, a member of the new echinocandin class of compounds, may be an effective alternative that is better tolerated than amphotericin B. METHODS: In this randomized, double-blind, multinational trial, we assessed the efficacy and safety of caspofungin as compared with liposomal amphotericin B as empirical antifungal therapy. At study entry, patients were stratified according to risk and according to whether they had previously received antifungal prophylaxis. A successful outcome was defined as the fulfillment of all components of a five-part composite end point. RESULTS: Efficacy was evaluated in 1095 patients (556 receiving caspofungin and 539 receiving liposomal amphotericin B). After adjustment for strata, the overall success rates were 33.9 percent for caspofungin and 33.7 percent for liposomal amphotericin B (95.2 percent confidence interval for the difference, -5.6 to 6.0 percent), fulfilling statistical criteria for the noninferiority of caspofungin. Among patients with baseline fungal infections, a higher proportion of those treated with caspofungin had a successful outcome (51.9 percent vs. 25.9 percent, P=0.04). The proportion of patients who survived at least seven days after therapy was greater in the caspofungin group (92.6 percent vs. 89.2 percent, P=0.05). Premature study discontinuation occurred less often in the caspofungin group than in the amphotericin B group (10.3 percent vs. 14.5 percent, P=0.03). The rates of breakthrough fungal infections and resolution of fever during neutropenia were similar in the two groups. Fewer patients who received caspofungin sustained a nephrotoxic effect (2.6 percent vs. 11.5 percent, P<0.001), an infusion-related event (35.1 percent vs. 51.6 percent, P<0.001), or a drug-related adverse event or discontinued therapy because of drug-related adverse events. CONCLUSIONS: Caspofungin is as effective as and generally better tolerated than liposomal amphotericin B when given as empirical antifungal therapy in patients with persistent fever and neutropenia. C1 NCI, NIH, Bethesda, MD 20892 USA. Merck Res Labs, W Point, PA USA. Univ Virginia Hlth Syst, Charlottesville, VA USA. Univ Ziekenhuis Leuven, Louvain, Belgium. Brigham & Womens Hosp, Boston, MA 02115 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Clin Hosp 4, Lublin, Poland. Univ Cologne Klinikum, Cologne, Germany. Univ Hosp St Radboud, Nijmegen, Netherlands. RP Walsh, TJ (reprint author), NCI, NIH, Bldg 10,Rm 13N-240,10 Ctr Dr, Bethesda, MD 20892 USA. NR 27 TC 513 Z9 562 U1 2 U2 13 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 SEP 30 PY 2004 VL 351 IS 14 BP 1391 EP 1402 DI 10.1056/NEJMoa040446 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 857XT UT WOS:000224153900007 PM 15459300 ER PT J AU Legler, JM Davis, WW Potosky, AL Hoffman, RM AF Legler, JM Davis, WW Potosky, AL Hoffman, RM TI Latent variable modelling of recovery trajectories: sexual function following radical prostatectomy SO STATISTICS IN MEDICINE LA English DT Article DE quality of life; latent class; recovery trajectory; prostatectomy; mixture model ID QUALITY-OF-LIFE; CANCER OUTCOMES; LONGITUDINAL DATA; REGRESSION; SELECTION; INTERVENTIONS; NONCOMPLIANCE; DISEASE AB As treatments improve and survival time lengthens, the course of recovery and long-term quality of life (QoL) is of greater interest. The application of latent class growth models to longitudinal QoL data provides unique insights into recovery that are not evident with marginal analyses. We examine this approach in the context of a large population-based observational study. This is the first attempt to characterize individuals' recovery over time following prostate cancer surgery, and to determine factors associated with varying recovery experiences of prostate cancer patients. Four major patterns emerged that illustrate typical patterns of recovery following radical prostatectomy. Given a man's baseline data, this method produces estimates of the probability of belonging to each recovery class. The method is presented as a useful tool for identifying hypotheses associated with recovery and potential antecedents of importance. Published in 2004 by John Wiley Sons, Ltd. C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. St Olaf Coll, Dept Math, Northfield, MN 55057 USA. New Mexico VA Hlth Care Syst, Albuquerque, NM 87108 USA. RP Davis, WW (reprint author), NCI, Div Canc Control & Populat Sci, 6116 Execut Blvd,Suite 504,MSC8317, Bethesda, MD 20892 USA. EM davisbi@mail.nih.gov NR 28 TC 4 Z9 4 U1 0 U2 2 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 SEP 30 PY 2004 VL 23 IS 18 BP 2875 EP 2893 DI 10.1002/sim.1864 PG 19 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 851FC UT WOS:000223670000007 PM 15344192 ER PT J AU Peters, JM Nicol, CJ Yim, SH Kim, DJ Marin, HE Gonzalez, FJ AF Peters, JM Nicol, CJ Yim, SH Kim, DJ Marin, HE Gonzalez, FJ TI Central role of PPAR beta(delta) in attenuating toxicity and carcinogenesis SO TOXICOLOGY LA English DT Meeting Abstract CT BTS 2004 Annual Congress CY APR 21-24, 2004 CL Heriot Watt Univ, Edinburgh, SCOTLAND SP BTS HO Heriot Watt Univ C1 Penn State Univ, Dept Vet Sci, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. NCI, Lab Metab, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 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 SEP 30 PY 2004 VL 202 IS 1-2 BP 50 EP 51 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 858EA UT WOS:000224171900030 ER PT J AU Maronpot, RR AF Maronpot, RR TI The bioassay grail - a 40-year crusade & a new vision SO TOXICOLOGY LA English DT Meeting Abstract CT BTS 2004 Annual Congress CY APR 21-24, 2004 CL Heriot Watt Univ, Edinburgh, SCOTLAND SP BTS HO Heriot Watt Univ C1 NIEHS, Res Triangle Pk, NC 27709 USA. Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NR 1 TC 0 Z9 0 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 SEP 30 PY 2004 VL 202 IS 1-2 BP 53 EP 54 PG 2 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 858EA UT WOS:000224171900035 ER PT J AU Zhao, M Boja, ES Hoodbhoy, T Nawrocki, J Kaufman, JB Kresge, N Ghirlando, R Shiloach, J Pannell, L Levine, RL Fales, HM Dean, J AF Zhao, M Boja, ES Hoodbhoy, T Nawrocki, J Kaufman, JB Kresge, N Ghirlando, R Shiloach, J Pannell, L Levine, RL Fales, HM Dean, J TI Mass spectrometry analysis of recombinant human ZP3 expressed in glycosylation-deficient CHO cells SO BIOCHEMISTRY LA English DT Article ID ZONA-PELLUCIDA GLYCOPROTEINS; SPERM-EGG INTERACTION; FURIN CLEAVAGE-SITE; MOUSE SPERM; STRUCTURAL-CHARACTERIZATION; KNOCKOUT MICE; INNER-EAR; RECEPTOR; GENE; PROTEINS AB The zona pellucida is an extracellular matrix that mediates taxon-specific fertilization in which human sperm will not bind to mouse eggs. The mouse zona pellucida is composed of three glycoproteins (ZP1, ZP2, ZP3). The primary structure of each has been deduced from the cDNA nucleic acid sequence, and each has been analyzed by mass spectrometry. However, determination of the secondary structure and processing of the human zona proteins have been hampered by the paucity of biological material. To investigate if taxon-specific sperm-egg recognition was ascribable to structural differences in a zona protein required for matrix formation, recombinant human ZP3 was expressed in CHO-Lec3.2.8.1 cells and compared to mouse ZP3. With nearly complete coverage, LC-QTOF mass spectrometry was used to determine the cleavage of an N-terminal signal peptide (amino acids 1-22) and the release of secreted ZP3 from a C-terminal transmembrane domain (amino acids 379-424). The resultant N-terminal glutamine was cyclized to pyroglutamate (pyrGln(23)), and several C-terminal peptides were detected, including one ending at Asn(350). The disulfide bond linkages of eight cysteine residues in the conserved zona domain were ascertained (Cys(46)/Cys(140), Cys(78)/Cys(99), Cys(217)/Cys(282), Cys(239)/Cys(300)), but the precise linkage of two additional disulfide bonds was indeterminate due to clustering of the remaining four cysteine residues (Cys(319), Cys(321) Cys(322) Cys(327)). Three of the four potential N-linked oligosaccharide binding sites (Asn(125), Asn(147), Asn(272)) were occupied, and clusters of O-glycans were observed within two regions, amino acids 156-173 and 260-281. Taken together, these data indicate that human and mouse ZP3 proteins are quite similar, and alternative explanations of taxon-specific sperm binding warrant exploration. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Dean, J (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM jurrien@helix.nih.gov RI Ghirlando, Rodolfo/A-8880-2009; Levine, Rodney/D-9885-2011 NR 53 TC 22 Z9 24 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 28 PY 2004 VL 43 IS 38 BP 12090 EP 12104 DI 10.1021/bi048958k PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 856GE UT WOS:000224032900017 PM 15379548 ER PT J AU Reyes, DR Perruccio, EM Becerra, SP Locascio, LE Gaitan, M AF Reyes, DR Perruccio, EM Becerra, SP Locascio, LE Gaitan, M TI Micropatterning neuronal cells on polyelectrolyte multilayers SO LANGMUIR LA English DT Article ID SURFACES; ADHESION; GROWTH; FILMS; MONOLAYERS; ATTACHMENT; MORPHOLOGY; VIABILITY; ULTRATHIN; PROTEINS AB This paper describes an approach to adhere retinal cells on micropatterned polyelectrolyte multilayer (PEM) lines adsorbed on poly(dimethylsiloxane) (PDMS) surfaces using microfluidic networks. PEMs were patterned on flat, oxidized PDMS surfaces by sequentially flowing polyions through a microchannel network that was placed in contact with the PDMS surface. Polyethyleneimine (PEI) and poly(allylamine hydrochloride) (PAH) were the polyions used as the top layer cellular adhesion material. The microfluidic network was lifted off after the patterning was completed and retinal cells were seeded on the PEM/PDMS surfaces. The traditional practice of using blocking agents to prevent the adhesion of cells on unpatterned areas was avoided by allowing the PDMS surface to return to its uncharged state after the patterning was completed. The adhesion of rat retinal cells on the patterned PEMs was observed 5 h after seeding. Cell viability and morphology on the patterned PEMs were assayed. These materials proved to be nontoxic to the cells used in this study regardless of the number of stacked PEM layers. Phalloidin staining of the cytoskeleton revealed no apparent morphological differences in retinal cells compared with those plated on polystyrene or the larger regions of PEI and PAH; however, cells were relatively more elongated when cultured on the PEM lines. Cell-to-cell communication between cells on adjacent PEM lines was observed as interconnecting tubes containing actin that were a few hundred nanometers in diameter and up to 55 mum in length. This approach provides a simple, fast, and inexpensive method of patterning cells onto micrometer-scale features. C1 NIST, Div Semicond Elect, Gaithersburg, MD 20899 USA. NEI, NIH, Bethesda, MD 20892 USA. NIST, Analyt Chem Div, Gaithersburg, MD 20899 USA. RP Reyes, DR (reprint author), NIST, Div Semicond Elect, 100 Bur Dr,MS 8120, Gaithersburg, MD 20899 USA. EM darwin.reyes@nist.gov NR 39 TC 49 Z9 49 U1 1 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD SEP 28 PY 2004 VL 20 IS 20 BP 8805 EP 8811 DI 10.1021/la049249a PG 7 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 856IN UT WOS:000224039000059 PM 15379510 ER PT J AU Day, PM Baker, CC Lowy, DR Schiller, JT AF Day, PM Baker, CC Lowy, DR Schiller, JT TI Establishment of papillomavirus infection is enhanced by promyelocytic leukemia protein (PML) expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NUCLEAR DOMAIN 10; MINOR CAPSID PROTEIN; IN-VITRO; REPLICATION COMPARTMENTS; BODIES ASSOCIATE; VIRUS-INFECTION; PORE COMPLEX; DNA; CELLS; ND10 AB Previous studies have suggested that most papillomaviruses enter the host cell via clathrin-dependent receptor-mediated endocytosis but have not addressed later steps in viral entry. To examine these events, we followed the localization of L2 and packaged DNA after entry of infectious virions or L1/L2 pseudovirions. Confocal microscopic analyses of HeLa cells showed a time-dependent uncoating of capsids in cytoplasmic vesicles and the accumulation of both L2 and viral DNA at distinct nuclear domains identified as nuclear domain 10 (ND10). Both L2 and the pseudogenome had a punctate distribution and localized to ND10 in promyelocytic leukemia protein (PML)-expressing cells, whereas L2 had a diffuse nuclear distribution in PML-/- cells. The number of pseudovirus-infected cells was an order of magnitude higher in the PML+ cells compared with the PML-/- cells, and viral genome transcription after infection with authentic bovine papillomavirus virions was similarly elevated in PML+ cells. The results identify a role for PML in the enhancement of viral infectivity in the early part of the life cycle. We propose a model in which L2 chaperones the viral genome to ND10 to efficiently initiate viral transcription. C1 NCI, Ctr Canc Res, Lab Cellular Oncol, NIH, Bethesda, MD 20892 USA. RP Day, PM (reprint author), NCI, Ctr Canc Res, Lab Cellular Oncol, NIH, Bethesda, MD 20892 USA. EM pmd@nih.gov NR 58 TC 122 Z9 130 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 SEP 28 PY 2004 VL 101 IS 39 BP 14252 EP 14257 DI 10.1079/pnas.0404229101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 858SG UT WOS:000224211400052 PM 15383670 ER PT J AU Karbowski, M Jeong, SY Youle, RJ AF Karbowski, M Jeong, SY Youle, RJ TI Endophilin B1 is required for the maintenance of mitochondrial morphology SO JOURNAL OF CELL BIOLOGY LA English DT Article DE endocytosis; LPAAT; dynamin; membrane tubulation; scission ID MAMMALIAN-CELLS; ENDOPLASMIC-RETICULUM; LYSOPHOSPHATIDIC ACID; MEMBRANE-PROTEIN; OUTER-MEMBRANE; SH3 DOMAIN; FISSION; DYNAMIN; FUSION; APOPTOSIS AB W e report that a fatty acyl transferase, endophilin Bl, is required for maintenance of mitochondrial morphology. Down-regulation of this protein or overexpression of endophilin B1 lacking the NH2-terminal lipid-modifying domain causes striking alterations of the mitochondrial distribution and morphology. Dissociation of the outer mitochondrial membrane compartment from that of the matrix, and formation of vesicles and tubules of outer mitochondrial membrane, was also observed in both endophilin B1 knockdown cells and after overexpression of the truncated protein, indicating that endophilin B1 is required for the regulation of the outer mitochondrial membrane dynamics. We also show that endophilin B1 translocates to the mitochondria during the synchronous remodeling of the mitochondrial network that has been described to occur during apoptosis. Double knockdown of endophilin B1 and Drp1 leads to a mitochondrial phenotype identical to that of the Drp1 single knockdown, a result consistent with Drp1 acting upstream of endophilin B1 in the maintenance of morphological dynamics of mitochondria. C1 NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), Bldg 35,Rm 907,MSC 3407,35 Lincoln Dr, Bethesda, MD 20892 USA. EM youter@ninds.nih.gov NR 42 TC 161 Z9 167 U1 1 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 27 PY 2004 VL 166 IS 7 BP 1027 EP 1039 DI 10.1083/jcb.200407046 PG 13 WC Cell Biology SC Cell Biology GA 859BE UT WOS:000224236100010 PM 15452144 ER PT J AU Connaughton, VP Graham, D Nelson, R AF Connaughton, VP Graham, D Nelson, R TI Identification and morphological classification of horizontal, bipolar, and amacrine cells within the zebrafish retina SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE retinal slice; gene gun; neurons; retinal circuitry ID TIGER SALAMANDER RETINA; INNER PLEXIFORM LAYER; GANGLION-CELLS; CAT RETINA; GOLDFISH RETINA; CARP RETINA; AXON TERMINALS; NERVOUS-SYSTEM; CYPRINID FISH; ON-CENTER AB Horizontal, bipolar, and amacrine cells in the zebrafish retina were morphologically characterized using DiOlistic techniques. In this method, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-coated microcarriers are shot at high speed onto the surfaces of living retinal slices where the DiI then delineates axons, somata, and dendrites of isolated neurons. Zebrafish retinal somata were 5-10 mum in diameter. Three horizontal cell types (H-A-1, H-A-2, and H-B) were identified; dendritic tree diameters averaged 25-40 mum. H-A somata were round. Cells classified as H-A-2 were larger than H-A-1 cells and possessed an axon. H-A somata were flattened, without an axon, although short fusiform structure(s) projected from the soma. Bipolar cells were separated into 17 morphological types. Dendritic trees ranged from 10 to 70 muM. There were six B-on types with axon boutons only in the ON sublamina of the inner plexiform layer (IPL), and seven B-off types with axon boutons or branches only in the OFF sublamina. Four types of bistratified bipolar cells displayed boutons in both ON and OFF layers. Amacrine cells occurred in seven types. A(off) cells (three types) were monostratified and ramified in the IPL OFF sublamina. Dendritic fields were 60-150 muM. A(on) pyriform cells (three types) branched in the ON sublamina. Dendritic fields were 50-170 muM. A(diffuse) cells articulated processes in all IPL strata. Dendritic fields were 15-90 muM. These findings are important for studies examining signal processing in zebrafish retina and for understanding changes in function resulting from mutations and perturbations of retinal organization. C1 American Univ, Dept Biol, Washington, DC 20016 USA. NINDS, Basic Neurosci Program, NIH, Bethesda, MD 20892 USA. RP Connaughton, VP (reprint author), American Univ, Dept Biol, 4400 Massachusetts Ave NW, Washington, DC 20016 USA. EM vconn@american.edu NR 43 TC 64 Z9 65 U1 0 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD SEP 27 PY 2004 VL 477 IS 4 BP 371 EP 385 DI 10.1002/cne.20261 PG 15 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 851QU UT WOS:000223700700004 PM 15329887 ER PT J AU Hwang, K Piekarz, RL Bates, SE Figg, WD Sparreboom, A AF Hwang, K Piekarz, RL Bates, SE Figg, WD Sparreboom, A TI Determination of the cyclic depsipeptide FK228, a histone deacetylase inhibitor, by liquid chromatography-mass spectrometry SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE cyclic depsipeptide; FK228 ID DOWN-REGULATION; FR901228; APOPTOSIS; PHARMACOKINETICS; ACETYLATION; NSC-630176; EXPRESSION; LC/MS/MS; LYMPHOMA; PROTEIN AB An analytical method was developed for the quantitative determination of the novel histone deacetylase inhibitor, depsipeptide FK228 (formerly FR901228; NSC630176), in human plasma. Calibration curves were constructed in the range of 0.5-100 ng/ml, and were analyzed using a weight factor proportional to the nominal concentration. Sample pretreatment involved a liquid-liquid extraction with ethyl acetate using 500 mul aliquots of plasma. The analyte was separated on a column (50 mm x 4.6 mm i.d.) packed with 3.5 mum C8 material, and cluted with methanol-10 mM ammonium formate, (55:45; v/v; pH 8). The column effluent was monitored by mass spectrometry with electrospray ionization. The values for precision and accuracy were always <7.88% and <3.33% relative error, respectively. The method was successfully applied to examine the pharmacokinetics of FK228 in a cancer patient. (C) 2004 Elsevier B.V. All rights reserved. C1 Ctr Canc Res, Clin Pharmacol Res Core, NCI, Bethesda, MD 20892 USA. NCI, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), Ctr Canc Res, Clin Pharmacol Res Core, NCI, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 21 TC 6 Z9 6 U1 0 U2 0 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 SEP 25 PY 2004 VL 809 IS 1 BP 81 EP 86 DI 10.1016/j.jchromb.2004.06.007 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 845KE UT WOS:000223240500012 PM 15282096 ER PT J AU Singleton, A Gwinn-Hardy, K AF Singleton, A Gwinn-Hardy, K TI Parkinson's disease and dementia with Lewy bodies: a difference in dose? SO LANCET LA English DT Editorial Material ID ALPHA-SYNUCLEIN; LOCUS TRIPLICATION; MUTATION; SNCA C1 NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NINDS, Parkinsons Unit, Neurogenet Branch, NIH, Bethesda, MD USA. RP Singleton, A (reprint author), NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Gwinn, Katrina/C-2508-2009; Singleton, Andrew/C-3010-2009 NR 10 TC 45 Z9 49 U1 0 U2 3 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD SEP 25 PY 2004 VL 364 IS 9440 BP 1105 EP 1107 DI 10.1016/S0140-6736(04)17117-1 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 857FT UT WOS:000224102400006 PM 15451205 ER PT J AU Salnikow, K Donald, SP Bruick, RK Zhitkovich, A Phang, JM Kasprzak, KS AF Salnikow, K Donald, SP Bruick, RK Zhitkovich, A Phang, JM Kasprzak, KS TI Depletion of intracellular ascorbate by the carcinogenic metals nickel and cobalt results in the induction of hypoxic stress SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROLYL 4-HYDROXYLASE; INDUCIBLE FACTOR; VITAMIN-C; TRANSCRIPTION FACTORS; PROLINE HYDROXYLATION; DEHYDROASCORBIC ACID; ERYTHROPOIETIN GENE; EPITHELIAL-CELLS; AMINO-ACIDS; HIF-ALPHA AB Exposure of cells to carcinogenic compounds of nickel( II) and cobalt( II) causes activation of the HIF-1 transcription factor and up-regulates a battery of hypoxia-inducible genes. However, the mechanism of HIF-1 activation by these metals is not known. It was shown recently that hydroxylation of prolines in the HIFalpha subunit of HIF-1 is required for its binding with the von Hippel-Lindau tumor suppressor protein and the subsequent proteasomal destruction. Here we show that responsible prolyl hydroxylases are targets for both nickel( II) and cobalt( II) because degradation of a reporter protein containing the oxygen-dependent degradation domain (Pro-402/564) of HIFalpha was abolished in a von Hippel-Lindau-dependent manner in cells exposed to nickel( II) or cobalt( II). The enzymatic activity of prolyl hydroxylases depends on iron as the activating metal, 2-oxoglutarate as a co-substrate, and ascorbic acid as a cofactor. Hydroxylase activity can be impaired by the depletion of any of these factors. We found that exposure of cells to nickel( II) or cobalt( II) did not affect the level of intracellular iron. Instead, nickel( II) or cobalt( II) exposure greatly depleted intracellular ascorbate. Co-exposure of cells to metals and ascorbate resulted in the increase of intracellular ascorbate and reversed both metal-induced stabilization of HIF-1alpha and HIF-1-dependent gene transcription. Because ascorbate is essential for maintaining iron in prolyl hydroxylases in the active iron( II) state, we suggest that the observed depletion of ascorbate by nickel( II) or cobalt( II) favors iron oxidation and thus inactivation of the enzyme. C1 NCI, NIH, Frederick, MD 21702 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. Brown Univ, Dept Pathol & Lab Med, Providence, RI 02912 USA. RP Salnikow, K (reprint author), NCI, NIH, Bldg 538,Rm 205 E, Frederick, MD 21702 USA. EM salnikow@ncifcrf.gov FU NIEHS NIH HHS [ES008786, R01 ES008786] NR 49 TC 186 Z9 198 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 SEP 24 PY 2004 VL 279 IS 39 BP 40337 EP 40344 DI 10.1074/jbc.M403057200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 854PW UT WOS:000223916800015 PM 15271983 ER PT J AU Vazquez, G Wedel, BJ Kawasaki, BT Bird, GS Putney, JW AF Vazquez, G Wedel, BJ Kawasaki, BT Bird, GS Putney, JW TI Obligatory role of Src kinase in the signaling mechanism for TRPC3 cation channels SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CAPACITATIVE CA2+ ENTRY; GROWTH-FACTOR RECEPTOR; PANCREATIC ACINAR-CELLS; SMOOTH-MUSCLE-CELLS; TRANSIENT RECEPTOR; PROTEIN-KINASE; CALCIUM-ENTRY; TYROSINE PHOSPHORYLATION; PLASMA-MEMBRANE; HUMAN PLATELETS AB Members of the canonical transient receptor potential (TRPC) subfamily of cation channels are candidates for capacitative and non-capacitative Ca2+ entry channels. When ectopically expressed in cell lines, TRPC3 can be activated by phospholipase C-mediated generation of diacylglycerol or by addition of synthetic diacylglycerols, independently of Ca2+ store depletion. Apart from this mode of regulation, little is known about other receptor-dependent signaling events that modulate TRPC3 activity. In the present study the role of tyrosine kinases in receptor- and diacylglycerol-dependent activation of TRPC3 was investigated. In HEK293 cells stably expressing TRPC3, pharmacological inhibition of tyrosine kinases, and specifically of Src kinases, abolished activation of TRPC3 by muscarinic receptor stimulation and by diacylglycerol. Channel regulation was lost following expression of a dominant-negative mutant of Src, or when TRPC3 was expressed in an Src-deficient cell line. In both instances, wild-type Src restored TRPC3 regulation. We conclude that Src plays an obligatory role in the mechanism for receptor and diacylglycerol activation of TRPC3. C1 NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Vazquez, G (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM vazquez@niehs.nih.gov NR 51 TC 109 Z9 117 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 SEP 24 PY 2004 VL 279 IS 39 BP 40521 EP 40528 DI 10.1074/jbc.M405280200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 854PW UT WOS:000223916800039 PM 15271991 ER PT J AU Morinobu, A Kanno, Y O'Shea, JJ AF Morinobu, A Kanno, Y O'Shea, JJ TI Discrete roles for histone acetylation in human T helper 1 cell-specific gene expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IFN-GAMMA-PRODUCTION; CD4(+) T-CELLS; INTERFERON-GAMMA; CHROMATIN-STRUCTURE; LINEAGE COMMITMENT; CUTTING EDGE; IMMUNE-RESPONSES; TH1 DEVELOPMENT; IL-18 RECEPTOR; BET AB To better understand the control of T helper (T-H) 1-expressed genes, we compared and contrasted acetylation and expression for three key genes, IFNG, TBET, and IL18RAP and found them to be distinctly regulated. The TBET and the IFNG genes, but not the IL18RAP gene, showed preferential acetylation of histones H3 and H4 during T(H)1 differentiation. Analysis of acetylation of specific histone residues revealed that H3(Lys-9), H4(Lys-8), and H4(Lys-12) were preferentially modified in T(H)1 cells, suggesting a possible contribution of acetylation of these residues for induction of these genes. On the other hand, the acetylation of IL18RAP gene occurred both in T(H)1 and T(H)2 cells with the similar kinetics and on the same residues, demonstrating that selective histone acetylation was not universally the case for all T(H)1-expressed genes. Histone H3 acetylation of IFNG and TBET genes occurred with different kinetics, however, and was distinctively regulated by cytokines. Interleukin (IL)-12 and IL-18 enhanced the histone acetylation of the IFNG gene. By contrast, histone acetylation of the TBET gene was markedly suppressed by IL-4, whereas IL-12 and IL-18 had only modest effects suggesting that histone acetylation during T(H)1 differentiation is a process that is regulated by various factors at multiple levels. By treating Th2 cells with a histone deacetylase inhibitor, we restored histone acetylation of the IFNG and TBET genes, but it did not fully restore their expression in T(H)2 cells, again suggesting that histone acetylation explains one but not all the aspects of T(H)1-specific gene expression. C1 NIAMS, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMS, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bldg 10,Rm 9N252,10 Ctr Dr,MSC-1820, Bethesda, MD 20892 USA. EM morinobu@med.kobe-u.ac.jp; osheajo@mail.nih.gov RI Kanno, Yuka/B-5802-2013; OI Kanno, Yuka/0000-0001-5668-9319 NR 46 TC 45 Z9 54 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 SEP 24 PY 2004 VL 279 IS 39 BP 40640 EP 40646 DI 10.1074/jbc.M407576200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 854PW UT WOS:000223916800053 PM 15280353 ER PT J AU Shang, WH Adachi, Y Nakamura, A Copeland, T Kim, SR Kamata, T AF Shang, WH Adachi, Y Nakamura, A Copeland, T Kim, SR Kamata, T TI Regulation of amphiphysin1 by mitogen-activated protein kinase - Its significance in nerve growth factor receptor-mediated endocytosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SYNAPTIC VESICLE ENDOCYTOSIS; CDK5; PHOSPHORYLATION; DOMAIN AB Amphiphysin1, which can simultaneously bind to dynamin1 and the clathrin adaptor AP-2, is essential for dynamin1 recruitment during receptor-mediated endocytosis, but little is known about its regulatory mechanism. Here, we purified a 120-kDa mitogen-activated protein kinase ( MAPK) substrate protein from porcine brains and identified the protein as amphiphysin1. Serine phosphorylation of amphiphysin1 was rapidly induced by nerve growth factor (NGF) in PC12 cells, and the induction was blocked by a MAPK inhibitor. Furthermore, when phosphorylated by MAPK in vitro or by NGF treatment in vivo, amphiphysin1 failed to bind to AP-2, but its association with dynamin1 was unaffected. Consistent with this, mutation of consensus MAPK phosphorylation sites increased amphiphysin1 binding to AP-2 and their intracellular colocalization. Thus, we propose that MAPK phosphorylation of amphiphysin1 controls NGF receptor/TrkA-mediated endocytosis by terminating the amphiphysin1-AP-2 interaction. This perhaps helps to regulate the availability of amphiphysin1-dynamin1 complexes for binding to the endocytic vesicle. C1 Shinshu Univ, Dept Mol Biol & Biochem, Sch Med, Nagano 3908621, Japan. Shinshu Univ, Inst Aging & Adaptat, Sch Med, Grad Sch, Nagano 3908621, Japan. NCI, Frederick Canc Res & Dev Ctr, NIH, Frederick, MD 21702 USA. Chungbuk Natl Univ, Dept Biochem, Coll Med, Cheongju, South Korea. RP Kamata, T (reprint author), Shinshu Univ, Dept Mol Biol & Biochem, Sch Med, Asahi 3-1-1, Nagano 3908621, Japan. EM kamatat@sch.md.shinshu-u.ac.jp NR 18 TC 13 Z9 14 U1 1 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 SEP 24 PY 2004 VL 279 IS 39 BP 40890 EP 40896 DI 10.1074/jbc.M404527200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 854PW UT WOS:000223916800085 PM 15262992 ER PT J AU Bream, JH Hodge, DL Gonsky, R Spolski, R Leonard, WJ Krebs, S Targan, S Morinobu, A O'Shea, JJ Young, HA AF Bream, JH Hodge, DL Gonsky, R Spolski, R Leonard, WJ Krebs, S Targan, S Morinobu, A O'Shea, JJ Young, HA TI A distal region in the interferon-gamma gene is a site of epigenetic remodeling and transcriptional regulation by interleukin-2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID T-CELL DIFFERENTIATION; NATURAL-KILLER-CELLS; IFN-GAMMA; CUTTING EDGE; LINEAGE COMMITMENT; PROMOTER ELEMENTS; TOXOPLASMA-GONDII; SELECTIVE EXPRESSION; HISTONE ACETYLATION; LYMPHOCYTES-T AB Interferon-gamma (IFN-gamma) is a multifunctional cytokine that defines the development of Th1 cells and is critical for host defense against intracellular pathogens. IL-2 is another key immunoregulatory cytokine that is involved in T helper differentiation and is known to induce IFN-gamma expression in natural killer (NK) and T cells. Despite concerted efforts to identify the one or more transcriptional control mechanisms by which IL-2 induces IFN-gamma mRNA expression, no such genomic regulatory regions have been described. We have identified a DNase I hypersensitivity site similar to3.5-4.0 kb upstream of the transcriptional start site. Using chromatin immunoprecipitation assays we found constitutive histone H3 acetylation in this distal region in primary human NK cells, which is enhanced by IL-2 treatment. This distal region is also preferentially acetylated on histones H3 and H4 in primary Th1 cells as compared with Th2 cells. Within this distal region we found a Stat5-like motif, and in vitro DNA binding assays as well as in vivo chromosomal immunoprecipitation assays showed IL-2-induced binding of both Stat5a and Stat5b to this distal element in the IFNG gene. We examined the function of this Stat5-binding motif by transfecting human peripheral blood mononuclear cells with -3.6 kb of IFNG-luciferase constructs and found that phorbol 12-myristate 13-acetate/ionomycin-induced transcription was augmented by IL-2 treatment. The effect of IL-2 was lost when the Stat5 motif was disrupted. These data led us to conclude that this distal region serves as both a target of chromatin remodeling in the IFNG locus as well as an IL-2-induced transcriptional enhancer that binds Stat5 proteins. C1 NCI, Cellular & Mol Immunol Sect, Expt Immunol Lab, NIH, Frederick, MD 21702 USA. NIAMSD, Lymphocyte & Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, Dept Gastroenterol, Los Angeles, CA 90048 USA. NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Kobe Univ, Grad Sch Med, Dept Clin Pathol & Immunol, Chuo Ku, Kobe, Hyogo 6500017, Japan. RP Bream, JH (reprint author), NCI, Cellular & Mol Immunol Sect, Expt Immunol Lab, NIH, Frederick, MD 21702 USA. EM youngh@ncifcrf.gov RI Young, Howard/A-6350-2008 OI Young, Howard/0000-0002-3118-5111 FU NIDDK NIH HHS [DK43211] NR 66 TC 55 Z9 56 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 SEP 24 PY 2004 VL 279 IS 39 BP 41249 EP 41257 DI 10.1074/jbc.M401168200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 854PW UT WOS:000223916800124 PM 15271977 ER PT J AU King, RA Markov, D Sen, R Severinov, K Weisberg, RA AF King, RA Markov, D Sen, R Severinov, K Weisberg, RA TI A conserved zinc binding domain in the largest subunit of DNA-dependent RNA polymerase modulates intrinsic transcription termination and antitermination but does not stabilize the elongation complex SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE E. coli; phage HK022; beta ' subunit ID ESCHERICHIA-COLI; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; PHAGE HK022; PROTEIN; PROMOTER; TEMPERATURE; HOLOENZYME; SITE AB An evolutionarily conserved zinc-binding motif is found close to the amino terminus of the largest subunits of DNA-dependent RNA polymerases from bacteria, archaea, and eukaryotes. In bacterial RNA polymerase, this motif, the zinc binding domain, has been implicated in protein-DNA interactions that stabilize the transcription elongation complex and that occur downstream of the catalytic center. Here, we show that this view is incorrect, and instead, the zinc binding domain interacts with product RNA located upstream of the catalytic center and the RNA-DNA hybrid, a view consistent with structural studies of the elongation complex. We engineered mutations that alter or remove the zinc binding domain of Escherichia coli RNA polymerase. Several mutants, including one that lacked all four zinc ligands and another that lacked the entire domain, produced enzymes that were active in vitro and formed stable elongation complexes. However, they were defective in two functions that require interaction of polymerase with product RNA. First, they terminated less efficiently than the wild-type at intrinsic transcription terminators. Second, enzymes lacking the tip of the zinc binding domain or the zinc ligands did not antiterminate in response to an intrinsic antiterminator encoded by the put site of phage HK022. Termination, but not antitermination, was restored by the bacterial termination factor NusA. Surprisingly, a mutant that lacks the entire zinc binding domain regained a partial response to put. To account for this we suggest that put RNA interacts with an additional site in the elongation complex to mediate antitermination, and that this site is occluded by the wild-type zinc binding domain. Published by Elsevier Ltd. C1 Rutgers State Univ, Waksman Inst, Piscataway, NJ 08854 USA. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Severinov, K (reprint author), Rutgers State Univ, Waksman Inst, Piscataway, NJ 08854 USA. EM severik@waksman.rutgers.edu; rweisberg@nih.gov RI Severinov, Konstantin/C-8545-2016 FU NIGMS NIH HHS [GM64530] NR 38 TC 16 Z9 17 U1 0 U2 2 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 SEP 24 PY 2004 VL 342 IS 4 BP 1143 EP 1154 DI 10.1016/j.jmb.2004.07.072 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 855WL UT WOS:000224005500007 PM 15351641 ER PT J AU Voloshin, ON Camerini-Otero, RD AF Voloshin, ON Camerini-Otero, RD TI Synaptic complex revisited: A homologous recombinase flips and switches bases SO MOLECULAR CELL LA English DT Editorial Material ID CRYSTAL-STRUCTURE; DNA HELICASE; RECA PROTEIN; REPAIR AB While it is still unclear how RecA and its eukaryotic homologs conduct genome-wide homology searches, Radding and colleagues report in this issue of Molecular Cell (Folta-Stogniew et al., 2004) that the latter stages of homologous recognition or alignment involve base flipping (localized melting) and switching (annealing) at A:T rich regions. C1 NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Voloshin, ON (reprint author), NIDDKD, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. NR 9 TC 14 Z9 15 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 24 PY 2004 VL 15 IS 6 BP 846 EP 847 DI 10.1016/j.molcel.2004.09.010 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 857VX UT WOS:000224148400003 PM 15383274 ER PT J AU Chesebro, B AF Chesebro, B TI Biomedicine - A fresh look at BSE SO SCIENCE LA English DT Editorial Material ID BOVINE SPONGIFORM ENCEPHALOPATHY; CREUTZFELDT-JAKOB-DISEASE; PRION PROTEIN C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Chesebro, B (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. EM bschesebro@nih.gov NR 12 TC 14 Z9 15 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 SEP 24 PY 2004 VL 305 IS 5692 BP 1918 EP + DI 10.1126/science.1103581 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 857RM UT WOS:000224136000033 PM 15448258 ER PT J AU Janak, PH Chen, MT Caulder, T AF Janak, PH Chen, MT Caulder, T TI Dynamics of neural coding in the accumbens during extinction and reinstatement of rewarded behavior SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE extinction; reinstatement; reinforcement; instrumental conditioning; ventral striatum; electrophysiology; single-unit ID FREELY MOVING RATS; IBOTENIC ACID LESIONS; NUCLEUS-ACCUMBENS; PREFRONTAL CORTEX; EXCITOTOXIC LESIONS; NEURONAL RESPONSES; VENTRAL STRIATUM; SINGLE NEURONS; COCAINE; ADDICTION AB Neural correlates of reward-seeking behavior are observed in the nucleus accumbens (NAC). The dependence of these correlates upon the presence of a reward was studied by comparing the behavioral correlates observed when the presence of the reward was manipulated within a single behavioral session. Rats were well-trained on a continuous reinforcement instrumental task reinforced by 0.1 ml drops of 5% sucrose. Extracellular single-unit neural activity was recorded from electrode arrays implanted into the NAC when instrumental behavior was and then was not reinforced with sucrose (within-session extinction). A variable delay between the instrumental response and the sucrose delivery allowed for separation of neural activity related to these task events. A spike activity increase around the time of the instrumental response was the most common behavioral correlate, while a decrease in spike activity upon sucrose delivery was the second most common behavioral correlate. Following removal of the reinforcer, subjects continued to perform the instrumental response, allowing for the examination of response-related spike activity under extinction conditions in which the response was no longer reinforced by sucrose. A majority of the response-related neural activity patterns were lost when sucrose was no longer available. New neural responses also were detected during this period. For some subjects, the reinforcer was again made available during the same session. Encoding of the primary behavioral events during this period of reinstated reinforcer was similar, but not identical, to that observed during the first period of reinforced responding. These findings reveal that instrumental task-associated spike activity within the NAC is partially dependent upon the presence of the reinforcer, and that encoding across the population is distinct under reinforced and extinction conditions. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Dept Neurol, Emeryville, CA 94608 USA. Natl Yang Ming Univ, Taipei Vet Gen Hosp, Neurol Inst, Dept Neurosurg, Taipei 11217, Taiwan. Natl Inst Drug Abuse, Intramural Res Program, Cellular Neurobiol Branch, NIH, Baltimore, MD 21224 USA. RP Janak, PH (reprint author), Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Dept Neurol, 5858 Horton St,Suite 200, Emeryville, CA 94608 USA. EM pjanak@itsa.ucsf.edu NR 39 TC 17 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD SEP 23 PY 2004 VL 154 IS 1 BP 125 EP 135 DI 10.1016/j.bbr.2004.02.003 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 848WY UT WOS:000223500000013 PM 15302118 ER PT J AU Huth, JR Yu, LP Collins, I Mack, J Mendoza, R Isaac, B Braddock, DT Muchmore, SW Comess, KM Fesik, SW Clore, GM Levens, D Hajduk, PJ AF Huth, JR Yu, LP Collins, I Mack, J Mendoza, R Isaac, B Braddock, DT Muchmore, SW Comess, KM Fesik, SW Clore, GM Levens, D Hajduk, PJ TI NMR-driven discovery of benzoylanthranilic acid inhibitors of far upstream element binding protein binding to the human oncogene c-myc promoter SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HIGH-AFFINITY LIGANDS; SINGLE-STRANDED-DNA; MOLECULAR-BASIS; MINOR-GROOVE; KH DOMAINS; RECOGNITION; COMPLEXES; SPECTROSCOPY; EXPRESSION; DYNAMICS AB Reversal of aberrant gene expression that is induced by the proto-oncogene c-myc is likely to be effective for treating a variety of tumors that rely on this pathway for growth. One strategy to down-regulate the c-myc pathway is to target transcription factors that regulate its own expression. A host of proteins act in coordination to regulate c-myc expression and any one of them are theoretical targets for small-molecule therapy. Experimentally, it has been shown that the far upstream element (FUSE) binding protein (FBP) is essential for c-myc expression, and reductions in FBP levels both reduce c-myc expression and correlate with slower cell growth. FBP binds to ssDNA by capturing exposed DNA bases in a hydrophobic pocket. This suggests that a small molecule could be designed to occupy this pocket and inhibit FBP function. Using a variety of screening methodologies, we have identified ligands that bind to the DNA binding pockets of the KH domains of FBP. Gel shift analyses using full length FBP and a related transcription factor confirm that a small-molecule lead compound inhibits DNA binding in a specific manner. The benzoylanthranilic acid compounds described here represent leads in the design of FBP inhibitors that can serve as useful tools in the study of c-myc regulation and in the development of therapeutics that target the c-myc pathway. C1 Abbott Labs, Abbott Pk, IL 60064 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hajduk, PJ (reprint author), Abbott Labs, 100 Abbott Pk Rd, Abbott Pk, IL 60064 USA. EM philip.hajduk@abbott.com RI Clore, G. Marius/A-3511-2008; Levens, David/C-9216-2009 OI Clore, G. Marius/0000-0003-3809-1027; Levens, David/0000-0002-7616-922X NR 43 TC 28 Z9 31 U1 0 U2 6 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 SEP 23 PY 2004 VL 47 IS 20 BP 4851 EP 4857 DI 10.1021/jm0497803 PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 854UI UT WOS:000223928500009 PM 15369388 ER PT J AU Tamamura, H Sigano, DM Lewin, NE Peach, ML Nicklaus, MC Blumberg, PM Marquez, VE AF Tamamura, H Sigano, DM Lewin, NE Peach, ML Nicklaus, MC Blumberg, PM Marquez, VE TI Conformationally constrained analogues of diacylglycerol (DAG). 23. Hydrophobic ligand-protein interactions versus ligand-lipid interactions of DAG-lactones with protein kinase C (PK-C) SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID GREEN FLUORESCENT PROTEIN; TUMOR-PROMOTING ACTIVITY; PHORBOL ESTERS; HIGH-AFFINITY; LIVING CELLS; MOUSE SKIN; ACTIVATORS; 13-ACETATE; CALCIUM AB The constrained glycerol backbone of DAG-lactones, when combined with highly branched alkyl chains, has engendered a series of DAG-lactone ligands capable of binding protein kinase C (PK-C) with affinities that approximate those of phorbol esters. These branched chains not only appear to be involved in making important hydrophobic contacts with the protein (specific interactions) but also provide adequate lipophilicity to facilitate partitioning into the lipid-rich membrane environment (nonspecific interactions). With the idea of minimizing the nonspecific interactions without reducing lipophilicity, the present work explores the strategy of relocating lipophilicity from the side chain to the lactone "core". Such a transfer of lipophilicity, exemplified by compounds I and 3, was conceived to allow the new hydrophobic groups on the lactone to engage in specific hydrophobic contacts inside the binding pocket without any expectation of interfering with the hydrogen-bonding network of the DAG-lactone pharmacophore. Surprisingly, both (E)-3 and (Z)-3 showed a significant decrease in binding affinity. From the molecular docking studies performed with the new ligands, we conclude that the binding pocket of the C I domain of PK-C is sterically restricted and prevents the methyl groups at the C-3 position of the lactone from engaging in productive hydrophobic contacts with the receptor. C1 NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Marquez, VE (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH, Bldg 376,Room 104, Frederick, MD 21702 USA. EM marquezv@mail.nih.gov RI Sigano, Dina/M-6144-2014; Nicklaus, Marc/N-4183-2014; OI Sigano, Dina/0000-0001-7489-9555; Nicklaus, Marc/0000-0002-4775-7030 NR 30 TC 6 Z9 6 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 SEP 23 PY 2004 VL 47 IS 20 BP 4858 EP 4864 DI 10.1021/jm049723+ PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 854UI UT WOS:000223928500010 PM 15369389 ER PT J AU Chen, HM Honse, Y Ikeda, SR AF Chen, HM Honse, Y Ikeda, SR TI Alternative modalities of adenovirus-mediated gene expression in hippocampal neurons cultured on microisland substrate SO NEUROSCIENCE LETTERS LA English DT Article DE adenovirus; lysate; autapse; infection; microisland ID FOREST-VIRUS VECTORS; PRESYNAPTIC INHIBITION; LOCALIZATION; SYNAPSES; CHANNELS; RELEASE AB Previously, we have used CsCl gradient-purified recombinant adenovirus (AdV) to successfully transfer genes into hippocampal neurons cultured on microisland substrate. Here, we report that purification of AdV particles is not required and efficient gene expression can be achieved using either crude AdV lysates or HEK 293 cells infected with AdV The advantages of the simplified procedure are greatly reduced preparation time and reduced requirements for equipment and expertise. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIAAA, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. RP Chen, HM (reprint author), NIAAA, Lab Mol Physiol, NIH, Pk Bldg,Room 150,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. EM huanchen@mail.nih.gov OI Ikeda, Stephen/0000-0002-4088-9508 NR 19 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 23 PY 2004 VL 368 IS 2 BP 221 EP 225 DI 10.1016/j.neulet.2004.07.022 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 855IW UT WOS:000223967800022 PM 15351453 ER PT J AU Hostetter, TH AF Hostetter, TH TI Chronic kidney disease predicts cardiovascular disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; ASSOCIATION; ADULTS; PROTEINURIA; PREVALENCE; STATEMENT; MARKERS C1 NIDDK, Natl Kidney Dis Educ Program, NIH, Bethesda, MD 20892 USA. RP Hostetter, TH (reprint author), NIDDK, Natl Kidney Dis Educ Program, NIH, Bethesda, MD 20892 USA. NR 15 TC 104 Z9 111 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD SEP 23 PY 2004 VL 351 IS 13 BP 1344 EP 1346 DI 10.1056/NEJMe048211 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 855TP UT WOS:000223997700016 PM 15385664 ER PT J AU Smith, L Rindflesch, T Wilbur, WJ AF Smith, L Rindflesch, T Wilbur, WJ TI MedPost: a part-of-speech tagger for bioMedical text SO BIOINFORMATICS LA English DT Article AB We present a part-of-speech tagger that achieves over 97% accuracy on MEDLINE citations. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Comp Biol Branch, Bethesda, MD 20894 USA. Lister Hill Natl Ctr Biomed Commun, Cognit Sci Branch, Bethesda, MD 20894 USA. RP Smith, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Comp Biol Branch, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM lsmith@ncbi.nlm.nih.gov NR 8 TC 77 Z9 87 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 SEP 22 PY 2004 VL 20 IS 14 BP 2320 EP 2321 DI 10.1093/bioinformatics/bth227 PG 2 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 856YX UT WOS:000224083100027 PM 15073016 ER PT J AU Dalakas, MC AF Dalakas, MC TI Intravenous immunoglobulin and quality of life - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID AUTOIMMUNE NEUROMUSCULAR DISEASES C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. NR 3 TC 1 Z9 1 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 SEP 22 PY 2004 VL 292 IS 12 BP 1429 EP 1430 DI 10.1001/jama.292.12.1429-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 856FT UT WOS:000224031800018 ER PT J AU Ho, VB Bakalov, VK Cooley, M Van, PL Hood, MN Burklow, TR Bondy, CA AF Ho, VB Bakalov, VK Cooley, M Van, PL Hood, MN Burklow, TR Bondy, CA TI Major vascular anomalies in Turner syndrome - Prevalence and magnetic resonance angiographic features SO CIRCULATION LA English DT Article DE Turner syndrome; angiography; magnetic resonance imaging; aorta; veins ID PULMONARY VENOUS DRAINAGE; CONGENITAL HEART-DISEASE; CARDIOVASCULAR MALFORMATIONS; FLOW PATTERNS; AORTA; COARCTATION; PSEUDOCOARCTATION; PATIENT; RETURN; NECK AB Background-Turner syndrome (TS) is associated with aortic coarctation and dissection; hence, echocardiographic evaluation of all patients is currently recommended. X-ray angiography in clinically symptomatic patients has suggested a range of other vascular anomalies, but the true prevalence of such lesions in TS is unknown. To better understand the prevalence and pathogenesis of cardiovascular defects in TS, we prospectively evaluated a group of asymptomatic adult volunteers with TS using magnetic resonance (MR) angiography. Methods and Results-A total of 85 adults with TS and 27 normal female adult volunteers underwent gadolinium-enhanced 3D MR angiography. A high prevalence of aortic anomalies was seen in women with TS, including elongation of the transverse arch (49%), aortic coarctation (12%), and aberrant right subclavian artery (8%). Venous anomalies were also prominent, including persistent left superior vena cava (13%) and partial anomalous pulmonary venous return (13%). None of these anomalies were found in healthy female controls. The constellation of elongation of the transverse arch, aortic coarctation, and persistent left superior vena cava was significantly associated with women with TS. Neck webbing and increased thoracic anterior-to-posterior dimension diameters were strong predictors for arterial and venous anomalies. Conclusions-Thoracic vascular anomalies are common in TS, occurring in approximate to50% of a group not preselected for cardiovascular disease. The highly significant association between neck webbing, increased chest diameter, and these vascular anomalies suggests that in utero, centrally localized lymphatic obstruction may contribute to these cardiovascular deformities in TS. Improved recognition of these often-undetected vascular lesions may be important for identification of patients in need of closer cardiovascular monitoring. C1 Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. NIH, Dept Diagnost Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Ho, VB (reprint author), Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM vho@usuhs.mil NR 38 TC 128 Z9 135 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 21 PY 2004 VL 110 IS 12 BP 1694 EP 1700 DI 10.1161/01.CIR.0000142290.35842.B0 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 855MP UT WOS:000223977700028 PM 15353492 ER PT J AU Kumar, R Clermont, G Vodovotz, Y Chow, CC AF Kumar, R Clermont, G Vodovotz, Y Chow, CC TI The dynamics of acute inflammation SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE systemic inflammation; sepsis; ordinary differential equation (ODE) models; phase-space and bifurcation analysis ID MEDICINE CONSENSUS CONFERENCE; CHEST-PHYSICIANS SOCIETY; SEPTIC SHOCK; ORGAN FAILURE; INNOVATIVE THERAPIES; MONOCLONAL-ANTIBODY; RESPONSE SYNDROME; AMERICAN-COLLEGE; CONTROLLED-TRIAL; SEVERE SEPSIS AB When the body is infected, it mounts an acute inflammatory response to rid itself of the pathogens and restore health. Uncontrolled acute inflammation due to infection is defined clinically as sepsis and can culminate in organ failure and death. We consider a three-dimensional ordinary differential equation model of inflammation consisting of a pathogen, and two inflammatory mediators. The model reproduces the healthy outcome and diverse negative outcomes, depending on initial conditions and parameters. We analyze the various bifurcations between the different outcomes when key parameters are changed and suggest various therapeutic strategies. We suggest that the clinical condition of sepsis can arise from several distinct physiological states, each of which requires a different treatment approach. Published by Elsevier Ltd. C1 Univ Pittsburgh, Dept Phys, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Astron, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Crit Care Med, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Surg, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Math, Pittsburgh, PA 15260 USA. RP Chow, CC (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM ccchow@pitt.edu RI Chow, Carson/A-7970-2009 FU NIGMS NIH HHS [R01-GM-67240] NR 28 TC 96 Z9 100 U1 1 U2 7 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD SEP 21 PY 2004 VL 230 IS 2 BP 145 EP 155 DI 10.1016/j.jtbi.2004.04.044 PG 11 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 849EM UT WOS:000223521500001 PM 15321710 ER PT J AU Lan, L Nakajima, S Oohata, Y Takao, M Okano, S Masutani, M Wilson, SH Yasui, A AF Lan, L Nakajima, S Oohata, Y Takao, M Okano, S Masutani, M Wilson, SH Yasui, A TI In situ analysis of repair processes for oxidative DNA damage in mammalian cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID BASE EXCISION-REPAIR; SINGLE-STRAND BREAKS; POLYMERASE-BETA; INDUCED CYTOTOXICITY; XRCC1; GLYCOSYLASE; REQUIREMENT; PROTECTION; LETHALITY; LESIONS AB Oxidative DNA damage causes blocks and errors in transcription and replication, leading to cell death and genomic instability. Although repair mechanisms of the damage have been extensively analyzed in vitro, the actual in vivo repair processes remain largely unknown. Here, by irradiation with an UVA laser through a microscope lens, we have conditionally produced single-strand breaks and oxidative base damage at restricted nuclear regions of mammalian cells. We showed, in real time after irradiation by using antibodies and GFP-tagged proteins, rapid and ordered DNA repair processes of oxidative DNA damage in human cells. Furthermore, we characterized repair pathways by using repair-defective mammalian cells and found that DNA polymerase 13 accumulated at single-strand breaks and oxidative base damage by means of its 31- and 8-kDa domains, respectively, and that XRCC1 is essential for both polymerarse beta-dependent and proliferating cell nuclear antigen-dependent repair pathways of single-strand breaks. Thus, the repair of oxidative DNA damage is based on temporal and functional interactions among various proteins operating at the site of DNA damage in living cells. C1 Tohoku Univ, Dept Mol Genet, Inst Dev Aging & Canc, Sendai, Miyagi 9808575, Japan. Yamagata Univ, Res Lab Mol Genet, Yamagata 9909585, Japan. Natl Canc Ctr, Res Inst, Div Biochem, Tokyo 1040045, Japan. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Yasui, A (reprint author), Tohoku Univ, Dept Mol Genet, Inst Dev Aging & Canc, Seiryomachi 4-1, Sendai, Miyagi 9808575, Japan. EM ayasui@idac.tohoku.ac.jp NR 30 TC 184 Z9 187 U1 1 U2 7 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 SEP 21 PY 2004 VL 101 IS 38 BP 13738 EP 13743 DI 10.1073/pnas.04069048101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 856UF UT WOS:000224069800010 PM 15365186 ER PT J AU Fujii, K Zhu, GZ Liu, Y Hallam, J Chen, L Herrero, J Shaw, S AF Fujii, K Zhu, GZ Liu, Y Hallam, J Chen, L Herrero, J Shaw, S TI Kinase peptide specificity: Improved determination and relevance to protein phosphorylation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SUBSTRATE-SPECIFICITY; SEQUENCE MOTIFS; WIDE PREDICTION; ACTIVATION; LIBRARIES; RECEPTOR; SIGNALS; GENOME; ALPHA AB Specificity of phosphorylation is critical to signal transduction. Recent emphasis on colocalization of substrate and kinase has eclipsed emphasis on peptide specificity, i.e., kinase preference for particular amino acids surrounding the phosphorylation site. We describe an approach to determining peptide specificity by using positional scanning of biotinylated oriented peptide libraries and insights emerging from those determinations. We accurately determine preference (or disfavor) for residues at a given substrate position (such as P+2) by comparison of in vitro phosphorylation of peptide libraries differing by a single residue at that position. By analysis of all positions near the phosphorylation site, position-specific scoring matrices are generated and used both to understand the basis of specificity and to predict phosphorylation. PKC-delta and -zeta predictions have been validated rigorously by comparisons with measured phosphorylation. The results demonstrate specificity and sensitivity (80-90%) much better than the previous predictive method. These predictions can be accessed at http://mpr.nci.nih.gov. The accuracy of the specificity determination allows identification of an important difference in peptide specificity between these closely related kinases; Ile/Leu at the P-1 position is disfavored by PKC-zeta but not PKC-delta. Our findings and visual representation of peptide specificity highlight the importance of disfavored residues. Finally, analysis of 124 experimentally determined PKC sites from the literature demonstrates a very strong role of peptide specificity in many of those sites. Thus, position-specific scoring matrices generated by this method provide a foundation for quantitative analyses of kinase specificity and improved predictions of previously determined physiologically relevant phosphorylation sites. C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. AxCell Biosci, Newtown, PA 18940 USA. Univ Occupat & Environm Hlth, Dept Internal Med 1, Fukuoka 8078555, Japan. RP NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. EM sshaw@nih.gov NR 32 TC 68 Z9 71 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 21 PY 2004 VL 101 IS 38 BP 13744 EP 13749 DI 10.1073/pnas.0401881101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 856UF UT WOS:000224069800011 PM 15356339 ER PT J AU Chain, PSG Carniel, E Larimer, FW Lamerdin, J Stoutland, PO Regala, WM Georgescu, AM Vergez, LM Land, ML Motin, VL Brubaker, RR Fowler, J Hinnebusch, J Marceau, M Medigue, C Simonet, M Chenal-Francisque, V Souza, B Dacheux, D Elliott, JM Derbise, A Hauser, LJ Garcia, E AF Chain, PSG Carniel, E Larimer, FW Lamerdin, J Stoutland, PO Regala, WM Georgescu, AM Vergez, LM Land, ML Motin, VL Brubaker, RR Fowler, J Hinnebusch, J Marceau, M Medigue, C Simonet, M Chenal-Francisque, V Souza, B Dacheux, D Elliott, JM Derbise, A Hauser, LJ Garcia, E TI Insights into the evolution of Yersinia pestis through whole-genome comparison with Yersinia pseudotuberculosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HIGH-PATHOGENICITY ISLAND; PASTEURELLA PESTIS; ESCHERICHIA-COLI; GLYOXYLATE CYCLE; FLEA VECTOR; VIRULENCE; PLASMID; PLAGUE; ENTEROCOLITICA; SEQUENCE AB Yersinia pestis, the causative agent of plague, is a highly uniform clone that diverged recently from the enteric pathogen Yersinia pseudotuberculosis. Despite their close genetic relationship, they differ radically in their pathogenicity and transmission. Here, we report the complete genomic sequence of Y. pseudotuberculosis IP32953 and its use for detailed genome comparisons with available Y. pestis sequences. Analyses of identified differences across a panel of Yersinia isolates from around the world reveal 32 Y. pestis chromosomal genes that, together with the two Y. pestis-specific plasmids, to our knowledge, represent the only new genetic material in Y. pestis acquired since the the divergence from Y. pseudotuberculosis. In contrast, 149 other pseudogenes (doubling the previous estimate) and 317 genes absent from Y. pestis were detected, indicating that as many as 13% of Y. pseudotuberculosis genes no longer function in Y. pestis. Extensive insertion sequence-mediated genome rearrangements and reductive evolution through massive gene loss, resulting in elimination and modification of preexisting gene expression pathways, appear to be more important than acquisition of genes in the evolution of Y. pestis. These results provide a sobering example of how a highly virulent epidemic clone can suddenly emerge from a less virulent, closely related progenitor. C1 Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, Livermore, CA 94550 USA. Inst Pasteur, Yersinia Res Unit, F-75724 Paris 15, France. Oak Ridge Natl Lab, Div Life Sci, Oak Ridge, TN 37831 USA. Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. Univ Lille 2, Inst Natl Sante & Rech Med, Inst Pasteur, F-59021 Lille, France. CNRS, UMR 8030, F-91006 Evry, France. RP Garcia, E (reprint author), Lawrence Livermore Natl Lab, Biol & Biotechnol Res Program, 7000 E Ave,L-452, Livermore, CA 94550 USA. EM garcia12@llnl.gov RI Land, Miriam/A-6200-2011; Hauser, Loren/H-3881-2012; chain, patrick/B-9777-2013; Motin, Vladimir/O-1535-2013; MARCEAU, Michael/O-6497-2016 OI Land, Miriam/0000-0001-7102-0031; MARCEAU, Michael/0000-0002-4403-8081 NR 46 TC 387 Z9 1273 U1 5 U2 42 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 SEP 21 PY 2004 VL 101 IS 38 BP 13826 EP 13831 DI 10.1073/pnas.0401412101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 856UF UT WOS:000224069800025 PM 15358858 ER PT J AU Rothfork, JM Timmins, GS Harris, MN Chen, X Lusis, AJ Otto, M Cheung, AL Gresham, HD AF Rothfork, JM Timmins, GS Harris, MN Chen, X Lusis, AJ Otto, M Cheung, AL Gresham, HD TI Inactivation of a bacterial virulence pheromone by phagocyte-derived oxidants: New role for the NADPH oxidase in host defense SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; RESISTANT STAPHYLOCOCCUS-AUREUS; QUORUM-SENSING SYSTEM; AUTOINDUCING PEPTIDES; IN-VITRO; INFECTION; COMMUNICATION; MODEL; MYELOPEROXIDASE; DETERMINANTS AB Quorum sensing triggers virulence factor expression in medically important bacterial pathogens in response to a density-dependent increase in one or more autoinducing pheromones. Here, we show that phagocyte-derived oxidants target these autoinducers for inactivation as an innate defense mechanism of the host. In a skin infection model, expression of phagocyte NADPH oxidase, myelo-peroxidase, or inducible nitric oxide synthase was critical for defense against a quorum-sensing pathogen, Staphylococcus aureus, but not for defense against a quorum sensing-deficient mutant. A virulence-inducing peptide of S. aureus was inactivated in vitro and in vivo by reactive oxygen and nitrogen intermediates, including HOCl and ONOO-. Inactivation of the autoinducer prevented both the up-regulation of virulence gene expression and the downstream sequelae. MS analysis of the inactivated peptide demonstrated that oxidation of the C-terminal methionine was primarily responsible for loss of activity. Treatment of WT but not NADPH oxidase-deficient mice with N-acetyl methionine to scavenge the inhibitory oxidants increased in vivo quorum sensing independently of the bacterial burden at the site of infection. Thus, oxidant-mediated inactivation of an autoinducing peptide from S. aureus is a critical innate defense mechanism against infection with this pathogen. C1 Vet Affairs Med Ctr, Res Serv, Albuquerque, NM 87108 USA. Univ New Mexico, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. Univ New Mexico, Coll Pharm, Albuquerque, NM 87131 USA. Los Alamos Natl Lab, Biosci Div, Los Alamos, NM 87545 USA. Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA. NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Dartmouth Coll Sch Med, Dept Microbiol, Hanover, NH 03755 USA. RP Gresham, HD (reprint author), Univ New Mexico 1, MSCO8 4660, Albuquerque, NM 87131 USA. EM hgresham@salud.unm.edu OI timmins, graham/0000-0002-4971-718X; Otto, Michael/0000-0002-2222-4115 FU NHLBI NIH HHS [HL30568, P01 HL030568]; NIAID NIH HHS [AI46615, AI47441, R01 AI046615, R01 AI047441] NR 38 TC 69 Z9 72 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 21 PY 2004 VL 101 IS 38 BP 13867 EP 13872 DI 10.1073/pnas.0402996101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 856UF UT WOS:000224069800032 PM 15353593 ER PT J AU Chen, QR Bilke, S Wei, JS Whiteford, CC Cenacchi, N Krasnoselsky, AL Greer, BT Son, CG Westermann, F Berthold, F Schwab, M Catchpoole, D Khan, J AF Chen, QR Bilke, S Wei, JS Whiteford, CC Cenacchi, N Krasnoselsky, AL Greer, BT Son, CG Westermann, F Berthold, F Schwab, M Catchpoole, D Khan, J TI CDNA array-CGH profiling identifies genomic alterations specific to stage and MYCN-amplification in neuroblastoma SO BMC GENOMICS LA English DT Article ID N-MYC; COPY-NUMBER; CELL-LINES; 17Q GAIN; GENE; DNA; TUMORS; HYBRIDIZATION; MICROARRAYS; EXPRESSION AB Background: Recurrent non-random genomic alterations are the hallmarks of cancer and the characterization of these imbalances is critical to our understanding of tumorigenesis and cancer progression. Results: We performed array-comparative genomic hybridization (A-CGH) on cDNA microarrays containing 42,000 elements in neuroblastoma ( NB). We found that only two chromosomes (2p and 12q) had gene amplifications and all were in the MYCN amplified samples. There were 6 independent non-contiguous amplicons (10.4 - 69.4 Mb) on chromosome 2, and the largest contiguous region was 1.7 Mb bounded by NAG and an EST ( clone: 757451); the smallest region was 27 Kb including an EST ( clone: 241343), NCYM, and MYCN. Using a probabilistic approach to identify single copy number changes, we systemically investigated the genomic alterations occurring in Stage 1 and Stage 4 NBs with and without MYCN amplification ( stage 1-, 4-, and 4+). We have not found genomic alterations universally present in all (100%) three subgroups of NBs. However we identified both common and unique patterns of genomic imbalance in NB including gain of 7q32, 17q21, 17q23-24 and loss of 3p21 were common to all three categories. Finally we confirm that the most frequent specific changes in Stage 4+ tumors were the loss of 1p36 with gain of 2p24-25 and they had fewer genomic alterations compared to either stage 1 or 4-, indicating that for this subgroup of poor risk NB requires a smaller number of genomic changes are required to develop the malignant phenotype. Conclusions: cDNA A-CGH analysis is an efficient method for the detection and characterization of amplicons. Furthermore we were able to detect single copy number changes using our probabilistic approach and identified genomic alterations specific to stage and MYCN amplification. C1 NCI, Oncogenom Sect, Pediat Oncol Branch, Ctr Adv Technol, Gaithersburg, MD 20877 USA. Daejeon Univ, Coll Oriental Med, Dept Internal Med, Taejon 301724, South Korea. German Canc Res Ctr, Dept Cytogenet, D-69120 Heidelberg, Germany. Univ Cologne, Klin Kinderheilkunde, Dept Pediat, D-50924 Cologne, Germany. Childrens Hosp Westmead, Tumour Bank, Westmead, NSW 2145, Australia. RP Khan, J (reprint author), NCI, Oncogenom Sect, Pediat Oncol Branch, Ctr Adv Technol, 8717 Grovement Circle, Gaithersburg, MD 20877 USA. EM chenqi@mail.nih.gov; bilkes@mail.nih.gov; weij@mail.nih.gov; whitefoc@mail.nih.gov; cenacchn@mail.nih.gov; krasnosa@mail.nih.gov; greerb@mail.nih.gov; sonc@mail.nih.gov; frank.berthold@medizin.uni-koeln.de; frank.berthold@medizin.uni-koeln.de; M.Schwab@DKFZ-Heidelberg.de; DanielC@chw.edu.au; khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 NR 41 TC 67 Z9 69 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD SEP 20 PY 2004 VL 5 AR 70 DI 10.1186/1471-2164-5-70 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 859NX UT WOS:000224276300002 PM 15380028 ER PT J AU Butcher, DT Mancini-DiNardo, DN Archer, TK Rodenhiser, DI AF Butcher, DT Mancini-DiNardo, DN Archer, TK Rodenhiser, DI TI DNA binding sites for putative methylation boundaries in the unmethylated region of the BRCA1 promoter SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE DNA methylation; BRCA1; boundaries; Sp1; CTCF; breast cancer ID TUMOR-SUPPRESSOR GENE; CPG ISLAND METHYLATION; CARCINOMA IN-SITU; SPORADIC BREAST; OVARIAN-CANCER; TRANSCRIPTIONAL ACTIVITY; HOMONUCLEOTIDE TRACTS; MAMMALIAN DEVELOPMENT; COLORECTAL-CANCER; CPG/CPNPG MOTIFS AB Changes in DNA methylation patterns are frequently observed in human cancers and are associated with a decrease in tumor suppressor gene expression. Hypermethylation of the BRCAI promoter has been reported in a portion of sporadic breast tumours that correspond to a reduction in BRCAI transcription and expression. Questions remain concerning the maintenance of methylation free zones in promoter regions of tumor suppressor genes in normal tissues. Sodium bisulfite based analysis of the BRCAI promoter defines a methylation free zone in normal breast tissue that starts 650 bp upstream of the transcription start site and extends for 1.4 kb through most of the BRCAI CpG island. We provide data implicating 2 proteins, SpI and CTCF, in the maintenance of this methylation-free zone. Both of these proteins have been shown to function as methylation boundaries in other genes. Four SpI sites have been identified in the BRCAI promoter by gel shift assays. In vivo binding of SpI has been confirmed at 2 of these sites in the BRCAI promoter and at 2 CTCF sites that flank the unmethylated region. Our data suggest that these DNA binding sites for SpI and CTCF may act as boundary elements that are important in maintaining genomic integrity by delineating the normal methylation free BRCAI promoter. Inactivation or disruption of these boundaries may facilitate an epigenetic "hit", in this case DNA methylation, leading to BRCAI downregulation and contributing to tumorigenesis, particularly the genesis of sporadic breast tumours. (C) 2004 Wiley-Liss, Inc. C1 London Reg Canc Ctr, Child Hlth Res Inst, London, ON N6A 4L6, Canada. Univ Western Ontario, Dept Biochem Paediat & Oncol, London, ON, Canada. Princeton Univ, Dept Biol Mol, Princeton, NJ 08544 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Rodenhiser, DI (reprint author), London Reg Canc Ctr, Child Hlth Res Inst, 790 Commissioners Rd E, London, ON N6A 4L6, Canada. EM drodenhi@uwo.ca NR 60 TC 44 Z9 45 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 20 PY 2004 VL 111 IS 5 BP 669 EP 678 DI 10.1002/ijc.20324 PG 10 WC Oncology SC Oncology GA 845SD UT WOS:000223263700004 PM 15252835 ER PT J AU Brenchley, JM Schacker, TW Ruff, LE Price, DA Taylor, JH Beilman, GJ Nguyen, PL Khoruts, A Larson, M Haase, AT Douek, DC AF Brenchley, JM Schacker, TW Ruff, LE Price, DA Taylor, JH Beilman, GJ Nguyen, PL Khoruts, A Larson, M Haase, AT Douek, DC TI CD4(+) T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE HIV pathogenesis; CD4(+) T cell depletion; lymph nodes; gastrointestinal tract; HIV-specific T cells ID IMMUNODEFICIENCY-VIRUS-INFECTION; ACTIVE ANTIRETROVIRAL THERAPY; FOLLICULAR DENDRITIC CELLS; LYMPHOID-TISSUES; TYPE-1 INFECTION; INTRAEPITHELIAL LYMPHOCYTES; LYMPHATIC TISSUES; RHESUS MACAQUES; LAMINA PROPRIA; VIRAL LOAD AB The mechanisms underlying CD4(+) T cell depletion in human immunodeficiency virus (HIV) infection are not well understood. Comparative studies of lymphoid tissues, where the vast majority of T cells reside, and peripheral blood can potentially illuminate the pathogenesis of HIV-associated disease. Here, we studied the effect of HIV infection on the activation and depletion of defined subsets of CD4(+) and CD8(+) T cells in the blood, gastrointestinal (GI) tract, and lymph node (LN). We also measured HIV-specific T cell frequencies in LNs and blood, and LN collagen deposition to define architectural changes associated with chronic inflammation. The major findings to emerge are the following: the GI tract has the most substantial CD4(+) T cell depletion at all stages of HIV disease; this depletion occurs preferentially within CCR5(+) CD4(+) T cells; HIV-associated immune activation results in abnormal accumulation of effector-type T cells within LNs; HIV-specific T cells in LNs do not account for all effector T cells; and T cell activation in LNs is associated with abnormal collagen deposition. Taken together, these findings define the nature and extent of CD4(+) T cell depletion in lymphoid tissue and point to mechanisms of profound depletion of specific T cell subsets related to elimination of CCR5(+) CD4(+) T cell targets and disruption of T cell homeostasis that accompanies chronic immune activation. C1 NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Surg, Div Surg Crit Care, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Microbiol, Minneapolis, MN 55455 USA. Mayo Clin, Div Hematopathol, Rochester, MN 55905 USA. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr,Room 3509, Bethesda, MD 20892 USA. EM ddouek@nih.gov RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Beilman, Gregory/0000-0001-5036-3027 FU NIAID NIH HHS [R01 AI054232, K24 AI056986, K24 AIO56986, R01 AI54232, R37 AI028246]; NIDCR NIH HHS [R01 DE-12934] NR 53 TC 1063 Z9 1094 U1 5 U2 33 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 SEP 20 PY 2004 VL 200 IS 6 BP 749 EP 759 DI 10.1084/jem.20040874 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 857GX UT WOS:000224105500006 PM 15365096 ER PT J AU Yu, Q Erman, B Park, JH Feigenbaum, L Singer, A AF Yu, Q Erman, B Park, JH Feigenbaum, L Singer, A TI IL-7 receptor signals inhibit expression of transcription factors TCF-1, LEF-1, and ROR gamma t: Impact on thymocyte development SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE ISP thymocytes; IL-7R alpha transgene; developmental arrest ID INTERLEUKIN-7 RECEPTOR; CELL DEVELOPMENT; DEFICIENT MICE; DIFFERENTIATION; CYTOKINE; BCL-2; ALPHA; SURVIVAL; CHAIN; LYMPHOCYTES AB Intrathymic T cell development depends on signals transduced by both T cell receptor and cytokine receptors. Early CD4(-)CD8(-) (double negative) thymocytes require interleukin (IL)-7 receptor (IL-7R) signals for survival and proliferation, but IL-7R signals are normally extinguished by the immature single positive (ISP) stage of thymocyte development. We now demonstrate that IL-7R signals inhibit expression of transcription factors TCF-1, LEF-1, and ROR-gammat that are required for the ISP to double positive (DP) transition in the thymus. In addition, we demonstrate that IL-7R signals also inhibit TCF-1 and LEF-1 expression in mature peripheral T cells. Thus, the present work has identified several important downstream target genes of IL-7R signaling in T cells and thymocytes that provide a molecular mechanism for the inhibitory influence of IL-7R signaling on DP thymocyte development. We conclude that IL-7R signals down-regulate transcription factors required for the ISP to DP transition and so must be terminated by the ISP stage of thymocyte development. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, SAIC Frederick, Frederick Canc Res & Dev Ctr, Frederick, MD 21702 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. EM SingerA@uih.gov RI Park, Jung Hyun /B-5712-2015 OI Park, Jung Hyun /0000-0002-9547-9055 NR 30 TC 74 Z9 75 U1 0 U2 0 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 SEP 20 PY 2004 VL 200 IS 6 BP 797 EP 803 DI 10.1084/jem.20032183 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 857GX UT WOS:000224105500010 PM 15365098 ER PT J AU Chesney, MA Straus, SE AF Chesney, MA Straus, SE TI Complementary and alternative medicine: the convergence of public interest and science in the United States SO MEDICAL JOURNAL OF AUSTRALIA LA English DT Article ID NATIONAL-SURVEY C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Chesney, MA (reprint author), NIH, Natl Ctr Complementary & Alternat Med, Bldg 10, Bethesda, MD 20892 USA. EM chesneym@mail.nih.gov NR 6 TC 4 Z9 4 U1 3 U2 3 PU AUSTRALASIAN MED PUBL CO LTD PI SYDNEY PA LEVEL 1, 76 BERRY ST, SYDNEY, NSW 2060, AUSTRALIA SN 0025-729X J9 MED J AUSTRALIA JI Med. J. Aust. PD SEP 20 PY 2004 VL 181 IS 6 BP 335 EP 336 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 859AM UT WOS:000224234200017 PM 15377249 ER PT J AU Shukla, S Sauna, ZE Prasad, R Ambudkar, SV AF Shukla, S Sauna, ZE Prasad, R Ambudkar, SV TI Disulfiram is a potent modulator of multidrug transporter Cdr1p of Candida albicans SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE ABC transporter; ATP hydrolysis; antifungal agents; multidrug resistance; photoaffinity labeling; yeast ID P-GLYCOPROTEIN; ANTIFUNGAL AGENTS; CYCLOSPORINE-A; IN-VITRO; RESISTANCE; DERIVATIVES; INHIBITION; MECHANISMS; CELLS AB To find novel drugs for effective antifungal therapy in candidiasis, we examined disulfiram, a drug used for the treatment of alcoholism, for its role as a potential modulator of Candida multidrug transporter Cdr1p. We show that disulfiram inhibits the oligomycin-sensitive ATPase activity of Cdr1p and 2.5 mM dithiothreitol reverses this inhibition. Disulfiram inhibited the binding of photoaffinity analogs of both ATP ([alpha-P-32]8-azidoATP; IC50 = 0.76 muM) and drug-substrates ([H-3]azidopine and [I-125]iodoarylazidoprazosin; IC50 similar to 12 muM) to Cdr1p in a concentration-dependent manner, suggesting that it can interact with both ATP and substrate-binding site(s) of Cdr1p. Furthermore, a non-toxic concentration of disulfiram (1 muM) increased the sensitivity of Cdr1p expressing Saccharomyces cerevisiae cells to antifungal agents (fluconazole, miconazole, nystatin, and cycloheximide). Collectively these results demonstrate that disulfiram reverses Cdr1p-mediated drug resistance by interaction with both ATP and substrate-binding sites of the transporter and may be useful for antifungal therapy. Published by Elsevier Inc. C1 NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Jawaharlal Nehru Univ, Sch Life Sci, Membrane Biol Lab, New Delhi 110067, India. RP Ambudkar, SV (reprint author), NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ambudkar@helix.nih.gov RI Ambudkar, Suresh/B-5964-2008 NR 21 TC 26 Z9 30 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 SEP 17 PY 2004 VL 322 IS 2 BP 520 EP 525 DI 10.1016/j.bbrc.2004.07.151 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 851HI UT WOS:000223675800024 PM 15325261 ER PT J AU Necela, BM Cidlowski, JA AF Necela, BM Cidlowski, JA TI A single amino acid change in the first zinc finger of the DNA binding domain of the glucocorticoid receptor regulates differential promoter selectivity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESTROGEN RESPONSE ELEMENTS; NUCLEAR HORMONE-RECEPTORS; NF-KAPPA-B; STRUCTURAL DETERMINANTS; PROGESTERONE-RECEPTOR; ALLOSTERIC REGULATION; FUNCTIONAL DOMAINS; ANDROGEN RECEPTOR; GENE-EXPRESSION; IN-VIVO AB Mammalian species are well known to differ in their sensitivity to glucocorticoids, but the molecular basis for this difference remains largely uncharacterized. To address this issue, the transcriptional activity of the mouse and human glucocorticoid receptor (GR) was analyzed on two model glucocorticoid-responsive promoters. Mouse GR (mGR) displayed unique promoter discrimination in response to a range of glucocorticoids, with enhanced activity on a simple glucocorticoid response element (GRE)-based promoter and diminished activity on the complex mouse mammary tumor virus promoter compared with human GR (hGR). Promoter discrimination between mGR and hGR was mapped to a single amino acid change at residue 437 ( glycine to valine) of mGR and to sequence differences within individual GREs of the different promoters. Mouse GR displayed higher activation on GREs with a guanine rather than a thymine at the -6 position. Binding studies indicated mGR (mGR437V) displayed a weaker affinity for GREs containing a thymine at the - 6 position than a mGR mutant containing a glycine at residue 437 (mGR437G). Despite distinct transcriptional activities, both receptors had similar affinities for response elements that contain a guanine at the - 6 position. Our findings support a model by which the presence of a valine residue at position 437 of mGR induces a conformational change that leads to alterations in affinity and/or transcriptional activation in a promoter-dependent context. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, 111 Alexander Dr,Bldg 101,MD F3-07, Res Triangle Pk, NC 27709 USA. EM cidlowski@niehs.nih.gov NR 62 TC 9 Z9 10 U1 1 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 SEP 17 PY 2004 VL 279 IS 38 BP 39279 EP 39288 DI 10.1074/jbc.M405489200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 852YA UT WOS:000223791500012 PM 15220338 ER PT J AU Tian, LG Sayer, JM Jerina, DM Shuman, S AF Tian, LG Sayer, JM Jerina, DM Shuman, S TI Individual nucleotide bases, not base pairs, are critical for triggering site-specific DNA cleavage by vaccinia topoisomerase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID VIRUS TOPOISOMERASE; DUPLEX DNA; CRYSTAL-STRUCTURE; IB; TRANSESTERIFICATION; MECHANISM; BINDING; ENTOMOPOXVIRUS; CATALYSIS; PROTEINS 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 abasic lesions at individual positions of the scissile and nonscissile strands on the rate of single-turnover DNA transesterification and the cleavage-religation equilibrium. The rate of DNA incision was reduced by factors of 350, 250, 60, and 10 when abasic sites replaced the - 1N, + 1T, + 2T, and + 4C bases of the scissile strand, but abasic lesions at + 5C and + 3C had little or no effect. Abasic lesions in the nonscissile strand in lieu of + 4G, + 3G, + 2A, and + 1A reduced the rate of cleavage by factors of 130, 150, 10, and 5, whereas abasic lesions at + 5G and - 1N had no effect. The striking positional asymmetry of abasic interference on the scissile and nonscissile strands highlights the importance of individual bases, not base pairs, in promoting DNA cleavage. The rate of single-turnover DNA religation by the covalent topoisomerase-DNA complex was insensitive to abasic sites within the CCCTT sequence of the scissile strand, but an abasic lesion at the 5'-OH nucleoside ( - 1N) of the attacking DNA strand slowed the rate of religation by a factor of 600. Nonscissile strand abasic lesions at + 1A and - 1N slowed the rate of religation by factors of similar to 140 and 20, respectively, and strongly skewed the cleavage-religation equilibrium toward the covalent complex. Thus, abasic lesions immediately flanking the cleavage site act as topoisomerase poisons. C1 Sloan Kettering Inst, Program Mol Biol, New York, NY 10021 USA. NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 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 37 TC 16 Z9 17 U1 1 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 SEP 17 PY 2004 VL 279 IS 38 BP 39718 EP 39726 DI 10.1074/jbc.M407376200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 852YA UT WOS:000223791500064 PM 15252055 ER PT J AU Hu, HY Horton, JK Gryk, MR Prasad, R Naron, JM Sun, DA Hecht, SM Wilson, SH Mullen, GP AF Hu, HY Horton, JK Gryk, MR Prasad, R Naron, JM Sun, DA Hecht, SM Wilson, SH Mullen, GP TI Identification of small molecule synthetic inhibitors of DNA polymerase beta by NMR chemical shift mapping SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BASE-EXCISION-REPAIR; TERMINAL 8-KDA DOMAIN; REVERSE-TRANSCRIPTASE; INDUCED CYTOTOXICITY; DAMAGING AGENTS; LYASE ACTIVITY; BINDING; SITE; CELLS; ACID AB DNA polymerase beta (beta-pol) plays a central role in repair of damaged DNA bases by base excision repair (BER) pathways. A predominant phenotype of beta-pol null mouse fibroblasts is hypersensitivity to the DNA-methylating agent methyl methanesulfonate. Residues in the 8-kDa domain of beta-pol that seem to interact with a known natural product beta-pol inhibitor, koetjapic acid, were identified by NMR chemical shift mapping. The data implicate the binding pocket as the hydrophobic cleft between helix-2 and helix-4, which provides the DNA binding and deoxyribose phosphate lyase activities of the enzyme. Nine structurally related synthetic compounds, containing aromatic or other hydrophobic groups in combination with two carboxylate groups, were then tested. They were found to bind to the same or a very similar region on the surface of the enzyme. The ability of these compounds to potentiate methyl methanesulfonate cytotoxicity, an indicator of cellular BER capacity, in wild-type and beta-pol null mouse fibroblasts, was next ascertained. The most active and beta-pol-specific of these agents, pamoic acid, was further characterized and found to be an inhibitor of the deoxyribose phosphate lyase and DNA polymerase activities of purified beta-pol on a BER substrate. Our results illustrate that NMR-based mapping techniques can be used in the design of small molecule enzyme inhibitors including those with potential use in a clinical setting. C1 Univ Connecticut, Ctr Hlth, Dept Biochem, Farmington, CT 06032 USA. Univ Connecticut, Ctr Hlth, Dept Mol Microbial & Structr Biol, Farmington, CT 06032 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Virginia, Dept Chem, Charlottesville, VA 22901 USA. Univ Virginia, Dept Biol, Charlottesville, VA 22901 USA. RP Wilson, SH (reprint author), 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU NCI NIH HHS [CA50771]; NIEHS NIH HHS [ES09847]; NIGMS NIH HHS [GM52738] NR 39 TC 68 Z9 70 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 SEP 17 PY 2004 VL 279 IS 38 BP 39736 EP 39744 DI 10.1074/jbc.M402842200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 852YA UT WOS:000223791500066 PM 15258144 ER PT J AU Aoki, K Matsumoto, S Hirayama, Y Wada, T Ozeki, Y Niki, M Domenech, P Umemori, K Yamamoto, S Mineda, A Matsumoto, M Kobayashi, K AF Aoki, K Matsumoto, S Hirayama, Y Wada, T Ozeki, Y Niki, M Domenech, P Umemori, K Yamamoto, S Mineda, A Matsumoto, M Kobayashi, K TI Extracellular mycobacterial DNA-binding protein 1 participates in mycobacterium-lung epithelial cell interaction through hyaluronic acid SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BACILLUS-CALMETTE-GUERIN; NITRIC-OXIDE SYNTHASE; HISTONE-LIKE PROTEINS; SUPEROXIDE-DISMUTASE; BACTERIAL CHROMOSOME; MURINE MACROPHAGES; CHROMATIN PROTEIN; TUBERCULOSIS; HEMAGGLUTININ; IDENTIFICATION AB Mycobacterium tuberculosis infects not only host macrophages but also nonprofessional phagocytes, such as alveolar epithelial cells. Glycosaminoglycans (GAGs) are considered as the component of mycobacterial adherence to epithelial cells. Here we show that extracellularly occurring mycobacterial DNA-binding protein 1 (MDP1) promotes mycobacterial infection to A549 human lung epithelial cells through hyaluronic acid ( HA). Both surface plasmon resonance analysis and enzyme-linked immunosorbent assay revealed that MDP1 bound to HA, heparin, and chondroitin sulfate. Utilizing synthetic peptides, we next defined heparin-binding site of 20 amino acids from 31 to 50 of MDP1, which is responsible for the specific DNA-binding site of MDP1. MDP1 bound to A549 cells, and exogenous DNA and HA interfered with the interaction. The binding was also abolished by treatment of A549 cells with hyaluronidase, suggesting that HA participates in the MDP1-A549 cell interaction. Adherence of bacillus Calmette-Guerin ( BCG) and M. tuberculosis to A549 cells was inhibited by addition of HA, DNA, and anti-MDP1 antibody, showing that MDP1 participates in the interaction between mycobacteria-alveolar epithelial cells. Simultaneous treatment of intratracheal BCG-infected mice with HA reduced the growth of BCG in vivo. Taken together, theses results suggest that HA participates in Mycobacterium-lung epithelium interaction and has potential for therapeutic and prophylactic interventions in mycobacterial infection. C1 Osaka City Univ, Grad Sch Med, Dept Host Def, Abeno Ku, Osaka 5458585, Japan. Osaka City Inst Publ Hlth & Environm Sci, Osaka 5458585, Japan. Osaka Int Coll Women, Osaka 5708555, Japan. NIAID, TB Res Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. Natl Inst Infect Dis, Dept Bacterial & Blood Prod, Musashimurayama, Tokyo 2080011, Japan. Nagasaki Univ, Grad Sch Biomed Sci, Dept Oral Histol, Nagasaki 8528588, Japan. Otsuka Pharmaceut Co Ltd, Tokushima 7710192, Japan. RP Matsumoto, S (reprint author), Osaka City Univ, Grad Sch Med, Dept Host Def, Abeno Ku, 1-4-3 Asahi Machi, Osaka 5458585, Japan. EM sohkichi@med.osaka-cu.ac.jp NR 48 TC 50 Z9 51 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 SEP 17 PY 2004 VL 279 IS 38 BP 39798 EP 39806 DI 10.1074/jbc.M402677200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 852YA UT WOS:000223791500074 PM 15234978 ER PT J AU Schwanbeck, R Xiao, H Wu, C AF Schwanbeck, R Xiao, H Wu, C TI Spatial contacts and nucleosome step movements induced by the NURF chromatin remodeling complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HISTONE OCTAMER; TRANSCRIPTION FACTOR; ANGSTROM RESOLUTION; DNA TRANSLOCATION; GENE-EXPRESSION; CORE PARTICLE; IN-VIVO; ISWI; PROTEIN; DROSOPHILA AB The nucleosome remodeling factor NURF is a four-subunit, ISWI-containing chromatin remodeling complex that catalyzes nucleosome sliding in an ATP-dependent fashion, thereby modulating the accessibility of the DNA. To elucidate the mechanism of nucleosome sliding, we have investigated by hydroxyl radical footprinting how NURF makes initial contact with a nucleosome positioned at one end of a DNA fragment. NURF binds to two separate locations on the nucleosome: a continuous stretch of linker DNA up to the nucleosome entry site and a region asymmetrically surrounding the nucleosome dyad within the minor grooves, close to residues of the histone H4 tail that have been implicated in the activation of ISWI activity. Kinetic analysis reveals that nucleosome sliding occurs in apparent increments or steps of 10 bp. Furthermore, single nucleoside gaps as well as nicks about two helical turns before the dyad interfere with sliding, indicating that structural stress at this region assists the relative movement of DNA. These findings support a sliding model in which the position-specific tethering of NURF forces a translocating ISWI ATPase to pump a DNA distortion over the histone octamer, thereby changing the translational position of the nucleosome. C1 NCI, Mol Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wu, C (reprint author), NCI, Mol Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37,Rm 6068, Bethesda, MD 20892 USA. EM carlwu@helix.nih.gov RI Schwanbeck, Ralf/A-2648-2008 OI Schwanbeck, Ralf/0000-0003-0925-929X NR 56 TC 73 Z9 74 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 SEP 17 PY 2004 VL 279 IS 38 BP 39933 EP 39941 DI 10.1074/jbc.M406060200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 852YA UT WOS:000223791500090 PM 15262970 ER PT J AU Koh, HJ Lee, SM Son, BG Lee, SH Ryoo, ZY Chang, KT Park, JW Park, DC Song, BJ Veech, RL Song, HB Huh, TL AF Koh, HJ Lee, SM Son, BG Lee, SH Ryoo, ZY Chang, KT Park, JW Park, DC Song, BJ Veech, RL Song, HB Huh, TL TI Cytosolic NADP(+)-dependent isocitrate dehydrogenase plays a key role in lipid metabolism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL-SPECIFIC EXPRESSION; PPAR-GAMMA; PHOSPHOENOLPYRUVATE CARBOXYKINASE; OXIDATIVE DAMAGE; TRANSGENIC MICE; ANIMAL TISSUES; ADIPOSE-TISSUE; C/EBP-ALPHA; ADIPOGENESIS; PATHWAY AB NADPH is an essential cofactor for many enzymatic reactions including glutathione metabolism and fat and cholesterol biosynthesis. We have reported recently an important role for mitochondrial NADP(+)-dependent isocitrate dehydrogenase in cellular defense against oxidative damage by providing NADPH needed for the regeneration of reduced glutathione. However, the role of cytosolic NADP(+)-dependent isocitrate dehydrogenase (IDPc) is still unclear. We report here for the first time that IDPc plays a critical role in fat and cholesterol biosynthesis. During differentiation of 3T3-L1 adipocytes, both IDPc enzyme activity and its protein content were increased in parallel in a time-dependent manner. Increased expression of IDPc by stable transfection of IDPc cDNA positively correlated with adipogenesis of 3T3-L1 cells, whereas decreased IDPc expression by an antisense IDPc vector retarded adipogenesis. Furthermore, transgenic mice with overexpressed IDPc exhibited fatty liver, hyperlipidemia, and obesity. In the epididymal fat pads of the transgenic mice, the expressions of adipocyte-specific genes including peroxisome proliferator-activated receptor gamma were markedly elevated. The hepatic and epididymal fat pad contents of acetylCoA and malonyl-CoA in the transgenic mice were significantly lower, whereas the total triglyceride and cholesterol contents were markedly higher in the liver and serum of transgenic mice compared with those measured in wild type mice, suggesting that the consumption rate of those lipogenic precursors needed for fat biosynthesis must be increased by elevated IDPc activity. Taken together, our findings strongly indicate that IDPc would be a major NADPH producer required for fat and cholesterol synthesis. C1 Kyungpook Natl Univ, Dept Genet Engn, Taegu 702701, South Korea. Kyungpook Natl Univ, Dept Biochem, Taegu 702701, South Korea. Catholic Univ Korea, Catholic Res Inst Med Sci, Res Inst Expt Anim, Seoul 133701, South Korea. Korea Res Inst Biosci & Biotechnol, Genet Resources Ctr, Taejon 305333, South Korea. Kyungpook Natl Univ, TG Biotech Co Ltd, Taegu, South Korea. NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. RP Huh, TL (reprint author), Kyungpook Natl Univ, Dept Genet Engn, Taegu 702701, South Korea. EM tlhuh@knu.ac.kr NR 32 TC 90 Z9 93 U1 2 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 SEP 17 PY 2004 VL 279 IS 38 BP 39968 EP 39974 DI 10.1074/jbc.M402260200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 852YA UT WOS:000223791500093 PM 15254034 ER PT J AU Boshoff, HIM Myers, TG Copp, BR McNeil, MR Wilson, MA Barry, CE AF Boshoff, HIM Myers, TG Copp, BR McNeil, MR Wilson, MA Barry, CE TI The transcriptional responses of Mycobacterium tuberculosis to inhibitors of metabolism - Novel insights into drug mechanisms of action SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GENE-EXPRESSION DATA; ESCHERICHIA-COLI; ARABINAN BIOSYNTHESIS; ETHAMBUTOL; SMEGMATIS; RESISTANCE; OXIDASE; GROWTH; TARGET; POLYPHOSPHATE AB The differential transcriptional response of Mycobacterium tuberculosis to drugs and growth-inhibitory conditions was monitored to generate a data set of 430 microarray profiles. Unbiased grouping of these profiles independently clustered agents of known mechanism of action accurately and was successful at predicting the mechanism of action of several unknown agents. These predictions were validated biochemically for two agents of previously uncategorized mechanism, pyridoacridones and phenothiazines. Analysis of this data set further revealed 150 underlying clusters of coordinately regulated genes offering the first glimpse at the full metabolic potential of this organism. A signature subset of these gene clusters was sufficient to classify all known agents as to mechanism of action. Transcriptional profiling of both crude and purified natural products can provide critical information on both mechanism and detoxification prior to purification that can be used to guide the drug discovery process. Thus, the transcriptional profile generated by a crude marine natural product recapitulated the mechanistic prediction from the pure active component. The underlying gene clusters further provide fundamental insights into the metabolic response of bacteria to drug-induced stress and provide a rational basis for the selection of critical metabolic targets for screening for new agents with improved activity against this important human pathogen. C1 NIAID, TB Res Sect, NIH, Rockville, MD 20852 USA. NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. Univ Auckland, Dept Chem, Auckland 1020, New Zealand. Colorado State Univ, Dept Microbiol, Ft Collins, CO 80523 USA. RP Boshoff, HIM (reprint author), Twinbrook 2,Rm 239,12441 Parklawn Dr, Rockville, MD 20852 USA. EM HBOSHOFF@niaid.nih.gov RI Copp, Brent/D-3706-2009; Barry, III, Clifton/H-3839-2012 OI Copp, Brent/0000-0001-5492-5269; FU Intramural NIH HHS [Z01 AI000783-11] NR 54 TC 323 Z9 336 U1 4 U2 36 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 SEP 17 PY 2004 VL 279 IS 38 BP 40174 EP 40184 DI 10.1074/jbc.M406796200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 852YA UT WOS:000223791500116 PM 15247240 ER PT J AU Tian, GL Zhang, U Zhang, TY Yang, FQ Ito, Y AF Tian, GL Zhang, U Zhang, TY Yang, FQ Ito, Y TI Separation of flavonoids from the seeds of Vernonia anthelmintica Willd by high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Vernonia anthelmintica Willd; 2 ',3,4,4 '-tetrahydroxychalcone; 5,6,7,4 '-tetrahydroxyflavone; butin ID PURIFICATION; EXTRACT AB Several flavonoids including 2',3,4,4'-tetrahydroxychalcone, 5,6,7,4'-tetrahydroxyflavone and butin, were separated from the seeds of Vernonia anthelinintica Willd by high-speed counter-current chromatography using a two-step operation. Two different types of solvent systems were used: chloroform-dichloromethane-in ethanol-water (2:2:3:2, v/v) and 1,2 dichloroethane-methanol-acetonitrile-water (4:1.1:0.25:2, v/v). From I kg of seeds of Vernonia anthelmintica Willd the method yielded about 45 mg of 2',3,4,4'-tetrahydroxychalcone, 40 mg of 5,6,7,4'-tetrahydroxyflavone, and 55 mg of butin. Each isolated component showed 95-97% purity as determined by high-performance liquid chromatography analysis. These purified compounds were characterized by MS and NMR. (C) 2004 Elsevier B.V. All rights reserved. C1 NIH, Lab Biophys Chem Heart Lung & Blood Inst, Bethesda, MD 20892 USA. Beijing Inst New Technol Applicat, Beijing 100035, Peoples R China. RP Ito, Y (reprint author), NIH, Lab Biophys Chem Heart Lung & Blood Inst, Bldg 50,Room 3334,South Dr MSC 8014, Bethesda, MD 20892 USA. EM itoy@nhlbi.nih.gov NR 10 TC 34 Z9 42 U1 2 U2 11 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 SEP 17 PY 2004 VL 1049 IS 1-2 BP 219 EP 222 DI 10.1016/j.chroma.2004.07.072 PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 858BO UT WOS:000224165300026 PM 15499936 ER PT J AU George, SL Freidlin, B Korn, EL AF George, SL Freidlin, B Korn, EL TI Strength of accumulating evidence and data monitoring committee decision making SO STATISTICS IN MEDICINE LA English DT Article DE decision making; data monitoring committees; likelihood principle AB The data monitoring committee (DMC) is a vital component of a randomized clinical trial. Its responsibilities include stopping the trial early for extreme results. The decision to stop the trial must be based on a careful synthesis of statistical methodology and clinical judgment. It is critical to ensure the validity of this complex process. In this paper we present results of a survey of 21 DMC members conducted to investigate how they evaluate accumulating evidence. The results indicate that some DMC members may be over-interpreting developing trends in the data. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Duke Univ, Ctr Med, Duke Comprehens Canc Ctr, Dept Biostat & Bioinformat, Durham, NC 27710 USA. NCI, Div Canc Treatment & Diagnost, Biometr Res Branch, Bethesda, MD 20892 USA. RP George, SL (reprint author), Duke Univ, Ctr Med, Duke Comprehens Canc Ctr, Dept Biostat & Bioinformat, Box 3958, Durham, NC 27710 USA. EM stephen.george@duke.edu NR 3 TC 1 Z9 1 U1 0 U2 0 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 SEP 17 PY 2004 VL 23 IS 17 BP 2659 EP 2672 DI 10.1002/sim.1859 PG 14 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 849GB UT WOS:000223525600003 PM 15316949 ER PT J AU De Angelis, C Drazen, JM Frizelle, FA Haug, C Hoey, J Horton, R Kotzin, S Laine, C Marusic, A Overbeke, AJPM Schroeder, TV Sox, HC Van der Weyden, MB AF De Angelis, C Drazen, JM Frizelle, FA Haug, C Hoey, J Horton, R Kotzin, S Laine, C Marusic, A Overbeke, AJPM Schroeder, TV Sox, HC Van der Weyden, MB TI Clinical trial registration: A statement from the International Committee of Medical Journal Editors SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 Natl Lib Med, Bethesda, MD 20894 USA. RI Marusic, Ana/E-7683-2013; OI Marusic, Ana/0000-0001-6272-0917; Schroeder, Torben/0000-0002-9827-9438 NR 0 TC 350 Z9 361 U1 1 U2 11 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 SEP 16 PY 2004 VL 351 IS 12 BP 1250 EP 1251 DI 10.1056/NEJMe048225 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 853WS UT WOS:000223861300015 PM 15356289 ER PT J AU Davies, GC Ettenberg, SA Coats, AO Mussante, M Ravichandran, S Collins, J Nau, MM Lipkowitz, S AF Davies, GC Ettenberg, SA Coats, AO Mussante, M Ravichandran, S Collins, J Nau, MM Lipkowitz, S TI Cbl-b interacts with ubiquitinated proteins; differential functions of the UBA domains of c-Cbl and Cbl-b SO ONCOGENE LA English DT Article DE Cbl proteins; ubiquitin associated (UBA) domain; ubiquitin ID GROWTH-FACTOR RECEPTOR; DAMAGE-INDUCIBLE PROTEINS; T-CELL-ACTIVATION; CUE DOMAIN; TYROSINE PHOSPHORYLATION; BINDING-PROTEIN; RING FINGER; HIV-1 VPR; V-CBL; PROTEASOME AB Cbl proteins are ubiquitin protein ligases, which ubiquitinate activated tyrosine kinases and target them for degradation. Both c-Cbl and Cbl-b have an ubiquitin associated (UBA) domain at their C-terminal end. We observed that high molecular weight ubiquitinated proteins constitutively coimmunoprecipitated with transfected and endogenous Cbl-b, but not c-Cbl. The binding site for these ubiquitinated proteins was mapped to the UBA domain of Cbl-b (UBAb). GST-fusion proteins containing the UBAb interacted with ubiquitinated proteins and polyubiquitin chains in vitro, whereas those containing the UBA domain of c-Cbl (UBA(c)) did not. The UBAb had a much greater affinity for polyubiquitin chains than for monoubiquitin. Analysis of the UBA(b) and UBA(c) demonstrate that the affinity for ubiquitin is determined by multiple amino-acid differences between the two domains. Overexpression of the UBA(b), but not overexpression of the UBA(c), inhibited a variety of ubiquitin-mediated processes such as degradation of ubiquitinated proteins (i.e. EGFR, Mdm-2, and Siah-1). This in vivo result is consistent with the differences in ubiquitin binding observed in vitro between the UBA(b) and UBA(c). This difference in ubiquitin-binding may reflect distinct regulatory functions of c-Cbl and Cbl-b. C1 NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Adv Biomed Comp Ctr, NIH, Bethesda, MD 20892 USA. RP Lipkowitz, S (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37,Rm 2066, Bethesda, MD 20892 USA. EM lipkowitz@nih.gov NR 60 TC 58 Z9 60 U1 1 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 SEP 16 PY 2004 VL 23 IS 42 BP 7104 EP 7115 DI 10.1038/sj.onc.1207952 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 854EX UT WOS:000223885100011 PM 15273720 ER PT J AU Hardy, J AF Hardy, J TI The genetics of Alzheimer's disease and other dementias SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 NIA, Neurogenet Lab, 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 4 EP 4 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600008 ER PT J AU Merikangas, K AF Merikangas, K TI The design of genetic epidemiology studies SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 NIMH, Sect Dev Genet Epidemiol, 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 4 EP 4 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600009 ER PT J AU Hardy, J AF Hardy, J TI Genetic dissection of the etiologies and pathogeneses of Alzheimer's and Parkinson's diseases and related disorders SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 NIH, 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 5 EP 6 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600017 ER PT J AU Straub, R AF Straub, R TI Dysbindin-haplotypes, intermediate phenotypes and dysregulation of transcript and protein expression SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 6 EP 7 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600023 ER PT J AU Weinberger, DR Callicott, JH Pezawas, L Egan, MF Hariri, AR Mattay, VS Goldberg, TE Verchinski, BA Straub, RS AF Weinberger, DR Callicott, JH Pezawas, L Egan, MF Hariri, AR Mattay, VS Goldberg, TE Verchinski, BA Straub, RS TI Variation in DISC1 affects hippocampal structure and function and risk for schizophrenia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 NIH, Bethesda, MD 20892 USA. RI Hariri, Ahmad/D-5761-2011 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 7 EP 7 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600024 ER PT J AU Bocklandt, S Roselli, CE DuPree, M Vilain, E Hamer, DH AF Bocklandt, S Roselli, CE DuPree, M Vilain, E Hamer, DH TI A role for genomic imprinting in male sexual orientation SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA USA. Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR USA. NCI, Biochem Lab, 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 9 EP 9 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600034 ER PT J AU McMahon, FJ Austin, L Steele, CJM Foroud, T Meyer, ET AF McMahon, FJ Austin, L Steele, CJM Foroud, T Meyer, ET TI Genome-wide genetic linkage analysis of the NIMH Genetics Initiative "Wave 4" Bipolar Disorder pedigrees SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 NIMH, Bethesda, MD 20892 USA. Indiana Univ, Indianapolis, IN 46204 USA. Univ Chicago, Chicago, IL 60637 USA. Johns Hopkins, Baltimore, MD USA. Univ Iowa, Iowa City, IA 52242 USA. Univ Penn, Philadelphia, PA 19104 USA. Washington Univ, St Louis, MO 63130 USA. RI McMahon, Francis/A-7290-2009; Meyer, Eric/C-1029-2011 OI Meyer, Eric/0000-0002-1998-7162 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 11 EP 11 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600044 ER PT J AU Schulze, TT Ohlraun, S DePaulo, JR Maier, W Rietschel, M McMahon, FJ AF Schulze, TT Ohlraun, S DePaulo, JR Maier, W Rietschel, M McMahon, FJ TI What is familial about familial bipolar disorder, part II: Psychosocial functioning and comorbid conditions are at least as familial as clinical features SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 Cent Inst Mental Hlth, Div Genet Epidemiol, D-6800 Mannheim, Germany. NIMH, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. RI McMahon, Francis/A-7290-2009 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 13 EP 14 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600053 ER PT J AU Myers, AJ Pittman, A Duckworth, J Fung, P Evans, J Evans, W Bryden, L Hanson, M Abou-Sleiman, P Wood, NW Lees, A de Silva, R Hardy, JA AF Myers, AJ Pittman, A Duckworth, J Fung, P Evans, J Evans, W Bryden, L Hanson, M Abou-Sleiman, P Wood, NW Lees, A de Silva, R Hardy, JA TI Investigation of the microtubule associated protein tau locus SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. UCL, Reta Lila Weston Inst Neurol Studies, London, England. Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. RI de Silva, Rohan/C-1734-2008; Myers, Amanda/B-1796-2010; Pittman, Alan/D-6231-2012; Lees, Andrew/A-6605-2009 OI de Silva, Rohan/0000-0002-5052-5775; Myers, Amanda/0000-0002-3100-9396; NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 16 EP 16 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600062 ER PT J AU Malhotra, AK Lipsky, R Burdick, KE Bilder, RM Goldman, D Szeszko, PR AF Malhotra, AK Lipsky, R Burdick, KE Bilder, RM Goldman, D Szeszko, PR TI New evidence for a role of BDNF genotype on human hippocampal structure and function SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 Zucker Hillside Hosp, Glen Oaks, NY USA. NIAAA, Bethesda, MD USA. RI Bilder, Robert/A-8894-2008 OI Bilder, Robert/0000-0001-5085-7852 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 25 EP 25 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600094 ER PT J AU Potash, JB Buervenich, S Rathe, JA Steele, CJM Akula, N Detera-Wadleigh, SD Gershon, ES DePaulo, JR Feinberg, AP McMahon, FJ AF Potash, JB Buervenich, S Rathe, JA Steele, CJM Akula, N Detera-Wadleigh, SD Gershon, ES DePaulo, JR Feinberg, AP McMahon, FJ TI Gene-based SNP mapping of a psychotic bipolar disorder linkage region on 22q12.3 implicates a large haplotype block including HMG2L1 and TOM1 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 Johns Hopkins Sch Med, Baltimore, MD USA. NIMH, Bethesda, MD 20892 USA. Univ Chicago, Chicago, IL 60637 USA. RI McMahon, Francis/A-7290-2009 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 27 EP 28 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600103 ER PT J AU Ohlraun, S Schulze, TG Czerski, PM Schumacher, J Kassem, L Deschner, M Gross, M Tullius, M Heidmann, V Kovalenko, S Abou Jamra, R Becker, T Leszczynska-Rodziewicz, A Hauser, J Illig, T Klopp, N Wellek, S Cichon, S Henn, FA McMahon, FJ Maier, W Propping, P Noethen, MM Rietschel, M AF Ohlraun, S Schulze, TG Czerski, PM Schumacher, J Kassem, L Deschner, M Gross, M Tullius, M Heidmann, V Kovalenko, S Abou Jamra, R Becker, T Leszczynska-Rodziewicz, A Hauser, J Illig, T Klopp, N Wellek, S Cichon, S Henn, FA McMahon, FJ Maier, W Propping, P Noethen, MM Rietschel, M TI Are bipolar patients with and without persecutory delusions genetically distinct? Results from a phenotype-genotype correlation analysis on the G72/G30 locus SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 Cent Inst Mental Hlth, Div Genet Epidemiol Psychiat, D-6800 Mannheim, Germany. Univ Bonn, Dept Psychiat, D-5300 Bonn, Germany. NIMH, Mood & Anxiety Disorders Program, Genet Unit, Bethesda, MD 20892 USA. Poznan Univ Med Sci, Dept Adult Psychiat, Poznan, Poland. Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. Univ Bonn, Inst Biometry Informat & Epidemiol, D-5300 Bonn, Germany. GSF Natl Res Ctr Environm & Hlth, Inst Epidemiol, Neuherberg, Germany. Cent Inst Mental Hlth, Div Biostat, D-6800 Mannheim, Germany. RI McMahon, Francis/A-7290-2009; Czerski, Piotr/B-8446-2011; Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Abou Jamra, Rami/I-4805-2015 OI Czerski, Piotr/0000-0003-0745-5916; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Abou Jamra, Rami/0000-0002-1542-1399 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 28 EP 28 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600104 ER PT J AU Schulze, TG Xu, W DePaulo, JR McMahon, FJ Greenwood, C AF Schulze, TG Xu, W DePaulo, JR McMahon, FJ Greenwood, C TI Recursive partitioning: A data mining strategy to detect genotype-phenotype correlations in linkage samples SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 Univ Heidelberg, Cent Inst Mental Hlth, Div Genet Epidemiol, D-6800 Mannheim, Germany. NIMH, NIH, Bethesda, MD 20892 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Johns Hopkins Univ, Dept Psychiat, Baltimore, MD USA. RI McMahon, Francis/A-7290-2009; Schulze, Thomas/H-2157-2013 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 30 EP 31 PG 2 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600114 ER PT J AU Low, NCP Angst, J Cui, L Merikangas, KR AF Low, NCP Angst, J Cui, L Merikangas, KR TI Patterns of comorbidity of migraine and mental disorders SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 NIMH, Bethesda, MD 20892 USA. Univ Zurich, Zurich, Switzerland. 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 39 EP 39 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600144 ER PT J AU Greenwood, TA Schork, NJ Dick, DM Reich, T Foroud, T Nurnberger, JI Berrettini, W Byerley, W Coryell, W DePaulo, R McInnis, M Gershon, ES McMahon, FJ Scheftner, W Kelsoe, JR AF Greenwood, TA Schork, NJ Dick, DM Reich, T Foroud, T Nurnberger, JI Berrettini, W Byerley, W Coryell, W DePaulo, R McInnis, M Gershon, ES McMahon, FJ Scheftner, W Kelsoe, JR TI Linkage heterogeneity and marker informativity analysis of the NIMH bipolar families from waves 3 and 4 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 Univ Calif San Diego, La Jolla, CA 92093 USA. Washington Univ, St Louis, MO USA. Indiana Univ, Indianapolis, IN 46204 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Calif Irvine, Irvine, CA USA. Univ Iowa, Iowa City, IA USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Chicago, Chicago, IL 60637 USA. NIMH, Mood & Anxiety Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. Rush Presbyterian Med Ctr, Chicago, IL USA. RI McMahon, Francis/A-7290-2009 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 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 47 EP 47 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600175 ER PT J AU Lipsky, RH Jiang, X Hobermann, J Waheed, JF Harris, CR Marini, AM Xu, K Enoch, MA AF Lipsky, RH Jiang, X Hobermann, J Waheed, JF Harris, CR Marini, AM Xu, K Enoch, MA TI BDNF and mood disorders: A novel functional promoter polymorphism and Val66Met are associated with anxiety but have opposing effects SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 NIAAA, NIH, Rockville, MD 20852 USA. USUHS, 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 66 EP 66 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600253 ER PT J AU Arnold, PD Summerfeldt, LJ Sicard, T Geronimo, J Trakalo, J Zai, G Hu, X Goldman, D Hanna, GL Pato, M Richter, MA Kennedy, JL AF Arnold, PD Summerfeldt, LJ Sicard, T Geronimo, J Trakalo, J Zai, G Hu, X Goldman, D Hanna, GL Pato, M Richter, MA Kennedy, JL TI A family-based association study of novel serotonin polymorphisms in OCD and OCD symptom subgroups SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 Ctr Addict & Mental Hlth, Toronto, ON, Canada. Trent Univ, Peterborough, ON K9J 7B8, Canada. NIAAA, NIH, Rockville, MD 20852 USA. Univ Michigan, Ann Arbor, MI 48109 USA. Vet Affairs Med Ctr, Washington, DC 20422 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 69 EP 69 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600265 ER PT J AU Yamada, K Detera-Wadleigh, SD Iwayama-Shigeno, Y Takao, H Toyota, T Hattori, E Yoshikawa, T AF Yamada, K Detera-Wadleigh, SD Iwayama-Shigeno, Y Takao, H Toyota, T Hattori, E Yoshikawa, T TI Confirmation of association at the MRDS1 (OFCC1) locus in Japanese schizophrenia samples SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 RIKEN, Brain Sci Inst, Lab Mol Psychiat, Wako, Saitama 35101, Japan. NIMH, Mood & Anxiety Disorders Program, 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 82 EP 82 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600316 ER PT J AU Gornick, MC AF Gornick, MC TI Dysbindin (DTNBP1, 6p22.3) is associated with childhood onset psychosis and endophenotypes measured by the premorbid adjustment scale (PAS) SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 NIMH, NIH, Child Psychiat 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 106 EP 106 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600405 ER PT J AU Low, N Angst, J Cui, L Merikangas, KR AF Low, N Angst, J Cui, L Merikangas, KR TI Patterns of comorbidity of migraine and mental disorders SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 NIMH, Bethesda, MD 20892 USA. Univ Zurich, Zurich, Switzerland. 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 120 EP 120 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600459 ER PT J AU Egan, MF Cheng, J Kolachana, BS Straub, RE Kleinman, JE Weinberger, DR AF Egan, MF Cheng, J Kolachana, BS Straub, RE Kleinman, JE Weinberger, DR TI COMT: Evidence that val158met is the functional variant affecting risk for schizophrenia SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 NIMH, 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 140 EP 140 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600537 ER PT J AU Talkowski, M Bassett, AS Brzustowicz, LM Chen, X Chowdari, KV Collier, DA Cordeiro, Q Corvin, AP Deshpande, S Egan, MF Gill, M Kendler, KS Kirov, G Levitt, P Lewis, DA Li Mirnics, K Morris, DW O'Donovan, MC Owen, MJ Seltman, H Semwall, P Sobell, JL Thelma, BK Weinberger, DR Williams, NM Wood, J Nimgaonkar, VL AF Talkowski, M Bassett, AS Brzustowicz, LM Chen, X Chowdari, KV Collier, DA Cordeiro, Q Corvin, AP Deshpande, S Egan, MF Gill, M Kendler, KS Kirov, G Levitt, P Lewis, DA Li Mirnics, K Morris, DW O'Donovan, MC Owen, MJ Seltman, H Semwall, P Sobell, JL Thelma, BK Weinberger, DR Williams, NM Wood, J Nimgaonkar, VL TI Evaluating an association of RGS4 polymorphisms with schizophrenia: Mega-analysis of over 12,000 individuals from 11 international sites SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 Univ Pittsburgh, Pittsburgh, PA USA. Carnegie Mellon Univ, Pittsburgh, PA 15213 USA. Univ Wales Coll Med, Cardiff CF4 4XN, S Glam, Wales. Trinity Coll Dublin, Dublin, Ireland. Virginia Commonwealth Univ, Richmond, VA USA. Univ Sao Paulo, Sao Paulo, Brazil. Dr RML Hosp, New Delhi, India. Univ Delhi, New Delhi, India. Rutgers State Univ, Newark, NJ 07102 USA. Univ Toronto, Toronto, ON, Canada. Univ So Calif, Los Angeles, CA USA. Inst Psychiat, London, England. NIMH, Bethesda, MD 20892 USA. Vanderbilt Univ, Nashville, TN USA. RI Mirnics, Karoly/E-6730-2010 OI Mirnics, Karoly/0000-0002-5521-0254 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 142 EP 142 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600545 ER PT J AU McDonald, MP Siesser, WB Cheng, SY AF McDonald, MP Siesser, WB Cheng, SY TI Transgenic mice expressing a human mutant beta 1 thyroid receptor are hyperactive, impulsive, and inattentive SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 Vanderbilt Univ, Med Ctr, Nashville, TN USA. NCI, 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 150 EP 150 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600578 ER PT J AU Siesser, WB Cheng, SY McDonald, MP AF Siesser, WB Cheng, SY McDonald, MP TI Hyperactivity, impaired learning, and an abnormal response to methylphenidate in mice with a mutation in the thyroid receptor beta gene SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Meeting Abstract CT 12th World Congress of Psychiatric Genetics CY OCT 09-13, 2004 CL Dublin, IRELAND SP Int Soc Psychiat Genet C1 Vanderbilt Univ, Nashville, TN USA. NCI, 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 0148-7299 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 15 PY 2004 VL 130B IS 1 BP 150 EP 150 PG 1 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 852GE UT WOS:000223742600577 ER PT J AU Busse, W Banks-Schlegel, S Noel, P Ortega, H Taggart, V Elias, L AF Busse, W Banks-Schlegel, S Noel, P Ortega, H Taggart, V Elias, L TI Future research directions in asthma - An NHLBI working group report SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE airway lung disease; asthma; innate immunity; asthma genetics; asthma exacerbations ID ENDOTHELIAL GROWTH-FACTOR; REGULATORY T-CELLS; BRONCHIAL-ASTHMA; BETA(2)-ADRENERGIC RECEPTOR; CHILDHOOD ASTHMA; SMOOTH-MUSCLE; LUNG-FUNCTION; AIRWAY; EXPOSURE; CHILDREN AB Over the last 20 years, the prevalence of asthma has nearly doubled and now affects 8-10% of the population in the United States. Asthma also remains a major illness in terms of morbidity and suffering, and is the leading cause of hospitalizations in children under 15 years of age. Because asthma poses a lifelong burden to patients and society, efforts to increase the understanding of its pathogenesis are a key factor leading to its control and cure. Consequently, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of extramural experts, entitled "Future Research Directions in Asthma," on April 9-10, 2003, to identify research areas of greatest promise and opportunity in the field of asthma. The priority areas identified for research in asthma include: (1) innate immunity, adaptive immunity, and tolerance; (2) mechanisms and consequences of persistent asthma and asthma exacerbations; (3) airway remodeling: clinical consequences and reversibility (clinical relevance and resolution); (4) genetics/gene-enviromment interactions, pharmacogenetics; (5) intervention/prevention/therapeutics; and (6) vascular basis of asthma. C1 NHLBI, DLD, Bethesda, MD 20892 USA. Univ Wisconsin Hosp & Clin, Dept Med, Madison, WI 53792 USA. Yale Univ, Dept Internal Med, New Haven, CT USA. RP Banks-Schlegel, S (reprint author), NHLBI, DLD, 2 Rockledge Ctr,Room 10018,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM Schleges@nih.gov NR 49 TC 55 Z9 58 U1 2 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 15 PY 2004 VL 170 IS 6 BP 683 EP 690 DI 10.1164/rccm.200311-1539WS PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 853BJ UT WOS:000223800900018 PM 15215155 ER PT J AU Ajiro, K Th'ng, J Yau, J Nishi, Y AF Ajiro, K Th'ng, J Yau, J Nishi, Y TI Isolation and characterization of mammalian cells that are undergoing apoptosis by a bovine serum albumin density gradient SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID CASPASE-ACTIVATED DNASE; HL-60 CELLS; SIGNAL-TRANSDUCTION; FLOW-CYTOMETRY; HISTONE H2B; PHOSPHORYLATION; FRAGMENTATION; DEATH; ENDONUCLEASE; THYMOCYTES AB When cells are treated with cytotoxic agents, they enter apoptosis asynchronously to yield cells at various stages of cellular deterioration. This mixture makes it difficult to Study the biochemical pathways leading to cell death. We have fractionated apoptotic mammalian cells in a simple discontinuous bovine serum albumin (BSA) density gradient centrifugation into five layers, each containing cells at different stages of apoptosis, (1) nonapoptotic, (2) undergoing apoptosis, and (3) mature apoptotic cells, as judged by light and electron microscopy of chromatin condensation and by the extent of DNA fragmentation. Modifications of apoptosis markers including c-Jun N-terminal kinase/stress-activated protein kinase and procaspase 3 cleavage were apparent in those cells that are undergoing apoptosis. Apoptosis-specific histone H2B phosphorylation was highly elevated and DNA fragmentation activity in the cytoplasm was observed in those cells that are undergoing apoptosis, but not much was observed in the cells of other fractions. Results show that apoptotic cells can be fractionated easily by the BSA gradient method, and this method will be invaluable for studying the biochemical processes that drive apoptosis. (C) 2004 Elsevier Inc. All rights reserved. C1 Aichi Canc Ctr, Res Inst, Cell Biol Lab, Nagoya, Aichi 4648681, Japan. Aichi Canc Ctr, Res Inst, Biophys Lab, Nagoya, Aichi 4648681, Japan. NW Ontario Reg Canc Ctr, Res Lab, Thunder Bay, ON P7A 7T1, Canada. RP Ajiro, K (reprint author), NIEHS, Lab Signal Transduct, 111 Alexander Dr,MD F3-07,Room F347, Res Triangle Pk, NC 27709 USA. EM ajiro@niehs.nih.gov NR 45 TC 2 Z9 2 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 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 15 PY 2004 VL 332 IS 2 BP 226 EP 233 DI 10.1016/j.ab.2004.05.035 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 850II UT WOS:000223604100003 PM 15325289 ER PT J AU Nikolovska-Coleska, Z Wang, RX Fang, XL Pan, HG Tomita, Y Li, P Roller, PP Krajewski, K Saito, NG Stuckey, JA Wang, SM AF Nikolovska-Coleska, Z Wang, RX Fang, XL Pan, HG Tomita, Y Li, P Roller, PP Krajewski, K Saito, NG Stuckey, JA Wang, SM TI Development and optimization of a binding assay for the XIAP BIR3 domain using fluorescence polarization SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE apoptosis; XIAP; Smac/DIABLO; fluorescence polarization assay; high-throughput screening; Cheng-Prusoff equation; mathematical model; K-i calculation ID X-LINKED INHIBITOR; APOPTOSIS PROTEIN XIAP; STRUCTURAL BASIS; CANCER CELLS; SMAC/DIABLO; IAP; DEATH; ACTIVATION; CASPASES; LIGAND AB The X-linked inhibitor of apoptosis protein (XIAP) is a potent cellular inhibitor of apoptosis. Designing small-molecule inhibitors that target the BIR3 domain of XIAP, where Smac/DIABLO (second mitochondria-derived activator of caspase/direct IAP-binding protein with low pI) and caspase-9 bind, is a promising strategy for inhibiting the antiapoptotic activity of XIAP and for overcoming apoptosis resistance of cancer cells mediated by XIAP. Herein, we report the development of a homogeneous high-throughput assay based on fluorescence polarization for measuring the binding affinities of small-molecule inhibitors to the BIR3 domain of XIAP. Among four fluorescent probes tested, a initiated N-terminal Smac peptide (AbuRPFK-(5-Fam)-NH2) showed the highest affinity (K-d = 17.92 nM) and a large dynamic range (DeltamP = 231 +/- 0.9), and was selected as the most suitable probe for the binding assay. The binding conditions (DMSO tolerance and stability) have been investigated. Under optimized conditions, a Z' factor of 0.88 was achieved in a 96-well format for high-throughput screening. It was found that the popular Cheng-Prusoff equation is invalid for the calculation of the competitive inhibition constants (K-i values) for inhibitors in the FP-based competitive binding assay conditions.. and accordingly, a new mathematical equation was developed, validated, and used to compute the Ki values. An associated Web-based computer program was also developed for this task. Several known Smac peptides with high and low affinities have been evaluated under the assay conditions and the results obtained indicated that the FP-based competitive binding assay performs correctly as designed: it can quantitatively and accurately determine the binding affinities of Smac-based peptide inhibitors with a wide range of affinities, and is suitable for high-throughput screening of inhibitors binding to the XIAP BIR3 domain. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Michigan, Dept Internal Med, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Med Chem, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20057 USA. NCI, Frederick Canc Res & Dev Ctr, Med Chem Lab, Frederick, MD 21702 USA. Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. RP Wang, SM (reprint author), Univ Michigan, Dept Internal Med, Ctr Comprehens Canc, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM shaomeng@umich.edu NR 40 TC 201 Z9 203 U1 5 U2 21 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 15 PY 2004 VL 332 IS 2 BP 261 EP 273 DI 10.1016/j.ab.2004.05.055 PG 13 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 850II UT WOS:000223604100008 PM 15325294 ER PT J AU Kim, YJ Pannell, LK Sackett, DL AF Kim, YJ Pannell, LK Sackett, DL TI Mass spectrometric measurement of differential reactivity of cysteine to localize protein-ligand binding sites. Application to tubulin-binding drugs SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE cysteine; reactivity; drug binding; tubulin; mass spectrometry; HPLC-MS HPLC-MS/MS; monobromobimane; alkylation; T138067; colchicine; podophyllotoxin ID BETA-TUBULIN; COLCHICINE-BINDING; TUMOR-GROWTH; IN-VIVO; IDENTIFICATION; MICROTUBULE; PODOPHYLLOTOXIN; T138067; RESIDUE; AGENTS AB A new method for localizing binding sites of noncovalent drugs on proteins is presented. We have developed an accurate and high-throughput method based on the mass spectrometric measurement of differential reaction yield of cysteine alkylation (MS-DRC). This method, essentially a semi quantitative footprinting approach, is applicable to any type of ligand targeting cysteine-rich proteins because the method measures the reactivity change of each cysteine toward an alkylating agent instead of monitoring the drug itself. Thus, no modification of the drug is needed. In this study, the method is evaluated using tubulin as a model system. Tubulin and drug-treated tubulin were alkylated separately with several alkylating reagents, followed by proteolysis and high-performance liquid chromatography (HPLC)-tandem mass spectrometry (MS/MS) and HPLC-MS. Relative alkylation yields of each cysteine toward the reagents were measured by mass spectrometric quantitation. The reaction yields of each cysteine of two samples were compared to detect a particular cysteine (or cysteines) for which reaction yield was markedly decreased following drug binding. Monobromobimane (mBrB) showed the highest differential. Thus, the MS-DRC method with mBrB was evaluated with various tubulin agents, including the covalent agent T138067 and the noncovalent agents colchicine, podophyllotoxin, and 2-methoxyestradiol. Conformational changes induced by drug binding, as well as sites of direct binding, may be identified. Published by Elsevier Inc. C1 NICHHD, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDDKD, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Sackett, DL (reprint author), NICHHD, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM sackettd@mail.nih.gov NR 33 TC 18 Z9 19 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 15 PY 2004 VL 332 IS 2 BP 376 EP 383 DI 10.1016/j.ab.2004.06.033 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 850II UT WOS:000223604100021 PM 15325307 ER PT J AU Ciruela, F Burgueno, J Casado, V Canals, M Marcellino, D Goldberg, SR Bader, M Fuxe, K Agnati, LF Lluis, C Franco, R Ferre, S Woods, AS AF Ciruela, F Burgueno, J Casado, V Canals, M Marcellino, D Goldberg, SR Bader, M Fuxe, K Agnati, LF Lluis, C Franco, R Ferre, S Woods, AS TI Combining mass spectrometry and pull-down techniques for the study of receptor heteromerization. Direct epitope-epitope electrostatic interactions between adenosine A(2A) and dopamine D-2 receptors SO ANALYTICAL CHEMISTRY LA English DT Article ID METABOTROPIC GLUTAMATE RECEPTORS; BIOLUMINESCENCE ENERGY-TRANSFER; PROTEIN-COUPLED RECEPTORS; QUANTITATIVE ASSESSMENT; BINDING CHARACTERISTICS; MGLU5 RECEPTORS; HIGH-AFFINITY; RAT STRIATUM; DIMERIZATION; D2 AB Previous results from FRET and BRET experiments and computational analysis (docking simulations) have suggested that a portion of the third intracellular loop (13) of the human dopamine D-2 receptor (D2R) and the C-tail from the human adenosine A(2A) receptor (A(2A)R) are involved in A(2A)R-D2R heteromerization. The results of the present studies, using pull-down and mass spectrometry experiments, suggest that A(2A)R-D2R heteromerization depends on an electrostatic interaction between an Arg-rich epitope from the I3 of the D2R (217RRRRKR222) and two adjacent Asp residues (DD401-402) or a phosphorylated Ser (S-374) residue in the C-tail of the A(2A)R. A GST-fusion protein containing the C-terminal domain of the A(2A)R (GST-A2A(CT)) was able to pull down the whole D2R solubilized from D2R-tranfected HEK-293 cells. Second, a peptide corresponding to the Arg-rich 13 region of the D2R (215VLRRRRKRVN224) and bound to Sepharose was able to pull down both GST-A2A(CT) and the whole A(2A)R solubilized from A(2A)R-tranfected HEK-293 cells. Finally, mass spectometry and pull-down data showed that the Arg-rich D2R epitope binds to two different epitopes from the C-terminal part of the A(2A)R, containing the two adjacent Asp residues or the phosphorylated Ser residue ((388)HELKGVCPEPPGLDDPLAQDGAVGS(412) and (370)SAQ-EpSQGNT(378)). The present results are the first example of epitope-epitope electrostatic interaction underlying receptor heteromerization, a new, expanding area of protein-protein interactions. C1 Natl Inst Drug Abuse, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. Univ Barcelona, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain. Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. Karolinska Inst, Dept Neurosci, Div Cellular & Mol Neurochem, S-17177 Stockholm, Sweden. Univ Modena, Dept Biomed Sci, Physiol Sect, I-41100 Modena, Italy. RP Woods, AS (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov RI Ferre, Sergi/K-6115-2014; Ciruela, Francisco/A-5096-2013; Franco, Rafael/C-3694-2015; Casado, Vicent/K-1660-2014; OI Ferre, Sergi/0000-0002-1747-1779; Ciruela, Francisco/0000-0003-0832-3739; Franco, Rafael/0000-0003-2549-4919; Marcellino, Daniel/0000-0002-4618-7267; Canals, Meritxell/0000-0002-7942-5006; Casado, Vicent/0000-0002-1764-3825; Bader, Michael/0000-0003-4780-4164 NR 29 TC 140 Z9 141 U1 0 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD SEP 15 PY 2004 VL 76 IS 18 BP 5354 EP 5363 DI 10.1021/ac049295f PG 10 WC Chemistry, Analytical SC Chemistry GA 854UL UT WOS:000223928800014 PM 15362892 ER PT J AU Jin, CZ Nagasawa, H Shimamura, M Uto, Y Inayama, S Takeuchi, Y Kirk, KL Hori, H AF Jin, CZ Nagasawa, H Shimamura, M Uto, Y Inayama, S Takeuchi, Y Kirk, KL Hori, H TI Angiogenesis inhibitor TX-1898: syntheses of the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazole hypoxic cell radiosensitizers SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE angiogenesis inhibitor; hypoxic cell radiosensitizer; halo-acetylcarbamoyl-2-nitroimidazole ID EHRLICH ASCITES-CARCINOMA; TUMOR-GROWTH; METHIONINE AMINOPEPTIDASE; PHASE-I; BIOLOGICAL-ACTIVITIES; KINASE INHIBITOR; CANCER; FUMAGILLIN; TNP-470; DESIGN AB (R)- and (S)-Epichlorohydrins were used to prepare the enantiomers of sterically diverse haloacetylcarbamoyl-2-nitroimidazoles that function as hypoxic cell radiosensitizers. The synthetic design allowed for introduction of a side chain of varying bulk that permitted an examination of the steric effects on enantio-discrimination in biological assay systems. The single stereocenter also connected the two pharmacophores-a 2-nitroimidazole moiety critical to hypoxic cell radiosensitization, and a haloacetylcarbamoyl group to function as an anti-angiogenesis pharmacophore. In the chick embryo chorioallantoic membrane (CAM) assay, the R-enantiomers possessing the bulky p-tert-butylphenyl group showed higher anti-angiogenic activity than the corresponding S-enantiomers, while there were no differences in the activity between the enantiomers containing the less bulky methyl and tert-butyl groups. Among the compounds we report, R-p-tert-butylphenyl-bromoacetylcarbamoyl-2-nitroimidazole, TX-1898, was found to be the most promising candidate for further development of as anti-angiogenic hypoxic cell radiosensitizer. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Tokushima, Fac Engn, Dept Biol Sci & Technol, Tokushima 7708506, Japan. Tokyo Metropolitan Inst Med Sci, Med Res & Dev Ctr, Bunkyo Ku, Tokyo 1138613, Japan. Inst Oriental Med Sci, Shibuya Ku, Tokyo 1550021, Japan. Toyama Med & Pharmacuet Univ, Fac Pharmaceut Sci, Toyama 9300194, Japan. NIDDKD, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. Univ Yanbian, Pharmaceut Sch, Yanji 133000, Peoples R China. RP Hori, H (reprint author), Univ Tokushima, Fac Engn, Dept Biol Sci & Technol, Tokushima 7708506, Japan. EM hori@bio.tokushima-u.ac.jp NR 44 TC 18 Z9 22 U1 1 U2 3 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 SEP 15 PY 2004 VL 12 IS 18 BP 4917 EP 4927 DI 10.1016/j.bmc.200406.039 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 853RN UT WOS:000223845300017 PM 15336271 ER PT J AU Heath, V Suh, HC Holman, M Renn, K Gooya, JM Parkin, S Klarmann, KD Ortiz, M Johnson, P Keller, J AF Heath, V Suh, HC Holman, M Renn, K Gooya, JM Parkin, S Klarmann, KD Ortiz, M Johnson, P Keller, J TI C/EBP alpha deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; BINDING-PROTEIN-ALPHA; GRANULOCYTIC DIFFERENTIATION; FACTOR-RECEPTOR; KNOCKOUT MICE; STEM-CELLS; TRANSCRIPTION FACTORS; MYELOID-LEUKEMIA; GENE-EXPRESSION; UP-REGULATION AB CCAAT enhancer binding protein-alpha (C/ EBPalpha) inhibits proliferation in multiple cell types; therefore, we evaluated whether C/EBPalpha-deficient hematopoietic progenitor cells (HPCs) have an increased proliferative potential in vitro and in vivo. In this study we demonstrate that C/EBPalpha(-/-) fetal liver (FL) progenitors are hyperproliferative, show decreased differentiation potential, and show increased self-renewal capacity in response to hematopoietic growth factors (HGFs). There are fewer committed bipotential progenitors in C/EBPalpha(-/-) FL, whereas multipotential progenitors are unaffected. HGF-dependent progenitor cell lines can be derived by directly culturing C/EBPalpha(-/-) FL cells in vitro. Hyperproliferative spleen colonies and myelodysplastic syndrome (MDS) are observed in mice reconstituted with C/EBPalpha(-/-) FL cells, indicating progenitor hyperproliferation in vitro and in vivo. C/EBPalpha(-/-) FL lacked macrophage progenitors in vitro and had impaired ability to generate macrophages in vivo. These findings show that C/EBPalpha(-/-) deficiency results in hyperproliferation of HPCs and a block in the ability of multipotential progenitors to differentiate into bipotential granulocyte/macrophage progenitors and their progeny. (C) 2004 by The American Society of Hematology. C1 SAIC Frederick Inc, NCI, Basic Res Program, Sci Applicat Int Corp,Lab Prot Dynam & Signaling, Frederick, MD 20702 USA. Ctr Canc Res, Lab Mol Immunoregulat, NCI, Frederick, MD USA. RP Keller, J (reprint author), SAIC Frederick Inc, NCI, Basic Res Program, Sci Applicat Int Corp,Lab Prot Dynam & Signaling, Bldg 560,Rm 12-03, Frederick, MD 20702 USA. EM kellerj@ncifcrf.gov RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 FU NCI NIH HHS [N01-CO-12400] NR 41 TC 65 Z9 69 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2004 VL 104 IS 6 BP 1639 EP 1647 DI 10.1182/blood-2003-11-3963 PG 9 WC Hematology SC Hematology GA 853HT UT WOS:000223818600016 PM 15073037 ER PT J AU Chen, J Lipovsky, K Ellison, FM Calado, RT Young, NS AF Chen, J Lipovsky, K Ellison, FM Calado, RT Young, NS TI Bystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure SO BLOOD LA English DT Article ID MEDIATED APLASTIC-ANEMIA; VERSUS-HOST-DISEASE; LYMPH-NODE CELLS; IRRADIATED MICE; AUTOIMMUNE; LYMPHOCYTES; MECHANISMS; BUSULFAN; NUMBERS; AA AB Infusion of parental lymph node (LN) cells into sublethally irradiated hybrid F1 recipients created a murine model for bone marrow (BM) failure. Affected animals developed fatal pancytopenia within 2 to 3 weeks, accompanied by BM oligoclonal T-cell infiltration and severe marrow hypoplasia indicated by approximately 10-fold declines in total BM cellularity, 15-fold declines in BM Lin(-)Sca1(+)c-Kit(+) cells, 100-fold declines in spleen colony-forming units, and 100-fold declines in hematopoietic progenitor and stem cells as estimated by irradiation protection in vivo. LN cells of both H2(b/b) and H2(d/d) haplo-types were effectors. Serum interferon-gamma (IFN-gamma) concentration increased 2- to 3-fold. Marrow cells were severely apoptotic, with high proportions of Fas(+) and annexin V+ cells. Cotransplantation of 5 x 10(5) BM cells from clinically affected donors and 10(6) BM cells from H2 identical healthy mice could not rescue lethally irradiated recipients. Recipients had significantly lower cellularity in peripheral blood and BM, and cell mixtures failed to produce a stromal feeder layer to support marrow cell growth in vitro. Pathogenic T cells from donors after BM failure appeared capable of destroying hematopoietic progenitor, stem, and stromal cells from fully compatible healthy donors as "innocent bystanders." This effect can be partially abrogated by anti-IFN-gamma antibody. (C) 2004 by The American Society of Hematology. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Chen, J (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Rm 7C118,9000 Rockville Pike, Bethesda, MD 20892 USA. EM chenji@nhlbi.nih.gov RI Calado, Rodrigo/G-2619-2011 NR 34 TC 34 Z9 45 U1 2 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2004 VL 104 IS 6 BP 1671 EP 1678 DI 10.1182/blood-2004-03-1115 PG 8 WC Hematology SC Hematology GA 853HT UT WOS:000223818600020 PM 15166031 ER PT J AU Goldin, LR Pfeiffer, RM Li, XJ Hemminki, K AF Goldin, LR Pfeiffer, RM Li, XJ Hemminki, K TI Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database SO BLOOD LA English DT Article ID ONSET ANTICIPATION; LINKAGE ANALYSIS; ATM MUTATIONS; B-CLL; BLOOD AB The importance of genetic factors in etiology of chronic lymphocytic leukemia (CLL) is suggested by family and population studies. However, the spectrum of malignancies sharing common genetic factors with CLL and the effects of sex and age on familial risk are unknown. We used the Swedish Family-Cancer Database to test for increased familial risks of CLL and other lymphoproliferative tumors. Cancer diagnoses from 1958 to 1998 were assessed in 14 336 first-degree relatives of 5918 CLL cases and in 28 876 first-degree relatives of 11 778 controls. Cancer risks in relatives of cases were compared with those in relatives of controls using marginal survival models. Relatives of cases were at significantly increased risk for CLL (relative risk [RR] = 7.52; 95% confidence interval [Cl], 3.63-15.56), for non-Hodgkin lymphoma (FIR = 1.45; 95% Cl, 0.98-2.16), and for Hodgkin lymphoma (RR = 2.35; 95% Cl, 1.08-5.08). CLL risks were similar in parents, siblings, and offspring of cases, in male and female relatives, and were not affected by the case's age at diagnosis. Anticipation was not significant when analyzed using life table methods. We conclude that the familial component of CLL is shared with other lymphoproliferative malignances, suggesting common genetic pathways. However, because clinically diagnosed CLL is uncommon, absolute excess risk to relatives is small. (C) 2004 by The American Society of Hematology. C1 NCI, Genet Epidemiol Branch, DCEG, Bethesda, MD 20892 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Karolinska Inst, Novum, Dept Biosci, Stockholm, Sweden. German Canc Res Ctr, Div Mol Genet Epidemiol, DKFZ, D-6900 Heidelberg, Germany. RP Goldin, LR (reprint author), NCI, Genet Epidemiol Branch, DCEG, 6120 Execut Blvd,MSC 7236, Bethesda, MD 20892 USA. EM goldinl@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 NR 36 TC 118 Z9 123 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2004 VL 104 IS 6 BP 1850 EP 1854 DI 10.1182/blood-2004-01-0341 PG 5 WC Hematology SC Hematology GA 853HT UT WOS:000223818600043 PM 15161669 ER PT J AU Amundson, SA Grace, MB McLeland, CB Epperly, MW Yeager, A Zhan, QM Greenberger, JS Fornace, AJ AF Amundson, SA Grace, MB McLeland, CB Epperly, MW Yeager, A Zhan, QM Greenberger, JS Fornace, AJ TI Human in vivo radiation-induced biomarkers: Gene expression changes in radiotherapy patients SO CANCER RESEARCH LA English DT Article ID CDNA MICROARRAY; HUMAN CANCER; PCR ASSAY; RESPONSES; EXPOSURE; ARREST; CELLS AB After initially identifying potential biomarkers of radiation exposure through microarray studies of ex vivo irradiated human peripheral white blood cells, we have now measured the in vivo responses of several of these biomarker genes in patients undergoing total body irradiation. Microarray analysis has identified additional in vivo radiation-responsive genes, although the general in vivo patterns of stress-gene induction appear similar to those obtained from ex vivo white blood cell experiments. Additional studies may reveal correlations between responses and either diagnosis or prognosis, and such in vivo validation marks an important step in the development of potentially informative radiation exposure biomarkers. C1 NIH, Ctr Canc Res, NCI, Bethesda, MD USA. Armed Forces Radiobiol Res Inst, Biol Dosimetry Team, Bethesda, MD USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. RP Amundson, SA (reprint author), Columbia Univ, Ctr Radiol Res, 630 W 168th St VC11-215, New York, NY 10032 USA. EM saa2108@columbia.edu RI Fornace, Albert/A-7407-2008 OI Fornace, Albert/0000-0001-9695-085X NR 15 TC 140 Z9 149 U1 2 U2 6 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 SEP 15 PY 2004 VL 64 IS 18 BP 6368 EP 6371 DI 10.1158/0008-5472.CAN-04-1883 PG 4 WC Oncology SC Oncology GA 857BG UT WOS:000224089700003 PM 15374940 ER PT J AU De Fabo, EC Noonan, FP Fears, T Merlino, G AF De Fabo, EC Noonan, FP Fears, T Merlino, G TI Ultraviolet B but not ultraviolet A radiation initiates melanoma SO CANCER RESEARCH LA English DT Article ID MALIGNANT-MELANOMA; SUN EXPOSURE; SKIN-CANCER; SUPPRESSION; INDUCTION; MOUSE; RISK; MICE AB Cutaneous malignant melanoma is one of the fastest increasing cancers with an incidence that has more than doubled in the last 25 years. Sunlight exposure is strongly implicated in the etiology of cutaneous malignant melanoma and the UV portion of the sunlight spectrum is considered responsible. Data are, however, conflicting on the roles of ultraviolet B [UVB; 280-320 nanometers (nm)] and ultraviolet A (UVA; 320-400 nm), which differ in their ability to initiate DNA damage, cell signaling pathways and immune alterations. To address this issue, we have used specialized optical sources, emitting isolated or combined UVB or UVA wavebands or solar simulating radiation, together with our hepatocyte growth factor/scatter factor-transgenic mouse model of UV-induced melanoma that uniquely recapitulates human disease. Only UVB-containing sources initiated melanoma. These were the isolated UVB waveband (>96% 280-320 nm), the unfiltered F40 sunlamp (250-800 nm) and the solar simulator (290-800 nm). Kaplan-Meier survival analysis indicated that the isolated UVB waveband was more effective in initiating melanoma than either the F40 sunlamp or the solar simulator (modified log rank P < 0.02). The latter two sources showed similar melanoma effectiveness (P = 0.38). In contrast, transgenic mice irradiated with either the isolated UVA waveband (>99.9% 320-400 nm, 150 kK/m(2))9 or an F40 sunlamp filtered to remove > 96% of the UVB, responded like unirradiated control animals. We conclude that, within the constraints of this animal model, UVB is responsible for the induction of mammalian cutaneous malignant melanoma whereas UVA is ineffective even at doses considered physiologically relevant. This finding may have major implications with respect both to risk assessment from exposure to solar and artificial UVB, and to development of effective protection strategies against melanoma induction by UVB. Moreover, these differences in wavelength effectiveness can now be exploited to identify UV pathways relevant to melanomagenesis. C1 George Washington Univ, Ctr Med, Dept Environm & Occupat Hlth, Sch Publ Hlth & Hlth Serv,Lab Photobiol & Photoim, Washington, DC 20037 USA. NCI, Biostat Branch, Bethesda, MD USA. NCI, Lab Mol Biol, Mol Genet Sect, Bethesda, MD USA. RP De Fabo, EC (reprint author), George Washington Univ, Ctr Med, Dept Environm & Occupat Hlth, Sch Publ Hlth & Hlth Serv,Lab Photobiol & Photoim, 112 Ross Hall,2300 1 St NW, Washington, DC 20037 USA. EM drmecd@gwumc.edu FU NCI NIH HHS [CA53765S, CA92258] NR 24 TC 140 Z9 142 U1 1 U2 13 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2004 VL 64 IS 18 BP 6372 EP 6376 DI 10.1158/0008-5472.CAN-04-1454 PG 5 WC Oncology SC Oncology GA 857BG UT WOS:000224089700004 PM 15374941 ER PT J AU Li, F Wang, F Haraldson, K Protopopov, A Duh, FM Geil, L Kuzmin, I Minna, JD Stanbridge, E Braga, E Kashuba, VI Klein, G Lerman, MI Zabarovsky, ER AF Li, F Wang, F Haraldson, K Protopopov, A Duh, FM Geil, L Kuzmin, I Minna, JD Stanbridge, E Braga, E Kashuba, VI Klein, G Lerman, MI Zabarovsky, ER TI Functional characterization of the candidate tumor suppressor gene NPRL2/G21 located in 3p21.3C SO CANCER RESEARCH LA English DT Article ID HUMAN-CHROMOSOME 3P21.3; HOMOZYGOUS DELETION REGION; CANCER CELL-LINE; REAL-TIME PCR; SACCHAROMYCES-CEREVISIAE; EPITHELIAL MALIGNANCIES; IN-VITRO; LUNG; 3P; IDENTIFICATION AB Initial analysis identified the NPRL2/G21 gene located in 3p21.3C, the lung cancer region, as a strong candidate tumor suppressor gene. Here we provide additional evidence of the tumor suppressor function of NPRL2/G21. The gene has highly conserved homologs/orthologs ranging from yeast to humans. The yeast ortholog, NPR2, shows three highly conserved regions with 32 to 36% identity over the whole length. By sequence analysis, the main product of NPRL2/G21 encodes a soluble protein that has a bipartite nuclear localization signal, a protein-binding domain, similarity to the MutS core domain, and a newly identified nitrogen permease regulator 2 domain with unknown function. The gene is highly expressed in many tissues. We report inactivating mutations in a variety of tumors and cancer cell lines, growth suppression of tumor cells with tet-controlled NPRL2/G21 transgenes on plastic Petri dishes, and suppression of tumor formation in SCID mice. Screening of 7 renal, 5 lung, and 7 cervical carcinoma cell lines showed homozygous deletions in the 3' end of NPRL2 in 2 renal, 3 lung, and I cervical (HeLa) cell line. Deletions in the 3' part of NPRL2 could result in improper splicing, leading to the loss of the 1.8 kb functional NPRL2 mRNA. We speculate that the NPRL2/G21 nuclear protein may be involved in mismatch repair, cell cycle checkpoint signaling, and activation of apoptotic pathway(s). The yeast NPR2 was shown to be a target of cisplatin, suggesting that the human NPRL2/G21 may play a similar role. At least two homozygous deletions of NPRL2/G21 were detected in 6 tumor biopsies from various locations and with microsatellite instability. This study, together with previously obtained results, indicates that NPRL2 is a multiple tumor suppressor gene. C1 Karolinska Inst, Microbiol & Tumor Biol Ctr, Ctr Genom & Bioinformat, S-17177 Stockholm, Sweden. NCI, Ctr Canc Res, Lab Immunobiol, Canc Causing Genes Sect, Frederick, MD USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol, Dallas, TX USA. Univ Calif Irvine, Coll Med, Dept Microbiol & Mol Genet, Irvine, CA USA. Russian State Genet Ctr, Moscow, Russia. Natl Acad Sci Ukraine, Inst Mol Biol & Genet, Kiev, Ukraine. Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow, Russia. RP Zabarovsky, ER (reprint author), Karolinska Inst, Microbiol & Tumor Biol Ctr, Ctr Genom & Bioinformat, Box 280, S-17177 Stockholm, Sweden. EM eugzab@ki.se RI Zabarovsky, Eugene/A-6645-2010; Braga, Eleonora/P-5574-2016 NR 25 TC 3 Z9 3 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 SEP 15 PY 2004 VL 64 IS 18 BP 6438 EP 6443 PG 6 WC Oncology SC Oncology GA 857BG UT WOS:000224089700015 ER PT J AU Martinez, A Zudaire, E Portal-Nunez, S Guedez, L Libutti, SK Stetler-Stevenson, WG Cuttitta, F AF Martinez, A Zudaire, E Portal-Nunez, S Guedez, L Libutti, SK Stetler-Stevenson, WG Cuttitta, F TI Proadrenomedullin NH2-terminal 20 peptide is a potent angiogenic factor, and its inhibition results in reduction of tumor growth SO CANCER RESEARCH LA English DT Article ID ADRENOMEDULLIN EXPRESSION; CELL-LINES; IN-VIVO; AUTOCRINE GROWTH; FACTOR ANTIBODY; HYPOXIA; CARCINOGENESIS; SECRETION; INDUCTION; MECHANISM AB We have found through ex vivo and in vivo angiogenesis models that the adrenomedullin gene-related peptide, proadrenomedullin NH2-terminal 20 peptide (PAMP), exhibits a potent angiogenic potential at femtomolar concentrations, whereas classic angiogenic factors such as vascular endothelial growth factor and adrenomedullin mediate a comparable effect at nanomolar concentrations. We found that human microvascular endothelial cells express PAMP receptors and respond to exogenous addition of PAMP by increasing migration and cord formation. Exposure of endothelial cells to PAMP increases gene expression of other angiogenic factors such as adrenomedullin, vascular endothelial growth factor, basic fibroblast growth factor, and platelet-derived growth factor C. In addition, the peptide fragment PAMP(12-20) inhibits tumor cell-induced angiogenesis in vivo and reduces tumor growth in xenograft models. Together, our data demonstrate PAMP to be an extremely potent angiogenic factor and implicate this peptide as an attractive molecular target for angiogenesis-based antitumor therapy. C1 NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Vasc Biol Fac, NIH, Bethesda, MD 20892 USA. RP Martinez, A (reprint author), NCI, Cell & Canc Biol Branch, NIH, Bldg 10,Room 13N262, Bethesda, MD 20892 USA. EM martinea@mail.nih.gov RI Stetler-Stevenson, William/H-6956-2012; Guedez, Liliana/H-4951-2012; Martinez, Alfredo/A-3077-2013; Portal-Nunez, Sergio/L-7391-2014 OI Stetler-Stevenson, William/0000-0002-5500-5808; Martinez, Alfredo/0000-0003-4882-4044; Portal-Nunez, Sergio/0000-0003-0659-1545 NR 34 TC 37 Z9 38 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 SEP 15 PY 2004 VL 64 IS 18 BP 6489 EP 6494 DI 10.1158/0008-5472.CAN-04-0103 PG 6 WC Oncology SC Oncology GA 857BG UT WOS:000224089700022 PM 15374959 ER PT J AU Loercher, A Lee, TL Ricker, JL Howard, A Geoghegen, J Chen, Z Sunwoo, JB Sitcheran, R Chuang, EY Mitchell, JB Baldwin, AS Van Waes, C AF Loercher, A Lee, TL Ricker, JL Howard, A Geoghegen, J Chen, Z Sunwoo, JB Sitcheran, R Chuang, EY Mitchell, JB Baldwin, AS Van Waes, C TI Nuclear factor-kappa B is an important modulator of the altered gene expression profile and malignant phenotype in squamous cell carcinoma SO CANCER RESEARCH LA English DT Article ID PROINFLAMMATORY CYTOKINE EXPRESSION; TUMOR-GROWTH; HUMAN HEAD; NECK-CANCER; IN-VIVO; CONSTITUTIVE ACTIVATION; POINT MUTATION; ONCOGENIC RAS; CYCLIN D1; TRANSCRIPTION AB We reported previously that transcription factor nuclear factor (NF)-kappaB is constitutively activated in human and marine squamous cell carcinomas (SCCs). The role of NF-kappaB in the cumulative changes in gene expression with transformation and progression of the murine SCC Pam 212 and after switching off NF-kappaB by a dominant negative inhibitor KB mutant (IkappaBalphaM) was explored by profiling with a 15,000-element cDNA micoarrray. Remarkably, NF-kappaB modulated the expression of >60% of the 308 genes differentially expressed between normal keratinocytes and metastatic SCCs. NF-kappaB directly or indirectly modulated expression of programs of genes functionally linked to proliferation, apoptosis, adhesion, and angiogenesis. Among these, changes in expression of cyclin D1, inhibitor of apoptosis-1, mutant Trp53, and beta-catenin detected with modulation of NF-kappaB by microarray were confirmed by Western and Northern blot. NF-kappaB DNA binding motifs were detected in the promoter of similar to63% of genes showing increased expression and 33% of the genes showing decreased expression. The ACTACAG motif implicated in the NF-kappaB-dependent down-regulation of mRNA expression of MyoD and Sox9 was detected in the coding portion of about 15% of genes showing increased or decreased expression. Inactivation of NF-kappaB inhibited malignant phenotypic features including proliferation, cell survival, migration, angiogenesis, and tumorigenesis. These results provide evidence that NF-kappaB is an important modulator of gene expression programs that contribute to the malignant phenotype of SCC. C1 Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Rockville, MD 20892 USA. NCI, Radiat Oncol Serv Program, Bethesda, MD USA. Univ N Carolina, Lineberger Canc Ctr, Chapel Hill, NC USA. RP Van Waes, C (reprint author), Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Bldg 10,Room 5D55,10 Ctr Dr,MSC-1419, Rockville, MD 20892 USA. EM vanwaesc@nidcd.nih.gov RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU NIDCD NIH HHS [DC-00016] NR 44 TC 118 Z9 139 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2004 VL 64 IS 18 BP 6511 EP 6523 DI 10.1158/0008-5472.CAN-04-0852 PG 13 WC Oncology SC Oncology GA 857BG UT WOS:000224089700025 PM 15374962 ER PT J AU Lucas, PJ McNeil, N Hilgenfeld, E Choudhury, B Kim, SJ Eckhaus, MA Ried, T Gress, RE AF Lucas, PJ McNeil, N Hilgenfeld, E Choudhury, B Kim, SJ Eckhaus, MA Ried, T Gress, RE TI Transforming growth factor-beta pathway serves as a primary tumor suppressor in CD8(+) T cell tumorigenesis SO CANCER RESEARCH LA English DT Article ID TGF-BETA; TRANSGENIC MICE; CANCER CELLS; MICROSATELLITE INSTABILITY; COLON-CANCER; CYCLE ARREST; II RECEPTOR; IN-VIVO; MUTANT; GENE AB Turnorigenesis in rodents, as well as in humans, has been shown to be a multistep process, with each step reflecting an altered gene product or gene regulatory process leading to autonomy of cell growth. Initial genetic mutations are often associated with dysfunctional growth regulation, as is demonstrated in several transgenic mouse models. These changes are often followed by alterations in tumor suppressor gene function, allowing unchecked cell cycle progression and, by genomic instability, additional genetic mutations responsible for tumor metastasis. Here we show that reduced transforming growth factor-beta signaling in T lymphocytes leads to a rapid expansion of a CD8(+) memory T-cell population and a subsequent transformation to leukemia/lymphoma as shown by multiple criteria, including peripheral blood cell counts histology, T-cell receptor monoclonality, and host transferability. Furthermore, spectral karyotype analysis of the tumors shows that the tumors have various chromosomal aberrations. These results suggest that reduced transforming growth factor-beta signaling acts as a primary carcinogenic event, allowing uncontrolled proliferation with consequent accumulation of genetic defects and leukemic transformation. C1 NIH, Expt Immunol Branch, NCI, Bethesda, MD 20892 USA. NIH, Genet Branch, Ctr Canc Res, NCI, Bethesda, MD 20892 USA. NIH, Lab Cell Regulat & Carcinogenesis, NCI, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD USA. RP Gress, RE (reprint author), NIH, Expt Immunol Branch, NCI, 10-4B-36,10 Ctr Dr, Bethesda, MD 20892 USA. EM gressr@exchange.nih.gov NR 51 TC 22 Z9 24 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 SEP 15 PY 2004 VL 64 IS 18 BP 6524 EP 6529 DI 10.1158/0008-5472.CAN-04-0896 PG 6 WC Oncology SC Oncology GA 857BG UT WOS:000224089700026 PM 15374963 ER PT J AU Hartley, JA Spanswick, VJ Brooks, N Clingen, PH McHugh, PJ Hochhauser, D Pedley, RB Kelland, LR Alley, MC Schultz, R Hollingshead, MG Schweikart, KM Tomaszewski, JE Sausville, EA Gregson, SJ Howard, PW Thurston, DE AF Hartley, JA Spanswick, VJ Brooks, N Clingen, PH McHugh, PJ Hochhauser, D Pedley, RB Kelland, LR Alley, MC Schultz, R Hollingshead, MG Schweikart, KM Tomaszewski, JE Sausville, EA Gregson, SJ Howard, PW Thurston, DE TI SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity. Part 1: Cellular pharmacology, in vitro and initial in vivo antitumor activity SO CANCER RESEARCH LA English DT Article ID ELECTROPHORESIS COMET ASSAY; ANTICANCER DRUG SCREEN; SEQUENCE SPECIFICITY; INTERACTIVE AGENT; PHASE-I; TUMOR; CELLS; BIZELESIN; BINDING; CANINE AB SJG-136 (NSC 694501) is a rationally designed pyrrolobenzodiazepine dimer that binds in the minor groove of DNA. It spans 6 bp with a preference for binding to purine-GATC-pyrimidine sequences. The agent has potent activity in the National Cancer Institute (NCI) anticancer drug screen with 50% net growth inhibition conferred by 0.14 to 320 nmol/L (7.4 nmol/L mean). Sensitive cell lines exhibit total growth inhibition and 50% lethality after treatment with as little as 0.83 and 7.1 nmol/L SJG136, respectively. COMPARE and molecular target analysis of SJG-136 data versus that of >60,000 compounds tested in the NCI 60 cell line screen shows that, although the agent has similarity to other DNA binding agents, the pattern of activity for SJG-136 does not fit within the clusters of any known agents, suggesting that SJG-136 possesses a distinct mechanism of action. Testing in the NCI standard hollow fiber assay produced prominent growth inhibition in 20 of 24 i.p. and 7 of 24 s.c. test combinations with 5 of 12 cell lines exhibiting cell kill. In addition, SJG-136 produced antitumor activity in mice bearing CHI and CHIcisR xenografts, a cisplatin-resistant human ovarian tumor model, and also in mice bearing LS174T xenografts, a human colon tumor model. SJG-136 produces DNA interstrand cross-links between two N-2 guanine positions on opposite strands and separated by 2 bp. In human tumor cell lines, the cross-links form rapidly and persist compared with those produced by conventional cross-linking agents such as nitrogen mustards. In mice bearing the LS174T human colon xenograft, DNA interstrand cross-links can be detected in tumor cells using a modification of the single cell gel electrophoresis (comet) assay after administration of a therapeutic dose. Cross-links in the tumor increase with dose and are clearly detectable at I hour after i.v. administration. The level of cross-linking persists over a 24-hour period in this tumor in contrast to cross-links produced by conventional cross-linking agents observed over the same time period. C1 UCL, Royal Free & Univ Coll Med Sch, Dept Oncol, Canc Res UK Drug DNA Interact Res Grp, London W1W 7BS, England. Royal Free & Univ Coll Med Sch, Dept Oncol, Canc Res UK Targeting & Imaging Res Grp, London W1W 7BS, England. Canc Res Inst, Canc Res UK Ctr Canc Therapeut, Sutton, Surrey, England. NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Univ London, Sch Pharm, Canc Res UK Gene Targeted Drug Design Res Grp, London WC1N 1AX, England. RP Hartley, JA (reprint author), UCL, Royal Free & Univ Coll Med Sch, Dept Oncol, Canc Res UK Drug DNA Interact Res Grp, 91 Riding House St, London W1W 7BS, England. EM john.hartley@ucl.ac.uk FU NCI NIH HHS [N01-CM-87028, N01-CO-12400] NR 41 TC 78 Z9 78 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2004 VL 64 IS 18 BP 6693 EP 6699 DI 10.1158/0008-5472.CAN-03-2941 PG 7 WC Oncology SC Oncology GA 857BG UT WOS:000224089700049 PM 15374986 ER PT J AU Alley, MC Hollingshead, MG Pacula-Cox, CM Wand, WR Hartley, JA Howard, PW Gregson, SJ Thurston, DE Sausville, EA AF Alley, MC Hollingshead, MG Pacula-Cox, CM Wand, WR Hartley, JA Howard, PW Gregson, SJ Thurston, DE Sausville, EA TI SJG-136 (NSC 694501), a novel rationally designed DNA minor groove interstrand cross-linking agent with potent and broad spectrum antitumor activity. Part 2: Efficacy evaluations SO CANCER RESEARCH LA English DT Article ID TUMOR-CELL-LINES; IN-VITRO; BINDING AB Pyrrolo[2,1-c][1,4]benzodiazepine dimer SJG-136 (NSC 694501) selectively cross-links guanine residues located on opposite strands of DNA, and exhibits potent in vitro cytotoxicity. In addition, SJG-136 is highly active in vivo in hollow fiber assays. In the current investigation, SJG-136 was evaluated for in vivo efficacy in 10 tumor models selected on the basis of sensitivity of cells grown in the hollow fiber and in vitro time course assays: LOX IMVI and UACC-62 (melanomas); OVCAR-3 and OVCAR-5 (ovarian carcinomas); MDA-MB-435 (breast carcinoma); SF295 and C-6 (gliomas); LS-174T (colon carcinoma); HL-60 TB (promyelocytic leukemia); and NCI-H522 (lung carcinoma). SJG-136 was active against small (150 mg) and large (250-400 mg) xenografts with tumor mass reductions in all 10 models. In addition, significant growth delays occurred in nine models, cell kill in six models ranged between 1.9 and 7.2 logs, and there were 1 to 4/6 tumor-free responses in six models. SJG-136 is active following i.v. bolus injections, as well as by 5-day continuous infusions. Of all of the schedules tested, bolus administrations for 5 consecutive days (qd X 5) conferred the greatest efficacy. SJG-136 is active over a wide dosage range in athymic mouse xenografts: on a qdx5 schedule, the maximum-tolerated dose was similar to120 mug/kg/dose (total dose: 0.6 mg/kg = 1.8 mg/m(2)) and the minimum effective dose in the most sensitive model (SF-295) was -16 mug/kg/dose (total dose: 0.08 mg/ kg = 0.24 Mg/m(2)). Results of this study extend the initial in vivo observations reported in the reference above and confirm the importance of expediting more detailed preclinical evaluations on this novel agent in support of phase I clinical trials in the United Kingdom and the United States, which are planned to commence shortly. C1 NCI, Biol Testing Branch, DTP, DCTD,FCRDC, Frederick, MD 21701 USA. So Res Inst, Birmingham, AL 35255 USA. UCL Royal Free & Univ Coll Med Sch, Dept Oncol, Canc Res UK Drug DNA Interact Res Grp, London, England. Univ London, Sch Pharm, Canc Res UK Gene Targeted Drug Design Res Grp, London WC1N 1AX, England. RP Alley, MC (reprint author), NCI, Biol Testing Branch, DTP, DCTD,FCRDC, 1003 W 7th St,FVC 205, Frederick, MD 21701 USA. FU NCI NIH HHS [N01-CM-07002, N01-CO-12400] NR 21 TC 57 Z9 58 U1 2 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 SEP 15 PY 2004 VL 64 IS 18 BP 6700 EP 6706 DI 10.1158/0008-5472.CAN-03-2942 PG 7 WC Oncology SC Oncology GA 857BG UT WOS:000224089700050 PM 15374987 ER PT J AU Smart, DDK Ortiz, KL Mattson, D Bradbury, CM Bisht, KS Sieck, LK Brechbiel, MW Gius, D AF Smart, DDK Ortiz, KL Mattson, D Bradbury, CM Bisht, KS Sieck, LK Brechbiel, MW Gius, D TI Thioredoxin reductase as a potential molecular target for anticancer agents that induce oxidative stress SO CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; RADIATION-INDUCED ACTIVATION; DNA-BINDING ACTIVITY; IONIZING-RADIATION; GENE-EXPRESSION; CANCER-CELLS; HEAT-SHOCK; INDUCED RADIOSENSITIZATION; TRANSCRIPTION FACTORS; INDUCED CYTOTOXICITY AB Redox-sensitive signaling factors regulate multiple cellular processes, including proliferation, cell cycle, and prosurvival signaling cascades, suggesting their potential as molecular targets for anticancer agents. It is logical-to set constraints that a molecular target should meet at least one of the following criteria: (1) inhibition of prosurvival signaling pathways; (2) inhibition of cell cycle progression; or (3) enhancement of the cytotoxic effects of anticancer agents. Therefore, we hypothesized that thioredoxin reductase 1 (TR), a component of several redox-regulated pathways, might represent a potential molecular target candidate in response to agents that induce oxidative stress. To address this issue, permanent cell lines overexpressing either the wild-type (pCXN2-myc-TR-wt) or a CysSer mutant (pCXN2-mye-mTR) TR gene were used, as were parental HeLa cells treated with 1-methyl-1-propyl-2-imidazolyl disullide (IV-2), a pharmacologic inhibitor of TR. Cells were exposed to the oxidative stressors, H2O2 and ionizing radiation (IR), and analyzed for changes in signal transduction, cell cycle, and cytotoxicity. Analysis of HeLa cells overexpressing the pCXN2-mye-TR-wt gene showed increased basal activity of nuclear factor kappaB (NFkappaB) and activator protein (AP-1), whereas HeLa cells expressing a pCXN2-myc-mTR gene and HeLa cells treated with IV-2 were unable to induce NFkappaB or AP-1 activity following H2O2 or IR exposure. Fluorescence-activated cell sorting analysis showed a marked accumulation of PCXN2-myc-mTR cells in the late G, phase, whereas pCXN2-myc-TR-wt cells showed a decreased G, subpopulation. Chemical inhibition of TR with IV-2 also completely inhibited cellular proliferation at concentrations between 10 and 25 mumol/L, resulting in a G, phase cell cycle arrest consistent with the results from cells expressing the pCXN2myc-mTR gene. Following exposure to H2O2 and IR, pCXN2-myc-MTRand IV-2-treated cells were significantly more sensitive to oxidative stress-induced cytotoxicity as measured by clonogenic survival assays. Finally, IV-2-treated cells showed increased tumor cell death when treated with 1120, and IR. These results identify TR as a potential target to enhance the cytotoxic effects of agents that induce oxidative stress, including IR. C1 NCI, Radiat Oncol Branch, Canc Res Ctr,Mol Radiat Oncol Sect, NIH,Radiat Oncol Sci Program, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Canc Res Ctr,Radioimmune & Inorgan Chem Sect, NIH,Radiat Oncol Sci Program, Bethesda, MD 20892 USA. RP NCI, Radiat Oncol Branch, Canc Res Ctr,Mol Radiat Oncol Sect, NIH,Radiat Oncol Sci Program, 9000 Rockville Pike,Bldg 10,Room B3B69, Bethesda, MD 20892 USA. FU NCI NIH HHS [1 K08 CA72602-01] NR 48 TC 81 Z9 86 U1 1 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2004 VL 64 IS 18 BP 6716 EP 6724 DI 10.1158/0008-5472.CAN-03-3990 PG 9 WC Oncology SC Oncology GA 857BG UT WOS:000224089700052 PM 15374989 ER PT J AU Lou, YY Wang, G Lizee, G Kim, GJ Finkelstein, SE Feng, CG Restifo, NP Hwu, P AF Lou, YY Wang, G Lizee, G Kim, GJ Finkelstein, SE Feng, CG Restifo, NP Hwu, P TI Dendritic cells strongly boost the antitumor activity of adoptively transferred T cells in vivo SO CANCER RESEARCH LA English DT Article ID TUMOR-INFILTRATING LYMPHOCYTES; MELANOMA-ASSOCIATED ANTIGENS; METASTATIC MELANOMA; VIRUS-INFECTION; CANCER-PATIENTS; INDUCTION; PEPTIDE; IMMUNOTHERAPY; IMMUNITY; THERAPY AB Dendritic cells (DCs) have been well characterized for their ability to initiate cell-mediated immune responses by stimulating naive T cells. However, the use of DCs to stimulate antigen-activated T cells ill vivo has not been investigated. In this study, we determined whether DC vaccination could improve the efficacy of activated, adoptively transferred T cells to induce an enhanced antitumor immune response. Mice bearing B16 melanoma tumors expressing the gp100 tumor antigen were treated with cultured, activated T cells transgenic for a T-cell receptor specifically recognizing gp100, with or without concurrent peptide-pulsed DC vaccination. In this model, anti gen-specific DC vaccination induced cytokine production, enhanced proliferation, and increased tumor infiltration of adoptively transferred T cells. Furthermore, the combination of DC vaccination and adoptive T-cell transfer led to a more robust antitumor response than the use of each treatment individually. Collectively, these findings illuminate a new potential application for DCs in the ill vivo stimulation of adoptively transferred T cells and may be a useful approach for the immunotherapy of cancer. C1 Univ Texas, MD Anderson Canc Ctr, Unit 430, Dept Melanoma Med Oncol, Houston, TX 77030 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Hwu, P (reprint author), Univ Texas, MD Anderson Canc Ctr, Unit 430, Dept Melanoma Med Oncol, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM phwu@mdanderson.org RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z99 CA999999, Z01 BC010763-01] NR 51 TC 78 Z9 79 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 SEP 15 PY 2004 VL 64 IS 18 BP 6783 EP 6790 DI 10.1158/0008-5472.CAN-04-1621 PG 8 WC Oncology SC Oncology GA 857BG UT WOS:000224089700060 PM 15374997 ER PT J AU Berman, DM Wang, YF Liu, ZY Dong, Q Burke, LA Liotta, LA Fisher, R Wu, XF AF Berman, DM Wang, YF Liu, ZY Dong, Q Burke, LA Liotta, LA Fisher, R Wu, XF TI A functional polymorphism in RGS6 modulates the risk of bladder cancer SO CANCER RESEARCH LA English DT Article ID TRANSFORMING G-PROTEINS; GENE-EXPRESSION; DRUG TARGETS; GGL DOMAIN; REGULATOR; LOCALIZATION; ASSOCIATION; INTERACTS; HYPERTENSION; ACTIVATION AB RGS proteins negatively regulate heterotrimeric G protein signaling. Recent reports have shown that RGS proteins modulate neuronal, cardiovascular, and lymphocytic activity, yet their role in carcinogenesis has not been explored. In an epidentiologic study of 477 bladder cancer patients and 446 matched controls, three noncoding single-nucleotide polymorphisms (SNPs) in RGS2 and RGS6 were each associated with a statistically significant reduction in bladder cancer risk. The risk of bladder cancer was reduced by 74% in those individuals with the variant genotype at all three SNPs (odds ratio, 0.26; 95% confidence interval, 0.09-0.71). When the SNPs were analyzed separately, the RGS6rs2074647 (C-T) polymorphism conferred the greatest overall reduction in risk of bladder cancer (odds ratio, 0.66; 95% confidence interval, 0.46-0.95). These reductions in risk were more pronounced in ever smokers, suggesting a gene-environment interaction. In transfection assays, the RGS6-rs2O74647 (C-->T) polymorphism increased the activity of a luciferase-RGS fusion protein by 2.9-fold, suggesting that this SNP is functionally significant. Finally, we demonstrate that RGS2 transcripts and several splice variants of RGS6 are expressed in bladder cancer cells. These data provide the first evidence that RGS proteins may be important modulators of cancer risk and validate RGS6 as a target for further study. C1 NCI, Pathol Lab, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. Univ Iowa, Dept Pharmacol, Iowa City, IA 52242 USA. RP Berman, DM (reprint author), NCI, Pathol Lab, Bldg 10-2N212,10 Ctr Dr, Bethesda, MD 20892 USA. EM bermand@mail.nih.gov RI Burke, Luke/C-7655-2011 FU NCI NIH HHS [CA 74880, CA 91846]; NIGMS NIH HHS [GM067881] NR 44 TC 41 Z9 42 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 SEP 15 PY 2004 VL 64 IS 18 BP 6820 EP 6826 DI 10.1158/0008-5472.CAN-04-1916 PG 7 WC Oncology SC Oncology GA 857BG UT WOS:000224089700065 PM 15375002 ER PT J AU Mulshine, JL Weinstein, JN AF Mulshine, JL Weinstein, JN TI Is the gene expression pattern of lung cancer detected by screening with spiral computed tomography different from that of symptom-detected lung cancer? SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID BASE-LINE; CT; PROJECT C1 NCI, Expt Intervent Sect, Cell & Canc Biol Branch, Canc Res Ctr,NIH,Dept Hlth & Human Serv,Lab Mol P, Bethesda, MD 20892 USA. Lung Canc & Aerodigest Chemoprevent Fac, Ctr Canc Res, Intervent Sect, Bethesda, MD USA. RP Mulshine, JL (reprint author), NCI, Expt Intervent Sect, Cell & Canc Biol Branch, Canc Res Ctr,NIH,Dept Hlth & Human Serv,Lab Mol P, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM mulshinj@mail.nih.gov NR 19 TC 6 Z9 6 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2004 VL 10 IS 18 BP 5973 EP 5974 DI 10.1158/1078-0432.CCR-04-1154 PN 1 PG 2 WC Oncology SC Oncology GA 856XU UT WOS:000224080200001 PM 15447979 ER PT J AU Hu, N Flaig, MJ Su, H Shou, JZ Roth, MJ Li, WJ Wang, CY Goldstein, AM Li, G Emmert-Buck, MR Taylor, PR AF Hu, N Flaig, MJ Su, H Shou, JZ Roth, MJ Li, WJ Wang, CY Goldstein, AM Li, G Emmert-Buck, MR Taylor, PR TI Comprehensive characterization of Annexin I alterations in esophageal squamous cell carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID TIME QUANTITATIVE PCR; ALLELIC LOSS; LIPOCORTIN-I; GENE; EXPRESSION; POPULATION; PROTEINS; MUTATION; FAMILY; CHINA AB Purpose: The purpose is to characterize alterations of the annexin I gene, its mRNA, and protein expression in esophageal squamous cell carcinoma. Experimental Design: Fifty-six cases of esophageal squamous cell carcinoma were analyzed using four micro-satellite markers flanking the annexin I gene (9q11-q21) to identify loss of heterozygosity. In addition, we performed (a) single-strand conformation polymorphism and DNA sequencing along the entire promoter sequence and coding region to identify mutations, (b) real-time quantitative reverse transcription-PCR of RNA from frozen esophageal squamous cell carcinoma tissue (n = 37) and in situ hybridization (n = 5) on selected cases to assess mRNA expression, and (c) inmumohistochemistry (n = 44) to evaluate protein expression. The prevalence of the allelic variants identified in the first 56 patients was refined in 80 additional esophageal squamous cell carcinoma patients and 232 healthy individuals. Results: Forty-six of 56 (82%) esophageal squamous cell carcinoma patients showed loss of an allele at one or more of the four microsatellite markers; however, only one (silent) mutation was seen. Two intragenic variants were identified with high frequency of allelic loss (A58G, 64%; L109L, 69%). Thirty of 37 (81%) esophageal squamous cell carcinoma patients showed reduced annexin I mRNA expression, which was confirmed by in situ hybridization, whereas annexin I protein expression was reduced in 79% of poorly differentiated tumor cell foci but in only 5% of well-differentiated tumor foci, although allelic loss on chromosome 9 was found in both tumor grades. Conclusions: Allelic loss of annexin I occurs frequently, whereas somatic mutations are rare, suggesting that annexin I is not inactivated in esophageal squamous cell carcinoma via a two-hit mechanism. A decrease in annexin I protein expression was confirmed, consistent with a quantitative decrease in mRNA expression, and appeared to be related to tumor cell differentiation. We conclude that annexin I is not the tumor suppressor gene corresponding to the high levels of loss of heterozygosity observed on chromosome 9 in esophageal squamous cell carcinoma; however, dysregulation of mRNA and protein levels is associated with this tumor type. C1 NCI, Canc Prevent Studies Branch, Canc Res Ctr, Bethesda, MD 20892 USA. Univ Munich, Klin & Poliklin Dermatol & Allergol, Munich, Germany. Chinese Acad Med Sci, Canc Inst & Hosp, Beijing 100037, Peoples R China. Shanxi Canc Hosp, Taiyuan, Shanxi, Peoples R China. NCI, Genet Epidemiol Branch, Div Canc Epidemiol, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Genet, Bethesda, MD 20892 USA. NCI, Pathogenet Unit, Pathol Lab, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. RP Taylor, PR (reprint author), NCI, Canc Prevent Studies Branch, Canc Res Ctr, 6116 Eecut Pl,Room 705, Bethesda, MD 20892 USA. EM ptaylor@mail.nih.gov NR 24 TC 59 Z9 68 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2004 VL 10 IS 18 BP 6013 EP 6022 DI 10.1158/1078-0432.CCR-04-0317 PN 1 PG 10 WC Oncology SC Oncology GA 856XU UT WOS:000224080200007 PM 15447985 ER PT J AU Camphausen, K Scott, T Sproull, M Tofilon, PJ AF Camphausen, K Scott, T Sproull, M Tofilon, PJ TI Enhancement of xenograft tumor radiosensitivity by the histone deacetylase inhibitor MS-275 and correlation with histone hyperacetylation SO CLINICAL CANCER RESEARCH LA English DT Article ID VIVO ANTITUMOR-ACTIVITY; SODIUM-BUTYRATE; CELLS; AGENTS; CYTOTOXICITY; EXPRESSION; LEUKEMIA; TRIAL AB Purpose: Histone deacetylase (HDAC) inhibitors are undergoing clinical evaluation in cancer therapy. Because HDAC modulation has been shown to enhance the radiosensitivity of tumor cells in vitro, we investigated the effects of the HDAC inhibitor MS-275 on the radioresponse of DU145 prostate carcinoma xenografts. Experimental Design: As an indicator of HDAC inhibition in vivo, the histone acetylation status in tumor lysates was determined after two, four, and six injections of MS-275 delivered at 12-hour intervals, as well as 24 and 48 hours after the last injection. Tumor growth delay studies were then performed using this DU-145 xenograft model with radiation administered to leg tumors after the fourth dose of MS-275, which corresponded to the time of maximum histone hyperacetylation. Results: An increase in histone hyperacetylation was detected in each tumor after two injections of MS-275 with a maximum hyperacetylation occurring after four to six injections. In tumor growth delay studies, the combination of MS-275 and radiation resulted in a greater than additive inhibition of tumor growth as compared with the individual modalities. As alternative sources for an indicator of drug radiosensitizing activity, histone hyperacetylation was determined in a series of normal tissues, including lymphocytes. Each of the normal tissues also had a maximal histone hyperacetylation after four to six injections of MS-275. Conclusions: These studies show that MS-275 enhances the radiosensitivity of DU145 xenografts and suggest that histone hyperacetylation status can serve as a useful marker for drug radiosensitizing activity. C1 NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. NCI, Mol Radiat Therapeut Branch, Bethesda, MD 20892 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr,Bldg 10,Room B3B69, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov NR 21 TC 105 Z9 114 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2004 VL 10 IS 18 BP 6066 EP 6071 DI 10.1158/1078-0432.CCR-04-0537 PN 1 PG 6 WC Oncology SC Oncology GA 856XU UT WOS:000224080200013 PM 15447991 ER PT J AU Eisenbeis, CF Grainger, A Fischer, B Baiocchi, RA Carrodeguas, L Roychowdhury, S Chen, L Banks, AL Davis, T Young, D Kelbick, N Stephens, J Byrd, JC Grever, MR Caligiuri, MA Porcu, P AF Eisenbeis, CF Grainger, A Fischer, B Baiocchi, RA Carrodeguas, L Roychowdhury, S Chen, L Banks, AL Davis, T Young, D Kelbick, N Stephens, J Byrd, JC Grever, MR Caligiuri, MA Porcu, P TI Combination immunotherapy of B-cell non-Hodgkin's lymphoma with rituximab and interleukin-2: A preclinical and phase I study SO CLINICAL CANCER RESEARCH LA English DT Article ID LOW-DOSE INTERLEUKIN-2; BONE-MARROW TRANSPLANTATION; NATURAL-KILLER-CELLS; SEVERE COMBINED IMMUNODEFICIENCY; ANTI-CD20 MONOCLONAL-ANTIBODY; CHRONIC LYMPHOCYTIC-LEUKEMIA; RECOMBINANT INTERLEUKIN-2; SIGNIFICANT TOXICITY; CONTINUOUS-INFUSION; PROLONGED INFUSION AB Purpose: Cytokine-induced modulation of innate immunity is being explored to enhance the activity of monoclonal antibodies. Severe combined immmmodeficient (SCID) mice engrafted with peripheral blood leukocytes (PBLs) from Epstein Barr virus-seropositive donors develop human B-cell non-Hodgkin's lymphomas [B-NHLs (hu-PBL-SCID mouse model)]. We used this hu-PBL-SCID mouse model to study the synergism between interleukin (IL)-2 and rituximab. We also conducted a phase I trial of IL-2 and rituximah in relapsed B-NHL to study whether expansion of natural killer (NK) cells and enhanced cellular cytotoxicity could be safely accomplished in vivo. Experimental Design: Hu-PBL-SCID mice were treated with various schedules of rituximalb and IL-2, with survival as the end point. Patients with relapsed B-NHL received rituximab (375 mg/m(2) weekly X 4) followed by daily lowdose IL-2 (I MIU/m(2)/day X 4 weeks) with pulses of intermediate-dose IL-2 (3-15 MIU/m(2)). Toxicity, NK cell numbers, and cellular cytotoxicity were measured. Results: In the hu-PBL-SCID mouse, the combination of rituximab and IL-2 showed greater activity against B-NHL than either agent alone. Treatment was most effective when IL-2 was given before rituximab. Twelve patients with heavily pretreated. B-NHL entered the phase I trial. Toxicity was manageable, and responses were observed. NK cell expansion and enhanced cellular cytotoxicity against a B-cell lymphoma target were observed but did not correlate with response. Conclusions: The combination of IL-2 and rituximab is synergistic against B-NHL in the hu-PBL-SCID model. In the phase I trial, a sequential combination of rituximah and IL-2 was well tolerated and achieved biological end points. Responses were observed. C1 Ohio State Univ, Div Hematol Oncol, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Caligiuri, MA (reprint author), Ohio State Univ, Div Hematol Oncol, A458 Starling Loving Hall,320 W 10th Ave, Columbus, OH 43210 USA. EM caligiuri-1@medetr.osu.edu FU NCI NIH HHS [K23 CA102155, CA076576-06, K08 CA93518-01, P01 CA95426-01A1] NR 42 TC 51 Z9 54 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2004 VL 10 IS 18 BP 6101 EP 6110 DI 10.1158/1078-0432.CCR-04-0525 PN 1 PG 10 WC Oncology SC Oncology GA 856XU UT WOS:000224080200018 PM 15447996 ER PT J AU Kioi, M Kawakami, K Puri, RK AF Kioi, M Kawakami, K Puri, RK TI Analysis of antitumor activity of an interleukin-13 (IL-13) receptor-targeted cytotoxin composed of IL-13 antagonist and Pseudomonas exotoxin SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL CARCINOMA-CELLS; HIGH-AFFINITY INTERLEUKIN-4; CHIMERIC PROTEIN; MUTATED FORM; CANCER-CELLS; GLIOMA-CELLS; HUMAN BREAST; TUMOR-CELLS; NECK-CANCER; GROWTH AB We have shown previously that a chimeric fusion protein composed of human interleukin-13 (IL-13) and Pseudomonas exotoxin (PE), termed IL-13 cytotoxin (IL13-PE38), is specifically cytotoxic to various cancer cell lines and primary cell cultures derived from a variety of solid cancers. In addition, we have shown that IL-13 mutant IL-13E13K, in which glutamic acid (E) residue at position 13 of IL-13 molecule was substituted by a lysine (K), is a powerful antagonist of IL-13 and binds to IL-13 receptor with a higher affinity compared with wild-type IL-13. In this study, we have generated an IL-13 cytotoxin IL13E13K-PE38, in which IL-13 antagonist is fused to PE to determine whether this molecule has improved cytotoxicity to tumor cells compared with wild type (wt)IL13-PE38. Highly purified IL13E13K-PE38 was tested in various tumor cell lines including seven glioblastoma multiforme cell lines to compare its binding to the cells, in vitro cytotoxicity, in vivo antitumor activity, and safety in mouse model with wtIL13-PE38. IL13E13K-PE38 bound to U251MG and IL-13Ralpha2 chain-transfected tumor cell lines with 3 to 10 times higher affinity compared with wtIL13-PE38.. However, IL13E13K-PE38 did not show higher cytotoxicity compared with wtIL13PE38 in glioblastoma multiforme or any other cell lines tested. The antitumor activity of IL13E13K-PE38, when administered intraperitoneally to nude mice bearing U251 tumors, was also similar to wtIL13-PE38. Some improvement in antitumor activity was observed when lower doses of IL13E13K-PE38 were injected intratumorally in subcutaneous tumors. These results indicate that in general, IL13E13K-PE38 mediates similar cytotoxicity and antitumor activity to wtIL13-PE38 despite its improved binding affinity to IL-13 receptors. C1 US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Puri, RK (reprint author), US FDA, Lab Mol Tumor Biol, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, NIH Bldg 29B,Room 2NN10,29 Lincoln Dr MSC 4555, Bethesda, MD 20892 USA. EM puri@cber.fda.gov OI Kioi, Mitomu/0000-0002-7981-3340 NR 27 TC 30 Z9 30 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2004 VL 10 IS 18 BP 6231 EP 6238 DI 10.1158/1078-0432.CCR-04-0700 PN 1 PG 8 WC Oncology SC Oncology GA 856XU UT WOS:000224080200034 PM 15448012 ER PT J AU Atkins, MB Avigan, DE Bukowski, RM Childs, RW Dutcher, JP Eisen, TG Figlin, RA Finke, JH Flanigan, RC George, DJ Goldberg, SN Gordon, MS Iliopoulos, O Kaelin, WG Linehan, WM Lipton, A Motzer, RJ Novick, AC Stadler, WM Teh, BT Yang, JC King, L AF Atkins, MB Avigan, DE Bukowski, RM Childs, RW Dutcher, JP Eisen, TG Figlin, RA Finke, JH Flanigan, RC George, DJ Goldberg, SN Gordon, MS Iliopoulos, O Kaelin, WG Linehan, WM Lipton, A Motzer, RJ Novick, AC Stadler, WM Teh, BT Yang, JC King, L TI Innovations and challenges in renal cancer: Consensus statement from the first international conference SO CLINICAL CANCER RESEARCH LA English DT Article ID TUMOR-SUPPRESSOR GENE; HOGG-DUBE-SYNDROME; CELL CARCINOMA; KIDNEY; MUTATIONS C1 Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. NHLBI, Bethesda, MD 20892 USA. New York Med Coll, Our Lady Mercy Med Ctr, Ctr Comprehens Canc, Bronx, NY USA. Royal Marsden Hosp, Inst Canc Res, Sutton, Surrey, England. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90024 USA. Loyola Univ, Stritch Sch Med, Maywood, IL 60153 USA. Duke Univ, Med Ctr, Durham, NC USA. Arizona Canc Ctr, Scottsdale, AZ USA. Massachusetts Gen Hosp, Ctr Canc, Med Oncol Labs, Boston, MA USA. Dana Farber Canc Inst, Howard Hughes Med Inst, Boston, MA 02115 USA. NCI, Bethesda, MD 20892 USA. Penn State Univ, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Van Andel Res Inst, Canc Genet Lab, Grand Rapids, MI USA. InforMED Commun Inc, Casisle, MA USA. RP Atkins, MB (reprint author), Beth Israel Deaconess Med Ctr, 300 Brookline Ave,KS-158, Boston, MA 02215 USA. EM matkins@bidmc.harvard.edu NR 20 TC 20 Z9 21 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2004 VL 10 IS 18 SU S BP 6277S EP 6281S DI 10.1158/1078-0432.CCR-040720 PN 2 PG 5 WC Oncology SC Oncology GA 856XY UT WOS:000224080600001 PM 15448017 ER PT J AU Linehan, WM Vasselli, J Srinivasan, R Walther, MM Merino, M Choyke, P Vocke, C Schmidt, L Isaacs, JS Glenn, G Toro, J Zbar, B Bottaro, D Neckers, L AF Linehan, WM Vasselli, J Srinivasan, R Walther, MM Merino, M Choyke, P Vocke, C Schmidt, L Isaacs, JS Glenn, G Toro, J Zbar, B Bottaro, D Neckers, L TI Genetic basis of cancer of the kidney: Disease specific approaches to therapy SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 1st International Conference on Innovations and Challenges in Renal Cancer CY MAR 19-20, 2004 CL Cambridge, MA ID RENAL-CELL CARCINOMA; TUMOR-SUPPRESSOR GENE; HOGG-DUBE-SYNDROME; VONHIPPEL-LINDAU DISEASE; HYPOXIA-INDUCIBLE FACTOR-1; MET TYROSINE KINASE; BRANCHING MORPHOGENESIS; VHL GENE; MUTATIONS; HEREDITARY AB Studies during the past two decades have shown that kidney cancer is not a single disease; it is made up of a number of different types of cancer that occur in this organ. Clear cell renal carcinoma is characterized by mutation of the VHL gene. The VHL gene product forms a heterotrimeric complex with elongin C, elongin B, and Cul-2 to target hypoxia-inducible factors 1 and 2alpha for ubiquitin-mediated degradation. VHL-/- clear cell renal carcinoma overexpresses epidermal growth factor receptor and transforming growth factor alpha. Both hypoxia-inducible factor 1alpha. and the epidermal growth factor receptor are potential therapeutic targets in clear cell renal carcinoma. Studies of the hereditary form of renal cell carcinoma (RCC) associated with hereditary papillary renal carcinoma (HPRC) determined that the c-Met proto-oncogene on chromosome 7 is the gene for HPRC and for a number of sporadic papillary RCCs. The HPRC c-Met mutations are activating mutations in the tyrosine kinase domain of the gene. The gene for a new form of hereditary RCC (Birt Hogg Dube syndrome) associated with cutaneous tumors, lung cysts, and colon polyps or cancer has recently been identified. Studies are currently under way to determine what type of gene BHD is and how damage to this gene leads to kidney cancer. Individuals affected with hereditary leiomyomatosis renal cell carcinoma are at risk for the development of cutaneous leiomyomas, uterine leiomyomas (fibroids), and type 2 papillary RCC. The HLRC gene has been found to be the Krebs cycle enzyme, fumarate hydratase. Studies are under way to understand the downstream pathway of this cancer gene. C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NCI, Immunobiol Lab, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp Frederick Inc, Basic Res Program, Frederick, MD 21701 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, Bldg 10,Room 2B47, Bethesda, MD 20892 USA. EM uob@nih.gov RI Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 FU PHS HHS [N01-C0-12400] NR 56 TC 41 Z9 44 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2004 VL 10 IS 18 SU S BP 6282S EP 6289S DI 10.1158/1078-0432.CCR-050013 PN 2 PG 8 WC Oncology SC Oncology GA 856XY UT WOS:000224080600002 PM 15448018 ER PT J AU Takahashi, Y Childs, RW AF Takahashi, Y Childs, RW TI Nonmyeloablative transplantation: An allogeneic-based immunotherapy for renal cell carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 1st International Conference on Innovations and Challenges in Renal Cancer CY MAR 19-20, 2004 CL Cambridge, MA ID BONE-MARROW-TRANSPLANTATION; GRAFT-VERSUS-LEUKEMIA; MINOR HISTOCOMPATIBILITY ANTIGENS; HOST-DISEASE; REDUCED-INTENSITY; MYELOABLATIVE THERAPY; BREAST-CANCER; CHEMOTHERAPY; LYMPHOMA; ENGRAFTMENT AB High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation has been explored as a method to enhance the efficacy of chemotherapy for advanced solid tumors. The failure of autologous hematopoietic stem cell transplantation to prolong survival in patients with metastatic solid tumors has sparked interest recently in studies exploring the potential of allogeneic hematopoietic stem cell transplantation for such patients. Allogeneic hematopoietic stem cell transplantation is widely accepted as a potent form of immunotherapy capable of curing patients with chemotherapy-refractory hematologic malignancies. However, it was not until the end of the 20th century that investigators initiated trials to test the potential of allogeneic hematopoietic stem cell transplantation as immunotherapy in malignancies of epithelial origin. Early pilot trials have established proof-of-principle that graft- versus-tumor effects can induce complete or partial remission in some treatment-refractorv metastatic solid tumors. In this review, we discuss the rationale for pilot trials investigating the potential of nonmyeloablative allogeneic hematopoietic stem cell transplantation in advanced cytokine-refractory renal cancer, highlighting the preliminary success, limitations, and future clinical directions of this approach. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Childs, RW (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10,Room 7B08,MSC 1652, Bethesda, MD 20892 USA. EM childsr@nhlbi.nih.gov RI Takahashi, Yoshiyuki/I-1929-2012 NR 45 TC 15 Z9 15 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2004 VL 10 IS 18 SU S BP 6353S EP 6359S DI 10.1158/1078-0432.CCR-050009 PN 2 PG 7 WC Oncology SC Oncology GA 856XY UT WOS:000224080600014 PM 15448030 ER PT J AU Yang, JC AF Yang, JC TI Bevacizumab for patients with metastatic renal cancer: An update SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 1st International Conference on Innovations and Challenges in Renal Cancer CY MAR 19-20, 2004 CL Cambridge, MA ID ENDOTHELIAL GROWTH-FACTOR; VON-HIPPEL-LINDAU; CELL CARCINOMA; ANGIOGENESIS; ANTIBODY; THERAPY AB Most clear cell renal cell cancer (RCC) is caused by biallelic loss of the von Hippel-Lindau gene. One consequence of this loss is up-regulation of vascular endothelial growth factor via a pathway involving accumulation of hypoxia inducible factor. Vascular endothelial growth factor, a potent angiogenic factor, is secreted by many human cancers, but clear cell RCC as a group produces particularly high levels and has a highly vascular histologic appearance. In a randomized, placebo-controlled, double-blind trial, we tested the use of a neutralizing antibody to vascular endothelial growth factor, bevacizumab, in patients with metastatic RCC. At 3 or 10 mg/kg every 2 weeks, toxic effects were minimal, with hypertension and proteinuria the most substantial events. There were four partial responses (10% response rate) and a highly substantial prolongation of time to tumor progression in patients who received the higher dose of bevacizumab. With a crossover design and very sensitive criteria for disease progression, no difference in survival was shown. Four patients have been undergoing long-term bevacizumab therapy without tumor progression for 3 to 5 years. Three have substantial proteinuria but retain normal renal function. A small pilot trial combining bevacizurnab and thalidomide showed no unexpected toxic effects. Future trials should consider combination therapies and strategies in which patients are treated through initial disease progression with antiangiogenic agents such as bevacizumab. C1 NCI, Surg Branch, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NCI, Surg Branch, 9000 Rockville Pike,Bldg 10,Room 2B37, Bethesda, MD 20892 USA. EM james_yang@nih.gov NR 8 TC 40 Z9 44 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2004 VL 10 IS 18 SU S BP 6367S EP 6370S DI 10.1158/1078-0432.CCR-050006 PN 2 PG 4 WC Oncology SC Oncology GA 856XY UT WOS:000224080600016 PM 15448032 ER PT J AU Bray, M AF Bray, M TI Henry kempe and the birth of vaccinia immune globulin SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID SMALLPOX VACCINATION; COMPLICATIONS; PROPHYLAXIS C1 NIAID, Biodef Clin Res Branch, OCR OD, NIH, Bethesda, MD 20892 USA. RP Bray, M (reprint author), NIAID, Biodef Clin Res Branch, OCR OD, NIH, Rm 5128,6700A Rockledge Dr, Bethesda, MD 20892 USA. EM mbray@niaid.nih.gov NR 13 TC 3 Z9 4 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 SEP 15 PY 2004 VL 39 IS 6 BP 767 EP 769 DI 10.1086/423005 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 904JD UT WOS:000227491500002 PM 15472805 ER PT J AU Krause, DS Simjee, AE van Rensburg, C Viljoen, J Walsh, TJ Goldstein, BP Wible, M Henkel, T AF Krause, DS Simjee, AE van Rensburg, C Viljoen, J Walsh, TJ Goldstein, BP Wible, M Henkel, T TI A randomized, double-blind trial of anidulafungin versus fluconazole for the treatment of esophageal candidiasis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID IN-VITRO ACTIVITY; ANTIFUNGAL AGENTS; AMPHOTERICIN-B; ECHINOCANDIN LY303366; NATURAL-HISTORY; SUSCEPTIBILITY; ITRACONAZOLE; VORICONAZOLE; FLUCYTOSINE; SPP. AB Anidulafungin is a novel antifungal agent of the echinocandin class. This randomized, double-blind, double-dummy study compared the efficacy and safety of intravenous anidulafungin to that of oral fluconazole in 601 patients with endoscopically and microbiologically documented esophageal candidiasis. Patients received intravenous anidulafungin (100 mg on day 1, followed by 50 mg per day) or oral fluconazole (200 mg on day 1, followed by 100 mg per day) for 7 days beyond resolution of symptoms (range, 14 - 21 days). At the end of therapy, the rate of endoscopic success for anidulafungin ( 242 [97.2%] of 249 treated patients) was found to be statistically noninferior to that for fluconazole (252 [98.8%] of 255 treated patients; treatment difference, - 1.6%; 95% confidence interval, - 4.1 to 0.8). The safety profile of anidulafungin was similar to that of fluconazole; treatment-related adverse events occurred in 9.3% and 12.0% of patients, respectively. Laboratory parameters were similar between treatment arms. Anidulafungin is as safe and effective as oral fluconazole for the treatment of esophageal candidiasis, when assessed at the completion of therapy. C1 Vicuron Pharmaceut, King Of Prussia, PA 19406 USA. NCI, Infect Dis Sect, Bethesda, MD 20892 USA. Nelson R Mandela Sch Med, Durban, South Africa. King Edward VIII Hosp, Durban, South Africa. Tigerberg Hosp, Cape Town, South Africa. RP Krause, DS (reprint author), Vicuron Pharmaceut, 455 S Gulph Rd,Ste 310, King Of Prussia, PA 19406 USA. EM dkrause@vicuron.com NR 30 TC 129 Z9 142 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 SEP 15 PY 2004 VL 39 IS 6 BP 770 EP 775 DI 10.1086/423378 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 904JD UT WOS:000227491500003 PM 15472806 ER PT J AU Philpott, S Burger, H Tarwater, PM Lu, M Gange, SJ Anastos, K Cohen, M Greenblatt, RM Kovacs, A Minkoff, H Young, M Miotti, P Dupuis, M Weiser, B AF Philpott, S Burger, H Tarwater, PM Lu, M Gange, SJ Anastos, K Cohen, M Greenblatt, RM Kovacs, A Minkoff, H Young, M Miotti, P Dupuis, M Weiser, B TI CCR2 genotype and disease progression in a treated population of HIV type 1-infected women SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID ANTIRETROVIRAL THERAPY; POLYMORPHISMS; TRANSMISSION AB Both antiretroviral therapy and the human coreceptor polymorphism CCR2-V64I slow progression of human immunodeficiency virus type 1 (HIV-1) disease. To examine the effect of V64I on disease progression in patients receiving therapy, we determined CCR2 genotypes in the Women's Interagency HIV Study cohort. We studied 2047 HIV-1-infected women, most of whom initiated treatment during the study. No association was seen between CCR2 genotype and either disease progression or therapeutic response, suggesting that the benefits of treatment most likely overshadow the salutary effects of the V64I polymorphism. C1 Albany Med Coll, Wadsworth Ctr, New York State Dept Hlth, Albany, NY 12208 USA. Albany Med Coll, Dept Med, Albany, NY 12208 USA. Montefiore Med Ctr, Dept Epidemiol & Social Med, Bronx, NY 10467 USA. SUNY Hlth Sci Ctr, Dept Obstet & Gynecol, Brooklyn, NY 11203 USA. Univ Texas, Hlth Sci Ctr, Sch Publ Hlth, Houston, TX USA. Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NIAID, Div Aids, Bethesda, MD 20892 USA. Cook Cty Hosp, Dept Med, Chicago, IL 60612 USA. Univ Calif San Francisco, Dept Med & Epidemiol, San Francisco, CA 94143 USA. Los Angeles Cty Med Ctr, Dept Pediat, Los Angeles, CA USA. Univ So Calif, Med Ctr, Los Angeles, CA USA. Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. RP Weiser, B (reprint author), Albany Med Coll, Wadsworth Ctr, New York State Dept Hlth, 120 New Scotland Ave, Albany, NY 12208 USA. EM weiser@wadsworth.org OI Gange, Stephen/0000-0001-7842-512X FU NCRR NIH HHS [M01 RR000083, M01-RR00083, M01 RR000079, M01-RR00079]; NIAID NIH HHS [U01-AI-34994, R01 AI052065, U01 AI034989, U01 AI035004, U01-AI-42590, U01-AI-34993, R01 AI052065-01, U01-AI-31834, U01 AI042590, U01 AI034994, U01-AI-34989, R01-AI-42555, U01 AI031834, U01 AI034993, U01-AI-35004]; NICHD NIH HHS [U01 HD032632, 1 F32 HD08478-01, F32 HD008478, U01-HD-32632] NR 12 TC 5 Z9 5 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 SEP 15 PY 2004 VL 39 IS 6 BP 861 EP 865 DI 10.1086/423386 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 904JD UT WOS:000227491500018 PM 15472820 ER PT J AU Han, JY Rosenzweig, SD Church, JA Holland, SM Ross, LA AF Han, JY Rosenzweig, SD Church, JA Holland, SM Ross, LA TI Variable presentation of disseminated nontuberculous mycobacterial infections in a family with an interferon-gamma receptor mutation SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID BACILLE CALMETTE-GUERIN; DEFICIENCY; SUSCEPTIBILITY; INTERLEUKIN-12; OSTEOMYELITIS; AVIUM; CHILD AB A previously healthy 13-year-old child who had disseminated Mycobacterium avium infection is described. Further history revealed disseminated mycobacterial infections in the patient's father and uncle, starting at 9 years old and 1 year old, respectively. Autosomal dominant interferon-gamma receptor mutation was subsequently identified. Clinical variability among the affected members of the same family is consistent with previous reports suggesting substantial variability in the clinical course of this disorder. C1 Childrens Hosp Los Angeles, Div Infect Dis, Los Angeles, CA 90033 USA. Childrens Hosp Los Angeles, Div Gen Pediat, Los Angeles, CA 90033 USA. Childrens Hosp Los Angeles, Div Clin Immunol & Allergy, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Ross, LA (reprint author), Childrens Hosp Los Angeles, Div Infect Dis, 4650 Sunset Blvd,MS 51, Los Angeles, CA 90033 USA. EM lross@chla.usc.edu NR 18 TC 11 Z9 11 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 SEP 15 PY 2004 VL 39 IS 6 BP 868 EP 870 DI 10.1086/423804 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 904JD UT WOS:000227491500019 PM 15472821 ER PT J AU Hertzano, R Montcouquiol, M Rashi-Elkeles, S Elkon, R Yucel, R Frankel, WN Rechavi, G Moroy, T Friedman, TB Kelley, MW Avraham, KB AF Hertzano, R Montcouquiol, M Rashi-Elkeles, S Elkon, R Yucel, R Frankel, WN Rechavi, G Moroy, T Friedman, TB Kelley, MW Avraham, KB TI Transcription profiling of inner ears from Pou4f3(ddl/ddl) identifies Gfi1 as a target of the Pou4f3 deafness gene SO HUMAN MOLECULAR GENETICS LA English DT Article ID ZINC-FINGER PROTEIN; COCHLEAR HAIR-CELLS; HEARING-LOSS; C-ELEGANS; REPRESSOR GFI1; AXON OUTGROWTH; KNOCKOUT MICE; MUTANT MICE; EXPRESSION; DIFFERENTIATION AB Pou4f3 (Brn3.1, Brn3c) is a class IV POU domain transcription factor that has a central function in the development of all hair cells in the human and mouse inner ear sensory epithelia. A mutation of POU4F3 underlies human autosomal dominant non-syndromic progressive hearing loss DFNA15. Through a comparison of inner ear gene expression profiles of E16.5 wild-type and Pou4f3 mutant deaf mice using a high density oligonucleotide microarray, we identified the gene encoding growth factor independence 1 (Gfi1) as a likely in vivo target gene regulated by Pou4f3. To validate this result, we performed semi-quantitative RT-PCR and in situ hybridizations for Gfi1 on wild-type and Pou4f3 mutant mice. Our results demonstrate that a deficiency of Pou4f3 leads to a statistically significant reduction in Gfi1 expression levels and that the dynamics of Gfi1 mRNA abundance closely follow the pattern of expression for Pou4f3. To examine the role of Gfi1 in the pathogenesis of Pou4f3-related deafness, we performed comparative analyses of the embryonic inner ears of Pou4f3 and Gfi1 mouse mutants using immunohistochemistry and scanning electron microscopy. The loss of Gfi1 results in outer hair cell degeneration, which appears comparable to that observed in Pou4f3 mutants. These results identify Gfi1 as the first downstream target of a hair cell specific transcription factor and suggest that outer hair cell degeneration in Pou4f3 mutants is largely or entirely a result of the loss of expression of Gfi1. C1 Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Rockville, MD 20850 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, David & Inez Myers Lab Genet Res, IL-69978 Tel Aviv, Israel. Univ Klinikum Essen, Inst Zellbiol Tumorforsch, D-45122 Essen, Germany. Jackson Lab, Bar Harbor, ME 04609 USA. Tel Aviv Univ, Sackler Sch Med, IL-52621 Tel Hashomer, Israel. Chaim Sheba Med Ctr, Inst Hematol, IL-52621 Tel Hashomer, Israel. Chaim Sheba Med Ctr, Dept Pediat Hematooncol, IL-52621 Tel Hashomer, Israel. Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Genet Mol Lab, NIH, Rockville, MD 20850 USA. RP Avraham, KB (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. EM karena@post.tau.ac.il RI Moroy, Tarik/D-9923-2011 FU NIDCD NIH HHS [DC000059-04, DC000039-07, DC03611, DC04376, R01 DC005641] NR 58 TC 88 Z9 95 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD SEP 15 PY 2004 VL 13 IS 18 BP 2143 EP 2153 DI 10.1093/hmg/ddh218 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 854ZB UT WOS:000223941400015 PM 15254021 ER PT J AU Chan, WKH Dickerson, A Ortiz, D Pimenta, AF Moran, CM Motil, J Snyder, SJ Malik, K Pant, HC Shea, TB AF Chan, WKH Dickerson, A Ortiz, D Pimenta, AF Moran, CM Motil, J Snyder, SJ Malik, K Pant, HC Shea, TB TI Mitogen-activated protein kinase regulates neurofilament axonal transport SO JOURNAL OF CELL SCIENCE LA English DT Article DE mitogen-activated protein kinase; neurofilaments; axonal transport; phosphorylation; axonal maturation; cytoskeleton; signal transduction ID C-TERMINAL PHOSPHORYLATION; KINESIN-MEDIATED TRANSPORT; CYCLIN-DEPENDENT KINASE-5; GANGLION-CELL NEURONS; MAP KINASE; NF-H; POSTTRANSLATIONAL MODIFICATION; SIGNALING MECHANISMS; HIPPOCAMPAL-NEURONS; ALZHEIMERS-DISEASE AB Mitogen-activated protein kinase (MAP) kinase plays a pivotal role in the development of the nervous system by mediating both neurogenesis and neuronal differentiation. Here we examined whether p42/44 MAP kinase plays a role in axonal transport and the organization of neurofilaments (NFs) in axonal neurites. Dominant-negative p42/44 MAP kinase, anti-MAP kinase antisense oligonucleotides and the MAP kinase inhibitor PD98059 all reduced NF phospho-epitopes and inhibited anterograde NF axonal transport of GFP-tagged NF subunits in differentiated NB2a/d1 neuroblastoma cells. Expression of constitutively active MAP kinase and intracellular delivery of active enzyme increased NF phospho-epitopes and increased NF axonal transport. Longer treatment with PD98059 shifted NF transport from anterograde to retrograde. PD98059 did not inhibit overall axonal transport nor compromise overall axonal architecture or composition. The p38 MAP kinase inhibitor SB202190 did not inhibit NF transport whereas the kinase inhibitor olomoucine inhibited both NF and mitochondrial transport. Axonal transport of NFs containing NF-H whose C-terminal region was mutated to mimic extensive phosphorylation was substantially less affected by PD98059 compared to a wild-type construct. These data suggest that p42/44 MAP kinase regulates NF anterograde transport by NF C-terminal phosphorylation. MAP kinase may therefore stabilize developing axons by promoting the accumulation of NFs within growing axonal neurites. C1 Univ Massachusetts, Ctr Cell Neurobiol & Neurodegenerat Res, Lowell, MA 01854 USA. Univ Massachusetts, Dept Biol Sci, Lowell, MA 01854 USA. Vanderbilt Univ, Dept Pharmacol, Nashville, TN 37232 USA. Univ Tennessee, Ctr Hlth Sci, Coll Med, Dept Pharmacol, Memphis, TN 38163 USA. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Shea, TB (reprint author), Univ Massachusetts, Ctr Cell Neurobiol & Neurodegenerat Res, Lowell, MA 01854 USA. EM thomas_shea@uml.edu NR 87 TC 38 Z9 39 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD SEP 15 PY 2004 VL 117 IS 20 BP 4629 EP 4642 DI 10.1242/jcs.01135 PG 14 WC Cell Biology SC Cell Biology GA 865QV UT WOS:000224718500005 PM 15331628 ER PT J AU Godder, K Eapen, M Laver, JH Zhang, MJ Camitta, BM Wayne, AS Gale, RP Doyle, JJ Yu, LC Chen, AR Garvin, JH Sandler, ES Yeager, AM Edwards, JR Horowitz, MM AF Godder, K Eapen, M Laver, JH Zhang, MJ Camitta, BM Wayne, AS Gale, RP Doyle, JJ Yu, LC Chen, AR Garvin, JH Sandler, ES Yeager, AM Edwards, JR Horowitz, MM TI Autologous hematopoietic stem-cell transplantation for children with acute myeloid leukemia in first or second complete remission: A prognostic factor analysis SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 43rd Annual Meeting of the American-Society-of-Hematology CY DEC 07-11, 2001 CL ORLANDO, FL SP Amer Soc Hematol ID BONE-MARROW-TRANSPLANTATION; ACUTE MYELOGENOUS LEUKEMIA; 10TH AML TRIAL; CANCER GROUP; CHEMOTHERAPY; DURATION; SURVIVAL; THERAPY AB Purpose To determine prognostic factors correlated with outcomes after autologous hematopoietic stem-cell transplantation (HSCT) in children with acute myeloid leukemia (AML). Patients and Methods We studied 219 children who received autologous HSCT for AML in first complete remission(CR) and 73 children in second CR and who were reported to the Autologous Blood and Marrow Transplant Registry. Among 29 of 73 patients who underwent transplantation in second CR, duration of first CR was greater than or equal to 12 months. Results Three-year cumulative incidences of relapse were 37% (95% Cl, 31% to 44%), 60% (95% Cl, 41% to 74%), and 36% (95% Cl, 20% to 53%) for children in first CR, second CR after a short (< 12 months) first CR, and second CR after a long (greater than or equal to 12 months) first CR, respectively. Corresponding 3-year probabilities of leukemia-free survival were 54% (95% Cl, 47% to 60%), 23% (95% Cl, 10% to 39%), and 60% (95% Cl, 42% to 75%). In multivariate analyses, risks of relapse, mortality, and treatment failure (relapse or death, inverse of leukemia-free survival) were higher for patients in second CR after a short first CR than for the other two groups. Transplant-related mortality, treatment failure, and overall mortality rates were higher in older (> 10 years) children. Conclusion Duration of first CR seems to be the most important determinant of outcome. Results in children who experience treatment failure with conventional chemotherapy support the use of autologous transplantation as salvage therapy if such patients achieve a subsequent CR. C1 Med Coll Wisconsin, Hlth Policy Inst, Autologous Blood & Marrow Transplant Registry, Milwaukee, WI USA. Hlth Sci Univ, Portland, OR USA. Virginia Commonwealth Univ Med Coll Virginia, Richmond, VA USA. NCI, Pediat Oncol Branch, Bethesda, MD USA. Ctr Adv Studies Leukemia, Los Angeles, CA USA. Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Louisiana State Univ, Hlth Sci Ctr, Childrens Hosp, New Orleans, LA USA. Columbia Univ Hosp, New York, NY USA. Nemours Childrens Clin, Jacksonville, FL USA. Florida Hosp Canc Inst, Orlando, FL USA. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Inst Canc Res, Pittsburgh, PA USA. RP Eapen, M (reprint author), Med Coll Wisconsin, Int Bone Marrow Transplant Registry, 8701 Watertown Plank Rd,POB 26509, Milwaukee, WI 53226 USA. EM meapen@mail.mcw.edu FU NCI NIH HHS [U24-CA76518] NR 21 TC 12 Z9 14 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 15 PY 2004 VL 22 IS 18 BP 3798 EP 3804 DI 10.1200/JCO.2004.12.142 PG 7 WC Oncology SC Oncology GA 855HR UT WOS:000223964500022 PM 15365077 ER PT J AU Haeryfar, SMM Hoskin, DW AF Haeryfar, SMM Hoskin, DW TI Thy-1: More than a mouse pan-T cell marker SO JOURNAL OF IMMUNOLOGY LA English DT Review ID GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHORED PROTEINS; MICROVASCULAR ENDOTHELIAL-CELLS; TYROSINE KINASE FYN; MONOCLONAL-ANTIBODY; IMMUNOLOGICAL SYNAPSE; PLASMA-MEMBRANE; LYMPHOID-CELLS; LIPID RAFTS; ACTIVATION; ANTIGEN AB Thy-1 (CD90) is a small GPI-anchored protein that is particularly abundant on the surface of mouse thymocytes and peripheral T cells. T cell proliferation and cytokine synthesis in response to Thy-1 cross-linking by specific mAb suggests a role for Thy-1 in mouse T lymphocyte activation. However, a physiological ligand or counterreceptor for murine Thy-1 in the lymphoid compartment has not yet been identified. Thy-1 cross-linking, in the context of strong costimulatory signaling through CD28, results in an activating signal that can at least partially substitute for TCR signaling during mouse T cell activation. Remarkably, Thy-1 cross-linking also results in the potent costimulation of T cells activated through the TCR. This novel dual signaling capacity suggests a possible role for Thy-1 in the maintenance of T cell homeostasis in the absence of TCR triggering, as well as potentiating Ag-induced T cell responses. C1 NIAID, Cellular Biol & Viral Immunol Sect, Viral Dis Lab, Bethesda, MD 20892 USA. Dalhousie Univ, Fac Med, Dept Pathol, Halifax, NS B3H 4H2, Canada. Dalhousie Univ, Fac Med, Dept Microbiol & Immunol, Halifax, NS B3H 4H2, Canada. RP Haeryfar, SMM (reprint author), NIAID, Cellular Biol & Viral Immunol Sect, Viral Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mhaeryfar@niaid.nih.gov NR 87 TC 83 Z9 86 U1 1 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2004 VL 173 IS 6 BP 3581 EP 3588 PG 8 WC Immunology SC Immunology GA 854CN UT WOS:000223878000001 PM 15356100 ER PT J AU Barber, DF Faure, M Long, EO AF Barber, DF Faure, M Long, EO TI LFA-1 contributes an early signal for NK cell cytotoxicity SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; CD8(+) T-CELLS; INHIBITORY RECEPTOR; DROSOPHILA-MELANOGASTER; INTERCELLULAR-ADHESION; ACTIN CYTOSKELETON; INTEGRIN LFA-1; DIRECT BINDING; TARGET-CELLS; ACTIVATION AB Cytotoxicity of human NK cells is activated by receptors that bind ligands on target cells, but the relative contribution of the many different activating and inhibitory NK cell receptors is difficult to assess. In this study, we describe an experimental system that circumvents some of the difficulties. Adhesion through beta(2) integrin LFA-1 is a common requirement of CTLs and NK cells for efficient lysis of target cells. However, the contribution of LFA-1 to activation signals for NK cell cytotoxicity, besides its role in adhesion, is unclear. The role of LFA-1 was evaluated by exposing NK cells to human ICAM-1 that was either expressed on a Drosophila insect cell line, or directly coupled to beads. Expression of ICAM-I on insect cells was sufficient to induce lysis by NK cells through LFA-1. Coexpression of peptide-loaded HLA-C with ICAM-1 on insect cells blocked the LFA-1-dependent cytotoxicity of NK cells that expressed HLA-C-specific inhibitory receptors. Polarization of cytotoxic granules in NK cells toward ICAM-1- and ICAM-2-coated beads showed that engagement of LFA-1 alone is sufficient to initiate activation signals in NK cells. Thus, in contrast to T cells, in which even adhesion through LFA-1 is dependent on signals from other receptors, NK cells receive early activation signals directly through LFA-1. C1 NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Long, EO (reprint author), NIAID, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM eLong@nih.gov RI Barber, Domingo/G-1257-2010; Long, Eric/G-5475-2011 OI Barber, Domingo/0000-0001-8824-5405; Long, Eric/0000-0002-7793-3728 NR 65 TC 137 Z9 142 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2004 VL 173 IS 6 BP 3653 EP 3659 PG 7 WC Immunology SC Immunology GA 854CN UT WOS:000223878000011 PM 15356110 ER PT J AU Mooney, JM Klem, J Wulfing, C Mijares, LA Schwartzberg, PL Bennett, M Schatzle, JD AF Mooney, JM Klem, J Wulfing, C Mijares, LA Schwartzberg, PL Bennett, M Schatzle, JD TI The murine NK receptor 2B4 (CD244) exhibits inhibitory function independent of signaling lymphocytic activation molecule-associated protein expression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; LINKED LYMPHOPROLIFERATIVE DISEASE; T-CELLS; IMMUNOGLOBULIN SUPERFAMILY; CUTTING EDGE; 2B4-MEDIATED ACTIVATION; IMMUNE-RESPONSE; SAP; CLONING; MEMBER AB 2B4 (CD244) is a receptor belonging to the CD2-signaling lymphocytic activation molecule family and is found on all murine NK cells and a subset of NKT and CD8(+) T cells. Murine 2B4 is expressed as two isoforms (2B4 short and 2B4 long) that arise by alternative splicing. They differ only in their cytoplasmic domains and exhibit opposing function when expressed in the RNK-16 cell line. The ligand for 2B4, CD48, is expressed on all hemopoietic cells. Previous studies have shown that treatment of NK cells with a 2B4 mAb results in increased cytotoxicity and IFN-gamma production. In this report, we used CD48(+/-) variants of the P815 tumor cell line and 2B4 knockout mice to show that engagement of 2B4 by its counterreceptor, CD48, expressed on target cells leads to an inhibition in NK cytotoxicity. The addition of 2B4 or CD48 mAb relieves this inhibition resulting in enhanced target cell lysis. This 2B4-mediated inhibition acts independently of signaling lymphocytic activation molecule-associated protein expression. Imaging studies show that 2B4 preferentially accumulates at the interface between NK and target cells during nonlytic events also indicative of an inhibitory receptor. This predominant inhibitory function of murine 2B4 correlates with increased 2B4 long isoform level expression over 2B4 short. C1 Univ Texas, SW Med Ctr, Grad Program Immunol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Ctr Immunol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Cell Biol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Ctr Immunol, Dallas, TX 75390 USA. Univ Texas, SW Med Ctr, Dept Pathol, Dallas, TX 75390 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Mooney, JM (reprint author), Univ Texas, SW Med Ctr, Grad Program Immunol, 5323 Harry Hines Blvd,NB7-230, Dallas, TX 75390 USA. EM Jill.Mooney@utsouthwestern.edu FU NIAID NIH HHS [R01AI054902, P01AI38938] NR 50 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 SEP 15 PY 2004 VL 173 IS 6 BP 3953 EP 3961 PG 9 WC Immunology SC Immunology GA 854CN UT WOS:000223878000045 PM 15356144 ER PT J AU Rosenzweig, SD Schwartz, OM Brown, MR Leto, TL Holland, SM AF Rosenzweig, SD Schwartz, OM Brown, MR Leto, TL Holland, SM TI Characterization of a dipeptide motif regulating IFN-gamma receptor 2 plasma membrane accumulation and IFN-gamma responsiveness SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MYCOBACTERIAL INFECTION; DEFICIENT MICE; T-CELLS; EXPRESSION; CHAIN; ACTIVATION; GROWTH; IDENTIFICATION; SUSCEPTIBILITY; TRAFFICKING AB The IFN-gammaR complex is composed of two IFN-gammaR1 and two IFN-gammaR2 polypeptide chains. Although IFN-gammaR1 is constitutively expressed on all nucleated cells, IFN-gammaR2 membrane display is selective and tightly regulated. We created a series of fluorescent-tagged IFN-gammaR2 expression constructs to follow the molecule's cell surface expression and intracellular distribution. Truncation of the receptor immediately upstream of Leu-Ile 255-256 (254X) created a receptor devoid of signaling that overaccumulated on the cell surface. In addition, this truncated receptor inhibited wild-type IFN-gammaR2 activity and therefore exerted a dominant negative effect. In-frame deletion (255Delta2) or alanine substitution (LI255-256AA) of these amino acids created mutants that overaccumulated on the plasma membrane, but had enhanced function. Single amino acid substitutions (L255A or I256A) had a more modest effect. In-frame deletions upstream (253Delta2), but not downstream (257Delta2), of Leu-Ile 255-256 also led to overaccumulation. A truncation within the IFN-gammaR2 Jak2 binding site (270X) led to a mutant devoid of function that did not overaccumulate and did not affect wild-type IFN-gammaR2 signaling. We have created a series of novel mutants of IFN-gammaR2 that have facilitated the identification of intracellular domains that control IFN-gammaR2 accumulation and IFN-gamma responsiveness. In contrast to IFN-gammaR1, not only dominant negative, but also dominant gain-of-function, mutations were created through manipulation of IFN-gammaR2 Leu-Ile 255-256. These IFN-gammaR2 mutants will allow fine dissection of the role of IFN-gamma signaling in immunity. C1 NIAID, Host Def Lab, Bethesda, MD 20892 USA. NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. NIAID, Biol Imaging Facil, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Clin Immunol Lab, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), Bldg 10,Room 11N103,10 Ctr Dr,MSC 1886, Bethesda, MD 20892 USA. EM smh@nih.gov FU FIC NIH HHS [R01TW006644] NR 33 TC 13 Z9 14 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 SEP 15 PY 2004 VL 173 IS 6 BP 3991 EP 3999 PG 9 WC Immunology SC Immunology GA 854CN UT WOS:000223878000049 PM 15356148 ER PT J AU Rosenzweig, SD Dorman, SE Uzel, G Shaw, S Scurlock, A Brown, MR Buckley, RH Holland, SM AF Rosenzweig, SD Dorman, SE Uzel, G Shaw, S Scurlock, A Brown, MR Buckley, RH Holland, SM TI A novel mutation in IFN-gamma receptor 2 with dominant negative activity: Biological consequences of homozygous and heterozygous states SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BACILLE CALMETTE-GUERIN; SMALL DELETION HOTSPOT; INTERFERON-GAMMA; MYCOBACTERIAL INFECTION; EXPRESSION; CHAIN; SUSCEPTIBILITY; DEFICIENCY; LYMPHOCYTES; DOMAIN AB We identified two siblings homozygous for a single base pair deletion in the IFN-gammaR2 transmembrane domain (791delG) who presented with multifocal Mycobacterium abscessus osteomyelitis (patient 1) and disseminated CMV and Mycobacterium avium complex infection (patient 2), respectively. Although the patients showed no IFN-gammaR activity, their healthy heterozygous parents showed only partial IFN-gammaR activity. An HLA-identical bone marrow transplant from the mother led patient 1 to complete hemopoietic reconstitution, but only partial IFN-gammaR function. We cloned and expressed fluorescent fusion proteins of the wild-type IFN-gammaR2, an IFN-gammaR2 mutant previously described to produce a complete autosomal recessive deficiency (278del2), and of 791delG to determine whether the intermediate phenotype in the 791delG heterozygous state was caused by haploinsufficiency or a dominant negative effect. When cotransfected together with the wild-type vector into IFN-gammaR2-deficient fibroblasts, the fusion protein with 791delG inhibited IFN-gammaR function by 48.7 +/- 5%, whereas fusion proteins with 278del2 had no inhibitory effect. Confocal microscopy of 791delG fusion proteins showed aberrant diffuse intracellular accumulation without plasma membrane localization. The fusion protein created by 791delG did not complete Golgi processing, and was neither expressed on the plasma membrane, nor shed extracellularly. The mutant construct 791delG exerts dominant negative effects on IFN-gamma signaling without cell surface display, suggesting that it is acting on pathways other than those involved in cell surface recognition of ligand. C1 NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. NIAID, Host Def Lab, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Clin Immunol Lab, Bethesda, MD 20892 USA. Duke Univ, Ctr Med, Dept Pediat, Durham, NC 27710 USA. Duke Univ, Ctr Med, Dept Immunol, Durham, NC 27710 USA. RP Holland, SM (reprint author), NIAID, Lab Clin Infect Dis, NIH, Bldg 10,Room 11N103,10 Ctr Dr,Mail Stop Code 1886, Bethesda, MD 20892 USA. EM smh@nih.gov FU FIC NIH HHS [R01 TW006644] NR 27 TC 51 Z9 54 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 SEP 15 PY 2004 VL 173 IS 6 BP 4000 EP 4008 PG 9 WC Immunology SC Immunology GA 854CN UT WOS:000223878000050 PM 15356149 ER PT J AU Kaviratne, M Hesse, M Leusink, M Cheever, AW Davies, SJ McKerrow, JH Wakefield, LM Letterio, JJ Wynn, TA AF Kaviratne, M Hesse, M Leusink, M Cheever, AW Davies, SJ McKerrow, JH Wakefield, LM Letterio, JJ Wynn, TA TI IL-13 activates a mechanism of tissue fibrosis that is completely TGF-beta independent SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; SCHISTOSOMA-MANSONI INFECTION; HEPATIC-FIBROSIS; T-CELLS; TARGETED DISRUPTION; SIGNAL-TRANSDUCTION; PERIPORTAL FIBROSIS; IFN-GAMMA; GRANULOMATOUS PATHOLOGY; INFLAMMATORY RESPONSE AB Fibrosis is a characteristic feature in the pathogenesis of a wide spectrum of diseases. Recently, it was suggested that IL-13-dependent fibrosis develops through a TGF-beta1 and matrix metalloproteinase-9-dependent (MMP-9) mechanism. However, the significance of this pathway in a natural disorder of fibrosis was not investigated. In this study, we examined the role of TGF-beta in IL-13-dependent liver fibrosis caused by Schistosoma mansoni infection. Infected IL-13(-/-) mice showed an almost complete abrogation of fibrosis despite continued and undiminished production of TGF-beta1. Although MMP-9 activity was implicated in the IL-13 pathway, MMP-9(-/-) mice displayed no reduction in fibrosis, even when chronically infected. To directly test the requirement for TGF-beta, studies were also performed with neutralizing anti-TGF-beta Abs, soluble antagonists (soluble TGF-betaR-Fc), and Tg mice (Smad3(-/-) and TGF-betaRII-Fc Tg) that have disruptions in all or part of the TGF-beta signaling cascade. In all cases, fibrosis developed normally and with kinetics similar to wild-type mice. Production of IL-13 was also unaffected. Finally, several genes, including interstitial collagens, several MMPs, and tissue inhibitors of metalloprotease-1 were up-regulated in TGF-beta1(-/-) mice by IL-13, demonstrating that IL-13 activates the fibrogenic machinery directly. Together, these studies provide unequivocal evidence of a pathway of fibrogenesis that is IL-13 dependent but TGF-beta1 independent, illustrating the importance of targeting IL-13 directly in the treatment of infection-induced fibrosis. C1 NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Biomed Res Inst, Rockville, MD 20852 USA. Vet Affairs Med Ctr, Trop Dis Res Unit, Dept Pathol, San Francisco, CA 94121 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bldg 50,Room 6154,MSC 8003, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 NR 79 TC 183 Z9 200 U1 3 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2004 VL 173 IS 6 BP 4020 EP 4029 PG 10 WC Immunology SC Immunology GA 854CN UT WOS:000223878000052 PM 15356151 ER PT J AU Glass, WG Subbarao, K Murphy, B Murphy, PM AF Glass, WG Subbarao, K Murphy, B Murphy, PM TI Mechanisms of host defense following severe acute respiratory syndrome-coronavirus (SARS-CoV) pulmonary infection of mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ADAPTIVE IMMUNITY; VIRUS-INFECTION; OPPORTUNISTIC INFECTIONS; FUNCTIONAL RECEPTOR; VERO CELLS; INTERFERON; SENSITIVITY; EXPRESSION; CHEMOKINES; DIAGNOSIS AB We describe a model of severe acute respiratory syndrome-coronavirus (SARS-CoV) infection in C57BL/6 mice. A clinical isolate of the virus introduced intranasally replicated transiently to high levels in the lungs of these mice, with a peak on day 3 and clearance by day 9 postinfection. Viral RNA localized to bronchial and bronchiolar epithelium. Expression of mRNA for angiotensin converting enzyme 2, the SARS-CoV receptor, was detected in the lung following infection. The virus induced production in the lung of the proinflammatory chemokines CCL2, CCL3, CCL5, CXCL9, and CXCL10 with differential kinetics. The receptors for these chemokines were also detected. Most impressively, mRNA for CXCR3, the receptor for CXCL9 and CXCL10, was massively up-regulated in the lungs of SARS-CoV-infected mice. Surprisingly Th1 (and Th2) cytokines were not detectable, and there was little local accumulation of leukocytes and no obvious clinical signs of pulmonary dysfunction. Moreover, beige, CD1(-/-), and RAG1(-/-) mice cleared the virus normally. Infection spread to the brain as it was cleared from the lung, again without leukocyte accumulation. Infected mice had a relative failure to thrive, gaining weight significantly more slowly than uninfected mice. These data indicate that C57BL/6 mice support transient nonfatal systemic infection with SARS-CoV in the lung, which is able to disseminate to brain. In this species, proinflammatory chemokines may coordinate a rapid and highly effective innate antiviral response in the lung, but NK cells and adaptive cellular immunity are not required for viral clearance. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Murphy, PM (reprint author), NIAID, Host Def Lab, NIH, Bldg 10,Room 11N113, Bethesda, MD 20892 USA. EM pmm@nih.gov NR 47 TC 100 Z9 107 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 SEP 15 PY 2004 VL 173 IS 6 BP 4030 EP 4039 PG 10 WC Immunology SC Immunology GA 854CN UT WOS:000223878000053 PM 15356152 ER PT J AU Dedicoat, M Newton, R Alkharsah, KR Sheldon, J Szabados, I Ndlovu, B Page, T Casabonne, D Gilks, CF Cassol, SA Whitby, D Schulz, TF AF Dedicoat, M Newton, R Alkharsah, KR Sheldon, J Szabados, I Ndlovu, B Page, T Casabonne, D Gilks, CF Cassol, SA Whitby, D Schulz, TF TI Mother-to-child transmission of human herpesvirus-8 in South Africa SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Meeting of the Federation-of-Infection-Societies CY NOV 19-21, 2003 CL Cardiff, ENGLAND SP Fed Infection Soc ID KAPOSIS-SARCOMA; HERPESVIRUS HUMAN-HERPESVIRUS-8; INFECTION; PREVALENCE; ANTIBODIES; HHV-8; MEN; SEROPREVALENCE; PERFORMANCE; POPULATION AB To investigate transmission of human herpesvirus (HHV)-8,2546 mother-child pairs were recruited from rural clinics in South Africa and were tested for antibodies against lytic and latent HHV-8 antigens. The prevalence of antibodies in children increased with increasing maternal antibody titer (lytic, chi(1)(2) and 26 and P<.001; latent, χ(2)(1)=55, and P<.001). HHV-8 DNA was detectable in 145 of 978 maternal saliva samples (mean virus load, 488,450 copies/mL; range, 1550-660,000 copies/mL) and in 12 of 43 breast-milk samples (mean virus load, 5800 copies/mL; range, 1550-12,540 copies/mL). The prevalence of HHV-8 DNA in maternal saliva was unrelated to latent anti-HHV-8 antibody status but was higher in mothers with the highest titers of lytic antibodies than in other mothers (34% vs. 8%; P<.001). The prevalence of lytic anti-HHV-8 antibodies in children was 13% (70/528) if the mother did not have HHV-8 in saliva and was 29% (8/28) if the mother had a high HHV-8 load (>50,000 copies/mL) in saliva (odds ratio, 2.6; 95% confidence interval, 1.1-6.2). The presence of HHV-8 DNA in maternal saliva was unrelated to latent antibodies in children. Saliva could be a route of transmission of HHV-8 from person to person, although other routes cannot be ruled out. C1 Univ Liverpool, Liverpool Sch Trop Med, Liverpool L3 5QA, Merseyside, England. Canc Res UK Epidemiol Unit, Oxford, England. Hlabisa Hosp, Hlabisa, South Africa. Africa Ctr Populat & Hlth Res, Hlabisa, South Africa. Hannover Med Sch, Dept Virol, D-3000 Hannover, Germany. NCI, Viral Epidemiol Branch, Frederick, MD 21701 USA. RP Dedicoat, M (reprint author), Radcliffe Infirm, Canc Res UK Epidemiol Unit, Gibson Bldg, Oxford OX2 6HE, England. EM martded@aol.com RI Gilks, Charles/B-4184-2012; Casabonne, Delphine/H-6425-2014; Alkharsah, Khaled/A-6726-2012; Alkharsah, Khaled/O-9087-2016; OI Alkharsah, Khaled/0000-0002-4641-2604; Alkharsah, Khaled/0000-0002-4641-2604; Sheldon, Julie/0000-0002-8240-0010 NR 31 TC 73 Z9 79 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 SEP 15 PY 2004 VL 190 IS 6 BP 1068 EP 1075 DI 10.1086/423326 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 850SS UT WOS:000223633400005 PM 15319855 ER PT J AU Aston, C Jiang, LX Sokolov, BP AF Aston, C Jiang, LX Sokolov, BP TI Microarray analysis of postmortem temporal cortex from patients with schizophrenia SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE microarray; myelination; epigenetic; chromatin; synapse; circadian rhythms ID PROBE LEVEL DATA; GENE-EXPRESSION; PSYCHIATRIC-DISORDERS; PLANUM TEMPORALE; BIPOLAR DISORDER; MESSENGER-RNAS; BRAIN; SLEEP; ABNORMALITIES; FRACTALKINE AB To examine molecular mechanisms associated with schizophrenia this study measured expression of approximately 12,000 genes in the middle temporal gyrus from 12 subjects with schizophrenia and 14 matched normal controls. Among the most consistent changes in genes with robust expression were significant decreases in the expression of myelination-related genes MAG, PLLP (TM4SF11), PLP1, ERBB3 in subjects with schizophrenia. There was also altered expression of genes regulating neurodevelopment (TRAF4, Neurod1, histone deacetylase 3), a circadian pacemaker (PER1), and several other genes involved in regulation of chromatin function and signaling mechanisms. These findings support the hypothesis that schizophrenia is associated with abnormalities in oligodendroglia and provide initial evidence suggesting a role for epigenetic mechanisms and altered circadian rhythms in this disorder. (C) 2004 Wiley-Liss, Inc. C1 NIDA, Mol Neuropsychiat Branch, DHHS, NIH, Baltimore, MD 21224 USA. Wyeth Ayerst Res, Neurosci Discovery Res, Princeton, NJ 08543 USA. RP Sokolov, BP (reprint author), NIDA, Mol Neuropsychiat Branch, DHHS, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM bsokolov@intra.nida.nih.gov NR 36 TC 201 Z9 207 U1 0 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD SEP 15 PY 2004 VL 77 IS 6 BP 858 EP 866 DI 10.1002/jnr.20208 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 852DN UT WOS:000223735500008 PM 15334603 ER PT J AU Amsden, BG Stubbe, BG Horkay, F De Smedt, SC Demeester, J AF Amsden, BG Stubbe, BG Horkay, F De Smedt, SC Demeester, J TI Modeling the swelling pressure of degrading hydroxyethylmethacrylate-grafted dextran hydrogels SO JOURNAL OF POLYMER SCIENCE PART B-POLYMER PHYSICS LA English DT Article DE drug delivery systems; hydrogels; modeling; scaling theory ID POLYMER NETWORKS; DEGRADATION; RELEASE AB Degrading hydroxyethylmethacrylate-grafted dextran (dex-HEMA) hydrogels generate a relatively sudden increase in osmotic pressure upon degradation into dextran solutions. This phenomenon is currently being examined as a possible means of developing a pulsatile drug-delivery system. Here a mathematical model based on scaling concepts is presented to describe this sudden increase in swelling pressure and to provide a framework for the rational design of pulsatile delivery systems based on this phenomena. The model provides a good fit to the swelling pressures measured for dex-HEMA gel/free dextran mixtures that simulate degrading dex-HEMA gels. (C) 2004 Wiley Periodicals, Inc. C1 Queens Univ, Dept Chem Engn, Kingston, ON K7L 3N6, Canada. State Univ Ghent, Dept Pharmaceut, Lab Gen Biochem & Phys Pharm, B-9000 Ghent, Belgium. Natl Inst Child Hlth & Dev, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. RP Amsden, BG (reprint author), Queens Univ, Dept Chem Engn, Kingston, ON K7L 3N6, Canada. EM amsden@chec.queensu.ca NR 16 TC 0 Z9 0 U1 1 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-6266 J9 J POLYM SCI POL PHYS JI J. Polym. Sci. Pt. B-Polym. Phys. PD SEP 15 PY 2004 VL 42 IS 18 BP 3397 EP 3404 DI 10.1002/polb.20227 PG 8 WC Polymer Science SC Polymer Science GA 851NM UT WOS:000223691800009 ER PT J AU Potosky, AL Davis, WW Hoffman, RM Stanford, JL Stephenson, RA Penson, DF Harlan, LC AF Potosky, AL Davis, WW Hoffman, RM Stanford, JL Stephenson, RA Penson, DF Harlan, LC TI Five-year outcomes after prostatectomy or radiotherapy for prostate cancer: The prostate cancer outcomes study SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID QUALITY-OF-LIFE; ANDROGEN-DEPRIVATION THERAPY; LONG-TERM SURVIVAL; RADICAL PROSTATECTOMY; SEXUAL FUNCTION; RADIATION-THERAPY; PRACTICE PATTERNS; CARCINOMA; MEN; RELIABILITY AB Background: Men treated for clinically localized prostate cancer with either radical prostatectomy or external beam radiotherapy usually survive many years with the side effects of these treatments. We present treatment-specific quality-of-life outcomes for prostate cancer patients 5 years after initial diagnosis. Methods: The cohort consisted of men aged 55-74 years who were newly diagnosed with clinically localized prostate cancer in 1994-1995 and were treated with radical prostatectomy (n = 901) or external beam radiotherapy (n = 286). We used clinical and quality-of-life data previously collected at the time of diagnosis (i.e., baseline) and at the 2-year follow-up and data newly collected at 5 years after diagnosis to compare urinary, bowel, and sexual function and to examine temporal changes in those functions. Odds ratios (ORs) and adjusted percentages were calculated by logistic regression. All statistical tests were two-sided. Results: At 5 years after diagnosis, overall sexual function declined in both groups to approximately the same level. However, at 5 years after diagnosis, erectile dysfunction was more prevalent in the radical prostatectomy group than in the external beam radiotherapy group (79.3% versus 63.5%; OR = 2.5, 95% confidence interval [CI] = 1.6 to 3.8). Approximately 14%-16% of radical prostatectomy and 4% of external beam radiotherapy patients were incontinent at 5 years (OR = 4.4, 95% CI = 2.2 to 8.6). Bowel urgency and painful hemorrhoids were more common in the external beam radiotherapy group than in the radical prostatectomy group. All of these differences remained statistically significant after adjustment for confounders and for differences between treatment groups in some baseline characteristics. Conclusions: At 5 years after diagnosis, men treated with radical prostatectomy for localized prostate cancer continue to experience worse urinary incontinence than men treated with external beam radiotherapy. However, the two treatment groups were more similar to each other with respect to overall sexual function, mostly because of a continuing decline in erectile function among the external beam radiotherapy patients between years 2 and 5. C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. New Mexico VA Hlth Care Syst, Albuquerque, NM USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Utah, Dept Med, Div Urol, Salt Lake City, UT 84112 USA. Univ So Calif, Keck Sch Med, Norris Canc Ctr, Los Angeles, CA USA. RP Potosky, AL (reprint author), NCI, Div Canc Control & Populat Sci, EPN Rm 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM potosky@nih.gov FU NCI NIH HHS [N01-PC-67005, N01-PC-67000, N01-PC-67006, N01-PC-67007, N01-PC-67009, N01-PC-67010] NR 37 TC 348 Z9 356 U1 1 U2 18 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 SEP 15 PY 2004 VL 96 IS 18 BP 1358 EP 1367 DI 10.1093/jnci/djh259 PG 10 WC Oncology SC Oncology GA 855UK UT WOS:000224000200006 PM 15367568 ER PT J AU Engels, EA Viscidi, RP Galloway, DA Carter, JJ Cerhan, JR Davis, S Cozen, W Severson, RK de Sanjose, S Colt, JS Hartge, P AF Engels, EA Viscidi, RP Galloway, DA Carter, JJ Cerhan, JR Davis, S Cozen, W Severson, RK de Sanjose, S Colt, JS Hartge, P TI Case-control study of simian virus 40 and non-Hodgkin lymphoma in the United States SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BK VIRUS; LYMPHOPROLIFERATIVE DISORDERS; POLIOVIRUS VACCINE; SEROLOGIC EVIDENCE; JC VIRUS; INFECTION; SV40; ASSOCIATION; EXPOSURE; MESOTHELIOMAS AB Background: Recent studies have reported detection of simian virus 40 (SV40) DNA in tumor tissues from 15%-43% of U.S. non-Hodgkin lymphoma (NHL) patients. SV40 accidentally contaminated U.S. poliovirus vaccines that were widely administered from 1955 through 1962. However, epidemiologic data linking SV40 with NHL are lacking. Methods: We obtained serum samples from 724 incident NHL case patients and 622 control subjects from a population-based U.S. case-control study. SV40 serostatus was analyzed by two independent laboratories (designated A and B) using similar virus-like particle (VLP) enzyme immunoassays. Associations with serostatus were assessed with logistic regression, adjusting for sex, race, birth year, and study site. VLPs for the human polyomaviruses BK and JC were used in competitive inhibition experiments to assess the specificity of SV40 reactivity. Statistical tests were two-sided. Results: SV40 antibody results from the two laboratories were correlated (R = 0.59; P < .001). Laboratories A and B detected SV40 seropositivity in 7.2% and 9.8% of NHL case patients, respectively, and in 10.5% and 9.6% of control subjects, respectively. SV40 seropositivity was not associated with increased NHL risk (laboratory A: adjusted odds ratio [OR] = 0.68, 95% confidence interval [CI] = 0.46 to 1.00; laboratory B: adjusted OR = 1.02, 95% CI = 0.71 to 1.47). SV40 seropositivity was not associated with NHLs of any specific histology or site. Among subjects born before 1963, 1.0%-1.6% showed SV40-specific reactivity, i.e., SV40 reactivity confirmed in competitive inhibition experiments, whereas (based on limited data) none born subsequently demonstrated SV40-specific reactivity. Conclusions: In persons born before 1963, the presence of SV40-specific antibodies, although rare, could reflect exposure to SV40-contaminated vaccines. Nevertheless, NHL risk was unrelated to serologic evidence of SV40 exposure or infection. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Mayo Clin, Rochester, MN USA. Univ So Calif, Los Angeles, CA USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Inst Catala Oncol, Barcelona, Spain. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8010, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov RI de Sanjose Llongueras, Silvia/H-6339-2014; OI Cerhan, James/0000-0002-7482-178X NR 32 TC 31 Z9 34 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 15 PY 2004 VL 96 IS 18 BP 1368 EP 1374 DI 10.1093/jnci/djh266 PG 7 WC Oncology SC Oncology GA 855UK UT WOS:000224000200007 PM 15367569 ER PT J AU Rusiecki, JA De Roos, A Lee, WJ Dosemeci, M Lubin, JH Hoppin, JA Blair, A Alavanja, MCR AF Rusiecki, JA De Roos, A Lee, WJ Dosemeci, M Lubin, JH Hoppin, JA Blair, A Alavanja, MCR TI Cancer incidence among pesticide applicators exposed to atrazine in the agricultural health study SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID NON-HODGKINS-LYMPHOMA; HERBICIDE MANUFACTURING WORKERS; RISK-FACTORS; TRIAZINE; IOWA; MEN; RATS; MINNESOTA; EXPOSURES; COUNTIES AB Background. Atrazine is the most heavily applied agricultural pesticide for crop production in the United States. Both animal and human studies have suggested that atrazine is possibly carcinogenic, but results have been mixed. We evaluated cancer incidence in atrazine-exposed pesticide applicators among 53 943 participants in the Agricultural Health Study, a prospective cohort study of licensed pesticide applicators in Iowa and North Carolina. Methods: We obtained detailed pesticide exposure information using a self-administered questionnaire completed at the time of enrollment (1993-1997). Cancer incidence was followed through December 31, 2001. We used adjusted Poisson regression to calculate rate ratios (RRs) and 95% confidence intervals (CIs) of multiple types of cancer among atrazine exposed applicators. P-trend values were calculated using atrazine exposure as a continuous variable, and all statistical tests were two-sided. Two exposure metrics were used: quartiles of lifetime days of exposure and quartiles of intensity-weighted lifetime days of exposure. Results: 36 513 (68%) applicators reported ever using atrazine; exposure was not associated with overall cancer incidence. Comparisons of cancer incidence in applicators with the highest atrazine exposure and those with the lowest exposure, assessed by lifetime days (RRLD) and intensity-weighted lifetime days (RRIWLD) Of exposure yielded the following results: prostate cancer, RRLD = 0.88, 95% CI = 0.63 to 1.23, P-trend = .26, and RRIWLD = 0.89, 95 % CI = 6.43 to 1.25, P-trend = .35; lung cancer, RRLD 1.91, 95% CI = 0.93 to 3.94, P-trend = .08, and RRIWLD = 1.37, 95% CI = 0.65 to 2.86, P-trend = .19; bladder cancer, RRLD = 3.06, 95 % CI = 0.86 to 10.81, P-trend = .18, and RRIWLD = 0.85, 95% CI = 0.24 to 2.94, P-trend = .71; non-Hodgkin lymphomaq RRLD = 1.61, 95 % CI = 0.62 to 4.169, P-trend =.35, and RRIWLD = 1.75, 95% CI = 0.73 to 4.20, P-trend = .14; and multiple myeloma, RRLD = 1.60, 95% CI = 0.37 to 7.01, P-trend =.41, and RRIWLD = 2.17, 95% CI = 0.45 to 10.32, P-trend = .21. Conclusions: Our analyses did not find any clear associations between atrazine exposure and any cancer analyzed. However, further studies are warranted for tumor types in which there was a suggestion of trend (lung, bladder, non-Hodgkin lymphoma, and multiple myeloma). C1 NCI, Occupat & Environm Epidemiol Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NCI, Biostat Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Alavanja, MCR (reprint author), NCI, Occupat & Environm Epidemiol Branch, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd,EPS 8000, Bethesda, MD 20892 USA. EM alavanjm@mail.nih.gov NR 42 TC 78 Z9 83 U1 0 U2 20 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 SEP 15 PY 2004 VL 96 IS 18 BP 1375 EP 1382 PG 8 WC Oncology SC Oncology GA 855UK UT WOS:000224000200008 PM 15367570 ER PT J AU Djousse, L Schatzkin, A Chibnik, LB D'Agostino, RB Kreger, BE Ellison, RC AF Djousse, L Schatzkin, A Chibnik, LB D'Agostino, RB Kreger, BE Ellison, RC TI Alcohol consumption and the risk of bladder cancer in the Framingham Heart Study SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BEVERAGE CONSUMPTION; DRINKING; SMOKING; EPIDEMIOLOGY; COHORT AB The association between alcohol consumption and bladder cancer is controversial. We used data from 10 125 participants in the Framingham Heart Study to assess the association between total and beverage-specific alcohol consumption and the risk of bladder cancer. For each case of bladder cancer, up to five control subjects were selected and matched on major confounders using a risk set method. We used conditional logistic regression to assess the risk of bladder cancer according to categories of alcohol consumption. During a mean follow-up of 27.3 +/- 10.1 years, there were 126 incident cases of bladder cancer. There was no statistically significant association between alcohol consumption and risk of bladder cancer (P-trend = .3). In beverage-specific analyses, beer consumption was associated with a reduced risk of bladder cancer (P-trend = .03), whereas wine (P-trend = .7) and spirit (P-trend = .2) consumption were not. Our data suggest that total and beverage-specific alcohol consumption are not associated with an increased risk of bladder cancer. C1 Boston Univ, Sch Med, Evans Dept Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Evans Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. RP Djousse, L (reprint author), Boston Univ, Sch Med, Evans Dept Med, Prevent Med & Epidemiol Sect, Rm B-612,715 Albany St, Boston, MA 02118 USA. EM ldjousse@bu.edu RI Djousse, Luc/F-5033-2017 OI Djousse, Luc/0000-0002-9902-3047 FU NHLBI NIH HHS [N01-HC-38038, 05K01 HL-070444-02] NR 18 TC 20 Z9 22 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 15 PY 2004 VL 96 IS 18 BP 1397 EP 1400 DI 10.1093/jnc/djh263 PG 4 WC Oncology SC Oncology GA 855UK UT WOS:000224000200011 PM 15367573 ER PT J AU Solomon, D Schiffman, M AF Solomon, D Schiffman, M TI Re: Have we resolved how to triage equivocal cervical cytology? Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Div Canc Prevent, NIH, Rockville, MD 20852 USA. NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Solomon, D (reprint author), NCI, Div Canc Prevent, NIH, 6130 Execut Blvd,EPN RM 2130, Rockville, MD 20852 USA. EM ds87v@nih.gov NR 4 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 15 PY 2004 VL 96 IS 18 BP 1402 EP 1402 DI 10.1093/jnci/djh278 PG 1 WC Oncology SC Oncology GA 855UK UT WOS:000224000200013 ER PT J AU Umar, A AF Umar, A TI Re: Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, NIH, Bethesda, MD 20892 USA. RP Umar, A (reprint author), NCI, NIH, 6130 Execut Blvd,EPN 2141, Bethesda, MD 20892 USA. EM asad.umar@nih.gov NR 7 TC 0 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 15 PY 2004 VL 96 IS 18 BP 1403 EP 1404 DI 10.1093/jnci/djh281 PG 2 WC Oncology SC Oncology GA 855UK UT WOS:000224000200015 ER PT J AU Le Foll, B Goldberg, SR AF Le Foll, B Goldberg, SR TI Rimonabant, a CB1 antagonist, blocks nicotine-conditioned place preferences SO NEUROREPORT LA English DT Article DE CBI receptors; discrimination; rats; reward; smoking ID DOPAMINE D-3 RECEPTOR; COCAINE-SEEKING BEHAVIOR; CANNABINOID RECEPTOR; RATS; SENSITIZATION; BUPROPION; AGONIST; REWARD; BRAIN; CUES AB The effects of Rimonabant (SR141716), an antagonist at cannabinoid CB, receptors, were evaluated in animal models for subjective and rewarding effects of nicotine. Acute administration of I or 3 mg/kg SR141716 blocked expression of nicotine-induced conditioned place preferences. SR141716 (0.3-3 mg/kg) was also studied in rats trained to discriminate nicotine from saline under a fixed-ratio schedule of food delivery In contrast to nicotine replacement therapy and bupropion, SR141716 did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings support the proposed use of SR141716 for smoking cessation and indicate that it would selectively reduce the influence of environmental stimuli that contribute to persistent smoking behavior, without affecting subjective responses to nicotine. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Le Foll, B (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM blefoll@intra.nida.nih.gov RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 NR 23 TC 107 Z9 110 U1 2 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD SEP 15 PY 2004 VL 15 IS 13 BP 2139 EP 2143 DI 10.1097/00001756-200409150-00028 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 871NU UT WOS:000225141200028 PM 15486497 ER PT J AU Yang, YK Yeh, TL Chiu, NT Lee, IH Chen, PS Lee, LC Jefffies, KJ AF Yang, YK Yeh, TL Chiu, NT Lee, IH Chen, PS Lee, LC Jefffies, KJ TI Association between cognitive performance and striatal dopamine binding is higher in timing and motor tasks in patients with schizophrenia SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE cognitive function; striatal D-2 receptor density; neuroleptics; schizophrenia ID CARD SORTING TEST; EMISSION COMPUTED-TOMOGRAPHY; PARKINSONS-DISEASE; BASAL GANGLIA; HUNTINGTONS-DISEASE; RECEPTOR OCCUPANCY; TIME PERCEPTION; IMPAIRMENT; MECHANISMS; NEUROLEPTICS AB The basal ganglia have received increasing attention with regard to their role in time pacing, motor function and other components of cognition. The aim of this study was to test whether the finer the motor activity and/or time perception performance were, the higher the striatal dopamine D-2 binding would be. Single photon emission computed tomography (SPEC Gamma) with [I-123]iodobenzamide (IBZM) was performed to measure striatal D-2 receptor densities. A battery of neuropsychological tests, including the Wisconsin Card Sorting Test (WCST), the finger tapping test (FTT), and an attention test: was performed by patients with schizophrenia. Results indicated a strong correlation between the FTT score and striatal D-2 receptor binding. Neuroleptic dosage plays an important role in the relationship between cognitive tasks and striatal dopamine receptor densities. In addition, the striatal D-2 receptor density is more significantly correlated with attentional tests that consider the tune effect than those that do not. Among the three tests performed, the WCST was least significantly correlated with striatal D-2 receptor densities. A decrease in striatal dopamine D-2 receptor density seems to be associated with impaired performance on optimal timing tasks and motor processing in patients with schizophrenia. (C) 2001 Elsevier Ireland Ltd. All rights reserved. C1 Natl Cheng Kung Univ Hosp, Coll Med, Dept Psychiat, Tainan 70428, Taiwan. Natl Cheng Kung Univ Hosp, Coll Med, Dept Nucl Med, Tainan 70428, Taiwan. Johns Hopkins Univ, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NIH, Bethesda, MD 20892 USA. RP Yang, YK (reprint author), Natl Cheng Kung Univ Hosp, Coll Med, Dept Psychiat, 138 Sheng Li Rd, Tainan 70428, Taiwan. EM ykyang@mail.ncku.edu.tw NR 38 TC 29 Z9 29 U1 1 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD SEP 15 PY 2004 VL 131 IS 3 BP 209 EP 216 DI 10.1016/j.pscychresns.2003.07.002 PG 8 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 864BV UT WOS:000224608800003 PM 15465290 ER PT J AU Wang, XY Baumann, MH Xu, H Rothman, RB AF Wang, XY Baumann, MH Xu, H Rothman, RB TI 3,4-methylenedioxymethamphetamine (MDMA) administration to rats decreases brain tissue serotonin but not serotonin transporter protein and glial fibrillary acidic protein SO SYNAPSE LA English DT Article DE 3,4-methylenedioxymethamphetamine; serotonin transporter; glial fibrillary acidic protein; neurotoxicity; fenfluramine ID BIOGENIC-AMINE TRANSPORTERS; NEURONAL DEGENERATION; NEUROTOXICITY; ECSTASY; METHYLENEDIOXYMETHAMPHETAMINE; METHAMPHETAMINE; PHARMACOLOGY; PROJECTIONS; BINDING; ANIMALS AB Previous experiments conducted in this laboratory showed that administration of high-dose D-fenfluramine (D-FEN) and p-chloroamphetamine (PCA) decreased 5-HT transporter (SERT) binding and tissue 5-HT by 30-60% in caudate and whole brain tissue 2 days and 2 weeks after drug administration. However, protein expression as determined by Western blot analysis did not change in either tissue or time point, except for a 30% decrease in the caudate 2 days after PCA administration. In the present study, we studied the effect of MDMA and 5,7-dihydroxytryptamine (5,7-DHT) on tissue 5-HT levels and the protein expression level of SERT and glial fibrillary acidic protein (GFAP), a validated neurotoxicity marker. Hypothesis. MDMA administration decreases SERT expression. Methods. Two weeks after MDMA administration (7.5 mg/kg i.p., q 2 h X 3 doses) or 2 weeks after i.c.v. administration of 5,7,-DHT (150 mug/rat), male Sprague-Dawley rats were sacrificed and the caudate, cortex, and hippocampal tissue collected. Western blots for SERT and GFAP were generated using published methods. Tissue 5-HT levels were determined by HPLC coupled to electrochemical detection. Results. MDMA treatment decreased tissue 5-HT in cortex, hippocampus, and caudateby about 50%. However, MDMA treatment had no significant effect on expression level of SERT and GFAP in any brain region. In contrast, 5,7-DHT reduced tissue 5-HT by more than 90%, decreased SERT protein expression by 20-35%, and increased GFAP by 30-39%. Conclusion. These data suggest the MDMA treatment regimen used here does not cause degeneration of 5-HT nerve terminals. Viewed collectively with our previous results and other published data, these data indicate that MDMA-induced persistent 5-HT depletion may occur in the absence of axotomy. Published 2004 Wiley-Liss, Inc. (dagger) C1 NIDA, CPS, DIR,Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Rothman, RB (reprint author), NIDA, CPS, DIR,Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rrothman@intra.nida.nih.gov NR 34 TC 54 Z9 55 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD SEP 15 PY 2004 VL 53 IS 4 BP 240 EP 248 DI 10.1002/syn.20058 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 844YH UT WOS:000223197100007 PM 15266556 ER PT J AU Bock, A Bliss, RL Matas, A Little, JA AF Bock, A Bliss, RL Matas, A Little, JA TI Human leukocyte antigen type as a risk factor for nonmelanomatous skin cancer in patients after renal transplantation SO TRANSPLANTATION LA English DT Article ID RECIPIENTS; LESIONS; FREQUENCIES AB Renal-transplant recipients are at an increased risk for developing nonmelanomatous skin cancer (NMSC). Recipient human leukocyte antigen (HLA) type has been suggested as a possible risk factor. We studied the association between HLA type and posttransplant NMSC in 2,433 renal-transplant recipients in a Northern climate, for whom HLA type and clinical follow-up were available. One hundred six (4.3%) patients developed NMSC between 1984 and 1997. Of previously reported HLA-associated risk factors, only HLA A11 showed an increased incidence of posttransplant skin cancer, at 8% (P = 0.0137, odds ratio 2.03 with 95% confidence interval 1.11-3.53) in 1998. This effect persisted at follow-up, in a limited reanalysis in 2004. HLA A11 may be a useful marker, in some populations, for identifying at the time of transplantation those patients that are at an increased risk for NMSC and who may therefore be good candidates for preventative clinical trials. C1 NIDDK, LCDB, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Med, Residency Program, Minneapolis, MN 55455 USA. Univ Minnesota, Clin Res Ctr, Minneapolis, MN 55455 USA. Univ Minnesota, Ctr Canc, Biostat Core, Minneapolis, MN USA. Univ Minnesota, Dept Surg, Minneapolis, MN 55455 USA. RP Little, JA (reprint author), NIDDK, LCDB, NIH, 9000 Rockville Pike Bldg 50 3154, Bethesda, MD 20892 USA. EM janel@intra.niddk.nih.gov FU NIDDK NIH HHS [DK 13083 5] NR 11 TC 8 Z9 10 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 SEP 15 PY 2004 VL 78 IS 5 BP 775 EP 778 DI 10.1097/01.TP.0000131666.17216.11 PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 854WV UT WOS:000223935400028 PM 15371688 ER PT J AU Bristow, MR Krause-Steinrauf, H Nuzzo, R Liang, CS Lindenfeld, J Lowes, BD Hattler, B Abraham, WT Olson, L Krueger, S Thaneemit-Chen, S Hare, JM Loeb, HS Domanski, MJ Eichhorn, EJ Zelis, R Lavori, P AF Bristow, MR Krause-Steinrauf, H Nuzzo, R Liang, CS Lindenfeld, J Lowes, BD Hattler, B Abraham, WT Olson, L Krueger, S Thaneemit-Chen, S Hare, JM Loeb, HS Domanski, MJ Eichhorn, EJ Zelis, R Lavori, P TI Effect of baseline or changes in adrenergic activity on clinical outcomes in the beta-blocker evaluation of survival trial SO CIRCULATION LA English DT Article DE nervous system, sympathetic; mortality; risk factors; heart failure ID CHRONIC HEART-FAILURE; SUSTAINED-RELEASE MOXONIDINE; PLASMA NOREPINEPHRINE; MORTALITY; ACTIVATION; HEFT AB Background-Adrenergic activation is thought to be an important determinant of outcome in subjects with chronic heart failure (CHF), but baseline or serial changes in adrenergic activity have not been previously investigated in a large patient sample treated with a powerful antiadrenergic agent. Methods and Results-Systemic venous norepinephrine was measured at baseline, 3 months, and 12 months in the beta-Blocker Evaluation of Survival Trial (BEST), which compared placebo treatment with the beta-blocker/sympatholytic agent bucindolol. Baseline norepinephrine level was associated with a progressive increase in rates of death or death plus CHF hospitalization that was independent of treatment group. On multivariate analysis, baseline norepinephrine was also a highly significant (P<0.001) independent predictor of death. In contrast, the relation of the change in norepinephrine at 3 months to subsequent clinical outcomes was complex and treatment group-dependent. In the placebo-treated group but not in the bucindolol-treated group, marked norepinephrine increase at 3 months was associated with increased subsequent risks of death or death plus CHF hospitalization. In the bucindolol-treated group but not in the placebo-treated group, the 1st quartile of marked norepinephrine reduction was associated with an increased mortality risk. A likelihood-based method indicated that 18% of the bucindolol group but only 1% of the placebo group were at an increased risk for death related to marked reduction in norepinephrine at 3 months. Conclusions-In BEST, a subset of patients treated with bucindolol had an increased risk of death as the result of sympatholysis, which compromised the efficacy of this third-generation β-blocker. C1 Univ Colorado, Hlth Sci Ctr, Div Cardiol, Denver, CO 80262 USA. NHLBI, Palo Alto, CA USA. Stanford Univ, Div Cardiol, Stanford, CA 94305 USA. Univ Rochester, Rochester, NY USA. Ohio State Univ, Columbus, OH 43210 USA. Mayo Clin Rochester, Rochester, MN USA. Bryan Mem Hosp, Lincoln, NE USA. VA Cooperat Clin Trials Program, Data Coordinating Ctr, Palo Alto, CA USA. Johns Hopkins Univ, Baltimore, MD USA. Vet Affairs Hosp, Dept Med, Hines, IL USA. Penn State Univ, Coll Med, Hershey, PA USA. RP Bristow, MR (reprint author), Univ Colorado, Hlth Sci Ctr, Div Cardiol, 4200 E 9th Ave, Denver, CO 80262 USA. EM michael.Bristow@uchsc.edu RI bristow, michael/G-7850-2011; OI Liang, Chang-seng/0000-0002-0328-0277; Lowes, Brian/0000-0002-5919-2540 NR 19 TC 61 Z9 62 U1 1 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 14 PY 2004 VL 110 IS 11 BP 1437 EP 1442 DI 10.1161/01.CIR.0000141297.50027.A4 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 853MC UT WOS:000223830700017 PM 15337700 ER PT J AU Ledee, DR Chen, J Tonelli, LH Takase, H Gery, I Zelenka, PS AF Ledee, DR Chen, J Tonelli, LH Takase, H Gery, I Zelenka, PS TI Differential expression of splice variants of chemokine CCL27 mRNA in lens, cornea, and retina of the normal mouse eye SO MOLECULAR VISION LA English DT Article ID CD4(+) T-CELLS; HUMAN TRANSCRIPTOME; ACUTE REJECTION; NONCODING RNAS; INFLAMMATION; INDUCTION; MIGRATION; UVEITIS; MICE AB PURPOSE: Constitutive expression of RNA sequences complementary to the chemokine CCL27 mRNA has been found in the normal mouse eye. This study examines the nature and location of these endogenous RNAs in ocular tissues. METHODS: Conventional RT-PCR, 5' RACE, and dideoxy DNA sequencing were used to examine the sequences of CCL27 related RNAs in the eye. Expression levels of specific RNAs were measured by real time PCR. Tissue distribution of RNA transcripts was determined by RT-PCR using RNA from microdissected tissues and by in situ hybridization with radiolabeled riboprobes. RESULTS: We detect 5 distinct splice variants derived from transcription of the CCL27 gene locus. The most abundant form codes for a non-secreted protein, PESKY, and is expressed in lens, cornea, and retina. Another variant corresponds to the mRNA of the secreted chemokine and is synthesized in the cornea, but not in retina or lens. The remaining splice variants are novel and may be eye specific, but have only short open reading frames (<50 amino acids). CCL27 transcripts are most abundantly expressed in the retina, as judged by in situ hybridization. CONCLUSIONS: PESKY and other CCL27 splice variants of unknown function are widely expressed in ocular tissues. Analysis of CCL27 transcripts from lens, retina, and cornea indicates that mRNA for the secreted chemokine, CCL27, is endogenously expressed only in the cornea and may play a role in ocular immune responses involving CD4 lymphocytes in this tissue. C1 NEI, NIH, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Zelenka, PS (reprint author), Bldg 7,Room 201,7 Mem Dr,MSC 0704, Bethesda, MD 20892 USA. EM zelenkap@nei.nih.gov NR 18 TC 12 Z9 13 U1 0 U2 2 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD SEP 14 PY 2004 VL 10 IS 79-80 BP 663 EP 667 PG 5 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 856QE UT WOS:000224058900001 PM 15448618 ER PT J AU Elkins, JS O'Meara, ES Longstreth, WT Carlson, MC Manolio, TA Johnston, SC AF Elkins, JS O'Meara, ES Longstreth, WT Carlson, MC Manolio, TA Johnston, SC TI Stroke risk factors and loss of high cognitive function SO NEUROLOGY LA English DT Article ID MINI-MENTAL-STATE; ISCHEMIC VASCULAR DEMENTIA; CARDIOVASCULAR-HEALTH; BLOOD-PRESSURE; ALZHEIMERS-DISEASE; LEISURE ACTIVITIES; ELDERLY-PEOPLE; BRAIN INFARCTS; NORMATIVE DATA; IMPAIRMENT AB Background: Modifiable stroke risk factors may contribute to age-associated declines in cognitive function. Individuals with high levels of cognitive function after midlife may have less exposure to these stroke risk factors or may be less susceptible to their effects on cognition. Methods: The Cardiovascular Health Study (CHS)* is a population-based, longitudinal cohort study of 5,888 people age 65 years and older. Participants ( n = 4,129) who were free of dementia, stroke, or TIA at the time of baseline cranial MRI were selected for analysis. High cognitive function at baseline was defined by performance at or above midlife norms on the Modified Mini-Mental State Examination (3MS). Results: The odds of having high cognitive function at baseline decreased by quartile of stroke risk ( highest vs lowest risk quartile, adjusted odds ratio [OR] 0.68; 95% CI 0.52 to 0.88; p for trend = 0.005). Stroke risk was a predictor of decline on the 3MS in those with typical levels of cognitive function at baseline, even in the absence of incident stroke or TIA ( highest vs lowest risk quartile for 3MS decline, adjusted OR 2.11; 95% CI 1.42 to 3.13; p for trend < 0.001). In contrast, stroke risk was not associated with decline on the 3MS in those with high cognitive function at baseline ( p = 0.03 for interaction). Conclusions: In a cohort of older adults without stroke, TIA, or dementia, cognitive function and incident cognitive decline were associated with risk for stroke. Additional studies are needed to determine whether modification of stroke risk factors can reduce the cognitive decline that is often attributed to normal aging. C1 Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Univ Washington, Seattle, WA 98195 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. NHLBI, Bethesda, MD 20892 USA. RP Johnston, SC (reprint author), Univ Calif San Francisco, Dept Neurol, Box 0114,505 Parnassus Ave,M-798, San Francisco, CA 94143 USA. EM Clay.Johnston@ucsfmedctr.org FU NHLBI NIH HHS [N01-HC-35129, N01-HC-85081, N01-HC-85083, N01-HC-85085, N01 HC-15103, N01-HC-85079, N01-HC-85080, N01-HC-85082, N01-HC-85084, N01-HC-85086] NR 45 TC 25 Z9 27 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 14 PY 2004 VL 63 IS 5 BP 793 EP 799 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 853ME UT WOS:000223830900007 PM 15365125 ER PT J AU Jallow, Z Jacobi, UG Weeks, DL Dawid, IB Veenstra, GJC AF Jallow, Z Jacobi, UG Weeks, DL Dawid, IB Veenstra, GJC TI Specialized and redundant roles of TBP and a vertebrate-specific TBP paralog in embryonic gene regulation in Xenopus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RNA-POLYMERASE-II; TATA-BINDING PROTEIN; TRANSCRIPTION FACTOR; ACTIVATED TRANSCRIPTION; MICE LACKING; C-ELEGANS; COMPLEX; DNA; INITIATION; SPERMIOGENESIS AB The general transcription factor TATA-binding protein (TBP) is a key initiation factor involved in transcription by all three eukaryotic RNA polymerases. In addition, the related metazoan-specific TBP-like factor (TLF/TRF2) is essential for transcription of a distinct subset of genes. Here we characterize the vertebrate-specific TBP-like factor TBP2, using in vitro assays, in vivo antisense knockdown, and mRNA rescue experiments, as well as chromatin immunoprecipitation. We show that TBP2 is recruited to promoters in Xenopus oocytes in the absence of detectable TBP recruitment. Furthermore, TBP2 is essential for gastrulation and for the transcription of a subset of genes during Xenopus embryogenesis. In embryos, TBP2 protein is much less abundant than TBP, and moderate overexpression of TBP2 partially rescues an antisense knockdown of TBP levels and restores transcription of many TBP-dependent genes. TBP2 may be a TBP replacement factor in oocytes, whereas in embryos both TBP and TBP2 are required even though they exhibit partial redundancy and gene selectivity. C1 Radboud Univ Nijmegen, Ctr Mol Life Sci, Dept Mol Biol, NL-6500 HB Nijmegen, Netherlands. Univ Iowa, Dept Biochem, Iowa City, IA 52242 USA. NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Veenstra, GJC (reprint author), Radboud Univ Nijmegen, Ctr Mol Life Sci, Dept Mol Biol, NL-6500 HB Nijmegen, Netherlands. EM g.veenstra@ncmls.kun.nl RI Weeks, Daniel/F-6216-2010; Veenstra, Gert Jan C./D-4963-2012 OI Veenstra, Gert Jan C./0000-0002-7787-4940 FU NHLBI NIH HHS [P50 HL062178, P50 HL062178-050003]; NIGMS NIH HHS [R01 GM069944, R01 GM069944-01, R01 GM069944-02, R01 GM069944-03, R01 GM069944-04] NR 41 TC 62 Z9 64 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 14 PY 2004 VL 101 IS 37 BP 13525 EP 13530 DI 10.1073/pnas.0405536101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 854QH UT WOS:000223917900025 PM 15345743 ER PT J AU Jonas, EA Hickman, JA Chachar, M Polster, BM Brandt, TA Fannjiang, Y Ivanovska, I Basanez, G Kinnally, KW Zimmerberg, J Hardwick, JM Kaczmarek, LK AF Jonas, EA Hickman, JA Chachar, M Polster, BM Brandt, TA Fannjiang, Y Ivanovska, I Basanez, G Kinnally, KW Zimmerberg, J Hardwick, JM Kaczmarek, LK TI Proapoptotic N-truncated BCL-xL protein activates endogenous mitochondrial channels in living synaptic terminals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CYTOCHROME-C RELEASE; APOPTOTIC CELL-DEATH; OUTER-MEMBRANE; CONDUCTANCE CHANNEL; YEAST MITOCHONDRIA; BH3 DOMAIN; BAX; CLEAVAGE; PERMEABILITY; BCL-X(L) AB Neuronal death is often preceded by functional alterations at nerve terminals. Anti- and proapoptotic BCL-2 family proteins not only regulate the neuronal death pathway but also affect excitability of healthy neurons. We found that exposure of squid stellate ganglia to hypoxia, a death stimulus for neurons, causes a cysteine protease-dependent loss of full-length antiapoptotic BCL-xL, similar to previous findings in mammalian cells. Therefore, to determine the direct effect of the naturally occurring proapoptotic cleavage product of BCL-xL on mitochondria, recombinant N-truncated BCL-xL was applied to mitochondria inside the squid presynaptic terminal and to purified mitochondria isolated from yeast. N-truncated BCL-xL rapidly induced large multi-conductance channels with a maximal conductance significantly larger than those produced by full-length BCL-xL. This activity required the hydrophobic C terminus and the BH3 domain of BCL-xL. Moreover, N-truncated BCL-xL failed to produce any channel activity when applied to plasma membranes, suggesting that a component of the mitochondrial membrane is necessary for its actions. Consistent with this idea, the large channels induced by N-truncated BCL-xL are inhibited by NADH and require the presence of VDAC, a voltage-dependent anion channel present in the outer mitochondrial membrane. These observations suggest that the mitochondrial channels specific to full-length and N-truncated BCL-xL contribute to their opposite effects on synaptic transmission, and are consistent with their opposite effects on the cell death pathway. C1 Marine Biol Lab, Woods Hole, MA 02543 USA. Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. Inst Rech Servier, F-78290 Croissy Sur Seine, France. Johns Hopkins Univ, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. Natl Inst Child Hlth Hlth & Dev, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. NYU, Coll Dent, Dept Basic Sci, New York, NY 10010 USA. RP Marine Biol Lab, Woods Hole, MA 02543 USA. EM hardwick@jhu.edu; leonard.kaczmarek@yale.edu RI Basanez, Gorka/L-9509-2014 OI Basanez, Gorka/0000-0002-7475-7861 FU NIGMS NIH HHS [GM 57249, R01 GM057249]; NINDS NIH HHS [R37 NS045876, R01 NS045876, NS 34175, NS 37402, NS 18496, R01 NS034175, R01 NS037402]; ONDIEH CDC HHS [ND 45876] NR 52 TC 64 Z9 66 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 SEP 14 PY 2004 VL 101 IS 37 BP 13590 EP 13595 DI 10.1073/pnas.0401372101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 854QH UT WOS:000223917900036 PM 15342906 ER PT J AU Degerman, E Manganiello, V Holst, JJ Ahren, B AF Degerman, E Manganiello, V Holst, JJ Ahren, B TI Milrinone efficiently potentiates insulin secretion induced by orally but not intravenously administered glucose in C57BL6J mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE phosphodiesterase; type 2 diabetes; milrinone; glucagon-like peptide-1; insulin secretion ID SELECTIVE PHOSPHODIESTERASE INHIBITORS; CYCLIC-NUCLEOTIDE PHOSPHODIESTERASES; GLUCAGON-LIKE PEPTIDE-1; IN-VIVO; CAMP; RAT; POLYPEPTIDE; MODULATION; LIPOLYSIS; ISLETS AB To study the effect of phosphodiesterase (PDE) 3 inhibition on plasma insulin and glucose levels, the selective PDE 3 inhibitor milrinone (0.25, 1.0, and 2.5 mg/kg) was given orally to anesthetized CL57B1/6J mice 10 min before a gastric glucose gavage (150 mg/mouse). It was found that milrinone augmented the glucose-mediated increase in plasma insulin at 1.0 and 2.5 mg/kg without, however, any improvement in glucose elimination. In contrast, when given 10 min before intravenous glucose (1 g/kg), milrinone (I mg/kg) did not affect the insulin response to glucose. The increase in glucagon-like peptide-1 (GLP-1) levels after gastric glucose was not altered by milrinone. However, the PDE3 inhibitor augmented the insulin response to intravenous GLP-1 (2.8 nmol/kg). We therefore conclude that PDE3 inhibition by milrinone augments insulin secretion in vivo in mice after oral but not after intravenous glucose, which may be explained by enhanced response to the cAMP-dependent insulinotropic action of endogenously released GLP-1. (C) 2004 Elsevier B.V. All rights reserved. C1 Lund Univ, Dept Med, Lund, Sweden. Biomed Ctr, Dept Mol & Cell Biol, S-22184 Lund, Sweden. NIH, Bethesda, MD 20892 USA. Univ Copenhagen, Dept Physiol, Copenhagen, Denmark. RP Ahren, B (reprint author), Lund Univ, Dept Med, Lund, Sweden. EM Bo.Ahren@med.lu.se OI Holst, Jens Juul/0000-0001-6853-3805 NR 27 TC 7 Z9 7 U1 0 U2 0 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 SEP 13 PY 2004 VL 498 IS 1-3 BP 319 EP 323 DI 10.1016/j.ejphar.2004.07.096 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 856KM UT WOS:000224044100043 PM 15364011 ER PT J AU Sengupta, S Robles, AI Linke, SP Sinogeeva, NI Zhang, R Pedeux, R Ward, IM Celeste, A Nussenzweig, A Chen, JJ Halazonetis, TD Harris, CC AF Sengupta, S Robles, AI Linke, SP Sinogeeva, NI Zhang, R Pedeux, R Ward, IM Celeste, A Nussenzweig, A Chen, JJ Halazonetis, TD Harris, CC TI Functional interaction between BLM helicase and 53BP1 in a Chk1-mediated pathway during S-phase arrest SO JOURNAL OF CELL BIOLOGY LA English DT Article DE replication arrest; gamma-H2AX; p53; homologous recombination; signal transduction ID MODULATES HOMOLOGOUS RECOMBINATION; BLOOMS-SYNDROME HELICASE; DNA-DAMAGE CHECKPOINT; DOUBLE-STRAND BREAKS; HISTONE H2AX; GENOMIC INSTABILITY; REPLICATION FORKS; SYNDROME PROTEIN; NUCLEAR FOCI; P53 AB Bloom's syndrome is a rare autosomal recessive genetic disorder characterized by chromosomal aberrations, genetic instability, and cancer predisposition, all of which may be the result of abnormal signal transduction during DNA damage recognition. Here, we show that BLM is an intermediate responder to stalled DNA replication forks. BLM colocalized and physically interacted with the DNA damage response proteins 53BP1 and H2AX. Although BLM facilitated physical interaction between p53 and 53BP1, 53BP1 was required for efficient accumulation of both BLM and p53 at the sites of stalled replication. The accumulation of BLM/53BP1 foci and the physical interaction between them was independent of gamma-H2AX. The active Chk1 kinase was essential for both the accurate focal colocalization of 53BP1 with BLM and the consequent stabilization of BLM. Once the ATR/Chk1- and 53BP1-mediated signal from replicational stress is received, BLM functions in multiple downstream repair processes, thereby fulfilling its role as a caretaker tumor suppressor. C1 NCI, Lab Human Carcinogenesis, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Mayo Clin, Div Oncol Res, Rochester, MN 55905 USA. Wistar Inst Anat & Biol, Dept Mol Genet, Philadelphia, PA 19104 USA. RP Harris, CC (reprint author), NCI, Lab Human Carcinogenesis, NIH, 37 Convent Dr,Bldg 37,Rm 3068, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov RI Halazonetis, Thanos/D-7923-2011; OI Sengupta, Sagar/0000-0002-6365-1770 NR 43 TC 73 Z9 75 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD SEP 13 PY 2004 VL 166 IS 6 BP 801 EP 813 DI 10.1083/jcb.200405128 PG 13 WC Cell Biology SC Cell Biology GA 854VP UT WOS:000223932000005 PM 15364958 ER PT J AU Xiao, XD Feng, Y Chakraborti, S Dimitrov, DS AF Xiao, XD Feng, Y Chakraborti, S Dimitrov, DS TI Oligomerization of the SARS-CoV S glycoprotein: dimerization of the N-terminus and trimerization of the ectodomain SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE SARS-CoV; S glycoprotein; S protein; S oligomerization; membrane fusion ID ACUTE RESPIRATORY SYNDROME; CORONAVIRUS SPIKE PROTEIN; ANGIOTENSIN-CONVERTING ENZYME-2; FUNCTIONAL-CHARACTERIZATION; FUSION PROTEIN; CORE; IDENTIFICATION; INHIBITORS; RECEPTOR; COMPLEX AB Viral envelope glycoproteins are oligomeric and the quaternary structure is critical for their membrane fusion activity. Typically the transmembrane glycoproteins of class I fusion proteins contain the oligomerization domains and the surface glycoproteins (SU) are monomeric. However, it has been previously demonstrated [J. Biol. Chem. 277 (2002) 19727] that the SU of a murine hepatitis coronavirus (MHV) forms dimers, the dimerization domain overlaps the receptor-binding domain (RBD) and that this dimeric state is important for binding to receptor molecules that initiates entry into cells. We have previously expressed various soluble fragments of the SARS-CoV SU and identified stably folded fragments (residues 272-537) that contain the RBD [Biochem. Biophys. Res. Commun. 312 (2003) 1159]. Here, we further characterize these and other fragments in an attempt to identify possible dimerization domains and their role for membrane fusion. We demonstrate that the SU and a shorter 260-amino acid N-terminal fragment (residues 17-276), which folds independently, form dimers. In contrast to the previously characterized MHV SU dimerization, this fragment is upstream and distinct from the RBD. Its deletion abolished S-mediated cell membrane fusion but retained the SU-receptor-binding function indicating the possibility for a role in post-receptor binding steps of the virus entry mechanism. Interestingly, the whole soluble S ectodomain (Se) that contains the dimerization domain but not the transmembrane domain and the cytoplasmic tail forms trimers suggesting the existence of a trimerization domain in the TM subunit in its prefusion state that may lead to a conformation unfavorable for formation of higher-order multimeric structures. These results demonstrate the existence of SU dimers and Se trimers, and indicate the possibility for an unknown mechanism of their role in entry. They also further characterize the S-mediated membrane fusion and could be important for understanding the mechanisms of virus entry, and in the development of therapeutics and vaccines. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI Frederick, CCR, LECB, Prot Interact Grp,NIH, Frederick, MD 21702 USA. RP Dimitrov, DS (reprint author), NCI Frederick, CCR, LECB, Prot Interact Grp,NIH, Frederick, MD 21702 USA. EM dimitrov@ncifcrf.gov NR 19 TC 13 Z9 15 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 10 PY 2004 VL 322 IS 1 BP 93 EP 99 DI 10.1016/j.bbrc.2004.07.084 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 849ZS UT WOS:000223581000014 PM 15313178 ER PT J AU Robertson, AK Geiman, TM Sankpal, UT Hager, GL Robertson, KD AF Robertson, AK Geiman, TM Sankpal, UT Hager, GL Robertson, KD TI Effects of chromatin structure on the enzymatic and DNA binding functions of DNA methyltransferases DNMT1 and Dnmt3a in vitro SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE DNMT1; Dnmt3a; enzyme kinetics; chromatin; EMSA; 5S rDNA; mononucleosome; hSNF2H ID NUCLEOSOME CORE PARTICLES; RECOMBINANT HUMAN DNA; DE-NOVO; CYTOSINE-5 METHYLTRANSFERASES; ALLOSTERIC ACTIVATION; METHYLATION PATTERNS; HISTONE DEACETYLASE; EXCISION-REPAIR; XENOPUS-LAEVIS; TRANSCRIPTION AB DNA methylation is an epigenetic modification of the genome critical for numerous processes, including transcriptional repression and maintenance of chromatin structure. Recent studies have revealed connections between DNA methylation and other epigenetic modifications such as ATP-dependent chromatin remodeling. It remains unclear, however, exactly how chromatin and epigenetic chromatin modifications affect the biological properties of the DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B). Using a highly purified system and the 5S rDNA gene as free DNA or assembled into a mononucleosome, we have compared the effects of chromatin structure on DNMT1 and Dnmt3a. The catalytic efficiency for both enzymes decreased on the mononucleosome, similar to8-fold for DNMT1 and 17-fold for Dnmt3a. DNMT1 and Dnmt3a bound to DNA and mononucleosomal substrates in gel shift experiments with approximately equal affinity and in a cooperative manner. We also show that DNMT1 interacts with hSNF2H chromatin remodeling enzyme and that DNMT1 binds mononucleosomes with higher affinity in the presence of hSNF2H. These findings raise interesting implications about the interactions of mammalian DNA methyltransferases with chromatin and provide the first evidence that a chromatin remodeling enzyme can alter the biological properties of a DNMT. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, LRBGE, Epigenet Gene Regulat & Canc Sect, NIH, Bethesda, MD 20892 USA. NCI, HAO, LRBGE, NIH, Bethesda, MD 20892 USA. RP Robertson, KD (reprint author), Univ Florida, Dept Biochem & Mol Biol, Box 100245, Gainesville, FL 32610 USA. EM keithr@ufl.edu FU NCI NIH HHS [CA84535-01] NR 45 TC 42 Z9 49 U1 1 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 10 PY 2004 VL 322 IS 1 BP 110 EP 118 DI 10.1016/j.bbrc.2004.07.083 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 849ZS UT WOS:000223581000017 PM 15313181 ER PT J AU Daly, NL Gustafson, KR Craik, DJ AF Daly, NL Gustafson, KR Craik, DJ TI The role of the cyclic peptide backbone in the anti-HIV activity of the cyclotide kalata B1 SO FEBS LETTERS LA English DT Article DE cyclotide; cystine knot; circular protein; acyclic permutant ID INHIBITORY MACROCYCLIC PEPTIDES; CYSTINE-KNOT; CIRCULAR PROTEINS; PLANT CYCLOTIDES; STRUCTURAL MOTIF; CHASSALIA-PARVIFOLIA; FOLDING PATHWAYS; BETA-SHEET; POLYPEPTIDE; FRAMEWORK AB The plant cyclotides, the largest known family of circular proteins, have tightly folded structures and a range of biological activities that lend themselves to potential pharmaceutical and agricultural applications. Based on sequence homology, they are classified into the bracelet and Mobius subfamilies. The bracelet subfamily has previously been shown to display anti-HIV activity. We show here that a member of the Mobius subfamily, kalata B1, also exhibits anti-HIV activity despite extensive sequence differences between the subfamilies. In addition, acyclic permutants of kalata B1 displayed no anti-HIV activity, suggesting that this activity is critically dependent on an intact circular backbone. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. NCI, Mol Targets Dev Program, Canc Res Ctr, Frederick, MD 21702 USA. RP Craik, DJ (reprint author), Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. EM d.craik@imb.uq.edu.au RI Daly, Norelle/D-4302-2013; Craik, David/B-1695-2010 OI Craik, David/0000-0003-0007-6796 NR 33 TC 70 Z9 73 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD SEP 10 PY 2004 VL 574 IS 1-3 BP 69 EP 72 DI 10.1016/j.febslet.2004.08.007 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 856JN UT WOS:000224041600012 PM 15358541 ER PT J AU Tanimura, A Nezu, A Morita, T Turner, RJ Tojyo, Y AF Tanimura, A Nezu, A Morita, T Turner, RJ Tojyo, Y TI Fluorescent biosensor for quantitative real-time measurements of inositol 1,4,5-trisphosphate in single living cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RESONANCE ENERGY-TRANSFER; LIGAND-BINDING SITE; CALCIUM-RELEASE; LUMINAL CA2+; HSY CELLS; RECEPTOR; PROTEIN; TRISPHOSPHATE; VISUALIZATION; OSCILLATIONS AB The second messenger inositol 1,4,5-trisphosphate (IP3) plays a central role in the generation of a variety of spatiotemporally complex intracellular Ca2+ signals involved in the regulation of many essential physiological processes. Here we describe the development of "LIBRA", a novel ratiometric fluorescent IP3 biosensor that allows for the quantitative monitoring of intracellular IP3 concentrations in single living cells in real time. LIBRA consists of the IP3-binding domain of the rat type 3 IP3 receptor fused between the fluorescence resonance energy transfer pair cyan fluorescent protein and yellow fluorescent protein and preceded by a membrane-targeting signal. We show that the LIBRA fluorescent signal is highly selective for IP3 and unaffected by concentrations of Ca2+ and ATP in the physiological range. In addition, LIBRA can be calibrated in situ. We demonstrate the utility of LIBRA by monitoring the temporal relationship between the responses intracellular IP3 and Ca2+ concentrations in SH-SY5Y cells following acetylcholine stimulation. C1 Hlth Sci Univ Hokkaido, Sch Dent, Dept Dent Pharmacol, Ishikari, Hokkaido 0610293, Japan. NIDCR, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Tanimura, A (reprint author), Hlth Sci Univ Hokkaido, Sch Dent, Dept Dent Pharmacol, Ishikari, Hokkaido 0610293, Japan. EM tanimura@hoku-iryo-u.ac.jp NR 30 TC 68 Z9 71 U1 2 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 SEP 10 PY 2004 VL 279 IS 37 BP 38095 EP 38098 DI 10.1074/jbc.C400312200 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 851KN UT WOS:000223684100005 PM 15272011 ER PT J AU Sauer, B Vogler, R von Wenckstern, H Fujii, M Anzano, MB Glick, AB Schafer-Korting, M Roberts, AB Kleuser, B AF Sauer, B Vogler, R von Wenckstern, H Fujii, M Anzano, MB Glick, AB Schafer-Korting, M Roberts, AB Kleuser, B TI Involvement of Smad signaling in sphingosine 1-phosphate-mediated biological responses of keratinocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; GROWTH-FACTOR-BETA; SMOOTH-MUSCLE-CELLS; FACTOR-BINDING PROTEIN-3; FOCAL ADHESION KINASE; BREAST-CANCER CELLS; TGF-BETA; SPHINGOSINE-1-PHOSPHATE RECEPTORS; EGF RECEPTOR; ENDOTHELIAL-CELLS AB The lysophospholipid sphingosine 1-phosphate and the cytokine-transforming growth factor beta are both released from degranulating platelets at wound sites, suggesting a broad spectrum of effects involved in wound healing. Interestingly, both of these molecules have been previously shown to induce chemotaxis but to strongly inhibit the growth of keratinocytes, while stimulating the proliferation of fibroblasts. In contrast to sphingosine 1-phosphate, the signaling cascade of the growth factor has been extensively examined. Specifically, Smad3 has been shown to be an essential mediator of transforming growth factor beta-dependent chemotaxis of keratinocytes and mediates, in part, its growth-inhibitory effect. Here we show that sphingosine 1-phosphate, independently of transforming growth factor beta secretion, induces a rapid phosphorylation of Smad3 on its C-terminal serine motif and induces its partnering with Smad4 and the translocation of the complex into the nucleus. Moreover, sphingosine 1-phosphate fails to induce chemotaxis or inhibit the growth of Smad3-deficient keratinocytes, suggesting that Smad3 plays an unexpected functional role as a new target in sphingosine 1-phosphate signaling. Both sphingosine 1-phosphate receptors and the transforming growth factor beta-type I receptor serine/threonine kinase are essential for activation of Smad3 by this lysophospholipid and the dependent biological responses, indicating a novel crosstalk between serine/threonine kinase receptors and G-protein coupled receptors. C1 Free Univ Berlin, Inst Pharm Pharmacol & Toxicol, D-14195 Berlin, Germany. NCI, Lab Cellular Carcinogenesis & Tumor Promot, NIH, Bethesda, MD 20892 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Kleuser, B (reprint author), Free Univ Berlin, Inst Pharm Pharmacol & Toxicol, Konigin Luise Str 2&4, D-14195 Berlin, Germany. EM kleuser@zedat.fu-berlin.de NR 65 TC 46 Z9 48 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 SEP 10 PY 2004 VL 279 IS 37 BP 38471 EP 38479 DI 10.1074/jbc.M313557200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 851KN UT WOS:000223684100051 PM 15247277 ER PT J AU Swietnicki, W O'Brien, S Holman, K Cherry, S Brueggemann, E Tropea, JE Hines, HB Waugh, DS Ulrich, RG AF Swietnicki, W O'Brien, S Holman, K Cherry, S Brueggemann, E Tropea, JE Hines, HB Waugh, DS Ulrich, RG TI Novel protein-protein interactions of the Yersinia pestis type III secretion system elucidated with a matrix analysis by surface plasmon resonance and mass spectrometry SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID N-TERMINAL DOMAIN; YOP SECRETION; HELA-CELLS; SALMONELLA-TYPHIMURIUM; TRANSLOCATORS YOPB; VIRULENCE FACTORS; CHAPERONE SYCE; ENTEROCOLITICA; PSEUDOTUBERCULOSIS; BACTERIAL AB Binary complexes formed by components of the Yersinia pestis type III secretion system were investigated by surface plasmon resonance (SPR) and matrix-assisted laser desorption time-of-flight mass spectrometry. Pairwise interactions between 15 recombinant Yersinia outer proteins (Yops), regulators, and chaperones were first identified by SPR. Mass spectrometry confirmed over 80% of the protein-protein interactions suggested by SPR, and new binding partners were further characterized. The Yop secretion protein (Ysc) M2 of Yersinia enterocolitica and LcrQ of Y. pestis, formerly described as ligands only for the specific Yop chaperone (Syc) H, formed stable complexes with SycE. Additional previously unreported complexes of YscE with the translocation regulator protein TyeA and the thermal regulator protein YmoA and multiple potential protein contacts by YscE, YopK, YopH, and LcrH were also identified. Because only stably folded proteins were examined, the interactions we identified are likely to occur either before or after transfer through the injectosome to mammalian host cells and may have relevance to understanding disease processes initiated by the plague bacterium. C1 USA, Med Res Inst Infect Dis, Lab Mol Immunol, Frederick, MD 21702 USA. NCI, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA. RP Ulrich, RG (reprint author), USA, Med Res Inst Infect Dis, Lab Mol Immunol, 1425 Porter St, Frederick, MD 21702 USA. EM ulrich@ncifcrf.gov NR 46 TC 26 Z9 27 U1 2 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 10 PY 2004 VL 279 IS 37 BP 38693 EP 38700 DI 10.1074/jbc.M405217200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 851KN UT WOS:000223684100078 PM 15213222 ER PT J AU Munshi, HG Wu, YI Mukhopadhyay, S Ottaviano, AJ Sassano, A Koblinski, JE Platanias, LC Stack, MS AF Munshi, HG Wu, YI Mukhopadhyay, S Ottaviano, AJ Sassano, A Koblinski, JE Platanias, LC Stack, MS TI Differential regulation of membrane type 1-matrix metalloproteinase activity by ERK1/2-and p38 MAPK-modulated tissue inhibitor of metalloproteinases 2 expression controls transforming growth factor-beta 1-induced pericellular collagenolysis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR-BETA; ACTIVATED PROTEIN-KINASE; SQUAMOUS-CELL CARCINOMA; HUMAN GINGIVAL FIBROBLASTS; HT1080 FIBROSARCOMA CELLS; IV COLLAGENASE EXPRESSION; LYMPH-NODE METASTASIS; MATRIX-METALLOPROTEINASE; TGF-BETA; EXTRACELLULAR-MATRIX AB Acquisition of matrix metalloproteinase-2 (MMP-2) activity is temporally associated with increased migration and invasiveness of cancer cells. ProMMP-2 activation requires multimolecular complex assembly involving proMMP-2, membrane type 1-MMP (MT1-MMP, MMP-14), and tissue inhibitor of metalloproteinases-2 (TIMP-2). Because transforming growth factor-beta1 (TGF-beta1) promotes tumor invasion in advanced squamous cell carcinomas, the role of TGF-beta1 in the regulation of MMP activity in a cellular model of invasive oral squamous cell carcinoma was examined. Treatment of oral squamous cell carcinoma cells with TGF-beta1 promoted MMP-dependent cell scattering and collagen invasion, increased expression of MMP-2 and MT1-MMP, and enhanced MMP-2 activation. TGF-beta1 induced concomitant activation of ERK1/2 and p38 MAPK, and kinase inhibition studies revealed a negative regulatory role for ERK1/2 in modulating acquisition of MMP-2 activity. Thus, a reciprocal effect on proMMP-2 activation was observed whereupon blocking ERK1/2 phosphorylation promoted proMMP-2 activation and MT1-MMP activity, whereas inhibiting p38 MAPK activity decreased proteolytic potential. The cellular mechanism for the control of MT1-MMP catalytic activity involved concurrent reciprocal modulation of TIMP-2 expression by ERK1/2 and p38 MAPKs, such that inhibition of ERK1/2 phosphorylation decreased TIMP-2 production, and downregulation of p38 MAPK activity enhanced TIMP-2 synthesis. Further, p38 MAPK inhibition promoted ERK1/2 phosphorylation, providing additional evidence for cross-talk between MAPK pathways. These observations demonstrate the complex reciprocal effects of ERK1/2 and p38 MAPK in the regulation of MMP activity, which could complicate the use of MAPK-specific inhibitors as therapeutic agents to down-regulate the biologic effects of TGF-beta1 on pericellular collagen degradation and tumor invasion. C1 Northwestern Univ, Feinberg Sch Med, Dept Med, Div Hematol Oncol, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. NIDCR, Craniofacial Dev Biol & Regenerat Branch, NIH, Bethesda, MD 20892 USA. RP Stack, MS (reprint author), Northwestern Univ, Sch Med, Dept Cell & Mol Biol, 303 E Chicago Ave,Tarry 8-715, Chicago, IL 60611 USA. EM mss130@northwestern.edu FU NCI NIH HHS [R01CA77816, R01CA94079, R01CA85870, T32 CA70085, K08CA94877]; NIDCR NIH HHS [P01DE12328] NR 75 TC 110 Z9 115 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 SEP 10 PY 2004 VL 279 IS 37 BP 39042 EP 39050 DI 10.1074/jbc.M404958200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 851KN UT WOS:000223684100119 PM 15247230 ER PT J AU Legler, PM Cai, ML Peterkofsky, A Clore, GM AF Legler, PM Cai, ML Peterkofsky, A Clore, GM TI Three-dimensional solution structure of the cytoplasmic B domain of the mannitol transporter IIMannitol of the Escherichia coli phosphotransferase system SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; PHOSPHORYL TRANSFER COMPLEX; C-TERMINAL DOMAIN; NMR STRUCTURE REFINEMENT; CRYSTAL-STRUCTURE; ENZYME-II; BACILLUS-SUBTILIS; PHOSPHOTYROSYL PHOSPHATASE; RESOLUTION STRUCTURE; MOLECULAR-DYNAMICS AB The solution structure of the cytoplasmic B domain of the mannitol (Mtl) transporter (IIMtl) from the mannitol branch of the Escherichia coli phosphotransferase system has been solved by multidimensional NMR spectroscopy with extensive use of residual dipolar couplings. The ordered IIBMtl domain (residues 375-471 of IIMtl) consists of a four-stranded parallel beta-sheet flanked by two helices (alpha(1) and alpha(3)) on one face and helix alpha(2) on the opposite face with a characteristic Rossmann fold comprising two right-handed beta(1)alpha(1)beta(2) and beta(3)alpha(2)beta(4) motifs. The active site loop is structurally very similar to that of the eukaryotic protein tyrosine phosphatases, with the active site cysteine (Cys-384) primed in the thiolate state (pK(a)less than or equal to5.6) for nucleophilic attack at the phosphorylated histidine (His-554) of the IIA(Mtl) domain through stabilization by hydrogen bonding interactions with neighboring backbone amide groups at positions i+2/3/4 from Cys-384 and with the hydroxyl group of Ser-391 at position i+7. Modeling of the phosphorylated state of IIBMtl suggests that the phosphoryl group can be readily stabilized by hydrogen bonding interactions with backbone amides in the i+2/4/5/6/7 positions as well as with the hydroxyl group of Ser390 at position i+6. Despite the absence of any significant sequence identity, the structure of IIBMtl is remarkably similar to the structures of bovine protein tyrosine phosphatase (which contains two long insertions relative to IIBMtl) and the cytoplasmic B component of enzyme IIChb, which fulfills an analogous role to IIBMtl in the N,N'-diacetylchitobiose branch of the phosphotransferase system. All three proteins utilize a cysteine residue in the nucleophilic attack of a phosphoryl group covalently bound to another protein. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5,Rm B1-301, 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 NR 78 TC 28 Z9 29 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 SEP 10 PY 2004 VL 279 IS 37 BP 39115 EP 39121 DI 10.1074/jbc.M406764200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 851KN UT WOS:000223684100127 PM 15258141 ER PT J AU Miller, GJ Hurley, JH AF Miller, GJ Hurley, JH TI Crystal structure of the catalytic core of inositol 1,4,5-trisphosphate 3-kinase SO MOLECULAR CELL LA English DT Article ID DEPENDENT PROTEIN-KINASE; PHOSPHATE; POLYPHOSPHATES; BINDING; DOMAIN; MULTIKINASE; REFINEMENT; EXPRESSION; METABOLISM; RESIDUES AB Soluble inositol polyphosphates are ubiquitous second messengers in eukaryotes, and their levels are regulated by an array of specialized kinases. The structure of an archetypal member of this class, inositol 1,4,5-trisphosphate 3-kinase (IP3K), has been determined at 2.2 Angstrom resolution in complex with magnesium and adenosine diphosphate. IP3K contains a catalytic domain that is a variant of the protein kinase superfamily, and a novel four-helix substrate binding domain. The two domains are in an open conformation with respect to each other, suggesting that substrate recognition and catalysis by IP3K involves a dynamic conformational cycle. The unique helical domain of IP3K blocks access to the active site by membrane-bound phosphoinositides, explaining the structural basis for soluble inositol polyphosphate specificity. C1 US Dept HHS, NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), US Dept HHS, NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM jh8e@nih.gov NR 43 TC 44 Z9 45 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 10 PY 2004 VL 15 IS 5 BP 703 EP 711 DI 10.1016/j.molcel.2004.08.005 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 853VJ UT WOS:000223856700004 PM 15350215 ER PT J AU Knepper, MA Agre, P AF Knepper, MA Agre, P TI The atomic architecture of a gas channel SO SCIENCE LA English DT Editorial Material ID AMMONIUM TRANSPORT; PROTEIN; KIDNEY C1 NIH, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Knepper, MA (reprint author), NIH, Kidney & Electrolyte Metab Lab, Bldg 10, Bethesda, MD 20892 USA. EM kneperm@nhlbi.nih.gov; pagre@jhmi.edu FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21] NR 8 TC 19 Z9 19 U1 0 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 SEP 10 PY 2004 VL 305 IS 5690 BP 1573 EP 1574 DI 10.1126/science.1103191 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 854GV UT WOS:000223891200028 PM 15361612 ER PT J AU Rouault, TA AF Rouault, TA TI Pathogenic bacteria prefer heme SO SCIENCE LA English DT Editorial Material ID STAPHYLOCOCCUS-AUREUS; IRON; ACQUISITION C1 NICHHD, Sect Human Iron Metab, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Rouault, TA (reprint author), NICHHD, Sect Human Iron Metab, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM trou@helix.nih.gov NR 16 TC 39 Z9 42 U1 0 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 SEP 10 PY 2004 VL 305 IS 5690 BP 1577 EP 1578 DI 10.1126/science.1102975 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 854GV UT WOS:000223891200031 PM 15361615 ER PT J AU Karev, GP Wolf, YI Berezovskaya, FS Koonin, EV AF Karev, GP Wolf, YI Berezovskaya, FS Koonin, EV TI Gene family evolution: an in-depth theoretical and simulation analysis of non-linear birth-death-innovation models SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID PROTEIN-INTERACTION NETWORKS; GENOME EVOLUTION; ORGANIZATION; DUPLICATION; EUKARYOTES; DIVERGENCE; PROFILES; UNIVERSE; BIOLOGY; EVOLVE AB Background: The size distribution of gene families in a broad range of genomes is well approximated by a generalized Pareto function. Evolution of ensembles of gene families can be described with Birth, Death, and Innovation Models (BDIMs). Analysis of the properties of different versions of BDIMs has the potential of revealing important features of genome evolution. Results: In this work, we extend our previous analysis of stochastic BDIMs. In addition to the previously examined rational BDIMs, we introduce potentially more realistic logistic BDIMs, in which birth/death rates are limited for the largest families, and show that their properties are similar to those of models that include no such limitation. We show that the mean time required for the formation of the largest gene families detected in eukaryotic genomes is limited by the mean number of duplications per gene and does not increase indefinitely with the model degree. Instead, this time reaches a minimum value, which corresponds to a non-linear rational BDIM with the degree of approximately 2.7. Even for this BDIM, the mean time of the largest family formation is orders of magnitude greater than any realistic estimates based on the timescale of life's evolution. We employed the embedding chains technique to estimate the expected number of elementary evolutionary events ( gene duplications and deletions) preceding the formation of gene families of the observed size and found that the mean number of events exceeds the family size by orders of magnitude, suggesting a highly dynamic process of genome evolution. The variance of the time required for the formation of the largest families was found to be extremely large, with the coefficient of variation much greater than 1. This indicates that some gene families might grow much faster than the mean rate such that the minimal time required for family formation is more relevant for a realistic representation of genome evolution than the mean time. We determined this minimal time using Monte Carlo simulations of family growth from an ensemble of simultaneously evolving singletons. In these simulations, the time elapsed before the formation of the largest family was much shorter than the estimated mean time and was compatible with the timescale of evolution of eukaryotes. Conclusions: The analysis of stochastic BDIMs presented here shows that non-linear versions of such models can well approximate not only the size distribution of gene families but also the dynamics of their formation during genome evolution. The fact that only higher degree BDIMs are compatible with the observed characteristics of genome evolution suggests that the growth of gene families is self-accelerating, which might reflect differential selective pressure acting on different genes. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Howard Univ, Dept Math, Washington, DC 20059 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM karev@ncbi.nlm.nih.gov; wolf@ncbi.nlm.nih.gov; fsberezo@hotmail.com; koonin@ncbi.nlm.nih.gov NR 55 TC 28 Z9 28 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD SEP 9 PY 2004 VL 4 AR 32 DI 10.1186/1471-2148-4-32 PG 23 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 863QE UT WOS:000224575900002 PM 15357876 ER PT J AU Hierro, A Sun, J Rusnak, AS Kim, J Prag, G Emr, SD Hurley, JH AF Hierro, A Sun, J Rusnak, AS Kim, J Prag, G Emr, SD Hurley, JH TI Structure of the ESCRT-II endosomal trafficking complex SO NATURE LA English DT Article ID RECEPTOR DOWN-REGULATION; MULTIVESICULAR-BODY; UBIQUITIN LIGASE; PROTEIN; TSG101; MACHINERY; PATHWAY; SYSTEM; BODIES; DELTA AB The multivesicular-body (MVB) pathway delivers transmembrane proteins and lipids to the lumen of the endosome. The multivesicular-body sorting pathway has crucial roles in growth-factor-receptor downregulation(1), developmental signalling(2-4), regulation of the immune response(5) and the budding of certain enveloped viruses such as human immunodeficiency virus(6). Ubiquitination is a signal for sorting into the MVB pathway(7,8), which also requires the functions of three protein complexes, termed ESCRT-I, -II and -III (endosomal sorting complex required for transport)(7,9,10). Here we report the crystal structure of the core of the yeast ESCRT-II complex, which contains one molecule of the Vps protein Vps22, the carboxy-terminal domain of Vps36 and two molecules of Vps25, and has the shape of a capital letter 'Y'. The amino-terminal coiled coil of Vps22 and the flexible linker leading to the ubiquitin-binding NZF domain of Vps36 both protrude from the tip of one branch of the 'Y'. Vps22 and Vps36 form nearly equivalent interactions with the two Vps25 molecules at the centre of the 'Y'. The structure suggests how ubiquitinated cargo could be passed between ESCRT components of the MVB pathway through the sequential transfer of ubiquitinated cargo from one complex to the next. C1 NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov RI Hierro, Aitor/F-9998-2011 OI Hierro, Aitor/0000-0002-7721-1581 NR 30 TC 96 Z9 103 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 SEP 9 PY 2004 VL 431 IS 7005 BP 221 EP 225 DI 10.1038/nature02914 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 852HI UT WOS:000223746000052 PM 15329733 ER PT J AU Morgan, WJ Crain, EF Gruchalla, RS O'Connor, GT Kattan, M Evans, RI Stout, J Malindzak, G Smartt, E Plaut, M Walter, M Vaughn, B Mitchell, H AF Morgan, WJ Crain, EF Gruchalla, RS O'Connor, GT Kattan, M Evans, RI Stout, J Malindzak, G Smartt, E Plaut, M Walter, M Vaughn, B Mitchell, H CA Inner-City Asthma Study Grp TI Results of a home-based environmental intervention among urban children with asthma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HOUSE-DUST-MITE; INNER-CITY CHILDREN; COCKROACH ALLERGEN EXPOSURE; RANDOMIZED CONTROLLED-TRIAL; DOUBLE-BLIND TRIAL; AVOIDANCE MEASURES; TOBACCO-SMOKE; RISK-FACTORS; LOW-INCOME; REDUCTION AB Background: Children with asthma who live in the inner city are exposed to multiple indoor allergens and environmental tobacco smoke in their homes. Reductions in these triggers of asthma have been difficult to achieve and have seldom been associated with decreased morbidity from asthma. The objective of this study was to determine whether an environmental intervention tailored to each child's allergic sensitization and environmental risk factors could improve asthma-related outcomes. Methods: We enrolled 937 children with atopic asthma (age, 5 to 11 years) in seven major U.S. cities in a randomized, controlled trial of an environmental intervention that lasted one year (intervention year) and included education and remediation for exposure to both allergens and environmental tobacco smoke. Home environmental exposures were assessed every six months, and asthma-related complications were assessed every two months during the intervention and for one year after the intervention. Results: For every 2-week period, the intervention group had fewer days with symptoms than did the control group both during the intervention year (3.39 vs. 4.20 days, P<0.001) and the year afterward (2.62 vs. 3.21 days, P<0.001), as well as greater declines in the levels of allergens at home, such as Dermatophagoides farinae (Derf1) allergen in the bed (P<0.001) and on the bedroom floor (P=0.004), D. pteronyssinus in the bed (P=0.007), and cockroach allergen on the bedroom floor (P<0.001). Reductions in the levels of cockroach allergen and dust-mite allergen (Derf1) on the bedroom floor were significantly correlated with reduced complications of asthma (P<0.001). Conclusions: Among inner-city children with atopic asthma, an individualized, home-based, comprehensive environmental intervention decreases exposure to indoor allergens, including cockroach and dust-mite allergens, resulting in reduced asthma-associated morbidity. C1 Univ Arizona, Arizona Resp Ctr, Coll Med, Tucson, AZ 85724 USA. Albert Einstein Coll Med, Jacobi Med Ctr, Bronx, NY 10467 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Boston Univ, Sch Med, Boston, MA 02118 USA. CUNY Mt Sinai Sch Med, New York, NY 10029 USA. Childrens Mem Hosp, Chicago, IL 60614 USA. Univ Washington, Sch Med & Publ Hlth, Seattle, WA USA. NIEHS, Res Triangle Pk, NC 27709 USA. NIAID, Bethesda, MD 20892 USA. Rho, Chapel Hill, NC USA. RP Morgan, WJ (reprint author), Univ Arizona, Arizona Resp Ctr, Coll Med, 1501 N Campbell Ave, Tucson, AZ 85724 USA. OI O'Connor, George/0000-0002-6476-3926 FU NCRR NIH HHS [M01 RR00533]; NIAID NIH HHS [AI-39761, AI-39769, AI-39776, AI-39785, AI-39789, AI-39900, AI-39901, AI-39902] NR 45 TC 542 Z9 566 U1 2 U2 47 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 SEP 9 PY 2004 VL 351 IS 11 BP 1068 EP 1080 DI 10.1056/NEJMoa032097 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 852CX UT WOS:000223733900006 PM 15356304 ER PT J AU Henry, MD Triplett, AA Oh, KB Smith, GH Wagner, KU AF Henry, MD Triplett, AA Oh, KB Smith, GH Wagner, KU TI Parity-induced mammary epithelial cells facilitate tumorigenesis in MMTV-neu transgenic mice SO ONCOGENE LA English DT Article DE mammary gland; differentiation; Cre recombinase; tumorigenesis; mouse mammary tumor virus; transgenics ID PROGENITOR CELLS; EXPRESSION; GLAND; POPULATION; PREGNANCY; PATHOLOGY; DELETION; TSG101; BREAST AB Using a Cre-lox-based genetic labeling technique, we have recently discovered a parity-induced mammary epithelial subtype that is abundant in nonlactating and nonpregnant, parous females. These mammary epithelial cells serve as alveolar progenitors in subsequent pregnancies, and transplantation studies revealed that they possess features of multipotent progenitors such as self-renewal and the capability to contribute to ductal and alveolar morphogenesis. Here, we report that these cells are the cellular targets for transformation in MMTV-neu transgenic mice that exhibit accelerated mammary tumorigenesis in multiparous animals. The selective ablation of this epithelial subtype reduces the onset of tumorigenesis in multiparous MMTV-neu transgenics. There is, however, experimental evidence to suggest that parity-induced mammary epithelial cells may not be the only cellular targets in other MMTV-promoter-based transgenic strains. In particular, the heterogeneous MMTV-wnt1 lesions predominantly express the ductal differentiation marker Nkcc1 that is absent in MMTV-neu-derived tumors. Our observations support the idea that tumors originate from distinctly different epithelial subtypes in selected MMTV-promoter-driven cancer models and that diverse oncogenes might exert discrete effects on particular mammary epithelial subtypes. C1 Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wagner, KU (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, 986805 Nebraska Med Ctr,Room 8009, Omaha, NE 68198 USA. EM kuwagner@unmc.edu RI Wagner, Kay-Uwe/B-6044-2009 FU NCI NIH HHS [CA036727, CA93797] NR 20 TC 77 Z9 81 U1 0 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 SEP 9 PY 2004 VL 23 IS 41 BP 6980 EP 6985 DI 10.1038/sj.onc.1207827 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 852JD UT WOS:000223750700014 PM 15286714 ER PT J AU Puaux, AL Marsac, D Prost, S Singh, MK Earl, P Moss, B Le Grand, R Riviere, Y Michel, ML AF Puaux, AL Marsac, D Prost, S Singh, MK Earl, P Moss, B Le Grand, R Riviere, Y Michel, ML TI Efficient priming of simian/human immunodeficiency virus (SHIV)-specific T-cell responses with DNA encoding hybrid SHIV/hepatitis B surface antigen particles SO VACCINE LA English DT Article DE SHIV; rhesus macaque; DNA immunisation; HBsAg ID RHESUS-MONKEYS; IMMUNE-RESPONSES; CD8(+) LYMPHOCYTES; NEUTRALIZING ANTIBODIES; DISEASE PROGRESSION; VIRAL REPLICATION; HIV; INFECTION; MACAQUES; HEPATITIS AB Recent efforts to design an human immunodeficiency virus type 1 (HIV-1) vaccine candidate have focused on means of eliciting anti-viral T-cell responses. We tried to improve the immunogenicity of DNA vaccines by designing hybrid DNA constructs encoding hepatitis B surface antigen (HBsAg) fused to antigenic domains of simian/human immunodeficiency virus (SHIV 89.6P). Immunisation with hybrid DNA induced both effector and long-lasting precursor T-cells. Following boosting with a recombinant modified vaccinia Ankara (rMVA) producing full-length SIV and HIV antigens, it appeared that priming with hybrid DNA had increased virus-specific T-cell responses in terms of both the number of virus-specific IFN-gamma-secreting T-cells and virus-specific lymphoproliferation. After intrarectal challenge with SHIV 89.6P, immunised animals demonstrated early control of SHIV 89.6P replication and stable CD4+ T-cell counts. (C) 2004 Elsevier Ltd. All rights reserved. C1 Inst Pasteur, Dept Mol Med, INSERM, U 370, F-75724 Paris 15, France. Univ Chile, Fac Med, ICBM, Programa Inmunol, Santiago 7, Chile. CEA, CRSSA, DRM, DSV,Serv Neurovirol,Lab Immunopathol Expt, F-92265 Fontenay Aux Roses, France. Inst Pasteur, Dept Mol Med, CNRS, URA 1930,Lab Immunopathol Virale, F-75724 Paris, France. Allegheny Singer Res Inst, Ctr Genom Sci, Pittsburgh, PA 15212 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Michel, ML (reprint author), Inst Pasteur, Dept Mol Med, INSERM, U 370, 28 Rue Dr Roux, F-75724 Paris 15, France. EM maloum@pasteur.fr RI PROST, Stephane/I-8362-2015 OI PROST, Stephane/0000-0002-8567-8253 NR 52 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 9 PY 2004 VL 22 IS 27-28 BP 3535 EP 3545 DI 10.1016/j.vaccine.2004.03.044 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 853GL UT WOS:000223815100003 PM 15315833 ER PT J AU Varma, S Simon, R AF Varma, S Simon, R TI Iterative class discovery and feature selection using Minimal Spanning Trees SO BMC BIOINFORMATICS LA English DT Article ID MOLECULAR CLASSIFICATION; CANCER AB Background: Clustering is one of the most commonly used methods for discovering hidden structure in microarray gene expression data. Most current methods for clustering samples are based on distance metrics utilizing all genes. This has the effect of obscuring clustering in samples that may be evident only when looking at a subset of genes, because noise from irrelevant genes dominates the signal from the relevant genes in the distance calculation. Results: We describe an algorithm for automatically detecting clusters of samples that are discernable only in a subset of genes. We use iteration between Minimal Spanning Tree based clustering and feature selection to remove noise genes in a step-wise manner while simultaneously sharpening the clustering. Evaluation of this algorithm on synthetic data shows that it resolves planted clusters with high accuracy in spite of noise and the presence of other clusters. It also shows a low probability of detecting spurious clusters. Testing the algorithm on some well known micro-array data-sets reveals known biological classes as well as novel clusters. Conclusions: The iterative clustering method offers considerable improvement over clustering in all genes. This method can be used to discover partitions and their biological significance can be determined by comparing with clinical correlates and gene annotations. The MATLAB(C) programs for the iterative clustering algorithm are available from http://linus.nci.nih.gov/supplement.html. C1 NCI, Biometr Res Branch, Rockville, MD USA. RP Varma, S (reprint author), NCI, Biometr Res Branch, Rockville, MD USA. EM varmas@mail.nih.gov; rsimon@mail.nih.gov RI Varma, Sudhir/N-8763-2014 OI Varma, Sudhir/0000-0002-4096-4782 NR 22 TC 23 Z9 27 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD SEP 8 PY 2004 VL 5 AR 126 DI 10.1186/1471-2105-5-126 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 858LB UT WOS:000224192200001 PM 15355552 ER PT J AU Fox, CS Vasan, RS Benjamin, EJ AF Fox, CS Vasan, RS Benjamin, EJ TI Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID POPULATION C1 NHLBI, Framingham Heart Study, Framingham, MA 01701 USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, Framingham, MA 01701 USA. EM foxca@nhlbi.nih.gov NR 6 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 SEP 8 PY 2004 VL 292 IS 10 BP 1175 EP 1175 DI 10.1001/jama.292.10.1175-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 851ZA UT WOS:000223723800014 ER PT J AU Wessel, TR Arant, CB Olson, MB Johnson, BD Reis, SL Sharaf, BL Shaw, LJ Handberg, E Sopko, G Kelsey, SF Pepine, CJ Merz, CNB AF Wessel, TR Arant, CB Olson, MB Johnson, BD Reis, SL Sharaf, BL Shaw, LJ Handberg, E Sopko, G Kelsey, SF Pepine, CJ Merz, CNB TI Relationship of physical fitness vs body mass index with coronary artery disease and cardiovascular events in women SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SYNDROME EVALUATION WISE; LIPID RESEARCH CLINICS; NHLBI-SPONSORED WISE; RISK-FACTORS; WEIGHT-LOSS; FOLLOW-UP; MYOCARDIAL-INFARCTION; POSTMENOPAUSAL WOMEN; ENDOTHELIAL DYSFUNCTION; INFLAMMATORY MARKERS AB Context Individual contributions of obesity and physical fitness (physical activity and functional capacity) to risk of coronary heart disease in women remain unclear. Objective To investigate the relationships of measures of obesity (body mass index [BMI], waist circumference, waist-hip ratio, and waist-height ratio) and physical fitness (self-reported Duke Activity Status Index [DASI] and Postmenopausal Estrogen-Progestin Intervention questionnaire [PEPI-Q] scores) with coronary artery disease (CAD) risk factors, angiographic CAD, and adverse cardiovascular (CV) events in women evaluated for suspected myocardial ischemia. Design, Setting, and Participants The National Heart, Lung, and Blood Institute-sponsored Women's Ischemia Syndrome Evaluation (WISE) is a multicenter prospective cohort study. From 1996-2000, 936 women were enrolled at 4 US academic medical centers at the time of clinically indicated coronary angiography and then assessed (mean follow-up, 3.9 [SD, 1.8] years) for adverse outcomes. Main Outcome Measures Prevalence of obstructive CAD (any angiographic stenosis greater than or equal to50%) and incidence of adverse CV events (all-cause death or hospitalization for nonfatal myocardial infarction, stroke, congestive heart failure, unstable angina, or other vascular events) during follow-up. Results Of 906 women (mean age, 58 [SD, 12] years) with complete data, 19% were of nonwhite race, 76% were overweight (BMI greater than or equal to25), 70% had low functional capacity (DASI scores <25, equivalent to &LE;7 metabolic equivalents [METs]), and 39% had obstructive CAD. During follow-up, 337 (38%) women had a first adverse event, 118 (13%) had a major adverse event, and 68 (8%) died. Overweight women were more likely than normal weight women to have CAD risk factors, but neither BMI nor abdominal obesity measures were significantly associated with obstructive CAD or adverse CV events after adjusting for other risk factors (P=.05 to .88). Conversely, women with lower DASI scores were significantly more likely to have CAD risk factors and obstructive CAD (44% vs 26%, P<.001) at baseline, and each 1-MET increase in DASI score was independently associated with an 8% (hazard ratio, 0.92; 95% confidence interval, 0.85-0.99; P=.02) decrease in risk of major adverse CV events during follow-up. Conclusions Among women undergoing coronary angiography for suspected ischemia, higher self-reported physical fitness scores were independently associated with fewer CAD risk factors, less angiographic CAD, and lower risk for adverse CV events. Measures of obesity were not independently associated with these outcomes. C1 Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL 32610 USA. Univ Pittsburgh, Med Ctr, Cardiovasc Inst, Pittsburgh, PA USA. Univ Pittsburgh, Med Ctr, Dept Epidemiol, Pittsburgh, PA USA. Rhode Isl Hosp, Div Cardiol, Providence, RI USA. Atlanta Cardiovasc Res Inst, Atlanta, GA USA. NHLBI, Div Heart & Vasc Dis, NIH, Bethesda, MD 20892 USA. Cedars Sinai Med Ctr, Cedars Sinai Res Inst, Dept Med, Div Cardiol, Los Angeles, CA 90048 USA. RP Wessel, TR (reprint author), Univ Florida, Coll Med, Div Cardiovasc Med, POB 100277, Gainesville, FL 32610 USA. EM twessel@ufl.edu FU NHLBI NIH HHS [N01-HV-68162, N01-HV-68161, N01-HV-68163, N01-HV-68164, U01-HL64829-01, U01-HL64914-01, U01-HL64924-01] NR 42 TC 181 Z9 188 U1 0 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 SEP 8 PY 2004 VL 292 IS 10 BP 1179 EP 1187 DI 10.1001/jama.292.10.1179 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 851ZA UT WOS:000223723800017 PM 15353530 ER PT J AU Straus, SE AF Straus, SE TI Pharmacotherapy of chronic fatigue syndrome - Another gallant attempt SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; COGNITIVE-BEHAVIOR THERAPY; GRADED-EXERCISE; DEFINITION C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Straus, SE (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 31 Ctr Dr,Bldg 31,Room 2B11, Bethesda, MD 20892 USA. EM strauss@mail.nih.gov NR 17 TC 3 Z9 3 U1 1 U2 3 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 SEP 8 PY 2004 VL 292 IS 10 BP 1234 EP 1235 DI 10.1001/jama.292.10.1234 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 851ZA UT WOS:000223723800025 PM 15353538 ER PT J AU Rohrbough, J Rushton, E Palanker, L Woodruff, E Matthies, HJG Acharya, U Acharya, JK Broadie, K AF Rohrbough, J Rushton, E Palanker, L Woodruff, E Matthies, HJG Acharya, U Acharya, JK Broadie, K TI Ceramidase regulates synaptic vesicle exocytosis and trafficking SO JOURNAL OF NEUROSCIENCE LA English DT Review DE Drosophila; synaptic transmission; synapse; presynaptic; ceramidase; ceramide; sphingolipids; lipid regulation ID READILY RELEASABLE POOL; LIPID RAFTS; NEUROMUSCULAR-JUNCTION; SYNAPSIN-I; GOLGI-APPARATUS; SNARE PROTEINS; POSTEMBRYONIC DEVELOPMENT; DROSOPHILA EMBRYOGENESIS; CULTURED FIBROBLASTS; HIPPOCAMPAL SYNAPSES AB A screen for Drosophila synaptic dysfunction mutants identified slug-a-bed ( slab). The slab gene encodes ceramidase, a central enzyme in sphingolipid metabolism and regulation. Sphingolipids are major constituents of lipid rafts, membrane domains with roles in vesicle trafficking, and signaling pathways. Null slab mutants arrest as fully developed embryos with severely reduced movement. The SLAB protein is widely expressed in different tissues but enriched in neurons at all stages of development. Targeted neuronal expression of slab rescues mutant lethality, demonstrating the essential neuronal function of the protein. C-5-ceramide applied to living preparations is rapidly accumulated at neuromuscular junction (NMJ) synapses dependent on the SLAB expression level, indicating that synaptic sphingolipid trafficking and distribution is regulated by SLAB function. Evoked synaptic currents at slab mutant NMJs are reduced by 50 - 70%, whereas postsynaptic glutamate-gated currents are normal, demonstrating a specific presynaptic impairment. Hypertonic saline-evoked synaptic vesicle fusion is similarly impaired by 50 - 70%, demonstrating a loss of readily releasable vesicles. In addition, FM1-43 dye uptake is reduced in slab mutant presynaptic terminals, indicating a smaller cycling vesicle pool. Ultrastructural analyses of mutants reveal a normal vesicle distribution clustered and docked at active zones, but fewer vesicles in reserve regions, and a twofold to threefold increased incidence of vesicles linked together and tethered at the plasma membrane. These results indicate that SLAB ceramidase function controls presynaptic terminal sphingolipid composition to regulate vesicle fusion and trafficking, and thus the strength and reliability of synaptic transmission. C1 Vanderbilt Univ, Vanderbilt Brain Inst, Vanderbilt Kennedy Ctr, Dept Biol Sci, Nashville, TN 37235 USA. Univ Utah, Dept Biol, Salt Lake City, UT 84112 USA. NCI, Regulat Cell Growth Lab, Frederick, MD 21702 USA. RP Broadie, K (reprint author), Vanderbilt Univ, Vanderbilt Brain Inst, Vanderbilt Kennedy Ctr, Dept Biol Sci, VU Stn B,Box 351634, Nashville, TN 37235 USA. EM kendal.broadie@vanderbilt.edu RI Matthies, Heinrich/B-7284-2017; OI Matthies, Heinrich/0000-0003-3615-7571; Musselman, Laura/0000-0002-8478-2526 FU NIGMS NIH HHS [GM54544, R01 GM054544, R01 GM054544-03, R01 GM054544-07] NR 105 TC 61 Z9 65 U1 1 U2 5 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 SEP 8 PY 2004 VL 24 IS 36 BP 7789 EP 7803 DI 10.1523/JNEUROSCI.1146-04.2004 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 852TL UT WOS:000223779200003 PM 15356190 ER PT J AU Bryce, DL Boisbouvier, J Bax, A AF Bryce, DL Boisbouvier, J Bax, A TI Experimental and theoretical determination of nucleic acid magnetic susceptibility: Importance for the study of dynamics by field-induced residual dipolar couplings SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NMR EXPERIMENTS; RNA; SENSITIVITY; PARAMETERS; MOTIONS C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov RI Bryce, David/A-3534-2008 OI Bryce, David/0000-0001-9989-796X NR 19 TC 23 Z9 23 U1 1 U2 10 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 SEP 8 PY 2004 VL 126 IS 35 BP 10820 EP 10821 DI 10.1021/ja047179o PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 851NH UT WOS:000223691300012 PM 15339148 ER PT J AU Pickhardt, PJ Nugent, PA Mysliwiec, PA Choi, JR Schindler, WR AF Pickhardt, PJ Nugent, PA Mysliwiec, PA Choi, JR Schindler, WR TI Location of adenomas missed by optical colonoscopy SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID VIRTUAL COLONOSCOPY; COLORECTAL NEOPLASIA; POLYPS; POLYPECTOMY; SURVEILLANCE; COLONOGRAPHY; CANCER; COLON; RATES AB Background: Previous estimates of the adenoma miss rate with optical colonoscopy (OC) are hindered by the use of OC as its own reference standard. Objective: To evaluate the frequency and characteristics of colorectal neoplasms that are missed prospectively on OC by using virtual colonoscopy (VC) as a separate reference standard. Design: Prospective, multicenter screening trial. Setting: 3 medical centers. Participants: 1233 asymptomatic adults who underwent same-day VC and OC. Measurements: Colorectal neoplasms (adenomatous polyps) missed at OC before VC results were unblinded. Results: Fourteen (93.3%) of 15 nonrectal neoplasms were located on a fold; 10 (71.4%) of these were located on the backside of a fold. Five (83.3%) of 6 rectal lesions were located within 10 cm of the anal verge. Limitations: Estimation of the OC miss rate depended on polyp detection on both VC and second-look OC and therefore underestimates the true OC miss rate, particularly for smaller polyps. Conclusions: Most clinically significant adenomas missed prospectively on OC are located behind a fold or near the anal verge. The 12% OC miss rate for large adenomas (greater than or equal to10 mm) when state-of-the-art 3-dimensional VC is used as a separate reference standard is increased from the previous 0% to 6% estimates derived by using OC as its own reference standard. C1 Univ Wisconsin, Sch Med, Dept Radiol, Clin Sci Ctr E3311, Madison, WI 53792 USA. Uniformed Serv Univ Hlth Sci, Natl Naval Med Ctr, Bethesda, MD 20814 USA. NCI, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. Naval Med Ctr San Diego, San Diego, CA USA. RP Pickhardt, PJ (reprint author), Univ Wisconsin, Sch Med, Dept Radiol, Clin Sci Ctr E3311, 600 Highland Ave, Madison, WI 53792 USA. EM ppickhardt@mail.radiology.wisc.edu NR 19 TC 258 Z9 261 U1 1 U2 5 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 7 PY 2004 VL 141 IS 5 BP 352 EP 359 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 852CW UT WOS:000223733800003 PM 15353426 ER PT J AU Shemer, G Suissa, M Kolotuev, I Nguyen, KCQ Hall, DH Podbilewicz, B AF Shemer, G Suissa, M Kolotuev, I Nguyen, KCQ Hall, DH Podbilewicz, B TI EFF-1 is sufficient to initiate and execute tissue-specific cell fusion in C. elegans SO CURRENT BIOLOGY LA English DT Article ID CAENORHABDITIS-ELEGANS; MEMBRANE-FUSION; MYOBLAST FUSION; ELECTRON-MICROSCOPY; PROTEIN; VULVA; MORPHOGENESIS; RAS AB Despite the identification of essential processes in which cell fusion plays spectacular roles such as in fertilization and development of muscle, bone, and placenta [1-5], there are no identified proteins that directly mediate developmental cell fusion reactions. C. elegans has recently become among the best-characterized models to use for studying developmental cell fusion [5-15]. The eff-1 (epithelial fusion failure) gene encodes novel type I membrane proteins required for epithelial cell fusion. Analysis of eff-1 mutants showed that cell fusion normally restricts routes for cell migration and establishes body and organ shape and size [ 5, 8, 9, 11]. Here, we explored cell fusion by using time-lapse confocal and electron microscopy of different organs. We found that ectopic expression of eff-1 is sufficient to fuse epithelial cells that do not normally fuse. This ectopic fusion results in cytoplasmic content mixing and disappearance of apical junctions, starting less than 50 min after the start of eff-1 transcription. We found that eff-1 is necessary to initiate and expand multiple microfusion events between pharyngeal muscle cells. Surprisingly, eff-1 is not required to fuse the gonadal anchor cell to uterine cells. Thus, eff-1 is sufficient and essential for most but not all cell fusion events during C. elegans development. C1 Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. Albert Einstein Coll Med, Ctr C Elegans Anat, Dept Neurosci, Bronx, NY 10461 USA. NICHHD, Sect Membrane Biol, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Podbilewicz, B (reprint author), Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. EM podbilew@tx.technion.ac.il RI Podbilewicz, Benjamin/N-4825-2014; OI Podbilewicz, Benjamin/0000-0002-0411-4182; Oren-Suissa, Meital/0000-0001-9937-8326 FU NCRR NIH HHS [R24 RR012596, RR 12596]; NIH HHS [R24 OD010943] NR 34 TC 46 Z9 51 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD SEP 7 PY 2004 VL 14 IS 17 BP 1587 EP 1591 DI 10.1016/j.cub.2004.07.059 PG 5 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 853FW UT WOS:000223813500026 PM 15341747 ER PT J AU Dudko, OK Weiss, GH Chernomordik, V Gandjbakhche, AH AF Dudko, OK Weiss, GH Chernomordik, V Gandjbakhche, AH TI Photon migration in turbid media with anisotropic optical properties SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID SCALING RELATIONSHIPS; LIGHT-PROPAGATION; RANDOM-WALKS AB We analyse properties of photon migration in reflectance measurements made on a semi-infinite medium bounded by a plane, in which optical parameters may vary in directions neither parallel to, nor perpendicular to the bounding plane. Our aim in doing this is to develop the formulae necessary to deduce parameters of directionality from both time-gated and continuous wave measurements. The mathematical development is based on a diffusion picture, in which the bounding plane is regarded as being totally absorbing so that all photons reaching the surface contribute to the reflectance. C1 NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Dudko, OK (reprint author), NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. NR 11 TC 15 Z9 15 U1 1 U2 2 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD SEP 7 PY 2004 VL 49 IS 17 BP 3979 EP 3989 AR PII S0031-9155(04)80369-5 DI 10.1088/0031-9155/49/17/011 PG 11 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 854IQ UT WOS:000223896700011 PM 15470918 ER PT J AU Stepchenko, A Nirenberg, M AF Stepchenko, A Nirenberg, M TI Mapping activation and repression domains of the vnd/NK-2 homeodomain protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; DNA-BINDING TARGETS; HOMEOBOX GENE; TRANSCRIPTIONAL ACTIVATOR; DROSOPHILA NEUROGENESIS; COLUMN IDENTITY; IN-VIVO; VND; NEUROECTODERM; EXPRESSION AB A transient transfection assay using Drosophila S2 tissue culture cells and WT and mutant Drosophila vnd/NK-2 homeobox cDNAs was used to localize repression and activation domains of vnd/NK-2 homeodomain protein. A repression domain was identified near the N terminus of vnd/NK-2 homeodomain protein (amino acid residues 154-193), which contains many hydrophobic amino acid residues. The major determinants of the repression domain were shown to be amino acid residues F155, W158,1161, L162, L163, and W166. Truncated protein consisting of the N-terminal repression domain and the DNA-binding homeodomain repressed transcription as efficiently as WT vnd/NK-2 protein. An activation domain was identified between the tinman domain and the homeodomain (amino acid residues 277-543), which consists of a glutamine-rich subdomain and two acidic subdomains. No effect was detected of the tinman domain or the NK-2-specific domain on either activation or repression of a beta-galactosidase reporter gene. C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20882 USA. RP Nirenberg, M (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 10,Room 7N-315, Bethesda, MD 20882 USA. EM mnirenberg@nih.gov NR 45 TC 15 Z9 15 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 7 PY 2004 VL 101 IS 36 BP 13180 EP 13185 DI 10.1073/PNAS.0404775101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 853AT UT WOS:000223799100017 PM 15340160 ER PT J AU Angata, T Margulies, EH Green, ED Varki, A AF Angata, T Margulies, EH Green, ED Varki, A TI Large-scale sequencing of the CD33-related Siglec gene cluster in five mammalian species reveals rapid evolution by multiple mechanisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SIALIC ACIDS; NATURAL-SELECTION; RECEPTORS; DOMAIN; SIALOADHESIN; MACROPHAGES; RESOLUTION; DIVERSITY; APOPTOSIS; MUTATION AB Siglecs are a recently discovered family of animal lectins that belong to the Ig superfamily and recognize sialic acids (Sias). CD33-related Siglecs (CD33rSigiecs) are a subgroup with as-yet-unknown functions, characterized by sequence homology, expression on innate immune cells, conserved cytosolic tyrosine-based signaling motifs, and a clustered localization of their genes. To better understand the biology and evolution of CD33rSiglecs, we sequenced and compared the CD33rSiglec gene cluster from multiple mammalian species. Within the sequenced region, the segments containing CD33rSiglec genes showed a lower degree of sequence conservation. In contrast to the adjacent conserved kallikrein-like genes, the CD33rSiglec genes showed extensive species differences, including expansions of gene subsets; gene deletions, including one human-specific loss of a novel functional primate Siglec (Siglec-13); exon shuffling, generating hybrid genes; accelerated accumulation of nonsynonymous substitutions in the Sia-recognition domain; and multiple instances of mutations of an arginine residue essential for Sia recognition in otherwise intact Siglecs. Nonsynonymous differences between human and chimpanzee orthologs showed uneven distribution between the two 13 sheets of the Sia-recognition domain, suggesting biased mutation accumulation. These data indicate that CD33rSiglec genes are undergoing rapid evolution via multiple genetic mechanisms, possibly due to an evolutionary "arms race" between hosts and pathogens involving Sia recognition. These studies, which reflect one of the most complete comparative sequence analyses of a rapidly evolving gene cluster, provide a clearer picture of the ortholog status of CD33rSiglecs among primates and rodents and also facilitate rational recommendations regarding their nomenclature. C1 Univ Calif San Diego, Glycobiol Res & Training Ctr, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Varki, A (reprint author), Natl Inst Adv Ind Sci & Technol, Res Ctr Glycosci, 1-1-1 Higashi, Tsukuba, Ibaraki 3058562, Japan. EM varkiadmin@ucsd.edu FU NHLBI NIH HHS [P01 HL057345, P01 HL57345]; NIGMS NIH HHS [R01 GM032373, R01GM-32373] NR 37 TC 94 Z9 96 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 SEP 7 PY 2004 VL 101 IS 36 BP 13251 EP 13256 DI 10.1073/pnas.0404833101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 853AT UT WOS:000223799100029 PM 15331780 ER PT J AU Hahn, Y Bera, TK Gehlhaus, K Kirsch, IR Pastan, IH Lee, B AF Hahn, Y Bera, TK Gehlhaus, K Kirsch, IR Pastan, IH Lee, B TI Finding fusion genes resulting from chromosome rearrangement by analyzing the expressed sequence databases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID FULL-LENGTH HUMAN; MESSENGER-RNA; BREAST-CANCER; HUMAN CDNAS; COMPLEX AB Chromosomal rearrangements resulting in gene fusions are frequently involved in carcinogenesis. Here, we describe a semiautomatic procedure for identifying fusion gene transcripts by using publicly available mRNA and EST databases. With this procedure, we have identified 96 transcript sequences that are derived from 60 known fusion genes. Also, 47 or more additional sequences appear to be derived from 20 or more previously unknown putative fusion genes. We have experimentally verified the presence of a previously unknown IRA1/RGS17 fusion in the breast cancer cell line MCF7. The fusion gene encodes the full-length RGS17 protein, a regulator of G protein-coupled signaling, under the control of the IRA1 gene promoter. This study demonstrates that databases of ESTs can be used to discover fusion genes resulting from structural rearrangement of chromosomes. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bera, TK (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5120A, Bethesda, MD 20892 USA. EM bk@nih.gov NR 25 TC 41 Z9 42 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 SEP 7 PY 2004 VL 101 IS 36 BP 13257 EP 13261 DI 10.1073/pnas.0405490101 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 853AT UT WOS:000223799100030 PM 15326299 ER PT J AU Istrail, S Florea, L Halldorsson, BV Kohlbacher, O Schwartz, RS Yap, VB Yewdell, JW Hoffman, SL AF Istrail, S Florea, L Halldorsson, BV Kohlbacher, O Schwartz, RS Yap, VB Yewdell, JW Hoffman, SL TI Comparative immunopeptidomics of humans and their pathogens SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID NEWLY SYNTHESIZED PROTEINS; COMPLETE GENOME SEQUENCE; DATABASE; RESPONSES; BIOLOGY; BINDING AB Major histocompatibility complex class I molecules present peptides of 8-10 residues to CD8+ T cells. We used 19 predicted proteomes to determine the influence of CD8+ T cell immune surveillance on protein evolution in humans and microbial pathogens by predicting immunopeptidomes, i.e., sets of class I binding peptides present in proteomes. We find that class I pepticle binding specificities (i) have had little, if any, influence on the evolution of immunopeptidomes and (ii) do not take advantage of biases in amino acid distribution in proteins other than the concentration of hydrophobic residues in NH2-terminal leader sequences. C1 Celera Genomics, Rockville, MD 20850 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Berkeley, Dept Math, Berkeley, CA 94720 USA. RP Sanaria Inc, Rockville, MD 20852 USA. EM slhoffman@sanaria.com RI yewdell, jyewdell@nih.gov/A-1702-2012; Kohlbacher, Oliver/B-7310-2008; Schwartz, Russell/A-1998-2016; OI Kohlbacher, Oliver/0000-0003-1739-4598; Schwartz, Russell/0000-0002-4970-2252; Halldorsson, Bjarni/0000-0003-0756-0767 NR 18 TC 19 Z9 19 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 SEP 7 PY 2004 VL 101 IS 36 BP 13268 EP 13272 DI 10.1073/pnas.0404740101 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 853AT UT WOS:000223799100032 PM 15326311 ER PT J AU Pisitkun, T Shen, RF Knepper, MA AF Pisitkun, T Shen, RF Knepper, MA TI Identification and proteomic profiling of exosomes in human urine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID COLLECTING DUCT; PROTEIN; VASOPRESSIN; MEMBRANE; ENDOSOME; PATHWAY; COMPLEX; RAT; HYPERTENSION; AQUAPORIN-2 AB Urine provides an alternative to blood plasma as a potential source of disease biomarkers. One urinary biomarker already exploited in clinical studies is aquaporin-2. However, it remains a mystery how aquaporin-2 (an integral membrane protein) and other apical transporters are delivered to the urine. Here we address the hypothesis that these proteins reach the urine through the secretion of exosomes [membrane vesicles that originate as internal vesicles of multivesicular bodies (MVBs)]. Low-density urinary membrane vesicles from normal human subjects were isolated by differential centrifugation. lmmunoGold electron microscopy using antibodies directed to cytoplasmic or anticytoplasmic epitopes revealed that the vesicles are oriented "cytoplasmic-side inward," consistent with the unique orientation of exosomes. The vesicles were small (<100 nm), consistent with studies of MVBs and exosomes from other tissues. Proteomic analysis of urinary vesicles through nanospray liquid chromatography-tandem mass spectrometry identified numerous protein components of MVBs and of the endosomal pathway in general. Full liquid chromatography-tandem MS analysis revealed 295 proteins, including multiple protein products of genes already known to be responsible for renal and systemic diseases, including autosomal dominant polycystic kidney disease, Gitelman syndrome, Bartter syndrome, autosomal recessive syndrome of osteopetrosis with renal tubular acidosis, and familial renal hypomagnesemia. The results indicate that exosome isolation may provide an efficient first step in biomarker discovery in urine. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, NIH, Bldg 10,Room 6N260,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01-HL-01282-KE] NR 37 TC 759 Z9 786 U1 32 U2 152 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 SEP 7 PY 2004 VL 101 IS 36 BP 13368 EP 13373 DI 10.1073/pnas.0403453101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 853AT UT WOS:000223799100050 PM 15326289 ER PT J AU Choo, RE Huestis, MA Schroeder, JR Shin, AS Jones, HE AF Choo, RE Huestis, MA Schroeder, JR Shin, AS Jones, HE TI Neonatal abstinence syndrome in methadone-exposed infants is altered by level of prenatal tobacco exposure SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE perinatal; methadone; nicotine; withdrawal ID BIRTH-WEIGHT; NARCOTIC WITHDRAWAL; CIGARETTE-SMOKING; DEPENDENT WOMEN; DRUG-USE; PREGNANCY; MANAGEMENT; NICOTINE; DOSAGE; TERM AB Maternal tobacco consumption during pregnancy has been associated with lower birth weight infants, preterm births, intrauterine growth retardation, smaller head circumference and increase in morbidity, yet few studies have examined the role tobacco has on the opiate neonatal abstinence syndrome (NAS). This study examined the effect of prenatal tobacco exposure on NAS for infants born to mothers maintained on methadone during gestation. Twenty-nine pregnant women and their newborn infants participated in this study. Tobacco exposure was based on maternal self-report with 16 women reporting cigarette consumption of 10 or less per day and 13 reporting smoking 20 cigarettes or more a day. The onset, peak, and duration of NAS were examined. Results showed that infants born to mothers who reported smoking 20 or more cigarettes per day had significantly higher NAS peak scores of 9.8 versus 4.8, and took longer to peak (113.0 h versus 37.8 h), than light smokers of 10 or fewer cigarettes per day. We concluded that tobacco use in conjunction with methadone plays an important role in the timing and severity of NAS in prenatally exposed infants. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Johns Hopkins Bayview Med Ctr, Ctr Addict & Pregnancy, Baltimore, MD 21224 USA. Natl Inst Drug Abuse, Chem & Drug Metab Sect, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. Natl Inst Drug Abuse, Treatment Sect, Clin Pharmacol & Therapeut Res Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21224 USA. RP Jones, HE (reprint author), Johns Hopkins Bayview Med Ctr, Ctr Addict & Pregnancy, 4940 Eastern Ave,D4 E 442, Baltimore, MD 21224 USA. EM hejones@jhmi.edu FU NIDA NIH HHS [DA12403-02] NR 40 TC 69 Z9 71 U1 1 U2 6 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD SEP 6 PY 2004 VL 75 IS 3 BP 253 EP 260 DI 10.1016/j.drugalcdep.2604.03.012 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 846JY UT WOS:000223313000004 PM 15283946 ER PT J AU Moir, S Malaspina, A Pickeral, OK Donoghue, ET Vasquez, J Miller, NJ Krishnan, SR Planta, MA Turney, JE Justement, JS Kottilil, S Dybul, M Mican, JM Kovacs, C Chun, TW Birse, CE Fauci, AS AF Moir, S Malaspina, A Pickeral, OK Donoghue, ET Vasquez, J Miller, NJ Krishnan, SR Planta, MA Turney, JE Justement, JS Kottilil, S Dybul, M Mican, JM Kovacs, C Chun, TW Birse, CE Fauci, AS TI Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE terminal differentiation; interferon; immune activation; gene expression; microarray ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; FAMILY-MEMBERS BAFF; PLASMA-CELLS; ANTIGEN RECEPTOR; T-CELLS; LYMPHOCYTE STIMULATOR; INFECTED INDIVIDUALS; ALPHA-INTERFERON; MULTIPLE-MYELOMA AB Human immunodeficiency virus (HIV) infection leads to numerous perturbations of B cells through mechanisms that remain elusive. We performed DNA microarray, phenotypic, and functional analyses in an effort to elucidate mechanisms of B cell perturbation associated with ongoing HIV replication. 42 genes were up-regulated in B cells of HIV-viremic patients when compared with HIV-aviremic and HIV-negative patients, the majority of which were interferon (IFN)-stimulated or associated with terminal differentiation. Flow cytometry confirmed these increases and indicated that CD21(low) B cells, enhanced in HIV-viremic patients, were largely responsible for the changes. Increased expression of the tumor necrosis factor (TNF) superfamily (TNFSF) receptor CD95 correlated with increased susceptibility to CD95-mediated apoptosis of CD21(low) B cells, which, in turn, correlated with HIV plasma viremia. Increased expression of BCMA, a weak TNFSF receptor for B lymphocyte stimulator (BLyS), on CD21(low) B cells was associated with a concomitant reduction ill the expression of the more potent BLyS receptor, BAFF-R, that resulted in reduced BLyS binding and BLyS-mediated survival. These findings demonstrate that altered expression of genes associated with IFN stimulation and terminal differentiation in B cells of HIV-viremic patients lead to an increased propensity to cell death, which may have substantial deleterious effects on B cell responsiveness to antigenic stimulation. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Human Genome Sci Inc, Rockville, MD 20850 USA. Univ Toronto, Dept Med, Toronto, ON M5S 1A1, Canada. RP Moir, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Rm 6A01,10 Ctr Dr, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov NR 71 TC 143 Z9 144 U1 0 U2 5 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 SEP 6 PY 2004 VL 200 IS 5 BP 587 EP 599 DI 10.1084/jem.20032236 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 854IC UT WOS:000223895300006 PM 15353552 ER PT J AU Fisher, B Jeong, JH Bryant, J Anderson, S Dignam, J Fisher, ER Wolmark, N AF Fisher, B Jeong, JH Bryant, J Anderson, S Dignam, J Fisher, ER Wolmark, N TI Treatment of lymph-node-negative, oestrogen-recept-postive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials SO LANCET LA English DT Article ID PROGESTERONE-RECEPTOR; POSITIVE TUMORS; CHEMOTHERAPY; TAMOXIFEN; COMBINATION; THERAPY; RESPONSIVENESS; REGRESSION; PATIENT AB Background Findings from the National Surgical Adjuvant Breast and Bowel Project B-14 and B-20 trials showed that tamoxifen benefited women with oestrogen-receptor-positive tumours and negative axillary nodes, and that chemotherapy plus tamoxifen was more effective than tamoxifen alone. We present long-term findings from those trials and relate them to age, menopausal status, and tumour oestrogen-receptor concentrations. We also discuss the extent of progress made in the treatment of such patients. Methods B-14 patients were randomly assigned to placebo (n=1453) or tamoxifen (n=1439); B-20 patients to tamoxifen (n=788) or cyclophosphamide, methotrexate, fluorouracil, and tamoxifen (CMFT, n=789). Primary endpoints were recurrence-free survival and overall survival estimated according to patients' age, menopausal status, and tumour oestrogen-receptor concentration. Smoothed recurrence rates were used to measure patterns of recurrence as a continuous function of age. Findings Compared with placebo, tamoxifen benefited women in B-14 through 15 years, irrespective of age, menopausal status, or tumour oestrogen-receptor concentration (hazard ratio [HR] for recurrence-free survival 0.58, 95% CI 0.50-0.67, p<0.0001; HR for overall survival 0.80, 0.71-0.91, p=0.0008). In B-20, the benefit from CMFT over 12 years was greater than that from tamoxifen alone (HR for recurrence-free survival 0.52, 0.39-0.68, p<0.0001; HR for overall survival 0.78, 0.60-1.01, p=0.063). When CMFT was compared with placebo, there were reductions in treatment failure of about 65% in all age-groups. Interpretation Much benefit has been achieved in treatment of women with oestrogen-receptor-positive tumours and negative nodes. When planning systemic therapy for such patients of all ages, it should be understood that some have tumours with variable concentrations of oestrogen-receptors, a surrogate for other biomarkers associated with tumour growth and response to treatment. Older women tend to have higher tumour oestrogen-receptor concentrations and are more likely to benefit from tamoxifen than from chemotherapy; in younger women, the converse is true. Consequently, the notion that use of tamoxifen or chemotherapy should be based only on age is too restrictive. C1 Natl Surg Adjuvant Breast & Bowel Project, Operat Ctr, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Ctr Biostat, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Pathol Ctr, Pittsburgh, PA USA. RP Fisher, B (reprint author), 4 Allegheny Ctr,Suite 602, Pittsburgh, PA 15212 USA. EM bernard.fisher@nsabp.org OI Anderson, Stewart/0000-0001-8948-0650; Jeong, Jong/0000-0003-0596-2201 FU NCI NIH HHS [U10-CA-37377, U10-CA-69651, U10-CA-69974, U10-CA-12027] NR 34 TC 190 Z9 199 U1 1 U2 7 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD SEP 4 PY 2004 VL 364 IS 9437 BP 858 EP 868 DI 10.1016/S0140-6736(04)16981-X PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 851KY UT WOS:000223685200032 PM 15351193 ER PT J AU Farel, C Suzman, DL McLaughlin, M Campbell, C Koratich, C Masur, H Metcalf, JA Robinson, MR Polis, MA Kottilil, S AF Farel, C Suzman, DL McLaughlin, M Campbell, C Koratich, C Masur, H Metcalf, JA Robinson, MR Polis, MA Kottilil, S TI Serious ophthalmic pathology compromising vision in HCV/HIV co-infected patients treated with peginterferon alpha-2b and ribavirin SO AIDS LA English DT Article DE pegylated interferon; ribavirin; hepatitis C; HIV; HCV/HIV co-infection; ophthalmology; color vision ID CHRONIC HEPATITIS-C; HUMAN-IMMUNODEFICIENCY-VIRUS; PLUS RIBAVIRIN; INTERFERON TREATMENT; COMPLICATIONS; THERAPY AB Objective: To characterize the ocular changes associated with peginterferon alpha 2b (peg-IFN alpha-2b) and ribavirin therapy for chronic hepatitis C infection in HIV co-infected individuals. Methods: A prospective, open-label trial treating HIV/hepatitis C (HCV) co-infected individuals with peg-IFN alpha-2b and ribavirin at the Warren Grant Magnusson Clinical Center, National Institutes of Health, Bethesda, Maryland, USA. Twenty-three patients with a high mean CD4+ T-cell count were treated with peg-IFN alpha-2b and ribavirin and followed for 40 to 88 weeks. Ophthalmologic evaluations including visual acuity, visual field testing, color vision examination and indirect ophthalmoscopy were performed at baseline and every 3 months. Results: Eight of the 23 patients (35%) developed ophthalmologic pathology, including cotton wool spots, cataracts, and two patients developed decreased color vision. These two patients regained their color vision, one after cessation of anti-HCV therapy. Conclusions: Although retinal pathologies have been reported in patients treated with interferon-alpha, they have not been reported during peg-IFN alpha-2b therapy nor in HIV/HCV co-infected patients. The incidence of serious ocular pathology associated with anti-HCV therapy may be very high and is probably associated with peg-IFN alpha-2b. Increased monitoring of patients treated with peg-IFN alpha-2b for retinal and visual changes is warranted. (C) 2004 Lippincott Williams Wilkins. C1 NEI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD USA. NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), NEI, NIH, Dept Hlth & Human Serv, Bldg 10,Room 6A11, Bethesda, MD 20892 USA. EM Skottilil@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268 NR 10 TC 16 Z9 18 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 SEP 3 PY 2004 VL 18 IS 13 BP 1805 EP 1809 DI 10.1097/00002030-200409030-00009 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 851EI UT WOS:000223667900009 PM 15316341 ER PT J AU Zudaire, E Martinez, A Ozbun, LL Cuttitta, F AF Zudaire, E Martinez, A Ozbun, LL Cuttitta, F TI Characterization of adrenomedullin in non-human primates SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE adrenomedullin; rhesus monkey; TGF-beta 1; hypoxia; glucocorticoid; retinoic acid ID SMOOTH-MUSCLE-CELLS; INDUCIBLE FACTOR-I; TRANSFORMING GROWTH-FACTOR-BETA-1; TRANSCRIPTION FACTOR; DNA-SEQUENCES; GLUCOCORTICOID RECEPTOR; HUMAN LUNG; GENE; EXPRESSION; BINDING AB Adrenomedullin (AM) is a 52 amino acid peptide involved in the pathophysiology of several human diseases. Here we show the gene structure, organ distribution, and regulated expression of AM in monkey. The monkey AM (mAM) gene is located on the short arm of chromosome 9 and it codes for a 185 amino acid preprohormone, which contains two araidated peptides identical to the human AM and proadrenomedullin N-terminal 20 peptide. The promoter region of the mAM gene contains a variety of transcription factor binding motifs. mAM is widely expressed throughout many organs as shown by real-time PCR and immunohistochemical techniques.. and we have found similar levels of circulating plasma AM in monkeys and humans. A significant upregulation of the mAM mRNA was observed in monkey cells exposed to low oxygen tension conditions, TGF-beta1, all-trans-retinoic acid, and dexamethasone. Our collective data show a high degree of homology between mAM and hAM, which renders the monkey an attractive animal model for future pharmacological and pre-clinical studies targeting AM. Published by Elsevier Inc. C1 NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. RP Zudaire, E (reprint author), NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. EM zudairee@mail.nih.gov RI Martinez, Alfredo/A-3077-2013 OI Martinez, Alfredo/0000-0003-4882-4044 NR 66 TC 11 Z9 11 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 3 PY 2004 VL 321 IS 4 BP 859 EP 869 DI 10.1016/j.bbrc.2004.07.032 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 847GQ UT WOS:000223381100016 PM 15358106 ER PT J AU Chen, J Blackford, JA Simons, SS AF Chen, J Blackford, JA Simons, SS TI PCR expression mutagenesis: a high-throughput mutation assay applied to the glucocorticoid receptor ligand-binding domain SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE high-throughput point mutation analysis; PCR mutagenesis; glucocorticoid receptors; ligand binding domain; transactivation activity; ligand binding activity ID NUCLEAR HORMONE-RECEPTORS; ANTAGONIST COMPLEXES; INDUCTION PROPERTIES; DETERMINANTS; COREPRESSORS; COACTIVATORS; AGONIST AB Glucocorticoid receptors (GRs) are extensively studied members of the steroid hormone receptor superfamily that regulate the transcription rates of numerous genes. Notwithstanding, the role of each GR amino acid in the various steps of transactivation is still unknown. A recent report shows that linear DNA has the same capacity as super-helical plasmid DNA for gene expression in transient transfection assays. Based on this observation, we describe a high-throughput assay to analyze a large set of alanine point mutations that are introduced by two rounds of PCR. The PCR products are then directly transfected into cells. This PCR expression mutagenesis (PEM) technique is used to identify several new residues of the GR ligand binding domain that influence ligand binding and/or transactivation. PEM thus provides a quick method for screening large quantities of mutant proteins. In combination with automation, PEM provides a more rapid and efficient too] for probing the role of each amino acid in the biological functions of a given protein. (C) Published by Elsevier Inc. C1 NIDDK, Steroid Hormones Sect, LMCB, NIH, Bethesda, MD USA. RP Chen, J (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pharmacol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM jchen@usuhs.mil; steroids@helix.nih.gov NR 19 TC 4 Z9 4 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 3 PY 2004 VL 321 IS 4 BP 893 EP 899 DI 10.1016/j.bbrc.2004.07.047 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 847GQ UT WOS:000223381100020 PM 15358110 ER PT J AU Stonik, JA Remaley, AT Demosky, SJ Neufeld, EB Bocharov, A Brewer, HB AF Stonik, JA Remaley, AT Demosky, SJ Neufeld, EB Bocharov, A Brewer, HB TI Serum Amyloid a promotes ABCA1-dependent and ABCA1-independent lipid efflux from cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE serum amyloid A; apolipoprotein A-I; ABCA1 transporter; cholesterol; atherosclerosis ID HIGH-DENSITY-LIPOPROTEINS; ACUTE-PHASE PROTEIN; MACROPHAGE CHOLESTEROL EFFLUX; CARDIOVASCULAR-DISEASE; CELLULAR AFFINITY; APOLIPOPROTEIN; IDENTIFICATION; TRANSPORTER; EXPRESSION; BINDING AB Serum amyloid A (SAA) is an acute phase protein that associates with HDL. In order to examine the role of SAA in reverse-cholesterol transport, lipid efflux was tested to SAA from HeLa cells before and after transfection with the ABCA1 transporter. ABCA1 expression increased efflux of cholesterol and phospholipid to SAA by 3-fold and 2-fold, respectively. In contrast to apoA-I, SAA also removed lipid without ABCA1; cholesterol efflux from control cells to SAA was 10-fold higher than for apoA-I. Furthermore, SAA effluxed cholesterol from Tangier disease fibroblasts and from cells after inhibition of ABCA1 by fixation with paraformaldehyde. In summary, SAA can act as a lipid acceptor for ABCA1, but unlike apoA-I, it can also efflux lipid without ABCA1, by most likely a detergent-like extraction process. These results suggest that SAA may play a unique role as an auxiliary lipid acceptor in the removal of lipid from sites of inflammation. (C) 2004 Elsevier Inc. All rights reserved. C1 NHLBI, Natl Inst Hlth, Mol Dis Branch, Bethesda, MD 20892 USA. Natl Inst Diabet & Kidney Dis, Natl Inst Hlth, Bethesda, MD USA. RP Remaley, AT (reprint author), NHLBI, Natl Inst Hlth, Mol Dis Branch, Bldg 10, Bethesda, MD 20892 USA. EM aremaley@nih.gov NR 32 TC 60 Z9 63 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 3 PY 2004 VL 321 IS 4 BP 936 EP 941 DI 10.1016/j.bbrc.2004.07.052 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 847GQ UT WOS:000223381100027 PM 15358117 ER PT J AU Seubert, J Yang, BC Bradbury, JA Graves, J Degraff, LM Gabel, S Gooch, R Foley, J Newman, J Mao, L Rockman, HA Hammock, BD Murphy, E Zeldin, DC AF Seubert, J Yang, BC Bradbury, JA Graves, J Degraff, LM Gabel, S Gooch, R Foley, J Newman, J Mao, L Rockman, HA Hammock, BD Murphy, E Zeldin, DC TI Enhanced postischemic functional recovery in CYP2J2 transgenic hearts involves mitochondrial ATP-sensitive K+ channels and p42/p44 MAPK pathway SO CIRCULATION RESEARCH LA English DT Article DE arachidonic acid; cytochrome P450; eicosanoid; ischemia/reperfusion; mitoK(ATP) channel; MAPK ID RAT VENTRICULAR MYOCYTES; ARACHIDONIC-ACID; EPOXYEICOSATRIENOIC ACIDS; INDUCED CARDIOPROTECTION; HYPERPOLARIZING FACTOR; MOLECULAR-CLONING; CYTOCHROME-P450; METABOLITES; EXPRESSION; ACTIVATION AB Human CYP2J2 is abundant in heart and active in the biosynthesis of epoxyeicosatrienoic acids (EETs); however, the functional role of this P450 and its eicosanoid products in the heart remains unknown. Transgenic mice with cardiomyocyte-specific overexpression of CYP2J2 were generated. CYP2J2 transgenic (Tr) mice have normal heart anatomy and basal contractile function. CYP2J2 Tr hearts have improved recovery of left ventricular developed pressure (LVDP) compared with wild-type (WT) hearts after 20 minutes ischemia and 40 minutes reperfusion. Perfusion with the selective P450 epoxygenase inhibitor N-methylsulphonyl-6-(2-proparglyloxyphenyl) hexanamide (MS-PPOH) for 20 minutes before ischemia results in reduced postischemic LVDP recovery in WT hearts and abolishes the improved postischemic LVDP recovery in CYP2J2 Tr hearts. Perfusion with the ATP-sensitive K+ channel (K-ATP) inhibitor glibenclamide (GLIB) or the mitochondrial K-ATP (mitoK(ATP)) inhibitor 5-hydroxydecanoate (5-HD) for 20 minutes before ischemia abolishes the cardioprotective effects of CYP2J2 overexpression. Flavoprotein fluorescence, a marker of mitoK(ATP) activity, is higher in cardiomyocytes from CYP2J2 Tr versus WT mice. Moreover, CYP2J2-derived EETs (1 to 5 mumol/L) increase flavoprotein fluorescence in WT cardiomyocytes. CYP2J2 Tr mice exhibit increased expression of phospho-p42/p44 mitogen-activated protein kinase ( MAPK) after ischemia, and addition of the p42/p44 MAPK kinase (MEK) inhibitor PD98059 during reperfusion abolishes the cardioprotective effects of CYP2J2 overexpression. Together, these data suggest that CYP2J2-derived metabolites are cardioprotective after ischemia, and the mechanism for this cardioprotection involves activation of mitoK(ATP) and p42/p44 MAPK. C1 NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. Univ Calif Davis, Ctr Canc Res, Davis, CA 95616 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Zeldin, DC (reprint author), NIEHS, Div Intramural Res, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov FU NHLBI NIH HHS [HL61558]; NICHD NIH HHS [N01-HD-53229]; NIDCR NIH HHS [N01-DE-12634]; NIEHS NIH HHS [ES02710, ES04699] NR 35 TC 164 Z9 172 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD SEP 3 PY 2004 VL 95 IS 5 BP 506 EP 514 DI 10.1161/01.RES.0000139436.89654.c8 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 851CX UT WOS:000223664100009 PM 15256482 ER PT J AU Calleri, E Marrubini, G Massolini, G Lubda, D de Fazio, SS Furlanetto, S Wainer, IW Manzo, L Caccialanza, G AF Calleri, E Marrubini, G Massolini, G Lubda, D de Fazio, SS Furlanetto, S Wainer, IW Manzo, L Caccialanza, G TI Development of a chromatographic bioreactor based on immobilized beta-glucuronidase on monolithic support for the determination of dextromethorphan and dextrorphan in human urine SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE beta-glucuronidase; immobilized enzyme reactor; dextromethorphan; dextrorphan; cytochrome P-450 2D6 ID PERFORMANCE LIQUID-CHROMATOGRAPHY; MAIN METABOLITES; HUMAN PLASMA; COLUMN; HYDROLYSIS; PHENOTYPE; CYP2D6; PHASE; 2D6 AB We here reported the development and application of an immobilized enzyme reactor (IMER) based on beta-glucuronidase to the on-line determination of urinary molar ratios of dextromethorphan (DOMe)/dextrorphan (DOH) for the assessment of the metabolic activity of CYP2D6, a genetically variable isoform of cytochrome P-450 (CYP). beta-Glucuronidase was immobilized on an HPLC monolithic aminopropyl silica support. Catalytic activity and stability of the chromatographic reactor were evaluated using 8-hydroxyquinoline glucuronide (8-HQG) as substrate. The IMER was coupled through a switching valve to a reversed-phase column (C8) for the simultaneous determination of dextromethorphan and its main metabolite dextrorphan. On purpose a selective reversed-phase ion pair HPLC method coupled with fluorescence detection was developed. Urine samples were first centrifuged to remove insoluble materials and then aliquots of the supernatants were injected into the coupled-column analyser. Linearity, precision and accuracy of the method were established. The method reliability was verified by comparing our data with previous data of a phenotyping study carried out by the Poison Control Centre of Pavia-Clinical Toxicology Division. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Pavia, Dept Pharmaceut Chem, I-27100 Pavia, Italy. Univ Pavia, Dept Internal Med, Clin Toxicol Div, I-27028 Pavia, Italy. Merck KGaA, LSP, R&D, MDA, D-64293 Darmstadt, Germany. Univ Florence, Dept Pharmaceut Sci, I-50019 Sesto Fiorentino, Italy. NIA, Gerontol Res Ctr, Bioanalyt & Drug Discovery Unit, NIH, Baltimore, MD 21224 USA. RP Calleri, E (reprint author), Univ Pavia, Dept Pharmaceut Chem, Via Taramelli 12, I-27100 Pavia, Italy. EM enrica.calleri@unipv.it OI CALLERI, ENRICA/0000-0002-4246-460X NR 23 TC 13 Z9 15 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD SEP 3 PY 2004 VL 35 IS 5 BP 1179 EP 1189 DI 10.1016/j.jba.2004.02.033 PG 11 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 859KG UT WOS:000224261500020 PM 15336363 ER PT J AU Dennis, PA AF Dennis, PA TI Disparities in cancer funding SO SCIENCE LA English DT Letter C1 NCI, Bethesda, MD 20889 USA. RP Dennis, PA (reprint author), NCI, Bethesda, MD 20889 USA. NR 2 TC 1 Z9 1 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 SEP 3 PY 2004 VL 305 IS 5689 BP 1401 EP 1402 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 852NK UT WOS:000223761900019 PM 15353780 ER PT J AU Roth, GS Mattison, JA Ottinger, MA Chachich, ME Lane, MA Ingram, DK AF Roth, GS Mattison, JA Ottinger, MA Chachich, ME Lane, MA Ingram, DK TI Aging in rhesus monkeys: Relevance to human health interventions SO SCIENCE LA English DT Editorial Material ID TERM DIETARY RESTRICTION; NONHUMAN PRIMATE MODELS; AGE-RELATED DECLINE; CALORIE RESTRICTION; MACACA-MULATTA; CYTOKINE PRODUCTION; METABOLIC SYNDROME; MACAQUE MONKEYS; BRAIN; MENOPAUSE AB Progress in gerontologicat research has been promoted through the use of numerous animal models, which have helped identify possible mechanisms of aging and age-related chronic diseases and evaluate possible interventions with potential relevance to human aging and disease. Further development of nonhuman primate models, particularly rhesus monkeys, could accelerate this progress, because their closer genetic relationship to humans produces a highly similar aging phenotype. Because the relatively tong lives of primates increase the administrative and economic demands on research involving them, new emphasis has emerged on increasing the efficient use of these valuable resources through cooperative, interdisciplinary research. C1 NIA, Lab Expt Gerontol, Intramural Res Program, Gerontol Res Ctr,NIH, Baltimore, MD 21224 USA. Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. RP Ingram, DK (reprint author), NIA, Lab Expt Gerontol, Intramural Res Program, Gerontol Res Ctr,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ingramd@grc.nia.nih.gov NR 61 TC 182 Z9 189 U1 2 U2 11 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 SEP 3 PY 2004 VL 305 IS 5689 BP 1423 EP 1426 DI 10.1126/science.1102541 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 852NK UT WOS:000223761900036 PM 15353793 ER PT J AU Lodmell, DL Ewalt, LC AF Lodmell, DL Ewalt, LC TI Rabies cell culture vaccines reconstituted and stored at 4 degrees C for 1 year prior to use protect mice against rabies virus SO VACCINE LA English DT Article DE rabies; cell culture vaccines; refrigerated storage; reduced cost ID STORAGE AB Human exposure to rabid dogs in developing countries is an ongoing problem that continues to demand effective, safe, and affordable post-exposure rabies vaccinations. Sheep and suckling mouse brain rabies vaccines used in developing countries are being replaced by expensive inactivated-virus cell culture vaccines. Human studies using cell culture vaccines have determined that cost is reduced and protection is maintained by injecting the unused portion of vaccines that have been reconstituted and stored refrigerated for 1 week. Here we determined whether reconstituted purified chick embryo cell and human diploid cell vaccine that had been stored at 4 degreesC for intervals up to 1 year elicit neutralizing antibody, and protect mice against rabies virus. Undiluted, or 1:5 and 1:25 dilutions of both vaccines injected immediately after reconstitution, or after reconstitution and storage at 4 degreesC for 1 week, 1 month, 3 months, 6 months or 1 year elicited high levels of neutralizing antibody and protected 100% of the mice injected with rabies virus. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. RP Lodmell, DL (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. EM dlodmell@nih.gov NR 9 TC 5 Z9 6 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 3 PY 2004 VL 22 IS 25-26 BP 3237 EP 3239 DI 10.1016/j.vaccine.2004.02.045 PG 3 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 853GJ UT WOS:000223814900005 PM 15308344 ER PT J AU Lodmell, DL Esposito, JJ Ewalt, LC AF Lodmell, DL Esposito, JJ Ewalt, LC TI Live vaccinia-rabies virus recombinants, but not an inactivated rabies virus cell culture vaccine, protect B-lymphocyte-deficient A/WySnJ mice against rabies: considerations of recombinant defective poxviruses for rabies immunization of immunocompromised individuals SO VACCINE LA English DT Article DE rabies virus; A/WySnJ mice; vaccinia virus recombinant; cell culture vaccine; immunosuppression ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIBODY-RESPONSE; T-CELLS; GLYCOPROTEIN; IMMUNOGENICITY; NUCLEOPROTEIN; PREEXPOSURE; SUPERANTIGEN; PROPHYLAXIS; CHLOROQUINE AB Presently, commercially available cell culture rabies vaccines for humans and animals consist of the five inactivated rabies virus proteins. The vaccines elicit a CD4(+) helperT-cell response and a humoral B-cell response against the viral glycoprotein (G) resulting in the production of virus neutralizing antibody. Antibody against the viral nucleoprotein (N) is also present, but the mechanism(s) of its protection is unclear. HIV-infected individuals with low CD4+ T-lymphocyte counts and individuals undergoing treatment with immunosuppressive drugs have an impaired neutralizing antibody response after pre- and post-exposure immunization with rabies cell culture vaccines. Here we show the efficacy of live vaccinia-rabies virus recombinants, but not a cell culture vaccine consisting of inactivated rabies virus, to elicit elevated levels of neutralizing antibody in B-lymphocyte deficient A/WySnJ mice. The cell culture vaccine also failed to protect the mice, whereas a single immunization of a vaccinia recombinant expressing the rabies virus G or co-expressing G and N equally protected the mice up to 18 months after vaccination. The data suggest that recombinant poxviruses expressing the rabies virus G, in particular replication defective poxviruses such as canarypox or MVA vaccinia virus that undergo abortive replication in non-avian cells, or the attenuated vaccinia virus NYVAC, should be evaluated as rabies vaccines in immunocompromised individuals. Published by Elsevier Ltd. C1 NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Sci Resources Program, Biotechnol Core Facil Branch, Atlanta, GA 30329 USA. RP Lodmell, DL (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. EM dlodmell@nih.gov NR 43 TC 7 Z9 10 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 3 PY 2004 VL 22 IS 25-26 BP 3329 EP 3333 DI 10.1016/j.vaccine.2004.02.039 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 853GJ UT WOS:000223814900017 PM 15308356 ER PT J AU Hanley, KA Manlucu, LR Manipon, GG Hanson, CT Whitehead, SS Murphy, BR Blaney, JE AF Hanley, KA Manlucu, LR Manipon, GG Hanson, CT Whitehead, SS Murphy, BR Blaney, JE TI Introduction of mutations into the non-structural genes or 3 ' untranslated region of an attenuated dengue virus type 4 vaccine candidate further decreases replication in rhesus monkeys while retaining protective immunity SO VACCINE LA English DT Article DE dengue; vaccine; mutagenesis ID CLINICAL LABORATORY RESPONSES; AMINO-ACID SUBSTITUTIONS; HUMAN LIVER-CELLS; CHIMERIC VACCINE; HUMAN VOLUNTEERS; SERIAL PASSAGE; KIDNEY-CELLS; HOST-RANGE; VERO CELLS; L PROTEIN AB A dengue virus vaccine candidate, rDEN4Delta30, has been previously reported to be safe and immunogenic in humans, but a subset of vaccinees developed asymptomatic rash, elevation of liver enzymes and/or mild neutropenia. In the current study, mutations that had previously been shown to reduce replication of DEN4 virus in suckling mice and/or in SCID mice engrafted with human liver cells (SCID-HuH-7 mice) were introduced into rDEN4Delta30 in an attempt to further attenuate this virus. Three of the five resulting modified rDEN4Delta30 viruses showed decreased replication in SCID-HuH-7 mice relative to rDEN4Delta30. Moreover, in rhesus monkeys, two of the modified rDEN4Delta30 viruses showed a decrease in replication relative to rDEN4Delta30 while generating levels of neutralizing antibody similar to rDEN4Delta30 virus. All of the modified rDEN4Delta30 viruses completely protected immunized rhesus monkeys from challenge with wild-type DEN4 virus. Based on their attenuation for both human liver cells and rhesus monkeys, two of the modified rDEN4Delta30 vaccine candidates are currently being prepared for use in clinical trials. The application of these attenuating mutations to flavivirus vaccine development is discussed. Published by Elsevier Ltd. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Blaney, JE (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6515,50 South Dr,MSC 8007, Bethesda, MD 20892 USA. EM jblaney@niaid.nih.gov NR 48 TC 36 Z9 37 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 3 PY 2004 VL 22 IS 25-26 BP 3440 EP 3448 DI 10.1016/j.vaccine.2004.02.031 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 853GJ UT WOS:000223814900031 PM 15308370 ER PT J AU Villinger, F Miller, R Mori, K Mayne, AE Bostik, P Sundstrom, JB Sugimoto, C Ansari, AA AF Villinger, F Miller, R Mori, K Mayne, AE Bostik, P Sundstrom, JB Sugimoto, C Ansari, AA TI IL-15 is superior to IL-2 in the generation of long-lived antigen specific memory CD4 and CD8 T cells in rhesus macaques SO VACCINE LA English DT Article DE macaque; T cell; IL-2; IL-15 ID SIV-INDUCED DISEASE; IN-VIVO; IMMUNE STIMULATION; GAMMA-CHAIN; BETA-CHAIN; RESPONSES; INFECTION; DEATH; INTERLEUKIN-2; LYMPHOCYTES AB Using tetanus toxoid (TT) and influenza (Flu) immunization of rhesus macaques as a model, the effect of IL-2 and IL-15 on the generation and maintenance of antigen specific memory T cells was evaluated following primary and secondary immunization. Daily cytokine administration expanded primarily effector but not memory cells, while spacing cytokine administration to q3-7 days markedly enhanced TT and Flu specific memory responses. Following primary immunization, TT specific CD4 and influenza matrix protein (Flu-NIP) specific CD8 effector responses were enhanced by IL-2 administration but CD8 specific memory responses were no different from cytokine non-treated monkeys. In contrast, expansion of Flu specific CD8 cells with IL-15 was only modest but resulted in significantly elevated levels of memory cells at 6 months. IL-15 also significantly enhanced early and late TT specific CD4 responses. The highest levels of primary effector and memory T cells were observed following alternate administration of both IL-2 and IL-15. Following booster immunization, however, only IL-15 appeared able to enhance CD8 T cell responses while IL-2 or IL2/IL-15 administration were less effective. (C) 2004 Elsevier Ltd. All rights reserved. C1 Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. NCI, NIH, AIDS Res Ctr, Bethesda, MD 20892 USA. Natl Inst Infect Dis, Primate Ctr Med Sci, AIDS Res Ctr, Tsukuba, Ibaraki, Japan. RP Villinger, F (reprint author), Emory Univ, Dept Pathol & Lab Med, Woodruff Mem Bldg 2339,1639 Pierce Dr, Atlanta, GA 30322 USA. EM fvillin@emory.edu FU NCRR NIH HHS [NIH-1R24-RR16988-01]; PHS HHS [NIH-1R01-27057] NR 53 TC 76 Z9 78 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD SEP 3 PY 2004 VL 22 IS 25-26 BP 3510 EP 3521 DI 10.1016/j.vaccine.2003.07.022 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 853GJ UT WOS:000223814900040 PM 15308379 ER PT J AU Siok, WT Perfetti, CA Jin, Z Tan, LH AF Siok, WT Perfetti, CA Jin, Z Tan, LH TI Biological abnormality of impaired reading is constrained by culture SO NATURE LA English DT Article ID LEFT PREFRONTAL CORTEX; HUMAN FRONTAL-CORTEX; WORKING-MEMORY; BRAIN ACTIVATION; NATIVE LANGUAGE; NEURAL SYSTEMS; FUNCTIONAL MRI; WORD FORM; DYSLEXIA; CHINESE AB Developmental dyslexia is characterized by a severe reading problem in people who have normal intelligence and schooling(1-3). Impaired reading of alphabetic scripts is associated with dysfunction of left temporoparietal brain regions(2-5). These regions perform phonemic analysis and conversion of written symbols to phonological units of speech (grapheme-to-phoneme conversion); two central cognitive processes that mediate reading acquisition(6-7). Furthermore, it has been assumed that, in contrast to cultural diversities, dyslexia in different languages has a universal biological origin(1,8). Here we show using functional magnetic resonance imaging with reading-impaired Chinese children and associated controls, that functional disruption of the left middle frontal gyrus is associated with impaired reading of the Chinese language ( a logographic rather than alphabetic writing system). Reading impairment in Chinese is manifested by two deficits: one relating to the conversion of graphic form ( orthography) to syllable, and the other concerning orthography-to-semantics mapping. Both of these processes are critically mediated by the left middle frontal gyrus, which functions as a centre for fluent Chinese reading(9-11) that coordinates and integrates various information about written characters in verbal and spatial working memory. This finding provides an insight into the fundamental pathophysiology of dyslexia by suggesting that rather than having a universal origin, the biological abnormality of impaired reading is dependent on culture. C1 Univ Hong Kong, Dept Linguist, Cognit Neurosci Lab, Hong Kong, Hong Kong, Peoples R China. Univ Pittsburgh, Ctr Learning Res & Dev, Pittsburgh, PA 15260 USA. Beijing 306 Hosp, MRI Div, Beijing 100101, Peoples R China. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Tan, LH (reprint author), Univ Hong Kong, Dept Linguist, Cognit Neurosci Lab, Hong Kong, Hong Kong, Peoples R China. EM lihaitan@intra.nimh.nih.gov NR 31 TC 206 Z9 230 U1 1 U2 32 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 2 PY 2004 VL 431 IS 7004 BP 71 EP 76 DI 10.1038/nature02865 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 850VC UT WOS:000223641500043 PM 15343334 ER PT J AU Reed, MB Domenech, P Manca, C Su, H Barczak, AK Kreiswirth, BN Kaplan, G Barry, CE AF Reed, MB Domenech, P Manca, C Su, H Barczak, AK Kreiswirth, BN Kaplan, G Barry, CE TI A glycolipid of hypervirulent tuberculosis strains that inhibits the innate immune response SO NATURE LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; GLOBAL DISSEMINATION; LEPRAE; COMPLEX; GENE; SUPPRESSION; MICE; BIOSYNTHESIS; VIRULENCE; FAMILY AB Fifty million new infections with Mycobacterium tuberculosis occur annually, claiming 2 - 3 million lives from tuberculosis worldwide(1). Despite the apparent lack of significant genetic heterogeneity between strains of M. tuberculosis(2,3), there is mounting evidence that considerable heterogeneity exists in molecules important in disease pathogenesis. These differences may manifest in the ability of some isolates to modify the host cellular immune response, thereby contributing to the observed diversity of clinical outcomes(4-7). Here we describe the identification and functional relevance of a highly biologically active lipid species - a polyketide synthase-derived phenolic glycolipid (PGL) produced by a subset of M. tuberculosis isolates belonging to the W-Beijing family(8) that show 'hyperlethality' in murine disease models. Disruption of PGL synthesis results in loss of this hypervirulent phenotype without significantly affecting bacterial load during disease. Loss of PGL was found to correlate with an increase in the release of the pro-inflammatory cytokines tumour-necrosis factor-alpha and interleukins 6 and 12 in vitro. Furthermore, the overproduction of PGL by M. tuberculosis or the addition of purified PGL to monocyte-derived macrophages was found to inhibit the release of these pro-inflammatory mediators in a dose-dependent manner. C1 NIAID, TB Res Sect, NIH, Rockville, MD 20852 USA. Publ Hlth Res Inst, Lab Mycobacterial Immun & Pathogenesis, Newark, NJ 07103 USA. Publ Hlth Res Inst, TB Ctr, Newark, NJ 07103 USA. RP Barry, CE (reprint author), NIAID, TB Res Sect, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM clifton_barry@nih.gov RI Barry, III, Clifton/H-3839-2012 FU Intramural NIH HHS [Z01 AI000783-11]; NIAID NIH HHS [R01 AI054338, R01 AI054338-01] NR 30 TC 458 Z9 477 U1 3 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 2 PY 2004 VL 431 IS 7004 BP 84 EP 87 DI 10.1038/nature02837 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 850VC UT WOS:000223641500046 PM 15343336 ER PT J AU Meyer-Lindenberg, A Kohn, P Mervis, CB Kippenhan, JS Olsen, RK Morris, CA Berman, KF AF Meyer-Lindenberg, A Kohn, P Mervis, CB Kippenhan, JS Olsen, RK Morris, CA Berman, KF TI Neural basis of genetically determined visuospatial construction deficit in Williams syndrome SO NEURON LA English DT Article ID SYNDROME COGNITIVE PROFILE; HUMAN BRAIN; CORTEX; FACE; MRI; ABNORMALITIES; DISSOCIATION; PERCEPTION; PHENOTYPE; DELETIONS AB A unique opportunity to understand genetic determinants of cognition is offered by Williams syndrome (WS), a well-characterized hemideletion on chromosome 7q11.23 that causes extreme, specific weakness in visuospatial construction (the ability to visualize an object as a set of parts or construct a replica). Using multimodal neuroimaging, we identified a neural mechanism underlying the WS visuoconstructive deficit. Hierarchical assessment of visual processing with fMRI showed isolated hypoactivation in WS in the parietal portion of the dorsal stream. In the immediately adjacent parietooccipital/intraparietat sulcus, structural neuroimaging showed a gray matter volume reduction in participants with WS. Path analysis demonstrated that the functional abnormalities could be attributed to impaired input from this structurally altered region. Our observations confirm a longstanding hypothesis about dorsal stream dysfunction in WS, demonstrate effects of a localized abnormality on visual information processing in humans, and define a systems-level phenotype for mapping genetic determinants of visuoconstructive function. C1 NIMH, Unit Integrat Neuroimaging, Clin Brain Disorders Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Louisville, Neurodev Sci Lab, Dept Psychol & Brain Sci, Louisville, KY 40292 USA. Univ Nevada, Sch Med, Dept Pediat, Las Vegas, NV 89102 USA. RP Meyer-Lindenberg, A (reprint author), NIMH, Unit Integrat Neuroimaging, Clin Brain Disorders Branch, NIH,Dept Hlth & Human Serv, 10-4C101,9000 Rockville Pike, Bethesda, MD 20892 USA. EM andreasml@nih.gov OI Olsen, Rosanna/0000-0002-2918-4152; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU NINDS NIH HHS [R01 NS035102, NS35102] NR 44 TC 194 Z9 198 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 2 PY 2004 VL 43 IS 5 BP 623 EP 631 DI 10.1016/j.neuron.2004.08.014 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 851NN UT WOS:000223691900009 PM 15339645 ER PT J AU Calon, F Lim, GP Yang, FS Morihara, T Teter, B Ubeda, O Rostaing, P Triller, A Salem, N Ashe, KH Frautschy, SA Cole, GM AF Calon, F Lim, GP Yang, FS Morihara, T Teter, B Ubeda, O Rostaing, P Triller, A Salem, N Ashe, KH Frautschy, SA Cole, GM TI Docosahexaenoic acid protects from dendritic pathology in an Alzheimer's disease mouse model SO NEURON LA English DT Article ID AMYLOID-PRECURSOR-PROTEIN; POLYUNSATURATED FATTY-ACIDS; NICOTINIC ACETYLCHOLINE-RECEPTOR; LONG-TERM POTENTIATION; TRANSGENIC MICE; A-BETA; COGNITIVE IMPAIRMENT; LIPID-PEROXIDATION; PHOSPHATIDYLINOSITOL 3-KINASE; POSTSYNAPTIC DENSITY-95 AB Learning and memory depend on dendritic spine actin assembly and docosahexaenoic acid (DHA), an essential n-3 (omega-3) polyunsaturated fatty acid (PFA). High DHA consumption is associated with reduced Alzheimer's disease (AD) risk, yet mechanisms and therapeutic potential remain elusive. Here, we report that reduction of dietary n-3 PFA in an AD mouse model resulted in 80%-90% losses of the p85alpha subunit of phosphatidylinositol 3-kinase and the postsynaptic actin-regulating protein drebrin, as in AD brain. The loss of postsynaptic proteins was associated with increased oxidation, without concomitant neuron or presynaptic protein loss. N-3 PFA depletion increased caspase-cleaved actin, which was localized in dendrites ultrastructurally. Treatment of n-3 PFA-restricted mice with DHA protected against these effects and behavioral deficits and increased antiapoptotic BAD phosphorylation. Since n-3 PFAs are essential for p85-mediated CNS insulin signaling and selective protection of postsynaptic proteins, these findings have implications for neurodegenerative diseases where synaptic loss is critical, especially AD. C1 Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90095 USA. Greater Los Angeles Vet Affairs Healthcare Syst, Geriatr Res Educ & Clin Ctr, Sepulveda, CA 91343 USA. INSERM, Lab Biol Cellulaire Synapse Normale & Pathol, U497, Ecole Normale Super, F-75005 Paris, France. NIAAA, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys, Div Intramural Clin & Biol Res, Rockville, MD 20852 USA. Univ Minnesota, Dept Neurol, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Neurosci, Minneapolis, MN 55455 USA. RP Cole, GM (reprint author), Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA. EM gmcole@ucla.edu FU NIA NIH HHS [AG10685, AG16793, P01 AG16570, P50 AG 16570, P50 AG005142, P50 AG016570, P50 AG05142, R01 AG010685, R01 AG013741, R01 AG016793, R01 AG13741]; NINDS NIH HHS [NS43946, R01 NS043946] NR 81 TC 433 Z9 458 U1 7 U2 49 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 2 PY 2004 VL 43 IS 5 BP 633 EP 645 DI 10.1016/j.neuron.2004.08.013 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 851NN UT WOS:000223691900010 PM 15339646 ER PT J AU Clarimon, J Eerola, J Hellstrom, I Tienari, PJ Singleton, A AF Clarimon, J Eerola, J Hellstrom, I Tienari, PJ Singleton, A TI Paraoxonase 1 (PON1) gene polymorphisms and Parkinson's disease in a Finnish population SO NEUROSCIENCE LETTERS LA English DT Article DE Parkinson's disease; Finland; genetic association; PON1; polymorphism; complex disorder ID MOLECULAR-BASIS; SUSCEPTIBILITY; ASSOCIATION AB Paraoxonase 1 (PON1) is involved in the metabolism and detoxification of insecticides and pesticides. Two polymorphisms within the gene affect the enzyme activity. One is a methionine to leucine change at position 54 (M54L) and the other is a glutamine to arginine variant at position 192 (Q192R). There are contrasting reports assessing the role of these variants in Parkinson's disease (PD). We performed a case-control association study in order to elucidate the possible contribution of variability within PON1 to the risk of sporadic PD in a Finnish population. There was no statistically significant association of the allele, genotype or haplotype distribution with PD (all P values > 0.75). Our results suggest that the M54L and Q192R polymorphisms are not major risk factors for PD in the Finnish population. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIH, Lab Neurogenet, Mol Genet Sect, Bethesda, MD 20892 USA. Helsinki Univ, Cent Hosp, Dept Neurol, Helsinki, Finland. Helsinki Univ, Biomed Helsinki, Neurosci Programme, Helsinki, Finland. Seinajoki Cent Hosp, Dept Neurol, Seinajoki, Finland. RP Clarimon, J (reprint author), NIH, Lab Neurogenet, Mol Genet Sect, Bldg 10,Room 6C103,MSC 1589,9000 Rockville Pike, Bethesda, MD 20892 USA. EM clarimon@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Tienari, Pentti/A-4893-2012; OI Clarimon, Jordi/0000-0002-6824-6942 NR 21 TC 19 Z9 19 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 2 PY 2004 VL 367 IS 2 BP 168 EP 170 DI 10.1016/j.neulet.2004.05.108 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 852UW UT WOS:000223783200008 PM 15331145 ER PT J AU Xiong, KM Stewart, RR Weight, FF Li, CY AF Xiong, KM Stewart, RR Weight, FF Li, CY TI Role of extracellular histidines in antagonist sensitivity of the rat P2X(4) receptor SO NEUROSCIENCE LETTERS LA English DT Article DE ATP; P2X; P2X(4) receptor; histidine; suramin; PPADS ID INHIBITION; PURINOCEPTOR; MODULATION; MECHANISM; RESIDUES; ZINC; PH AB The pharmacological property that most distinguishes rat P2X(4) receptors from other P2X receptors is their insensitivity to the purinoceptor antagonists. suramin and pyridoxal-phosphate-6-azophenyl-2',4'-disulphoinic acid (PPADS). The molecular basis of this insensitivity is not known. Her e, we investigated the possibility that histidine residues in the extracellular loop of P2X4 receptors may be involved in the antagonist sensitivity of these receptors. We found that histidine mutation H241A in the rat P2X4 receptor produced receptors that are sensitive to suramin and PPADS. In contrast, mutation H140A or H286A did not significantly alter antagonist sensitivity. In addition, mutation H241A in the human P2X4 receptor significantly increased antagonist sensitivity. The results suggest that histidine 241 of P2X4 receptors is involved in regulating the antagonist sensitivity of these receptors. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIAAA, Lab Mol & Cellular Neurobiol, NIH, Bethesda, MD 20892 USA. RP Li, CY (reprint author), NIAAA, Lab Mol & Cellular Neurobiol, NIH, Bethesda, MD 20892 USA. EM chaoying.li@astrazeneca.com NR 18 TC 4 Z9 6 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 2 PY 2004 VL 367 IS 2 BP 197 EP 200 DI 10.1016/j.neulet.2004.06.008 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 852UW UT WOS:000223783200015 PM 15331152 ER PT J AU Furuta, M Weil, RJ Vortmeyer, AO Huang, S Lei, JQ Huang, TN Lee, YS Bhowmick, DA Lubensky, IA Oldfield, EH Zhuang, ZP AF Furuta, M Weil, RJ Vortmeyer, AO Huang, S Lei, JQ Huang, TN Lee, YS Bhowmick, DA Lubensky, IA Oldfield, EH Zhuang, ZP TI Protein patterns and proteins that identify subtypes of glioblastoma multiforme SO ONCOGENE LA English DT Article DE malignant glioma; astrocytoma; microdissection; two-dimensional gel electrophoresis; protein sequencing; mass spectrometry ID GENE-EXPRESSION; GLIOMAS; DNA; CLASSIFICATION; IDENTIFICATION; SURVIVAL; MICROARRAY; PROFILES; DATABASE; TUMORS AB Glioblastoma multiforme (GBM) has been subdivided into two types based on clinical and genetic findings: primary tumors, which arise de novo, and secondary tumors, which progress from lower grade gliomas to GBMs. To analyse this dichotomy at the protein level, we employed selective tissue microdissection to obtain pure populations of tumor cells, which we studied using two-dimensional protein gel electrophoresis (2-DGE) and protein sequencing of select target proteins. Protein patterns were analysed in a blinded manner from the clinical and genetic data. 2-DGE clearly identified two distinct populations of tumors. 2-DGE was reproducible and reliable, as multiple samples analysed from the same patient gave identical results. In addition, we isolated and sequenced 11 proteins that were uniquely expressed in either the primary or the secondary GBMs, but not both. We demonstrate that specific proteomic patterns can be reproducibly identified by two-dimensional gel electrophoresis from limited numbers of selectively procured, microdissected tumor cells and that two patterns of GBMs, primary versus secondary, previously distinguished by clinical and genetic differences, can be recognized at the protein level. Proteins that are expressed distinctively may have important implications for the diagnosis, prognosis, and treatment of patients with GBM. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Saga Med Sch, Dept Neurosurg, Saga, Japan. Vanderbilt Univ, Sch Med, Dept Neurosurg, Nashville, TN 37212 USA. Transmedix Inc, Rockville, MD USA. Linden Biosci, Woburn, MA USA. RP Weil, RJ (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D 37, Bethesda, MD 20892 USA. EM weilr@ninds.nih.gov NR 36 TC 63 Z9 65 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 SEP 2 PY 2004 VL 23 IS 40 BP 6806 EP 6814 DI 10.1038/sj.onc.1207770 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 850ZT UT WOS:000223653600012 PM 15286718 ER PT J AU Danthi, SN Pandit, SD Li, KCP AF Danthi, SN Pandit, SD Li, KCP TI A primer on molecular biology for imagers: VII. Molecular imaging probes SO ACADEMIC RADIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; SOMATOSTATIN RECEPTORS; CANCER; NANOPARTICLES; ANGIOGENESIS; PEPTIDE C1 NIH, Mol Imaging Lab, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Li, KCP (reprint author), NIH, Mol Imaging Lab, Dept Diagnost Radiol, Ctr Clin, Bldg 10,9000 Rockville Pike,1N306, Bethesda, MD 20892 USA. EM kingli@nih.gov RI Danthi, Simhan/B-7639-2014 NR 21 TC 5 Z9 7 U1 0 U2 2 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD SEP PY 2004 VL 11 IS 9 BP 1047 EP 1054 DI 10.1016/j.acra.2004.06.007 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 854UN UT WOS:000223929000010 PM 15350586 ER EF