FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Rosenberg, SA Yang, JC Restifo, NP AF Rosenberg, SA Yang, JC Restifo, NP TI Cancer immunotherapy: moving beyond current vaccines SO NATURE MEDICINE LA English DT Article ID COLONY-STIMULATING FACTOR; PHASE-I TRIAL; HUMAN CARCINOEMBRYONIC ANTIGEN; METASTATIC MELANOMA PATIENTS; PULSED DENDRITIC CELLS; SHOCK-PROTEIN GP96; CD8(+) T-CELLS; IMMUNE-RESPONSES; SOLID TUMORS; PEPTIDE VACCINATION AB Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models. C1 NCI, Ctr Canc Res, Surg Branch, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Ctr Canc Res, Surg Branch, Bldg 10,Room 2B42,10 Ctr Dr,MSC 1502, Bethesda, MD 20892 USA. EM sar@mail.nih.gov RI Restifo, Nicholas/A-5713-2008; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 74 TC 1664 Z9 1742 U1 59 U2 351 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 SEP PY 2004 VL 10 IS 9 BP 909 EP 915 DI 10.1038/nm1100 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 851AZ UT WOS:000223658400026 PM 15340416 ER PT J AU Yao, RS Lemon, WJ Yian, W Grubbs, CJ Lubet, RA Ming, Y AF Yao, RS Lemon, WJ Yian, W Grubbs, CJ Lubet, RA Ming, Y TI Altered gene expression profile in mouse bladder cancers induced by hydroxybutyl(butyl)nitrosamine SO NEOPLASIA LA English DT Article DE mouse bladder cancer; expression profile; Affymetrix microarray; differential expression; signaling pathway ID TRANSITIONAL-CELL-CARCINOMA; EPIDERMAL GROWTH-FACTOR; HA-RAS; RETINOBLASTOMA PROTEIN; TUMOR PROGRESSION; BINDING PROTEINS; P53 MUTATIONS; PATHWAYS; N-BUTYL-N-(4-HYDROXYBUTYL)NITROSAMINE; CARCINOGENESIS AB A variety of genetic alterations and gene expression changes are involved in the pathogenesis of bladder tumor. To explore these changes, oligonucleotide array analysis was performed on RNA obtained from carcinogen-induced mouse bladder tumors and normal mouse bladder epithelia using Affymetrix (Santa Clara, CA) MGU74Av2 GeneChips. Analysis yielded 1164 known genes that were changed in the tumors. Certain of the upregulated genes included EGFR-Ras signaling genes, transcription factors, cell cycle-related genes, and intracellular signaling cascade genes. However, downregulated genes include mitogen-activated protein kinases, cell cycle checkpoint genes, Rab subfamily genes, Rho subfamily genes, and SH2 and SH3 domains-related genes. These genes are involved in a broad range of different pathways including control of cell proliferation, differentiation, cell cycle, signal transduction, and apoptosis. Using the pathway visualization tool GenMAPP, we found that several genes, including TbR-I, STAT1, Smad1, Smad2, Jun, NFkappaB, and so on, in the TGF-beta signaling pathway and p115 RhoGEF, RhoGDI3, MEKK4A/MEKK4B, P13KA, and JNK in the G13 signaling pathway were differentially expressed in the tumors. In summary, we have determined the expression profiles of genes differentially expressed during mouse bladder tumorigenesis. Our results suggest that activation of the EGFR-Ras pathway, uncontrolled cell cycle, aberrant transcription factors, and G13 and TGF-beta pathways are involved, and the cross-talk between these pathways seems to play important roles in mouse bladder tumorigenesis. C1 Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. Univ Alabama, Dept Genet & Med, Birmingham, AL 35294 USA. NCI, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP Ming, Y (reprint author), Washington Univ, Sch Med, Dept Surg, 660 S Euclid Ave,Campus Box 8109, St Louis, MO 63110 USA. EM youm@msnotes.wustl.edu NR 50 TC 19 Z9 21 U1 0 U2 1 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD SEP-OCT PY 2004 VL 6 IS 5 BP 569 EP 577 DI 10.1593/neo.04223 PG 9 WC Oncology SC Oncology GA 864UG UT WOS:000224657800017 PM 15548366 ER PT J AU Heinz, A Braus, DF Romero, B Gallinat, J Puis, I Juckel, G Weinberger, DR AF Heinz, A Braus, DF Romero, B Gallinat, J Puis, I Juckel, G Weinberger, DR TI Genetic and pharmacological effects on prefrontal cortical function in schizophrenia SO NERVENARZT LA German DT Review DE PFC; working memory; COMT; neurodevelopmenta hypothesis; atypical neuroleptics ID CEREBRAL-BLOOD-FLOW; EMISSION COMPUTED-TOMOGRAPHY; CARD-SORTING-TEST; WORKING-MEMORY; NEUROLEPTIC-NAIVE; ANTIPSYCHOTIC-DRUGS; STRIATAL DOPAMINE; COGNITIVE ACTIVATION; NEURONAL VIABILITY; N-ACETYLASPARTATE AB Brain imaging studies with PET, SPECT, functional magnetic resonance imaging, and spectroscopy provide evidence of prefrontal dysfunction in schizophrenia. Dysfunction of the prefrontal cortex is associated with cognitive impairment and negative symptoms. Combined multimodal imaging shows that a developmentally early disturbance of frontotemporal-limbic neuronal networks is associated with a disinhibition of subcortical dopaminergic neurotransmission. Current studies imply genetic factors in the regulation of dopaminergic neurotransmission and their effects on prefrontal cortex function. Some studies also indicate that atypical neuroleptics may at least partially improve frontal cortex function. We review the literature and discuss genotype and medication effects on frontal dysfunction in schizophrenia. Molecular brain imaging combines imaging techniques with the assessment of genotype effects and represents a powerful tool for the understanding of neuropsychiatric disorders. C1 Univ Med Berlin, Charite, Klin Psychiat & Psychotherapie, D-10117 Berlin, Germany. Univ Hamburg, Klinikum Eppendorf, Klin Psychiat & Psychotherapie, Arbeitsbereich Bildgebung, Hamburg, Germany. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Heinz, A (reprint author), Univ Med Berlin, Charite, Klin Psychiat & Psychotherapie, Charite Campus Mitte,Schumannstr 10-21, D-10117 Berlin, Germany. EM andreas.heinz@charite.de NR 77 TC 5 Z9 5 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0028-2804 J9 NERVENARZT JI Nervenarzt PD SEP PY 2004 VL 75 IS 9 BP 845 EP + DI 10.1007/s00115-004-1713-8 PG 12 WC Clinical Neurology; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 859PF UT WOS:000224279700001 PM 15372159 ER PT J AU Fields, RD AF Fields, RD TI Volume transmission in activity-dependent regulation of myelinating glia SO NEUROCHEMISTRY INTERNATIONAL LA English DT Article DE volume transmission; myelinating glia; axon ID L1 ADHESION MOLECULE; RAT OPTIC-NERVE; SCHWANN-CELLS; ACTION-POTENTIALS; CALCIUM TRANSIENTS; NEURAL IMPULSES; PATTERNS; NEURONS; SYSTEM; DIFFERENTIATION AB The importance of neural impulse activity in regulating neuronal plasticity is widely appreciated; increasingly, it is becoming apparent that activity-dependent communication between neurons and glia is critical in regulating many aspects of nervous system development and plasticity. This communication takes place not only at the synapse, but also between premyelinating axons and glia, which form myelin in the PNS and CNS. Recent work indicates that neural impulse activity releases ATP and adenosine from non-synaptic regions of neurons, which activates purinergic receptors on myelinating glia. Acting through this receptor system, neural impulse activity can regulate gene expression, mitosis, differentiation, and myelination of Schwann cells (SCs) and oligodendrocytes, helping coordinate nervous system development with functional activity in the perinatal period. ATP and adenosine have opposite effects on differentiation of Schwann cells and oligodendrocytes, providing a possible explanation for the opposite effects of impulse activity reported on myelination in the CNS and PNS. (C) 2003 Elsevier Ltd. All rights reserved. C1 NICHD, Nervous Syst Dev & Plast Sect, NIH, Bethesda, MD 20892 USA. RP Fields, RD (reprint author), NICHD, Nervous Syst Dev & Plast Sect, NIH, Bldg 49,Room 5A78, Bethesda, MD 20892 USA. EM fields@helix.nih.gov NR 31 TC 18 Z9 18 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0197-0186 J9 NEUROCHEM INT JI Neurochem. Int. PD SEP PY 2004 VL 45 IS 4 BP 503 EP 509 DI 10.1016/j.neuint.2003.11.015 PG 7 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 832VM UT WOS:000222295500007 PM 15186916 ER PT J AU Koslow, SH Hirsch, MD AF Koslow, SH Hirsch, MD TI Celebrating a decade of neuroscience databases - Looking to the future of high-throughput data analysis, data integration, and discovery neuroscience SO NEUROINFORMATICS LA English DT Editorial Material C1 NIMH, Off Neuroinformat, NIH, DHHS, Bethesda, MD 20892 USA. RP Koslow, SH (reprint author), NIMH, Off Neuroinformat, NIH, DHHS, Bethesda, MD 20892 USA. EM koz@helix.nih.gov NR 0 TC 13 Z9 13 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1539-2791 J9 NEUROINFORMATICS JI Neuroinformatics PD FAL PY 2004 VL 2 IS 3 BP 267 EP 269 DI 10.1385/NI:2:3:267 PG 3 WC Computer Science, Interdisciplinary Applications; Neurosciences SC Computer Science; Neurosciences & Neurology GA 860HJ UT WOS:000224332800001 PM 15365190 ER PT J AU Laplante, F Sibley, DR Quirion, R AF Laplante, F Sibley, DR Quirion, R TI Reduction in acetylcholine release in the hippocampus of dopamine D5 receptor-deficient mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE microdialysis; muscarinic receptor; receptor autoradiography; dopamine transgenic mouse ID ALZHEIMERS-DISEASE; COGNITIVE PERFORMANCE; CHOLINERGIC SYSTEMS; D2 RECEPTORS; RAT; D1; EXPRESSION; CLONING; NEURONS; MEMORY AB Activation of the dopamine D-1-like receptor stimulates acetylcholine (ACh) release in the hippocampus, apparently through the molecularly defined d5 receptor. In the present study, we used a transgenic mouse completely deprived of functional d5 receptor (d5-/-) to confirm the role and elucidate the possible function of the d5 receptor subtype on hippocampal cholinergic neurotransmission. ACh release was measured using in vivo microdialysis in the mouse dorsal hippocampus of 4 months old homozygous ( d5-/-), heterozygous ( d5+/-), and the wild-type ( d5+/+) littermates. Using the no net flux technique, a significant reduction in basal hippocampal ACh level was found in the d5 -/- compared to d5+/- and d5+/+ mice. Moreover, the administration of SKF 38393, a D-1-like receptor agonist, systemically (2.0 and 10.0 mg/kg ip), or locally through the dialysis probe ( 10 and 50 muM), produced a dose-dependent enhancement of ACh release in the d5+/+, a moderate stimulation in the d5+/- but had no effect in the d5 -/- mice. Quantitative receptor autoradiography revealed significant increases in M-1-like but not in M-2-like muscarinic receptor binding sites in the hippocampal formation. These results confirm and extend the role of the d5 receptor in the modulation of hippocampal ACh release and provide evidence for long-term alteration of hippocampal cholinergic neurotransmission resulting from the absence of the d5 receptors including chronically reduced ACh release and change in M-1-like receptor levels. C1 Douglas Hosp, Res Ctr, Verdun, PQ H4H 1R3, Canada. McGill Univ, Dept Pharmacol Therapeut, Montreal, PQ, Canada. McGill Univ, Dept Psychiat, Montreal, PQ, Canada. NINDS, NIH, Bethesda, MD 20892 USA. RP Quirion, R (reprint author), Douglas Hosp, Res Ctr, 6875 Boul LaSalle, Verdun, PQ H4H 1R3, Canada. EM quirem@douglas.mcgill.ca NR 46 TC 29 Z9 30 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 SEP PY 2004 VL 29 IS 9 BP 1620 EP 1627 DI 10.1038/sj.npp.1300467 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 848LD UT WOS:000223468100004 PM 15100705 ER PT J AU Chudasama, Y Robbins, TW AF Chudasama, Y Robbins, TW TI Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE rat; attention; working memory; dopamine; modulation; SKF 81297 ID REACTION-TIME-TASK; DEFICIT HYPERACTIVITY DISORDER; 6-HYDROXYDOPAMINE LESIONS; SELECTIVE ATTENTION; EXECUTIVE FUNCTIONS; CORTICAL DOPAMINE; AGED MONKEYS; D1 RECEPTORS; PERFORMANCE; RAT AB Converging evidence suggests that dopaminergic projections to the prefrontal cortex (PFC) modulate both attention and working memory processes that may be related to either insufficient or excessive dopamine activity specific to a D-1 receptor mechanism. We examined the effects of bilateral intraprefrontal cortical infusions of the D-1 agonist (SKF 81297) on a novel task specifically designed to assess the animals' ability to attend to a visual target (0.7 or 0.5 s) and then remember the location of that target over a variable delay ( 0 16 s) within the same test session. Bilateral prefrontal infusions of the low dose of SKF 81297 (0.01 mug) had no effect on visual attention or memory throughout the entire testing schedule. The medium ( 0.06 mug) dose preferentially increased attention to the stimulus target but only improved memory for that stimulus at a duration of 0.7 s, although in a delay-independent manner. The high dose (0.3 mug) of the D-1 agonist also increased attentional accuracy. However, it was only under the more attention challenging condition ( 0.5 s) that this high dose also produced a baseline delay-dependent modulation of memory for the stimulus target. Specifically, good memory at the short delay was impaired and poor memory at the long delay was improved. These data provide the first demonstration that dopamine D-1 receptor stimulation sufficient to improve attentional accuracy, can also disrupt, and facilitate short-term working memory performance in a delay-dependent manner. C1 Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. RP Chudasama, Y (reprint author), NIMH, Neuropsychol Lab, 49 Convent Dr,Bldg 49,Room 1B80, Bethesda, MD 20892 USA. EM yogita@ln.nimh.nih.gov NR 51 TC 114 Z9 117 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2004 VL 29 IS 9 BP 1628 EP 1636 DI 10.1038/sj.npp.1300490 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 848LD UT WOS:000223468100005 PM 15138446 ER PT J AU Ide, S Minami, M Satoh, M Uhl, GR Sora, I Ikeda, K AF Ide, S Minami, M Satoh, M Uhl, GR Sora, I Ikeda, K TI Buprenorphine antinociception is abolished, but naloxone-sensitive reward is retained, in mu-opioid receptor knockout mice SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE opioid receptor; knockout mice; buprenorphine; antinociception; reward; detoxification ID HEROIN-DEPENDENT VOLUNTEERS; MORPHINE-INDUCED ANALGESIA; CXBK MICE; PLACE-PREFERENCE; ANTAGONIST; AGONIST; WITHDRAWAL; ACTIVATION; BLOCKADE; GENE AB Buprenorphine is a relatively nonselective opioid receptor partial agonist that is used in the management of both pain and addiction. To improve understanding of the opioid receptor subtypes important for buprenorphine effects, we now report the results of our investigation on the roles of mu-, delta-, and kappa-opioid receptors in antinociceptive responses and place preferences induced by buprenorphine. Buprenorphine antinociception, assessed by hot-plate and tail-flick tests, was significantly reduced in heterozygous m- opioid receptor knockout (MOR-KO) mice and abolished in homozygous MOR-KO mice. In contrast, buprenorphine retained its ability to establish a conditioned place preference (CPP) in homozygous MOR-KO, although the magnitude of place preference was reduced as the number of copies of wild-type mu-opioid receptor genes was reduced. The remaining CPP of buprenorphine was abolished by pretreatment with the nonselective opioid antagonist naloxone, but only partially blocked by pretreatment with either the d- selective opioid antagonist naltrindole or the kappa-selective opioid antagonist norbinaltorphimine. These data, and biochemical confirmation of buprenorphine actions as a partial delta-, mu-, and kappa-agonist, support the ideas that mu-opioid receptors mediate most of analgesic properties of buprenorphine, but that mu- and delta- and/or kappa-opioid receptors are each involved in the rewarding effects of this drug. C1 Tokyo Inst Psychiat, Dept Mol Psychiat, Setagaya Ku, Tokyo 1568585, Japan. Kyoto Univ, Fac Pharmaceut Sci, Dept Mol Pharmacol, Kyoto 606, Japan. NIDA, Baltimore, MD USA. Tohoku Univ, Grad Sch Med, Div Psychobiol, Dept Neurosci, Sendai, Miyagi 980, Japan. RP Tokyo Inst Psychiat, Dept Mol Psychiat, Setagaya Ku, 2-1-8 Kamikitazawa, Tokyo 1568585, Japan. EM ikedak@prit.go.jp RI Ide, Soichiro/D-5472-2012; Minami, Masabumi/A-3883-2012; Ikeda, Kazutaka/I-4694-2013 OI Minami, Masabumi/0000-0002-0144-0679; Ikeda, Kazutaka/0000-0001-8342-0278 NR 39 TC 40 Z9 41 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2004 VL 29 IS 9 BP 1656 EP 1663 DI 10.1038/sj.npp.1300463 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 848LD UT WOS:000223468100008 PM 15100703 ER PT J AU Longnecker, MP Hoffman, HJ Klebanoff, MA Brock, JW Zhou, HB Needham, L Adera, T Guo, XG Gray, KA AF Longnecker, MP Hoffman, HJ Klebanoff, MA Brock, JW Zhou, HB Needham, L Adera, T Guo, XG Gray, KA TI In utero exposure to polychlorinated biphenyls and sensorineural hearing loss in 8-year-old children SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE in utero exposure; polychlorinated biphenyls; sensorineural hearing loss ID HUMAN-MILK; DEVELOPMENTAL EXPOSURE; PCB; SERUM; RATS; DEFICITS; ORGANOCHLORINES; DIBENZOFURANS; AROCLOR-1254; PESTICIDES AB Early-life exposure to polychlorinated biphenyls (PCBs), a ubiquitous environmental contaminant, increases the hearing threshold at selected frequencies in rats. Among humans from the Faroe Islands with unusually high early-life PCB exposure, exposure was directly associated with increased hearing thresholds at two frequencies, although the deficits were present in the left ear but not the right. We examined PCB levels in maternal pregnancy serum in relation with audiometrically determined hearing thresholds among offspring when they were of school age. Complete data were available for 195 children with sensorineural hearing loss (SNHL) and 615 children selected at random, all of whom were born in 1959-1966 in the Collaborative Perinatal Project (CPP) U.S. cohort. The median exposure among those selected at random, as reflected by the mother's third trimester serum total PCB concentration, was 2.8 mug/l, about twofold higher than recent background levels in the United States. Based on the average hearing threshold across the frequencies essential for speech recognition in the "worst ear," the maternal serum PCB level was unrelated to the adjusted odds of SNHL or to adjusted mean hearing threshold. Overall, an adverse effect of early-life, background-level PCB exposure on SNHL was not supported by these data. (C) 2004 Elsevier Inc. All rights reserved. C1 NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Natl Inst Deafness & Other Commun Disorders, Bethesda, MD USA. NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. Univ N Carolina, Sch Publ Hlth, Dept Biostat, Chapel Hill, NC USA. Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC USA. Virginia Commonwealth Univ, Med Coll Virginia, Sch Med, Dept Prevent Med, Richmond, VA USA. Constella Grp Inc, Durham, NC USA. NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC USA. RP Longnecker, MP (reprint author), NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. EM longnecker@niehs.nih.gov RI Needham, Larry/E-4930-2011; OI Longnecker, Matthew/0000-0001-6073-5322 NR 45 TC 22 Z9 22 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD SEP-OCT PY 2004 VL 26 IS 5 BP 629 EP 637 DI 10.1016/j.ntt.2004.04.007 PG 9 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 852LF UT WOS:000223756100002 PM 15315812 ER PT J AU Story, M Sherwood, NE Obarzanek, E AF Story, M Sherwood, NE Obarzanek, E TI Correlates of BMI, body fat, dietary intake, and physical activity among 8- to 10-year-old African-American girls: Girls health enrichment multisite studies phase 1 - Introduction SO OBESITY RESEARCH LA English DT Editorial Material C1 Univ Minnesota, Div Epidemiol, Sch Publ Hlth, Minneapolis, MN 55455 USA. HealthPartners Res Fdn, Minneapolis, MN USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Rockville, MD USA. RP Story, M (reprint author), Univ Minnesota, Div Epidemiol, Sch Publ Hlth, Minneapolis, MN 55455 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD SEP PY 2004 VL 12 SU S BP 1S EP 2S DI 10.1038/oby.2004.262 PG 2 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 863SH UT WOS:000224581800001 ER PT J AU Sherwood, NE Story, M Obarzanek, E AF Sherwood, NE Story, M Obarzanek, E TI Correlates of obesity in African-American girls: An overview SO OBESITY RESEARCH LA English DT Article ID NUTRITION EXAMINATION SURVEY; WEIGHT-RELATED ATTITUDES; PHYSICAL-ACTIVITY; NHLBI GROWTH; BODY-IMAGE; WHITE GIRLS; CHILDHOOD OBESITY; BIRACIAL COHORT; NATIONAL-HEALTH; RISK-FACTORS C1 HealthPartners Res Fdn, Minneapolis, MN USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Sherwood, NE (reprint author), HealthPartners Res Fdn, Minneapolis, MN USA. FU NHLBI NIH HHS [UO1-HL65160, UO1-HL62662, UO1-HL62668, UO1-HL62732, UO1-HL62663] NR 36 TC 11 Z9 11 U1 1 U2 1 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD SEP PY 2004 VL 12 SU S BP 3S EP 6S DI 10.1038/oby.2004.263 PG 4 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 863SH UT WOS:000224581800002 PM 15489462 ER PT J AU Beech, BM Kumanyika, SK Baranowski, T Davis, M Robinson, TN Sherwood, NE Taylor, WC Relyea, G Zhou, AN Pratt, C Owens, A Thompson, NS AF Beech, BM Kumanyika, SK Baranowski, T Davis, M Robinson, TN Sherwood, NE Taylor, WC Relyea, G Zhou, AN Pratt, C Owens, A Thompson, NS TI Parental cultural perspectives in relation to weight-related behaviors and concerns of African-American girls SO OBESITY RESEARCH LA English DT Article DE acculturation; cultural identity; preadolescent girls; weight gain prevention; African-American girls ID HEALTH ENRICHMENT MULTISITE; WHITE GIRLS; PHYSICAL-ACTIVITY; NHLBI GROWTH; RISK-FACTORS; TELEVISION; FOOD; GEMS; SOCIALIZATION; CONSUMPTION AB BEECH, BETTINA M., SHIRIKI K. KUMANYIKA, TOM BARANOWSKI, MARSHA DAVIS, THOMAS N. ROBINSON, NANCY E. SHERWOOD, WENDELL C. TAYLOR, GEORGE RELYEA, AINONG ZHOU, CHARLOTTE PRATT, AYISHA OWENS, AND NIKKO S. THOMPSON. Parental cultural perspectives in relation to weight-related behaviors and concerns of African-American girls. Obes Res. 2004;12:7S-19S. Objective: To determine whether cultural perspectives of parents may influence children's eating and physical activity behaviors and patterns of weight gain. Research Methods and Procedures: African-American girls (ages 8 to 10 years) and their parents (or caregivers) (n = 210) participated at one of four Girls Health Enrichment Multisite Studies Phase 1 Field Centers. At baseline, parents completed questionnaires adapted from the AfricanAmerican Acculturation Scale (AAAS), the Multiethnic Identity Scale (MEIS), and an original question on Global Cultural Identity. Girls' baseline measures included physical activity assessment by accelerometer, 24-hour dietary recalls, and questionnaires about body image and weight concerns. Results: Principal components analysis indicated the expected AAAS and MEIS factor structures, with moderate to good internal consistency (Cronbach's alpha = 0.61 to 0.82) and some intercorrelation among these measures (r = 0.17 to 0.57). Overall mean (SD) AAAS subscale scores of 4.1 (2. 1) and 5.5 (1.8) of a possible 7 and 3.0 (0.9) of a possible 4 on the MEIS indicated, respectively, moderate to high levels of parental African-American cultural orientation and identity with moderate variability. Parental AAAS and MEIS scores were inversely correlated with girls' body image discrepancy and weight concern. One AAAS subscale was positively associated with total energy intake and percentage energy from fat. Overall, however, parental AAAS and MEIS scores were unrelated or inconsistently related to girls' physical activity and diet measures. Discussion: The AAAS and MEIS measures had acceptable psychometric properties, except for weight concern, but did not give a consistent picture of how parental perspectives related to the girls' baseline attitudes and behaviors. C1 Univ Memphis, Dept Psychol, Memphis, TN 38152 USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Baylor Coll Med, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX 77030 USA. Vanderbilt Univ, Dept Human & Org Dev, Nashville, TN USA. Stanford Univ, Sch Med, Div Gen Pediat, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Ctr Res Dis Prevent, Stanford, CA 94305 USA. HealthPartners Res Fdn, Minneapolis, MN USA. Univ Texas, Hlth Sci Ctr, Sch Publ Hlth, Ctr Hlth Promot & Prevent Res, Houston, TX USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Beech, BM (reprint author), Univ Memphis, Dept Psychol, 202 Psychol Bldg, Memphis, TN 38152 USA. EM bbeech@memphis.edu FU NHLBI NIH HHS [UO1-HL62663, UO1-HL62732, UO1-HL62668, UO1-HL62662, UO1-HL65160] NR 42 TC 10 Z9 10 U1 0 U2 2 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD SEP PY 2004 VL 12 SU S BP 7S EP 19S DI 10.1038/oby.2004.264 PG 13 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 863SH UT WOS:000224581800003 PM 15489463 ER PT J AU Cullen, KW Baranowski, T Klesges, LM Watson, K Sherwood, NE Story, M Zakeri, I Leachman-Slawson, D Pratt, C AF Cullen, KW Baranowski, T Klesges, LM Watson, K Sherwood, NE Story, M Zakeri, I Leachman-Slawson, D Pratt, C TI Anthropometric, parental, and psychosocial correlates of dietary intake of African-American girls SO OBESITY RESEARCH LA English DT Article DE diet; BMI; African-American girls; parent; psychosocial ID HEALTH ENRICHMENT MULTISITE; BODY-MASS INDEX; CHILDHOOD OBESITY; VEGETABLE INTAKE; FRUIT; CHILDREN; CONSUMPTION; RELIABILITY; ADOLESCENTS; PREDICTORS AB Objective: This paper identifies the anthropometric, parental, and psychosocial characteristics and meal practices (e.g., breakfast skipping and number of meals and snacks consumed) associated with consumption of total energy, percent energy from fat, fruit, 100% fruit juice, vegetables, sweetened beverages, and water among 8- to 10-year-old African-American girls. Research Methods and Procedures: This study included 114 8- to 10-year-old African-American girls and a parent or primary care-giver. Girls and a parent or primary caregiver completed several dietary questionnaires. Two 24-hour dietary recalls were conducted with each girl. Height and weight were measured. Separate hierarchical regression analyses were conducted for each dependent dietary variable; potential field center differences were examined. Results: The number of meals and snacks consumed was correlated with energy intake. Lower BMI was related to higher vegetable consumption, and the number of snacks consumed was positively related to sweetened beverage consumption. Greater low-fat food preparation practices reported by parents were related to lower consumption of fat as a percentage of total energy. Discussion: Dietary behavior differed across geographic areas. Low-fat food preparation practices in the home seemed to be an important influence on the percentage of energy consumed from fat. Greater vegetable consumption was associated with lower BMI. Interventions to prevent excessive weight gain in African-American girls should encourage low-fat food preparation in the home and greater consumption of vegetables. C1 Baylor Coll Med, Childrens Nutr Res Ctr, Dept Pediat, Houston, TX 77030 USA. Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. HealthPartners Res Fdn, Minneapolis, MN USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. Univ Memphis, Ctr Community Hlth, Memphis, TN 38152 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Cullen, KW (reprint author), Baylor Coll Med, Childrens Nutr Res Ctr, Dept Pediat, 1100 Bates St, Houston, TX 77030 USA. EM kcullen@bcm.tmc.edu FU NHLBI NIH HHS [U01 HL62668, U01 HL65160, U01 HL62732, U01 HL62663, U01 HL62662] NR 33 TC 41 Z9 42 U1 1 U2 2 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD SEP PY 2004 VL 12 SU S BP 20S EP 31S DI 10.1038/oby.2004.265 PG 12 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 863SH UT WOS:000224581800004 PM 15489464 ER PT J AU Jago, R Baranowski, T Yoo, S Cullen, KW Zakeri, I Watson, K Himes, JH Pratt, C Sun, WJ Pruitt, LA Matheson, DM AF Jago, R Baranowski, T Yoo, S Cullen, KW Zakeri, I Watson, K Himes, JH Pratt, C Sun, WJ Pruitt, LA Matheson, DM TI Relationship between physical activity and diet among African-American girls SO OBESITY RESEARCH LA English DT Article DE energy balance; physical activity; dietary fat ID HEALTH ENRICHMENT MULTISITE; BODY-MASS INDEX; ENERGY-EXPENDITURE; ACTIVITY MONITOR; NUTRIENT INTAKE; US CHILDREN; SELF-REPORT; OBESITY; CONSUMPTION; ADOLESCENCE AB Objective: To examine the cross-sectional relationships between physical activity and dietary behaviors among 8- to 10-year-old African-American girls. Research Methods and Procedures: Two hundred ten 8- to 10-year-old African-American girls from four field centers participated. Computer Science and Applications (CSA) activity monitors were worn for 3 days. CSA data were expressed as mean CSA counts per minute, mean minutes of moderate to vigorous activity per day, and mean metabolic equivalents (METS) per minute. Two nonconsecutive 24 hour dietary recalls were analyzed for kilocalories; percent kilocalories from fat; daily servings of fruit, 100% fruit juice, and vegetables; sweetened beverages; and water consumption. Height and weight were measured, and information on household income, material possessions, and participant age were obtained. Results: All three expressions of physical activity were significantly negatively associated with percentage calories from fat (r = -0.147 to -0.177, p < 0.01), and mean METS per minute were significantly positively associated with percentage calories from carbohydrate (r = 0.149, p < 0.05) after controlling for household income, material possessions, field center, and total caloric intake. Income was inversely associated with percentage calories from fat. Discussion: Physical activity and dietary fat consumption were inversely related among African-American girls. Efforts to prevent obesity in preadolescent African-American girls should focus on increasing physical activity and lowering dietary fat consumption. C1 Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX 77030 USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Stanford Univ, Sch Med, Stanford Ctr Res Dis Prevent, Stanford, CA 94305 USA. RP Jago, R (reprint author), Baylor Coll Med, Childrens Nutr Res Ctr, 1100 Bates St, Houston, TX 77030 USA. EM rjago@bcm.tmc.edu FU NHLBI NIH HHS [U01 HL62662, U01 HL62663, U01 HL62668, U01 HL65160, U01 HL62732] NR 48 TC 20 Z9 20 U1 0 U2 1 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD SEP PY 2004 VL 12 SU S BP 55S EP 63S DI 10.1038/oby.2004.269 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 863SH UT WOS:000224581800008 PM 15489468 ER PT J AU Himes, JH Obarzanek, E Baranowski, T Wilson, DM Rochon, J McClanahan, BS AF Himes, JH Obarzanek, E Baranowski, T Wilson, DM Rochon, J McClanahan, BS TI Early sexual maturation, body composition, and obesity in African-American girls SO OBESITY RESEARCH LA English DT Article DE anthropometry; breast development; pubic hair development; African Americans; puberty ID NUTRITION EXAMINATION SURVEYS; BLOOD-INSTITUTE GROWTH; X-RAY ABSORPTIOMETRY; OVERWEIGHT PREVALENCE; EXPERT COMMITTEE; ADOLESCENT GIRLS; NATIONAL-HEALTH; MASS INDEX; CHILDREN; HEART AB Objective: To describe associations between sexual maturation and body composition in a sample of African-American girls who were participants in phase 1 pilot interventions of the Girls Health Enrichment Multisite Studies. Research Methods and Procedures: Stature, weight, and waist circumference were measured. Pubic hair and breast development were assessed, and body composition was measured by DXA for 147 African-American girls who were 8 to 10 years of age from three field centers. Participants had BMI greater than or equal to 25th percentile for age (one site) or BMI greater than or equal to 50th percentile for age. Results: Girls Health Enrichment Multisite Studies girls had greater BMI, fat mass, and percentage body fat than national norms and relatively earlier initiation of breast development and pubic hair. Increasing stages of breast development, but not stages of pubic hair, were related to increased stature, waist circumference, BMI, lean mass, fat mass, and percentage of body fat. Pubescent girls (breast stage greater than or equal to 2) were greater than six times as likely to be classified as at risk of overweight (BMI greater than or equal to 85th percentile) and greater than eight times as likely to be classified as overweight (BMI greater than or equal to 95th percentile) as prepubescent counterparts. Adjusted odds ratios for advanced breast development [breast stage greater than or equal to 2 (8 years) or greater than or equal to 3 (9 and 10 years)] were 3.6 for risk of overweight and for overweight compared to girls with average or less than average breast development. Discussion: Sexual maturation is important to consider in understanding the classification of overweight and the development of obesity during adolescence. Breast development and pubic hair development should be considered separately for their associations with growth and body composition. C1 Univ Minnesota, Div Epidemiol, Minneapolis, MN 55454 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Baylor Univ, Dept Pediat, Childrens Nutr Res Ctr, Houston, TX 77030 USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Duke Univ, Duke Clin Res Inst, Durham, NC USA. Univ Memphis, Memphis, TN 38152 USA. RP Himes, JH (reprint author), Univ Minnesota, Div Epidemiol, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM himes@epi.umn.edu FU NHLBI NIH HHS [UO1-HL62662, UO1-HL62668, UO1-HL65160]; PHS HHS [UO1-62663, UO1-62732] NR 50 TC 37 Z9 39 U1 1 U2 8 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD SEP PY 2004 VL 12 SU S BP 64S EP 72S DI 10.1038/oby.2004.270 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 863SH UT WOS:000224581800009 PM 15489469 ER PT J AU Tanofsky-Kraff, M Yanovski, SZ AF Tanofsky-Kraff, M Yanovski, SZ TI Eating disorder or disordered eating? Non-normative eating patterns in obese individuals SO OBESITY RESEARCH LA English DT Article DE binge eating disorder; night eating syndrome; non-normative eating patterns ID BULIMIA-NERVOSA; RISK-FACTORS; WEIGHT-LOSS; ANOREXIA-NERVOSA; FOOD-INTAKE; BINGE; WOMEN; PSYCHOPATHOLOGY; OVERWEIGHT; CHILDREN AB Binge eating disorder (BED) and night eating syndrome (NES) are putative eating disorders frequently seen in obese individuals. Data suggest that BED fulfills criteria for a mental disorder. Criteria for NES are evolving but at present do not require distress or functional impairment. It remains unclear whether BED and NES, as they are currently defined, are optimally useful for characterizing distinct patient subgroups. We propose that a distinction be made between "eating disorders" and "non-normative" eating patterns without associated distress or impairment. Although non-normative eating patterns may not be considered mental disorders, they may be very important in terms of their impact on body weight and health. More precise behavioral and metabolic characterization of subgroups with eating disorders and non-normative eating behaviors has important implications for understanding the etiology, pathophysiology, and treatment of obesity. Ultimately, better understanding of the many pathways to increased energy intake may lead to targeted strategies for prevention of overweight and obesity in at-risk individuals and populations. C1 Natl Inst Child Hlth & Human Dev, Dev Endocrinol Branch, Unit Growth & Obes, NIH, Bethesda, MD 20892 USA. NIDDKD, Div Digest Dis & Nutr, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. RP Tanofsky-Kraff, M (reprint author), Natl Inst Child Hlth & Human Dev, Dev Endocrinol Branch, Unit Growth & Obes, NIH, 10 Ct Dr,Bldg 10,Room 10N262 MSC 1862, Bethesda, MD 20892 USA. EM tanofskm@mail.nih.gov FU NICHD NIH HHS [Z01 HD-00641] NR 48 TC 51 Z9 52 U1 0 U2 2 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD SEP PY 2004 VL 12 IS 9 BP 1361 EP 1366 DI 10.1038/oby.2004.171 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 862RX UT WOS:000224509700001 PM 15483199 ER PT J AU Lee, WJ Lijinsky, W Heineman, EF Markin, RS Weisenburger, DD Ward, MH AF Lee, WJ Lijinsky, W Heineman, EF Markin, RS Weisenburger, DD Ward, MH TI Agricultural pesticide use and adenocarcinomas of the stomach and oesophagus SO OCCUPATIONAL AND ENVIRONMENTAL MEDICINE LA English DT Article ID N-NITROSO COMPOUNDS; GASTRIC CARDIA; HUMAN CANCER; RISK; FARMERS; PATTERNS; EXPOSURE; CARCINOGENESIS; EPIDEMIOLOGY; NITROSAMINES AB Aims: To evaluate the risk of the stomach and oesophageal adenocarcinomas associated with farming and agricultural pesticide use. Methods: Population based case-control study in eastern Nebraska. Telephone interviews were conducted with men and women diagnosed with adenocarcinoma of the stomach (n = 170) or oesophagus ( n = 137) between 1988 and 1993, and controls ( n = 502) randomly selected from the same geographical area. Unconditional logistic regression was used to calculate adjusted odds ratios (ORs) for farming and for use of individual and chemical classes of insecticides and herbicides, including pesticides classified as nitrosatable ( able to form N-nitroso compounds on reaction with nitrite). Non-farmers were used as the reference category for all analyses. Results: Ever living or working on a farm, duration of farming, and size of the farm were not associated with stomach or oesophageal adenocarcinomas. There was no association for either cancer with ever-use of insecticides ( stomach OR 0.9, 95% CI 0.6 to 1.4; oesophagus OR 0.7, 95% CI 0.4 to 1.1) or herbicides ( stomach OR 0.9, 95% CI 0.5 to 1.4; oesophagus OR 0.7, 95% CI 0.4 to 1.2). Likewise, individual pesticides, including individual nitrosatable pesticides, were not significantly associated with risk. Conclusions: No significant associations were found between specific agricultural pesticide exposures and the risk of stomach or oesophageal adenocarcinomas among Nebraska farmers. C1 NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Omaha, NE USA. RP Ward, MH (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8104, Rockville, MD 20852 USA. EM Wardm@mail.nih.gov NR 46 TC 13 Z9 14 U1 0 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1351-0711 J9 OCCUP ENVIRON MED JI Occup. Environ. Med. PD SEP PY 2004 VL 61 IS 9 BP 743 EP 749 DI 10.1136/oem.2003.011858 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 847MY UT WOS:000223398500004 PM 15317914 ER PT J AU Saxman, S Schoenfeldt, M AF Saxman, S Schoenfeldt, M CA Natl Cancer Inst Emmes Corp TI Current clinical trials in mesothelioma SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID MALIGNANT PLEURAL MESOTHELIOMA; CHEMOTHERAPY C1 NCI, Bethesda, MD 20892 USA. Emmes Corp, Rockville, MD USA. RP Saxman, S (reprint author), NCI, Bethesda, MD 20892 USA. NR 3 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 SEP PY 2004 VL 18 IS 10 BP 1280 EP + PG 3 WC Oncology SC Oncology GA 052DQ UT WOS:000238211800010 PM 15526831 ER PT J AU Hartmuller, VW Desmond, SM AF Hartmuller, VW Desmond, SM TI Professional and patient perspectives on nutritional needs of patients with cancer SO ONCOLOGY NURSING FORUM LA English DT Article ID BREAST-CANCER; WEIGHT-GAIN; INFORMATION; LITERACY; HEALTH; ISSUES; WOMEN; CARE; INTERVENTION; DIETITIANS AB Purpose/Objectives: To identify and compare perceptions of RNs registered dietitians (RDs), and patients regarding the best format and key nutrition information component that should be provided to patients during cancer treatment. Design: Cross-sectional study using an opinion-based questionnaire. Setting: Outpatients cancer centers. Sample: 506 RNs and 367 RDs as well as 653 patients undergoing cancer treatment. Methods: Two similar self-administered questionnaires were developed, one for the patients and one for the healthcare professionals. Face and content validity were assessed by a panel of experts. Data were analyzed using descriptive statistics, Chi-square statistics, and a Spearman Correlation Coefficient to compare responses. Main Reasearch Variables: Patient nutrition concerns as well as format and content of printed eductaional materials. Findings: Significant differences existed among groups regarding the most common nutrition concerns, the perception of importance for eight items typically provided to patients. The dietary information format preferred by all groups was an all-inclusive booklet; RNs (75%) were more likely than RDs (43%) or patients (47%) recieved no dietary counseling including 18% who experienced significant weight loss. Conclusions: RNs and RDs who provide nutrition education to patients with cancer should consider the need to develop and use a variety of printed materials to meet individual needs. Because major concerns of patients and healthcare professionals were related to patients' ability to consume adequate amounts of food, this should be the primary focus of any nutrition education materials. Implications for Nursing: These findings provide information that can be applied to the development of informational materials and counseling practices. C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Maryland, Dept Publ & Community Hlth, College Pk, MD 20742 USA. RP Hartmuller, VW (reprint author), NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM hartmulv@mail.nih.gov NR 52 TC 9 Z9 9 U1 0 U2 1 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD SEP PY 2004 VL 31 IS 5 BP 989 EP 996 DI 10.1188/04.ONF.989-996 PG 8 WC Oncology; Nursing SC Oncology; Nursing GA 875RP UT WOS:000225439700020 PM 15378100 ER PT J AU Makishima, T Kurima, K Brewer, TC Griffith, AJ AF Makishima, T Kurima, K Brewer, TC Griffith, AJ TI Early onset and rapid progression of dominant nonsyndromic DFNA36 hearing loss SO OTOLOGY & NEUROTOLOGY LA English DT Article DE deafness; dominant; DFNA36; genetic; hearing; progressive hearing loss; TMC1 ID AUTOSOMAL-DOMINANT; INNER-EAR; LOSS MAPS; COCHLEOSACCULAR DEGENERATION; GJB2-RELATED DEAFNESS; MISSENSE MUTATION; MID-FREQUENCY; GENE; IMPAIRMENT; LOCUS AB Objective: To characterize the auditory and vestibular phenotype of autosomal dominant nonsyndromic DFNA36 hearing loss. Study Design: Clinical evaluation of individuals with DFNA36 hearing loss linked to the D572N mutation of transmembrane channel-like gene 1 (TMC1). Medical history interviews, physical examinations, and pure-tone air conduction andiometry were performed in the field. Audiology and radiology reports were available and retrospectively reviewed for a subset of subjects. Setting: Primary, secondary, and tertiary referral centers (retrospectively reviewed studies); subjects' homes (prospective clinical evaluations). Patients: Thirteen affected members of a North American Caucasian family segregating DFNA36 hearing loss. Main Outcome Measures: Pure-tone audiometric thresholds and their rates of progression. Results: Subjects had bilateral, symmetric, sensorineural hearing loss with a postlingual onset in the first decade of life. High frequencies were initially affected, followed by rapid progression (5.9 dB/yr for the 0.5/1/2/4-kHz pure-tone average) to profound deafness across all frequencies by the second decade of life. Two individuals had excellent auditory-verbal communication after rehabilitation with cochlear implants placed over two decades after total deafening. Conclusions: DFNA36 has one of the earliest onsets and most rapid rates of progression among the autosomal dominant nonsyndromic hearing loss phenotypes. These distinctive features should facilitate its clinical detection and the development of clinical-molecular genetic diagnostic algorithms for dominant nonsyndromic hearing loss. C1 NIDCD, NIH, Hearing Sect, Rockville, MD 20850 USA. NIDCD, NIH, Sect Gene Struct & Funct, Rockville, MD 20850 USA. RP Griffith, AJ (reprint author), NIDCD, NIH, Hearing Sect, 5 Res Court,Room 2A01, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov FU NIDCD NIH HHS [Z01-DC-00060-02, Z01-DC-000039-06, Z01-DC-00064-02] NR 45 TC 15 Z9 15 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1531-7129 J9 OTOL NEUROTOL JI Otol. Neurotol. PD SEP PY 2004 VL 25 IS 5 BP 714 EP 719 DI 10.1097/00129492-200409000-00011 PG 6 WC Clinical Neurology; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 853ML UT WOS:000223831600012 PM 15354000 ER PT J AU Ta, LE Dionne, RA AF Ta, LE Dionne, RA TI Treatment of painful temporomandibular joints with a cyclooxygenase-2 inhibitor: a randomized placebo-controlled comparison of celecoxib to naproxen SO PAIN LA English DT Article DE non-steroidal anti-inflammatory drug; coxibs; temporomandibular disorder; chronic pain; clinical trial ID SMALLEST DETECTABLE DIFFERENCE; RHEUMATOID-ARTHRITIS; INFLAMMATORY PAIN; CLINICAL-TRIAL; SPINAL-CORD; IN-VIVO; OSTEOARTHRITIS; EFFICACY; PROSTAGLANDINS; COX-2 AB To compare the efficacy and adverse effects of celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, with naproxen, a non-steroidal anti-inflammatory drug, and placebo in the treatment of painful temporomandibular joints (TMJs). In this randomized, double-blind, placebo-controlled trial, 68 subjects with painful TMJs secondary to disc-displacement with reduction, received celecoxib 100 mg twice a day; naproxen, 500 mg twice a day; or placebo for 6 weeks. Subjects were evaluated with standard measures of efficacy: pain intensity measured by visual analogue scale, maximal comfortable mandibular opening, and quality of life (SF-36), at baseline (1 week after discontinuing previous analgesic therapy) and again after 6 weeks of drug treatment. Naproxen significantly reduced the symptoms of painful temporomandibular joint disc-displacement (TMJ DD) with reduction as determined by most efficacy measures. Significant improvement in pain intensity occurred within 3 weeks of treatment, and was sustained throughout the 6-week study. Clinically significant improvement in mandibular range of motion was observed for naproxen compared to celecoxib and placebo. Celecoxib showed slightly better pain reduction than placebo, but was not significantly effective for temporomandibular disorder pain. Celecoxib and naproxen were well tolerated, with similar number of reported adverse effects. Dual COX-1 and COX-2 inhibition with naproxen was demonstrated to be effective for the treatment of painful TMJs, as seen by significant improvement in clinical signs and symptoms of TMJ DD with reduction compared to celecoxib and placebo. Inhibition of both COX isozymes is needed to achieve effective analgesia for this type of musculoskeletal pain. (C) 2004 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved. C1 NIDCR, Pain & Neurosensory Mechanisms Branch, NIH, Bethesda, MD 20892 USA. RP Dionne, RA (reprint author), NIDCR, Pain & Neurosensory Mechanisms Branch, NIH, 10 Ctr Dr,Room 1N-103, Bethesda, MD 20892 USA. EM ta.lauren@mayo.edu; raymond.dionne@nih.gov NR 59 TC 36 Z9 37 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD SEP PY 2004 VL 111 IS 1-2 BP 13 EP 21 DI 10.1016/j.pain.2004.04.029 PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 854AI UT WOS:000223871900004 PM 15327804 ER PT J AU Nathan, PC Furlong, W Barr, RD AF Nathan, PC Furlong, W Barr, RD TI Challenges to the measurement of health-related quality of life in children receiving cancer therapy SO PEDIATRIC BLOOD & CANCER LA English DT Review DE cancer; children; health-related quality of life; measurement; therapy ID PEDIATRIC ONCOLOGY; CHILDHOOD-CANCER; ISSUES; SURVIVORS; SYSTEM; INSTRUMENTS; ADOLESCENTS; PROXIES; END AB Measures of health-related quality of life (HRQL) assess those areas of a patient's functioning that are affected by their cancer and its therapy. Although HRQL measures are integrated frequently into studies of survivors of childhood cancer, their use in the assessment of children receiving therapy has been limited by several methodological challenges. These arise from issues specific to measuring HRQL in young children, who comprise a large proportion of the pediatric oncology population, and from issues associated with assessing HRQL during therapy, when the patient's health status is in constant flux. This study summarizes the commonly used HRQL measures, and examines factors that impact their broad application. These include the influence of developmental changes on the content and format of HRQL measures, the role of proxy assessors, the important characteristics of measurement tools used to assess patients receiving active therapy, and the issues related to the ideal timing of serial HRQL assessments in prospective trials. (C) 2004 Wiley-Liss, Inc. C1 McMaster Univ, Ctr Hlth Econ & Policy Anal, Hamilton, ON L8N 3Z5, Canada. McMaster Univ, Med Ctr, Dept Clin Epidemiol & Biostat, Hamilton, ON L8N 3Z5, Canada. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Hlth Util Inc, Dundas, ON, Canada. McMaster Univ, McMaster Childrens Hosp, Hamilton Hlth Sci Corp, Dept Pediat, Hamilton, ON L8N 3Z5, Canada. RP Barr, RD (reprint author), McMaster Univ, Med Ctr, Dept Clin Epidemiol & Biostat, Room 3N27B,1200 Main St W, Hamilton, ON L8N 3Z5, Canada. EM rbarr@mcmaster.ca RI Furlong, William/A-1077-2008 NR 47 TC 20 Z9 20 U1 0 U2 3 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 SEP PY 2004 VL 43 IS 3 BP 215 EP 223 DI 10.1002/pbc.20096 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 844FF UT WOS:000223142200003 PM 15266404 ER PT J AU Uren, A Wolf, V Sun, YF Azari, A Rubin, JS Toretsky, JA AF Uren, A Wolf, V Sun, YF Azari, A Rubin, JS Toretsky, JA TI Wnt/frizzled signaling in Ewing sarcoma SO PEDIATRIC BLOOD & CANCER LA English DT Article DE beta-catenin; Ewing sarcoma; frizzled; Wnt ID FRIZZLED-RELATED PROTEINS; BETA-CATENIN; GENE FAMILY; CYCLIN D1; EXPRESSION; CELLS; GROWTH; CANCER; ALPHA; TUMORIGENESIS AB Background. The Ewing sarcoma family of tumors (ESFT) is a set of neuroectodermal malignancies that typically presents in the second decade and has a poor prognosis due to metastatic disease. Wnt signaling has a critical role in the normal development of multiple neuroectodermal tissues and also contributes to the neoplastic properties of tumor cells of neuroectodermal origin. Procedure. We surveyed the expression of Wnts and their receptors in nine ESFT cell lines by RT-PCR analysis. We also tested biological response of ESFT cell lines to exogenous Wnts in beta-catenin stabilization, actin stress fiber formation, and chemotaxis assays. Results. We detected Wnt-10b in all the lines, and most also expressed Wnt-5a, Wnt-11, and Wnt-13. Several Frizzleds (Fz) and the Wnt co-receptors, low density lipoprotein-receptor-like proteins 5 and 6 were also expressed. We observed a marked stimulation of the beta-catenin/canonical Wnt pathway in ESFT cells treated with Wnt-3a. Wnt-3a induced morphologic changes characterized by the formation of long cytoplasmic extensions in ESFT cells. We also observed chemotaxis of ESFT cells in response to Wnt-3a. Conclusions. These results provide evidence that components of Wnt/Fz pathway are expressed and an intact Wnt/Frizzled signaling pathway exists in ESFT cell lines. Activation of the Wnt pathway in ESFT suggests that Wnt modulates cell motility rather than cell proliferation. Hence, activation of this pathway may influence metastatic potential of ESFT. (C) 2004 Wiley-Liss, Inc. C1 Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20057 USA. NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Uren, A (reprint author), Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Res Bldg,Room W316,3970 Reservoir Rd NW,Box 57146, Washington, DC 20057 USA. EM au26@georgetown.edu FU NCI NIH HHS [CA 88004, R01 CA088004, R01 CA088004-08] NR 43 TC 42 Z9 44 U1 0 U2 1 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 SEP PY 2004 VL 43 IS 3 BP 243 EP 249 DI 10.1002/bpc.20124 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 844FF UT WOS:000223142200007 PM 15266408 ER PT J AU Kordy, FN Al-Mohsen, IZ Hashem, F Almodovar, E Al Hajjar, S Walsh, TJ AF Kordy, FN Al-Mohsen, IZ Hashem, F Almodovar, E Al Hajjar, S Walsh, TJ TI Successful treatment of a child with posttraumatic necrotizing fasciitis caused by Apophysomyces elegans: Case report and review of literature SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Review DE fungal; necrotizing fasciitis; Apophysomyces ID ZYGOMYCOSIS AB Apophysomyces elegans is an uncommon human pathogen that causes deeply invasive infections in immunocompromised patients and cutaneous infection in immumocompetent patients. We report the development of severe deep soft tissue zygomycosis caused by A. elegans in an otherwise healthy child after trauma. She was successfully treated with surgical debridements and antifungal therapy with liposomal amphotericin B. A review of the literature indicates that zygomycosis caused by A. elegans is associated with traumatic inoculation. C1 King Faisal Specialist Hosp & Res Ctr, Dept Pediat, Riyadh 11211, Saudi Arabia. King Faisal Specialist Hosp & Res Ctr, Dept Surg, Riyadh 11211, Saudi Arabia. King Faisal Specialist Hosp & Res Ctr, Dept Pathol & Lab Med, Riyadh 11211, Saudi Arabia. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Al-Mohsen, IZ (reprint author), King Faisal Specialist Hosp & Res Ctr, Dept Pediat, POB 3354, Riyadh 11211, Saudi Arabia. EM imohsen@kfshrc.edu.sa NR 10 TC 24 Z9 24 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD SEP PY 2004 VL 23 IS 9 BP 877 EP 879 DI 10.1097/01.inf.0000136870.17071.fd PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 854KC UT WOS:000223900500017 PM 15361732 ER PT J AU Hunt, CE AF Hunt, CE TI Genes and Sudden Infant Death Syndrome SO PEDIATRIC RESEARCH LA English DT Editorial Material ID DIAGNOSIS C1 Natl Heart Lung & Blood Inst, Natl Ctr Sleep Disorders Res, NIH, Bethesda, MD 20892 USA. RP Hunt, CE (reprint author), Natl Heart Lung & Blood Inst, Natl Ctr Sleep Disorders Res, NIH, 1 Rockledge Ctr,Room 6022,6705 Rocklege Dr,MSC 79, Bethesda, MD 20892 USA. EM huntc@nhlbi.nih.gov NR 10 TC 6 Z9 6 U1 0 U2 0 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 SEP PY 2004 VL 56 IS 3 BP 321 EP 322 DI 10.1203/01.PDR.0000135999.55443.8B PG 2 WC Pediatrics SC Pediatrics GA 850FT UT WOS:000223597300004 PM 15240865 ER PT J AU Finer, NN Carlo, WA Duara, S Fanaroff, AA Donovan, EF Wright, LL Kandefer, S Poole, WK AF Finer, NN Carlo, WA Duara, S Fanaroff, AA Donovan, EF Wright, LL Kandefer, S Poole, WK CA Natl Inst Child Hlth Human Dev Neo TI Delivery room continuous positive airway pressure/positive end-expiratory pressure in extremely low birth weight infants: A feasibility trial SO PEDIATRICS LA English DT Article DE premature; ELBW; resuscitation; CPAP; PEEP; intubation; surfactant ID RESPIRATORY-DISTRESS SYNDROME; CHRONIC LUNG-DISEASE; NEONATAL RESUSCITATION; SURFACTANT; INTUBATION; PROPHYLAXIS; PERFORMANCE; NEWBORNS; THERAPY; RATES AB Objective. Although earlier studies have suggested that early continuous airway positive pressure (CPAP) may be beneficial in reducing ventilator dependence and subsequent chronic lung disease in the extremely low birth weight (ELBW) infant, the time of initiation of CPAP has varied, and there are no prospective studies of infants who have received CPAP or positive end-expiratory pressure (PEEP) from initial resuscitation in the delivery room (DR). Current practice for the ELBW infant includes early intubation and the administration of prophylactic surfactant, often in the DR. The feasibility of initiating CPAP in the DR and continuing this therapy without intubation for surfactant has never been determined prospectively in a population of ELBW infants. This study was designed to determine the feasibility of randomizing ELBW infants of <28 weeks' gestation to CPAP/PEEP or no CPAP/PEEP during resuscitation immediately after delivery, avoiding routine DR intubation for surfactant administration, initiating CPAP on neonatal intensive care unit (NICU) admission, and assessing compliance with subsequent intubation criteria. Methods. Infants who were of <28 weeks' gestation, who were born in 5 National Institute of Child Health and Human Development Neonatal Research Network NICUs from July 2002 to January 2003, and for whom a decision had been made to provide full treatment after birth were randomized to receive either CPAP/PEEP or not using a neonatal T-piece resuscitator (NeoPuff). Infants would not be intubated for the sole purpose of surfactant administration in the DR. After admission to the NICU, all nonintubated infants were placed on CPAP and were to be intubated for surfactant administration only after meeting specific criteria: a fraction of inspired oxygen of >0.3 with an oxygen saturation by pulse oximeter of <90% and/or an arterial oxygen pressure of <45 mm Hg, an arterial partial pressure of carbon dioxide of >55 mm Hg, or apnea requiring bag and mask ventilation. Results. A total of 104 infants were enrolled over a 6-month period: 55 CPAP and 49 control infants. No infant was intubated in the DR for the exclusive purpose of surfactant administration. Forty-seven infants were intubated for resuscitation in the DR: 27 of 55 CPAP infants and 20 of 49 control infants. Only 4 of the 43 infants who had a birth weight of <700 g and 3 of the 37 infants of <25 weeks' gestation were resuscitated successfully without positive pressure ventilation, and no difference was observed between the treatment groups. All infants of 23 weeks' gestation required intubation in the DR, irrespective of treatment group, whereas only 3 (14%) of 21 infants of 27 weeks' required such intubation. For infants who were not intubated in the DR, 36 infants (16 CPAP infants and 20 control infants) were subsequently intubated in the NICU by day 7, in accordance with the protocol. Overall, 80% of studied infants required intubation within the first 7 days of life. The care provided for 52 (95%) of 55 CPAP infants and 43 (88%) of the 49 control infants was in compliance with the study protocol, with an overall compliance of 91%. Conclusions. This study demonstrated that infants could be randomized successfully to a DR intervention of CPAP/PEEP compared with no CPAP/PEEP, with intubation provided only for resuscitation indications, and subsequent intubation for prespecified criteria. Forty-five percent (47 of 104) of infants <28 weeks' gestation required intubation for resuscitation in the DR. CPAP/PEEP in the DR did not affect the need for intubation at birth or during the subsequent week. Overall, 20% of infants did not need intubation by 7 days of life. This experience should be helpful in facilitating the design of subsequent prospective studies of ventilatory support in ELBW infants. C1 Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. Univ Alabama, Dept Pediat, Birmingham, AL USA. Univ Miami, Dept Pediat, Miami, FL 33152 USA. Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA. NICHHD, Bethesda, MD 20892 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. RP Finer, NN (reprint author), Univ Calif San Diego, Dept Pediat, 200 W Arbor Dr,8774, San Diego, CA 92103 USA. EM nfiner@ucsd.edu FU NCRR NIH HHS [M01 RR00750, M01 RR02172, M01 RR01032, M01 RR00997, M01 RR00070, M01 RR06022, M01 RR02635, M01 RR08084]; NICHD NIH HHS [U10 HD34216, U10 HD27904, U10 HD27880, U10 HD27871, U10 HD27856, U10 HD27853, U10 HD21415, U10 HD21397, U10 HD21385, U10 HD21373, U10 HD21364, U10 HD27881, U10 HD27851, U01 HD36790, U10 HD34167] NR 25 TC 124 Z9 130 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD SEP PY 2004 VL 114 IS 3 BP 651 EP 657 DI 10.1542/peds.2004-0394 PG 7 WC Pediatrics SC Pediatrics GA 851AU UT WOS:000223657600012 PM 15342835 ER PT J AU Lewin, MB McBride, KL Pignatelli, R Fernbach, S Combes, A Menesses, A Lam, W Bezold, LI Kaplan, N Towbin, JA Belmont, JW AF Lewin, MB McBride, KL Pignatelli, R Fernbach, S Combes, A Menesses, A Lam, W Bezold, LI Kaplan, N Towbin, JA Belmont, JW TI Echocardiographic evaluation of asymptomatic parental and sibling cardiovascular anomalies associated with congenital left ventricular outflow tract lesions SO PEDIATRICS LA English DT Article DE congenital heart disease; genetics; recurrence risk; aortic valve; coarctation; hypoplastic left heart syndrome ID BICUSPID AORTIC-VALVE; LEFT-HEART SYNDROME; UNITED-STATES; COARCTATION; DISEASE; MALFORMATIONS; DILATATION; MECHANISMS; DEFECTS; RISK AB Objective. Left ventricular outflow tract obstructive (LVOTO) malformations are a leading cause of infant mortality from birth defects. Genetic mechanisms are likely, and there may be a higher rate of asymptomatic LVOTO anomalies in relatives of affected children. This study sought to define the incidence of cardiac anomalies in first-degree relatives of children with congenital aortic valve stenosis (AVS), coarctation of the aorta (CoA), and hypoplastic left heart syndrome (HLHS). Methods. A total of 113 probands with a nonsyndromic LVOTO malformation of AVS (n=25), BAV (n=3), CoA (n=52), HLHS (n=30), and aortic hypoplasia with mitral valve atresia (n=2) were ascertained through chart review or enrolled at the time of diagnosis. Echocardiography was performed on 282 asymptomatic first-degree relatives. Results. Four studies had poor acoustic windows, leaving 278 studies for analysis. BAV were found in 13 (4.68%) first-degree relatives. The relative risk of BAV in the relatives was 5.05 (95% confidence interval: 2.2-11.7), and the broad sense heritability was 0.49, based on a general population frequency of 0.9%. BAV was more common in multiplex families compared with sporadic cases. An additional 32 relatives had anomalies of the aorta, aortic valve, left ventricle, or mitral valve. Conclusions. The presence of an LVOTO lesion greatly increases the risk of identifying BAV in a parent or sibling, providing additional support for a complex genetic cause. The parents and siblings of affected patients should be screened by echocardiography as the presence of an asymptomatic BAV may carry a significant long-term health risk. C1 Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Div Cardiol, Houston, TX 77030 USA. NIEHS, Environm Dis & Med Program, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Belmont, JW (reprint author), Baylor Coll Med, Dept Mol & Human Genet, 1 Baylor Plaza, Houston, TX 77030 USA. EM jbelmont@bcm.tmc.edu RI McBride, Kim/A-5879-2008; OI McBride, Kim/0000-0002-8407-8942; Belmont, John/0000-0001-7409-3578 FU NHLBI NIH HHS [K23 HL070823, K23 HL70823]; NICHD NIH HHS [R01 HD039056, R01 HD39056] NR 36 TC 48 Z9 48 U1 2 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD SEP PY 2004 VL 114 IS 3 BP 691 EP 696 DI 10.1542/peds.2003-0782-L PG 6 WC Pediatrics SC Pediatrics GA 851AU UT WOS:000223657600017 PM 15342840 ER PT J AU Ulrich, CM Grady, C Wendler, D AF Ulrich, CM Grady, C Wendler, D TI Palliative care: A supportive adjunct to pediatric phase I clinical trials for anticancer agents? SO PEDIATRICS LA English DT Editorial Material ID OF-LIFE CARE; CHILDREN; CANCER; CONDUCT; END; ONCOLOGY C1 NIH, Dept Clin Bioeth, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Ulrich, CM (reprint author), Univ Penn, Sch Nursing, Room 357 NEB,420 Guardian Dr, Philadelphia, PA 19104 USA. EM culrich@nursing.upenn.edu NR 22 TC 9 Z9 9 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD SEP PY 2004 VL 114 IS 3 BP 852 EP 855 DI 10.1542/peds.2003-0913-L PG 6 WC Pediatrics SC Pediatrics GA 851AU UT WOS:000223657600040 PM 15342863 ER PT J AU Schechter, AN Perlman, RL Rettig, RA AF Schechter, AN Perlman, RL Rettig, RA TI Editors' introduction: Why is revitalizing clinical reseach so important, yet so difficult? SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Editorial Material ID PHYSICIAN-SCIENTIST; BIOMEDICAL-RESEARCH; RESEARCH ENTERPRISE; COMPLEX DISEASE; CHALLENGES; NIH; INVESTIGATOR; INNOVATION; PRIORITIES; SCIENCES AB We believe that support for academic clinical research has greatly declined in recent decades. Here we discuss our views on why this has happened. We define clinical or patient-oriented research as limited to the study of human beings or populations of individuals, and argue that its eclipse in favor of basic and "translational" research is the result of inappropriate conceptual paradigms or "models" for medical advances. We believe that medical history shows that the "bench-to-bedside" model is inadequate to explain most recent progress and that clinical advances themselves often lead to new basic research. Discussion of alternate conceptual frameworks for biomedical research should help lead to changes in funding and organizational structures that might finally revitalize clinical research. C1 NIDDK, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. RAND Corp, Arlington, VA USA. RP Schechter, AN (reprint author), NIDDK, Biol Chem Lab, NIH, Bldg 10,Room 9N-307, Bethesda, MD 20892 USA. EM aschecht@helix.nih.gov NR 36 TC 13 Z9 14 U1 2 U2 2 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD FAL PY 2004 VL 47 IS 4 BP 476 EP 486 DI 10.1353/pbm.2004.0070 PG 11 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA 862KM UT WOS:000224489500002 PM 15467172 ER PT J AU Hashimoto, S Huang, YNG Castrop, H Hansen, PB Mizel, D Briggs, J Schnermann, J AF Hashimoto, S Huang, YNG Castrop, H Hansen, PB Mizel, D Briggs, J Schnermann, J TI Effect of carbonic anhydrase inhibition on GFR and renal hemodynamics in adenosine-1 receptor-deficient mice SO PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY LA English DT Article DE tubuloglomerular feedback; benzolamide; candesartan; perfused arterioles; plasma renin ID GLOMERULAR-FILTRATION RATE; FEEDBACK-MEDIATED REDUCTION; TUBULOGLOMERULAR FEEDBACK; KNOCKOUT MICE; ANGIOTENSIN-II; NEURONAL NOS; ACETAZOLAMIDE; MECHANISM; RAT; BENZOLAMIDE AB The reduction of glomerular filtration rate (GFR) caused by inhibitors of carbonic anhydrase (CA) is thought to be initiated by activation of the tubuloglomerular feedback (TGF) mechanism. We determined the effect of the CA inhibitor benzolamide (Bz) on renal hemodynamics in adenosine-1 receptor (A1AR) knockout mice that have been shown previously to lack a TGF response. In A1AR(+/+) mice, Bz (150 mug plus 2 mug/min) reduced RBF by 19.8% (from 829 +/- 42 to 666 +/- 44 mul/min; n=7), and GFR by 19.8% (from 396 +/- 43 to 324 +/- 46 mul/min; n=9, P=0.001). In A1AR(-/-) mice, RBF fell by 15.9 % (from 809 +/- 24 to 680 +/- 40 mul/min; n=7), and GFR by 21.1% (from 358 +/- 27 to 287 +/- 32 mul/min; n=10, P=0.0003; NS compared with A1AR(+/+)). The absence of TGF responses both before and during Bz infusion in A1AR(-/-) mice was confirmed by micropuncture. Following angiotensin II-receptor blockade with candesartan, Bz did not alter RBF (1.4 +/- 0.2 vs. 1.4 +/- 0.15 ml/min in A1AR(+/+), and 1.4 +/- 0.22 vs. 1.39 +/- 0.2 ml/min in A1AR(-/-) n=5/genotype) while GFR changed by -8.9 % in A1AR(+/+) mice (n=7), and by -1% in A1AR(-/-) mice (n=9; NS compared with A1AR(+/+)). Bz caused a significant rise of plasma renin concentration in both A1AR(+/+) and A1AR(-/-) mice. Our data show that the absence of a functional TGF mechanism does not prevent the reduction in GFR or RBF caused by CA inhibition. Acute angiotensin II receptor blockade, on the other hand, diminishes the effect of CA inhibition on GFR and RBF. The causes for the GFR reduction appear to be complex and include an effect of the renin-angiotensin system. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), NIDDKD, NIH, Bldg 10,Room 4 D51,10 Ctr Dr MSC 1370, Bethesda, MD 20892 USA. EM jurgens@intra.niddk.nih.gov NR 34 TC 10 Z9 10 U1 0 U2 0 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 SEP PY 2004 VL 448 IS 6 BP 621 EP 628 DI 10.1007/s00424-004-1330-1 PG 8 WC Physiology SC Physiology GA 859FX UT WOS:000224249900009 PM 15309539 ER PT J AU Feng, Z Prentice, R Srivastava, S AF Feng, Z Prentice, R Srivastava, S TI Research issues and strategies for genomic and proteomic biornarker discovery and validation: a statistical perspective SO PHARMACOGENOMICS LA English DT Article DE biomarker; validation; disease association; early detection; genomics; molecular profiling; proteomics ID PROSTATE-CANCER; LOGISTIC-REGRESSION; BREAST-CANCER; SERUM; CLASSIFICATION; AMPLIFICATION; ASSOCIATION; MORTALITY; PATTERNS; ERROR AB The development and validation of clinically useful biomarkers from high-dimensional genomic and proteomic information pose great research challenges. Present bottlenecks include: that few of the biomarkers showing promise in initial discovery were found to warrant subsequent validation; and biomarker validation is expensive and time consuming. Biomarker evaluation should proceed in an orderly fashion to enhance rigor and efficiency. A molecular profiling approach, although promising, has a high chance of yielding biased results and overfitted models. Specimens from cohorts or intervention trials are essential to eliminate biases. The high cost for biomarker validation motivates some novel study design features, including sequential filtering and DNA pooling. For data analysis, logistic regression (in particular, boosting logistic regression) has features of robustness against model misspecification, and has resistance to model overfitting. Model assessment and cross-validation are critical components of data analysis. Having an independent test set is a vital feature of study design. C1 Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Feng, Z (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM zfeng@fhcrc.org NR 38 TC 65 Z9 69 U1 0 U2 5 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 SEP PY 2004 VL 5 IS 6 BP 709 EP 719 DI 10.1517/14622416.5.6.709 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 864CT UT WOS:000224611400015 PM 15335291 ER PT J AU Eisenhofer, G Kopin, IJ Goldstein, DS AF Eisenhofer, G Kopin, IJ Goldstein, DS TI Catecholamine metabolism: A contemporary view with implications for physiology and medicine SO PHARMACOLOGICAL REVIEWS LA English DT Review ID CONGESTIVE-HEART-FAILURE; FAILING HUMAN HEART; ENDOGENOUS DOPAMINERGIC NEUROTOXIN; VESICULAR MONOAMINE TRANSPORTER; TYROSINE-HYDROXYLASE ACTIVITY; TRANSIENT FOREBRAIN ISCHEMIA; HYDROGEN-PEROXIDE PRODUCTION; PARKINSONS-DISEASE; NOREPINEPHRINE METABOLISM; 3,4-DIHYDROXYMANDELIC ACID AB This article provides an update about catecholamine metabolism, with emphasis on correcting common misconceptions relevant to catecholamine systems in health and disease. Importantly, most metabolism of catecholamines takes place within the same cells where the amines are synthesized. This mainly occurs secondary to leakage of catecholamines from vesicular stores into the cytoplasm. These stores exist in a highly dynamic equilibrium, with passive outward leakage counterbalanced by inward active transport controlled by vesicular monoamine transporters. In catecholaminergic neurons, the presence of monoamine oxidase leads to formation of reactive catecholaldehydes. Production of these toxic aldehydes depends on the dynamics of vesicular-axoplasmic monoamine exchange and enzyme-catalyzed conversion to nontoxic acids or alcohols. In sympathetic nerves, the aldehyde produced from norepinephrine is converted to 3,4-dihydroxyphenylglycol, not 3,4-dihydroxymandelic acid. Subsequent extraneuronal O-methylation consequently leads to production of 3-methoxy-4-hydroxyphenylglycol, not vanillylmandelic acid. Vanillylmandelic acid is instead formed in the liver by oxidation of 3-methoxy-4-hydroxyphenylglycol catalyzed by alcohol and aldehyde dehydrogenases. Compared to intraneuronal deamination, extraneuronal O-methylation of norepinephrine and epinephrine to metanephrines represent minor pathways of metabolism. The single largest source of metanephrines is the adrenal medulla. Similarly, pheochromocytoma tumor cells produce large amounts of metanephrines from catecholamines leaking from stores. Thus, these metabolites are particularly useful for detecting pheochromocytomas. The large contribution of intraneuronal deamination to catecholamine turnover, and dependence of this on the vesicular-axoplasmic monoamine exchange process, helps explain how synthesis, release, metabolism, turnover, and stores of catecholamines are regulated in a coordinated fashion during stress and in disease states. C1 Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Eisenhofer, G (reprint author), Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. EM ge@box-g.nih.gov NR 223 TC 343 Z9 350 U1 14 U2 56 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD SEP PY 2004 VL 56 IS 3 BP 331 EP 349 DI 10.1124/pr.56.3.1 PG 19 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 847EJ UT WOS:000223375200001 PM 15317907 ER PT J AU Podgornik, R AF Podgornik, R TI Electrostatic contribution to the persistence length of a semiflexible dipolar chain SO PHYSICAL REVIEW E LA English DT Article ID POLYELECTROLYTES; POLYMERS; LIMIT; FLUCTUATIONS; COLLAPSE AB We investigate the electrostatic contribution to the persistence length of a semiflexible polymer chain whose segments interact via a screened Debye-Huckel dipolar interaction potential. We derive the expressions for the renormalized persistence length on the level of a 1/D-expansion method already successfully used in other contexts of polyelectrolye physics. We investigate different limiting forms of the renormalized persistence length of the dipolar chain and show that, in, general, it depends less strongly on the screening length than in the context of a monopolar chain. We show that for a dipolar chain the electrostatic persistence length in the same regime of the parameter phase space as the original Odijk-Skolnick-Fixman (OSF) form for a monopolar chain depends logarithmically on the screening length rather than quadratically. This can be understood solely on the basis of a swifter decay of the dipolar interactions with separation compared to the monopolar electrostatic interactions. We comment also on the general contribution of higher multipoles to the electrostatic renormalization of the bending rigidity. C1 Univ Ljubljana, Dept Phys, Ljubljana 1000, Slovenia. Jozef Stefan Inst, Dept Theoret Phys, SI-1000 Ljubljana, Slovenia. NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Podgornik, R (reprint author), Univ Ljubljana, Dept Phys, Jadranska 19, Ljubljana 1000, Slovenia. RI Podgornik, Rudolf/C-6209-2008 OI Podgornik, Rudolf/0000-0002-3855-4637 NR 27 TC 6 Z9 6 U1 0 U2 6 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD SEP PY 2004 VL 70 IS 3 AR 031801 DI 10.1103/PhysRevE.70.031801 PN 1 PG 11 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 859XR UT WOS:000224302200046 PM 15524541 ER PT J AU Salzberg, SL Church, D DiCuccio, M Yaschenko, E Ostell, J AF Salzberg, SL Church, D DiCuccio, M Yaschenko, E Ostell, J TI The genome assembly archive: A new public resource SO PLOS BIOLOGY LA English DT Editorial Material ID SINGLE NUCLEOTIDE POLYMORPHISMS C1 Inst Genom Res, Rockville, MD USA. Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Salzberg, SL (reprint author), Inst Genom Res, Rockville, MD USA. EM salzberg@tigr.org RI Salzberg, Steven/F-6162-2011 OI Salzberg, Steven/0000-0002-8859-7432 FU NLM NIH HHS [R01-LM06845, R01 LM006845] NR 8 TC 19 Z9 20 U1 0 U2 2 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 SEP PY 2004 VL 2 IS 9 BP 1273 EP 1275 AR e285 DI 10.1371/journal.pbio.0020285 PG 3 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 857HW UT WOS:000224108100006 PM 15367931 ER PT J AU Ball, CA Brazma, A Causton, H Chervitz, S Edgar, R Hingamp, P Matese, JC Parkinson, H Quackenbush, J Ringwald, M Sansone, SA Sherlock, G Spellman, P Stoeckert, C Tateno, Y Taylor, R White, J Winegarden, N AF Ball, CA Brazma, A Causton, H Chervitz, S Edgar, R Hingamp, P Matese, JC Parkinson, H Quackenbush, J Ringwald, M Sansone, SA Sherlock, G Spellman, P Stoeckert, C Tateno, Y Taylor, R White, J Winegarden, N TI Submission of microarray data to public repositories SO PLOS BIOLOGY LA English DT Editorial Material ID GENE-EXPRESSION; INFORMATION; STANDARDS C1 Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. European Bioinformat Inst, European Mol Biol Lab, Hinxton, England. Univ London Imperial Coll Sci Technol & Med, Ctr Clin Sci, Microarray Ctr, London, England. Affymetrix, CIS Enterprise Data Grp, Emeryville, CA USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Univ Aix Marseille 2, Ctr Immunol Marseille Luminy, Fac Sci Luminy, Lab Technol Avancees Genome & Clin, F-13284 Marseille, France. Princeton Univ, Lewis Sigler Inst Integrat Genomics, Carl Icahn Lab, Princeton, NJ 08544 USA. Inst Genomic Res, Rockville, MD USA. Jackson Lab, Bar Harbor, ME 04609 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. Univ Calif Berkeley, Lawrence Berkeley Lab, Berkeley, CA 94720 USA. Univ Penn, Ctr Bioinformat, Dept Genet, Philadelphia, PA 19104 USA. Natl Inst Genet Res Org Informat & Syst, Ctr Informat Biol, Mishima, Shizuoka, Japan. Natl Inst Genet Res Org Informat & Syst, DNA Data Bank Japan, Mishima, Shizuoka, Japan. Pacific NW Natl Lab, Div Biol Sci, Computat BioSci Grp, Richland, WA USA. Univ Toronto, Hlth Network, Microarray Ctr, Toronto, ON, Canada. RP Brazma, A (reprint author), European Bioinformat Inst, European Mol Biol Lab, Hinxton, England. EM brazma@ebi.ac.uk RI Sherlock, Gavin/B-1831-2009; Sherlock, Gavin/E-9110-2012; OI Hingamp, Pascal/0000-0002-7463-2444; Parkinson, Helen/0000-0003-3035-4195; Matese, John/0000-0002-9432-8909; Taylor, Ronald/0000-0001-9777-9767; Sherlock, Gavin/0000-0002-1692-4983; Brazma, Alvis/0000-0001-5988-7409 NR 7 TC 77 Z9 81 U1 0 U2 3 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 SEP PY 2004 VL 2 IS 9 BP 1276 EP 1277 AR e317 DI 10.1371/journal.pbio.0020317 PG 2 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 857HW UT WOS:000224108100007 PM 15340489 ER PT J AU Mazza, V Di Monte, I Pati, M Contu, G Ottolenghi, C Forabosco, A Volpe, A AF Mazza, V Di Monte, I Pati, M Contu, G Ottolenghi, C Forabosco, A Volpe, A TI Sonographic biometrical range of external genitalia differentiation in the first trimester of pregnancy: analysis of 2593 cases SO PRENATAL DIAGNOSIS LA English DT Article DE fetal gender; prenatal diagnosis; sonography; biparietal diameter ID FETAL GENDER ASSIGNMENT; PRENATAL-DIAGNOSIS; SEX-DIFFERENTIATION; ULTRASOUND; GESTATION; EMBRYO; GROWTH AB Objectives The aim of this study was to establish the accuracy of fetal gender assignment by sonography in the biometrical range of 18 to 29 mm of biparietal diameter (BPD). Methods Transvaginal and/or transabdominal sonography was used to detect the sagittal sign as a marker of fetal gender in 2593 fetuses with BPD between 18 and 29 mm. The results of sonographic examination were compared with the gender at birth or with karyotype obtained from amniotic fluid cells or chorionic villus sampling. Results Fetal gender assignment was feasible in 2374 of 2593 cases (91%). Of the 2188 fetuses with known fetal sex outcome, 1025 were males and 1157 were females, and 6 had genital anomalies. In fetuses without genital anomalies, an accuracy rate of 100% was achieved at a BPD of greater than or equal to 24 mm. The results of the six cases with genital malformations were considered separately. Conclusion Sonography is a reliable method for the study of the morphological development of the external genitalia in fetuses 'in vivo'; it is possible to assign fetal gender in 95 to 99% starting at a BPD of 20 mm and to achieve an accuracy rate of 99 to 100% from a BPD of 22 mm, but fetal sex assignment should not be undertaken below a BPD of 22 mm, and especially not in cases where fetal sexing affects pregnancy management. Copyright (C) 2004 John Wiley Sons, Ltd. C1 Univ Modena, Dipartimento Sci Ostet Ginecol & Pediat, Sez Ginecol & Ostet, I-41100 Modena, Italy. NIA, Genet Lab, NIH, IRP, Baltimore, MD USA. Univ Modena, Dipartimento Sci Ostet Ginecol & Pediat, Med Genet Unit, I-41100 Modena, Italy. RP Mazza, V (reprint author), Univ Modena, Dipartimento Sci Ostet Ginecol & Pediat, Sez Ginecol & Ostet, Via Pozzo 71, I-41100 Modena, Italy. EM mazza@unimo.it NR 29 TC 17 Z9 21 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0197-3851 J9 PRENATAL DIAG JI Prenat. Diagn. PD SEP PY 2004 VL 24 IS 9 BP 677 EP 684 DI 10.1002/pd.945 PG 8 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 858CC UT WOS:000224166800002 PM 15386456 ER PT J AU Dierker, LC Avenevoli, S Goldberg, A Glantz, M AF Dierker, LC Avenevoli, S Goldberg, A Glantz, M TI Defining subgroups of adolescents at risk for experimental and regular smoking SO PREVENTION SCIENCE LA English DT Article DE smoking; risk factors; substance use; adolescents ID MIDWESTERN COMMUNITY SAMPLE; PEER CLUSTER THEORY; CIGARETTE-SMOKING; ALCOHOL-USE; SUBSTANCE-ABUSE; DRUG-USE; GENDER-DIFFERENCES; BLACK-ADOLESCENTS; UNITED-STATES; TOBACCO AB If multiple etiologies of substance use are truly at work in the population, then further strides in the accurate prediction of smoking and the use of other substances will likely be built on diverse pattern-centered approaches that explore the presence of multiple population subgroups across various substance use stages. The present study aimed to identify population subgroups defined by individual risk factors or risk factor constellations that prospectively predict specific smoking stages. Using data from the National Longitudinal Study of Adolescent Health (Add Health), analyses were conducted on the sample that took part in the baseline and 1 year follow-up assessment between 1994 and 1996. Classification and regression tree procedures were used to investigate the structure of individual risk factors, or constellations of risk, that define population subgroups with high rates of both experimental and established smoking. For each level of smoking, a relatively simple model including two subgroups predicted over half of the smoking cases. Findings also indicated that the two group models identified higher rates of regular smokers compared to experimental smokers. Deviant behaviors and alcohol use without permission independently predicted movement to experimentation at follow-up. Progression to regular smoking from both a nonsmoking and experimental smoking status at baseline were each predicted by smoking friends. Additionally, baseline levels of experimental use predicted movement from experimental to regular smoking, while a relatively low grade point average predicted rapid progression from baseline nonuse to regular use at follow-up. By identifying first approximations of patterns, these analyses may lead to clues regarding the major multiple mechanisms at work for the progression of smoking among adolescents. C1 Wesleyan Univ, Dept Psychol, Middletown, CT 06459 USA. NIMH, Mood & Anxiety Disorders Program, Intramural Res Program, US Dept HHS,NIH, Bethesda, MD 20892 USA. Univ Massachusetts, Amherst, MA 01003 USA. NIDA, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. RP Dierker, LC (reprint author), Wesleyan Univ, Dept Psychol, 207 High St, Middletown, CT 06459 USA. EM ldierker@wesleyan.edu FU NICHD NIH HHS [P01-HD31921] NR 76 TC 29 Z9 30 U1 4 U2 6 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1389-4986 J9 PREV SCI JI Prev. Sci. PD SEP PY 2004 VL 5 IS 3 BP 169 EP 183 DI 10.1023/B:PREV.0000037640.66607.6b PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 845HI UT WOS:000223232500003 PM 15470937 ER PT J AU Klassen, AC Curriero, FC Hong, JH Williams, C Kulldorff, M Meissner, HI Alberg, A Ensminger, M AF Klassen, AC Curriero, FC Hong, JH Williams, C Kulldorff, M Meissner, HI Alberg, A Ensminger, M TI The role of area-level influences on prostate cancer grade and stage at diagnosis SO PREVENTIVE MEDICINE LA English DT Article DE census; hierarchical modeling; prostate cancer; social factors; disparities ID MULTILEVEL ANALYSIS; SOCIOECONOMIC-STATUS; INCOME INEQUALITY; UNITED-STATES; RISK-FACTORS; NEIGHBORHOOD DETERMINANTS; MORTALITY-RATES; BLACK-MEN; HEALTH; US AB Background. This research explores area-level social influences on prostate cancer, to test whether area-level influences explain disparities in U.S. prostate cancer burden. Methods. The authors geocoded 23,993 1992-1997 Maryland prostate cancer cases, and linked cases to 1990 census data. The authors examined the effect of 17 area-level social variables, measured at block group, tract, and county, modeling individual and multilevel predictors of later stage and higher tumor grade. Results. Younger age, black race, higher grade or ungraded tumors, and earlier year of diagnosis were associated with later stage. Block group percentage of white-collar workers (OR. = 0.93, 95% C.I. = 0.89, 0.98), and county resources (OR. = 0.94, 95% C.I. = 0.89, 0.98), were protective of later stage. Older age, black race, and earlier year of diagnosis were associated with higher grade. Block group income was protective for white men (OR. = 0.92, 95% C.I. = 0.87, 0.96), but for all men, county resources increased risk of higher grade (OR. = 1.23, 95% C.I. = 1.16, 1.31). Conclusions. Social resources did not significantly reduce racial differences. Results suggest tumor biology is related to relative resources, with better outcomes associated with greater small-area wealth in low-resource counties, but stage at diagnosis is associated with absolute resources, with better outcomes associated with higher small-area social class in high-resource counties. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 Johns Hopkins Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD 21205 USA. Johns Hopkins Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02115 USA. Harvard Pilgrim Hlth Care, Boston, MA 02115 USA. NCI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. RP Klassen, AC (reprint author), Johns Hopkins Sch Publ Hlth, Dept Hlth Policy & Management, Room 745,724 N Broadway, Baltimore, MD 21205 USA. EM aklassen@jhsph.edu RI Kulldorff, Martin/H-4282-2011; OI Kulldorff, Martin/0000-0002-5284-2993 NR 56 TC 33 Z9 33 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 0091-7435 J9 PREV MED JI Prev. Med. PD SEP PY 2004 VL 39 IS 3 BP 441 EP 448 DI 10.1016/j.ypmed.2004.04.031 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 852MS UT WOS:000223760000002 PM 15313082 ER PT J AU Glanz, K Yaroch, AL AF Glanz, K Yaroch, AL TI Strategies for increasing fruit and vegetable intake in grocery stores and communities: policy, pricing, and environmental change SO PREVENTIVE MEDICINE LA English DT Article; Proceedings Paper CT Fruit and Vegetable Environment, Policy, and Pricing Workshop CY SEP 26-27, 2002 CL Atlanta, GA DE grocery stores community; fruits and vegetables; nutrition; environment; policy; pricing ID NUTRITION EDUCATION-PROGRAM; AFRICAN-AMERICAN CHURCHES; BLACK CHURCHES; HEALTH-PROMOTION; HEART HEALTH; SUPERMARKET INTERVENTION; INFORMATION PROGRAM; SHOP SMART; LOW-INCOME; PROJECT AB Background. Grocery stores and community settings are important and promising venues for environmental, policy, and pricing initiatives to increase fruit and vegetable intake. This article examines supermarket-based and community environmental, policy, and pricing strategies for increasing intake of fruits and vegetables and identifies promising strategies, research needs, and innovative opportunities for the future. Methods. The strategies, examples, and research reported here were identified through an extensive search of published journal articles, reports, and inquiries to leaders in the field. Recommendations were expanded with input from participants in the CDC/ACS-sponsored Fruit and Vegetable, Environment Policy and Pricing Workshop held in September of 2002. Results. Four key types of grocery-store-based interventions include point-of-purchase (POP) information; reduced prices and coupons; increased availability, variety, and convenience; and promotion and advertising. There is strong support for the feasibility of these approaches and modest evidence of their efficacy in influencing eating behavior. Church-based programs, child care center policies, and multisectoral community approaches show promise. Conclusions. Both descriptive and intervention research are needed to develop and evaluate more effective environmental strategies to increase F&V intake in grocery stores and communities. Innovative strategies, partnerships, grass roots action involving economic development for low-income communities, and sustainability are important considerations. (C) 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. C1 Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. NCI, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. RP Glanz, K (reprint author), Emory Univ, Rollins Sch Publ Hlth, 1518 Clifton Rd,NE,Room 526, Atlanta, GA 30322 USA. EM kglanz@sph.emory.edu NR 51 TC 109 Z9 110 U1 5 U2 39 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 SEP PY 2004 VL 39 SU 2 BP S75 EP S80 DI 10.1016/j.ypmed.2004.01.004 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 853SI UT WOS:000223847600002 PM 15313075 ER PT J AU Seymour, JD Yaroch, AL Serdula, M Blanck, HM Khan, LK AF Seymour, JD Yaroch, AL Serdula, M Blanck, HM Khan, LK TI Impact of nutrition environmental interventions on point-of-purchase behavior in adults: a review SO PREVENTIVE MEDICINE LA English DT Article; Proceedings Paper CT Fruit and Vegetable Environment, Policy, and Pricing Workshop CY SEP 26-27, 2002 CL Atlanta, GA DE nutrition; environment; policy; worksite; restaurant; grocery store; university ID FOLIC-ACID FORTIFICATION; LOCALLY GROWN PRODUCE; LOW-FAT; WORKSITE CAFETERIA; FOOD FORTIFICATION; UNITED-STATES; SUPERMARKET INTERVENTION; INFORMATION PROGRAM; EDUCATION-PROGRAM; PUBLIC CAFETERIA AB Background. Nutrition interventions targeted to individuals are unlikely to significantly shift US dietary patterns as a whole. Environmental and policy interventions are more promising for shifting these patterns. We review interventions that influenced the environment through food availability, access, pricing, or information at the point-of-purchase in worksites, universities, grocery stores, and restaurants. Methods. Thirty-eight nutrition environmental intervention studies in adult populations, published between 1970 and June 2003, were reviewed and evaluated on quality of intervention design, methods, and description (e.g., sample size, randomization). No policy interventions that met inclusion criteria were found. Results. Many interventions were not thoroughly evaluated or lacked important evaluation information. Direct comparison of studies across settings was not possible, but available data suggest that worksite and university interventions have the most potential for success. Interventions in grocery stores appear to be the least effective. The dual concerns of health and taste of foods promoted were rarely considered. Sustainability of environmental change was never addressed. Conclusions. Interventions in "limited access" sites (i.e., where few other choices were available) had the greatest effect on food choices. Research is needed using consistent methods, better assessment tools, and longer durations; targeting diverse populations; and examining sustainability. Future interventions should influence access and availability, policies, and macroenvironments. Published by The Institute For Cancer Prevention and Elsevier Inc. C1 Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Nutr & Phys Activ, Atlanta, GA 30341 USA. NCI, Div Canc Control & Populat Sci, Hlth Promot Res Branch, Behav Res Program, Bethesda, MD 20892 USA. RP Seymour, JD (reprint author), Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Nutr & Phys Activ, Mail Stop K-26,4770 Buford Highway NE, Atlanta, GA 30341 USA. EM jseymour1@cdc.gov NR 73 TC 94 Z9 96 U1 4 U2 36 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 SEP PY 2004 VL 39 SU 2 BP S108 EP S136 DI 10.1016/j.ypmed.2004.04.002 PG 29 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 853SI UT WOS:000223847600007 PM 15313080 ER PT J AU Seymour, JD Fenley, MA Yaroch, AL Khan, LK Serdula, M AF Seymour, JD Fenley, MA Yaroch, AL Khan, LK Serdula, M TI Fruit and Vegetable Environment, Policy, and Pricing Workshop: Introduction to the conference proceedings SO PREVENTIVE MEDICINE LA English DT Article; Proceedings Paper CT Fruit and Vegetable Environment, Policy, and Pricing Workshop CY SEP 26-27, 2002 CL Atlanta, GA DE diet; fruit and vegetables; environment; policy; price AB Americans' consumption of fruits and vegetables has increased slightly over the last 10 years, but most people still do not meet the Dietary Guidelines recommendation to consume 5 to 9 servings per day. New and innovative strategies are needed if we are to significantly increase the mean population intake of fruits and vegetables. To help formulate such strategies as well as to evaluate evidence and identify research gaps, the American Cancer Society and the Centers for Disease Control and Prevention convened the Fruit and Vegetable Environment, Policy, and Pricing Workshop, which brought together experts in how environmental change, policy, and pricing affect fruit and vegetable consumption. The papers in this supplement consist of a review of environmental interventions to improve nutrition and papers covering pricing and consumer value and how fruit and vegetable consumption can be promoted at worksites, restaurants, grocery stores and other community settings, and schools. Conclusions from the workshop were that existing intervention strategies need to be evaluated, promising example programs need to be disseminated, and new innovative interventions and programs need to be created and evaluated. Published by The Institute For Cancer Prevention and Elsevier Inc. C1 Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Nutr & Phys Activ, Atlanta, GA 30341 USA. Task Force Child Survival & Dev, Atlanta, GA 30341 USA. NCI, Hlth Promot Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Seymour, JD (reprint author), Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Nutr & Phys Activ, 4770 Bldg Hwy,NE MS K-26, Atlanta, GA 30341 USA. EM jseymour1@cdc.gov NR 9 TC 3 Z9 4 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD SEP PY 2004 VL 39 SU 2 BP S71 EP S74 DI 10.1016/j.ypmed.2004.07.009 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 853SI UT WOS:000223847600001 PM 15313074 ER PT J AU Barzilai, A Kumar, S Wolfson, H Nussinov, R AF Barzilai, A Kumar, S Wolfson, H Nussinov, R TI Potential folding-function interrelationship in proteins SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE protein folding; protein function; protein building block; protein design; folding and function; structure and function ID CANONICAL LOOP CONFORMATION; BUILDING-BLOCKS; CRYSTAL-STRUCTURE; STRUCTURAL GENOMICS; SECONDARY STRUCTURE; GLOBULAR-PROTEINS; TRANSITION-STATE; HIV-1 PROTEASE; BINDING; SEQUENCES AB The possibility is addressed that protein folding and function may be related via regions that are critical for both folding and function. This approach is based on the building blocks folding model that describes protein folding as binding events of conformationally fluctuating building blocks. Within these, we identify building block fragments that are critical for achieving the native told. A library of such critical building blocks (CBBs) is constructed. Then, it is asked whether the functionally important residues fall in these CBB fragments. We find that for over two-thirds of the proteins in our. library with available functional information, the catalytic or binding site residues lie within the CBB regions. From the evolutionary standpoint, a folding-function relationship is advantageous, since the need to guard against mutations is limited to one region. Furthermore, conformationally similar CBBs are found in globally unrelated proteins with different functions. Hence, substituting CBBs may lead to designed proteins with altered functions. We further find that the CBBs in our library are conformationally unstable. (C) 2004 Wiley-Liss, Inc. C1 NCI, FCRF, Frederick, MD 21702 USA. RP Nussinov, R (reprint author), NCI, FCRF, Bldg 469,Room 151, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov RI Wolfson, Haim/A-1837-2011 FU NCI NIH HHS [N01-CO-12400] NR 93 TC 3 Z9 3 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD SEP 1 PY 2004 VL 56 IS 4 BP 635 EP 649 DI 10.1002/prot.20132 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 845DQ UT WOS:000223216500001 PM 15281117 ER PT J AU Anantharaman, V Aravind, L AF Anantharaman, V Aravind, L TI The SHS2 module is a common structural theme in functionally diverse protein groups, like Rpb7p, FtsA, gyrI, and MTH1598/Tm1083 superfamilies SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE cell division; dodecin; RNA polymerase; duplication; transcription; BmrR; Zsig11 ID MULTIPLE SEQUENCE ALIGNMENT; DNA GYRASE INHIBITOR; RNA-POLYMERASE-II; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; TRANSCRIPTION ACTIVATOR; MUTATIONAL ANALYSIS; HELIX PROTEINS; DOMAIN COMMON; EVOLUTION AB Using structural comparisons, we identified a novel domain with a simple fold in the bacterial cell division ATPase FtsA, the archaeo-eukaryotic RNA polymerase subunit Rpb7p, the GyrI superfamily, and the uncharacterized MTH1598/Tm1083-like proteins. The fold contains a core of 3 strands, forming a curved sheet, and a single helix in a strand-helix-strand-strand (SHS2) configuration. The SHS2 domain may exist either in single or duplicate copies within the same polypeptide. The single-copy versions of the domain in FtsA and Rbp7p are most closely related, and appear to mediate protein-protein interactions by means of strand 1, and the loop between strand 2 and strand 3 of the domain. We predict that the interactions between FtsA and its functional partners in bacterial cell division are likely to be similar to the interactions of Rbp7p in the archaeo-eukaryotic RNA polymerase complex. The dimeric versions typified by the GyrI superfamily appear to have been adapted for small-molecule binding. Sequence profiles searches helped us to identify several new versions of the GyrI superfamily, including a family of secreted forms that is found only in animals and the bacterial pathogen Leptospira. Through sequence-structure comparisons, we predict the positions that are likely to be important for ligand specificity in the GyrI superfamily. In the MTH1598/Tm1083-like proteins, a SHS2 domain is inserted into the loop between strand 1 and helix 1 of another SHS2 domain. This has resulted in a structure that has convergent similarities with the Hsp33 and green fluorescent protein folds. The sequence conservation pattern and its phyletic profile suggest that it might function as an enzyme in some conserved aspect of nucleic acid metabolism. Thus, the SHS2 domain is an example of a simple module that has been adapted to perform an entire spectrum of functions ranging from protein-protein interactions to small-molecule recognition and catalysis. (C) 2004 Wiley-Liss, Inc. C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov OI Anantharaman, Vivek/0000-0001-8395-0009 NR 53 TC 14 Z9 14 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD SEP 1 PY 2004 VL 56 IS 4 BP 795 EP 807 DI 10.1002/prot.20140 PG 13 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 845DQ UT WOS:000223216500015 PM 15281131 ER PT J AU Krieg, RC Knuechel, R Schiffmann, E Liotta, LA Petricoin, EF Herrmann, PC AF Krieg, RC Knuechel, R Schiffmann, E Liotta, LA Petricoin, EF Herrmann, PC TI Mitochondrial proteome: Cancer-altered metabolism associated with cytochrome c oxidase subunit level variation SO PROTEOMICS LA English DT Article DE cell lines; cytochrome c oxidase; mitochondria; prostate; protein expression ID PROSTATE-CANCER; GENE-EXPRESSION; CELL CULTURES; CARCINOMA; TISSUE; ASSIGNMENT; GLYCOLYSIS; ULTRASTRUCTURE; RESPIRATION; MICROARRAYS AB Shifts in metabolism associated with tumorigenesis were first noted by Otto Warburg in the 1920s. In the ensuing decades many examples of the phenomenon have been elucidated while the underlying molecular mechanism has remained elusive. As the enzyme complex at the crux of oxidative phosphorylation, cytochrome c oxidase is uniquely positioned to have a very high impact on cellular metabolism. In this study, we test the hypothesis that there is a specific association between altered cytochrome c oxidase subunit levels and altered metabolism by combining the technique of reverse-phase protein microarray with radiolabeled glucose metabolic studies. Such a relationship is observed with five different cell lines, two of which (1542N and 1542T) are a matched set of normal and tumor-based lineages derived from the same prostate gland. By measuring the [C-14]carbon dioxide production of a cell line metabolizing [1-C-14]glucose and comparing those measurements to values obtained for the same cell line metabolizing [6-C-14]glucose, we determined the relative utilization of the hexose monophosphate shunt and glycolysis progressing through the Krebs cycle metabolic pathway in each cell line. In all cases there is an increased utilization of hexose monophosphate shunt relative to glycolysis progressing through the Krebs cycle in tumor derived relative to normal derived cell lines. Additionally, there is an associated increase in the ratio of nuclear encoded cytochrome c oxidase subunits to mitochondrially encoded cytochrome c oxidase subunits in the tumor-derived cell lines. These results demonstrate an alteration in subunit levels of a single enzyme complex (cytochrome c oxidase) commensurate with tumor-altered metabolism. C1 NCI, Lab Pathol, FDA NCI Clin Proteom Program, NIH, Bethesda, MD 20892 USA. UKAachen RWTH, Inst Pathol, Aachen, Germany. CBER, Food & Drug Adm, Div Therapeut Prot, FDA NCI Clin Proteom Program, Bethesda, MD USA. RP Herrmann, PC (reprint author), NCI, Lab Pathol, FDA NCI Clin Proteom Program, NIH, 10 Ctr Dr,Bldg 10,Room 2N212, Bethesda, MD 20892 USA. EM herrmanp@mail.nih.gov NR 40 TC 42 Z9 48 U1 1 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD SEP PY 2004 VL 4 IS 9 BP 2789 EP 2795 DI 10.1002/pmic.200300796 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 853BN UT WOS:000223801300028 PM 15352252 ER PT J AU Heishman, SJ Saha, S Singleton, EG AF Heishman, SJ Saha, S Singleton, EG TI Imagery-induced tobacco craving: Duration and lack of assessment reactivity bias SO PSYCHOLOGY OF ADDICTIVE BEHAVIORS LA English DT Article ID NICOTINE DEPENDENCE; CUE-REACTIVITY; SMOKING CUE; REAL-TIME; QUESTIONNAIRE; RELIABILITY; VALIDITY; LAPSES AB The duration of imagery-induced tobacco craving and whether craving responses are biased by repeated assessment (reactivity) was studied. Nonabstinent smokers (n = 40) either imagined a scene describing smoking urges or rested. They then either completed the Tobacco Craving Questionnaire (TCQ; S. J. Heishman, E. G. Singleton, & E. T. Moolchan, 2003) every minute for 15 min or completed it after imagery or rest (Minute 1) and 15 min later. TCQ scores were greater after imagery compared with rest and remained significantly elevated at Minute 15. There was no evidence that TCQ responses were affected by repeated measurement. These data suggest that imagery-induced craving can persist for at least 15 min and that craving responses are not biased by assessment reactivity. C1 NIDA, Clin Pharmacol & Therapeut Branch, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Heishman, SJ (reprint author), NIDA, Clin Pharmacol & Therapeut Branch, NIH, Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM heishman@nih.gov OI Singleton, Edward G./0000-0003-3442-877X NR 15 TC 14 Z9 14 U1 1 U2 2 PU EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST, NE, WASHINGTON, DC 20002-4242 USA SN 0893-164X J9 PSYCHOL ADDICT BEHAV JI Psychol. Addict. Behav. PD SEP PY 2004 VL 18 IS 3 BP 284 EP 288 DI 10.1037/0893-164X.18.3.284 PG 5 WC Substance Abuse; Psychology, Multidisciplinary SC Substance Abuse; Psychology GA 858GV UT WOS:000224181200010 PM 15482084 ER PT J AU Harvey, DM Yasar, S Heishman, SJ Panlilio, LV Henningfield, JE Goldberg Sr AF Harvey, DM Yasar, S Heishman, SJ Panlilio, LV Henningfield, JE Goldberg, SR TI Nicotine serves as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers SO PSYCHOPHARMACOLOGY LA English DT Article DE nicotine; human; tobacco, smoking behavior; drug self-administration; intravenous; fixed-ratio schedule ID PROGRESSIVE-RATIO; SQUIRREL-MONKEYS; COCAINE ABUSERS; SCHEDULE; INJECTIONS; MAINTENANCE; CAFFEINE; SMOKING; ACQUISITION; ECONOMICS AB Rationale: Although numerous studies have documented that nicotine can function as an effective reinforcer of intravenous self-administration behavior in animals, it has not been clearly shown to maintain intravenous self-administration behavior above vehicle placebo levels in humans. Objectives: To compare the reinforcing effectiveness of nicotine versus saline placebo in human research volunteers responding under fixed-ratio (FR) schedules of intravenous drug self-administration while systematically increasing response requirements. Methods: Eight male cigarette smokers resided in an inpatient research unit. During 3-h sessions, intravenous injections of nicotine and saline were available concurrently and were contingent on responding (pulling a lever). Nicotine dose (0.75, 1.5, 3.0 mg/injection), time out (TO) value after each injection (1-20 min) and FR response requirement (10-1600) were varied in different subjects over consecutive sessions. Results: Number of nicotine injections/session significantly decreased as dose/injection increased and the number of self-administered nicotine injections was significantly greater than the number of self-administered saline injections across conditions. When FR value was progressively increased over sessions, response rates for nicotine, but not saline, injections increased, with maximal rates at the highest FR values. Rates of responding and injections/session were markedly and significantly higher for nicotine than for saline at FR values of 200 and above. Subjects rated effects of nicotine as both significantly more positive and more negative than saline placebo, with positive ratings significantly higher than negative ratings. Conclusions: Nicotine functioned as a prototypic drug of abuse, serving as an effective reinforcer of intravenous drug-taking behavior in human cigarette smokers. Subjects adjusted their responding to response requirements in a way that maintained relatively constant levels of nicotine injections per session. C1 NIDA, Preclin Pharmacol Sect, NIH, DHHS, Baltimore, MD 21224 USA. NIDA, Clin Pharmacol & Therapeut Branch, NIH, DHHS, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. NIDA, Behav Neurosci Sect, NIH, DHHS, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. Pinney Associates, Bethesda, MD USA. RP Goldberg Sr (reprint author), NIDA, Preclin Pharmacol Sect, NIH, DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sgoldber@intra.nida.nih.gov NR 45 TC 81 Z9 82 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2004 VL 175 IS 2 BP 134 EP 142 DI 10.1007/s00213-004-1818-6 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 855EV UT WOS:000223956900002 PM 14997277 ER PT J AU Romieu, P Meunier, J Garcia, D Zozime, N Martin-Fardon, R Bowen, WD Maurice, T AF Romieu, P Meunier, J Garcia, D Zozime, N Martin-Fardon, R Bowen, WD Maurice, T TI The sigma(1) (sigma(1)) receptor activation is a key step for the reactivation of cocaine conditioned place preference by drug priming SO PSYCHOPHARMACOLOGY LA English DT Article DE cocaine relapse; conditioned place preference; sigma(1) (sigma(1)) receptor; sensitization; dehydroepiandrosterone; mouse ID METHYL-D-ASPARTATE; THERAPEUTIC OPPORTUNITIES; NEUROACTIVE STEROIDS; NUCLEUS-ACCUMBENS; SEEKING BEHAVIOR; RAT HIPPOCAMPUS; LIGANDS; NEUROSTEROIDS; REINSTATEMENT; EXTINCTION AB Rationale: Cocaine-seeking behavior can be investigated in rodents using the conditioned place preference (CPP) paradigm, in which the drug-paired environment serves as a conditioned stimulus. Such approach allowed to previously demonstrate the importance of the neuromodulatory sigma(1) (sigma(1)) receptor in acquisition of cocaine-induced CPP. CPP can be extinguished and then reactivated, notably using a cocaine challenge (i.e., priming). Objectives and methods: In order to examine the role of the a, receptor in reinstatement of Cocaine-seeking, Swiss mice acquired CPP with cocaine (30 mg/kg, ip) and then CPP was extinguished. Results: A challenge cocaine priming (15 mg/kg) reactivated CPP up to 140% of the post-conditioning response. Pre-administration of the sigma(1) receptor antagonist BD1047 (330 mg/kg, ip) or repeated treatment with an antisense probe targeting the a, receptor prevented CPP reactivation. The a, agonist igmesine (1-10 mg/kg, ip) or the steroid dehydroepiandrosterone (DHEA, 10-40 mg/kg, sc) reactivated CPP, in a BD1047-sensitive manner. Moreover, the in vivo [H-3](+)-SKF-10,047 binding levels to the a, receptor were increased after cocaine conditioning in numerous brain structures and these increases subsisted after extinction. Finally, cross-reactivation of cocaine-induced CPP was observed after phencyclidine (PCP), morphine, nicotine and ethanol administration. However, BD1047 blocked reactivation of CPP induced by PCP, morphine and nicotine but not ethanol. Conclusions: Since activation of the a, receptor is not sufficient to sustain CPP in naive animals [Neuropsychopharmacology 26 (2002) 444], it is concluded that or, receptor activation is a key event for relapse to drug seeking. Activation may occur via sensitization due to enhanced in vivo available of receptors. C1 Univ Montpellier 2, CNRS, FRE 2693, F-34095 Montpellier 5, France. Scripps Res Inst, Dept Neuropharmacol, La Jolla, CA 92037 USA. NIDDK, Unit Receptor Biochem & Pharmacol, Med Chem Lab, NIH, Bethesda, MD 20892 USA. RP Maurice, T (reprint author), Univ Montpellier 2, CNRS, FRE 2693, Pl Eugene Bataillon, F-34095 Montpellier 5, France. EM maurice@univ-montp2.fr NR 43 TC 51 Z9 52 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2004 VL 175 IS 2 BP 154 EP 162 DI 10.1007/s00213-004-1814-x PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 855EV UT WOS:000223956900005 PM 14985920 ER PT J AU Grillon, C Cordova, J Morgan, CA Charney, DS Davis, M AF Grillon, C Cordova, J Morgan, CA Charney, DS Davis, M TI Effects of the beta-blocker propranolol on cued and contextual fear conditioning in humans SO PSYCHOPHARMACOLOGY LA English DT Article DE emotional memories; beta-adrenergic receptors; propranolol; fear conditioning; context conditioning; fear-potentiated startle; electrodermal activity ID POTENTIATED STARTLE; MEMORY STORAGE; RETROGRADE-AMNESIA; EMOTIONAL EVENTS; PANIC DISORDER; AMYGDALA; ANXIETY; STRESS; NOREPINEPHRINE; INVOLVEMENT AB Rationale: Beta-adrenergic receptors are involved in the consolidation of emotional memories. Yet, a number of studies using Pavlovian cued fear conditioning have been unable to demonstrate an effect of beta-adrenergic blockade on acquisition or retention of fear conditioning. Evidence for the involvement of beta-adrenergic receptors in emotional memories comes mostly from studies using fear inhibitory avoidance in rodents. It is possible that fear inhibitory avoidance is more akin to contextual conditioning than to cued fear conditioning, suggesting that context conditioning may be disrupted by beta-adrenergic blockade. Objective: This study investigated the effects of the beta-adrenergic blocker propranolol on cued and contextual fear conditioning in humans. Methods: Subjects were given either placebo (n=15) or 40 mg propranolol (n=15) prior to differential cued conditioning. A week later, they were tested for retention of context and cued fear conditioning using physiological (startle reflex and electrodermal activity) and subjective measures of emotional arousal. Results: The results were consistent with the hypothesis. The skin conductance level (SCL) and the subjective measure of arousal suggested reduced emotional arousal upon returning to the conditioning context in the propranolol group, compared to the placebo group. The acquisition and retention of cued fear conditioning were not affected by propranolol. Conclusions: These results suggest that beta-adrenergic receptors are involved in contextual fear conditioning. C1 NIMH, Mood Anxiety Disorder Program, NIH, DHHS, Bethesda, MD 20892 USA. Connecticut VA Med Ctr, West Haven, CT 06516 USA. Emory Univ, Sch Med, Atlanta, GA 30322 USA. RP Grillon, C (reprint author), NIMH, Mood Anxiety Disorder Program, NIH, DHHS, 15K North Dr, Bethesda, MD 20892 USA. EM christian.grillon@nih.gov FU NIMH NIH HHS [MH 47840, MH 52384, MH 57250, MH 59906] NR 46 TC 65 Z9 65 U1 6 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2004 VL 175 IS 3 BP 342 EP 352 DI 10.1007/s00213-004-1819-5 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 862YI UT WOS:000224527000009 PM 15007536 ER PT J AU Christian, TF Rettmann, DW Aletras, AH Liao, SL Taylor, JL Balaban, RS Arai, AE AF Christian, TF Rettmann, DW Aletras, AH Liao, SL Taylor, JL Balaban, RS Arai, AE TI Absolute myocardial perfusion in canines measured by using dual-bolus first-pass MR imaging SO RADIOLOGY LA English DT Article DE animals; experimental study; heart, MR; heart, perfusion; magnetic resonance (MR), perfusion study ID MAGNETIC-RESONANCE; CORONARY STENOSIS; WATER EXCHANGE; TRANSIT-TIME; QUANTIFICATION; DECONVOLUTION; RESERVE; MODEL; BLOOD; FLOW AB PURPOSE: To compare fluorescent microsphere measurements of myocardial blood flow (MBF) with qualitative, semiquantitative, and fully quantitative measurements of first-pass perfusion at magnetic resonance (MR) imaging. MATERIALS AND METHODS: Coronary artery occlusion or intracoronary adenosine infusion was successfully performed in 16 beagles; both procedures were performed simultaneously in one animal. MBF was assessed at microsphere analysis. First-pass myocardial perfusion MR imaging was performed during a dual-bolus administration of gadopentetate dimeglumine (0.0025 mmol/kg followed by 0.10 mmol/kg). The absolute myocardial perfusion at MR imaging was calculated by using Fermi function deconvolution methods. Qualitative, semiquantitative, and absolute myocardial perfusion MR imaging measurements were compared with microsphere MBF measurements by using paired t tests, linear correlation, and Bland-Altman analysis. RESULTS: Fully quantitative (ie, absolute) analysis of MBF at MR imaging correlated with microsphere MBF measurement (r = 0.95, P <.001) across the full range of blood flow rates encountered (from 0 to >5.0 mL/min/g). Similar close correlations were observed in endocardial and epicardial segments (representing approximately 0.85 g of the myocardium). With modest increases in MBF, qualitative measurements plateaued in the hyperemic zones. Semiquantitative measurements did not correlate with MBF as well (r = 0.69-0.89); they plateaued around 3.0 mL/min/g. CONCLUSION: Dual-bolus MR imaging enabled accurate measurement of absolute epicardial and endocardial perfusion across a wide range of blood flow rates (0 to >5.0 mL/min/g). Use of qualitative MR imaging measures such as the contrast enhancement ratio led to substantially underestimated hyperemic blood flow measurements. (C) RSNA, 2004. C1 NHLBI, Cardiac Energet Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, Cardiac Energet Lab, NIH, Dept Hlth & Human Serv, Bldg 10,Rm B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov RI Balaban, Robert/A-7459-2009; Rettmann, Dan/G-5265-2015; OI Balaban, Robert/0000-0003-4086-0948; Aletras, Anthony/0000-0002-3786-3817 NR 22 TC 165 Z9 166 U1 0 U2 6 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 SEP PY 2004 VL 232 IS 3 BP 677 EP 684 DI 10.1148/radiol.2323030573 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 848GG UT WOS:000223455000006 PM 15284436 ER PT J AU Armato, SG McLennan, G McNitt-Gray, MF Meyer, CR Yankelevitz, D Aberle, DR Henschke, CI Hoffman, EA Kazerooni, EA MacMahon, H Reeves, AP Croft, BY Clarke, LP AF Armato, SG McLennan, G McNitt-Gray, MF Meyer, CR Yankelevitz, D Aberle, DR Henschke, CI Hoffman, EA Kazerooni, EA MacMahon, H Reeves, AP Croft, BY Clarke, LP CA Lung Image Database Consortium TI Lung image database consortium: Developing a resource for the medical imaging research community SO RADIOLOGY LA English DT Article ID COMPUTER-AIDED DIAGNOSIS; AUTOMATED NODULE DETECTION; NATIONAL-CANCER-INSTITUTE; SMALL PULMONARY NODULES; SECTION CT IMAGES; NOMENCLATURE COMMITTEE; PRELIMINARY EXPERIENCE; FLEISCHNER-SOCIETY; TOMOGRAPHY IMAGES; NEURAL NETWORKS AB To stimulate the advancement of computer-aided diagnostic (CAD) research for lung nodules in thoracic computed tomography (CT), the National Cancer Institute launched a cooperative effort known as the Lung Image Database Consortium (LIDC). The LIDC is composed of five academic institutions from across the United States that are working together to develop an image database that will serve as an international research resource for the development, training, and evaluation of CAD methods in the detection of lung nodules on CT scans. Prior to the collection of CT images and associated patient data, the LIDC has been engaged in a consensus process to identify, address, and resolve a host of challenging technical and clinical issues to provide a solid foundation for a scientifically robust database. These issues include the establishment of (a) a governing mission statement, (b) criteria to determine whether a CT scan is eligible for inclusion in the database, (c) an appropriate definition of the term qualifying nodule, (d) an appropriate definition of "truth" requirements, (e) a process model through which the database will be populated, and (f) a statistical framework to guide the application of assessment methods by users of the database. Through a consensus process in which careful planning and proper consideration of fundamental issues have been emphasized, the LIDC database is expected to provide a powerful resource for the medical imaging research community. This article is intended to share with the community the breadth and depth of these key issues. (C) RSNA, 2004. C1 Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. Univ Iowa, Iowa City, IA USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Michigan, Ann Arbor, MI 48109 USA. Cornell Univ, New York, NY 10021 USA. NCI, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. RP Armato, SG (reprint author), Univ Chicago, Dept Radiol, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM s-armato@uchicago.edu RI Croft, Barbara/D-1248-2013; OI Croft, Barbara/0000-0003-2544-150X; Aberle, Denise/0000-0002-8858-3401; McNItt-Gray, Michael/0000-0003-3004-4613 FU NCI NIH HHS [U01 CA091099, U01 CA091085, U01 CA091090, U01 CA091103, U01CA091085, U01CA091090, U01CA091099, U01CA091100, U01CA091103] NR 52 TC 183 Z9 189 U1 1 U2 9 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 SEP PY 2004 VL 232 IS 3 BP 739 EP 748 DI 10.1148/radiol.2323032035 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 848GG UT WOS:000223455000014 PM 15333795 ER PT J AU Menard, C Citrin, D Susil, R Choyke, P Gharib, A Ning, H Miller, R Ullman, K Guion, P Sears-Crouse, N Smith, S Pouliot, J Camphausen, K Coleman, N AF Menard, C Citrin, D Susil, R Choyke, P Gharib, A Ning, H Miller, R Ullman, K Guion, P Sears-Crouse, N Smith, S Pouliot, J Camphausen, K Coleman, N TI 1.5T interventional MRI for HDR prostate brachytherapy SO RADIOTHERAPY AND ONCOLOGY LA English DT Meeting Abstract CT Annual Scientific Meeting on Exporing Genomics in Radiation Oncology CY SEP 09-12, 2004 CL Halifax, CANADA C1 NCI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Biomed Engn, Baltimore, MD 21218 USA. CCNIH, Dept Diagnost Radiol, Bethesda, MD USA. Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA. RI Gharib, Ahmed/O-2629-2016 OI Gharib, Ahmed/0000-0002-2476-481X NR 0 TC 0 Z9 0 U1 1 U2 2 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 SEP PY 2004 VL 72 SU 1 MA 62 BP S19 EP S19 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 879IB UT WOS:000225708500063 ER PT J AU Muanza, TM Camphausen, K Coleman, CN AF Muanza, TM Camphausen, K Coleman, CN TI Ionizing radiation induces an early differential gene expression profile in normal mouse brain SO RADIOTHERAPY AND ONCOLOGY LA English DT Meeting Abstract CT Annual Scientific Meeting on Exporing Genomics in Radiation Oncology CY SEP 09-12, 2004 CL Halifax, CANADA C1 NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. McGill, MUHC, Montreal, PQ, 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 SEP PY 2004 VL 72 SU 1 MA 85 BP S26 EP S26 DI 10.1016/S0167-8140(04)80586-3 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 879IB UT WOS:000225708500085 ER PT J AU Parliament, M Damaraju, S Murray, D Dufour, J Myrehaug, S Anderson, S Fallone, G Field, C Greiner, R Menard, C Hanson, J AF Parliament, M Damaraju, S Murray, D Dufour, J Myrehaug, S Anderson, S Fallone, G Field, C Greiner, R Menard, C Hanson, J TI Association of radiation and tissue homeostasis response gene polymorphisms 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 Annual Scientific Meeting on Exporing Genomics in Radiation Oncology CY SEP 09-12, 2004 CL Halifax, CANADA C1 Univ Alberta, Cross Canc Inst, Polyomx Program, Edmonton, AB T6G 2M7, Canada. Univ Alberta, Dept Comp Sci, Edmonton, AB T6G 2M7, Canada. NCI, Radiat Oncol Branch, NIH, 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 SEP PY 2004 VL 72 SU 1 MA 80 BP S25 EP S25 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 879IB UT WOS:000225708500081 ER PT J AU Cabello-Villegas, J Giles, KE Soto, AM Yu, P Mougin, A Beemon, KL Wang, YX AF Cabello-Villegas, J Giles, KE Soto, AM Yu, P Mougin, A Beemon, KL Wang, YX TI Solution structure of the pseudo-5 ' splice site of a retroviral splicing suppressor SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE U1 snRNP binding site; NRS; NMR structure; UUGU tetraloop; U bulge ID ROUS-SARCOMA-VIRUS; PRE-MESSENGER-RNA; SMALL NUCLEAR RIBONUCLEOPROTEIN; RESIDUAL DIPOLAR COUPLINGS; NEGATIVE REGULATOR; SECONDARY STRUCTURE; THERMODYNAMIC PARAMETERS; INTRONIC SEQUENCES; HYDROGEN-BONDS; SNRNP BINDING AB Control of Rous sarcoma virus RNA splicing depends in part on the interaction of U1 and U11 snRNPs with an intronic RNA element called the negative regulator of splicing (NRS). A 23mer RNA hairpin (NRS23) of the NRS directly binds U1 and U11 snRNPs. Mutations that disrupt base-pairing between the loop of NRS23 and U1 snRNA abolish its negative control of splicing. We have determined the solution structure of NRS23 using NOEs, torsion angles, and residual dipolar couplings that were extracted from multidimensional heteronuclear NMR spectra. Our structure showed that the 6-bp stem of NRS23 adopts a nearly A-form duplex conformation. The loop, which consists of 11 residues according to secondary structure probing, was in a closed conformation. U913, the first residue in the loop, was bulged out or dynamic, and loop residues G914-C923, G915-U922, and U916-A921 were base-paired. The remaining UUGU tetraloop sequence did not adopt a stable structure and appears flexible in solution. This tetraloop differs from the well-known classes of tetraloops (GNRA, CUYG, UNCG) in terms of its stability, structure, and function. Deletion of the bulged U913, which is not complementary to U1 snRNA, increased the melting temperature of the RNA hairpin. This hyperstable hairpin exhibited a significant decrease in binding to U1 snRNP. Thus, the structure of the NRS RNA, as well as its sequence, is important for interaction with U1 snRNP and for splicing suppression. C1 Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. NCI, Frederick Canc Res & Dev Ctr, CCR, Struct Biophys Lab,Prot Nucl Acid Interact Sect, Frederick, MD 21702 USA. Univ Nancy 1, CNRS, UMR 7567, Lab Maturat ARN & Enzymol Mol, F-54506 Vandoeuvre Les Nancy, France. RP Wang, YX (reprint author), Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. EM wangyru@ncifcrf.gov FU NCI NIH HHS [R01 CA048746, R01CA48745]; NIGMS NIH HHS [T32GM07231, T32 GM007231] NR 65 TC 17 Z9 17 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD SEP PY 2004 VL 10 IS 9 BP 1388 EP 1398 DI 10.1261/rna.7020804 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 850RB UT WOS:000223629000008 PM 15317975 ER PT J AU Lauronen, E Karhu, M Miettunen, J Veijola, J Fenton, W Jones, P Isohanni, M AF Lauronen, E Karhu, M Miettunen, J Veijola, J Fenton, W Jones, P Isohanni, M TI Predictors of good and poor outcomes in schizophrenia - The northern Finland 1966 birth cohort SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 4th International Conference on Early Psychosis CY SEP 28-OCT 01, 2004 CL Vancouver, CANADA C1 Oulu Univ, Dept Psychiat, SF-90220 Oulu, Finland. NIMH, Bethesda, MD 20892 USA. Univ Cambridge, Dept Psychiat, Cambridge CB2 1TN, England. Oulu Univ, Dept Publ Hlth & Gen Practice, Oulu, Finland. EM llaurone@paju.oulu.fi NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2004 VL 70 IS 1 SU S BP 83 EP 83 PG 1 WC Psychiatry SC Psychiatry GA 863HE UT WOS:000224551100228 ER PT J AU Lauronen, E Koskinen, J Veijola, J Miettunen, J Jones, P Fenton, W Isohanni, M AF Lauronen, E Koskinen, J Veijola, J Miettunen, J Jones, P Fenton, W Isohanni, M TI Recovery from schizophrenic psychoses within the northern Finland 1966 birth cohort SO SCHIZOPHRENIA RESEARCH LA English DT Meeting Abstract CT 4th International Conference on Early Psychosis CY SEP 28-OCT 01, 2004 CL Vancouver, CANADA C1 Univ Oulu, Dept Psychiat, Oulu, Finland. Univ Cambridge, Dept Psychiat, Cambridge CB2 1TN, England. NIMH, Bethesda, MD 20892 USA. Univ Oulu, Dept Psychiat, Oulu, Finland. Univ Oulu, Dept Publ Hlth & Gen Practice, Oulu, Finland. EM llaurone@paju.oulu.fi NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2004 VL 70 IS 1 SU S BP 83 EP 83 PG 1 WC Psychiatry SC Psychiatry GA 863HE UT WOS:000224551100227 ER PT J AU Vega, VL de Cabo, R De Maio, A AF Vega, VL de Cabo, R De Maio, A TI Age and caloric restriction diets are confounding factors that modify the response to lipopolysaccharide by peritoneal macrophages in C57BL/6 mice SO SHOCK LA English DT Article DE aging; endotoxin; diet; CD14; cytokines; food restriction; genetics; inflammation ID MULTIPLE ORGAN FAILURE; INTENSIVE-CARE-UNIT; AGING IMMUNE-SYSTEM; HEAT-STRESSED RATS; RHESUS-MONKEYS; INFLAMMATORY RESPONSE; ICU PATIENTS; EXPRESSION; INFECTIONS; ANTIGENS AB Aging is the result of several detrimental changes that lead to a decrease in homeostasis, an increase in the incidence of degenerative diseases, and death. A caloric-restricted diet (CR), which consists of a significant reduction in calorie intake (40%) without malnutrition, has been shown to delay the onset of age-related diseases and pathologies and to extend life span. The aims of this study were to assess the effects of aging and CR on lipopolysaccharide (LPS)-dependant cytokine production by peritoneal macrophages (PMphis). Resident naive PMphis were isolated from 2- to 24-month-old male C57BL/6 mice and were stimulated with Escherichia coli LPS (100 ng/mL) for 1 to 5 h in culture conditions. A linear decrease in the production of LPS-induced tumor necrosis factor alpha (TNF-alpha) and interleukin (IL) 10 was observed with age. LPS-incluced IL-6 and IL-1beta levels were also reduced with age, but in a nonlinear fashion. Expression of CD14, the major receptor for LPS, on the PMphi surface was also observed to decline with age. Moreover, TNF-alpha production by PMphis was reduced in mice undergoing the two different CR diets of limited daily feeding and intermittent fasting, as compared with ad libitum-fed mice. The results of this study add the new variables age and diet to the paradigm proposing that the response to LPS is modulated by multiple components, including genetic background and sex. C1 Johns Hopkins Univ, Sch Med, Div Pediat Surg, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Physiol, Baltimore, MD 21205 USA. NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP De Maio, A (reprint author), Johns Hopkins Univ, Sch Med, Div Pediat Surg, 720 Rutland Ave,Ross 746, Baltimore, MD 21205 USA. EM ademaio@jhmi.edu RI de Cabo, Rafael/E-7996-2010; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU NIGMS NIH HHS [GM-57317] NR 46 TC 28 Z9 29 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD SEP PY 2004 VL 22 IS 3 BP 248 EP 253 DI 10.1097/01.shk.0000133590.09659.a1 PG 6 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 847LL UT WOS:000223394000009 PM 15316395 ER PT J AU Boshoff, HIM Barry, CE Mizrahi, V AF Boshoff, HIM Barry, CE Mizrahi, V TI Mutational dynamics in Mycobacterium tuberculosis: implications for the evolution of drug resistance SO SOUTH AFRICAN JOURNAL OF SCIENCE LA English DT Article ID HYPOXIC RESPONSE; GENOME SEQUENCE; BINDING PROTEIN; GLOBAL TRENDS; DNA; GENE; COMPLEX; MACROPHAGES; SMEGMATIS; REPLICATION AB The major human pathogen, Mycobacterium tuberculosis, is responsible for the largest number of deaths attributable to a single infectious organism. Multidrug chemotherapy is a central pillar of the global strategy for controlling tuberculosis (TB) and, for this reason, the emergence and spread of isolates of M. tuberculosis that are resistant to one or more of the first-line anti-tubercular drugs presents a major threat to the control of this devastating disease. Drug resistance in M. tuberculosis is caused by mutations in chromosomal genes that are associated, in some way, with drug action. In order to develop interventions to combat the problem of multidrug-resistant TB, it is important to understand the mutational mechanisms in M. tuberculosis that underlie the emergence of drug resistance in this organism. In this paper, we review our work on a damage-inducible mutagenesis pathway in mycobacteria that led to the identification of the novel repair polymerase, DnaE2. The dnaE2 gene of M. tuberculosis was shown to be upregulated by DNA-damaging agents in vitro and during infection of mice. This protein was shown to be solely responsible for the damage-induced increase in mutation of M. tuberculosis to resistance to the anti-tubercular drugs, rifampicin and streptomycin. Loss of the DnaE2 protein by targeted knockout of its encoding gene rendered M. tuberculosis hypersensitive to killing by UV light and impaired its ability to persistently infect mice. The effects of dnaE2 gene knockout on bacterial survival are most likely attributable to the ability of DnaE2 to catalyse error-prone translesion synthesis across sites of DNA damage. Significantly, DnaE2, and not any member of the Y-family of error-prone DNA polymerases, is the primary mediator of inducible mutagenesis by base substitutions in M. tuberculosis and this activity appears to contribute to the emergence of drug resistance in vivo. C1 Univ Witwatersrand, Sch Pathol, Mol Mycobacteriol Res Unit, MRC,NHLS,WITS, ZA-2000 Johannesburg, South Africa. Natl Hlth Lab Serv, ZA-2000 Johannesburg, South Africa. NIAID, NIH, TB Res Sect, Lab Host Def, Rockville, MD USA. RP Mizrahi, V (reprint author), Univ Witwatersrand, Sch Pathol, Mol Mycobacteriol Res Unit, MRC,NHLS,WITS, POB 1038, ZA-2000 Johannesburg, South Africa. EM mizrahiv@pathology.wits.ac.za RI Barry, III, Clifton/H-3839-2012 NR 50 TC 0 Z9 0 U1 0 U2 8 PU ACAD SCIENCE SOUTH AFRICA A S S AF PI LYNWOOD RIDGE PA PO BOX 72135, LYNWOOD RIDGE 0040, SOUTH AFRICA SN 0038-2353 J9 S AFR J SCI JI S. Afr. J. Sci. PD SEP-OCT PY 2004 VL 100 IS 9-10 BP 471 EP 474 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 886PJ UT WOS:000226240500018 ER PT J AU Mueller, SO Katzenellenbogen, JA Korach, KS AF Mueller, SO Katzenellenbogen, JA Korach, KS TI Endogenous estrogen receptor beta is transcriptionally active in primary ovarian cells from estrogen receptor knockout mice SO STEROIDS LA English DT Article DE ER alpha; ER beta; ERKO; THC; PPT; indenestrol; DES ID ER-ALPHA; SELECTIVE LIGANDS; SEX REVERSAL; NULL MICE; WILD-TYPE; IN-VIVO; MOUSE; GENE; ANTIESTROGENS; ACTIVATION AB The estrogen receptor (ER) alpha is a hormone-inducible transcription factor that has a pivotal physiological role. Intriguingly, a clear and undisputed physiological function of the recently described ERbeta remains elusive, with the exception of the ovary where a cooperative role of ERalpha and ERbeta has been demonstrated. We have, therefore, investigated whether endogenous ERs, in particular ERbeta, act as ligand-inducible transcription factors in primary ovarian cells derived from wild-type, ERalpha or ERbeta knockout mice. Granulosa-enriched cell fractions naturally expressing ERbeta and thecal cell fractions that express ERalpha were analyzed in transactivation assays using the vitellogenin A2 consensus estrogen response element and potent ER agonists diethylstilbestrol and S-indenestrol A. We studied also the potency-selective ERbeta agonist R-indenestrol A, the pure ERalpha agonist and ERbeta antagonist R,R-diethyl-tetrahydrochrysene and the pure ERalpha agonist propylpyrazole-triol. Using ER subtype-specific physiological cell models and these ER subtype- specific structural probes, we analyzed trans-activation of ERa and ERbeta. This analysis revealed that endogenously expressed ERbeta is indeed functional as a transcription factor, that it responds to estrogens appropriately, and that the ligands used are true ER subtype-specific probes in primary ovarian cells. In conclusion, this study demonstrates that endogenously expressed ERbeta is capable of regulating gene transcription independent of ERalpha. Published by Elsevier Inc. C1 NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Illinois, Dept Chem, Urbana, IL 61801 USA. RP Mueller, SO (reprint author), Merck KGaA, Inst Toxicol, POB 64271, Darmstadt, Germany. EM stefan.o.mueller@merck.de; korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X NR 27 TC 3 Z9 5 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 SEP PY 2004 VL 69 IS 10 BP 681 EP 686 DI 10.1016/j.steroids.2004.06.004 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 864GZ UT WOS:000224623300012 PM 15465114 ER PT J AU LaRonde-LeBlanc, N Wlodawer, A AF LaRonde-LeBlanc, N Wlodawer, A TI Crystal structure of A-fulgidus Rio2 defines a new family of serine protein kinases SO STRUCTURE LA English DT Article ID PRE-RIBOSOMAL-RNA; SACCHAROMYCES-CEREVISIAE; WINGED-HELIX; CATALYTIC SUBUNIT; PEPTIDE INHIBITOR; SUPERFAMILY; REFINEMENT; COMPLEXES; BINDING; MOTIF AB The RIO family of atypical serine/threonine kinases contains two subfamilies, Rio1 and Rio2, highly conserved from archaea to man. Both RIO proteins from Saccharomyces cerevisiae catalyze serine phosphorylation in vitro, and the presence of conserved catalytic residues is required for cell viability. The activity of Rio2 is necessary for rRNA cleavage in 40S ribosomal subunit maturation. We solved the X-ray crystal structure of Archaeoglobus fulgidus Rio2, with and without bound nucleotides, at 2.0 Angstrom resolution. The C-terminal RIO domain is indeed structurally homologous to protein kinases, although it differs from known serine kinases in ATP binding and lacks the regions important for substrate binding. Unexpectedly, the N-terminal Rio2-specific domain contains a winged helix fold, seen primarily in DNA-binding proteins. These discoveries have implications in determining the target and function of RIO proteins and define a distinct new family of protein kinases. C1 NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Wlodawer, A (reprint author), NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM wlodawer@ncifcrf.gov RI LaRonde-LeBlanc, Nicole/C-3399-2009 OI LaRonde-LeBlanc, Nicole/0000-0002-2778-8358 NR 37 TC 52 Z9 57 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD SEP PY 2004 VL 12 IS 9 BP 1585 EP 1594 DI 10.1016/j.str.2004.06.016 PG 10 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 855JN UT WOS:000223969500004 PM 15341724 ER PT J AU Rajan, SS Yang, XJ Collart, F Yip, VLY Withers, SG Varrot, A Thompson, J Davies, GJ Anderson, WF AF Rajan, SS Yang, XJ Collart, F Yip, VLY Withers, SG Varrot, A Thompson, J Davies, GJ Anderson, WF TI Novel catalytic mechanism of glycoside hydrolysis based on the structure of an NAD(+)/Mn(2+)-dependent phospho-alpha-glucosidase from Bacillus subtilis SO STRUCTURE LA English DT Article ID GLUCOSYL-D-FRUCTOSES; CRYSTAL-STRUCTURE; THERMOTOGA-MARITIMA; ESCHERICHIA-COLI; FAMILY 4; KLEBSIELLA-PNEUMONIAE; HIGH-THROUGHPUT; DEHYDROGENASE; REFINEMENT; ASSIGNMENT AB GlvA, a 6-phospho-alpha-glucosidase from Bacillus subtilis, catalyzes the hydrolysis of maltose-6'-phosphate and belongs to glycoside hydrolase family GH4. GH4 enzymes are unique in their requirement for NAD(H) and a divalent metal for activity. We have determined the crystal structure of GlvA in complex with its ligands to 2.05 Angstrom resolution. Analyses of the active site architecture, in conjunction with mechanistic studies and precedent from the nucleotide diphosphate hexose dehydratases and other systems, suggest a novel mechanism of glycoside hydrolysis by GlvA that involves both the NAD(H) and the metal. C1 Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Univ British Columbia, Dept Chem, Vancouver, BC V6T 1Z1, Canada. Argonne Natl Lab, Biosci Div, Argonne, IL 60439 USA. Univ York, Dept Chem, York YO1 5DD, N Yorkshire, England. NIDCR, Microbial Biochem & Genet Unit, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Anderson, WF (reprint author), Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. EM wf-anderson@northwestern.edu OI Varrot, Annabelle/0000-0001-6667-8162 FU NIGMS NIH HHS [GM62414] NR 42 TC 56 Z9 58 U1 0 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD SEP PY 2004 VL 12 IS 9 BP 1619 EP 1629 DI 10.1016/j.str.2004.06.020 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 855JN UT WOS:000223969500007 PM 15341727 ER PT J AU Lee, SS Robinson, MR Morris, JC Mirtsching, BC Shen, DF Chan, CC AF Lee, SS Robinson, MR Morris, JC Mirtsching, BC Shen, DF Chan, CC TI Conjunctival involvement with T-cell prolymphocytic leukemia: Report of a case and review of the literature SO SURVEY OF OPHTHALMOLOGY LA English DT Review DE conjunctiva; immunohistochemistry; prolymphocytic leukemia; T cell; therapy ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ACUTE MYELOMONOCYTIC LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; GRANULOCYTIC SARCOMA; ATAXIA-TELANGIECTASIA; SPLENIC IRRADIATION; MONOCLONAL-ANTIBODY; LYMPHATIC-LEUKEMIA; INDOLENT COURSE; INFILTRATION AB T-cell prolymphocytic leukemia is a rare and highly aggressive hematological neoplasm. A patient with T-cell prolymphocytic leukemia presented with bilateral perilimbal conjunctival infiltrates. Conjunctival biopsy showed aggregates of large atypical lymphocytes in the substantia propria with a concentration of atypical cells in the perivascular areas. Immunophenotyping of the malignant cells identified an abnormal clonal T-cell population consistent with T-cell prolymphocytic leukemia. A literature review of all reports of conjunctival involvement with leukemia was performed. The three cases of ocular prolymphocytic leukemia, including the one case of ocular T-cell prolymphocytic leukemia, are discussed in detail as well as 14 reported clinical cases of biopsy-proven conjunctival leukemia. The majority of cases occurred in the setting of acute leukemia, and conjunctival involvement was frequently a presenting sign of the disease or signified disease relapse. Conjunctival involvement with leukemia was consistent with good visual acuity; however, it portended a poor prognosis. C1 NEI, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Med City Hosp, Ctr Oncol Res & Treatment, Dallas, TX USA. RP Robinson, MR (reprint author), NEI, NIH, 10-10S229,10 Ctr Dr,MSC 1863, Bethesda, MD 20892 USA. NR 75 TC 10 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-6257 J9 SURV OPHTHALMOL JI Surv. Ophthalmol. PD SEP-OCT PY 2004 VL 49 IS 5 BP 525 EP 536 DI 10.1016/j.survophthal.2004.06.005 PG 12 WC Ophthalmology SC Ophthalmology GA 852KY UT WOS:000223755400006 PM 15325197 ER PT J AU Nandi, A Dersch, CM Kulshrestha, M Ananthan, S Rothman, RB AF Nandi, A Dersch, CM Kulshrestha, M Ananthan, S Rothman, RB TI Identification and characterization of a novel allosteric modulator (SoRI-6238) of the serotonin transporter SO SYNAPSE LA English DT Article DE serotonin; transporter; allosteric; cocaine; depression; norepinephrine ID BIOGENIC-AMINE TRANSPORTERS; NEUROTRANSMITTER TRANSPORTERS; DOPAMINE TRANSPORTER; BINDING; AGENTS; ANTAGONISTS AB In the present study we describe a novel agent, SoRI-6238 (ethyl 5-amino-3-(3,4-dichlorophenyl)-1,2-dihydropyrido[3,4-b]pyrazin-7-ylcarbamate) that partially inhibits 5-HT transporter (SERT) binding and allosterically modulates SERT function. Membranes were prepared from rat brain. SoRI-6238 partially inhibited SERT binding to brain membranes with a plateau at about 40% of control. SoRI-6238 fully inhibited norepinephrine transporter (NET) and dopamine transporter (DAT) binding with IC50 values of 12.1 muM and 5.8 muM, respectively. The apparent K-d of [I-125]RTI-55 binding to SERT increased, then reached a plateau with increasing concentrations of SoRI-6238. SoRI-6238 fully inhibited [H-3]5-HT uptake, acting to decrease the V-max (noncompetitive inhibition). In kinetic experiments, SoRI-6238 slowed the dissociation of [I-125]RTI-55 from SERT and slowed the initial association rate. We conclude that SoRI-6238 partially inhibits SERT binding and function, most likely via an allosteric mechanism. Published 2004 whey-hiss, Inc.(dagger) C1 NIDA, IRP, Clin Psychopharmacol Sect, NIH, Baltimore, MD 21224 USA. So Res Inst, Dept Organ Chem, Birmingham, AL 35255 USA. RP Rothman, RB (reprint author), NIDA, IRP, Clin Psychopharmacol Sect, NIH, Baltimore, MD 21224 USA. EM rrothman@belite.com NR 17 TC 16 Z9 16 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 1 PY 2004 VL 53 IS 3 BP 176 EP 183 DI 10.1002/syn.20048 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 840NS UT WOS:000222866400005 PM 15236350 ER PT J AU Ding, YS Fowler, JS Logan, J Wang, GJ Telang, F Garza, V Biegon, A Pareto, D Rooney, W Shea, C Alexoff, D Volkow, ND Vocci, F AF Ding, YS Fowler, JS Logan, J Wang, GJ Telang, F Garza, V Biegon, A Pareto, D Rooney, W Shea, C Alexoff, D Volkow, ND Vocci, F TI 6-[F-18]fluoro-A-85380, a new PET tracer for the nicotinic acetylcholine receptor: Studies in the human brain and in vivo demonstration of specific binding in white matter SO SYNAPSE LA English DT Article DE nicotinic acetylcholine receptors; nicotine; tobacco dependence; A-85380; white matter; positron emission tomography ID PARKINSONS-DISEASE; GRAPHICAL ANALYSIS; SMOKING; EXPRESSION; SUBUNIT; HIPPOCAMPUS; TOXICITY; DEMENTIA C1 Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA. Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. NIDA, Bethesda, MD 20892 USA. RP Ding, YS (reprint author), Brookhaven Natl Lab, Dept Chem, Upton, NY 11973 USA. OI Logan, Jean/0000-0002-6993-9994 FU NIBIB NIH HHS [EB002630]; NIDA NIH HHS [DA-06278] NR 40 TC 74 Z9 74 U1 1 U2 3 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 1 PY 2004 VL 53 IS 3 BP 184 EP 189 DI 10.1002/syn.20051 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 840NS UT WOS:000222866400006 PM 15236351 ER PT J AU Sills, RC Morgan, DL Herr, DW Little, PB George, NM Ton, TV Love, NE Maronpot, RR Johnson, GA AF Sills, RC Morgan, DL Herr, DW Little, PB George, NM Ton, TV Love, NE Maronpot, RR Johnson, GA TI Contribution of magnetic resonance microscopy in the 12-week neurotoxicity evaluation of carbonyl sulfide in Fischer 344 rats SO TOXICOLOGIC PATHOLOGY LA English DT Article DE carbonyl sulfide; brain; neurotoxicity; magnetic resonance microscopy; auditory system ID METABOLISM; ANIMALS AB In this carbonyl sulfide (COS) study, magnetic resonance microscopy (MRM) and detailed light microscopic evaluation effectively functioned in parallel to assure that the distribution and degree of pathology in the brain was accurately represented. MRM is a powerful imaging modality that allows for excellent identification of neuroanatomical structures coupled with the ability to acquire 200 or more cross-sectional images of the brain, and the ability to display them in multiple planes. F344 rats were exposed to 200-600 ppm COS for up to 12 weeks. Prior to MRM, rats were anesthetized and cardiac perfused with McDowell Trump's fixative containing a gadolinium MR contrast medium. Fixed specimens were scanned at the Duke Center for In Vivo Microscopy on a 9.4 Tesla magnetic resonance system adapted explicitly for microscopic imaging. An advantage of MRM in this study was the ability to identify lesions in rats that appeared clinically normal prior to sacrifice and the opportunity to identify lesions in areas of the brain which would not be included in conventional studies. Other advantages include the ability to examine the brain in multiple planes (transverse, dorsal, sagittal) and obtain and save the MRM images in a digital format that allows for postexperimental data processing and manipulation. MRM images were correlated with neuroanatomical and neuropathological findings. All suspected MRM images were compared to corresponding H&E slides. An important aspect of this study was that MRM was critical in defining our strategy for sectioning the brain, and for designing mechanistic studies (cytochrome oxidase evaluations) and functional assessments (electrophysiology studies) on specifically targeted anatomical sites following COS exposure. C1 NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. US EPA, Div Neurotoxicol, ORD, NHEERL, Res Triangle Pk, NC 27711 USA. Pathol Associates Inc, Durham, NC 27713 USA. Duke Univ, Med Ctr, Vet Ctr Amer, Durham, NC 27701 USA. Duke Univ, Med Ctr, Ctr In Vivo Microscopy, Durham, NC 27701 USA. RP Sills, RC (reprint author), NIEHS, Lab Expt Pathol, MD B3-08,POB 12233, Res Triangle Pk, NC 27709 USA. EM sills@niehs.nih.gov OI Johnson, G.Allan/0000-0002-7606-5447 FU NCI NIH HHS [5R24-CA92656]; PHS HHS [P41 05959] NR 20 TC 13 Z9 13 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD SEP-OCT PY 2004 VL 32 IS 5 BP 501 EP 510 DI 10.1080/01926230490493918 PG 10 WC Pathology; Toxicology SC Pathology; Toxicology GA 887GF UT WOS:000226293000001 PM 15603534 ER PT J AU Dunnick, J Johnson, JA Horton, J Nyska, A AF Dunnick, J Johnson, JA Horton, J Nyska, A TI Bis(2-chloroethoxy) methane-induced mitochondrial and myofibrillar damage: Short-term time-course study SO TOXICOLOGICAL SCIENCES LA English DT Article DE bis(2-chloroethoxy)methane (CEM); thiodiglycolic acid; cardiotoxicity; vacuolation; mitochondria; sarcoplasmic reticulum (SR); recovery ID THIODIGLYCOLIC ACID; INDUCED APOPTOSIS; HEART-FAILURE; DOXORUBICIN; RATS; METABOLISM; KIDNEY; CARDIOMYOPATHY; IFOSFAMIDE; INTESTINE AB Cardiotoxicity induced by 2-, 3-, 5-, and 12-day dermal administration of 400 and 600 mg/kg/day of bis(2-chloroethoxy)methane to F344/N male and female rats was characterized. The severity and incidence of lesions were similar among males and females and in all three regions of the heart examined (atrium, ventricle, interventricular septum). Damage induced by bis(2-chloroethoxy)methane consisted of time-related development of myofiber vacuolation, necrosis, mononuclear-cell infiltration, fibrosis, and atrial thrombosis. Changes were pronounced at day 2, increased in severity at day 3, appeared to decrease at day 5, and resolved by study-day 16 that corresponded to 12 dosings. Ultrastructural analysis of 2- and 5-day 600 mg/kg/day-treated females elucidated the primary site of damage, the mitochondrion, and two types of vacuolation, one that formed as damaged mitochondria. became devoid of cristae and their bounding double membranes became reduced to singleness, and the other manifested as distention of the sarcoplasmic reticulum. After the initial damage induced by bis(2-chloroethoxy)methane, or its metabolite, thiodiglycolic acid, protective mechanisms within the heart were apparently initiated, enabling it to cope with the continued exposure to the toxicant while eliminating some damaged myofibers. C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Dunnick, J (reprint author), NIEHS, Environm Toxicol Program, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM dunnickj@niehs.nih.gov NR 35 TC 11 Z9 11 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2004 VL 81 IS 1 BP 243 EP 252 DI 10.1093/toxsci/kfh194 PG 10 WC Toxicology SC Toxicology GA 850CP UT WOS:000223589100027 PM 15201436 ER PT J AU Anderson, LM AF Anderson, LM TI Introduction and overview. Perinatal carcinogenesis: growing a node for epidemiology, risk management, and animal studies SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Editorial Material DE permatal carcinogenesis; epidemiology; risk assessment ID BREAST-CANCER RISK; CHILDHOOD ENERGY-INTAKE; BIRTH-WEIGHT; LIFE; BIOAVAILABILITY; MORTALITY; TOXICITY; TUMORS; COHORT; TRENDS AB Perinatal carcinogenesis as a cross-disciplinary concern is the subject of this special issue of Toxicology and Applied Pharmacology, which consists of a total of eight reviews or commentaries in the areas of epidemiology, risk assessment, and animal models. Some of the conclusions from these articles, and the Questions and Answers section that follows most of them, are summarized here. There is adequate reason to suspect that perinatal exposures contribute to human cancer risk, both childhood cancers, and those appearing later in life. The latter type of risk may actually be quantitatively the more important, and involve a wide range of types of effects, but has received only limited attention. With regard to childhood cancers, fetal irradiation and diethylstilbestrol exposure are known etiological agents, and it is likely, but not yet certain, there are additional external causes of a portion of these. Some current focal points of interest here include nitroso compounds, DNA topoisomerase inhibitors, viruses, anti-AIDS drugs, and endocrine disruptors. Regulatory agencies must rely heavily on animal data for estimation of human risk due to perinatal exposures to chemicals, and the quantity and quality of these data presently available for this purpose are greatly limiting. Correctly designed conventional animal studies with suspect chemicals are still needed. Furthermore, genetically engineered mouse models for childhood cancers, especially medulloblastoma, have become available, and could be used for screening of candidate causative agents for this cancer type, and for better understanding of gene-environment interactions. Published by Elsevier Inc. C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Anderson, LM (reprint author), NCI, Comparat Carcinogenesis Lab, Bldg 538,Ft Detrick, Frederick, MD 21702 USA. EM Andersol@mail.neifcrf.gov NR 28 TC 26 Z9 26 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 1 PY 2004 VL 199 IS 2 BP 85 EP 90 DI 10.1016/j.taap.2004.02.015 PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 849YF UT WOS:000223576900001 PM 15313581 ER PT J AU Newbold, RR AF Newbold, RR TI Lessons learned from perinatal exposure to diethylstilbestrol SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Review DE cancer; diethylstilbestrol; environmental estrogens; estrogen receptor; trans-generational carcinogenesis; transplacental carcinogenesis; perinatal exposure; endocrine disruptors ID ADENOSIS-LIKE LESIONS; REPRODUCTIVE-TRACT; ESTROGEN-RECEPTOR; MOUSE UTERUS; UTERINE ADENOCARCINOMA; DEVELOPMENTAL EXPOSURE; NEONATAL EXPOSURE; PRENATAL EXPOSURE; RETE TESTIS; FEMALE MICE AB The synthetic estrogen diethylstilbestrol (DES) is well documented to be a perinatal carcinogen in both humans and experimental animals. Exposure to DES during critical periods of differentiation permanently alters the programming of estrogen target tissues resulting in benign and malignant abnormalities in the reproductive tract later in life. Using the perinatal DES-exposed rodent model, cellular and molecular mechanisms have been identified that play a role in these carcinogenic effects. Although DES is a potent estrogenic chemical, effects of low doses of the compound are being used to predict health risks of weaker environmental estrogens. Therefore, it is of particular interest that developmental exposure to very low doses of DES has been found to adversely affect fertility and to increase tumor incidence in murine reproductive tract tissues. These adverse effects are seen at environmentally relevant estrogen dose levels. New studies from our lab verify that DES effects are not unique; when numerous environmental chemicals with weak estrogenic activity are tested in the experimental neonatal mouse model, developmental exposure results in an increased incidence of benign and malignant tumors including uterine leiomyomas and adenocarcinomas that are similar to those shown following DES exposure. Finally, growing evidence in experimental animals suggests that some adverse effects can be passed on to subsequent generations, although the mechanisms involved in these transgenerational events remain unknown. Although the complete spectrum of risks to DES-exposed humans are uncertain at this time, the scientific community continues to learn more about cellular and molecular mechanisms by which perinatal carcinogenesis occurs. These advances in knowledge of both genetic and epigenetic mechanisms will be significant in ultimately predicting risks to other environmental estrogens and understanding more about the role of estrogens in normal and abnormal development. Published by Elsevier Inc. C1 NIEHS, Dev Endocrinol Sect, Mol Toxicol Lab, Environm Toxicol Program,Div Intramural Res, Res Triangle Pk, NC 27709 USA. RP Newbold, RR (reprint author), NIEHS, Dev Endocrinol Sect, Mol Toxicol Lab, Environm Toxicol Program,Div Intramural Res, Mail Drop E4-02, Res Triangle Pk, NC 27709 USA. EM newbold1@niehs.nih.gov NR 61 TC 163 Z9 170 U1 4 U2 14 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 SEP 1 PY 2004 VL 199 IS 2 BP 142 EP 150 DI 10.1016/j.taap.2003.11.033 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 849YF UT WOS:000223576900006 PM 15313586 ER PT J AU Poirier, MC Olivero, OA Walker, DM Walker, VE AF Poirier, MC Olivero, OA Walker, DM Walker, VE TI Perinatal genotoxicity and carcinogenicity of anti-retroviral nucleoside analog drugs SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Review DE HIV/AIDS; zidovudine (AZT); lamivudine (3TC); combivir; NRTIs; fetus; mice; monkey; DNA incorporation; mutagenesis; tumor; telomere shortening; newborn; infant ID HUMAN-IMMUNODEFICIENCY-VIRUS; TERM RHESUS MACAQUES; EXPOSED IN-UTERO; DNA INCORPORATION; 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE AZT; 3'-AZIDO-3'-DEOXYTHYMIDINE AZT; PREFERENTIAL INCORPORATION; ZIDOVUDINE TREATMENT; MUTANT FREQUENCY; CHILDHOOD-CANCER AB The current worldwide spread of the human immunodeficiency virus-1 (HIV-1) to the heterosexual population has resulted in approximately 800000 children born yearly to HIV-1-infected mothers. In the absence of anti-retroviral intervention, about 25% of the approximately 7000 children born yearly to HIV-1-infected women in the United States are HIV-1 infected. Administration of zidovudine (AZT) prophylaxis during pregnancy reduces the rate of infant HIV-1 infection to approximately 7%, and further reductions are achieved with the addition of lamivudine (3TC) in the clinical formulation Combivir. Whereas clinically this is a remarkable achievement, AZT and 3TC are DNA replication chain terminators known to induce various types of genotoxicity. Studies in rodents have demonstrated AZT-DNA incorporation, HPRT mutagenesis, telomere shortening, and tumorigenicity in organs of fetal mice exposed transplacentally to AZT. In monkeys, both AZT and 3TC become incorporated into the DNA from multiple fetal organs taken at birth after administration of human-equivalent protocols to pregnant dams during gestation, and telomere shortening has been found in monkey fetuses exposed to both drugs. In human infants, AZT-DNA and 3TC-DNA incorporation as well as HPRT and GPA mutagenesis have been documented in cord blood from infants exposed in utero to Combivir. In infants of mice, monkeys, and humans, levels of AZT-DNA incorporation were remarkably similar, and in newborn mice and humans, mutation frequencies were also very similar. Given the risk-benefit ratio, these highly successful drugs will continue to be used for prevention of vertical viral transmission, however evidence of genotoxicity in mouse and monkey models and in the infants themselves would suggest that exposed children should be followed well past adolescence for early detection of potential cancer hazard. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, Carcinogen DNA Interact Sect, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Lovelace Resp Res Inst, Albuquerque, NM 87108 USA. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, Canc Res Ctr, NIH, Bldg 37 Room 4032,37 Convent Dr,MSC-4255, Bethesda, MD 20892 USA. EM poirierm@exchange.nih.gov FU NCI NIH HHS [R01 CA95741]; NICHD NIH HHS [R01 HD33648] NR 60 TC 81 Z9 88 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 SEP 1 PY 2004 VL 199 IS 2 BP 151 EP 161 DI 10.1016/j.taap.2003.11.034 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 849YF UT WOS:000223576900007 PM 15313587 ER PT J AU Anderson, LM AF Anderson, LM TI Predictive values of traditional animal bioassay studies for human perinatal carcinogenesis risk determination SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Review DE human permatal carcinogenesis; animal bioassay studies; human ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CLEAR-CELL ADENOCARCINOMA; DIETHYLSTILBESTROL IN-UTERO; FETAL MOUSE SUSCEPTIBILITY; CHILDRENS CANCER GROUP; GENETIC POLYMORPHISMS; PRENATAL EXPOSURE; INFANT LEUKEMIA; X-IRRADIATION; DNA-DAMAGE AB The many physiological, biochemical, and structure differences between rodents and humans, especially with regard to gestation and fetal development, invite questions as to the utility of rodent models for the prediction of risk of perinatal carcinogenesis in humans and for extrapolation of mechanistic studies. Here, the relevance of basic generalities, derived from rodent perinatal studies, to human contexts is considered. The cross-species usefulness of these generalities was upheld by the example of carcinogen activation and detoxification as determining factors. These have been established in rodent studies and recently indicted in humans by investigations of genetic polymorphisms in cytochromes P450, N-acetyltransferase, mycloperoxidase, quinone reductase, and glutathione S-transferase. Also, published data have been analyzed comparatively for diethylstilbestrol and irradiation, the two known human transplacental carcinogenic agents. At similar doses to those experienced by humans, both diethylstilbestrol and X- and gamma-irradiation in rodents and dogs yielded increased tumors at rates similar to those for humans. In rodents, there was a clearly negative relationship between total diethylstilbestrol dose and tumors per dose unit, and a similar pattern was suggested for radiation. Diethylstilbestrol had transgenerational effects that did not diminish over three generations. Overall, this analysis of the published literature indicates that there are basic qualitative and quantitative similarities in the responsiveness of human and rodent fetuses to carcinogens, and that dose effects may be complex and in need of further investigation. Published by Elsevier Inc. C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Anderson, LM (reprint author), NCI, Comparat Carcinogenesis Lab, Bldg 538, Frederick, MD 21702 USA. EM Andersol@mail.ncifcrf.gov NR 102 TC 20 Z9 21 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 1 PY 2004 VL 199 IS 2 BP 162 EP 174 DI 10.1016/j.taap.2004.02.008 PG 13 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 849YF UT WOS:000223576900008 PM 15313588 ER PT J AU Huizing, M Hess, R Dorward, H Claassen, DA Helip-Wooley, A Kleta, R Kaiser-Kupfer, MI White, JG Gahl, WA AF Huizing, M Hess, R Dorward, H Claassen, DA Helip-Wooley, A Kleta, R Kaiser-Kupfer, MI White, JG Gahl, WA TI Cellular, molecular and clinical characterization of patients with Hermansky-Pudlak syndrome type 5 SO TRAFFIC LA English DT Article DE gene-dosage polymerase chain reaction (PCR); Hermansky-Pudlak syndrome (HPS); lysosome-related organelle; melanosome; organelle biogenesis; platelet dense granule ID LYSOSOME-RELATED ORGANELLES; PROTEIN COMPLEX; OCULOCUTANEOUS ALBINISM; HEMORRHAGIC DIATHESIS; PULMONARY-FIBROSIS; VESICLE FORMATION; BETA-3A SUBUNIT; GENE; MUTATIONS; ADAPTER AB Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelles such as melanosomes and platelet dense granules. Seven genes are now associated with HPS in humans. An accurate diagnosis of each HPS subtype has important prognostic and treatment implications. Here we describe the cellular, molecular, and clinical aspects of the recently identified HPS-5 subtype. We first analyzed the genomic organization and the RNA expression pattern of HPS5, located on chromosome 11p14, and demonstrated tissue-specific expression of at least three alternatively spliced HPS5 mRNA transcripts, coding for HPS5A and HPS5B proteins, that differ at their 5'-ends. Genetic screening of 15 unassigned HPS patients yielded six new HPS5 mutations in four patients. Clinically, our HPS-5 patients exhibited iris transillumination, variable hair and skin pigmentation, and absent platelet dense bodies, but not pulmonary fibrosis or granulomatous colitis. In two patients with homozygous missense mutations, hemizygosity was ruled out by gene-dosage multiplex polymerase chain reaction, and immunocytochemical analyses of their fibroblasts supported the HPS-5 diagnosis. Specifically, LAMP-3 distribution was restricted to the perinuclear region in HPS-5 fibroblasts, in contrast to the normal LAMP-3 distribution, which extended to the periphery. This specific intracellular vesicle distribution in fibroblasts, in combination with the clinical features, will improve the characterization of the HPS-5 subtype. C1 NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. NEI, Off Rare Dis, Intramural Program, NIH, Bethesda, MD 20892 USA. NEI, Ophthalm Genet & Clin Serv Branch, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA. RP Huizing, M (reprint author), NHGRI, Sect Human Biochem Genet, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM mhuizing@mail.nih.gov NR 41 TC 34 Z9 36 U1 1 U2 1 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1398-9219 J9 TRAFFIC JI Traffic PD SEP PY 2004 VL 5 IS 9 BP 711 EP 722 DI 10.1111/j.1600-0854.2004.00208.x PG 12 WC Cell Biology SC Cell Biology GA 843TU UT WOS:000223110300007 PM 15296495 ER PT J AU Patel, HD Byrne, KM Horne, M Leitman, SF Stroncek, DF AF Patel, HD Byrne, KM Horne, M Leitman, SF Stroncek, DF TI Factors affecting the formations of white particulate matter SO TRANSFUSION LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 23-26, 2004 CL Baltimore, MD SP Amer Assoc Blood Banks C1 NIH, Bethesda, MD 20892 USA. NR 0 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 SEP PY 2004 VL 44 IS 9 SU S BP 72A EP 73A PG 2 WC Hematology SC Hematology GA 849XS UT WOS:000223575600243 ER PT J AU Illoh, OC Greb, BL Davis, JM Illoh, K AF Illoh, OC Greb, BL Davis, JM Illoh, K TI Flow cytometric analysis of chemokine receptor expression on lymphocytes in packed red cell units SO TRANSFUSION LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 23-26, 2004 CL Baltimore, MD SP Amer Assoc Blood Banks C1 Univ Virginia, Med Ctr, Charlottesville, VA USA. NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. NR 0 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 SEP PY 2004 VL 44 IS 9 SU S BP 74A EP 74A PG 1 WC Hematology SC Hematology GA 849XS UT WOS:000223575600249 ER PT J AU Gao, G Leparc, GF Nemo, G Tabor, E AF Gao, G Leparc, GF Nemo, G Tabor, E TI Absence of Chlamydia pneumoniae DNA in normal blood donors SO TRANSFUSION LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 23-26, 2004 CL Baltimore, MD SP Amer Assoc Blood Banks C1 US FDA, CBER, Rockville, MD 20857 USA. Florida Blood Serv, St Petersburg, FL USA. NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 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 SEP PY 2004 VL 44 IS 9 SU S BP 97A EP 97A PG 1 WC Hematology SC Hematology GA 849XS UT WOS:000223575600334 ER PT J AU Atkins, JW Sullivan, J Gibble, J Cantilena, C Sandler, SG AF Atkins, JW Sullivan, J Gibble, J Cantilena, C Sandler, SG TI A community approach to implementing a multi-faceted AABB standard SO TRANSFUSION LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 23-26, 2004 CL Baltimore, MD SP Amer Assoc Blood Banks C1 NIH, Bethesda, MD 20892 USA. Amer Assoc Blood Banks, Bethesda, MD USA. Amer Red Cross, Baltimore, MD USA. Amer Red Cross, Bethesda, MD USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. NR 0 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 SEP PY 2004 VL 44 IS 9 SU S BP 176A EP 177A PG 2 WC Hematology SC Hematology GA 849XS UT WOS:000223575600605 ER PT J AU Tudisco, CT Jett, BW Atkins, JW Byrne, K Oblitas, JM Leitman, SF Stroncek, DF AF Tudisco, CT Jett, BW Atkins, JW Byrne, K Oblitas, JM Leitman, SF Stroncek, DF TI pH as a quality control indicator for apheresis platelets SO TRANSFUSION LA English DT Meeting Abstract CT 57th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 23-26, 2004 CL Baltimore, MD SP Amer Assoc Blood Banks C1 NIH, Bethesda, MD 20892 USA. NR 0 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 SEP PY 2004 VL 44 IS 9 SU S BP 178A EP 178A PG 1 WC Hematology SC Hematology GA 849XS UT WOS:000223575600609 ER PT J AU Stroncek, DF Byrne, KM Noguchi, CT Schechter, AN Leitman, SE AF Stroncek, DF Byrne, KM Noguchi, CT Schechter, AN Leitman, SE TI Increasing hemoglobin oxygen saturation levels in sickle trait donor whole blood prevents hemoglobin S polymerization and allows effective white blood cell reduction by filtration SO TRANSFUSION LA English DT Article ID WBC REDUCTION; COMPONENTS AB BACKGROUND: Red blood cell (RBC) components from donors with sickle cell trait (Hb AS) often occlude white blood cell (WBC) reduction filters. Techniques were investigated to successfully filter Hb AS donor blood by increasing the Hb oxygen saturation with storage bags and conditions suitable for transfusion products. STUDY DESIGN AND METHODS: Oxygenation kinetics were measured over 3 days in whole-blood units stored in standard-sized 600-mL polyvinylchloride (PVC) bags and whole-blood units divided into three equal parts and stored in standard-sized blood bags made from PVC, tri2-(ethylhexyl)trimellitate (CLX) plastic, or Teflon. The filterability of Hb AS blood stored for 3 days was tested with whole-blood filters. RESULTS: Oxygen saturation levels did not increase in full whole-blood units from donors without sickle cell trait during 3 days of storage in 600-mL PVC bags. In divided Hb AS whole-blood units stored for 3 days, oxygen saturation levels increased from baseline levels of 45 to 56, 66, and 94 percent after storage in 600-mL PVC, CLX, and Teflon bags, respectively (n = 5, p < 0.02), and all components filtered completely. When full Hb AS whole-blood units from eight donors were stored for 3 days in 1.5-L CLX bags, all units filtered completely, but one had a high residual WBC count. CONCLUSION: Storage of Hb AS whole blood in large-capacity oxygen-permeable bags increases oxygen tension and allows more effective WBC reduction by filtration. C1 NIDDK, Dept Transfus Med, Warren G Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. NIDDK, Biol Chem Lab, NIH, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIDDK, Dept Transfus Med, Warren G Magnuson Clin Ctr, NIH, Bldg 10,Room 1C711,10 Ctr Dr,MSC-1184, Bethesda, MD 20892 USA. EM dstroncek@mail.cc.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 NR 12 TC 9 Z9 9 U1 0 U2 1 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2004 VL 44 IS 9 BP 1293 EP + DI 10.1111/j.0041-1132.2004.04086.x PG 8 WC Hematology SC Hematology GA 849XO UT WOS:000223575100005 PM 15318851 ER PT J AU Elster, EA Hale, DA Mannon, RB Cendales, LC Swanson, SJ Kirk, AD AF Elster, EA Hale, DA Mannon, RB Cendales, LC Swanson, SJ Kirk, AD TI The road to tolerance: renal transplant tolerance induction in nonhuman primate studies and clinical trials SO TRANSPLANT IMMUNOLOGY LA English DT Article DE tolerance; costimulation blockade; lymphocyte depletion; mixed chimerism ID REGULATORY T-CELLS; DOSE CYCLOSPORINE MONOTHERAPY; DONOR BONE-MARROW; ALLOGRAFT TOLERANCE; MONOCLONAL-ANTIBODY; MIXED CHIMERISM; LYMPHOHEMATOPOIETIC CHIMERISM; KIDNEY-TRANSPLANTATION; CARDIAC ALLOGRAFTS; MULTIPLE-MYELOMA AB Organ transplantation has become a standard life-saving therapy for many causes of end stage organ failure. Although valuable, it remains hampered by the requirement for, and complications of, immunosuppression to prevent immune rejection of the transplanted organ. It is now clear that rejection can be avoided in some experimental systems without a requirement of immunosuppressive medication, and these experimental concepts are now making their way into the clinic in the form of early transplantation tolerance trials. This manuscript will discuss the most promising techniques for tolerance induction, namely, costimulation blockade, lymphocyte depletion, and mixed chimerism. Seminal preclinical studies will be cited and the results of initial clinical trials will be reviewed. The data to date indicate that while tolerance remains elusive, immunosuppression minimization is a feasible near-term alternative. Published by Elsevier B.V. C1 NIDDKD, Dept Hlth & Human Serv, Transplantat Branch, NIH, Bethesda, MD 20892 USA. USN, Naval Med Res Ctr, Radiat & Combat Repair Dept, Washington, DC USA. USA, Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC USA. RP Kirk, AD (reprint author), Room 11s219,Bldg 10 Ctr Dr, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 NR 84 TC 28 Z9 30 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0966-3274 J9 TRANSPL IMMUNOL JI Transpl. Immunol. PD SEP-OCT PY 2004 VL 13 IS 2 BP 87 EP 99 DI 10.1016/j.trim.2004.05.010 PG 13 WC Immunology; Transplantation SC Immunology; Transplantation GA 859QJ UT WOS:000224282700003 PM 15380539 ER PT J AU Wu, LG AF Wu, LG TI Kinetic regulation of vesicle endocytosis at synapses SO TRENDS IN NEUROSCIENCES LA English DT Review ID FROG NEUROMUSCULAR-JUNCTION; RETINAL BIPOLAR CELLS; SINGLE PRESYNAPTIC BOUTONS; READILY RELEASABLE POOL; MOTOR-NERVE TERMINALS; KISS-AND-RUN; SYNAPTIC VESICLES; HIPPOCAMPAL SYNAPSES; TRANSMITTER RELEASE; CALCIUM-DEPENDENCE AB Studies from a variety of synapses indicate that the time course of endocytosis ranges from less than a second to hundreds of seconds. This raises questions about how the time course of endocytosis is regulated and why different rates of endocytosis are needed. Recent progress sheds light on these issues. Neuronal firing frequency and duration determine the time course of endocytosis. The dynamic nature of this time course could be a result of multiple endocytic pathways and/or of regulation by a variety of modulators. Because endocytosis is crucial for maintaining transmitter release during repetitive stimulation, regulation of endocytosis could thus provide a mechanism by which synaptic plasticity is achieved. C1 NINDS, Bethesda, MD 20892 USA. RP Wu, LG (reprint author), NINDS, 36 Convent Dr,Bldg 36,Room 1C12, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov NR 66 TC 41 Z9 43 U1 1 U2 6 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD SEP PY 2004 VL 27 IS 9 BP 548 EP 554 DI 10.1016/j.tins.2004.07.001 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 854XN UT WOS:000223937300009 PM 15331237 ER PT J AU Rosenthal, I Sostaric, JZ Riesz, P AF Rosenthal, I Sostaric, JZ Riesz, P TI Sonodynamic therapy - a review of the synergistic effects of drugs and ultrasound SO ULTRASONICS SONOCHEMISTRY LA English DT Review DE ultrasound; sonochemistry; acoustic cavitation; sonodynamic therapy; sonosensitizer; free radical; cancer ID INDUCED CELL-DAMAGE; HEMOLYSIS IN-VITRO; GALLIUM-PORPHYRIN COMPLEX; FREE-RADICAL GENERATION; LOW-LEVEL ULTRASOUND; AQUEOUS-SOLUTIONS; PHOTOFRIN-II; HIGH-INTENSITY; FOCUSED ULTRASOUND; HYDROGEN-PEROXIDE AB Sonodynamic therapy, the ultrasound dependent enhancement of cytotoxic activities of certain compounds (sonosensitizers) in studies with cells in vitro and in tumor bearing animals, is reviewed. The attractive features of this modality for cancer treatment emerges from the ability to focus the ultrasound energy on malignancy sites buried deep in tissues and to locally activate a preloaded sonosensitizer. Possible mechanisms of sonodynamic therapy include generation of sonosensitizer derived radicals which initiate chain peroxidation of membrane lipids via peroxyl and/or alkoxyl radicals, the physical destabilization of the cell membrane by the sonosensitizer thereby rendering the cell more susceptible to shear forces or ultrasound enhanced drug transport across the cell membrane (sonoporation). Evidence against the role of singlet oxygen in sonodynamic therapy is discussed. The mechanism of sonodynamic therapy is probably not governed by a universal mechanism, but may be influenced by multiple factors including the nature of the biological model, the sonosensitizer and the ultrasound parameters. The current review emphasizes the effect of ultrasound induced free radicals in sonodynamic therapy. Published by Elsevier B.V. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Agr Res Org, Volcani Ctr, Dept Food Sci, IL-50250 Bet Dagan, Israel. RP Riesz, P (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. EM rieszp@mail.nih.gov RI Sostaric, Joe/A-6033-2008 NR 116 TC 279 Z9 308 U1 15 U2 112 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1350-4177 J9 ULTRASON SONOCHEM JI Ultrason. Sonochem. PD SEP PY 2004 VL 11 IS 6 BP 349 EP 363 DI 10.1016/j.ultsonch.2004.03.004 PG 15 WC Acoustics; Chemistry, Multidisciplinary SC Acoustics; Chemistry GA 849IK UT WOS:000223531700002 PM 15302020 ER PT J AU Gelderblom, H Martin, R Marques, AR AF Gelderblom, H Martin, R Marques, AR TI Research opportunities on human neuroborreliosis SO VECTOR-BORNE AND ZOONOTIC DISEASES LA English DT Article DE Borrelia burgdorferi; central nervous system; neuroborreliosis ID LINKED-IMMUNOSORBENT-ASSAY; BORRELIA-BURGDORFERI LIPOPROTEINS; IMMUNODOMINANT CONSERVED REGION; EXPERIMENTAL LYME ARTHRITIS; NERVOUS-SYSTEM INFECTION; MOTOR-NEURON DISEASE; SURFACE PROTEIN-A; MULTIPLE-SCLEROSIS; PENICILLIN-G; T-CELLS AB A workshop, sponsored by the National Institutes of Health, was convened in September 2001 to evaluate the current knowledge in neurological Lyme disease. The meeting was centered into discussion of both clinical and basic aspects of the disease. Participants included researchers from the fields of infectious diseases, neurology, rheumatology, autoinununity and basic immunology, largely but not exclusively focused on Lyme disease. This report summarizes the presentations made at the meeting. C1 NIAID, Clin Studies Unit, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. NINDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD USA. RP Marques, AR (reprint author), NIAID, Clin Studies Unit, Lab Clin Infect Dis, NIH, Bldg 10,Room 11N228,10 Ctr Dr MSC 1888, Bethesda, MD 20892 USA. EM amarques@niaid.nih.gov NR 82 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 1530-3667 J9 VECTOR-BORNE ZOONOT JI Vector-Borne Zoonotic Dis. PD FAL PY 2004 VL 4 IS 3 BP 261 EP 272 PG 12 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 858IV UT WOS:000224186400011 PM 15631071 ER PT J AU Ober, CP Spaulding, K Breitschwerdt, EB Malarkey, DE Hegarty, BC AF Ober, CP Spaulding, K Breitschwerdt, EB Malarkey, DE Hegarty, BC TI Orchitis in two dogs with Rocky Mountain spotted fever SO VETERINARY RADIOLOGY & ULTRASOUND LA English DT Article DE orchitis; rickettsia; testicle; ultrasound ID RICKETTSIA-RICKETTSII; INFLAMMATORY DISEASE; SONOGRAPHIC FEATURES; ULTRASOUND; SCROTUM; ULTRASONOGRAPHY; EPIDIDYMITIS; EHRLICHIOSIS; INFECTION; EFFICACY AB Two dogs with testicular swelling were sonographically diagnosed with orchitis and were subsequently diagnosed with Rocky Mountain spotted fever (RMSF). Use of both gray scale and color Doppler sonography allowed for differentiation of orchitis from neoplasia and torsion. While only experimentally induced RMSF is reported to cause orchitis in dogs, it should be considered in any dog with vascular insult to the testes, especially when other signs of systemic illness are involved. C1 N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27606 USA. N Carolina State Univ, Coll Vet Med, Dept Clin Sci, Raleigh, NC 27606 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. RP Spaulding, K (reprint author), N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, 4700 Hillsborough St, Raleigh, NC 27606 USA. EM kathy_spaulding@ncsu.cdu NR 28 TC 4 Z9 4 U1 1 U2 4 PU AMER COLL VETERINARY RADIOLOGY PI RALEIGH PA 2520 BEECHRIDGE RD, RALEIGH, NC 27608 USA SN 1058-8183 J9 VET RADIOL ULTRASOUN JI Vet. Radiol. Ultrasound PD SEP-OCT PY 2004 VL 45 IS 5 BP 458 EP 465 DI 10.1111/j.1740-8261.2004.04079.x PG 8 WC Veterinary Sciences SC Veterinary Sciences GA 856MD UT WOS:000224048400011 PM 15487571 ER PT J AU Nouraie, M Pourshams, A Kamangar, F Sotoudeh, M Derakhshan, MH Akbari, MR Fakheri, H Zahedi, MJ Caldwell, K Abnet, CC Taylor, PR Malekzadeh, R Dawsey, SM AF Nouraie, Mehdi Pourshams, Akram Kamangar, Farin Sotoudeh, Masood Derakhshan, Mohammad Hossein Akbari, Mohammad Reza Fakheri, Hafez Zahedi, Mohammad Javad Caldwell, Kathleen Abnet, Christian C. Taylor, Philip R. Malekzadeh, Reza Dawsey, Sanford M. TI Ecologic study of serum selenium and upper gastrointestinal cancers in Iran SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article AB AIM: Both observational and experimental studies have shown that higher selenium status reduces the risk of upper gastrointestinal cancers in selenium deficient populations. Recent cancer registry data have shown very different rates of esophageal cancer (EC) and gastric cancer (GC) in four Provinces of Iran, namely Ardabil, Mazandaran, Golestan, and Kerman. The aim of this study was to have a preliminary assessment of the hypothesis that high rates of EC in Golestan and high rates of GC in Ardabil may be partly attributable to selenium deficiency. METHODS: We measured serum selenium in 300 healthy adults from Ardabil (n = 100), Mazandaran (n = 50), Golestan (n = 100), and Kerman (n = 50), using inductively coupled plasma, with dynamic reaction cell, mass spectrometry (ICP-DRC-MS) at the US Centers for Disease Control (Atlanta, Georgia). RESULTS: The median serum selenium concentrations were very different in the four Provinces. The medians (IQR) for selenium in Ardabil, Mazandarn, Golestan, and Kerman were 82 (75-94), 123 (111-132), 155 (141-173), and 119 (110-128) mu g/L, respectively (P<0.001). The results of linear regression showed that the Province variable, by itself, explained 76% of the variance in log selenium (r(2) = 0.76). The proportion of the populations with a serum selenium more than 90 mu g/L (the concentration at which serum selenoproteins are saturated) was 100% in Golestan, Kerman, and Mazandaran but only 29% in Ardabil. CONCLUSION: Our findings suggest that selenium deficiency is not a major contributor to the high incidence of EC seen in northeastern Iran, but it may play a role in the high incidence of GC in Ardabil Province. C1 [Dawsey, Sanford M.] NCI, Canc Prevent Studies Branch, CCR, NIH, Bethesda, MD 20895 USA. [Nouraie, Mehdi; Pourshams, Akram; Sotoudeh, Masood; Derakhshan, Mohammad Hossein; Akbari, Mohammad Reza; Fakheri, Hafez; Zahedi, Mohammad Javad; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Ctr, Tehran, Iran. [Caldwell, Kathleen] Ctr Dis Control, Atlanta, GA 30333 USA. RP Dawsey, SM (reprint author), NCI, Canc Prevent Studies Branch, CCR, NIH, 6116 Execut Blvd,Suite 705, Bethesda, MD 20895 USA. EM dawseys@mail.nih.gov RI Abnet, Christian/C-4111-2015; Derakhshan, Mohammad/K-8694-2016; OI Abnet, Christian/0000-0002-3008-7843; Malekzadeh, Reza/0000-0003-1043-3814 NR 17 TC 6 Z9 6 U1 0 U2 1 PU BAISHIDENG PUBL GRP CO LTD PI BEIJING PA RM 903, BLDG D, OCEAN INTERNATIONAL CTR, NO 62 DONGSIHUAN ZHONGLU, BEIJING, CHAOYANG DISTRICT 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD SEP 1 PY 2004 VL 10 IS 17 BP 2544 EP 2546 PG 3 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V19UI UT WOS:000208096900017 ER PT J AU Lloyd-Jones, DM Wang, TJ Leip, EP Larson, MG Levy, D Vasan, RS D'Agostino, RB Massaro, JM Beiser, A Wolf, PA Benjamin, EJ AF Lloyd-Jones, DM Wang, TJ Leip, EP Larson, MG Levy, D Vasan, RS D'Agostino, RB Massaro, JM Beiser, A Wolf, PA Benjamin, EJ TI Lifetime risk for development of atrial fibrillation - The Framingham Heart Study SO CIRCULATION LA English DT Article DE atrial fibrillation; epidemiology; risk factors ID QUALITY-OF-LIFE; RHYTHM CONTROL; FOLLOW-UP; TRENDS; POPULATION; DISEASE; HYPERTENSION; PREVALENCE; COMMUNITY; FAILURE AB Background-Atrial fibrillation (AF) is the most common cardiac dysrhythmia and a source of considerable morbidity and mortality, but lifetime risk for AF has not been estimated. Methods and Results-We included all participants in the Framingham Heart Study who were free of AF at index ages of 40 years and older. We estimated lifetime risks for AF (including atrial flutter) to age 95 years, with death free of AF as a competing event. We followed 3999 men and 4726 women from 1968 to 1999 (176166 person-years); 936 participants had development of AF and 2621 died without prior AF. At age 40 years, lifetime risks for AF were 26.0% (95% CI, 24.0% to 27.0%) for men and 23.0% (21.0% to 24.0%) for women. Lifetime risks did not change substantially with increasing index age despite decreasing remaining years of life because AF incidence rose rapidly with advancing age. At age 80 years, lifetime risks for AF were 22.7% (20.1% to 24.1%) in men and 21.6% (19.3% to 22.7%) in women. In further analyses, counting only those who had development of AF without prior or concurrent congestive heart failure or myocardial infarction, lifetime risks for AF were approximately 16%. Conclusions-Lifetime risks for development of AF are 1 in 4 for men and women 40 years of age and older. Lifetime risks for AF are high (1 in 6), even in the absence of antecedent congestive heart failure or myocardial infarction. These substantial lifetime risks underscore the major public health burden posed by AF and the need for further investigation into predisposing conditions, preventive strategies, and more effective therapies. C1 Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. NHLBI, Framingham Heart Study, NIH, Framingham, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Cardiol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02118 USA. RP Lloyd-Jones, DM (reprint author), Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, 680 N Lake Shore Dr,Suite 1102, Chicago, IL 60611 USA. EM dlj@northwestern.edu RI Lloyd-Jones, Donald/C-5899-2009; OI Massaro, Joseph/0000-0002-2682-4812; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Beiser, Alexa/0000-0001-8551-7778 FU NHLBI NIH HHS [K23 HL04253, N01-HC-25195] NR 41 TC 820 Z9 874 U1 3 U2 29 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 31 PY 2004 VL 110 IS 9 BP 1042 EP 1046 DI 10.1161/01.CIR.0000140263.20897.42 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 850FD UT WOS:000223595700004 PM 15313941 ER PT J AU Ahmet, I Krawczyk, M Heller, P Moon, C Lakatta, EG Talan, MI AF Ahmet, I Krawczyk, M Heller, P Moon, C Lakatta, EG Talan, MI TI Beneficial effects of chronic pharmacological manipulation of beta-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy SO CIRCULATION LA English DT Article DE receptors,adrenergic, beta; heart failure; pharmacology; myocardial infarction; remodeling ID CARDIAC MYOCYTE APOPTOSIS; CONGESTIVE-HEART-FAILURE; MYOCARDIAL-INFARCTION; CELL-DEATH; METOPROLOL; BETA(2)-ADRENOCEPTOR; HYPERTROPHY; PROTEINS; STIMULATION; CARVEDILOL AB Background-Studies in isolated cardiac myocytes have demonstrated that signaling via specific beta(1)-adrenergic receptor subtypes (beta(1)ARs) promotes but that signaling via beta(2)ARs protects from cell death. We hypothesized that prolonged beta(2)AR stimulation or beta(1)AR blockade would each protect myocytes from death and thereby ameliorate cardiac remodeling in chronic heart failure. Methods and Results-A large myocardial infarction (MI) induced in rats by coronary artery ligation resulted in a dilated cardiomyopathy (DCM) characterized by infarct expansion and a progressive increase in left ventricular (LV) end-diastolic volume, accompanied by a reduction in ejection fraction (EF), as assessed by repeated echocardiography. Pressure-volume analysis at 8 weeks after ligation showed that diastolic stiffness (Eed) and arterial elastance (Ea) were increased, end-systolic elastance (Ees) was decreased, and arterioventricular (AV) coupling (Ea/Ees) had deteriorated. Apoptosis was present in both peri-infarct and remote myocardium. Chronic (6-week) administration of the beta(2)AR agonists fenoterol or zinterol, starting at 2 weeks after MI, reduced the extent of LV dilation, infarct expansion, and EF decline. The beta(1)AR blocker metoprolol did not affect the former and preserved EF to a lesser extent than did the beta(2)AR agonists. At 8 weeks after ligation, apoptosis was reduced by all drugs but to a greater extent by beta(2)AR agonists than by the beta(1)AR blocker. Both beta(2)AR agonists and the beta(1)AR blocker improved AV coupling, the former mainly by reducing Ea and the latter mainly by increasing Ees. Only the beta(2)AR agonists reduced the Eed and the MI size by reducing infarct expansion. Conclusions-These results provide proof of concept for the efficacy of chronic beta(2)AR stimulation in this DCM model. C1 NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Talan, MI (reprint author), NIA, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM talanm@grc.nia.nih.gov NR 24 TC 80 Z9 86 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 31 PY 2004 VL 110 IS 9 BP 1083 EP 1090 DI 10.1161/01.CIR.0000139844.15045.F9 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 850FD UT WOS:000223595700010 PM 15313944 ER PT J AU Seo, HR Kwan, YW Cho, CK Bae, S Lee, SJ Soh, JW Chung, HY Lee, YS AF Seo, HR Kwan, YW Cho, CK Bae, S Lee, SJ Soh, JW Chung, HY Lee, YS TI PKC alpha induces differentiation through ERK1/2 phosphorylation in mouse keratinocytes SO EXPERIMENTAL AND MOLECULAR MEDICINE LA English DT Article DE Ca(2+)-mediated differentiation; ERK1/2; mouse keratinocytes; p38 MAPK; PKC alpha ID PROTEIN-KINASE-C; EPIDERMAL-KERATINOCYTES; GENE-EXPRESSION; TUMOR PROMOTER; CELLS; CALCIUM; ACTIVATION; INDUCTION; 12-O-TETRADECANOYLPHORBOL-13-ACETATE; INVOLVEMENT AB Epidermal keratinocyte differentiation is a tightly regulated stepwise process that requires protein kinase C (PKC) activation. Studies on cultured mouse keraitnocytes induced to differentiate with Ca(2+) have indirectly implicated the involvement of PKCalpha isoform. When PKCalpha was overexpressed in undifferentiated keratinocytes using adenoviral system, expressions of differentiation markers such as loricrin, filaggrin, keratin 1 (MK1) and keratin 10 (MK10) were increased, and ERK1/2 phosphorylation was concurrently induced without change of other MAPK such as p38 MAPK and JNK1/2. Similarly, transfection of PKCalpha kinase active mutant (PKCalpha-CAT) in the undifferentiated keratinocyte, but not PKCbeta-CAT, also increased differentiation marker expressions. On the other hand, PKCa dominant negative mutant (PKCbeta-KR) reduced Ca(2+)-mediated differentiation marker expressions, while PKCbeta-KR did not, suggesting that PKCalpha is responsible for keratinocyte differentiation. When downstream pathway of PKCa in Ca(2+)- mediated differentiation was examined, ERK1/2, p38 MAPK and JNK1/2 phosphorylations were increased by Ca(2+) shift. Treatment of keratinocytes with PD98059, MEK inhibitor, and SB20358, p38 MAPK inhibitor, before Ca(2+) shift induced morphological changes and reduced expressions of differentiation markers, but treatment with SP60012, JNK1/2 inhibitor, did not change at all. Dominant negative mutants of ERK1/2 and p38 MAPK also inhibited the expressions of differentiation marker expressions in Ca(2+) shifted cells. The above results indicate that both ERK1/2 and p38 MAPK may be involved in Ca(2+)- mediated differentiation, and that only ERK1/2 pathway is specific for PKCalpha-mediated differentiation in mouse keratinocytes. C1 Korea Inst Radiol & Med Sci, Lab Radiat Effect, Seoul 139706, South Korea. NIADI, Immunopathol Lab, NIH, Rockville, MD USA. Inha Univ, Dept Chem, Inchon 402751, South Korea. Hanyang Univ, Coll Med, Dept Microbiol, Seoul 133791, South Korea. RP Lee, YS (reprint author), Korea Inst Radiol & Med Sci, Lab Radiat Effect, 215-4 Gongneung Dong, Seoul 139706, South Korea. EM yslee@kcch.re.kr NR 40 TC 22 Z9 22 U1 0 U2 2 PU KOREAN SOC MED BIOCHEMISTRY MOLECULAR BIOLOGY PI SEOUL PA #812 KOFST, 635-4 YOKSAM-DONG KANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1226-3613 J9 EXP MOL MED JI Exp. Mol. Med. PD AUG 31 PY 2004 VL 36 IS 4 BP 292 EP 299 PG 8 WC Biochemistry & Molecular Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Research & Experimental Medicine GA 855LJ UT WOS:000223974500002 PM 15365248 ER PT J AU Gaede, HC Luckett, KM Polozov, IV Gawrisch, K AF Gaede, HC Luckett, KM Polozov, IV Gawrisch, K TI Multinuclear NMR studies of single lipid bilayers supported in cylindrical aluminum oxide nanopores SO LANGMUIR LA English DT Article ID MAGNETIC-RESONANCE; LATERAL DIFFUSION; PHOSPHOLIPID-BILAYERS; PLANAR MEMBRANES; FORCE MICROSCOPY; ACYL-CHAIN; SURFACES; MODEL; WATER; SPECTROSCOPY AB Lipid bilayers were deposited inside the 0.2 mum pores of anodic aluminum oxide (AAO) filters by extrusion of multilamellar liposomes and their properties studied by H-2, P-31, and H-1 solid-state NMR. Only the first bilayer adhered strongly to the inner surface of the pores. Additional layers were washed out easily by a flow of water as demonstrated by H-1 magic angle spinning NMR experiments with addition of Pr3+ ions to shift accessible lipid headgroup resonances. A 13 mm diameter Anopore filter of 60 mum thickness oriented approximately 2.5 x 10(-7) mol of lipid as a single bilayer, corresponding to a total membrane area of about 500 cm(2). The 2H NMR spectra of chain deuterated POPC are consistent with adsorption of wavy, tubular bilayers to the inner pore surface. By NMR diffusion experiments, we determined the average length of those lipid tubules to be approximately 0.4 mum. There is evidence for a thick water layer between lipid tubules and the pore surface. The ends of tubules are well sealed against the pore such that Pr3+ ions cannot penetrate into the water underneath the bilayers. We successfully trapped poly(ethylene glycol) (PEG) with a molecular weight of 8000 in this water layer. From the quantity of trapped PEG, we calculated an average water layer thickness of 3 nm. Lipid order parameters and motional properties are unperturbed by the solid support, in agreement with existence of a water layer. Such unperturbed, solid supported membranes are ideal for incorporation of membrane-spanning proteins with large intra- and extracellular domains. The experiments suggest the promise of such porous filters as membrane support in biosensors. C1 NIAAA, Lab Membrance Biochem & Biophys, NIH, Rockville, MD 20852 USA. RP Gawrisch, K (reprint author), NIAAA, Lab Membrance Biochem & Biophys, NIH, Rockville, MD 20852 USA. EM gawrisch@helix.nih.gov RI Gaede, Holly/B-7392-2015 OI Gaede, Holly/0000-0003-4444-4394 NR 42 TC 40 Z9 42 U1 0 U2 16 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0743-7463 J9 LANGMUIR JI Langmuir PD AUG 31 PY 2004 VL 20 IS 18 BP 7711 EP 7719 DI 10.1021/la0493114 PG 9 WC Chemistry, Multidisciplinary; Chemistry, Physical; Materials Science, Multidisciplinary SC Chemistry; Materials Science GA 849UZ UT WOS:000223567900053 PM 15323523 ER PT J AU Carlson, BA Xu, XM Kryukov, GV Rao, M Berry, MJ Gladyshev, VN Hatfield, DL AF Carlson, BA Xu, XM Kryukov, GV Rao, M Berry, MJ Gladyshev, VN Hatfield, DL TI Identification and characterization of phosphoseryl-tRNA([Ser]Sec) kinase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SELENOCYSTEYL-TRANSFER RNA; PHOSPHOSERYL-TRANSFER RNA; GLOBIN READTHROUGH PROTEIN; SUPPRESSOR TRANSFER-RNA; RABBIT BETA-GLOBIN; SELENOPROTEIN SYNTHESIS; ESCHERICHIA-COLI; MAMMALIAN-CELLS; COMPLETE GENOME; CODON AB In 1970, a kinase activity that phosphorylated a minor species of seryl-tRNA to form phosphoseryi-tRNA was found in rooster liver [Maenpaa, P. H. & Bernfield, M. R. (1970) Proc. Natl. Acad Sci. USA 67, 688-695], and a minor seryl-tRNA that decoded the nonsense UGA was detected in bovine liver. The phosphoseryl-tRNA and the minor UGA-decoding seryl-tRNA were subsequently identified as selenocysteine (Sec) tRNA([Ser]Sec), but the kinase activity remained elusive. Herein, by using a comparative genomics approach that searched completely sequenced archaeal genomes for a kinase-like protein with a pattern of occurrence similar to that of components of Sec insertion machinery, we detected a candidate gene for mammalian phosphoseryl-tRNA([Ser]Sec) kinase (pstk). Mouse pstk was cloned, and the gene product (PSTK) was expressed and characterized. PSTK specifically phosphorylated the seryl moiety on seryl-tRNA([Ser]Sec) and, in addition, had a requirement for ATP and Mg2+. Proteins with homology to mammalian PSTK occur in Drosophila, Caenorhabditis elegans, Methanopyrus kandleri, and Methanococcus jannaschii, suggesting a conservation of its f unction across archaea and eukaryotes that synthesize selenoproteins and the absence of this function in bacteria, plants, and yeast. The fact that PSTK has been highly conserved in evolution suggests that it plays an important role in selenoprotein biosynthesis and/or regulation. C1 NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. Univ Hawaii Manoa, Dept Cell & Mol Biol, Honolulu, HI 96822 USA. Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Hatfield, DL (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. EM hatfield@dc37a.nci.nih.gov RI Kryukov, Gregory/A-9592-2008; Gladyshev, Vadim/A-9894-2013 FU NIGMS NIH HHS [GM061603, R01 GM061603] NR 29 TC 100 Z9 104 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 31 PY 2004 VL 101 IS 35 BP 12848 EP 12853 DI 10.1073/pnas.0402636101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 851OP UT WOS:000223694700015 PM 15317934 ER PT J AU Reilly, KM Tuskan, RG Christy, E Loisel, DA Ledger, J Bronson, RT Smith, CD Tsang, S Munroe, DJ Jacks, T AF Reilly, KM Tuskan, RG Christy, E Loisel, DA Ledger, J Bronson, RT Smith, CD Tsang, S Munroe, DJ Jacks, T TI Susceptibility to astrocytoma in mice mutant for Nf1 and Trp53 is linked to chromosome 11 and subject to epigenetic effects SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LI-FRAUMENI-SYNDROME; NEUROFIBROMATOSIS TYPE-1; IMPRINTED GENE; HUMAN GRB10; STEM-CELLS; TUMORS; P53; HETEROZYGOSITY; IDENTIFICATION; MEG1/GRB10 AB Astrocytoma is the most common malignant brain tumor in humans. Loss of the p53 signaling pathway and up-regulation of the ras signaling pathway are common during tumor progression. We have shown previously that mice mutant for Trp53 and NO develop astrocytoma, progressing to glioblastoma, on a C57BL/6J strain background. In contrast, here we present data that mice mutant for Trp53 and Nf1 on a 129S4/SvJae background are highly resistant to developing astrocytoma. Through analysis of F-1 progeny, we demonstrate that susceptibility to astrocytoma is linked to chromosome 11, and that the modifier gene(s) responsible for differences in susceptibility is closely linked to Nf1 and Trp53. Furthermore, this modifier of astrocytoma susceptibility is itself epigenetically modified. These data demonstrate that epigenetic effects can have a strong effect on whether cancer develops in the context of mutant ras signaling and mutant p53, and that this mouse model of astrocytoma can be used to identify modifier phenotypes with complex inheritance patterns that would be unidentifiable in humans. Because analysis of gene function in the mouse is often performed on a mixed C57BL/6,129 strain background, these data also provide a powerful example of the potential of these strains to mask interesting gene functions. C1 NCI, Mouse Canc Genet Program, Ft Detrick, MD 21702 USA. MIT, Dept Biol, Cambridge, MA 02169 USA. MIT, Ctr Canc Res, Cambridge, MA 02169 USA. MIT, Howard Hughes Med Inst, Cambridge, MA 02169 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Sci Applicat Int Corp, Lab Anim Sci Program, Ft Detrick, MD 21702 USA. Sci Applicat Int Corp, Lab Mol Technol, Ft Detrick, MD 21702 USA. RP Reilly, KM (reprint author), NCI, Mouse Canc Genet Program, Ft Detrick, MD 21702 USA. EM kreilly@ncifcrf.gov RI Loisel, Dagan/A-6671-2010 FU NCI NIH HHS [N01CO12400, N01-CO-12400] NR 33 TC 63 Z9 64 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 31 PY 2004 VL 101 IS 35 BP 13008 EP 13013 DI 10.1073/pnas.0401236101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 851OP UT WOS:000223694700043 PM 15319471 ER PT J AU Staprans, SI Barry, AP Silvestri, G Safrit, JT Kozyr, N Sumpter, B Nguyen, H McClure, H Montefiori, D Cohen, JI Feinberg, MB AF Staprans, SI Barry, AP Silvestri, G Safrit, JT Kozyr, N Sumpter, B Nguyen, H McClure, H Montefiori, D Cohen, JI Feinberg, MB TI Enhanced SIV replication and accelerated progression to AIDS in macaques primed to mount a CD4 T cell response to the SIV envelope protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; ANTIBODY-DEPENDENT ENHANCEMENT; IN-VITRO; VIRAL REPLICATION; HEALTHY-CHILDREN; SUBUNIT VACCINES; INFECTION; VARICELLA; PATHOGENESIS; VACCINATION AB Given the dual role of CD4 T cells as both immune effectors and targets for HIV infection, the balance of CD4 versus CD8 T cell-mediated responses induced by candidate AIDS vaccines may be critical in determining postvaccination infection outcomes. An attenuated recombinant varicella-zoster virus vaccine expressing the simian immunodeficiency virus (SIV) envelope (Env) elicited nonneutralizing Env-binding antibodies and little if any cytotoxic T lymphocyte responses in rhesus macaques (Macaca mulatta). After challenge with SIV, Env vaccinees manifested increased levels of SIV replication, more rapid CD4 depletion, and accelerated progression to AIDS compared with controls. Enhanced SIV replication correlated with increased CD4 T cell proliferation soon after SIV challenge, apparently the result of an anamnestic response to SIV antigens. Thus activation of vinus-specific CD4 T cells at the time of exposure to a CD4 T cell-tropic lentivirus, in the absence of an effective CD8 response, may enhance virus replication and disease. These data suggest suggest that candidate AIDS vaccines may not simply be either efficacious or neutral; they may also have the potential to be harmful. C1 Emory Vaccine Ctr, Atlanta, GA 30329 USA. Emory Univ, Sch Med, Div Infect Dis, Dept Med, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), Emory Vaccine Ctr, 954 Gatewood Rd, Atlanta, GA 30329 USA. EM jcohen@niaid.nih.gov; mbf@sph.emory.edu FU NIAID NIH HHS [P01 AI 46007, P30 AI 50409, P01 AI046007, P30 AI050409] NR 46 TC 99 Z9 103 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 AUG 31 PY 2004 VL 101 IS 35 BP 13026 EP 13031 DI 10.1073/pnas.0404739101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 851OP UT WOS:000223694700046 PM 15326293 ER PT J AU Jiang, DW Xiao, BL Yang, DM Wang, RW Choi, P Zhang, L Cheng, HP Chen, SRW AF Jiang, DW Xiao, BL Yang, DM Wang, RW Choi, P Zhang, L Cheng, HP Chen, SRW TI RyR2 mutations linked to ventricular tachycardia and sudden death reduce the threshold for store-overload-induced Ca2+ release (SOICR) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CHANNEL RYANODINE RECEPTOR; SARCOPLASMIC-RETICULUM; HEART-FAILURE; INTRACELLULAR CALCIUM; MEMBRANE CURRENT; PURKINJE-FIBERS; CARDIAC-MUSCLE; CELLULAR BASIS; MYOCYTES; FLUCTUATIONS AB The cardiac ryanodine receptor (RyR2) governs the release of Ca2+ from the sarcoplasmic reticulum, which initiates muscle contraction. Mutations in RyR2 have been linked to ventricular tachycardia (VT) and sudden death, but the precise molecular mechanism is unclear. It is known that when the sarcoplasmic reticulum store Ca2+ content reaches a critical level, spontaneous Ca2+ release occurs, a process we refer to as store-overload-induced Ca2+ release (SOICR). In view of the well documented arrhythmogenic nature of SOICR, we characterized the effects of disease-causing RyR2 mutations on SOICR in human embryonic kidney (HEK)293 cells and found that, at elevated extracellular Ca2+ levels, HEK293 cells expressing RyR2 displayed SOICR in a manner virtually identical to that observed in cardiac cells. Using this cell model, we demonstrated that the RyR2 mutations linked to VT and sudden death, N4104K, R4496C, and N14895D, markedly increased the occurrence of SOICR. At the molecular level, we showed that these RyR2 mutations increased the sensitivity of single RyR2 channels to activation by luminal Ca2+ and enhanced the basal level of [H-3]ryanodine binding. We conclude that disease-causing RyR2 mutations, by enhancing RyR2 luminal Ca2+ activation, reduce the threshold for SOICR, which in turn increases the propensity for triggered arrhythmia. Abnormal RyR2 luminal Ca2+ activation likely contributes to the enhanced SOICR commonly observed in various cardiac conditions, including heart failure, and may represent a unifying mechanism for Ca2+ overload-associated VT. C1 Univ Calgary, Cardiovasc Res Grp, Dept Physiol & Biophys, Calgary, AB T2N 4N1, Canada. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Chen, SRW (reprint author), Univ Calgary, Cardiovasc Res Grp, Dept Physiol & Biophys, Calgary, AB T2N 4N1, Canada. EM swchen@ucalgary.ca RI Xiao, Bailong/B-6187-2012 NR 39 TC 223 Z9 231 U1 1 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 31 PY 2004 VL 101 IS 35 BP 13062 EP 13067 DI 10.1073/pnas.0402388101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 851OP UT WOS:000223694700052 PM 15322274 ER PT J AU Biesecker, LG AF Biesecker, LG TI Surrendered autonomy for genetic screening SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Editorial Material ID DISEASE TYPE-I C1 NHGRI, Bethesda, MD 20892 USA. RP Biesecker, LG (reprint author), NHGRI, Bldg 49,Room 4A80, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov NR 7 TC 4 Z9 4 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG 30 PY 2004 VL 129A IS 2 BP 165 EP 165 DI 10.1002/ajmg.a.30233 PG 1 WC Genetics & Heredity SC Genetics & Heredity GA 848PF UT WOS:000223478900011 PM 15316958 ER PT J AU Agnati, LF Leo, G Vergoni, AV Martinez, E Hockemeyer, J Lluis, C Franco, R Fuxe, K Ferre, S AF Agnati, LF Leo, G Vergoni, AV Martinez, E Hockemeyer, J Lluis, C Franco, R Fuxe, K Ferre, S TI Neuroprotective effect of L-DOPA co-administered with the adenosine A(2A) receptor agonist CGS 21680 in an animal model of Parkinson's disease SO BRAIN RESEARCH BULLETIN LA English DT Article DE Parkinson's disease; adenosine A(2A) receptor; dopamine D-2 receptor; 6-hydroxydopamine; dyskinesia; rat ID MESSENGER-RNA LEVELS; INDUCED DYSKINESIA; RAT MODEL; 6-HYDROXYDOPAMINE-LESIONED RAT; ANTAGONIST KW-6002; OXIDATIVE STRESS; QUINOLINIC ACID; BASAL GANGLIA; STRIATUM; PREPROENKEPHALIN AB Adenosine A(2A) receptors are a new target for drug development in Parkinson's disease. Some experimental and clinical data suggest that A(2A) receptor antagonists can provide symptomatic improvement by potentiating the effects of (L)-DOPA as well as a decrease in secondary effects such as (L)-DOPA-induced dyskinesia. (L)-DOPA-induced behavioral sensitization in unilateral 6-hydroxydopamine-lesioned rats is frequently used as an experimental model of (L)-DOPA-induced dyskinesia. In the present work this model was used to evaluate the effect of the A(2A) receptor agonist CGS 21680 and the AA receptor antagonist MSX-3 on (L)-DOPA-induced behavioral sensitization and 6-hydroxydopamine-induced striatal dopamine denervation. (L)-DOPA-induced behavioral sensitization was determined as an increase in (L)-DOPA-induced abnormal involuntary movements and enhancement of apomorphine-induced turning behavior. Striatal dopamine innervation was determined by measuring tyro sine-hydroxylase immunoreactivity. Chronic administration of MSX-3 was not found to be effective at counteracting (L)-DOPA-induced behavioral sensitization. On the other hand, CGS 21680 completely avoided the development of (L)-DOPA-induced behavioral sensitization. The analysis of the striatal dopamine innervation showed that (L)-DOPA-CGS 21680 co-treatment conferred neuroprotection to the toxic effects of 6-hydroxydopamine. This neuroprotective effect was dependent on A(2A) and D-2 receptor stimulation, since it was counteracted by MSX-3 and by the D-2 receptor antagonist haloperidol. These results open new therapeutic avenues in early events in Parkinson's disease. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Modena & Reggio Emilia, Dept Biomed Sci, Modena, Italy. Inst Invest Biomed Barcelona, CSIC, IDIBAPS, Dept Neurochem, Barcelona, Spain. Univ Bonn, Inst Pharmaceut, D-5300 Bonn, Germany. Univ Barcelona, Dept Biochem & Mol Biol, Barcelona, Spain. Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. NIDA, IRP, NIH, DHHS, Baltimore, MD USA. RP Agnati, LF (reprint author), Univ Modena & Reggio Emilia, Dept Biomed Sci, Modena, Italy. EM luigiagnati@tin.it RI Vergoni, Anna Valeria/I-4214-2014; Ferre, Sergi/K-6115-2014; MARTINEZ, EMILI/K-8009-2014; Franco, Rafael/C-3694-2015 OI Vergoni, Anna Valeria/0000-0003-2580-4163; Ferre, Sergi/0000-0002-1747-1779; MARTINEZ, EMILI/0000-0002-3624-6489; Franco, Rafael/0000-0003-2549-4919 NR 58 TC 23 Z9 24 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD AUG 30 PY 2004 VL 64 IS 2 BP 155 EP 164 DI 10.1016/j.brainresbull.2004.06.003 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 856HF UT WOS:000224035600008 PM 15342103 ER PT J AU Mazumdar, M Sundareshan, S Misteli, T AF Mazumdar, M Sundareshan, S Misteli, T TI Human chromokinesin KIF4A functions in chromosome condensation and segregation SO JOURNAL OF CELL BIOLOGY LA English DT Article DE chromokinesin; spindle; chromosome condensation; molecular motor ID MITOTIC CHROMOSOME; TOPOISOMERASE-II; METAPHASE PLATE; PROTEIN KLP3A; RNAI ANALYSIS; DNA-BINDING; MEMBER 4; MITOSIS; SPINDLE; CELLS AB Accurate chromosome alignment at metaphase and subsequent segregation of condensed chromosomes is a complex process involving elaborate and only partially characterized molecular machinery. Although several spindle associated molecular motors have been shown to be essential for mitotic function, only a few chromosome arm-associated motors have been described. Here, we show that human chromokinesin human HKIF4A (HKIF4A) is an essential chromosome-associated molecular motor involved in faithful chromosome segregation. HKIF4A localizes in the nucleoplasm during interphase and on condensed chromosome arms during mitosis. It accumulates in the mid-zone from late anaphase and localizes to the cytokinetic ring during cytokinesis. RNA interference-mediated depletion of HKIF4A in human cells results in defective prometaphase organization, chromosome mis-alignment at metaphase, spindle defects, and chromosome mis-segregation. HKIF4A interacts with the condensin I and II complexes and HKIF4A depletion results in chromosome hypercondensation, suggesting that HKIF4A is required for maintaining normal chromosome architecture. Our results provide functional evidence that human KIF4A is a novel component of the chromosome condensation and segregation machinery functioning in multiple steps of mitotic division. C1 NCI, NIH, Bethesda, MD 20892 USA. Bangalore Genev Pvt Ltd, BDA Ind Suburb, Bangalore 560058, Karnataka, India. RP Mazumdar, M (reprint author), NCI, NIH, Bldg 41,Rm B 507,41 Lib Dr, Bethesda, MD 20892 USA. EM mazumdam@mail.nih.gov NR 45 TC 84 Z9 90 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 AUG 30 PY 2004 VL 166 IS 5 BP 613 EP 620 DI 10.1083/jcb.200401142 PG 8 WC Cell Biology SC Cell Biology GA 851TJ UT WOS:000223708100001 PM 15326200 ER PT J AU Abrami, L Lindsay, M Parton, RG Leppla, SH van der Goot, FG AF Abrami, L Lindsay, M Parton, RG Leppla, SH van der Goot, FG TI Membrane insertion of anthrax protective antigen and cytoplasmic delivery of lethal factor occur at different stages of the endocytic pathway SO JOURNAL OF CELL BIOLOGY LA English DT Article DE diphtheria toxin; LBPA; ALIX; MAPK; multivesicular; COP ID DIPHTHERIA-TOXIN; MULTIVESICULAR ENDOSOMES; PROTEIN; INHIBITION; TRANSPORT; CELLS; COP; TRANSLOCATION; BIOGENESIS; LYSOSOMES AB The protective antigen (PA) of anthrax toxin binds to a cell surface receptor, undergoes heptamerization, and binds the enzymatic subunits, the lethal factor (LF) and the edema factor (EF). The resulting complex is then endocytosed. Via mechanisms that depend on the vacuolar ATPase and require membrane insertion of PA, LF and EF are ultimately delivered to the cytoplasm where their targets reside. Here, we show that membrane insertion of PA already occurs in early endosomes, possibly only in the multivesicular regions, but that subsequent delivery of LF to the cytoplasm occurs preferentially later in the endocytic pathway and relies on the dynamics of internal vesicles of multivesicular late endosomes. C1 Univ Geneva, Dept Microbiol & Mol Med, CH-1211 Geneva, Switzerland. Univ Queensland, Inst Mol Biosci, Ctr Microscopy & Microanal, Brisbane, Qld 4072, Australia. Univ Queensland, Dept Physiol & Pharmacol, Brisbane, Qld 4072, Australia. NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP van der Goot, FG (reprint author), Univ Geneva, Dept Microbiol & Mol Med, 1 Rue Michel Server, CH-1211 Geneva, Switzerland. EM gisou.vandergoot@medecine.unige.ch RI Parton, Robert/C-5673-2009; van der Goot, Francoise/B-2279-2012; OI Parton, Robert/0000-0002-7494-5248; van der Goot, Gisou/0000-0002-8522-274X FU NIAID NIH HHS [AI053270-01, R21 AI053270] NR 26 TC 133 Z9 138 U1 0 U2 1 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 AUG 30 PY 2004 VL 166 IS 5 BP 645 EP 651 DI 10.1083/jcb.200312072 PG 7 WC Cell Biology SC Cell Biology GA 851TJ UT WOS:000223708100005 PM 15337774 ER PT J AU Oz, M Spivak, CE Lupica, CR AF Oz, M Spivak, CE Lupica, CR TI The solubilizing detergents, Tween 80 and Triton X-100 non-competitively inhibit alpha(7)-nicotinic acetylcholine receptor function in Xenopus oocytes SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Tween 80; triton X-100; detergents; acetylcholine; nicotinic receptor; Xenopus oocyte ID NICOTINIC RECEPTORS; LAEVIS OOCYTES; ION CHANNELS; MEMBRANE; RAT; MICE; DELTA-9-TETRAHYDROCANNABINOL; MODULATION; RESPONSES; VEHICLES AB Because many studies rely upon detergents to solubilize lipophilic agents such as cannabinoid drugs, we examined the effect of commonly employed detergents on the function of the cloned alpha(7) subunit of the nicotinic ACh receptor. Homomeric alpha(7) receptors were expressed in Xenopus oocytes and the two-microelectrode voltage-clamp technique was used to assess their electrophysiological properties. The detergents Tween 80 and Triton X-100 reversibly inhibited ACh (100 muM)-induced inward currents in a concentration-dependent manner, with IC50 values of 610 nM and 1.4 muM, respectively. The effects of these detergents were independent of membrane potential, and they were not meditated by endogenous Ca2+-dependent Cl- channels, since they were unaffected by intracellularly injected BAPTA, and recorded in Ca2+-free bathing solution containing 2 nM Ba2+. Both detergents also decreased the maximal effect of ACh, without significantly affecting its EC50, indicating a non-competitive interaction with the nACh alpha(7) receptors. In contrast to the effects of these detergents, we found that cholic acid (10 muM), DMSO (10 muM) and Tocrisol(R) (0.01% v/v) did not cause a significant effect on nicotinic responses. In conclusion, we demonstrate that the detergents Tween 80 and Triton X-100 are potent inhibitors of neuronal nACh alpha(7) receptors expressed in Xenopus oocytes, and we suggest that studies utilizing these detergents to solubilize lipophilic drugs should be scrutinized for such effects. Published by Elsevier B.V. C1 Natl Inst Drug Abuse, NIH, DHHS,Cellular Neurophysiol Sect, Intramural Res Program,Cellular Neurobiol Branch, Baltimore, MD 21224 USA. RP Lupica, CR (reprint author), Natl Inst Drug Abuse, NIH, DHHS,Cellular Neurophysiol Sect, Intramural Res Program,Cellular Neurobiol Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM clupica@intra.nida.nih.gov RI Oz, Murat/E-2148-2012 NR 30 TC 28 Z9 28 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 30 PY 2004 VL 137 IS 2 BP 167 EP 173 DI 10.1016/j.jneumeth.2004.02.016 PG 7 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 845KZ UT WOS:000223242800005 PM 15262057 ER PT J AU Peinado, JR Kacprzak, MM Leppla, SH Lindberg, I AF Peinado, JR Kacprzak, MM Leppla, SH Lindberg, I TI Cross-inhibition between furin and lethal factor inhibitors SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID TOXIN PROTECTIVE ANTIGEN; ANTHRAX TOXIN; BACILLUS-ANTHRACIS; CRYSTAL-STRUCTURE; SPECIFICITY; PROTEASE AB Bacillus anthracis synthesizes two toxins composed of the three proteins: protective antigen (PA), lethal factor (U), and edema factor (EF). The cleavage of PA on the cell surface by the convertase furin leads to the translocation of LF and EF into the cytosol. We have investigated the cross-inhibitory activities of the furin inhibitors hexa-D-arginine amide (D6R) and nona-D-arginine amide (D9R), which block the proteolytic activation of PA; and of the LF inhibitor In-2-LF, a peptide hydroxamate. D6R and D9R inhibit LF with IC50s of 300 and 10muM, respectively; conversely, In-2-LF also inhibits furin (IC50 2muM). In-2-LF was efficiently cleaved by furin with the concomitant loss of inhibitory activity on both LF and furin. Incubation of In-2-LF with LF however generated a product that retained partial inhibitory activity against LF. Combined treatment of cells with D6R and In-2-LF enhanced protection against anthrax lethal toxin, indicating that combined administration of inhibitors could represent an effective therapeutic approach. (C) 2004 Elsevier Inc. All rights reserved. C1 Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, New Orleans, LA 70112 USA. NIAID, Div Intramural Res, Microbial Pathogenesis Sect, Bethesda, MD 20892 USA. RP Lindberg, I (reprint author), Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, 1901 Perdido St, New Orleans, LA 70112 USA. EM ilindb@lsuhsc.edu RI Peinado, Juan/A-3450-2011 OI Peinado, Juan/0000-0002-0004-7963 FU NIAID NIH HHS [AI053517] NR 21 TC 25 Z9 26 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 AUG 27 PY 2004 VL 321 IS 3 BP 601 EP 605 DI 10.1016/bbrc.2004.07.012 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 845XC UT WOS:000223277600012 PM 15358148 ER PT J AU Zhao, B Huang, W Zhang, WY Ishii, I Kruth, HS AF Zhao, B Huang, W Zhang, WY Ishii, I Kruth, HS TI Retention of aggregated LDL by cultured human coronary artery endothelial cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE endothelial cells; aggregated LDL; PMA; cholesterol; atherosclerosis ID LOW-DENSITY-LIPOPROTEIN; SMOOTH-MUSCLE-CELLS; RECEPTOR-MEDIATED ENDOCYTOSIS; HUMAN AORTIC TISSUE; MACROPHAGE RECEPTOR; LIPID-ACCUMULATION; SCAVENGER RECEPTOR; CHOLESTERYL ESTER; SR-BI; ATHEROSCLEROSIS AB Aggregated LDL (AgLDL) accumulates within the subendothelial space of developing atherosclerotic lesions. We were interested to learn whether endothelial cells can interact with AgLDL. Incubation of endothelial cells with AgLDL resulted in apparent cholesterol retention. Microscopic examination revealed that cholesterol retention resulted mainly from endothelial cell surface attachment of AgLDL. Little AgLDL entered endothelial cells consistent with the small amount of endothelial cell degradation of AgLDL. Although endothelial cell retention of AgLDL was inhibited by LDL, AgLDL retention was not blocked by lactoferrin, C7 anti-LDL receptor monoclonal antibody, or receptor-associated protein, suggesting that LDL receptor family members did not mediate this retention. Surface retention of AgLDL depended on microtubule function and could be regulated by the protein kinase C activator, PMA. Treatment of endothelial cells with PMA either before or during, but not after incubation with AgLDL, inhibited retention of AgLDL. Our findings show that endothelial cells can retain AgLDL but internalize and metabolize little of this AgLDL. Thus, it is unlikely that endothelial cells can transport AgLDL out of atherosclerotic lesions, but it is likely that retention of AgLDL affects endothelial function. Published by Elsevier Inc. C1 NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. Chiba Univ, Grad Sch Pharmaceut Sci, Dept Clin Pharmacol, Chiba, Japan. RP Kruth, HS (reprint author), NHLBI, Sect Expt Atherosclerosis, NIH, Bethesda, MD 20892 USA. EM kruthh@nhlbi.nih.gov RI Huang, Wei/E-3270-2011 NR 38 TC 1 Z9 1 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 AUG 27 PY 2004 VL 321 IS 3 BP 728 EP 735 DI 10.1016/j.bbrc.2004.07.017 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 845XC UT WOS:000223277600031 PM 15358167 ER PT J AU Dash, C Yi-Brunozzi, HY Le Grice, SFJ AF Dash, C Yi-Brunozzi, HY Le Grice, SFJ TI Two modes of HIV-1 polypurine tract cleavage are affected by introducing locked nucleic acid analogs into the (-) DNA template SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYPE-1 REVERSE-TRANSCRIPTASE; MURINE LEUKEMIA-VIRUS; PRIMER GRIP REGION; SEQUENCE FEATURES IMPORTANT; GROOVE BINDING TRACK; ALPHA-L-LNA; IMMUNODEFICIENCY-VIRUS; RNASE-H; THUMB SUBDOMAIN; SCANNING MUTAGENESIS AB Unusual base-pairing in a co-crystal of reverse transcriptase (RT) and a human immunodeficiency virus type 1 (HIV-1) polypurine tract (PPT)-containing RNA/DNA hybrid suggests local nucleic acid flexibility mediates selection of the plus-strand primer. Structural elements of HIV-1 RT potentially participating in recognition of this duplex include the thumb subdomain and the ribonuclease H (RNase H) primer grip, the latter comprising elements of the connection subdomain and RNase H domain. To investigate how stabilizing HIV-1 PPT structure influences its recognition, we modified the (-) DNA template by inserting overlapping locked nucleic acid (LNA) doublets and triplets. Modified RNA/DNA hybrids were evaluated for cleavage at the PPT/U3 junction. Altered specificity was observed when the homopolymeric dA.rU tract immediately 5' of the PPT was modified, whereas PPT/U3 cleavage was lost after substitutions in the adjacent dT.rA tract. In contrast, the "unzipped" portion of the PPT was moderately insensitive to LNA insertions. Although a portion of the dC.rG and neighboring dT.rA tract were minimally affected by LNA insertion, RNase H activity was highly sensitive to altering the junction between these structural elements. Using 3'-end-labeled PPT RNA primers, we also identified novel cleavage sites ahead (+5/+6) of the PPT/U3 junction. Differential cleavage at the PPT/U3 junction and U3 +5/+6 site in response to LNA-induced template modification suggests two binding modes for HIV-1 RT, both of which may be controlled by the interaction of its thumb subdomain (potentially via the minor groove binding track) at either site of the unzipped region. C1 NCI, Reverse Transcriptase Biochem Sect, HIV Drug Resistance Program, Resistance Mech Lab,NIH, Frederick, MD 21702 USA. RP Le Grice, SFJ (reprint author), NCI, Reverse Transcriptase Biochem Sect, HIV Drug Resistance Program, Resistance Mech Lab,NIH, Frederick, MD 21702 USA. EM slegrice@ncifcrf.gov NR 59 TC 12 Z9 13 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 27 PY 2004 VL 279 IS 35 BP 37095 EP 37102 DI 10.1074/jbc.M403306200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 848FS UT WOS:000223453600113 PM 15220330 ER PT J AU Espada, J Ballestar, E Fraga, MF Garea, AV Juarranz, A Stockert, JC Robertson, KD Fuks, FO Esteller, M AF Espada, J Ballestar, E Fraga, MF Garea, AV Juarranz, A Stockert, JC Robertson, KD Fuks, FO Esteller, M TI Human DNA methyltransferase 1 is required for maintenance of the histone H3 modification pattern SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN CANCER-CELLS; CPG ISLANDS; NUCLEAR ARCHITECTURE; LYSINE-9 METHYLATION; INTERPHASE NUCLEI; MAMMALIAN-CELLS; HP1 PROTEINS; DNMT1; GENE; DEACETYLASE AB DNA methyltransferase 1 (DNMT1) plays an essential role in murine development and is thought to be the enzyme primarily responsible for maintenance of the global methylation status of genomic DNA. However, loss of DNMT1 in human cancer cells affects only the methylation status of a limited number of pericentromeric sequences. Here we show that human cancer cells lacking DNMT1 display at least two important differences with respect to wild type cells: a profound disorganization of nuclear architecture, and an altered pattern of histone H3 modification that results in an increase in the acetylation and a decrease in the dimethylation and trimethylation of lysine 9. Additionally, this phenotype is associated with a loss of interaction of histone deacetylases (HDACs) and HP1 (heterochromatin protein 1) with histone H3 and pericentromeric repetitive sequences (satellite 2). Our data indicate that DNMT1 activity, via maintenance of the appropriate histone H3 modifications, contributes to the preservation of the correct organization of large heterochromatic regions. C1 Spanish Natl Canc Ctr CNIO, Epigenet Lab, Madrid 28029, Spain. Autonomous Univ Madrid, Fac Sci, Dept Biol, E-28049 Madrid, Spain. NCI, Epigenet Gene Regulat & Canc Sect, NIH, Bethesda, MD 20892 USA. Free Univ Brussels, Fac Med, Mol Virol Lab, B-1070 Brussels, Belgium. RP Esteller, M (reprint author), Spanish Natl Canc Ctr CNIO, Epigenet Lab, Melchor Fernandez Almagro 3, Madrid 28029, Spain. EM mesteller@cnio.es RI Esteller, Manel/L-5956-2014; Juarranz, Angeles/L-2446-2013; OI Esteller, Manel/0000-0003-4490-6093; Juarranz, Angeles/0000-0002-6574-2887; Ballestar, Esteban/0000-0002-1400-2440 NR 52 TC 123 Z9 131 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 AUG 27 PY 2004 VL 279 IS 35 BP 37175 EP 37184 DI 10.1074/jbc.M404842200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 848FS UT WOS:000223453600121 PM 15220328 ER PT J AU Gunasekaran, K Tsai, CJ Nussinov, R AF Gunasekaran, K Tsai, CJ Nussinov, R TI Analysis of ordered and disordered protein complexes reveals structural features discriminating between stable and unstable monomers SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE disordered proteins; natively unstructured proteins; protein-protein interactions; folding mechanisms; two-state and three-state complexes ID INTRINSICALLY UNSTRUCTURED PROTEINS; DIFFERENTIAL SCANNING CALORIMETRY; NATIVELY UNFOLDED PROTEINS; ESCHERICHIA-COLI; MOLECULAR RECOGNITION; OLIGOMERIC PROTEINS; SUBUNIT INTERFACES; DIMERIC PROTEINS; STABILITY; BINDING AB Most proteins exist in the cell as multi-component assemblies. However, which proteins need to be present simultaneously in order to perform a given function is frequently unknown. The first step toward this goal would be to predict proteins that can function only when in a complexed form. Here, we propose a scheme to distinguish whether the protein components are ordered (stable) or disordered when separated from their complexed partners. We analyze structural characteristics of several types of complexes, such as natively unstructured proteins, ribosomal proteins, two-state and three-state complexes, and crystal-packing dimers. Our analysis makes use of the fact that natively unstructured proteins, which, undergo a disorder-to-order transition upon binding their partner, and stable monomeric proteins, which exist as dimers only in their crystal form, provide examples of two vastly different scenarios. We find that ordered monomers can be distinguished from disordered monomers on the basis of the per-residue surface and interface areas, which are significantly smaller for ordered proteins. With this scale, two-state dimers (where the monomers unfold upon dimer separation) and ribosomal proteins are shown to resemble disordered proteins. On the other hand, crystal-packing dimers, whose monomers are stable in solution, fall into the ordered protein category. While there should be a continuum in the distributions, nevertheless, the per-residue scale measures the confidence in the determination of whether a protein can exist as a stable monomer. Further analysis, focusing on the chemical and contact preferences at the interface, interior and exposed surface areas, reveals that disordered proteins lack a strong hydrophobic core and are composed of highly polar surface area. We discuss the implication of our results for de novo design of stable monomeric proteins and peptides. (C) 2004 Elsevier Ltd. All rights reserved. C1 NCI, SAIC Frederick, Basic Res Program, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Gunasekaran, K (reprint author), NCI, SAIC Frederick, Basic Res Program, Lab Expt & Computat Biol, Frederick, MD 21702 USA. EM guna@ncifcrf.gov; ruthn@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 71 TC 93 Z9 94 U1 1 U2 12 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 AUG 27 PY 2004 VL 341 IS 5 BP 1327 EP 1341 DI 10.1016/j.jmb.2004.07.002 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 848PQ UT WOS:000223480000015 PM 15321724 ER PT J AU Lim, JH Catez, F Birger, Y West, KL Prymakowska-Bosak, M Postnikov, YV Bustin, M AF Lim, JH Catez, F Birger, Y West, KL Prymakowska-Bosak, M Postnikov, YV Bustin, M TI Chromosomal protein HMGN1 modulates histone H3 phosphorylation SO MOLECULAR CELL LA English DT Article ID EARLY GENE INDUCTION; MAP KINASE; MITOTIC PHOSPHORYLATION; H3 PHOSPHORYLATION; CHROMATIN; NUCLEOSOMES; HMG-14; ACTIVATION; BINDING; DOMAIN AB Here we demonstrate that HMGN1, a nuclear protein that binds to nucleosomes and reduces the compaction of the chromatin fiber, modulates histone posttranslational modifications. In Hmgn1(-/-) cells, loss of HMGN1 elevates the steady-state levels,of phospho-S10-H3 and enhances the rate of stress-induced phosphorylation of S10-H3. In vitro, HMGN1 reduces the rate of phospho-S10-H3 by hindering the ability of kinases to modify nucleosomal, but not free, H3. During anisomycin treatment, the phosphorylation of HMGN1 precedes that of H3 and leads to a transient weakening of the binding of HMGN1 to chromatin. We propose that the reduced binding of HMGN1 to nucleosomes, or the absence of the protein, improves access of anisomysin-induced kinases to H3. Thus, the levels of posttranslational modifications in chromatin are modulated by nucleosome binding proteins that alter the ability of enzymatic complexes to access and modify their nucleosomal targets. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Postnikov, YV (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM yupo@helix.nih.gov RI Bustin, Michael/G-6155-2015 NR 37 TC 83 Z9 84 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 27 PY 2004 VL 15 IS 4 BP 573 EP 584 DI 10.1016/j.molcel.2004.08.006 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 849UA UT WOS:000223565200011 PM 15327773 ER PT J AU Lu, XB Bocangel, D Nannenga, B Yamaguchi, H Appella, E Donehower, LA AF Lu, XB Bocangel, D Nannenga, B Yamaguchi, H Appella, E Donehower, LA TI The p53-induced oncogenic phosphatase PPM1D interacts with uracil DNA glycosylase and suppresses base excision repair SO MOLECULAR CELL LA English DT Article ID IN-VIVO; IONIZING-RADIATION; UV-RADIATION; P53; WIP1; GENE; PHOSPHORYLATION; AMPLIFICATION; CANCER; ACTIVATION AB The wild-type p53-induced phosphatase PPM1D (or Wip1) is a serine/threonine phosphatase that is transcriptionally upregulated by p53 following ultraviolet and ionizing radiation. PPM1D is an oncogene in transformation assays and is amplified or overexpressed in several human tumor types. Here, we demonstrate that PPM1D interacts with the nuclear isoform of uracil DNA glycosylase, UNG2, and suppresses base excision repair (BER). Point mutations that inactivate PPM1D phosphatase activity abrogate BER suppression, indicating that dephosphorylation by PPM1D is important for BER inhibition. We have identified UNG2 phosphorylation sites at threonines 6 and 126 that exhibit enhanced phosphorylation following UV irradiation. The UV-induced phosphorylated forms of UNG2 are more active than nonphosphorylated forms in mediating uracil-associated DNA cleavage. PPM1D dephosphorylation of UNG2 at phosphothreonine 6 is associated with reduced UNG2 activity. Thus, PPM1D may inhibit BER by dephosphorylating UNG2 to facilitate its inactivation after completion of DNA repair. C1 Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Donehower, LA (reprint author), Baylor Coll Med, Dept Mol Virol & Microbiol, Houston, TX 77030 USA. EM larryd@bcm.tmc.edu NR 46 TC 82 Z9 85 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 27 PY 2004 VL 15 IS 4 BP 621 EP 634 DI 10.1016/j.molcel.2004.08.007 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 849UA UT WOS:000223565200015 PM 15327777 ER PT J AU Singh, BB Lockwich, TP Bandyopadhyay, BC Liu, XB Bollimuntha, S Brazer, SC Combs, C Das, S Leenders, AGM Sheng, ZH Knepper, MA Ambudkar, SV Ambudkar, IS AF Singh, BB Lockwich, TP Bandyopadhyay, BC Liu, XB Bollimuntha, S Brazer, SC Combs, C Das, S Leenders, AGM Sheng, ZH Knepper, MA Ambudkar, SV Ambudkar, IS TI VAMP2-dependent exocytosis regulates plasma membrane insertion of TRPC3 channels and contributes to agonist-stimulated Ca2+ influx SO MOLECULAR CELL LA English DT Article ID CAPACITATIVE CALCIUM-ENTRY; SIGNALING COMPLEX; SNARE PROTEINS; ACTIVATION; TRANSLOCATION; EXPRESSION; TRAFFICKING; ASSOCIATION; MECHANISM; RECEPTORS AB The mechanism(s) involved in agonist-stimulation of TRPC3 channels is not yet known. Here we demonstrate that TRPC3-N terminus interacts with VAMP2 and alphaSNAP. Further, endogenous and exogenously expressed TRPC3 colocalized and coimmunoprecipitated with SNARE proteins in neuronal and epithelial cells. Imaging of GFP-TRPC3 revealed its localization in the plasma membrane region and in mobile intracellular vesicles. Recovery of TRPC3-GFP fluorescence after photobleaching of the plasma membrane region was decreased by brefeldin-A or BAPTA-AM. Cleavage of VAMP2 with tetanus toxin (TeNT) did not prevent delivery of TRPC3 to the plasma membrane region but reduced its surface expression. TeNT also decreased carbachol and OAG, but not thapsigargin, stimulated Ca2+ influx. Importantly, carbachol, not thapsigargin, increased surface expression of TRPC3 that was attenuated by TeNT and not by BAPTA. In aggregate, these data suggest that VAMP2-dependent exocytosis regulates plasma membrane insertion of TRPC3 channels and contributes to carbachol-stimulation of Ca2+ influx. C1 Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. NHLBI, Light Microscopy Core Facil, Bethesda, MD 20892 USA. NINDS, Synapt Funct Unit, Bethesda, MD 20892 USA. NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), Natl Inst Dent & Craniofacial Res, Secretory Physiol Sect, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. EM indu.ambudkar@nih.gov RI Ambudkar, Suresh/B-5964-2008; OI Singh, Brij/0000-0003-0535-5997 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 41 TC 148 Z9 156 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 27 PY 2004 VL 15 IS 4 BP 635 EP 646 DI 10.1016/j.molcel.2004.07.010 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 849UA UT WOS:000223565200016 PM 15327778 ER PT J AU Boukari, H Nossal, R Sackett, DL Schuck, P AF Boukari, H Nossal, R Sackett, DL Schuck, P TI Hydrodynamics of nanoscopic tubulin rings in dilute solutions SO PHYSICAL REVIEW LETTERS LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; SIZE-DISTRIBUTION ANALYSIS; ANALYTICAL ULTRACENTRIFUGATION; MACROMOLECULES; MODEL; MICROSCOPY; RESOLUTION; DIMER AB We combine fluorescence correlation spectroscopy and sedimentation velocity measurements to probe the hydrodynamic behavior of tubulin dimers and nanoscopic tubulin rings. The rings are rigid, have circular geometry, and are monodisperse in size. We use the high-precision ratio of the sedimentation coefficients and that of the translational diffusion coefficients to validate theories for calculating the hydrodynamic properties of supramolecular structures. C1 NICHD, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, ORS OD, Bethesda, MD 20892 USA. RP Boukari, H (reprint author), NICHD, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. EM boukarih@mail.nih.gov NR 29 TC 12 Z9 12 U1 0 U2 2 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD AUG 27 PY 2004 VL 93 IS 9 AR 098106 DI 10.1103/PhysRevLett.93.098106 PG 4 WC Physics, Multidisciplinary SC Physics GA 849QS UT WOS:000223555600071 PM 15447147 ER PT J AU Hahn, P Dentchev, T Qian, Y Rouault, T Harris, ZL Dunaief, JL AF Hahn, P Dentchev, T Qian, Y Rouault, T Harris, ZL Dunaief, JL TI Immunolocalization and regulation of iron handling proteins ferritin and ferroportin in the retina SO MOLECULAR VISION LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; BLOOD-BRAIN-BARRIER; MITOCHONDRIAL FERRITIN; NEURODEGENERATIVE DISORDERS; MACULAR DEGENERATION; PIGMENT EPITHELIUM; METABOLISM; CERULOPLASMIN; TRANSFERRIN; CELLS AB Purpose: CNS iron accumulation is associated with several neurodegenerative diseases, including age-related macular degeneration. Intracellular overload of free iron is prevented, in part, by the iron export protein, ferroportin, and the iron storage protein, ferritin. The purpose of this study was to assess retinal localization and regulation of ferroportin and ferritin. Methods: Normal murine retinas were analyzed by immunohistochemistry to localize ferroportin, cytosolic ferritin, and mitochondrial ferritin, with double-labeling using cell-specific markers to identify cell types. Retinas deficient in the ferroxidases, ceruloplasmin and hephaestin, accumulate iron in their retinas and RPE, while retinas deficient in iron regulatory proteins (IRPs) lack the ability to regulate several proteins involved in iron metabolism; retinas from these knockout mice along with their age matched wild type littermates were also examined to study regulation of ferritin and ferroportin. To enable visualization of label in the retinal pigment epithelial cells, sections from pigmented mice were bleached with H2O2 prior to IHC, a novel use of this technique for study of the RPE. Results: In normal retinas, cytosolic ferritins were found predominantly in rod bipolar cells and photoreceptors. Ferroportin was found in RPE and MUller cells. Iron accumulation in mice deficient in ceruloplasmin and hephaestin was associated with upregulation of ferritin and ferroportin. Mice deficient in IRPs showed upregulation of ferritin and ferroportin, likely because of their inability to repress translation. Conclusions: Normal retinas contain ferritin and ferroportin, whose levels are regulated by iron-responsive, iron regulatory proteins. Ferroportin colocalizes with ceruloplasmin and hephaestin to RPE and MUller cells, supporting a potential cooperation between these ferroxidases and the iron exporter. Cytosolic ferritin accumulates in rod bipolar synaptic terminals, suggesting that ferritin may be involved in axonal iron transport. Mitochondrial ferritin increases with iron accumulation, suggesting a role in iron storage. C1 Scheie Eye Inst, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA USA. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. Johns Hopkins Univ, Div Pediat Anesthesiol & Crit Care Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. RP Dunaief, JL (reprint author), Stellar Chance Labs 305, 422 Curie Blvd, Philadelphia, PA 19104 USA. EM jdunaief@mail.med.upenn.edu FU NEI NIH HHS [K08EY00417, R01EY015240]; NIDDK NIH HHS [DK02464, DK58086]; NIGMS NIH HHS [T32GM7170] NR 43 TC 49 Z9 52 U1 0 U2 0 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 AUG 26 PY 2004 VL 10 IS 72 BP 598 EP 607 PG 10 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 852EG UT WOS:000223737400001 PM 15354085 ER PT J AU Liotta, LA Kohn, E AF Liotta, LA Kohn, E TI Anoikis - Cancer and the homeless cell SO NATURE LA English DT Editorial Material ID ACTIVATION; 3-KINASE C1 NCI, NIH, Bethesda, MD 20892 USA. RP Liotta, LA (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM lance@helix.nih.gov NR 11 TC 107 Z9 122 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 26 PY 2004 VL 430 IS 7003 BP 973 EP 974 DI 10.1038/430973a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 849CD UT WOS:000223514900023 PM 15329701 ER PT J AU Edskes, HK Wickner, RB AF Edskes, HK Wickner, RB TI Transmissible spongiform encephalopathies - Prion proof in progress SO NATURE LA English DT Editorial Material ID SCRAPIE PRION; PROTEIN; IDENTIFICATION; GENE; PRP; RESISTANT; STRAINS; ANALOG; MICE C1 NIH, Lab Biochem & Genet, Bethesda, MD 20892 USA. RP Edskes, HK (reprint author), NIH, Lab Biochem & Genet, 8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov NR 17 TC 4 Z9 4 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 26 PY 2004 VL 430 IS 7003 BP 977 EP 979 DI 10.1038/430977a PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 849CD UT WOS:000223514900027 PM 15329705 ER PT J AU de Souza-Pinto, NC Harris, CC Bohr, VA AF de Souza-Pinto, NC Harris, CC Bohr, VA TI p53 functions in the incorporation step in DNA base excision repair in mouse liver mitochondria SO ONCOGENE LA English DT Article DE p53; mitochondrial DNA; DNA repair; BER; uracil ID MICROSATELLITE INSTABILITY; IN-VIVO; POLYMERASE-GAMMA; LYASE ACTIVITY; NUCLEAR; URACIL; IDENTIFICATION; GLYCOSYLASES; INVOLVEMENT; INCISION AB The tumor suppressor p53 protein stimulates nuclear base excision repair (BER) in vitro. In response to certain cellular stresses, p53 translocates to mitochondria, where it can trigger an apoptotic response. However, a potential role for p53 in modulating mitochondrial DNA repair has not yet been examined. In this study, we show that p53 also modulates mitochondrial BER. Uracil-initiated BER incorporation, which measures flux through the entire BER pathway, was lower in mitochondrial extracts from nonstressed p53 knockout mice than in wild type. The addition of recombinant p53 complemented the BER incorporation in p53 knockout extracts and stimulated BER in wt extracts. The activities of three major mitochondrial DNA glycosylases were similar in extracts from wild-type and knockout animals. Likewise, AP endonuclease activity was unaffected by the absence of p53. Gel shift experiments with recombinant p53 demonstrated that p53 did not bind to the uracil-containing substrate used in the repair assay. Polymerase gamma gap-filing activity was less efficient in p53 knockout extracts, but it was complemented with the addition of recombinant p53. Thus, we conclude that p53 may participate in mtBER by stimulating the repair synthesis incorporation step. C1 NIA, Lab Mol Gerontol, GRC,IRP, NIH, Baltimore, MD 21224 USA. NCI, Human Carcinogenesis Lab, CTR, NIH, Bethesda, MD 20892 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, GRC,IRP, NIH, 5600 Nathon Shock Dr,Box 1, Baltimore, MD 21224 USA. EM vbohr@nih.gov RI Souza-Pinto, Nadja/C-3462-2013 OI Souza-Pinto, Nadja/0000-0003-4206-964X NR 38 TC 64 Z9 64 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 AUG 26 PY 2004 VL 23 IS 39 BP 6559 EP 6568 DI 10.1038/sj.onc.1207874 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 849IB UT WOS:000223530800003 PM 15208669 ER PT J AU Shan, ZH Parker, T Wiest, JS AF Shan, ZH Parker, T Wiest, JS TI Identifying novel homozygous deletions by microsatellite analysis and characterization of tumor suppressor candidate 1 gene, TUSC1, on chromosome 9p in human lung cancer SO ONCOGENE LA English DT Article DE homozygous deletion; chromosome 9; lung cancers; TUSC1; expression; tumor suppressor gene ID CARCINOMA; MELANOMA; HETEROZYGOSITY; REGION; EPIGENETICS; METHYLATION; LEUKEMIA; 9P21-22; P15 AB Loss of heterozygosity (LOH) studies indicate that genetic alterations of chromosome 9p occur in numerous tumor types, suggesting the presence of tumor suppressor genes (TSGs) on chromosome 9p critical in carcinogenesis. Our previous LOH analyses in primary lung tumors led us to propose that chromosome 9p harbors other TSGs important in lung tumorigenesis. In this study, 30 non-small-cell lung cancer and 12 small-cell lung cancer cell lines were screened with 55 markers to identify new regions of homozygous deletion (HD) on chromosome 9p. Three novel noncontiguous homozygously deleted regions were detected and ranged in size from 840 kb to 7.4 Mb. One gene identified in the deletion at D9S126, TUSC1 ( tumor suppressor candidate 1), is an intronless gene. Multiplex polymerase chain reaction and Southern blot confirmed the HD of TUSC1. Northern blot analysis of TUSC1 demonstrated two transcripts of approximately 2 and 1.5 kb that are likely generated by alternative polyadenylation signals. Both transcripts are expressed in several human tissues and share an open-reading frame encoding a peptide of 209 amino acids. Analysing cell line cDNAs by reverse transcriptase (RT)-PCR demonstrated downregulation of TUSC1 in cell lines with or without HDs, suggesting that TUSC1 may play a role in lung tumorigenesis. C1 NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wiest, JS (reprint author), NCI, Cellular Carcinogenesis & Tumor Promot Lab, Ctr Canc Res, Bldg 37,Room 4008,37 Convent Dr MSC4258, Bethesda, MD 20892 USA. EM wiestj@mail.nih.gov FU Intramural NIH HHS [ZIA BC010448-09] NR 26 TC 19 Z9 23 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 AUG 26 PY 2004 VL 23 IS 39 BP 6612 EP 6620 DI 10.1038/sj.onc.1207857 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 849IB UT WOS:000223530800008 PM 15208665 ER PT J AU Izquierdo, A Suda, RK Murray, EA AF Izquierdo, A Suda, RK Murray, EA TI Bilateral orbital prefrontal cortex lesions in rhesus monkeys disrupt choices guided by both reward value and reward contingency SO JOURNAL OF NEUROSCIENCE LA English DT Article DE orbital prefrontal cortex; reinforcer devaluation; decision making; reward value; reward contingency; rhesus monkey ID ORBITOFRONTAL CORTEX; FRONTAL-CORTEX; BASOLATERAL AMYGDALA; UNCINATE FASCICLE; NEURONAL-ACTIVITY; OBJECT; MEMORY; REINFORCEMENT; ACQUISITION; DISCONNECTION AB The orbital prefrontal cortex (PFo) operates as part of a network involved in reward-based learning and goal-directed behavior. To test whether the PFo is necessary for guiding behavior based on the value of expected reward outcomes, we compared four rhesus monkeys with two-stage bilateral PFo removals and six unoperated controls for their responses to reinforcer devaluation, a task that assesses the monkeys' abilities to alter choices of objects when the value of the underlying food has changed. For comparison, the same monkeys were tested on a standard test of flexible stimulus - reward learning, namely object reversal learning. Relative to controls, monkeys with bilateral PFo removals showed a significant attenuation of reinforcer devaluation effects on each of two separate assessments, one performed shortly after surgery and the other similar to 19 months after surgery; the operated monkeys were also impaired on object reversal learning. The same monkeys, however, were unimpaired in acquisition of object discrimination learning problems and responded like controls when allowed to choose foods alone, either on a food preference test among six different foods or after selective satiation. Thus, satiety mechanisms and the ability to assign value to familiar foods appear to be intact in monkeys with PFo lesions. The pattern of results suggests that the PFo is critical for response selection based on predicted reward outcomes, regardless of whether the value of the outcome is predicted by affective signals ( reinforcer devaluation) or by visual signals conveying reward contingency ( object reversal learning). C1 NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Izquierdo, A (reprint author), NIMH, Sect Neurobiol Learning & Memory, Neuropsychol Lab, NIH, 49 Convent Dr,Bldg 49,Room 1B80, Bethesda, MD 20892 USA. EM izquiera@mail.nih.gov OI Murray, Elisabeth/0000-0003-1450-1642 NR 43 TC 313 Z9 316 U1 0 U2 17 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 AUG 25 PY 2004 VL 24 IS 34 BP 7540 EP 7548 DI 10.1523/JNEUROSCI.1921-04.2004 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 849EJ UT WOS:000223521200014 PM 15329401 ER PT J AU Clore, GM Schwieters, CD AF Clore, GM Schwieters, CD TI Amplitudes of protein backbone dynamics and correlated motions in a small alpha/beta protein: Correspondence of dipolar coupling and heteronuclear relaxation measurements SO BIOCHEMISTRY LA English DT Article ID MODEL-FREE APPROACH; MACROMOLECULAR STRUCTURE DETERMINATION; PANCREATIC TRYPSIN-INHIBITOR; LIQUID-CRYSTALLINE PHASE; MOLECULAR-DYNAMICS; NMR-SPECTROSCOPY; STRUCTURE REFINEMENT; INTERNAL DYNAMICS; MULTIPLE ALIGNMENTS; CROSS-VALIDATION AB Backbone residual dipolar coupling (N-H, Calpha-Halpha, N-C', and Ca-C') data collected in five different media on the B3 IgG binding domain of streptococcal protein G (GB3) have been analyzed by simultaneous refinement of the coordinates and optimization of the magnitudes and orientations of the alignment tensors using single and multiple structure representations. We show, using appropriate error analysis, that agreement between observed and calculated dipolar couplings at the level of experimental uncertainty is obtained with a two-structure (N-e = 2) ensemble representation which represents the simplest equilibrium description of anisotropic motions. The data permit one to determine the magnitude of the anisotropic motions along the four different backbone bond vectors in terms of (S-2(jump)) order parameters. The order parameters, (S-NH(2)(jump)), for the N-H bond vectors are in qualitative agreement with the generalized order parameters, S-NH(2)(relaxation), derived from N-15 relaxation measurements, with a correlation coefficient of 0.84. S-NH(2)(relaxation) can be regarded as the product of an anisotropic order parameter, corresponding to (S-NH(2)(jump)) derived from the residual dipolar couplings, and an axially symmetric order parameter, S-NH(2)(axial), corresponding to bond librations which are expected to be essentially uniform along the polypeptide chain. The current data indicate that the average value of S-NH(2)(axial) is similar to0.9. The close correspondence of (S-NH(2)(jump)) and S-NH(2)(relaxation) indicates that any large-scale displacements from the mean coordinate positions on time scales longer than the rotational correlation time are rare and hence do not perturb the observed dipolar couplings. Analysis of a set of 100 N-e = 2 ensembles reveals the presence of some long-range correlated motions of N-H and Calpha-Halpha vectors involving residues far apart in the sequence but close together in space. In addition, direct evidence is obtained for ubiquitous crankshaft motions along the entire length of the polypeptide backbone manifested by the anticorrelation of the backbone torsion angles phi(i) and psi(i-1). C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, 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 70 TC 110 Z9 111 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 24 PY 2004 VL 43 IS 33 BP 10678 EP 10691 DI 10.1021/bi049357w PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 848CQ UT WOS:000223445200008 PM 15311929 ER PT J AU Youn, HS Liang, QL Cha, JK Cai, ML Timkovich, R AF Youn, HS Liang, QL Cha, JK Cai, ML Timkovich, R TI Compound 800, a natural product isolated from genetically engineered Pseudomonas: Proposed structure, reactivity, and putative relation to heme d(1) SO BIOCHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; PROSTHETIC GROUP; PORPHYRIN BIOSYNTHESIS; CYTOCHROME CD(1); DESULFOVIBRIO; PURIFICATION; REDUCTASE; PROTEINS; STUTZERI; PATHWAY AB Genetically engineered strains of Escherichia coli and Pseudomonas aeruginosa were prepared harboring the gene cluster nirFDLGH from Pseudomonas stutzeri substrain ZoBell on a high copy plasmid. These genes have been previously implicated as being essential for the biosynthesis of heme d(1), the prosthetic group of dissimilatory nitrite reductases in anaerobic, denitryfying bacteria. Tetrapyrroles detectable at steady-state levels were identified from both organisms, and cell-free extracts from each were also used to transform uroporphyrinogen in vitro. E. coli does not naturally produce d(1), and the engineered strain failed to produce d(1) or any tetrapyrrole foreign to E. coli. Therefore, while nirFDLGH may be necessary for d(1) biosynthesis, it is not sufficient. In the denitrifier P. aeruginosa, the results were more positive. The presence of the plasmid led to increased levels of d(1). In addition, a previously unidentified tetrapyrrole was detected. This compound was characterized by visible absorption spectroscopy, infrared spectroscopy, X-ray photoelectron spectroscopy, mass spectrometry, and NMR, and a tentative structure was proposed for this compound. The tetrapyrrole has structural features similar to sirohydrochlorin (as precorrin-2 or sirotetrahydrochlorin, a known intermediate of d(1)) and d(1) itself. The most unusual substituents are epoxide and sulfoxide moieties. When this tetrapyrrole was treated with strong mineral acid and heat, it was converted into natural d(1). C1 Univ Alabama, Dept Chem, Tuscaloosa, AL 35487 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Timkovich, R (reprint author), Univ Alabama, Dept Chem, Box 870336, Tuscaloosa, AL 35487 USA. EM rtimkovi@bama.ua.edu FU NIGMS NIH HHS [GM35956, GM59035] NR 31 TC 2 Z9 3 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 24 PY 2004 VL 43 IS 33 BP 10730 EP 10738 DI 10.1021/bi0491954 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 848CQ UT WOS:000223445200013 PM 15311934 ER PT J AU Stevenson, LW Miller, LW Desvigne-Nickens, P Ascheim, DD Parides, MK Renlund, DG Oren, RM Krueger, SK Costanzo, MR Wann, LS Levitan, RG Mancini, D AF Stevenson, LW Miller, LW Desvigne-Nickens, P Ascheim, DD Parides, MK Renlund, DG Oren, RM Krueger, SK Costanzo, MR Wann, LS Levitan, RG Mancini, D CA REMATCH Investigators TI Left ventricular assist device as destination for patients undergoing intravenous inotropic therapy - A subset analysis from REMATCH (Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure) SO CIRCULATION LA English DT Article DE heart failure; transplantation; heart-assist device ID CONTROLLED TRIAL; MORTALITY; END; SURVIVAL; TRANSPLANTATION; MILRINONE AB Background - Left ventricular assist devices (LVADs) have improved survival in patients with end-stage heart failure. Compared with previous trials, the Randomized Evaluation of Mechanical Assistance in Treatment of Chronic Heart Failure ( REMATCH) trial enrolled patients with more advanced heart failure and high prevalence of intravenous inotropic therapy. This study analyzes, on a post hoc basis, outcomes in patients undergoing inotropic infusions at randomization. Methods and Results - Of 129 patients randomized, 91 were receiving intravenous inotropic therapy at randomization to LVAD or optimal medical management (OMM). Mean systolic pressure was 100 versus 107 mm Hg in those not receiving inotropes, serum sodium was 134 versus 137 mEq/L, and left ventricular ejection fraction was 17% for both groups. LVADs improved survival throughout follow-up for patients undergoing baseline inotropic infusions ( P = 0.0014); for the LVAD group versus the OMM group, respectively, 6-month survival was 60% versus 39%, 1-year survival rates were 49% versus 24%, and 2-year survival rates were 28% versus 11%. For 38 patients not undergoing inotropic infusions, 6-month survival was 61% for those with LVADs and 67% for those with OMM, whereas 1-year rates were 57% and 40%, respectively ( P = 0.55). Quality-of-life scores for survivors improved. Median days out of hospital for patients on inotropic therapy at randomization were 255 with LVAD and 105 with OMM. Conclusions - Despite severe compromise, patients undergoing inotropic infusions at randomization derived major LVAD survival benefit with improved quality of life. Patients not undergoing inotropic infusions had higher survival rates both with and without LVAD, but differences did not reach significance. Future studies should prespecify analyses of inotropic and other therapies to determine how disease severity and parallel medical treatment influence the benefits offered by mechanical circulatory support. C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. NHLBI, Bethesda, MD 20892 USA. Columbia Presbyterian Med Ctr, Heart Failure Ctr, New York, NY 10032 USA. Columbia Univ, Int Ctr Hlth Outcomes & Innovat Res, New York, NY USA. IHC LDS, Hosp Heart Failure Prevent & Treatment Program, Salt Lake City, UT USA. Univ Iowa Hosp & Clin, Heart Failure Treatment Program, Iowa City, IA 52242 USA. BryanLGH Heart Inst, Lincoln, NE USA. Edward Heart Hosp, Naperville, IL USA. Wisconsin Heart & Vasc Clin, Milwaukee, WI USA. RP Stevenson, LW (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM lstevenson@partners.org NR 21 TC 111 Z9 114 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 24 PY 2004 VL 110 IS 8 BP 975 EP 981 DI 10.1161/01.CIR.0000139862.48167.23 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 848UG UT WOS:000223492700014 PM 15313942 ER PT J AU Sverdlov, AV Rogozin, IB Babenko, VN Koonin, EV AF Sverdlov, AV Rogozin, IB Babenko, VN Koonin, EV TI Reconstruction of ancestral protosplice sites SO CURRENT BIOLOGY LA English DT Article ID PROTO-SPLICE SITES; INTRON ORIGIN; SNRNP PROTEIN; SEQUENCES; 3'-SPLICE-SITE; CONSERVATION; RECOGNIZES; POSITIONS; EVOLUTION; PHASES AB Most of the eukaryotic protein-coding genes are interrupted by multiple introns. A substantial fraction of introns occupy the same position in orthologous genes from distant eukaryotes, such as plants and animals, and consequently are inferred to have been inherited from the common ancestor of these organisms. In contrast to these conserved introns, many other introns appear to have been gained during evolution of each major eukaryotic lineage. The mechanism(s) of insertion of new introns into genes remains unknown. Because the nucleotides that flank splice junctions are nonrandom, it has been proposed that introns are preferentially inserted into specific target sequences termed protosplice sites. However, it remains unclear whether the consensus nucleotides flanking the splice junctions are remnants of the original protosplice sites or if they evolved convergently after intron insertion. Here, we directly address the existence of protosplice sites by examining the context of introns inserted within codons that encode amino acids conserved in all eukaryotes and accordingly are not subject to selection for splicing efficiency. We show that introns are either predominantly inserted into specific protosplice sites, which have the consensus sequence (A/C)AG/Gt, or that they are inserted randomly but are preferentially fixed at such sites. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nim.nih.gov RI Babenko, Vladimir/K-5609-2014; OI Babenko, Vladimir/0000-0002-3077-9559 NR 25 TC 33 Z9 34 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 24 PY 2004 VL 14 IS 16 BP 1505 EP 1508 DI 10.1016/j.cub.2004.08.027 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 850BV UT WOS:000223586900030 PM 15324669 ER PT J AU Cutler, RG Haughey, NJ Tammara, A McArthur, JC Nath, A Reid, R Vargas, DL Pardo, CA Mattson, MP AF Cutler, RG Haughey, NJ Tammara, A McArthur, JC Nath, A Reid, R Vargas, DL Pardo, CA Mattson, MP TI Dysregulation of sphingolipid and sterol metabolism by ApoE4 in HIV dementia SO NEUROLOGY LA English DT Article ID APOLIPOPROTEIN-E RECEPTOR; ALZHEIMERS-DISEASE; LIPOPROTEIN RECEPTOR; OXIDATIVE STRESS; CALCIUM DYSREGULATION; INFECTED PATIENTS; CERAMIDE; PROTEIN; ALLELE; CELLS AB Background: Polymorphisms in apolipoprotein E have been associated with worse prognoses in numerous neurodegenerative conditions, including HIV dementia (HIVD). Despite these correlative observations, there has been little evidence suggesting a mechanism whereby the expression of ApoE4 renders neurons susceptible to insult. Methods: Electrospray ionization tandem mass spectrometry was used to quantify levels of sphingolipids and sterols in brains of HIVD patients. Data were stratified according to APOE genotype. Results: The authors found evidence of dysregulated lipid and sterol metabolism in HIVD patients with an APOE4 genotype. They also found elevations of sphingomyelin, ceramide, and cholesterol in the medial frontal cortex, parietal cortex, and cerebellum of HIVD patients with an APOE3/4 or APOE4/4 genotype compared with HIVD patients with an APOE3/3 genotype. There was no difference in the number of astrocytes or activated microglia in any brain region of the two patient populations, suggesting that modification of lipid metabolism in HIVD patients with an APOE4 genotype was not the result of increased CNS inflammation. Conclusions: HIV dementia patients with an APOE4 genotype may be sensitized to neural insults because of dysregulations in lipid metabolism. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21287 USA. NIA, Neurosci Lab, Gerontol Res Ctr, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA. RP Haughey, NJ (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, Meyer 6-109,600 N Wolfe St, Baltimore, MD 21287 USA. EM nhaughe1@jhmi.edu RI Mattson, Mark/F-6038-2012 FU NIA NIH HHS [R01 AG023471-0]; NIDA NIH HHS [K08 DA016160, K08 DA016160-01A1]; NINDS NIH HHS [NS049465] NR 41 TC 48 Z9 51 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 24 PY 2004 VL 63 IS 4 BP 626 EP 630 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 848UP UT WOS:000223493800007 PM 15326233 ER PT J AU Gottlieb, DJ DeStefano, AL Foley, DJ Mignot, E Redline, S Givelber, RJ Young, T AF Gottlieb, DJ DeStefano, AL Foley, DJ Mignot, E Redline, S Givelber, RJ Young, T TI APOE epsilon 4 is associated with obstructive sleep apnea/hypopnea - The Sleep Heart Health Study SO NEUROLOGY LA English DT Article ID APOLIPOPROTEIN-E GENOTYPE; CARDIOVASCULAR-DISEASE; ALZHEIMERS-DISEASE; RISK-FACTORS; APNEA; PATHOGENESIS; POPULATION; ADULTS; GENE; AGE AB Background: Obstructive sleep apnea/hypopnea (OSAH) has a strong heritable component, although its genetic basis remains largely unknown. One epidemiologic study found a significant association between the APOE epsilon4 allele and OSAH in middle-aged adults, a finding that was not replicated in a cohort of elderly adults. The objective of this study was to further examine the association of the APOE epsilon4 allele with OSAH in a community-dwelling cohort, exploring age dependency of the association. Methods: A genetic association study was performed, nested within a prospective cohort study of the cardiovascular consequences of OSAH. Unattended, in-home nocturnal polysomnography was used to measure apnea-hypopnea index (AHI) in 1,775 participants age 40 to 100 years. OSAH was defined as an AHIgreater than or equal to15. The relation of APOE genotype to prevalent OSAH was analyzed using generalized estimating equations to account for non-independent observations of individuals from the same sibship. Results: At least one APOE epsilon4 allele was present in 25% of subjects, with 1.3% epsilon4/epsilon4 homozygotes. The prevalence of OSAH was 19%. After adjustment for age, sex, and BMI, the presence of any APOE epsilon4 allele was associated with increased odds of OSAH (OR 1.41, 95% CI 1.06 to 1.87, p=0.02). The effect was approximately twice as great in subjects <75 (OR 1.61, CI 1.02 to 2.54) as in those &GE;75 years old ( OR 1.32, CI 0.91 to 1.90). Exploratory analyses revealed that the strongest effect of APOE ε4 was in subjects age <65 (OR 3.08, CI 1.43 to 6.64), and was stronger in those with hypertension or cardiovascular disease than in those without. Conclusion: The APOE epsilon4 allele is associated with increased risk of OSAH, particularly in individuals under age 65. The mechanisms underlying this association are uncertain. Age-dependency of the APOE-OSAH association may explain previous conflicting results. C1 Boston Univ, Sch Med, Ctr Pulm, Boston, MA 02118 USA. VA Boston Healthcare Syst, Boston, MA USA. Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. NIA, Bethesda, MD 20892 USA. Stanford Univ, Stanford, CA 94305 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Wisconsin, Madison, WI USA. RP Gottlieb, DJ (reprint author), Boston Univ, Sch Med, Ctr Pulm, 715 Albany St,R-304, Boston, MA 02118 USA. EM dgottlieb@lung.bumc.bu.edu FU NHLBI NIH HHS [U01 HL53934, R01 HL71515, U01 HL53916, U01 HL53931, U01 HL53937, U01 HL53938, U01 HL53940, U01 HL53941, U01 HL63429, U01 HL63463, U01 HL64360] NR 27 TC 91 Z9 95 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 24 PY 2004 VL 63 IS 4 BP 664 EP 668 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 848UP UT WOS:000223493800013 PM 15326239 ER PT J AU Egan, MF Straub, RE Goldberg, TE Yakub, I Callicott, JH Hariri, AR Mattay, VS Bertolino, A Hyde, TM Shannon-Weickert, C Akil, M Crook, J Vakkalanka, RK Balkissoon, R Gibbs, RA Kleinman, JE Weinberger, DR AF Egan, MF Straub, RE Goldberg, TE Yakub, I Callicott, JH Hariri, AR Mattay, VS Bertolino, A Hyde, TM Shannon-Weickert, C Akil, M Crook, J Vakkalanka, RK Balkissoon, R Gibbs, RA Kleinman, JE Weinberger, DR TI Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RELATIVE RISK; GENE; CORTEX; SIBLINGS; EXPRESSION; SUSCEPTIBILITY; DYSFUNCTION; HIPPOCAMPUS; POPULATION; RECEPTORS AB GRM3, a metabotropic glutamate receptor-modulating synaptic glutamate, is a promising schizophrenia candidate gene. in a family-based association study, a common GRM3 haplotype was strongly associated with schizophrenia (P = 0.0001). Within this haplotype, the A allele of single-nucleotide polymorphism (SNP) 4 (hCV11245618) in intron 2 was slightly overtransmitted to probands (P = 0.02). We studied the effects of this SNP on neurobiological traits related to risk for schizophrenia and glutamate neurotransmission. The SNP4 A allele was associated with poorer performance on several cognitive tests of prefrontal and hippocampal function. The physiological basis of this effect was assessed with functional MRI, which showed relatively deleterious activation patterns in both cortical regions in control subjects homozygous for the SNP4 A allele. We next looked at SNP4's effects on two indirect measures of prefrontal glutamate neurotransmission. Prefrontal N-acetylaspartate, an in vivo MRI measure related to synaptic activity and closely correlated with tissue glutamate, was lower in SNP4 AA homozygotes. In postmortem human prefrontal cortex, AA homozygotes had lower mRNA levels of the glial glutamate transporter EAAT2, a protein regulated by GRM3 that critically modulates synaptic glutamate. Effects of SNP4 on prefrontal GRM3 mRNA and protein levels were marginal. Resequencing revealed no missense or splice-site SNIPS, suggesting that the intronic SNP4 or related haplotypes may exert subtle regulatory effects on GRM3 transcription. These convergent data point to a specific molecular pathway by which GRM3 genotype alters glutamate neurotransmission, prefrontal and hippocampal physiology and cognition, and thereby increased risk for schizophrenia. C1 NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA. Univ Bari, Clin Psichiatr 2, I-70121 Bari, Italy. ES Cell Int Pte Ltd, Melbourne, Vic 8008, Australia. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bldg 10,Ctr Dr,Room 45-227,MSC 1384, Bethesda, MD 20892 USA. EM weinberd@intra.nimh.nih.gov RI Shannon Weickert, Cynthia/G-3171-2011; Hariri, Ahmad/D-5761-2011; Callicott, Joseph/C-9102-2009 OI Callicott, Joseph/0000-0003-1298-3334 NR 36 TC 240 Z9 257 U1 0 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 24 PY 2004 VL 101 IS 34 BP 12604 EP 12609 DI 10.1073/pnas.040577101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 850FI UT WOS:000223596200039 PM 15310849 ER PT J AU Ivanov, KA Hertzig, T Rozanov, M Bayer, S Thiel, V Gorbalenya, AE Ziebuhr, J AF Ivanov, KA Hertzig, T Rozanov, M Bayer, S Thiel, V Gorbalenya, AE Ziebuhr, J TI Major genetic marker of nidoviruses encodes a replicative endoribonuclease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID ACUTE RESPIRATORY SYNDROME; SUBGENOMIC RNA-SYNTHESIS; CORONAVIRUS GENOME; SARS-CORONAVIRUS; SEQUENCE MOTIFS; IN-VITRO; VIRUS; TRANSCRIPTION; PROTEINASE; IDENTIFICATION AB Coronaviruses are important pathogens that cause acute respiratory diseases in humans. Replication of the approximate to30-kb positive-strand RNA genome of coronaviruses and discontinuous synthesis of an extensive set of subgenome-length RNAs (transcription) are mediated by the replicase-transcriptase, a barely characterized protein complex that comprises several cellular proteins and up to 16 viral subunits. The coronavirus replicase-transcriptase was recently predicted to contain RNA-processing enzymes that are extremely rare or absent in other RNA viruses. Here,we established and characterized the activity of one of these enzymes, replicative nidoviral uridylate-specific endoribonuclease (NendoU). It is considered a major genetic marker that discriminates nidoviruses (Coronaviridae, Arteriviridae, and Roniviridae) from all other RNA virus families. Bacterially expressed forms of NendoU of severe acute respiratory syndrome coronavirus and human coronavirus 229E were revealed to cleave single-stranded and double-stranded RNA in a Mn2+-dependent manner. Single-stranded RNA was cleaved less specifically and effectively, suggesting that double-stranded RNA is the biologically relevant NendoU substrate. Double-stranded RNA substrates were cleaved upstream and downstream of uridylates at GUU or GU sequences to produce molecules with 2'-3'cyclic phosphate ends. 2'-O-ribose-methylated RNA substrates proved to be resistant to cleavage by NendoU, indicating a functional link with the 2'-O-ribose methyltransferase located adjacent to NendoU in the coronavirus replicative polyprotein. A mutagenesis study verified potential active-site residues and allowed us to inactivate NendoU in the full-length human coronavirus 229E clone. Substitution of D6408 by Ala was shown to abolish viral RNA synthesis, demonstrating that NendoU has critical functions in viral replication and transcription. C1 Univ Wurzburg, Inst Immunol & Virol, D-97078 Wurzburg, Germany. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Cantonal Hosp, Res Dept, CH-9007 St Gallen, Switzerland. Leiden Univ, Med Ctr, Dept Med Microbiol, Mol Virol Lab, NL-2300 RC Leiden, Netherlands. RP Ziebuhr, J (reprint author), Univ Wurzburg, Inst Immunol & Virol, Versbacher Str 7, D-97078 Wurzburg, Germany. EM j.ziebuhr@mail.uni-wuerzburg.de RI Gorbalenya, Alexander/J-4818-2012 OI Gorbalenya, Alexander/0000-0002-4967-7341 NR 29 TC 136 Z9 143 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 24 PY 2004 VL 101 IS 34 BP 12694 EP 12699 DI 10.1073/pnas.0403127101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 850FI UT WOS:000223596200054 PM 15304651 ER PT J AU O'Farrell, C Lockhart, PJ Lincoln, S De Lucia, M Singleton, AB Dickson, DW Cookson, MR AF O'Farrell, C Lockhart, PJ Lincoln, S De Lucia, M Singleton, AB Dickson, DW Cookson, MR TI Biochemical characterization of torsinB SO MOLECULAR BRAIN RESEARCH LA English DT Article DE torsin; dystonia; DYT1; glycosylation; Lewy bodies ID TOR1A DYT1 GENE; ALPHA-SYNUCLEIN; MUTANT TORSINA; MESSENGER-RNAS; LEWY BODIES; HUMAN BRAIN; DYSTONIA; PROTEINS; MUTATIONS; ATPASES AB Mutations in torsinA, a member of the AAA(+) family of ATPases, are associated with early onset-dystonia. A closely related homologue, torsinB, has also been described but the significance of this second form is not clear. Here, we demonstrate that in transfected cells, torsinB has similar electrophoretic mobility to torsinA but is more basic consistent with predictions from the cDNA sequence. Like torsinA, torsinB is glycosylated and localized to PDI-positive structures in cells. However, torsinB unlike torsinA has a tendency to form intracellular inclusions when expressed at similar levels. We were able to confirm previous reports that torsinA is present in brainstem Lewy bodies, but we saw no torsinB-like immunoreactivity in the same structures. These results show that torsins A and B are similar proteins, although there are differences in the abundance of the two homologues and in their recruitment into Lewy bodies. Published by Elsevier B.V. C1 NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. Mayo Clin Jacksonville, Dept Neurosci, Jacksonville, FL 32224 USA. RP Cookson, MR (reprint author), NIA, Lab Neurogenet, NIH, Bldg 10 Room 6C103,MSC1589,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Cookson@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Lockhart, Paul/E-7753-2011; OI Lockhart, Paul/0000-0003-2531-8413; Dickson, Dennis W/0000-0001-7189-7917 NR 24 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD AUG 23 PY 2004 VL 127 IS 1-2 BP 1 EP 9 DI 10.1016/j.molbrainres.2004.05.005 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 849UU UT WOS:000223567300001 ER PT J AU Austin, CP AF Austin, CP TI NIH director's roadmap: From genome to drugs. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NHGRI, NIH, Bethesda, MD 20892 USA. EM austinc@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 1-BTEC BP U530 EP U530 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713802781 ER PT J AU Betz, JM AF Betz, JM TI Development and validation of analytical methods for botanical dietary supplements. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. EM betzj@od.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 178-ANYL BP U162 EP U162 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800664 ER PT J AU Boyer, PL Marquez, VE Julias, JG Hughes, SH AF Boyer, PL Marquez, VE Julias, JG Hughes, SH TI Fixed conformation nucleoside analogs are effective against excision-proficient HIV-1 RTs. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NIH, Retroviral Replicat Lab, NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. NCI, HIV Drug Resistance Program, FCRDC, Frederick, MD 21702 USA. EM boyerp@ncifcrf.gov; hughes@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 167-MEDI BP U937 EP U937 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712804000 ER PT J AU Brechbiel, MW Kobayashi, H Kawamoto, S Sakai, Y Choyke, P Morris, J Waldmann, TA AF Brechbiel, MW Kobayashi, H Kawamoto, S Sakai, Y Choyke, P Morris, J Waldmann, TA TI Development of nano-sized dendrimer based MR contrast agents for imaging of breast cancer sentinel nodes. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Radioimmune & Inorgan Chem Sect, CCR, Bethesda, MD 20892 USA. NCI, Metab Branch, CCR, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21218 USA. NIH, DRD, Ctr Clin, Bethesda, MD 20892 USA. NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 347-INOR BP U831 EP U831 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803391 ER PT J AU Brechbiel, MW Milenic, DE Garmestani, K Brady, E Abdulla, A Overstreet, T Flynn, J AF Brechbiel, MW Milenic, DE Garmestani, K Brady, E Abdulla, A Overstreet, T Flynn, J TI Radioimmunotherapy of intraperitoneal disseminated disease: Combined modalities of radiolabeled monoclonal antibodies and chemotherapeutics. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Radioimmune & Inorgan Chem Sect, CCR, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. Walter Reed Med Ctr, Washington, DC USA. EM martinwb@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 12-NUCL BP U6 EP U6 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713800013 ER PT J AU Che, Y Marshall, GR Brooks, BR AF Che, Y Marshall, GR Brooks, BR TI Towards novel therapeutics against HIV infection and drug resistance. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Washington Univ, Ctr Computat Biol, St Louis, MO 63130 USA. Washington Univ, Dept Biochem & Mol Biophys, St Louis, MO 63130 USA. EM chey@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 190-COMP BP U529 EP U529 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712802217 ER PT J AU Chennasamudram, SP Feng, J AF Chennasamudram, SP Feng, J TI Changes in secondary structure of proteins based on amino acid sequence patterns. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, Basic Res Program,SAIC, Frederick, MD 21702 USA. Inst Adv Study, Princeton, NJ 08540 USA. EM sudhac@temple.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 135-BIOL BP U193 EP U193 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800828 ER PT J AU Clifford, T Brechbiel, MW AF Clifford, T Brechbiel, MW TI Chelates suitable for the preparation of metal ion labeled peptides in conventional peptide synthesizers. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Radionimmune & Inorgan Chem Sect, ROB,DCS, NIH, Bethesda, MD 20892 USA. EM clifford@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 491-INOR BP U854 EP U854 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803533 ER PT J AU Danthi, N Burnett, CA Xie, JW Shen, ZM Li, KCP AF Danthi, N Burnett, CA Xie, JW Shen, ZM Li, KCP TI Second generation alpha(v)beta(3) integrin antagonists. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Ctr Clin, Mol Imaging Lab, NIH, Bethesda, MD 20892 USA. NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. EM ndanthi@cc.nih.gov RI Danthi, Simhan/B-7639-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 282-MEDI BP U958 EP U959 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712804115 ER PT J AU Duan, DH Peach, ML Lai, CC Lewin, NE Kelley, JA Blumberg, PM Marquez, VE AF Duan, DH Peach, ML Lai, CC Lewin, NE Kelley, JA Blumberg, PM Marquez, VE TI The discovery of protein kinase C (PK-C) isozyme: Specific ligands driven by a solid-phase combinatorial synthesis of diacylglycerol-lactones (DAG-lactones). SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA. NIH, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. EM duand@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 177-MEDI BP U939 EP U939 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712804010 ER PT J AU Gilbert, KM Matecka, D Prisinzano, T Rice, KC Venanzi, CA AF Gilbert, KM Matecka, D Prisinzano, T Rice, KC Venanzi, CA TI Clustering analysis of flexible GBR 12909 dialkyl piperazine and piperidine analogs. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 New Jersey Inst Technol, Dept Chem & Environm Sci, Newark, NJ 07102 USA. NIDDK, Med Chem Lab, DHHS, NIH, Bethesda, MD 20892 USA. EM kxg2248@njit.edu RI Prisinzano, Thomas/B-7877-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 178-COMP BP U527 EP U527 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712802205 ER PT J AU Goehl, TJ AF Goehl, TJ TI Importance of information sharing and capacity building. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NIEHS, Res Triangle Pk, NC 27709 USA. EM goehl@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 005-CHAS BP U302 EP U302 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712801160 ER PT J AU Grigorenko, B Nemukhin, A Topol, IA Cachau, RE Burt, SK AF Grigorenko, B Nemukhin, A Topol, IA Cachau, RE Burt, SK TI Mechanism of the guanosine triphosphate hydrolysis by RAS-GAP proteins as studied by the flexible effective fragment QM/MM technique. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. NCI, Adv Biomed Comp Ctr, Frederick, MD 21701 USA. NCI, Adv Biomed Comp Ctr, Bethesda, MD 20892 USA. EM bella@lcc.chem.msu.ru RI Nemukhin, Alexander/P-9662-2015 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 638-PHYS BP U295 EP U295 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713801586 ER PT J AU Horkay, F Horkayne-Szakaly, I Basser, PJ AF Horkay, F Horkayne-Szakaly, I Basser, PJ TI Swelling behavior of tissue engineered cartilage samples. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 147-BIOL BP U195 EP U195 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800839 ER PT J AU Horkay, F Basser, PJ Hecht, AM Geissler, E AF Horkay, F Basser, PJ Hecht, AM Geissler, E TI Osmotic and small-angle neutron scattering properties of DNA gels. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Univ Grenoble 1, CNRS, UMR 5588, Spectrometrie Phys Lab, Grenoble, France. EM horkay@helix.nih.gov RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 474-POLY BP U396 EP U396 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713802148 ER PT J AU Hu, ZJ Ma, BY Nussinov, R Southerland, WM AF Hu, ZJ Ma, BY Nussinov, R Southerland, WM TI Molecular dynamics simulation of E-coli dihydrofolate reductase and its circular permuted variants: Relative stabilities in experiment and simulations. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. Howard Univ, Drug Discovery Unit, Washington, DC 20059 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC, Lab Expt & Computat Biol,Basic Res Program, Bethesda, MD 20892 USA. NCI, SAIC Frederick Inc, Basic Res Program, Bethesda, MD 20892 USA. EM zhu@howard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 123-COMP BP U519 EP U519 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712802150 ER PT J AU Huffman, SW Levin, IW AF Huffman, SW Levin, IW TI Reorganizational dynamics of multilamellar lipid bilayer assemblies using high-pressure fourier transform infrared spectroscopy. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. EM huffman@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 102-AEI BP U42 EP U42 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800120 ER PT J AU Jameson, CW AF Jameson, CW TI Report on carcinogens: History and process. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NIEHS, Res Triangle Pk, NC 27709 USA. EM jameson@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 008-CHAS BP U303 EP U303 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712801163 ER PT J AU Jones, PA Cheng, JC Yoo, C Liang, GN Marquez, VE AF Jones, PA Cheng, JC Yoo, C Liang, GN Marquez, VE TI Zebularine induces and sustains DNA cytosine demethylation in human cancer cells. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Univ So Calif, Keck Sch Med, Dept Biochem & Mol Biol, Los Angeles, CA 90089 USA. Natl Canc Inst, Ctr Canc Res, Med Chem Lab, Frederick, MD USA. EM jones_p@ccnt.hsc.usc.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 163-MEDI BP U937 EP U937 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803996 ER PT J AU Joy, A Seidman, M Schuster, GB AF Joy, A Seidman, M Schuster, GB TI Investigation of the role of long range charge transfer in stimulation of gene mutations. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Georgia Inst Technol, Dept Chem & Biochem, Atlanta, GA 30332 USA. NIA, Sect Gene Targeting, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 060-AEI BP U35 EP U35 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800078 ER PT J AU Kalish, H Yocum, GT Jordan, EK Talbot, T Arbab, AS Frank, JA AF Kalish, H Yocum, GT Jordan, EK Talbot, T Arbab, AS Frank, JA TI Complexing protamine sulfate with ferumoxides produces a more efficient Mr T-2 contrast agent. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NIH, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Engn & Phys Sci, Bethesda, MD 20892 USA. EM hkalish@cc.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 608-INOR BP U872 EP U872 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803644 ER PT J AU Koder, RL Lichtenstein, BR Walsh, J Witterbort, R Miller, AF AF Koder, RL Lichtenstein, BR Walsh, J Witterbort, R Miller, AF TI Solid-state NMR studies of active site and model flavins. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Univ Penn, Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA. NCI, Struct Biophys Lab, Bethesda, MD 20892 USA. Univ Louisville, Dept Chem, Louisville, KY 40292 USA. Univ Kentucky, Dept Chem, Lexington, KY 40506 USA. EM afm@uky.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 234-BIOL BP U209 EP U209 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800925 ER PT J AU Leary, G Ross, JB Kavanaugh, MP AF Leary, G Ross, JB Kavanaugh, MP TI Combining fluorescence and electrophysiology to probe glutamate transporter structure and function. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Univ Montana, Ctr Struct & Funct Neurosci, NIH, COBRE, Missoula, MT 59803 USA. EM michael.kavanaugh@umontana.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 002-MEDI BP U907 EP U907 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803836 ER PT J AU Lee, YS Krauss, M AF Lee, YS Krauss, M TI Reversible proton transfer dynamics in bacteriorhodopsin SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NIH, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. EM leeys@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 312-PHYS BP U247 EP U247 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713801269 ER PT J AU Levin, IW Huffman, SW Schlucker, S Fenandez, DC Bhargava, R AF Levin, IW Huffman, SW Schlucker, S Fenandez, DC Bhargava, R TI Vibrational spectroscopic imaging: From macromolecular assemblies to biological tissues. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD USA. EM iwl@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 197-AMYL BP U165 EP U165 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800683 ER PT J AU Lewis, CD AF Lewis, CD TI NIH programs in single molecule biophysics, cellular imaging and nanoscience. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Natl Inst Gen Med Sci, NIH, Bethesda, MD 20892 USA. EM lewisc@nigms.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 200-PHYS BP U231 EP U231 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713801158 ER PT J AU Lin-Gibson, S Jones, R Washburn, NR Horkay, F AF Lin-Gibson, S Jones, R Washburn, NR Horkay, F TI Structure-property relationships of photopolymerizable PEGDM hydrogels. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Natl Inst Stand & Technol, Div Polymers, Gaithersburg, MD 20899 USA. NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 294-POLY BP U369 EP U369 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713801970 ER PT J AU Ma, BY AF Ma, BY TI From philosophy of computational ouantum chemistry to philosophy of computational biology. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, FCRDC, Basic Res Program, Lab Expt & Computat Biol, Frederick, MD 21702 USA. EM mab@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 012-COMP BP U502 EP U502 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712802042 ER PT J AU Ma, BY Pan, YP Gunasekaran, K Venkataraghavan, B Levine, AJ Nussinov, R AF Ma, BY Pan, YP Gunasekaran, K Venkataraghavan, B Levine, AJ Nussinov, R TI Computational study of p53 core domain dimers: What is the biological interface? SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Frederick Canc Res & Dev Ctr, Lab Expt & Computat Biol, Basic Res Program,SAIC, Frederick, MD 21702 USA. Inst Adv Study, Princeton, NJ 08540 USA. EM mab@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 136-BIOL BP U193 EP U193 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800829 ER PT J AU Mertz, EL AF Mertz, EL TI Physics behind conformance of microscopic dielectric response of dipolar solvents to macroscopic continuum model. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NICHD, NIH, Bethesda, MD 20892 USA. EM mertze@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 388-PHYS BP U258 EP U258 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713801344 ER PT J AU Metaferia, BB Bewley, CA AF Metaferia, BB Bewley, CA TI Synthesis of substrate-mimic analogues of mycothiol as inhibitors of Rv1170 and Rv1082 of mycobacterium tuberculosis. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NIH, NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. EM belhum@intra.niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 151-MEDI BP U935 EP U935 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803984 ER PT J AU Nelson, ME Loktionova, N Pegg, AE Moschel, RC AF Nelson, ME Loktionova, N Pegg, AE Moschel, RC TI 2-amino-O-4-benzylpteridines and O-4-benzylfolic acid: Potent inactivators of O-6-alkylguanine-DNA alkyltransferase and potential chemotherapy adjuvants. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. Penn State Univ, Coll Med, Milton S Hershey Med Ctr, University Pk, PA 16802 USA. EM nelsonm@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 110-MEDI BP U927 EP U927 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803943 ER PT J AU Nemukhin, A Grigorenko, B Topol, IA Burt, SK AF Nemukhin, A Grigorenko, B Topol, IA Burt, SK TI Applications of the flexible effective fragment QM/MM technique for modeling biomolecular processes. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Moscow MV Lomonosov State Univ, Dept Chem, Moscow 119992, Russia. NCI, Adv Biomed Comp Ctr, Bethesda, MD 20892 USA. NCI, Adv Biomed Comp Ctr, SAIC, Frederick, MD 21701 USA. EM anem@lcc.chem.msu.ru RI Nemukhin, Alexander/P-9662-2015 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 269-PHYS BP U240 EP U241 PN 2 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713801226 ER PT J AU Pan, YP Ma, B Nussinov, R AF Pan, YP Ma, B Nussinov, R TI Characterization of unbound conformations of gp120 core domain. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, FCRDC, SAIC, Basic Res Program,Lab Expt & Computat Biol, Frederick, MD 21702 USA. NCI, Basic Res Program, SAIC Frederick Inc, Bethesda, MD 20892 USA. EM pany@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 177-COMP BP U527 EP U527 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712802204 ER PT J AU Pandit, B Li, PK Hu, ZG Sackett, DL Xiao, Z Cheah, C AF Pandit, B Li, PK Hu, ZG Sackett, DL Xiao, Z Cheah, C TI SU-5416 analogs with anti-proliferative, anti-microtubuile and apoptosis inducing properties. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Ohio State Univ, Coll Pharm, Dept Med Chem & Pharmacognosy, Columbus, OH 43210 USA. NICHHD, Lab Integrat & Med Biophys, Bethesda, MD 20892 USA. EM pandit.6@osu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 093-MEDI BP U924 EP U924 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803926 ER PT J AU Pandit, D Roosma, W Misra, M Gilbert, KM Matecka, D Prisinzano, T Rice, KC Venanzi, CA AF Pandit, D Roosma, W Misra, M Gilbert, KM Matecka, D Prisinzano, T Rice, KC Venanzi, CA TI Conformational analysis of piperazine and piperidine analogs of GBR12909: Effect of force field and solvent. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 New Jersey Inst Technol, Dept Chem & Environm Sci, Newark, NJ 07102 USA. NIDDK, Med Chem Lab, DHHS, NIH, Bethesda, MD 20892 USA. New Jersey Inst Technol, Dept Comp Sci, Newark, NJ 07102 USA. EM dnp5@njit.edu RI Prisinzano, Thomas/B-7877-2010 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 134-COMP BP U520 EP U520 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712802161 ER PT J AU Patil, SS Shkriabai, N Zhang, XC Pais, GCG Svarovskaia, ES Merchand, C Pathak, VK Pommier, Y Le Grice, S Kvaratskhelia, M Burke, TR AF Patil, SS Shkriabai, N Zhang, XC Pais, GCG Svarovskaia, ES Merchand, C Pathak, VK Pommier, Y Le Grice, S Kvaratskhelia, M Burke, TR TI Caffeoyl-based affinity acetylators of HIV-1 integrase as novel pharmacological SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT Meeting of the Division of Chemical Toxicology of the American-Chemical-Society held at the 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc, Div Chem Toxicol C1 NCI, Med Chem Lab, CCR, NIH, Ft Detrick, MD 21702 USA. Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, Hlth Sci Ctr, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Hlth Sci Ctr, Columbus, OH 43210 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. NIH, HIV Drug Resistant Program, Bethesda, MD USA. EM sachin@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 329-MEDI BP U967 EP U967 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712804159 ER PT J AU Planalp, RP Ye, N Park, GS Przyborowska, AM Sloan, PE Clifford, T Bauer, CB Broker, GA Rogers, RD Ma, R Torti, SV Brechbiel, MW AF Planalp, RP Ye, N Park, GS Przyborowska, AM Sloan, PE Clifford, T Bauer, CB Broker, GA Rogers, RD Ma, R Torti, SV Brechbiel, MW TI Nickel(II), copper(II) and zinc(II) binding properties and cytotoxicity of tripodal, hexadentate tris(ethylenediamine)analogue chelators. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ Alabama, Dept Chem, Tuscaloosa, AL 35487 USA. Univ Alabama, Ctr Green Mfg, Tuscaloosa, AL 35487 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27103 USA. NCI, CCR, Radioimmune & Inorgan Chem Sect, Bethesda, MD 20892 USA. EM roy.planalp@unh.edu RI Rogers, Robin/C-8265-2013 OI Rogers, Robin/0000-0001-9843-7494 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 424-INOR BP U843 EP U843 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803468 ER PT J AU Regino, CA Deal, KA Stein, W AF Regino, CA Deal, KA Stein, W TI Double-stranded DNA hydrolysis using copper(II) tripodal ligands under both aerobic and anaerobic conditions. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NIH, Radiat Biol Branch, Bethesda, MD 20892 USA. EM reginoc@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 449-INOR BP U847 EP U847 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803492 ER PT J AU Regino, CA Torti, SV Torti, FM Rong, M Planalp, RP Brechbiel, MW AF Regino, CA Torti, SV Torti, FM Rong, M Planalp, RP Brechbiel, MW TI N-picolyl derivatives of Kemp's triamine as potential antitumor agents: Preliminary investigations. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Biochem, Sch Med, Winston Salem, NC 27109 USA. Wake Forest Univ, Dept Canc Biol, Winston Salem, NC 27109 USA. Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. EM reginoc@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 103-INOR BP U792 EP U792 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803148 ER PT J AU Sanabia, JE Goldner, LS Lacaze, PA Hawkins, ME AF Sanabia, JE Goldner, LS Lacaze, PA Hawkins, ME TI Single molecule detection and fluorescence characterization of 3-MI, a guanosine analog SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Natl Inst Stand & Technol, Phys Lab, Gaithersburg, MD 20899 USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. EM lori.goldner@nist.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 167-PHYS BP U226 EP U226 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713801125 ER PT J AU Shi, ZD Liu, HP Zhang, M Roberts, LR Fisher, RJ Yang, DJ Bottaro, D Linehan, M Burke, TR AF Shi, ZD Liu, HP Zhang, M Roberts, LR Fisher, RJ Yang, DJ Bottaro, D Linehan, M Burke, TR TI Design and synthesis biotinylated ligands exhibiting high GRB2 SH2 domain-binding affinity. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, CCR, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA. Univ Michigan, Sch Med, Dept Hematol & Oncol, Ann Arbor, MI USA. SAIC Frederick, Prot Chem Lab, Frederick, MD USA. NCI, Urol Oncol Branch, CCR, NIH, Bethesda, MD USA. EM shiz@ncifcrf.gov RI Fisher, Robert/B-1431-2009; Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 242-MEDI BP U951 EP U951 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712804075 ER PT J AU Sigano, DM Tamamura, H Lewin, NE Peach, ML Nicklaus, MC Blumberg, PM Marquez, VE AF Sigano, DM Tamamura, H Lewin, NE Peach, ML Nicklaus, MC Blumberg, PM Marquez, VE TI Hydrophobic ligand-protein interactions vs. ligand-lipid interactions of DAG-lactones with protein kinase C (PK-C). SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Med Chem Lab, NIH, Ft Detrick, MD 21702 USA. NIH, Cellular Carcinogenesis & Tumor Promot Lab, Bethesda, MD 20892 USA. EM dsigano@nih.gov RI Sigano, Dina/M-6144-2014 OI Sigano, Dina/0000-0001-7489-9555 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 229-MEDI BP U949 EP U949 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712804062 ER PT J AU Srinivasan, A Citro, ML Davies, KM Espey, MG Keefer, LK Miranda, KM Ridnour, LA Saavedra, JE Thomas, L Thomas, DD Waterhouse, DJ Wink, DA AF Srinivasan, A Citro, ML Davies, KM Espey, MG Keefer, LK Miranda, KM Ridnour, LA Saavedra, JE Thomas, L Thomas, DD Waterhouse, DJ Wink, DA TI Chemistry of the diazeniumdiolates. Rhn[N(O)NO](-) ions as progenitors of both nitroxyl and nitric oxide. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, BRP, Frederick, MD 21701 USA. George Mason Univ, Dept Chem, Fairfax, VA 22030 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. EM srinin@aol.com RI Miranda, Katrina/B-7823-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 054-TOXI BP U383 EP U383 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712801641 ER PT J AU Sun, GY AF Sun, GY TI Structure and stability of lower fullerenes C-38-C-50 and nitrogen-substituted heterofullerenes. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 082-COMP BP U512 EP U513 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712802109 ER PT J AU Sun, GY Voigt, JH Marquez, VE Nicklaus, MC AF Sun, GY Voigt, JH Marquez, VE Nicklaus, MC TI Pseudorotational and conformational analysis of nucleosides and nucleotides using the online prosit service and ouantum mechanical calculations. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Frederick Canc Res & Dev Ctr, CCR, NIH,Lab Med Chem, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 026-CARB BP U221 EP U222 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800984 ER PT J AU Sun, HY Nikolovska-Coleska, Z Yang, CY Xu, L Tomita, Y Krajewski, K Roller, PP Wang, SM AF Sun, HY Nikolovska-Coleska, Z Yang, CY Xu, L Tomita, Y Krajewski, K Roller, PP Wang, SM TI Structure-based design synthesis and evaluation of conformationally constrained smac mimetics that target XIAP/caspase-9 interaction site. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Georgetown Univ, Washington, DC 20057 USA. NCI, Med Chem Lab, NIH, Bethesda, MD 20892 USA. EM haiyings@med.umich.edu NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 109-MEDI BP U927 EP U927 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803942 ER PT J AU Talanov, VS Yordanov, AT Garmestani, K Milenic, DE Arora, HC Plascjak, PS Eckelman, WC Waldman, TA Brechbiel, MW AF Talanov, VS Yordanov, AT Garmestani, K Milenic, DE Arora, HC Plascjak, PS Eckelman, WC Waldman, TA Brechbiel, MW TI Preparation and in vivo evaluation of novel linkers for 211At labeling of proteins. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Radiat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD USA. EM talanovv@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 18-NUCL BP U7 EP U7 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713800019 ER PT J AU Talanova, GG Talanov, VS Hwang, HS Park, C Surowiec, K Bartsch, RA AF Talanova, GG Talanov, VS Hwang, HS Park, C Surowiec, K Bartsch, RA TI Rigid vs. flexible: The effect of ligand "preorganization" on metal ion recognition by lower rim-functionalized calix[4]arenes. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Howard Univ, Dept Chem, Washington, DC 20059 USA. Texas Tech Univ, Dept Chem, Lubbock, TX 79409 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gtalanova@howard.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 276-INOR BP U820 EP U820 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803320 ER PT J AU Tang, C Simo, O O'Malley, S Nagata, M Goldman, M Cregar, L Nguyen, D Kuzmic, P Moayeri, M Leppla, S Liddington, R Hemscheidt, T Jiao, GS AF Tang, C Simo, O O'Malley, S Nagata, M Goldman, M Cregar, L Nguyen, D Kuzmic, P Moayeri, M Leppla, S Liddington, R Hemscheidt, T Jiao, GS TI Discovery of cationic inhibitors of anthrax lethal factor protease. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Hawaii Biotech Inc, Dept Chem, Aiea, HI 96701 USA. Hawaii Biotech Inc, Dept Drug Discovery, Aiea, HI 96701 USA. NIAID, Bethesda, MD USA. Univ Hawaii Manoa, Honolulu, HI 96822 USA. EM ctang@hibiotech.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 332-MEDI BP U967 EP U968 PN 1 PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712804162 ER PT J AU Venditto, VJ Torti, SV Torti, FM Ma, R Planalp, RP Brechbiel, MW AF Venditto, VJ Torti, SV Torti, FM Ma, R Planalp, RP Brechbiel, MW TI Synthesis of N,N ',N '' trispyridylmethylene(2-aminoethyl)amine walkylated derivatives as potential anti-tumor agents. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27103 USA. Wake Forest Univ, Dept Canc Biol, Winston Salem, NC 27103 USA. Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. EM vendittv@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 440-INOR BP U846 EP U846 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712803483 ER PT J AU Wang, YZ Schnetz-Boutaud, NC Kroth, H Yagi, H Sayer, JM Kumar, S Donald, JM Stone, MP AF Wang, YZ Schnetz-Boutaud, NC Kroth, H Yagi, H Sayer, JM Kumar, S Donald, JM Stone, MP TI Structures of the 1S and 1R trans-opened benzo[c]phenanthrene diol epoxide DG adducts in a frameshift-prone (CPG)3 repeat sequence from the Salmonella typhimurium HISD3052 gene. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Vanderbilt Univ, Dept Chem, Ctr Mol Toxicol, Nashville, TN 37235 USA. Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Nashville, TN 37235 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. SUNY Buffalo, Great Lakes Lab, Buffalo, NY 14260 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 042-TOXI BP U381 EP U381 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712801629 ER PT J AU Wilson, SH AF Wilson, SH TI Molecular origin of DNA polymerase fidelity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 303-PHYS BP U246 EP U246 PN 2 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851VJ UT WOS:000223713801260 ER PT J AU Woods, AS Wang, HYJ AF Woods, AS Wang, HYJ TI Blocking the neuronal nicotinic acetylcholine receptor without side effects. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 NIDA, IRP, NIH, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 213-ANYL BP U167 EP U167 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800694 ER PT J AU Wu, YB Pradhan, P Havener, J Cambell, S Chaney, S AF Wu, YB Pradhan, P Havener, J Cambell, S Chaney, S TI Solution structure of an oxaliplatin 1,2-d(GG) intrastrand cross-link in a DNA dodecamer duplex by NMR. SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract CT 228th National Meeting of the American-Chemical-Society CY AUG 22-26, 2004 CL Philadelphia, PA SP Amer Chem Soc C1 Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. NIH, Dept Chem, New York, NY 10031 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 22 PY 2004 VL 228 MA 045-BIOL BP U178 EP U178 PN 1 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA 851UZ UT WOS:000223712800739 ER PT J AU Espinoza, LA Tone, LG Neto, JB Costa, RS Wang, QMJ Ballejo, G AF Espinoza, LA Tone, LG Neto, JB Costa, RS Wang, QMJ Ballejo, G TI Enhanced TGF alpha-EGFR expression and P53 gene alterations contributes to gastric tumors aggressiveness SO CANCER LETTERS LA English DT Article DE TGF alpha; EGFR; p53; p21(WAF1/CIP1); p16(INK4); gastric adenocarcinomas ID EPIDERMAL-GROWTH-FACTOR; FACTOR-RECEPTOR; PROLIFERATIVE ACTIVITY; CLINICAL-SIGNIFICANCE; CANCER PROGRESSION; CARCINOMA; PROTEIN; PROGNOSIS; SURVIVAL; P21(WAF1/CIP1) AB We determined whether alterations in the expression of p53, p16(INK4) and p21(WAF1/CIP1) influence the invasiveness of a subset of gastric adenocarcinomas co-expressing TGFalpha and EGFR. Immunopositivity for TGFalpha-EGFR (26%) was observed in both early and advanced adenocarcinomas, and 88% of these showed immunoreactivity for p53. SSCP analysis revealed that in 81% of these tumors the p53 gene was mutated in exons 5-8. The intensity of p53 immunoreactivity was significantly higher (P < 0.013) in deeply invasive tumors. p16(INK4) and p21(WAF1/CIP1) immunoreactivity was detected in 93 and 76% of the samples co-expressing TGFalpha-EGFR but the levels were not correlated with those of p53 and other clinico-pathological parameters. We conclude that gastric adenocarcinomas potentially dependent upon the TGFalpha-EGFR autocrine loop for growing exhibit increased aggressiveness in the presence of aberrant p53. (C) 2004 Published by Elsevier Ireland Ltd. C1 Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Genet, BR-1404900 Ribeirao Preto, SP, Brazil. Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pediat, BR-1404900 Ribeirao Preto, SP, Brazil. Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pathol, BR-1404900 Ribeirao Preto, SP, Brazil. NCI, Lab Cellular Carcinogenesis & Tumor Promot, Mol Mech Tumor Promot Sect, NIH, Bethesda, MD 20892 USA. Univ Sao Paulo, Sch Med Ribeirao Preto, Dept Pharmacol, BR-1404900 Ribeirao Preto, SP, Brazil. RP Espinoza, LA (reprint author), Georgetown Univ, Sch Med, Dept Biochem & Mol Biol, Basic Sci Bldg,R345,3900 Reservoir Rd NW, Washington, DC 20057 USA. EM lae2@georgetown.edu RI Wang, Qiming/B-6064-2012; Tone, Luiz/D-3934-2012 NR 36 TC 11 Z9 12 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD AUG 20 PY 2004 VL 212 IS 1 BP 33 EP 41 DI 10.1016/j.canlet.2004.03.037 PG 9 WC Oncology SC Oncology GA 842YZ UT WOS:000223041900005 PM 15246559 ER PT J AU Steven, AC AF Steven, AC TI Signal transduction at a protein synapse SO CELL LA English DT Editorial Material ID BACTERIOPHAGE-T4 AB Contraction of the bacteriophage T4 tail in the act of host cell penetration represents a massive structural change powered by conformational free energy. A paper in this issue of Cell by Leiman et al. (2004) compares cryo-electron microscopic reconstructions of the initial and final states and reveals that the basic underlying mechanism is concerted rigid-body movements of the constituent protein subunits, akin to the tumbling of gears in a lock. C1 NIAMS, Struct Biol Lab, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMS, Struct Biol Lab, Bldg 50,Room 1517,50 South Dr MSC 8025, Bethesda, MD 20892 USA. NR 9 TC 0 Z9 0 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 20 PY 2004 VL 118 IS 4 BP 403 EP 404 DI 10.1016/j.cell.2004.08.004 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 850YS UT WOS:000223650900001 PM 15315751 ER PT J AU Ramiro, AR Jankovic, M Eisenreich, T Difilippantonio, S Chen-Kiang, S Muramatsu, M Hongo, T Nussenzweig, A Nussenzweig, MC AF Ramiro, AR Jankovic, M Eisenreich, T Difilippantonio, S Chen-Kiang, S Muramatsu, M Hongo, T Nussenzweig, A Nussenzweig, MC TI AID is required for c-myc/IgH chromosome translocations in vivo SO CELL LA English DT Article ID CLASS-SWITCH RECOMBINATION; CYTIDINE DEAMINASE AID; DOUBLE-STRAND BREAKS; MYC ONCOGENE; SOMATIC HYPERMUTATION; B-CELLS; BURKITT-LYMPHOMA; CIRCULAR DNA; NEOPLASTIC DEVELOPMENT; MURINE PLASMACYTOMAS AB Chromosome translocations between c-myc and immunoglobulin (Ig) are associated with Burkitt's lymphoma in humans and with pristane- and IL6-induced plasmacytomas in mice. These translocations frequently involve Ig switch regions, suggesting that they might be the result of aberrant Ig class switch recombination (CSR). However, a direct link between CSR and chromosome translocations has not been established. We have examined c-myc/IgH translocations in IL6 transgenic mice that are mutant for activation induced cytidine deaminase (AID), the enzyme that initiates CSR. Her a we report that AID is essential for the c-myc/IgH chromosome translocations induced by IL6. C1 Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Dept Pathol, New York, NY 10021 USA. Kyoto Univ, Grad Sch Med, Dept Med Chem, Kyoto 6068501, Japan. RP Ramiro, AR (reprint author), Rockefeller Univ, Lab Mol Immunol, 1230 York Ave, New York, NY 10021 USA. EM nussen@mail.rockefeller.edu RI Muramatsu, Masamichi/C-4339-2015; Ramiro, Almudena/H-6037-2015 OI Muramatsu, Masamichi/0000-0002-0153-3533; Ramiro, Almudena/0000-0002-7539-3844 NR 59 TC 271 Z9 279 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD AUG 20 PY 2004 VL 118 IS 4 BP 431 EP 438 DI 10.1016/j.cell.2004.08.006 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 850YS UT WOS:000223650900006 PM 15315756 ER PT J AU Lee, WJ Cantor, KP Berzofsky, JA Zahn, SH Blair, A AF Lee, WJ Cantor, KP Berzofsky, JA Zahn, SH Blair, A TI Non-Hodgkin's lymphoma among asthmatics exposed to pesticides SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE asthma; insecticide; farmer; non-Hodgkin's lymphoma; pesticide exposure ID AGRICULTURAL HEALTH; NATURAL-KILLER; RISK-FACTORS; FARMERS; CANCER; MEN; APPLICATORS; RESPONDENTS; INHIBITION; MECHANISM AB We conducted a pooled analysis of population-based case-control studies in Iowa, Minnesota and Nebraska to investigate whether asthma modifies risk of non-Hodgkin's lymphoma (NHL) associated with pesticide exposures. Cases (n=872) diagnosed with NHL from 1980 to 1986 and frequency-matched controls (n=2,381) randomly selected from the same geographic areas as the cases were included Information on use of pesticides and history of asthma was based on interviews. Unconditional logistic regression was used to calculate ORs, adjusted for age, state and vital status. Of all subjects, 177 (45 cases, 132 controls) reported having been told by their doctor that they had asthma. Subjects with an asthma history had a nonsignificantly lower risk of NHL than nonasthmatics (OR=0.6, 95% CI 0.3-1.4), and there was no main effect of pesticide exposure (OR=1.0, 95% Cl 0.8-1.2). However, asthmatics tended to have larger ORs associated with exposure to pesticides than nonasthmatics. The OR among asthmatics was 1.8 (95% CI 1.1-3.2) for ever-use of crop insecticides, 2.7 (95% CI 1.0-7.2) for chlordane, 2.4 (95% CI 1.0-5.7) for lindane and 3.7 (95% CI 1.3-10.9) for fonofos. Among nonasthmatics, ORs were 1.1 (0.9-1.3),1.5 (1.1-2.2), 1.3 (0.97-1.8) and 1.6 (1.0-2.4), respectively. Although there is limited power for assessing interaction, our results suggest that the risk of NHL among asthmatics with pesticide exposure may be higher than among nonasthmatics with pesticide exposure. (C) 2004 Wiley-Liss, Inc. C1 NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemol & Genet, NIH, Rockville, MD 20852 USA. NCI, Mol Immunogenet & Vaccine Res Sect, Metab Branch, NIH, Bethesda, MD 20892 USA. RP Lee, WJ (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemol & Genet, NIH, 6120 Execut Blvd,EPS 8111, Rockville, MD 20852 USA. EM Leewj@mail.nih.gov NR 42 TC 20 Z9 20 U1 0 U2 3 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 AUG 20 PY 2004 VL 111 IS 2 BP 298 EP 302 DI 10.1002/ijc.20273 PG 5 WC Oncology SC Oncology GA 837PA UT WOS:000222646400020 PM 15197786 ER PT J AU Kovacs, M Toth, J Hetenyi, C Malnasi-Csizmadia, A Sellers, JR AF Kovacs, M Toth, J Hetenyi, C Malnasi-Csizmadia, A Sellers, JR TI Mechanism of blebbistatin inhibition of myosin II SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DEPENDENT ADENOSINE-TRIPHOSPHATASE; RABBIT SKELETAL-MUSCLE; TRYPTOPHAN RESIDUE; NEURITE OUTGROWTH; MOTOR DOMAIN; BINDING; ACTIN; CONTRACTION; TRANSITION; RESOLUTION AB Blebbistatin is a recently discovered small molecule inhibitor showing high affinity and selectivity toward myosin II. Here we report a detailed investigation of its mechanism of inhibition. Blebbistatin does not compete with nucleotide binding to the skeletal muscle myosin subfragment-1. The inhibitor preferentially binds to the ATPase intermediate with ADP and phosphate bound at the active site, and it slows down phosphate release. Blebbistatin interferes neither with binding of myosin to actin nor with ATP-induced actomyosin dissociation. Instead, it blocks the myosin heads in a products complex with low actin affinity. Blind docking molecular simulations indicate that the productive blebbistatin-binding site of the myosin head is within the aqueous cavity between the nucleotide pocket and the cleft of the actin-binding interface. The property that blebbistatin blocks myosin II in an actin-detached state makes the compound useful both in muscle physiology and in exploring the cellular function of cytoplasmic myosin II isoforms, whereas the stabilization of a specific myosin intermediate confers a great potential in structural studies. C1 NIH, Mol Cardiol Lab, NHLBI, Bethesda, MD 20892 USA. Eotvos Lorand Univ, Dept Biochem, H-1117 Budapest, Hungary. RP Sellers, JR (reprint author), NIH, Mol Cardiol Lab, NHLBI, Bldg 10,Rm 8N202, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov RI Hetenyi, Csaba/G-5249-2010; Kovacs, Mihaly/A-6841-2011 OI Hetenyi, Csaba/0000-0002-8013-971X; NR 31 TC 413 Z9 419 U1 6 U2 56 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 AUG 20 PY 2004 VL 279 IS 34 BP 35557 EP 35563 DI 10.1074/jbc.M405319200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 846GJ UT WOS:000223303400051 PM 15205456 ER PT J AU Kadyrov, FA Drake, JW AF Kadyrov, FA Drake, JW TI UvsX recombinase and Dda helicase rescue stalled bacteriophage T4 DNA replication forks in vitro SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IRRADIATED ESCHERICHIA-COLI; HOMOLOGOUS RECOMBINATION; GENETIC-RECOMBINATION; DEPENDENT ATPASE; STRAND EXCHANGE; REPAIR; PROTEIN; PURIFICATION; DAMAGE; CELLS AB The rescue of stalled replication forks via a series of steps that include fork regression, template switching, and fork restoration often has been proposed as a major mechanism for accurately bypassing non-coding DNA lesions. Bacteriophage T4 encodes almost all of the proteins required for its own DNA replication, recombination, and repair. Both recombination and recombination repair in T4 rely on UvsX, a RecA-like recombinase. We show here that UvsX plus the T4-encoded helicase Dda suffice to rescue stalled T4 replication forks in vitro. This rescue is based on two sequential template-switching reactions that allow DNA replication to bypass a non-coding DNA lesion in a non-mutagenic manner. C1 NIEHS, Lab Mol Genet E3 01, NIH, Res Triangle Pk, NC 27709 USA. RP Drake, JW (reprint author), NIEHS, Lab Mol Genet E3 01, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM drake@niehs.nih.gov NR 49 TC 24 Z9 24 U1 1 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 20 PY 2004 VL 279 IS 34 BP 35735 EP 35740 DI 10.1074/jbc.M403942200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 846GJ UT WOS:000223303400072 PM 15194689 ER PT J AU Svarovskaia, ES Xu, HZ Mbisa, JL Barr, R Gorelick, RJ Ono, A Freed, EO Hu, WS Pathak, VK AF Svarovskaia, ES Xu, HZ Mbisa, JL Barr, R Gorelick, RJ Ono, A Freed, EO Hu, WS Pathak, VK TI Human apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is incorporated into HIV-1 Virions through interactions with viral and nonviral RNAs SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; VIF PROTEIN; ANTIVIRAL ACTIVITY; INFECTIVITY FACTOR; REPLICATION CYCLE; T-LYMPHOCYTES; IN-VIVO; DNA; HYPERMUTATION; DEGRADATION AB Apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G (APOBEC3G) is a host cytidine deaminase that is packaged into virions and confers resistance to retroviral infection. APOBEC3G deaminates deoxycytidines in minus strand DNA to deoxyuridines, resulting in G to A hypermutation and viral inactivation. Human immunodeficiency virus type 1 (HIV-1) virion infectivity factor counteracts the antiviral activity of APOBEC3G by inducing its proteosomal degradation and preventing virion incorporation. To elucidate the mechanism of viral suppression by APOBEC3G, we developed a sensitive cytidine deamination assay and analyzed APOBEC3G virion incorporation in a series of HIV-1 deletion mutants. Virus-like particles derived from constructs in which pol, env, and most of gag were deleted still contained high levels of cytidine deaminase activity; in addition, coimmunoprecipitation of APOBEC3G and HIV-1 Gag in the presence and absence of RNase A indicated that the two proteins do not interact directly but form an RNase-sensitive complex. Viral particles lacking HIV-1 genomic RNA which were generated from the gag-pol expression constructs pC-Help and pSYNGP packaged APOBEC3G at 30-40% of the wild-type level, indicating that interactions with viral RNA are not necessary for incorporation. In addition, viral particles produced from an nucleocapsid zinc finger mutant contained similar to1% of the viral genomic RNA but similar to30% of the cytidine deaminase activity. The reduction in APOBEC3G incorporation was equivalent to the reduction in the total RNA present in the nucleocapsid mutant virions. These results indicate that interactions with viral proteins or viral genomic RNA are not essential for APOBEC3G incorporation and suggest that APOBEC3G interactions with viral and nonviral RNAs that are packaged into viral particles are sufficient for APOBEC3G virion incorporation. C1 NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. NCI, AIDS Vaccine Program, Sci Appl Int Corp Inc, NIH, Frederick, MD 21702 USA. RP Pathak, VK (reprint author), NCI, HIV Drug Resistance Program, Ctr Canc Res, POB B,Bldg 535,Rm 334, Frederick, MD 21702 USA. EM vpathak@ncifcrf.gov OI Ono, Akira/0000-0001-7841-851X FU NCI NIH HHS [N01-CO-12400] NR 33 TC 187 Z9 193 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 20 PY 2004 VL 279 IS 34 BP 35822 EP 35828 DI 10.1074/jbc.M405761200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 846GJ UT WOS:000223303400083 PM 15210704 ER PT J AU Zhu, PP Patterson, A Stadler, J Seeburg, DP Sheng, M Blackstone, C AF Zhu, PP Patterson, A Stadler, J Seeburg, DP Sheng, M Blackstone, C TI Intra- and intermolecular domain interactions of the C-terminal GTPase effector domain of the multimeric dynamin-like GTPase Drp1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RATE-LIMITING STEP; MITOCHONDRIAL DIVISION; ENDOPLASMIC-RETICULUM; MAMMALIAN-CELLS; MEDIATED ENDOCYTOSIS; OUTER-MEMBRANE; PROTEIN DLP1; MXA GTPASE; FISSION; YEAST AB Mammalian Drp1 is a dynamin-like GTPase required for mitochondrial fission. Although it exists primarily as a cytosolic homo-tetramer in vivo, it can also self-assemble into higher order structures on the mitochondrial outer membrane, where it is required for proper mitochondrial division. Functional studies and sequence comparisons have revealed four different structural domains in Drp1, comprising N-terminal GTP-binding, middle, insert B, and C-terminal GTPase effector (GED) domains. Here we describe an intramolecular interaction within Drp1 between the GED and the N-terminal GTP-binding and middle domains. A point mutation (K679A) within the C-terminal GED domain inhibits this intramolecular association, without affecting the formation of Drp1 tetramers or the intermolecular associations among isolated C-terminal domains. Mutant Drp1 K679A exhibits impaired GTPase activity, and when overexpressed in mammalian cells it decreases mitochondrial division. Sedimentation experiments indicate that the K679A mutation either increases Drp1 complex formation or, more likely, decreases complex disassembly as compared with wild-type Drp1. Taken together, these data suggest that the C-terminal GED domain is important for stimulation of GTPase activity, formation and stability of higher order complexes, and efficient mitochondrial division. C1 NINDS, Cellular Neurol Unit, NIH, Bethesda, MD 20892 USA. NIH, NIH George Washington Univ Grad Partnerships Prog, Bethesda, MD 20892 USA. MIT, Howard Hughes Med Inst, RIKEN MIT Neurosci Res Ctr, Picower Ctr Learning & Memory, Cambridge, MA 02139 USA. RP Blackstone, C (reprint author), NINDS, Cellular Neurol Unit, NIH, Bldg 35,Rm 2C-913,9000 Rockville Pike, Bethesda, MD 20892 USA. EM blackstc@ninds.nih.gov RI Patterson, Andrew/G-3852-2012 OI Patterson, Andrew/0000-0003-2073-0070 NR 47 TC 103 Z9 105 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 AUG 20 PY 2004 VL 279 IS 34 BP 35967 EP 35974 DI 10.1074/jbc.M404105200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 846GJ UT WOS:000223303400098 PM 15208300 ER PT J AU Bocharov, AV Baranova, IN Vishnyakova, TG Remaley, AT Csako, G Thomas, F Patterson, AP Eggerman, TL AF Bocharov, AV Baranova, IN Vishnyakova, TG Remaley, AT Csako, G Thomas, F Patterson, AP Eggerman, TL TI Targeting of scavenger receptor class B type I by synthetic amphipathic alpha-helical-containing peptides blocks lipopolysaccharide (LPS) uptake and LPS-induced pro-inflammatory cytokine responses in THP-1 monocyte cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIGH-DENSITY-LIPOPROTEIN; TOLL-LIKE RECEPTOR-4; APOLIPOPROTEIN-A-I; INTESTINAL EPITHELIAL-CELLS; BACTERIAL LIPOPOLYSACCHARIDE; GOLGI-APPARATUS; SR-BI; SIGNAL-TRANSDUCTION; MEDIATED ACTIVATION; CHOLESTERYL ESTER AB Human scavenger receptor class B type I, CLA-1, mediates lipopolysaccharide (LPS) binding and internalization (Vishnyakova, T.G., Bocharov, A.V., Baranova, I.N., Chen, Z., Remaley, A.T., Csako, G., Eggerman, T.L., and Patterson, A. P. (2003) J. Biol. Chem. 278, 22771-22780). Because one of the recognition motifs in SR-B1 ligands is the anionic amphipathic alpha-helix, we analyzed the effects of model amphipathic alpha-helical-containing peptides on LPS uptake and LPS-stimulated cytokine production. The L-37pA model peptide, containing two class A amphipathic helices, bound with high affinity (K-d=0.94 mug/ml) to CLA-1-expressing HeLa cells with a 10-fold increased capacity when compared with mock transfected HeLa cells. Both LPS and L-37pA colocalized with anti-CLA-1 antibody and directly bound CLA-1 as determined by cross-linking. SR-BI/CLA-1 ligands such as HDL, apoA-I, and L-37pA efficiently competed against iodinated L-37pA. Bacterial LPS, lipoteichoic acid, and hsp60 also competed against iodinated L-37pA. Model peptides blocked uptake of iodinated LPS in both mock transfected and CLA-1-overexpressing HeLa cells. Bound and internalized Alexa-L-37pA and BODIPY-LPS colocalized at the cell surface and perinuclear compartment. Both ligands were predominantly transported to the Golgi complex, colocalizing with the Golgi markers bovine serum albumin-ceramide, anti-Golgin97 antibody, and cholera toxin subunit B. A 100-fold excess of L-37pA nearly eliminated BODIPY-LPS binding and internalization. L-37pA and its D-amino acid analogue, D-37pA peptide were similarly effective in blocking LPS, Gram-positive bacterial wall component lipoteichoic acid and bacterial heat shock protein Gro-EL-stimulated cytokine secretion in THP-1 cells. In the same culture media used for the cytokine stimulation study, neither L-37pA nor D-37pA affected the Limulus amebocyte lysate activity of LPS, indicating that LPS uptake and cytokine stimulation were blocked independently of LPS neutralization. These results demonstrate that amphipathic helices of exchangeable apolipoproteins may represent a general host defense mechanism against inflammation. C1 NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Bocharov, AV (reprint author), NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, 6707 Democracy Blvd,Rm 697,MSC5460, Bethesda, MD 20892 USA. EM abocharov@mail.cc.nih.gov; eggermant@extra.niddk.nih.gov NR 58 TC 42 Z9 44 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 20 PY 2004 VL 279 IS 34 BP 36072 EP 36082 DI 10.1074/jbc.M314264200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 846GJ UT WOS:000223303400109 PM 15199068 ER PT J AU Lee, YS Krauss, M AF Lee, YS Krauss, M TI Reversible proton transfer dynamics in bacteriorhodopsin SO JOURNAL OF MOLECULAR STRUCTURE LA English DT Article; Proceedings Paper CT 15th International Conference on Horizons in Hydrogen Bond Research CY SEP 16-21, 2003 CL Berlin, GERMANY SP Freie Univ, Inst Chem, Deutsch Bunsen Gesell Physikal Chem DE ab initio dynamics; bacteriorhodopsin; quantum mechanics/molecular mechanics ID PROTEIN CONFORMATIONAL-CHANGES; INFRARED-SPECTRA; N-INTERMEDIATE; M-STATE; PHOTOCYCLE; TRANSPORT; MECHANISM; TRANSLOCATION; POTENTIALS; QUANTUM AB In a previous study of ab initio dynamics, the proton transfer in bacteriorhodopsin from protonated asp96 in the cytoplasmic region toward the deprotonated Schiff base was investigated. A quantum mechanics/molecular mechanics model was constructed from the X-ray structure of bacteriorhodopsin E204Q mutant. In this model, asp96, asp85, and thr89 as well as most of the retinal chromophore and the Schiff base link of lys216 were treated quantum mechanically while the rest of the atoms were treated molecular mechanically. A channel was found in the X-ray structure allowing a water chain to form between the asp96 and Schiff base. In the present study, a chain of four waters from asp96 to the Schiff base N coupled with one branching water supports proton transfer as a concerted event in about 3.5 ps. With both a neutral asp85 and a branched water, the dynamics is now found to be more complicated than observed in the initial study for the transition from the photocycle late M state to the N state. Proton transfer is also observed from the Schiff base back to asp96 demonstrating that there is no effective barrier to proton transfer larger than kT in a strong H-bonded network. The binding of the branched water to the four water chains can dynamically hinder the proton transfer. (C) 2004 Elsevier B.V. All rights reserved. C1 NIH, Ctr Informat Technol, Ctr Mol Modeling, Bethesda, MD 20892 USA. NIST, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. RP Lee, YS (reprint author), NIH, Ctr Informat Technol, Ctr Mol Modeling, Bldg 10, Bethesda, MD 20892 USA. EM leeys@mail.nih.gov NR 21 TC 14 Z9 15 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-2860 J9 J MOL STRUCT JI J. Mol. Struct. PD AUG 20 PY 2004 VL 700 IS 1-3 SI SI BP 243 EP 246 DI 10.1016/j.molstruc.2004.02.004 PG 4 WC Chemistry, Physical SC Chemistry GA 842DC UT WOS:000222982200032 ER PT J AU Santelli, E Bankston, LA Leppla, SH Liddington, RC AF Santelli, E Bankston, LA Leppla, SH Liddington, RC TI Crystal structure of a complex between anthrax toxin and its host cell receptor SO NATURE LA English DT Article ID CAPILLARY MORPHOGENESIS PROTEIN-2; ELECTRON-DENSITY MAPS; PROTECTIVE ANTIGEN; A-DOMAIN; I-DOMAIN; BINDING; IDENTIFICATION; MUTATIONS; PATHWAY; CHANNEL AB Anthrax toxin consists of the proteins protective antigen (PA), lethal factor (LF) and oedema factor (EF)(1). The first step of toxin entry into host cells is the recognition by PA of a receptor on the surface of the target cell. Subsequent cleavage of receptor-bound PA enables EF and LF to bind and form a heptameric PA(63) prepore, which triggers endocytosis. Upon acidification of the endosome, PA(63) forms a pore that inserts into the membrane and translocates EF and LF into the cytosol(2). Two closely related host cell receptors, TEM8 and CMG2, have been identified. Both bind to PA with high affinity and are capable of mediating toxicity(3,4). Here, we report the crystal structure of the PA-CMG2 complex at 2.5 Angstrom resolution. The structure reveals an extensive receptor-pathogen interaction surface mimicking the nonpathogenic recognition of the extracellular matrix by integrins(5). The binding surface is closely conserved in the two receptors and across species, but is quite different in the integrin domains, explaining the specificity of the interaction. CMG2 engages two domains of PA, and modelling of the receptor-bound PA(63) heptamer(6-8) suggests that the receptor acts as a pH-sensitive brace to ensure accurate and timely membrane insertion. The structure provides new leads for the discovery of anthrax antitoxins, and should aid the design of cancer therapeutics(9). C1 Burnham Inst, Program Cell Adhes, La Jolla, CA 92037 USA. NIAID, Microbial Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Liddington, RC (reprint author), Burnham Inst, Program Cell Adhes, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM rlidding@burnham.org NR 29 TC 159 Z9 166 U1 1 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 19 PY 2004 VL 430 IS 7002 BP 905 EP 908 DI 10.1038/nature02763 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847DA UT WOS:000223369800045 PM 15243628 ER PT J AU Wood, MJ Storz, G Tjandra, N AF Wood, MJ Storz, G Tjandra, N TI Structural basis for redox regulation of Yap1 transcription factor localization SO NATURE LA English DT Article ID SACCHAROMYCES-CEREVISIAE; NUCLEAR-LOCALIZATION; OXIDATIVE STRESS; RECEPTOR; DOMAIN; NMR; MACROMOLECULES; ACTIVATION; MECHANISM; TRANSPORT AB The ability of organisms to alter their gene expression patterns in response to environmental changes is essential for viability. A central regulator of the response to oxidative stress in Saccharomyces cerevisiae is the Yap1 transcription factor. Upon activation by increased levels of reactive oxygen species, Yap1 rapidly redistributes to the nucleus where it regulates the expression of up to 70 genes(1-3). Here we identify a redox-regulated domain of Yap1 and determine its high-resolution solution structure. In the active oxidized form, a nuclear export signal (NES) in the carboxy-terminal cysteine-rich domain is masked by disulphide-bond-mediated interactions with a conserved amino-terminal alpha-helix. Point mutations that weaken the hydrophobic interactions between the N-terminal alpha-helix and the C-terminal NES-containing domain abolished redox-regulated changes in subcellular localization of Yap1. Upon reduction of the disulphide bonds, Yap1 undergoes a change to an unstructured conformation that exposes the NES and allows redistribution to the cytoplasm. These results reveal the structural basis of redox-dependent Yap1 localization and provide a previously unknown mechanism of transcription factor regulation by reversible intramolecular disulphide bond formation. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Storz, G (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM storzg@mail.nih.gov; nico@helix.nih.gov OI Storz, Gisela/0000-0001-6698-1241 NR 29 TC 108 Z9 111 U1 1 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 AUG 19 PY 2004 VL 430 IS 7002 BP 917 EP 921 DI 10.1038/nature02790 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847DA UT WOS:000223369800048 PM 15318225 ER PT J AU Carucci, D AF Carucci, D TI Know thine enemy SO NATURE LA English DT Article ID PLASMODIUM-FALCIPARUM; LIFE-CYCLE; PROTEINS; INVASION; SEQUENCE; GENOME C1 Fdn Natl Inst Hlth, Bethesda, MD USA. RP Fdn Natl Inst Hlth, Bethesda, MD USA. NR 10 TC 4 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD AUG 19 PY 2004 VL 430 IS 7002 BP 944 EP 945 DI 10.1038/430944a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847DA UT WOS:000223369800064 PM 15318241 ER PT J AU Li, YH Tacey, K Doil, L van Luchene, R Garcia, V Rowland, C Schrodi, S Leong, D Lau, K Catanese, J Sninsky, J Nowotny, P Holmans, P Hardy, J Powell, J Lovestone, S Thal, L Owen, M Williams, J Goate, A Grupe, A AF Li, YH Tacey, K Doil, L van Luchene, R Garcia, V Rowland, C Schrodi, S Leong, D Lau, K Catanese, J Sninsky, J Nowotny, P Holmans, P Hardy, J Powell, J Lovestone, S Thal, L Owen, M Williams, J Goate, A Grupe, A TI Association of ABCA1 with late-onset Alzheimer's disease is not observed in a case-control study SO NEUROSCIENCE LETTERS LA English DT Article DE Alzheimer's disease; ATP-binding cassette A1 transporter; ABCA1; polymorphism ID TRAITS AB Genetic association of ABCA1 or the ATP-binding cassette Al transporter with late-onset Alzheimer's disease (LOAD) has recently been proposed for a haplotype comprised of three single nucleotide polymorphisms (SNPs). We have genotyped these and other ABCA1 SNPs in a LOAD case-control series of 796 individuals (419 cases versus 377 controls) collected at Washington University. While our sample series is larger and thus presumably has greater power than any of the series used to implicate ABCA1, we were unable to replicate the published association, using either single markers or multiple marker haplotypes. Further, we did not observe significant and replicated association of other ABCA1 SNPs we examined with the disease, thus these ABCA1 variants do not appear to influence the risk of LOAD in this study. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Celera Diagnost, Alameda, CA USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Cardiff Univ, Coll Med, Biostat & Bioinformat Unit, Cardiff CF1 3NS, S Glam, Wales. NIA, Bethesda, MD 20892 USA. Kings Coll London, Inst Psychiat, Dept Neurosci, London WC2R 2LS, England. Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA. Cardiff Univ, Coll Med, Dept Psychol Med, Cardiff, S Glam, Wales. RP Grupe, A (reprint author), Celera Diagnost, Alameda, CA USA. EM andrew.grupe@celeradiagnostics.com RI Lovestone, Simon/E-8725-2010; turton, miranda/F-4682-2011; Powell, John/G-4412-2011; Hardy, John/C-2451-2009; Holmans, Peter/F-4518-2015; OI Powell, John/0000-0001-6124-439X; Holmans, Peter/0000-0003-0870-9412; Schrodi, Steven/0000-0003-2304-8528 FU NIA NIH HHS [AG05681, AG16208, P 50 AG0 5131, U24 AG021886] NR 13 TC 44 Z9 46 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 AUG 19 PY 2004 VL 366 IS 3 BP 268 EP 271 DI 10.1016/j.neulet.2004.05.047 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 848AD UT WOS:000223438400009 PM 15288432 ER PT J AU Dong, G Lee, TL Yeh, NT Geoghegan, J Van Waes, C Chen, Z AF Dong, G Lee, TL Yeh, NT Geoghegan, J Van Waes, C Chen, Z TI Metastatic squamous cell carcinoma cells that overexpress c-Met exhibit enhanced angiogenesis factor expression, scattering and metastasis in response to hepatocyte growth factor SO ONCOGENE LA English DT Article DE HGF/c-Met; angiogenesis; squamous cell carcinoma; metastasis; Gro-1/KC; VEGF ID PROINFLAMMATORY CYTOKINE EXPRESSION; PAPILLARY RENAL-CARCINOMAS; HOST ENVIRONMENT PROMOTES; FACTOR-KAPPA-B; TUMOR PROGRESSION; IN-VIVO; PROANGIOGENIC CYTOKINES; CANCER PATIENTS; CDNA ARRAYS; ONCOGENE AB We previously performed gene expression pro. ling in a multistep squamous cell carcinoma (SCC) progression model, and identified growth-regulated oncogene-1 (Gro1/KC) as a factor that contributes to enhanced angiogenesis, tumorigenesis and metastasis. In the present study, we explored molecular pathways coactivated with Gro-1/KC, and identified a transcript that encodes c-Met, the receptor for hepatocyte growth factor/scatter factor (HGF). Northern, Western blot, and immunohistochemical analyses confirm that expression of c-Met mRNA and protein is increased with SCC progression. In vitro, HGF preferentially promoted scattering in the metastatic LY-1 and LY-2 lines, and enhanced angiogenesis factors Gro-1/KC and vascular endothelial growth factor (VEGF) production by all tumor cell lines. In vivo, tumor growth and lung metastasis were promoted by transfection and overexpression of HGF cDNA in metastatic LY-1 cells. Our data indicate that metastatic SCC cells that overexpress c-Met exhibit angiogenesis factor expression and enhanced scattering in response to HGF in vitro, and tumorigenesis and metastasis in response to HGF in the tumor microenvironment in vivo. C1 Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Tumor Biol Sect, NIH, Bethesda, MD 20892 USA. RP Chen, Z (reprint author), Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Tumor Biol Sect, NIH, 10-5D55,MSC-1419, Bethesda, MD 20892 USA. EM chenz@nided.nih.gov RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU NIDCD NIH HHS [Z01-DC-00016] NR 50 TC 36 Z9 40 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 19 PY 2004 VL 23 IS 37 BP 6199 EP 6208 DI 10.1038/sj.onc.1207851 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 847NC UT WOS:000223399000004 PM 15221009 ER PT J AU Park, SS Eom, YW Kim, EH Lee, JH Min, DS Kim, S Kim, SJ Choi, KS AF Park, SS Eom, YW Kim, EH Lee, JH Min, DS Kim, S Kim, SJ Choi, KS TI Involvement of c-Src kinase in the regulation of TGF-beta 1-induced apoptosis SO ONCOGENE LA English DT Article DE TGF-beta 1; apoptosis; c-Src; hepatocellular carcinoma; caspases ID FOCAL ADHESION KINASE; GROWTH-FACTOR-BETA; HUMAN HEPATOCELLULAR-CARCINOMA; FAO HEPATOMA-CELLS; TGF-BETA; TYROSINE KINASES; BINDING-SITE; II RECEPTOR; ACTIVATION; SMAD2 AB Transforming growth factor-beta1 (TGF-beta1) is a potent inducer of apoptosis in normal hepatocytes, and acquiring resistance to TGF-beta1 may be a critical step in the development of hepatocellular carcinoma (HCC). In this study, we investigated the possible involvement of c-Src in the regulation of TGF-beta1-induced apoptosis. TGF-beta1 induced transient activation of c-Src and its subsequent caspase-mediated degradation concomitant with cell death in FaO hepatoma cells, which are sensitive to TGF-beta1. In response to TGF-beta1, activated c-Src was translocated into the cytoplasmic membrane, then relocated to the nuclei of apoptotic cells during its cleavage. In TGF-beta1-induced apoptotic cells, c-Src maintained its tight association with p85 FAK fragment cleaved by caspases, possibly contributing to focal adhesion disassembly. TGF-beta1-induced apoptosis was enhanced by either inhibition of c-Src activity using PP1 or PP2, or by overexpression of dominant-negative c-Src. In contrast, overexpression of constitutively active c-Src inhibited apoptosis suppressing TGF-beta1-induced activation of p38, JNK and caspases. In many HCC cell lines resistant to TGF-beta1, enhanced c-Src activity was detected. We hypothesize that activated c-Src in HCC may contribute to resistance against the apoptotic and/or antiproliferative properties of TGF-beta1. C1 Ajou Univ, Sch Med, Inst Med Sci, Suwon 442749, South Korea. Catholic Univ Korea, Coll Med, Dept Physiol, Seoul, South Korea. LG Life Sci, Taejon, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Choi, KS (reprint author), Ajou Univ, Sch Med, Inst Med Sci, 5 Wonchon Dong, Suwon 442749, South Korea. EM kschoi@ajou.ac.kr RI Kim, Eunhee/Q-9162-2016 OI Kim, Eunhee/0000-0001-7143-7769 NR 36 TC 45 Z9 48 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 AUG 19 PY 2004 VL 23 IS 37 BP 6272 EP 6281 DI 10.1038/sj.onc.1207856 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 847NC UT WOS:000223399000011 PM 15208664 ER PT J AU Sverdlov, AV Babenko, VN Rogozin, IB Koonin, EV AF Sverdlov, AV Babenko, VN Rogozin, IB Koonin, EV TI Preferential loss and gain of introns in 3 ' portions of genes suggests a reverse-transcription mechanism of intron insertion SO GENE LA English DT Article DE intron evolution; splicing; duplication; old introns; new introns ID EXON DUPLICATION; EVOLUTION; POSITIONS; ORIGIN; RNA; DNA AB In an attempt to gain insight into the dynamics of intron evolution in eukaryotic protein-coding genes, the distributions of old introns, that are conserved between distant phylogenctic lineages, and new, lineage-specific introns along the gene length, were examined. A significant excess of old introns in 5' -regions of genes was detected. New introns, when analyzed in bulk, showed a nearly flat distribution from the 5' to the 3' -end. However, analysis of new intron distributions in individual genomes revealed notable lineage-specific features. While in intron-poor genomes, particularly yeast Schizosaccharomyces pombe (Sp), the 5' -portions of genes contain a significantly greater number of new introns than the 3' -portions, the intron-rich genomes of humans and Arabidopsis show the opposite trend. These observations seem to be compatible with the view that introns are both lost and inserted in 3' -terminal portions of genes more often than in 5' -portions. Overrepresentation of 3' -terminal sequences among cDNAs that mediate intron loss appears to be the most likely explanation for the apparent preferential loss of introns in the distal parts of genes. Preferential insertion of introns in the 3' -portions suggests that introns might be inserted via a reverse-transcription-mediated pathway similar to that implicated in intron loss. This mechanism could involve duplication of a portion of the coding region during reverse transcription followed by homologous recombination and subsequent rapid sequence divergence in the copy that becomes a new intron. (C) 2004 Elsevier B.V. All rights reserved. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike,Bldg 38A, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov RI Babenko, Vladimir/K-5609-2014; OI Babenko, Vladimir/0000-0002-3077-9559 NR 25 TC 56 Z9 56 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD AUG 18 PY 2004 VL 338 IS 1 BP 85 EP 91 DI 10.1016/j.gene.2004.05.027 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 850EI UT WOS:000223593600009 PM 15302409 ER PT J AU Gaydos, CA McKee, KT Quinn, TC Gaydos, JC AF Gaydos, CA McKee, KT Quinn, TC Gaydos, JC TI Prevalence of chlamydial and gonococcal infections among young adults SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID TRACHOMATIS INFECTIONS; ARMY RECRUITS C1 Johns Hopkins Univ, Baltimore, MD 21218 USA. USA, Camber Corp, Med Res Inst Infect Dis, Ft Detrick, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. US Dept Def, Global Emerging Infect Surveillance & Response Sy, Silver Spring, MD USA. RP Gaydos, CA (reprint author), Johns Hopkins Univ, Baltimore, MD 21218 USA. EM cgaydos@jhmi.edu RI Gaydos, Charlotte/E-9937-2010 NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 18 PY 2004 VL 292 IS 7 BP 801 EP 801 DI 10.1001/jama.292.7.801-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 847FO UT WOS:000223378300012 PM 15315990 ER PT J AU Compton, WM Colliver, JD Glantz, MD Grant, BF Stinson, FS AF Compton, WM Colliver, JD Glantz, MD Grant, BF Stinson, FS TI Marijuana arrests and increase in marijuana use disorders - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. RP Compton, WM (reprint author), Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM wcompton@nida.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD AUG 18 PY 2004 VL 292 IS 7 BP 802 EP 803 DI 10.1001/jama.292.7.802-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 847FO UT WOS:000223378300015 ER PT J AU March, J Silva, S Petrycki, S Curry, J Wells, K Fairbank, J Burns, B Domino, M Vitiello, B Severe, J AF March, J Silva, S Petrycki, S Curry, J Wells, K Fairbank, J Burns, B Domino, M Vitiello, B Severe, J CA TADS Team TI Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression - Treatment for adolescents with depression study (TADS) randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID CLINICAL-TRIALS; MOOD DISORDERS; DOUBLE-BLIND; CHILDREN; PLACEBO; SUICIDE; PSYCHOTHERAPY; PHARMACOTHERAPY; MEDICATIONS; CHILDHOOD AB Context Initial treatment of major depressive disorder in adolescents may include cognitive-behavioral therapy (CBT) or a selective serotonin reuptake inhibitor (SSRI). However, little is known about their relative or combined effectiveness. Objective To evaluate the effectiveness of 4 treatments among adolescents with major depressive disorder. Design, Setting, and Participants Randomized controlled trial of a volunteer sample of 439 patients between the ages of 12 to 17 years with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of major depressive disorder. The trial was conducted at 13 US academic and community clinics between spring 2000 and summer 2003. Interventions Twelve weeks of (1) fluoxetine alone (10 to 40 mg/d), (2) CBT alone, (3) CBT with fluoxetine (10 to 40 mg/d), or (4) placebo (equivalent to 10 to 40 mg/d). Placebo and fluoxetine alone were administered double-blind; CBT alone and CBT with fluoxetine were administered unblinded. Main Outcome Measures Children's Depression Rating Scale-Revised total score and, for responder analysis, a (dichotomized) Clinical Global Impressions improvement score. Results Compared with placebo, the combination of fluoxetine with CBT was statistically significant (P=.001) on the Children's Depression Rating Scale-Revised. Compared with fluoxetine alone (P=.02) and CBT alone (P=.01), treatment of fluoxetine with CBT was superior. Fluoxetine alone is a superior treatment to CBT alone (P=.01). Rates of response for fluoxetine with CBT were 71.0% (95% confidence interval [Cl], 62%-80%); fluoxetine alone, 60.6% (95% Cl, 51%-70%); CBT alone, 43.2% (95% Cl, 34%-52%); and placebo, 34.8% (95% Cl, 26%-44%). On the Clinical Global Impressions improvement responder analysis, the 2 fluoxetine-containing conditions were statistically superior to CBT and to placebo. Clinically significant suicidal thinking, which was present in 29% of the sample at baseline, improved significantly in all 4 treatment groups. Fluoxetine with CBT showed the greatest reduction (P=.02). Seven (1.6%) of 439 patients attempted suicide; there were no completed suicides. Conclusion The combination of fluoxetine with CBT offered the most favorable tradeoff between benefit and risk for adolescents with major depressive disorder. C1 Duke Univ, Med Ctr, Dept Psychiat, Duke Clin Res Inst, Durham, NC 27710 USA. NIMH, Rockville, MD 20857 USA. RP March, J (reprint author), Duke Univ, Med Ctr, Dept Psychiat, Duke Clin Res Inst, 718 Rutherford St,Box 3527, Durham, NC 27710 USA. EM jsmarch@acpub.duke.edu RI Fairbank, John/F-8972-2013 OI Fairbank, John/0000-0003-2604-7256 FU DS NIH HHS [98-DS-0008] NR 51 TC 874 Z9 884 U1 30 U2 195 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 AUG 18 PY 2004 VL 292 IS 7 BP 807 EP 820 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 847FO UT WOS:000223378300021 PM 15315995 ER PT J AU Shultz, MD Ham, YW Lee, SG Davis, DA Brown, C Chmielewski, J AF Shultz, MD Ham, YW Lee, SG Davis, DA Brown, C Chmielewski, J TI Small-molecule dimerization inhibitors of wild-type and mutant HIV protease: A focused library approach SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID LINKED INTERFACIAL PEPTIDES; RESISTANCE C1 Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. NIH, Bethesda, MD 20892 USA. RP Chmielewski, J (reprint author), Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. EM chml@purdue.edu FU NIGMS NIH HHS [GM52379] NR 16 TC 38 Z9 38 U1 0 U2 2 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 AUG 18 PY 2004 VL 126 IS 32 BP 9886 EP 9887 DI 10.1021/ja048139n PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA 845XS UT WOS:000223279300006 PM 15303839 ER PT J AU Wacholder, S AF Wacholder, S TI Bias in intervention studies that enroll patients from high-risk clinics SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID BRCA2 MUTATION CARRIERS; BILATERAL PROPHYLACTIC MASTECTOMY; BREAST-CANCER RISK; OVARIAN-CANCER; ORAL-CONTRACEPTIVES; OOPHORECTOMY; WOMEN; EFFICACY AB It is important to evaluate the effects of proposed interventions to reduce the risk of disease among carriers of a highly penetrant mutation, such as the mutations in BRCA1 and BRCA2 for breast and ovarian cancers or in APC and MLH1 or MSH2 for colon cancer. However, some studies that evaluate the effects of interventions designed to reduce risk in mutation carriers may be susceptible to a serious selection bias when they are based in clinics that care for persons at high risk for the disease. A study design in which a large fraction of the case patients were diagnosed before being seen at the clinic and all control subjects are persons previously seen at the clinic can create a false impression of intervention efficacy if, as is likely, mutation carriers seen at the clinic were more likely to receive the intervention than mutation carriers in the general population. C1 NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. RP Wacholder, S (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. EM wacholder@nih.gov NR 23 TC 14 Z9 14 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 AUG 18 PY 2004 VL 96 IS 16 BP 1204 EP 1207 DI 10.1093/jnci/djh229 PG 4 WC Oncology SC Oncology GA 848TB UT WOS:000223488900011 PM 15316055 ER PT J AU Gillanders, EM Xu, JF Chang, BL Lange, EM Wiklund, F Bailey-Wilson, JE Baffoe-Bonnie, A Jones, M Gildea, D Riedesel, E Albertus, J Isaacs, SD Wiley, KE Mohai, CE Matikainen, MP Tammela, TLJ Zheng, SL Brown, WM Rokman, A Carpten, JD Meyers, DA Walsh, PC Schleutker, J Gronberg, H Cooney, KA Isaacs, WB Trent, JM AF Gillanders, EM Xu, JF Chang, BL Lange, EM Wiklund, F Bailey-Wilson, JE Baffoe-Bonnie, A Jones, M Gildea, D Riedesel, E Albertus, J Isaacs, SD Wiley, KE Mohai, CE Matikainen, MP Tammela, TLJ Zheng, SL Brown, WM Rokman, A Carpten, JD Meyers, DA Walsh, PC Schleutker, J Gronberg, H Cooney, KA Isaacs, WB Trent, JM TI Combined genome-wide scan for prostate cancer susceptibility genes SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID AUTOSOMAL-DOMINANT INHERITANCE; GERMLINE MUTATIONS; SEGREGATION ANALYSIS; LINKAGE ANALYSIS; FAMILIES; CHROMOSOME; LOCUS; RISK; FINLAND; TWINS AB Background: Prostate cancer represents a substantial public health burden worldwide. It is the second leading cause of cancer death among men in the United States. A family history of the disease is among the most well-established risk factors for prostate cancer. Efforts to localize prostate cancer susceptibility alleles by using genetic linkage analysis methods have been hindered by genetic heterogeneity, incomplete penetrance, disease phenocopies, and the lack of DNA samples from parents of individuals with late-onset prostate cancer. Methods: We performed a combined genome-wide linkage analysis among 426 families from four existing hereditary prostate cancer (HPC) study populations to systematically search for prostate cancer susceptibility genes. To decrease the degree of locus heterogeneity, we analyzed subsets of families with similar clinical and demographic characteristics. Nonparametric multipoint linkage was the primary method of analysis. Results are presented as allele-sharing logarithm of the odds (LOD) scores, and all reported P values are two-sided. Results: The strongest evidence for prostate cancer linkage was found at chromosome region 17q22 (nonparametric multipoint Kong and Cox allele-sharing LOD score = 3.16 at marker D17S787; P = .00007). Stratified analyses revealed several additional chromosomal regions that are likely to segregate prostate cancer susceptibility genes among specific subsets of HPC families, including 15q11 among families with late-onset disease (allele-sharing LOD = 5.57 at marker D15S128; P < .00001) and 4q35 among families with four or more affected family members (allele-sharing LOD = 3.10 at marker D4S1615; P = .00008). Conclusion: Fine mapping studies to facilitate identification of prostate cancer susceptibility genes in these linked regions are warranted. C1 NHGRI, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Ctr Human Genome, Winston Salem, NC 27109 USA. Wake Forest Univ, Sch Med, Dept Publ Hlth, Winston Salem, NC 27109 USA. Umea Univ, Dept Radiat Sci, Umea, Sweden. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. Johns Hopkins Med Inst, Dept Urol, Baltimore, MD 21205 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA. Tampere Univ, Dept Urol, Tampere, Finland. Tampere Univ, Inst Med Technol, Tampere, Finland. Tampere Univ Hosp, Tampere, Finland. Translat Genom Res Inst, Phoenix, AZ USA. RP Xu, JF (reprint author), Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jxu@wfubmc.edu OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU NCI NIH HHS [CA95052-01, CA58236, CA69568, CA79596, CA89600-02] NR 38 TC 50 Z9 51 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 18 PY 2004 VL 96 IS 16 BP 1240 EP 1247 DI 10.1093/jnci/djh228 PG 8 WC Oncology SC Oncology GA 848TB UT WOS:000223488900015 PM 15316059 ER PT J AU Mysliwiec, PA Brown, ML Klabunde, CN Ransohoff, DF AF Mysliwiec, PA Brown, ML Klabunde, CN Ransohoff, DF TI Are physicians doing too much colonoscopy? A national survey of colorectal surveillance after polypectomy SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CANCER-SOCIETY GUIDELINES; SCREENING COLONOSCOPY; ASYMPTOMATIC ADULTS; CLINICAL GUIDELINES; POLYP GUIDELINE; UNITED-STATES; UPDATE; RISK; CARE; PREVALENCE AB Background: increasing use of colonoscopy for colorectal cancer screening and surveillance of colorectal adenomas after polypectomy has given rise to concerns about the availability of endoscopic resources in the United States. Guidelines recommend surveillance after polypectomy at 3 to 5 years for a small adenoma, and follow-up is not advised for hyperplastic polyps. The intensity of physicians' surveillance is largely unstudied. Objective: To survey practicing gastroenterologists and general surgeons about their perceived need for the frequency of surveillance after polypectomy, to compare survey responses to practice guidelines, and to identify factors influencing their recommendations for surveillance. Design: Survey study conducted by the National Cancer Institute. Setting: A nationally representative study of physicians in the United States. Participants: 349 gastroenterologists and 316 general surgeons. Measurements: Questionnaires mailed in 1999 and 2000 assessed physicians' recommendations for surveillance after polypectomy in asymptomatic, average-risk patients. Results: Response rates were 83%. Among gastroenterologists (317 of 349) and surgeons (125 of 316) who perform screening colonoscopy, 24% (95% Cl, 19.3% to 28.7%) of gastroenterologists and 54% (Cl, 44.9% to 62.5%) of surgeons recommend surveillance for a hyperplastic polyp. For a small adenoma, most physicians recommended surveillance colonoscopy and more than 50% recommended examinations every 3 years or more often. Physicians indicated that published evidence was very influential in their practice (83% [Cl, 78.8% to 87.2%] of gastroenterologists and 78% [Cl, 72.5% to 86.8%] of surgeons). By contrast, only half of respondents reported that guidelines were very influential. Limitations: The study was based on physicians' self-reported practice patterns. Results may overestimate or underestimate the performance of surveillance colonoscopy. Conclusions: Some surveillance colonoscopy seems to be inappropriately performed and in excess of guidelines, particularly for hyperplastic polyps and low-risk lesions such as a small adenoma. These results suggest unnecessary demand for endoscopic resources. C1 NCI, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. RP Brown, ML (reprint author), NCI, Executive Plaza N 4005,6130 Executive Blvd, Bethesda, MD 20892 USA. EM mb53o@nih.gov FU NCI NIH HHS [N01-PC-85169] NR 45 TC 212 Z9 214 U1 1 U2 1 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 AUG 17 PY 2004 VL 141 IS 4 BP 264 EP 271 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 846BX UT WOS:000223290900003 PM 15313742 ER PT J AU Emanuel, EJ Wood, A Fleischman, A Bowen, A Getz, KA Grady, C Levine, C Hammerschmidt, DE Faden, R Eckenwiler, L Muse, CT Sugarman, J AF Emanuel, EJ Wood, A Fleischman, A Bowen, A Getz, KA Grady, C Levine, C Hammerschmidt, DE Faden, R Eckenwiler, L Muse, CT Sugarman, J TI Oversight of human participants research: Identifying problems to evaluate reform proposals SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID CONFLICTS-OF-INTEREST; POLICIES; TRIALS; BOARD AB The oversight of research involving human participants is widely believed to be inadequate. The U.S. Congress, national commissions, the Department of Health and Human Services, the Institute of Medicine, numerous professional societies, and others are proposing remedies based on the assumption that the main problems are researchers' conflict of interest, lack of institutional review board ORB) resources, and the volume and complexity of clinical research. Developing appropriate reform proposals requires carefully delineating the problems of the current system to know what reforms are needed. To stimulate a more informed and meaningful debate, we delineate 15 current problems into 3 broad categories. First, structural problems encompass 8 specific problems related to the way the research oversight system is organized. Second, procedural problems constitute 5 specific problems related to the operations of IRB review. Finally, performance assessment problems include 2 problems related to absence of systematic assessment of the outcomes of the oversight system. We critically assess proposed reforms, such as accreditation and central IRBs, according I to how well they address these 15 problems. None of the reforms addresses all 15 problems. Indeed, most focus on the procedural problems, failing to address either the structure or the performance assessment problems. Finally, on the basis of the delineation of problems, we outline components of a more effective reform proposal, including bringing all research under federal oversight, a permanent advisory committee to address recurrent ethical issues in clinical research, mandatory single-time review for multicenter research protocols, additional financial support for IRB functions, and a standardized system for collecting and disseminating data on both adverse events and the performance assessment of IRBs. C1 Warren G Magnuson Clin Ctr, Dept Clin Bioeth, NIH, Bethesda, MD 20892 USA. New York Acad Med, New York, NY USA. Western IRB, Olympia, WA USA. Thomson Ctr Watch, Boston, MA USA. United Hosp Fund, New York, NY USA. Univ Minnesota, Minneapolis, MN USA. Johns Hopkins Univ, Phoebe R Berman Bioeth Inst, Baltimore, MD USA. Old Dominion Univ, Norfolk, VA USA. Duke Univ, Ctr Med, Durham, NC USA. RP Emanuel, EJ (reprint author), Warren G Magnuson Clin Ctr, Dept Clin Bioeth, NIH, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM eemanuel@nih.gov NR 58 TC 86 Z9 88 U1 0 U2 1 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 AUG 17 PY 2004 VL 141 IS 4 BP 282 EP 291 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 846BX UT WOS:000223290900005 PM 15313744 ER PT J AU Blasie, CA Berg, JM AF Blasie, CA Berg, JM TI Entropy-enthalpy compensation in ionic interactions probed in a zinc finger peptide SO BIOCHEMISTRY LA English DT Article ID ELECTROSTATIC INTERACTIONS; HELICAL PEPTIDES; METAL-BINDING; PROTEINS; DESIGN; PAIRS; GLU AB Zinc(11) and cobalt(II) binding to a series of zinc finger peptides with different charged residue pairs across from one another in a beta-sheet were examined. Previous studies revealed a narrow range of interaction free energies (<0.5 kcal/mol) between these residues. Here, isothermal titration calorimetry studies were performed, revealing a range of over 3 kcal/mol in relative binding enthalpies. Double mutant cycle analysis revealed a range of interaction enthalpies ranging from -3.1 to -3.4 kcal/mol for the Arg-Asp pair to -0.8 kcal/mol for the Lys-Glu pair. The large range of interaction enthalpies coupled with the small range of interaction free energies reveals substantial entropy-enthalpy compensation. The magnitudes of the effects are consistent with the formation of a structurally rigid Arg-Asp contact ion pair but less direct and more mobile interactions involving the other combinations. C1 Johns Hopkins Univ, Sch Med, Dept Biochem & Biophys Sci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Chem, Baltimore, MD 21218 USA. RP Berg, JM (reprint author), Natl Inst Gen Med Sci, 45 Ctr Dr, Bethesda, MD 20892 USA. EM bergj@mail.nih.gov OI Berg, Jeremy/0000-0003-3022-0963 NR 17 TC 19 Z9 19 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 17 PY 2004 VL 43 IS 32 BP 10600 EP 10604 DI 10.1021/bi0363230 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 845XM UT WOS:000223278700031 PM 15301557 ER PT J AU Yeh, IC Hummer, G AF Yeh, IC Hummer, G TI Nucleic acid transport through carbon nanotube membranes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MOLECULAR-DYNAMICS; DNA-MOLECULES; WATER; CHANNEL; TRANSLOCATION; NANOPORES; PORE; ELECTROPHORESIS; CONDUCTION; POLYMERS AB We study the electrophoretic transport of single-stranded RNA molecules through 1.5-nm-wide pores of carbon nanotube membranes by molecular dynamics simulations. From approximate to170 individual RNA translocation events analyzed at full atomic resolution of solvent, membrane, and RNA, we identify key factors in membrane transport of biopolymers. RNA entry into the nanotube pores is controlled by conformational dynamics, and exit by hydrophobic attachment of RNA bases to the pores. Without electric field, RNA remains hydrophobically trapped in the membrane despite large entropic and energetic penalties for confining charged polymers inside nonpolar pores. Differences in RNA conformational flexibility and hydrophobicity result in sequence-dependent rates of translocation, a prerequisite for nanoscale separation devices. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 43 TC 138 Z9 140 U1 4 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 AUG 17 PY 2004 VL 101 IS 33 BP 12177 EP 12182 DI 10.1073/pnas.0402699101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847QN UT WOS:000223410100049 PM 15302940 ER PT J AU Ishikawa, T Cheng, NQ Liu, X Korn, ED Steven, AC AF Ishikawa, T Cheng, NQ Liu, X Korn, ED Steven, AC TI Subdomain organization of the Acanthamoeba myosin IC tail from cryo-electron microscopy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HEAVY-CHAIN PHOSPHORYLATION; ELECTRON-MICROSCOPY; BINDING PROPERTIES; ACTIN-FILAMENTS; DENSITY MAPS; ADP RELEASE; LOCALIZATION; PROTEIN; DOMAIN; CASTELLANII AB Acanthamoeba myosin IC (AMIC) is a single-headed myosin comprised of one heavy chain (129 kDa) and one light chain (17 kDa). The heavy chain has head, neck (light chain-binding), and tail domains. The tail consists of four subdomains: a basic region (13111) (23 kDa) and two Gly/Pro/Ala-rich (GPA) regions, GPA1 (6 kDa) and GPA2 (15 kDa), flanking an Src homology 3 region (6 kDa). Although the AMIC head is similar in sequence, structure, and function (ATPase motor) to other myosin heads, the organization of the tail has been less clear as has its function beyond an assumed role in binding interaction partners, e.g., the BR has a membrane affinity and the GPA components bind F-actin in an ATP-independent manner. To investigate the spatial arrangement of subdomains in the tail, we have used cryo-electron microscopy and image reconstruction to compare actin filaments decorated with WT AMIC and tail-truncated mutants of various lengths. The BR forms an oval-shaped feature, approximate to40 Angstrom long, that diverges obliquely from the head, extending azimuthally around the actin filament and toward its barbed end. GPA2 and GPA1 are located together on the inner (actin-proximal) side of the tail, close enough to act in concert in binding the same or another actin filament. The outer face of the BR is strategically exposed for membrane or vesicle binding. C1 NIAMSD, Struct Biol Res Lab, Bethesda, MD 20892 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, Bethesda, MD 20892 USA. EM alasdair_steven@nih.gov RI Korn, Edward/F-9929-2012; Ishikawa, Takashi/E-5023-2017 OI Ishikawa, Takashi/0000-0002-1976-7477 NR 42 TC 6 Z9 6 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 AUG 17 PY 2004 VL 101 IS 33 BP 12189 EP 12194 DI 10.1073/pnas.0404835101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847QN UT WOS:000223410100051 PM 15302934 ER PT J AU Jacobson, C Duggan, D Fischbach, G AF Jacobson, C Duggan, D Fischbach, G TI Neuregulin induces the expression of transcription factors and myosin heavy chains typical of muscle spindles in cultured human muscle SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EPSILON-SUBUNIT GENE; GLIAL GROWTH-FACTOR; ACETYLCHOLINE-RECEPTOR; SKELETAL-MUSCLE; NERVOUS-SYSTEM; NEUROMUSCULAR-JUNCTIONS; CHICK MUSCLE; SPINAL-CORD; FACTOR EGR3; AGRIN AB Neuregulin (NRG) (also known as ARIA, GGF, and other names) is a heparin sulfate proteoglycan secreted into the neuromuscular junction by innervating motor and sensory neurons. An integral part of synapse formation, we have analyzed NRG-induced changes in gene expression over 48 h in primary human myotubes. We show that in addition to increasing the expression of acetylcholine receptors on the myotube surface, NRG treatment results in a transient increase of several members of the early growth response (Egr) family of transcription factors. Three Egrs, Egr1, -2, and -3, are induced within the first hour of NRG treatment, with Egr1 and -3 RNA levels showing the most significant increases of approximate to9- and 16-fold, respectively. Also noted was a corresponding increase in protein levels for both of these transcription factors. Previous literature indicates that Egr3 expression is required for the formation of muscle spindle fibers, sensory organs that are distinct from skeletal muscle contractile fibers. At the molecular level, muscle spindle fibers express a unique subset of myosin heavy chains. Two isoforms of the myosin heavy chain, the slow development and neonatal, were found to be increased in our myotube cultures after 48 h of treatment with NRG. Taken together, these results indicate that not only can NRG induce the expression of a transcription factor key to spindle fiber development (Egr3), but that a portion of this developmental process can be replicated in vitro. C1 Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. NIAMSD, NIH, Microarray Unit, Genet & Genom Sect, Bethesda, MD 20892 USA. Translat Genom Res Inst, TGen, Phoenix, AZ 85004 USA. RP Fischbach, G (reprint author), Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. EM gdf@columbia.edu NR 68 TC 38 Z9 40 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 AUG 17 PY 2004 VL 101 IS 33 BP 12218 EP 12223 DI 10.1073/pnas.0404240101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847QN UT WOS:000223410100056 PM 15302938 ER PT J AU Messer, RJ Dittmer, U Peterson, KE Hasenkrug, KJ AF Messer, RJ Dittmer, U Peterson, KE Hasenkrug, KJ TI Essential role for virus-neutralizing antibodies in sterilizing immunity against Friend retrovirus infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; CD4(+) T-CELLS; HIV-1/SIV CHIMERIC VIRUS; MONOCLONAL-ANTIBODIES; INDUCED ERYTHROLEUKEMIA; ENVELOPE GLYCOPROTEIN; UNINFECTED VOLUNTEERS; PROTECTIVE IMMUNITY; PASSIVE INFUSION AB The current experiments use the Friend retrovirus model to demonstrate that vaccine-primed B cells are essential for sterilizing immunity, and the results indicate that the requisite function of these cells is the production of virus-neutralizing antibodies rather than priming or reactivation of T cells. B cell-deficient mice were poorly protected by vaccination, but adoptive transfer experiments showed that the T cells from B cell-deficient mice were primed as well as those from wild-type mice. Furthermore, passive transfer of virus-neutralizing antibodies completely compensated for B cell deficiency. The presence of virus-neutralizing antibodies at the time of infection was crucial for vaccine efficacy. Interestingly, virus-neutralizing antibodies worked synergistically with vaccine-primed T cells to provide a level of protection many orders of magnitude greater than either antibodies or immune T cells alone. Nonneutralizing antibodies also contributed to protection and acted cooperatively with neutralizing antibodies to reduce infection levels. These results emphasize the importance of inducing both T cell responses and virus-neutralizing antibody responses for effective retroviral vaccine protection. C1 NIAID, Rocky Mt Labs, NIH, Lab Persistent Viral Dis, Hamilton, MT 59840 USA. Univ Klinikum Essen, Inst Virol, D-45122 Essen, Germany. RP Hasenkrug, KJ (reprint author), NIAID, Rocky Mt Labs, NIH, Lab Persistent Viral Dis, Hamilton, MT 59840 USA. EM khasenkrug@nih.gov RI Peterson, Karin/D-1492-2016 OI Peterson, Karin/0000-0003-4177-7249 NR 73 TC 35 Z9 35 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 17 PY 2004 VL 101 IS 33 BP 12260 EP 12265 DI 10.1073/pnas.0404769101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847QN UT WOS:000223410100064 PM 15297622 ER PT J AU Scherer, A Frater, J Oxenius, A Agudelo, J Price, DA Gunthard, HF Barnardo, M Perrin, L Hirschel, B Phillips, RE McLean, AR AF Scherer, A Frater, J Oxenius, A Agudelo, J Price, DA Gunthard, HF Barnardo, M Perrin, L Hirschel, B Phillips, RE McLean, AR CA Swiss HIV Cohort Study TI Quantifiable cytotoxic T lymphocyte responses and HLA-related risk of progression to AIDS SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID CTL ESCAPE; HIV-INFECTION; DISEASE PROGRESSION; VIRUS; TRANSMISSION; RECOGNITION; POPULATION; ADVANTAGE; SELECTION; REVERSION AB There are significant associations between possession of certain HLA class I alleles and rate of progression to AIDS. Immunological data provide an explanatory mechanism for this relationship. Patients with HLA types associated with rapid disease progression recognize a significantly smaller fraction of their known repertoire of viral epitopes than do patients with HLA types associated with slow progression. Population frequency of HILA types (or supertypes) and their capacity to elicit cytotoxic T lymphocyte responses are also negatively correlated. These data provide an immunological mechanism to explain HLA-related risk of progression to AIDS and emphasize the central role of viral evolution in the pathogenesis of HIV. C1 Univ Oxford, Dept Zool, Oxford OX1 3PS, England. John Radcliffe Hosp, Nuffield Dept Clin Med, Oxford OX1 3SY, England. ETH, Inst Microbiol, CH-8092 Zurich, Switzerland. Churchill Hosp, Oxford OX3 7LJ, England. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Zurich Hosp, Div Infect Dis & Hosp Epidemiol, CH-8091 Zurich, Switzerland. Univ Hosp Geneva, Div Infect Dis, CH-1211 Geneva, Switzerland. Univ Hosp Geneva, Virol Lab, CH-1211 Geneva, Switzerland. CHU Vaudois, CH-1011 Lausanne, Switzerland. RP McLean, AR (reprint author), Univ Oxford, Dept Zool, S Parks Rd, Oxford OX1 3PS, England. EM angela.mclean@zoo.ox.ac.uk RI gunthard, huldrych/F-1724-2011; Infektiologie, USZ/A-6921-2011; Price, David/C-7876-2013; SHCS, all/G-4072-2011; SHCS, ch/G-4077-2011; SHCS, only/G-4080-2011; Oxenius, Annette/G-7794-2015 OI gunthard, huldrych/0000-0002-1142-6723; Price, David/0000-0001-9416-2737; FU Medical Research Council [G108/626] NR 29 TC 66 Z9 70 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 17 PY 2004 VL 101 IS 33 BP 12266 EP 12270 DI 10.1073/pnas.0404091101 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847QN UT WOS:000223410100065 PM 15302942 ER PT J AU Nishimura, Y Igarashi, T Donau, OK Buckler-White, A Buckler, C Lafont, BAP Goeken, RM Goldstein, S Hirsch, VM Martin, MA AF Nishimura, Y Igarashi, T Donau, OK Buckler-White, A Buckler, C Lafont, BAP Goeken, RM Goldstein, S Hirsch, VM Martin, MA TI Highly pathogenic SHIVs and SIVs target different CD4+ T cell subsets in rhesus monkeys, explaining their divergent clinical courses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN LYMPHOID-TISSUE; IN-VIVO; DISEASE PROGRESSION; 1-INFECTED INDIVIDUALS; VIRAL REPLICATION; SMALL-MOLECULE; HIV-1; DEPLETION; INFECTION AB In contrast to simian immunodeficiency viruses (SIVs), which induce immunodeficiency over a 1- to 3-year period, highly pathogenic simian-human immunodeficiency viruses (SHIVs) cause a complete, irreversible, and systemic depletion of CD4(+) T lymphocytes in rhesus monkeys within weeks of infection. By using small-molecule competitors specific for CCR5 and CXCR4 in ex vivo assays, we found that highly pathogenic SHIVDH12R exclusively uses CXCR4 for infection of rhesus peripheral blood mononuclear cells, whereas SIVma239 and SIVsmE543 use CCR5 for entry into the same cells. During the period of peak virus production in SHIVDH12R- or SHIV89.6P-infected rhesus monkeys, massive elimination of CXCR4(+) naive CD4(+) T cells occurred. In contrast, circulating CCR5(+) memory CD4(+) T cells were selectively depleted in rapidly progressing SIV-infected monkeys. At the time of their death, two SIV rapid progressors had experienced a nearly complete loss of the memory CD4(+) T cell subset from the blood and mesenteric lymph nodes. Thus, pathogenic SHIVs and SIVs target different subsets of CD4(+) T cells in vivo, with the pattern of CD4(+) T lymphocyte depletion being inextricably linked to chemokine receptor use. In the context of developing an effective prophylactic vaccine, which must potently control virus replication during the primary infection, regimens that suppress SHIVs might not protect monkeys against SIV or humans against HIV-1. C1 Natl Inst Allergy & Infect Dis, Lab Mol Microbiol, NIH, Bethesda, MD 20892 USA. RP Martin, MA (reprint author), Natl Inst Allergy & Infect Dis, Lab Mol Microbiol, NIH, Bethesda, MD 20892 USA. EM mmartin@niaid.nih.gov RI Lafont, Bernard/B-7236-2014 FU NIMHD NIH HHS [L60 MD003100] NR 45 TC 113 Z9 117 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 17 PY 2004 VL 101 IS 33 BP 12324 EP 12329 DI 10.1073/pnas.0404620101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847QN UT WOS:000223410100075 PM 15297611 ER PT J AU Liu, Z Richmond, BJ Murray, EA Saunders, RC Steenrod, S Stubblefield, BK Montague, DM Ginns, EI AF Liu, Z Richmond, BJ Murray, EA Saunders, RC Steenrod, S Stubblefield, BK Montague, DM Ginns, EI TI DNA targeting of rhinal cortex D2 receptor protein reversibly blocks learning of cues that predict reward SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LONG-TERM POTENTIATION; PERIRHINAL CORTEX; STIMULUS ASSOCIATION; TEMPORAL CORTEX; RHESUS-MONKEYS; ANTISENSE RNA; PARAHIPPOCAMPAL CORTICES; SYNAPTIC PLASTICITY; DOPAMINE-RECEPTORS; ENTORHINAL CORTEX AB When schedules of several operant trials must be successfully completed to obtain a reward, monkeys quickly learn to adjust their behavioral performance by using visual cues that signal how many trials have been completed and how many remain in the current schedule. Bilateral rhinal (perirhinal and entorhinal) cortex ablations irreversibly prevent this learning. Here, we apply a recombinant DNA technique to investigate the role of dopamine D2 receptor in rhinal cortex for this type of learning. Rhinal cortex was injected with a DNA construct that significantly decreased D2 receptor ligand binding and temporarily produced the same profound learning deficit seen after ablation. However, unlike after ablation, the D2 receptor-targeted, DNA-treated monkeys recovered cue-related learning after 11-19 weeks. Injecting a DNA construct that decreased N-methyl-D-aspartate but not D2 receptor ligand binding did not interfere with learning associations between the cues and the schedules. A second D2 receptor-targeted DNA treatment administered after either recovery from a first D2 receptor-targeted DNA treatment (one monkey), after N-methyl-D-aspartate receptor-targeted DNA treatment (two monkeys), or after a vector control treatment (one monkey) also induced a learning deficit of similar duration. These results suggest that the D2 receptor in primate rhinal cortex is essential for learning to relate the visual cues to the schedules. The specificity of the receptor manipulation reported here suggests that this approach could be generalized in this or other brain pathways to relate molecular mechanisms to cognitive functions. C1 Natl Inst Mental Hlth, Lab Neuropsychol, NIH, Bethesda, MD 20892 USA. Natl Inst Mental Hlth, Clin Neurosci Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Mental Hlth, Behav Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIMH, Human Serv, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Brudnick Neuropsychiat Res Inst, Worcester, MA 01604 USA. RP Richmond, BJ (reprint author), Natl Inst Mental Hlth, Lab Neuropsychol, NIH, Bethesda, MD 20892 USA. EM bjr@in.nimh.nih.gov OI Steenrod, Sara/0000-0002-7932-7385; Murray, Elisabeth/0000-0003-1450-1642 NR 45 TC 55 Z9 56 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 17 PY 2004 VL 101 IS 33 BP 12336 EP 12341 DI 10.1073/pnas.0403639101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847QN UT WOS:000223410100077 PM 15302926 ER PT J AU Barr, CS Newman, TK Schwandt, M Shannon, C Dvoskin, RL Lindell, SG Taubman, J Thompson, B Champoux, M Lesch, KP Goldman, D Suomi, SJ Higley, JD AF Barr, CS Newman, TK Schwandt, M Shannon, C Dvoskin, RL Lindell, SG Taubman, J Thompson, B Champoux, M Lesch, KP Goldman, D Suomi, SJ Higley, JD TI Sexual dichotomy of an interaction between early adversity and the serotonin transporter gene promoter variant in rhesus macaques SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; PITUITARY-ADRENAL AXIS; ANXIETY-RELATED TRAITS; PRENATAL STRESS; LIFE STRESS; FEMALE RATS; POLYMORPHISM; MICE; REGION; CORTISOL AB A polymorphism in the human serotonin transporter gene promoter (5-HTTLPR) is associated with anxiety and increased risk for developing depression in the face of adversity. Here, we report that among infant rhesus macaques, an orthologous polymorphism (rh5-HTTLPR) interacts with adversity in the form of peer rearing to influence adrenocorticotropic hormone (ACTH) response to stress and, further, that this interaction is sexually dichotomous. ACTH responses to separation are higher in I/s than in I/I males. in females, however, it is only among those with a history of adversity that the s allele is associated with increased ACTH responses to stress. Of interest, peer-reared animals, in particular females carrying the s allele, also exhibit lower cortisol responses to stress, a pattern that has been recognized in association with certain stress-related neuropsychiatric disorders. By extension, our findings suggest the intriguing possibility that human females carrying the 5-HTTLPR s allele could be more vulnerable to the effects of early adversity. This interactive effect may underlie the increased incidence of certain stress-related disorders in women. C1 NICHHD, Primate Unit, Lab Clin Studies, Div Intramural Clin & Biol Res,NIAAA, Poolesville, MD 20837 USA. NICHHD, Lab Comparat Ethol, NIH, Poolesville, MD 20837 USA. NIAAA, Lab Neurogenet, NIH, Rockville, MD 20852 USA. Univ Wurzburg, Dept Psychiat & Psychotherapy, D-97080 Wurzburg, Germany. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. RP Barr, CS (reprint author), NICHHD, Primate Unit, Lab Clin Studies, Div Intramural Clin & Biol Res,NIAAA, Poolesville, MD 20837 USA. EM cbarr@mail.nih.gov RI Schwandt, Melanie/L-9866-2016; Lesch, Klaus-Peter/J-4906-2013; Goldman, David/F-9772-2010 OI Lesch, Klaus-Peter/0000-0001-8348-153X; Goldman, David/0000-0002-1724-5405 NR 47 TC 146 Z9 150 U1 3 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 17 PY 2004 VL 101 IS 33 BP 12358 EP 12363 DI 10.1073/pnas.0403763101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 847QN UT WOS:000223410100081 PM 15302939 ER PT J AU Park, SW Ludes-Meyers, J Zimonjic, DB Durkin, ME Popescu, NC Aldaz, CM AF Park, SW Ludes-Meyers, J Zimonjic, DB Durkin, ME Popescu, NC Aldaz, CM TI Frequent downregulation and loss of WWOX gene expression in human hepatocellular carcinoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE WWOX gene expression; tumour suppressor gene; hepatocellular carcinoma; chromosome rearrangements; fragile sites ID COMMON FRAGILE SITES; TUMOR-SUPPRESSOR GENE; HUMAN-CHROMOSOMES; BREAST-CANCER; CELL-GROWTH; DNA; PROTEIN; FRA16D; DLC-1; REARRANGEMENTS AB The WWOX (WW-domain containing oxidoreductase) is a candidate tumour suppressor gene spanning the same chromosome region, 16q23, as the second most common fragile site (FS), FRA16D. Deletions detected by comparative genomic hybridisation (CGH) and loss of heterozygosity at microsatellite markers on chromosome 16q are common in many human cancers including hepatocellular carcinoma (HCC). The development of human HCC is closely associated with exposure to oncogenic viruses and chemical carcinogens, agents known to frequently target common FS. We examined the status of WWOX genomic DNA, RNA and protein in 18 cell lines derived from human HCC and found recurrent alterations of the gene. Loss of DNA copy-number confined to band 16q23 was detected by CGH in several cell lines. Although homozygous deletions of the WWOX gene were not detected, WWOX mRNA expression was absent or lower in 60% of cell lines. The occurrence of aberrant WWOX reverse transcription-PCR products with deletion of exons 6-8 correlated significantly with altered WWOX expression. All of the cell lines showing mRNA downregulation had a decreased or undetectable level of WWOX protein as demonstrated by Western blotting with antibody to WWOX. Furthermore, 13 out of the 18 cell lines expressed decreased levels or no WWOX protein when compared with normal liver. These results show that WWOX gene is frequently altered in HCC and raise the possibility that this gene is implicated in hepatocarcinogenesis. C1 NCI, Expt Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX 78957 USA. RP Popescu, NC (reprint author), 37 Convent Dr MSC 4262,Bldg 37,Room 4128B, Bethesda, MD 20892 USA. EM popescun@dc37a.nci.nih.gov FU NCI NIH HHS [R01 CA102444-01, R01 CA 102444, R01 CA102444, R01 CA102444-02, R01 CA102444-03, R01 CA102444-04, R01 CA102444-05, R01 CA102444-06A1, R01 CA102444-07]; NIEHS NIH HHS [ES 07784, P30 ES007784] NR 38 TC 63 Z9 70 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD AUG 16 PY 2004 VL 91 IS 4 BP 753 EP 759 DI 10.1038/sj.bjc.6602023 PG 7 WC Oncology SC Oncology GA 844YT UT WOS:000223201600026 PM 15266310 ER PT J AU Elshal, MF Elsayed, IH El Kady, IM Badra, G El-Refaei, A El-Batanony, M Hendy, OM AF Elshal, MF Elsayed, IH El Kady, IM Badra, G El-Refaei, A El-Batanony, M Hendy, OM TI Role of concurrent S-mansoni infection in H-pylori-associated gastritis: a flow cytometric DNA-analysis and oxyradicals correlations SO CLINICA CHIMICA ACTA LA English DT Article DE Helicobacter; Schistosomiasis; DNA-synthesis; proliferation; oxyradicals; antioxidants ID HELICOBACTER-PYLORI; APOPTOSIS; MUCOSA; PREVALENCE; EXPRESSION; RESPONSES; HELMINTH; CHILDREN; DAMAGE; ULCER AB Background/aim: Helicobacter pylori infection is associated with the development of atrophic gastritis and increased gastric epithelial proliferation that is important in developing gastric carcinoma. Some countries with a high prevalence of H. pylori infection have high gastric cancer rates, whereas in others these rates are low. Several theories have been advanced to explain this phenomenon. One of these explanations is that the concurrent parasitic infection that is common in the African population might alter the immune response to H. pylori infection and reduce the incidence of atrophic gastritis. The aim of the present study was to assess whether concurrent Schistosoma mansoni infection with H. pylori has an effect on gastric mucosal injury in view of cell proliferation, apoptosis, pathological changes, nitric oxide (NO), oxyradicals and antioxidant capacity status. Patients/methods: Between April 2001 and March 2002, 73 patients were subjected to upper gastrointestinal endoscopy for dyspepsia and liver cirrhosis in the National Liver Institute, Menoufiya University. Biopsies were obtained from any lesion as well as from apparently healthy mucosa. Specimens were preserved in RNA later solution, and then kept at - 80 degreesC until utilized for estimation of DNA-flow cytometric assay, reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), NO and lipid peroxidation (LPO) product malondialdehyde (MDA). Diagnosis of bilharziasis was done by stool analysis, or by sigmoidoscopy and rectal snip. Results: Of the 73 patients, 48 were H. pylori-positive, 34 of them were positive and 14 were negative for S. mansoni. Of the 25 H. pylori-negative cases, 18 were positive and 7 were negative for S. mansoni. Concurrent infection with S. mansoni occurred in 34 patients and they had reduced DNA S-phase (7.57 +/- 4.99 vs. 14.5 +/- 3.11, P = 0.001), reduced proliferation activity (9.95 +/- 3.95 vs. 16.78, P<0.004) and reduced apoptosis (21.83 +/- 11.64 vs. 26.0 +/- 8.31, P>0.05) compared with H. pylori infected patients alone. Conclusions: The results demonstrate that concurrent helminthes infection may modify the inflammatory response to gastric H. pylori infection manifested by the reduction of oxyradical-induced DNA-damage, apoptosis and cellular. proliferation activity, and the increase in antioxidant production. Concurrent S. mansoni infection may have a protective effect against the possible progression of H. pylori-induced gastritis towards gastric carcinoma. (C) 2004 Elsevier B.V. All rights reserved. C1 NIH, Bethesda, MD 20892 USA. RP NIH, Bldg 10 Rm 4A07,9000 Rockville Pike, Bethesda, MD 20892 USA. EM melshal2002@yahoo.com RI Elshal, Mohamed/H-7953-2012 NR 25 TC 8 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 EI 1873-3492 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD AUG 16 PY 2004 VL 346 IS 2 BP 191 EP 198 DI 10.1016/j.cccn.2004.03.023 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 842ZH UT WOS:000223042700010 PM 15256320 ER PT J AU Min, B Prout, M Hu-Li, J Zhu, JF Jankovic, D Morgan, ES Urban, JF Dvorak, AM Finkelman, FD LeGros, G Paul, WE AF Min, B Prout, M Hu-Li, J Zhu, JF Jankovic, D Morgan, ES Urban, JF Dvorak, AM Finkelman, FD LeGros, G Paul, WE TI Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE CD4 T cells; cytokine; green fluorescent protein; Nippostrongylus brasiliensis; liver ID NON-T CELLS; SPLENIC NON-B; HUMAN BLOOD BASOPHILS; HUMAN IGE SYNTHESIS; IMMUNITY IN-VIVO; NIPPOSTRONGYLUS-BRASILIENSIS; SCHISTOSOMA-MANSONI; INTERLEUKIN-4 PRODUCTION; MOUSE BASOPHIL; DEFICIENT MICE AB Using mice in which the eGfp gene replaced the first exon of the Il4 gene (G4 mice), we examined production of interleukin (IL)-4 during infection by the intestinal nematode Nippostrongylus brasiliensis (Nb). Nb infection induced green fluorescent protein (GFP)(pos) cells that were FcepsilonRI(pos), CD49b(bright), c-kit(neg), and Gr1(neg). These cells had lobulated nuclei and granules characteristic of basophils. They were found mainly in the liver and lung, to a lesser degree in the spleen, but not in the lymph nodes. Although some liver basophils from naive mice express GFP, Nb infection enhanced GFP expression and increased the number of tissue basophils. Similar basophil GFP expression was found in infected Stat6(-/-) mice. Basophils did not increase in number in infected kag2(-/-) mice; Rag2(-/-) mice reconstituted with CD4 T cells allowed significant basophil accumulation, indicating that CD4 T cells can direct both tissue migration of basophils and enhanced IL-4 production. IL-4 production was immunoglobulin independent and only partially dependent on IL-3. Thus, infection with a parasite that induces a "Th2-type response" resulted in accumulation of tissue basophils, and these cells, stimulated by a non-FcR cross-linking mechanism, are a principal source of in vivo IL-4 production. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Malaghan Inst Med Res, Wellington, New Zealand. Beth Israel Deaconess Med Ctr, Dept Pathol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. USDA, Beltsville Human Nutr Res Ctr, Nutrient Requirements & Funct Lab, Beltsville, MD 20705 USA. Univ Cincinnati, Coll Med, Dept Med, Cincinnati, OH 45267 USA. RP Paul, WE (reprint author), NIAID, Immunol Lab, NIH, 20 Ctr Dr,Bldg 10,Rm 11N314, Bethesda, MD 20892 USA. EM wpaul@niaid.nih.gov RI Zhu, Jinfang/B-7574-2012; OI Urban, Joseph/0000-0002-1590-8869 FU NIAID NIH HHS [AI33372, R01 AI033372] NR 52 TC 251 Z9 258 U1 0 U2 4 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 AUG 16 PY 2004 VL 200 IS 4 BP 507 EP 517 DI 10.1084/jem.20040590 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 848GN UT WOS:000223455700010 PM 15314076 ER PT J AU Engels, EA Chen, J Viscidi, RP Shah, KV Daniel, RW Chatterjee, N Klebanoff, MA AF Engels, EA Chen, J Viscidi, RP Shah, KV Daniel, RW Chatterjee, N Klebanoff, MA TI Poliovirus vaccination during pregnancy, maternal seroconversion to simian virus 40, and risk of childhood cancer SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE BK virus; brain neoplasms; child; leukemia; neoplasms; poliovirus; poliovirus vaccines; simian virus 40 ID HUMAN BRAIN-TUMORS; LARGE T-ANTIGEN; SIMIAN VIRUS 40; VACUOLATING VIRUS; SEROLOGIC EVIDENCE; DNA-SEQUENCES; JC VIRUS; BK VIRUS; SV40; INFECTION AB Before 1963, poliovirus vaccine produced in the United States was contaminated with simian virus 40 (SV40), which causes cancer in animals. To examine whether early-life SV40 infection can cause human cancer, the authors studied 54,796 children enrolled in the US-based Collaborative Perinatal Project (CPP) in 1959-1966, 52 of whom developed cancer by their eighth birthday. Those children whose mothers had received pre-1963 poliovirus vaccine during pregnancy (22.5% of the children) had an increased incidence of neural tumors (hazard ratio = 2.6, 95% confidence interval: 1.0, 6.7; 18 cases) and hematologic malignancies (hazard ratio = 2.8, 95% confidence interval: 1.2, 6.4; 22 cases). For 50 CPP children with cancer and 200 CPP control children, the authors tested paired maternal serum samples from pregnancy for SV40 antibodies using a virus-like particle enzyme immunoassay and a plaque neutralization assay. Overall, mothers exhibited infrequent, low-level SV40 antibody reactivity, and only six case mothers seroconverted by either assay. Using the two SV40 assays, maternal SV40 seroconversion during pregnancy was not consistently related to children's case/control status or mothers' receipt of pre-1963 vaccine. The authors conclude that an increased cancer risk in CPP children whose mothers received pre-1963 poliovirus vaccine was unlikely to have been due to SV40 infection transmitted from mothers to their children. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD USA. 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 NR 40 TC 16 Z9 18 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2004 VL 160 IS 4 BP 306 EP 316 DI 10.1093/aje/kwh219 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 844EX UT WOS:000223141400002 PM 15286015 ER PT J AU Rollison, DEM Page, WF Crawford, H Gridley, G Wacholder, S Martin, J Miller, R Engels, EA AF Rollison, DEM Page, WF Crawford, H Gridley, G Wacholder, S Martin, J Miller, R Engels, EA TI Case-control study of cancer among US army veterans exposed to simian virus 40-contaminated adenovirus vaccine SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article ID PLEURAL MESOTHELIOMA; VACUOLATING VIRUS; DNA-SEQUENCES; JC VIRUS; BK VIRUS; SIMIAN-VIRUS-40 INFECTION; POLIOVIRUS VACCINES; SV40-LIKE SEQUENCES; BRAIN-TUMORS; SV40 AB Simian virus 40 (SV40) was an accidental contaminant of vaccines produced in monkey kidney tissue cultures in the 1950s and early 1960s, including a parenteral adenovirus vaccine given to several hundred thousand US military recruits. Detection of SV40 DNA in tumor tissues by some laboratories suggests that SV40 contributes to human cancers. To determine if entry into US Army service during periods of administration of SV40-contaminated adenovirus vaccine was associated with an increased risk of cancer, the authors conducted a case-control study of cancer occurring in male Army veterans who entered service in 1959-1961. Cases of brain tumors (n = 181), mesothelioma (n = 10), and non-Hodgkin's lymphoma (n = 220) were identified through a Veterans Administration hospital discharge database, as were colon cancer and lung cancer controls (n = 221). Exposure to adenovirus vaccine was assigned on the basis of known periods of adenovirus vaccine administration and dates of Army entry obtained for cancer cases and controls. The odds ratios associated with exposure to SV40-contaminated adenovirus vaccine were 0.81 (95% confidence interval (CI): 0.52, 1.24) for brain tumors, 1.41 (95% CI: 0.39, 5.15) for mesothelioma, and 0.97 (95% CI: 0.65, 1.44) for non-Hodgkin's lymphoma. These findings do not support a role for SV40 in the development of these cancers. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Natl Acad, Med Followup Agcy, Inst Med, Washington, DC USA. NCI, Div Canc Epidemiol & Genet, US Dept HHS, Rockville, MD USA. RTI Int, Rockville, MD USA. RP Engels, EA (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, US Dept HHS, 6120 Execut Blvd,EPS 8010, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov NR 48 TC 25 Z9 27 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2004 VL 160 IS 4 BP 317 EP 324 DI 10.1093/aje/kwh212 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 844EX UT WOS:000223141400003 PM 15286016 ER PT J AU Zhang, YW Holford, TR Leaderer, B Boyle, P Zahm, SH Owens, PH Morton, LM Zhang, B Zou, K Flynn, S Tallini, G Zheng, TZ AF Zhang, YW Holford, TR Leaderer, B Boyle, P Zahm, SH Owens, PH Morton, LM Zhang, B Zou, K Flynn, S Tallini, G Zheng, TZ TI Blood transfusion and risk of non-hodgkin's lymphoma in connecticut women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE blood transfusion; Connecticut; lymphoma; non-Hodgkin; risk; women ID TIME TRENDS; UNITED-STATES; SKIN-CANCER; OLDER WOMEN; HISTORY; POPULATIONS; ASSOCIATION; LEUKEMIA; VIRUSES; SEARCH AB The incidence and mortality rates of non-Hodgkin's lymphoma have been increasing worldwide. Allogeneic blood transfusion has been suggested as a risk factor for non-Hodgkin's lymphoma, but the results from epidemiologic studies have been inconsistent. Data from a population-based case-control study of Connecticut women were analyzed to evaluate this relation. A total of 601 histologically confirmed, non-Hodgkin's lymphoma incident cases identified between 1996 and 2000 and 717 randomly selected controls were included in this study. Allogeneic blood transfusion was not associated with the increased risk of non-Hodgkin's lymphoma overall (odds ratio = 1.0, 95% confidence interval: 0.7, 1.3) or by subtype of the disease. The risk also did not vary by number of allogeneic blood transfusions, age at first transfusion, or time since first transfusion. When the reason for blood transfusion was considered, an increased risk of non-Hodgkin's lymphoma was found only for allogeneic blood transfusion for reason of anemia. In summary, the authors' findings do not support the hypothesis that allogeneic blood transfusion increases the risk of non-Hodgkin's lymphoma. C1 Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. Europe Inst Oncol, Dept Epidemiol & Biostat, Milan, Italy. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ, Canada. Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA. Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. RP Zheng, TZ (reprint author), 129 Church St,Suite 700, New Haven, CT 06510 USA. EM tongzhang.zheng@yale.edu RI Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015; Morton, Lindsay/B-5234-2015; OI Boyle, Peter/0000-0001-6251-0610; Morton, Lindsay/0000-0001-9767-2310; Tallini, Giovanni/0000-0003-0113-6682 FU NCI NIH HHS [CA62006] NR 37 TC 22 Z9 23 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2004 VL 160 IS 4 BP 325 EP 330 DI 10.1093/aje/kwh233 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 844EX UT WOS:000223141400004 PM 15286017 ER PT J AU Flegal, KM Graubard, BI Williamson, DF AF Flegal, KM Graubard, BI Williamson, DF TI Methods of calculating deaths attributable to obesity SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE anthropometry; body mass index; body weight; cause of death; epidemiologic methods; risk; statistics; vital statistics ID UNITED-STATES; MORTALITY; WEIGHT; RISK; AGE AB Previously reported estimates of deaths attributable to obesity in the United States have been based on a method that only partially adjusts for confounding and does not allow for effect modification. In this study, the authors investigated the possible magnitude and direction of bias in estimating deaths attributable to obesity when such a method is used. Hypothetical examples are based on 1991 US population data and published relative risks. Incomplete adjustment for confounding of the obesity-mortality relation by age and sex led to a 17% overestimation of deaths due to obesity. Additional bias resulted from slight differences between the derivation cohort and the target population. For example, a difference of three percentage points in the proportion of people 80 years of age or older led to a 42% overestimation of deaths due to obesity. In addition, these estimates appear to be sensitive to minor differences in relative risks between a derivation cohort and the target population. A difference of 0.20 in relative risks almost doubled the number of deaths (97% overestimation). Estimates of deaths attributable to obesity can be biased if confounding and effect modification are not properly taken into account or if the relative risks are not estimated accurately. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. Univ Calif Berkeley, Ctr Weight & Height, Berkeley, CA 94720 USA. NCI, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 4311, Hyattsville, MD 20782 USA. EM kflegal@cdc.gov RI Flegal, Katherine/A-4608-2013; OI Flegal, Katherine/0000-0002-0838-469X NR 17 TC 59 Z9 60 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2004 VL 160 IS 4 BP 331 EP 338 DI 10.1093/aje/kwh222 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 844EX UT WOS:000223141400005 PM 15286018 ER PT J AU Radimer, K Bindewald, B Hughes, J Ervin, B Swanson, C Picciano, MF AF Radimer, K Bindewald, B Hughes, J Ervin, B Swanson, C Picciano, MF TI Dietary supplement use by US adults: Data from the National Health and Nutrition Examination Survey, 1999-2000 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adult; antacids; dietary supplements; health surveys; minerals; nutrition surveys; vitamins ID UNITED-STATES; VITAMIN-D; MINERAL SUPPLEMENTS; DAIRY-PRODUCTS; CALCIUM; VALIDITY; CANCER; COHORT; RISK AB Data from the 1999-2000 National Health and Nutrition Examination Survey, a nationally representative, cross-sectional survey of US health and nutrition, were analyzed to assess prevalence of dietary supplement use overall and in relation to lifestyle and demographic characteristics. Fifty-two percent of adults reported taking a dietary supplement in the past month; 35% took a multivitamin/multimineral. Vitamin C, vitamin E, B-complex vitamins, calcium, and calcium-containing antacids were taken by more than 5% of adults. In bivariate analyses, female gender, older age, more education, non-Hispanic White race/ethnicity, any physical activity, normal/underweight, more frequent wine or distilled spirit consumption, former smoking, and excellent/very good self-reported health were associated with greater use of any supplement and of multivitamin/multiminerals; in multivariable comparisons, the latter three characteristics were not associated with supplement use. Most supplements were taken daily and for at least 2 years. Forty-seven percent of adult supplement users took just one supplement; 55% of women and 63% of adults aged greater than or equal to60 years took more than one. These findings suggest that, to minimize possible spurious associations, epidemiologic studies of diet, demography, or lifestyle and health take dietary supplement use into account because of 1) supplements' large contribution to nutrient intake and 2) differential use of supplements by demographic and lifestyle characteristics. C1 Ctr Dis Control & Prevent, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. RP Radimer, K (reprint author), Ctr Dis Control & Prevent, Div Hlth & Nutr Examinat Surveys, Natl Ctr Hlth Stat, 3311 Toledo Rd, Hyattsville, MD 20782 USA. EM kir5@cdc.gov NR 27 TC 440 Z9 457 U1 1 U2 20 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2004 VL 160 IS 4 BP 339 EP 349 DI 10.1093/aje/kwh207 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 844EX UT WOS:000223141400006 PM 15286019 ER PT J AU Slavotinek, AM Dutra, A Kpodzo, D Pak, E Nakane, T Turner, J Whiteford, M Biesecker, LG Stratton, P AF Slavotinek, AM Dutra, A Kpodzo, D Pak, E Nakane, T Turner, J Whiteford, M Biesecker, LG Stratton, P TI A female with complete lack of Mullerian fusion, postaxial polydactyly, and tetralogy of Fallot: Genetic heterogeneity of McKusick-Kaufman syndrome or a unique syndrome? SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE McKusick-Kaufman syndrome; genetic heterogeneity; Bardet-Biedl syndrome; Mayer-Rokitansky-Kuster-Hausersyndrome; complete lack of Mullerian fusion; vaginal agenesis ID BARDET-BIEDL-SYNDROME; PALLISTER-HALL SYNDROME; KUSTER-HAUSER SYNDROME; ALAGILLE-SYNDROME; TRIALLELIC INHERITANCE; PHENOTYPIC OVERLAP; HUMAN-CHROMOSOMES; HUMAN JAGGED1; MUTATIONS; HYDROMETROCOLPOS AB We report a 19-year-old, non-Amish Caucasian female patient with primary amenorrhea. caused by complete lack of Mullerian fusion with vaginal agenesis or Muillerian aplasia (MA), postaxial polydactyly (PAP), and tetralogy of Fallot. The genital tract anomaly of MA with and without renal or skeletal anomalies comprises Mayer-Rokitansky-Kuster-Hauser syndrome, which has not been reported with tetralogy of Fallot. The phenotypic triad of anomalies most closely resembled McKusick-Kaufman syndrome (MKS; OMIM 236700), a rare multiple congenital anomaly syndrome comprised of hydrometrocolpos (HMC), PAP, and congenital heart malformation that is inherited in an autosomal recessive pattern. While upper reproductive tract anomalies have not been reported with MKS, they have been reported with Bardet-Biedl syndrome (BBS), a syndrome that significantly overlaps with MKS. Both MKS and BBS can be caused by mutations in the MKKS or BBS6 gene on chromosome 20p12 and BBS is also associated with mutations in other genes (BBS1, BBS2, BBS4, and BBS7). To address this heterogenity, we sequenced the causative genes in MKS and BBS but no mutations in these five genes were identified. Fluorescence in situ hybridization (FISH) excluded large deletions of chromosome 20p12 and microsatellite marker studies confirmed biparental inheritance for all of the known BBS loci. The dual midline fusion defects of tetralogy of Fallot and MA suggests that either this patient has a unique syndrome with a distinct genetic etiology or that she has a genetically heterogeneous or variant form of MKS. Published 2004 Wiley-Liss, Inc.dagger C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Yorkhill NHS Trust, Duncan Guthrie Inst Med Genet, Glasgow, Lanark, Scotland. RP Stratton, P (reprint author), NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bldg 10,Room 9D42,10 Ctr Dr MSC 1583, Bethesda, MD 20892 USA. EM ps79c@nih.gov NR 42 TC 8 Z9 8 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0148-7299 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD AUG 15 PY 2004 VL 129A IS 1 BP 69 EP 72 DI 10.1002/ajmg.a.30071 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 842AP UT WOS:000222975000014 PM 15266619 ER PT J AU King, KC Budihas, SR Le Grice, SFJ Parniak, MA Crouch, RJ Gaidamakov, SA Isaaq, HJ Wamiru, A McMahon, JB Beutler, JA AF King, KC Budihas, SR Le Grice, SFJ Parniak, MA Crouch, RJ Gaidamakov, SA Isaaq, HJ Wamiru, A McMahon, JB Beutler, JA TI A capillary electrophoretic assay for ribonuclease H activity SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE capillary electrophoresis; ribonuclease H; HIV-1; reverse transcriptase; fluorescence ID IMMUNODEFICIENCY VIRUSES TYPE-1; HIV-1 REVERSE-TRANSCRIPTASE; ZONE-ELECTROPHORESIS; INHIBITORS; PROTEIN; DNA; OLIGONUCLEOTIDES; RESOLUTION; BUFFERS; RNA AB A capillary electrophoretic assay was developed to measure the ribonuclease (RNase) H activity of human immunodeficiency virus (HIV) type I reverse transcriptase. Cleavage of a fluorescein-labeled RNA-DNA heteroduplex was monitored by capillary electrophoresis. This new assay was used as a secondary assay to confirm hits from a high-throughput screening program. Since autofluorescent compounds in samples migrated differently from both substrate and product in most cases, the assay was extremely robust for assaying enzymatic inhibition of such samples, in contrast to a simple well-based approach. The assay was broadly applicable to other RNases H, specifically those from human, Escherichia coli, and HIV-2, although product profiles varied for each enzyme. Published by Elsevier Inc. C1 NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21702 USA. SAIC Frederick Inc, NCI, Ctr Canc Res, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. NCI, HIV Drug Resistance Program, Ctr Canc Res, Frederick, MD 21702 USA. Univ Pittsburgh, Sch Med, Div Infect Dis, Pittsburgh, PA 15213 USA. NICHHD, Mol Genet Lab, Bethesda, MD 20892 USA. RP Beutler, JA (reprint author), NCI, Mol Targets Dev Program, Ctr Canc Res, Frederick, MD 21702 USA. EM jb123w@nih.gov RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 NR 25 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 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD AUG 15 PY 2004 VL 331 IS 2 BP 296 EP 302 DI 10.1016/j.ab.2004.05.017 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 842LI UT WOS:000223005200012 ER PT J AU Williams, DA Farrell, MJ Cunningham, J Gracely, RH Ambrose, K Cupps, T Mohan, N Clauw, DJ AF Williams, DA Farrell, MJ Cunningham, J Gracely, RH Ambrose, K Cupps, T Mohan, N Clauw, DJ TI Knee pain and radiographic osteoarthritis interact in the prediction of levels of self-reported disability SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article DE pain; osteoarthritis; disability ID OUTCOMES AB Objective. To determine predictors of disability depending on whether joint deformity and pain reporting exist independently or concurrently. Methods. Subjects were 154 volunteers for an osteoarthritis screening examination. Eligible subjects completed questionnaires for physical function, pain, and depressive symptoms; underwent evoked pain testing for tenderness assessment; and had anteroposterior and lateral radiographs taken of both knees. Two blinded rheumatologists scored the images using Kellgren-Lawrence criteria to determine presence of deformity. Results. Subjects were divided into 3 subgroups based on radiographic evidence of deformity and self-reported pain. Disability was greatest when pain and deformity occurred together (F[2,151] = 18.8, P < 0.0001). Self-reported disability in the absence of deformity was predicted by body mass index, pain threshold, and anxiety symptoms; disability was predicted by the number of osteophytes and depressive symptoms when pain and deformity occurred together. Conclusion. Self-reported disability in osteoarthritis of the knee is greatest with concurrent pain and joint deformity. When pain and deformity do not cooccur, disability appears to be related to separate factors, including anxiety and pain threshold (e.g., tenderness). C1 Univ Michigan, Chron Pain & Fatigue Res Program, Ann Arbor, MI 48106 USA. Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. Georgetown Univ, Med Ctr, Washington, DC 20007 USA. Avera Res Inst, Sioux Falls, SD USA. RP Williams, DA (reprint author), Univ Michigan, Chron Pain & Fatigue Res Program, 24 Frank Lloyd Wright Dr,POB 385, Ann Arbor, MI 48106 USA. EM daveawns@med.umich.edu RI Williams, David/A-1180-2007; OI Farrell, Michael/0000-0003-4126-8911 NR 8 TC 23 Z9 23 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD AUG 15 PY 2004 VL 51 IS 4 BP 558 EP 561 DI 10.1002/art.20537 PG 4 WC Rheumatology SC Rheumatology GA 844TL UT WOS:000223183100008 PM 15334427 ER PT J AU Pillemer, SR Brennan, MT Sankar, V Leakan, RA Smith, JA Grisius, M Ligier, S Radfar, L Kok, MR Kingman, A Fox, PC AF Pillemer, SR Brennan, MT Sankar, V Leakan, RA Smith, JA Grisius, M Ligier, S Radfar, L Kok, MR Kingman, A Fox, PC TI Pilot clinical trial of dehydroepiandrosterone (DHEA) versus placebo for Sjogren's Syndrome SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article DE dehydroepiandrosterone; Sjogren's syndrome; clinical trial ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; DOUBLE-BLIND; WOMEN; CLASSIFICATION; CRITERIA AB Objective. To screen for potential efficacy and assess feasibility and safety of dehydroepiandrosterone (DHEA) as a treatment for Sjogren's syndrome (SS). Methods. A 24-week randomized, double-blinded, pilot trial of oral DHEA (200 mg/day) versus placebo was conducted. The primary comparison was to a hypothesized 20% placebo response rate. If 14 consecutive subjects on DHEA did not respond, a Phase III trial would be considered futile. A placebo group of 14 subjects was planned to verify placebo response rate and estimate sample size required for a definitive trial. Response criteria required 20% improvement in at least 2 of 3 domains. Analysis of covariance was used to adjust for baseline differences and for stratified randomization. Outcome measures included visual analog scale questionnaires for dry eye and dry mouth symptoms, lissamine green ocular dye staining and Schirmer I tests, stimulated salivary flow, IgG, and erythrocyte sedimentation rate (ESR). Results. Randomization resulted in 14 DHEA and 14 placebo group subjects. At baseline, mean +/- SD for DHEA versus placebo groups were Schirmer I tests 4.5 +/- 4.5 versus 5.4 +/- 6.1 mm/5 minutes; Van Bijsterveld score 5.3 +/- 2.1 versus 5.5 +/- 2.2; unstimulated saliva 0.03 +/- 0.05 versus 0.04 +/- 0.10 ml/minute; IgG 1,699 749 versus 1,712 +/- 621 g/dl; and ESR 40 +/- 31 versus 44 +/- 28 mm/hour. Apart from changes over the trial in dry mouth symptoms, no significant differences were noted between the DHEA and placebo groups for dry eye symptoms, objective measures of ocular dryness, stimulated salivary flow; IgG, or ESR. Four DHEA and one placebo group patient dropped out because of adverse effects. Although 7 subjects met response criteria in the DHEA group, 5 met the criteria in the placebo group, and there was no significant difference between groups. Conclusion. DHEA showed no evidence of efficacy in SS. Without evidence for efficacy, patients with SS should avoid using unregulated DHEA supplements, since long-term adverse consequences of exposure to this hormone are unknown. C1 NIDCR, NIH, Sjogrens Syndrome Clin, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. Carolinas Med Ctr, Charlotte, NC USA. NEI, Bethesda, MD 20892 USA. Hop Maison Neuve Rosemont, Montreal, PQ H1T 2M4, Canada. Acad Med Ctr, Amsterdam, Netherlands. RP Pillemer, SR (reprint author), NIDCR, NIH, Sjogrens Syndrome Clin, Gene Therapy & Therapeut Branch, 10 Ctr Dr,Room 1N113,MSC 1190, Bethesda, MD 20892 USA. EM PillemerS@medimmune.com NR 15 TC 26 Z9 26 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD AUG 15 PY 2004 VL 51 IS 4 BP 601 EP 604 DI 10.1002/art.20540 PG 4 WC Rheumatology SC Rheumatology GA 844TL UT WOS:000223183100014 PM 15334433 ER PT J AU Ward, MM AF Ward, MM TI Education level and mortality in systemic lupus erythematosus (SLE): Evidence of underascertainment of deaths due to SLE in ethnic minorities with low education levels SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article DE education; mortality; socioeconomic status; systemic lupus erythematosus; ethnic minorities; health disparities ID 513 DANISH PATIENTS; RHEUMATOID-ARTHRITIS; UNITED-STATES; SOCIOECONOMIC-STATUS; STROKE MORTALITY; SOCIAL-CLASS; RACE; DISEASE; PREDICTORS; MORBIDITY AB Objective. To determine if socioeconomic status, as measured by education level, is associated with mortality due to systemic lupus erythematosus (SLE), and to determine if these associations differ among ethnic groups. Methods. Sex- and race-specific mortality rates due to SLE by education level were computed for persons age 25-64 years using US Multiple Causes of Death data from 1994 to 1997. SLE-specific mortality rates were compared with all-cause mortality rates in 1997 to determine if the association between education level and mortality in SLE was similar to that in other causes of death. Results. Among whites, the risk of death due to SLE was significantly higher among those with lower levels of education, and the risk gradient closely paralleled the 1997 all-cause mortality risks by education level. However, in African American women and men and Asian/Pacific Islander women, the risk of death due to SLE was lower among those with lower education levels, contrary to the associations between education level and all-cause mortality in these groups. Comparing the distribution of education levels among deaths due to SLE and all deaths in 1997, persons with lower education levels were underrepresented among deaths due to SLE in African Americans and Asian/Pacific Islanders. Conclusion. Among whites, higher education levels are associated with lower mortality due to SLE. These associations were not present in ethnic minorities, likely due to underascertainment of deaths due to SLE in less-well educated persons. This underascertainment may be due to underreporting of SLE on death certificates, but may also represent underdiagnosis of SLE in ethnic minorities with slow education levels. C1 IRP, NIAMS, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), IRP, NIAMS, NIH, Bldg 10,Room 9S205,10 Ctr Dr,MSC 1828, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov NR 40 TC 32 Z9 32 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD AUG 15 PY 2004 VL 51 IS 4 BP 616 EP 624 DI 10.1002/art.20526 PG 9 WC Rheumatology SC Rheumatology GA 844TL UT WOS:000223183100017 PM 15334436 ER PT J AU Leibenluft, E Gobbini, MI Harrison, T Haxby, JV AF Leibenluft, E Gobbini, MI Harrison, T Haxby, JV TI Mothers' neural activation in response to pictures of their children and other children SO BIOLOGICAL PSYCHIATRY LA English DT Article DE amygdala; emotion; face processing; fMRI; insula; theory of mind ID FUNCTIONAL MAGNETIC-RESONANCE; HUMAN AMYGDALA; FACIAL EXPRESSION; MATERNAL-BEHAVIOR; FACES; RECOGNITION; FAMILIAR; EMOTION; MIND; PERCEPTION AB Background. Considerable literature has focused on neural responses evoked by face viewing. We extend that literature and explore the neural correlates of maternal attachment with an fMRI study in which mothers view photographs of their own children. Methods: Seven mothers performed a one-back repetition detection task while viewing photographs of their own child, friends of their child, unfamiliar children, and unfamiliar adults. Results. Viewing one's own child versus a familiar child was associated with activation in the amygdala, insula, anterior paracingulate cortex, and posterior superior temporal sulcus (STS). Viewing familiar versus unfamiliar children elicited increased activation in regions associated with familiarity in adults. Viewing unfamiliar children versus unfamiliar adults was associated with activation in the fusiform gyrus, intraparietal sulcus, precuneus, and posterior STS. Conclusions: The sight of one's own child versus that of a familiar child activates regions that mediate emotional responses (amygdala, insula) and are associated with theory of mind functions (anterior paracingulate cortex, posterior superior temporal sulcus). These activations may reflect the intense attachment, vigilant protectiveness, and empathy that characterize normal maternal attachment. The sight of an unfamiliar child's face compared with that of an unfamiliar adult engages areas associated with attention as well as face perception. C1 NIMH, Pediat & Dev Neuropsychiat Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NIMH, Lab Brain & Cognit, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Leibenluft, E (reprint author), 10 Ctr Dr,MSC 1255, Bethesda, MD 20892 USA. EM Leibs@mail.nih.gov NR 50 TC 232 Z9 239 U1 5 U2 20 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 2004 VL 56 IS 4 BP 225 EP 232 DI 10.1016/j.biopsych.2004.05.017 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 846PG UT WOS:000223327300003 PM 15312809 ER PT J AU Ghelardoni, S Tomita, YA Bell, JM Rapoport, SI Bosetti, F AF Ghelardoni, S Tomita, YA Bell, JM Rapoport, SI Bosetti, F TI Chronic carbamazepine selectively downregulates cytosolic phospholipase A(2) expression and cyclooxygenase activity in rat brain SO BIOLOGICAL PSYCHIATRY LA English DT Article DE arachidonic acid; brain; bipolar disorder; prostaglandin; mood stabilizer; carbamazepine ID PERFORMANCE LIQUID-CHROMATOGRAPHY; ARACHIDONIC-ACID; BIPOLAR DISORDER; CHRONIC LITHIUM; ANTIEPILEPTIC DRUGS; TREATMENT DECREASES; MOOD STABILIZERS; GENE-EXPRESSION; ANTICONVULSANTS; PLASMA AB Background. Carbamazepine is a mood stabilizer used as monotherapy or as an adjunct to lithium in the treatment of acute mania or the prophylaxis of bipolar disorder. Based on evidence that lithium and valproate, other mood stabilizers, reduce brain arachidonic acid turnover and its conversion via cyclooxygenase to prostaglandin E-2 in rat brain, one possibility is that carbamazepine also targets the arachidonic acid cascade. Methods: To test this hypothesis, carbamazepine was administered to rats by intraperitoneal injection at a daily dose of 25 mg/kg for 30 days. Results. Carbamazepine decreased brain phospholipase A(2) activity and cytosolic phospholipase A(2) protein and messenger RNA levels without changing significantly protein and activity levels of calcium-independent pbospbolipase A(2) or secretory pbospbolipase A(2). Cyclooxygenase activity was decreased in carbamazepine-treated rats without any change in cyclooxygenase-1 or cyclooxygenase-2 protein levels. Brain prostaglandin E-2 concentration also was reduced. The protein levels of other arachidonic acid metabolizing enzymes, 5-lipoxygenase and cytocbrome P450 epoxygenase, were not significantly changed nor was the brain concentration of the 5-lipoxygenase product leukotriene B-4. Conclusions. Carbamazepine downregulates cytosolic pbospbolipase A(2)-mediated release of aracbidonic acid and its subsequent conversion to prostaglandin E-2 by cyclooxygenase. These effects may contribute to its therapeutic actions in bipolar disorder. C1 NIA, Brain Physiol & Mebab Sect, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Lombardi Canc Ctr, Dept Oncol, Washington, DC USA. RP Bosetti, F (reprint author), NIA, Brain Physiol & Mebab Sect, NIH, 9000 Rockville Pike,Bldg 10,Room 6N202, Bethesda, MD 20892 USA. EM frances@mail.nih.gov NR 47 TC 71 Z9 73 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 15 PY 2004 VL 56 IS 4 BP 248 EP 254 DI 10.1016/j.biophysc.2004.05.012 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 846PG UT WOS:000223327300006 PM 15312812 ER PT J AU Kim, IJ Dersch, CM Rothman, RB Jacobson, AE Rice, KC AF Kim, IJ Dersch, CM Rothman, RB Jacobson, AE Rice, KC TI A critical structural determinant of opioid receptor interaction with phenolic 5-phenylmorphans SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE opioids; phenolic 5-phenylmorphans; 2-azabicyclo[3.3.1]non-5-yl)-phenols; opioid binding affinity ID CONFORMATIONAL-CHANGES; MORPHINE; ANTAGONISTS; ANALOGS; LIGANDS; BINDING AB The opioid receptor binding affinities of N-methyl- and N-phenethyl-5-phenylmorphans with a meta-hydroxy substituent [3-(2-methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (1a), and 3-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (1b)] were compared with the affinities of four new ligands bearing an ortho- or para-hydroxyl substituent (2-(2-metliyl-2-azabicyclo[3.3.1]non-5-yl)phenol (2a) and 2-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (2b), 4-(2-methyl-2-azabicyclo[3.3.1]non-5-yl)-phenol(3a), and 4-(2-phenethyl-2-azabicyclo[3.3.1]non-5-yl)-phenol (3b)) that were synthesized from 2-bromoanisole or the known 2-methyl-5phenyl-2-azabicyclo[3.3.1]nonane (13), respectively. The data indicated that either the electronic state of the phenolic ring is critical for the ligand's interaction with an opioid receptor, or that there must be a specific distance and angle for a hydrogen bond between the phenolic moiety and an amino acid in the binding domain that cannot be altered. (C) 2004 Elsevier Ltd. All riahts reserved. C1 NIDDKD, Dept Hlth & Human Serv, Lab Med Chem, NIH, Bethesda, MD 20892 USA. NIDA, Addict Res Ctr, Dept Hlth & Human Serv, Clin Psychopharmacol Sect, Baltimore, MD 21224 USA. RP Rice, KC (reprint author), NIDDKD, Dept Hlth & Human Serv, Lab Med Chem, NIH, Bldg 8,Rm B1-23, Bethesda, MD 20892 USA. EM kr21f@nih.gov NR 28 TC 13 Z9 13 U1 0 U2 1 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 AUG 15 PY 2004 VL 12 IS 16 BP 4543 EP 4550 DI 10.1016/j.bmc.2004.05.038 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 844SW UT WOS:000223181300019 PM 15265502 ER PT J AU Washington, AV Schubert, RL Quigley, L Disipio, T Feltz, R Cho, EH McVicar, DW AF Washington, AV Schubert, RL Quigley, L Disipio, T Feltz, R Cho, EH McVicar, DW TI A TREM family member, TLT-1, is found exclusively in the alpha-granules of megakaryocytes and platelets SO BLOOD LA English DT Article ID INFLAMMATORY RESPONSES; DOMAIN RECEPTORS; CELL-ADHESION; MONOCYTES; PROTEINS; IDENTIFICATION; NEUTROPHILS; ACTIVATION; MUTATIONS; CLONING AB The triggering receptors expressed on myeloid cells (TREMs) have drawn considerable attention due to their ability to activate multiple cell types within the innate immune system, including neutrophils, monocyte/macrophages, and dendritic cells, via their association with DAP12. TLT-1 (TREM-like transcript-1) lies within the TREM gene cluster and contains the characteristic single V-set immunoglobulin (Ig) domain of the family, but its longer cytoplasmic tail is composed of both a proline-rich region and an immune receptor tyrosine-based inhibitory motif, the latter known to be used for interactions with protein tyrosine phosphatases. Here we report that TLT-1 is expressed exclusively in platelets and megakaryocytes (MKs) and that TLT-1 expression is up-regulated dramatically upon platelet activation. Consistent with this observation, confocal microscopy demonstrates that TLT-1 is prepackaged, along with CD62P, into both MK and platelet alpha-granules. Differences in thrombin-induced redistribution of CD62P and TLT-1 indicate that TLT-1 is not simply cargo of a-granules but may instead regulate granule construction or dispersal. Together these data show that that TLT-1 does not function to inhibit members of the TREM family but instead may play a role in maintaining vascular hemostasis and regulating coagulation and inflammation at sites of injury. (C) 2004 by The American Society of Hematology. C1 NCI, Lab Expt Immunol, Sci Applicat Int Corp Frederick, Ft Detrick, MD 21702 USA. NCI, Image Anal Lab, Sci Applicat Int Corp Frederick, Ft Detrick, MD 21702 USA. RP McVicar, DW (reprint author), NCI, Lab Expt Immunol, Sci Applicat Int Corp Frederick, 560-Rm 31-46, Ft Detrick, MD 21702 USA. EM mcvicar@nih.gov RI McVicar, Daniel/G-1970-2015 NR 33 TC 49 Z9 53 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2004 VL 104 IS 4 BP 1042 EP 1047 DI 10.1182/blood-2004-01-0315 PG 6 WC Hematology SC Hematology GA 844GK UT WOS:000223145800027 PM 15100151 ER PT J AU Chu, YW Memon, SA Sharrow, SO Hakim, FT Eckhaus, M Lucas, PJ Gress, RE AF Chu, YW Memon, SA Sharrow, SO Hakim, FT Eckhaus, M Lucas, PJ Gress, RE TI Exogenous IL-7 increases recent thymic emigrants in peripheral lymphoid tissue without enhanced thymic function SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; T-CELL FUNCTION; IN-VIVO; INFECTED PATIENTS; EXCISION CIRCLES; TRANSGENIC MICE; INTERLEUKIN-7; THYMOCYTE; DIFFERENTIATION; EXPRESSION AB Interleukin 7 (IL-7) is critical in maintaining thymic-dependent and thymic-independent pathways of T-cell homeostasis. T-cell receptor (TCR) rearrangement excision circles (TRECs) have been used as markers for recent thymic emigrants (RTEs) in assessing human thymic function. To study the thymic and peripheral effects of IL-7 on RTEs, we measured TREC content and peripheral naive T-cell subsets and turnover in IL-7-treated mice. Short-term administration of IL-7 into thymus-intact mice resulted in increased total TREC numbers, consistent with RTE accumulation. Decreases in TREC frequency were attributable to dilution secondary to increased cell turnover. Significantly, IL-7 administration into thymectomized mice resulted in patterns of decreased TREC frequency and increased total TREC number similar to those in IL-7-treated thymus-intact mice. Distinct patterns of naive cell and RTE distribution among peripheral immune organs and altered expression of CD11a were observed following IL-7 treatment in thymus-intact and thymectomized mice. These results demonstrate (1) that total TREC number and not TREC frequency accurately reflects quantitative changes in RTEs; (2) that short-term IL-7 administration results in preferential accumulations of RTEs among peripheral immune organs, accounting for the increase in TRECs in the total peripheral lymphoid pool; and (3) no evidence for regulation of thymic function by short-term IL-7 administration. (C) 2004 by The American Society of Hematology. C1 NIH, Expt Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NIH, Expt Transplantat & Immunol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NIH, Off Res Serv, Vet Resources Program, Bethesda, MD 20892 USA. RP Chu, YW (reprint author), NIH, Expt Immunol Branch, Ctr Canc Res, Bldg 10,Rm 4B14,10 Ctr Dr, Bethesda, MD 20892 USA. EM chuy@mail.nih.gov RI Memon, Sarfraz/E-1198-2013 NR 45 TC 74 Z9 76 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2004 VL 104 IS 4 BP 1110 EP 1119 DI 10.1182/blood-2003-10-3635 PG 10 WC Hematology SC Hematology GA 844GK UT WOS:000223145800035 PM 15130942 ER PT J AU Gurevich, RM Aplan, PD Humphries, RK AF Gurevich, RM Aplan, PD Humphries, RK TI NUP98-Topoisomerase I acute myeloid leukemia-associated fusion gene has potent leukemogenic activities independent of an engineered catalytic site mutation SO BLOOD LA English DT Article ID DNA TOPOISOMERASE-I; INV(11)(P15Q22) CHROMOSOME-TRANSLOCATION; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; HOMEOBOX GENES; NUP98 GENE; DE-NOVO; NORMAL HEMATOPOIESIS; NUCLEOPORIN NUP98; RAP1GDS1 GENES AB Chromosomal rearrangements of the 11p15 locus have been identified in hematopoetic malignancies, resulting in translocations involving the N-terminal portion of the nucleoporin gene NUP98. Fifteen different fusion partner genes have been identified for NUP98, and more than one half of these are homeobox transcription factors. By contrast, the NUP98 fusion partner in t(11;20) is Topoisomerase 1 (TOP1), a catalytic enzyme recognized for its key role in relaxing supercoiled DNA. We now show that retrovirally engineered expression of NUP98-TOP1 in murine bone marrow confers a potent in vitro growth advantage and a block in differentiation in hematopoietic precursors, evidenced by a competitive growth advantage in liquid culture, increased replating efficient of colony-forming cells (CFCs), and a marked increase in spleen colony-forming cell output. Moreover, in a murine bone marrow transplantation model, NUP98-TOP1 expression led to a lethal, transplantable leukemia characterized by extremely high white cell counts, splenomegaly, and mild anemia. Strikingly, a mutation to a TOP1 site to inactivate the isomerase activity essentially left unaltered the growth-promoting and leukemogenic effects of NUP98-TOP1. These findings, together with similar biologic effects reported for NUP98-HOX fusions, suggest unexpected, overlapping functions of NUP98 fusion genes, perhaps related to common DNA binding properties. (C) 2004 by The American Society of Hematology. C1 British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. Natl Canc Inst, Natl Navel Med Ctr, Bethesda, MD USA. Univ British Columbia, Dept Med, Vancouver, BC, Canada. RP Humphries, RK (reprint author), British Columbia Canc Agcy, Terry Fox Lab, 601 W 10th Ave, Vancouver, BC V5Z 1L3, Canada. EM khumphri@bccrc.ca RI Aplan, Peter/K-9064-2016; OI Humphries, Richard/0000-0003-0540-7005 NR 65 TC 31 Z9 31 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2004 VL 104 IS 4 BP 1127 EP 1136 DI 10.1182/blood-2003-10-3550 PG 10 WC Hematology SC Hematology GA 844GK UT WOS:000223145800037 PM 15100157 ER PT J AU Dicko, A Klion, AD Thera, MA Sagara, I Yalcouye, D Niambele, MB Sogoba, M Dolo, G Dao, A Diallo, DA Doumbo, OK Miller, LH AF Dicko, A Klion, AD Thera, MA Sagara, I Yalcouye, D Niambele, MB Sogoba, M Dolo, G Dao, A Diallo, DA Doumbo, OK Miller, LH TI The etiology of severe anemia in a village and a periurban area in Mali SO BLOOD LA English DT Article ID PLACEBO-CONTROLLED TRIAL; FALCIPARUM-MALARIA; INTERMITTENT TREATMENT; TANZANIAN INFANTS; CHILDREN; MONKEYS AB Severe anemia is one of the major complications of malaria in Africa. We studied 2 populations, one in a village and the second in a periurban area in Mali, to understand the preventable factors in the disease. The 2 correlates of disease were parasitemia above 100 000 parasitized red blood cells per microliter (0.1 x 10(12)/L) and a low baseline hemoglobin level. All cases of moderate to severe anemia occurred in children under 3.2 years of age. Raising the baseline hemoglobin level and lowering peak parasitemia in infants and young children may reduce the incidence of severe anemia resulting from malarial infection. (C) 2004 by The American Society of Hematology. C1 Univ Bamako, Fac Med Pharm & Odonto Stomatol, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Malaria Vaccine Dev Unit, NIH, Bethesda, MD 20892 USA. RP Miller, LH (reprint author), Univ Bamako, Fac Med Pharm & Odonto Stomatol, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, POB 1805, Bamako, Mali. EM lmiller@niaid.nih.gov OI Klion, Amy/0000-0002-4986-5326 NR 14 TC 28 Z9 29 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2004 VL 104 IS 4 BP 1198 EP 1200 DI 10.1182/blood-2003-11-3884 PG 3 WC Hematology SC Hematology GA 844GK UT WOS:000223145800046 PM 15113756 ER PT J AU Arbab, AS Yocum, GT Kalish, H Jordan, EK Anderson, SA Khakoo, AY Read, EJ Frank, JA AF Arbab, AS Yocum, GT Kalish, H Jordan, EK Anderson, SA Khakoo, AY Read, EJ Frank, JA TI Efficient magnetic cell labeling with protamine sulfate complexed to ferumoxides for cellular MRI SO BLOOD LA English DT Article ID SUPERPARAMAGNETIC IRON-OXIDE; MESENCHYMAL STEM-CELLS; IN-VIVO; TRANSFECTION AGENTS; CONTRAST AGENTS; HEPARIN THERAPY; MAMMALIAN-CELLS; T-CELLS; TRACKING; TRAFFICKING AB Recently, there have been several reports using various superparamagnetic iron oxide (SPIO) nanoparticles to label mammalian cells for monitoring their temporal and spatial migration in vivo by magnetic resonance imaging (MRI). The purpose of this study was to evaluate the efficiency and toxicity of labeling cells using 2 commercially available Food and Drug Administration (FDA)-approved agents, ferumoxides, a suspension of dextran-coated SPIO used as an MRI contrast agent, and protamine sulfate, conventionally used to reverse heparin anticoagulation but also used ex vivo as a cationic transfection agent. After labeling of human mesenchymal stem cells (MSCs) and hematopoietic (CD34(+)) stem cells and other mammalian cells with ferumoxides-protamine sulfate complexes (FE-Pro), cellular toxicity, functional capacity, and quantitative cellular iron incorporation were determined. FE-Pro-labeled cells demonstrated no short-or long-term toxicity, changes in differentiation capacity of the stem cells, or changes in phenotype when compared with unlabeled cells. Efficient labeling with FE-Pro was observed with iron content per cell varying between 2.01 +/- 0.1 pg for CD34(+) cells and 10.94 +/- 1.86 pg for MSCs with 100% of cells labeled. Cell labeling using these agents should facilitate the translation of this method to clinical trials for evaluation of trafficking of infused or transplanted cells by MRI. C1 NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Arbab, AS (reprint author), NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bldg 10,Room B1N256, Bethesda, MD 20892 USA. EM saali@cc.nih.gov; jafrank@helix.nih.gov NR 28 TC 398 Z9 427 U1 6 U2 55 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 AUG 15 PY 2004 VL 104 IS 4 BP 1217 EP 1223 DI 10.1182/blood-2004-02-0655 PG 7 WC Hematology SC Hematology GA 844GK UT WOS:000223145800050 PM 15100158 ER PT J AU Levine, PH Pogo, BGT Klouj, A Coronel, S Woodson, K Melana, SM Mourali, N Holland, JF AF Levine, PH Pogo, BGT Klouj, A Coronel, S Woodson, K Melana, SM Mourali, N Holland, JF TI Increasing evidence for a human breast carcinoma virus with geographic differences SO CANCER LA English DT Article DE mammary tumor virus; breast carcinoma; epidemiology; wild mice ID MAMMARY-TUMOR VIRUS; LAMININ-RECEPTOR EXPRESSION; GENE-LIKE SEQUENCES; ENV GENE; CANCER; MOUSE; FEATURES; ANTIGEN; TUNISIA; LEUKEMIA AB BACKGROUND. An early immunologic study suggesting that a virus similar to the mouse mammary tumor virus (MMTV) was associated highly with breast carcinoma in Tunisian patients, compared with patients in the United States, led the authors to examine different breast carcinoma populations by using more Current molecular techniques. METHODS. Thirty-nine paraffin blocks were selected for sequencing of the 250-base pair segment of the MMTV from patients with breast carcinoma who were seen and treated at the Institut Salah Azaiz in Tunisia. Fifteen of those blocks were examined under code by a second laboratory, which used a different methodology and was blinded to the results of the first laboratory, and 14 blocks were analyzed successfully. RESULTS. The comparison of Tunisian patients and patients from other countries clearly showed a significantly higher proportion of tumors with MMTV-Iike sequences in the Tunisian series of patients. There was complete reproducibility of data between the two laboratories. Using the results from the first laboratory and similar studies from the literature, detection of the MMTV-Iike env gene sequence showed an important geographic pattern with a significantly higher percentage of positive patients with breast carcinoma in Tunisia (74%) compared with patients with breast carcinoma in the United States (36%), Italy (38%), Australia (42%), Argentina (31%), and Vietnam (0.8%) CONCLUSIONS. The findings provided increased evidence for a human breast carcinoma virus with geographic differences in prevalence. The geographic differences were compatible with studies of MMTV in wild mice; thus, the data were plausible biologically. Cancer 2004;101:721-6. (C) 2004 American Cancer Society. C1 George Washington Univ, Dept Epidemiol & Biostat, Sch Publ Hlth & Hlth Serv, Washington, DC 20037 USA. Mt Sinai Sch Med, Dept Med, New York, NY USA. Creighton Univ, Dept Prevent Med & Publ Hlth, Omaha, NE 68178 USA. Natl Canc Inst, Canc Prevent Studies Branch, Canc Res Ctr, Bethesda, MD USA. Inst Salah Azaiz, Tunis, Tunisia. RP Levine, PH (reprint author), George Washington Univ, Dept Epidemiol & Biostat, Sch Publ Hlth & Hlth Serv, 2300 Eye St NW,Ross Hall 118, Washington, DC 20037 USA. EM sphphl@gwumc.edu NR 32 TC 45 Z9 47 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD AUG 15 PY 2004 VL 101 IS 4 BP 721 EP 726 DI 10.1002/cncr.20436 PG 6 WC Oncology SC Oncology GA 843UD UT WOS:000223111200007 PM 15305401 ER PT J AU Pati, D Haddad, BR Haegele, A Thompson, H Kittrell, FS Shepard, A Montagna, C Zhang, NG Ge, GQ Otta, SK McCarthy, M Ullrich, RL Medina, D AF Pati, D Haddad, BR Haegele, A Thompson, H Kittrell, FS Shepard, A Montagna, C Zhang, NG Ge, GQ Otta, SK McCarthy, M Ullrich, RL Medina, D TI Hormone-induced chromosomal instability in p53-null mammary epithelium SO CANCER RESEARCH LA English DT Article ID DUCTAL BREAST-CANCER; TUMOR-DEVELOPMENT; GENE-EXPRESSION; CENTROSOME AMPLIFICATION; CHECKPOINT PROTEIN; TRANSGENIC MICE; P53; CELLS; ANEUPLOIDY; MAD2 AB The absence of p53 function increases risk for spontaneous tumorigenesis in the mammary gland. Hormonal stimulation enhances tumor risk in p53-null mammary epithelial cells as well as the incidence of aneuploidy. Aneuploidy appears in normal p53-null mammary epithelial cells within 5 weeks of hormone stimulation. Experiments reported herein assessed a possible mechanism of hormone-induced aneuploidy. Hormones increased DNA synthesis equally between wild-type (WT) and p53-null mammary epithelial cells. There were two distinct responses in p53-null cells to hormone exposure. First, Western blot analysis demonstrated that the levels of two proteins involved in regulating sister chromatid separation and the spindle checkpoint, Mad2 and separase (ESPL1) were increased in null compared with WT cells. In contrast, the levels of securin and Rad21 proteins were not increased in hormone-stimulated p53-null compared with WT cells. ESPL1 RNA was also increased in p53-null mouse mammary cells in vivo by 18 h of hormone stimulation and in human breast MCF7 cells in monolayer culture by 8 h of hormone stimulation. Furthermore, both promoters contained p53 and steroid hormone response elements. Mad2 protein was increased as a consequence of the absence of p53 function. The increase in Mad2 protein was observed also at the cellular level by immunohistochemistry. Second, hormones increased gene amplication in the distal arm of chromosome 2, as shown by comparative genomic hybridization. These results support the hypothesis that hormone stimulation acts to increase aneuploidy by several mechanisms. First, by increasing mitogenesis in the absence of the p53 checkpoint in G2, hormones allow the accumulation of cells that have experienced chromosome missegregation. Second, the absolute rate of chromosome missegregation may be increased by alterations in the levels of two proteins, separase and Mad2, which are important for maintaining chromosomal segregation and the normal spindle checkpoint during mitosis. C1 Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. Texas Childrens Canc Ctr, Dept Pediat Hematol Oncol, Houston, TX USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Inst Mol Human Genet, Washington, DC 20007 USA. NIH, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Dept Microbiol, Galveston, TX 77555 USA. Canc Res Ctr, AMC, Div Lab Res, Denver, CO USA. Colorado State Univ, Dept Radiol Hlth Sci, Ft Collins, CO 80523 USA. RP Medina, D (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, 1 Baylor Plaza, Houston, TX 77030 USA. EM dmedina@bcm.tmc.edu RI Thompson, Henry/K-7242-2012 OI Thompson, Henry/0000-0002-3730-9322 FU NCI NIH HHS [R01-CA43322, R01-CA84320, U01-CA84243] NR 50 TC 27 Z9 27 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 AUG 15 PY 2004 VL 64 IS 16 BP 5608 EP 5616 DI 10.1158/0008-5472.CAN-03-0629 PG 9 WC Oncology SC Oncology GA 846NH UT WOS:000223321900014 PM 15313898 ER PT J AU Meng, JP Tsai-Morris, CH Dufau, ML AF Meng, JP Tsai-Morris, CH Dufau, ML TI Human prolactin receptor variants in breast cancer: Low ratio of short forms to the long-form human prolactin receptor associated with mammary carcinoma SO CANCER RESEARCH LA English DT Article ID PROMOTER UTILIZATION; MESSENGER-RNA; HORMONE; TISSUES; EXPRESSION; EXON-11; ISOFORM; TUMORS; MICE; PRL AB Prolactin plays an essential role in the development of rodent mammary tumors and is a potent mitogen in human normal and cancerous breast tissues/cells. In this study, we have analyzed the expression of prolactin receptors, including the long receptor form (LF; stimulatory) and two novel short forms (SFs; S1a and S1b) derived from alternative splicing that are inhibitory of the activation induced by prolactin through the LF. Southern analysis of breast cancer profiling arrays revealed that 29 patients (group I) expressed an elevated LF, 10 patients (group II) showed decreased LF, and 8 patients (group III) had no change relative to the adjacent normal tissue. Their respective SF expression was increased in 21 patients of group I and generally decreased in groups II and III. However, the ratio of SF to LF was significantly decreased in 76% of the breast tumors and distributed evenly among the groups. Quantification of differential expression of prolactin receptor variants by real-time PCR in 15 pairs of human normal and tumor breast-matched tissues revealed a similar significant decrease in the ratio of SF to LF in the tumor tissue. Consistent lower ratio of SFs to Us was confirmed in 8 of ten different breast cancer cell lines compared with normal mammary Hs578Bst and MCF10A cells. Because SFs act as dominant negative regulators of the stimulatory actions of the LF in vitro, their relatively reduced expression in cancer could cause gradations of unopposed prolactin-mediated LF stimulatory function and contribute to breast tumor development/progression. C1 NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Dufau, ML (reprint author), NICHHD, Sect Mol Endocrinol, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36,49 Convent Dr,MSC 4510, Bethesda, MD 20892 USA. EM dufau@mail.nih.gov NR 19 TC 56 Z9 58 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2004 VL 64 IS 16 BP 5677 EP 5682 DI 10.1158/0008-5472.CAN-04-1019 PG 6 WC Oncology SC Oncology GA 846NH UT WOS:000223321900023 PM 15313907 ER PT J AU Zhang, ML Zhang, Z Garmestani, K Goldman, CK Ravetch, JV Brechbiel, MW Carrasquillo, JA Waldmann, TA AF Zhang, ML Zhang, Z Garmestani, K Goldman, CK Ravetch, JV Brechbiel, MW Carrasquillo, JA Waldmann, TA TI Activating Fc receptors are required for antitumor efficacy of the antibodies directed toward CD25 in a murine model of adult T-cell leukemia SO CANCER RESEARCH LA English DT Article ID MONOCLONAL-ANTIBODY; EFFECTIVE THERAPY; CANCER XENOGRAFTS; BREAST-CANCER; TAC ANTIGEN; LYMPHOMA; TARGET AB We previously showed therapeutic efficacy of humanized anti-Tac (HAT), marine anti-Tac (MAT), and 7G7/B6 monoclonal antibodies, which recognize CD25, for human adult T-cell leukemia (ALL) in a murine model. In this study, we investigated the mechanism underlying the tumor-killing action mediated by these antibodies on an ATL model in nonobese diabetic/severe combined immunodeficient (SCID/NOD) wildtype mice that lack effective T and natural killer (NK) cells and in SCID/NOD Fc receptor common gamma chain knockout (FcRgamma(-/-)) mice. The ATL model was established by i.p. injection of human ATL cells (MET-1) into SCID/NOD wild-type or SCID/NOD FcRgamma(-/-) mice. HAT, MAT, and 7G7/B6 were given to the leukemia-bearing mice at a dose of 100 mug weekly for 4 weeks. The three antibodies inhibited the leukemia growth significantly in SCID/NOD wild-type mice, as monitored by serum levels of human beta2-microglobulin (P < 0.01), and prolonged survival of the leukemia-bearing SCID/NOD wild-type mice (P < 0.01) as compared with the control group. However, none of the antibodies manifested efficacy on the leukemia growth and survival of the SCID/NOD FcRgamma(-/-) mice bearing MET-1 leukemia. In a pharmacokinetics study, the blood concentrations of the radiolabeled antibodies decreased with time similarly in SCID/NOD wild-type and SCID/NOD FcRgamma(-/-) mice. Although NK cells may play a role in humans, in this murine model FcRgamma receptors on non-NK cells, such as polymorphonuclear leukocytes or monocytes, are required for the tumor-killing action of the antibodies directed toward CD25. C1 NCI, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Nucl Med, Bethesda, MD 20892 USA. Rockefeller Univ, Lab Mol Genet & Immunol, New York, NY 10021 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, NIH, Bldg10,Room 4N115,10 Ctr Dr, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 24 TC 46 Z9 48 U1 1 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2004 VL 64 IS 16 BP 5825 EP 5829 DI 10.1158/0008-5472.CAN-04-1088 PG 5 WC Oncology SC Oncology GA 846NH UT WOS:000223321900042 PM 15313926 ER PT J AU Pepe, S van den Brink, OWV Lakatta, EG Xiao, RP AF Pepe, S van den Brink, OWV Lakatta, EG Xiao, RP TI Cross-talk of oploid peptide receptor and beta-adrenergic receptor signalling in the heart SO CARDIOVASCULAR RESEARCH LA English DT Review DE G protein-coupled receptors; beta-adrenergic receptors; opioid peptide receptors; receptor dimerization; cardiac contractility; cardiac preconditioning ID PROTEIN-KINASE-C; DELTA-OPIOID RECEPTOR; RAT VENTRICULAR MYOCYTES; K-ATP CHANNELS; PRIMARY HEREDITARY CARDIOMYOPATHY; PREPROENKEPHALIN MESSENGER-RNA; PRODYNORPHIN GENE-EXPRESSION; SENSITIVE POTASSIUM CHANNELS; EMBRYONIC STEM-CELLS; CARDIAC MYOCYTES AB Opioid peptide receptor (OPR) and beta-adrenergic receptor (beta-AR) are well-established members of G-protein-coupled receptor (GPCR) superfamily and are involved in regulating cardiac contractility, energy metabolism, myocyte survival or death. OPRs are typical G(i)/G(o)-coupled receptors and activated by opioid peptides derived from the endorphin, dynorphin and enkephalin families, whereas beta-AR stimulated by catecholamines is the model system for G(s)-coupled receptors. While it is widely accepted that beta-AR stimulation serves as the most powerful means to increase cardiac output in response to stress or exercise, we have only begun to appreciate functional roles of OPR stimulation in regulating cardiovascular performance. Cardiovascular regulatory effects of endogenous opioids were initially considered to originate from the central nervous system and involved the pre-synaptic co-release of norepinephrine with enkephalin from sympathetic neuronal terminals in the heart. However, opioid peptides of myocardial origin have been shown to play important roles in local regulation of the heart. Notably, OPR stimulation not only inhibits cardiac excitation-contraction coupling, but also protects the heart against hypoxic and ischemic injury via activation of G(i)-mediated signalling pathways. Further, OPRs functionally and physically cross-talk with beta-ARs via multiple hierarchical mechanisms, including heterodimerization of these receptors, counterbalance of functional opposing G protein signalling, and interface at downstream signalling events. As a result, the beta-AR-mediated positive inotropic effect and increase in cAMP are markedly attenuated by OPR activation in isolated cardiomyocytes as well as sympathectomized intact rat hearts. This brief review will focus on the interaction between beta-AR and OPR and its potential physiological and pathophysiological relevance in the heart. (C) 2004 European Society of Cardiology. Published by Elsevier B.V. C1 NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. Baker Heart Res Inst, Lab Cardiac Surg Res, Wynn Domain, Melbourne, Vic, Australia. Monash Univ, Fac Med, Alfred Hosp, Melbourne, Vic 3004, Australia. Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. Peking Univ, Inst Cardiovasc Sci, Beijing 100871, Peoples R China. RP Xiao, RP (reprint author), NIA, Cardiovasc Sci Lab, Ctr Gerontol Res, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM xiaor@grc.nia.nih.gov NR 126 TC 49 Z9 55 U1 3 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD AUG 15 PY 2004 VL 63 IS 3 BP 414 EP 422 DI 10.1016/j.cardiores.2004.04.022 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 845KP UT WOS:000223241600006 PM 15276466 ER PT J AU Nunez, NP Jelovac, D Macedo, L Berrigan, D Perkins, SN Hursting, SD Barrett, JC Brodie, A AF Nunez, NP Jelovac, D Macedo, L Berrigan, D Perkins, SN Hursting, SD Barrett, JC Brodie, A TI Effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on serum hormones and bone characteristics in a preclinical tumor model for breast cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-I; NUDE-MOUSE MODEL; POSTMENOPAUSAL WOMEN; OVARIECTOMIZED RAT; RANDOMIZED-TRIAL; IGF-I; LEPTIN; PREVENTION; ESTROGEN; THERAPY AB Purpose: The purpose of this study was to evaluate and compare the effects of the antiestrogen tamoxifen and the aromatase inhibitor letrozole on tumor growth, serum hormones, uterine weight, body composition, and bone characteristics in mice. Experimental Design: Human estrogen-dependent breast cancer cells stably transfected with the aromatase gene (MCF-7CA cells) were inoculated in Matrigel subcutaneously into ovariectomized nude mice. This model represents postmenopausal breast cancer in many respects, including the fact that estrogen is no longer produced by the ovaries and is not under feedback regulation by gonadotropins. Mice that received subcutaneously implanted MCF-7CA cancer cells were then treated with tamoxifen or letrozole for 7 weeks. Results: As reported previously, tumor growth was markedly inhibited by both tamoxifen (100 mug/day) and letrozole (10 mug/day). Tamoxifen treatment led to increased bone mineral density (BMD) and hyperplastic uteri. Mice treated with letrozole had significantly smaller uteri than the controls and tamoxifen-treated mice. Letrozole did not affect BMD. There was no significant difference in systemic leptin and insulin-like growth factor I levels as a result of tamoxifen or letrozole treatment. Conclusions: Tamoxifen treatment inhibited breast cancer cell growth and increased BMD but caused uterine hypertrophy in this preclinical model of postmenopausal breast cancer. Letrozole inhibited tumor growth without inducing uterine hypertrophy. In addition, letrozole had no effect on BMD. These findings provide experimental evidence that letrozole is an effective and safe (in terms of risk of endometrial cancer risk and osteoporosis) alternative or complement to tamoxifen treatment for breast cancer. C1 NCI, Lab Biosyst & Canc, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. RP Nunez, NP (reprint author), NCI, Lab Biosyst & Canc, NIH, 6116 Execut Blvd,Suite 702, Bethesda, MD 20892 USA. EM nunezn@mail.nih.gov NR 32 TC 15 Z9 15 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 AUG 15 PY 2004 VL 10 IS 16 BP 5375 EP 5380 DI 10.1158/1078-0432.CCR-04-0261 PG 6 WC Oncology SC Oncology GA 848GC UT WOS:000223454600012 PM 15328175 ER PT J AU Fabian, CJ Kimler, BF Anderson, J Tawfik, OW Mayo, MS Burak, WE O'Shaughnessy, JA Albain, KS Hyams, DM Budd, GT Ganz, PA Sauter, ER Beenken, SW Grizzle, WE Fruehauf, JP Arneson, DW Bacus, JW Lagios, MD Johnson, KA Browne, D AF Fabian, CJ Kimler, BF Anderson, J Tawfik, OW Mayo, MS Burak, WE O'Shaughnessy, JA Albain, KS Hyams, DM Budd, GT Ganz, PA Sauter, ER Beenken, SW Grizzle, WE Fruehauf, JP Arneson, DW Bacus, JW Lagios, MD Johnson, KA Browne, D TI Breast cancer chemoprevention phase I evaluation of biomarker modulation by arzoxifene, a third generation selective estrogen receptor modulator SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL NUCLEAR ANTIGEN; INSULIN-LIKE GROWTH; PROGESTERONE-RECEPTOR; PROLIFERATION MARKERS; PREDICTING RESPONSE; CLINICAL-TRIAL; KI-67 ANTIGEN; SEX-HORMONES; DOUBLE-BLIND; TAMOXIFEN AB Purpose: Arzoxifene, a new selective estrogen receptor modulator with strong breast antiestrogen activity and absence of uterine agonist activity, was explored as a potential chemoprevention agent. We performed a multi-institutional evaluation of arzoxifene in women with newly diagnosed ductal carcinoma in situ or T1/T2 invasive cancer. Experimental Design: In a Phase IA trial, 50 pre- or postmenopausal women were randomized to 10, 20, or 50 mg of arzoxifene daily in the interval between biopsy and re-excision or were enrolled as no-treatment controls. In a Phase JIB trial, 76 postmenopausal women were randomized to 20 mg of arzoxifene versus matched placebo. Serum specimens collected at entry and at re-excision were assayed for various hormones and growth factors. Tissue from biopsies (estrogen receptor + and/or progesterone receptor +) and re-excision specimens was evaluated immunohistochemically for proliferation (Ki-67 by MIB-1 and proliferating cell nuclear antigen) and other biomarkers. Results: In both trials, increases in serum sex hormone binding globulin were noted, as were decreases in insulin-like growth factor (IGF)-I and the IGF-I:IGF binding protein-3 ratio (P < 0.007 versus control/placebo). For 45 evaluable women in Phase IA, decreases in proliferation indices were more prevalent for arzoxifene (particularly 20 mg) than for controls. For 58 evaluable women in Phase IB, a decrease in estrogen receptor expression for arzoxifene was observed compared with no change with placebo (P = 0.0068). However, decreases in proliferation indices for arzoxifene were not statistically different from placebo, perhaps due to a confounding effect of stopping hormone replacement therapy before entry. Conclusion: Given the favorable side effect profile and the biomarker modulations reported here, arzoxifene remains a reasonable candidate for additional study as a breast cancer chemopreventian agent. C1 Univ Kansas, Med Ctr, Kansas City, KS 66160 USA. Ohio State Univ, Columbus, OH 43210 USA. US Oncol Inc, Dallas, TX USA. Loyola Univ, Med Ctr, Maywood, IL 60153 USA. Desert Comprehens Canc Ctr, Palm Springs, CA USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Univ Missouri, Columbia, MO USA. Univ Alabama, Birmingham, AL USA. Oncotech Inc, Irvine, CA USA. Midwest Res Inst, Kansas City, MO 64110 USA. Bacus Labs Inc, Elmhurst, NY USA. St Marys Hosp, San Francisco, CA USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Fabian, CJ (reprint author), Univ Kansas, Med Ctr, 3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM cfabian@kumc.edu RI Mayo, Matthew/E-3774-2015 FU NCI NIH HHS [N01-CN-85035] NR 57 TC 46 Z9 50 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 AUG 15 PY 2004 VL 10 IS 16 BP 5403 EP 5417 DI 10.1158/1078-0432.CCR-04-0171 PG 15 WC Oncology SC Oncology GA 848GC UT WOS:000223454600015 PM 15328178 ER PT J AU Chang, TS Jeong, WJ Lee, DY Cho, CS Rhee, SG AF Chang, TS Jeong, WJ Lee, DY Cho, CS Rhee, SG TI The RING-H2-finger protein APC11 as a target of hydrogen peroxide SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE anaphase-promoting complex 11; ubiquitin-protein ligase; RING finger; cysteine oxidation; zinc release; hydrogen peroxide; free radicals ID ANAPHASE-PROMOTING COMPLEX; UBIQUITIN-CONJUGATING ENZYME; CYTOCHROME-C RELEASE; CELL-CYCLE ARREST; OXIDATIVE STRESS; RING FINGER; ZINC-FINGER; REVERSIBLE INACTIVATION; INDUCED APOPTOSIS; LIGASE ACTIVITY AB The anaphase-promoting complex (APC) is a ubiquitin-protein ligase (E3) that targets cell cycle regulators such as cyclin B and securin for degradation. The APC11 subunit functions as the catalytic core of this complex and mediates the transfer of ubiquitin from a ubiquitin-conjugating enzyme (E2) to the substrate. APC11 contains a RING-H2-finger domain, which includes one histidine and seven cysteine residues that coordinate two Zn2+ ions. We now show that exposure of purified APC11 to H2O2 (0-1 to 1 mM) induced the release of bound zinc as a result of the oxidation of cysteine residues. It also impaired the physical interaction between APC11 and the E2 enzyme Ubc4 as well as inhibited the ubiquitination of cyclin B1 by APC11. The release of HeLa cells from metaphase arrest in the presence of exogenous H2O2 inhibited the ubiquitination of cyclin B1 as well as the degradation of cyclin B I and securin that were apparent in the absence of H2O2. The presence of H2O2 also blocked the co-immunoprecipitation of Ubc4 with APC11 and delayed the exit of cells from mitosis. Inhibition of APC11 function by H2O2 thus likely contributes to the delay in cell cycle progression through mitosis that is characteristic of cells subjected to oxidative stress. Published by Elsevier Inc. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. Ewha Womans Univ, Ctr Cell Signaling Res, 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 73 TC 16 Z9 17 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD AUG 15 PY 2004 VL 37 IS 4 BP 521 EP 530 DI 10.1016/j.freeradbiomed.2004.05.006 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 843CQ UT WOS:000223053600009 PM 15256223 ER PT J AU Schubert, R Erker, L Yakushiji, H Larson, D Russo, A Mitchell, JB Wynshaw-Boris, A AF Schubert, R Erker, L Yakushiji, H Larson, D Russo, A Mitchell, JB Wynshaw-Boris, A TI Cancer chemoprevention by the antioxidant tempol in Atm-deficient mice SO HUMAN MOLECULAR GENETICS LA English DT Article ID ATAXIA-TELANGIECTASIA GENE; OXIDATIVE STRESS; NITROXIDE TEMPOL; SUPEROXIDE-DISMUTASE; CALORIE RESTRICTION; ISCHEMIA-REPERFUSION; SIGNAL-TRANSDUCTION; HYDROGEN-PEROXIDE; STABLE NITROXIDE; DAMAGE AB Reactive oxygen species (ROS) are important endogenous etiological agents for DNA damage, and ROS perform critical signaling functions in apoptosis, stress responses and proliferation. The correlation between a lower incidence of cancer in people who consume a diet high in naturally occurring antioxidants and the observed increased ROS in cancerous tissues suggest that antioxidants may be used in cancer chemoprevention. We tested this hypothesis by determining whether the well-described nitroxide antioxidant, tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), acts as a chemopreventative agent in Atm mutant mice, a model of the human cancer prone syndrome ataxia-telangiectasia. Tempol administered continuously via the diet after weaning resulted in an increased lifespan of these mice by prolonging the latency to thymic lymphomas. Tempol treatment reduced ROS, restored mitochondrial membrane potential, reduced tissue oxidative damage and oxidative stress, consistent with antioxidant effects. In addition, this nitroxide lowered weight gain of tumor prone mice without changes in food intake, metabolism or activity level and exhibited an anti-proliferative effect in vitro. Thus, tempol acts as a novel chemopreventative agent in this mouse model of a human cancer prone syndrome, associated with broad antioxidant effects. C1 Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Sch Med, Ctr Comprehens Canc, La Jolla, CA 92093 USA. NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. RP Wynshaw-Boris, A (reprint author), Univ Calif San Diego, Sch Med, Dept Pediat, 9500 Gilman Dr,Mail Stop 0627, La Jolla, CA 92093 USA. EM awynshawboris@ucsd.edu NR 60 TC 92 Z9 93 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD AUG 15 PY 2004 VL 13 IS 16 BP 1793 EP 1802 DI 10.1093/hmg/ddh189 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 840SU UT WOS:000222880700011 PM 15213104 ER PT J AU Bazinet, RP Douglas, H McMillan, EG Wilkie, BN Cunnane, SC AF Bazinet, RP Douglas, H McMillan, EG Wilkie, BN Cunnane, SC TI Dietary 18 : 3 omega 3 influences immune function and the tissue fatty acid response to antigens and adjuvant SO IMMUNOLOGY LETTERS LA English DT Article DE polyunsaturated fatty acid; linoleic acid; alpha-linotenic acid; pig; docosahexaenoic acid; arachidonic acid; antigen; inflammation; immune function ID DELAYED-TYPE HYPERSENSITIVITY; BETA-OXIDATION; RAT-BRAIN; N-3 PUFA; METABOLISM; ALPHA; LIPIDS; PROLIFERATION; LYMPHOCYTES; MODULATION AB alpha-Linolenic acid (18:3omega3) has many important physiological functions including being beta-oxidized, serving a precursor to the synthesis of other lipids and it has immunomodulation properties. The objective of the present study was to test the effects of immunization and dietary 18:3omega3 on immune function and the fatty acid profile of immunized pig tissues. Piglets suckled from sows consuming either a control or high 18:3omega3 diet until 14 days old when they were weaned onto a similar diet as the sow and were moved to a segregated nursery for the remainder of the study. At 35 days of age, pigs on both diets (2 x 2 factorial design) received either an injection containing hen eggwhite lysozyme (HEWL), killed Mycobacterium tuberculosis and Freund's complete adjuvant (immunized) or phosphate buffered saline (PBS) (non-immunized) into the neck followed by a booster injection 2 weeks later and induction of delayed-type hypersensitivity (DTH) one week later. Immunization increased (compared to non-immunized) while the high 18:3omega3 diet decreased haptoglobin by 30% compared to pigs consuming the control diet. Immunized pigs had a seven-fold increase in antibodies to HEWL and pigs consuming the high 18:3omega3 diet also had transiently higher levels of serum antibodies. There was a diet by immunization interaction on the DTH reaction such that immunized pigs consuming the high 18:3omega3 had the largest DTH reaction. The neck muscle proximal to the site of injection of immunized pigs had 10-30% lower levels of triglyceride and phospholipid linoleic (18:2omega6) and 18:3omega3 compared to non-immunized pigs. Thus, a high 18:3omega3 intake in pigs modulates immune function and tissue fatty acids in response to immunization. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Toronto, Fac Med, Dept Nutr Sci, Toronto, ON, Canada. Maple Leaf Foods Agresearch, Guelph, ON, Canada. Univ Guelph, Dept Pathobiol, Guelph, ON N1G 2W1, Canada. RP Bazinet, RP (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 10,Rm 6N 202,9000 Rockville Pike, Bethesda, MD 20892 USA. EM rbazinet@mail.nih.gov NR 42 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD AUG 15 PY 2004 VL 95 IS 1 BP 85 EP 90 DI 10.1016/j.imlet.2004.06.007 PG 6 WC Immunology SC Immunology GA 855WC UT WOS:000224004600012 PM 15325802 ER PT J AU Gao, CY Stepp, MA Fariss, R Zelenka, P AF Gao, CY Stepp, MA Fariss, R Zelenka, P TI Cdk5 regulates activation and localization of Src during corneal epithelial wound closure SO JOURNAL OF CELL SCIENCE LA English DT Article DE cyclin-dependent kinase; Src family kinase; translocation; wound healing; transgenic mice ID CYCLIN-DEPENDENT KINASE-5; C-SRC; N-CADHERIN; CELL-ADHESION; UP-REGULATION; EXPRESSION; PHOSPHORYLATION; MIGRATION; ACTIN; LENS AB Recent studies have shown that Cdk5, a member of the cyclin-dependent-kinase family, regulates adhesion and migration in a mouse corneal epithelial cell line. Here, we extend these findings to corneal wound healing in vivo and examine the mechanism linking Cdk5 to cytoskeletal reorganization and migration. Cdk5 was overexpressed in the corneal epithelium of transgenic mice under control of the ALDH3 promoter. Elevated Cdk5 expression retarded corneal debridement wound closure in these animals and suppressed remodeling of the actin cytoskeleton. Conversely, the Cdk5 inhibitor, olomoucine, accelerated debridement wound healing in organ cultured eyes of normal mice, caused migrating cells to separate from the epithelial cell sheet, and increased the level of activated Src(pY416) along the wound edge. To explore the relationship between Cdk5 and Src in greater detail, we examined scratch-wounded cultures of corneal epithelial cells. Src was activated in cells along the wound edge and blocking this activation with the Src kinase inhibitor, PP1, inhibited wound closure by 85%. Inhibiting Cdk5 activity with olomoucine or a dominant negative construct, Cdk5T33, increased the concentration of Src(pY416), shifted its subcellular localization to the cell periphery and enhanced wound closure. Cdk5(pY15), an activated form of Cdk5, also appeared along the wound edge. Inhibiting Src activity with PP1 blocked the appearance of Cdk5(pY15), suggesting that Cdk5 phosphorylation is Src dependent. Cdk5 and Src co-immunoprecipitated from scratch-wounded cultures, demonstrating that both kinases are part of an intracellular protein complex. These findings indicate that Cdk5 exerts its effects on cell migration during corneal epithelial wound healing by regulating the activation and localization of Src. C1 NEI, NIH, Bethesda, MD 20892 USA. George Washington Univ, Med Ctr, Dept Anat & Cell Biol, Washington, DC 20037 USA. George Washington Univ, Med Ctr, Dept Ophthalmol, Washington, DC 20037 USA. RP Zelenka, P (reprint author), NEI, NIH, Bldg 7,7 Mem Dr MSC 0704, Bethesda, MD 20892 USA. EM zelenkap@nei.nih.gov OI Stepp, Mary Ann/0000-0001-5623-2538 NR 38 TC 37 Z9 37 U1 1 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 AUG 15 PY 2004 VL 117 IS 18 BP 4089 EP 4098 DI 10.1242/jcs.01271 PG 10 WC Cell Biology SC Cell Biology GA 859SA UT WOS:000224287000009 PM 15280426 ER PT J AU Potosky, AL Saxman, S Wallace, RB Lynch, CF AF Potosky, AL Saxman, S Wallace, RB Lynch, CF TI Population variations in the initial treatment of non-small-cell lung cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID RACIAL-DIFFERENCES; UNITED-STATES; CHEMOTHERAPY; GUIDELINES; CARCINOMA; PATTERNS AB Purpose Dissemination of recommended therapies for non-small-cell lung cancer (NSCLC) have not been described comprehensively. We report the patterns of initial therapy focusing on the investigation of differences in receipt of recommended therapies according to multiple clinical and nonclinical patient characteristics. Methods A population-based random sample of newly diagnosed NSCLC patients diagnosed in 10 separate geographic areas was collected in 1996 (n = 898). Data were obtained from medical records. Multiple logistic regression was used to assess the use of recommended therapies. Results Overall, 52% of NSCLC patients received recommended therapy. Approximately 69%, 48%, and 41% of patients with stages I and II, III, or IV NSCLC received recommended therapy, respectively. For all stages combined, the use of recommended therapy was significantly inversely associated with age and stage at diagnosis. Recommended therapy also was more common in white versus black patients, and in married versus single patients. Stage-specific analyses revealed a significant decline in the use of recommended surgery with increasing age at diagnosis for early-stage NSCLC only, and a significantly lower use of recommended therapy (primarily chemoradiotherapy) for stage III black and Hispanic patients compared with white patients. Conclusion The overall use of recommended therapies for NSCLC is low. Large variations exist in the use of such therapies according to age, race or ethnicity, and marital status. Research combining medical record reviews with other sources of data is needed to better understand the contributions of both patient preferences and physician judgment to these treatment variations. C1 NCI, Appl Res Program, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diagnost, Bethesda, MD 20892 USA. NCI, Dept Epidemiol, Bethesda, MD 20892 USA. RP Potosky, AL (reprint author), NCI, Appl Res Program, 6130 Execut Blvd,EPN Room 4005, Bethesda, MD 20892 USA. EM potosky@pin.gov FU NCI NIH HHS [N01-PC-67000, N01-PC-67005, N01-PC-65107, N01-PC-67006, N01-PC-67007, N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010] NR 22 TC 99 Z9 101 U1 1 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 AUG 15 PY 2004 VL 22 IS 16 BP 3261 EP 3268 DI 10.1200/JCO.2004.02.051 PG 8 WC Oncology SC Oncology GA 846NY UT WOS:000223323700010 PM 15310770 ER PT J AU Sung, L Nathan, PC Lange, B Beyene, J Buchanan, GR AF Sung, L Nathan, PC Lange, B Beyene, J Buchanan, GR TI Prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor decrease febrile neutropenia after chemotherapy in children with cancer: A meta-analysis of randomized controlled trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; NON-HODGKINS-LYMPHOMA; T-CELL LEUKEMIA; MYELOSUPPRESSIVE CHEMOTHERAPY; SOLID TUMORS; GM-CSF; INTENSIVE CHEMOTHERAPY; INDUCTION CHEMOTHERAPY; PEDIATRIC-ONCOLOGY; FACTOR FILGRASTIM AB Purpose To determine whether prophylactic hematopoietic colony-stimulating factors (CSFs) used in children for Sick with cancer reduce the rate of febrile neutropenia, hospitalization duration, documented infection rate, parenteral antibiotic duration, amphotericin B use, or infection-related mortality. Methods We included studies in this meta-analysis if their populations consisted of children, if there was randomization between CSFs and placebo or no therapy, if CSFs were administered prophylactically (before neutropenia or febrile neutropenia), and if chemotherapy treatments preceding CSFs and placebo or no therapy were identical. From 971 reviewed study articles, 16 were included. Results The mean rate of febrile neutropenia in the control arms was 57% (range, 39% to 100%). Using a random effects model, CSFs were associated with a reduction in febrile neutropenia, with a rate ratio of 0.80 (95% CI, 0.67 to 0.95; P = .01), and a decrease in hospitalization length, with a weighted mean difference of -1.9 days (95% CI, -2.7 to -1.1 days; P < .00001). CSF use was also associated with reduction in documented infections (rate ratio, 0.78; 95% CI, 0.62 to 0.97; P = .02) and reduction in amphotericin B use (rate ratio, 0.50; 95% CI, 0.28 to 0 87; P = .02). There was no difference in duration of parenteral antibiotic therapy (weighted mean difference, -4.3; 95% CI, -10.6 to 2.0 days; P = .2) or infection-related mortality (rate ratio, 1.02; 95% CI, 0.34 to 3.06; P = .97). Conclusion CSFs were associated with a 20% reduction in febrile neutropenia and shorter duration of hospitalization; however, CSFs did not reduce infection-related mortality. C1 Hosp Sick Children, Div Hematol Oncol, Toronto, ON M5G 1X8, Canada. Univ Toronto, Dept Pediat, Toronto, ON, Canada. Univ Toronto, Dept Hlth Policy Management & Evaluat, Toronto, ON, Canada. Univ Toronto, Dept Publ Hlth Sci, Toronto, ON, Canada. Natl Canc Inst, Pediat Oncol Branch, Rockville, MD USA. Childrens Hosp Philadelphia, Div Oncol, Philadelphia, PA 19104 USA. Univ Texas, SW Med Ctr, Dept Pediat, Dallas, TX 75230 USA. RP Sung, L (reprint author), Hosp Sick Children, Div Hematol Oncol, 555 Univ Ave, Toronto, ON M5G 1X8, Canada. EM Lillian.sung@sickkids.ca NR 44 TC 56 Z9 62 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 AUG 15 PY 2004 VL 22 IS 16 BP 3350 EP 3356 DI 10.1200/JCO.2004.09.106 PG 7 WC Oncology SC Oncology GA 846NY UT WOS:000223323700022 PM 15310780 ER PT J AU Jankovic, D Kullberg, MC Caspar, P Sher, A AF Jankovic, D Kullberg, MC Caspar, P Sher, A TI Parasite-induced Th2 polarization is associated with down-regulated dendritic cell responsiveness to Th1 stimuli and a transient delay in T lymphocyte cycling SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IN-VIVO; TOXOPLASMA-GONDII; HELPER-CELL; RESPONSE INDUCTION; ADAPTIVE IMMUNITY; RECEPTOR LIGATION; LEISHMANIA-MAJOR; IL-4 EXPRESSION; CUTTING EDGE; DIFFERENTIATION AB The nature of the signals that bias Th effector choice is still not completely understood. Using parasite extracts from pathogens known to induce polarized Th1 or Th2 responses and an in vitro experimental model for priming murine CD4(+) cells, we demonstrated that splenic dendritic cells (DC), but not B cells, promote Th1/Th2 differentiation of naive CD4(+) lymphocytes. Th polarization in this system was found not to depend on DC secretion of the polarizing cytokines IL-12/IL-4, but instead correlated with distinct states of DC activation induced by the different parasite preparations. As expected, conditioning of DC for Th1 development was associated with up-regulation of costimulatory molecules and enhanced chemokine production and required intact MyD88 signaling. In contrast, conditioning of DC for Th2 differentiation correlated with down-regulation of many of the same functions and was MyD88 independent. This dampened DC activation was accompanied in the cocultures by a reduction in the frequency of CD4(+) lymphocytes exiting the first division of the cell cycle. When the latter was mimicked by drug-induced arrest of peptide-primed CD4(+) cells after the S phase of the first cycle, a marked Th2 polarization was also observed. Together, these findings suggest that the emergence of IL-4-producing CD4(+) lymphocytes results from a suppression in DC function leading to a temporary delay in initial T cell cycling. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Jankovic, D (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bldg 50,Room 6142,50 S Dr,MSC 8003, Bethesda, MD 20892 USA. EM djankovic@niaid.nih.gov NR 68 TC 63 Z9 67 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 AUG 15 PY 2004 VL 173 IS 4 BP 2419 EP 2427 PG 9 WC Immunology SC Immunology GA 845AV UT WOS:000223208900027 PM 15294955 ER PT J AU Chen, Q Wade, D Kurosaka, K Wang, ZY Oppenheim, BJ Yang, D AF Chen, Q Wade, D Kurosaka, K Wang, ZY Oppenheim, BJ Yang, D TI Temporin a and related frog antimicrobial peptides use formyl peptide receptor-like 1 as a receptor to chemoattract phagocytes SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; LIPOXIN A(4) RECEPTOR; DENDRITIC CELLS; HOST-DEFENSE; DIFFERENTIAL REGULATION; ADAPTIVE IMMUNITY; INNATE IMMUNITY; TRANSGENIC MICE; HYBRID PEPTIDE; P42/44 MAPK AB Many mammalian antimicrobial peptides (AMPs) have multiple effects on antimicrobial immunity. We found that temporin A (TA), a representative frog-derived AMP, induced the migration of human monocytes, neutrophils, and macrophages with a bell-shaped response curve in a pertussis toxin-sensitive manner, activated p44/42 MAPK, and stimulated Ca2+ flux in monocytes, suggesting that TA is capable of chemoattracting phagocytic leukocytes by the use of a G(ialpha) protein-coupled receptor. TA-induced Ca2+ flux in monocytes was cross-desensitized by an agonistic ligand MMK-1 specific for formyl peptide receptor-like 1 (FPRL1) and vice versa, suggesting that TA uses FPRL1 as a receptor. This conclusion was confirmed by data showing that TA selectively stimulated chemotaxis of HEK 293 cells transfected with human FPRL1 or its mouse ortholog, murine formyl peptide receptor 2. In addition, TA elicited the infiltration of neutrophils and monocytes into the injection site of mice, indicating that TA is also functionally chemotactic in vivo. Examination of two additional temporins revealed that Rana-6 was also able to attract human phagocytes using FPRL1, but temporin 1P selectively induced the migration of neutrophils using a distinct receptor. Comparison of the chemotactic and antimicrobial activities of several synthetic analogues suggested that these activities are likely to rely on different structural characteristics. Overall, the results demonstrate that certain frog-derived temporins have the capacity to chemoattract phagocytes by the use of human FPRL1 (or its orthologs in other species), providing the first evidence suggesting the potential participation of certain amphibian antimicrobial peptides in host antimicrobial immunity. C1 Natl Canc Inst, Basic Res Program, Sci Appl Int Corp Frederick,Ctr Canc Res, Natl Inst Hlth, Frederick, MD 21702 USA. Natl Inst Hlth, Mol Immunoregulat Lab, Canc Res Ctr, Frederick, MD 21702 USA. Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. RP Yang, D (reprint author), Natl Canc Inst, Basic Res Program, Sci Appl Int Corp Frederick,Ctr Canc Res, Natl Inst Hlth, Bldg 560,Room 31-19, Frederick, MD 21702 USA. EM dyang@mail.ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 66 TC 38 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 AUG 15 PY 2004 VL 173 IS 4 BP 2652 EP 2659 PG 8 WC Immunology SC Immunology GA 845AV UT WOS:000223208900054 PM 15294982 ER PT J AU Hu, PQ Fertig, N Medsger, TA Wright, TM AF Hu, PQ Fertig, N Medsger, TA Wright, TM TI Molecular recognition patterns of serum anti-DNA topoisomerase I antibody in systemic sclerosis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EPSTEIN-BARR VIRUS; B-CELL EPITOPE; SCLERODERMA PATIENTS; AUTOANTIBODY RESPONSE; IMMUNODOMINANT EPITOPE; LUPUS-ERYTHEMATOSUS; AUTOIMMUNITY; ASSOCIATIONS; FREQUENCY; TOLERANCE AB Autoreactive anti-DNA topoisomerase I (anti-Topo I) Abs are commonly detected in sera of systemic sclerosis (SSc) patients. Our studies have established a positive correlation between the levels of serum anti-Topo I Abs and both disease severity and activity of SSc. The molecular targets of anti-Topo I Ab on Topo I domains remain to be further defined. In this report, we studied the molecular recognition pattern of serum anti-Topo I Ab in 52 SSc patients. The highest reactivity of serum anti-Topo I Abs was against the core subdomains I and II (aa 207-441) and, to a lesser extent, against the core subdomain III (aa 433-636) of Topo I. The linker domain (aa 636-712) and the C-terminal domain (aa 713-765) had much less reactivity than the core domain (aa 207-636). Strikingly, very little reactivity was directed against the N-terminal domain (aa 1-213) by serum anti-Topo I Ab. This molecular recognition pattern was consistent among all SSc serum samples studied. Results from patients with serial serum samples indicated that this pattern remained unchanged over time. Interestingly, some naive B cells from healthy controls, upon transformation by EBV, produced IgM Abs against Topo I. These Abs had low affinity for Topo I and reacted equally to all domains of Topo I. The molecular recognition pattern of serum anti-Topo I Ab in SSc suggests the presence of a unique antigenic stimulation in vivo in this disease. C1 Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Med, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Div Clin Immunol & Rheumatol, Pittsburgh, PA 15213 USA. RP Hu, PQ (reprint author), NCI, Lab Mol Immunoregulat, NIH, Bldg 560,Room 31-19,1050 Boyles St,POB B, Frederick, MD 21702 USA. EM hu1@nciferf.gov FU NCI NIH HHS [5T32 CA82084, P01 CA 73743]; NIAMS NIH HHS [N01 AR 92239] NR 39 TC 7 Z9 10 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 AUG 15 PY 2004 VL 173 IS 4 BP 2834 EP 2841 PG 8 WC Immunology SC Immunology GA 845AV UT WOS:000223208900074 PM 15295002 ER PT J AU Oxenius, A Price, DA Trkola, A Edwards, C Gostick, E Zhang, HT Easterbrook, PJ Tun, T Johnson, A Waters, A Holmes, EC Phillips, RE AF Oxenius, A Price, DA Trkola, A Edwards, C Gostick, E Zhang, HT Easterbrook, PJ Tun, T Johnson, A Waters, A Holmes, EC Phillips, RE TI Loss of viral control in early HIV-1 infection is temporally associated with sequential escape from CD8(+) T cell responses and decrease in HIV-1-specific CD4(+) and CD8(+) T cell frequencies SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNE-RESPONSES; HOST DETERMINANTS; TYPE-1; VIREMIA; LYMPHOCYTES; ANTIBODY; EPITOPE; DISEASE AB The outcome of human immunodeficiency virus type 1 (HIV-1) infection is related to the set-point plasma virus load (pVL) that emerges after primary HIV-1 infection ( PHI). This set-point pVL generally remains stable but eventually increases with progression to disease. However, the events leading to loss of viremic control are poorly understood. Here, we describe an individual who presented with symptomatic PHI and subsequently progressed rapidly, after an initial period of 1 year during which viral replication was well controlled. Escalation of viral replication in this atypical case was preceded by the emergence of escape variants in many epitopes targeted by dominant CD8(+) T cell responses and a marked decrease in HIV-1-specific CD4(+) and CD8(+) T cell frequencies. There were no changes in viral tropism, replication kinetics, or neutralizing antibody titers. These findings demonstrate the temporal relationship between viral escape from CD8(+) T cell activity, decrease in HIV-1-specific T cell frequencies, and loss of control of viral replication. C1 ETH, Inst Microbiol, CH-8092 Zurich, Switzerland. Univ Hosp, Div Infect Dis, Zurich, Switzerland. NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. John Radcliffe Hosp, Nuffield Dept Clin Med, Oxford OX3 9DU, England. Univ Oxford, Dept Zool, Oxford OX1 3PS, England. Guys Kings & St Thomas Sch Med, Dept HIV & Genitourinary Med, London, England. Avidex, Abingdon, Oxon, England. RP Oxenius, A (reprint author), ETH, Inst Microbiol, LFV B31,Schmelzbergstr 7, CH-8092 Zurich, Switzerland. EM oxenius@micro.biol.ethz.ch RI Infektiologie, USZ/A-6921-2011; Price, David/C-7876-2013; Oxenius, Annette/G-7794-2015; Trkola, Alexandra/K-2115-2012; OI Price, David/0000-0001-9416-2737; Trkola, Alexandra/0000-0003-1013-876X; Holmes, Edward/0000-0001-9596-3552 NR 25 TC 55 Z9 56 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 AUG 15 PY 2004 VL 190 IS 4 BP 713 EP 721 DI 10.1086/422760 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 841CP UT WOS:000222907200009 PM 15272399 ER PT J AU Banks, DJ Porcella, SF Barbian, KD Beres, SB Philips, LE Voyich, JM DeLeo, FR Martin, JM Somerville, GA Musser, JM AF Banks, DJ Porcella, SF Barbian, KD Beres, SB Philips, LE Voyich, JM DeLeo, FR Martin, JM Somerville, GA Musser, JM TI Progress toward characterization of the group a Streptococcus metagenome: Complete genome sequence of a macrolide-resistant serotype M6 strain SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID PYROGENIC EXOTOXIN-A; SURFACE-PROTEINS; INHIBITING PROTEIN; M3 STRAIN; GENE; PYOGENES; IDENTIFICATION; VIRULENCE; ALLELES; TRANSCRIPTION AB We describe the genome sequence of a macrolide-resistant strain (MGAS10394) of serotype M6 group A Streptococcus (GAS). The genome is 1,900,156 bp in length, and 8 prophage-like elements or remnants compose 12.4% of the chromosome. A 8.3-kb prophage remnant encodes the SpeA4 variant of streptococcal pyrogenic exotoxin A. The genome of strain MGAS10394 contains a chimeric genetic element composed of prophage genes and a transposon encoding the mefA gene conferring macrolide resistance. This chimeric element also has a gene encoding a novel surface-exposed protein (designated "R6 protein"), with an LPKTG cell-anchor motif located at the carboxyterminus. Surface expression of this protein was confirmed by flow cytometry. Humans with GAS pharyngitis caused by serotype M6 strains had antibody against the R6 protein present in convalescent, but not acute, serum samples. Our studies add to the theme that GAS prophage-encoded extracellular proteins contribute to host-pathogen interactions in a strain-specific fashion. C1 Baylor Coll Med, Dept Pathol, Ctr Human Bacterial Pathogenesis Res, Houston, TX 77030 USA. NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. Univ Pittsburgh, Childrens Hosp Pittsburgh, Sch Med, Dept Pediat,Div Allergy Immunol & Infect Dis, Pittsburgh, PA USA. RP Musser, JM (reprint author), Baylor Coll Med, Dept Pathol, Ctr Human Bacterial Pathogenesis Res, 1 Baylor Plaza, Houston, TX 77030 USA. EM musser@bcm.tmc.edu RI Somerville, Greg/B-1326-2013; OI Somerville, Greg/0000-0002-0991-8737; DeLeo, Frank/0000-0003-3150-2516 NR 39 TC 122 Z9 567 U1 1 U2 4 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 AUG 15 PY 2004 VL 190 IS 4 BP 727 EP 738 DI 10.1086/422697 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 841CP UT WOS:000222907200011 PM 15272401 ER PT J AU Otto, M O'Mahoney, DS Guina, T Klebanoff, SJ AF Otto, M O'Mahoney, DS Guina, T Klebanoff, SJ TI Activity of Staphylococcus epidermidis phenol-soluble modulin peptides expressed in Staphylococcus carnosus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID AMINO-ACID-SEQUENCE; LONG TERMINAL REPEAT; DELTA-HEMOLYSIN; ION CHANNELS; TOXIN; AUREUS; POLYPEPTIDE; ACTIVATION AB Staphylococcus epidermidis releases a group of peptides termed phenol-soluble modulin (PSM) that stimulate macrophages. The structure of 3 peptides (PSMalpha, PSMbeta, and PSMgamma) have been described. We report a fourth peptide (PSMdelta), which is a 23mer with the structure fMSIVSTIIEVVKTIVDIVKKFKK. The gene for each of the 4 peptides was introduced singly into Staphylococcus carnosus, and the PSM-like activity of culture medium and bacterial extract were significantly greater than those of the parent strain. PSM peptides from each of the S. carnosus - expressing strains were purified and analyzed by liquid chromatography - mass spectrometry. The products, which appeared to form aggregates, were active in the activation of human immunodeficiency virus type 1 long-terminal repeat and the production of tumor necrosis factor - a by the macrophage cell line THP-1. These findings suggest that PSM peptides are responsible, in part, for the modulin-like activity of staphylococci and may contribute to the development of severe staphylococcal sepsis. C1 Univ Washington, Sch Med, Dept Med, Seattle, WA 98195 USA. NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. Univ Washington, Sch Med, Dept Pediat, Seattle, WA 98195 USA. RP Klebanoff, SJ (reprint author), Univ Washington, Sch Med, Dept Med, Box 357185, Seattle, WA 98195 USA. EM seym@u.washington.edu OI Otto, Michael/0000-0002-2222-4115 NR 25 TC 20 Z9 22 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 AUG 15 PY 2004 VL 190 IS 4 BP 748 EP 755 DI 10.1086/422157 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 841CP UT WOS:000222907200013 PM 15272403 ER PT J AU Jarrett, CO Deak, E Isherwood, KE Oyston, PC Fischer, ER Whitney, AR Kobayashi, SD DeLeo, FR Hinnebusch, BJ AF Jarrett, CO Deak, E Isherwood, KE Oyston, PC Fischer, ER Whitney, AR Kobayashi, SD DeLeo, FR Hinnebusch, BJ TI Transmission of Yersinia pestis from an infectious biofilm in the flea vector SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID STORAGE HMS(+) PHENOTYPE; BACTERIAL BIOFILMS; STAPHYLOCOCCUS-EPIDERMIDIS; CAENORHABDITIS-ELEGANS; PIGMENTATION PHENOTYPE; STRUCTURAL GENES; PLAGUE; EXPRESSION; SEQUENCE; LOCUS AB Transmission of plague by fleas depends on infection of the proventricular valve in the insect's foregut by a dense aggregate of Yersinia pestis. Proventricular infection requires the Y. pestis hemin storage (hms) genes; here, we show that the hms genes are also required to produce an extracellular matrix and a biofilm in vitro, supporting the hypothesis that a transmissible infection in the flea depends on the development of a biofilm on the hydrophobic, acellular surface of spines that line the interior of the proventriculus. The development of biofilm and proventricular infection did not depend on the 3 Y. pestis quorum-sensing systems. The extracellular matrix enveloping the Y. pestis biofilm in the flea appeared to incorporate components from the flea's blood meal, and bacteria released from the biofilm were more resistant to human polymorphonuclear leukocytes than were in vitro-grown Y. pestis. Enabling arthropod-borne transmission represents a novel function of a bacterial biofilm. C1 NIAID, NIH, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, Hamilton, MT 59840 USA. NIAID, NIH, Rocky Mt Labs, Intracellular Parasites Lab, Hamilton, MT 59840 USA. Def Sci & Technol Lab, Salisbury, Wilts, England. RP Hinnebusch, BJ (reprint author), NIAID, NIH, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, 903 S 4th St, Hamilton, MT 59840 USA. EM jhinnebusch@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516 NR 47 TC 158 Z9 167 U1 1 U2 15 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 AUG 15 PY 2004 VL 190 IS 4 BP 783 EP 792 DI 10.1086/422695 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 841CP UT WOS:000222907200017 PM 15272407 ER PT J AU Feng, HQ Bai, YW AF Feng, HQ Bai, YW TI Repacking of hydrophobic residues in a stable mutant of apocytochrome b(562) selected by phage-display and proteolysis SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE phage display; NMR structure; hydrophobic core; hydrophobic repacking; core-directed protein design ID DIRECTED PROTEIN DESIGN; BACKBONE FLEXIBILITY; CORE; NMR AB To test a hydrophobic core-directed protein design approach, we previously have used phage-display and proteolysis to select stably folded proteins from a library of mutants of apocytochrome b(562). The consensus sequence of the selected mutants has hydrophilic residues at two of the three positions that are designed to form a hydrophobic core. To understand this unexpected result, we determined the high-resolution structure of one of the selected mutants using multi-dimensional nuclear magnetic resonance (NMR). The structure shows that the two hydrophilic residues in the consensus sequence were on the surface of the structure. Instead, two of their neighboring hydrophobic residues reorganized their side-chain conformations and formed the hydrophobic core. This result suggests that the hydrophobic core-directed protein design by phage-display and proteolysis is a valid method in, general but alternative hydrophobic packing needs to be considered in the initial design. The unexpected repacking of the hydrophobic residues also highlights the plastic nature of protein structures. (C) 2004 Wiley-Liss, Inc. C1 NCI, Biochem Lab, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, Bldg 37,Room 6114E, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov NR 16 TC 8 Z9 8 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD AUG 15 PY 2004 VL 56 IS 3 BP 426 EP 429 DI 10.1002/prot.20161 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 837XR UT WOS:000222675200003 PM 15229877 ER PT J AU Bethge, WA Wilbur, DS Storb, R Hamlin, DK Santos, EB Brechbiel, MW Sandmaier, BM AF Bethge, WA Wilbur, DS Storb, R Hamlin, DK Santos, EB Brechbiel, MW Sandmaier, BM TI Radioimmunotherapy with bismuth-213 as conditioning for nonmyeloablative allogeneic hematopoietic cell transplantation in dogs: A dose deescalation study SO TRANSPLANTATION LA English DT Article DE radioimmunotherapy; allogeneic hematopoietic cell transplantation; nonmyeloablative ID TOTAL-BODY IRRADIATION; TCR-ALPHA-BETA; MARROW TRANSPLANTATION; MONOCLONAL-ANTIBODIES; HEMATOLOGIC MALIGNANCIES; MYELODYSPLASTIC SYNDROME; ANTI-CD45 ANTIBODY; MYELOID-LEUKEMIA; PHASE-I; REGIMEN AB Background. Using a canine model of nonmyeloablative hematopoietic cell transplantation (HCT), the authors demonstrated that pretransplant radioimmunotherapy with the alpha-emitter bismuth-213 (Bi-213) coupled to anti-CD45 or anti-T-cell receptor alphabeta (TCRalphabeta) monoclonal antibodies (mAb), together with postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine A (CsA), achieved stable engraftment of dog leukocyte antigen (DLA)-identical marrow. Engraftment was achieved with doses of 3.6 to 8.8 mCi/kg Bi-213, but signs of liver toxicity were noted in all dogs. To find a safe and effective dose for further trials, the authors performed a dose deescalation study in 15 dogs with 2.7 to 0.8 mCi/kg Bi-213. Methods. Bi-213 was linked to the mAb using the metal-binding chelate CHX-A"-DTPA. All dogs received three to six injections of Bi-213 linked to anti-CD45 or anti-TCRalphabeta mAb followed by marrow grafts from DLA-identical littermates and postgrafting MMF and CsA. Results. During follow-up of greater than 30 weeks, engraftment remained stable in all evaluable dogs conditioned with 1.4 to 2.1 mCi/kg Bi-213-anti-CD45 or 2.0 to 2.7 mCi/kg Bi-213-anti-TCRalphabeta. Only one dog conditioned with 1.5 mCi/kg Bi-213-anti-TCRalphabeta had stable engraftment, whereas two rejected their grafts. In both groups, all dogs conditioned with less than 1.3 mCi/kg Bi-213 rejected their grafts. No signs of graft-versus-host disease or other toxicities were noted. Only mild and transient elevation of liver function tests occurred in 4 of 15 dogs. Conclusions. This study demonstrates that dose deescalation of radioimmunotherapy with Bi-213 labeled to anti-CD45 or anti-TCRalphabeta as conditioning for nonmyeloablative HCT minimizes toxicity without compromising engraftment. With a dose of 2 mCi/kg Bi-213, further trials using radioimmunotherapy with Bi-213 for nonmyeloablative HCT seem feasible. C1 Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Sandmaier, BM (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D1-100,POB 19024, Seattle, WA 98109 USA. EM bsandmai@fhcrc.org FU NCI NIH HHS [P01 CA078902, CA78902, CA15704]; NHLBI NIH HHS [HL36444] NR 30 TC 11 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 15 PY 2004 VL 78 IS 3 BP 352 EP 359 DI 10.1097/01.TP.0000128853.62545.B2 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 846QI UT WOS:000223330300007 PM 15316362 ER PT J AU Akpinar, E Craighead, N Smoot, D Hale, DA AF Akpinar, E Craighead, N Smoot, D Hale, DA TI Potent skin allograft survival prolongation using a committed progenitor fraction of bone marrow in mice SO TRANSPLANTATION LA English DT Article DE tolerance; bone marrow infusion; chimerism; antilymphocyte serum ID DONOR-SPECIFIC TOLERANCE; HEMATOPOIETIC STEM-CELLS; ANTI-LYMPHOCYTE SERUM; ANTILYMPHOCYTE-SERUM; TRANSPLANTATION TOLERANCE; INDUCTION; CHIMERISM; CYCLOSPORINE; RAPAMYCIN; UNRESPONSIVENESS AB Background. The infusion of donor bone marrow (BM) into mice conditioned with antilymphocyte serum (ALS) and sirolimus (Sir) prolongs skin allograft survival and produces chimerism. This study identifies the BM cell(s) responsible for this effect and determines whether enrichment for these cells will improve efficacy. Methods. Skin grafts from BALB/C mice were transplanted into C57BL/6 or C57BL/10 recipients by using ALS, Sir, and BM (or fractions). BM was fractionated by using immunomagnetic beads. Flow cytometry was used for phenotyping and detecting chimerism. Results. The median graft survival in mice receiving 25 million BM cells was 61 days. Infusion of BM depleted of cells expressing CD 19, CD3, CD11c, and c-kit had no effect on median graft survival, whereas infusion of fractions enriched for those cells resulted in median graft survival of 38, 48, 28, and 83 days, respectively. The administration of higher doses (4 x 10(6) and 8 x 10(6)) of fractions enriched for c-kit resulted in median graft survival of 124 and 197 days, respectively, without chimerism. This favorably compared with mice receiving 150 million BM cells that demonstrated transient mixed chimerism and a median graft survival of 190 days. The majority of cells in the c-kit+-enriched fraction expressed lineage markers. Removal of lineage positive cells from BM before infusion shortened median graft survival (90 days), indicating that the c-kit+ lin+ population is largely responsible for prolongation of graft survival. Conclusions. Cells enriched for C-kit+ lin+ constitute approximately 5% of murine BM cells and are more potent than whole BM at prolonging skin allograft survival in mice treated with ALS and Sir. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Hale, DA (reprint author), Room 11S-219,Bldg 10,Ctr Dr, Bethesda, MD 20892 USA. EM douglash@intra.niddk.nih.gov RI AKPINAR, Edip/C-3402-2014 OI AKPINAR, Edip/0000-0003-1445-8680 NR 30 TC 6 Z9 7 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD AUG 15 PY 2004 VL 78 IS 3 BP 383 EP 391 DI 10.1097/01.TP.0000128833.38229.4F PG 9 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 846QI UT WOS:000223330300011 PM 15316366 ER PT J AU Kvaratskhelia, M Clark, PK Hess, S Melder, DC Federspiel, MJ Hughes, SH AF Kvaratskhelia, M Clark, PK Hess, S Melder, DC Federspiel, MJ Hughes, SH TI Identification of glycosylation sites in the SU component of the Avian Sarcoma/Leukosis virus Envelope Glycoprotein (Subgroup A) by mass spectrometry SO VIROLOGY LA English DT Article DE avian; retrovirus; envelope; glycosylation; Tva ID LEUKOSIS VIRUS; CELLULAR RECEPTOR; LOW PH; SARCOMA-VIRUSES; BINDING; PROTEIN; FUSION; CELLS; RETROVIRUSES; SEQUENCE AB We used enzymatic digestion and mass spectrometry to identify the sites of glycosylation on the SU component of the Avian Sarcoma/ Leukosis virus (ASLV) Envelope Glycoprotein (Subgroup A). The analysis was done with an SU(A)-rlgG fusion protein that binds the cognate receptor (Tva) specifically. PNGase F removed all the carbohydrate from the SU(A)-rlgG fusion. PNGase F is specific for N-linked carbohydrates; this shows that all the carbohydrate on SU(A) is N-linked. There are 10 modified aspargines in SU(A) (N17, N59, N80, N97, N117, N196, N230, N246, N254, and N330). All conform to the consensus site for N-linked glycosylation NXS/T. There is one potential glycosylation site (N236) that is not modified. Removing most of the carbohydrate from the mature SU(A)-rIgG by PNGase F treatment greatly reduces the ability of the protein to bind Tva, suggesting that carbohydrate may play a direct role in receptor binding. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. Ohio State Univ, Hlth Sci Ctr, Coll Pharm, Ctr Retrovirus Res, Columbus, OH 43210 USA. Ohio State Univ, Hlth Sci Ctr, Coll Pharm, Ctr Comprehens Canc, Columbus, OH 43210 USA. SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. NIDDK, Natl Inst Hlth, Bethesda, MD 20892 USA. Mayo Clin, Coll Med, Program Mol Med, Rochester, MN 55905 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Romm 130A,Bldg 539,POB B, Frederick, MD 21702 USA. EM hughes@ncifcrf.gov RI Hess, Sonja/K-4842-2013 OI Hess, Sonja/0000-0002-5904-9816 NR 23 TC 13 Z9 13 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 0042-6822 J9 VIROLOGY JI Virology PD AUG 15 PY 2004 VL 326 IS 1 BP 171 EP 181 DI 10.1016/j.virol.2004.05.020 PG 11 WC Virology SC Virology GA 840IV UT WOS:000222852800017 PM 15262505 ER PT J AU Petricoin, EF Liotta, LA AF Petricoin, EF Liotta, LA TI Importance of disclosure of patent applications - Reply SO LANCET LA English DT Letter C1 US FDA, CBER, OCTGT, Bethesda, MD 20892 USA. NCI, NIH, CCR, Pathol Lab, Bethesda, MD USA. RP Petricoin, EF (reprint author), US FDA, CBER, OCTGT, 8800 Rockville Pike, Bethesda, MD 20892 USA. EM petricoin@cber.fda.gov NR 2 TC 0 Z9 0 U1 0 U2 1 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 14 PY 2004 VL 364 IS 9434 BP 578 EP 579 DI 10.1016/S0140-6736(04)16839-6 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 845WD UT WOS:000223275100019 ER PT J AU Jin, P Zhao, YD Ngalame, Y Panelli, MC Nagorsen, D Monsurro, V Smith, K Hu, N Su, H Taylor, PR Marincola, FM Wang, E AF Jin, P Zhao, YD Ngalame, Y Panelli, MC Nagorsen, D Monsurro, V Smith, K Hu, N Su, H Taylor, PR Marincola, FM Wang, E TI Selection and validation of endogenous reference genes using a high throughput approach SO BMC GENOMICS LA English DT Article ID MESSENGER-RNA LEVELS; MELANOMA-ASSOCIATED ANTIGENS; GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE; BETA-ACTIN; CELL-LINES; HOUSEKEEPING GENES; T-LYMPHOCYTES; RAT HEPATOMA; NITRIC-OXIDE; ERROR RATES AB Background: Endogenous reference genes are commonly used to normalize expression levels of other genes with the assumption that the expression of the former is constant in different tissues and in different physiopathological conditions. Whether this assumption is correct it is, however, still matter of debate. In this study, we searched for stably expressed genes in 384 cDNA array hybridization experiments encompassing different tissues and cell lines. Results: Several genes were identified whose expression was highly stable across all samples studied. The usefulness of 8 genes among them was tested by normalizing the relative gene expression against test genes whose expression pattern was known. The range of accuracy of individual endogenous reference genes was wide whereas consistent information could be obtained when information pooled from different endogenous reference genes was used. Conclusions: This study suggests that even when the most stably expressed genes in array experiments are used as endogenous reference, significant variation in test gene expression estimates may occur and the best normalization is achieved when data from several endogenous reference genes are pooled together to minimize minimal but significant variation among samples. We are presently optimizing strategies for the preparation of endogenous reference gene mixtures that could yield information comparable to that of data pooled from individual endogenous reference gene normalizations. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, Canc Prevent Studies Branch,NIH, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM pjin@mail.cc.nih.gov; zhaoy@ctep.nci.nih.gov; yngalame@mail.cc.nih.gov; mpanelli@mail.cc.nih.gov; nagorsen@medizin.fu-berlin.de; VMousurro@mail.cc.nih.gov; ksmith2@mail.cc.nih.gov; hun@dcpcepn.nci.nih.gov; suhu@mail.nih.gov; ptaylor@mail.nih.gov; fmarincola@mail.cc.nih.gov; ewang@mail.cc.nih.gov NR 46 TC 41 Z9 42 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD AUG 13 PY 2004 VL 5 AR 55 DI 10.1186/1471-2164-5-55 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 851MJ UT WOS:000223688900002 PM 15310404 ER PT J AU Rosenfeldt, H Vazquez-Prado, J Gutkind, JS AF Rosenfeldt, H Vazquez-Prado, J Gutkind, JS TI P-REX2, a novel PI-3-kinase sensitive Rac exchange factor SO FEBS LETTERS LA English DT Article DE guanine nucleotide exchange factor; PI-3K; G-protein ID GENOMIC DNA; ACTIVATION; IQGAP1; CDC42; BLAST; LINK; RHO AB We have identified an activator of Rac, P-REX2, that is structurally related to the exchange factor PtdIns(3,4,5)-dependent Rac exchanger (P-REX1), but exhibits distinct tissue-specific expression. P-REX2 is spliced into two RNA species, similar to3.5 and similar to10 kb in size. The cDNA corresponding to the smaller transcript encodes a protein that exhibits strong similarity with P-REX1 within its N-terminal domains, but differs in the C-terminal region. P-REX2 promoted increased levels of GTP-bound Rac that could be further stimulated by enhancing PI-3K activity. Thus, P-REX2 may serve as a novel link between Rac activation and the PI-3 kinase pathway. (C) 2004 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 NIDCR, Oral & Pharyngeol Canc Branch, DHHS, NIH, Bethesda, MD 20892 USA. Inst Politecn Nacl, CINVESTAV, Dept Pharmacol, Mexico City 07000, DF, Mexico. RP Gutkind, JS (reprint author), NIDCR, Oral & Pharyngeol Canc Branch, DHHS, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009; VAZQUEZ-PRADO, JOSE/C-1630-2017 FU FIC NIH HHS [D43 TW06664] NR 16 TC 52 Z9 53 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD AUG 13 PY 2004 VL 572 IS 1-3 BP 167 EP 171 DI 10.1016/j.febslet.2004.06.097 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 849DQ UT WOS:000223519300030 PM 15304342 ER PT J AU Le Stunff, H Mikami, A Giussani, P Hobson, JP Jolly, PS Milstien, S Spiegel, S AF Le Stunff, H Mikami, A Giussani, P Hobson, JP Jolly, PS Milstien, S Spiegel, S TI Role of sphingosine-1-phosphate phosphatase 1 in epidermal growth factor-induced chemotaxis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; SPHINGOSINE 1-PHOSPHATE; SIGNAL-TRANSDUCTION; CELL-MIGRATION; EGF RECEPTOR; ENDOPLASMIC-RETICULUM; KINASE; MOTILITY; PHOSPHOHYDROLASE; TRANSACTIVATION AB Sphingosine-1-phosphate (S1P) is the ligand for a family of specific G protein-coupled receptors that regulate a wide variety of cellular functions, including cytoskeletal rearrangements and cell motility. Because of the pivotal role of S1P, its levels are low and tightly regulated in a spatial-temporal manner through its synthesis catalyzed by sphingosine kinases and degradation by an S1P lyase and specific S1P phosphatases (SPP). Surprisingly, down-regulation of SPP-1 enhanced migration toward epidermal growth factor (EGF); conversely, overexpression of SPP-1, which is localized in the endoplasmic reticulum, attenuated migration toward EGF. To determine whether the inhibitory effect on EGF-induced migration was because of decreased S1P or increased ceramide as a consequence of acylation of increased sphingosine by ceramide synthase, we used fumonisin B1, a specific inhibitor of ceramide synthase. Although fumonisin B1 blocked ceramide production and increased sphingosine, it did not reverse the negative effect of SPP-1 expression on EGF- or S1P-induced chemotaxis. EGF activated the epidermal growth factor receptor to the same extent in SPP-1-expressing cells, yet ERK1/2 activation was impaired. In agreement, PD98059, an inhibitor of the ERK-activating enzyme MEK, decreased EGF- stimulated migration. We next examined the possibility that intracellularly generated S1P might be involved in activating a G protein-coupled S1P receptor important for EGF- directed migration. Treatment with pertussis toxin to inactivate Galpha(i) suppressed EGF- induced migration. Moreover, expression of regulator of G protein signaling 3, which inhibits S1P receptor signaling and completely prevented ERK1/2 activation mediated by S1P receptors, not only reduced migration toward S1P but also markedly reduced migration toward EGF. Collectively, these results suggest that metabolism of S1P by SPP-1 is important for EGF- directed cell migration. C1 Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. NIMH, Lab Cellular & Mol Regulat, NIH, 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 FU NIGMS NIH HHS [GM 43880] NR 57 TC 36 Z9 36 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 AUG 13 PY 2004 VL 279 IS 33 BP 34290 EP 34297 DI 10.1074/jbc.M404907200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844CL UT WOS:000223134800027 PM 15180992 ER PT J AU Zhang, Y Karas, M Zhao, H Yakar, S LeRoith, D AF Zhang, Y Karas, M Zhao, H Yakar, S LeRoith, D TI 14-3-3 sigma mediation of cell cycle progression is p53-independent in response to insulin-like growth factor-I receptor activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BREAST-CANCER CELLS; FORKHEAD TRANSCRIPTION FACTOR; ACCELERATES G(1) PHASE; NF-KAPPA-B; PHOSPHATIDYLINOSITOL 3-KINASE; PROTEIN-KINASE; CYCLIN-D1 EXPRESSION; SIGNAL TRANSDUCTION; DNA-DAMAGE; IGF-I AB We investigated the role of 14-3-3sigma protein in insulin-like growth factor-I (IGF-I) receptor signaling. It has been previously shown that 14-3-3sigma negatively regulates cell cycle especially in response to p53-sensitive DNA damage. In this study we demonstrated that 14-3-3sigma is a positive mediator of IGF-I receptor-induced cell proliferation. Treatment with IGF-I increased 14-3-3sigma mRNA and protein levels about 4-fold, in a time-dependent manner in MCF-7 breast cancer cells. Preincubation with the phosphoinositide 3'-kinase inhibitor LY294002 significantly reduced the effects of IGF-I on 14-3-3sigma gene expression in these cells, suggesting that this effect of IGF-I occurs via the phosphoinositide 3'-kinase pathway. 14-3-3sigma is induced by IGF-I in MCF-7 cells, which express wild-type p53, as well as in MCF-7 cells transfected with a small interference RNA targeting duplex that reduced p53 expression levels. These results suggest that IGF-I induces 14-3-3sigma expression in a manner that is independent of p53. Using the small interference RNA strategy, we demonstrated that a 70-75% reduction of 14-3-3sigma mRNA levels resulted in a similar decrease in the effects of IGF-I on cell cycle progression and proliferation in MCF-7 cells. This effect was also associated with a reduction in IGF-I-induced cyclin D1 expression. Taken together, these results suggest that 14-3-3sigma positively mediates IGF-I-induced cell cycle progression. C1 NIDDK, Diabet Branch, NIH, Sect Mol & Cellular Physiol, Bethesda, MD 20892 USA. RP LeRoith, D (reprint author), NIDDK, Diabet Branch, NIH, Sect Mol & Cellular Physiol, Rm 8D12,Bldg 10, Bethesda, MD 20892 USA. EM derek@helix.nih.gov NR 59 TC 22 Z9 22 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 AUG 13 PY 2004 VL 279 IS 33 BP 34353 EP 34360 DI 10.1074/jbc.M401300200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844CL UT WOS:000223134800035 PM 15187095 ER PT J AU Choudhary, S Sommers, JA Brosh, RM AF Choudhary, S Sommers, JA Brosh, RM TI Biochemical and kinetic characterization of the DNA helicase and exonuclease activities of Werner syndrome protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COLI RECQ HELICASE; SYNDROME CELLS; S-PHASE; HOMOLOGOUS RECOMBINATION; REPLICATION ARREST; REPAIR PROCESSES; SYNDROME GENE; POLYMERASE-I; WRN HELICASE; INVITRO AB The WRN gene, defective in the premature aging and genome instability disorder Werner syndrome, encodes a protein with DNA helicase and exonuclease activities. In this report, cofactor requirements for WRN catalytic activities were examined. WRN helicase performed optimally at an equimolar concentration ( 1 mM) of Mg2+ and ATP with a K-m of 140 muM for the ATP-Mg2+ complex. The initial rate of WRN helicase activity displayed a hyperbolic dependence on ATP-Mg2+ concentration. Mn2+ and Ni2+ substituted for Mg2+ as a cofactor for WRN helicase, whereas Fe2+ or Cu2+ ( 10 muM) profoundly inhibited WRN unwinding in the presence of Mg2+. Zn2+ ( 100 muM) was preferred over Mg2+ as a metal cofactor for WRN exonuclease activity and acts as a molecular switch, converting WRN from a helicase to an exonuclease. Zn2+ strongly stimulated the exonuclease activity of a WRN exonuclease domain fragment, suggesting a Zn2+ binding site in the WRN exonuclease domain. A fluorometric assay was used to study WRN helicase kinetics. The initial rate of unwinding increased with WRN concentration, indicating that excess enzyme over DNA substrate improved the ability of WRN to unwind the DNA substrate. Under presteady state conditions, the burst amplitude revealed a 1: 1 ratio between WRN and DNA substrate, suggesting an active monomeric form of the helicase. These are the first reported kinetic parameters of a human RecQ unwinding reaction based on real time measurements, and they provide mechanistic insights into WRN-catalyzed DNA unwinding. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM BroshR@grc.nia.nih.gov NR 57 TC 46 Z9 46 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 AUG 13 PY 2004 VL 279 IS 33 BP 34603 EP 34613 DI 10.1074/jbc.M401901200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844CL UT WOS:000223134800065 PM 15187093 ER PT J AU Kennedy, MN Mullen, GED Leifer, CA Lee, C Mazzoni, A Dileepan, KN Segal, DM AF Kennedy, MN Mullen, GED Leifer, CA Lee, C Mazzoni, A Dileepan, KN Segal, DM TI A complex of soluble MD-2 and lipopolysaccharide serves as an activating ligand for Toll-like receptor 4 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BACTERIAL LIPOPOLYSACCHARIDE; DENDRITIC CELLS; CUTTING EDGE; TLR4; ENDOTOXIN; CONFERS; MICE; RESPONSIVENESS; RECOGNITION; EXPRESSION AB MD-2, a glycoprotein that is essential for the innate response to lipopolysaccharide (LPS), binds to both LPS and the extracellular domain of Toll-like receptor 4 (TLR4). Following synthesis, MD-2 is either secreted directly into the medium as a soluble, active protein, or binds directly to TLR4 in the endoplasmic reticulum before migrating to the cell surface. Here we investigate the function of the secreted form of MD-2. We show that secreted MD-2 irreversibly loses activity over a 24-h period at physiological temperature. LPS, but not lipid A, prevents this loss in activity by forming a stable complex with MD-2, in a CD14-dependent process. Once formed, the stable MD-2 . LPS complex activates TLR4 in the absence of CD14 or free LPS indicating that the activating ligand of TLR4 is the MD-2 . LPS complex. Finally we show that the MD-2 . LPS complex, but not LPS alone, induces epithelial cells, which express TLR4 but not MD-2, to secrete interleukin-6 and interleukin-8. We propose that the soluble MD-2 . LPS complex plays a crucial role in the LPS response by activating epithelial and other TLR4(+)/MD-2(-) cells in the inflammatory microenvironment. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Kansas, Med Ctr, Dept Med, Kansas City, KS 66160 USA. RP Segal, DM (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. EM dave_segal@nih.gov NR 29 TC 87 Z9 90 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 13 PY 2004 VL 279 IS 33 BP 34698 EP 34704 DI 10.1074/jbc.M405444200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844CL UT WOS:000223134800075 PM 15175334 ER PT J AU Miyazaki, M Dobrzyn, A Sampath, H Lee, SH Man, WC Chu, K Peters, JM Gonzalez, FJ Ntambi, JM AF Miyazaki, M Dobrzyn, A Sampath, H Lee, SH Man, WC Chu, K Peters, JM Gonzalez, FJ Ntambi, JM TI Reduced adiposity and liver steatosis by stearoyl-CoA desaturase deficiency are independent of peroxisome proliferator-activated receptor-alpha SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FATTY-ACID OXIDATION; CAUSES INSULIN-RESISTANCE; MESSENGER-RNA LEVELS; GENE-EXPRESSION; PROTEIN-KINASE; PPAR-GAMMA; TARGETED DISRUPTION; TISSUE DISTRIBUTION; SKELETAL-MUSCLE; UP-REGULATION AB Stearoyl-CoA desaturase catalyzes the rate-limiting step in the biosynthesis of monounsaturated fatty acids, which are required for normal rates of synthesis of triglycerides, cholesterol esters, and phospholipids. Mice with a targeted disruption of the stearoyl-CoA desaturase 1 (SCD1) isoform are protected against diet and leptin deficiency-induced adiposity, have increased energy expenditure, and have up-regulated expression of hepatic genes encoding enzymes of fatty acid beta-oxidation. Because peroxisome proliferator-activated receptor-alpha( PPARalpha) is a key transcription factor that induces the transcription of fatty acid beta-oxidation and thermogenic genes, we hypothesized that the increased fatty acid oxidation observed in SCD1 deficiency is dependent on activation of the PPARalpha pathway. Here we show that mice nullizygous for SCD1 and PPARalpha are still protected against adiposity, have increased energy expenditure, and maintain high expression of PPARalpha target genes in the liver and brown adipose tissue. The SCD1 deficiency rescued hepatic steatosis of the PPARalpha(-/-) mice. The SCD1 mutation increased the phosphorylation of both AMP-activated protein kinase and acetylCoA carboxylase, thereby increasing CPT activity and stimulating the oxidation of liver palmitoyl-CoA in the PPARalpha null mice. The findings indicate that the reduced adiposity, reduced liver steatosis, increased energy expenditure, and increased expression of PPARalpha target genes associated with SCD1 deficiency are independent of activation of the PPARalpha pathway. C1 Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA. Penn State Univ, Dept Vet Sci, University Pk, PA 16802 USA. Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Ntambi, JM (reprint author), Univ Wisconsin, Dept Biochem, 433 Babcock Dr, Madison, WI 53706 USA. EM ntambi@biochem.wisc.edu RI Peters, Jeffrey/D-8847-2011; Dobrzyn, Agnieszka/R-4073-2016 OI Dobrzyn, Agnieszka/0000-0002-6331-9460 FU NIDDK NIH HHS [R01 DK 62388] NR 61 TC 77 Z9 80 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 AUG 13 PY 2004 VL 279 IS 33 BP 35017 EP 35024 DI 10.1074/jbc.M405327200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 844CL UT WOS:000223134800114 PM 15180999 ER PT J AU Opi, S Peloponese, JM Esquieu, D Watkins, J Campbell, G de Mareuil, J Jeang, KT Yirrell, DL Kaleebu, P Loret, EP AF Opi, S Peloponese, JM Esquieu, D Watkins, J Campbell, G de Mareuil, J Jeang, KT Yirrell, DL Kaleebu, P Loret, EP TI Full-length HIV-1 Tat protein necessary for a vaccine SO VACCINE LA English DT Article DE HIV vaccine; Tat; conformational epitopes ID KAPOSIS-SARCOMA; STRUCTURAL CHARACTERIZATION; TRANSACTIVATOR; AIDS; PATHOGENESIS; ASSIGNMENT; VARIANTS; GROWTH; CELLS; RNA AB AIDS vaccines now use a truncated version of 86 residues of the Tat protein related to the HIV-1 HXB2 strain predominant in Europe and North America. We compared antibodies raised in rabbits using a B subtype short Tat HXB2(86) and a full-length Tat HXB2(100). Serum against HXB2(86) recognizes only B and D subtypes while serum against HXB2(100) recognizes B, D, and C subtype variants. Conformational epitopes appear to be involved in the capacity of anti-Tat HXB2 sera to recognized non-homologous Tat variants. A linear B-epitope identified in sequence 71-81 in HXB2(86) disappears in HXB2(100), which has a new linear B-epitope identified at the C-terminus. Anti-HXB2(100) serum has a higher titer in neutralizing antibody against homologous and non-homologous variants compared to anti-HXB2(86) serum. We suggest that a Tat vaccine should contain a Tat variant with regular size, up to 99-101 residues now found in the field. (C) 2004 Elsevier Ltd. All rights reserved. C1 Fac Pharm Marseille, CNRS FRE 2737, F-13385 Marseille 5, France. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Gartnavel Royal Hosp, Glasgow G12 0ZA, Lanark, Scotland. MRC UK Programme AIDS Uganda, Uganda Virus Res Inst, Entebbe, Uganda. RP Loret, EP (reprint author), Fac Pharm Marseille, CNRS FRE 2737, 27 Bd Jean Moulin, F-13385 Marseille 5, France. EM erwann.loret@pharmacie.univ-mrs.fr RI Jeang, Kuan-Teh/A-2424-2008; OI Campbell, Grant/0000-0003-3927-1994 NR 27 TC 22 Z9 28 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 AUG 13 PY 2004 VL 22 IS 23-24 BP 3105 EP 3111 DI 10.1016/j.vaccine.2004.01.057 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 849AO UT WOS:000223509800020 PM 15297062 ER PT J AU Kongkasuriyachai, D Bartels-Andrews, L Stowers, A Collins, WE Sullivan, J Sattabongkot, J Torii, M Tsuboi, T Kumar, N AF Kongkasuriyachai, D Bartels-Andrews, L Stowers, A Collins, WE Sullivan, J Sattabongkot, J Torii, M Tsuboi, T Kumar, N TI Potent immunogenicity of DNA vaccines encoding Plasmodium vivax transmission-blocking vaccine candidates Pvs25 and Pvs28 - evaluation of homologous and heterologous antigen-delivery prime-boost strategy SO VACCINE LA English DT Article DE Plasmodium vivax; transmission-blocking immunity; Pvs25; Pvs28; DNA vaccine ID OOKINETE SURFACE; MALARIA; PFS25; ANTIBODIES; FALCIPARUM; PROTEINS AB Transmission-blocking vaccines target the sexual stages of the malaria parasite and prevent further development within the mosquito vector halting the transmission of the parasite. Zygote/ookinetes are potential targets of antibodies inhibiting oocyst development in the mosquito midgut and rendering mosquitoes non-infectious. DNA vaccine constructs were developed expressing Pvs25 and Pvs28 (Plasmodium vivax zygote/ookinete surface proteins) fused at the amino terminus with tissue plasminogen activator signal peptide. Antibodies produced in mice after immunization with three doses recognized respective antigens in the parasites and in an ELISA,and these antibodies when tested in membrane feeding assay were potent blockers of R vivax transmission. Co-immunization with Pvs25 and Pvs28 DNA vaccine constructs did not affect the antigen specific antibody responses against individual antigens, and the antibodies remained effective in blocking parasite transmission demonstrating 91-99% reduction in oocyst number in the mosquito midgut. Several combinations of homologous and heterologous antigen-delivery prime boost strategy were also evaluated and the results suggested that antibody titers and transmission-blocking activities by the three prime-boost strategies (DNA prime/DNA boost, DNA prime/protein boost, and protein prime/protein boost) were comparable with slightly better immunogenicity of heterologous antigen-delivery prime/boost as compared to DNA/DNA alone. These results demonstrate potent immunogenicity of DNA vaccines encoding Pvs25 and Pvs28 and warrant further evaluation in non-human primates. (C) 2004 Elsevier Ltd. All rights reserved. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Malaria Res Inst, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD 20852 USA. Ctr Dis Control & Prevent, Div Parasit Dis, Atlanta, GA 30341 USA. Ctr Dis Control & Prevent, Anim Resources Branch, Atlanta, GA 30341 USA. Armed Forces Res Inst Med Sci, Dept Entomol, Bangkok 10400, Thailand. Ehime Univ, Sch Med, Dept Mol Parasitol, Shigenobu, Ehime 7918503, Japan. Ehime Univ, Cell Free Sci & Technol Res Ctr, Matsuyama, Ehime 7908577, Japan. RP Kumar, N (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Malaria Res Inst, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. EM nkumar@jhsph.edu RI Kongkasuriyachai, Darin/F-2123-2011 FU NIAID NIH HHS [AI47089] NR 20 TC 29 Z9 33 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 AUG 13 PY 2004 VL 22 IS 23-24 BP 3205 EP 3213 DI 10.1016/j.vaccine.2003.11.060 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 849AO UT WOS:000223509800033 PM 15297075 ER PT J AU Glazko, GV Koonin, EV Rogozin, IB AF Glazko, GV Koonin, EV Rogozin, IB TI Mutation hotspots in the p53 gene in tumors of different origin: correlation with evolutionary conservation and signs of positive selection SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION LA English DT Article DE hotspot; p53 gene; p63/73 family members; classification; cancer; comparative analysis ID HUMAN CANCERS; LUNG CANCERS; FUNCTIONAL DOMAIN; FAMILY-MEMBERS; ANALYSIS TOOLS; TOBACCO-SMOKE; DNA-DAMAGE; SPECTRA; TP53; DATABASE AB We present a classification analysis of the mutation spectra of the p53 gene and construct maps of hotspots for the germline (Li-Fraumein syndrome), different types of tumors and their derived cell lines. While spectra from solid tumors share common hotspots with the germline spectrum, they also contain unique sets of somatic hotspots that are not observed in the germline. All these hotspots correspond to amino acid replacements in the DNA-binding interface of p53. The mutation spectra of lymphomas and cell lines derived from lymphomas and lung cancers contained few hotspots compared to solid tumors. Thus, the distribution of hotspots in the p53 gene appears to depend on the tumor type and cell growth conditions; this specificity is missed by the bulk hotspot analysis. A negative correlation was detected between the amino acid replacement propensity in tumors and evolutionary variability: the hotspots are located in the positions that are highly conserved in p53 and its paralogs, p63 and p73. In all the mutation spectra, substitutions leading to amino acid replacements strongly dominate over silent substitutions, indicating that functional sites evolving under strong purifying selection are subject to intensive positive selection in p53-dependent tumors. These results are compatible with the gain-of-function concept of the role of p53 in tumorigenesis. (C) 2004 Elsevier B.V. All rights reserved. C1 Stowers Inst Med Res, Kansas City, MO 64110 USA. Russian Acad Sci, Siberian Branch, Inst Cytol & Genet, Novosibirsk 630090, Russia. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Glazko, GV (reprint author), Stowers Inst Med Res, 1000 E 50th St, Kansas City, MO 64110 USA. EM gvg@Stowers-Institute.org NR 81 TC 22 Z9 22 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4781 J9 BBA-GENE STRUCT EXPR JI Biochim. Biophys. Acta-Gene Struct. Expression PD AUG 12 PY 2004 VL 1679 IS 2 BP 95 EP 106 DI 10.1016/j.bbaexp.2004.05.004 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 847GS UT WOS:000223381300002 PM 15297143 ER PT J AU Sun, HY Nikolovska-Coleska, Z Yang, CY Xu, L Tomita, Y Krajewski, K Roller, PP Wang, SM AF Sun, HY Nikolovska-Coleska, Z Yang, CY Xu, L Tomita, Y Krajewski, K Roller, PP Wang, SM TI Structure-based design, synthesis, and evaluation of conformationally constrained mimetics of the second mitochondria-derived activator of caspase that target the X-linked inhibitor of apoptosis protein/caspase-9 interaction site SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROMOTES APOPTOSIS; IAP PROTEINS; SMAC/DIABLO; BINDING; XIAP; SMAC; AGENTS; DIABLO; DOMAIN AB A successful structure-based design of conformationally constrained second mitochondria-derived activator of caspase (Smac) mimetics that target the XIAP/caspase-9 interaction site is described. The most potent Smac mimetic 12d has a K-i of 350 nM for binding to the XIAP BIR3 domain protein. 12d is found to be effective in enhancing apoptosis induced by cisplatin in PC-3 human prostate cancer cells. C1 Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Med Chem, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. NCI, FCRDC, Med Chem Lab, Frederick, MD 21702 USA. RP Wang, SM (reprint author), Univ Michigan, Dept Internal Med, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM shaomeng@umich.edu RI Wang, Shaomeng/E-9686-2010 NR 19 TC 110 Z9 114 U1 0 U2 14 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 AUG 12 PY 2004 VL 47 IS 17 BP 4147 EP 4150 DI 10.1021/jm0499108 PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 844FH UT WOS:000223142500007 PM 15293984 ER PT J AU Goldstein, S Rosen, GM Russo, A Samuni, A AF Goldstein, S Rosen, GM Russo, A Samuni, A TI Kinetics of spin trapping superoxide, hydroxyl, and aliphatic radicals by cyclic nitrones SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID NITRIC-OXIDE SYNTHASE; TIME-RESOLVED ESR; N-OXIDE; GENERATES SUPEROXIDE; THEORETICAL-ANALYSIS; ADDUCT DECAY; TETRAHYDROBIOPTERIN; TRAPS; 5,5-DIMETHYL-1-PYRROLINE-N-OXIDE; MECHANISMS AB Spin trapping coupled with electron paramagnetic resonance (EPR) spectroscopy has surfaced as one of the most specific and reliable methods for identifying free radicals in biological systems. Despite extensive studies focused on the kinetics of radical trapping by cyclic nitrones, the mechanism has not been fully elucidated. Moreover, major controversies still persist even regarding the efficiency and the rate constants of the trapping reaction. The present research used pulse radiolysis for studying the reaction of 5,5-dimethyl-1-pyrroline N-oxide 1 (DMPO) and of the ester-containing derivative, 5-tert-butoxycarbonyl-5-methyl-1-pyrroline N-oxide 4, with (OH)-O-., O-2(.-), CO2.-, C-.(OH)(CH3)(2), (CH2OH)-C-., and (CH3)-C-.. The results reveal that radical trapping is far more complex then previously realized. Radiation chemical experiments combined with EPR demonstrate that about 30% of (OH)-O-. add to nitrones 1 and 4 at position 2, yielding the corresponding persistent aminoxyls. The remaining (OH)-O-. radicals form transient intermediates that rapidly decay bimolecularly. These transient intermediates react with oxygen with rate constants that are significantly lower than those generally reported for alkyl radicals, which suggests that they are not simple carbon-centered radicals generated as a result of H-abstraction from the methyl or methylene groups of the nitrones. It is also shown that the addition of O-2(.-) and various aliphatic radicals to the nitrones is an equilibrium process. The upper limit for the rate constant of the reaction of nitrone 4 with O-2(.-) was 3 M-1 s(-1). The rate constant for the reaction of nitrone 1 with O-2(.-) was determined to be 170 +/- 40 M-1 s(-1). This value is significantly higher than those previously determined by following the formation of the corresponding aminoxyl by EPR, which indicates that the yield of the aminoxyl is only a small fraction of the reacting O-2(.-). C1 Hebrew Univ Jerusalem, Dept Phys Chem, IL-91904 Jerusalem, Israel. Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. Univ Maryland, Inst Biotechnol, Ctr Med Biotechnol, Baltimore, MD 21201 USA. Univ Maryland, Ctr Low Frequency EPR Imaging In Vivo Physiol, Baltimore, MD 21201 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Mol Biol, IL-91120 Jerusalem, Israel. RP Goldstein, S (reprint author), Hebrew Univ Jerusalem, Dept Phys Chem, IL-91904 Jerusalem, Israel. NR 44 TC 17 Z9 17 U1 6 U2 27 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD AUG 12 PY 2004 VL 108 IS 32 BP 6679 EP 6685 DI 10.1021/jp048441i PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 844TH UT WOS:000223182700010 ER PT J AU You, L He, B Xu, ZD Uematsu, K Mazieres, J Mikami, I Reguart, N Moody, TW Kitajewski, J McCormick, F Jablons, DM AF You, L He, B Xu, ZD Uematsu, K Mazieres, J Mikami, I Reguart, N Moody, TW Kitajewski, J McCormick, F Jablons, DM TI Inhibition of Wnt-2-mediated signaling induces programmed cell death in non-small-cell lung cancer cells SO ONCOGENE LA English DT Article DE Wnt signaling; apoptosis; lung cancer ID HUMAN COLORECTAL-CANCER; BETA-CATENIN; SURVIVIN EXPRESSION; INDUCED APOPTOSIS; COLON-CARCINOMA; UP-REGULATION; C-MYC; PATHWAY; WNT-2; GENE AB In this report, we have demonstrated that Wnt-2 protein is overexpressed in freshly resected human non-small-cell lung cancer (NSCLC) tissues. We have also developed a monoclonal antibody against the N-terminus of human Wnt-2 protein. This monoclonal antibody induces apoptosis in human NSCLC cell lines that overexpress Wnt-2 protein. Incubation of this antibody with normal human airway cells lacking Wnt-2 expression does not induce apoptosis. Wnt-2 signaling blockade by the anti-Wnt-2 antibody is confirmed by downregulation of cytosolic beta-catenin and reduction in TCF-dependent transcriptional activity (TOPFLASH assay). In addition, Wnt-2-specific small interfering RNA (siRNA) treatment in the NSCLC cell line A549 also downregulated cytosolic beta-catenin and induced apoptosis. Moreover, downregulation of an inhibitor of apoptosis family protein, Survivin, was noticed both in the Wnt-2 antibody- and siRNA-treated NSCLC cells, suggesting that inhibition of Wnt-2-mediated signaling induces apoptosis through inactivating Survinin. C1 Univ Calif San Francisco, Ctr Comprehens Canc, Dept Surg, Thorac Oncol Lab, San Francisco, CA 94115 USA. NCI, Off Director, Ctr Canc Res, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, Dept Pathol & Obstet & Gynecol, New York, NY 10032 USA. RP Jablons, DM (reprint author), Ctr Canc, Dept Surg, 1600 Divisadero St,C322C,Box 1674, San Francisco, CA 94115 USA. EM jablonsd@surgery.ucsf.edu RI MAZIERES, JULIEN/M-3986-2014; OI MAZIERES, JULIEN/0000-0002-5921-7613 FU NCI NIH HHS [R01 CA093708, R01 CA093708-01A3] NR 38 TC 173 Z9 183 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 12 PY 2004 VL 23 IS 36 BP 6170 EP 6174 DI 10.1038/sj.onc.1207844 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 845RC UT WOS:000223261000017 PM 15208662 ER PT J AU Jaffe, H Vinade, L Dosemeci, A AF Jaffe, H Vinade, L Dosemeci, A TI Identification of novel phosphorylation sites on postsynaptic density proteins SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; TANDEM MASS-SPECTROMETRY; PHOSPHOPROTEOME ANALYSIS; CAM KINASE; PSD-95; BETA; LOCALIZATION; FRACTIONS; NEURONS; DOMAIN AB Phosphorylation of the components of the postsynaptic density (PSD), a protein complex lining the postsynaptic membrane, may regulate synaptic structure and function. We carried out mass spectrometric analyses to identify phosphorylation sites on PSD proteins. Phosphopeptides were isolated from the total tryptic digest of a PSD fraction by immobilized metal affinity chromatography and analyzed by liquid chromatography and tandem mass spectrometry. The phosphorylated residues detected following in vitro phosphorylation in the presence of Ca2+/calmodulin included S-1058 on SynGAP and S-1662 and S-1668 on Shank3. Other phosphorylated residues were identified in control samples, presumably reflecting phosphorylation in the intact cell. These included the homologous residues, S-295 on PSD-95 and S-365 on PSD-93, located between the PDZ2 and PDZ3 domains of these proteins; and S-367 located on the actin-binding domain of beta-CaMKII. The sequence RXXSPV emerged as a common phosphorylation motif of three specialized PSD scaffolding proteins, PSD-95, PSD-93, and Shank3. Phosphorylated serine residues in several of the identified phosphorylation sites were followed by prolines, suggesting prominent involvement of proline directed kinases in the regulation of PSD components. (C) 2004 Elsevier Inc. All rights reserved. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Prot & Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. Marine Biol Lab, Program Mol Physiol, Woods Hole, MA 02543 USA. RP Dosemeci, A (reprint author), NINDS, Neurobiol Lab, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM dosemeca@mail.nih.gov NR 35 TC 32 Z9 33 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 EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 11 PY 2004 VL 321 IS 1 BP 210 EP 218 DI 10.1016/j.bbrc.2004.06.122 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 842VP UT WOS:000223032800032 PM 15358237 ER PT J AU Xie, T Tong, LQ McCann, UD Yuan, J Becker, KG Mechan, AO Cheadle, C Donovan, DM Ricaurte, GA AF Xie, T Tong, LQ McCann, UD Yuan, J Becker, KG Mechan, AO Cheadle, C Donovan, DM Ricaurte, GA TI Identification and characterization of metallothionein-1 and-2 gene expression in the context of (+/-)3,4-methylenedioxymethamphetamine-induced toxicity to brain dopaminergic neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE dopamine; MDMA; neurotoxicity; metallothioneins; amphetamines; microarray ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; II-DEFICIENT MICE; TRANSGENIC MICE; 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE NEUROTOXICITY; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; MOUSE-BRAIN; RAT-BRAIN AB In mice, the recreational drug (+/-)3,4-methylenedioxymethamphetamine [ MDMA ("ecstasy")] produces a selective toxic effect on brain dopamine (DA) neurons. Using cDNA microarray technology in combination with an approach designed to facilitate recognition of relevant changes in gene expression, the present studies sought to identify genes potentially involved in murine MDMA-induced toxicity to DA neurons. Of 15,000 mouse cDNA fragments studied, metallothionein (Mt)-1 and Mt2 emerged as candidate genes possibly involved in MDMA-induced toxicity to DA neurons. Northern blot analysis confirmed the microarray findings and revealed a dynamic upregulation of Mt1 and Mt2 mRNA in the ventral midbrain within 4-12 hr after MDMA treatment. Western blot analysis showed a similar increase in MT protein levels, with peak times occurring subsequent to increases in mRNA levels. Mt1-2 double knock-out mice were more vulnerable to MDMA-induced toxicity to DA neurons than corresponding wild-type mice. Stimulation of endogenous expression of MT protein with zinc acetate conferred complete protection against MDMA-induced toxicity to DA neurons, and administration of exogenous MT protein afforded partial protection. Collectively, these results indicate that MDMA-induced toxicity to DA neurons is associated with increased Mt1 and Mt2 gene transcription and translation, possibly as part of a neuroprotective mechanism. The present findings may have therapeutic implications for neuropathological conditions involving DA neurons. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21224 USA. NIA, cDNA Microarray Unit, Res Resources Branch, Intramural Res Program,NIH, Baltimore, MD 21224 USA. ARS, Biotechnol & Germplasm Lab, USDA, Anim & Natl Resources Inst, Beltsville, MD 20705 USA. RP Ricaurte, GA (reprint author), Johns Hopkins Med Inst, Dept Neurol, 5501 Hopkins Bayview Circle,Room 5B-71E, Baltimore, MD 21224 USA. EM ricaurte@jhmi.edu OI Becker, Kevin/0000-0002-6794-6656 FU NIDA NIH HHS [DA00206, DA09487, DA10217] NR 42 TC 27 Z9 28 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 11 PY 2004 VL 24 IS 32 BP 7043 EP 7050 DI 10.1523/JNEUROSCI.1626-04.2004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 846QP UT WOS:000223331100002 PM 15306638 ER PT J AU Gow, A Davies, C Southwood, CM Frolenkov, G Chrustowski, M Ng, L Yamauchi, D Marcus, DC Kachar, B AF Gow, A Davies, C Southwood, CM Frolenkov, G Chrustowski, M Ng, L Yamauchi, D Marcus, DC Kachar, B TI Deafness in Claudin 11-null mice reveals the critical contribution of basal cell tight junctions to stria vascularis function SO JOURNAL OF NEUROSCIENCE LA English DT Article DE evoked potentials; targeted deletion; oligodendrocyte-specific protein; alpha-galactosidase; freeze fracture; homologous recombination ID OUTER HAIR-CELLS; PELIZAEUS-MERZBACHER-DISEASE; COCHLEAR AMPLIFIER; MOTOR PROTEIN; MYELIN; FUROSEMIDE; BRAIN; PRESTIN; GENE; OLIGODENDROCYTE AB Generation of a strong electrical potential in the cochlea is uniquely mammalian and may reflect recent evolutionary advances in cellular voltage-dependent amplifiers. This endocochlear potential is hypothesized to dramatically improve hearing sensitivity, a concept that is difficult to explore experimentally, because manipulating cochlear function frequently causes rapid degenerative changes early in development. Here, we examine the deafness phenotype in adult Claudin 11-null mice, which lack the basal cell tight junctions that give rise to the intrastrial compartment and find little evidence of cochlear pathology. Potassium ion recycling is normal in these mutants, but endocochlear potentials were below 30 mV and hearing thresholds were elevated 50 dB sound pressure level across the frequency spectrum. Together, these data demonstrate the central importance of basal cell tight junctions in the stria vascularis and directly verify the two-cell hypothesis for generation of endocochlear potential. Furthermore, these data indicate that endocochlear potential is an essential component of the power source for the mammalian cochlear amplifier. C1 Wayne State Univ, Sch Med, Ctr Mol Med & Genet, CArman & Ann Adams Dept Pediat,Dept Nuerol, Detroit, MI 48201 USA. NAtl Inst Deafness & Other Commun Disorders, Sect Struct Biol, NIH, Bethesda, MD 20892 USA. CUNY Mt Sinai Sch Med, Dept Genet, New York, NY 10029 USA. Kansas State Univ, Dept Anat & Physiol, Manhattan, KS 66506 USA. RP Gow, A (reprint author), Wayne State Univ, Sch Med, Ctr Mol Med & Genet, CArman & Ann Adams Dept Pediat,Dept Nuerol, 3216 Scott Hall,541 E Canfield, Detroit, MI 48201 USA. EM agow@genetics.wayne.edu; kacharb@nidcd.nih.gov OI Frolenkov, Gregory/0000-0002-9810-5024 FU NIDCD NIH HHS [R01 DC000212, R01 DC00212, R01 DC006262]; NINDS NIH HHS [R01 NS043783, R01 NS43783] NR 44 TC 118 Z9 121 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 11 PY 2004 VL 24 IS 32 BP 7051 EP 7062 DI 10.1523/JNEUROSCI.1640-04.2004 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 846QP UT WOS:000223331100003 PM 15306639 ER PT J AU Mutsuga, N Shahar, T Verbalis, JG Brownstein, MJ Xiang, CC Bonner, RF Gainer, H AF Mutsuga, N Shahar, T Verbalis, JG Brownstein, MJ Xiang, CC Bonner, RF Gainer, H TI Selective gene expression in magnocellular neurons in rat supraoptic nucleus SO JOURNAL OF NEUROSCIENCE LA English DT Article DE oxytocin; vasopressin; hypothalamus; gene expression; microarray; laser microdissection ID ZINC-FINGER GENE; TRANSCRIPTION FACTOR-IIA; HYPOTHALAMONEUROHYPOPHYSEAL SYSTEM; ZEBRAFISH FOREBRAIN; RNA; BINDING; IDENTIFICATION; PROTEIN; RECEPTOR; OXYTOCIN AB Oxytocin- and vasopressin-producing magnocellular neurons (MCNs) of the hypothalamo-neurohypophysial system are the only neuronal phenotypes present in the rat supraoptic nucleus ( SON). Laser microdissection of the SON, extraction and T7-based amplification of its RNAs, and analysis of the resulting cDNAs by hybridization on a 35, 319 element DNA microarray have provided a detailed composite view of the gene expression profile of the MCNs. The genes expressed in the SON were compared with those expressed in a reference tissue consisting of total hypothalamus, and this "expression ratio" indicated which genes were preferentially expressed in the SON. Of the 26,000 unique genes on the array, 1385 were found to be expressed in the SON at levels more than two times greater than in the hypothalamus as a whole. Of these, 123 were expressed greater than or equal to3.4-fold higher in the SON versus hypothalamus. Most of these preferentially expressed genes were not previously known to be expressed in the MCNs. Quantitative and double-label in situ hybridization histochemistry was used selectively to confirm a number of these microarray observations and to evaluate the osmotic regulation and cell-specific expression of these genes, respectively. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NIMH, Genet Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Med, Div Endocrinol & Metab, Washington, DC 20007 USA. NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. EM gainerh@ninds.nih.gov RI Bonner, Robert/C-6783-2015 NR 57 TC 31 Z9 31 U1 1 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 11 PY 2004 VL 24 IS 32 BP 7174 EP 7185 DI 10.1523/JNEUROSCI.2022-04.2004 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 846QP UT WOS:000223331100015 PM 15306651 ER PT J AU Marchan, V Cieslak, J Livengood, V Beaucage, SL AF Marchan, V Cieslak, J Livengood, V Beaucage, SL TI 2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinyl group for 5 '-hydroxyl protection of deoxyribonucleoside phosphoramidites in the solid-phase preparation of DNA oligonucleotides SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID MODIFIED PHOSPHOTRIESTER METHOD; GENE-EXPRESSION PATTERNS; LIGHT-DIRECTED SYNTHESIS; SULFUR-TRANSFER REAGENT; A-U-A; OLIGODEOXYRIBONUCLEOTIDE SYNTHESIS; 3H-1,2-BENZODITHIOL-3-ONE 1,1-DIOXIDE; LEVULINIC ACID; ARRAYS; MICROARRAYS AB Several nitrogen-sulfur reagents have been investigated as potential 5'-hydroxyl protecting groups for deoxyribonucleoside phosphoramidites to improve the synthesis of oligonucleotides on glass microarrays. Out of the nitrogen-sulfur-based protecting groups so far investigated, the 2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinyl group exhibited near optimal properties for 5'-hydroxyl protection by virtue of the mildness of its deprotection conditions. Specifically, the iterative cleavage of a terminal 5'-sulfamidite group in the synthesis of 5'-d(ATCCGTAGCCAAGGTCATGT) on controlled-pore glass is efficiently accomplished by treatment with iodine in the presence of an acidic salt. Hydrolysis of the oligonucleotide to its 2'-deoxyribonucleosides upon exposure to snake venom phosphodiesterase and bacterial alkaline phosphatase did not reveal the formation of any nucleobase adducts or other modifications. These findings indicate that the 2,2,5,5-tetramethylpyrrolidin-3-one-1-sulfinyl group for 5'-hydroxyl protection of phosphoramidites, such as 10a-d, may lead to the production of oligonucleotide microarrays exhibiting enhanced specificity and sensitivity in the detection of nucleic acid targets. C1 US FDA, Ctr Drug Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Beaucage, SL (reprint author), US FDA, Ctr Drug Evaluat & Res, Div Therapeut Prot, 8800 Rockville Pike, Bethesda, MD 20892 USA. EM beaucage@cber.fda.gov RI Marchan, Vicente/K-9751-2014 OI Marchan, Vicente/0000-0002-1905-2156 NR 51 TC 4 Z9 4 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD AUG 11 PY 2004 VL 126 IS 31 BP 9601 EP 9610 DI 10.1021/ja0483771 PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 843TS UT WOS:000223110100053 PM 15291564 ER PT J AU de Alba, E Tjandra, N AF de Alba, E Tjandra, N TI Structural studies on the Ca2+-binding domain of human nucleobindin (calnuc) SO BIOCHEMISTRY LA English DT Article ID AUTOIMMUNE MRL/LPR/LPR MICE; CALCIUM-BINDING PROTEIN; N-15 NMR RELAXATION; REGULATORY DOMAIN; ORIENTED MACROMOLECULES; BACKBONE DYNAMICS; NATURAL OCCURRENCE; TERMINAL DOMAIN; CALBINDIN D-9K; VECTOR PROTEIN AB Nucleobindin, also known as calnuc, participates in Ca2+ storage in the Golgi, as well as in other biological processes that involve DNA-binding and protein-protein interactions. We have determined the three-dimensional solution structure of the Ca2+-binding domain of nucleobindin by NMR showing that it consists of two EF-hand motifs. The NMR structure indicates that the phi and psi angles of residues in both motifs are very similar, despite the noncanonical sequence of the C-terminal EF-hand, which contains an arginine residue instead of the typical glycine at the sixth position of the 12-residue loop. The relative orientation of the a-helices in the N-terminal EF-hand falls within the common arrangement found in most EF-hand structures. In contrast, the noncanonical EF-hand deviates from the average orientation. The two helix-loop-helix moieties are in the open conformation characteristic of the Ca2+- bound state. We find that both motifs bind Ca2+ with apparent dissociation constants of 47 and 40 muM for the noncanonical and the canonical EF-hand, respectively. The Ca2+-binding domain of nucleobindin is unstructured in the absence of Ca2+ and folds upon Ca2+ addition. NMR relaxation data and structural studies of the folded domain indicate that it undergoes slow dynamics, suggesting that it is floppier and less compact than a globular domain. C1 NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Biophys Chem Lab, NIH, 50 Ctr Dr, Bethesda, MD 20892 USA. EM nico@helix.nih.gov NR 60 TC 19 Z9 20 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 10 PY 2004 VL 43 IS 31 BP 10039 EP 10049 DI 10.1021/bi049310a PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 843XS UT WOS:000223121200011 PM 15287731 ER PT J AU Bi, XL Wei, SCD Rong, YKS AF Bi, XL Wei, SCD Rong, YKS TI Telomere protection without a telornerase: The role of ATM and Mre11 in Drosophila telomere maintenance SO CURRENT BIOLOGY LA English DT Article ID CELL-CYCLE; DNA-SEQUENCES; COMPLEX; HETEROCHROMATIN; PROTEIN; YEAST; RECOMBINATION; MELANOGASTER; DYSFUNCTION; CHECKPOINT AB The conserved ATM checkpoint kinase and the Mre11 DNA repair complex play essential and overlapping roles in maintaining genomic integrity. We conducted genetic and cytological studies on Drosophila atm and mre11 knockout mutants and discovered a telomere defect that was more severe than in any of the non-Drosophila systems studied. In mutant mitotic cells, an average of 30% of the chromosome ends engaged in telomere fusions. These fusions led to the formation and sometimes breakage of dicentric chromosomes, thus starting a devastating breakage-fusion-bridge cycle. Some of the fusions depended on DNA ligase IV, which suggested that they occurred by a nonhomologous end-joining (NHEJ) mechanism. Epistasis analyses results suggest that ATM and Mre11 might also act in the same telomere maintenance pathway in metazoans. Since Drosophila telomeres are not added by a telomerase, our findings support an additional role for both ATM and Mre11 in telomere maintenance that is independent of telomerase regulation. C1 NCI, Lab Mol Cell Biol, NIH, Bethesda, MD 20892 USA. RP Rong, YKS (reprint author), NCI, Lab Mol Cell Biol, NIH, Bethesda, MD 20892 USA. EM rongy@mail.nih.gov RI Bi, Xiaolin/E-7469-2010; rong, yikang/G-6179-2011; Bi, Xiaolin/C-7038-2014 OI Bi, Xiaolin/0000-0002-7172-7851; Bi, Xiaolin/0000-0003-2837-9457 NR 35 TC 78 Z9 84 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 AUG 10 PY 2004 VL 14 IS 15 BP 1348 EP 1353 DI 10.1016/j.cub.2004.06.063 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 846HJ UT WOS:000223306200026 PM 15296751 ER PT J AU Engels, EA Chatterjee, N Cerhan, JR Davis, S Cozen, W Severson, RK Whitby, D Colt, JS Hartge, P AF Engels, EA Chatterjee, N Cerhan, JR Davis, S Cozen, W Severson, RK Whitby, D Colt, JS Hartge, P TI Hepatitis C virus infection and non-Hodgkin lymphoma: Results of the NCI-SEER multi-center case-control study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE hepatitis C virus; non-Hodgkin's lymphoma; case-control study ID B-CELL LYMPHOMA; LYMPHOPROLIFERATIVE DISORDERS; MIXED CRYOGLOBULINEMIA; VIRAL-INFECTION; ASSOCIATION; PREVALENCE; TRANSLOCATION; RISK; HCV AB Several studies have noted elevated hepatitis C virus (HCV) prevalence among patients with non-Hodgkin lymphoma (NHL), suggesting that HCV infection increases NHL risk through chronic immune stimulation. Population-based data from the U.S. are lacking. In a population-based case-control study of NHL in the United States, we identified HCV infection using an enzyme immunoassay, confirmed by recombinant immunoblot assay or HCV RNA detection. The association between HCV and NHL was assessed using logistic regression, adjusting for demographic factors, illicit drug use or medical history. Thirty-two of 813 (3.9%) NHL cases and 14 of 684 (2.1%) controls were HCV-infected [odds ratio (OR) 1.96, 95%Cl 1.07-4.03]. For separate NHL subtypes, numbers were limited. Nonetheless, positive associations were noted for follicular (OR 2.46, 95%Cl 1.01-5.81), marginal zone (3.99, 0-13.6) and mucosa-associated lymphoid tissue (2.04,0-7.20) NHLs. For all NHLs combined, the HCV-NHL association changed little after adjustment for sex, age, race and study center (OR 1.89, 95%Cl 1.00-4.00). HCV was common in controls who had injected drugs (40%) or used other illicit drugs (6.5%), but adjustment for drug use did not affect the HCV-NHL association (OR 1.87, 95%Cl 0.95-4.10). Transfusion history was unrelated to HCV status, and adjustment for this exposure did not attenuate the HCV-NHL association (OR 2.15, 95%Cl 1.12-4.76). Excluding 4 subjects with a history of hemodialysis or 3 subjects with organ transplants also did not affect the results. Our study demonstrates an association between HCV infection and NHL in the United States. HCV infection may be a cause of NHL. (C) 2004 Wiley-Liss, Inc. C1 NCI, DHHS, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, Rockville, MD 20892 USA. Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ So Calif, Los Angeles, CA USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Wayne State Univ, Dept Family Med, Detroit, MI USA. Natl Canc Inst, AIDS Vaccine Program, Viral Epidemiol Sect, Frederick, MD USA. RP Engels, EA (reprint author), NCI, DHHS, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, 6120 Executive Blvd,EPS 8010, Rockville, MD 20892 USA. EM engelse@exchange.nih.gov OI Cerhan, James/0000-0002-7482-178X FU NCI NIH HHS [N01-PC-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N01-PC-71105] NR 34 TC 74 Z9 76 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 10 PY 2004 VL 111 IS 1 BP 76 EP 80 DI 10.1002/ijc.20021 PG 5 WC Oncology SC Oncology GA 834XZ UT WOS:000222445500011 PM 15185346 ER PT J AU De Sanjose, S Nieters, A Goedert, JJ Domingo-Domenech, E De Sevilla, AF Bosch, R Herrera, P Domingo, A Petit, J Bosch, X Kallinowski, B AF De Sanjose, S Nieters, A Goedert, JJ Domingo-Domenech, E De Sevilla, AF Bosch, R Herrera, P Domingo, A Petit, J Bosch, X Kallinowski, B TI Role of hepatitis C virus infection in malignant lymphoma in Spain SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE hepatitis C; lymphoma; case-control studies ID NON-HODGKINS-LYMPHOMA; LYMPHOPROLIFERATIVE DISORDERS; MIXED CRYOGLOBULINEMIA; LIVER-TRANSPLANTATION; PREVALENCE; RISK; HCV; REARRANGEMENT; LYMPHOCYTES; HEMOPHILIA AB Hepatitis C virus (HCV) has been implicated in the etiology of malignant lymphomas. We estimated the risk of lymphoma associated with detection of HCV infection. Cases (n = 529) were consecutive patients newly diagnosed with a lymphoid malignancy between 1998 and 2002 in 4 centers in Spain. Lymphomas were diagnosed and classified using the WHO Classification. Controls (n = 600) were hospitalized patients matched to the cases by 5-year age group, gender and study center. Several medical conditions associated with severe immunosuppression precluded the eligibility of controls. Patients underwent a personal interview and blood sampling. HCV positive subjects were considered those with antibody response to third generation ELISA or detection of HCV RNA with Amplicor 2.0. Cases were systematically tested for HIV antibodies. We used the chi(2) test and unconditional logistic regression to estimate the odds ratio (OR) and 95% confidence interval (95%. Cl) for lymphoma associated with HCV. HCV infection was detected in 40 cases (73%) and 23 (3.8%) control subjects. Six of 16 patients with HIV-related lymphomas and 4 of 8 organ-recipient-related lymphomas were HCV positive. The analysis, excluding HIV-infected subjects and organ recipients, led to a prevalence of HCV of 5.9% among cases and 3.8% among controls. The age-, gender- and center-adjusted OR for all lymphomas was 1.58 (95% Cl = 0.89-2.79). Among all lymphoma categories, HCV was associated with an increased risk of low grade B-cell lymphomas not otherwise specified (NOS) (OR = 35.98, 95% Cl = 4.70-275.4). A 2-fold excess risk associated to HCV was observed for marginal B-cell lymphomas, diffuse large B-cell lymphoma and lymphoma B NOS but the associations were not statistically significant. HCV infection is associated with an increased risk of a broad spectrum of lymphoid neoplasms among non severely immunocompromised subjects in Spain. (C) 2004 Wiley-Liss, Inc. C1 Hosp Ll, Inst Catala Oncol, Serv Epidemiol Registre Canc, Barcelona 08907, Spain. NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. German Canc Res Ctr, D-6900 Heidelberg, Germany. Inst Catala Oncol, Barcelona, Spain. Hosp Verge Cinta, Tortosa, Spain. Ciutat Sanitaria & Univ Bellvitge, Barcelona, Spain. Univ Heidelberg Hosp, Dept Internal Med 4, Heidelberg, Germany. RP De Sanjose, S (reprint author), Hosp Ll, Inst Catala Oncol, Serv Epidemiol Registre Canc, Gran Via Km 2-7, Barcelona 08907, Spain. EM s.sanjose@ico.scs.es RI de Sanjose Llongueras, Silvia/H-6339-2014; BOSCH JOSE, FRANCESC XAVIER/J-6339-2012 OI BOSCH JOSE, FRANCESC XAVIER/0000-0002-7172-3412 NR 37 TC 29 Z9 29 U1 0 U2 3 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 AUG 10 PY 2004 VL 111 IS 1 BP 81 EP 85 DI 10.1002/ijc.11727 PG 5 WC Oncology SC Oncology GA 834XZ UT WOS:000222445500012 PM 15185347 ER PT J AU Pickard, A Chen, CJ Diehl, SR Liu, MY Cheng, YJ Hsu, WL Sun, B Hsu, MM Chen, IH Chen, JY Yang, CS Mittl, BL Chou, SP Ruggles, DD Goldstein, AM Hildesheim, A AF Pickard, A Chen, CJ Diehl, SR Liu, MY Cheng, YJ Hsu, WL Sun, B Hsu, MM Chen, IH Chen, JY Yang, CS Mittl, BL Chou, SP Ruggles, DD Goldstein, AM Hildesheim, A TI Epstein-Barr virus seroreactivity among unaffected individuals within high-risk nasopharyngeal carcinoma families in Taiwan SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Epstein-Barr virus; nasopharyngeal carcinoma; susceptibility ID GENETIC POLYMORPHISMS; WUZHOU-CITY; ANTIBODIES; CHINA; DNASE; MALIGNANCIES; FORMALDEHYDE; FREQUENCY; INFECTION; PATTERNS AB Most adults have been infected with EBV. Many studies have indicated that antibodies against specific EBV antigens, particularly IgA antibodies, can be predictive or prognostic of EBV-associated malignancies, such as NPC. We hypothesized that healthy individuals from families with a history of multiple members affected with NPC (who therefore might be genetically susceptible to NPC themselves) might have an EBV antibody profile that is distinct from that seen in healthy individuals from the community at large. To explore this possibility and examine determinants of anti-EBV antibody levels in healthy, high-risk individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which included 1,229 healthy members of families in which 2 or more individuals were affected with NPC and 320 controls from the community at large. Blood collected from participants was tested for IgA antibodies against EBV VCA and EBNA-I and for neutralizing antibodies against EBV DNase using standard assays. We observed evidence of familial aggregation of EBV seroreactivity among individuals from high-risk, multiplex NPC families. Anti-VCA IgA and anti-EBNA-I IgA antibody seroprevalence in unaffected family members of NPC cases was 5-6 times higher than in members of the community (p < 0.01). This elevated seroprevalence among unaffected individuals from high-risk families was observed regardless of the relationship of the unaffected individual to the closest affected relative (siblings, parents, children or spouses). No sociodemographic or environmental factors examined were found to strongly and consistently correlate with elevated seroprevalence, but patterns emerged of increasing seroprevalence among older individuals and among females. Unaffected individuals from high-risk NPC families have elevated anti-EBV IgA antibody titers. The etiologic and clinical implications of this finding remain to be established. (C) 2004 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol, Taipei 10764, Taiwan. Univ Med & Dent New Jersey, New Jersey Dent Sch, Ctr Pharmacogenom & Complex Dis Res, Newark, NJ 07103 USA. Natl Taipei Coll Nursing, Dept Gen Educ, Taipei, Taiwan. Westat Corp, Rockville, MD USA. Natl Taiwan Univ Hosp, Dept Ear Nose & Throat, Taipei, Taiwan. Chang Gung Mem Hosp, Dept Ear Nose & Throat, Taipei 10591, Taiwan. Natl Hlth Res Inst, Taipei, Taiwan. Natl Taiwan Univ, Coll Med, Grad Inst Microbiol, Taipei, Taiwan. RP Hildesheim, A (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7062, Rockville, MD 20852 USA. EM Hildesha@exchange.nih.gov RI Chen, Chien-Jen/C-6976-2008; Chen, Jen-Yang/D-2085-2010 NR 41 TC 26 Z9 28 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 AUG 10 PY 2004 VL 111 IS 1 BP 117 EP 123 DI 10.1002/ijc.20222 PG 7 WC Oncology SC Oncology GA 834XZ UT WOS:000222445500017 PM 15185352 ER PT J AU Johnson, J Hague, SM Hanson, M Gibson, A Wilson, KE Evans, EW Singleton, AA McInerney-Leo, A Nussbaum, RL Hernandez, DG Gallardo, M McKeith, IG Burn, DJ Ryu, M Hellstrom, O Ravina, B Eerola, J Perry, RH Jaros, E Tienari, P Weiser, R Gwinn-Hardy, K Morris, CM Hardy, J Singleton, AB AF Johnson, J Hague, SM Hanson, M Gibson, A Wilson, KE Evans, EW Singleton, AA McInerney-Leo, A Nussbaum, RL Hernandez, DG Gallardo, M McKeith, IG Burn, DJ Ryu, M Hellstrom, O Ravina, B Eerola, J Perry, RH Jaros, E Tienari, P Weiser, R Gwinn-Hardy, K Morris, CM Hardy, J Singleton, AB TI SNCA multiplication is not a common cause of Parkinson disease or dementia with Lewy bodies SO NEUROLOGY LA English DT Article ID ALPHA-SYNUCLEIN; EARLY-ONSET; DIAGNOSIS; MUTATIONS AB The authors recently have shown that triplication of the a-synuclein gene (SNCA) can cause Parkinson disease (PD) and diffuse Lewy body disease within the same kindred. The authors assessed 101 familial PD probands, 325 sporadic PD cases, 65 patients with dementia with Lewy bodies, and 366 neurologically normal control subjects for SNCA multiplication. The authors did not identify any subjects with multiplication of SNCA and conclude this mutation is a rare cause of disease. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. Univ Newcastle Upon Tyne, Inst Hlth Elderly, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Univ Newcastle Upon Tyne, Wolfson Res Ctr, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Univ Newcastle Upon Tyne, Inst Human Genet, Int Ctr Life, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Newcastle Gen Hosp, Dept Neurol, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. Newcastle Gen Hosp, Dept Neuropathol, Newcastle Upon Tyne NE4 6BE, Tyne & Wear, England. Hosp Univ Caracas, Dept Neurol, Movement Disorders Unit, Caracas, Venezuela. Univ Helsinki, Cent Hosp, Dept Neurol, FIN-00014 Helsinki, Finland. Univ Helsinki, Biomedicum Helsinki, Neurosci Programme, FIN-00014 Helsinki, Finland. RP Singleton, AB (reprint author), NIA, Neurogenet Lab, NIH, Bldg 10,Room 6C103,MSC1589, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Gwinn, Katrina/C-2508-2009; Johnson, Janel/A-7136-2010; Singleton, Andrew/C-3010-2009; Tienari, Pentti/A-4893-2012; Hardy, John/C-2451-2009 NR 10 TC 40 Z9 42 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD AUG 10 PY 2004 VL 63 IS 3 BP 554 EP 556 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 845GK UT WOS:000223229100029 PM 15304594 ER PT J AU Smith, JL Freebern, WJ Collins, I De Siervi, A Montano, I Haggerty, CM McNutt, MC Butscher, WG Dzekunova, I Petersen, DW Kawasaki, E Merchant, JL Gardner, K AF Smith, JL Freebern, WJ Collins, I De Siervi, A Montano, I Haggerty, CM McNutt, MC Butscher, WG Dzekunova, I Petersen, DW Kawasaki, E Merchant, JL Gardner, K TI Kinetic profiles of p300 occupancy in vivo predict common features of promoter structure and coactivator recruitment SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRANSCRIPTION FACTOR; GENE-EXPRESSION; BINDING-PROTEIN; REGULATORY MODULES; ACTIVATION; GROWTH; CELLS; P21(WAF1/CIP1); INHIBITION; PROGRAMS AB Understanding the language encrypted in the gene regulatory regions of the human genome is a challenging goal for the genomic era. Although customary extrapolations from steady-state mRNA levels have been effective, deciphering these regulatory codes will require additional empirical data sets that more closely reflect the dynamic progression of molecular events responsible for inducible transcription. We describe an approach using chromatin immunoprecipitation to profile the kinetic occupancy of the transcriptional coactivator and histone acetyltransferase p300 at numerous mitogen-induced genes in activated T cells. Comparison of these profiles reveals a class of promoters that share common patterns of inducible expression, p300 recruitment, dependence on selective p300 domains, and sensitivity to histone deacetylase inhibitors. Remarkably, this class also shares an evolutionarily conserved promoter composition and structure that accurately predicts additional human genes with similar functional attributes. This "reverse genomic" approach will have broad application for the genome-wide classification of promoter structure and function. C1 NCI, Ctr Adv Technol, Lab Receptor Biol, Bethesda, MD 20892 USA. NCI, Ctr Adv Technol, Gene Express & Microarray Facil, Bethesda, MD 20892 USA. Univ Michigan, Dept Internal Med & Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. RP Gardner, K (reprint author), NIH, Ctr Adv Technol, Room 134C,8717 Grovemont Circle, Bethesda, MD 20892 USA. EM gardnerk@mail.nih.gov FU NIDDK NIH HHS [R01 DK055732, R01 DK55732] NR 33 TC 33 Z9 33 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 AUG 10 PY 2004 VL 101 IS 32 BP 11554 EP 11559 DI 10.1073/pnas.0402156101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 845WT UT WOS:000223276700007 PM 15286281 ER PT J AU Khan, MAS Oubrahim, H Stadtman, ER AF Khan, MAS Oubrahim, H Stadtman, ER TI Inhibition of apoptosis in acute promyelocytic leukemia cells leads to increases in levels of oxidized protein and LMP2 immunoproteasome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE arsenic trioxide; programmed cell death; protein carbonyl NB4 cells; H2O2 ID ARSENIC TRIOXIDE; HYDROGEN-PEROXIDE; RHEUMATOID-ARTHRITIS; SIGNAL-TRANSDUCTION; OXIDATIVE STRESS; ACTIVATION; RESISTANT; PROLIFERATION; THIOREDOXIN; INVOLVEMENT AB On reaching maturity, animal organs cease to increase in size because of inhibition of cell replication activities. It follows that maintenance of optimal organ function depends on the elimination of oxidatively damaged cells and their replacement with new cells. To examine the effects of oxidative stress and apoptosis on the accumulation of oxidized proteins, we exposed acute promyelocytic leukemia cells to arsenic trioxide (As2O3) in the presence and absence of a general caspase inhibitor (benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone), which is known to inhibit caspase-induced apoptosis. We confirm that treatment of cells with As2O3 induces apoptosis and leads to the accumulation of oxidized proteins. Furthermore, inhibition of caspase activities prevented As2O3-induced apoptosis and led to a substantial increase in accumulation of oxidized proteins. Moreover, inhibition of caspase activity in the absence of As2O3 led to elevated levels of the LMP2 immunoproteasome protein. We also show that caspase inhibition leads to increases in the levels of oxidized proteins obtained by treatments with hydrogen peroxide plus ferrous iron. Collectively, these results suggest the possibility that an age-related loss in capacity to carry out apoptosis might contribute to the observed accumulation of oxidized proteins during aging and in age-related diseases. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Stadtman, ER (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2140,50 South Dr,MSC 8012, Bethesda, MD 20892 USA. EM erstadtman@nih.gov NR 36 TC 16 Z9 16 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 10 PY 2004 VL 101 IS 32 BP 11560 EP 11565 DI 10.1073/pnas.0404101101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 845WT UT WOS:000223276700008 PM 15284441 ER PT J AU Wu, ZB Alexandratos, J Ericksen, B Lubkowski, J Gallo, RC Lu, WY AF Wu, ZB Alexandratos, J Ericksen, B Lubkowski, J Gallo, RC Lu, WY TI Total chemical synthesis of N-myristoylated HIV-1 matrix protein p17: Structural and mechanistic implications of p17 myristoylation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; NUCLEAR-LOCALIZATION SIGNAL; PHASE PEPTIDE-SYNTHESIS; UNNATURAL AMINO-ACIDS; ROUS-SARCOMA-VIRUS; MEMBRANE-BINDING; NONDIVIDING CELLS; ESCHERICHIA-COLI; GENETIC-CODE; GAG-PROTEIN AB The HIV-1 matrix protein p17, excised proteolytically from the IN terminus of the Gag polyprotein, forms a protective shell attached to the inner surface of the plasma membrane of the virus. During the late stages of the HIV-1 replication cycle, the N-terminally myristoylated p17 domain targets the Gag polyprotein to the host-cell membrane for particle assembly. In the early stages of HIV-1 replication, however, some p17 molecules dissociate from the viral membrane to direct the preintegration complex to the host-cell nucleus. These two opposing targeting functions of p17 require that the protein be capable of reversible membrane interaction. It is postulated that a significant structural change in p17 triggered by proteolytic cleavage of the Gag polyprotein sequesters the N-terminal myristoyl group, resulting in a weaker membrane binding by the matrix protein than the Gag precursor. To test this "myristoyl switch" hypothesis, we obtained highly purified synthetic HIV-1 p17 of 131 amino acid residues and its N-myristoylated form in large quantity. Both forms of p17 were characterized by circular dichroism spectroscopy, protein chemical denaturation, and analytical centrifugal sedimentation. Our results indicate that although N-myristoylation causes no spectroscopically discernible conformational change in p17, it stabilizes the protein by 1 kcal/mol and promotes protein trimerization in solution. These findings support the premise that the myristoyl switch in p17 is triggered not by a structural change associated with proteolysis, but rather by the destabilization of oligomeric structures of membrane-bound p17 in the absence of downstream Gag subdomains. C1 Univ Maryland, Inst Human Virol, Inst Biotechnol, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. NCI, Macromol Assembly Stuct & Cell Signalling Sect, Ft Detrick, MD 21702 USA. RP Lu, WY (reprint author), Univ Maryland, Inst Human Virol, Inst Biotechnol, 725 W Lombard St, Baltimore, MD 21201 USA. EM luw@umbi.umd.edu RI Lu, Wuyuan/B-2268-2010; Fitzmaurice, Richard/C-1508-2008; Ericksen, Bryan/F-9047-2012; OI Ericksen, Bryan/0000-0002-8016-8289 FU NIAID NIH HHS [AI056264, AI058939, R21 AI056264, R21 AI058939] NR 67 TC 33 Z9 33 U1 0 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 AUG 10 PY 2004 VL 101 IS 32 BP 11587 EP 11592 DI 10.1073/pnas.0404649101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 845WT UT WOS:000223276700013 PM 15280532 ER PT J AU Yoon, S Govind, CK Qiu, HF Kim, SJ Dong, JS Hinnebusch, AG AF Yoon, S Govind, CK Qiu, HF Kim, SJ Dong, JS Hinnebusch, AG TI Recruitment of the ArgR/Mcm1p repressor is stimulated by the activator Gcn4p: A self-checking activation mechanism SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MADS-BOX PROTEINS; RNA-POLYMERASE-II; SACCHAROMYCES-CEREVISIAE; ARGININE METABOLISM; TRANSCRIPTIONAL ACTIVATION; GENE-EXPRESSION; YEAST; COMPLEX; SEQUENCE; COACTIVATORS AB Transcription of the arginine biosynthetic gene ARG1 is repressed by the ArgR/Mcm1p complex in arginine-replete cells and activated by Gcn4p, a transcription factor induced by starvation for any amino acid. We show that all four subunits of the arginine repressor are recruited to ARG1 by Gcn4p in cells replete with arginine but starved for isoleucine/valine. None of these proteins is recruited to the Gcn4p target genes ARG4 and SNZ1, which are not regulated by ArgR/Mcm1p. Mcm1p and Arg80p were found in a soluble complex lacking Arg81p and Arg82p, and both Mcm1p and Arg80p were efficiently recruited to ARG1 in wild-type cells in the presence or absence of exogenous arginine, and also in arg81Delta cells. By contrast, the recruitment of Arg81p and Arg82p was stimulated by exogenous arginine. These findings suggest that Gcn4p constitutively recruits an Mcmlp/Arg80p heterodimer and that efficient assembly of a functional repressor also containing Arg81p and Arg82p occurs only in arginine excess. By recruiting an arginine-regulated repressor, Gcn4p can precisely modulate its activation function at ARG1 according to the availability of arginine. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bldg 6A Room 81A-13, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov NR 25 TC 20 Z9 20 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 AUG 10 PY 2004 VL 101 IS 32 BP 11713 EP 11718 DI 10.1073/pnas.0404652101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 845WT UT WOS:000223276700035 PM 15289616 ER PT J AU Calin, GA Liu, CG Sevignani, C Ferracin, M Felli, N Dumitru, CD Shimizu, M Cimmino, A Zupo, S Dono, M Dell'Aquila, ML Alder, H Rassenti, L Kipps, TJ Bullrich, F Negrini, M Croce, CM AF Calin, GA Liu, CG Sevignani, C Ferracin, M Felli, N Dumitru, CD Shimizu, M Cimmino, A Zupo, S Dono, M Dell'Aquila, ML Alder, H Rassenti, L Kipps, TJ Bullrich, F Negrini, M Croce, CM TI MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID EXPRESSION; IDENTIFICATION; GENES; ASSOCIATION; LYMPHOMA; SURVIVAL; CANCERS; TARGETS; TISSUE; MOUSE AB Little is known about the expression levels or function of microRNAs (miRNAs) in normal and neoplastic cells, although it is becoming clear that miRNAs play important roles in the regulation of gene expression during development [Ambros, V. (2003) Cell 113, 673-676; McManus, M. T. (2003) Semin. Cancer Biol. 13, 253-258]. We now report the genomewide expression profiling of miRNAs in human B cell chronic lymphocytic leukemia (CLL) by using a microarray containing hundreds of human precursor and mature miRNA oligonucleotide probes. This approach allowed us to identify significant differences in miRNome expression between CLL samples and normal CD5+ B cells; data were confirmed by Northern blot analyses and real-time RT-PCR. At least two distinct clusters of CLL samples can be identified that were associated with the presence or absence of Zap-70 expression, a predictor of early disease progression. Two miRNA signatures were associated with the presence or absence of mutations in the expressed Ig variable-region genes or with deletions at 13q14, respectively. These data suggest that miRNA expression patterns have relevance to the biological and clinical behavior of this leukemia. C1 Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19104 USA. Univ Ferrara, Dept Expt & Diagnost Med, I-44700 Ferrara, Italy. Univ Ferrara, Interdepartmental Ctr Canc Res, I-44700 Ferrara, Italy. Ist Super Sanita, Dept Hematol Oncol & Mol Med, I-00161 Rome, Italy. Natl Canc Inst, I-16123 Genoa, Italy. Osped Civile La Spezia, Lab Anal Clin, I-19126 La Spezia, Italy. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Lymphocyt Leukemia Res Consortium, La Jolla, CA 92093 USA. RP Croce, CM (reprint author), Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19104 USA. EM c-croce@mail.jci.tju.edu RI felli, nadia/G-2088-2012; Negrini, Massimo/J-2377-2016; Ferracin, Manuela/K-2097-2016 OI Negrini, Massimo/0000-0002-0007-1920; Ferracin, Manuela/0000-0002-1595-6887 FU NCI NIH HHS [CA076259, P01 CA076259, P01 CA081534, P01-CA81534] NR 27 TC 862 Z9 949 U1 3 U2 57 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 AUG 10 PY 2004 VL 101 IS 32 BP 11755 EP 11760 DI 10.1073/pnas.0404432101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 845WT UT WOS:000223276700042 PM 15284443 ER PT J AU Keay, SK Szekely, Z Conrads, TP Veenstra, TD Barchi, JJ Zhang, CO Koch, KR Michejda, CJ AF Keay, SK Szekely, Z Conrads, TP Veenstra, TD Barchi, JJ Zhang, CO Koch, KR Michejda, CJ TI An antiproliferative factor from interstitial cystitis patients is a frizzled 8 protein-related sialoglycopeptide SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE frizzled-related peptide; growth inhibitor; bladder epithelium ID BLADDER EPITHELIAL-CELLS; GLYCOPEPTIDE BUILDING-BLOCKS; EPIDERMAL GROWTH-FACTOR; GENE-EXPRESSION; URINE; PURIFICATION; INHIBITOR; FEATURES; RECEPTOR AB Approximately 1 million people in the United States suffer from interstitial cystitis, a chronic painful urinary bladder disorder characterized by thinning or ulceration of the bladder epithelial lining; its etiology is unknown. We have identified a glycosylated frizzled-related peptide inhibitor of cell proliferation that is secreted specifically by bladder epithelial cells from patients with this disorder. This antiproliferative factor (APF) profoundly inhibits bladder cell proliferation by means of regulation of cell adhesion protein and growth factor production. The structure of APF was deduced by using ion trap mass spectrometry (MS), enzymatic digestion, lectin affinity chromatography, and total synthesis, and confirmed by coelution of native and synthetic APF derivatives on microcapillary reversed-phase liquid chromatography (muRPLC)/MS. APF was determined to be an acidic, heat-stable sialoglycopeptide whose peptide chain has 100% homology to the putative sixth transmembrane domain of frizzled 8. Both synthetic and native APF had identical biological activity in normal bladder epithelial cells and T24 bladder cancer cells. Northern blot analysis indicated binding of a probe containing the sequence for the frizzled 8 segment with mRNA extracted from cells of patients with interstitial cystitis but not controls. APF is therefore a frizzled-related peptide growth inhibitor shown to contain exclusively a transmembrane segment of a frizzled protein and is a potential biomarker for interstitial cystitis. C1 Vet Affairs Maryland Hlth Care Syst, Res Serv, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21201 USA. NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA. SAIC, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. SAIC, Canc Res Ctr, Mol Aspects Drug Design Sect, Frederick, MD 21702 USA. RP Keay, SK (reprint author), Vet Affairs Med Ctr, Room 3B-184,10 N Greene St, Baltimore, MD 21201 USA. EM skeay@medicine.umaryland.edu RI Barchi Jr., Joseph/N-3784-2014 FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NIDDK NIH HHS [R01 DK052596, R01 DK52596] NR 23 TC 104 Z9 105 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 AUG 10 PY 2004 VL 101 IS 32 BP 11803 EP 11808 DI 10.1073/pnas.0404509101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 845WT UT WOS:000223276700050 PM 15282374 ER PT J AU Beres, SB Sylva, GL Sturdevant, DE Granville, CN Liu, MY Ricklefs, SM Whitney, AR Parkins, LD Hoe, NP Adams, GJ Low, DE DeLeo, FR McGeer, A Musser, JM AF Beres, SB Sylva, GL Sturdevant, DE Granville, CN Liu, MY Ricklefs, SM Whitney, AR Parkins, LD Hoe, NP Adams, GJ Low, DE DeLeo, FR McGeer, A Musser, JM TI Genome-wide molecular dissection of serotype M3 group A Streptococcus strains causing two epidemics of invasive infections SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE population genetics; evolution; phage; subdone ID FIELD GEL-ELECTROPHORESIS; M-PROTEIN; PYOGENES; SEQUENCE; EXPRESSION; COMPLEMENT; DIVERSITY; INSIGHTS; ONTARIO; SIZE AB Molecular factors that contribute to the emergence of new virulent bacterial subdones and epidemics are poorly understood. We hypothesized that analysis of a population-based strain sample of serotype M3 group A Streptococcus (GAS) recovered from patients with invasive infection by using genome-wide investigative methods would provide new insight into this fundamental infectious disease problem. Serotype M3 GAS strains (n = 255) cultured from patients in Ontario, Canada, over 11 years and representing two distinct infection peaks were studied. Genetic diversity was indexed by pulsed-field gel electrophoresis, DNA-DNA microarray, whole-genome PCR scanning, prophage genotyping, targeted gene sequencing, and single-nucleotide polymorphism genotyping. All variation in gene content was attributable to acquisition or loss of prophages, a molecular process that generated unique combinations of proven or putative virulence genes. Distinct serotype M3 genotypes experienced rapid population expansion and caused infections that differed significantly in character and severity. Molecular genetic analysis, combined with immunologic studies, implicated a 4-aa duplication in the extreme N terminus of M protein as a factor contributing to an epidemic wave of serotype M3 invasive infections. This finding has implications for GAS vaccine research. Genome-wide analysis of population-based strain samples cultured from clinically well defined patients is crucial for understanding the molecular events underlying bacterial epidemics. 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 77030 USA. Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. RP Musser, JM (reprint author), NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM musser@bmc.tmc.edu RI Low, Donald/B-1726-2012; mcgeer, allison /H-7747-2014; OI mcgeer, allison /0000-0001-5647-6137; DeLeo, Frank/0000-0003-3150-2516 NR 42 TC 87 Z9 91 U1 2 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 AUG 10 PY 2004 VL 101 IS 32 BP 11833 EP 11838 DI 10.1073/pnas.0404163101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 845WT UT WOS:000223276700055 PM 15282372 ER PT J AU Foster, JA Puchowicz, MJ McIntyre, DC Herkenham, M AF Foster, JA Puchowicz, MJ McIntyre, DC Herkenham, M TI Activin mRNA induced during amygdala kindling shows a spatiotemporal progression that tracks the spread of seizures SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE amygdala kindling; seizures; activin; in situ hybridization; epilepsy; neurotrophins; brain-derived neurotrophic factor ID LIMBIC STATUS EPILEPTICUS; IMMEDIATE-EARLY GENE; RAT-BRAIN; TGF-BETA; PERIRHINAL CORTEX; C-14 2-DEOXYGLUCOSE; FUNCTIONAL-ANATOMY; KINASE RECEPTORS; PIRIFORM CORTEX; MOTOR SEIZURE AB The progressive development of seizures in rats by amygdala kindling, which models temporal lobe epilepsy, allows the study of molecular regulators of enduring synaptic changes. Neurotrophins play important roles in synaptic plasticity and neuroprotection. Activin, a member of the transforming growth factor-beta superfamily of growth and differentiation factors, has recently been added to the list of candidate synaptic regulators. We mapped the induction of activin betaA mRNA in amygdala and cortex at several stages of seizure development. Strong induction, measured 2 hours after the first stage 2 (partial) seizure, appeared in neurons of the ipsilateral amygdala (confined to the lateral, basal, and posterior cortical nuclei) and insular, piriform, orbital, and infralimbic cortices. Activin betaA mRNA induction, after the first stage 5 (generalized) seizure, had spread to the contralateral amygdala (same nuclear distribution) and cortex, and the induced labeling covered much of the convexity of neocortex as well as piriform, perirhinal, and entorhinal cortices in a nearly bilaterally symmetrical pattern. This pattern had filled in by the sixth stage 5 seizure. Induced labeling in cortical neurons was confined mainly to layer II. A similar temporal and spatial pattern of increased mRNA expression of brain-derived neurotrophic factor (BDNF) was found in the amygdala and cortex. Activin betaA and BDNF expression patterns were similar at 1, 2, and 6 hours after the last seizure, subsiding at 24 hours; in contrast, c-fos mRNA induction appeared only at 1 hour throughout cortex and then subsided. In double-label studies, activin betaA mRNA-positive neurons were also BDNF mRNA positive, and they did not colocalize with GAD67 mRNA (a marker of gamma-aminobutyric acidergic neurons). The data suggest that activin and BDNF transcriptional activities accurately mark excitatory neurons participating in seizure-induced synaptic alterations and may contribute to the enduring changes that underlie the kindled state. Published 2004 Wiley-Liss, Inc. C1 NIMH, Funct Neuroanat Sect, NIH, US Dept HHS, Bethesda, MD 20892 USA. Carleton Univ, Dept Psychol, Ottawa, ON K1S 5B6, Canada. RP Herkenham, M (reprint author), NIMH, Funct Neuroanat Sect, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM herkenh@mail.nih.gov OI Herkenham, Miles/0000-0003-2228-4238 NR 70 TC 25 Z9 25 U1 0 U2 1 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 AUG 9 PY 2004 VL 476 IS 1 BP 91 EP 102 DI 10.1002/cne.20197 PG 12 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 835LU UT WOS:000222485600007 PM 15236469 ER PT J AU Barker, PE Wang, W Wagner, PD Pinsky, P AF Barker, PE Wang, W Wagner, PD Pinsky, P TI Inter-rater agreement on chromosome 5 breakage in FISH-based mutagen sensitivity assays (MSAs) SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE karyotype; mutagen sensitivity; cancer susceptibility; bleomycin; FISH; inter-observer validation ID LUNG-CANCER; DNA-REPAIR; BLEOMYCIN; LYMPHOCYTES; POPULATION; ABERRATIONS; SUSCEPTIBILITY; INSTABILITY; EXPOSURE; MARKER AB In chromosome breakage assays, validated, universal criteria for selection of cells and classification of chromosome aberrations may enhance their utility for cancer susceptibility screening. To standardize a fluorescence in situ hybridization (FISH) modification of the mutagen sensitivity assay (MSA), scoring criteria were evaluated by web-based validation. Two hundred digital FISH images were assigned random identification numbers. With this set of images, criteria for inclusion of cells and measurement of the frequency of abnormal cells were evaluated by eight observers, all of whom had five or more years of experience. Observers included doctoral and MS/BS level cytogeneticists, and were drawn from a randomized pool of 54 volunteers. Questions addressed were: (1) how uniformly were criteria applied to analysis of a standard digital FISH image set and (2) did concordance vary with educational level? These data suggest inter-rater agreement within a factor of 2 for average breakage frequency, but revealed greater variability in cell selection. These results aid in estimating the components of assay variance due to definitions, technical parameters and biological variables. Published by Elsevier B.V. C1 NIST, Chem Sci & Technol Lab, DNA Technol Grp, Div Biotechnol,NCI Biomarkers Validat Project, Gaithersburg, MD 20899 USA. NCI, Div Canc Prevent, Canc Biomarkers Res Grp, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Early Detect Res Branch, Bethesda, MD 20892 USA. RP Barker, PE (reprint author), NIST, Chem Sci & Technol Lab, DNA Technol Grp, Div Biotechnol,NCI Biomarkers Validat Project, Gaithersburg, MD 20899 USA. EM peter.barker@nist.gov FU NCI NIH HHS [Y1-CN-0103-01] NR 34 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD AUG 8 PY 2004 VL 562 IS 1-2 BP 133 EP 142 DI 10.1016/j.mrgentox.2004.06.001 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 848BT UT WOS:000223442800012 PM 15279836 ER PT J AU Murphy, BR Blaney, JE Whitehead, SS AF Murphy, BR Blaney, JE Whitehead, SS TI Arguments for live flavivirus vaccines SO LANCET LA English DT Letter ID DENGUE VIRUS TYPE-4 C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Murphy, BR (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6517,50 South Dr, Bethesda, MD 20892 USA. EM bmurphy@niaid.nih.gov NR 5 TC 20 Z9 20 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD AUG 7 PY 2004 VL 364 IS 9433 BP 499 EP 500 DI 10.1016/S0140-6736(04)16801-3 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 844BS UT WOS:000223132700023 PM 15302187 ER PT J AU Rosen, TC Yoshida, S Kirk, KL Haufe, G AF Rosen, TC Yoshida, S Kirk, KL Haufe, G TI Fluorinated phenylcyclopropylamines as inhibitors of monoamine oxidases SO CHEMBIOCHEM LA English DT Review DE aminocyclopropanes; fluorine; inhibitors; oxidases; structure-activity relationships ID SENSITIVE AMINE OXIDASE; OXIDATIVE HALF-REACTION; CRYSTAL-STRUCTURES; TOPA-QUINONE; SELECTIVE INHIBITORS; DEVELOPMENT SETTINGS; BENZYLAMINE ANALOGS; ESTIMATE SOLUBILITY; ESCHERICHIA-COLI; TYRAMINE OXIDASE C1 Univ Munster, Inst Organ Chem, D-48149 Munster, Germany. NIDDKD, Bioorgan Chem Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Haufe, G (reprint author), Univ Munster, Inst Organ Chem, Corrensstr 40, D-48149 Munster, Germany. EM houfe@uni-muenster.de NR 96 TC 25 Z9 25 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI Chembiochem PD AUG 6 PY 2004 VL 5 IS 8 BP 1033 EP 1043 DI 10.1002/cbic.200400053 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 846BY UT WOS:000223291000001 PM 15300824 ER PT J AU Zorov, DB Kobrinsky, E Juhaszova, M Sollott, SJ AF Zorov, DB Kobrinsky, E Juhaszova, M Sollott, SJ TI Examining intracellular organelle function using fluorescent probes - From animalcules to quantum dots SO CIRCULATION RESEARCH LA English DT Review DE microscopy; calcium; redox; mitochondria; fluorescent proteins ID MITOCHONDRIAL PERMEABILITY TRANSITION; NF-KAPPA-B; TARGETED RECOMBINANT AEQUORIN; RESONANCE ENERGY-TRANSFER; PROTEIN-KINASE-C; ENDOPLASMIC-RETICULUM; LIVING CELLS; NITRIC-OXIDE; INTACT-CELLS; CA2+ CONCENTRATION AB Fluorescence microscopy imaging has become one of the most useful techniques to assess the activity of individual cells, subcellular trafficking of signals to and between organelles, and to appreciate how organelle function is regulated. The past 2 decades have seen a tremendous advance in the rational design and development in the nature and selectivity of probes to serve as reporters of the intracellular environment in live cells. These probes range from small organic fluorescent molecules to fluorescent biomolecules and photoproteins ingeniously engineered to follow signaling traffic, sense ionic and nonionic second messengers, and report various kinase activities. These probes, together with recent advances in imaging technology, have enabled significantly enhanced spatial and temporal resolution. This review summarizes some of these developments and their applications to assess intracellular organelle function. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. NIA, Clin Invest Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. AN Belozersky Inst Physicochem Biol, Moscow, Russia. RP Sollott, SJ (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Box 13,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM sollotts@grc.nia.nih.gov NR 108 TC 49 Z9 56 U1 4 U2 29 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 AUG 6 PY 2004 VL 95 IS 3 BP 239 EP 252 DI 10.1161/01.RES.0000137875.42385.8e PG 14 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 843VX UT WOS:000223116000005 PM 15297386 ER PT J AU Kim-Shapiro, DB Patel, RP Schechter, AN Gladwin, MT Cannon, RO Hogg, N AF Kim-Shapiro, DB Patel, RP Schechter, AN Gladwin, MT Cannon, RO Hogg, N TI How do red blood cells dilate blood vessels? - Reply SO CIRCULATION RESEARCH LA English DT Letter ID NITRIC-OXIDE; HEMOGLOBIN C1 Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. RP Kim-Shapiro, DB (reprint author), Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. EM shapiro@wfu.edu; mgladwin@nih.gov NR 8 TC 1 Z9 1 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 6 PY 2004 VL 95 IS 3 BP E10 EP E10 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 843VX UT WOS:000223116000016 PM 15297387 ER PT J AU Chae, C Sharma, S Hoskins, JR Wickner, S AF Chae, C Sharma, S Hoskins, JR Wickner, S TI CbpA, a DnaJ homolog, is a DnaK co-chaperone, and its activity is modulated by CbpM SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK PROTEINS; ESCHERICHIA-COLI; MOLECULAR CHAPERONE; THERMUS-THERMOPHILUS; FUNCTIONAL CYCLE; REPLICATION; BINDING; SYSTEM; HSP70; GRPE AB The DnaK chaperone system, consisting of DnaK, DnaJ, and GrpE, remodels and refolds proteins during both normal growth and stress conditions. CbpA, one of several DnaJ analogs in Escherichia coli, is known to function as a multicopy suppressor for dnaJ mutations and to bind nonspecifically to DNA and preferentially to curved DNA. We found that CbpA functions as a DnaJ-like co-chaperone in vitro. CbpA acted in an ATP-dependent reaction with DnaK and GrpE to remodel inactive dimers of plasmid P1 RepA into monomers active in P1 DNA binding. Additionally, CbpA participated with DnaK in an ATP-dependent reaction to prevent aggregation of denatured rhodanese. The cbpA gene is in an operon with an open reading frame, yccD, which encodes a protein that has some homology to DafA of Thermus thermophilus. DafA is a protein required for the assembly of ring-like particles that contain trimers each of T. thermophilus DnaK, DnaJ, and DafA. The E. coli YccD was isolated because of its potential functional relationship to CbpA. Purified YccD specifically inhibited both the co-chaperone activity and the DNA binding activity of CbpA, suggesting that YccD modulates the activity of CbpA. We named the product of the yccD gene CbpM for "CbpA modulator." C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Rm 5144,37 Convent Dr,MSC37-4264, Bethesda, MD 20892 USA. EM suewick@helix.nih.gov NR 23 TC 27 Z9 29 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 AUG 6 PY 2004 VL 279 IS 32 BP 33147 EP 33153 DI 10.1074/jbc.M404862200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 842YD UT WOS:000223039700017 PM 15184371 ER PT J AU Seko, Y Azmi, H Fariss, R Ragheb, JA AF Seko, Y Azmi, H Fariss, R Ragheb, JA TI Selective cytoplasmic translocation of HuR and site-specific binding to the interleukin-2 mRNA are not sufficient for CD28-mediated stabilization of the mRNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID T-CELL-ACTIVATION; 3' UNTRANSLATED REGION; AU-RICH ELEMENTS; PROTEIN HUR; 3'-UNTRANSLATED REGION; SIGNAL INTEGRATION; CLONAL ANERGY; ELAV PROTEIN; GM-CSF; STABILITY AB The interleukin-2 mRNA is a labile transcript containing AU-rich elements that is transiently stabilized by CD28 receptor signaling. For a number of protooncogenes and cytokines, the HuR protein has been shown to avidly bind the AU-rich elements that confer instability upon their mRNAs. HuR was originally thought to participate in mRNA degradation but subsequent studies indicated that it actually functions to stabilize mRNA. Binding of HuR to the mouse interleukin-2 mRNA has not been studied. We tested if HuR binds the interleukin-2 mRNA and whether such binding is related to CD28-mediated stabilization of the mRNA. First, we confirm that T cell receptor signaling, which is sufficient to induce interleukin-2 transcription, also triggers translocation of HuR from the nucleus to the cytoplasm. Interestingly, T cell receptor-triggered translocation is selective as heterogeneous nuclear ribonucleoprotein A1 does not shuttle under the same conditions. Engagement of both the T cell and CD28 receptors, which enhance interleukin-2 transcription and induce stabilization of the mRNA, did not further increase the level of cytoplasmic HuR. Using an in vitro binding assay, we demonstrate that HuR binds the interleukin-2 mRNA and localize binding to a sequence downstream of the single nonameric AU-rich element that is present in its 3'-untranslated region. However, we conclude that HuR binding to the interleukin-2 mRNA, both in vitro and in vivo, is not associated with alterations in mRNA stability. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Biol Imaging Core, NIH, Bethesda, MD 20892 USA. RP Ragheb, JA (reprint author), Bldg 10,Rm 10N112,10 Ctr Dr,MSC-1857, Bethesda, MD 20892 USA. EM jr50b@nih.gov NR 54 TC 22 Z9 23 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 AUG 6 PY 2004 VL 279 IS 32 BP 33359 EP 33367 DI 10.1074/jbc.M312306200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 842YD UT WOS:000223039700043 PM 15020598 ER PT J AU Oliva, JL Zarich, N Martinez, N Jorge, R Castrillo, A Azanedo, M Garcia-Vargas, S Gutierrez-Eisman, S Juarranz, A Bosca, L Gutkind, JS Rojas, JM AF Oliva, JL Zarich, N Martinez, N Jorge, R Castrillo, A Azanedo, M Garcia-Vargas, S Gutierrez-Eisman, S Juarranz, A Bosca, L Gutkind, JS Rojas, JM TI The P34G mutation reduces the transforming activity of K-ras and N-ras in NIH 3T3 cells but not of H-ras SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOINOSITIDE 3-OH KINASE; EXCHANGE FACTORS; PROTEIN-KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; ENDOPLASMIC-RETICULUM; BINDING PROTEIN; ACTIVATE RAF-1; GROWTH; MEMBRANE; PATHWAY AB Ras proteins (H-, N-, and K-Ras) operate as molecular switches in signal transduction cascades controlling cell proliferation, differentiation, or apoptosis. The interaction of Ras with its effectors is mediated by the effector-binding loop, but different data about Ras location to plasma membrane subdomains and new roles for some docking/scaffold proteins point to signaling specificities of the different Ras proteins. To investigate the molecular mechanisms for these specificities, we compared an effector loop mutation (P34G) of three Ras isoforms ( H-, N-, and K-Ras4B) for their biological and biochemical properties. Although this mutation diminished the capacity of Ras proteins to activate the Raf/ERK and the phosphatidylinositol 3-kinase/AKT pathways, the H- Ras V12G34 mutant retained the ability to cause morphological transformation of NIH 3T3 fibroblasts, whereas both the N- Ras V12G34 and the K-Ras4B V12G34 mutants were defective in this biological activity. On the other hand, although both the N- Ras V12G34 and the K-Ras4B V12G34 mutants failed to promote activation of the Ral-GDS/Ral A/PLD and the Ras/Rac pathways, the H- Ras V12G34 mutant retained the ability to activate these signaling pathways. Interestingly, the P34G mutation reduced specifically the N- Ras and K-Ras4B in vitro binding affinity to Ral-GDS, but not in the case of H- Ras. Thus, independently of Ras location to membrane subdomains, there are marked differences among Ras proteins in the sensitivity to an identical mutation ( P34G) affecting the highly conserved effector-binding loop. C1 Inst Salud Carlos III, Ctr Nacl Microbiol, Unidad Biol Celular, Madrid 28220, Spain. Univ Complutense, Fac Farm, Ctr Mixto CSIC UCM, Inst Bioquim, E-28040 Madrid, Spain. Univ Autonoma Madrid, Fac Biol, Dept Biol, E-28049 Madrid, Spain. NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Rojas, JM (reprint author), Inst Salud Carlos III, Ctr Nacl Microbiol, Unidad Biol Celular, Carretera Majadohonda Pozuelo,Km 2, Madrid 28220, Spain. EM jmrojas@isciii.es RI Gutkind, J. Silvio/A-1053-2009; Bosca, Lisardo/A-2059-2008; Juarranz, Angeles/L-2446-2013 OI Bosca, Lisardo/0000-0002-0253-5469; Juarranz, Angeles/0000-0002-6574-2887 NR 42 TC 23 Z9 24 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 AUG 6 PY 2004 VL 279 IS 32 BP 33480 EP 33491 DI 10.1074/jbc.M404058200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 842YD UT WOS:000223039700057 PM 15181015 ER PT J AU Miller, SLH Malotky, E O'Bryan, JP AF Miller, SLH Malotky, E O'Bryan, JP TI Analysis of the role of ubiquitin-interacting motifs in ubiquitin binding and ubiquitylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID 26 S PROTEASOME; DEUBIQUITINATING ENZYME; MULTIUBIQUITIN CHAINS; PROTEIN-DEGRADATION; FAT FACETS; IN-VIVO; DOMAIN; HRS; RECEPTOR; SUBUNIT AB The ubiquitin-interacting motif (UIM) is a short peptide motif with the dual function of binding ubiquitin and promoting ubiquitylation. This motif is conserved throughout eukaryotes and is present in numerous proteins involved in a wide variety of cellular processes including endocytosis, protein trafficking, and signal transduction. We previously reported that the UIMs of epsin were both necessary and sufficient for its ubiquitylation. In this study, we found that many, but not all, UIM-containing proteins were ubiquitylated. When expressed as chimeric fusion proteins, most UIMs promoted ubiquitylation of the chimera. In contrast to previous studies, we found that UIMs do not exclusively promote monoubiquitylation but rather a mixture of mono-, multi-, and polyubiquitylation. However, UIM-dependent polyubiquitylation does not lead to degradation of the modified protein. UIMs also bind polyubiquitin chains of varying lengths and to different degrees, and this activity is required for UIM-dependent ubiquitylation. Mutational analysis of the UIM revealed specific amino acids that are important for both polyubiquitin binding and ubiquitin conjugation. Finally we provide evidence that UIM-dependent ubiquitylation inhibits the interaction of UIM-containing proteins with other ubiquitylated cellular proteins. Our results suggest a new model for the ubiquitylation of UIM-containing proteins. C1 NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Med, Dept Biomed Engn, Chapel Hill, NC 27599 USA. RP O'Bryan, JP (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Bldg Rm 101-F336,MD F3-06,POB 12233, Res Triangle Pk, NC 27709 USA. EM obryan@niehs.nih.gov NR 42 TC 72 Z9 75 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 AUG 6 PY 2004 VL 279 IS 32 BP 33528 EP 33537 DI 10.1074/jbc.M313097200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 842YD UT WOS:000223039700061 PM 15155768 ER PT J AU Khurana, B Kristie, TM AF Khurana, B Kristie, TM TI A protein sequestering system reveals control of cellular programs by the transcriptional coactivator HCF-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HERPES-SIMPLEX-VIRUS; LEUCINE-ZIPPER PROTEIN; DNA-DAMAGE; C1 HCF; VP16-INDUCED COMPLEX; ATF3 INDUCTION; HOMEO DOMAIN; VP16; PROLIFERATION; FAMILY AB The mammalian transcriptional coactivator HCF-1 is a critical component of the multiprotein herpes simplex virus immediate early gene enhancer core complex. The protein has also been implicated in basic cellular processes such as cell-cycle progression, transcriptional coactivation, and mRNA processing. Functions have been attributed to HCF-1 primarily from analyses of protein-protein interactions and from the cell-cycle-arrested phenotype of an HCF-1 temperature-sensitive mutant. However, neither the mechanisms involved nor specific cellular transcriptional targets have been identified. As the protein is essential for cell viability and proliferation, a genetic system was developed to specifically sequester the nuclear factor in the cell cytoplasm in a regulated manner. This approach exhibits no significant cell toxicity yet clearly demonstrates the requirement of available nuclear HCF-1 for herpes simplex virus immediate early gene expression during productive infection. Additionally, cellular transcriptional events were identified that contribute to understanding the functions ascribed to the protein and implicate the protein in events that impact the regulation of critical cellular processes. C1 NIH, Viral Dis Lab, Bethesda, MD 20892 USA. RP Kristie, TM (reprint author), NIH, Viral Dis Lab, Bldg 4,Rm 131,4 Ctr Dr, Bethesda, MD 20892 USA. EM thomas_Kristie@nih.gov NR 59 TC 15 Z9 17 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 AUG 6 PY 2004 VL 279 IS 32 BP 33673 EP 33683 DI 10.1074/jbc.M401255200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 842YD UT WOS:000223039700077 PM 15190068 ER PT J AU Dimcheff, DE Faasse, MA McAtee, FJ Portis, JL AF Dimcheff, DE Faasse, MA McAtee, FJ Portis, JL TI Endoplasmic reticulum (ER) stress induced by a neurovirulent mouse retrovirus is associated with prolonged BiP binding and retention of a viral protein in the ER SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MURINE LEUKEMIA-VIRUS; INDUCED SPONGIFORM NEURODEGENERATION; C RNA VIRUS; CELL-DEATH; ECOTROPIC RETROVIRUS; OXIDATIVE STRESS; GENE-EXPRESSION; PRION PROTEIN; WILD MICE; DISEASE AB Some murine retroviruses cause a spongiform neurodegenerative disease exhibiting pathology resembling that observed in transmissible spongiform encephalopathies. The neurovirulence of these "spongiogenic retroviruses" is determined by the sequence of their respective envelope proteins, although the mechanisms of neurotoxicity are not understood. We have studied a highly neurovirulent virus called FrCas(E) that causes a rapidly progressive form of this disease. Recently, transcriptional markers of endoplasmic reticulum ( ER) stress were detected during the early preclinical period in the brains of FrCas(E)-infected mice. In contrast, ER stress was not observed in mice infected with an avirulent virus, F43, which carries a different envelope gene, suggesting a role for ER stress in disease pathogenesis. Here we have examined in NIH 3T3 cells the cause of this cellular stress response. The envelope protein of F43 bound BiP, a major ER chaperone, transiently and was processed normally through the secretory pathway. In contrast, the envelope protein of FrCasE bound to BiP for a prolonged period, was retained in the ER, and was degraded by the proteasome. Furthermore, engagement of the FrCasE envelope protein by ER quality control pathways resulted in decreased steady-state levels of this protein, relative to that of F43, both in NIH 3T3 cells and in the brains of infected mice. Thus, the ER stress induced by FrCasE appears to be initiated by inefficient folding of its viral envelope protein, suggesting that the neurodegenerative disease caused by this virus represents a protein misfolding disorder. C1 NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Portis, JL (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM jportis@nih.gov OI Faasse, Mark/0000-0002-1524-7239 NR 57 TC 53 Z9 54 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 AUG 6 PY 2004 VL 279 IS 32 BP 33782 EP 33790 DI 10.1074/jbc.M403304200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 842YD UT WOS:000223039700087 PM 15178688 ER PT J AU Sordet, O Liao, ZY Liu, H Antony, S Stevens, EV Kohlhagen, G Fu, HQ Pommier, Y AF Sordet, O Liao, ZY Liu, H Antony, S Stevens, EV Kohlhagen, G Fu, HQ Pommier, Y TI Topoisomerase I-DNA complexes contribute to arsenic trioxide-induced apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; CLEAVAGE COMPLEXES; CELL APOPTOSIS; MULTIPLE-MYELOMA; MAMMALIAN-CELLS; DAMAGE; GLUTATHIONE; ACTIVATION; CAMPTOTHECIN; INDUCTION AB Topoisomerase I is an essential enzyme that relaxes DNA supercoiling by forming covalent DNA cleavage complexes, which are normally transient. Topoisomerase I-DNA complexes can be trapped by anticancer drugs (camptothecins) as well as by endogenous and exogenous DNA lesions. We show here that arsenic trioxide (a potent inducer of apoptosis that induces the intracellular accumulation of reactive oxygen species and targets mitochondria) induces cellular topoisomerase I cleavage complexes. Bcl-2 overexpression and quenching of reactive oxygen species, which prevent arsenic trioxide-induced apoptosis, also prevent the formation of topoisomerase I-DNA complexes, whereas enhancement of reactive oxygen species accumulation promotes these complexes. The caspase inhibitor, benzyloxycarbonyl-VAD partially prevents arsenic trioxide-induced topoisomerase I-DNA complexes and apoptosis, suggesting that activated caspases further maintain intracellular levels of reactive oxygen species that induce the formation of topoisomerase I-DNA complexes. Down-regulation of topoisomerase I expression decreases arsenic trioxide-induced apoptotic DNA fragmentation. Thus, we propose that arsenic trioxide induces topoisomerase I-DNA complexes that participate in chromatin fragmentation and programmed cell death during apoptosis. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 37,Rm 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Sordet, Olivier/M-3271-2014 NR 55 TC 32 Z9 35 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 AUG 6 PY 2004 VL 279 IS 32 BP 33968 EP 33975 DI 10.1074/jbc.M404620200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 842YD UT WOS:000223039700107 PM 15178684 ER PT J AU Hashimoto, A Przybyl, AK Linders, JTM Kodato, S Tian, XR Deschamps, JR George, C Flippen-Anderson, JL Jacobson, AE Rice, KC AF Hashimoto, A Przybyl, AK Linders, JTM Kodato, S Tian, XR Deschamps, JR George, C Flippen-Anderson, JL Jacobson, AE Rice, KC TI Probes for narcotic receptor-mediated phenomena. 33. Construction of a strained trans-5,6-ring system by displacement of a nitro-activated aromatic fluorine. Synthesis of the penultimate oxide-bridged phenylmorphans SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID HETEROATOM DIRECTED PHOTOARYLATION; ARYL VINYL ETHERS; ANTAGONISTS; MORPHINE; ISOMERS; 5-(META-HYDROXYPHENYL)MORPHAN; HEXAHYDRODIBENZOFURANS; PHOTOCYCLIZATION; STEREOCHEMISTRY; DERIVATIVES AB The synthesis of the ortho- and para-e isomers in the oxide-bridged 5-phenylmorphan series of rigid tetracyclic compounds was accomplished via rac-5-(2-fluoro-5-nitrophenyl)-2-methyl-2azabicyclo[3.3.1]nonan-9beta-ol ((+/-)-10), an intermediate containing an aromatic nitro-activated fluorine atom. The fluorine atom was used as the leaving group for the formation of the strained tetracyclic trans-fused 5,6-ring system in rac-(1alpha,4aalpha,9aalpha)-1,3,4,9a-tetrahydro-2-methyl-6-nitro-2H-1,4a-propanobenzofuro[2,3-c]pyridine ((+/-)-11), although preference for cis ring fusion during the formation of tricyclic tetra- and hexahydrodibenzofurans has been well-documented. Single-crystal X-ray crystallographic study of the desired para-e isomer ((+/-)-2), as well as of two intermediates in its synthesis, provided assurance of the correct structures. The e-isomers are among the last of the 12 oxide-bridged 5-phenylmorphans to be synthesized. We envisioned the syntheses of these rigid, tetracyclic compounds in order to determine the three-dimensional pattern of a ligand that would enable interaction with opioid receptors as agonists or antagonists. C1 NIDDKD, Med Chem Lab, US Dept HHS, NIH, Bethesda, MD 20892 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. RP Rice, KC (reprint author), NIDDKD, Med Chem Lab, US Dept HHS, NIH, Bldg 8,Room B1-23, Bethesda, MD 20892 USA. EM kr21f@nih.gov NR 28 TC 12 Z9 12 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD AUG 6 PY 2004 VL 69 IS 16 BP 5322 EP 5327 DI 10.1021/jo040159k PG 6 WC Chemistry, Organic SC Chemistry GA 842MJ UT WOS:000223008100021 PM 15287777 ER PT J AU LaBuda, CJ Usdin, TB AF LaBuda, CJ Usdin, TB TI Tuberoinfundibular peptide of 39 residues decreases pain-related affective behavior SO NEUROREPORT LA English DT Article DE affect; inflammation; behavior; hot-plate; neuropeptide; pain; parathyroid hormone 2 receptor; place escape/avoidance paradigm ID ESCAPE/AVOIDANCE BEHAVIOR; MECHANICAL HYPERALGESIA; NEUROPATHIC PAIN; NERVOUS-SYSTEM; RAT MODEL; MORPHINE; RECEPTOR; NEURONS; TIP39 AB Tuberoinfundibular peptide of 39 residues (TIP39) is a recently identified parathyroid hormone 2 receptor ligand. Their CNS distributions suggest potential involvement in neuroendocrine, limbic and sensory processing functions. Herein we investigate the analgesic and antinociceptive actions of brain delivery of TIP39 in adult male rats. Intracerebroventricular (i.c.v.) TIP39 did not change hot-plate paw withdrawal latency or formalin test behavioral responses. TIP39 partially reversed tactile withdrawal hypersensitivity following carageenan administration. In the place/escape avoidance paradigm (PEAP), which evaluates affective components of responses to noxious stimuli by presenting a choice between a naturally preferred environment paired with stimulation of a carrageenan sensitized paw and a less preferred environment paired with stimulation of a less sensitive paw, TIP39 decreased the apparent aversiveness of sensitive paw stimulation. Because acute sensory thresholds were unaffected by TIP39, and the effects of i.c.v. TIP39 were opposite in direction from previously described effects of intrathecal TIP39, this suggests that TIP39 may modulate an affective component of nociception within the brain. C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), NIMH, Genet Lab, Bldg 36,Rm 3D06,36 Convent Dr MSC 4094, Bethesda, MD 20892 USA. EM Usdint@mail.nih.gov NR 22 TC 17 Z9 17 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD AUG 6 PY 2004 VL 15 IS 11 BP 1779 EP 1782 DI 10.1097/01.wnr.0000134849.63755.15 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 871NQ UT WOS:000225140800018 PM 15257146 ER PT J AU Nettles, JH Li, HL Cornett, B Krahn, JM Snyder, JP Downing, KH AF Nettles, JH Li, HL Cornett, B Krahn, JM Snyder, JP Downing, KH TI The binding mode of epothilone A on alpha,beta-tubulin by electron crystallography SO SCIENCE LA English DT Article ID CONFORMATION-ACTIVITY RELATIONSHIPS; POLYKETIDE NATURAL-PRODUCTS; COMMON PHARMACOPHORE; BIOLOGICAL-ACTIVITY; BETA-TUBULIN; CHEMICAL-SYNTHESIS; DRUG-RESISTANCE; OVARIAN-CANCER; SIDE-CHAIN; TAXOL AB The structure of epothilone A, bound to alpha, beta-tubulin in zinc-stabilized sheets, was determined by a combination of electron crystallography at 2.89 angstrom resolution and nuclear magnetic resonance-based conformational analysis. The complex explains both the broad-based epothilone structure-activity relationship and the known mutational resistance pro. le. Comparison with Taxol shows that the longstanding expectation of a common pharmacophore is not met, because each ligand exploits the tubulin-binding pocket in a unique and independent manner. C1 Emory Univ, Dept Chem, Atlanta, GA 30322 USA. Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. RP Snyder, JP (reprint author), Emory Univ, Dept Chem, 1515 Pierce Dr, Atlanta, GA 30322 USA. EM snyder@euch4e.chem.emory.edu; khdowning@lbl.gov NR 32 TC 307 Z9 317 U1 1 U2 16 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 AUG 6 PY 2004 VL 305 IS 5685 BP 866 EP 869 DI 10.1126/science.1099190 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 843RT UT WOS:000223104900049 PM 15297674 ER PT J AU Khakoo, SI Thio, CL Martin, MP Brooks, CR Gao, XJ Astemborski, J Cheng, J Goedert, JJ Vlahov, D Hilgartner, M Cox, S Little, AM Alexander, GJ Cramp, ME O'Brien, SJ Rosenberg, WMC Thomas, DL Carrington, M AF Khakoo, SI Thio, CL Martin, MP Brooks, CR Gao, XJ Astemborski, J Cheng, J Goedert, JJ Vlahov, D Hilgartner, M Cox, S Little, AM Alexander, GJ Cramp, ME O'Brien, SJ Rosenberg, WMC Thomas, DL Carrington, M TI HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection SO SCIENCE LA English DT Article ID RECOGNITION; CYTOMEGALOVIRUS; ACTIVATION; ARTHRITIS; DIVERSITY; LOCUS; BLOOD AB Natural killer (NK) cells provide a central defense against viral infection by using inhibitory and activation receptors for major histocompatibility complex class I molecules as a means of controlling their activity. We show that genes encoding the inhibitory NK cell receptor KIR2DL3 and its human leukocyte antigen C group1 (HLA-C1) ligand directly influence resolution of hepatitis C virus (HCV) infection. This effect was observed in Caucasians and African Americans with expected low infectious doses of HCV but not in those with high-dose exposure, in whom the innate immune response is likely overwhelmed. The data strongly suggest that inhibitory NK cell interactions are important in determining antiviral immunity and that diminished inhibitory responses confer protection against HCV. C1 Univ Southampton, Div Infect Inflammat & Repair, Liver Grp, Southampton 5016 6YD, Hants, England. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21231 USA. NCI Federick, Basic Res Program, Sci Applicat Int Corp Frederick Inc, Lab Gen Divers, Frederick, MD 21702 USA. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. New York Acad Med, New York, NY 10029 USA. Cornell Med Ctr, New York Presbyterian Hosp, Dept Pediat, New York, NY 10021 USA. Royal Free Hosp, Anthony Nolan Res Inst, London NW3 2PF, England. Univ Cambridge, Dept Med, Cambridge CD2 2QQ, England. Derriford Hosp, Dept Gastroenterol, Plymouth PL6 8DH, Devon, England. NCI, Lab Gen Divers, Frederick, MD 21702 USA. RP Carrington, M (reprint author), Univ Southampton, Div Infect Inflammat & Repair, Liver Grp, Southampton 5016 6YD, Hants, England. EM sik@soton.ac.uk; carringt@ncifcrf.gov RI Yang, Chen/G-1379-2010; OI Khakoo, Salim/0000-0002-4057-9091; Rosenberg, William/0000-0002-2732-2304 FU NCI NIH HHS [N01-CP-33002, N01-CO-12400, N01-CP-01004]; NICHD NIH HHS [N01-HD-4-3200]; NIDA NIH HHS [DA00441, DA04334, DA13324] NR 23 TC 691 Z9 727 U1 4 U2 19 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 AUG 6 PY 2004 VL 305 IS 5685 BP 872 EP 874 DI 10.1126/science.1097670 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 843RT UT WOS:000223104900051 PM 15297676 ER PT J AU Mattson, MP AF Mattson, MP TI Pathways towards and away from Alzheimer's disease SO NATURE LA English DT Review ID AMYLOID PRECURSOR PROTEIN; PRESENILIN-1 TRANSGENIC MICE; CENTRAL-NERVOUS-SYSTEM; REVERSIBLE MEMORY LOSS; NECROSIS-FACTOR-ALPHA; A-BETA; SECRETASE CLEAVAGE; CELL-DEATH; NEURODEGENERATIVE DISORDERS; SYNAPTIC PLASTICITY AB Slowly but surely, Alzheimer's disease ( AD) patients lose their memory and their cognitive abilities, and even their personalities may change dramatically. These changes are due to the progressive dysfunction and death of nerve cells that are responsible for the storage and processing of information. Although drugs can temporarily improve memory, at present there are no treatments that can stop or reverse the inexorable neurodegenerative process. But rapid progress towards understanding the cellular and molecular alterations that are responsible for the neuron's demise may soon help in developing effective preventative and therapeutic strategies. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 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 FU Intramural NIH HHS [Z01 AG000312-07, Z01 AG000313-07, Z01 AG000314-07, Z01 AG000317-07, Z01 AG000331-01] NR 99 TC 1545 Z9 1641 U1 39 U2 402 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 5 PY 2004 VL 430 IS 7000 BP 631 EP 639 DI 10.1038/nature02621 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 843LM UT WOS:000223085400034 PM 15295589 ER PT J AU Wertz, IE O'Rourke, KM Zhou, HL Eby, M Aravind, L Seshagiri, S Wu, P Wiesmann, C Baker, R Boone, DL Ma, A Koonin, EV Dixit, VM AF Wertz, IE O'Rourke, KM Zhou, HL Eby, M Aravind, L Seshagiri, S Wu, P Wiesmann, C Baker, R Boone, DL Ma, A Koonin, EV Dixit, VM TI De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappa B signalling SO NATURE LA English DT Article ID ZINC-FINGER PROTEIN; TNF RECEPTOR; CELL-DEATH; DEUBIQUITINATING ENZYME; CYSTEINE PROTEASES; KINASE RIP; ACTIVATION; TRAF2; IKK; RECRUITMENT AB NF-kappaB transcription factors mediate the effects of pro-inflammatory cytokines such as tumour necrosis factor-alpha and interleukin-1beta(1). Failure to downregulate NF-kappaB transcriptional activity results in chronic inflammation and cell death, as observed in A20-deficient mice(2). A20 is a potent inhibitor of NF-kappaB signalling, but its mechanism of action is unknown(2). Here we show that A20 downregulates NF-kappaB signalling through the cooperative activity of its two ubiquitin-editing domains. The amino-terminal domain of A20, which is a de-ubiquitinating (DUB) enzyme of the OTU (ovarian tumour) family(3), removes lysine-63 (K63)-linked ubiquitin chains from receptor interacting protein ( RIP), an essential mediator of the proximal TNF receptor 1 (TNFR1) signalling complex(4,5). The carboxy-terminal domain of A20, composed of seven C-2/C-2 zinc fingers(6), then functions as a ubiquitin ligase by polyubiquitinating RIP with K48-linked ubiquitin chains, thereby targeting RIP for proteasomal degradation. Here we define a novel ubiquitin ligase domain and identify two sequential mechanisms by which A20 downregulates NF-kappaB signalling. We also provide an example of a protein containing separate ubiquitin ligase and DUB domains, both of which participate in mediating a distinct regulatory effect. C1 Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA. Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA. Genentech Inc, Dept Prot Engn, San Francisco, CA 94080 USA. Univ Calif Davis, Sch Med, Dept Biol Chem, Davis, CA 95616 USA. NCBI, Computat Biol Branch, Natl Lib Med, NIH, Bethesda, MD 20894 USA. Australian Natl Univ, John Curtin Sch Med Res, Div Mol Biosci, Canberra, ACT 2601, Australia. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. RP Dixit, VM (reprint author), Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA. EM dixit@gene.com RI dixit, vishva/A-4496-2012 OI dixit, vishva/0000-0001-6983-0326 NR 30 TC 986 Z9 1027 U1 4 U2 48 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 5 PY 2004 VL 430 IS 7000 BP 694 EP 699 DI 10.1038/nature02794 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 843LM UT WOS:000223085400050 PM 15258597 ER PT J AU Shen, J Cookson, MR AF Shen, J Cookson, MR TI Mitochondria and dopamine: New insights into recessive parkinsonism SO NEURON LA English DT Editorial Material ID CELL-DEATH; PROTEASOME INHIBITION; OXIDATIVE DAMAGE; ALPHA-SYNUCLEIN; DEFICIENT MICE; DISEASE; DYSFUNCTION; DROSOPHILA; MUTATIONS; DJ-1 AB Recessively inherited mutations in parkin, DJ-1, and PINK1 have recently been linked to familial forms of parkinsonism. These syndromes are often clinically indistinguishable from Parkinson's disease, as similar neuronal groups, notably dopaminergic neurons, are selectively affected. Studies of the functions of these gene products may provide insights into the pathogenic mechanisms underlying the selective degeneration of dopaminergic neurons. Emerging evidence that one or several of these genes play important roles in mitochondrial function and the dopaminergic system suggests that these events may be early steps of the pathophysiological changes of the disease. This review will summarize recent advances in our understanding of these gene products, with emphasis on the surprising convergence of their functions. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Neurosci Program,Ctr Neurol Dis, Boston, MA 02115 USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Cookson, MR (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Neurosci Program,Ctr Neurol Dis, Boston, MA 02115 USA. EM cookson@mail.nih.gov NR 23 TC 77 Z9 85 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 5 PY 2004 VL 43 IS 3 BP 301 EP 304 DI 10.1016/j.neuron.2004.07.012 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 844KL UT WOS:000223156900004 PM 15294138 ER PT J AU Hasegawa, RP Peterson, BW Goldberg, ME AF Hasegawa, RP Peterson, BW Goldberg, ME TI Prefrontal neurons coding suppression of specific saccades SO NEURON LA English DT Article ID FRONTAL EYE FIELD; GO/NO-GO DISCRIMINATION; LATERAL INTRAPARIETAL AREA; MONKEY SUPERIOR COLLICULUS; INFERIOR TEMPORAL CORTEX; VISUAL-DISCRIMINATION; RHESUS-MONKEYS; ELECTRICAL-STIMULATION; PERCEPTUAL DECISION; PARIETAL CORTEX AB The prefrontal cortex has been implicated in the suppression of unwanted behavior, based upon observations of humans and monkeys with prefrontal lesions. Despite this, there has been little direct neurophysiological evidence for a mechanism that suppresses specific behavior. In this study, we used an oculomotor delayed match/nonmatch-to-sample task in which monkeys had to remember a stimulus location either as a marker of where to look or as a marker of where not to look. We found a group of neurons in both the frontal eye field and the caudal prefrontal cortex that carried signals selective for the forbidden stimulus. The activity of these "don't look" neurons correlated with the monkeys' success or failure on the task. These results demonstrate a frontal signal that is related to the active suppression of one action while the subject performs another. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Ctr Neurobiol & Behav, New York, NY 10032 USA. Northwestern Univ, Sch Med, Dept Physiol, Chicago, IL 60611 USA. Natl Inst Adv Ind Sci & Technol, Neurosci Res Inst, Tsukuba, Ibaraki 3058568, Japan. Northwestern Univ, Dept Neurobiol & Physiol, Evanston, IL 60208 USA. RP Hasegawa, RP (reprint author), NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. EM r-hasegawa@aist.go.jp FU NEI NIH HHS [R01 EY017039, P30 EY019007] NR 61 TC 58 Z9 58 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD AUG 5 PY 2004 VL 43 IS 3 BP 415 EP 425 DI 10.1016/j.neuron.2004.07.013 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 844KL UT WOS:000223156900014 PM 15294148 ER PT J AU Wolfraim, LA Fernandez, TM Mamura, M Fuller, WL Kumar, R Cole, DE Byfield, S Felici, A Flanders, KC Walz, TM Roberts, AB Aplan, PD Balis, FM Letterio, JJ AF Wolfraim, LA Fernandez, TM Mamura, M Fuller, WL Kumar, R Cole, DE Byfield, S Felici, A Flanders, KC Walz, TM Roberts, AB Aplan, PD Balis, FM Letterio, JJ TI Loss of Smad3 in acute T-cell lymphoblastic leukemia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID TGF-BETA; P27(KIP1); EXPRESSION; INHIBITOR; LYMPHOMAS; GROWTH; MICE AB BACKGROUND: The receptors for transforming growth factor (beta) (TGF-(beta)) and their signaling intermediates make up an important tumor-suppressor pathway. The role of one of these intermediates -- Smad3 -- in the pathogenesis of lymphoid neoplasia is unknown. METHODS: We measured Smad3 messenger RNA (mRNA) and protein in leukemia cells obtained at diagnosis from 19 children with acute leukemia, including 10 with T-cell acute lymphoblastic leukemia (ALL), 7 with pre-B-cell ALL, and 2 with acute nonlymphoblastic leukemia (ANLL). All nine exons of the SMAD3 gene (MADH3) were sequenced. Mice in which one or both alleles of Smad3 were inactivated were used to evaluate the role of Smad3 in the response of normal T cells to TGF-(beta) and in the susceptibility to spontaneous leukemogenesis in mice in which both alleles of the tumor suppressor p27(sup Kip1) were deleted. RESULTS: Smad3 protein was absent in T-cell ALL but present in pre-B-cell ALL and ANLL. No mutations were found in the MADH3 gene in T-cell ALL, and Smad3 mRNA was present in T-cell ALL and normal T cells at similar levels. In mice, the loss of one allele for Smad3 impairs the inhibitory effect of TGF-(beta) on the proliferation of normal T cells and works in tandem with the homozygous inactivation of p27(sup Kip1) to promote T-cell leukemogenesis. CONCLUSIONS: Loss of Smad3 protein is a specific feature of pediatric T-cell ALL. A reduction in Smad3 expression and the loss of p27(sup Kip1) work synergistically to promote T-cell leukemogenesis in mice. C1 NCI, LCRC, CCR, NIH, Bethesda, MD 20892 USA. NCI, Pediat Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. NCI, Genet Branch, CCR, NIH, Bethesda, MD 20892 USA. Linkoping Univ Hosp, Fac Hlth Sci, Div Oncol, Dept Biomed & Surg, S-58185 Linkoping, Sweden. RP Letterio, JJ (reprint author), NCI, LCRC, CCR, NIH, Bldg 41,Rm C629,41 Lib Dr, Bethesda, MD 20892 USA. EM letterij@mail.nih.gov RI Aplan, Peter/K-9064-2016; OI Mamura, Mizuko/0000-0003-4531-0144 NR 13 TC 88 Z9 96 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC/NEJM PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD AUG 5 PY 2004 VL 351 IS 6 BP 552 EP 559 DI 10.1056/NEJMoa031197 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 843HS UT WOS:000223069900008 PM 15295048 ER PT J AU Li, JF Wang, FL Protopopov, A Malyukova, A Kashuba, V Minna, JD Lerman, MI Klein, G Zabarovsky, E AF Li, JF Wang, FL Protopopov, A Malyukova, A Kashuba, V Minna, JD Lerman, MI Klein, G Zabarovsky, E TI Inactivation of RASSF1C during in vivo tumor growth identifies it as a tumor suppressor gene SO ONCOGENE LA English DT Article DE tumor suppressor gene; human chromosome 3p; gene mutation; lung cancer; renal carcinoma; prostate cancer ID HUMAN-CHROMOSOME 3P21.3; HOMOZYGOUS DELETION REGION; EPIGENETIC INACTIVATION; CELL-GROWTH; LUNG; CANCER; CARCINOMA; BREAST; SEARCH; CONSTRUCTION AB RASSF1A, a major member of the RASSF1 gene family, is silenced by promoter methylation at a high frequency in a large number of human solid tumors. Controlled expression of RASSF1A reverts the tumorigenic phenotype of several human cancer cell lines. Here we investigated another main isoform, RASSF1C, and compared it with RASSF1A in the gene inactivation test (GIT), based on a tetracycline regulation system. In the small-cell lung cancer (SCLC) line U2020, only RASSF1A has shown growth inhibitory activity in vitro, while in the prostate cell line LNCaP and renal cell carcinoma (RCC) line KRC/Y both RASSF1A and RASSF1C showed similar (approximately 90%) suppressing activity in vitro. Both RASSF1C and RASSF1A suppressed the tumorigenicity of the KRC/Y RCC cell line in SCID mice. Mutations, deletions and loss of expression of RASSF1A and RASSF1C transgenes were identified in all 15 grown SCID tumors. In contrast, the mutant RASSF1A containing Cys65Arg and Val211Ala had reduced growth suppression activity both in vitro and in vivo and did not show any further changes in four grown SCID tumors. In addition, RASSF1C was shown to induce cell cycle arrest in KRC/Y cells. These results strongly imply that like RASSF1A the RASSF1C gene could serve a tumor suppressor function. C1 Karolinska Inst, Microbiol & Tumorbiol Ctr, S-17177 Stockholm, Sweden. Natl Acad Sci Ukraine, Inst Mol Biol & Genet, UA-03143 Kiev, Ukraine. Univ Texas, SW Med Ctr, Hamon Ctr Therapeut Oncol, Dallas, TX 75390 USA. Natl Canc Inst, Canc Causing Genes Sect, Immunobiol Lab, Ctr Canc Res, Frederick, MD 21702 USA. Russian Acad Sci, Engelhardt Inst Mol Biol, Moscow 119991, Russia. Karolinska Inst, Ctr Genom & Bioinformat, S-17177 Stockholm, Sweden. RP Li, JF (reprint author), Karolinska Inst, Microbiol & Tumorbiol Ctr, S-17177 Stockholm, Sweden. EM jinli@ki.se; eugzab@ki.se RI Zabarovsky, Eugene/A-6645-2010 FU NCI NIH HHS [CA71618, N01-CO-56000, P50 CA 70907] NR 31 TC 36 Z9 42 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD AUG 5 PY 2004 VL 23 IS 35 BP 5941 EP 5949 DI 10.1038/sj.onc.1207789 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 841OV UT WOS:000222941100008 PM 15208682 ER PT J AU Srinivasan, P Libbus, B AF Srinivasan, Padmini Libbus, Bisharah TI Mining MEDLINE for implicit links between dietary substances and diseases SO BIOINFORMATICS LA English DT Article AB Motivation: Text mining systems aim at knowledge discovery from text collections. This work presents our text mining algorithm and demonstrates its use to uncover information that could form the basis of new hypotheses. In particular, we use it to discover novel uses for Curcuma longa, a dietary substance, which is highly regarded for its therapeutic properties in Asia. Results: Several disease were identified that offer novel research contexts for curcumin. We analyze select suggestions, such as retinal diseases, Crohn's disease and disorders related to the spinal cord. Our analysis suggests that there is strong evidence in favor of a beneficial role for curcumin in these diseases. The evidence is based on curcumin's influence on several genes, such as COX-2, TNF-alpha, JNK, p38 MAPK and TGF-beta. This research suggests that our discovery algorithm may be used to suggest novel uses for dietary and pharmacological substances. More generally, our text mining algorithm may be used to uncover information that potentially sheds new light on a given topic of interest. C1 [Srinivasan, Padmini] Univ Iowa, Sch Lib & Informat Sci, Iowa City, IA 52242 USA. [Libbus, Bisharah] Natl Lib Med, Lister Hill Res Ctr, Bethesda, MD 20852 USA. RP Srinivasan, P (reprint author), Univ Iowa, Sch Lib & Informat Sci, Iowa City, IA 52242 USA. EM padmini-srinivasan@uiowa.edu NR 15 TC 37 Z9 40 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD AUG 4 PY 2004 VL 20 SU 1 BP 290 EP 296 DI 10.1093/bioinformatics/bth914 PG 7 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 V24DZ UT WOS:000208392400038 ER PT J AU Ronning, DR Li, Y Perez, ZN Ross, PD Hickman, AB Craig, NL Dyda, F AF Ronning, DR Li, Y Perez, ZN Ross, PD Hickman, AB Craig, NL Dyda, F TI The carboxy-terminal portion of TnsC activates the Tn7 transposase through a specific interaction with TnsA SO EMBO JOURNAL LA English DT Article DE differential scanning calorimetry; protein-protein complex; Tn7 transposition; X-ray crystallography ID OF-FUNCTION MUTANTS; RESTRICTION ENDONUCLEASES; TN7-ENCODED PROTEINS; DNA BREAKAGE; RECOGNITION; SYSTEM; ATP; PURIFICATION; ASSOCIATION; ALIGNMENT AB Tn7 transposition requires the assembly of a nucleoprotein complex containing four self-encoded proteins, transposon ends, and target DNA. Within this complex, TnsC, the molecular switch that regulates transposition, and TnsA, one part of the transposase, interact directly. Here, we demonstrate that residues 504-555 of TnsC are responsible for TnsA/TnsC interaction. The crystal structure of the TnsA/TnsC(504-555) complex, resolved to 1.85 Angstrom, illustrates the burial of a large hydrophobic patch on the surface of TnsA. One consequence of sequestering this patch is a marked increase in the thermal stability of TnsA as shown by differential scanning calorimetry. A model based on the complex structure suggested that TnsA and a slightly longer version of the cocrystallized TnsC fragment (residues 495-555) might cooperate to bind DNA, a prediction confirmed using gel mobility shift assays. Donor DNA binding by the TnsA/TnsC(495-555) complex is correlated with the activation of the TnsAB transposase, as measured by double-stranded DNA cleavage assays, demonstrating the importance of the TnsA/TnsC interaction in affecting Tn7 transposition. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. RP Dyda, F (reprint author), NIDDK, Mol Biol Lab, NIH, Bldg 5,Room 303,5 Ctr Dr,MSC 0560, Bethesda, MD 20892 USA. EM dyda@helix.nih.gov NR 33 TC 9 Z9 9 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 4 PY 2004 VL 23 IS 15 BP 2972 EP 2981 DI 10.1038/sj.emboj.7600311 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 852BE UT WOS:000223729400007 PM 15257292 ER PT J AU Lal, A Mazan-Mamczarz, K Kawai, T Yang, XL Martindale, JL Gorospe, M AF Lal, A Mazan-Mamczarz, K Kawai, T Yang, XL Martindale, JL Gorospe, M TI Concurrent versus individual binding of HuR and AUF1 to common labile target mRNAs SO EMBO JOURNAL LA English DT Article DE exosome; mRNA stability; polysome; RNA-binding protein; RNA motif ID RICH ELEMENT; PROTEIN HUR; 3'-UNTRANSLATED REGION; HNRNP PROTEINS; HEAT-SHOCK; IDENTIFICATION; EXPRESSION; TURNOVER; STABILITY; EXPORT AB RNA-binding proteins HuR and AUF1 bind to many common AU-rich target mRNAs and exert opposing influence on target mRNA stability, but the functional interactions between HuR and AUF1 have not been systematically studied. Here, using common target RNAs encoding p21 and cyclin D1, we provide evidence that HuR and AUF1 can bind target transcripts on both distinct, nonoverlapping sites, and on common sites in a competitive fashion. In the nucleus, both proteins were found together within stable ribonucleoprotein complexes; in the cytoplasm, HuR and AUF1 were found to bind to target mRNAs individually, HuR colocalizing with the translational apparatus and AUF1 with the exosome. Our results indicate that the composition and fate (stability, translation) of HuR- and/or AUF1-containing ribonucleoprotein complexes depend on the target mRNA of interest, RNA-binding protein abundance, stress condition, and subcellular compartment. C1 NIA, LCMB, IRP, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, LCMB, IRP, NIH, Box 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov NR 46 TC 313 Z9 319 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0261-4189 J9 EMBO J JI Embo J. PD AUG 4 PY 2004 VL 23 IS 15 BP 3092 EP 3102 DI 10.1038/sj.emboj.7600305 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 852BE UT WOS:000223729400019 PM 15257295 ER PT J AU Bera, TK Huynh, N Maeda, H Sathyanarayana, BK Lee, B Pastan, I AF Bera, TK Huynh, N Maeda, H Sathyanarayana, BK Lee, B Pastan, I TI Five POTE paralogs and their splice variants are expressed in human prostate and encode proteins of different lengths SO GENE LA English DT Article DE primate-specific gene; membrane-associated protein; ankyrin repeats; spectrin motif; noncoding RNA ID GENE; CANCER; TESTIS; REPEAT; CELLS AB POTE is a new gene that contains ankyrin and spectrin domains and is expressed in prostate, testis, ovary, and placenta. In humans, 10 highly homologous variants of the gene are dispersed among eight chromosomes. POTE paralogs are detected in primates but not in other species. Using prostate RNA, we characterized cDNAs from five paralogs and their splice variants. The proteins encoded by the POTE paralogs and their variants range from 80 to 32 kDa. Transfection of POTE constructs into 293T cells shows that the POTE protein, like spectrin, is localized on the inner aspect of the plasma membrane. We also detect a noncoding transcript expressed on the opposite strand from POTE on chromosome 14 or 22. We speculate that POTE has an important signaling function in the reproductive system. (C) 2004 Elsevier B.V. All rights reserved. C1 NCI, Ctr Canc Res, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Ctr Canc Res, Mol Biol Lab, NIH, Bldg 37,MSC 4264,37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov NR 11 TC 21 Z9 28 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD AUG 4 PY 2004 VL 337 BP 45 EP 53 DI 10.1016/j.gene.2004.05.009 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 847HJ UT WOS:000223383000005 PM 15276201 ER PT J AU Francischetti, IMB My-Pham, V Harrison, J Garfield, MK Ribeiro, JMC AF Francischetti, IMB My-Pham, V Harrison, J Garfield, MK Ribeiro, JMC TI Bitis gabonica (Gaboon viper) snake venom gland: toward a catalog for the full-length transcripts (cDNA) and proteins SO GENE LA English DT Article DE snake venom; Bitis gabonica; metalloprotease; cDNA library; Viperidae; toxins ID THROMBIN-LIKE ENZYME; AMINO-ACID-SEQUENCE; PLATELET-AGGREGATION; SERINE PROTEINASE; EVOLUTION; FAMILY; PURIFICATION; DISINTEGRIN; EXPRESSION; DIVERSITY AB The venom gland of the snake Bitis gabonica (Gaboon viper) was used for the first time to construct a unidirectional cDNA phage library followed by high-throughput sequencing and bioinformatic analysis. Hundreds of cDNAs were obtained and clustered into contigs. We found mostly novel full-length cDNA coding for metalloproteases (P-II and P-III classes), Lys49-phospholipase A2, serine proteases with essential mutations in the active site, Kunitz protease inhibitors, several C-type lectins, bradykinin-potentiating peptide, vascular endothelial growth factor, nucleotidases and nucleases, nerve growth factor, and L-amino acid oxidases. Two new members of the recently described short coding region family of disintegrin, displaying RGD and MLD motifs are reported. In addition, we have identified for the first time a cytokine-like molecule and a multi-Kunitz protease inhibitor in snake venoms. The CLUSTAL alignment and the unrooted cladograms for selected families of B. gabonica venom proteins are also presented. A significant number of sequences were devoid of database matches, suggesting that their biologic function remains to be identified. This paper also reports the N-terminus of the 15 most abundant venom proteins and the sequences matching their corresponding transcripts. The electronic version of this manuscript, available on request, contains spreadsheets with hyperlinks to FASTA-formatted files for each contig and the best match to the GenBank and Conserved Domain Databases, in addition to CLUSTAL alignments of each contig. We have thus generated a comprehensive catalog of the B. gabonica venom gland, containing for each secreted protein: (i) the predicted molecular weight, (ii) the predicted isoelectric point, (iii) the accession number, and (iv) the putative function. The role of these molecules is discussed in the context of the envenomation caused by the Gaboon viper. (C) 2004 Elsevier B.V. All rights reserved. C1 NIAID, Med Entomol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. Kentucky Reptile Zoo, Slade, KY 40376 USA. NIAID, Res Technol Branch, NIH, Rockville, MD 20852 USA. RP Francischetti, IMB (reprint author), NIAID, Med Entomol Sect, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Bldg Twinbrook 2,Room 2E-28, Rockville, MD 20852 USA. EM ifrancischetti@niaid.nih.gov OI Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS [Z01 AI000810-11, Z99 AI999999] NR 32 TC 79 Z9 92 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD AUG 4 PY 2004 VL 337 BP 55 EP 69 DI 10.1016/j.gene.2004.03.024 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 847HJ UT WOS:000223383000006 PM 15276202 ER PT J AU Thim, S Sath, S Sina, M Tsai, EY Delgado, JC Shapiro, AE AF Thim, S Sath, S Sina, M Tsai, EY Delgado, JC Shapiro, AE TI A community-based tuberculosis program in Cambodia SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Cambodian Hlth Comm, Phnom Penh, Cambodia. Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA USA. NIAID, NIH, TB Res Sect, Rockville, MD USA. Inst Pasteur Cambodge, Phnom Penh, Cambodia. Harvard Univ, Sch Med, CBR Inst Biomed Res, Cambridge, MA 02138 USA. RP Thim, S (reprint author), Cambodian Hlth Comm, Phnom Penh, Cambodia. FU Intramural NIH HHS [Z01 AI000734-12] NR 5 TC 11 Z9 11 U1 0 U2 2 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 AUG 4 PY 2004 VL 292 IS 5 BP 566 EP 568 DI 10.1001/jama.292.5.566-c PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 843AE UT WOS:000223045500012 PM 15292081 ER PT J AU Zemkova, H He, ML Koshimizu, T Stojilkovic, SS AF Zemkova, H He, ML Koshimizu, T Stojilkovic, SS TI Identification of ectodomain regions contributing to gating, deactivation, and resensitization of purinergic P2X receptors SO JOURNAL OF NEUROSCIENCE LA English DT Article DE purinergic receptors; P2X(2); P2X(3); gating; deactivation; desensitization ID GATED ION CHANNELS; C-TERMINAL DOMAIN; SENSORY NEURONS; STRUCTURAL MOTIF; AGONIST AFFINITY; EXTRACELLULAR PH; ATP; DESENSITIZATION; PURINOCEPTOR; KINETICS AB The P2X receptors (P2XRs) are a family of ligand-gated channels activated by extracellular ATP through a sequence of conformational transitions between closed, open, and desensitized states. In this study, we examined the dependence of the activity of P2XRs on ectodomain structure and agonist potency. Experiments were done in human embryonic kidney 293 cells expressing rat P2X(2a)R, P2X(2b)R, and P2X(3)R, and chimeras having the V60-R180 or V60-F301 ectodomain sequences of P2X(3)R instead of the I66-H192 or I66-Y310 sequences of P2X(2a)R and P2X(2b)R. Chimeric P2X(2a)/V60-F301X(3)R and P2X(2b)/V60-F301X(3)R inherited the P2X(3)R ligand-selective profile, whereas the potency of agonists for P2X(2a)/V60-R180X(3)R was in between those observed at parental receptors. Furthermore, P2X(2a)/V60F301X(3)R and P2X(2a)/V60-R180X(3)R desensitized in a P2X(2a)R-specific manner, and P2X(2b)/V60-F301X(3)R desensitized with rates comparable with those of P2X(2b)R. In striking contrast to parental receptors, the rates of decay in P2X(2a)/V60-F301X(3)R and P2X(2b)/V60-F301X(3)R currents after agonist withdrawal were 15- to 200-fold slower. For these chimeras, the decays in currents were not dependent on duration of stimuli and reflected both continuous desensitization and deactivation of receptors. Also, participation of deactivation in closure of channels inversely correlated with potency of agonists to activate receptors. The delay in deactivation was practically abolished in P2X(2a)/V60-R180X(3)R-expressing cells. However, the recovery from desensitization of P2X(2a)/V60-F301X(3)R and P2X(2a)/V60-R180X(3)R was similar and substantially delayed compared with that of parental receptors. These results indicate that both ectodomain halves participate in gating, but that the C and N halves influence the stability of open and desensitized conformation states, respectively, which in turn reflects on rates of receptor deactivation and resensitization. C1 NICHHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Stojilkovic, SS (reprint author), NICHHD, Sect Cellular Signaling, Endocrinol & Reprod Res Branch, NIH, Bldg 49,Room 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov RI Zemkova, Hana/C-1844-2012; OI Koshimizu, Taka-aki/0000-0001-5292-7535 NR 43 TC 37 Z9 37 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD AUG 4 PY 2004 VL 24 IS 31 BP 6968 EP 6978 DI 10.1523/JNEUROSCI.1471-04.2004 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 843RN UT WOS:000223102500014 PM 15295032 ER PT J AU Arai, AE Hirsch, GA AF Arai, AE Hirsch, GA TI Q-wave and non-Q-wave myocardial infarctions through the eyes of cardiac magnetic resonance imaging SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; CONSERVATIVE STRATEGIES; STRESS ECHOCARDIOGRAPHY; UNSTABLE ANGINA; MANAGEMENT; MRI; VISUALIZATION; DYSFUNCTION; COMMITTEE; ELEVATION C1 NHLBI, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Arai, AE (reprint author), NHLBI, Dept Hlth & Human Serv, NIH, Bldg 10,Room B1D416,MSC 1061,10 Ctr Dr, Bethesda, MD 20892 USA. EM araia@nih.gov NR 25 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 4 PY 2004 VL 44 IS 3 BP 561 EP 563 DI 10.1016/j.jacc.2004.05.007 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 843AV UT WOS:000223047900011 PM 15358020 ER PT J AU Najjar, SS Schulman, SP Gerstenblith, G Fleg, JL Kass, DA O'Connor, F Becker, LC Lakatta, EG AF Najjar, SS Schulman, SP Gerstenblith, G Fleg, JL Kass, DA O'Connor, F Becker, LC Lakatta, EG TI Age and gender affect ventricular-vascular coupling during aerobic exercise SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID EFFECTIVE ARTERIAL ELASTANCE; PRESSURE; LOAD; CARDIOMYOPATHY; IMPACT; HEART; REST AB OBJECTIVES The goal of this study was to examine the age-associated differences in ventricular-vascular coupling, defined by the ratio of arterial elastance (EaI) to left ventricular systolic elastance (ELVI), and its components, at rest and during exercise. BACKGROUND Ejection fraction (EF) increases during exercise, but the EF reserve decreases with aging. Ejection fraction is inversely related to EaI/ELVI, an index of the interaction between arterial and ventricular properties, which is an important determinant of cardiac performance. Thus, age differences in EaI/ELVI during exercise, due to age differences in EaI, ELVI, or both, may help to explain the age deficit in EF reserve. METHODS We noninvasively characterized EaI/ELVI = end-systolic volume index (ESVI)/stroke volume index (SVI) and its two determinants EaI = end-systolic pressure/SVI, and ELVI = end-systolic pressure/ESVI, at rest and during exercise in 239 healthy men and women (age range, 21 to 87 years). Blood pressures were assessed with cuff sphygomanometry, and cardiac volumes with gated blood pool scintingraphy. RESULTS Resting EaI/ELVI was not age related in men or women. In both sexes, EaI/ELVI decreased during exercise and declined to a lesser extent in older subjects. There were gender differences in the components of EaI/ELVI during exercise: EaI was greater in older versus young women (p = 0.01) but was unaffected by age in men. Left ventricular systolic elastance increased to a greater extent in young versus older subjects (p = 0.0001 for men, p = 0.07 for women). CONCLUSIONS Age-associated differences in EaI/ELVI occur in both genders during exercise. Sub-optimal ventricular-vascular coupling helps to explain the age-associated blunting of maximal exercise EF, and its underlying mechanisms appear to differ between men and women. (C) 2004 by the American College of Cardiology Foundation. C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. RP Najjar, SS (reprint author), NIA, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM NajjarSa@grc.nia.nih.gov FU NIA NIH HHS [N0-1 AG8-2109] NR 18 TC 81 Z9 87 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 4 PY 2004 VL 44 IS 3 BP 611 EP 617 DI 10.1016/j.jacc.2004.04.041 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 843AV UT WOS:000223047900020 PM 15358029 ER PT J AU Smith, RE Colangelo, L Wieand, HS Begovic, M Wolmark, N AF Smith, RE Colangelo, L Wieand, HS Begovic, M Wolmark, N TI Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01 SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID FLUOROURACIL; CANCER; LEUCOVORIN AB Background: The National Surgical Adjuvant Breast and Bowel Project C-01 trial reported in 1988 that, for patients with adenocarcinoma of the colon, compared with surgery alone, 1) postoperative chemotherapy with 1-(2-chloroethyl)-3-(4-trans-methylcyclohexyl)-1-nitrosourea (i.e., MeCCNU or semustine), vincristine, and 5-fluorouracil was associated with better 5-year disease-free and overall survival and 2) postoperative immunotherapy with bacillus Calmette-Guerin was associated with better 5-year overall, but not disease-free, survival. We now provide a 10-year update of this trial. Methods: Between November 11, 1977, and February 28, 1983, 1166 patients with resected Dukes' stage B and C adenocarcinoma of the colon were stratified by Dukes' stage, sex, and age (<65 years or greater than or equal to65 years) and then randomly assigned to receive no further treatment (surgery alone; 394 patients), adjuvant chemotherapy (379 patients), or adjuvant immunotherapy (393 patients). Those eligible for follow-up included 375 (95.2%) patients in the surgery-alone group, 349 (92.1%) patients in the adjuvant-chemotherapy group, and 372 (94.7%) patients in the adjuvant-immunotherapy group. All statistical tests were two-sided. Results: No difference was observed between patients in the chemotherapy group and those in the surgery-alone group in 10-year disease-free survival (hazard ratio [HR] = 1.14, 95% confidence interval [CI] = 0.94 to 1.39; P = .17) or overall survival (HR = 1.12, 95% CI = 0.91 to 1.38; P = .27). Immunotherapy did not appear to prevent tumor relapse after 10 years (for surgery alone versus immunotherapy, relative risk [RR] = 0.99, 95% CI = 0.78 to 1.25; P = .93) but had a beneficial effect on 10-year overall survival (for surgery alone versus immunotherapy, RR = 1.27, 95% CI = 1.03 to 1.56; P = .02) that apparently results from a reduction in deaths associated with comorbidities in the immunotherapy group. Conclusion: The disease-free and overall survival benefit associated with chemotherapy in this patient population is of limited duration, disappearing after 10 years. C1 NSABP, Operat Ctr, Pittsburgh, PA 15212 USA. NSABP, Ctr Biostat, Pittsburgh, PA USA. RP Smith, RE (reprint author), NSABP, Operat Ctr, E Commons Profess Bldg,4 Allegheny Ctr,5th Floor, Pittsburgh, PA 15212 USA. EM melissa.wolfe@nsabp.org FU NCI NIH HHS [U10-CA-69651, U10-CA-37377, U10-CA-12027, U10-CA-69974] NR 9 TC 49 Z9 50 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 AUG 4 PY 2004 VL 96 IS 15 BP 1128 EP 1132 DI 10.1093/jnci/djh220 PG 5 WC Oncology SC Oncology GA 844PN UT WOS:000223172200007 PM 15292384 ER PT J AU Castle, PE AF Castle, PE TI Re: Human papillomavirus in oral exfoliated cells and risk of head and neck cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Castle, PE (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov NR 7 TC 3 Z9 3 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 AUG 4 PY 2004 VL 96 IS 15 BP 1181 EP 1182 DI 10.1093/jnci/djh232 PG 2 WC Oncology SC Oncology GA 844PN UT WOS:000223172200013 PM 15292390 ER PT J AU Singh, SV Varma, V Zimniak, P Srivastava, SK Marynowski, SW Desai, D Amin, S Ji, XH AF Singh, SV Varma, V Zimniak, P Srivastava, SK Marynowski, SW Desai, D Amin, S Ji, XH TI Structural basis for catalytic differences between alpha class human glutathione transferases hGSTA1-1 and hGSTA2-2 for glutathione conjugation of environmental carcinogen benzo[a]pyrene-7,8-diol-9,10-epoxide SO BIOCHEMISTRY LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; REGION DIOL EPOXIDES; S-TRANSFERASE; EXCEPTIONAL ACTIVITY; DNA-DAMAGE; OPTICAL ENANTIOMERS; LIPID-PEROXIDATION; ELLAGIC ACID; HUMAN-LIVER; BAY-REGION AB The ultimate diol epoxide carcinogens derived from polycyclic aromatic hydrocarbons, such as benzo[a]pyrene (BP), are metabolized primarily by glutathione (GSH) conjugation reaction catalyzed by GSH transferases (GSTs). In human liver and probably lung, the (x class GSTs are likely to be responsible for the majority of this reaction because of their high abundance. The catalytic efficiency for GSH conjugation of the carcinogenic (+)-anti-benzo[a]pyrene-7,8-diol-9,10-epoxide [(+)-anti-BPDE] is more than 5-fold higher for hGSTA1-1 than for hGSTA2-2. Here, we demonstrate that mutation of isoleucine-11 of hGSTA2-2, a residue located in the hydrophobic substrate-binding site (H-site) of the enzyme, to alanine (which is present in the same position in hGSTA1-1) results in about a 7-fold increase in catalytic efficiency for (+)-anti-BPDE-GSH conjugation. Thus, a single amino acid substitution is sufficient to convert hGSTA2-2 to a protein that matches hGSTA1-1 in its catalytic efficiency. The increased catalytic efficiency of hGSTA2/I11A is accompanied by greater enantioselectivity for the carcinogenic (+)-anti-BPDE over (-)-anti-BPDE. Further remodeling of the H-site of hGSTA2-2 to resemble that of hGSTA1-1 (S9F, I11A, F110V, and S215A mutations, SIFS mutant) results in an enzyme whose catalytic efficiency is approximately 13.5-fold higher than that of the wild-type hGSTA2-2, and about 2.5-fold higher than that of the wild-type hGSTA1-1. The increased activity upon mutations can be rationalized by the interactions of the amino acid side chains with the substrate and the orientation of the substrate in the active site, as visualized by molecular modeling. Interestingly, the catalytic efficiency of hGSTA2-2 toward (-)-anti-BPDE was increased to a level close to that of hGSTA1-1 upon F110V, not I11A, mutation. Similar to (+)-anti-BPDE, however, the SIFS mutant was the most efficient enzyme for GSH conjugation of (-)-anti-BPDE. C1 Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. Univ Arkansas Med Sci, Dept Pharmacol & Toxicol, Little Rock, AR 72205 USA. Cent Arkansas Vet Healthcare Syst, Little Rock, AR 72205 USA. Inst Canc Prevent, Valhalla, NY 10595 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Singh, SV (reprint author), Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15213 USA. EM singhs@upmc.edu RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU NCI NIH HHS [CA076348]; NIEHS NIH HHS [ES09140] NR 52 TC 12 Z9 12 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 3 PY 2004 VL 43 IS 30 BP 9708 EP 9715 DI 10.1021/bi049435f PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841XI UT WOS:000222965100014 PM 15274625 ER PT J AU Ball, LE Garland, DL Crouch, RK Schey, KL AF Ball, LE Garland, DL Crouch, RK Schey, KL TI Post-translational modifications of Aquaporin 0 (AQP0) in the normal human lens: Spatial and temporal occurrence SO BIOCHEMISTRY LA English DT Article ID PROTEIN CARBOXYL METHYLTRANSFERASE; MAJOR INTRINSIC PROTEIN; ALPHA-A-CRYSTALLIN; ELECTROSPRAY-IONIZATION; WATER PERMEABILITY; MASS-SPECTROMETRY; JUNCTION PROTEIN; CONGENITAL CATARACT; EYE LENS; KINASE-C AB Because of the lack of protein turnover in fiber cells of the ocular lens, Aquaporin 0 (AQP0), the most abundant membrane protein in the lens, undergoes extensive post-translational modification with fiber cell age. To map the distribution of modified forms of AQP0 within the lens, normal human lenses ranging in age from 34 to 38 were concentrically dissected into several cortical and nuclear sections. Membrane proteins still embedded in the membranes were digested with trypsin, and the resulting C-terminal peptides of AQP0 were analyzed by HPLC tandem mass spectrometry, permitting the identification of modifications and estimation of their abundance. Consistent with earlier reports, the major phosphorylation site was Ser 235, and the major sites of backbone cleavage occurred at residues 246 and 259. New findings suggest that cleavage at these sites may be a result of nonenzymatic truncation at asparagine residues. In addition, this approach revealed previously undetected sites of truncation at residues 249, 260, 261, and 262; phosphorylation at Ser 231 and to a lower extent at Ser 229; and racemization/isomerization Of L-Asp 243 to D-Asp and D-iso-Asp. The spatial distribution of C-terminally modified AQP0 within the lens indicated an increase in truncation and racemization/isomerization with fiber cell age, whereas the level of Ser 235 phosphorylation increased from the outer to inner cortex but decreased in the nucleus. Furthermore, the remarkably similar pattern and distribution of truncation products from lenses from three donors suggest specific temporal mechanisms for the modification of AQP0. C1 Med Univ S Carolina, Dept Cell & Mol Pharmacol, Charleston, SC 29403 USA. Med Univ S Carolina, Dept Ophthalmol, Charleston, SC 29403 USA. NEI, Bethesda, MD 20205 USA. RP Schey, KL (reprint author), Med Univ S Carolina, Dept Cell & Mol Pharmacol, Charleston, SC 29403 USA. EM scheykl@musc.edu OI Ball, Lauren/0000-0001-6780-1679 FU NEI NIH HHS [EY-014793, EY-13462] NR 54 TC 67 Z9 67 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 3 PY 2004 VL 43 IS 30 BP 9856 EP 9865 DI 10.1021/bi0496034 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 841XI UT WOS:000222965100029 PM 15274640 ER PT J AU Fox, CS Evans, JC Larson, MG Kannel, WB Levy, D AF Fox, CS Evans, JC Larson, MG Kannel, WB Levy, D TI Temporal trends in coronary heart disease mortality and sudden cardiac death from 1950 to 1999 - The Framingham Heart Study SO CIRCULATION LA English DT Article DE coronary disease; death, sudden; epidemiology; prevention ID ACUTE MYOCARDIAL-INFARCTION; CERTIFICATE DIAGNOSIS; IMPROVING SURVIVAL; MEDICAL-CARE; EVENT RATES; Q-WAVE; MINNESOTA; DECLINE; RISK; VALIDATION AB Background - Throughout the past 50 years, heart disease has been the leading cause of death in the United States. Although declines in coronary heart disease (CHD) mortality have been noted, there is still uncertainty about the magnitude of the decline and whether the trend is similar for sudden cardiac death (SCD). Methods and Results - We examined temporal trends in SCD and nonsudden CHD death in the Framingham Heart Study original and offspring cohorts from 1950 to 1999. SCD was defined as a death attributed to CHD with preceding symptoms that lasted less than 1 hour; all deaths were adjudicated by a physician panel. Log-linear Poisson regression was used to estimate CHD mortality and SCD risk ratios (RRs); RRs were adjusted for age and gender. There were 811 CHD deaths: 453 nonsudden and 358 SCDs. Ninety-one (20%) of nonsudden CHD deaths and 173 (48%) of SCDs were in subjects free of antecedent CHD. From 1950 - 1969 to 1990 - 1999, overall CHD death rates decreased by 59% (95% CI 47% to 68%, P-trend < 0.001). Nonsudden CHD death decreased by 64% (95% CI 50% to 74%, P-trend < 0.001), and SCD rates decreased by 49% (95% CI 28% to 64%, P-trend < 0.001). These trends were seen in men and women, in subjects with and without a prior history of CHD, and in smokers and nonsmokers. Conclusions - The risks of SCD and nonsudden CHD mortality have decreased by 49% to 64% over the past 50 years. These trends were evident in subjects with and without heart disease, which suggests important contributions of primary and secondary prevention to the decreasing risk of CHD death and SCD. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Dept Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Fox, CS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Larson, Martin/0000-0002-9631-1254 FU NHLBI NIH HHS [N01-HC-25195] NR 38 TC 210 Z9 221 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 3 PY 2004 VL 110 IS 5 BP 522 EP 527 DI 10.1161/01.CIR.0000136993.34344.41 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 843DJ UT WOS:000223055600009 PM 15262842 ER PT J AU McLeod, CJ Jeyabalan, AP Minners, JO Clevenger, R Hoyt, RF Sack, MN AF McLeod, CJ Jeyabalan, AP Minners, JO Clevenger, R Hoyt, RF Sack, MN TI Delayed ischemic preconditioning activates nuclear-encoded electron-transfer-chain gene expression in parallel with enhanced postanoxic mitochondrial respiratory recovery SO CIRCULATION LA English DT Article DE ischemia; preconditioning; mitochondria; metabolism ID LATE-PHASE; CONSCIOUS RABBITS; ENERGY-METABOLISM; CYTOCHROME-C; RAT-HEART; PROTECTION; BIOGENESIS; STRESS; CELLS AB Background - Delayed ischemic preconditioning promotes cardioprotection via genomic reprogramming. We hypothesize that molecular regulation of mitochondrial energetics is integral to this cardioprotective program. Methods and Results - Preconditioning was induced by use of 3 episodes of 3-minute coronary artery occlusion separated by 5 minutes of reperfusion. Twenty-four hours later, infarct size was reduced by 58% after preconditioning compared with sham-operated controls (P < 0.001). Cardiac mitochondria were isolated from sham and preconditioned rat hearts. Mitochondrial respiration and ATP production were similar between the groups; however, preconditioned mitochondria exhibit modest hyperpolarization of the inner mitochondrial membrane potential (&GE;22% versus control, P < 0.001). After 35-minute anoxia and reoxygenation, preconditioned mitochondria demonstrated a 191 +/- 12% improvement in ADP-sensitive respiration (P = 0.002) with preservation of electron-transfer-chain (ETC) activity versus controls. This augmented mitochondrial recovery was eradicated when preconditioning was abolished by the antioxidant 2-mercaptopropionyl glycine (2-MPG). These biochemical modulations appear to be regulated at the genomic level in that the expression of genes encoding rate-controlling complexes in the ETC was significantly upregulated in preconditioned myocardium, with a concordant induction of steady-state protein levels of cytochrome oxidase, cytochrome c, and adenine nucleotide translocase-1. 2-MPG abolished preconditioning induction of these transcripts. Moreover, transcripts of nuclear regulatory peptides known to orchestrate mitochondrial biogenesis, nuclear respiratory factor-1 and peroxisome-proliferator - activated receptor gamma coactivator 1alpha, were significantly induced in preconditioned myocardium. Conclusions - Delayed preconditioned mitochondria display increased tolerance against anoxia-reoxygenation in association with modifications in mitochondrial bioenergetics, with concordant genomic induction of a mitochondrial energetic gene regulatory program. This program appears to be mediated by reactive oxygen species signaling. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Lab Anim Med & Surg, NIH, Bethesda, MD 20892 USA. Univ Cape Town, Sch Med, Hatter Inst Cardiol Res, ZA-7925 Cape Town, South Africa. RP Sack, MN (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10,Room 7B-15,10 Ctr Dr, Bethesda, MD 20892 USA. EM sackm@nih.gov NR 32 TC 36 Z9 38 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 3 PY 2004 VL 110 IS 5 BP 534 EP 539 DI 10.1161/01.CIR.0000136997.53612.6C PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 843DJ UT WOS:000223055600011 PM 15277332 ER PT J AU Harrison, SC Alberts, B Ehrenfeld, E Enquist, L Fineberg, H McKnight, SL Moss, B O'Donnell, M Ploegh, H Schmid, SL Walter, KP Theriot, J AF Harrison, SC Alberts, B Ehrenfeld, E Enquist, L Fineberg, H McKnight, SL Moss, B O'Donnell, M Ploegh, H Schmid, SL Walter, KP Theriot, J TI Discovery of antivirals against smallpox SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID VACCINIA VIRUS; DNA-REPLICATION; TRANSCRIPTION; POXVIRUSES; MOTILITY; PROTEIN C1 Harvard Univ, Sch Med, Howard Hughes Med Inst, Boston, MA 02115 USA. Natl Acad Sci, Washington, DC 20418 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Princeton Univ, Schultz Lab 314, Princeton, NJ 08544 USA. Inst Med, Washington, DC 20418 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Howard Hughes Med Inst, Lab DNA Replicat, New York, NY 10021 USA. Harvard Univ, Sch Med, NRB, Dept Pathol, Boston, MA 02115 USA. Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. Univ Calif San Francisco, Sch Med, Howard Hughes Med Inst, Dept Biochem & Biophys, San Francisco, CA 94143 USA. Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. RP Harrison, SC (reprint author), Harvard Univ, Sch Med, Howard Hughes Med Inst, Seeley Mudd Bldg,Room 130,250 Longwood Ave, Boston, MA 02115 USA. EM harrison@crystal.harvard.edu OI O'Donnell, Michael/0000-0001-9002-4214 NR 27 TC 58 Z9 59 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 3 PY 2004 VL 101 IS 31 BP 11178 EP 11192 DI 10.1073/pnas.0403600101 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 844CH UT WOS:000223134400002 PM 15249657 ER PT J AU Kobayashi, M Iaccarino, C Saiardi, A Heidt, V Bozzi, Y Picetti, R Vitale, C Westphal, H Drago, J Borrelli, E AF Kobayashi, M Iaccarino, C Saiardi, A Heidt, V Bozzi, Y Picetti, R Vitale, C Westphal, H Drago, J Borrelli, E TI Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE knockout mice; motor function; feeding behavior; gastrointestinal system ID TARGETED GENE DELETION; DEFICIENT MICE; MUTANT MICE; FEEDING-BEHAVIOR; HYPOTHALAMIC NEUROPEPTIDES; NERVOUS-SYSTEM; MESSENGER-RNA; BODY-WEIGHT; LACKING; RATS AB Dopamine (DA) controls a wide variety of physiological functions in the central nervous system as well as in the neuroendocrine and gastrointestinal systems. DA signaling is mediated by five cloned receptors named D1-D5. Knockout mouse models for the five receptors have been generated, and, albeit impaired for some important DA-mediated functions, they are viable and can reproduce. 1311 and D2 receptors are the most abundant and widely expressed DA receptors. Cooperative/synergistic effects mediated by these receptors have been suggested, in particular, in the control of motor behaviors. To analyze the extent of such interrelationship, we have generated double D1/D2 receptor mutants. Interestingly, in contrast to single knockouts, we found that concurrent ablation of the D1 and D2 receptors is lethal during the second or third week after birth. This dramatic phenotype is likely to be related to altered feeding behavior and dysfunction of the gastrointestinal system, especially because major anatomical changes were not identified in the brain. Similarly, in the absence of functional D1, heterozygous D2 mutants (D1r(-/-);D2r(+/-)) showed severe growth retardation and did not survive their postweaning period. The analysis of motor behavior in D1r/D2r compound mutants showed that loss of D2-mediated functions reduces motor abilities, whereas the effect of D1r ablation on locomotion strongly depends on the experimental paradigms used. These studies highlight the interrelationship between D1 and D2 receptor-mediated control of motor activity, food intake, and gastrointestinal functions, which has been elusive in the single-gene ablation studies. C1 Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, France. Natl Inst Hlth, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. Univ Melbourne, Howard Florey Inst, Parkville, Vic 3010, Australia. RP Borrelli, E (reprint author), Inst Genet & Biol Mol & Cellulaire, 1 Rue Laurent Fries, F-67404 Illkirch Graffenstaden, France. EM eb@igbmc.u-strasbg.fr RI Picetti, Roberto/B-9944-2011 OI Picetti, Roberto/0000-0003-4756-5271 NR 60 TC 38 Z9 39 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 AUG 3 PY 2004 VL 101 IS 31 BP 11465 EP 11470 DI 10.1073/pnas.0402028101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 844CH UT WOS:000223134400051 PM 15272078 ER PT J AU Wang, XD Tanus-Santos, JE Reiter, CD Dejam, A Shiva, S Smith, RD Hogg, N Gladwin, MT AF Wang, XD Tanus-Santos, JE Reiter, CD Dejam, A Shiva, S Smith, RD Hogg, N Gladwin, MT TI Biological activity of nitric oxide in the plasmatic compartment SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID RED-BLOOD-CELLS; ENDOTHELIUM-DEPENDENT RELAXATION; HAPTOGLOBIN PHENOTYPE; S-NITROSOTHIOLS; SERUM-ALBUMIN; CARDIOVASCULAR-DISEASE; HUMAN CIRCULATION; RISK-FACTOR; N-NITROSO; HEMOGLOBIN AB There exist reaction products of nitric oxide (NO) with blood that conserve its bioactivity and transduce an endocrine vasomotor function under certain conditions. Although S-nitrosated albumin has been considered the major species subserving this activity, recent data suggest that additional NO species, such as nitrite, nitrated lipids, N-nitrosamine, and iron-nitrosyl complexes, may contribute. We therefore examined the end products of NO reactions. in plasma and blood in vitro and in vivo by using reductive chemiluminescent assays and electron paramagnetic resonance spectroscopy. We found that NO complexes in plasma previously considered to be S-nitrosated albumin were <10 nM after elimination of nitrite and were mercury-stable, consistent with iron-nitrosyl or N-nitrosamine complex. During clinical NO gas inhalation protocols or in vitro NO donor treatment of human plasma, S-nitroso-albumin did not form with NO exposure <2 muM, but plasma methemoglobin was detectable by paramagnetic resonance spectroscopy. Consistent with this formation of methemoglobin, human plasma was found to consume approximate to2 muM NO at a rate equivalent to that of hemoglobin. This NO consumption was mediated by the reaction of NO with plasma haptoglobin-hemoglobin complexes and limited slower reaction pathways required for S-nitrosation. These data suggest that high-affinity, metal-based reactions in plasma with the haptoglobin-hemoglobin complex modulate plasmatic NO reaction products and limit S-nitrosation at low NO flux. The studies further suggest that alternative NO reaction end products in plasma, such as nitrite, N-nitrosamines, iron-nitrosyls, and nitrated lipids, should be evaluated in blood NO transport along the vasculature. C1 Warren G Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. NIDDK, Biol Chem Lab, Bethesda, MD 20892 USA. NIDDK, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Free Radical Res Ctr, Milwaukee, WI 53226 USA. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NIH, Bldg 10,Room 7D43,10 Ctr Dr, Bethesda, MD 20892 USA. EM mgladwin@nih.gov RI Tanus-Santos, Jose/A-4451-2008 NR 47 TC 107 Z9 109 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 3 PY 2004 VL 101 IS 31 BP 11477 EP 11482 DI 10.1073/pnas.0402201101 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 844CH UT WOS:000223134400053 PM 15258287 ER PT J AU Richards, GP Hammer, CH Garfield, MK Parveen, S AF Richards, GP Hammer, CH Garfield, MK Parveen, S TI Characterization of a lysyl aminopeptidase activity associated with phosphoglucose isomerase of Vibrio vulnificus SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Article DE Vibrio vulnificus; phosphoglucose isomerase; characterization; lysyl aminopeptidase ID AUTOCRINE MOTILITY FACTOR; PHOSPHOHEXOSE ISOMERASE; FACTOR NEUROLEUKIN; FACTOR-RECEPTOR; SACCHAROMYCES-CEREVISIAE; MICROBIAL PROTEINASES; ELASTOLYTIC PROTEASE; NEUROTROPHIC FACTOR; MOLECULAR-CLONING; FLUOROGENIC ASSAY AB Phosphoglucose isomerase (PGI) is a multifunctional enzyme involved in glycolysis and gluconeogenesis and, in mammalian cells, functions as neuroleukin, autocrine motility factor (AMF), and differentiation and maturation factor (MF). We isolated and characterized PGI with a novel lysyl aminopeptidase (LysAP) activity (PGI-LysAP) from vibrio vulnificus. Mass spectrometry revealed that PGI-LysAP is a heterodimer consisting of 23.4- and 60.8-kDa subunits. Only the heterodimer displayed LysAP activity. PGI-LysAP has a pI around 6.0 and high specificity toward the synthetic, fluorogenic substrate L-lysyl-7-amino-4-methylcoumarin. LysAP activity is optimal at pH 8.0, is 64% higher at 37 degreesC than at 21 degreesC, does not directly correlate with virulence, and is strongly inhibited by serine protease and metalloprotease inhibitors. PGI-LysAP was also identified in vibrio parahaemolyticus and V cholerae, but was absent from non-vibrio human pathogens. Sequencing of the pgi gene revealed 1653 bp coding for a 550-amino-acid protein. Cloned and expressed PGI formed a homodimer with isomerase activity, but not LysAP activity. The finding of LysAP activity associated with heterodimeric PGI should foster a broad search for putative substrates in an effort to elucidate the role of PGI-LysAP in bacteria and its roles in the pathophysiology of diseases. Published by Elsevier B.V. C1 Delaware State Univ, USDA ARS, James WW Baker Ctr, Dover, DE 19901 USA. NIAID, Res Technol Branch, NIH, Rockville, MD 20852 USA. Delaware State Univ, Dept Agr & Nat Resources, Dover, DE 19901 USA. RP Richards, GP (reprint author), Delaware State Univ, USDA ARS, James WW Baker Ctr, Dover, DE 19901 USA. EM grichard@desu.edu NR 55 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD AUG 2 PY 2004 VL 1700 IS 2 BP 219 EP 229 DI 10.1016/j.bbapap.2004.05.005 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 842VD UT WOS:000223031600010 PM 15262231 ER PT J AU Toman, RE Payne, SG Watterson, KR Maceyka, M Lee, NH Milstien, S Bigbee, JW Spiegel, S AF Toman, RE Payne, SG Watterson, KR Maceyka, M Lee, NH Milstien, S Bigbee, JW Spiegel, S TI Differential transactivation of sphingosine-1-phosphate receptors modulates NGF-induced neurite extension SO JOURNAL OF CELL BIOLOGY LA English DT Article DE NGF; neurite extension; TrkA; dorsal root ganglion; PC12 ID NERVE GROWTH-FACTOR; PROTEIN-COUPLED RECEPTOR; SPHINGOSINE 1-PHOSPHATE RECEPTOR; ROOT GANGLION NEURONS; SENSORY AXON GROWTH; SMOOTH-MUSCLE-CELLS; PC12 CELLS; PHOSPHOINOSITIDE 3-KINASE; EXPRESSION PATTERN; SIGNALING PATHWAYS AB The process of neurite extension after activation of the TrkA tyrosine kinase receptor by nerve growth factor (NGF) involves complex signaling pathways. Stimulation of sphingosine kinase 1 (SphK1), the enzyme that phosphorylates sphingosine to form sphingosine-1-phosphate (S1P), is part of the functional TrkA signaling repertoire. In this paper, we report that in PC12 cells and dorsal root ganglion neurons, NGF translocates SphK1 to the plasma membrane and differentially activates the S1P receptors S1P(1) and S1P(2) in a SphK1-dependent manner, as determined with specific inhibitors and small interfering RNA targeted to SphK1. NGF-incluced neurite extension was suppressed by down-regulation of S1P(1) expression with antisense RNA. Conversely, when overexpressed in PC12 cells, transactivation of S1P(1) by NGF markedly enhanced neurite extension and stimulation of the small GTPase Rac, important for the cytoskeletal changes required for neurite extension. Concomitantly, differentiation down-regulated expression Of S1P(2) whose activation would stimulate Rho and inhibit neurite extension. Thus, differential transactivation of S1P receptors by NGF regulates antagonistic signaling pathways that modulate neurite extension. C1 Virginia Commonwealth Univ, Med Ctr, Sch Med, Dept Biochem, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Sch Med, Dept Anat & Neurobiol, Richmond, VA 23298 USA. Georgetown Univ, Med Ctr, Interdisciplinary Program Neurosci, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Biochem & Mol Biol, Washington, DC 20007 USA. NIMH, Lab Cellular & Mol Regulat, NIH, Bethesda, MD 20892 USA. Inst Genom Res, Dept Mol & Cellular Biol, Rockville, MD 20850 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Med Ctr, Sch Med, Dept Biochem, POB 980614,1101 E Marshall St, Richmond, VA 23298 USA. EM sspiegel@vcu.edu RI Maceyka, Michael/B-9277-2008 FU NCI NIH HHS [P30 CA16059, P30 CA016059, CA61774, R01 CA061774]; NINDS NIH HHS [NS41706, F31 NS041706] NR 45 TC 94 Z9 97 U1 0 U2 4 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 AUG 2 PY 2004 VL 166 IS 3 BP 381 EP 392 DI 10.1083/jcb.200402016 PG 12 WC Cell Biology SC Cell Biology GA 844ET UT WOS:000223141000012 PM 15289497 ER PT J AU Kinter, AL Hennessey, M Bell, A Kern, S Lin, Y Daucher, M Planta, M McGlaughlin, M Jackson, R Ziegler, SE Fauci, AS AF Kinter, AL Hennessey, M Bell, A Kern, S Lin, Y Daucher, M Planta, M McGlaughlin, M Jackson, R Ziegler, SE Fauci, AS TI CD25(+) CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article DE cytokine; proliferation; human; suppression; FoxP3 ID HUMAN-IMMUNODEFICIENCY-VIRUS; DENDRITIC CELLS; FUNCTIONAL-CHARACTERIZATION; RETROVIRAL INFECTION; EFFECTOR FUNCTION; CANDIDA-ALBICANS; EX-VIVO; INDUCTION; PROLIFERATION; ACTIVATION AB Human immunodeficiency virus (HIV) disease is associated with loss of CD4(+) T cells, chronic immune activation, and progressive immune dysfunction. HIV-specific responses, particularly those of CD4(+) T cells, become impaired early after infection, before the loss of responses directed against other antigens; the basis for this diminution has not been elucidated fully. The potential role of CD25(+)CD4(+) regulatory T cells (T reg cells), previously shown to inhibit immune responses directed against numerous pathogens, as suppressors of HIV-specific T cell responses was investigated. In the majority of healthy HIV-infected individuals, CD25(+)CD4(+) T cells significantly suppressed cellular proliferation and cytokine production by CD4(+) and CD8(+) T cells in response to HIV antigens/peptides in vitro; these effects were cell contact dependent and IL-10 and TGF-beta independent. Individuals with strong HIV-specific CD25(+) T reg cell function in vitro had significantly lower levels of plasma viremia and higher CD4(+): CD8(+) T cell ratios than did those individuals in whom this activity could not be detected. These in vitro data suggest that CD25(+)CD4(+) T reg cells may contribute to the diminution of HIV-specific T cell immune responses in vivo in the early stages of HIV disease. C1 NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. NIH, Dept Clin Ctr Med, Bethesda, MD 20892 USA. Benaroya Res Inst, Virginia Mason Med Ctr, Seattle, WA 98111 USA. RP Kinter, AL (reprint author), NIAID, Immunoregulat Lab, 10 Ctr Dr,Bldg 10,Rm 6A33,MSC-1576, Bethesda, MD 20892 USA. EM AKinter@niaid.nih.gov FU NIAID NIH HHS [R01 AI048779, AI48779] NR 78 TC 337 Z9 366 U1 2 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD AUG 2 PY 2004 VL 200 IS 3 BP 331 EP 343 DI 10.1084/jem.20032069 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 844RX UT WOS:000223178500007 PM 15280419 ER PT J AU Azok, JT Pandit, SD Li, KCP AF Azok, JT Pandit, SD Li, KCP TI A primer on molecular biology for imagers: VI. proteomics: The large-scale study of proteins SO ACADEMIC RADIOLOGY LA English DT Article ID ELECTROPHORESIS 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, 10-1N306,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 14 TC 2 Z9 2 U1 0 U2 0 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 AUG PY 2004 VL 11 IS 8 BP 940 EP 950 DI 10.1016/j.acra.2004.05.006 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 844DN UT WOS:000223137600012 PM 15358272 ER PT J AU Leon, X Rinaldo, A Saffiotti, U Ferlito, A AF Leon, X Rinaldo, A Saffiotti, U Ferlito, A TI Laryngeal cancer in non-smoking and non-drinking patients SO ACTA OTO-LARYNGOLOGICA LA English DT Editorial Material ID SQUAMOUS-CELL CARCINOMA; UPPER AERODIGESTIVE TRACT; GASTROESOPHAGEAL-REFLUX DISEASE; NECK-CANCER; HUMAN-PAPILLOMAVIRUS; VERRUCOUS CARCINOMA; OCCUPATIONAL-EXPOSURE; MUTAGEN SENSITIVITY; RISK FACTOR; HEAD C1 Univ Udine, Policlin Univ, ENT Clin, Dept Surg Sci, IT-33100 Udine, Italy. Hosp Santa Cruz & San Pablo, Dept Otolaryngol, E-08025 Barcelona, Spain. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Environm & Occupat Hlth, Washington, DC USA. RP Ferlito, A (reprint author), Univ Udine, Policlin Univ, ENT Clin, Dept Surg Sci, Piazzale S Maria Misercordia, IT-33100 Udine, Italy. EM a.ferlito@uniud.it NR 52 TC 7 Z9 7 U1 0 U2 1 PU TAYLOR & FRANCIS AS PI OSLO PA CORT ADELERSGT 17, PO BOX 2562, SOLLI, 0202 OSLO, NORWAY SN 0001-6489 J9 ACTA OTO-LARYNGOL JI Acta Oto-Laryngol. PD AUG PY 2004 VL 124 IS 6 BP 664 EP 669 DI 10.1080/00016480410017008 PG 6 WC Otorhinolaryngology SC Otorhinolaryngology GA 838PC UT WOS:000222724300002 PM 15515487 ER PT J AU Hansen, PB Yang, T Huang, Y Mizel, D Briggs, J Schnermann, J AF Hansen, PB Yang, T Huang, Y Mizel, D Briggs, J Schnermann, J TI Plasma renin in mice with one or two renin genes SO ACTA PHYSIOLOGICA SCANDINAVICA LA English DT Article; Proceedings Paper CT 10th APS International Symposium on Functional Genomics of the Juxtaglomerular Apparatus CY OCT 14-16, 2003 CL Univ S Denmark, Odense, DENMARK SP Acta Physiologica Scandinavica HO Univ S Denmark DE aldosterone; mice strains; Ren-1; Ren-2; renin mRNA ID TUBULOGLOMERULAR FEEDBACK; REN-2 LOCI; MOUSE; ADENOSINE; GLAND; ANGIOTENSINOGEN; SUBMAXILLARY; HOMEOSTASIS; EXPRESSION AB Aim: In the present study we have investigated whether the presence of a second renin gene exerts an overriding influence on plasma renin such that mice with two renin genes have consistently higher renin levels than mice with only one renin gene. Methods: Plasma renin was determined as the rate of angiotensin I generation using a radioimmunoassay (RIA) kit with (plasma renin concentration, PRC) or without (plasma renin activity, PRA) the addition of purified rat angiotensinogen as substrate. Results: In male 129SvJ, DBA/2 and Swiss Webster mice, strains possessing both Ren-1 and Ren-2, PRC (ng Ang I mL(-1) h(-1)) averaged 178 +/- 36, 563 +/- 57 and 550 +/- 43 while PRA was 2.9 +/- 0.5, 3.6 +/- 0.8 and 7.8 +/- 1.2. In male C57BL/6, C3H and BALB/c mice that express only Ren-1, PRC averaged 426 +/- 133, 917 +/- 105 and 315 +/- 72, and PRA was 3.4 +/- 1.0, 6.9 +/- 1.7 and 4.5 +/- 1.2. In the two renin gene A1AR-/- mice compared with the one renin gene A1AR+/+, PRC averaged 538 +/- 321 and 415 +/- 159 while PRA averaged 3.2 +/- 1.1 and 4.4 +/- 1.4 ng Ang I mL(-1) h(-1). Aldosterone levels showed no significant differences between one renin (C57BL/6, C3H and BALB/c) and two renin (129SvJ, DBA/2 and Swiss Webster) gene mice. Furthermore, by quantitative real-time polymerase chain reaction (RT-PCR) we found no correlation between the number of renin genes and whole kidney renin mRNA levels from one and two renin gene mice. Conclusion: Our data show that baseline plasma renin is not systematically higher in mice with two renin genes than in one renin gene mice. Thus, the presence of a second renin gene does not seem to be a major determinant of differences in PRC between different mouse strains. C1 NIDDK, NIH, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), NIDDK, NIH, Bldg 10,Room 1 D51,10 Ctr Dr,MSC 1370, Bethesda, MD 20892 USA. RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 NR 19 TC 15 Z9 15 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0001-6772 J9 ACTA PHYSIOL SCAND JI Acta Physiol. Scand. PD AUG PY 2004 VL 181 IS 4 BP 431 EP 437 DI 10.1111/j.1365-201X.2004.01315.x PG 7 WC Physiology SC Physiology GA 842XB UT WOS:000223036800010 PM 15283755 ER PT J AU Hashimoto, S Huang, Y Mizel, D Briggs, J Schnermann, J AF Hashimoto, S Huang, Y Mizel, D Briggs, J Schnermann, J TI Compensation of proximal tubule malabsorption in AQP1-deficient mice without TGF-mediated reduction of GFR SO ACTA PHYSIOLOGICA SCANDINAVICA LA English DT Article; Proceedings Paper CT 10th APS International Symposium on Functional Genomics of the Juxtaglomerular Apparatus CY OCT 14-16, 2003 CL Univ S Denmark, Odense, DENMARK SP Acta Physiologica Scandinavica HO Univ S Denmark DE adenosine 1 receptors; gene knockout; micropuncture; Na excretion; single nephron glomerular filtration rate ID AQUAPORIN-1 NULL MICE; TUBULOGLOMERULAR FEEDBACK; BARTTERS-SYNDROME; SODIUM-TRANSPORT; ENAC SUBUNIT; MOUSE MODEL; LACKING; PSEUDOHYPOALDOSTERONISM; REABSORPTION; ADENOSINE AB Aim: By crossing aquaporin 1 (AQP1)-/- and adenosine 1 receptor (A1AR)-/- mice, we generated an animal model that combines a proximal tubular absorption defect with absence of tubuloglomerular feedback (TGF) regulation of glomerular filtration rate (GFR). The aim of studies in these animals was to determine whether a TGF-induced reduction of GFR is a prerequisite for preventing potentially fatal fluid losses. Methods and Results: In contrast to AQP1 deficient mice, AQP1/A1AR-/- mice were found to have a normal GFR. TGF responses were abolished in these animals, in contrast to AQP1-/- mice in which TGF responses of single nephron glomerular filtration rate (SNGFR) were left-shifted. Proximal tubule fluid absorption in AQP1/A1AR-/- mice was reduced to levels previously reported for AQP1-/- mice. However, SNGFR was significantly higher in AQP1/A1AR-/- than AQP1-/- mice (10.6 +/- 0.8 nL min(-1) vs. 5.9 +/- 0.7 nL min(-1)). As a consequence of the normal GFR and the reduced proximal reabsorption distal fluid delivery was markedly higher in the double knockout compared with normal or AQP1-/- mice (5.5 +/- 0.5 nL min(-1) vs. 2.35 +/- 0.3 nL min(-1) in AQP1-/-). Despite the approximate doubling of distal fluid and Cl delivery, AQP1/A1AR-/- mice have a normal salt excretion, normal arterial blood pressure, and only a small increase in plasma renin concentration. Conclusion: The ability to compensate for proximal tubule malabsorption without a TGF-induced reduction of GFR attests to a remarkable adaptability of distal tubule transport mechanisms. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. RP Schnermann, J (reprint author), Bldg 10,Room 4 D51,10 Ctr Dr MSC 1370, Bethesda, MD USA. NR 21 TC 7 Z9 9 U1 0 U2 1 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0001-6772 J9 ACTA PHYSIOL SCAND JI Acta Physiol. Scand. PD AUG PY 2004 VL 181 IS 4 BP 455 EP 462 DI 10.1111/j.1365-201X.2004.01318.x PG 8 WC Physiology SC Physiology GA 842XB UT WOS:000223036800013 PM 15283758 ER PT J AU Cavazzini, C Conti, M Bandinelli, S Gangemi, S Gallinella, M Lauretani, F Lucci, G Windham, BG Guralnik, JM Ferrucci, L AF Cavazzini, C Conti, M Bandinelli, S Gangemi, S Gallinella, M Lauretani, F Lucci, G Windham, BG Guralnik, JM Ferrucci, L TI Screening for poor performance of lower extremity in primary care: the Camucia Project SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article; Proceedings Paper CT 2nd Congress of the European-Union-Geriatric-Medicine-Society (EUGMS) CY 2003 CL Firenze, ITALY SP European Union Geriatr Med Soc DE elderly; lower extremity performance; prevention of disability; primary care ID NONDISABLED OLDER PERSONS; SUBSEQUENT DISABILITY; COMMUNITY; HEALTH; CHALLENGES; PREDICTOR; ILLNESS; TRIAL AB Background and aims: Individuals with poor lower extremity performance are prime candidates for disability prevention. The Camucia Project is a collaborative study between geriatricians and primary care physicians (PCPs) testing the hypothesis that PCPs can use a simple performance-based test to identify older persons with poor lower extremity function, without excessive interference with their clinical routine. We also hypothesized that the number needed to screen (NNTS) a positive case would be lower in physicians' clinics than in the general population. Methods: 23 PCPs administered the short physical performance battery (SPPB) to 360 consecutive, non-disabled and non-demented, 70- to 79-year-old outpatients. PCPs were asked to: 1) evaluate the feasibility and usefulness of administering the SPPB; 2) ascertain selected diseases according to predefined criteria; 3) identify causes of poor lower extremity function in patients with a SPPB score less than or equal to9 NNTS from this study were compared with those estimated in non-disabled and non-demented, 70- to 79-year-old persons randomly selected from the InCHIANTI study population. Results: The majority of PCPs (20/23) reported that using the SPPB to evaluate older patients was feasible and useful. The NNTS in the outpatient clinics was lower than in the InCHIANTI participants (1.6 vs 4.3). Poor lower extremity performance was attributed to musculo-skeletal diseases in 75%, to more than one cause in 55% (128/234), and to no specific cause in 16.2% (37/234) of the participants with SPPB less than or equal to9. Conclusions: Screening of older persons with poor lower extremity performance by PCPs is feasible and efficient. (C) 2004, Editrice Kurtis. C1 Harbor Hosp, ASTRA Unit, Clin Res Branch, Longitudinal Studies Sect,NIA, Baltimore, MD 21225 USA. Italian Natl Inst Res & Care Aging, Lab Clin Epidemiol, Florence, SC USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD USA. Etruria Med Cooperat, Arezzo, Italy. RP Ferrucci, L (reprint author), Harbor Hosp, ASTRA Unit, Clin Res Branch, Longitudinal Studies Sect,NIA, 5th Floor,3001 Hanover St, Baltimore, MD 21225 USA. EM FerrucciLu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 NR 22 TC 12 Z9 12 U1 4 U2 4 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD AUG PY 2004 VL 16 IS 4 BP 331 EP 336 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 869DU UT WOS:000224964400012 PM 15575129 ER PT J AU Wang, SW Bertley, FMN Kozlowski, PA Herrmann, L Manson, K Mazzara, G Piatak, M Johnson, RP Carville, A Mansfield, K Aldovini, A AF Wang, SW Bertley, FMN Kozlowski, PA Herrmann, L Manson, K Mazzara, G Piatak, M Johnson, RP Carville, A Mansfield, K Aldovini, A TI An SHIV DNA/MVA rectal vaccination in macaques provides systemic and mucosal virus-specific responses and protection against AIDS SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; CYTOTOXIC T-LYMPHOCYTES; POLYMERASE CHAIN-REACTION; IMMUNE-RESPONSES; VIRAL LOAD; TYPE-1 INFECTION; RHESUS MACAQUES; CELL RESPONSES; DISEASE PROGRESSION; HIV-1 INFECTION AB We explored the use of a simian-human immunodeficiency virus (SHIV) DNA vaccine as an effective mucosal priming agent to stimulate a protective immune response for AIDS prevention. Rhesus macaques were vaccinated rectally with a DNA construct producing replication-defective SHIV particles, and boosted with either the same DNA construct or recombinant modified vaccinia virus Ankara (MVA) expressing SIV Gag, SIV Pol, and HIV Env (MVA-SHIV). Virus-specific mucosal and systemic humoral and cell-mediated immune responses could be stimulated by this approach but were present inconsistently among the vaccinated animals. Rectal vaccination with either SHIV DNA alone or SHIV DNA followed by MVA-SHIV induced SIV Gag/Pol- or HIV gp120-specific IgA in rectal secretions of four of seven animals. However, the gp120-specific rectal IgA antibody responses were not durable and had become undetectable in all but one animal shortly before rectal challenge with pathogenic SHIV 89.6P. Only the macaques primed with SHIV DNA and boosted with MVA-SHIV demonstrated SHIV-specific IgG in plasma. In addition, these animals developed more consistent antiviral cell-mediated responses and had better preservation of CD4 T cells following challenge with SHIV 89.6P. Our study demonstrates the utility of a rectal DNA/MVA vaccination protocol for the induction of diverse responses in different immunological compartments. In addition, the immunity achieved with this mucosal vaccination regimen is sufficient to delay progression to AIDS. C1 Childrens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. Therion, Cambridge, MA 02142 USA. NCI, Frederick Canc Res & Dev Ctr, Retroviral Pathogenesis Lab, AIDS Vaccine Program,SAIC Frederick, Frederick, MD 21702 USA. Harvard Univ, New England Primate Res Ctr, Sch Med, Southborough, MA 01772 USA. Massachusetts Gen Hosp, Partners AIDS Res Ctr, Charlestown, MA 02129 USA. Massachusetts Gen Hosp, Infect Dis Unit, Charlestown, MA 02129 USA. RP Aldovini, A (reprint author), Childrens Hosp, Dept Med, Enders 861,300 Longwood Ave, Boston, MA 02115 USA. EM anna.aldovini@childrens.harvard.edu FU NCI NIH HHS [N01-CO-124000]; NIAID NIH HHS [AI41365] NR 82 TC 37 Z9 37 U1 0 U2 0 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD AUG PY 2004 VL 20 IS 8 BP 846 EP 859 DI 10.1089/0889222041725253 PG 14 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 852AF UT WOS:000223726900009 PM 15320989 ER PT J AU Villamide-Herrera, L Ignatius, R Eller, MA Wilkinson, K Griffin, C Mehlhop, E Jones, J Han, SY Lewis, MG Parrish, S Vancott, TC Lifson, JD Schlesinger, S Mascola, JR Pope, M AF Villamide-Herrera, L Ignatius, R Eller, MA Wilkinson, K Griffin, C Mehlhop, E Jones, J Han, SY Lewis, MG Parrish, S Vancott, TC Lifson, JD Schlesinger, S Mascola, JR Pope, M TI Macaque dendritic cells infected with SIV-recombinant canarypox ex vivo induce SIV-specific immune responses in vivo SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID CD4(+) T-CELLS; SIMIAN IMMUNODEFICIENCY VIRUS; RHESUS-MONKEYS; LYMPHOID-TISSUE; HIV-1 INFECTION; AIDS VACCINE; ANTIGEN; CD8(+); BLOOD; MATURE AB Dendritic cells (DCs) infected with recombinant avipox vectors express the introduced genes and activate antigen-specific T cells. DCs exhibit distinct differentiation-dependent immune functions. Moreover, immature DCs are readily infected by canarypox vectors, but undergo tumor necrosis factor (TNF)-alpha-dependent death, while fewer mature DCs get infected and resist dying. A pilot study was performed using the rhesus macaque system to explore whether immature and mature DCs infected with SIV-recombinant canarypox (vCP180) ex vivo could induce primary virus-specific immune responses in vivo. After subcutaneous (sc) reinjection, functional monocyte-derived DCs migrated to lymph nodes (LNs) within 1-2 days and primed T cells in vivo. This was observed by monitoring dye-labeled DCs in the draining LNs and tetanus toxoid (TT)-specific T cell responses after injection of TT-loaded DCs. DCs from simian immunodeficiency virus (SIV)-naive rhesus macaques were infected with vCP180 (SIVmac142 gag, pol, and env genes), and sc reinjected into donor animals. Low-level SIV-specific T cell proliferation, but little if any interferon (IFN)-gamma production was detected. DCs pulsed with vCP180 in combination with TT and keyhole limpet hemocyanin (KLH) ( to activate additional T cells and provide "helper" cytokines) induced SIV-, TT-, and KLH-specific T cell responses, including IFN-gamma responses not seen when vCP180-carrying DCs were used alone. Interleukin (IL)-10 and low-level antibody responses were also observed. This pilot study provides the proof of principle that sc injected ex vivo SIV-recombinant canarypox-infected DCs safely induce low-level SIV-specific immune responses in vivo. C1 Populat Council, Ctr Biomed Res, New York, NY 10021 USA. Charite Univ Med, Dept Med Microbiol & Immunol Infect, Berlin, Germany. Henry M Jackson Fdn, Rockville, MD 20850 USA. Washington Univ, St Louis, MO 63130 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. BIOQUAL Inc, Rockville, MD 20850 USA. NCI, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21702 USA. Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10016 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Pope, M (reprint author), Populat Council, Ctr Biomed Res, 1230 York Ave, New York, NY 10021 USA. EM mpope@popcouncil.org FU NCI NIH HHS [N01-CO-12400] NR 51 TC 12 Z9 12 U1 0 U2 1 PU MARY ANN LIEBERT INC PUBL PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD AUG PY 2004 VL 20 IS 8 BP 871 EP 884 DI 10.1089/0889222041725136 PG 14 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 852AF UT WOS:000223726900011 PM 15320991 ER PT J AU Purohit, V Russo, D Coates, PA AF Purohit, V Russo, D Coates, PA TI Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium SO ALCOHOL LA English DT Article; Proceedings Paper CT Symposium on Role of Fatty Liver Dietary Fatty Acid Supplements and Obesity in the Progression of Alcoholic Liver Disease CY OCT 03, 2003 CL Bethesda, MD DE alcoholic fatty liver; dietary fatty acids; obesity; nonalcoholic steatohepatitis; fatty liver transplant ID TUMOR-NECROSIS-FACTOR; CHRONIC ETHANOL-CONSUMPTION; FACTOR-ALPHA; RAT-LIVER; MITOCHONDRIAL GLUTATHIONE; HEPATIC-NECROSIS; OXIDATIVE STRESS; OXIDIZING SYSTEM; INJURY; INCREASES AB Alcoholic liver disease is a major cause of illness and death in the United States. In the initial stages of the disease, fat accumulation in hepatocytes leads to the development of fatty liver (steatosis), which is a reversible condition. If alcohol consumption is continued, steatosis may progress to hepatitis and fibrosis, which may lead to liver cirrhosis. Alcoholic fatty liver has long been considered benign; however, increasing evidence supports the idea that it is a pathologic condition. Blunting of the accumulation of fat within the liver during alcohol consumption may block or delay the progression of fatty liver to hepatitis and fibrosis. To achieve this goal, it is important to understand the underlying biochemical and molecular mechanisms by which chronic alcohol consumption leads to fat accumulation in the liver and fatty liver progresses to hepatitis and fibrosis. In addition to alcohol consumption, dietary fatty acids and obesity have been shown to affect the degree of fat accumulation within the liver. Again, it is important to know how these factors modulate the progression of alcoholic liver disease. The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on "Role of Fatty Liver, Dietary Fatty Acid Supplements, and Obesity in the Progression of Alcoholic Liver Disease" in Bethesda, Maryland, USA, October 2003. The following is a summary of the symposium. Alcoholic fatty liver is a pathologic condition that may predispose the liver to further injury (hepatitis and fibrosis) by cytochrome P450 2E1 induction, free radical generation, lipid peroxidation, nuclear factor-kappa B activation, and increased transcription of proinflammatory mediators, including tumor necrosis factor-alpha. Increased acetaldehyde production and lipopolysaccharide-induced Kupffer cell activation may further exacerbate liver injury. Acetaldehyde may promote hepatic fat accumulation by impairing the ability of peroxisome proliferator-activated receptor alpha to bind DNA, and by increasing the synthesis of sterol regulatory binding protein-1. Unsaturated fatty acids (corn oil, fish oil) exacerbate alcoholic liver injury by accentuating oxidative stress, whereas saturated fatty acids are protective. Polyenylphosphatidylcholine may prevent liver injury by down-regulating cytochrome P450 2E1 activity, attenuating oxidative stress, reducing the number of activated hepatic stellate cells, and up-regulating collagenase activity. Nonalcoholic steatohepatitis may develop through several mechanisms, such as oxidative stress, mitochondrial dysfunction and associated impaired fat metabolism, dysregulated cytokine metabolism, insulin resistance, and altered methionine/S-adenosylmethionine/homocysteine metabolism. Obesity (adipose tissue) may contribute to the development of alcoholic liver disease by generating free radicals, increasing tumor necrosis factor-alpha production, inducing insulin resistance, and producing fibrogenic agents, such as angiotensin 11, norepinephrine, neuropeptide Y, and leptin. Finally, alcoholic fatty liver transplant failure may be linked to oxidative stress. In vitro treatment of fatty livers with interleukin-6 may render allografts safer for clinical transplantation. (C) 2005 Elsevier Inc. All rights reserved. C1 NIAAA, Div Metab & Hlth Effects, NIH, Bethesda, MD 20892 USA. Off Dietary Supplements, NIH, Bethesda, MD 20892 USA. RP NIAAA, Div Metab & Hlth Effects, NIH, 5623 Fishers Lane,Room 2035, Bethesda, MD 20892 USA. EM vpurohit@mail.nih.gov NR 26 TC 41 Z9 43 U1 1 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD AUG PY 2004 VL 34 IS 1 BP 3 EP 8 DI 10.1016/j.alcohol.2004.06.008 PG 6 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 898KB UT WOS:000227074600002 PM 15670659 ER PT J AU Pawlosky, RJ Salem, N AF Pawlosky, RJ Salem, N TI Perspectives on alcohol consumption: liver polyunsaturated fatty acids and essential fatty acid metabolism SO ALCOHOL LA English DT Article; Proceedings Paper CT Symposium on Role of Fatty Liver Dietary Fatty Acid Supplements and Obesity in the Progression of Alcoholic Liver Disease CY OCT 03, 2003 CL Bethesda, MD DE fatty liver; essential fatty acids; human beings; animals; docosahexaenoic acid; arachidonic acid; fatty acid desaturation; metabolism; ethanol ID DELTA-5 DESATURASE ACTIVITIES; LIPID-PEROXIDATION; RAT-LIVER; ETHANOL INGESTION; ARACHIDONIC-ACID; RHESUS-MONKEYS; MALONDIALDEHYDE; MITOCHONDRIA; ACETALDEHYDE; MICROSOMES AB In this article, subjects diagnosed with alcoholic liver disease are shown to have lower concentrations of several polyunsaturated fatty acids (PUFAs), including 18:2n6, 18:3n6, 20:3n6, 18:3n3, 22:50, and 22:6n3, but not 20:4n6 and 22:4n6, nor 22:5n6, in the total lipid extracts of their livers compared with findings for specimens obtained from patients diagnosed with primary biliary cirrhosis and from control subjects. Findings of studies in animals have demonstrated that prolonged alcohol consumption reduces liver polyunsaturate content. However, the effect of ethanol on the elongation/desaturation of essential fatty acids is complex, as in vitro study results indicate that the direction of the effect of alcohol may be related to the dose of alcohol. Findings of studies in hepatocyte cell culture indicate that ethanol increased delta-5 and delta-6 desaturase activities throughout a broad concentration range. In contrast, lower liver desaturase activity has been reported in animals consuming high concentrations of alcohol (36%-40% energy) over a period of several months. Findings from in vivo isotope tracers studies in nonhuman primates and felines indicate that prolonged periods of moderate (mean consumption 2.6 g kg(-1) d(-1) and 1.2 g kg(-1) d(-1), respectively) alcohol consumption bad no effect on the uptake of either linoleic (18:2n6) or alpha-linolenic (18:3n3) acids into the plasma and lead to an increased incorporation of these deuterated precursors into 20:4n6 and 22:6n3. Thus, this likely reflects a stimulated, rather than an inhibited, production of long-chain PUFAs. In numerous studies in various species, investigators have documented that alcohol consumption can increase the level of lipid peroxidation in tissues, and sustained periods of ethanol-induced peroxidation can deplete tissues of PUFAs. A hypothesis to rationalize the long-term effects of alcohol consumption on liver PUFA concentration that takes into consideration the effect of ethanol on essential fatty acid metabolism is presented. (C) 2005 Elsevier Inc. All rights reserved. C1 NIAAA, Div Intramural Clin & Biol Res, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys,NIH, Rockville, MD 20852 USA. RP Salem, N (reprint author), NIAAA, Div Intramural Clin & Biol Res, Sect Nutr Neurosci, Lab Membrane Biochem & Biophys,NIH, 5625 Fishers Lane,Room 3C-07, Rockville, MD 20852 USA. EM nsalem@niaaa.nih.gov NR 32 TC 28 Z9 30 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0741-8329 J9 ALCOHOL JI Alcohol PD AUG PY 2004 VL 34 IS 1 BP 27 EP 33 DI 10.1016/j.alcohol.2004.07.009 PG 7 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 898KB UT WOS:000227074600005 PM 15670662 ER PT J AU Gao, B AF Gao, B TI Therapeutic potential of interleukin-6 in preventing obesity- and alcohol-associated fatty liver transplant failure SO ALCOHOL LA English DT Article; Proceedings Paper CT Symposium on Role of Fatty Liver Dietary Fatty Acid Supplements and Obesity in the Progression of Alcoholic Liver Disease CY OCT 03, 2003 CL Bethesda, MD DE IL-6; fatty liver transplantation; alcohol; STAT3 ID ISCHEMIA-REPERFUSION INJURY; ZUCKER RAT LIVERS; ISCHEMIA/REPERFUSION INJURY; INDUCED APOPTOSIS; GRAFT FUNCTION; PIG-LIVER; PROTECTS; REGENERATION; MECHANISMS; STEATOSIS AB Donor organ shortage significantly hinders orthotopic liver transplantation therapy, the only effective treatment for chronic end-stage liver disease and acute liver failure. Further complicating this matter is the prevalence of steatosis in 13% to 50% of donor livers obtained from obese and alcoholic individuals. When transplanted, these livers are associated with primary nonfunction and an elevated risk of dysfunction. New therapeutic approaches to render marginal fatty livers worthy for clinical transplantation are actively being sought. Study findings obtained from my group show that in vitro treatment with interleukin-6 (IL-6) dramatically reduces mortality, liver injury, and necrapoptosis in steatotic Zucker rat liver isografts. Findings of additional studies indicate that IL-6 induces hepatoprotection of steatotic liver isografts by preventing sinusoidal endothelial cell damage and, consequently, the amelioration of hepatic microcirculation, and by protecting against hepatocyte death, which is likely mediated through activation of signal transducer and activator of transcription 3/Bcl-X-L. Finally, in vitro IL-6 treatment also prevents mortality associated with alcoholic fatty liver transplants. Relative to the protective effect of IL-6 on steatotic Zucker rat liver, EL-6 is less effective in alcoholic fatty livers, which may be due to the inhibitory effects of ethanol on IL-6 activation of signal transducer and activator of transcription 3 in hepatocytes and sinusoidal endothelial cells. Collectively, these results support the assertion that in vitro IL-6 treatment of steatotic livers may render allografts usable for clinical transplantation, thereby decreasing the gap between the short supply of cadaver liver allografts and high demands for replacement livers. Higher concentrations of EL-6 may be required to protect against alcoholic fatty liver isograft injury because alcohol inhibits IL-6 signaling in the liver. (C) 2005 Elsevier Inc. All rights reserved. C1 NIAAA, Lab Physiol Studies, Sect Liver Biol, NIH, Bethesda, MD 20892 USA. RP Gao, B (reprint author), NIAAA, Lab Physiol Studies, Sect Liver Biol, NIH, Park Bldg Room 120,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov NR 53 TC 22 Z9 23 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0741-8329 J9 ALCOHOL JI Alcohol PD AUG PY 2004 VL 34 IS 1 BP 59 EP 65 DI 10.1016/j.alcohol.2004.07.006 PG 7 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 898KB UT WOS:000227074600010 PM 15670667 ER PT J AU Enoch, MA Waheed, J Harris, C Goldman, D AF Enoch, MA Waheed, J Harris, C Goldman, D TI The influence of COMT on mood, alcoholism and smoking in American Indians. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 29-OCT 02, 2004 CL Heidelberg, GERMANY SP Int Soc Biomed Res Alcoholism C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2004 VL 28 IS 8 SU S BP 30A EP 30A DI 10.1097/00000374-200408002-00143 PG 1 WC Substance Abuse SC Substance Abuse GA 850LS UT WOS:000223613600144 ER PT J AU Akinshola, BE Moykkynen, T Korpi, ER Lovinger, DM AF Akinshola, BE Moykkynen, T Korpi, ER Lovinger, DM TI Ethanol interaction with desensitization of AMPA-type glutamate receptors SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 29-OCT 02, 2004 CL Heidelberg, GERMANY SP Int Soc Biomed Res Alcoholism C1 Howard Univ, Coll Med, Washington, DC 20059 USA. Univ Helsinki, FIN-00014 Helsinki, Finland. NIAAA, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2004 VL 28 IS 8 SU S BP 38A EP 38A DI 10.1097/00000374-200408002-00189 PG 1 WC Substance Abuse SC Substance Abuse GA 850LS UT WOS:000223613600190 ER PT J AU Sommer, W Arlinde, C Rimondini, R Heilig, M AF Sommer, W Arlinde, C Rimondini, R Heilig, M TI Candidate treatment targets for alcoholism: Leads from functional genomics approaches. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 29-OCT 02, 2004 CL Heidelberg, GERMANY SP Int Soc Biomed Res Alcoholism C1 Karolinska Inst, NEUROTEC, Div Psychiat, S-10401 Stockholm, Sweden. NIAAA, NIH, Clin Sci Lab, Bethesda, MD USA. RI Rimondini, Roberto/B-2500-2010 OI Rimondini, Roberto/0000-0003-4099-513X NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2004 VL 28 IS 8 SU S BP 54A EP 54A DI 10.1097/00000374-200408002-00282 PG 1 WC Substance Abuse SC Substance Abuse GA 850LS UT WOS:000223613600282 ER PT J AU Litten, R AF Litten, R TI A perspective from NIAAA. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 29-OCT 02, 2004 CL Heidelberg, GERMANY SP Int Soc Biomed Res Alcoholism C1 NIAAA, Medicat Dev Sect, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2004 VL 28 IS 8 SU S BP 59A EP 59A DI 10.1097/00000374-200408002-00315 PG 1 WC Substance Abuse SC Substance Abuse GA 850LS UT WOS:000223613600315 ER PT J AU Higuchi, S Matsushita, S Yokoyama, A Masaki, T Hara, S Imazeki, H Adachi, J Ramchandani, VJ O'Connor, SJ Li, TK AF Higuchi, S Matsushita, S Yokoyama, A Masaki, T Hara, S Imazeki, H Adachi, J Ramchandani, VJ O'Connor, SJ Li, TK TI Influence of genetic variations of ethanol-metabolizing enzymes on pharmacokinetics of ethanol and phenotypes of alcohol-related disorders. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 29-OCT 02, 2004 CL Heidelberg, GERMANY SP Int Soc Biomed Res Alcoholism C1 NHO, Kurihama Alcoholism Ctr, Yokosuka, Kanagawa 2390841, Japan. Kobe Univ, Grad Sch Med, Kobe, Hyogo 6500017, Japan. NIAAA, DICBR, Bethesda, MD 20892 USA. Indiana Univ Purdue Univ, Sch Med, Indianapolis, IN 46202 USA. NIAAA, Rockville, MD 20852 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2004 VL 28 IS 8 SU S BP 70A EP 70A DI 10.1097/00000374-200408002-00380 PG 1 WC Substance Abuse SC Substance Abuse GA 850LS UT WOS:000223613600379 ER PT J AU Aguayo, LG Yevenes, GE Peoples, RW AF Aguayo, LG Yevenes, GE Peoples, RW TI Modulation of glycine receptor sensitivity to ethanol by G proteins. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 29-OCT 02, 2004 CL Mannheim, GERMANY SP Int Soc Biomed Res Alcoholism C1 Univ Concepcion, Dept Physiol, Concepcion, Chile. NIAAA, Unit Cell Neuropharmacol, NIH, Bethesda, MD USA. 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 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2004 VL 28 IS 8 SU S BP 73A EP 73A DI 10.1097/00000374-200408002-00399 PG 1 WC Substance Abuse SC Substance Abuse GA 850LS UT WOS:000223613600398 ER PT J AU Hommer, DW Bjork, JM Momenan, R Schottenbauer, M AF Hommer, DW Bjork, JM Momenan, R Schottenbauer, M TI Brain growth and shrinkage. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 29-OCT 02, 2004 CL Heidelberg, GERMANY SP Int Soc Biomed Res Alcoholism C1 NIAAA, DICBR, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2004 VL 28 IS 8 SU S BP 75A EP 75A DI 10.1097/00000374-200408002-00412 PG 1 WC Substance Abuse SC Substance Abuse GA 850LS UT WOS:000223613600411 ER PT J AU Lovinger, DM AF Lovinger, DM TI Actions of ethanol and relapse-preventing agents at the NMDA receptor. SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Meeting Abstract CT 12th International Congress of the International-Society-for-Biomedical-Research-on-Alcoholism CY SEP 29-OCT 02, 2004 CL Heidelberg, GERMANY SP Int Soc Biomed Res Alcoholism C1 NIAAA, Rockville, MD 20852 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD AUG PY 2004 VL 28 IS 8 SU S BP 87A EP 87A DI 10.1097/00000374-200408002-00483 PG 1 WC Substance Abuse SC Substance Abuse GA 850LS UT WOS:000223613600481 ER PT J AU Black, S AF Black, S TI The origin of proteins SO AMERICAN BIOLOGY TEACHER LA English DT Letter C1 NIH, Bethesda, MD 20892 USA. RP Black, S (reprint author), NIH, Room 2A04,Bldg 8, Bethesda, MD 20892 USA. EM SimonB@BDG8.NIDDK.NIH.GOV NR 2 TC 1 Z9 1 U1 0 U2 1 PU NATL ASSOC BIOLOGY TEACHERS INC PI RESTON PA 12030 SUNRISE VALLEY DR, #110, RESTON, VA 20191 USA SN 0002-7685 J9 AM BIOL TEACH JI Am. Biol. Teach. PD AUG PY 2004 VL 66 IS 6 BP 407 EP 407 PG 1 WC Biology; Education, Scientific Disciplines SC Life Sciences & Biomedicine - Other Topics; Education & Educational Research GA 844RP UT WOS:000223177600003 ER PT J AU Cury, RC Ferencik, M Hoffmann, U Ferullo, A Moselewski, F Abbara, S Booth, SL O'Donnell, CJ Brady, TJ Achenbach, S AF Cury, RC Ferencik, M Hoffmann, U Ferullo, A Moselewski, F Abbara, S Booth, SL O'Donnell, CJ Brady, TJ Achenbach, S TI Epidemiology and association of vascular and valvular calcium quantified by multidetector computed tomography in elderly asymptomatic subjects SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY-DISEASE; AORTIC-VALVE SCLEROSIS; MITRAL ANNULAR CALCIUM; ROW CT; CALCIFICATION; ATHEROSCLEROSIS; STENOSIS; MARKER AB The epidemiology of and association between vascular and valvular calcium as quantified by multidetector computed tomography (MDCT) were studied in 416 elderly subjects with no history of coronary artery disease. Coronary calcium (CC), descending thoracic aortic calcium (DTAC), aortic valve calcium (AVC), and mitral valve calcium [MVC] were present in 282 (68%), 214 (51%), 152 (37%), and 68 (16%) subjects, respectively. Multiple logistic regression analysis showed that after adjusting for age and gender, subjects with AVC (odds ratio [OR] 2.3), MVC (OR 2.81), and DTAC (OR 2.79) were independently and significantly more likely to have CC. Further evidence is provided for the notion that calcifications in those regions are associated and that MDCT can be used as a tool for the, global assessment of vascular and valvular calcium. (C) 2004 by Excerpta Medica, Inc. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Human Nutr Res Ctr Aging, Jean Mayer USDA, Boston, MA USA. NHLBI, Framingham Heart Dis Epidemiol Study, Framingham, MA USA. RP Cury, RC (reprint author), Massachusetts Gen Hosp, Dept Radiol, 100 Charles River Plaza,Suite 400, Boston, MA 02114 USA. EM rcury@partners.org FU NHLBI NIH HHS [HL69272]; NIA NIH HHS [AG19147] NR 18 TC 10 Z9 10 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD AUG 1 PY 2004 VL 94 IS 3 BP 348 EP 351 DI 10.1016/j.amjcard.2004.04.032 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 843AK UT WOS:000223046300015 PM 15276102 ER PT J AU McDuffie, JR Adler-Wailes, DC Elberg, J Steinberg, EN Fallon, EM Tershakovec, AM Arslanian, SA Delany, JP Bray, GA Yanovski, JA AF McDuffie, JR Adler-Wailes, DC Elberg, J Steinberg, EN Fallon, EM Tershakovec, AM Arslanian, SA Delany, JP Bray, GA Yanovski, JA TI Prediction equations for resting energy expenditure in overweight and normal-weight black and white children SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE child; prediction equation; energy expenditure; metabolic rate; race; obesity ID BASAL METABOLIC-RATE; AFRICAN-AMERICAN; CROSS-VALIDATION; BODY-COMPOSITION; NONOBESE ADOLESCENTS; HEALTHY-CHILDREN; SKELETAL-MUSCLE; CAUCASIAN GIRLS; OBESE; AGREEMENT AB Background: Accurate estimation of children's resting energy expenditure (REE) is important for planning dietary therapy. Objective: Our objective was to compare the utility of 5 REE prediction equations in a diverse sample of young children. Design: REE was obtained in 502 black and white girls and boys aged 6-11 y by using indirect calorimetry at 4 US sites. Measured REE and REE predicted from the equations were compared. Results: None of the equations provided both accurate and unbiased estimates of REE. Two new sets of sex-specific equations including race as a factor were generated and evaluated. One set used easily measured variables-females: REE = 0.046 X weight - 4.492 X 1/height(2) - 0.151 X race + 5.841; males: REE = 0.037 X weight - 4.67 x 1/height(2) - 0.159 X race + 6.792-and accounted for 72% and 69%, respectively, of REE variance. The other set used body-composition variables-females: REE = 0.101 X fat-free mass + 0.025 X fat mass + 0.293 X height(3) -0.185 X race + 1.643; males: REE = 0.078 X fat-free mass + 0.026 X fat mass 2.646 X l[height(2) - 0.244 X race + 4.8-and accounted for 75 % and 71%. respectively, of REE variance. When split by race and adiposity, the small bias generated could be corrected to within 0.25 MJ (60 kcal) of the mean measured value. Conclusion: Sex-specific equations must take race into account to predict REE adequately in children. C1 NICHHD, Unit Growth & Obes, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP McDuffie, JR (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Nutr, Campus Box 7461, Chapel Hill, NC 27599 USA. EM mcduffj@unc.edu FU Intramural NIH HHS [Z01 HD000641-12, Z99 HD999999]; NCRR NIH HHS [M01 RR 00084, M01 RR000084]; NICHD NIH HHS [HD 28020, K24 HD 01357, K24 HD001357, R01 HD 27503, R01 HD027503, Z01 HD 00641, Z01 HD000641] NR 39 TC 31 Z9 33 U1 0 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2004 VL 80 IS 2 BP 365 EP 373 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 841ET UT WOS:000222912800018 PM 15277157 ER PT J AU Moore, SE Jalil, F Ashraf, R Szu, SC Prentice, AM Hanson, LA AF Moore, SE Jalil, F Ashraf, R Szu, SC Prentice, AM Hanson, LA TI Birth weight predicts response to vaccination in adults born in an urban slum in Lahore, Pakistan SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE birth weight; fetal origins; vaccine response; rabies; typhoid; Pakistan ID INFLUENZAE TYPE-B; EARLY CHILD HEALTH; CAPSULAR POLYSACCHARIDE; PRENATAL UNDERNUTRITION; SUBCLASS ANTIBODIES; TYPHOID-FEVER; GROWTH; SEASON; QUANTITATION; AGE AB Background: Substantial evidence exists linking small size at birth to later-life susceptibility to chronic disease. Evidence is also emerging that some components of immune function may be programmed in early life. However, this evidence is limited and requires confirmation. Objective: We investigated the association between size at birth and response to vaccination in a cohort of 257 adults (mean age: 29.4 y; 146 men) born in an urban slum in Lahore, Pakistan, during 1964-1978. Design: A single dose of Vi polysaccharide vaccine for Salmonella typhi and 2 doses of rabies vaccine were given to each subject. Antibody titers were measured in prevaccination serum samples (Vi) and in postvaccination samples (Vi and rabies). Results: The mean birth weight of the subjects was 3.24 kg; 14% of the subjects had low birth weights (<2.5 kg). Vaccine responses were not consistently associated with contemporary variables (month of study, sex, current age, or indicators of wealth). Response to typhoid vaccination was positively related to birth weight (anti-Vi immunoglobulin G: r = 0.138, P = 0.031; anti-Vi immunoglobulin M: r = 0. 197, P = 0.034). Response to the rabies vaccine was not significantly associated with birth weight. Conclusions: These findings add to a growing body of evidence suggesting that components of the immune system may be permanently programmed by events in early life. The contrasting effects on typhoid and rabies responses suggest that antibody generation to polysaccharide antigens, which have greater B cell involvement, is compromised by fetal growth retardation. C1 Univ London London Sch Hyg & Trop Med, MRC, Nutr & Publ Hlth Intervent Res Unit, Int Nutr Grp,Dept Epidemiol & Populat Hlth, London WC1E 7HT, England. King Edward Med Coll, Dept Social & Prevent Paediat, Lahore, Pakistan. Mayo Hosp, Lahore, Pakistan. Natl Inst Hlth, Bethesda, MD USA. Univ Gothenburg, Dept Clin Immunol, Gothenburg, Sweden. RP Moore, SE (reprint author), Univ London London Sch Hyg & Trop Med, MRC, Nutr & Publ Hlth Intervent Res Unit, Int Nutr Grp,Dept Epidemiol & Populat Hlth, Keppel St, London WC1E 7HT, England. EM sophie.moore@lshtm.ac.uk NR 26 TC 49 Z9 51 U1 1 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2004 VL 80 IS 2 BP 453 EP 459 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 841ET UT WOS:000222912800031 PM 15277170 ER PT J AU Lee, JS Kritchevsky, SB Tylavsky, FA Harris, T Everhart, J Simonsick, EM Rubin, SM Newman, AB AF Lee, JS Kritchevsky, SB Tylavsky, FA Harris, T Everhart, J Simonsick, EM Rubin, SM Newman, AB CA Hlth ABC Study TI Weight-loss intention in the well-functioning, community-dwelling elderly: associations with diet quality, physical activity, and weight change SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE weight-loss intention; weight-loss indication; diet quality; physical activity; Health ABC study ID STRUCTURED AEROBIC EXERCISE; SKELETAL-MUSCLE MASS; LIFE-STYLE ACTIVITY; UNITED-STATES; OLDER WOMEN; RANDOMIZED-TRIAL; HEALTHY WEIGHT; US ADULTS; BODY-FAT; OVERWEIGHT AB Background: Many older adults desire to lose weight, yet the proportion with a health-related weight-loss indication, weight-loss strategies, and success is unknown. Objective: We examined the associations of reported intention to lose weight with health-related indications for weight loss, diet quality, physical activity, and weight-loss success in well-functioning older adults. Design: This prospective, community-based cohort included 2708 elderly persons aged 70-79 y at baseline. We determined indication for weight loss by using the modified National Institutes of Health guidelines, diet quality by using the Healthy Eating Index, and weight-loss intention and physical activity by using questionnaires. Measured weight change over 1 y was assessed. Results: Twenty-seven percent of participants reported an intention to lose weight, and 67% of those participants had an indication for weight loss. Participants who reported a weight-loss intention were heavier than those who did not, had more depressive symptoms, and were more likely to be dissatisfied with their weight, regardless of weight-loss indication. Participants with an intention to lose weight reported better eating behaviors and a more active lifestyle than did participants without a weight-loss intention, independent of other health conditions. No significant difference in actual weight loss was found between participants intending and not intending to lose weight, regardless of indication for weight loss. Conclusions: Despite being associated with healthier behaviors, the intention to lose weight did not predict greater weight loss in this well-functioning elderly cohort. More attention needs to be focused on the necessity and efficacy of specific strategies for weight loss in older adults. C1 Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15213 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Univ Tennessee, Memphis, TN USA. NIA, Bethesda, MD 20892 USA. NIDDK, Bethesda, MD USA. NIA, Intramural Res Program, Baltimore, MD 21224 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Lee, JS (reprint author), Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, 130 N Bellefield Ave,5th Floor, Pittsburgh, PA 15213 USA. EM leej@edc.pitt.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 55 TC 16 Z9 16 U1 4 U2 11 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2004 VL 80 IS 2 BP 466 EP 474 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 841ET UT WOS:000222912800033 PM 15277172 ER PT J AU Newby, PK Muller, D Hallfrisch, J Andres, R Tucker, KL AF Newby, PK Muller, D Hallfrisch, J Andres, R Tucker, KL TI Food patterns measured by factor analysis and anthropometric changes in adults SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE food patterns; dietary patterns; factor analysis; principal components; obesity; body composition; diet assessment; body mass index; BMI; waist circumference ID CORONARY-HEART-DISEASE; DIETARY-FAT INTAKE; BODY-MASS INDEX; EATING PATTERNS; FREQUENCY QUESTIONNAIRE; CARDIOVASCULAR-DISEASE; ENERGY DENSITY; OBESITY; WOMEN; RISK AB Background: Sixty-five percent of US adults are overweight, and 31% of these adults are obese. Obesity results from weight gains over time; however, dietary determinants of weight gain remain controversial. Objective: Our objective was to examine whether food patterns derived from exploratory factor analysis are related to anthropometric changes. We hypothesized that we would derive a healthy food pattern and that it would predict smaller changes in body mass index (BMI; in kg/m(2)) and waist circumference (in cm) than would other food patterns in models adjusted for baseline anthropometric measures. Design: The subjects were 459 healthy men and women participating in the Baltimore Longitudinal Study of Aging. Diet was assessed by using 7-d dietary records, from which 40 food groups were formed and entered into a factor analysis. Results: Six food patterns were derived. Factor 1 (reduced-fat dairy products, fruit, and fiber) was most strongly associated with fiber (r = 0.39) and loaded heavily on reduced-fat dairy products, cereal, and fruit and loaded moderately on fruit juice, nonwhite bread, nuts and seeds, whole grains, and beans and legumes. In a multivariate-adjusted model in which the highest and lowest quintiles were compared, factor 1 was inversely associated with annual change in BMI (beta = -0.51; 95% CI: -0.82, -0.20; P < 0.05; P for trend < 0.01) in women and inversely associated with annual change in waist Circumference (P = - 1.06 cm; 95% CI: - 1.88, -0.24 cm; P < 0.05; P for trend = 0.04) in both sexes. Conclusion: Our results suggest that a pattern rich in reduced-fat dairy products and high-fiber foods may lead to smaller gains in BMI in women and smaller gains in waist circumference in both women and men. C1 Tufts Univ, Jean Mayer USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. NIA, Natl Inst Hlth, Baltimore, MD 21224 USA. RP Newby, PK (reprint author), Tufts Univ, Jean Mayer USDA, Human Nutr Res Ctr Aging, 711 Washington St,9th Floor, Boston, MA 02111 USA. EM pknewby@post.harvard.edu RI Tucker, Katherine/A-4545-2010; OI Tucker, Katherine/0000-0001-7640-662X NR 51 TC 160 Z9 167 U1 3 U2 20 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD AUG PY 2004 VL 80 IS 2 BP 504 EP 513 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 841ET UT WOS:000222912800038 PM 15277177 ER PT J AU Castle, PE Wheeler, CM Solomon, D Schiffman, M Peyton, CL AF Castle, PE Wheeler, CM Solomon, D Schiffman, M Peyton, CL CA ALTS Grp TI Interlaboratory reliability of Hybrid Capture 2 SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE human papillomavirus; HPV; cervical cancer; Hybrid Capture 2; polymerase chain reaction; PCR; reproducibility ID ATYPICAL SQUAMOUS-CELLS; ASCUS-LSIL TRIAGE; HUMAN-PAPILLOMAVIRUS; UNDETERMINED SIGNIFICANCE; RANDOMIZED-TRIAL; CERVICAL-CANCER; CYTOLOGY INTERPRETATIONS; MANAGEMENT STRATEGIES; WOMEN; RISK AB We evaluated the interlaboratory reproducibility of the Hybrid Capture 2 (HC2; Digene, Gaithersburg, MD), a test for oncogenic human papillomavirus (HPV) DNA, using data from 4 clinical center (CC) laboratories and the quality control (QC) laboratory participating in the ASCUS (atypical squamous cells of undetermined significance) and LSIL (low-grade squamous intraepithelial lesion) Triage Study (ALTS). Residual liquid cytology specimens were tested routinely throughout the duration of ALTS at CC laboratories, and a stratified (by time in the study) random sample of specimens was retested by the HPV QC laboratory using equivalent protocols. Of the specimens selected (N = 1, 175, 5.50% of all specimens obtained), 1, 072 (91.23%) had sufficient specimen volume for retesting. The kappa value between all CC laboratories and the HPV QC laboratory was 0.84 (95% confidence interval, 0.78-0.89), with kappa values for individual CCs and the HPV QC laboratory ranging from 0.79 to 0.89. Agreement between test results was lowest among results for women with negative cytologic findings (0.73); among those with equivocal or abnormal cytologic findings, kappa values were 0.80 or more. These data show that HC2 is a reliable test for detecting clinically relevant oncogenic HPV DNA. C1 Univ New Mexico, Dept Mol Genet & Microbiol, Ctr Hlth Sci, Sch Med, Albuquerque, NM 87131 USA. Univ New Mexico, Dept Obstet & Gynecol, Ctr Hlth Sci, Sch Med, Albuquerque, NM 87131 USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. Natl Canc Inst, Div Canc Prevent, Natl Inst Hlth, DHHS, Bethesda, MD USA. RP Wheeler, CM (reprint author), Univ New Mexico, Dept Mol Genet & Microbiol, Ctr Hlth Sci, Sch Med, Room 347,915 Camino Salud NE, Albuquerque, NM 87131 USA. FU NCI NIH HHS [CN-55105, CN-55153, CN-55154, CN-55155, CN-55156, CN-55157, CN-55158, CN-55159] NR 21 TC 78 Z9 78 U1 0 U2 4 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD AUG PY 2004 VL 122 IS 2 BP 238 EP 245 DI 10.1309/BA43HMCAJ26VWQH3 PG 8 WC Pathology SC Pathology GA 841RN UT WOS:000222949200011 PM 15323141 ER PT J AU Klebanoff, MA Schoendorf, KC AF Klebanoff, MA Schoendorf, KC TI Invited commentary: What's so bad about curves crossing anyway? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID BIRTH-WEIGHT; PRETERM LABOR; MORTALITY; INFANTS C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. CDCP, Infant & Child Hlth Studies Branch, Natl Ctr Hlth Stat, US Dept HHS, Hyattsville, MD USA. RP Klebanoff, MA (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, 6100 Bldg,7B05, Bethesda, MD 20892 USA. EM mk90h@nih.gov OI Platt, Robert/0000-0002-5981-8443 NR 11 TC 21 Z9 21 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2004 VL 160 IS 3 BP 211 EP 212 DI 10.1093/aje/kwh203 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 843FF UT WOS:000223063200004 PM 15257991 ER PT J AU Wilcox, AJ Weinberg, CR AF Wilcox, AJ Weinberg, CR TI Invited commentary: Analysis of gestational-age-specific mortality - On what biologic foundations? SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID STILLBIRTH; RISK C1 NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biometry Branch, NIH, Durham, NC USA. RP Wilcox, AJ (reprint author), NIEHS, Epidemiol Branch, NIH, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM wilcox@niehs.nih.gov OI Platt, Robert/0000-0002-5981-8443; Wilcox, Allen/0000-0002-3376-1311 NR 7 TC 18 Z9 18 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 1 PY 2004 VL 160 IS 3 BP 213 EP 214 DI 10.1093/aje/kwh204 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 843FF UT WOS:000223063200005 PM 15257992 ER PT J AU Goldschmidt, N Gural, A Kornberg, A Spectre, G Shopen, A Paltiel, O AF Goldschmidt, N Gural, A Kornberg, A Spectre, G Shopen, A Paltiel, O TI Prolonged fever of unknown origin and hemophagocytosis evolving into acute lymphoblastic leukemia SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE hemophagocytic syndrome; fever of unknown origin; cytokines; acute lymphoblastic leukemia ID LYMPHOHISTIOCYTOSIS; INFECTION AB Hemophagocytic syndrome (HPS) is an unusual acute syndrome presenting with fever, hepatosplenomegaly, and cytopenias. The hallmark of HPS is the accumulation of activated macrophages that engulf hematopoietic cells in the reticuloendothelial system. Most cases of HIPS in adults are secondary to infection or malignancy, and thus investigation of the underlying disease is necessary. We describe a patient with prolonged fever, HPS, and chromosomal abnormalities in the bone marrow who underwent thorough evaluation for the cause of his symptoms. A final diagnosis of acute lymphoblastic leukemia (ALL) was established in a fourth, repeated bone marrow biopsy performed more than 2 months after the first presenting symptom appeared. This unusual case demonstrates the importance of cytogenetic abnormalities found in cases of HPS and the importance of repeated testing when an underlying disease is suspected. (C) 2004 Wiley-Liss, Inc. C1 Hadassah Med Ctr, Dept Social Med, IL-91120 Jerusalem, Israel. Assaf Harofeh Med Ctr, Dept Internal Med D, IL-70300 Zerifin, Israel. Assaf Harofeh Med Ctr, Inst Hematol, IL-70300 Zerifin, Israel. Hadassah Med Ctr, Dept Hematol, IL-91120 Jerusalem, Israel. RP Goldschmidt, N (reprint author), NIH, Bldg 10,9000 Rockville Pike,RM 4N114, Bethesda, MD 20892 USA. EM goldschn@mail.nih.gov NR 10 TC 5 Z9 5 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD AUG PY 2004 VL 76 IS 4 BP 364 EP 367 DI 10.1002/ajh.20123 PG 4 WC Hematology SC Hematology GA 841RO UT WOS:000222949300009 PM 15282670 ER PT J AU Marazita, ML Murray, JC Lidral, AC Arcos-Burgos, M Cooper, ME Goldstein, T Maher, BS Daack-Hirsch, S Schultz, R Mansilla, MA Field, LL Liu, Y Prescott, N Malcolm, S Winter, R Ray, A Moreno, L Valencia, C Neiswanger, K Wyszynski, DF Bailey-Wilson, JE Albacha-Hejazi, H Beaty, TH McIntosh, I Hetmanski, JB Tuncbilek, G Edwards, M Harkin, L Scott, R Roddick, LG AF Marazita, ML Murray, JC Lidral, AC Arcos-Burgos, M Cooper, ME Goldstein, T Maher, BS Daack-Hirsch, S Schultz, R Mansilla, MA Field, LL Liu, Y Prescott, N Malcolm, S Winter, R Ray, A Moreno, L Valencia, C Neiswanger, K Wyszynski, DF Bailey-Wilson, JE Albacha-Hejazi, H Beaty, TH McIntosh, I Hetmanski, JB Tuncbilek, G Edwards, M Harkin, L Scott, R Roddick, LG TI Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32-35 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID LINKAGE ANALYSIS; PALATE CL/P; PART I; LIP; FAMILIES; IDENTIFICATION; HETEROGENEITY; ASSOCIATION; PHENOTYPE; POWER AB Isolated or nonsyndromic cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex etiology. A 10-cM genome scan of 388 extended multiplex families with CL/P from seven diverse populations (2,551 genotyped individuals) revealed CL/P genes in six chromosomal regions, including a novel region at 9q21 (heterogeneity LOD score [HLOD] = 6.6). In addition, meta-analyses with the addition of results from 186 more families ( six populations; 1,033 genotyped individuals) showed genomewide significance for 10 more regions, including another novel region at 2q32-35 (P = .0004). These are the first genomewide significant linkage results ever reported for CL/P, and they represent an unprecedented demonstration of the power of linkage analysis to detect multiple genes simultaneously for a complex disorder. C1 Univ Pittsburgh, Ctr Craniofacial & Dent Genet, Div Oral Biol, Sch Dent Med, Pittsburgh, PA 15219 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15219 USA. Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. Univ Iowa, Dept Orthodont, Iowa City, IA USA. Univ Iowa, Dow Inst Dent Res, Iowa City, IA USA. Univ Antioquia, Medellin, Colombia. Univ British Columbia, Dept Med Genet, Vancouver, BC, Canada. British Columbia Res Inst Childrens & Womens Hlth, Vancouver, BC, Canada. Zhabei Genet Inst, Shanghai, Peoples R China. Inst Child Hlth, Mol Genet Unit, London, England. Univ Toronto, Dept Anthropol Emeritus, Toronto, ON, Canada. Boston Univ, Dept Epidemiol, Boston, MA 02215 USA. Boston Univ, Dept Med, Genet Program, Boston, MA 02215 USA. NHGRI, Stat Genet Sect, NIH, Baltimore, MD USA. Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Sch Med, Inst Med Genet, Baltimore, MD USA. Ibn Al Nafees Hosp, Damascus, Syria. Hacettepe Univ, Dept Plast Surg, Ankara, Turkey. Hunter Area Hlth Serv, Newcastle, NSW, Australia. Univ Newcastle, Sch Biomed Sci, Discipline Med Genet, Newcastle, NSW 2308, Australia. John Hunter Childrens Hosp, Hunter Med Res Inst, Newcastle, NSW, Australia. Univ Adelaide, Dept Paediat, Adelaide, SA, Australia. Univ Adelaide, Womens & Childrens Hosp, Dept Med Genet, Adelaide, SA, Australia. RP Marazita, ML (reprint author), Univ Pittsburgh, Ctr Craniofacial & Dent Genet, Div Oral Biol, Sch Dent Med, 100 Technol Dr,Suite 500 Cellom Bldg, Pittsburgh, PA 15219 USA. EM marazita@sdmgenetics.pitt.edu RI Maher, Brion/F-9185-2010; Prescott, Natalie/F-6490-2011; Edwards, Matthew/A-7560-2011; OI Prescott, Natalie/0000-0002-5901-7371; Edwards, Matthew/0000-0001-8437-8120; Bailey-Wilson, Joan/0000-0002-9153-2920 FU NCRR NIH HHS [M01 RR000084, RR-00084]; NIDCR NIH HHS [P60 DE013076-03S10005, K02 DE015291, K02 DE015291-01, K02 DE015291-02, K02 DE015291-03, K02 DE015291-04, K02 DE015291-05, P60 DE013076, P60 DE013076-010005, P60 DE013076-01S10005, P60 DE013076-020005, P60 DE013076-030005, P60 DE013076-040005, P60 DE013076-050005, P60 DE013078, P60-DE-13076, P60-DE-13078, P60-DE13076, R01 DE008559, R01 DE009886, R01 DE014667, R01 DE014667-01, R01 DE014667-02, R01 DE014667-03, R01 DE014667-04, R01 DE014667-05, R01 DE014667-06, R01 DE014667-07, R01 DE014667-08, R01 DE016148, R01-DE-08559, R01-DE-09886, R01-DE-12472, R01-DE-14667] NR 57 TC 126 Z9 135 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 2004 VL 75 IS 2 BP 161 EP 173 DI 10.1086/422475 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 838GR UT WOS:000222702000002 PM 15185170 ER PT J AU Begovich, AB Carlton, VEH Honigberg, LA Schrodi, SJ Chokkalingam, AP Alexander, HC Ardlie, KG Huang, QQ Smith, AM Spoerke, JM Conn, MT Chang, M Chang, SYP Saiki, RK Catanese, JJ Leong, DU Garcia, VE McAllister, LB Jeffery, DA Lee, AT Batliwalla, F Remmers, E Criswell, LA Seldin, MF Kastner, DL Amos, CI Sninsky, JJ Gregersen, PK AF Begovich, AB Carlton, VEH Honigberg, LA Schrodi, SJ Chokkalingam, AP Alexander, HC Ardlie, KG Huang, QQ Smith, AM Spoerke, JM Conn, MT Chang, M Chang, SYP Saiki, RK Catanese, JJ Leong, DU Garcia, VE McAllister, LB Jeffery, DA Lee, AT Batliwalla, F Remmers, E Criswell, LA Seldin, MF Kastner, DL Amos, CI Sninsky, JJ Gregersen, PK TI A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE LINKAGE; AUTOIMMUNE-DISEASES; T-CELLS; SUSCEPTIBILITY LOCUS; KINASE P50(CSK); COMPLEX; PEP; LYP; FREQUENCY; FAMILIES AB Rheumatoid arthritis (RA) is the most common systemic autoimmune disease, affecting similar to1% of the adult population worldwide, with an estimated heritability of 60%. To identify genes involved in RA susceptibility, we investigated the association between putative functional single-nucleotide polymorphisms (SNPs) and RA among white individuals by use of a case-control study design; a second sample was tested for replication. Here we report the association of RA susceptibility with the minor allele of a missense SNP in PTPN22 (discovery-study allelic P = 6.6 x 10(-4); replication-study allelic P = 5.6 x 10(-8)), which encodes a hematopoietic-specific protein tyrosine phosphatase also known as "Lyp." We show that the risk allele, which is present in similar to17% of white individuals from the general population and in similar to28% of white individuals with RA, disrupts the P1 proline-rich motif that is important for interaction with Csk, potentially altering these proteins' normal function as negative regulators of T-cell activation. The minor allele of this SNP recently was implicated in type 1 diabetes, suggesting that the variant phosphatase may increase overall reactivity of the immune system and may heighten an individual carrier's risk for autoimmune disease. C1 Celera Diagnost, Alameda, CA 94502 USA. Celera Genom, San Francisco, CA USA. Genom Collaborat Inc, Cambridge, MA USA. Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. N Shore LIJ Res Inst, Ctr Genom & Human Genet, Manhasset, NY USA. NIAMSD, Genet & Genom Branch, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Med, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA USA. Univ Calif Davis, Dept Med, Rowe Program Human Genet, Davis, CA 95616 USA. RP Begovich, AB (reprint author), Celera Diagnost, 1401 Harbor Bay Pkwy, Alameda, CA 94502 USA. EM Ann.Begovich@celeradiagnostics.com OI Schrodi, Steven/0000-0003-2304-8528 FU NCRR NIH HHS [5 M01 RR-00079, M01 RR000079]; NHGRI NIH HHS [HG 02275, R01 HG002275]; NIAMS NIH HHS [N01-AR-7-2232, R01-AR44222] NR 37 TC 878 Z9 911 U1 7 U2 39 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD AUG PY 2004 VL 75 IS 2 BP 330 EP 337 DI 10.1086/422827 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 838GR UT WOS:000222702000018 PM 15208781 ER PT J AU Abbott, KC Swanson, SJ Richter, ER Bohen, EM Agodoa, LY Peters, TG Barbour, G Lipnick, R Cruess, DF AF Abbott, KC Swanson, SJ Richter, ER Bohen, EM Agodoa, LY Peters, TG Barbour, G Lipnick, R Cruess, DF TI Late urinary tract infection after renal transplantation in the United States SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE US Renal Data System (USRDS); urinary tract infection; pyelonephritis; death; graft loss; survival; women; sepsis; creatinine; renal insufficiency; cardiovascular disease; cytomegalovirus ID PERIOPERATIVE ANTIBIOTIC-PROPHYLAXIS; KIDNEY-TRANSPLANTATION; GRAFT LOSS; COMPLICATIONS; DISEASE; SEPTICEMIA; RECIPIENTS; RISK AB Background Although urinary tract infection (UTI) occurring late after renal transplantation has been considered "benign," this has not been confirmed in a national population of renal transplant recipients. Methods: We conducted a retrospective cohort study of 28,942 Medicare primary renal transplant recipients in the United States Renal Data System (USRDS) database from January 1, 1996, through July 31, 2000, assessing Medicare claims for UTI occurring later than 6 months after transplantation based on International Classification of Diseases, 9th Revision (ICD-9), codes and using Cox regression to calculate adjusted hazard ratios (AHRs) for time to death and graft loss (censored for death), respectively. Results:The cumulative incidence of UTI during the first 6 months after renal transplantation was 17% (equivalent for both men and women), and at 3 years was 60% for women and 47% for men (P < 0.001 in Cox regression analysis). Late UTI was significantly associated with an increased risk of subsequent death in Cox regression analysis (P < 0.001; AHR, 2.93; 95% confidence interval [CI], 2.22, 3.85); and AHR for graft loss was 1.85 (95% Cl, 1.29, 2.64). The association of UTI with death persisted after adjusting for cardiac and other infectious complications, and regardless of whether UTI was assessed as a composite of outpatient/Inpatient claims, primary hospitalized UTI, or solely outpatient UTI. Conclusion: Whether due to a direct effect or as a marker for serious underlying illness, UTI occurring late after renal transplantation, as coded by clinicians in the United States, does not portend a benign outcome. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Walter Reed Army Med Ctr, Organ Transplant Serv, Washington, DC 20307 USA. NIDDK, NIH, Bethesda, MD USA. Jacksonville Transplant Ctr Shands, Jacksonville, FL USA. Univ Florida, HSCS, Dept Surg, Jacksonville, FL USA. Uniformed Serv Univ Hlth Sci, Dept Prevent Med, Div Hlth Serv Adm, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Prevent Med, Div Epidemiol, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. EM kevin.abbott@na.amedd.army.mil OI Abbott, Kevin/0000-0003-2111-7112 NR 29 TC 105 Z9 110 U1 0 U2 1 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD AUG PY 2004 VL 44 IS 2 BP 353 EP 362 DI 10.1053/j.ajkd.2004.04.040 PG 10 WC Urology & Nephrology SC Urology & Nephrology GA 844PP UT WOS:000223172400022 PM 15264195 ER PT J AU Biesecker, L AF Biesecker, L TI Endangered species SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Editorial Material C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Biesecker, L (reprint author), NHGRI, NIH, 49 Convent Dr Room 4A80, Bethesda, MD 20892 USA. EM leslieb@helix.nih.gov NR 4 TC 4 Z9 4 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 A JI Am. J. Med. Genet. A PD AUG 1 PY 2004 VL 128A IS 4 BP 429 EP 430 DI 10.1002/ajmg.a.30202 PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 841RV UT WOS:000222950000015 PM 15264292 ER PT J AU Chrousos, GP AF Chrousos, GP TI The glucocorticoid receptor gene, longevity, and the complex disorders of western societies SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID PITUITARY-ADRENAL AXIS; METABOLIC SYNDROME; STRESS; NEUROENDOCRINE; RESISTANCE; FEATURES; INSULIN C1 NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Chrousos, GP (reprint author), NICHD, NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM chrousosg@mail.nih.gov NR 20 TC 27 Z9 27 U1 0 U2 3 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 1 PY 2004 VL 117 IS 3 BP 204 EP 207 DI 10.1016/j.amjmed.2004.05.006 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 843BG UT WOS:000223049500012 PM 15300973 ER PT J AU Simon, A Bodar, EJ van der Hilst, JCH van der Meer, JWM Fiselier, TJW Cuppen, MPJM Drenth, JPH AF Simon, A Bodar, EJ van der Hilst, JCH van der Meer, JWM Fiselier, TJW Cuppen, MPJM Drenth, JPH TI Beneficial response to interleukin I receptor antagonist in traps SO AMERICAN JOURNAL OF MEDICINE LA English DT Letter ID PERIODIC SYNDROME TRAPS; RHEUMATOID-ARTHRITIS; ANAKINRA; PROTEIN; SAFETY; PYRIN C1 Univ Med Ctr St Radboud, Nijmegen, Netherlands. Slingeland Hosp, Doetinchem, Netherlands. NICHHD, Bethesda, MD 20892 USA. RP Simon, A (reprint author), Univ Med Ctr St Radboud, Nijmegen, Netherlands. RI Simon, Anna/D-3757-2009; Drenth, J.P.H./H-8025-2014; van der Meer, Jos/C-8521-2013 OI Simon, Anna/0000-0002-6141-7921; van der Meer, Jos/0000-0001-5120-3690 NR 10 TC 105 Z9 108 U1 0 U2 0 PU EXCERPTA MEDICA INC PI NEW YORK PA 650 AVENUE OF THE AMERICAS, NEW YORK, NY 10011 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD AUG 1 PY 2004 VL 117 IS 3 BP 208 EP 210 DI 10.1016/j.amjmed.2004.02.039 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 843BG UT WOS:000223049500014 PM 15300976 ER PT J AU Zhang, J Hamilton, B Martin, J Trumble, A AF Zhang, Jun Hamilton, Brady Martin, Joyce Trumble, Ann TI Delayed interval delivery and infant survival: A population-based study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE delayed interval delivery; infant; multiple gestation; survival; twin AB Objective: Delaying delivery of the remaining fetus(es) in a multifetal pregnancy is feasible in some cases. However, the impact of this procedure on infant survival is unclear. Study design: We used the US 1995-1998 Matched Multiple Birth File. We identified 200 twin pregnancies in which the first twin was delivered between 17 and 29 weeks of gestation and the second twin was delivered 2 or more days later. We individually matched the delayed deliveries with 374 twin pregnancies in which the second twin was delivered on the same or next calendar day. Perinatal outcomes and infant survival were compared between the delayed and nondelayed twins. Results: Among the 200 pregnancies with delayed delivery, the mean gestational age at first delivery was 23 weeks and the median duration of delay was 6 days (ranging from 2-107 days). One week of delay in delivery was associated with an increase in infant birth weight of 131 g on average (95% CI: 115-147 g). Moreover, 56% of the delayed second twins survived to 1 year of age, whereas only 24% of the nondelayed second twins survived to 1 year of age (P < .001). However, 11% of the second twin in delayed delivery (95% CI: 6%-16%) experienced fetal death before 24 weeks. Conclusion: Delayed delivery of the remaining fetus(es) before 30 weeks of gestation for 2 or more days was associated with improved infant survival. (C) 2004 Elsevier Inc. All rights reserved. C1 [Zhang, Jun; Trumble, Ann] NICHHD, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Bethesda, MD 20892 USA. [Hamilton, Brady; Martin, Joyce] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Bethesda, MD USA. RP Zhang, J (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, DHHS, Bethesda, MD 20892 USA. NR 8 TC 22 Z9 23 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD AUG PY 2004 VL 191 IS 2 BP 470 EP 476 DI 10.1016/j.ajog.2004.03.002 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA V58VL UT WOS:000203976500013 PM 15343223 ER PT J AU Knudtson, EJ Smith, K Mercer, BM Miodovnik, M Thurnau, GR Goldenberg, RL Meis, PJ Moawad, AH Vandorsten, JP Sorokin, Y Roberts, JM Das, A AF Knudtson, Eric J. Smith, Kenneth Mercer, Brian M. Miodovnik, Menachem Thurnau, Gary R. Goldenberg, Robert L. Meis, Paul J. Moawad, Atef H. Vandorsten, J. Peter Sorokin, Yoram Roberts, James M. Das, Anita CA Natl Inst Child Hlth Human Dev Mat TI Serum homocysteine levels after preterm premature rupture of the membranes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE fetal-membranes-premature-rupture; prematurity; homocysteine; smoking; body mass index ID CARDIOVASCULAR-DISEASE; RISK-FACTORS; PREGNANCY; PLASMA; HYPERHOMOCYSTEINEMIA; PREDICTION; BIRTH; WOMEN AB Objective: Preterm premature rupture of the membranes (PPROM) is believed to be caused, in part, by abnormalities of collagen and increased levels of oxidative stress. Elevated homocysteine levels have been shown to induce these same pathophysiologic changes. We tested the hypothesis that serum homocysteine levels would be higher in women with PPROM when compared with matched control women. Study design: A secondary analysis derived from 2 previously completed studies performed in the National Institutes of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network. We identified 99 study cases with PPROM (24 to 32 weeks' gestation) and matched them with 99 asymptomatic control women from an observational study of preterm birth prediction. Cases and control women were matched for race, gestational age at sampling, and MFMU Network center. Serum homocysteine levels were determined by immunoassay in batch fashion by personnel masked to study arm and clinical outcomes. Serum homocysteine levels were compared between groups, as were the baseline characteristics of maternal age, cigarette smoking, nulliparity, infections during pregnancy, and body mass index (BMI) < 19.8 kg/m(2). Serum homocysteine levels were dichotomized as > 75th, 90th, and 95th %ile of control women, and the likelihood of elevated homocysteine levels was determined in women who smoked, had a BMI < 19.8 kg/m(2), or who had PPROM. Statistical analyses included the Wilcoxon rank sum, chi-square, and Pearson correlation coefficient, where appropriate. Baseline characteristics were controlled with a logistic regression model. Results: Serum homocysteine levels measured in patients with PPROM were not significantly different from matched control women: median and (25th to 75th %ile): 4.9 (3.5-6.2) vs 4.8 (3.9-6.2 mu mol/L), P = .73. In our population, neither the number of cigarettes smoked (r = -0.08, P = . 57), nor BMI (r = -0.08, P = .24) correlated with serum homocysteine levels. The strongest association was seen in women with PPROM having serum homocysteine levels >95th %ile of control women (odds ratio [OR] 2.7, P = . 10). After adjusting for baseline characteristics, no correlation between serum homocysteine level and the presence of PPROM was seen, OR 1.0 (. 9-1.1); P = .99. Conclusion: Women presenting with PPROM did not have significantly increased serum homocysteine levels when compared with control women. (C) 2004 Elsevier Inc. All rights reserved. C1 [Knudtson, Eric J.; Smith, Kenneth; Mercer, Brian M.; Miodovnik, Menachem; Thurnau, Gary R.; Goldenberg, Robert L.; Meis, Paul J.; Moawad, Atef H.; Vandorsten, J. Peter; Sorokin, Yoram; Roberts, James M.; Das, Anita; Natl Inst Child Hlth Human Dev Mat] NICHHD, Maternal Fetal Med Units Network, Bethesda, MD 20892 USA. RP Knudtson, EJ (reprint author), NICHHD, Maternal Fetal Med Units Network, Bethesda, MD 20892 USA. FU National Institutes of Child Health and Human Development [U10-HD-21434, U10-HD-27917, U10-HD-27915, U10-HD-27869, U10-HD-27905, U10-HD-27861, U10-HD-27860, U10-HD-27889, U10-HD-27883, U10-HD-21414, U01-HD-36801, U10-HD-19897] FX Supported by National Institutes of Child Health and Human Development grants U10-HD-21434, U10-HD-27917, U10-HD-27915, U10-HD-27869, U10-HD-27905, U10-HD-27861, U10-HD-27860, U10-HD-27889, U10-HD-27883, U10-HD-21414, U01-HD-36801, and U10-HD-19897. NR 18 TC 7 Z9 7 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD AUG PY 2004 VL 191 IS 2 BP 537 EP 541 DI 10.1016/j.ajog.2003.12.005 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA V58VL UT WOS:000203976500023 PM 15343233 ER PT J AU Parker, JD Alvero, RJ Luterzo, J Segars, JH Armstrong, AY AF Parker, Jason D. Alvero, Ruben J. Luterzo, Julie Segars, James H. Armstrong, Alicia Y. TI Assessment of resident competency in the performance of sonohysterography: Does the level of training impact the accuracy? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE saline sonohysterography; resident training AB Objective: The objective of this study was to examine the true-positive rates by level of training of the operator and to determine whether the accuracy of the procedure differed by the level of education after formalized training. Study design: This was a retrospective analysis. The records of patients who underwent surgery for the indication of an abnormal saline sonohysterography were reviewed from January 2001 to April 2003 (n = 73 patients). The nature of the saline sonohysterography abnormality, the intraoperative findings, and the level of training of the provider were recorded. Findings at saline sonohysterography were compared with findings at hysteroscopy or surgery. Statistical significance was determined by c 2 test. Results: The overall true-positive rate was 86.3% (63/73 patients). The true-positive rates for nurse practitioners, second- and fourth-year residents, and fellows were 84%, 80%, 90%, and 89%, respectively. There was no significant difference among providers (P=.96). Conclusion: The true-positive rates for saline hysterography were comparable among different provider levels. (c) 2004 Elsevier Inc. All rights reserved. C1 [Armstrong, Alicia Y.] NIH, NICHD, Pediat & Reprod Endocrine Branch 9D42, Bethesda, MD 20892 USA. [Parker, Jason D.; Luterzo, Julie] Walter Reed Army Med Ctr, Dept Obstet & Gynecol, Washington, DC 20307 USA. [Parker, Jason D.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Alvero, Ruben J.] Univ Colorado, Hlth Sci Ctr, Div Reprod Endocrinol & Infertil, Aurora, CO USA. RP Armstrong, AY (reprint author), NIH, NICHD, Pediat & Reprod Endocrine Branch 9D42, Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM armstroa@mail.nih.gov NR 25 TC 5 Z9 5 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD AUG PY 2004 VL 191 IS 2 BP 582 EP 586 DI 10.1016/j.ajog.2004.03.011 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA V58VL UT WOS:000203976500031 PM 15343241 ER PT J AU Schaefer, L Mihalik, D Babelova, A Krzyzankova, M Grone, HJ Iozzo, RV Young, MF Seidler, DG Lin, GQ Reinhardt, DP Schaefer, RM AF Schaefer, L Mihalik, D Babelova, A Krzyzankova, M Grone, HJ Iozzo, RV Young, MF Seidler, DG Lin, GQ Reinhardt, DP Schaefer, RM TI Regulation of fibrillin-1 by biglycan and decorin is important for tissue preservation in the kidney during pressure-induced injury SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; ABNORMAL COLLAGEN FIBRILS; MARFAN-SYNDROME; SMALL PROTEOGLYCANS; DEFICIENT EXPRESSION; TARGETED DISRUPTION; MESANGIAL CELLS; TERNARY COMPLEX; SKIN FRAGILITY; FIBROMODULIN AB There is growing evidence that the two small leucine-rich proteoglycans biglycan and decorin regulate the assembly of connective tissues and alter cell behavior during development and pathological processes. in this study, we have used an experimental animal model of unilateral ureteral ligation and mice deficient in either biglycan or decorin. We discovered that pressure-induced injury to the wild-type kidneys led to overexpression of decorin, biglycan, fibrillin-1, and fibrillin-2. In contrast, in biglycan-deficient kidneys the overexpression of fibrillin-1 was markedly attenuated and this was associated with cystic dilatation of Bowman's capsule and proximal tubules. Notably, we found that in ligated kidneys from decorin-null mice, fibrillin-1 expression was initially enhanced to the same extent as in wild-type animals. However, long-term obstruction resulted in down-regulation of fibrillin-1 and concurrent cystic dilatation of Bowman's capsule in 33% of kidneys at 5 months after obstruction. in all of the genotypes, no differences in fibrillin-2 expression were observed. These in vivo data correlated with a significant induction of fibrillin-1 expression in renal fibroblasts and mesangial cells by recombinant biglycan and decorin. Our results indicate a novel role for decorin and biglycan during pressure-induced renal injury by stimulating fibrillin-1 expression. C1 Univ Munster, Dept Internal Med D, D-4400 Munster, Germany. Univ Munster, Dept Physiol Chem & Pathobiochem, D-4400 Munster, Germany. German Canc Res Ctr, Dept Cellular & Mol Pathol, D-6900 Heidelberg, Germany. Univ Lubeck, Dept Med Mol Biol, Lubeck, Germany. Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. Natl Inst Dental Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Schaefer, RM (reprint author), Med Klin & Poliklin D, Albert Schweitzer Str 33, D-48149 Munster, Germany. EM schaefl@uni-muenster.de RI Reinhardt, Dieter/A-3102-2008; OI Reinhardt, Dieter/0000-0001-6535-9872; Iozzo, Renato/0000-0002-5908-5112 FU NCI NIH HHS [R01 CA039481, R01 CA39481] NR 50 TC 38 Z9 39 U1 1 U2 4 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD AUG PY 2004 VL 165 IS 2 BP 383 EP 396 DI 10.1016/S0002-9440(10)63305-6 PG 14 WC Pathology SC Pathology GA 840XL UT WOS:000222893400004 PM 15277214 ER PT J AU Jaruga, B Hong, F Kim, WH Sun, R Fan, S Gao, B AF Jaruga, B Hong, F Kim, WH Sun, R Fan, S Gao, B TI Chronic alcohol consumption accelerates liver injury in T cell-mediated hepatitis: alcohol disregulation of NF-kappa B and STAT3 signaling pathways SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE alcoholic liver injury; concanavalin A; nuclear factor-kappa B; STAT3 ID TUMOR-NECROSIS-FACTOR; TNF-ALPHA PRODUCTION; CHRONIC ETHANOL; CONCANAVALIN-A; AUTOIMMUNE HEPATITIS; MESSENGER-RNA; DISEASE; ACTIVATION; EXPRESSION; RAT AB Alcohol consumption is a major risk factor accelerating the progression of liver disease in patients with chronic hepatitis virus infection. However, the mechanism underlying the enhanced susceptibility of alcoholics to liver injury is not fully understood. Here, we demonstrate that chronic ethanol consumption increases the susceptibility of C57BL/6 mice to concanavalin A (Con A)-induced T cell-mediated hepatitis. Injection of a low dose of Con A (5 mug/g) causes severe liver damage in ethanol-fed mice as evidenced by a significant elevation of serum alanine amino-transaminase levels, massive necrosis, and infiltration of leukocytes but only slightly induces liver injury in control pair-fed mice. In ethanol-fed mice, the activation and cytotoxicity of natural killer T cells, cells that play key roles in Con A-induced T cell hepatitis, are not significantly enhanced relative to pair-fed mice. Moreover, Con A-induced activation of hepatic NF-kappaB is increased, whereas activation of STAT1 and STAT3 is attenuated in ethanol-fed mice. Consistent with this result, the expression of chemokines and adhesion molecules [such as ICAM-1, macrophage inflammatory protein (MIP)-1, MIP-2, and MCP-1] controlled by NF-kappaB is upregulated, whereas STAT1-controlled expression of chemokines (such as MIG and IP-10) is downregulated in ethanol-fed mice compared with pair-fed mice. In conclusion, chronic alcohol consumption accelerates T cell-mediated hepatitis via upregulation of the NF-kappaB signaling pathway and subsequently enhances expression of chemokines/adhesive molecules and recruitment of leukocytes into the liver. Downregulation of the antiapoptotic STAT3 signal may also contribute to alcohol potentiation of T cell hepatitis. C1 NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Mol Oncol Lab, Washington, DC 20007 USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Park Bldg,Rm 120,12420 Parklawn Dr,MSC 8115, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov NR 51 TC 33 Z9 33 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD AUG PY 2004 VL 287 IS 2 BP G471 EP G479 DI 10.1152/ajpgi.00018.2004 PG 9 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 836JT UT WOS:000222552500021 PM 15064234 ER PT J AU Satow, T Ikeda, A Yamamoto, J Begum, T Dinh, HDT Matsuhashi, M Mima, T Nagamine, T Baba, K Mihara, T Inoue, Y Miyamoto, S Hashimoto, N Shibasaki, H AF Satow, T Ikeda, A Yamamoto, J Begum, T Dinh, HDT Matsuhashi, M Mima, T Nagamine, T Baba, K Mihara, T Inoue, Y Miyamoto, S Hashimoto, N Shibasaki, H TI Role of primary sensorimotor cortex and supplementary motor area in volitional swallowing: a movement-related cortical potential study SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE deglutition; electrophysiology; human ID DYSPHAGIA; REPRESENTATION; DEGLUTITION; MASTICATION; ACTIVATION; TOPOGRAPHY; PATTERNS; HUMANS; STROKE AB We investigated the role of the cerebral cortex, particularly the face/tongue area of the primary sensorimotor (SMI) cortex (face/tongue) and supplementary motor area (SMA), in volitional swallowing by recording movement-related cortical potentials (MRCPs). MRCPs with swallowing and tongue protrusion were recorded from scalp electrodes in eight normal right-handed subjects and from implanted subdural electrodes in six epilepsy patients. The experiment by scalp EEG in normal subjects revealed that premovement Bereitschaftspotentials (BP) activity for swallowing was largest at the vertex and lateralized to either hemisphere in the central area. The experiment by epicortical EEG in patients confirmed that face/tongue SMI and SMA were commonly involved in swallowing and tongue protrusion with overlapping distribution and interindividual variability. BP amplitude showed no difference between swallowing and tongue movements, either at face/tongue SMI or at SMA, whereas postmovement potential (PMP) was significantly larger in tongue protrusion than in swallowing only at face/tongue SMI. BP occurred earlier in swallowing than in tongue protrusion. Comparison between face/tongue SMI and SMA did not show any difference with regard to BP and PMP amplitude or BP onset time in either task. The preparatory role of the cerebral cortex in swallowing was similar to that in tongue movement, except for earlier activation in swallowing. Postmovement processing of swallowing was lesser than that of tongue movement in face/tongue SMI; probably suggesting that the cerebral cortex does not play a significant role in postmovement processing of swallowing. SMA plays a supplementary role to face/tongue SMI both in swallowing and tongue movements. C1 Kyoto Univ, Grad Sch Med, Dept Neurol, Sakyo Ku, Kyoto 6068507, Japan. Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Sakyo Ku, Kyoto 6068507, Japan. Kyoto Univ, Grad Sch Med, Dept Neurosurg, Sakyo Ku, Kyoto 6068507, Japan. Natl Epilepsy Ctr, Shizuoka Med Inst Neurol Disorders, Shizuoka 4200953, Japan. NINDS, NIH, Bethesda, MD 20892 USA. RP Ikeda, A (reprint author), Kyoto Univ, Grad Sch Med, Dept Neurol, Sakyo Ku, Kyoto 6068507, Japan. EM akio@kuhp.kyoto-u.ac.jp OI Mima, Tatsuya/0000-0001-7787-4855; Ikeda, Akio/0000-0002-0790-2598 NR 43 TC 30 Z9 31 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD AUG PY 2004 VL 287 IS 2 BP G459 EP G470 DI 10.1152/ajpgi.00323.2003 PG 12 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 836JT UT WOS:000222552500020 PM 14701719 ER PT J AU Batkai, S Pacher, P Jarai, Z Wagner, JA Kunos, G AF Batkai, S Pacher, P Jarai, Z Wagner, JA Kunos, G TI Cannabinoid antagonist SR-141716 inhibits endotoxic hypotension by a cardiac mechanism not involving CB1 or CB2 receptors SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE endotoxin; cannabinoids; negative inotropy ID PLATELET-ACTIVATING-FACTOR; ENDOGENOUS CANNABINOIDS; CONSCIOUS RATS; ANANDAMIDE; LIPOPOLYSACCHARIDE; ENDOCANNABINOIDS; PERFORMANCE; RESPONSES; MEDIATE; SHOCK AB Endocannabinoids and CB I receptors have been implicated in endotoxin (LPS)-induced hypotension: LPS stimulates the synthesis of anandamide in macrophages. and the CBI antagonist SR-141716 inhibits the hypotension induced by treatment of rats with LPS or LPS-treated macrophages. Recent evidence indicates the existence of cannabinoid receptors distinct from CB1 or CB2 that are inhibited by SR-141716 but not by other CB1 antagonists such as AM251. In pentobarbital-anesthetized rats, intravenous injection of 10 mg/kg LPS elicited hypotension associated with profound decreases in cardiac contractility, moderate tachycardia, and an increase in lower body vascular resistance. Pretreatment with 3 mg/kg SR-141716 prevented the hypotension and decrease in cardiac contractility, slightly attenuated the increase in peripheral resistance, and had no effect on the tachycardia caused by LPS, whereas pretreatment with 3 mg/kg AM251 did not affect any of these responses. SR-141716 also elicited an acute reversal of the hypotension and decreased contractility when administered after the response to LPS had fully developed. The LPS-induced hypotension and its inhibition by SR-141716 were similar in pentobarbital-anesthetized wild-type, CB1(-/-), and CB1(-/-)/CB2(-/-) mice. We conclude that SR-141716 inhibits the acute hemodynamic effects of LPS by interacting with a cardiac receptor distinct from CB1 or CB2 that mediates negative inotropy and may be activated by anandamide or a related endocannabinoid released during endotoxemia. C1 NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Kunos, G (reprint author), NIAAA, Lab Physiol Studies, NIH, 12420 Parklawn Dr,MSC-8115, Bethesda, MD 20892 USA. EM gkunos@mail.nih.gov RI Batkai, Sandor/G-3889-2010; Pacher, Pal/B-6378-2008; Batkai, Sandor/H-7983-2014 OI Pacher, Pal/0000-0001-7036-8108; FU Intramural NIH HHS [Z01 AA000351-07, Z99 AA999999] NR 51 TC 53 Z9 55 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD AUG PY 2004 VL 287 IS 2 BP H595 EP H600 DI 10.1152/apheart.00184.2004 PG 6 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 840HF UT WOS:000222848000022 PM 15059774 ER PT J AU Fine, LJ Philogene, GS Gramling, R Coups, EJ Sinha, S AF Fine, LJ Philogene, GS Gramling, R Coups, EJ Sinha, S TI Prevalence of multiple chronic disease risk factors - 2001 National Health Interview Survey SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID UNITED-STATES; PATTERNS; ADULTS; POPULATION; OBESITY AB Background: Four common factors-cigarette smoking, risky drinking of alcoholic beverages, physical inactivity, and overweight-contribute substantially to chronic disease prevalence. Methods: We used data from the 2001 National Health Interview Survey to provide an up-to-date picture of multiple risk factor prevalence and clustering in the U.S. population. We conducted a multinomial logit analysis to examine the independent association between each covariate and the dependent ordinal risk factor variable with three levels (none or one risk factor, two risk factors, and three or four risk factors). Results: Seventeen percent of the sample of 29,183 subjects had three or more risk factors. For the entire sample, the mean number of risk factors was 1.68 (95% confidence interval [CI] = 1.66-1.70). Many demographic and health factors were significantly associated with the mean number of risk factors including gender, age, ethnic/racial categories, education, martial status, presence of chronic diseases, level of mental distress, country of birth, and presence and type of health insurance. Using the risk factor score as the ordinal dependent variable, adjusted odds for having a risk score of three or four versus zero or one were as follows: men aged <65, 2.49 (95% CI=2.29-2.72); education attainment of high school graduate or less, 3.24 (95 % CI=2.86-3.67); and individuals with high levels of mental distress, 2.06 (95% CI=1.65-2.58). Conclusions: Our analyses confirm earlier reports of the high prevalence of multiple, clustered behavioral risk factors and underline the challenge this presents for primary care and public health systems. (C) 2004 American journal of Preventive Medicine. C1 NIH, Off Behav & Social Sci Res, Off Director, Bethesda, MD 20892 USA. Brown Med Sch, Dept Family Med, Providence, RI USA. Mem Sloan Kettering Canc Ctr, Dept Psychiat & Behav Sci, New York, NY USA. RP Fine, LJ (reprint author), NIH, Off Behav & Social Sci Res, Off Director, Room 256,Bldg 1,1 Ctr Dr, Bethesda, MD 20892 USA. EM FineL@od.nih.gov NR 17 TC 216 Z9 221 U1 1 U2 23 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2004 VL 27 IS 2 SU S BP 18 EP 24 DI 10.1016/j.amepre.2004.04.017 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 841YD UT WOS:000222967600003 PM 15275670 ER PT J AU Resnicow, K Campbell, MK Carr, C McCarty, F Wang, T Periasamy, S Rahotep, S Doyle, C Williams, A Stables, G AF Resnicow, K Campbell, MK Carr, C McCarty, F Wang, T Periasamy, S Rahotep, S Doyle, C Williams, A Stables, G TI Body and Soul - A dietary intervention conducted through African-American churches SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; RE-AIM FRAMEWORK; HEALTH-PROMOTION; BLACK CHURCHES; VEGETABLE INTAKE; FRUIT; BEHAVIOR; AUTONOMY; IMPACT; FAT AB Objectives: Body and Soul was a collaborative effort among two research universities, a national voluntary agency (American Cancer Society), and the National Institutes of Health to disseminate and evaluate under real-world conditions the impact of previously developed dietary interventions for African Americans. Methods: Body and Soul was constructed from two successful research-based interventions conducted in African-American churches. Components deemed essential from the prior interventions were combined, and then tested in a cluster randomized-effectiveness trial. The primary outcome was fruit and vegetable intake measured with two types of food frequency questionnaires at baseline and 6-month follow-up. Results: At the 6-month follow-tip, intervention participants showed significantly greater fruit and vegetable (F&V) intake relative to controls. Post-test differences were 0.7 and 1.4 servings for the 2-item and 17-item F&V frequency measures, respectively. Statistically significant positive changes in fat intake, motivation to eat F&V, social support, and efficacy to eat F&V were also observed. Conclusions: The results suggest that research-based interventions, delivered collaboratively by community volunteers and a health-related voluntary agency, can be effectively implemented under real-world conditions. (C) 2004 American journal of Preventive Medicine. C1 Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. Emory Univ, Dept Behav Sci & Hlth Educ, Atlanta, GA 30322 USA. Amer Canc Soc, Atlanta, GA 30329 USA. NCI, Bethesda, MD 20892 USA. RP Resnicow, K (reprint author), Univ Michigan, Sch Publ Hlth, 1420 Washington Hts SPH 2, Ann Arbor, MI 48109 USA. EM kresnic@umich.edu NR 34 TC 179 Z9 182 U1 3 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD AUG PY 2004 VL 27 IS 2 BP 97 EP 105 DI 10.1016/j.amepre.2004.04.009 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 840XJ UT WOS:000222893100002 PM 15261895 ER PT J AU Nolen, WA Luckenbaugh, DA Altshuler, LL Suppes, T McElroy, SL Frye, MA Kupka, RW Keck, PE Leverich, GS Post, RM AF Nolen, WA Luckenbaugh, DA Altshuler, LL Suppes, T McElroy, SL Frye, MA Kupka, RW Keck, PE Leverich, GS Post, RM TI Correlates of 1-year prospective outcome in bipolar disorder: Results from the Stanley foundation bipolar network SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID LIFE-CHART METHOD; PROPHYLACTIC EFFICACY; MAINTENANCE TREATMENT; GENDER-DIFFERENCES; I DISORDER; FOLLOW-UP; LITHIUM; ILLNESS; CARBAMAZEPINE; DEMOGRAPHICS AB Objective: The purpose of the study was to examine potential correlates of outcome in patients treated for bipolar disorder. Method: During a 1-year period, 258 patients with DSM-IV bipolar disorder or schizoaffective disorder were rated with the prospective NIMH-Life Chart Method, which characterizes each day in terms of the severity of manic and depressive symptoms on the basis of patients' mood-related impairment in their usual educational, social, or occupational roles. Mean ratings for the severity of mania, depression, and overall bipolar illness and the number of manic, depressive, and overall illness episodes were calculated. Potentia I risk factors were assessed at the start of the study, and multivariate linear regression analysis was used to determine the correlates of the six 1-year outcome measures. Results: Three of the six outcome measures were largely independent of each other and were used in the analysis. The mean rating for severity of mania was associated with comorbid substance abuse, history of more than 10 prior manic episodes, and poor occupational functioning at study entry. The mean rating for severity of depression was associated with a history of more than 10 prior depressive episodes and poor occupational functioning at study entry. The total number of overall illness episodes was associated with a positive family history of drug abuse, a history of prior rapid cycling, and poor occupational functioning. in addition, the mean rating for severity of mania and the total number of overall illness episodes were both initially associated with a history of childhood abuse, but these relationships were lost with the addition of other illness variables to the analysis. Conclusions: Clinicians who treat patients with bipolar disorder should consider a family history of drug abuse, a history of childhood abuse, prior course of illness, comorbid substance abuse, and occupational functioning in determining prognosis and setting goals for further treatment. C1 Univ Groningen Hosp, NL-9700 RB Groningen, Netherlands. Altrecht Inst Mental Hlth Care, Utrecht, Netherlands. NIMH, Bethesda, MD USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH USA. RP Nolen, WA (reprint author), Univ Groningen Hosp, POB 30001, NL-9700 RB Groningen, Netherlands. EM w.a.nolen@med.rug.nl RI Nolen, Willem/E-9006-2014 FU NIMH NIH HHS [R01 MH079261] NR 37 TC 82 Z9 86 U1 1 U2 3 PU AMER PSYCHIATRIC PRESS, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD AUG PY 2004 VL 161 IS 8 BP 1447 EP 1454 DI 10.1176/appi.ajp.161.8.1447 PG 8 WC Psychiatry SC Psychiatry GA 842BC UT WOS:000222976400019 PM 15285972 ER PT J AU Parry, MS Tedeschi, SK AF Parry, MS Tedeschi, SK TI Marth May Eliot: "Spinster in steel specs, adviser on maternity" SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 Natl Lib Med, Natl Inst Hlth, Hist Med Div, Bethesda, MD 20894 USA. RP Parry, MS (reprint author), Natl Lib Med, Natl Inst Hlth, Hist Med Div, 8600 Rockville Pike,Bldg 38,Rm 1E-21, Bethesda, MD 20894 USA. EM parrym@mail.nlm.mh.gov NR 1 TC 1 Z9 1 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2004 VL 94 IS 8 BP 1322 EP 1322 DI 10.2105/AJPH.94.8.1322 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 843AT UT WOS:000223047600017 ER PT J AU Saliba, D Buchanan, J Kington, RS AF Saliba, D Buchanan, J Kington, RS TI Function and response of nursing facilities during community disaster SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID LOMA-PRIETA EARTHQUAKE; NORTHRIDGE EARTHQUAKE; NATURAL DISASTERS; HEALTH-CARE; HOME; LESSONS; NEEDS; RESIDENTS; SYSTEM; RECOMMENDATIONS AB Objectives. We sought to describe the role and function of nursing facilities after disaster. Methods. We surveyed administrators at 144 widely dispersed nursing facilities after the Los Angeles Northridge earthquake. Results. Of the 113 (78%) nursing facilities that responded (11365 beds), 23 sustained severe damage, 5 closed (625 beds), and 72 lost vital services. Of 87 nursing facilities implementing disaster plans, 56 cited problems that plans did not adequately address, including absent staff, communication problems, and insufficient water and generator fuel. Fifty-nine (52%) reported disaster-related admissions from hospitals, nursing facilities, and community residences. Nursing facilities received limited postdisaster assistance. Five months after the earthquake, only half of inadequate nursing facility disaster plans had been revised. Conclusions. Despite considerable disaster-related stresses, nursing facilities met important community needs. To optimize disaster response, community-wide disaster plans should incorporate nursing facilities. C1 RAND Corp, Santa Monica, CA 90407 USA. NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Cambridge, MA 02138 USA. Univ Calif Los Angeles, Vet Adm Med Ctr, Multicampus Program Geriatr, Los Angeles, CA USA. Vet Adm Greater Los Angeles Hlth Care Syst, Los Angeles, CA 91343 USA. RP Saliba, D (reprint author), RAND Corp, 1700 Main St M-28, Santa Monica, CA 90407 USA. EM saliba@rand.org NR 44 TC 21 Z9 22 U1 0 U2 7 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 1015 FIFTEENTH ST NW, WASHINGTON, DC 20005 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD AUG PY 2004 VL 94 IS 8 BP 1436 EP 1441 DI 10.2105/AJPH.94.8.1436 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 843AT UT WOS:000223047600039 PM 15284056 ER PT J AU Butler, LM Koh, WP Lee, HP Yu, MC London, SJ AF Butler, LM Koh, WP Lee, HP Yu, MC London, SJ TI Dietary fiber and reduced cough with phlegm - A cohort study in Singapore SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE chronic bronchitis; chronic obstructive pulmonary disease; dietary fiber; fruit; soy ID OBSTRUCTIVE PULMONARY-DISEASE; MIDDLE-AGED MEN; LUNG-FUNCTION; BRITISH ADULTS; CHINESE HEALTH; EPIDEMIOLOGIC EVIDENCE; AIRWAY INFLAMMATION; GENERAL-POPULATION; CATECHIN CONTENTS; FRUIT INTAKE AB Smoking is the major risk factor for chronic respiratory symptoms, but dietary factors may also play a role. Most studies of diet and lung disease have been cross-sectional and conducted in populations with a Western-style diet. We analyzed the relation between dietary intake at baseline and new onset of cough with phlegm in a population-based cohort of 63,257 middle-aged Chinese men and women initiated in Singapore between 1993 and 1998. Beginning in 1999, we ascertained respiratory symptoms by telephone interview and have identified 571 incident cases of cough with phlegm among the 49,140 cohort members with completed follow-up. Nonstarch polysaccharides, a major component of dietary fiber, total fruit, and soy isoflavones had the strongest associations. Odds ratios comparing highest and lowest quartiles after adjustment for age, sex, dialect group, total energy intake, and smoking were 0.61 (95% confidence interval [CI]: 0.47, 0.78; p for trend < 0.001) for nonstarch polysaccharides, 0.67 (95% Cl: 0.52, 0.87; p for trend = 0.006) for fruit, and 0.67 (95% Cl: 0.53, 0.86; p for trend = 0.001) for soy isoflavones. These data suggest that a diet high in fiber from fruit and, possibly, soyfoods may reduce the incidence of chronic respiratory symptoms. Associated nutrients, such as flavonoids, may contribute to this association. C1 NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. Natl Univ Singapore, Singapore 117548, Singapore. RP Butler, LM (reprint author), Univ Calif Davis, Dept Epidemiol & Prevent Med, 1 Shields Ave, Davis, CA 95616 USA. EM lmbutler@ucdavis.edu OI London, Stephanie/0000-0003-4911-5290 FU NCI NIH HHS [R01 CA080205-01, R01 CA80205]; NIEHS NIH HHS [Z01 ES043012-07, ZO1 ES43012] NR 75 TC 26 Z9 28 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 1 PY 2004 VL 170 IS 3 BP 279 EP 287 DI 10.1164/rccm.200306-789OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 841DX UT WOS:000222910600019 PM 15117740 ER PT J AU Hashimoto, K Graham, BS Ho, SB Adler, KB Collins, RD Olson, SJ Zhou, WS Suzutani, T Jones, PW Goleniewska, K O'Neal, JF Peebles, RS AF Hashimoto, K Graham, BS Ho, SB Adler, KB Collins, RD Olson, SJ Zhou, WS Suzutani, T Jones, PW Goleniewska, K O'Neal, JF Peebles, RS TI Respiratory syncytial virus in allergic lung inflammation increases Muc5ac and Gob-5 SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE mucin; MUC5ac; gob-5; respiratory syncytial virus ID MESSENGER-RNA EXPRESSION; GOBLET CELL HYPERPLASIA; INDUCED AIRWAY HYPERRESPONSIVENESS; MUCIN GENE-EXPRESSION; MUCUS OVERPRODUCTION; CYTOKINE PRODUCTION; ASTHMA; INFECTION; MICE; IL-10 AB Respiratory syncytial virus (RSV) is associated with wheezing and childhood asthma. We previously reported that RSV infection prolongs methacholine-induced airway hyperresponsiveness in ovalbumin (OVA)-sensitized mice. In addition, allergically sensitized RSV-infected (OVA/RSV) mice had more abundant airway epithelial mucus production compared with OVA mice 14 days after infection whereas there was almost no mucus in mice that were only RSV infected. We hypothesized that this increased mucus was associated with mucosal expression of Muc5ac, a mucus gene expression in airways, and gob-5, a member of the Ca2+-activated chloride channel family. By histochemical analysis, we found that there was significantly increased staining for gob-5 and Muc5ac in the airways of OVA/RSV mice compared with either OVA mice or allergically sensitized mice that were challenged with inactivated RSV, and virtually no detectable staining in the RSV group. These findings were confirmed by Western blot analysis. The increased mucus expression in the OVA/RSV group was associated with increased lung levels of interleukin-17, a factor known to stimulate airway mucin gene expression. The impact of virus infection combined with allergic inflammation on mucus production may partially explain the more severe disease and airway hyperresponsiveness associated with RSV in the setting of atopy. C1 Vanderbilt Univ, Sch Med, Ctr Lung Res, Nashville, TN 37232 USA. NIH, Viral Pathogenesis Lab & Clin Trial Core, Bethesda, MD 20892 USA. Univ Minnesota, Vet Affairs Med Ctr, Minneapolis, MN 55455 USA. N Carolina State Univ, Coll Vet Med, Raleigh, NC 27695 USA. Fukushima Med Univ, Fukushima, Japan. RP Peebles, RS (reprint author), Vanderbilt Univ, Sch Med, Ctr Lung Res, T-1217 MCN, Nashville, TN 37232 USA. EM stokes.peebles@vanderbilt.edu FU NIAID NIH HHS [R01 AI-45512] NR 48 TC 73 Z9 79 U1 0 U2 1 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 AUG 1 PY 2004 VL 170 IS 3 BP 306 EP 312 DI 10.1164/rccm.200301-030OC PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 841DX UT WOS:000222910600022 PM 15130904 ER PT J AU Hsia, CCW Berberich, MA Driscoll, B Laubach, VE Lillehei, CW Massaro, C Perkett, EA Pierce, RA Rannels, DE Ryan, RM Tepper, RS Townsley, MI Veness-Meehan, KA Wang, N Warburton, D AF Hsia, CCW Berberich, MA Driscoll, B Laubach, VE Lillehei, CW Massaro, C Perkett, EA Pierce, RA Rannels, DE Ryan, RM Tepper, RS Townsley, MI Veness-Meehan, KA Wang, N Warburton, D CA ATS TI Mechanisms and limits of induced postnatal lung growth SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review ID CONGENITAL DIAPHRAGMATIC-HERNIA; NITRIC-OXIDE SYNTHASE; INDUCED HEART-FAILURE; HYPOBARIA AND/OR HYPOXIA; DEVELOPING RAT LUNG; PRIMARY PULMONARY-HYPERTENSION; MEMBRANE DIFFUSING-CAPACITY; ALVEOLAR EPITHELIAL-CELLS; ELASTIN GENE-EXPRESSION; PLATELET-DERIVED GROWTH C1 Univ Texas, SW Med Sch, Dept Internal Med, Dallas, TX 75230 USA. NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. Univ So Calif, Childrens Hosp Los Angeles, Res Inst, Los Angeles, CA 90089 USA. Univ Virginia, Charlottesville, VA USA. Harvard Univ, Childrens Hosp, Dept Surg, Boston, MA 02115 USA. Georgetown Univ, Sch Med, Lung Biol Lab, Washington, DC USA. Univ New Mexico, Albuquerque, NM 87131 USA. Washington Univ, Dept Med, St Louis, MO USA. Penn State Univ, Hershey, PA USA. SUNY Buffalo, Div Neonatol, Buffalo, NY 14260 USA. Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46204 USA. Univ S Alabama, Dept Physiol, Mobile, AL 36688 USA. Univ N Carolina, Chapel Hill, NC 27515 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Hsia, CCW (reprint author), Univ Texas, SW Med Sch, Dept Internal Med, Dallas, TX 75230 USA. RI Wang, Ning/B-6966-2008; Laubach, Victor/E-8818-2015 OI Laubach, Victor/0000-0001-9673-5383 NR 503 TC 89 Z9 89 U1 0 U2 12 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD AUG 1 PY 2004 VL 170 IS 3 BP 319 EP 343 DI 10.1164/rccm.200209-1062ST PG 25 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 841DX UT WOS:000222910600024 ER PT J AU Cho, PS Mueller, NJ Cameron, AM Cina, RA Coburn, RC Hettiaratchy, S Melendy, E Neville, DM Patience, C Fishman, JA Sachs, DH Huang, CA AF Cho, PS Mueller, NJ Cameron, AM Cina, RA Coburn, RC Hettiaratchy, S Melendy, E Neville, DM Patience, C Fishman, JA Sachs, DH Huang, CA TI Risk factors for the development of post-transplant lymphoproliferative disorder in a large animal model SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE hematopoietic cell transplantation; immunosuppression; miniature swine; porcine lymphotrophic herpes virus; post transplant lymphoproliferative disease ID EPSTEIN-BARR-VIRUS; HEMATOPOIETIC-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; MINIATURE SWINE; MIXED CHIMERISM; RECIPIENTS; LYMPHOMA; DISEASE; IMMUNOSUPPRESSION; TOLERANCE AB A high incidence of a post-transplant lymphoproliferative disorder (PTLD) is observed in miniature swine conditioned for allogeneic hematopoietic cell transplantation using a protocol involving T-cell depletion and cyclosporine therapy. This study was designed to assess contributing factors to disease development. Forty-six animals were studied including 12 (26%) that developed PTLD. A number of risk factors for PTLD were examined, including degree of immunosuppression, degree of MHC mismatch and infection by a porcine lymphotrophic herpesvirus (PLHV-1). Flow cytometry was used to measure host and donor T- and B-cell levels in the peripheral blood. Porcine lymphotrophic herpesvirus viral load was determined by quantitative PCR. Animals developing PTLD had significantly lower levels of T cells on the day of transplant. Cyclosporine levels did not differ significantly between animals with and without PTLD. Animals receiving transplants across a two-haplotype mismatch barrier showed an increased incidence of PTLD. All animals with PTLD had significant increases in PLHV-1 viral loads. Porcine lymphotrophic herpesvirus viral copy numbers remained at low levels in the absence of disease. The availability of a preclinical large-animal model with similarities to PTLD of humans may allow studies of the pathogenesis and treatment of that disorder. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Infect Dis, Boston, MA USA. NIMH, NIH, Bethesda, MD 20892 USA. Immerge BioTherapeut Inc, Cambridge, MA USA. RP Huang, CA (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Transplantat Biol Res Ctr, Boston, MA 02114 USA. EM huangc@helix.mgh.harvard.edu RI Mueller, Nicolas/B-6864-2013 OI Mueller, Nicolas/0000-0002-1059-3191 FU NCI NIH HHS [1R01 CA79989-01A1]; NHLBI NIH HHS [1R01 HL63430-01]; NIAID NIH HHS [5T3232-AI07529-04, P01-AI45897] NR 39 TC 15 Z9 15 U1 0 U2 2 PU BLACKWELL MUNKSGAARD PI COPENHAGEN PA 35 NORRE SOGADE, PO BOX 2148, DK-1016 COPENHAGEN, DENMARK SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD AUG PY 2004 VL 4 IS 8 BP 1274 EP 1282 DI 10.1111/j.1600-6143.2004.00506.x PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA 838HZ UT WOS:000222705500010 PM 15268728 ER PT J AU Breman, JG Alilio, MS Mills, A AF Breman, JG Alilio, MS Mills, A TI Objectives and acknowledgments the intolerable burden of malaria: What's new, what's needed SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Editorial Material C1 Fogarty Int Ctr, Dis Control Prior Dev Countries Project, NIH, Bethesda, MD USA. London Sch Hyg & Trop Med, Dept Hlth Econ & Policy, London, England. RP Breman, JG (reprint author), Fogarty Int Ctr, Dis Control Prior Dev Countries Project, NIH, Bethesda, MD USA. NR 0 TC 6 Z9 6 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD AUG PY 2004 VL 71 IS 2 SU S BP I EP I PG 1 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 850LM UT WOS:000223612900001 ER PT J AU Breman, JG Alilio, MS Mills, A AF Breman, JG Alilio, MS Mills, A TI Conquering the intolerable burden of malaria: What's new, what's needed: A summary SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID PLASMODIUM-FALCIPARUM; AFRICA; RESISTANCE; POPULATION; CHILDREN AB Each year, up to three million deaths due to malaria and close to five billion episodes of clinical illness possibly meriting antimalarial therapy occur throughout the world, with Africa having more than 90% of this burden. Almost 3% of disability adjusted life years are due to malaria mortality globally, 10% in Africa. New information is presented in this supplement on malaria-related perinatal mortality, occurrence of human immunodeficiency virus in pregnancy, undernutrition, and neurologic, cognitive, and developmental sequelae. The entomologic determinants of transmission and uses of modeling for program planning and disease prediction and prevention are discussed. New data are presented from the Democratic Republic of the Congo, Tanzania, Ethiopia, and Zimbabwe on the increasing urban malaria problem and on epidemic malaria. Between 6% and 28% of the malaria burden may occur in cities, which comprise less than 2% of the African surface. Macroeconomic projections show that the costs are far greater than the costs of individual cases, with a substantial deleterious impact of malaria on schooling of patients, external investments into endemic countries, and tourism. Poor populations are at greatest risk; 58% of the cases occur in the poorest 20% of the world's population and these patients receive the worst care and have catastrophic economic consequences from their illness. This social vulnerability requires better understanding for improving deployment, access, quality, and use of effective interventions. Studies from Ghana and elsewhere indicate that for every patient with febrile illness assumed to be malaria seen in health facilities, 4-5 episodes occur in the community. Effective actions for malaria control mandate rational public policies; market forces, which often drive sales and use of drugs and other interventions, are unlikely to guarantee their use. Artemisinin-based combination therapy (ACT) for malaria is rapidly gaining acceptance as an effective approach for countering the spread and intensity of Plasmodium falciparum resistance to chloroquine, sulfadoxine/pyrimethamine, and other antimalarial drugs. Although costly, ACT ($1.20-2.50 per adult treatment) becomes more cost-effective as resistance to alternative drugs increases; early use of ACT may delay development of resistance to these drugs and prevent the medical toll associated with use of ineffective drugs. The burden of malaria in one district in Tanzania has not decreased since the primary health care approach replaced the vertical malaria control efforts of the 1960s. Despite decentralization, this situation resulted, in part, from weak district management capacity, poor coordination, inadequate monitoring, and lack of training of key staff. Experience in the Solomon Islands showed that spraying with DDT, use of insecticide-treated bed nets (ITNs), and health education were all associated with disease reduction. The use of nets permitted a reduction in DDT spraying, but could not replace it without an increased malaria incidence. Baseline data and reliable monitoring of key outcome indicators are needed to measure whether the ambitious goals for the control of malaria and other diseases has occurred. Such systems are being used for evidence-based decision making in Tanzania and several other countries. Baseline cluster sampling surveys in several countries across Africa indicate that only 53% of the children with febrile illness in malarious areas are being treated; chloroquine (CQ) is used 84% of the time, even where the drug may be ineffective. Insecticide-treated bed nets were used only 2% of the time by children less than five years of age. Progress in malaria vaccine research has been substantial over the past five years; 35 candidate malaria vaccines are in development, many of which are in clinical trials. Development of new vaccines and drugs has been the result of increased investments and formation of public-private partnerships. Before malaria vaccine becomes deployed, consideration must be given to disease burden, cost-effectiveness, financing, delivery systems, and approval by regulatory agencies. Key to evaluation of vaccine effectiveness will be collection and prompt analysis of epidemiologic information. Training of persons in every aspect of malaria research and control is essential for programs to succeed. The Multilateral Initiative on Malaria (MIM) is actively promoting research capacity strengthening and has established networks of institutions and scientists throughout the African continent, most of whom are now linked by modern information-sharing networks. Evidence over the past century is that successful control malaria programs have been linked to strong research activities. To ensure effective coordination and cooperation between the growing number of research and control coalitions forming in support of, malaria activities, an umbrella group is needed. With continued support for scientists and control workers globally, particularly in low-income malarious countries, the long-deferred dream of malaria elimination can become a reality. C1 NIH, Fogarty Int Ctr, Dis Control Priorit Dev Countries Project, Bethesda, MD 20892 USA. Acad Educ Dev, Global Hlth Populat & Nutr Dept, Washington, DC 20009 USA. Univ London London Sch Hyg & Trop Med, Dept Hlth Econ & Policy, London WC1E 7HT, England. RP Breman, JG (reprint author), NIH, Fogarty Int Ctr, Dis Control Priorit Dev Countries Project, Bldg 16,Room 214,16 Ctr Dr,MSC 6705, Bethesda, MD 20892 USA. EM jbreman@nih.gov; Malilio@aed.org; Anne.Mills@lshtm.ac.uk OI Mills, Anne/0000-0001-9863-9950 NR 60 TC 361 Z9 371 U1 16 U2 161 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD AUG PY 2004 VL 71 IS 2 SU S BP 1 EP 15 PG 15 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 850LM UT WOS:000223612900004 PM 15331814 ER PT J AU McKenzie, FE Samba, EM AF McKenzie, FE Samba, EM TI The role of mathematical modeling in evidence-based malaria control SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article AB Mathematical models have long provided basic insights for malaria control. The recent success of the Onchocerciasis Control Program in west Africa shows that models can make great pragmatic contributions to intervention programs if the modeling is integrated into the overall program, and if the participants are clear about what models can and cannot do. This lesson can be applied to evidence-based malaria control. C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Reg Off Africa, World Hlth Org, Harare, Zimbabwe. RP McKenzie, FE (reprint author), NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. EM mckenzel@mail.nih.gov FU Intramural NIH HHS [Z99 TW999999] NR 18 TC 35 Z9 35 U1 1 U2 3 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD AUG PY 2004 VL 71 IS 2 SU S BP 94 EP 96 PG 3 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 850LM UT WOS:000223612900014 PM 15331824 ER PT J AU Alilio, MS Kitua, A Njunwa, K Medina, M Ronn, AM Mhina, JM Msuya, F Mahundi, J Depinay, JM Whyte, S Krasnik, A Bygbjerg, IC AF Alilio, MS Kitua, A Njunwa, K Medina, M Ronn, AM Mhina, JM Msuya, F Mahundi, J Depinay, JM Whyte, S Krasnik, A Bygbjerg, IC TI Malaria control at the district level in Africa: The case of the Muheza district in northeastern Tanzania SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID NORTH-EASTERN TANZANIA; PLASMODIUM-FALCIPARUM INFECTIONS; SULFADOXINE-PYRIMETHAMINE; CHLOROQUINE; MORBIDITY; CHILDREN; AREA; RESISTANCE; TRANSMISSION; PREVALENCE AB An assessment was done in Tanzania to determine the extent to which the primary health care services have contributed to reducing the burden of malaria since the system was initiated in the 1980s. Seven descriptive processes and outcome indicators of effectiveness were used: changes of malaria transmission and incidence over time; use of facility-based care services for malaria; patients' access to professional advice; the trend of treatment failure over time of sulfadoxine-pyrimethamine and chloroquine; survival rates of severe cases at the district hospital; a district malaria control strategy; number of malaria specific training for care providers; and the number of activities carried out on mosquito control measures. The data were collected from 1996 to 2003 in the Muheza district northeastern Tanzania. It covered household interviews with a stratified sample of 1,250 respondents, and in-depth interviews with all 175 health care providers in the 35 health facilities within the district. All six members of the district health management team were also interviewed. Additional data came from dispensary and hospital records, and published literature. The results show an unchanged malaria disease burden. The average number of clinical malaria episodes per child less than five years of age remained between 3 and 3.5 episodes per year in the district since the 1960s. The comparison of cases expected in the population less than five years old with those seen in the district health facilities shows a coverage rate of 33%. Furthermore, between 1990 and 2003, little training on malaria was provided to health staff. The findings imply a limited effectiveness of district health services on malaria control, suggesting a weak process of translating national malaria goals to activities at the district level. C1 Fogarty Int Ctr, NIH, Bethesda, MD 20892 USA. Natl Inst Med Res, Dar Es Salaam, Tanzania. Clarity Consulting Co, Copenhagen, Denmark. Rigshosp, Dept Infect Dis, DK-2100 Copenhagen, Denmark. Univ Copenhagen, Inst Anthropol, Inst Publ Hlth, Dept Hlth Serv Res, Copenhagen, Denmark. Univ Copenhagen, Dept Int Hlth, Copenhagen, Denmark. RP Alilio, MS (reprint author), Fogarty Int Ctr, NIH, Bldg 31,Room B2C29,Ctr Dr, Bethesda, MD 20892 USA. EM malilio@aed.org; Aliliom@mail.nih.gov; Nimr@twiga.com; Mim@clarity.dk; Ronn@dadlnet.dk; Susan.Reynolds.Whyte@anthro.ku.dk; Krasnik@pubhealth.ku.dk; I.Bygbjerg@pubhealth.ku.dk NR 56 TC 24 Z9 24 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD AUG PY 2004 VL 71 IS 2 SU S BP 205 EP 213 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 850LM UT WOS:000223612900029 PM 15331839 ER PT J AU Tabi, TE Befidi-Mengue, R Nutman, TB Horton, J Folefack, A Pensia, E Fualem, R Fogako, J Gwanmesia, P Quakyi, I Leke, R AF Tabi, TE Befidi-Mengue, R Nutman, TB Horton, J Folefack, A Pensia, E Fualem, R Fogako, J Gwanmesia, P Quakyi, I Leke, R TI Human loiasis in a cameroonian village: A double-blind, placebo-controlled, crossover clinical trial of a three-day albendazole regimen SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID LOA-LOA-MICROFILAREMIA; IVERMECTIN TREATMENT; ADVERSE REACTIONS; HUMAN FILARIASIS; ONCHOCERCIASIS; DIETHYLCARBAMAZINE; INFECTION; EFFICACY; MG AB Because of the life-threatening, post-treatment reactions that have occurred in patients with loiasis treated with ivermectin, evaluation of a short-course albendazole regimen was undertaken in a Loa-endemic region of Cameroon. In a placebo-con trolled, double-blinded, crossover study, 99 subjects with microfilaremia (100-3,3837/mL) were assigned to receive albendazole (400 mg; n = 48) or placebo (n = 51.) for three days and were followed for 180 days; at day 180, the groups were crossed over and followed for an additional six months. In those initially receiving albendazole (ALB/PLAC), microfilarial levels decreased significantly by day 90 (P < 0.043), but returned to baseline by day 180. In those receiving albendazole at day 180 (PLAC/ALB), microfilarial levels also decreased following albendazole (P = 0.005). Blood eosinophil and antifilarial IgG levels did not change significantly for either group, although antifilarial IgG4 levels did in the ALB/PLAC group at day 180. Most subjects continued to have elevations in microfilaremia, suggesting that more intensive regimens of albendazole will be necessary to reduce Loa microfilaremia to levels safe enough to allow for ivermectin use. C1 Ctr Biotechnol, Yaounde, Cameroon. Univ Yaounde, Fac Med & Biomed Sci, Yaounde, Cameroon. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Dept Biol, Washington, DC 20057 USA. GlaxoSKB, Brentford, England. RP Tabi, TE (reprint author), Ctr Biotechnol, Yaounde, Cameroon. EM tnutman@niaid.nih.gov NR 24 TC 19 Z9 19 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD AUG PY 2004 VL 71 IS 2 BP 211 EP 215 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 848AZ UT WOS:000223440700015 PM 15306713 ER PT J AU Ballou, WR Arevalo-Herrera, M Carucci, D Richie, TL Corradin, G Diggs, C Druilhe, P Giersing, BK Saul, A Heppner, DG Kester, KE Lanar, DE Lyon, J Hill, AVS Pan, WQ Cohen, JD AF Ballou, WR Arevalo-Herrera, M Carucci, D Richie, TL Corradin, G Diggs, C Druilhe, P Giersing, BK Saul, A Heppner, DG Kester, KE Lanar, DE Lyon, J Hill, AVS Pan, WQ Cohen, JD TI Update on the clinical development of candidate malaria vaccines SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article; Proceedings Paper CT 3rd Multilateral Initiative on Malaria Pan-African Malaria Conference CY NOV 17-22, 2002 CL ARUSHA, TANZANIA SP Ctr Dis Control & Prevent, US Agcy Int Dev, JHPIEGO Corp ID PLASMODIUM-FALCIPARUM MALARIA; CIRCUMSPOROZOITE PROTEIN VACCINE; APICAL MEMBRANE ANTIGEN-1; HUMORAL IMMUNE-RESPONSES; CYTOTOXIC T-LYMPHOCYTES; VIRUS ANKARA; DNA VACCINE; IN-VITRO; IMMUNOGENICITY; EFFICACY AB The recent availability of significantly increased levels of funding for unmet medical needs in the developing world, made available by newly created public-private-partnerships, has proven to be a powerful driver for stimulating clinical development of candidate vaccines for malaria. This new way forward promises to greatly increase the likelihood of bringing a safe and effective vaccine to licensure. The investigators bring together important published and unpublished information that illuminates the status of malaria vaccine development. They focus their comments on those candidate vaccines that are currently in or expected to enter clinical trials in the next 12 months. C1 GlaxoSmithKline Biol, Clin Res & Dev, Emerging Dis, Rixensart, Belgium. GlaxoSmithKline Biol, Res & Dev, Rixensart, Belgium. Malaria Vaccine & Drug Testing Ctr, Cali, Colombia. USN, Med Res Ctr, Malaria Program, Silver Spring, MD USA. Univ Lausanne, Lausanne, Switzerland. US Agcy Int Dev, Malaria Vaccine Dev Program, Washington, DC USA. Inst Pasteur, Paris, France. NIAID, Malaria Vaccine Dev Unit, NIH, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, Dept Immunol, Silver Spring, MD USA. Walter Reed Army Inst Res, Dept Clin Trials, Silver Spring, MD USA. Univ Oxford, Ctr Clin Vaccinol & Trop Med, Oxford, England. Second Mil Med Univ, Shanghai, Peoples R China. RP Ballou, WR (reprint author), GlaxoSmithKline Biol, Clin Res & Dev, Emerging Dis, 89 Rue Inst, Rixensart, Belgium. EM Ripley.Ballou@gskbio.com RI HILL, Adrian/C-1306-2008; Richie, Thomas/A-8028-2011; Kester, Kent/A-2114-2011; Lanar, David/B-3560-2011; Saul, Allan/I-6968-2013 OI Kester, Kent/0000-0002-5056-0802; Saul, Allan/0000-0003-0665-4091 NR 36 TC 87 Z9 88 U1 0 U2 3 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD AUG PY 2004 VL 71 IS 2 SU S BP 239 EP 247 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 850LM UT WOS:000223612900033 PM 15331843 ER PT J AU Royall, J Bennett, M Van Schayk, I Alilio, M AF Royall, J Bennett, M Van Schayk, I Alilio, M TI Tying up lions: Multilateral initiative on malaria communications: The first chapter of a malaria research network in Africa SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article AB "When spider webs unite, they can tie up a lion" (Ethiopian folk adage). The Multilateral Initiative on Malaria Communications Network (MIMCom) facilitates a new way of doing research in Africa and African scientists' participation in the international scientific community. The MIMCom supports full access to the Internet and the resources of the WorldWide Web at 19 research sites in 11 African countries. Furthermore, the MIMCom project comprises two websites: one includes links to resources, databases, and publications as well as a document delivery service for full text journal articles, and the other is a research agenda specific website with a server for a research network desiring to share raw data. Other important components of MIMCom are training and evaluation components. The MIMCom was conceived in 1997 by African researchers and has been designed, implemented, and overseen by the U.S. National Library of Medicine in collaboration with partners in Africa, the United States, and the United Kingdom. This project demonstrates clearly that it can make a positive difference in the functioning of remote research sites in Africa, in terms of site growth and productivity and in the professional lives of individual researchers. This report reviews the project's background, methods of operation with an emphasis on local needs and priorities, cost effectiveness, and local responsibility; results focusing on a technical network; documentation of the system and two-way exchange of information; the MIMCom website; a network approach to research; and financial sustainability. The report concludes with summaries of evaluations by an independent panel, the Multilateral Initiative on Malaria Secretariat, and the U.S. National Library of Medicine. C1 NIH, Natl Lib Med, Bethesda, MD 20894 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. AfriConnect Ltd, Unit 5, Cambridge, England. RP Royall, J (reprint author), NIH, Natl Lib Med, 8600 Rockville Pike Bldg 38,Room 2S-22, Bethesda, MD 20894 USA. EM jroyall@nlm.nih.gov; mbennett@africonnect.com; inga@mimcom.net; Aliliom@mail.nih.gov NR 7 TC 8 Z9 8 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD AUG PY 2004 VL 71 IS 2 SU S BP 259 EP 267 PG 9 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 850LM UT WOS:000223612900036 PM 15331846 ER PT J AU Alilio, MS Bygbjerg, IC Breman, JG AF Alilio, MS Bygbjerg, IC Breman, JG TI Are multilateral malaria research and control programs the most successful? Lessons from the past 100 years in Africa SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID PUBLIC-PRIVATE PARTNERSHIPS; ROLL BACK MALARIA; HEALTH SECTOR; INTERNATIONAL HEALTH; EXTERNAL RESOURCES; AID COORDINATION; TRANSMISSION; ROSS,RONALD; ERADICATION; OPPORTUNITY AB Multilateral malaria research and control programs in Africa have regained prominence recently as bilateral assistance has diminished. The transnational nature of the threat and the need for inspired leadership, good coordination, and new discoveries to decrease the impact of the disease has led to the founding of the Multilateral Initiative on Malaria, the Roll Back Malaria Project, Global Fund for HIV, Tuberculosis and Malaria (Global Fund), the Medicines for Malaria Venture, and the Malaria Vaccine Initiative, among other groups. Historically, the most striking feature of malaria control and elimination activities was the connectedness and balance between malaria research and control especially, from 1892 to 1949. A combination of scientific originality, perseverance in research, integrated approaches, and social concern were the keys for success. The elimination of Anopheles gambiae from Upper Egypt in 1942 using integrated vector control methods is a prime example of malaria control during the first half of the 20th century where those factors were brought together. After 1949, there were three decades of great optimism. Four notable landmarks characterized this period: the Kampala Conference in 1950; the Global Malaria Eradication Program beginning in 1955; the primary health care strategies adopted by most African States after attaining their political independence in the 1960s, and accelerating in the 1980s; and creation of the Special Program in Training and Research in Tropical Diseases at the World Health Organization in 1975. The initial highly encouraging operational results, largely obtained in temperate or subtropical areas where transmission was unstable, engendered undue expectations for the success of identical antimalarial measures elsewhere. Many were convinced that the eradication was in sight, such that support for malaria research virtually ceased. Young, bright scientists were discouraged from seeking a career in a discipline that appeared to soon become superfluous. It took more than three decades to modify antimalarial strategies and to rehabilitate long-term control as an intermediate objective. In Africa, although multilateral malaria programs have grown over the past half century and proved the most successful, fragmentation of co-ordination remains and is a major challenge. The proliferation of malaria programs in the late 1990s has brought substantial additional funds and expertise. However, excessive funding competition and failure of different programs to collaborate has resulted in poor communication and duplication of activities. The capacities of the African nations to conduct high-quality research and to coordinate control efforts are in great jeopardy. There is an urgent need for a non-partisan umbrella organ to coordinate and facilitate the network of alliances and programs in malaria research and control in Africa. C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Univ Copenhagen, Panum Inst, Dept Int Hlth, Inst Publ Hlth, DK-2200 Copenhagen, Denmark. RP Alilio, MS (reprint author), NIH, Fogarty Int Ctr, Bldg 16,Room 214,16 Ctr Dr,MSC 6705, Bethesda, MD 20892 USA. EM malilio@aed.org; I.Bygbjerg@pubhealth.ku.dk; jbreman@nih.gov NR 75 TC 30 Z9 32 U1 0 U2 11 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD AUG PY 2004 VL 71 IS 2 SU S BP 268 EP 278 PG 11 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 850LM UT WOS:000223612900037 PM 15331847 ER PT J AU Heddini, A Keusch, GT Davies, CS AF Heddini, A Keusch, GT Davies, CS TI The Multilateral Initiative on Malaria: Past, present, and future SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article C1 Stockholm Univ, Karolinska Inst, Multilateral Initiat Malaria, SE-10691 Stockholm, Sweden. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Wellcome Trust Res Labs, London, England. RP Heddini, A (reprint author), Stockholm Univ, Karolinska Inst, Multilateral Initiat Malaria, SE-10691 Stockholm, Sweden. EM andreas.heddini@mim.su.se NR 4 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD AUG PY 2004 VL 71 IS 2 SU S BP 279 EP 282 PG 4 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 850LM UT WOS:000223612900038 PM 15331848 ER PT J AU Singh, SS Qaqish, B Johnson, JL Ford, OH Foley, JE Maygarden, SJ Mohler, JL AF Singh, SS Qaqish, B Johnson, JL Ford, OH Foley, JE Maygarden, SJ Mohler, JL TI Sampling strategy for prostate tissue microarrays for Ki-67 and androgen receptor biomarkers SO ANALYTICAL AND QUANTITATIVE CYTOLOGY AND HISTOLOGY LA English DT Article DE prostate neoplasms; Ki-67 antigen; androgen; receptors; tissue microarrays ID VIDEO IMAGE-ANALYSIS; CANCER; PROLIFERATION; EXPRESSION; SPECIMENS; INDEX; MEN AB OBJECTIVE: To develop an optimal sampling strategy for tissue microarrays using automated digital analysis for androgen receptor (heterogeneous expression) and the cellular proliferation marker Ki-67 (homogeneous expression and evaluated by others using nonautomated methods). STUDY DESIGN: Tissue microarrays were constructed from 23 radical prostatectomy specimens and immunostained for androgen receptor expression and cellular proliferation. Automated digital image analysis was used, and the minimum number of cores necessary to capture variance change < 3% was determined. Androgen receptor immunostaining was described by percent positive nuclei (PN) and mean optical density (MOD). RESULTS: Androgen receptor PPN variance measurements showed that 5 cores should be obtained when a sin-gle block of a radical prostatectomy specimen contained cancer. If all of 15 blocks contained cancer, 2 cores should be obtained from each of 6 blocks. An optimal sampling strategy was developed for androgen receptor PPN, androgen receptor MOD and Ki-67 PPN. CONCLUSION: The selection of the number of cores to sample is a tradeoff between the number of cores available that contain cancer and the amount of work involved in the analysis. Sampling no fewer than 5 but no more than 12 cores per radical prostatectomy specimen can capture tissue heterogeneity. C1 Roswell Pk Canc Inst, Dept Urol Oncol, Buffalo, NY 14263 USA. SUNY Buffalo, Dept Urol, Buffalo, NY 14260 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biostat, Chapel Hill, NC 27514 USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27514 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Mohler, JL (reprint author), Roswell Pk Canc Inst, Dept Urol Oncol, Elm & Carlton St, Buffalo, NY 14263 USA. EM james.mohler@roswellpark.org FU NCI NIH HHS [CA77739] NR 16 TC 12 Z9 12 U1 0 U2 1 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0884-6812 J9 ANAL QUANT CYTOL JI Anal. Quant. Cytol. Histol. PD AUG PY 2004 VL 26 IS 4 BP 194 EP 200 PG 7 WC Cell Biology SC Cell Biology GA 848OP UT WOS:000223477300003 PM 15457671 ER PT J AU Brewer, MA Ranger-Moore, J Greene, MH Alberts, DS Liu, Y Bartels, HG Baruch, AC Bartels, PH AF Brewer, MA Ranger-Moore, J Greene, MH Alberts, DS Liu, Y Bartels, HG Baruch, AC Bartels, PH TI Preneoplastic changes in ovarian tissues SO ANALYTICAL AND QUANTITATIVE CYTOLOGY AND HISTOLOGY LA English DT Article DE ovarian neoplasms; ovarian cancer; karyometry; stromal cells; ovarian inclusion cysts ID MALIGNANCY-ASSOCIATED CHANGES; INTERMEDIATE CELLS; CHROMATIN TEXTURE; UTERINE-CANCER; BREAST; MICROENVIRONMENT; CARCINOMA; PROSTATE; MARKERS; LESIONS AB OBJECTIVE: To test whether histologically normal epithelium within ovarian inclusion cysts and stroma exhibit changes in nuclear chromatin pattern that indicate the presence of occult ovarian lesions. STUDY DESIGN: Ovaries were collected from 10 low-risk women, from 7 high-risk women and from 3 women with ovarian cancer. Histologic sections were cut at 5 mum and hematoxylin and eosin stained. High-resolution images were recorded from the epithelium lining inclusion cysts and from the underlying stroma of ovaries from these 20 subjects. A total of 2,860 epithelial nuclei and 3,610 stromal nuclei were recorded. Karyometric features and nuclear abnormality were computed. Discriminant analyses and unsupervised learning algorithms de- fined deviations from normal that were designated "above threshold" and used to compute average nuclear abnormality of a second nuclear phenotype. RESULTS: Histologically normal epithelium from inclusion cysts of ovaries harboring a malignant lesion was shown to exhibit changes in the nuclear chromatin pattern that were statistically significant using quantitative image analysis procedures. Similar changes were seen in the inclusion cyst epithelia of high-risk ovaries. A subpopulation of cells representing a new phenotype was detected in the underlying stroma of women harboring a malignant ovarian lesion and in women at high risk of ovarian cancer. CONCLUSION: The karyometric changes observed in the epithelia lining inclusion cysts and in the underlying stroma of ovaries either with ovarian cancer or at high risk of ovarian cancer suggest the presence of preneoplastic changes in histologically normal tissue. C1 Univ Arizona, Arizona Canc Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Tucson, AZ 85724 USA. Univ Arizona, Coll Publ Hlth, Tucson, AZ 85724 USA. Univ Arizona, Ctr Opt Sci, Tucson, AZ 85724 USA. Univ Arizona, Coll Med, Div Pathol, Tucson, AZ 85724 USA. Natl Canc Inst, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD USA. Univ Arizona, Arizona Canc Ctr, Coll Med, Tucson, AZ 85724 USA. Univ Arizona, Ctr Opt Sci, Tucson, AZ 85724 USA. RP Brewer, MA (reprint author), Univ Arizona, Arizona Canc Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Room 1968G,1515 N Campbell Ave, Tucson, AZ 85724 USA. EM mbrewer@azcc.arizona.edu FU NCI NIH HHS [CA 27502-22S1, CA 53877-13] NR 22 TC 9 Z9 10 U1 0 U2 0 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0884-6812 J9 ANAL QUANT CYTOL JI Anal. Quant. Cytol. Histol. PD AUG PY 2004 VL 26 IS 4 BP 207 EP 216 PG 10 WC Cell Biology SC Cell Biology GA 848OP UT WOS:000223477300005 PM 15457673 ER PT J AU Sinz, A Wang, K AF Sinz, A Wang, K TI Mapping spatial proximities of sulfhydryl groups in proteins using a fluorogenic cross-linker and mass spectrometry SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE chemical cross-linking; gamma-crystallin; dibromobimane; fluorescence; HPLC; MALDI-TOF mass spectrometry ID MYOSIN SUBFRAGMENT-1; LINKING; DIBROMOBIMANE; IDENTIFICATION; CONSTRAINTS; COMPLEXES; DOMAIN AB Chemical cross-linking of proteins in combination with mass spectrometric analysis of the reaction products has gained renewed interest as a method of obtaining distance constraints within a protein and determining a low-resolution three-dimensional structure. We present a method for identifying spatially close sulfhydryl groups in proteins employing chemical cross-linking with the fluorogenic, homobifunctional cross-linker dibromobimane, which cross-links thiol pairs within similar to3-6 Angstrom. The applicability of our strategy was demonstrated by cross-linking the sulfhydryl groups of Cys-18 and Cys-78 in gamma-crystallin F, which are within a distance of 3.57 Angstrom according to the X-ray structure. Intramolecularly cross-linked gamma-crystallin was first separated from reaction side products by reversed-phase chromatography on a C-4 column. Subsequently, the fraction containing the reacted protein was enzymatically digested with trypsin, and the resulting peptide mixture was separated by a second reversed-phase chromatographic step on a C-18 column, in which the cross-linked peptides were tracked by their fluorescence. The cross-linking product between Cys-18 and Cys-78 in gamma-crystallin F was identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry. This strategy presents a rapid method for mapping sulfhydryl groups separated by a distance of similar to3-6 Angstrom within a protein. (C) 2004 Elsevier Inc. All rights reserved. C1 NIAMSD, Muscle Proteom & Nanotechnol Sect, Muscle Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sinz, A (reprint author), Univ Leipzig, Fac Chem & Mineral, Biotechnol Biomed Ctr, D-04103 Leipzig, Germany. EM sinz@chemie.uni-leipzig.de NR 15 TC 18 Z9 20 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD AUG 1 PY 2004 VL 331 IS 1 BP 27 EP 32 DI 10.1016/j.ab.2004.03.075 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 838EV UT WOS:000222697200003 PM 15245993 ER PT J AU Keifer, PA Peterkofsky, A Wang, GS AF Keifer, PA Peterkofsky, A Wang, GS TI Effects of detergent alkyl chain length and chemical structure on the properties of a micelle-bound bacterial membrane targeting peptide SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE amphipathic helix; diffusion coefficient; IIA(Glc); lipid chain length; membrane anchor; micelle; NMR; short-chain phospholipids ID PROTEIN SECONDARY STRUCTURE; NMR-SPECTROSCOPY; ESCHERICHIA-COLI; PHOSPHOTRANSFERASE SYSTEM; ANTIMICROBIAL PEPTIDES; DIFFUSION; EXCHANGE; SPECTRA; SHIFT; MOTIF AB The effects of phospholipid or detergent chain length on the structure and translational diffusion coefficient of the membrane-targeting peptide corresponding to the N-terminal amphipathic sequence of Escherichia coli enzyme IIA(Glc) were investigated by nuclear magnetic resonance (NMR) spectroscopy. Three anionic phospholipids (dihexanoyl phosphatidylglycerol, dioctanoyl phosphatidylglycerol, and didecanoyl phosphatidylglycerol) and four lipid-mimicking anionic detergents (sodium hexanesulfonate, 2,2-dimethyl-sitapentane-5-sulfonate, sodium nonanesulfonate, and sodium dodecylsulfate) were evaluated. In all cases, the cationic peptide adopts an amphipathic helical structure. While the chain length of the two-chain phospholipids has a negligible effect on the peptide conformation, the effect of chain length of those single-chain detergents on the helix length is more pronounced. The diffusion coefficients of the peptide/micelle complexes were found to correlate with the chain lengths of both the lipid and the detergent groups. Taken together, short-chain anionic phospholipids are proposed to be useful membrane-mimetic models for the structural elucidation of membrane-binding peptides such as cationic antimicrobial peptides. DSS does not form micelles by itself according to the diffusion coefficient data, but it does associate with this cationic peptide. Consequently, both DSS and its analog may be chosen as NMR chemical shift reference compounds depending on the nature of the biomolecules under investigation. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Nebraska Med Ctr 986805, Omaha, NE 68198 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, GS (reprint author), Univ Nebraska, Med Ctr, Eppley Inst Res Canc & Allied Dis, Nebraska Med Ctr 986805, Omaha, NE 68198 USA. EM gwang@unmc.edu NR 37 TC 24 Z9 24 U1 2 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD AUG 1 PY 2004 VL 331 IS 1 BP 33 EP 39 DI 10.1016/j.ab.2004.03.074 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 838EV UT WOS:000222697200004 PM 15245994 ER PT J AU Acharya, MR Baker, SD Verweij, J Figg, WD Sparreboom, A AF Acharya, MR Baker, SD Verweij, J Figg, WD Sparreboom, A TI Determination of fraction unbound docetaxel using microequilibrium dialysis SO ANALYTICAL BIOCHEMISTRY LA English DT Editorial Material ID PHARMACOKINETICS; POLYSORBATE-80; CANCER C1 NCI, Clin Pharmacol Res Ctr, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sidney Kimmel Co mprehens Canc Ctr, Div Expt Therapeut, Baltimore, MD USA. Erasmus Univ MC, Dr Daniel Den Hoed Canc Ctr, Dept Med Oncol, Rotterdam, Netherlands. RP Figg, WD (reprint author), NCI, Clin Pharmacol Res Ctr, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 9 TC 12 Z9 12 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 AUG 1 PY 2004 VL 331 IS 1 BP 192 EP 194 DI 10.1016/j.ab.2004.03.045 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 838EV UT WOS:000222697200024 PM 15246014 ER PT J AU Scheidweiler, KB Huestis, MA AF Scheidweiler, KB Huestis, MA TI Simultaneous quantification of opiates, cocaine, and metabolites in hair by LC-APCI-MS/MS SO ANALYTICAL CHEMISTRY LA English DT Article ID FLIGHT MASS-SPECTROMETRY; GC-MS; QUANTITATIVE-DETERMINATION; RAT HAIR; CODEINE; MELANIN; CONTAMINATION; AMPHETAMINE; BENZOYLECGONINE; CHROMATOGRAPHY AB A quantitative LC-APCI-MS/MS method for simultaneous measurement of opiates, cocaine, and metabolites in hair was developed and validated. Cocaine and opiates were extracted from pulverized hair via sonication in methanol at 37 degreesC for 3 h. Samples were cleaned up using solid-phase extraction. LC separation was achieved in 20 min with identification and quantification by selected reaction monitoring. Calibration by linear regression analysis utilized deuterated internal standards and a weighting factor of 1/x (R-2 > 0.998). limits of quantification (LOQ) ranged from 17 to 50 pg/mg for cocaine and metabolites and were 83 pg/mg for opiates. Standard curves were linear from the LOQ to 5000 pg/mg for cocaine and metabolites, except benzoylecgonine (2500 pg/mg). Opiate standard curves were linear from the LOQ to 12500 pg/mg. Accuracy ranged from 84 to 115% for all quantitative analytes. Precision, % relative standard deviation, was less than 11.0% for all analytes. Methanolic sonication produced less than 5% hydrolysis of cocaine and 6-acetylmorphine. The method should be useful for studying cocaine and opiate distribution into hair. C1 Natl Inst Drug Abuse, Intramural Res Program, Chem & Drug Metab Sect, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Chem & Drug Metab Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov NR 28 TC 52 Z9 56 U1 0 U2 8 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 AUG 1 PY 2004 VL 76 IS 15 BP 4358 EP 4363 DI 10.1021/ac04955t PG 6 WC Chemistry, Analytical SC Chemistry GA 842NC UT WOS:000223010100029 PM 15283573 ER PT J AU Dudas, J Papoutsi, M Hecht, M Elmaouhoub, A Saile, B Christ, B Tomarev, SI von Kaisenberg, CS Schweigerer, L Ramadori, G Wilting, J AF Dudas, J Papoutsi, M Hecht, M Elmaouhoub, A Saile, B Christ, B Tomarev, SI von Kaisenberg, CS Schweigerer, L Ramadori, G Wilting, J TI The homeobox transcription factor Prox1 is highly conserved in embryonic hepatoblasts and in adult and transformed hepatocytes, but is absent from bile duct epithelium SO ANATOMY AND EMBRYOLOGY LA English DT Article DE liver development; chick; rat; human; MMH; hepatoma cells ID LIVER DEVELOPMENT; ENDOTHELIAL-CELLS; RAT-LIVER; GENE-EXPRESSION; ENDODERM; LYMPHATICS; PROSPERO; CULTURES; KUPFFER; MARKER AB Prox1 is a transcription factor with two highly conserved domains, a homeobox and a prospero domain. It has been shown that Prox1 knock-out mice die during early embryonic stages and display a rudimentary liver. We have studied the expression of Prox1 at RNA and protein levels in chick, rat, mouse and human liver and in transformed and non-transformed hepatic cell lines. Prox1 is expressed in early embryonic hepatoblasts and is still expressed in adult hepatocytes. Prox1 protein is located in the nuclei of hepatoblasts, which grow into the neighboring embryonic mesenchyme. The expression pattern in chick, mouse, rat and human embryos is highly conserved. Besides albumin and alpha-fetal protein, Prox1 belongs to the earliest markers of the developing liver. In adult liver, Prox1 is expressed in hepatocytes but is absent from bile duct epithelial and non-parenchymal cells (Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells and myofibroblasts). Isolated primary hepatocytes and hepatoma cell lines (HepG2, Hep3B) are Prox1 positive, whereas the immortalized murine liver cell-line MMH, which constitutively expresses the receptor c-met, is Prox1 negative. Transfection of MMH with Prox1 cDNA increases the expression level significantly as compared to control transfectants. In HepG2 and Hep3B, the Prox1 levels are even up to 100 times higher. Our studies show that Prox1 is a highly conserved transcription factor, expressed in hepatocytes from the earliest stages of development into adulthood and over-expressed in hepatoma cell lines. Its absence from bile duct epithelial cells suggests a function for the specification of hepatoblasts into hepatocytes. The genes controlled by Prox1 need to be studied in the future. C1 Univ Gottingen, Childrens Hosp, D-37075 Gottingen, Germany. Univ Gottingen, Dept Gastroenterol & Endocrinol, D-37075 Gottingen, Germany. Univ Freiburg, Inst Anat & Cell Biol, D-79104 Freiburg, Germany. NEI, Mol & Dev Biol Lab, Bethesda, MD 20892 USA. Univ Kiel, Frauenklin, D-24105 Kiel, Germany. RP Wilting, J (reprint author), Univ Gottingen, Childrens Hosp, Robert Koch Str 40, D-37075 Gottingen, Germany. EM joerg.wilting@med.uni-goettingen.de NR 38 TC 34 Z9 36 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-2061 J9 ANAT EMBRYOL JI Anat. Embryol. PD AUG PY 2004 VL 208 IS 5 BP 359 EP 366 DI 10.1007/s00429-004-0403-4 PG 8 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 845TB UT WOS:000223266100003 PM 15232737 ER PT J AU Giedzinska, AS Meyerowitz, BE Ganz, PA Rowland, JH AF Giedzinska, AS Meyerowitz, BE Ganz, PA Rowland, JH TI Health-related quality of life in a multiethnic sample of breast cancer survivors SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article ID AFRICAN-AMERICAN WOMEN; PSYCHOLOGICAL DISTRESS; DYADIC ADJUSTMENT; WHITE WOMEN; CARCINOMA; POPULATIONS; MASTECTOMY; ETHNICITY; OUTCOMES; SCALES AB Background: Little is known about the experiences of women from varying ethnic groups following treatment for breast cancer Purpose: This study provides a comprehensive description of heath-related quality of life (HRQL) and identifies problem areas and predictive factors for a multiethnic sample. Methods: Six hundred twenty-one breast cancer survivors from 2 major cities participated within 5 years of their diagnosis. Participants were African Americans, Latinas, Asian Americans, and Whites. Patients filled out questionnaire packets comprising standardized instruments related to HRQL, psychological adjustment, cancer-related treatment, and demographic variables. Data were analyzed using 2 methods: (a) observation of findings prior to controlling for demographic and treatment variables and (b) observation of findings after controlling for variables confounded with ethnicity. Results: Findings indicate that most women experienced good HRQL. Group differences revealed that African Americans found more meaning in life as a result of having breast cancer and Latinas reported more physical symptoms. Age predicted aspects of HRQL for African Americans and Whites. Conclusions: This study comprehensively assessed HRQL following breast cancer for ethnic minority women. Most breast cancer survivors in this study reported levels of HRQL comparable to established norms. However, some quality of life impediments surfaced in particular groups. Researchers should not assume that predictive models of breast cancer HRQL are the same across ethnic groups. C1 Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Meyerowitz, BE (reprint author), Univ So Calif, Dept Psychol, SGM 516,MC 1061, Los Angeles, CA 90089 USA. EM meyerow@usc.edu FU NCI NIH HHS [R01 CA63028] NR 38 TC 62 Z9 63 U1 2 U2 5 PU LAWRENCE ERLBAUM ASSOC INC PI MAHWAH PA 10 INDUSTRIAL AVE, MAHWAH, NJ 07430-2262 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD AUG PY 2004 VL 28 IS 1 BP 39 EP 51 DI 10.1207/s15324796abm2801_6 PG 13 WC Psychology, Multidisciplinary SC Psychology GA 840DF UT WOS:000222836500006 PM 15249258 ER PT J AU Sorlie, PD Coady, S Lin, C Arias, E AF Sorlie, PD Coady, S Lin, C Arias, E TI Factors associated with out-of-hospital coronary heart disease death: The National Longitudinal Mortality Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE mortality; coronary heart disease; ischemic heart disease; place of death; marital status; race; ethnicity ID ACUTE MYOCARDIAL-INFARCTION; PREHOSPITAL DELAY; TRENDS; INDEX; TIME AB PURPOSE: A significant portion of coronary heart disease deaths occur out of the hospital, prior to access to life saving medical care. Improving the immediacy of care could have important impact on coronary mortality. METHODS: The objective of this research is to identify factors associated with the occurrence of out-of-hospital coronary heart disease death as compared with in-hospital. Identification of these factors could lead to additional strategies for rapid treatment of coronary attack symptoms. A large national cohort study with individually identified characteristics was matched to the National Death Index to identify deaths by cause occurring in up to 11 years of follow-up. Approximately 60,000 deaths occurred in the cohort of approximately 700,000 participants aged 25 years or more. Location of death was defined as either in- or out-of-hospital. RESULTS: Among deaths classified as coronary heart disease (CHD), multivariate logistic models of the association between selected demographic and socioeconomic characteristics of individuals prior to death and place of death show that black persons are more likely to die out of hospital, as are persons who live alone or are unmarried, persons at the lowest end of the income distribution, and persons who live in rural areas vs. urban areas. CONCLUSIONS: The factors most strongly associated with a CHD death occurring out-of-hospital as compared with in-hospital are race (black persons are 1.23 times more likely to die out of hospital than white persons, net of demographic and socioeconomic differentials) and living status (persons who are not married are 1.60 times more likely to die out of hospital than persons who are married, net of demographic and socioeconomic characteristics). Attention should be paid to these groups to emphasize the need for rapid attention to the signs of a coronary attack so that rapid and potentially life saving intervention can be implemented. (C) 2004 Elsevier Inc. All rights reserved. C1 NHLBI, Epidemiol & Biometry Program, Rockledge Ctr 2, NIH, Bethesda, MD 20892 USA. US Bur Census, Demog & Stat Methods Div, Suitland, MD USA. Natl Ctr Hlth Stat, Div Vital Stat, Mortal Stat Branch, Hyattsville, MD 20782 USA. RP Sorlie, PD (reprint author), NHLBI, Epidemiol & Biometry Program, Rockledge Ctr 2, NIH, MSC 7934,6701 Rockledge Rd, Bethesda, MD 20892 USA. EM SorlieP@nih.gov NR 9 TC 10 Z9 11 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD AUG PY 2004 VL 14 IS 7 BP 447 EP 452 DI 10.1016/j.annepidem.2003.10.002 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 847PR UT WOS:000223407900001 PM 15301780 ER PT J AU Floel, A Nagorsen, U Werhahn, KJ Ravindran, S Birbaumer, N Knecht, S Cohen, LG AF Floel, A Nagorsen, U Werhahn, KJ Ravindran, S Birbaumer, N Knecht, S Cohen, LG TI Influence of somatosensory input on motor function in patients with chronic stroke SO ANNALS OF NEUROLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; ISCHEMIC NERVE BLOCK; INTERHEMISPHERIC INHIBITION; HEMIPARETIC STROKE; CORTEX; MODULATION; MOVEMENTS; MONKEYS; DEAFFERENTATION; PLASTICITY AB In healthy volunteers, reduction of somatosensory input from one hand leads to rapid performance improvements in the other hand. Thus, it is possible that reduction of somatosensory input from the healthy hand can influence motor function in the paretic hand of chronic stroke patients with unilateral hand weakness. To test this hypothesis, we had 13 chronic stroke patients perform motor tasks with the paretic hand and arm during cutaneous anesthesia of the healthy hand and healthy foot in separate sessions. Performance of a finger tapping task, but not a wrist flexion task, improved significantly with anesthesia of the hand, but not the foot. This effect progressed with the duration of anesthesia and correlated with baseline motor function. We conclude that cutaneous anesthesia of the healthy hand elicits transient site-specific improvements in motor performance of the moderately paretic hand in patients with chronic stroke, consistent with interhemispheric competition models of sensorimotor processing. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20817 USA. Univ Munster, Dept Neurol, D-4400 Munster, Germany. Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany. Univ Mainz, Dept Neurol, D-6500 Mainz, Germany. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20817 USA. EM cohenl@ninds.nih.gov RI Floel, Agnes/A-9426-2017; OI Knecht, Stefan/0000-0003-1056-9228 NR 55 TC 78 Z9 83 U1 1 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2004 VL 56 IS 2 BP 206 EP 212 DI 10.1002/ana.20170 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 847YT UT WOS:000223434700006 PM 15293272 ER PT J AU Dobson-Stone, C Velayos-Baeza, A Filippone, LA Westbury, S Storch, A Erdmann, T Wroe, SJ Leenders, KL Lang, AE Dotti, MT Federico, A Mohiddin, SA Fananapazir, L Daniels, G Danek, A Monaco, AP AF Dobson-Stone, C Velayos-Baeza, A Filippone, LA Westbury, S Storch, A Erdmann, T Wroe, SJ Leenders, KL Lang, AE Dotti, MT Federico, A Mohiddin, SA Fananapazir, L Daniels, G Danek, A Monaco, AP TI Chorein detection for the diagnosis of chorea-acanthocytosis SO ANNALS OF NEUROLOGY LA English DT Article ID PROTEIN; GENE; NEUROACANTHOCYTOSIS AB Chorea-acanthocytosis (ChAc) is a severe, neurodegenerative disorder that shares clinical features with Huntington's disease and McLeod syndrome. It is caused by mutations in VPS13A, which encodes a large protein called chorein. Using antichorein antisera, we found expression of chorein in all human cells analyzed. However, chorein expression was absent or noticeably reduced in ChAc patient cells, but not McLeod syndrome and Huntington's disease cells. This suggests that loss of chorein expression is a diagnostic feature of ChAc. C1 Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. Cornell Univ, Ithaca, NY USA. Univ Oxford, St Johns Coll, Oxford, England. Tech Univ Dresden, Dept Neurol, D-8027 Dresden, Germany. Vinznez Paul Hosp Rottemunster, Dept Neurol, Rottweil, Germany. Ipswich Hosp, Dept Clin Neurol, Ipswich, Suffolk, England. Univ Groningen Hosp, Groningen, Netherlands. Univ Toronto, Div Neurol, Toronto, ON, Canada. Univ Siena, Dept Neurobiol & Behav Sci, Sect Neurol & Neurometab Dis, Sch Med, I-53100 Siena, Italy. NHLBI, CardiovascBranch, Bethesda, MD 20892 USA. Bristol Inst Transfus Sci, Bristol, Avon, England. Univ Munich, Neurol Klin, Munich, Germany. RP Monaco, AP (reprint author), Univ Oxford, Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England. EM anthony.monaco@well.ox.ac.uk RI Monaco, Anthony/A-4495-2010; Danek, Adrian/G-7339-2011; OI Monaco, Anthony/0000-0001-7480-3197; Danek, Adrian/0000-0001-8857-5383; federico, antonio/0000-0002-5246-1621; Westbury, Sarah/0000-0002-0950-8148 NR 16 TC 68 Z9 71 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD AUG PY 2004 VL 56 IS 2 BP 299 EP 302 DI 10.1002/ana.20200 PG 4 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 847YT UT WOS:000223434700019 PM 15293285 ER PT J AU Marshall, J Chen, H Yang, D Figueira, M Bouker, KB Ling, Y Lippman, M Frankel, SR Hayes, DF AF Marshall, J Chen, H Yang, D Figueira, M Bouker, KB Ling, Y Lippman, M Frankel, SR Hayes, DF TI A phase I trial of a Bcl-2 antisense (G3139) and weekly docetaxel in patients with advanced breast cancer and other solid tumors SO ANNALS OF ONCOLOGY LA English DT Article DE advanced breast cancer; Bcl-2; docetaxel; G3139; solid tumors ID CELL LUNG-CANCER; PROSTATE-CANCER; OLIGONUCLEOTIDE THERAPY; PROTEIN; EXPRESSION; APOPTOSIS; LYMPHOMA; COMBINATION; OLIGODEOXYNUCLEOTIDES; PACLITAXEL AB Purpose: Expression of the Bcl-2 protein confers resistance to various apoptotic signals. G3139 [oblimersen sodium (Genasense(TM))] is a phosphorothioate antisense oligodeoxynucleotide that targets Bcl-2 mRNA, downregulates Bcl-2 protein translation, and enhances the antitumor effects of sub-therapeutic doses of docetaxel (Taxotere(TM)). Patients and methods: We performed a phase I trial to determine the maximum tolerated dose (MTD) and safety profile of combined therapy with G3139 and weekly docetaxel in patients with advanced Bcl-2-positive solid tumors. Cohorts of three to six patients were enrolled to escalating doses of G3139 and a fixed dose of weekly docetaxel using either of two schedules. In part 1, G3139 was administered by continuous infusion for 21 days (D1-22), and docetaxel (35 mg/m(2)) was given weekly on days 8, 15 and 22. In part II, G3139 was given by continuous infusion for 5 days before the first weekly dose of docetaxel, and for 48 It before the second and third weekly docetaxel doses. For both schedules, cycles were repeated every 4 weeks. Results: Twenty-two patients were enrolled. Thirteen patients were treated on the part I schedule with doses of G3139 escalated from I to 4 mg/kg/day. Nine patients were on the part 11 schedule of shorter G3139 infusion at G3139 doses of 5-9mg/kg/day. Hematologic toxicities were mild, except for one case of persistent grade 3 thrombocytopenia in part I. The most common adverse events were cumulative fatigue and transaminase elevation, which prevented further dose escalation beyond 4 mg/kg/day for 21 days with the part I schedule. In part 11 of the study, using the abbreviated G3139 schedule, even the highest daily doses were tolerated without dose-limiting toxicity or the need for dose modification. Objective tumor response was observed in two patients with breast cancer, including one whose cancer previously progressed on trastuzumab plus paclitaxel. Four patients had stable disease. Pharmacokinetic results for G3139 were similar to those of other trials. Conclusions: G3139 in combination with standard-dose weekly docetaxel was well tolerated. The shortened and intermittent G3139 infusion had less cumulative toxicities and still allowed similar total G3139 delivery as the longer infusion. Further studies should examine the molecular effect of the regimen, as well as clinical activities in malignancies for which taxanes are indicated. C1 Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Div Hematol Oncol, Washington, DC 20007 USA. NCI, Invest Drug Branch, Canc Treatment Evaluat Program, Bethesda, MD 20892 USA. Univ Michigan Hlth Syst, Dept Med, Div Hematol Oncol, Ann Arbor, MI USA. Genta Inc, Med Operat, Berkeley Hts, NJ USA. RP Marshall, J (reprint author), Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Div Hematol Oncol, 3800 Reservoir Rd NW, Washington, DC 20007 USA. EM marshalj@georgetown.edu NR 48 TC 52 Z9 57 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD AUG PY 2004 VL 15 IS 8 BP 1274 EP 1283 DI 10.1093/annonc/mdh317 PG 10 WC Oncology SC Oncology GA 846YK UT WOS:000223355400019 PM 15277270 ER PT J AU Finkelstein, SE Carrasquillo, JA Hoffman, JM Galen, B Choyke, P White, DE Rosenberg, SA Sherry, RM AF Finkelstein, SE Carrasquillo, JA Hoffman, JM Galen, B Choyke, P White, DE Rosenberg, SA Sherry, RM TI A prospective analysis of positron emission tomography and conventional imaging for detection of stage IV metastatic melanoma in patients undergoing metastasectomy SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article DE melanoma; cancer; FDG-PET; imaging; metastasectomy; surgery ID CUTANEOUS MALIGNANT-MELANOMA; SENTINEL NODE BIOPSY; MANAGEMENT; 2-FLUORINE-18-FLUORO-2-DEOXY-D-GLUCOSE; ONCOLOGY; PET AB Background: Positron emission tomography with 2-deoxy-2-[F-18]fluoro-D-glucose (FDG-PET) is available for evaluation of patients with melanoma. This study evaluates the potential of FDG-PET to improve on conventional imaging (CI) in patients with stage IV melanoma undergoing metastasectomy. Methods: This was a prospective study comparing radiological evaluation of patients who underwent metastasectomy for palliation or cure. Patients underwent preoperative evaluation by physical examination, CI by computed tomography and/or magnetic resonance imaging, and FDG-PET. Independent observers performed three separate analyses of CI alone, FDG-PET alone, or FDG-PET read with knowledge of CI (FDG-PET + C). Abnormalities were reported as benign or malignant and assessed by pathologic analysis or by clinical outcome determined by disease progression detected on serial evaluations. Results: Ninety-four lesions were noted in 18 patients who underwent preoperative assessment, metastasectomy, and long-term follow up (median, 24 months). Lesion-by-lesion analysis for CI demonstrated a sensitivity of 76%, a specificity of 87%, a positive predictive value (PPV) of 86%, and a negative predictive value (NPV) of 76%. FDG-PET demonstrated a sensitivity of 79%, a specificity of 87%, a PPV of 86%, and an NPV of 80%. For FDG-PET + CI, the sensitivity was 88%, specificity was 91%, and PPV and NPV were 91% and 88%, respectively. Conclusions: Combined use of FDG-PET and CI may be an accurate strategy to identify sites of disease in patients with stage IV melanoma being considered for metastasectomy. Interpreted independently, FDG-PET and CI seemed to be equivalent modalities. FDG-PET + CI had both the highest sensitivity on lesion-by-lesion analysis and the best accuracy on patient-by-patient analysis. C1 NCI, Ctr Canc Res, Surg Branch, NIH, Bethesda, MD 20892 USA. NCI, Warren Grant Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Diag, Canc Imaging Program, Mol Imaging Branch, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. RP Sherry, RM (reprint author), NCI, Ctr Canc Res, Surg Branch, NIH, Bldg 10,Room 2338,9000 Rockville Pike, Bethesda, MD 20892 USA. EM richard_sherry@nih.gov RI Carrasquillo, Jorge/E-7120-2010; OI Carrasquillo, Jorge/0000-0002-8513-5734 FU Intramural NIH HHS [Z01 SC003811-32] NR 22 TC 34 Z9 35 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD AUG PY 2004 VL 11 IS 8 BP 731 EP 738 DI 10.1245/ASO.2004.01.023 PG 8 WC Oncology; Surgery SC Oncology; Surgery GA 842NU UT WOS:000223011900005 PM 15249335 ER PT J AU Beseth, BD Cameron, RB Leland, P You, L Varricchio, F Kreitman, RJ Maki, RA Jablons, DM Husain, SR Puri, RK AF Beseth, BD Cameron, RB Leland, P You, L Varricchio, F Kreitman, RJ Maki, RA Jablons, DM Husain, SR Puri, RK TI Interleukin-4 receptor cytotoxin as therapy for human malignant pleural mesothelioma xenografts SO ANNALS OF THORACIC SURGERY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the Society-of-Thoracic-Surgeons CY JAN 31-FEB 02, 2003 CL SAN DIEGO, CA SP Soc Thorac Surg ID HIGH-AFFINITY INTERLEUKIN-4; GROWTH-FACTOR; CELL-GROWTH; IN-VITRO; PSEUDOMONAS EXOTOXIN; ANTITUMOR-ACTIVITY; CHIMERIC PROTEIN; KAPOSIS-SARCOMA; CARCINOMA-CELLS; CANCER-THERAPY AB Background. Malignant pleural mesothelioma (MPM) is an uncommon but highly fatal neoplasm for which only limited treatment is available. Methods. Immunohistochemical analysis was used to determine the expression of interleukin-4 receptors (IL-4R) on mesothelioma cell lines and resected mesothelioma tumors. Radioreceptor binding assays were used to show that these IL-4R were high-affinity receptors. Previously, we had shown that a chimeric protein composed of a circularly permuted IL-4 molecule fused to a truncated form of Pseudomonas exotoxin A, IL-4(38-37)PE38KDEL, could be used to kill IL-4R-bearing tumor cells in vitro. The toxicity of this molecule to mesothelioma cell lines was tested using a protein synthesis inhibition assay. A human mesothelioma xenograft model was then developed to assess the efficacy of this molecule in vivo. Results. All MPM cell lines tested were found to express high-affinity cell-surface IL-4R. Immunohistochemical analysis of resected mesothelioma tumor specimens from 13 patients revealed that all tumors expressed moderate-to-high levels of IL-4R. Coculture of malignant mesothelioma cell lines with IL-4(38-37)-PE38KDEL resulted in a dose-dependent inhibition of tumor cell protein synthesis through an interaction with cell-surf ace IL-4R. In a nude mouse xenograft model of human MPM, intratumoral administration of IL-4(38-37)-PE38KDEL mediated a dose-dependent decrease in tumor volume and a dose-dependent increase in survival. Conclusions. The chimeric protein, IL-4(38-37)PE38KDEL, has potent antitumor effects against MPM both in vitro and in vivo. (C) 2004 by The Society of Thoracic Surgeons. C1 Univ Calif Los Angeles, Sch Med, Dept Surg, Sect Gen Thorac Surg, Los Angeles, CA 90095 USA. US FDA, Ctr Biol Evaluat & Res, Lab Mol Tumor Biol, Div Cellular & Gene Therapy, Bethesda, MD 20014 USA. US FDA, Ctr Biol Evaluat & Res, Div Biostat, Bethesda, MD 20014 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Neurocrine Biosci, San Diego, CA USA. RP Cameron, RB (reprint author), Univ Calif Los Angeles, Sch Med, Dept Surg, Sect Gen Thorac Surg, 10833 Le Conte Ave,Room 62-215 CHS,POB 951741, Los Angeles, CA 90095 USA. EM rcameron@mednet.ucla.edu FU NCI NIH HHS [R01 CA093708, R01 CA093708-01A3] NR 30 TC 7 Z9 7 U1 2 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-4975 J9 ANN THORAC SURG JI Ann. Thorac. Surg. PD AUG PY 2004 VL 78 IS 2 BP 436 EP 443 DI 10.1016/j.athoracsur.2004.03.010 PG 8 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery SC Cardiovascular System & Cardiology; Respiratory System; Surgery GA 842JE UT WOS:000222999300009 PM 15276492 ER PT J AU ten Tije, AJ Loos, WJ Zhao, M Baker, SD Enting, RH van der Meulen, H Verweij, J Sparreboom, A AF ten Tije, AJ Loos, WJ Zhao, M Baker, SD Enting, RH van der Meulen, H Verweij, J Sparreboom, A TI Limited cerebrospinal fluid penetration of docetaxel SO ANTI-CANCER DRUGS LA English DT Article DE cerebrospinal fluid; docetaxel; pharmacokinetics; protein binding ID ADVANCED BREAST-CANCER; LEPTOMENINGEAL CARCINOMATOSIS; CLINICAL PHARMACOKINETICS AB Our purpose was to investigate the cerebrospinal fluid (CSF) penetration of docetaxel in cancer patients. Docetaxel was administered as a 1-h infusion at a dose of 75 mg/m(2) to two patients with metastatic breast cancer and leptomeningeal carcinomatosis. CSF samples were obtained using a lumbar puncture up to a 72-h time period. Total and unbound docetaxel concentrations in plasma and CSF were determined by liquid chromatography (lower limit of quantitation: 0.5 nM for plasma and 0.050 nM for CSF) and equilibrium dialysis, respectively. The pharmacokinetics of docetaxel in plasma are in line with data of previous studies. The concentrations of docetaxel in CSF did not follow the general pattern in plasma, with relatively stable concentrations over the 72-h time period. The fraction of unbound docetaxel in plasma ranged from 6 to 13%, while that in CSF ranged from 67 to 103%. For total and unbound docetaxel, the CSF to plasma concentration ratio progressively increased in 72 h from 0.01 to 0.6% and from 0.1 to 9%, respectively. These data suggest that measurement of unbound docetaxel is required to accurately assess the extent of drug penetration into CSF and that the drug can produce distribution to CSF at levels associated with significant antitumor activity in experimental models. (C) 2004 Lippincott Williams Wilkins. C1 Dr Daniel Den Hoed Canc Ctr, Dept Med Oncol, NL-3008 AE Rotterdam, Netherlands. Sydney Kimmel Comprehens Canc Ctr Johns Hopkins, Div Expt Therapeut, Baltimore, MD USA. Erasmus MC Daniel Hoed Canc Ctr, Dept Neurol, Rotterdam, Netherlands. NCI, Med Oncol Clin Res Unit, Bethesda, MD USA. RP Loos, WJ (reprint author), Dr Daniel Den Hoed Canc Ctr, Dept Med Oncol, POB 5201, NL-3008 AE Rotterdam, Netherlands. EM w.loos@erasmusmc.nl RI Sparreboom, Alex/B-3247-2008 NR 10 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD AUG PY 2004 VL 15 IS 7 BP 715 EP 718 DI 10.1097/01.cad.0000136882.19552.8f PG 4 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 848PI UT WOS:000223479200008 PM 15269603 ER PT J AU Leonard, GD Wagner, MR Quinn, MG Grem, JL AF Leonard, GD Wagner, MR Quinn, MG Grem, JL TI Severe disabling sensory-motor polyneuropathy during oxaliplatin-based chemotherapy SO ANTI-CANCER DRUGS LA English DT Article DE oxaliplatin-based chemotherapy; sensory-motor polyneuropathy ID COLORECTAL-CANCER; FLUOROURACIL; LEUCOVORIN AB Oxaliplatin-based combination chemotherapy is an option for first-line therapy of metastatic colorectal cancer. It is associated with acute hyperexcitability of motor and sensory nerves, and a cumulative sensory axonal neuropathy. We describe a 56-year-old male with metastatic colorectal cancer treated with oxaliplatin and capecitabine who developed a rapidly ascending motor and sensory neuropathy, which rendered him wheelchair-bound. Heightened clinical suspicion for possible oxaliplatin-induced motor neuropathies may be warranted. (C) 2004 Lippincott Williams Wilkins. C1 NCI, Navy Med Oncol, Bethesda, MD USA. USN Med Med, Charette Hlth Ctr, Dept Neurol, Portsmouth, VA USA. RP Grem, JL (reprint author), Univ Nebraska, Med Ctr, Dept Internal Med, Sect Oncol Hematol, 987680 Nebraska Med Ctr, Omaha, NE 68198 USA. EM jgrem@unmc.edu NR 8 TC 9 Z9 9 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD AUG PY 2004 VL 15 IS 7 BP 733 EP 735 DI 10.1097/01.cad.0000136683.27176.88 PG 3 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 848PI UT WOS:000223479200012 PM 15269607 ER PT J AU Bremer, JW Brambilla, DJ Granger, S Huang, DD Ussery, MA AF Bremer, JW Brambilla, DJ Granger, S Huang, DD Ussery, MA TI A proposed approach to proficiency testing for HIV-1 drug resistance genotyping SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 Rush Univ, Coll Med, Chicago, IL 60612 USA. New England Res Inst, Watertown, MA 02172 USA. NIAID, DAIDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U97 EP U98 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600148 ER PT J AU Huang, DD Brambilla, DJ Ussery, MA Bremer, JW AF Huang, DD Brambilla, DJ Ussery, MA Bremer, JW TI Complex patterns of resistance mutations distributed on individual HIV-1 genomes comprising predominant plasma populations circulating in treated individuals SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 Rush Univ, Coll Med, Chicago, IL 60612 USA. New England Res Inst, Watertown, MA 02172 USA. NIAID, DAIDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U52 EP U52 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600070 ER PT J AU Larder, BA Wang, D Revell, A Harrigan, R Montaner, J Lane, C AF Larder, BA Wang, D Revell, A Harrigan, R Montaner, J Lane, C TI Previous drug exposure data significantly increase the accuracy of artificial neural networks in predicting virological response to combination therapy SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 HIV Resistance Response Database Initiat, Cambridge, England. RDI Ltd, London, England. BC Ctr Excellence HIV AIDS, Vancouver, BC, Canada. NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U90 EP U90 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600133 ER PT J AU Lifson, JD AF Lifson, JD TI Monkey business: insights into AIDS virus pathogenesis from studies in non-human primates SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 SAIC Frederick Inc, AIDS Vaccine Program, NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U19 EP U19 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600024 ER PT J AU Maldarelli, F Kearney, M Palmer, S Polis, M Mican, J Stephens, R Rock, D Mellors, J Coffin, J AF Maldarelli, F Kearney, M Palmer, S Polis, M Mican, J Stephens, R Rock, D Mellors, J Coffin, J TI HIV-1 populations are large, highly diverse, and characterized by frequent recombination in drug-naive and drug-resistant individuals SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. SAIC, Frederick, MD USA. NIAID, CCMD Clin, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Infect Dis, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U51 EP U51 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600069 ER PT J AU Nikolenko, GN Palmer, S Maldarelli, F Mellors, JW Coffin, JM Pathak, VK AF Nikolenko, GN Palmer, S Maldarelli, F Mellors, JW Coffin, JM Pathak, VK TI Mutations in HIV-1 RNase H domain confer high-level resistance to nucleoside reverse transcriptase inhibitors and provide novel insights into the mechanism of nucleotide excision-mediated drug resistance SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U35 EP U36 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600044 ER PT J AU Nissley, DV Julias, J Mellors, J Hughes, S Strathern, J AF Nissley, DV Julias, J Mellors, J Hughes, S Strathern, J TI Detection and characterization of rare drug resistant HIV-1 RT variants using a sensitive phenotypic assay SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 SAIC Frederick, Frederick, MD USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U98 EP U99 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600150 ER PT J AU Palmer, S Boltz, V Maldarelli, F Kearney, M Halvas, E Mican, J Mellors, J Coffin, J AF Palmer, S Boltz, V Maldarelli, F Kearney, M Halvas, E Mican, J Mellors, J Coffin, J TI Mechanisms of persistence of NNRTI-resistant variants after discontinuation of NNRTI-containing regimens SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 NCI, HIV Drug Resistance Program, NIH, Frederick, MD USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U54 EP U55 PG 2 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600075 ER PT J AU Rhodes, T Nikolaitchik, O Chen, J Hu, WS AF Rhodes, T Nikolaitchik, O Chen, J Hu, WS TI High rates of HIV-1 recombination in T cells SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U51 EP U51 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600068 ER PT J AU Salzwedel, K Goila-Gaur, R Adamson, C Li, F Castillo, A Kilgore, N Reddick, M Matallana, C AF Salzwedel, K Goila-Gaur, R Adamson, C Li, F Castillo, A Kilgore, N Reddick, M Matallana, C TI Selection for and characterization of HIV-1 isolates resistant to the maturation inhibitor PA-457 SO ANTIVIRAL THERAPY LA English DT Meeting Abstract CT 13th International HIV Drug Resistance Workshop CY JUN 08-12, 2004 CL Tenerife, SPAIN C1 Panacos Pharmaceut, Gaithersburg, MD USA. NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU INT MEDICAL PRESS LTD PI LONDON PA 2-4 IDOL LANE, LONDON EC3R 5DD, ENGLAND SN 1359-6535 J9 ANTIVIR THER JI Antivir. Ther. PD AUG PY 2004 VL 9 IS 4 BP U24 EP U24 PG 1 WC Infectious Diseases; Pharmacology & Pharmacy; Virology SC Infectious Diseases; Pharmacology & Pharmacy; Virology GA 960TH UT WOS:000231615600028 ER PT J AU Gaines, JM Metter, EJ Talbot, LA AF Gaines, JM Metter, EJ Talbot, LA TI The effect of neuromuscular electrical stimulation on arthritis knee pain in older adults with osteoarthritis of the knee SO APPLIED NURSING RESEARCH LA English DT Article ID QUESTIONNAIRE; PROGRAM AB The objective of this study was to examine the short- and long-term effects of a home-based, 12-week neuromuscular electrical stimulation (MMES) of the quadriceps femoris to decrease arthritis knee pain in older adults with osteoarthritis of the knee. The study sample (N = 38) was randomly assigned to the MMES treatment plus education group or the arthritis education-only group. Pain was measured in both groups with the McGill Pain Questionnaire (MPQ) at baseline, during the intervention at weeks 4, 8, 12, and at follow-up and with the Arthritis Impact Measurement Scale 2-Pain Subscale (AIMS2-PS) at baseline and week 12. The MMES Pain Diary (PD) was completed 15 minutes before and after each stimulation session. There was a significant 22% decline in pain 15 minutes after as compared with immediately before each NMES treatment (p < .001), as measured by the PD. No significant group differences were found between the 2 groups over the course of the intervention and follow-up. These findings indicate that a home-based NMES intervention reduced arthritis knee pain 15 minutes after a NMES treatment. (C) 2004 Elsevier Inc. All rights reserved. C1 Erickson Fdn, Baltimore, MD 21228 USA. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. Uniformed Serv Univ Hlth Sci, Grad Sch Nursing, Bethesda, MD 20814 USA. RP Gaines, JM (reprint author), Erickson Fdn, 701 Maiden Choice Lane, Baltimore, MD 21228 USA. EM jgaines@ericksonmail.com NR 14 TC 26 Z9 32 U1 0 U2 2 PU W B SAUNDERS CO PI PHILADELPHIA PA INDEPENDENCE SQUARE WEST CURTIS CENTER, STE 300, PHILADELPHIA, PA 19106-3399 USA SN 0897-1897 J9 APPL NURS RES JI Appl. Nurs. Res. PD AUG PY 2004 VL 17 IS 3 BP 201 EP 206 DI 10.1016/j.apnr.2004.06.004 PG 6 WC Nursing SC Nursing GA 853VD UT WOS:000223856100009 PM 15343554 ER PT J AU Bhargava, R Levin, IW AF Bhargava, R Levin, IW TI Gram-Schmidt orthogonalization for rapid reconstructions of Fourier transform infrared spectroscopic imaging data SO APPLIED SPECTROSCOPY LA English DT Article DE Fourier transform infrared spectroscopy; FT-IR; infrared spectroscopic imaging; Gram-Schmidt orthogonalization; data processing; skin; time-resolved spectroscopy; time-resolved imaging ID SPECTROMETRY AB Increasingly voluminous Fourier transform infrared (FT-IR) spectroscopic imaging data sets are being generated with the advent of both faster array detectors and the implementation of time-resolved imaging techniques, resulting in data processing becoming the limiting step in visualizing sample heterogeneity and temporal profile evolution. We report the application of a Gram-Schmidt vector orthogonalization procedure in interferogram space to provide a significant time saving advantage in processing of one to two orders of magnitude in comparison to conventional spectral processing. Illustrative data from human skin biopsies and from dynamic molecular reorganizations within liquid crystalline microdomains is employed to discuss the capabilities and limitations of this information-extraction approach. C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. OI Bhargava, Rohit/0000-0001-7360-994X NR 15 TC 9 Z9 9 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0003-7028 EI 1943-3530 J9 APPL SPECTROSC JI Appl. Spectrosc. PD AUG PY 2004 VL 58 IS 8 BP 995 EP 1000 DI 10.1366/0003702041655412 PG 6 WC Instruments & Instrumentation; Spectroscopy SC Instruments & Instrumentation; Spectroscopy GA 847XW UT WOS:000223432400014 PM 15324507 ER PT J AU Nguyen, D Turner, JT Olsen, C Bieseckcr, LG Darling, TN AF Nguyen, D Turner, JT Olsen, C Bieseckcr, LG Darling, TN TI Cutaneous manifestations of Proteus syndrome - Correlations with general clinical severity SO ARCHIVES OF DERMATOLOGY LA English DT Article ID PTEN MUTATIONS; GERMLINE MUTATION; FORM; LIPOMATOSIS; MOSAICISM; CRITERIA; DEATH AB Background: Proteus syndrome is a rare congenital disorder with progressive asymetric overgrowth of multiple tissues. Objectives: To determine the range of cutaneous findings in Proteus syndrome and to correlate cutaneous findings with overall disease severity. Design: A prospective cohort study was performed at the National Institutes of Health, a tertiary referral center. Patients: Twenty-four consecutive children and adults with Proteus syndrome meeting recent diagnostic criteria. Interventions: Physical examination, including complete skin examination, and review of medical records. Main Outcome Measures: Frequency of skin findings correlation of skin findings with extracutaneous findings; cluster analysis of findings. Results: The 24 patients had skin abnormalities: 22 (92%) had lipomas, 21 (88%) had vascular malformations, 20 (83%) had cerebriform connective tissue nevi on the soles of the feet, 16 (67%) had epidermal nevi, 9 (38%) had partial lipohypoplasia, and 5 (21%) had patchy dermal hypoplasia. Some patients had localized alterations in skin pigmentation and hair or nail growth. Patients with a greater number of skin abnormalities tended to have a greater number of extracutaneous abnormalities. The number of abnormalities tended to increase with age up to 8 years. Conclusions: Patients with Proteus syndrome exhibit a variable but defined assortment of cutaneous findings. The correlation between numbers of cutaneous and extracutaneous abnormalities is consistent with the postulated mosaic basis for this syndrome. C1 Uniformed Serv Univ Hlth Sci, Dept Dermatol, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD USA. RP Darling, TN (reprint author), Uniformed Serv Univ Hlth Sci, Dept Dermatol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM tdarling@usuhs.mil OI Darling, Thomas/0000-0002-5161-1974 NR 23 TC 34 Z9 37 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD AUG PY 2004 VL 140 IS 8 BP 947 EP 953 DI 10.1001/archderm.140.8.947 PG 7 WC Dermatology SC Dermatology GA 844SO UT WOS:000223180300006 PM 15313810 ER PT J AU Neumeister, A Nugent, AC Waldeck, T Geraci, M Schwarz, M Bonne, O Bain, EE Luckenbaugh, DA Herscovitch, P Charney, DS Drevets, WC AF Neumeister, A Nugent, AC Waldeck, T Geraci, M Schwarz, M Bonne, O Bain, EE Luckenbaugh, DA Herscovitch, P Charney, DS Drevets, WC TI Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the American-College-of-Neuropsychopharmacology CY DEC, 2002 CL San Juan, PR SP Amer Coll Neuropsychopharmacol ID POSITRON-EMISSION-TOMOGRAPHY; SEROTONERGIC RESPONSIVITY; INTRAVENOUS TRYPTOPHAN; ANTIDEPRESSANT ACTION; GLUCOSE-METABOLISM; PLASMA TRYPTOPHAN; HEALTHY-SUBJECTS; RAPID DEPLETION; BRAIN; MOOD AB Context: An instructive paradigm for investigating the relationship between brain serotonin function and major depressive disorder (MDD) is the response to tryptophan depletion (TD) induced by oral loading with all essential amino acids except the serotonin precursor tryptophan. Objective: To determine whether serotonin dysfunction represents a trait abnormality in MDD in the context of specific neural circuitry abnormalities involved in the pathogenesis of MDD. Design: Randomized double-blind crossover study. Setting: Outpatient clinic. Participants: Twenty-seven medication-free patients with remitted MDD (18 women and 9 men; mean +/- SD age, 39.8 +/- 12.7 years) and 19 controls (10 women and 9 men; mean SD age, 34.4 +/- 11.5 years). Interventions: We induced TD, by administering capsules containing an amino acid mixture without tryptophan. Sham depletion used identical capsules containing hydrous lactose. Fluorodeoxyglucose F 18 positron emission tomography studies were performed 6 hours after TD. Magnetic resonance images were obtained for all participants. Main Outcome Measures: Quantitative Positron emission tomography of regional cerebral glucose utilization to study the neural effects of sham depletion and TD. Behavioral assessments used a modified (24-item) version of the Hamilton Depression Rating Scale. Results: Tryptophan depletion induced a transient return of depressive symptoms in patients with remitted MDD but not in controls (P < .001). Compared with sham depletion, TD was associated with an increase in regional cerebral glucose utilization in the orbitofrontal cortex, medial thalamus, anterior and posterior cingulate cortices, and ventral striatum in patients with remitted MDD but not in controls. Conclusion: The pattern of TD-induced regional-cerebral glucose utilization changes in patients with remitted MDD suggests that TD unmasks a disease-specific, serotonin system-related trait dysfunction and identifies a circuit that probably plays a key role in the pathogenesis of MDD. C1 NIMH, Sect Expt Therapeut & Pathophysiol, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NIMH, Sect Neuroimaging Mood & Anxiety Disorders, Bethesda, MD 20892 USA. Univ Hosp Psychiat, Dept Neurochem, Munich, Germany. NIH, Ctr Clin, PET Dept, Bethesda, MD 20892 USA. RP Neumeister, A (reprint author), Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. EM neumeisa@intra.nimh.nih.gov OI Nugent, Allison/0000-0003-2569-2480 NR 63 TC 181 Z9 183 U1 4 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD AUG PY 2004 VL 61 IS 8 BP 765 EP 773 DI 10.1001/archpsyc.61.8.765 PG 9 WC Psychiatry SC Psychiatry GA 844EN UT WOS:000223140400002 PM 15289275 ER PT J AU Brown, AS Begg, MD Gravenstein, S Schaefer, CA Wyatt, RJ Bresnahan, M Babulas, VP Susser, ES AF Brown, AS Begg, MD Gravenstein, S Schaefer, CA Wyatt, RJ Bresnahan, M Babulas, VP Susser, ES TI Serologic-evidence of prenatal influenza in the etiology of schizophrenia SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 58th Annual Convention of the Society-of-Biological-Psychiatry CY MAY 15-17, 2003 CL SAN FRANCISCO, CA SP Soc Biol Psychiat ID NEURAL-TUBE DEFECTS; ADULT SCHIZOPHRENIA; EXPOSURE; INFECTION; RISK; CYTOKINES; REELIN; BRAIN; COMPLICATIONS; DETERMINANTS AB Context: Some, but not all, previous studies suggest that prenatal influenza exposure increases the risk of schizophrenia. These studies used dates of influenza epidemics and maternal recall of infection to define influenza exposure, suggesting that discrepant findings may have resulted from exposure misclassification. Objective: To examine whether serologically documented prenatal exposure to influenza increases the risk of schizophrenia. Design: Nested case-control study of a large birth cohort, born from 1959 through 1966, and followed up for psychiatric disorders 30 to 38 years later. Setting: Population-based birth cohort. Participants: Cases were 64 birth cohort members diagnosed as having schizophrenia spectrum disorders (mostly schizophrenia and schizoaffective disorder). Controls were 125 members of the birth cohort, had not been diagnosed as having a schizophrenia spectrum or major affective disorder, and were matched to cases on date of birth, sex, length of time in the cohort, and availability of maternal serum. Main Outcome Measures: Archived maternal serum was assayed for influenza antibody in pregnancies giving rise to offspring with schizophrenia and matched control offspring. Results: The risk of schizophrenia was increased 7-fold for influenza exposure during the first trimester. There was no increased risk of schizophrenia with influenza during the second or third trimester. With the use of a broader gestational period of influenza exposure-early to midpregnancy- the risk of schizophrenia was increased 3-fold. The findings persisted after adjustment for potential confounders. Conclusions: These findings represent the first serologic evidence that prenatal influenza plays a role in schizophrenia. If confirmed, the results may have implications for the prevention of schizophrenia and for unraveling pathogenic mechanisms of the disorder. C1 Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, New York, NY 10032 USA. Columbia Univ, Dept Biostat, New York, NY USA. Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. Eastern Virginia Med Sch, Dept Internal Med, Norfolk, VA 23501 USA. Kaiser Permanente, Div Res, Oakland, CA USA. NIMH, Bethesda, MD 20892 USA. RP Brown, AS (reprint author), Columbia Univ Coll Phys & Surg, New York State Psychiat Inst, 1051 Riverside Dr,Unit 2, New York, NY 10032 USA. EM asb11@columbia.edu FU NIMH NIH HHS [K02 MH065422] NR 38 TC 492 Z9 509 U1 7 U2 35 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-990X EI 1538-3636 J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD AUG PY 2004 VL 61 IS 8 BP 774 EP 780 DI 10.1001/archpsyc.61.8.774 PG 7 WC Psychiatry SC Psychiatry GA 844EN UT WOS:000223140400003 PM 15289276 ER PT J AU Grant, BF Stinson, FS Dawson, DA Chou, SP Dufour, MC Compton, W Pickering, RP Kaplan, K AF Grant, BF Stinson, FS Dawson, DA Chou, SP Dufour, MC Compton, W Pickering, RP Kaplan, K TI Prevalence and co-occurrence of substance use disorders and independent mood and anxiety disorders - Results from the national epidemiologic survey on alcohol and related conditions SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID DSM-III-R; INTERVIEW SCHEDULE AUDADIS; PLACEBO-CONTROLLED-TRIAL; GENERAL-POPULATION SAMPLE; UNITED-STATES 1988; IV ALCOHOL; MAJOR DEPRESSION; ICD-10 ALCOHOL; DRUG MODULES; NOSOLOGICAL COMPARISONS AB Background: Uncertainties exist about the prevalence and comorbidity of substance use disorders and independent mood and anxiety disorders. Objective: To present nationally representative data on the prevalence and comorbidity of DSM-IV alcohol and. drug use disorders and independent mood and anxiety disorders (including only those that are not substance induced and that are not due to a general medical condition). Design: Face-to-face survey. Setting: The United States. Participants: Household and group quarters' residents. Main Outcome Measures: Prevalence and associations of substance use disorders and independent mood and anxiety disorders. Results: The prevalences of 12-month DSM-IV independent mood and anxiety disorders in the US population were 9.21% (95% confidence interval [CI], 8.78%-9.64%) and 11.08% (95% CI, 10.43%-11.73%), respectively. The rate of substance use disorders was 9.35% (95% CI, 8.86%-9.84%). Only a few individuals with mood or anxiety disorders were classified as having only substance-induced disorders. Associations between most substance use disorders and independent mood and anxiety disorders were positive and significant (P < .05). Conclusions: Substance use disorders and mood and anxiety disorders that develop independently of intoxication and withdrawal are among the most prevalent psychiatric disorders in the United States. Associations between most substance use disorders and independent mood and anxiety disorders were overwhelmingly positive and significant, suggesting that treatment for a comorbid mood or anxiety disorder should not be with-held from individuals with substance use disorders. C1 NIAAA, Div Intramural Clin & Biol Res, Lab Epidemiol & Biometry, NIH, Bethesda, MD 20892 USA. NIAAA, Off Director, Bethesda, MD 20892 USA. NIDA, Div Epidemiol Serv & Prevent Res, NIH, US Dept HHS, Bethesda, MD 20892 USA. US Bur Census, Demog Surveys Div, Suitland, MD USA. RP Grant, BF (reprint author), NIAAA, Div Intramural Clin & Biol Res, Lab Epidemiol & Biometry, NIH, Mail Stop 9304,5635 Fishers Ln,Room 3077, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov NR 62 TC 1341 Z9 1361 U1 16 U2 93 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD AUG PY 2004 VL 61 IS 8 BP 807 EP 816 DI 10.1001/archpsyc.61.8.807 PG 10 WC Psychiatry SC Psychiatry GA 844EN UT WOS:000223140400006 PM 15289279 ER PT J AU Morgan, CA Southwick, S Hazlett, G Rasmusson, A Hoyt, G Zimolo, Z Charney, D AF Morgan, CA Southwick, S Hazlett, G Rasmusson, A Hoyt, G Zimolo, Z Charney, D TI Relationships among plasma dehydroepiandrosterone sulfate and cortisol levels, symptoms of dissociation, and objective performance in humans exposed to acute stress SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID UNCONTROLLABLE STRESS; PREGNENOLONE-SULFATE; MAJOR DEPRESSION; NEUROPEPTIDE-Y; DHEA-S; RECEPTOR; MEN; BRAIN; CORTICOSTERONE; NEUROSTEROIDS AB Context: Recently, a growing body of research has provided evidence that dehydroepiandrosterone sulfate (DHEA-S) is involved in an organism's response to stress and that it may provide beneficial behavioral and neurotrophic effects. Objective: To investigate plasma DHEA-S and cortisol levels, psychological symptoms of dissociation, and military performance. Design: Prospective study. Setting and Participants: Twenty-five healthy subjects enrolled in military survival school. Results: The DHEA-S-cortisol ratios during stress were significantly higher in subjects who reported fewer symptoms of dissociation and exhibited superior military performance. Conclusions: These data provide prospective, empirical evidence that the DHEA-S level is increased by acute stress in healthy humans and that the DHEA-S-cortisol ratio may index the degree to which an individual is buffered against the negative effects of stress. C1 Vet Affairs New England Healthcare Syst, Natl Ctr Posttraumat Stress Disorder, West Haven, CT 06516 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. John F Kennedy Special Warfare Training Ctr & Sch, Psychol Applicat Directorate, Ft Bragg, NC USA. NIH, Bethesda, MD 20892 USA. USN, Air Stn N Isl, Fleet Aviat Special Operat Training Grp Pacific N, Coronado, CA USA. RP Morgan, CA (reprint author), Vet Affairs New England Healthcare Syst, Natl Ctr Posttraumat Stress Disorder, 950 Campbell Ave, West Haven, CT 06516 USA. EM charles.a.morgan@yale.edu NR 54 TC 130 Z9 135 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD AUG PY 2004 VL 61 IS 8 BP 819 EP 825 DI 10.1001/archpsyc.61.8.819 PG 7 WC Psychiatry SC Psychiatry GA 844EN UT WOS:000223140400007 PM 15289280 ER PT J AU Nansel, TR Craig, W Overpeck, MD Saluja, G Ruan, J AF Nansel, TR Craig, W Overpeck, MD Saluja, G Ruan, J CA Hlth Behav Sch Aged Children Bully TI Cross-national consistency in the relationship between bullying behaviors and psychosocial adjustment SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID PRIMARY-SCHOOL CHILDREN; BULLY/VICTIM PROBLEMS; PEER VICTIMIZATION; STUDENTS; VICTIMS; HEALTH; PREVALENCE; BULLIES; RISK; ADOLESCENCE AB Objective: To determine whether the relationship between bullying and psychosocial adjustment is consistent across countries by standard measures and methods. Design: Cross-sectional self-report surveys were obtained from nationally representative samples of students in 25 countries. Involvement in bullying, as bully, victim, or both bully and victim, was assessed. Setting: Surveys were conducted at public and private schools throughout the participating countries. Participants: Participants included all consenting students in sampled classrooms, for a total of 113 200 students at average ages of 11.5, 13.5, and 15.5 years. Main Outcome Measures: Psychosocial adjustment dimensions assessed included health problems, emotional adjustment, school adjustment, relationships with classmates, alcohol use, and weapon carrying. Results: Involvement in bullying varied dramatically across countries, ranging from 9% to 54% of youth. However, across all countries, involvement in bullying was associated with poorer psychosocial adjustment (P<.05). in all or nearly all countries, bullies, victims, and bully-victims reported greater health problems and poorer emotional and social adjustment. Victims and bully-victims consistently reported poorer relationships with classmates, whereas bullies and bully-victims reported greater alcohol use and weapon carrying. Conclusions: The association of bullying with poorer psychosocial adjustment is remarkably similar across countries. Bullying is a critical issue for the health of youth internationally. C1 NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. Queens Univ, Dept Psychol, Kingston, ON K7L 3N6, Canada. Maternal & Child Hlth Bur, US Hlth Resources & Serv Adm, Rockville, MD USA. RP Nansel, TR (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B13,MSC 7510, Bethesda, MD 20892 USA. EM nanselt@mail.nih.gov RI Gaspar de Matos, Margarida/H-3824-2012; OI Gaspar de Matos, Margarida/0000-0003-2114-2350; Nansel, Tonja/0000-0002-8298-7595 FU Intramural NIH HHS [Z99 HD999999] NR 39 TC 299 Z9 309 U1 8 U2 55 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD AUG PY 2004 VL 158 IS 8 BP 730 EP 736 DI 10.1001/archpedi.158.8.730 PG 7 WC Pediatrics SC Pediatrics GA 843GZ UT WOS:000223067900003 PM 15289243 ER PT J AU Saluja, G Iachan, R Scheidt, PC Overpeck, MD Sun, WY Giedd, JN AF Saluja, G Iachan, R Scheidt, PC Overpeck, MD Sun, WY Giedd, JN TI Prevalence of and risk factors for depressive symptoms among young adolescents SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID GENDER-DIFFERENCES; MAJOR DEPRESSION; DISORDER; ASSOCIATION; HEALTH; DYSTHYMIA; ADULTHOOD AB Objective: To determine the prevalence, risk factors, and risk behaviors associated with depressive symptoms in a nationally representative, cross-sectional sample of young adolescents. Design: A school-based survey collected through self administered questionnaires in grades 6,8, and 10 in 1996. Setting: Schools in the United States. Participants: 9863 students in grades 6, 8, and 10 (average ages, 11, 13, and 15). Main Outcome Measures: Depressive symptoms, substance use, somatic symptoms, scholastic behaviors, and involvement in bullying. Results: Eighteen percent of youths reported symptoms of depression. A higher proportion of females (25%) reported depressive symptoms than males (10%). Prevalence of depressive symptoms increased by age for both males and females. Among American Indian youths, 29% reported depressive symptoms, as compared with 22% of Hispanic, 18% of white, 17% of Asian American, and 15% of African American youths. Youths who were frequently involved in bullying, either as perpetrators or as victims, were more than twice as likely to report depressive symptoms than those who were not involved in bullying. A significantly higher percentage of youths who reported using substances reported depressive symptoms as compared with other youths. Similarly, youths who reported experiencing somatic symptoms also reported significantly higher proportions of depressive symptoms than other youths. Conclusions: Depression is a substantial and largely unrecognized problem among young adolescents that warrants an increased need and opportunity for identification and intervention at the middle school level. Understanding differences in prevalence between males and females and among racial/ethnic groups may be important to the recognition and treatment of depression among youths. C1 NICHHD, Rockville, MD USA. Macro Int Inc, Calverton, MD USA. Maternal & Child Hlth Bur, US Hlth Resources & Serv Adm, Rockville, MD 20857 USA. NIMH, Bethesda, MD 20892 USA. RP Saluja, G (reprint author), NIH, Div Epidemiol Stat & Prevent Res, Room 7B03 MSC 7510,6100 Execut Blvd, Bethesda, MD 20892 USA. EM salujag@mail.nih.gov 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 29 TC 221 Z9 232 U1 5 U2 33 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD AUG PY 2004 VL 158 IS 8 BP 760 EP 765 DI 10.1001/archpedi.158.8.760 PG 6 WC Pediatrics SC Pediatrics GA 843GZ UT WOS:000223067900008 PM 15289248 ER PT J AU Ghandour, RM Overpeck, MD Huang, ZHJ Kogan, MD Scheidt, PC AF Ghandour, RM Overpeck, MD Huang, ZHJ Kogan, MD Scheidt, PC TI Headache, stomachache, backache, and morning fatigue among adolescent girls in the United States - Associations with behavioral, sociodemographic, and. environmental factors SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID RISK-TAKING BEHAVIORS; PSYCHOSOMATIC SYMPTOMS; SOMATIC COMPLAINTS; BULLYING BEHAVIOR; MEDIA INFLUENCES; HEALTH-PROBLEMS; SELF-REPORT; PAIN; CHILDREN; PREVALENCE AB Background: Data on the prevalence and co-occurrence of multiple somatic symptoms among US adolescent females as they are influenced by sociodemographic, behavioral, and environmental factors is limited. Objectives: To describe the health status of adolescent US females measured by the prevalence, frequency, and co-occurrence of headache, stomachache, backache, and morning fatigue and to investigate associations between selected risk and protective factors. Design, Setting, and Participants: School-based, cross-sectional, nationally representative survey of adolescents in the 6th through 10th grades in the US. Data collected between 1997 and 1998. Main Outcome Measures: Prevalence of headache, stomachache, backache, and morning fatigue. Results: Among US adolescent girls, 29.1% experience headaches, 20.7% report stomachaches, 23.6% experience back pain, and 30.6% report morning fatigue at the rate of more than once a week. Co-occurrence of somatic complaints is common. Among girls who experienced headaches more than once a week, 3.2 million (53.3%) also reported stomach pain more than once a week and 4.1 million (74.3%) reported morning fatigue more than once a week. Heavy alcohol use, high caffeine intake, and smoking cigarettes every day were strongly associated with all symptoms, while parent and teacher support served as protective factors. Conclusions: Somatic complaints of headache, stomachache, backache, and morning fatigue are common among US adolescent girls and co-occur often. Effective clinical treatment of this population requires comprehensive assessment of all female adolescents presenting with seemingly isolated somatic complaints. C1 Maternal & Child Hlth Bur, Off Womens Hlth, US Hlth Resources & Serv Adm, Rockville, MD 20857 USA. Maternal & Child Hlth Bur, Off Data & Informat Management, US Hlth Resources & Serv Adm, Rockville, MD 20857 USA. NICHHD, NIH, Bethesda, MD 20892 USA. RP Ghandour, RM (reprint author), Maternal & Child Hlth Bur, Off Womens Hlth, US Hlth Resources & Serv Adm, Parklawn Bldg,Room 10C-09,5600 Fishers Lane, Rockville, MD 20857 USA. EM Rghandour@hrsa.gov NR 60 TC 93 Z9 94 U1 1 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD AUG PY 2004 VL 158 IS 8 BP 797 EP 803 DI 10.1001/archpedi.158.8.797 PG 7 WC Pediatrics SC Pediatrics GA 843GZ UT WOS:000223067900014 PM 15289254 ER PT J AU Spinetti, G Wang, MY Monticone, R Zhang, J Zhao, D Lakatta, EG AF Spinetti, G Wang, MY Monticone, R Zhang, J Zhao, D Lakatta, EG TI Rat aortic MCP-1 and its receptor CCR2 increase with age and alter vascular smooth muscle cell function SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE chemokines; aging; aorta; vascular smooth muscle cells; invasion ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; CARDIOVASCULAR-DISEASE ENTERPRISES; ENDOTHELIAL DYSFUNCTION; ANGIOTENSIN-II; MATRIX METALLOPROTEINASE-2; CHEMOTACTIC CYTOKINES; MAJOR SHAREHOLDERS; CIRCULATING LEVELS; GENE-EXPRESSION; DEFICIENT MICE AB Objective-With age, rat arterial walls thicken and vascular smooth muscle cells (VSMCs) exhibit enhanced migration and proliferation. Monocyte chemotactic protein-1 (MCP-1) affects these VSMC properties in vitro. Because arterial angiotensin II, which induces MCP-1 expression, increases with age, we hypothesized that aortic MCP-1 and its receptor CCR2 are also upregulated and affect VSMC properties. Methods and Results-Both MCP-1 and CCR2 mRNAs and proteins increased in old (30-month) versus young (8-month) F344XBN rat aortas in vivo. Cellular MCP-1 and CCR2 staining colocalized with that of alpha-smooth muscle actin in the thickened aortas of old rats and were expressed by early-passage VSMCs isolated from old aortas, which, relative to young VSMCs, exhibited increased invasion, and the age difference was abolished by vCCI, an inhibitor of CCR2 signaling. MCP-1 treatment of young VSMCs induced migration and increased their ability to invade a synthetic basement membrane. The MCP-1-dependent VSMC invasiveness was blocked by vCCI. After MCP-1 treatment, migration and invasion capacities of VSMCs from young aortas no longer differed from those of VSMCs isolated from older rats. Conclusions-Arterial wall and VSMC MCP-1/CCR2 increase with aging. MCP-1 enhances VSMC migration and invasion, and thus, MCP-1/CCR2 signaling may play a role in age-associated arterial remodeling. C1 NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Spinetti, G (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM spinettiga@grc.nia.nih.gov OI Spinetti, Gaia/0000-0001-7996-6809 NR 59 TC 94 Z9 100 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD AUG PY 2004 VL 24 IS 8 BP 1397 EP 1402 DI 10.1161/01.ATV.0000134529.65173.08 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 843WA UT WOS:000223116300013 PM 15178559 ER PT J AU Pavletic, SZ AF Pavletic, SZ TI Nonmyeloablative allogeneic hematopoietic stem cell transplantation for autoimmune disease SO ARTHRITIS AND RHEUMATISM LA English DT Editorial Material ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; CHRONIC MYELOGENOUS LEUKEMIA; RHEUMATOID-ARTHRITIS; MIXED CHIMERISM; GRAFT-REJECTION; APLASTIC-ANEMIA; DONOR; RECIPIENT; MICE C1 NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Pavletic, SZ (reprint author), NCI, Expt Transplantat & Immunol Branch, 9000 Rockville Pike,Bldg 10,Room 12S241, Bethesda, MD 20892 USA. EM pavletis@mail.nih.gov NR 27 TC 10 Z9 10 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2004 VL 50 IS 8 BP 2387 EP 2390 DI 10.1002/art.20452 PG 4 WC Rheumatology SC Rheumatology GA 844UG UT WOS:000223185500002 PM 15334449 ER PT J AU Lee, JS Cho, YJ Lipsky, PE AF Lee, JS Cho, YJ Lipsky, PE TI The V-lambda-J(lambda) repertoire of patients with systemic lupus erythematosus manifests characteristics of the natural antibody repertoire SO ARTHRITIS AND RHEUMATISM LA English DT Article ID VARIABLE REGION GENES; COMPLEMENTARITY-DETERMINING REGION; J-LAMBDA REPERTOIRE; B-CELL LYMPHOMA; HEAVY-CHAIN; JUNCTIONAL DIVERSITY; MUTATIONAL ACTIVITY; DNA AUTOANTIBODY; SELECTION; MOUSE AB Objective. To understand in detail the mechanisms of autoantibody production in patients with systemic lupus erythematosus (SLE), we performed a comprehensive analysis of the normal human immunoglobulin light chain V-lambda repertoire and compared it with the V-lambda repertoire in SLE patients. Methods. The SLE V-lambda repertoire of B cells obtained from 3 SLE patients was analyzed and compared in detail with the V-lambda repertoire of IgM+ B cells obtained from 3 human fetal spleens and IgM+,CD5+ B cells obtained from 2 normal adults. Conventional IgM+,CD5- B cells obtained from normal adults were used as controls. V-lambda-J(lambda) rearrangements were amplified from the genomic DNA of individual B cells by polymerase chain reaction. Results. The expressed V-lambda repertoire of SLE patients contained several similarities with the expressed repertoire of the fetus and the adult CD5+ B cells. The V-lambda genes K and 1G were overexpressed in the fetus, the adult CD5+ B cells, and the patients with SLE. The selection for rearrangements with restricted junctional diversity by utilization of homology-mediated joining, together with diminished N nucleotide addition, was a prominent feature of fetal, adult CD5+, and SLE B cell repertoires. Furthermore, profound expansion of V-lambda clones with identical third complementarity-determining regions was observed in the adult CD5+, fetal, and SLE B cell repertoires. Notably, significant numbers of expanded adult CD5+ B cells, fetal, and SLE V-lambda clones utilized homology-mediated joining at the V-lambda-J(lambda) junctions. Conclusion. These data demonstrate that the SLE V-lambda-J(lambda) repertoire manifests characteristics of normal adult IgM+,CD5+ and fetal B cell populations that are known to be enriched for the production of natural autoantibodies. C1 NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. Ewha Womans Univ, Coll Med, Seoul 120750, South Korea. RP Lipsky, PE (reprint author), NIAMSD, Autoimmun Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 9N228, Bethesda, MD 20892 USA. EM lipskyp@mail.nih.gov NR 44 TC 12 Z9 12 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2004 VL 50 IS 8 BP 2604 EP 2614 DI 10.1002/art.20439 PG 11 WC Rheumatology SC Rheumatology GA 844UG UT WOS:000223185500028 PM 15334475 ER PT J AU Meng, HC Griffiths, MM Remmers, EF Kawahito, Y Li, WT Neisa, R Cannon, GW Wilder, RL Gulko, PS AF Meng, HC Griffiths, MM Remmers, EF Kawahito, Y Li, WT Neisa, R Cannon, GW Wilder, RL Gulko, PS TI Identification of two novel female-specific non-major histocompatibility complex loci regulating collagen-induced arthritis severity and chronicity, and evidence of epistasis SO ARTHRITIS AND RHEUMATISM LA English DT Article ID QUANTITATIVE TRAIT LOCI; PRISTANE-INDUCED ARTHRITIS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; ADJUVANT-INDUCED ARTHRITIS; GENETIC-LINKAGE MAP; GENOME-WIDE SEARCH; RHEUMATOID-ARTHRITIS; SUSCEPTIBILITY LOCI; AUTOIMMUNE-DISEASES AB Objective. To identify additional sex-specific and epistatic quantitative trait loci (QTL) regulating collagen-induced arthritis (CIA) severity overall, as well as within different stages during the disease course, in an intercross between major histocompatibility complex-identical inbred rat strains DA/Bkl (susceptible) and ACI/Hsd (resistant). Methods. Arthritic male (DA X ACI)F-2 intercross offspring (n = 143) were analyzed separately from the females (n = 184). Phenotypic extremes (maximum arthritis scores [MAS]) were genotyped and used for QTL analysis. All 327 rats were genotyped with the simple sequence-length polymorphism (SSLP) markers closest to the peak of Cia7 and Cia10, the major loci previously identified in this intercross, and with SSLPs covering chromosomes 12 and 18. Phenotypes studied were disease onset, arthritis severity scores on days 14-39, MAS, mean and cumulative arthritis scores, delayed-type hypersensitivity, and antibody responses to rat type II collagen. Results. A new female-specific arthritis-severity recessive locus was identified on rat chromosome 12 (Cia25), with a maximum effect observed on day 28 (logarithm of odds [LOD] 4.7). The homozygous DA genotype at Cia25 was associated with a 45% higher median arthritis score in females. Sequencing analyses of the Cia25 candidate gene Ncf1 revealed polymorphisms between DA and ACL The previously identified locus, Cia10, was found to be male-specific. A 2-locus interaction model analysis identified a novel recessive chromosome 18 QTL, Cia26, which was dependent on Cia7, with its maximum effect observed at later stages during the disease course (peak LOD score of 3.6 for arthritis scores on day 39). Conclusion. This study identified 2 novel female-specific loci, and 1 male-specific locus. Cia25 regulates MAS and disease severity during the mid-to-late stages of the disease course and may be accounted for by Nef1 polymorphisms. Cia26 is in epistasis with Cia7 and regulates later stages of disease, suggesting an involvement in disease perpetuation and/or chronicity. C1 N Shore Long Isl Jewish Res Inst, Robert S Boas Ctr Genom & Human Genet, Lab Expt Rheumatol, Manhasset, NY 11030 USA. VAMC, Salt Lake City, UT USA. Univ Utah, Salt Lake City, UT USA. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Gulko, PS (reprint author), N Shore Long Isl Jewish Res Inst, Robert S Boas Ctr Genom & Human Genet, Lab Expt Rheumatol, 350 Community Dr,Room 139, Manhasset, NY 11030 USA. EM pgulko@nshs.edu OI Li, Wentian/0000-0003-1155-110X; Brenner, Max/0000-0002-8010-148X FU NIAID NIH HHS [R01-AI-54348]; NIAMS NIH HHS [R01-AR-47423, R01-AR-46213] NR 77 TC 26 Z9 28 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD AUG PY 2004 VL 50 IS 8 BP 2695 EP 2705 DI 10.1002/art.20366 PG 11 WC Rheumatology SC Rheumatology GA 844UG UT WOS:000223185500039 PM 15334486 ER PT J AU Sarkar, K Miller, FW AF Sarkar, K Miller, FW TI Possible roles and determinants of microchimerism in autoimmune and other disorders SO AUTOIMMUNITY REVIEWS LA English DT Review DE microchimerism; pregnancy; autoimmune diseases; HLA ID PRIMARY BILIARY-CIRRHOSIS; FETAL CELL MICROCHIMERISM; SYSTEMIC-SCLEROSIS; MATERNAL MICROCHIMERISM; QUANTITATIVE-ANALYSIS; SJOGRENS-SYNDROME; HEALTHY WOMEN; Y-CHROMOSOME; DNA; DISEASE AB Microchimerism is the presence of a low level of non-host stem cells or their progeny in an individual. The most, common source of microchimerism is pregnancy. During pregnancy, bi-directional trafficking of hematopoietic cells occurs through the placenta and these michrochimeric cells persist for decades after childbirth. A possible role of microchimerism in the pathogenesis of some, (systemic sclerosis, systemic lupus erythematosus, primary biliary cirrhosis, autoimmune thyroid diseases and juvenile myostitis)) but! not all autoimmune diseases has been suggested by recent studies. Contradictory reports exist regarding HLA allelic associations with persistent T lymphocyte microchimerism. Although much of the focus of past studies has been on microchimerism in the effector arm of the immune system, increasing evidence suggests that microchimeric cells may differentiate, into many lineages in different tissues raising additional possible roles for these cells. The possibility of microchimerism in many organs should induce an exploration of how persistent mixtures of cells of different genetic backgrounds throughout the body may, influence diverse physiologic processes during life. In the present review, we discuss possible influencing factors and, roles of all forms of microchimerism in autoimmune and non-autoimmune diseases. A better understanding of the immune mechanisms, along with the identification of environmental and genetic risk factors, is crucial for further deciphering the many possible implications of maternal-fetal and fetal maternal cell trafficking in health and disease. (C) 2004 Elsevier B.V. All rights reserved. C1 NIEHS, Environm Autoimmun Grp, NIH, HHS, Bethesda, MD 20892 USA. RP Sarkar, K (reprint author), NIEHS, Environm Autoimmun Grp, NIH, HHS, 9000 Rockville Pike,NIH 9-1W107, Bethesda, MD 20892 USA. EM sarkark@mail.nih.gov OI Miller, Frederick/0000-0003-2831-9593 NR 40 TC 26 Z9 28 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD AUG PY 2004 VL 3 IS 6 BP 454 EP 463 DI 10.1016/j.autrev.2004.06.004 PG 10 WC Immunology SC Immunology GA 861GJ UT WOS:000224403800005 PM 15351311 ER PT J AU Soltis, J AF Soltis, J TI The signal functions of early infant crying SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Review DE colic; crying; early infant crying; honest signaling; infanticide; parental care; parent-offspring conflict; separation call; vocalization ID PARENT-OFFSPRING CONFLICT; AUTONOMIC NERVOUS-SYSTEM; CHILD-ABUSE; SOCIAL SUPPORT; RISK-FACTORS; HANDICAP PRINCIPLE; ACOUSTIC FEATURES; UNITED-STATES; ADAPTIVE SIGNIFICANCE; PERCEPTUAL RESPONSES AB In this article I evaluate recent attempts to illuminate the human infant cry from an evolutionary perspective. Infants are born into an uncertain parenting environment, which can range from indulgent care of offspring to infanticide. Infant cries are in large part adaptations that maintain proximity to and elicit care from caregivers. Although there is I-lot strong evidence for acoustically distinct cry types, infant cries may function as a graded signal. During pain-induced autonomic nervous system arousal, for example, neural input to the vocal cords increases cry pitch. Caregivers may use this acoustic information, together with other cues, to guide caregiving behavior. Serious pathology, on the other hand, results in chronically and severely abnormal cry acoustics. Such abnormal crying may be a proximate cause of adaptive infant maltreatment, in circumstances in which parents cut their losses and reduce or withdraw investment from infants with low survival chances. An increase in the amount of crying during the first few months of life is a human universal, and excessive crying, or colic, represents the upper end of this normal increase. Potential signal functions of excessive crying include manipulation of parents to acquire additional resources, honest signaling of need, and honest signaling of vigor. Current evidence does not strongly support any one of these hypotheses, but the evidence is most consistent with the hypothesis that excessive early infant crying is a signal of vigor that evolved to reduce the risk of a reduction or withdrawal of parental care. C1 NICHHD, Unit Dev Neuroethol, Comparat Ethol Lab, NIH,US Dept HHS, Poolesville, MD 20837 USA. RP Soltis, J (reprint author), NICHHD, Unit Dev Neuroethol, Comparat Ethol Lab, NIH,US Dept HHS, Poolesville, MD 20837 USA. EM Joseph.Soltis@disney.com NR 198 TC 124 Z9 126 U1 2 U2 30 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD AUG PY 2004 VL 27 IS 4 BP 443 EP + PG 23 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 895KM UT WOS:000226860300001 PM 15773426 ER PT J AU Fouts, HN Lamb, ME Hewlett, BS AF Fouts, HN Lamb, ME Hewlett, BS TI Infant crying in hunter-gatherer cultures SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID ATTACHMENT ORGANIZATION AB By synthesizing evolutionary, attachment, and acoustic perspectives, Soltis has provided an innovative model of infant cry acoustics and parental responsiveness. We question some of his hypotheses, however, because of the limited extant data on infant crying among hunter-gatherers. We also question Soltis' distinction between manipulative and honest signaling based upon recent contributions from attachment theory. C1 NICHHD, Sect Social & Emot Dev, NIH, US Dept HHS, Bethesda, MD 20892 USA. Washington State Univ, Dept Anthropol, Vancouver, WA 98686 USA. RP Fouts, HN (reprint author), NICHHD, Sect Social & Emot Dev, NIH, US Dept HHS, Rockledge 1 Ctr, Bethesda, MD 20892 USA. EM foutsh@mail.nih.gov; michael_lamb@nih.gov; hewlett@vancouver.wsu.edu NR 11 TC 1 Z9 1 U1 1 U2 6 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD AUG PY 2004 VL 27 IS 4 BP 462 EP + PG 9 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 895KM UT WOS:000226860300006 ER PT J AU Newman, JD AF Newman, JD TI Infant crying and colic: What lies beneath SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID SQUIRREL-MONKEYS; ISOLATION CALL; VOCALIZATION; CORTEX AB The neural structures implicated in crying are reviewed, based on studies in animals. Brain regions involved include the anterior cingulate gyrus (a cortical structure), amygdala, thalamic tegmentum, periaqueductal gray of the midbrain, and the nucleus ambiguus of the caudal brainstem. It is hypothesized that the crying associated with colic may be a manifestation of differing developmental stages in the brain circuits involved. C1 NICHHD, Comparat Ethol Lab, NIH, US Dept HHS, Poolesville, MD 20837 USA. RP Newman, JD (reprint author), NICHHD, Comparat Ethol Lab, NIH, US Dept HHS, NIH Anim Ctr 112-205, Poolesville, MD 20837 USA. EM jdnewman@helix.nih.gov NR 10 TC 2 Z9 2 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD AUG PY 2004 VL 27 IS 4 BP 470 EP + PG 9 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 895KM UT WOS:000226860300014 ER PT J AU Soltis, J AF Soltis, J TI The developmental mechanisms and the signal functions of early infant crying SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material AB The majority of the commentaries focused on excessive crying and colic and included two major themes: the consideration of proximate physiological mechanisms, and challenges to lily interpretation of the signal functions of early infant crying amount. I initially concluded that none of the competing signaling hypotheses enjoyed strong support, but I nevertheless favored the signaling vigor hypothesis above the signaling need and manipulation hypotheses. Consideration of the neurobiological causation of the n-shaped crying curve and further evidence and argumentation concerning the potential signal functions, however, do not allow for the elevation of any one of these hypotheses above the others, and it remains the case that none are strongly supported. Taken together, however, the target article and commentary do provide a solid foundation for further research. In the target article, I also proposed a model of how infant cry acoustics can influence patterns of care and abuse. Commentary has enriched this model by including the consideration of developmental changes in cry acoustics across early infancy, and by further integrating the cry signal with other modalities of communication and with later development. I trust that the foregoing will show that the joint pursuit of the proximate mechanisms and the potential signal functions of early infant cry amount and cry acoustics should prove fruitful. Before embarking on my reevaluation, however, I begin this response by addressing the issue of consciousness in evolutionary accounts of signaling. C1 NICHHD, Unit Dev Neuroethol, Comparat Ethol Lab, NIH,US Dept HHS, Poolesville, MD 20837 USA. RP Soltis, J (reprint author), NICHHD, Unit Dev Neuroethol, Comparat Ethol Lab, NIH,US Dept HHS, Poolesville, MD 20837 USA. EM Joseph.Soltis@disney.com NR 7 TC 0 Z9 0 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD AUG PY 2004 VL 27 IS 4 BP 477 EP 490 PG 14 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 895KM UT WOS:000226860300022 ER PT J AU Newman, JD AF Newman, JD TI Motherese by any other name: Mother-infant communication in non-hominin mammals SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID BEHAVIOR; BRAIN AB The definition of motherese is extended to infant-directed vocalizations in non-hominin mammals. In many species, vocal interactions between mothers and their infants are common. The neural substrates mediating these interactions include the rostral limbic cortex of the frontal lobe. Spoken language may have arisen from hominin females vocalizing to their infants. C1 NICHHD, Comparat Ethol Lab, NIH, US Dept HHS, Poolesville, MD 20837 USA. RP Newman, JD (reprint author), NICHHD, Comparat Ethol Lab, NIH, US Dept HHS, Poolesville, MD 20837 USA. EM jdnewman@helix.nih.gov NR 9 TC 0 Z9 0 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD AUG PY 2004 VL 27 IS 4 BP 519 EP + PG 10 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 895KM UT WOS:000226860300042 ER PT J AU Rogalewski, A Breitenstein, C Floel, A Knecht, S AF Rogalewski, A Breitenstein, C Floel, A Knecht, S TI Prosody as an intermediary evolutionary stage between a manual communication system and a fully developed language faculty SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID SPEECH-PERCEPTION; PREMOTOR CORTEX; RECOGNITION; MONKEYS AB Based on the motor theory of language, which asserts an evolution from gestures along several stages to today's speech and language, we suggest that speech ontogeny may partly reflect speech phylogeny, in that perception of prosodic contours is an intermediary stage between a manual communication system and a fully developed language faculty. C1 Univ Munster, Dept Neurol, D-48129 Munster, Germany. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Rogalewski, A (reprint author), Univ Munster, Dept Neurol, D-48129 Munster, Germany. EM rogalewski@uni-muenster.de; caterina.breitenstein@uni-muenster.de; floela@ninds.nih.gov; knecht@uni-muenster.de RI Floel, Agnes/A-9426-2017; OI Knecht, Stefan/0000-0003-1056-9228 NR 15 TC 2 Z9 2 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD AUG PY 2004 VL 27 IS 4 BP 521 EP + PG 10 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 895KM UT WOS:000226860300044 ER PT J AU Ulvila, J Arpainen, S Pelkonen, A Aida, K Sueyoshi, T Negishi, V Hakkola, J AF Ulvila, J Arpainen, S Pelkonen, A Aida, K Sueyoshi, T Negishi, V Hakkola, J TI Regulation of Cyp2a5 transcription in mouse primary hepatocytes: roles of hepatocyte nuclear factor 4 and nuclear factor 1 SO BIOCHEMICAL JOURNAL LA English DT Article DE cytochrome P450; hepatocyte nuclear factor 4 (HNF-4); liver; nuclear factor I (NF-I); transcription ID FACTOR-I; STEROID 15-ALPHA-HYDROXYLASE; COUMARIN 7-HYDROXYLASE; HEPATOCELLULAR-CARCINOMA; CYTOCHROMES P450; OLFACTORY MUCOSA; GENE-EXPRESSION; CTF/NF-I; LIVER; BINDING AB The cytochrome P4502a5 (Cyp2a5) gene is expressed principally in liver and olfactory mucosa. In the present study, the transcriptional mechanisms of hepatocyte-specific expression of Cyp2a5 were studied in mouse primary hepatocytes. The Cyp2a5 5'-flanking region - 3033 to + 10 was cloned in front of a luciferase reporter gene and transfected into heparocytes. Deletion analysis revealed two major activating promoter regions localized at proximal 271 bp and at a more distal area from - 3033 to - 2014 bp. The proximal activation region was characterized further by DNase I footprinting, and a single clear footprint was detected in the studied area centred over a sequence similar to the NF-I (nuclear factor I)-binding site. The binding of NF-I was confirmed using an EMSA (electrophoretic mobility-shift assay). A putative HNF-4 (hepatocyte nuclear factor 4)-binding site was localized at the proximal promoter by computer analysis of the sequence, and HNF-4alpha was shown to interact with the site using an EMSA. The functional significance of HNF-4 and NF-I binding to the Cyp2a5 promoter was evaluated by site-directed mutagenesis of the binding motifs in reporter constructs. Both mutations strongly decreased transcriptional activation by the Cyp2a5 promoter in primary hepatocytes, and double mutation almost completely abolished transcriptional activity. Also, the functionality of the distal activation region was found to be dependent on the intact HNF-4 and NF-I sites at the proximal promoter. In conclusion, these results indicate that HNF-4 and NF-I play major roles in the constitutive regulation of hepatic expression of Cyp2a5. C1 Univ Oulu, Dept Pharmacol & Toxicol, Oulu 90014, Finland. NIEHS, Pharmacogenet Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hakkola, J (reprint author), Univ Oulu, Dept Pharmacol & Toxicol, POB 5000, Oulu 90014, Finland. EM jukka.hakkola@oulu.fi NR 46 TC 21 Z9 24 U1 0 U2 0 PU PORTLAND PRESS PI LONDON PA 59 PORTLAND PLACE, LONDON W1N 3AJ, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD AUG 1 PY 2004 VL 381 BP 887 EP 894 DI 10.1042/BJ20040387 PN 3 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 848AY UT WOS:000223440600037 PM 15115437 ER PT J AU Bertolino, A Blasi, G Caforio, G Latorre, V De Candia, M Rubino, V Callicott, JH Mattay, VS Bellomo, A Scarabino, T Weinberger, DR Nardini, M AF Bertolino, A Blasi, G Caforio, G Latorre, V De Candia, M Rubino, V Callicott, JH Mattay, VS Bellomo, A Scarabino, T Weinberger, DR Nardini, M TI Functional lateralization of the sensorimotor cortex in patients with schizophrenia: Effects of treatment with olanzapine SO BIOLOGICAL PSYCHIATRY LA English DT Article DE schizophrenia; lateralization; sensorimotor cortex; motor processing; fMRI; olanzapine ID DORSOLATERAL PREFRONTAL CORTEX; HUMAN MOTOR CORTEX; WORKING-MEMORY; BRAIN ACTIVATION; BASAL GANGLIA; HANDEDNESS; DYSFUNCTION; FMRI; MRI; HALOPERIDOL AB Background: Earlier cross-sectional studies with functional magnetic resonance imaging (fMRI) in treated patients with schizophrenia have reported abnormalities of cortical motor processing, including reduced lateralization of primary sensory motor cortex. The objective of the present longitudinal study was to evaluate whether such cortical abnormalities represent state or trait phenomena of the disorder. Methods: Seventeen acutely ill, previously untreated patients were studied after 4 weeks and after 8 weeks of olanzapine therapy. Seventeen matched healthy subjects served as control subjects. All subjects underwent two fMRI scans 4 weeks apart during a visually paced motor task using a simple periodic block design. Functional magnetic resonance imaging data were analyzed in Statistical Parametric Mapping (SPM99). Region of interest analyses were used to determine a laterality quotient (an index of lateralization) of motor cortical regions. Results: The fMRI data indicated that patients bad reduced activation of the primary sensory motor cortex at 4 weeks but not at 8 weeks; however, the laterality quotient in the primary sensory motor cortex was reduced in patients at both time points. Conclusions: These results suggest that some cortical abnormalities during motor processing represent state phenomena, whereas reduced functional lateralization of the primary sensory motor complex presents an enduring trait of schizophrenia. C1 Univ Bari, Dipartimento Sci Neurol & Psichiat, Grp Neurosci Psichiat, Sez Clin Malattie Mentali, I-70124 Bari, Italy. Univ Foggia, Dept Psychiat, Foggia, Italy. Inst Ricovero & Cura Carattere Sci, Dept Neuroradiol, San Giovanni Rotondo, Foggia, Italy. NIMH, Clin Brain Disorders Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Bertolino, A (reprint author), Univ Bari, Dipartimento Sci Neurol & Psichiat, Grp Neurosci Psichiat, Sez Clin Malattie Mentali, Piazza Giulio Cesare 9, I-70124 Bari, Italy. RI Bertolino, Alessandro/O-6352-2016 OI Bertolino, Alessandro/0000-0002-1251-1380 NR 60 TC 46 Z9 47 U1 2 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 2004 VL 56 IS 3 BP 190 EP 197 DI 10.1016/j.biopsych.2004.04.009 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 840SC UT WOS:000222878800009 PM 15271588 ER PT J AU Feder, A Coplan, JD Goetz, RR Mathew, SJ Pine, DS Dahl, RE Ryan, ND Greenwald, S Weissman, MM AF Feder, A Coplan, JD Goetz, RR Mathew, SJ Pine, DS Dahl, RE Ryan, ND Greenwald, S Weissman, MM TI Twenty-four-hour cortisol secretion patterns in prepubertal children with anxiety or depressive disorders SO BIOLOGICAL PSYCHIATRY LA English DT Article DE cortisol; prepubertal; children; anxiety disorders; major depression; hypothalamic-pituitary-adrenal axis ID CORTICOTROPIN-RELEASING-FACTOR; MAJOR DEPRESSION; INTERPERSONAL RELATIONSHIPS; BEHAVIORAL-INHIBITION; ADRENAL SECRETION; SALIVARY CORTISOL; GROWTH-HORMONE; ADOLESCENTS; SLEEP; EPISODE AB Background: Previous studies found few abnormalities in hypothalamic-pituitary-adrenal (HPA) axis function in prepubertal children with anxiety or depressive disorders. In this study, we combined data from two independent, consecutive studies to achieve a larger sample size. Our goal was to identify potential alterations in the circadian pattern of cortisol secretion in anxious or depressed children. Methods. A total of 124 prepubertal subjects from two independent samples (76 with major depressive disorder 31 with anxiety disorders, and 17 healthy control subjects) were studied. Blood samples collected for cortisol at hourly intervals over a 24-hour period were examined. Analyses were performed aligning cortisol samples by clock-time, Additional analyses aligning samples by sleep-onset time were performed with a subsample of subjects. Results: In the combined sample, significant findings emerged that were previous undetected. Anxious children exhibited significantly lower nighttime cortisol levels and an initially sluggish rise in cortisol during the nighttime when compared with depressed and healthy control children. In contrast, depressed children did not show a clear-cut pattern of differences compared with healthy control children. Conclusions: Anxious children seem to exhibit an altered pattern of nighttime cortisol secretion, with an initially sluggish or delayed nocturnal rise before reaching similar peak levels of cortisol near the time of awakening. These findings suggest subtle alterations in HPA axis function in prepubertal children with anxiety disorders. C1 New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY 10027 USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. NIMH, Intramural Res Program, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. RP Feder, A (reprint author), New York State Psychiat Inst & Hosp, Unit 24,1051 Riverside Dr, New York, NY 10032 USA. OI Weissman, Myrna/0000-0003-3490-3075 FU NIMH NIH HHS [MH50666] NR 51 TC 53 Z9 53 U1 3 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD AUG 1 PY 2004 VL 56 IS 3 BP 198 EP 204 DI 10.1016/j.biopsych.2004.05.005 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 840SC UT WOS:000222878800010 PM 15271589 ER PT J AU Welniak, LA Shorts, L Subleski, J Blazar, BR Wiltrout, RH Murphy, WJ AF Welniak, LA Shorts, L Subleski, J Blazar, BR Wiltrout, RH Murphy, WJ TI Tumor regression by anti-CD40 and interleukin-2: Role of CD40 in hematopoietic cells and organ-specific effects SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE bone marrow chimera; dendritic cell; CD8(+) T cell ID DOSE RECOMBINANT INTERLEUKIN-2; DENDRITIC CELLS; T-CELLS; CROSS-LINKING; ACTIVATION; CARCINOMA; GROWTH; LIGAND; MURINE; STIMULATION AB CD40 stimulation can synergize with interleukin (IL)-2 for antitumor responses against mouse metastatic renal cell carcinomas, with coincident increases in tumor-specific CD8(+) T-cell responses and dendritic cell numbers in both the spleen and liver. Because CD40 is present on various hematopoietic-derived cells, endothelial cells, and some tumors themselves, this study was performed to determine whether the antitumor effects of CD40 stimulation and IL-2 were primarily mediated by CD40(+) hematopoietic-derived cells. Bone marrow chimeras were created by reconstituting lethally irradiated CD40(+/+) recipients with bone marrow from CD40(-/-) or CD40(+/+) mice. Chimeric mice were then implanted orthotopically with renal cancer cells, followed by treatment with anti-CD40 agonist monoclonal antibodies and IL-2. Immune parameters of the spleen and liver were assessed after therapy and correlated with antitumor responses. The antitumor effects in the CD40(-/-) bone marrow transplantation chimeras were almost completely abrogated after treatment, and this shows that hematopoietically derived CD40(+) cells are the principal targets for CD40 stimulation in this model. Although both spleen and liver showed reductions in CD8(+) T-cell and dendritic cell expansion in the CD40(-/-) versus CD40(+/+) chimeras after therapy, only the liver exhibited no significant increases in either CD8(+) T cells or dendritic cells after treatment. CD40 cells on hematopoietic cells are the primary target for anti-CD40 and IL-2 therapy. The results also suggest that the immunologic events in the liver may be more revealing that those in lymphoid organs with regard to critical events related to responses after therapy. (C) 2004 American Society for Blood and Marrow Transplantation. C1 Univ Nevada, Dept Microbiol & Immunol, Reno, NV 89557 USA. NCI, Expt Immunol Lab, Canc Res Ctr, Frederick, MD 21701 USA. Univ Minnesota, Ctr Canc, Minneapolis, MN USA. Univ Minnesota, Dept Pediat, Div Bone Marrow Transplantat, Minneapolis, MN USA. RP Murphy, WJ (reprint author), Univ Nevada, Dept Microbiol & Immunol, Reno, NV 89557 USA. EM wmurphy@unr.edu FU NCI NIH HHS [R01 CA95572-01, N01-CO-12400] NR 18 TC 4 Z9 5 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD AUG PY 2004 VL 10 IS 8 BP 534 EP 539 DI 10.1016/j.bbmt.2004.05.006 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 845XW UT WOS:000223279700003 PM 15282531 ER PT J AU Inselman, A Handel, MA AF Inselman, A Handel, MA TI Mitogen-activated protein kinase dynamics during the meiotic G2/MI transition of mouse spermatocytes SO BIOLOGY OF REPRODUCTION LA English DT Article DE kinases; meiosis; spermatogenesis ID MAP KINASE; PACHYTENE SPERMATOCYTES; GERM-CELLS; MICROTUBULE ORGANIZATION; CHROMOSOME CONDENSATION; OOCYTE MATURATION; BOVINE OOCYTES; SPERMATOGENIC CELLS; MEIOSIS RESUMPTION; OKADAIC ACID AB Cellular and genetic approaches were used to investigate the requirements for activation during spermatogenesis of the extracellular signal-regulated protein kinases (ERKs), more commonly known as the mitogen-activated protein kinases (MAPKs). The MAPKS and their activating kinases, the MEKs, are expressed in specific developmental patterns. The MAPKs and MEK2 are expressed in all premeiotic germ cells and spermatocytes, while MEK1 is not expressed abundantly in pachytene spermatocytes. Phosphorylated (active) variants of these kinases are diminished in pachytene spermatocytes. Treatment of pachytene spermatocytes with okadaic acid (OA), to induce transition from meiotic prophase to metaphase I (G2/MI), resulted in phosphorylation and enzymatic activation of ERK1/2. However, U0126, an inhibitor of the ERK-activating kinases, MEK1/2, did not inhibit OA-induced MAPK activation or chromosome condensation. Analysis of spermatocytes lacking MOS, a mitogenactivated protein kinase kinase kinase responsible for MEK and MAPK activation, revealed that MOS is not required for OA-induced activation of the MAPKs. OA-induced MAPK activation was inhibited by butyrolactone 1, an inhibitor of cyclin-dependent kinases 1 and 2 (CDK1, CDK2); thus, these kinases may regulate MAPK activity. Additionally, spermatocytes lacking CDC25C condensed bivalent chromosomes and activated both MPF and MAPKs in response to OA treatment; therefore, there is a CDC25C-independent pathway for MPF and MAPK activation. These studies reveal that spermatocytes do not require either MOS or CDC25C for onset of the meiotic division phase or for activation of MPF and the MAPKs, thus implicating a novel pathway for activation of the ERK1/2 MAPKs in spermatocytes. C1 Univ Tennessee, Dept Biochem & Cellular & Mol Biol, Knoxville, TN 37996 USA. RP Handel, MA (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM mahandel@jax.org FU NICHD NIH HHS [HD 33816] NR 48 TC 21 Z9 23 U1 0 U2 0 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD AUG PY 2004 VL 71 IS 2 BP 570 EP 578 DI 10.1095/biolreprod.104.027938 PG 9 WC Reproductive Biology SC Reproductive Biology GA 841EK UT WOS:000222911900025 PM 15084480 ER PT J AU Yokochi, T Robertson, KD AF Yokochi, T Robertson, KD TI Dimethyl sulfoxide stimulates the catalytic activity of de novo DNA methyltransferase 3a (Dnmt3a) in vitro SO BIOORGANIC CHEMISTRY LA English DT Article DE DNA methyltransferase; Dnmt3a; enzymology; kinetics; catalytic stimulator; dimethyl sulfoxide ID CYTOSINE-5 METHYLTRANSFERASES; MAMMALIAN DEVELOPMENT; ENZYMATIC-PROPERTIES; METHYLATION; CELLS; EXPRESSION; LETHALITY; A9145; MOUSE AB Mammalian DNA methyltransferase Dnmt3a is required for de novo methylation of CpG dinucleotides in genomic DNA. While DNA methyltransferase inhibitors have been extensively utilized both in vitro and in vivo, no stimulator of catalytic activity has been identified thus far. Here we show that the methyltransfer activity of Dnmt3a is stimulated by the addition of dimethyl sulfoxide (DMSO) to the reaction solution in vitro. Enzymatic analysis of initial reaction velocity suggests that the DMSO stimulation effect depends on the interaction between DMSO and the reaction substrates (DNA and AdoMet), but not the enzyme itself. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, Epigenet Gene Regulat & Canc Sect, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. RP Robertson, KD (reprint author), NCI, Epigenet Gene Regulat & Canc Sect, Lab Receptor Biol & Gene Express, NIH, Bldg 41,Room B715, Bethesda, MD 20892 USA. EM robertk@mail.nih.gov NR 24 TC 11 Z9 13 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0045-2068 J9 BIOORG CHEM JI Bioorganic Chem. PD AUG PY 2004 VL 32 IS 4 BP 234 EP 243 DI 10.1016/j.bioorg.2004.04.005 PG 10 WC Biochemistry & Molecular Biology; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 835WC UT WOS:000222515200004 PM 15210338 ER PT J AU Wagner, S Kopka, K Law, MP Riemann, B Pike, VW Schober, O Schafers, M AF Wagner, S Kopka, K Law, MP Riemann, B Pike, VW Schober, O Schafers, M TI Synthesis and first in vivo evaluation of new selective high affinity beta(1)-adrenoceptor radioligands for SPECT based on ICI 89,406 SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE 3-arvloxy-2-propanolamine; ICI 89,406; selective beta(1)-adreno-ceptor ligand; SPECT-radioligand ID PROTEIN-COUPLED RECEPTORS; POSITRON-EMISSION-TOMOGRAPHY; BETA-ADRENOCEPTOR ANTAGONIST; CARDIAC SYMPATHETIC INNERVATION; ADRENERGIC-RECEPTOR; HEART-FAILURE; IN-VIVO; ASYMMETRIC-SYNTHESIS; LIGAND; BETA-1-ADRENOCEPTOR AB The results of cardiac biopsies suggest that myocardial PI-adrenoceptor (AR) density is reduced in patients with chronic heart failure, while changes in cardiac beta(2)-ARs vary. A technique for visualization and quantification of beta(1)-AR populations rather than total beta-AR densities in the human heart would be of great clinical interest. Molecular imaging techniques, either single photon emission computed tomography (SPECT) or positron emission tomography (PET), with appropriate radiopharmaceuticals offer the possibility to assess beta-AR density noninvasively in humans, but to date, neither a SPECT nor a PET-radioligand is clinically established for the selective imaging of cardiac beta(1)-ARs. The aim of this study was to design a high affinity selective beta(1)-AR radioligand for the noninvasive in vivo imaging of cardiac beta(1)-AR density in man using SPECT. Based on the well-known selective beta(1)-AR antagonist, ICI 89,406, both the racemic iodinated target compound 11a and the (S)-enantiomer 15a were synthesized. Competition studies using the nonselective AR ligand, [121 I]iodocyanopindolol ([I-125]ICYP), and ventricular membrane preparations from mice showed that 11a and 15a possess higher beta(1)-AR affinities (up to 265-fold) and beta(1)-AR selectivities (up to 245-fold) than ICI 89,406. Encouraged by these results, the radioiodinated counterparts of racemic 11a (11b: 1251, 11c: 121 1) and (S)-configurated 15a (15b: I-125 15c: I-123) were synthesized. The target compounds were evaluated in rats. Biodistribution and metabolism studies in rats indicated that there is a specific heart uptake of 11b-c and especially 15b-c accompanied by rapid metabolism of the radioligands. Therefore, radioiodinated 11c and 15c appeared to be unpromising SPECT-radioligands for assessing beta(1)-ARs in vivo in the rat. However, the rat may metabolize beta-AR ligands more rapidly than other species as demonstrated for (S)-[C-11]CGP 12177, a radioligand structurally related to 11a-c and 15a-c. Therefore further studies in a different animal model will be carried out. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Hosp Munster, Dept Nucl Med, D-48149 Munster, Germany. NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Wagner, S (reprint author), Univ Hosp Munster, Dept Nucl Med, Albert Schweitzer Str 33, D-48149 Munster, Germany. EM stwagner@uni-muenster.de RI Schober, Otmar/A-8670-2008 NR 60 TC 13 Z9 14 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD AUG 1 PY 2004 VL 12 IS 15 BP 4117 EP 4132 DI 10.1016/j.bmc.2004.05.027 PG 16 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 840UZ UT WOS:000222886700018 PM 15246089 ER PT J AU Kobrinsky, E Kepplinger, KJF Yu, A Harry, JB Kahr, H Romanin, C Abernethy, DR Soldatov, NM AF Kobrinsky, E Kepplinger, KJF Yu, A Harry, JB Kahr, H Romanin, C Abernethy, DR Soldatov, NM TI Voltage-gated rearrangements associated with differential beta-subunit modulation of the L-type Ca2+ channel inactivation SO BIOPHYSICAL JOURNAL LA English DT Article ID RESONANCE ENERGY-TRANSFER; CALCIUM-CHANNEL; ALPHA(1C) SUBUNIT; MOLECULAR DETERMINANTS; FUNCTIONAL EXPRESSION; SLOW INACTIVATION; OPEN PROBABILITY; SPLICE VARIANTS; HEART-CELLS; EXONS 40-42 AB Auxiliary beta-subunits bound to the cytoplasmic alpha(1)-interaction domain of the pore-forming alpha(1C)-subunit are important modulators of voltage-gated Ca2+ channels. The underlying mechanisms are not yet well understood. We investigated correlations between differential modulation of inactivation by beta(1a)- and beta(2)-subunits and structural responses of the channel to transition into distinct functional states. The NH2-termini of the alpha(1C)- and beta-subunits were fused with cyan or yellow fluorescent proteins, and functionally coexpressed in COS1 cells. Fluorescence resonance energy transfer ( FRET) between them or with membrane-trapped probes was measured in live cells under voltage clamp. It was found that in the resting state, the tagged NH2-termini of the alpha(1C)- and beta-subunit fluorophores are separated. Voltage-dependent inactivation generates strong FRET between alpha(1C) and beta(1a) suggesting mutual reorientation of the NH2-termini, but their distance vis-a-vis the plasma membrane is not appreciably changed. These voltage-gated rearrangements were substantially reduced when the b1a- subunit was replaced by beta(2). Differential beta-subunit modulation of inactivation and of FRET between alpha(1C) and beta were eliminated by inhibition of the slow inactivation. Thus, differential beta-subunit modulation of inactivation correlates with the voltage-gated motion between the NH2-termini of alpha(1C)- and beta-subunits and targets the mechanism of slow voltage-dependent inactivation. C1 NIA, NIH, Baltimore, MD 21224 USA. Univ Linz, Inst Biophys, A-4040 Linz, Austria. RP Soldatov, NM (reprint author), NIA, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM soldatovN@grc.nia.nih.gov RI Romanin, Christoph/D-5399-2009 OI Romanin, Christoph/0000-0003-3756-4136 NR 42 TC 25 Z9 25 U1 0 U2 0 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG PY 2004 VL 87 IS 2 BP 844 EP 857 DI 10.1529/biophysj.104.041152 PG 14 WC Biophysics SC Biophysics GA 844XZ UT WOS:000223195700012 PM 15298893 ER PT J AU Alcaraz, A Nestorovich, EM Aguilella-Arzo, M Aguilella, VM Bezrukov, SM AF Alcaraz, A Nestorovich, EM Aguilella-Arzo, M Aguilella, VM Bezrukov, SM TI Salting out the ionic selectivity of a wide channel: The asymmetry of OmpF SO BIOPHYSICAL JOURNAL LA English DT Article ID PHOSPHOLIPID SURFACE-CHARGE; CONSTANT FIELD ASSUMPTION; BROWNIAN DYNAMICS PROGRAM; ESCHERICHIA-COLI; MOLECULAR-DYNAMICS; MEMBRANE CHANNEL; MATRIX PROTEIN; LIPID BILAYERS; SINGLE-CHANNEL; PORIN CHANNELS AB Although the crystallographic structure of the bacterial porin OmpF has been known for a decade, the physical mechanisms of its ionic selectivity are still under investigation. We address this issue in a series of experiments with varied pH, salt concentrations, inverted salt gradient, and charged and uncharged lipids. Measuring reversal potential, we show that OmpF selectivity ( traditionally regarded as slightly cationic) depends strongly on pH and salt concentration and is conditionally asymmetric, that is, the calculated selectivity is sensitive to the direction of salt concentration gradient. At neutral pH and subdecimolar salt concentrations the channel exhibits nearly ideal cation selectivity (t(G)(+) = 0.98 +/- 0.01). Substituting neutral DPhPC with DPhPS, we demonstrate that the fixed charge of the host lipid has a small but measurable effect on the channel reversal potential. The available structural information allows for a qualitative explanation of our experimental findings. These findings now lead us to re-examine the ionization state of 102 titratable sites of the OmpF channel. Using standard methods of continuum electrostatics tailored to our particular purpose, we find the charge distribution in the channel as a function of solution acidity and relate the pH-dependent asymmetry in channel selectivity to the pH-dependent asymmetry in charge distribution. In an attempt to find a simple phenomenological description of our results, we also discuss different macroscopic models of electrodiffusion through large channels. C1 Univ Jaume 1, Dept Ciencias Expt, Castellon de La Plana 12080, Spain. NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Aguilella, VM (reprint author), Univ Jaume 1, Dept Ciencias Expt, Castellon de La Plana 12080, Spain. EM aguilell@exp.uji.es RI Aguilella, Vicente/B-7592-2008; Alcaraz, Antonio/F-8498-2016 OI Aguilella, Vicente/0000-0002-2420-2649; NR 59 TC 111 Z9 114 U1 3 U2 14 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG PY 2004 VL 87 IS 2 BP 943 EP 957 DI 10.1529/biophysj.104/043414 PG 15 WC Biophysics SC Biophysics GA 844XZ UT WOS:000223195700020 PM 15298901 ER PT J AU Kozlovsky, Y Zimmerberg, J Kozlov, MM AF Kozlovsky, Y Zimmerberg, J Kozlov, MM TI Orientation and interaction of oblique cylindrical inclusions embedded in a lipid monolayer: A theoretical model for viral fusion peptides SO BIOPHYSICAL JOURNAL LA English DT Article ID INFLUENZA HEMAGGLUTININ; MEMBRANE-FUSION; FLUID MEMBRANES; PROTEIN INTERACTION; ELASTIC PROPERTIES; BILAYER; ENERGY; VIRUS; TILT; POLYMORPHISM AB We consider the elastic behavior of flat lipid monolayer embedding cylindrical inclusions oriented obliquely with respect to the monolayer plane. An oblique inclusion models a fusion peptide, a part of a specialized protein capable of inducing merger of biological membranes in the course of fundamental cellular processes. Although the crucial importance of the fusion peptides for membrane merger is well established, the molecular mechanism of their action remains unknown. This analysis is aimed at revealing mechanical deformations and stresses of lipid monolayers induced by the fusion peptides, which, potentially, can destabilize the monolayer structure and enhance membrane fusion. We calculate the deformation of a monolayer embedding a single oblique inclusion and subject to a lateral tension. We analyze the membrane-mediated interactions between two inclusions, taking into account bending of the monolayer and tilt of the hydrocarbon chains with respect to the surface normal. In contrast to a straightforward prediction that the oblique inclusions should induce tilt of the lipid chains, our analysis shows that the monolayer accommodates the oblique inclusion solely by bending. We find that the interaction between two inclusions varies nonmonotonically with the interinclusion distance and decays at large separations as square of the distance, similar to the electrostatic interaction between two electric dipoles in two dimensions. This long-range interaction is predicted to dominate the other interactions previously considered in the literature. C1 Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Kozlov, MM (reprint author), Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. EM michk@post.tau.ac.il NR 37 TC 18 Z9 18 U1 1 U2 8 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD AUG PY 2004 VL 87 IS 2 BP 999 EP 1012 DI 10.1529/biophysj.104.041467 PG 14 WC Biophysics SC Biophysics GA 844XZ UT WOS:000223195700025 PM 15298906 ER PT J AU Kimchi-Sarfaty, C Alexander, NS Brittain, S Ali, S Gottesman, MM AF Kimchi-Sarfaty, C Alexander, NS Brittain, S Ali, S Gottesman, MM TI Transduction of multiple cell types using improved conditions for gene delivery and expression of SV40 pseudovirions packaged in vitro SO BIOTECHNIQUES LA English DT Article ID FLUORESCENT PROTEIN; THERAPY; VECTORS AB This comprehensive study demonstrates highly efficient transduction of a wide variety of human, murine, and monkey cell lines, using a procedure for in vitro packaging of plasmid DNA in recombinant simian virus 40 (SV40) capsid proteins to form pseudovirions. The pseudovirions are encapsidated by the VP1 major capsid protein, with no SV40 sequence requirement, and are able to carry up to 17.7 kb of supercoiled plasmid DNA. We developed a procedure to scale-up production of SV40 pseudovirions, as well as an efficient protocol to concentrate the virions with no loss of activity. We also developed a method that allows transduction of 10 times more cells than the original protocol. This protocol was tested using supercoiled in vitro-packaged plasmid carrying the human multidrug-resistance gene (MDRI encoding P-glycoprotein; P-gp), or the enhanced green fluorescent protein reporter gene (EGFP) in .45 human lymphoblastoid cells and in K562 human erythroleukemia cells. Multiple transductions at 24-h intervals were shown to increase expression using the EGFP reporter gene. The protocols developed in this study establish in vitro-packaged SV40 pseudovirions as one of the most efficient gene delivery systems. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov NR 10 TC 11 Z9 13 U1 0 U2 0 PU EATON PUBLISHING CO PI WESTBOROUGH PA ONE RESEARCH DRIVE, SUITE 400A, PO BOX 1070, WESTBOROUGH, MA 01581-6070 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD AUG PY 2004 VL 37 IS 2 BP 270 EP 275 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 845YB UT WOS:000223280200017 PM 15335219 ER PT J AU Berry, RM Schmitz, S Johnson, BD Dworecki, B Fritz, EA Roebuck, KA Hines, KK AF Berry, RM Schmitz, S Johnson, BD Dworecki, B Fritz, EA Roebuck, KA Hines, KK TI Elimination of background in film-based applications SO BIOTECHNIQUES LA English DT Article ID HYBRIDIZATION; SENSITIVITY; BLOTS; ASSAY AB Erase-It(R) Background Eliminator is a solution used directly on processed film to remove background or improve data resolution. Traditional methods, such as optimization of the scientific protocol or better estimation of exposure time, are tedious and uncertain. Nevertheless, autoradiography continues to be a simple, effective method to visualize data. Therefore, we evaluated the ability of Erase-It Working Solution to help solve background and resolution issues. To demonstrate the efficiency of the Background Eliminator we analyzed the product's ability to remove signal evenly, performance on several brands of film, and usefulness with various detection methods. Even reduction of signal was demonstrated by performing densitometric analysis on film generated from a dot blot with serial dilutions of analyte. In addition, overexposed films from various suppliers were effectively treated to remove background and visualize data. Autoradiographs, generated with P-32-labeled probes, and chemiluminescent substrate were also processed resulting in clearer images. Our results demonstrate that film data can be treated quickly and conveniently without fear of artificial enhancement. We show the Background Eliminator to be a universal and timesaving tool to visualize results that otherwise may be difficult to interpret. C1 Pierce Biotechnol Inc, Res & Dev, Rockford, IL 61101 USA. Perbio Sci, Bonn, Germany. Rush Univ, Chicago, IL 60612 USA. NIH, Bethesda, MD 20892 USA. RP Berry, RM (reprint author), Pierce Biotechnol Inc, Res & Dev, 3747 N Meridian Rd, Rockford, IL 61101 USA. EM rachael.berry@piercenet.com NR 13 TC 0 Z9 0 U1 0 U2 0 PU EATON PUBLISHING CO PI WESTBOROUGH PA ONE RESEARCH DRIVE, SUITE 400A, PO BOX 1070, WESTBOROUGH, MA 01581-6070 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD AUG PY 2004 VL 37 IS 2 BP 298 EP 302 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 845YB UT WOS:000223280200022 PM 15335223 ER PT J AU McPherson, E Huff, D Dunn, J Muenke, M AF McPherson, E Huff, D Dunn, J Muenke, M TI Anomalies of the forebrain with radial limb defects: Garcia-Lurie-Steinfeld syndrome? SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE atelencephaly; aprosencephaly; holoprosencephaly; forebrain malformations; radial limb defects; Steinfeld syndrome; Garcia Lurie syndrome ID MULTIPLE CONGENITAL-ANOMALIES; XK-APROSENCEPHALY SYNDROME; CHERSTVOY-SYNDROME; MALFORMATIONS; PHENOTYPE AB BACKGROUND: Severe anomalies of the forebrain together with radial limb anomalies have been reported in Steinfeld syndrome, XK aprosencephaly, and partial monosomy 13q. Steinfeld syndrome is an extremely variable autosomal dominant condition that, in severe cases, is characterized by holoprosencephaly, radial limb defects, and renal and/or cardiac defects. In mild cases there may be only thumb hypoplasia, ocular coloboma, or oral clefts. XK aprosencephaly, also called Garcia-Lurie syndrome (GLS), is a usually sporadic disorder with radial limb defects and aprosencephaly/atelencephaly. Based on two atypical sibships, autosomal recessive inheritance has been suggested. Two patients with variations of monosomy 13q have been described with atelencephaly but, generally, Steinfeld and XK aprosencephaly patients are chromosomally normal. Holoprosencephaly in 13q deletion patients appears to be due to ZIC2 mutations, but ZIC2 has not been previously tested in Steinfeld syndrome or GLS patients. CASES: We report three sporadic cases with clinical features intermediate between Steinfeld and GLS, including severe forebrain malformations and radial limb defects. All had normal karyotypes, and mutations in ZIC2 were absent in the two cases tested. CONCLUSIONS: In our cases and in the literature there is significant clinical overlap between Steinfeld syndrome and GLS. We propose these conditions may not be nosologically or etiologically distinct. The spectrum of severe forebrain anomalies in these conditions is broader than previously thought and may include some neural tube defects. Mild cases are difficult to identify and the full range of expression remains unknown. Autosomal dominant inheritance with incomplete penetrance and frequent new mutations is postulated. Thorough clinical evaluation is recommended for children with severe forebrain and radial limb defects. (C) 2004 Wiley-Liss, Inc. C1 Marshfield Clin Fdn Med Res & Educ, Dept Med Genet Serv 3C1, Marshfield, WI 54449 USA. Univ Wisconsin, Dept Pediat, Madison, WI USA. Childrens Hosp Philadelphia, Dept Pathol, Philadelphia, PA 19104 USA. Magee Womens Hosp, Dept Pathol, Pittsburgh, PA USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP McPherson, E (reprint author), Marshfield Clin Fdn Med Res & Educ, Dept Med Genet Serv 3C1, Marshfield, WI 54449 USA. EM mcpherson.elizabeth@marshfieldclinic.org NR 25 TC 9 Z9 9 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-0752 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD AUG PY 2004 VL 70 IS 8 BP 537 EP 544 DI 10.1002/bdra.20053 PG 8 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 851IF UT WOS:000223678100007 PM 15329833 ER PT J AU Hines, RN Adams, J Buck, GM Faber, W Holson, JE Jacobson, SW Keszler, M McMartin, K Segraves, RT Singer, LT Sipes, IG Williams, PL AF Hines, RN Adams, J Buck, GM Faber, W Holson, JE Jacobson, SW Keszler, M McMartin, K Segraves, RT Singer, LT Sipes, IG Williams, PL TI NTP-CERHR Expert Panel Report on the reproductive and developmental toxicity of fluoxetine SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Review ID SEROTONIN-REUPTAKE INHIBITORS; INDUCED SEXUAL DYSFUNCTION; CHRONIC ANTIDEPRESSANT TREATMENT; OBSESSIVE-COMPULSIVE DISORDER; CHILDHOOD ANXIETY DISORDERS; MAJOR DEPRESSIVE DISORDER; GROWTH-HORMONE RELEASE; IN-UTERO EXPOSURE; HUMAN BREAST-MILK; RAT VAS-DEFERENS C1 Med Coll Wisconsin, Milwaukee, WI 53226 USA. Univ Massachusetts, Boston, MA 02125 USA. NICHHD, Rockville, MD USA. WFT Consulting LLC, Victor, NY USA. WIL Res Labs Inc, Ashland, OH USA. Wayne State Univ, Sch Med, Detroit, MI USA. Georgetown Univ Hosp, Washington, DC 20007 USA. LSU, Ctr Hlth Sci, Shreveport, LA USA. MetroHlth Med Ctr, Cleveland, OH USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Arizona, Tucson, AZ USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Hines, RN (reprint author), Sci Int Inc, Ctr Evaluat Risks Human Reprod, 1800 Diagonal Rd,Suite 500, Alexandria, VA 22314 USA. OI Hines, Ronald/0000-0002-3094-4200; Keszler, Martin/0000-0002-9964-664X; Buck Louis, Germaine/0000-0002-1774-4490 NR 239 TC 17 Z9 18 U1 3 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD AUG PY 2004 VL 71 IS 4 BP 193 EP 280 DI 10.1002/bdrb.20014 PG 88 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 852JV UT WOS:000223752500001 PM 15334524 ER PT J AU Barrett, J AF Barrett, J TI Fludarabine finds its significant other? SO BLOOD LA English DT Editorial Material AB Fludarabine-based conditioning regimens for allogeneic stem cell transplantation offer distinct advantages for reducing treatment-related mortality; the problem is how to conserve low toxicity while maintaining antileukernic efficacy. C1 NHLBI, Bethesda, MD 20892 USA. RP Barrett, J (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 1 Z9 1 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2004 VL 104 IS 3 BP 603 EP 604 DI 10.1182/blood-2004-05-1755 PG 2 WC Hematology SC Hematology GA 840UW UT WOS:000222886400010 ER PT J AU Hideshima, T Bergsagel, PL Kuehl, WM Anderson, KC AF Hideshima, T Bergsagel, PL Kuehl, WM Anderson, KC TI Advances in biology of multiple myeloma: clinical applications SO BLOOD LA English DT Review ID NF-KAPPA-B; ENDOTHELIAL GROWTH-FACTOR; PROTEASOME INHIBITOR PS-341; BONE-MARROW MICROENVIRONMENT; OVERCOMES DRUG-RESISTANCE; NECROSIS-FACTOR-ALPHA; SOLUBLE INTERLEUKIN-6 RECEPTOR; CELL-DERIVED FACTOR-1-ALPHA; COOPERATIVE-ONCOLOGY-GROUP; GLOBAL GENE-EXPRESSION AB There appear to be 2 pathways involved in the early pathogenesis of premalignant monoclonal gammopathy of undetermined significance (MGUS) and malignant multiple myeloma (MM) tumors. Nearly half of these tumors are nonhyperdiploid and mostly have immunoglobulin H (IgH) translocations that involve 5 recurrent chromosomal loci, including 11q13 (cyclin D1), 6p21 (cyclin D3), 4p16 (fibroblast growth factor receptor 3 [FGFR3] and multiple myeloma SET domain [MMSET]), 16q23 (c-maf), and 20q11 (mafB). The remaining tumors are hyperdiploid and contain multiple trisomies involving chromosomes 3, 5, 75 9,115 15, 19, and 21, but infrequently have IgH translocations involving the 5 recurrent loci. Dysregulated expression of cyclin D1, D2, or D3 appears to occur as an early event in virtually all of these tumors. This may render the cells more susceptible to proliferative stimuli, resulting in selective expansion as a result of interaction with bone marrow stromal cells that produce interleukin-6 (IL-6) and other cytokines. There are 5 proposed tumor groups, defined by IgH translocations and/or cyclin D expression, that appear to have differences in biologic properties, including interaction with stromal cells, prognosis, and response to specific therapies. Delineation of the mechanisms mediating MM cell proliferation, survival, and migration in the bone marrow (BM) microenvironment may both enhance understanding of pathogenesis and provide the framework for identification and validation of novel molecular targets. C1 Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Cornell Univ, Weill Med Coll, New York, NY USA. NCI, Genet Branch, Bethesda, MD 20892 USA. RP Anderson, KC (reprint author), Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Mayer 557,44 Binney St, Boston, MA 02115 USA. EM kenneth_anderson@dfci.harvard.edu RI Bergsagel, Peter/A-7842-2011 OI Bergsagel, Peter/0000-0003-1523-7388 FU NCI NIH HHS [1P50 CA10070-01, R0-1 CA50947]; PHS HHS [P0-1 78378] NR 197 TC 420 Z9 440 U1 2 U2 28 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 AUG 1 PY 2004 VL 104 IS 3 BP 607 EP 618 DI 10.1182/blood-2004-01-0037 PG 12 WC Hematology SC Hematology GA 840UW UT WOS:000222886400012 PM 15090448 ER PT J AU Sereti, I Anthony, KB Martinez-Wilson, H Lempicki, R Adelsberger, J Metcalf, JA Hallahan, CW Follmann, D Davey, RT Kovacs, JA Lane, HC AF Sereti, I Anthony, KB Martinez-Wilson, H Lempicki, R Adelsberger, J Metcalf, JA Hallahan, CW Follmann, D Davey, RT Kovacs, JA Lane, HC TI IL-2-induced CD4(+) T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; RANDOMIZED CONTROLLED-TRIAL; INTERMITTENT INTERLEUKIN-2 THERAPY; PLACEBO-CONTROLLED TRIAL; IMMUNE ACTIVATION; SUBCUTANEOUS INTERLEUKIN-2; IN-VITRO; LYMPHOCYTES; TURNOVER AB Administration of interleukin 2 (IL-2) leads to selective and sustained CD4(+) T-cell expansions in patients infected with HIV. It has been hypothesized that persistent CD4+ T-cell proliferation is the primary mechanism maintaining these expansions. T-cell proliferation was studied by ex vivo bromodeoxyuridine (BrdU) incorporation and intracellular Ki67 staining in HIV-Infected patients treated with antiretroviral therapy (ART) with or without IL-2. In contrast to the tested hypothesis, HIV-infected patients treated with IL-2 had lower CD4(+) T-cell proliferation compared to patients treated with ART alone. Independently of viral load changes, administration of IL-2 led to a decrease in basal CD4(+) T-cell proliferation. Total numbers of CD4(+) T cells with naive and recall, but not effector, memory phenotype were increased. The degree of CD4(+) T-cell expansion correlated with the decreases in proliferation and a strong association was seen between these decreases and the expansion of the CD4(+)/CD25(+) subset. Intermittent IL-2 in HIV-infected patients leads to expansions of CD4(+)/CD25(+) T cells with naive and recall memory phenotypes that strongly correlate with decreases in proliferation. These data suggest that decreased T-cell proliferation is central in the CD4(+) T-cell expansions induced by IL-2. C1 NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Sereti, I (reprint author), NIAID, Clin & Mol Retrovirol Sect, Immunoregulat Lab, NIH, Bldg 10,Rm 11B-04,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU NCI NIH HHS [N01-CO-56000] NR 37 TC 75 Z9 77 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 1 PY 2004 VL 104 IS 3 BP 775 EP 780 DI 10.1182/blood-2003-12-4355 PG 6 WC Hematology SC Hematology GA 840UW UT WOS:000222886400033 PM 15090457 ER PT J AU Aoki, Y Tosato, G AF Aoki, Y Tosato, G TI HIV-1 Tat enhances Kaposi sarcoma-associated herpesvirus (KSHV) infectivity SO BLOOD LA English DT Article ID PROTEIN TRANSDUCTION DOMAIN; PRIMARY EFFUSION LYMPHOMA; ENDOTHELIAL-CELLS; IN-VIVO; HUMAN-HERPESVIRUS-8; DELIVERY; EXPRESSION; APOPTOSIS; ACTIVATION; RECEPTOR AB The high frequency of Kaposi sarcoma (KS) in immunodeficiency states, particularly in patients with AIDS, has been attributed to increased replication of KS-associated herpesvirus (KSHV), a necessary cofactor for KS development. However, experimental KSHV infection of endothelial lineage cells that compose KS lesions has been difficult even in the absence of immune cells. Here we show that HIV-1 Tat protein can directly promote KSHV transmission. Full-length HIV-1 Tat and a 13-amino-acid peptide corresponding to the basic region of Tat specifically enhances the entry of KSHV into endothelial and other cells, presenting evidence for an active role of HIV-1 in the development of KSHV-associated diseases. These results can explain why AIDS-KS is more frequent and clinically more aggressive than KS in other immunodeficiency states. C1 NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Aoki, Y (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,12N226, Bethesda, MD 20892 USA. EM aokiy@mail.nih.gov NR 40 TC 52 Z9 67 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 AUG 1 PY 2004 VL 104 IS 3 BP 810 EP 814 DI 10.1182/blood-2003-07-2533 PG 5 WC Hematology SC Hematology GA 840UW UT WOS:000222886400039 PM 15073028 ER PT J AU Barton, JJS Cherkasova, MV Hefter, R Cox, TA O'Connor, M Manoach, DS AF Barton, JJS Cherkasova, MV Hefter, R Cox, TA O'Connor, M Manoach, DS TI Are patients with social developmental disorders prosopagnosic? Perceptual heterogeneity in the Asperger and socio-emotional processing disorders SO BRAIN LA English DT Article DE Asperger's disorder; autism; face recognition; prosopagnosia ID RIGHT-HEMISPHERE; FACE RECOGNITION; LEARNING-DISABILITIES; AUTISTIC SYNDROME; COVERT RECOGNITION; FACIAL EXPRESSIONS; CHILDHOOD AUTISM; VISUAL AGNOSIA; CHILDREN; DISCRIMINATION AB It has been hypothesized that social developmental disorders (SDD) like autism, Asperger's disorder and the social-emotional processing disorder may be associated with prosopagnosic-like deficits in face recognition. We studied the ability to recognize famous faces in 24 adults with a variety of SDD diagnoses. We also measured their ability to discriminate changes in internal facial configuration, a perceptual function that is important in face recognition, and their imagery for famous faces, an index of their facial memory stores. We contrasted their performance with both healthy subjects and prosopagnosic patients. We also performed a cluster analysis of the SDD patients. One group of eight SDD subjects performed normally on all tests of face perception and recognition. The other 16 subjects were impaired in recognition, though most were better than prosopagnosic patients. One impaired SDD subgroup had poor perception of facial structure but relatively preserved imagery, resembling prosopagnosic patients with medial occipitotemporal lesions. Another subgroup had better perception than imagery, resembling one prosopagnosic with bilateral anterior temporal lesions. Overall, SDD subgroup membership by face recognition did not correlate with a particular SDD diagnosis or subjective ratings of social impairment. We conclude that the social disturbance in SDD does not invariably lead to impaired face recognition. Abnormal face recognition in some SDD subjects is related to impaired perception of facial structure in a manner suggestive of occipitotemporal dysfunction. Heterogeneity in the perceptual processing of faces may imply pathogenetic heterogeneity, with important implications for genetic and rehabilitative studies of SDD. C1 Beth Israel Deaconess Med Ctr, Dept Neurol, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Dept Ophthalmol, Boston, MA 02215 USA. Harvard Univ, Sch Med, Athinoula A Martinos Ctr, Boston, MA USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Boston Univ, Dept Bioengn, Boston, MA 02215 USA. NEI, NIH, Bethesda, MD 20892 USA. RP Barton, JJS (reprint author), Beth Israel Deaconess Med Ctr, Dept Neurol, KS 452,330 Brookline Ave, Boston, MA 02215 USA. EM jbarton@bidmc.harvard.edu RI Barton, Jason/A-6362-2012 FU NIMH NIH HHS [1R01 MH069898-01]; NINDS NIH HHS [1 K08 NS01920-01A1] NR 65 TC 53 Z9 53 U1 9 U2 21 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD AUG PY 2004 VL 127 BP 1706 EP 1716 DI 10.1093/brain/awh194 PN 8 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 845GJ UT WOS:000223228600003 PM 15215211 ER PT J AU Kupfer, L Hofman, K Jarawan, R McDermott, J Bridbord, K AF Kupfer, L Hofman, K Jarawan, R McDermott, J Bridbord, K TI Strategies to discourage brain drain SO BULLETIN OF THE WORLD HEALTH ORGANIZATION LA English DT Article DE research personnel/supply and distribution; brain drain; emigration and immigration; biomedical research/education; training support/organization and administration; research support; health priorities; HIV infections; developing countries; developed countries AB Building health research expertise in developing countries often requires personnel to receive training beyond national borders. For research funding agencies that sponsor this type of training, a major goal is to ensure that trainees return to their country of origin: attaining this objective requires the use of proactive strategies. The strategies described were developed under the extramural acquired immunodeficiency syndrome (AIDS) International Training and Research Program (AITRP) funded by the Fogarty international-Center(FIC) at the National Institutes of Health, United States. This programme supports universities in the United States that provide research training to scientists from developing countries to enable them to address the global epidemic of human immunodeficiency virus (HIV)/AIDS and the related tuberculosis (TB) epidemic. This paper describes the strategies employed to discourage brain drain by the principle investigators (PIs) of five of the longest-funded AITRPs (funded for 15 years). Long-term trainees in these programmes spent from 11 to 96 months (an average of 26 months) studying. Using scientific, political and economic strategies that address brain drain issues, PIs working in AITRPs have attained an average rate of return home for their trainees of 80%. C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Kupfer, L (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM kupferl@mail.nih.gov OI Kupfer, Linda/0000-0002-6886-6818 NR 2 TC 28 Z9 28 U1 0 U2 4 PU WORLD HEALTH ORGANIZATION PI GENEVA 27 PA MARKETING AND DISSEMINATION, CH-1211 GENEVA 27, SWITZERLAND SN 0042-9686 J9 B WORLD HEALTH ORGAN JI Bull. World Health Organ. PD AUG PY 2004 VL 82 IS 8 BP 616 EP 619 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 846PI UT WOS:000223327500012 PM 15375452 ER PT J AU Jovanovic, K Burke, RE AF Jovanovic, K Burke, RE TI Anatomical organization of motoneurons and interneurons in the mudpuppy (Necturus maculosus) brachial spinal cord: the neural substrate for central pattern generation SO CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY LA English DT Article; Proceedings Paper CT RB Stein Symposium Nerve, Muscle and Beyond held in conjunction with the Canadian-Physiological-Society Annual Meeting CY JAN 29-FEB 01, 2004 CL Vernon, CANADA SP Canadian Physiol Soc DE interneurons; motoneurons; sub-pial plexus; central pattern generator for locomotion ID IN-VITRO; LOCOMOTION; MACULATUS; NETWORKS; FROG; LOCALIZATION; COORDINATION; MODULATION; INVITRO; WALKING AB The isolated brachial spinal cord of the mudpuppy is useful for studies of neural networks underlying forelimb locomotion, but information about its anatomy is scarce. We addressed this issue by combining retrograde labeling with fluorescent tracers and confocal microscopy. Remarkably, the central region of gray matter was aneural and contained only a tenuous meshwork of glial fibers and large extracellular spaces. Somata of motoneurons (MNs) and interneurons (INs), labeled retrogradely from ventral roots or axons in the ventro-lateral funiculus, respectively, were confined within a gray neuropil layer abutting the white matter borders, while their dendrites projected widely throughout the white matter. A considerable fraction of labeled INs was found contralaterally with axons crossing beneath a thick layer of ependyma surrounding the central canal. Dorsal roots (DRs) produced dense presynaptic arbors within a restricted dorsal region containing afferent terminations, within which dorsally directed MN and IN dendrites mingled with dense collections of synaptic boutons. Our data suggest that a major fraction of synaptic interactions takes place within the white matter. This study provides a detailed foundation for electrophysiological experiments aimed at elucidating the neural circuits involved in locomotor pattern generation. C1 NINDS, Neural Control Lab, NIH, Bethesda, MD 20895 USA. RP Burke, RE (reprint author), NINDS, Neural Control Lab, NIH, 49 Convent Dr, Bethesda, MD 20895 USA. EM reburke@helix.nih.gov NR 46 TC 1 Z9 1 U1 0 U2 1 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 1200 MONTREAL ROAD, BUILDING M-55, OTTAWA, ON K1A 0R6, CANADA SN 0008-4212 J9 CAN J PHYSIOL PHARM JI Can. J. Physiol. Pharmacol. PD AUG-SEP PY 2004 VL 82 IS 8-9 BP 628 EP 636 DI 10.1139/Y04-055 PG 9 WC Pharmacology & Pharmacy; Physiology SC Pharmacology & Pharmacy; Physiology GA 876AR UT WOS:000225468200012 PM 15523520 ER PT J AU Spitz, DR Azzam, EI Li, JJ Gius, D AF Spitz, DR Azzam, EI Li, JJ Gius, D TI Metabolic oxidation/reduction reactions and cellular responses to ionizing radiation: A unifying concept in stress response biology SO CANCER AND METASTASIS REVIEWS LA English DT Review DE oxidative stress; redox regulation; metabolism; signal transduction; thioredoxin; superoxide; dismutase; non-targeted effects; mitochondria; cancer; aging ID INDUCED GENOMIC INSTABILITY; TUMOR-NECROSIS-FACTOR; OXIDATIVE STRESS; SUPEROXIDE-DISMUTASE; GENE-EXPRESSION; NITRIC-OXIDE; GLUCOSE DEPRIVATION; SIGNAL-TRANSDUCTION; ADAPTIVE RESPONSE; HYDROGEN-PEROXIDE AB Exposure of eukaryotic cells to ionizing radiation (IR) results in the immediate formation of free radicals that last a matter of milliseconds. It has been assumed that the subsequent alterations in multiple intracellular processes following irradiation is due to the initial oxidative damage caused by these free radicals. However, it is becoming increasingly clear that intracellular metabolic oxidation/reduction ( redox) reactions can be affected by this initial IR-induced free radical insult and may remain perturbed for minutes, hours, or days. It would seem logical that these cellular redox reactions might contribute to the activation of protective or damaging processes that could impact upon the damaging effects of IR. These processes include redox sensitive signaling pathways, transcription factor activation, gene expression, and metabolic activities that govern the formation of intracellular oxidants and reductants. The physiological manifestations of these radiation-induced alterations in redox sensitive processes have been suggested to contribute to adaptive responses, bystander effects, cell cycle perturbations, cytotoxicity, heat-induced radiosensitization, genomic instability, inflammation, and fibrosis. While a great deal is known about the molecular changes associated with the initial production of free radicals at the time of irradiation, the contribution of perturbations in redox sensitive metabolic processes to biological outcomes following exposure to IR is only recently becoming established. This review will focus on evidence supporting the concept that perturbations in intracellular metabolic oxidation/reduction reactions contribute to the biological effects of radiation exposure as well as new concepts emerging from the field of free radical biology that may be relevant to future studies in radiobiology. C1 Univ Iowa, Holden Comprehens Canc Ctr, Dept Radiat Oncol, Free Rad & Radiat Biol Program,Med Labs B180, Iowa City, IA 52242 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Radiol, Newark, NJ 07103 USA. City Hope Natl Med Ctr, Div Radiat Oncol, Duarte, CA 91010 USA. NCI, Radiat Oncol Branch, Radiat Oncol Sci Program, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Spitz, DR (reprint author), Univ Iowa, Holden Comprehens Canc Ctr, Dept Radiat Oncol, Free Rad & Radiat Biol Program,Med Labs B180, Iowa City, IA 52242 USA. EM douglas-spitz@uiowa.edu NR 109 TC 287 Z9 299 U1 3 U2 19 PU KLUWER ACADEMIC PUBL PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-7659 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD AUG-DEC PY 2004 VL 23 IS 3-4 BP 311 EP 322 DI 10.1023/B:CANC.0000031769.14728.bc PG 12 WC Oncology SC Oncology GA 829BG UT WOS:000222017400010 PM 15197331 ER PT J AU Acharya, MR Figg, WD AF Acharya, MR Figg, WD TI Histone deacetylase inhibitor enhances the anti-leukemic activity of an established nucleoside analogue SO CANCER BIOLOGY & THERAPY LA English DT Article DE histone deacetylase inhibitors; MS-275; fludarabine; leukemia; apoptosis ID VIVO ANTITUMOR-ACTIVITY; LEUKEMIA-CELLS; MYELOGENOUS LEUKEMIA; BCR/ABL(+) CELLS; INDUCE APOPTOSIS; CANCER; FLUDARABINE; MS-27-275; TUMORS AB Interest in histone deacetylase (HDAC) inhibitors as antineoplastic agents has been accelerating over the last several years and increasing number of compounds are in or entering clinical trials in humans. Recently, attention has been focused on the ability of HDAC inhibitors to induce perturbations in cell cycle regulatory proteins (e.g., p21(CIP1)), downregulation of survival signaling pathways (e.g., Raf/MAPkinase/ERK), and disruption of cellular redox state (e.g., reactive oxygen species, ROS). In the April 2004 issue of Cancer Research, Maggio et al. report that pre-treatment of human leukemic cells with a histone deacetylase inhibitor, MS-275 significantly enhances the abrogative capacity of an established nucleoside analogue, fludarabine. The study indicates that apart from promoting acetylation of histories and regulation of genes involved in differentiation and apoptosis, MS-275 also induces multiple perturbations in signal transduction, survival and cell cycle regulatory pathways that increase the fludarabine-mediated cell death. C1 NCI, Clin Pharmacol Res Core, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Med Coll Virginia, Dept Pharmaceut, Richmond, VA 23298 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Res Core, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 17 TC 7 Z9 8 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD AUG PY 2004 VL 3 IS 8 BP 719 EP 720 PG 2 WC Oncology SC Oncology GA 898RS UT WOS:000227094500014 PM 15254393 ER PT J AU Lee, FT Mountain, A Rigopoulos, A Smyth, F Johns, T Brechbiel, M Scott, A AF Lee, FT Mountain, A Rigopoulos, A Smyth, F Johns, T Brechbiel, M Scott, A TI Enhanced efficacy of radioimmunotherapy with Y-90-CHX-A"-DTPA-hu3S193 by inhibition of epidermal growth factor receptor (EGFR) signaling with EGFR tyrosine kinase inhibitor AG1478 SO CANCER BIOTHERAPY AND RADIOPHARMACEUTICALS LA English DT Meeting Abstract CT 10th Conference on Cancer Therapy with Antibodies and Immunoconjugates CY OCT 20-23, 2004 CL Princeton, NJ SP Bristol Myers Squibb, Berlex, biogen idec, Immunomedics Inc, Ctr Mol Med & Immunol, NCI C1 Ludwig Inst Canc Res, Tumor Targeting Program, Melbourne, Vic 3050, Australia. NCI, Radioimmune & Inorgan Chem Sect, ROB, CCR,NIH, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1084-9785 J9 CANCER BIOTHER RADIO JI Cancer Biother. Radiopharm. PD AUG PY 2004 VL 19 IS 4 MA 38 BP 528 EP 529 PG 2 WC Oncology; Medicine, Research & Experimental; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Research & Experimental Medicine; Pharmacology & Pharmacy; Radiology, Nuclear Medicine & Medical Imaging GA 857KN UT WOS:000224115300051 ER PT J AU Szakacs, G Annereau, JP Lababidi, S Shankavaram, U Arciello, A Bussey, KJ Reinhold, W Guo, YP Kruh, GD Reimers, M Weinstein, JN Gottesman, MM AF Szakacs, G Annereau, JP Lababidi, S Shankavaram, U Arciello, A Bussey, KJ Reinhold, W Guo, YP Kruh, GD Reimers, M Weinstein, JN Gottesman, MM TI Predicting drug sensitivity and resistance: Profiling ABC transporter genes in cancer cells SO CANCER CELL LA English DT Article ID MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; MOLECULAR PHARMACOLOGY; LINES; EXPRESSION; PROTEIN; PATTERNS; SCREEN; POLYMORPHISM; DATABASE AB For analysis of multidrug resistance, a major barrier to effective cancer chemotherapy, we profiled mRNA expression of the 48 known human ABC transporters in 60 diverse cancer cell lines (the NCI-60) used by the National Cancer Institute to screen for anticancer activity. The use of real-time RT-PCR avoided artifacts commonly encountered with microarray technologies. By correlating the results with the growth inhibitory profiles of 1,429 candidate anticancer drugs tested against the cells, we identified which transporters are more likely than others to confer resistance to which agents. Unexpectedly, we also found and validated compounds whose activity is potentiated, rather than antagonized, by the MDR1 multidrug transporter. Such compounds may serve as leads for development. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Div Med Sci, Philadelphia, PA 19111 USA. RP Szakacs, G (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37, Bethesda, MD 20892 USA. EM szakacsg@mail.nih.gov; mgottesman@nih.gov RI Szakacs, Gergely/A-2580-2009 OI Szakacs, Gergely/0000-0002-9311-7827 NR 45 TC 306 Z9 323 U1 2 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG PY 2004 VL 6 IS 2 BP 129 EP 137 DI 10.1016/j.ccr.2004.06.026 PG 9 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 850DR UT WOS:000223591900007 PM 15324696 ER PT J AU Cheng, JC Yoo, CB Weisenberger, DJ Chuang, J Wozniak, C Liang, GN Marquez, VE Greer, S Orntoft, TF Thykjaer, T Jones, PA AF Cheng, JC Yoo, CB Weisenberger, DJ Chuang, J Wozniak, C Liang, GN Marquez, VE Greer, S Orntoft, TF Thykjaer, T Jones, PA TI Preferential response of cancer cells to zebularine SO CANCER CELL LA English DT Article ID MESSENGER-RNA EXPRESSION; DE-NOVO METHYLATION; DNA METHYLTRANSFERASES; INHIBITOR 5-AZA-2'-DEOXYCYTIDINE; CYTIDINE DEAMINASE; PROTEIN-SYNTHESIS; NORMAL-TISSUES; TUMOR-CELLS; 5-AZACYTIDINE; GENE AB The frequent silencing of tumor suppressor genes by altered cytosine methylation and chromatin structural changes makes this process an attractive target for epigenetic therapy. Here we show that zebularine, a stable DNA cytosine methylation inhibitor, is preferentially incorporated into DNA and exhibits greater cell growth inhibition and gene expression in cancer cell lines compared to normal fibroblasts. In addition, zebularine preferentially depleted DNA methyltransferase 1 (DNMT1) and induced expression of cancer-related antigen genes in cancer cells relative to normal fibroblasts. Our results demonstrate that zebularine can be selective toward cancer cells and may hold clinical promise as an anticancer therapy. C1 Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Urol, Los Angeles, CA 90089 USA. Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Biochem, Los Angeles, CA 90089 USA. Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Mol Biol, Los Angeles, CA 90089 USA. NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. Univ Miami, Sch Med, Sylvester Canc Ctr, Dept Microbiol & Immunol, Miami, FL 33136 USA. Univ Miami, Sch Med, Sylvester Canc Ctr, Dept Biochem & Mol Biol, Miami, FL 33136 USA. Univ Miami, Sch Med, Sylvester Canc Ctr, Dept Radiat Oncol, Miami, FL 33136 USA. Aarhus Univ Hosp, Dept Clin Biochem, Mol Diagnost Lab, DK-8200 Aarhus N, Denmark. RP Jones, PA (reprint author), Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Urol, 1441 Eastlake Ave, Los Angeles, CA 90089 USA. EM jones_p@ccnt.hsc.usc.edu OI Liang, Gangning/0000-0001-8664-922X FU NCI NIH HHS [R01 CA 82422, T32 CA09659] NR 43 TC 181 Z9 194 U1 0 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD AUG PY 2004 VL 6 IS 2 BP 151 EP 158 DI 10.1016/j.ccr.2004.06.023 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 850DR UT WOS:000223591900009 PM 15324698 ER PT J AU Dorgan, JF Boakye, NA Fears, TR Schleicher, RL Helsel, W Anderson, C Robinson, J Guin, JD Lessin, S Ratnasinghe, LD Tangrea, JA AF Dorgan, JF Boakye, NA Fears, TR Schleicher, RL Helsel, W Anderson, C Robinson, J Guin, JD Lessin, S Ratnasinghe, LD Tangrea, JA TI Serum carotenoids and alpha-tocopherol and risk of nonmelanoma skin cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BASAL-CELL CARCINOMA; TRANS-BETA-CAROTENE; UNITED-STATES; VITAMIN-E; PREVENTION TRIAL; DNA PHOTODAMAGE; SUBSEQUENT RISK; CLINICAL-TRIAL; FOLLOW-UP; RETINOL AB Background: Carotenoids and tocopherols have been hypothesized to protect against cancer. Methods: We prospectively evaluated associations of several carotenoids and alpha-tocopherol with risk of nonmelanoma skin cancer using serum collected at baseline from 302 subjects in the Isotretinoin-Basal Cell Carcinoma Prevention Trial. All subjects had at least two BCCs in the 5 years prior to randomization. During 5 years of follow-up, 70 subjects did not develop a nonmelanoma skin cancer, 221 developed a BCC, and 85 developed a squamous cell carcinoma (SCC). Cox proportional hazards models were used to estimate risk ratios. Models were stratified by clinical center and gender and adjusted for age, solar damage, skin type, number of prior BCCs and/or SCCs, treatment group, body mass index, and serum low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol. Results: Risk of developing a subsequent BCC was not related to serum levels of any of the carotenoids measured or to alpha-tocopherol. Serum levels of alpha-carotene, beta-carotene, lycopene, and alpha-tocopherol also were not independently related to risk of a subsequent SCC. However, serum lutein, zeaxanthin, and beta-cryptoxanthin were positively related to SCC risk; risk ratios for subjects in the highest versus lowest tertiles of these micronutrients were 1.63 [95% confidence interval (95% Cl) 0.88-3.01; P for trend = 0.011, 2.40 (95% Cl 1.30-4.42; P for trend = 0.01), and 2.15 (95% Cl 1.21-3.83; P for trend = 0.09), respectively. Conclusion: Additional research is needed on the relationship of carotenoids to SCC risk in the general population and in subsets of the population who are at increased risk. C1 Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Temple Univ, Sch Med, Philadelphia, PA 19122 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div Sci Lab, Atlanta, GA USA. Informat Management Serv Inc, Silver Spring, MD USA. Loyola Univ, Cardinal Bernardin Canc Ctr, Maywood, IL 60153 USA. Univ Arkansas Med Sci, Little Rock, AR 72205 USA. US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Dorgan, JF (reprint author), Fox Chase Canc Ctr, 333 Cottman Ave, Philadelphia, PA 19111 USA. EM jf_dorgan@fccc.edu NR 47 TC 24 Z9 26 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2004 VL 13 IS 8 BP 1276 EP 1282 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 844JY UT WOS:000223155500003 PM 15298946 ER PT J AU Wang, SS Trunk, M Schiffman, M Herrero, R Sherman, ME Burk, RD Hildesheim, A Bratti, MC Wright, T Rodriguez, AC Chen, S Reichert, A Doeberitz, CV Ridder, R Doeberitz, MV AF Wang, SS Trunk, M Schiffman, M Herrero, R Sherman, ME Burk, RD Hildesheim, A Bratti, MC Wright, T Rodriguez, AC Chen, S Reichert, A Doeberitz, CV Ridder, R Doeberitz, MV TI Validation of p16(INK4a) as a marker of oncogenic human papillomavirus infection in cervical biopsies from a population-based cohort in Costa Rica SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article; Proceedings Paper CT 20th International Papillomavirus Conference CY OCT 04-09, 2002 CL PARIS, FRANCE ID LIQUID-BASED SPECIMENS; SURROGATE BIOMARKERS; HIGH-RISK; NEOPLASIA; OVEREXPRESSION; CANCER; EXPRESSION; DYSPLASIA; DIAGNOSIS; PROTEIN AB Due to the high prevalence of cancer-associated types of human papillomavirus (HPV) and the poorly reproducible histologic classification of low-grade lesions, identifying infected women at highest risk for cancer prior to neoplastic progression remains a challenge. We therefore explored the utility of p16(INK4), immunostaining as a potential diagnostic and prognostic biomarker for cervical neoplasia using paraffin-embedded tissue blocks (punch biopsies and loop electrosurgical excision procedures) obtained from women referred to colposcopy during the enrollment phase of the Guanacaste Project (1993 to 1994). All blocks from 292 women selected by HPV status (HPV negative, nononcogenic HPV positive, or oncogenic HPV positive) and representing the diagnostic spectrum of the population [normal to precancer: cervical intraepithelial neoplasia WIN) 31 were immunostained for p16(INK4a) using the p16(INK4), research kit based on the monoclonal antibody clone E6H4 (MTM Laboratories, Heidelberg, Germany). For CIN3, the sensitivity of diffuse p16(INK4a), immunostaining was 100% and the specificity was 95%. For CIN2, the sensitivity and specificity for diffuse staining were 81.1% and 95.4%, respectively. Generalized to the 10,000-woman cohort, this translated to positive predictive value and negative predictive value of 13.9% and 100% for CIN3, respectively, and 20.4% and 99.7% for CIN2 or CIN3, respectively. Of women with an initial diagnosis of less than CIN2 for whom follow-up data for up to 5 to 7 years were available, 44% with diffuse staining developed persistent infection (CIN2 or CIN3) Whereas our data support the diagnostic potential for p16(INK4a), further prospective studies with detailed follow-up determining the prognostic capacity of this marker are needed. C1 NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. MTM Labs, Heidelberg, Germany. Proyecto Epidemiol Guanacaste, Guanacaste, Costa Rica. Albert Einstein Coll Med, Bronx, NY 10467 USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. Informat Management Serv Inc, Silver Spring, MD USA. Univ Heidelberg, Inst Mol Pathol, Heidelberg, Germany. RP Wang, SS (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS MSC 7234, Bethesda, MD 20892 USA. EM wangso@mail.nih.gov FU NCI NIH HHS [N01CP31061, N01CP21081, R01CA78527] NR 20 TC 87 Z9 89 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD AUG PY 2004 VL 13 IS 8 BP 1355 EP 1360 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 844JY UT WOS:000223155500015 PM 15298958 ER PT J AU Basile, JR Barac, A Zhu, TQ Guan, KL Gutkind, JS AF Basile, JR Barac, A Zhu, TQ Guan, KL Gutkind, JS TI Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B SO CANCER RESEARCH LA English DT Article ID NUCLEOTIDE EXCHANGE FACTOR; ENDOTHELIAL GROWTH-FACTOR; HETEROTRIMERIC G-PROTEINS; LEUKEMIA-ASSOCIATED RHO; CELL-SURFACE MOLECULE; AXON GUIDANCE; PDZ-RHOGEF; VASCULAR ENDOTHELIUM; BASEMENT-MEMBRANE; INVASIVE GROWTH AB The semaphorins are a large family of secreted and cell surface proteins that provide attractive and repulsive cues for axon guidance during neuronal development. Semaphorins share a conserved NH2-terminal Sema domain with their receptors, the plexins, which mediate neuronal cell adhesion, axon guidance, and maintenance of established neuronal pathways in the adult. Both semaphorins and plexins share structural homology with the extracellular domain of c-Met, a member of the scatter factor family of receptors. However, the highly conserved cytoplasmic region of plexins has no homology with the c-Met tyrosine kinase or with any other known protein. Using a recently developed antibody and RNA analysis, we found that high levels of plexin-B1 are expressed in endothelial cells. Whereas c-Met, with which plexin-B1 can interact, is known to be a potent promoter of angiogenesis, the effects of semaphorin-mediated plexin activation in endothelial cells are still poorly understood. Here, we examined the role of plexin-B1 activation in angiogenesis using a purified, secreted form of its ligand, Semaphorin 4D (Sema4D). Sema4D potently induced chemotaxis and tubulogenesis in endothelial cells and enhanced blood vessel formation in an in vivo mouse model. Interestingly, responses to Sema4D did not require c-Met activation. Instead, the use of chimeric plexin-B1 receptors, Rho inhibitors, and lentiviral gene delivery of interfering molecules revealed that these proangiogenic effects are dependent on a COOH-terminal PDZ-binding motif of plexin-B1, which binds two guanine nucleotide exchange factors for the small GTPase Rho, PDZ-RhoGEF and LARG, and are mediated by the activation of Rho-initiated pathways. C1 NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Univ Michigan, Inst Life Sci, Dept Biol Chem, Ann Arbor, MI 48109 USA. Univ Michigan, Inst Gerontol, Ann Arbor, MI 48109 USA. RP Gutkind, JS (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009; OI Barac, Ana/0000-0002-9935-8904 NR 58 TC 145 Z9 163 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 AUG 1 PY 2004 VL 64 IS 15 BP 5212 EP 5224 DI 10.1158/0008-5472.CAN-04-0126 PG 13 WC Oncology SC Oncology GA 842XO UT WOS:000223038200029 PM 15289326 ER PT J AU Trzeciak, AR Nyaga, SG Jaruga, P Lohani, A Dizdaroglu, M Evans, MK AF Trzeciak, AR Nyaga, SG Jaruga, P Lohani, A Dizdaroglu, M Evans, MK TI Cellular repair of oxidatively induced DNA base lesions is defective in prostate cancer cell lines, PC-3 and DU-145 SO CARCINOGENESIS LA English DT Article ID HUMAN ENDONUCLEASE-III; EXCISION-REPAIR; MISMATCH REPAIR; IN-VITRO; GLYCOSYLASE ACTIVITY; ANTIOXIDANT ENZYMES; THYMINE GLYCOLS; AP-ENDONUCLEASE; FREE-RADICALS; DAMAGED DNA AB Mutagenic oxidative DNA base damage increases with age in prostatic tissue. Various factors may influence this increase including: increased production of reactive oxygen species, increased susceptibility to oxidative stress, alterations in detoxifying enzyme levels or defects in DNA repair. Using liquid chromatography/mass spectrometry and gas chromatography/mass spectrometry, we show increased levels of oxidative DNA base lesions, 8-hydroxyguanine (8-oxoG), 8-hydroxyadenine (8-oxoA) and 5-hydroxycytosine (5OHC) over the baseline in PC-3 and DU-145 prostate cancer cells following exposure to ionizing radiation and a repair period. Nuclear extracts from PC-3 and DU-145 prostate cancer cell lines are defective in the incision of 8-oxoG, 5OHC and thymine glycol (TG) relative to the non-malignant prostate cell line. Consistent with reduced expression of OGG1 2a, incision of 8-oxoG is reduced in PC-3 and DU-145 mitochondrial extracts. We also show a correlation between severely defective incision of TG and 5OHC and reduced levels of NTH1 in PC-3 mitochondria. The antioxidant enzymes, glutathione peroxidase (GPx), catalase and superoxide dismutases (SOD1, SOD2), have altered expression patterns in these cancer cell lines. Genetic analysis of the OGG1 gene reveals that both PC-3 and DU-145 cell lines harbor polymorphisms associated with a higher susceptibility to certain cancers. These data suggest that the malignant phenotype in PC-3 and DU-145 cell lines may be associated with defects in base excision repair and alterations in expression of antioxidant enzymes. C1 NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. Univ Maryland Baltimore Cty, Dept Chem & Biochem Engn, Baltimore, MD 21250 USA. NIST, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. RP Evans, MK (reprint author), NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. EM me42v@nih.gov RI Jaruga, Pawel/M-4378-2015 NR 91 TC 58 Z9 60 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD AUG PY 2004 VL 25 IS 8 BP 1359 EP 1370 DI 10.1093/carcin/bgh144 PG 12 WC Oncology SC Oncology GA 844FJ UT WOS:000223142700006 PM 15044326 ER PT J AU MacGowan, GA Evans, C Hu, TCC Debrah, D Mullet, S Chen, HH McTiernan, CF Stewart, AFR Koretsky, AP Shroff, SG AF MacGowan, GA Evans, C Hu, TCC Debrah, D Mullet, S Chen, HH McTiernan, CF Stewart, AFR Koretsky, AP Shroff, SG TI Troponin I protein kinase C phosphorylation sites and ventricular function SO CARDIOVASCULAR RESEARCH LA English DT Article DE protein kinase C; ventricular function; transgenic animal models; calcium (cellular); phosphorylation; contractile function ID CALCIUM-CHANNEL; RAT-HEART; RELAXATION; CARDIOMYOPATHY AB Objective: Cardiac Troponin I (cTnI) phosphorylation by protein kinase C (PKC) results in a reduction of maximal actomyosin ATPase activity, an effect that is more marked at higher levels of calcium (Ca2+) and is likely to reduce active force development. We postulated that there would be greater Ca2+-dependent changes in ventricular function in hearts of cTnI transgenic (TG) mice expressing mutant troponin I lacking PKC sites compared to wild-type (WT). Methods: We studied left ventricular function in isolated perfused hearts over a wide range of left ventricular volumes (Frank-Starling relationships) and mechanical restitution at three levels of perfusate Ca2+ (1.5, 2.5, and 3.5 mM). Manganese-enhanced magnetic resonance imaging (MRI) was used to study in-vivo sarcolemmal Ca2+ influx. The phosphorylation status of cTnI was examined by western blot analysis. Results: Systolic contractile function in TG mice was altered in a calcium-dependent manner such that ventricular contractility was significantly greater in TG mice only at 3.5 mM perfusate Ca2+. The relaxation process and passive mechanical properties were unaltered in TG mice. Mechanical restitution parameters were abnormal in TG mice only at 1.5 mM perfusate Ca2+. In-vivo MRI data demonstrated up to 48% reduction in Mn2+-induced contrast enhancement, indicating reduced sarcolemmal Ca2+ influx. Western blot analysis indicated increased cTnI phosphorylation in TG mice. Conclusions: (1) TG mice exhibit calcium-dependent positive inotropy without slowed relaxation and this phenotype is mitigated by concomitant (compensatory) changes of reduced intracellular Ca2+ and increased phosphorylation of remaining cTnI sites. (2) The contractile phenotype in TG mice can be interpreted as an amplification of the normal response to changes in cellular Ca2+ observed in WT mice. Thus, PKC phosphorylation sites on cTnI play a role in attenuating contractile responses to changes in intracellular Ca2+. (C) 2004 European Society of Cardiology. Published by Elsevier B.V All rights reserved. C1 Univ Pittsburgh, Dept Bioengn, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Cardiovasc Inst, Pittsburgh, PA 15261 USA. Carnegie Mellon Univ, Pittsburgh NMR Ctr Biomed Res, Pittsburgh, PA 15213 USA. NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20817 USA. RP Shroff, SG (reprint author), Univ Pittsburgh, Dept Bioengn, 749 Benedum Hall, Pittsburgh, PA 15261 USA. EM sshroff@pitt.edu RI Stewart, Alexandre/A-5677-2011; Koretsky, Alan/C-7940-2015; OI Koretsky, Alan/0000-0002-8085-4756; Stewart, Alexandre/0000-0003-2673-9164 FU Intramural NIH HHS [Z01 NS002989-08]; NHLBI NIH HHS [HL-03826, HL-68083] NR 19 TC 21 Z9 21 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD AUG 1 PY 2004 VL 63 IS 2 BP 245 EP 255 DI 10.1016/j.cardiores.2004.04.010 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 841PG UT WOS:000222942500009 PM 15249182 ER PT J AU Zemkova, H Balik, A Kretschmannova, K Mazna, P Stojilkovic, SS AF Zemkova, H Balik, A Kretschmannova, K Mazna, P Stojilkovic, SS TI Recovery of Ins(1,4,5)-trisphosphate-dependent calcium signaling in neonatal gonadotrophs SO CELL CALCIUM LA English DT Article ID INDUCED CA2+ OSCILLATIONS; PITUITARY GONADOTROPHS; HORMONE RECEPTOR; INTRACELLULAR CA-2+; CYTOPLASMIC CALCIUM; ANTERIOR-PITUITARY; CELLS; DESENSITIZATION; MELATONIN; CHANNELS AB Pituitary gonadotrophs express non-desensitizing gonadotropin-releasing hormone (GnRH) receptors and their activations leads to inositol 1,4,5-trisphosphate (InSP3)-dependent Ca2+ mobilization. When added in physiological concentration range GnRH induces baseline Ca2+ oscillations, whereas in higher concentrations it induces a prolonged spike response accompanied with non-oscillatory or oscillatory plateau response. Here, we studied the recovery of calcium signaling during repetitive stimulation with short (10-30s) GnRH pulses and variable interpulse intervals in neonatal gonadotrophs perfused with Ca2+/Na+-containing, Ca2+-deficient/Na+-containing, and Ca2+-containing/Na+-deficient media. In Ca2+/Na+-containing medium, baseline Ca2+ oscillations recovered without refractory period and with a time constant of similar to20 s, whereas the recovery of spike response occurred after 25-35 s refractory period and with a time constant of similar to30 s. During repetitive GnRH stimulation, removal of Ca2+ had only a minor effect on baseline oscillations but abolished spike response, whereas removal of Na+ slightly extended duration of baseline oscillations and considerably prolonged spike response. These results indicate that two calcium handling mechanisms are operative in gonadotrophs: redistribution of calcium within InsP(3)-sensitive and -insensitive pools and a sodium-dependent calcium efflux followed by calcium influx. Redistribution of Ca2+ within the cell leads to rapid recovery of InsP(3)-dependent pool, whereas the Na+-dependent Ca2+ efflux pathway is activated by spike response and limits the time of exposure to elevated cytosolic Ca2+ concentrations. (C) 2004 Elsevier Ltd. All rights reserved. C1 Acad Sci Czech Republ, Inst Physiol, CR-14220 Prague 4, Czech Republic. NICHD, ERRB, Sect Cellular Signaling, NIH, Bethesda, MD USA. RP Zemkova, H (reprint author), Acad Sci Czech Republ, Inst Physiol, Videnska 1083, CR-14220 Prague 4, Czech Republic. EM zemkova@biomed.cas.cz RI Zemkova, Hana/C-1844-2012; Balik, Ales/C-1900-2012 NR 40 TC 7 Z9 7 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 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD AUG PY 2004 VL 36 IS 2 BP 89 EP 97 DI 10.1016/j.ceca.2003.12.003 PG 9 WC Cell Biology SC Cell Biology GA 839GD UT WOS:000222770700001 PM 15193857 ER PT J AU Voeller, D Rahman, L Zajac-Kaye, M AF Voeller, D Rahman, L Zajac-Kaye, M TI Elevated levels of thymidylate synthase linked to neoplastic transformation of mammalian cells SO CELL CYCLE LA English DT Article DE thymidylate synthase; cellular transformation; apoptosis; E2F-1 ID PROGNOSTIC IMPORTANCE; EXPRESSION; CANCER; 5-FLUOROURACIL; RNA; RESISTANCE; ONCOGENE; PROTEIN; GENE; E2F AB Thymidylate synthase (TS), an enzyme that is essential for DNA synthesis and repair has been identified as an important biomarker for colorectal and other human cancers. The elevated steady-state levels of TS found in many common human malignancies have been thought to represent a secondary event in tumor formation. However, it has recently been demonstrated that the deregulated levels of ectopic TS may also have a causal effect on tumorgenesis since overexpression of human TS transforms immortalized mammalian cells to a malignant phenotype. Since the levels of TS are regulated by E2F-1 and thus are linked to the cell cycle pathway, regulating TS activity may be an important factor for the control of cell cycle progression and for the development of therapeutic strategies and cancer prevention. C1 NCI, Mol Therapeut Program, NIH, Bethesda, MD 20889 USA. RP Zajac-Kaye, M (reprint author), NCI, Mol Therapeut Program, NIH, Bldg 10,Rm 1B49, Bethesda, MD 20889 USA. EM kayem@exchange.nih.gov NR 21 TC 17 Z9 18 U1 1 U2 2 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD AUG PY 2004 VL 3 IS 8 BP 1005 EP 1007 PG 3 WC Cell Biology SC Cell Biology GA 857AW UT WOS:000224088700011 PM 15280655 ER PT J AU Jeong, MH Jin, YH Kang, EY Jo, WS Park, HT Lee, JD Yoo, YJ Jeong, SJ AF Jeong, MH Jin, YH Kang, EY Jo, WS Park, HT Lee, JD Yoo, YJ Jeong, SJ TI The modulation of radiation-induced cell death by genistein in K562 cells: Activation of thymidine kinase 1 SO CELL RESEARCH LA English DT Article DE K562; radiation; cell death; genistein; thymidine kinase 1; cell cycle ID MAMMALIAN-CELLS; GROWTH ARREST; CANCER CELLS; TUMOR-MARKER; SENESCENCE; EXPRESSION; IRRADIATION; INHIBITORS; APOPTOSIS; LEUKEMIA AB Ionizing radiation is one of the most effective tools in cancer therapy. In a previous study, we reported that protein tyrosine kinase (PTK) inhibitors modulate the radiation responses in the human chronic myelogenous leukemia (CML) cell line K562. The receptor tyrosine kinase inhibitor, genistein, delayed radiation-induced cell death, while non-recepter tyrosine kinase inhibitor, herbimycin A (HMA) enhances radiation-induced apoptosis. In this study, we focused on the modulation of radiation-induced cell death by genistein and performed PCR-select suppression subtractive hybridization (SSH) to understand its molecular mechanism. We identified human thymidine kinase 1 (TK1), which is cell cycle regulatory gene and confirmed expression of TK1 mRNA by Northern blot analysis. Expression of TK1 mRNA and TK1 enzymatic activity were parallel in their increase and decrease. TK1 is involved in G1-S phase transition of cell cycle progression. In cell cycle analysis, we showed that radiation induced G2 arrest in K562 cells but it was not able to sustain. However, the addition of genistein to irradiated cells sustained a prolonged G2 arrest up to 120 h. In addition, the expression of cell cycle-related proteins, cyclin A and cyclin B1, provided the evidences of G1/S progression and G2-arrest, and their relationship with TK1 in cells treated with radiation and genistein. These results suggest that the activation of TK1 may be critical to modulate the radiation-induced cell death and cell cycle progression in irradiated K562 cells. C1 Dong A Univ, Coll Med, BK Program 21, Res Support Ctr Med Sci, Pusan, South Korea. Pusan Natl Univ, Dept Microbiol, Pusan, South Korea. NCI, Virus Tumor Biol Sect, Cellular Oncol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Jeong, SJ (reprint author), Dong A Univ, Coll Med, BK Program 21, Res Support Ctr Med Sci, Pusan, South Korea. EM jeongs@mail.nih.gov NR 33 TC 15 Z9 18 U1 0 U2 2 PU SCIENCE CHINA PRESS PI BEIJING PA 16 DONGHUANGCHENGGEN NORTH ST, BEIJING 100717, PEOPLES R CHINA SN 1001-0602 J9 CELL RES JI Cell Res. PD AUG PY 2004 VL 14 IS 4 BP 295 EP 302 DI 10.1038/sj.cr.7290230 PG 8 WC Cell Biology SC Cell Biology GA 853PJ UT WOS:000223839200004 PM 15353126 ER PT J AU Agnati, LF Ferre, S Leo, G Lluis, C Canela, EI Franco, R Fuxe, K AF Agnati, LF Ferre, S Leo, G Lluis, C Canela, EI Franco, R Fuxe, K TI On the molecular basis of the receptor mosaic hypothesis of the engram SO CELLULAR AND MOLECULAR NEUROBIOLOGY LA English DT Article DE receptor-receptor interactions; receptor oligomerization; molecular networks ID CENTRAL-NERVOUS-SYSTEM; COTRANSFECTED FIBROBLAST CELLS; PROTEIN-COUPLED RECEPTORS/; ADENOSINE A(1) RECEPTORS; DOPAMINE D-1 RECEPTORS; NUCLEAR-LOCALIZATION; MODULATION; PROTEOMICS; DEAMINASE; BRAIN AB 1. This paper revisits the so-called "receptor mosaic hypothesis" for memory trace formation in the light of recent findings in "functional ( or interaction) proteomics." The receptor mosaic hypothesis maintains that receptors may form molecular aggregates at the plasma membrane level representing part of the computational molecular networks. 2. Specific interactions between receptors occur as a consequence of the pattern of transmitter release from the source neurons, which release the chemical code impinging on the receptor mosaics of the target neuron. Thus, the decoding of the chemical message depends on the receptors forming the receptor mosaics and on the type of interactions among receptors and other proteins in the molecular network with novel long-term mosaics formed by their stabilization via adapter proteins formed in target neurons through the incoming neurotransmitter code. The internalized receptor heteromeric complexes or parts of them may act as transcription factors for the formation of such adapter proteins. 3. Receptor mosaics are formed both at the pre- and postsynaptic level of the plasma membranes and this phenomenon can play a role in the Hebbian behavior of some synaptic contacts. The appropriate "matching" of the pre- with the postsynaptic receptor mosaic can be thought of as the "clamping of the synapse to the external teaching signal." According to our hypothesis the behavior of the molecular networks at plasma membrane level to which the receptor mosaics belong can be set in a "frozen" conformation (i.e. in a frozen functional state) and this may represent a mechanism to maintain constant the input to a neuron. 4. Thus, we are suggesting that molecular networks at plasma membrane level may display multiple "attractors" each of which stores the memory of a specific neurotransmitter code due to a unique firing pattern. Hence, this mechanism may play a role in learning processes where the input to a neuron is likely to remain constant for a while. C1 Univ Modena, Dept Biomed Sci, I-41100 Modena, Italy. NIDA, Preclin Pharmacol Sect, NIH, IRP,DHHS, Baltimore, MD USA. Univ Barcelona, Dept Biochem & Mol Biol, Barcelona, Spain. Karolinska Inst, Dept Neurosci, Stockholm, Sweden. RP Agnati, LF (reprint author), Univ Modena, Dept Biomed Sci, Via Campi 287, I-41100 Modena, Italy. EM agnati@tin.it RI Canela, Enric I./M-8726-2013; Ferre, Sergi/K-6115-2014; Franco, Rafael/C-3694-2015; OI Canela, Enric I./0000-0003-4992-7440; Ferre, Sergi/0000-0002-1747-1779; Franco, Rafael/0000-0003-2549-4919; Fuxe, Kjell/0000-0001-8491-4288 NR 51 TC 25 Z9 25 U1 0 U2 3 PU KLUWER ACADEMIC/PLENUM PUBL PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0272-4340 J9 CELL MOL NEUROBIOL JI Cell. Mol. Neurobiol. PD AUG PY 2004 VL 24 IS 4 BP 501 EP 516 DI 10.1023/B:CEMN.0000023626.35717.5d PG 16 WC Cell Biology; Neurosciences SC Cell Biology; Neurosciences & Neurology GA 812CS UT WOS:000220818200002 PM 15233375 ER PT J AU Taub, DD Mikovits, JA Nilsson, G Schaffer, EM Key, ML Petrow-Sadowski, C Ruscetti, FW AF Taub, DD Mikovits, JA Nilsson, G Schaffer, EM Key, ML Petrow-Sadowski, C Ruscetti, FW TI Alterations in mast cell function and survival following in vitro infection with human immunodeficiency viruses-1 through CXCR4 SO CELLULAR IMMUNOLOGY LA English DT Article DE mast cells; HIV; AIDS; hypersensitivity; X4 HIV infection; gp120; histamine release; cell death; CXCR4; CCR5; chemokine ID EPSILON-RI+ CELLS; CHEMOKINE RECEPTORS; AIDS PATIENTS; BASOPHIL LEUKOCYTES; CYTOKINE EXPRESSION; INDUCED RELEASE; HIV-INFECTION; HISTAMINE; BLOOD; LIGAND AB HIV-1 infection leads to a disease that attacks the central regulatory mechanisms of the immune response. As mucosal tissue is one of the primary sites infected with HIV in vivo, we examined the effects of HIV exposure on human mast cells, important components of mucosal defense. Using the human mast cell line, HMC-1, which expresses CXCR4 but not CCR5 on the cell surface, we found that several HIV-1 X4 tropic lab (IIIB, RF) and primary isolates but not R5 (BAL, ADA) isolates productively infected these cells. Furthermore, stem cell factor-dependent mast cells derived from primary fetal liver or cord blood cultures were also productively infected with both X4 and R5 HIV-1 strains. Infection was blocked at the level of viral entry using monoclonal antibodies to CXCR4 and CD4. Treatment of HMC-1 with TNF-alpha and TGF-beta stimulated cell surface expression of CCR5 and up-regulated expression of both CCR5 and CXCR4 on primary mast cells, leading to increased susceptibility to both X4 and R5 viral isolates. HIV-1 infection also resulted in histamine release from these mast cells, most due in part to HIV-mediated cell death. These results demonstrate that X4 viruses can use CD4 and the CXCR4 receptor to infect mast cells, suggesting that mast cell-T cell interactions may contribute to HIV mediated immune dysfunction in the mucosa. Published by Elsevier Inc. C1 NIA, Clin Immunol Sect, Immunol Lab, NIH, Baltimore, MD 21224 USA. NCI, Intramural Res Support Program, SAIC Frederick, Frederick Canc Res & Dev Program, Frederick, MD USA. Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden. NCI, FCRDC, Lab Leukocyte Biol, Frederick, MD USA. RP Taub, DD (reprint author), NIA, Clin Immunol Sect, Immunol Lab, NIH, Baltimore, MD 21224 USA. EM Taubd@grc.nia.nih.gov OI Nilsson, Gunnar/0000-0001-6795-5512 FU NCI NIH HHS [N01-CO-56000] NR 59 TC 15 Z9 16 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 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD AUG PY 2004 VL 230 IS 2 BP 65 EP 80 DI 10.1016/j.cellimm.2004.09.005 PG 16 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 884TX UT WOS:000226110400001 PM 15598422 ER PT J AU Sechler, JM Barlic, J Grivel, JC Murphy, PM AF Sechler, JM Barlic, J Grivel, JC Murphy, PM TI IL-15 alters expression and function of the chemokine receptor CX3CR1 inhuman NK cells SO CELLULAR IMMUNOLOGY LA English DT Article DE cytokine; IL-15; chemokine; fractalkine; human NK cell; CX3CR1 ID NATURAL-KILLER-CELLS; DEPENDENT CELLULAR CYTOTOXICITY; INTERLEUKIN (IL)-15; IN-VIVO; CRESCENTIC GLOMERULONEPHRITIS; FRACTALKINE CX3CL1; LYMPHOCYTES; CX(3)CR1; ADHESION; IDENTIFICATION AB The chemokine receptor CX3CR1 is thought to regulate inflammation in part by modulating NK cell adhesion, migration, and killing in response to its ligand CX3CL1 (fractalkine). Recent reports indicate that IL-15, which is essential for development and survival of NK cells; may negatively regulate CX3CR1 expression, however, the effects of the cytokine on human NK cell CX3CR1 expression and function have not been fully delineated. Here, we demonstrate that short term culture in IL-15 decreases surface expression of CX3CR1 on cultured CD56(+) cells from human blood resulting in diminished chemotaxis and calcium flux in response to CX3CL1. Cells cultured long term in IL-15 (more than five days) completely lost surface expression as well as mRNA and protein for CX3CR1. The effect was specific since mRNA for CCR5 was increased and mRNA for CXCR4 was unchanged in these cells by IL-15. Thus, exogenous IL-15 is a negative regulator of CX3CR1 expression and function in human CD56(+) NK cells. The data imply that the use of IL-15 alone to expand NK cells ex vivo for immunotherapy may produce cells impaired in their ability to traffic to sites of inflammation. Published by Elsevier Inc. C1 NIAID, Mol Signaling Sect, Host Def Lab, Bethesda, MD 20892 USA. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Murphy, PM (reprint author), NIAID, Mol Signaling Sect, Host Def Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pmm@nih.gov NR 42 TC 16 Z9 18 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 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD AUG PY 2004 VL 230 IS 2 BP 99 EP 108 DI 10.1016/j.cellimm.2004.10.001 PG 10 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 884TX UT WOS:000226110400004 PM 15598425 ER PT J AU Vuong, C Durr, M Carmody, AB Peschel, A Klebanoff , SJ Otto, M AF Vuong, C Durr, M Carmody, AB Peschel, A Klebanoff , SJ Otto, M TI Regulated expression of pathogen-associated molecular pattern molecules in Staphylococcus epidermidis: quorum-sensing determines pro-inflammatory capacity and production of phenol-soluble modulins SO CELLULAR MICROBIOLOGY LA English DT Article ID VIRULENCE FACTORS; JOINT PROSTHESES; NEUTROPHILS; INFECTIONS; STRAINS AB Phenol-soluble modulin (PSM) is a peptide complex produced by the nosocomial pathogen Staphylococcus epidermidis that has a strong capacity to activate the human innate immune response. We developed a novel method based on liquid chromatography-mass spectrometry (LC-MS) to quantify the production of the individual PSM components. Each PSM peptide was abundant in most of the 76 S epidermidis strains tested. Importantly, none of the PSM components were secreted by an agr mutant strain, indicating that PSM synthesis is regulated strictly by the agr quorum-sensing system. Furthermore, the agr mutant strain failed to elicit production of TNFalpha by human myeloid cells and induced significantly less neutrophil chemotaxis compared with the wild-type strain. Thus, quorum-sensing in S. epidermidis dramatically influenced activation of human host defence. We propose that an agr quorum-sensing mechanism facilitates growth and survival in infected hosts by adapting production of the pro-inflammatory PSMs to the stage of infection. C1 NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Univ Tubingen, D-72076 Tubingen, Germany. Univ Washington, Dept Med, Seattle, WA 98195 USA. RP Otto, M (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM motto@niaid.nih.gov NR 26 TC 79 Z9 86 U1 1 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD AUG PY 2004 VL 6 IS 8 BP 753 EP 759 DI 10.1111/j.1462-5822.2004.00401.x PG 7 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 835EB UT WOS:000222462200006 PM 15236642 ER PT J AU Jeng, RL Goley, ED D'Alessio, JA Chaga, OY Svitkina, TM Borisy, GG Heinzen, RA Welch, MD AF Jeng, RL Goley, ED D'Alessio, JA Chaga, OY Svitkina, TM Borisy, GG Heinzen, RA Welch, MD TI A Rickettsia WASP-like protein activates the Arp2/3 complex and mediates actin-based motility SO CELLULAR MICROBIOLOGY LA English DT Article ID LISTERIA-MONOCYTOGENES; SHIGELLA-FLEXNERI; DENDRITIC ORGANIZATION; ENA/VASP PROTEINS; VERO CELLS; F-ACTIN; NUCLEATION; POLYMERIZATION; PROFILIN; MOVEMENT AB Spotted fever group Rickettsia are obligate intracellular pathogens that exploit the host cell actin cytoskeleton to promote motility and cell-to-cell spread. Although other pathogens such as Listeria monocytogenes use an Arp2/3 complex-dependent nucleation mechanism to generate comet tails consisting of Y-branched filament arrays, Rickettsia polymerize tails consisting of unbranched filaments by a previously unknown mechanism. We identified genes in several Rickettsia species encoding proteins (termed RickA) with similarity to the WASP family of Arp2/3-complex activators. Rickettsia rickettsii RickA activated both the nucleation and Y-branching activities of the Arp2/3 complex like other WASP-family proteins, and was sufficient to direct the motility of microscopic beads in cell extracts. Actin tails generated by RickA-coated beads consisted of Y-branched filament networks. These data suggest that Rickettsia use an Arp2/3 complex-dependent actin-nucleation mechanism similar to that of other pathogens. We propose that additional Rickettsia or host factors reorganize the Y-branched networks into parallel arrays in a manner similar to a recently proposed model of filopodia formation. C1 Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. Northwestern Univ, Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. Univ Penn, Dept Biol, Philadelphia, PA 19104 USA. NIAID, Lab Intracellular Parasites, NIH, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Welch, MD (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. EM welch@berkeley.edu OI Borisy, Gary/0000-0002-0266-8018; Goley, Erin/0000-0002-8518-2303 FU NIGMS NIH HHS [R01 GM059609, R01 GM059609-05] NR 44 TC 80 Z9 84 U1 0 U2 6 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD AUG PY 2004 VL 6 IS 8 BP 761 EP 769 DI 10.1111/j.1462-5822.2004.00402.x PG 9 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 835EB UT WOS:000222462200007 PM 15236643 ER PT J AU Zhou, JH Zhong, Y AF Zhou, Juhua Zhong, Yin TI Breast Cancer Immunotherapy SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Review DE breast cancer; antibody based immunotherapy; cancer vaccine; adoptive T cell transfer; T cell receptor; gene transfer immunotherapy AB Breast cancer is a leading cause of cancer-related deaths in women worldwide. Although tumorectomy, radiotherapy, chemotherapy and hormone replacement therapy have been used for the treatment of breast cancer, there is no effective therapy for patients with invasive and metastatic breast cancer. Immunotherapy may be proved effective in treating patients with advanced breast cancer. Breast cancer immunotherapy includes antibody based immunotherapy, cancer vaccine immunotherapy, adoptive T cell transfer immunotherapy and T cell receptor gene transfer immunotherapy. Antibody based immunotherapy such as the monoclonal antibody against HER-2/neu (trastuzumab) is successfully used in the treatment of breast cancer patients with over-expressed HER-2/neu, however, HER-2/neu is over-expressed only in 25-30% of breast cancer patients. Cancer vaccine immunotherapy is a promising method to treat cancer patients. Cancer vaccines can be used to induce specific anti-tumor immunity in breast cancer patients, but cannot induce objective tumor regression. Adoptive T cell transfer immunotherapy is an effective method in the treatment of melanoma patients. Recent advances in anti-tumor T cell generation ex vivo and limited clinical trial data have made the feasibility of adoptive T cell transfer immunotherapy in the treatment of breast cancer patients. T cell receptor gene transfer can redirect the specificity of T cells. Chimeric receptor, scFv(anti-HER-2/neu)/zeta receptor, was successfully used to redirect cytotoxic T lymphocyte hybridoma cells to obtain anti-HER-2/neu positive tumor cells, suggesting the feasibility of treatment of breast cancer patients with T cell receptor gene transfer immunotherapy. Clinical trials will approve that immunotherapy is an effective method to cure breast cancer disease in the near future. C1 [Zhou, Juhua; Zhong, Yin] NCI, NIH, Bethesda, MD 20892 USA. RP Zhou, JH (reprint author), NCI, Surg Branch, NIH, Room 2B42,Bldg 10,9000 Rockville Pike, Bethesda, MD 20892 USA. EM juhua_zhou@nih.gov NR 79 TC 21 Z9 22 U1 2 U2 8 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD AUG PY 2004 VL 1 IS 4 BP 247 EP 255 PG 9 WC Immunology SC Immunology GA V32AG UT WOS:000208923500002 PM 16225767 ER PT J AU Wang, E Panelli, MC Monsurro, V Marincola, FM AF Wang, Ena Panelli, Monica C. Monsurro, Vladia Marincola, Francesco M. TI A Global Approach to Tumor Immunology SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Review DE tumor immunology; cDNA arrays; genetic profiling; vaccination; melanoma AB Biological and clinical advances in the understanding of tumor immunology suggest that immune responsiveness of human tumors is a complex biological phenomenon that could be best studied by a real-time comparison of tumor/ host interactions in the tumor microenvironment through a high-throughput discovery-driven approach. This conclusion is derived from our recognition that too many hypotheses or, in other words, no solid single hypothesis exist, based on experimental results, to further drive experimentation in human subjects. Functional genomic studies entertained during the last few years consolidated the belief that in humans the interactions between tumor and immune cells are too complex to be approached exclusively with a hypothesis driven method. We believe that immune cells suit cancer cells in a Yin and Yang balance by opposing and yet mutually depending on each other. Indeed, immune infiltration in tumors may play a dual role modulating in different circumstances cancer cell growth or destruction through a physiological modulation of inflammation. It is reasonable to question what induces inflammation at the tumor site. We hypothesize that inflammation is primarily driven by the phenotype of tumor cells that can modulate their microenvironment through cell-to-cell interactions or the secretion of soluble factors. Thus, in analogy the observation of immune cells within tumors parallels the presence of paramedics, police and firemen at the scene of an accident, which is reactive to and not causative of the occurrence. In this review we will explore this hypothesis by reporting and summarizing most of our recent work in the frame of available literature on the subject. C1 [Wang, Ena; Panelli, Monica C.; Monsurro, Vladia; Marincola, Francesco M.] NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Wang, E (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM EWang@mail.cc.nih.gov NR 85 TC 18 Z9 23 U1 0 U2 0 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD AUG PY 2004 VL 1 IS 4 BP 256 EP 265 PG 10 WC Immunology SC Immunology GA V32AG UT WOS:000208923500003 PM 16225768 ER PT J AU Merigan, WH Saunders, RC AF Merigan, WH Saunders, RC TI Unilateral deficits in visual perception and learning after unilateral inferotemporal cortex lesions in macaques SO CEREBRAL CORTEX LA English DT Article DE color; inferotemporal cortex; learning; matching; macaque; shape ID INFERIOR TEMPORAL NEURONS; RHESUS-MONKEYS; CORTICAL MAGNIFICATION; MOTION PERCEPTION; CEREBRAL-CORTEX; AREA V4; DISCRIMINATION; MEMORY; RESPONSES; STIMULI AB This study adapted the method of partial lesions, combined with controlled fixation, to study the perceptual role of macaque inferotemporal (IT) cortex. Unilateral lesions were made in IT cortex of three monkeys, without section of the corpus callosum, and visual function was tested ipsilateral and contralateral to the lesion. The observed changes were compared to the effects of bilateral lesions of IT cortex in one monkey, the approach used in most previous studies. Unilateral lesions produced far less profound, although more selective, loss on the tested visual abilities than did bilateral lesions. All three monkeys with unilateral lesions showed decreased chromatic sensitivity, but sparing of achromatic sensitivity, and severely disrupted learning and performance of visual matching to sample, and in all cases, the visual loss was contralateral to the site of the lesion. Unexpectedly, the magnitude of the contralateral loss was not increased by later section of the corpus callosum and anterior commissure in one of the monkeys, a lesion that removes interhemisperic input to contralateral from ipsilateral temporal cortex neurons. These results support physiological findings that show that the response of IT cortex neurons is dominated by the contralateral visual field, despite the bilateral activation many IT neurons receive. Comparison to earlier studies of lesions of area V4, which provides input to IT cortex, shows that V4 and IT lesions produce qualitatively different effects. C1 Univ Rochester, Med Ctr, Dept Ophthalmol, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Ctr Visual Sci, Rochester, NY 14642 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Merigan, WH (reprint author), Univ Rochester, Med Ctr, Dept Ophthalmol, Box 314, Rochester, NY 14642 USA. EM billm@cvs.rochester.edu OI Merigan, William/0000-0002-9359-5538 FU NEI NIH HHS [P30 EY01319, EY00898] NR 52 TC 12 Z9 12 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD AUG PY 2004 VL 14 IS 8 BP 863 EP 871 DI 10.1093/cercor/bhh045 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 836NT UT WOS:000222563300006 PM 15115739 ER PT J AU Dalley, JW Theobald, DE Bouger, P Chudasama, Y Cardinal, RN Robbins, TW AF Dalley, JW Theobald, DE Bouger, P Chudasama, Y Cardinal, RN Robbins, TW TI Cortical cholinergic function and deficits in visual attentional performance in rats following 192 IgG-saporin-induced lesions of the medial prefrontal cortex SO CEREBRAL CORTEX LA English DT Article DE 192 IgG-saporin; acetylcholine; five-choice serial reaction time task; impulsivity; medial prefrontal cortex; muscarinic receptors; visual attention ID SERIAL REACTION-TIME; NUCLEUS BASALIS MAGNOCELLULARIS; CEREBRAL-CORTEX; ACETYLCHOLINE-RELEASE; ALZHEIMERS-DISEASE; NGF RECEPTOR; SELECTIVE IMMUNOLESIONS; FOREBRAIN NEURONS; DIVIDED ATTENTION; FRONTAL-CORTEX AB Lesions of the basal forebrain (BF) cortical cholinergic system impair performance on a rodent five-choice visual attentional task. This study examines the effects on the same task of selective depletion of acetylcholine from the prefrontal cortex (PFC) using 192 IgG-saporin, the cholinergic immunotoxin. Rats were trained to detect brief visual stimuli, either presented unpredictably both temporally and spatially to increase attentional load, or under less demanding conditions where stimuli were temporally and spatially predictable. Following training, 192 IgG-saporin (50 ng or 100 ng/infusion) or its vehicle was infused bilaterally into the ventromedial PFC. The 100 ng lesion group exhibited post-operatively a transient increase in perseveration, specifically when the visual stimuli were temporally unpredictable. A vigilance decrement, as well as a reinstatement of perseverative responding occurred in both lesion groups under conditions of enhanced attentional load, specifically with high target frequency sustained over many trials. Lesioned subjects were also more impulsive with increased anticipatory errors. Systemic administration of the muscarinic receptor antagonist scopolamine further dissociated the groups with attentional accuracy in the 100 ng group decreasing relative to shams. These findings are consistent with an important modulatory influence of PFC function by BF cholinergic neurons, particularly during increased attentional demand. C1 Univ Cambridge, Dept Expt Psychol, Cambridge CB2 3EB, England. NIMH, NIH, Lab Neuropsychol, Bethesda, MD 20892 USA. RP Dalley, JW (reprint author), Univ Cambridge, Dept Expt Psychol, Downing St, Cambridge CB2 3EB, England. EM jwd20@cus.cam.ac.uk NR 60 TC 100 Z9 101 U1 0 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD AUG PY 2004 VL 14 IS 8 BP 922 EP 932 DI 10.1093/cercor/bhh052 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 836NT UT WOS:000222563300012 PM 15084496 ER PT J AU Fox, NL Hoogwerf, BJ Czajkowski, S Lindquist, R Dupuis, G Herd, JA Campeau, L Hickey, A Barton, FB Terrin, ML AF Fox, NL Hoogwerf, BJ Czajkowski, S Lindquist, R Dupuis, G Herd, JA Campeau, L Hickey, A Barton, FB Terrin, ML CA POST CABG Study Invest TI Quality of life after coronary artery bypass graft - Results from the POST CABG trial SO CHEST LA English DT Article DE anticoagulants; coronary artery bypass; health-related quality of life; lipid-lowering therapy ID DENSITY-LIPOPROTEIN CHOLESTEROL; SCANDINAVIAN SIMVASTATIN SURVIVAL; LOW-DOSE ANTICOAGULATION; PRIMARY-PREVENTION TRIAL; PLACEBO-CONTROLLED TRIAL; HEART-DISEASE; RANDOMIZED TRIAL; FOLLOW-UP; MEN; WOMEN AB Objectives: The POST CABG (Post Coronary Artery Bypass Graft) Trial showed that aggressive lowering of low-density lipoprotein (LDL) cholesterol levels reduced the progression of atherosclerosis in saphenous vein grafts. In the extended follow-up phase, aggressive lowering of LDL cholesterol levels was associated with reduced rates of clinical events. Low-dose anticoagulation therapy did not reduce the progression of atherosclerosis. We conducted this analysis to determine the effects of both lipid-lowering and low-dose anticoagulation therapy on health-related quality of life (HRQL). Design: Randomized clinical trial, factorial design. Setting: Outpatients in five tertiary care medical centers. Patients: A cohort of 852 patients enrolled in the POST CABG Trial completed an HRQL questionnaire at baseline, and at the year 2 and year 4 follow-up visits. Intervention: Aggressive LDL cholesterol lowering vs moderate LDL cholesterol lowering, and low-dose warfarin vs placebo. Measurements: Domains included emotional status, basic physical and social functioning, perceived health status, symptoms of pain, a variety of physical symptoms, and global life satisfaction. Results: Overall, there were no indications of systematic differences among treatment groups for any of the HRQL parameters at baseline, year 2, or year 4. Conclusions: These data indicate that patients did not experience detrimental or beneficial effects on HRQL parameters while receiving LDL cholesterol-lowering therapy that had demonstrable benefits for treatment of atherosclerosis. C1 Human Genome Sci Inc, Rockville, MD 20850 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. NHLBI, Bethesda, MD 20892 USA. Univ Minnesota, Minneapolis, MN USA. Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. Baylor Coll Med, Houston, TX 77030 USA. Maryland Med Res Inst, Baltimore, MD USA. RP Fox, NL (reprint author), Human Genome Sci Inc, Rockville, MD 20850 USA. EM normalynn_fox@HGSI.com FU NHLBI NIH HHS [N01-HC-75075, N01-HC-75072, N01-HC-75073, N01-HC-75076, N01-HC-75074, N01-HC-75071] NR 36 TC 11 Z9 12 U1 2 U2 2 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD AUG PY 2004 VL 126 IS 2 BP 487 EP 495 DI 10.1378/chest.126.2.487 PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 846CZ UT WOS:000223293900029 PM 15302735 ER PT J AU Porto, AF Santos, SB Alcantara, L Guerreiro, JB Passos, J Gonzalez, T Neva, F Gonzalez, D Ho, JL Carvalho, EM AF Porto, AF Santos, SB Alcantara, L Guerreiro, JB Passos, J Gonzalez, T Neva, F Gonzalez, D Ho, JL Carvalho, EM TI HTLV-1 modifies the clinical and immunological response to schistosomiasis SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE HTLV-1; schistosomiasis; liver fibrosis ID VIRUS TYPE-I; STRONGYLOIDES-STERCORALIS HYPERINFECTION; T-CELL LEUKEMIA; GRANULOMA-FORMATION; MANSONI INFECTION; INTERFERON-GAMMA; TYPE-1 INFECTION; IMMUNE-RESPONSE; IGE RESPONSES; EXPRESSION AB The immunological response in HTLV-1 infected individuals is characterized by a prominent Type-1 cytokine response with high production of IFN-gamma and TNF-alpha. In contrast, helminthic infections and in particular chronic schistosomiasis are associated with a predominant production of IL-4, IL-5, IL-10 and IL-13. Liver fibrosis is the main pathological finding in schistosomiasis that occurs after many years of infection. This pathology is T cell dependent but the immune response mechanisms are not completely understood. The North-east region of Brazil is endemic for both HTLV-1 and schistosomiasis. In the present study the immune response, clinical severity, and therapeutic response to praziquantel of patients with schistosomiasis coinfected with HTLV-1 were compared with patients infected only with S. mansoni. Patients with HTLV-1 and S. mansoni had lower levels of IL-5 (P < 0.05) and higher levels of IFN-gamma (P < 0.05) in cultures stimulated with S. mansoni antigen and decreased S. mansoni antigen specific IgE levels when compared with patients with schistosomiasis without HTLV-1 coinfection. Liver fibrosis was mild in all HTLV-1 coinfected patients and efficacy of praziquantel was lower in patients dually infected than in patients infected only with S. mansoni. C1 Hosp Univ Prof Edgard Santos, Serv Imunol, Lab Imunol, BR-40110160 Salvador, BA, Brazil. Univ Fed Bahia, Fac Farm, Parasitol Lab, Salvador, BA, Brazil. Clin Ultrassonog Delfin, Salvador, BA, Brazil. NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. Cornell Univ, Weill Med, New York, NY USA. RP Carvalho, EM (reprint author), Hosp Univ Prof Edgard Santos, Serv Imunol, Lab Imunol, 5 Andar,Rua Joao das Botas S-N Canela, BR-40110160 Salvador, BA, Brazil. EM edgar@ufba.br NR 39 TC 16 Z9 16 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD AUG PY 2004 VL 137 IS 2 BP 424 EP 429 DI 10.1111/j.1365-2249.2004.02508.x PG 6 WC Immunology SC Immunology GA 838KJ UT WOS:000222711900026 PM 15270862 ER PT J AU Sriuranpong, V Mutirangura, A Gillespie, JW Patel, V Amornphimoltham, P Molinolo, AA Kerekhanjanarong, V Supanakorn, S Supiyaphun, P Rangdaeng, S Voravud, N Gutkind, JS AF Sriuranpong, V Mutirangura, A Gillespie, JW Patel, V Amornphimoltham, P Molinolo, AA Kerekhanjanarong, V Supanakorn, S Supiyaphun, P Rangdaeng, S Voravud, N Gutkind, JS TI Global gene expression profile of nasopharyngeal carcinoma by laser capture microdissection and complementary DNA microarrays SO CLINICAL CANCER RESEARCH LA English DT Article ID EPSTEIN-BARR-VIRUS; SQUAMOUS-CELL CARCINOMAS; BREAST-CANCER; PROMOTER HYPERMETHYLATION; COLORECTAL-CANCER; BINDING-PROTEIN; HIGH-FREQUENCY; STROMELYSIN-3; SURVIVAL; RECEPTOR AB A number of genetic and epigenetic changes underlying the development of nasopharyngeal carcinomas have recently been identified. However, there is still limited information on the nature of the genes and gene products whose aberrant expression and activity promote the malignant conversion of nasopharyngeal epithelium. Here, we have performed a genome-wide transcriptome analysis by probing cDNA microarrays with fluorescent-labeled amplified RNA derived from laser capture microdissected cells procured from normal nasopharyngeal epithelium and areas of metaplasia-dysplasia and carcinoma from EBV-associated nasopharyngeal carcinomas. This approach enabled the identification of genes differentially expressed in each cell population, as well as numerous genes whose expression can help explain the aggressive clinical nature of this tumor type. For example, genes indicating cell cycle aberrations (cyclin D2, cyclin B1, activator of S-phase kinase, and the cell cycle checkpoint kinase, CHK1) and invasive-metastatic potential (matrix metalloproteinase 11, v-Ral, and integrin beta(4)) were highly expressed in tumor cells. In contrast, genes under-expressed in tumors included genes involved in apoptosis (B-cell CLL/lymphoma 6, secretory leukocyte protease inhibitor, and calpastatin), cell structure (keratin 7 and carcinoembryonic antigen-related cell adhesion molecule 6), and putative tumor suppressor genes (H-Ras-like suppressor 3, retinoic acid receptor responder 1, and growth arrested specific 8) among others. Gene expression patterns also suggested alterations in the Wnt/beta-catenin and transforming growth factor beta pathways in nasopharyngeal carcinoma. Thus, expression profiles indicate that aberrant expression of growth, survival, and invasion-promoting genes may contribute to the molecular pathogenesis of nasopharyngeal carcinoma. Ultimately, this approach may facilitate the identification of clinical useful markers of disease progression and novel potential therapeutic targets for nasopharyngeal carcinoma. C1 NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. Chulalongkorn Univ, Fac Med, Med Oncol Unit, Dept Med, Bangkok 10330, Thailand. Chulalongkorn Univ, Fac Med, Genet Unit, Dept Anat, Bangkok 10330, Thailand. Chulalongkorn Univ, Fac Med, Dept Otorhinolaryngol, Bangkok 10330, Thailand. Chiang Mai Univ, Fac Med, Dept Pathol, Chiang Mai 50000, Thailand. RP Gutkind, JS (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Bldg 30,Room 211, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Mutirangura, Apiwat /C-8197-2009 NR 69 TC 63 Z9 68 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2004 VL 10 IS 15 BP 4944 EP 4958 DI 10.1158/1078-0432.CCR-03-0757 PG 15 WC Oncology SC Oncology GA 845PQ UT WOS:000223257200007 PM 15297395 ER PT J AU Tan, AR Yang, XW Berman, A Zhai, SP Sparreboom, A Parr, AL Chow, C Brahim, JS Steinberg, SM Figg, WD Swain, SM AF Tan, AR Yang, XW Berman, A Zhai, SP Sparreboom, A Parr, AL Chow, C Brahim, JS Steinberg, SM Figg, WD Swain, SM TI Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL-CYCLE; CARCINOMA-CELLS; CONTINUOUS-INFUSION; SOLID TUMORS; HUMAN PLASMA; APOPTOSIS; INDUCTION; D1; ARREST; PROGRESSION AB Purpose: The purpose of this study was to determine the toxicities and characterize the pharmacokinetics of docetaxel and flavopiridol in patients with metastatic breast cancer. Experimental Design: Docetaxel was administered at an initial dose of 60 mg/m(2) followed in 24 hours by a 72-hour infusion of flavopiridol at 50 mg/m(2)/d every 3 weeks. Because dose-limiting myelosuppression occurred, the schedule was amended to docetaxel, 50 mg/m(2), followed by escalating doses of flavopiridol (starting dose, 26 mg/m(2)/d) as a 1-hour infusion daily for 3 days. Pharmacokinetic studies were performed. Ki67, p53, and phosphorylated retinoblastoma protein (phospho-Rb) in paired tumor and buccal mucosa biopsies (obtained pre- and posttreatment) were examined by immunohistochemistry. Results: Eleven patients were enrolled. Five patients received docetaxel and 72-hour flavopiridol. Dose-limiting toxicity was grade 4 neutropenia. Six patients received docetaxel and 1-hour flavopiridol, and the dose-limiting toxicity was grade 3 hypotension. Pharmacokinetics of flavopiridol and docetaxel were consistent with historical data. Nuclear staining with p53 increased and phospho-Rb decreased in 10 pairs of buccal mucosa biopsies posttreatment (P = 0.002 and P = 0.04, respectively). No significant changes in Ki67, p53, or phospho-Rb were detected in six paired tumors. Two patients sustained stable disease for >3 months (72-hour flavopiridol), and one partial response was observed (1-hour flavopiridol). Conclusions: Docetaxel combined with 72-hour flavopiridol was not feasible because of dose-limiting neutropenia. Dose escalation of a 1-hour infusion of flavopiridol with docetaxel was also not possible. The changes in p53 and phospho-Rb in buccal mucosa suggest that a biological effect with flavopiridol was achieved. C1 NCI, Canc Therapeut Branch, Canc Res Ctr, NIH, Bethesda, MD 20889 USA. NCI, Med Oncol Clin Res Unit, Canc Res Ctr, NIH, Bethesda, MD 20889 USA. NCI, Biostat & Data Management Sect, Canc Res Ctr, NIH, Bethesda, MD 20889 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Swain, SM (reprint author), NCI, Canc Therapeut Branch, Canc Res Ctr, NIH, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. EM swains@mail.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 39 TC 45 Z9 48 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 AUG 1 PY 2004 VL 10 IS 15 BP 5038 EP 5047 DI 10.1158/1078-0432.CCR-04-0025 PG 10 WC Oncology SC Oncology GA 845PQ UT WOS:000223257200017 PM 15297405 ER PT J AU Anderton, MJ Manson, MM Verschoyle, RD Gescher, A Lamb, JH Farmer, PB Steward, WP Williams, ML AF Anderton, MJ Manson, MM Verschoyle, RD Gescher, A Lamb, JH Farmer, PB Steward, WP Williams, ML TI Pharmacokinetics and tissue disposition of indole-3-carbinol and its acid condensation products after oral administration to mice SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL-CYCLE ARREST; BREAST-CANCER CELLS; DIETARY INDOLE-3-CARBINOL; IN-VIVO; RAT-LIVER; BRASSICA VEGETABLES; ENDOMETRIAL CANCER; CARCINOGENESIS; EXPRESSION; METABOLISM AB Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) are promising cancer chemopreventive agents in rodent models, but there is a paucity of data on their pharmacokinetics and tissue disposition. The disposition of I3C and its acid condensation products, DIM, [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LTr1), indolo[3,2b]carbazole (ICZ) and 1-(3-hydroxymethyl)-indolyl-3-indolylmethane (HI-IM) was studied, after oral administration of I3C (250 mg/kg) to female CD-1 mice. Blood, liver, kidney, lung, heart, and brain were collected between 0.25 and 24 h after administration and the plasma and tissue concentrations of I3C and its derivatives determined by high-performance liquid chromotography. I3C was rapidly absorbed, distributed, and eliminated from plasma and tissues, falling below the limit of detection by 1 h. Highest concentrations of I3C were detected in the liver where levels were approximately 6-fold higher than those in the plasma. Levels of DIM, LTr1, and HI-IM were much lower, although they persisted in plasma and tissues for considerably longer. DIM and HI-IM were still present in the liver 24 h after I3C administration. Tissue levels of DIM and LTr1 were found to be in equilibrium with plasma at almost every time point measured. In addition to acid condensation products of I3C, a major oxidative metabolite (indole-3-carboxylic acid) and a minor oxidative metabolite (indole-3-carboxaldehyde) were detected in plasma of mice after oral administration of I3C. ICZ was also tentatively identified in the liver of these mice. This study shows for the first time that, after oral administration to mice, I3C, in addition to its acid condensation products, is absorbed from the gut and distributed systemically into a number of well-perfused tissues, thus allowing the possibility for some pharmacological activity of the parent compound in vivo. C1 Univ Leicester, Dept Biochem, Canc Biomarkers & Prevent Grp, Leicester LE1 7RH, Leics, England. Univ Leicester, Dept Canc Studies, Canc Biomarkers & Prevent Grp, Leicester LE1 7RH, Leics, England. Univ Leicester, Dept Mol Med, Canc Biomarkers & Prevent Grp, Leicester LE1 7RH, Leics, England. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Manson, MM (reprint author), Bioctr, Univ Rd, Leicester LE1 7RH, Leics, England. EM mmm2@le.ac.uk NR 45 TC 112 Z9 115 U1 1 U2 10 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 AUG 1 PY 2004 VL 10 IS 15 BP 5233 EP 5241 DI 10.1158/1078-0432.CCR-04-0163 PG 9 WC Oncology SC Oncology GA 845PQ UT WOS:000223257200039 PM 15297427 ER PT J AU Dasmahapatra, GP Didolkar, P Alley, MC Ghosh, S Sausville, EA Roy, KK AF Dasmahapatra, GP Didolkar, P Alley, MC Ghosh, S Sausville, EA Roy, KK TI In vitro combination treatment with perifosine and UCN-01 demonstrates synergism against prostate (PC-3) and lung (A549) epithelial adenocarcinoma cell lines SO CLINICAL CANCER RESEARCH LA English DT Article ID PROTEIN-KINASE-C; HUMAN LEUKEMIA-CELLS; ANTITUMOR-ACTIVITY; CLINICAL-PHARMACOLOGY; SELECTIVE INHIBITOR; ANTICANCER AGENT; 3-KINASE PATHWAY; CANCER CELLS; PHASE-I; APOPTOSIS AB Purpose: Antineoplastic agents often achieve antitumor activity at the expense of close to unacceptable toxicity. One potential avenue to improve therapeutic index might combine agents targeting distinct components of the same growth regulatory pathway. This might lead to more complete modulation of the target pathway at concentrations lower than those associated with limiting adventitious toxicities from either agent alone. The protein kinase antagonist UCN-01 is currently used in Phase I/II trials and has recently been demonstrated to inhibit potently PDK1 (S. Sato et al., Oncogene, 21: 1727-1738, 2002). We have recently documented that the alkylphospholipid perifosine potently also inhibits Akt kinase (PKB) activation by interfering with membrane localization of Akt (S. Kondapaka et al., Mol. Cancer Ther., 2: 1093-1103, 2003). This leads to the hypothesis that these two agents might act synergistically through distinct mechanisms in the PI3K/Akt proliferation and survival-related signaling pathway. Experimental Design: The synergistic effects of UCN-01 and perifosine, on two cell lines (A-549 and PC-3), were examined using various long-term in vitro assays for cell growth, cell cycle distribution, clonogenicity, survival morphology, and apoptosis. Along with Western blotting experiments were performed to determine whether this synergistic combination of two drugs has significant effect on their downstream targets and on biochemical markers of apoptosis. Results: After 72 h, perifosine at concentrations of 1.5 and 10 mum UCN-01 at 40 and 250 nm did not significantly affect the growth of PC-3 and A459 cells, respectively. However, in combination at the same respective individual concentrations (1.5 mum and 40 nm of perifosine and UCN-01, respectively, in PC-3 cells and 10 mum perifosine and 0.25 mum UCN-01 in the somewhat more resistant A549 cells), virtually complete growth inhibition of both the cell lines resulted. Supra-additive inhibition of growth was also demonstrated in independent clonogenic assays. Mechanistic studies in cell culture models suggest enhanced depletion of the S-phase population in cells treated by the combination. This correlated with enhanced inactivation of Akt along with activation of caspases 3 and 9 and poly(ADP-ribose) polymerase cleavage. Evidence of synergy was formally demonstrated and occurred across a wide range of drug concentrations and was largely independent of the order or sequence of drug addition. Conclusions: As the concentrations of UCN-01 and perifosine causing synergistic inhibition of cell growth are clinically achievable without prominent toxicity, these data support the development of clinical studies with this combination. C1 NIH, Clin Trials Unit, Bethesda, MD 20892 USA. NIH, Dev Therapeut Program, Biol Testing Branch, Bethesda, MD 20892 USA. RP Roy, KK (reprint author), NIH, Clin Trials Unit, Bldg 10,10 Ctr Dr,Room 6N 113, Bethesda, MD 20892 USA. EM kr91w@nih.gov NR 51 TC 57 Z9 59 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 1 PY 2004 VL 10 IS 15 BP 5242 EP 5252 DI 10.1158/1078-0432.CCR-03-0534 PG 11 WC Oncology SC Oncology GA 845PQ UT WOS:000223257200040 PM 15297428 ER PT J AU Kawakami, K Kawakami, M Puri, RK AF Kawakami, K Kawakami, M Puri, RK TI Nitric oxide accelerates interleukin-13 cytotoxin-mediated regression in head and neck cancer animal model SO CLINICAL CANCER RESEARCH LA English DT Article ID RECEPTOR-TARGETED CYTOTOXIN; PSEUDOMONAS EXOTOXIN; IL-13 RECEPTOR; CELL-LINES; ALPHA-2 CHAIN; GLIOMA-CELLS; IN-VIVO; SIGNAL-TRANSDUCTION; MALIGNANT GLIOMA; FUSION CYTOTOXIN AB Receptors for interleukin-13 (IL-13R) are overexpressed on several types of solid cancers including gliobastoma, renal cell carcinoma, AIDS Kaposi's sarcoma, and head and neck cancer. Recombinant fusion proteins IL-13 cytotoxin (IL13-PE38QQR or IL13-PE38) have been developed to directly target IL-13R-expressing cancer cells. Although it has been found that IL-13 cytotoxin has a direct potent antitumor activity in vivo in nude mice models of human cancers, the involvement of indirect antitumor effecter molecules such as nitric oxide (NO) is unknown. To address this issue, we assessed the effect of NO inhibiter N-omega-monomethyl-L-arginine on IL-13 cytotoxin-mediated cytotoxicity and NO2/NO3 production in HN12 head and neck cancer cells. In addition, antitumor effects and NO levels in HN12 and KCCT873 head and neck tumors xenografted s.c. in nude mice when treated with IL-13 cytotoxin were evaluated by tumor measurement, Western blot, and immunohistochemistry analyses. Pretreatment of animals with N-omega-monomethyl-L-arginine significantly decreased the NO levels and IL-13 cytotoxin-mediated antitumor effects. In addition, depletion of macrophages, known to produce NO, also decreased antitumor activity of IL-13 cytotoxin. Based on these studies, we concluded that NO accelerates antitumor effect of IL-13 cytotoxin on head and neck tumor cells. Because IL-13 cytotoxin is currently being tested in the clinic for the treatment of patients with recurrent glioblastoma maltiforme, our current findings suggest maintaining macrophage and NO-producing cellular function for optimal therapeutic effect of this targeted agent. 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, Bldg 10,NIH Bldg 29B,Room 2NN10,HFM-735, Bethesda, MD 20892 USA. EM puri@cber.fda.gov NR 47 TC 9 Z9 9 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 AUG 1 PY 2004 VL 10 IS 15 BP 5264 EP 5270 DI 10.1158/1078-0432.CCR-04-0314 PG 7 WC Oncology SC Oncology GA 845PQ UT WOS:000223257200042 PM 15297430 ER PT J AU Petricoin, EF Liotta, LA AF Petricoin, EF Liotta, LA TI Proteomic pattern complexity reveals a rich and uncharted continent of biomarkers SO CLINICAL CHEMISTRY LA English DT Letter ID OVARIAN-CANCER; SERUM C1 US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. NCI, Ctr Canc Res, Clin Proteom Program, Lab Pathol,FDA, Bethesda, MD USA. RP Petricoin, EF (reprint author), FDA, CBER, Bldg 29A-2D12 8800 Rockville Pike, Bethesda, MD 20892 USA. EM petricoin@cber.fda.gov; liotta1@mail.nih.gov NR 7 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD AUG PY 2004 VL 50 IS 8 BP 1476 EP 1477 DI 10.1373/clinchem.2004.035097 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 840UN UT WOS:000222885500042 ER PT J AU Gilbert, DL Garvey, MA Bansal, AS Lipps, T Zhang, J Wassermann, EM AF Gilbert, DL Garvey, MA Bansal, AS Lipps, T Zhang, J Wassermann, EM TI Should transcranial magnetic stimulation research in children be considered minimal risk? SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE institutional review board; minimal risk; ethics; neurophysiology; transcranial magnetic stimulation; children ID CENTRAL MOTOR REORGANIZATION; CEREBRAL-PALSY; CORTICOSPINAL PROJECTIONS; EVOKED-POTENTIALS; IMPULSE NOISE; HEARING-LOSS; BRAIN; CONDUCTION; PERFORMANCE; THRESHOLD AB Objective: Transcranial magnetic stimulation (TMS) is a neurophysiologic technique with research applications. Institutional Review Boards (IRBs) must carefully consider potential risks and possible benefits in research involving children. The purpose of this study is to provide concise information for investigators and IRBs about the safety of single and paired pulse TMS research in children. Methods: This paper has 4 sections: (I) Regulations governing research in children are reviewed and applied to the use of TMS. (II) Energy imparted by TMS is assessed in terms of theoretical biological risks to human subjects. (III) Through MEDLINE review, the empirical evidence of risk from TMS is assessed. Reported adverse events, including issues related to risk of seizures and of hearing loss, are summarized. (IV) Safety data are presented from a study of TMS in children with Tourette Syndrome. Results: No published or empirical evidence was found to suggest that single or paired pulse TMS is associated with more than minimal risk in children. Conclusions: IRBs may consider well-designed studies using single and paired pulse TMS protocols similar to those described in this study as bearing minimal risk to children. Significance: This manuscript may be useful as a reference to IRBs and TMS investigators. (C) 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 Childrens Hosp, Med Ctr, Div Pediat Neurol, Movement Disorders Clin, Cincinnati, OH 45229 USA. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. NE Ohio Univ, Coll Med, Rootstown, OH USA. NINDS, Brain Stimulat Unit, NIH, Bethesda, MD 20892 USA. RP Gilbert, DL (reprint author), Childrens Hosp, Med Ctr, Div Pediat Neurol, Movement Disorders Clin, ML 2015,3333 Burnet Ave, Cincinnati, OH 45229 USA. EM d.gilbert@cchmc.org RI Gilbert, Donald/D-6443-2016 OI Gilbert, Donald/0000-0002-9245-6878 FU NINDS NIH HHS [K23 NS41920] NR 40 TC 62 Z9 64 U1 1 U2 8 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD AUG PY 2004 VL 115 IS 8 BP 1730 EP 1739 DI 10.1016/j.clinph.2003.10.037 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 850DP UT WOS:000223591700002 PM 15261851 ER PT J AU Cury-Boaventura, MF Pompeia, C Curi, R AF Cury-Boaventura, MF Pompeia, C Curi, R TI Comparative toxicity of oleic acid and linoleic acid on Jurkat cells SO CLINICAL NUTRITION LA English DT Article DE Jurkat cells; oleic acid; linoleic acid; apoptosis; necrosis ID POLYUNSATURATED FATTY-ACIDS; PARENTERAL LIPID EMULSIONS; OLIVE OIL; EICOSAPENTAENOIC ACID; HUMAN-LYMPHOCYTES; ARACHIDONIC-ACID; IMMUNE FUNCTION; IN-VITRO; C-MYC; APOPTOSIS AB Background: Lipid emulsions for parenteral nutrition commercially available are mainly composed of long-chain triacylglycerol containing a high proportion of omega-6 polyunsaturated fatty acids or omega-9 monounsaturated fatty acids. The immunological impact of such therapy is particularly important because parenteral and enteral diets are often administered to critical ill patients. The comparative toxicity of oleic acid and linoleic acid on Jurkat cells, a human T lymphocyte cell line, and the type of cell death induced by these fatty acids were determined. Methods: Cell death was investigated by cytometry: decrease in cell volume, increase of granularity, DNA fragmentation, phosphatidylserine externalization, mitochondrial depolarization, lipid accumulation; by fluorescence microscopy: chromatin condensation and acridine orange/ethidium bromide assay; and by RTPCR: mRNA expression of apoptotic genes. Results: Evidence is presented herein that oleic acid is much less toxic to Jurkat cells than linoleic acid. Both fatty acids promote apoptosis and necrosis of these cells. The mechanism of cell death induced by these fatty acids seem to involve with mitochondrial depolarization, lipid accumulation and the levels of C-MYC and P53 mRNA expression. Conclusion: Therefore, oleic acid may offer an immunological less harmful alternative to linoleic acid for parenteral and enteral diets preparation. (C) 2003 Elsevier Ltd. All rights reserved. C1 Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, BR-05508900 Sao Paulo, Brazil. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, NIH, Frederick, MD 21702 USA. RP Cury-Boaventura, MF (reprint author), Univ Sao Paulo, Inst Biomed Sci, Dept Physiol & Biophys, Av Prof Lineu Prestes, BR-05508900 Sao Paulo, Brazil. EM mafecury@fisio.icb.usp.br RI Cury-Boaventura, Maria Fernanda/B-3945-2012 NR 41 TC 90 Z9 92 U1 0 U2 8 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0261-5614 J9 CLIN NUTR JI Clin. Nutr. PD AUG PY 2004 VL 23 IS 4 BP 721 EP 732 DI 10.1016/j.clnu.2003.12.004 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 853UO UT WOS:000223854600035 PM 15297111 ER PT J AU Zheng, G Park, S AF Zheng, G Park, S TI On the Fisher information in multiply censored and progressively censored data SO COMMUNICATIONS IN STATISTICS-THEORY AND METHODS LA English DT Article DE asymptotics; Fisher information; life testing; multiple censoring; order statistics; type I censoring ID ORDER-STATISTICS AB In this article, we first show that the asymptotic Fisher information contained in multiple interval censored and multiple Type II censored data are asymptotically equivalent. We then extend the results to randomly censored data. Finally, we study the calculation of the exact Fisher information contained in Type II progressively censored data. In this case, the Fisher information can be written as a sum of several single integrations. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. Yonsei Univ, Dept Appl Stat, Seoul 120749, South Korea. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, Rockledge 2,6701 Rockledge Dr, Bethesda, MD 20892 USA. EM zhengg@nhlbi.nih.gov NR 23 TC 15 Z9 15 U1 0 U2 2 PU MARCEL DEKKER INC PI NEW YORK PA 270 MADISON AVE, NEW YORK, NY 10016 USA SN 0361-0926 J9 COMMUN STAT-THEOR M JI Commun. Stat.-Theory Methods PD AUG PY 2004 VL 33 IS 8 BP 1821 EP 1835 DI 10.1081/STA-120037443 PG 15 WC Statistics & Probability SC Mathematics GA 831BC UT WOS:000222166900006 ER PT J AU Tavares-Sanchez, OL Gomez-Anduro, GA Felipe-Ortega, X Islas-Osuna, MA Sotelo-Mundo, RR Barillas-Mury, C Yepiz-Plascencia, G AF Tavares-Sanchez, OL Gomez-Anduro, GA Felipe-Ortega, X Islas-Osuna, MA Sotelo-Mundo, RR Barillas-Mury, C Yepiz-Plascencia, G TI Catalase from the white shrimp Penaeus (Litopenaeus) vannamei: molecular cloning and protein detection SO COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY LA English DT Article DE catalase; cDNA; hepatopancreas; mRNA; shrimp ID FRESH-WATER PRAWN; DROSOPHILA-MELANOGASTER; ANTIOXIDANT ENZYMES; ACATALASEMIC MUTANTS; BINDING-PROTEIN; DEFENSE SYSTEM; LIPOPROTEIN; PREDICTION; ALIGNMENT; OXIDATION AB Catalase is an antioxidant enzyme that plays a very important role in the protection against oxidative damage by breaking down hydrogen peroxide. It is a very highly conserved enzyme that has been identified from numerous species including bacteria, fungi, plants and animals, but the information about catalase in crustaceans is very limited. A cDNA containing the complete coding sequence for catalase from the shrimp Penaeus (Litopenaeus) vannamei was sequenced and the mRNA was detected by RT-PCR in selected tissues. Catalase was detected in hepatopancreas crude extracts by Western blot analysis with anti-human catalase polyclonal antibodies. The nucleotide sequence is 1692 bp long, including a 72-bp 5'-UTR, a coding sequence of 1515 bp and a 104-bp 3'-UTR. The deduced amino acid sequence corresponds to 505 amino acids with high identity to invertebrate, vertebrate and even bacterial catalases and contains the catalytic residues His71, Asn144, and Tyr354. The predicted protein has a calculated molecular mass of 57 kDa; which coincides with the size of the subunit (similar to55 kDa) and the tetrameric protein(similar to230 kDa) detected in hepatopancreas extracts under native conditions. Catalase mRNA level was higher in hepatopancreas, followed by gills and was not detected in muscle. (C) 2004 Elsevier Inc. All rights reserved. C1 Ctr Invest Alimentac & Desarrollo, Aquat Mol Biol Lab, Hermosillo 83000, Sonora, Mexico. Inst Tecnol Sonora, Cd Obregon Son 85000, Mexico. NIH, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. RP Yepiz-Plascencia, G (reprint author), Ctr Invest Alimentac & Desarrollo, Aquat Mol Biol Lab, POB 1735, Hermosillo 83000, Sonora, Mexico. EM gyepiz@cascabel.ciad.mx RI Sotelo-Mundo, Rogerio/A-6097-2011 OI Sotelo-Mundo, Rogerio/0000-0001-5543-6889 NR 34 TC 36 Z9 42 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1096-4959 J9 COMP BIOCHEM PHYS B JI Comp. Biochem. Physiol. B-Biochem. Mol. Biol. PD AUG PY 2004 VL 138 IS 4 BP 331 EP 337 DI 10.1016/j.cbpc.2004.03.005 PG 7 WC Biochemistry & Molecular Biology; Zoology SC Biochemistry & Molecular Biology; Zoology GA 853JN UT WOS:000223823400003 PM 15325332 ER PT J AU Gu, YC Bauer, TR Ackermann, MR Smith, CW Kehrli, ME Starost, MF Hickstein, DD AF Gu, YC Bauer, TR Ackermann, MR Smith, CW Kehrli, ME Starost, MF Hickstein, DD TI The genetic immunodeficiency disease, leukocyte adhesion deficiency, in humans, dogs, cattle, and mice SO COMPARATIVE MEDICINE LA English DT Review ID CANINE GRANULOCYTOPATHY SYNDROME; BONE-MARROW-TRANSPLANTATION; COMMON BETA-SUBUNIT; CD18-DEFICIENT MICE; T-CELL; PASTEURELLA-HAEMOLYTICA; NEUTROPHIL DYSFUNCTION; P150,95 GLYCOPROTEINS; RECURRENT INFECTIONS; HOLSTEIN HEIFER AB This review highlights the genotype-phenotype relationship of the genetic immunodeficiency disease leukocyte adhesion deficiency (LAD) in humans, dogs, cattle, and mice, and provides assessment of the opportunities that each animal species provides in the understanding of leukocyte biology and in developing new therapeutic approaches to LAD in humans. This comparison is important since animal models of genetic diseases in humans provide the opportunity to test new therapeutic approaches in an appropriate, disease-specific model. The success of this approach is dependent on the relationship of the phenotype in the animal to the phenotype of the disease in humans. C1 NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Iowa State Univ, Coll Vet Med, Dept Vet Pathol, Ames, IA 50011 USA. Baylor Coll Med, Dept Pediat Immunol & Med, Sect Leukocyte Biol, Houston, TX 77030 USA. ARS, Virus & Prion Dis Livestock Res Unit, Natl Anim Dis Ctr, USDA, Ames, IA 50010 USA. NIH, Off Res Serv, Div Vet Resources, Bethesda, MD 20892 USA. RP Hickstein, DD (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 74 TC 17 Z9 17 U1 3 U2 8 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD AUG PY 2004 VL 54 IS 4 BP 363 EP 372 PG 10 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 847LD UT WOS:000223393100002 PM 15357315 ER PT J AU Yoo, TS AF Yoo, TS TI Taking stock of visualization in scientific computing SO COMPUTER GRAPHICS-US LA English DT Article ID VOLUME DATA C1 Natl Lib Med, Off High Performance Comp & Commun, NIH, Bethesda, MD 20894 USA. Univ Calif Davis, Dept Comp Sci, Davis, CA 95616 USA. RP Natl Lib Med, Off High Performance Comp & Commun, NIH, Bethesda, MD 20894 USA. NR 14 TC 0 Z9 0 U1 0 U2 2 PU ASSOC COMPUTING MACHINERY PI NEW YORK PA 2 PENN PLAZA, STE 701, NEW YORK, NY 10121-0701 USA SN 0097-8930 J9 COMPUT GRAPHICS-US JI Comput. Graph.-US PD AUG PY 2004 VL 38 IS 3 BP 4 EP 6 PG 3 WC Computer Science, Software Engineering SC Computer Science GA 022GH UT WOS:000236042900003 ER PT J AU Oddone, EZ Olsen, MK Lindquist, JH Orr, M Horner, R Reda, D Lavori, P Johnson, G Collins, J Feussner, JR AF Oddone, EZ Olsen, MK Lindquist, JH Orr, M Horner, R Reda, D Lavori, P Johnson, G Collins, J Feussner, JR TI Enrollment in clinical trials according to patients race: experience from the VA Cooperative Studies Program (1975-2000) SO CONTROLLED CLINICAL TRIALS LA English DT Article DE race; clinical trial enrollment; VA Cooperative Studies Program ID AFRICAN-AMERICANS; MEDICAL-RESEARCH; PARTICIPATION; DISPARITIES; DISTRUST; SURGERY; BLACKS; ACCESS; GENDER AB Background: Racial distribution of clinical trial participants is important because results from these studies serve to define evidence-based practice. This report summarizes the experience of the VA Cooperative Studies Program (CSP) in enrolling white, black and Hispanic patients. Methods: An analysis of enrollment in randomized controlled trials conducted by VA CSP between 1975 and 2000. A standardized enrollment ratio for each trial was calculated by dividing the observed number of enrolled white patients in the trial by the expected number of eligible white patients based on the proportion of white patients hospitalized at the enrolling VA Medical Centers. Results: 13 8 VA CSP clinical trials were initiated between 1975 and 2000, 83 contained information on race for 71,463 patients. Overall, 76% of enrolled patients were white, 20% were black, and 4% were Hispanic. Based on standardized enrollment ratios, 60 of the 83 trials had 95% confidence intervals that excluded 1.0. Of these, 32 studies enrolled more white patients than expected and 28 enrolled more Black and/or Hispanic patients than expected based on the racial distribution of patients hospitalized at sites involved in the trials. When trials were separated by interventiontype, 13 of the 19 trials that had an invasive arm enrolled fewer minority patients than expected. In trials that targeted diseases that affect minority populations to a greater degree than whites (diabetes, hypertension and end stage renal disease), 11 of the 14 trials enrolled more minority patients than expected. Conclusions: There were several trials that enrolled either more or less minority patients than expected based on patients hospitalized at study sites. Trials that included an invasive arm enrolled fewer minority participants than expected. Trials that involve invasive therapies may wish to adopt special recruitment strategies to reach minority populations. (C) 2004 Elsevier Inc. All rights reserved. C1 Vet Adm Med Ctr, Ctr Hlth Serv Res Primary Care, Durham, NC 27705 USA. Duke Univ, Ctr Med, Div Gen Internal Med, Durham, NC USA. Duke Univ, Ctr Med, Dept Biostat & Bioinformat, Durham, NC USA. Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. VA Med Ctr, Cooperat Studies Coordinating Ctr, Hines, IL USA. VA Med Ctr, Cooperat Studies Coodinating Ctr, Palo Alto, CA USA. VA Med Ctr, Cooperat Studies Coordinating Ctr, West Haven, CT USA. Univ Maryland, Sch Med, Baltimore, MD USA. VA Med Ctr, Cooperat Studies Coodinating Ctr, Perry Point, MD USA. Med Univ S Carolina, Dept Med, Charleston, SC USA. RP Oddone, EZ (reprint author), Vet Adm Med Ctr, Ctr Hlth Serv Res Primary Care, 558 Fulton St, Durham, NC 27705 USA. EM Oddon001@mc.duke.edu NR 21 TC 18 Z9 18 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-2456 J9 CONTROL CLIN TRIALS JI Controlled Clin. Trials PD AUG PY 2004 VL 25 IS 4 BP 378 EP 387 DI 10.1016/j.cct.2004.05.001 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 853IF UT WOS:000223819800004 PM 15296812 ER PT J AU Danis, M AF Danis, M TI The survival benefit of intensive care SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE survival benefit; intensive care; bed shortage; survival curves ID UNIT C1 NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Danis, M (reprint author), NIH, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. NR 13 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD AUG PY 2004 VL 32 IS 8 BP 1791 EP 1792 DI 10.1097/01.CCM.0000133426.30541.94 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 847QU UT WOS:000223410800027 PM 15286563 ER PT J AU Sambamurti, K Granholm, AC Kindy, MS Bhat, NR Greig, NH Lahiri, DK Mintzer, JE AF Sambamurti, K Granholm, AC Kindy, MS Bhat, NR Greig, NH Lahiri, DK Mintzer, JE TI Cholesterol and Alzheimer's disease: Clinical and experimental models suggest interactions of different genetic, dietary and environmental risk factors SO CURRENT DRUG TARGETS LA English DT Review DE aging; cognition; diets; dementia; high fats; apolipoprotein E; secretase; myelin; memory ID AMYLOID PRECURSOR PROTEIN; APOLIPOPROTEIN-E GENOTYPE; LOW-DENSITY-LIPOPROTEIN; ALPHA-SECRETASE CLEAVAGE; INSOLUBLE MEMBRANE COMPARTMENT; BETA-PEPTIDE PRODUCTION; TRANSGENIC MOUSE MODEL; NECROSIS-FACTOR-ALPHA; NERVE GROWTH-FACTOR; HIGH-FAT DIETS AB Alzheimer's disease (AD) is a progressive senile dementia characterized by deposition of a 4 kDa peptide of 39-42 residues known as amyloid beta-peptide (AD) in the form of senile plaques and the microtubule associated protein tau as paired helical filaments. Genetic studies have identified mutations in the Abeta precursor protein (APP) as the key triggers for the pathogenesis of AD. Other genes such as presenilins 1 and 2 (PS1/2) and apolipoprotein E (APOE) also play a critical role in increased Abeta deposition. Severial biochemical and molecular studies using transfected cultured cells and transgenic animals point to mechanisms by which AD is generated and aggregated to trigger the neurodegeneration that may cause AD. Three important enzymes collectively known as 'secretases' participate in APP processing leading to the generation of either Abeta or non-amyloid proteins. However, the mechanisms of neurotoxicity of Abeta and the role of APP function in AD remain important unanswered questions. Although early studies recognized the loss of cholesterol and other lipids in the brain, these findings have been poorly connected with AD pathogenesis, despite the identification of the epsilon4 allele of APOE as a major risk factor in AD. The recent finding that cholesterol can modulate the yield of potentially toxic Abeta has boosted research on its role in AD. Consequently, several cholesterol-reducing drugs are currently being evaluated for the treatment of AD. The present review summarizes our current understanding of the relationship of AD pathogenesis with cholesterol, lipids and other genetic and environmental risk factors. C1 Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. Med Univ S Carolina, Ctr Aging, Charleston, SC 29425 USA. Ralph H Johnson VA Med Ctr, Charleston, SC USA. Med Univ S Carolina, Dept Neurol, Charleston, SC 29425 USA. NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. Indiana Univ, Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. Dept Psychiat, N Charleston, SC USA. Ctr Aging, N Charleston, SC USA. RP Sambamurti, K (reprint author), Med Univ S Carolina, Dept Physiol & Neurosci, 173 Ashley Ave,BSB 403, Charleston, SC 29425 USA. EM sambak@musc.edu NR 165 TC 41 Z9 42 U1 1 U2 2 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1389-4501 J9 CURR DRUG TARGETS JI Curr. Drug Targets PD AUG PY 2004 VL 5 IS 6 BP 517 EP 528 DI 10.2174/1389450043345335 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 836GG UT WOS:000222543200004 PM 15270198 ER PT J AU Perry, TA Greig, NH AF Perry, TA Greig, NH TI A new Alzheimer's disease interventive strategy: GLP-1 SO CURRENT DRUG TARGETS LA English DT Review DE apoptosis; cyclic AMP; diabetes; excitotoxicity; insulinotropic; neurodegeneration; synaptic plasticity ID GLUCAGON-LIKE PEPTIDE-1; AMYLOID PRECURSOR PROTEIN; PANCREATIC BETA-CELLS; NERVE GROWTH-FACTOR; OXIDATIVE STRESS; HIPPOCAMPAL-NEURONS; MESSENGER-RNA; RAT-BRAIN; GLUCOSE-TRANSPORT; BINDING-SITES AB Glucagon-like peptide-1 (7-36)-amide (GLP-1) is an endogenous 30-amino acid gut peptide, which binds at the GLP-1 receptor coupled to the cyclic AMP second messenger pathway. GLP-1 receptor stimulation enhances pancreatic islet beta-cell proliferation, glucose-dependent insulin secretion and lowers blood glucose and food intake in patients with type 2 diabetes mellitus. Not limited to the pancreas, the chemo architecture of GLP-1 receptor distribution in the brain of rodents and humans correlates with a central role for GLP-1 in the regulation of food intake. However emerging evidence suggests that stimulation of neuronal GLP-1 receptors plays an important role in regulating neuronal plasticity and cell survival. GLP-1 has been documented to induce neurite outgrowth and to protect against excitotoxic cell death and oxidative injury in cultured neuronal cells. Moreover, GLP-1 and exendin-4, a naturally occurring more stable analogue of GLP-1 that likewise binds at the GLP-1 receptor, were shown to reduce endogenous levels of amyloid-beta peptide (Abeta) in mouse brain and to reduce levels of beta-amyloid precursor protein (LAPP) in neurons. Collectively these data suggest that treatment with GLP-1 or a related peptide beneficially affects a number of the therapeutic targets associated with Alzheimer's disease (AD). Although much remains to be elucidated with regards to the downstream signaling pathways involved in the pro-survival properties of GLP-1, modulation of calcium homeostasis may be critical. This review will consider the potential therapeutic relevance of GLP-1 to CNS disorders, such as AD. C1 NIA, Drug Design & Dev Sect, Neurosci Lab, Gerontol Res Ctr,Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Perry, TA (reprint author), NIA, Drug Design & Dev Sect, Neurosci Lab, Gerontol Res Ctr,Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM perryt@gre.nia.nih.gov; greign@grc.nia.nih.gov NR 84 TC 54 Z9 63 U1 1 U2 8 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 1389-4501 J9 CURR DRUG TARGETS JI Curr. Drug Targets PD AUG PY 2004 VL 5 IS 6 BP 565 EP 571 DI 10.2174/1389450043345245 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 836GG UT WOS:000222543200009 PM 15270203 ER PT J AU Kovarova, M Rivera, J AF Kovarova, M Rivera, J TI A molecular understanding of mast cell activation and the promise of anti-allergic therapeutics SO CURRENT MEDICINAL CHEMISTRY LA English DT Review DE allergy; mast cells; allergen; IgE; Fc epsilon RI; therapeutics; molecular mechanisms; degranulation ID HIGH-AFFINITY RECEPTOR; FC-EPSILON-RI; PROTEIN-KINASE-C; BASOPHILIC LEUKEMIA-CELLS; CROMOLYN BINDING-PROTEIN; IGE RECEPTOR; IMMUNOGLOBULIN-E; TYROSINE KINASES; CALCIUM SIGNAL; RBL-2H3 CELLS AB Mast cells are central to allergic disease. Their immediate (exocytosis of granule-stored allergic-mediators) and delayed (de novo synthesis of inflammatory mediators) response to an allergen underlies the symptoms seen in acute and chronic allergic disease. Thus, intervention in the allergen-mediated activation of mast cells is a long sought after goal in the treatment and management of allergic disease. The recent gain in deciphering the molecular mechanisms underlying immunoglobulin E (IgE)-mediated mast cell activation has provided optimism for the development of new therapeutic strategies. Among the most promising is the use of humanized anti-IgE antibodies that inhibit binding of IgE to its high affinity receptor (FcERI) on the mast cell. Other strategies target molecules proximal to FcepsilonR1, whose activities are central in mast cell activation. One such molecule, Syk kinase, has been targeted by various approaches including a small molecule inhibitor that specifically abrogates mast cell degranulation. More recently, various molecules that function to promote protein-protein interactions (adapters) were demonstrated as essential to mast cell degranulation and cytokine production. It remains to be seen if these molecules hold therapeutic promise for disease intervention. Additional studies identifying molecules required for mast cell granule fusion and content exocytosis also bodes well for discovery of new therapeutic targets. While our understanding of IgE-mediated mast cell activation is still at its inception, the modest success in identifying molecules essential to this process affords some confidence for better treatment of allergic disease. C1 NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bldg 10,Room 9N228,10 Ctr Dr,MSC 1820, Bethesda, MD 20892 USA. EM juan_rivera@nih.gov NR 107 TC 27 Z9 38 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI HILVERSUM PA PO BOX 1673, 1200 BR HILVERSUM, NETHERLANDS SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD AUG PY 2004 VL 11 IS 15 BP 2083 EP 2091 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 836CP UT WOS:000222533100009 PM 15279568 ER PT J AU Altan-Bonnet, N Sougrat, R Lippincott-Schwartz, J AF Altan-Bonnet, N Sougrat, R Lippincott-Schwartz, J TI Molecular basis for Golgi maintenance and biogenesis SO CURRENT OPINION IN CELL BIOLOGY LA English DT Review ID NUCLEOTIDE-EXCHANGE FACTOR; TETHERING PROTEIN P115; RETICULUM EXIT SITES; ENDOPLASMIC-RETICULUM; LIVING CELLS; MEMBRANE-TRANSPORT; MATRIX PROTEIN; ER; COMPLEX; GM130 AB The Golgi apparatus contains thousands of different types of integral and peripheral membrane proteins, perhaps more than any other intracellular organelle. To understand these proteins' roles in Golgi function and in broader cellular processes, it is useful to categorize them according to their contribution to Golgi creation and maintenance. This is because all of the Golgi's functions derive from its ability to maintain steady-state pools of particular proteins and lipids, which in turn relies on the Golgi's dynamic character - that is, its ongoing state of transformation and outgrowth from the endoplasmic reticulum. Here, we categorize the expanding list of Golgi-associated proteins on the basis of their role in Golgi reformation after the Golgi has been disassembled. Information gained on how different proteins participate in this process can provide important insights for understanding the Golgi's global functions within cells. C1 Natl Inst Child Hlth & Dev, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Altan-Bonnet, N (reprint author), Natl Inst Child Hlth & Dev, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM jlippin@helix.nih.gov OI Sougrat, Rachid/0000-0001-6476-1886 NR 78 TC 108 Z9 115 U1 0 U2 7 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD AUG PY 2004 VL 16 IS 4 BP 364 EP 372 DI 10.1016/j.ceb.2004.06.011 PG 9 WC Cell Biology SC Cell Biology GA 844BC UT WOS:000223130800004 PM 15261668 ER PT J AU Chitnis, AB Itoh, M AF Chitnis, AB Itoh, M TI Exploring alternative models of rostral-caudal patterning in the zebrafish neurectoderm with computer simulations SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID NEURAL PLATE; ISTHMIC ORGANIZER; PRECHORDAL PLATE; HOMEOBOX GENE; XENOPUS; MORPHOGEN; GBX2; SPECIFICATION; GASTRULATION; EXPRESSION AB The StarLogo and NetLogo programming environments allow developmental biologists to build computer models of cell-cell interactions in an epithelium and visualize emergent properties of hypothetical genetic regulatory networks operating in the cells. These environments were used to explore alternative models that show how a posteriorizing morphogen gradient might define gene-expression domains along the rostral-caudal axis in the zebrafish neurectoderm. The models illustrate how a hypothetical genetic network based on auto-activation and cross-repression could lead to establishment of discrete non-overlapping gene-expression domains. C1 NICHHD, Unit Vertebrate Neural Dev, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Chitnis, AB (reprint author), NICHHD, Unit Vertebrate Neural Dev, Mol Genet Lab, NIH, Bldg 6B,Room 315,6 Ctr Dr, Bethesda, MD 20892 USA. EM chitnisa@mail.nih.gov NR 37 TC 1 Z9 1 U1 2 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD AUG PY 2004 VL 14 IS 4 BP 415 EP 421 DI 10.1016/j.gde.2004.06.002 PG 7 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 845CY UT WOS:000223214600013 PM 15261658 ER EF