FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Zibell, G Unkruer, B Pekcec, A Hartz, AMS Bauer, B Miller, DS Potschka, H AF Zibell, Guido Unkrueer, Bernadette Pekcec, Anton Hartz, Anika M. S. Bauer, Bjoern Miller, David S. Potschka, Heidrun TI Prevention of seizure-induced up-regulation of endothelial P-glycoprotein by COX-2 inhibition SO NEUROPHARMACOLOGY LA English DT Article DE Epilepsy; Status epilepticus; P-glycoprotein; Pharmacoresistance; Multidrug transporter; Cyclooxygenase-2 ID BLOOD-BRAIN-BARRIER; NECROSIS-FACTOR-ALPHA; TEMPORAL-LOBE EPILEPSY; CELL-DEATH; CYCLOOXYGENASE-2 EXPRESSION; INTRACEREBRAL HEMORRHAGE; ADMINISTRATION INCREASES; PILOCARPINE MODEL; ARACHIDONIC-ACID; DRUG-RESISTANCE AB In the epileptic brain, seizure activity induces expression of the blood-brain barrier efflux transporter, P-glycoprotein, thereby limiting brain penetration and therapeutic efficacy of antiepileptic drugs. We recently provided the first evidence that seizures drive P-glycoprotein induction through a pathway that involves glutamate-signaling through the NMDA receptor and cyclooxygenase-2 (COX-2). Based on these data, we hypothesized that selective inhibition of COX-2 could prevent seizure-induced P-glycoprotein up-regulation. In the present study, we found that the highly selective COX-2 inhibitors, NS-398 and indomethacin heptyl ester, blocked the glutamate-induced increase in P-glycoprotein expression and transport function in isolated rat brain capillaries. Importantly, consistent with this, the COX-2 inhibitor, celecoxib, blocked seizure-induced up-regulation of P-glycoprotein expression in brain capillaries of rats in vivo. To explore further the role of COX-2 in signaling P-glycoprotein induction, we analyzed COX-2 protein expression in capillary endothelial cells in brain sections from rats that had undergone pilocarpine-induced seizures and in isolated capillaries exposed to glutamate and found no change from control levels. However, in isolated rat brain capillaries, the COX-2 substrate, arachidonic acid, significantly increased P-glycoprotein transport activity and expression indicating that enhanced substrate flux to COX-2 rather than increased COX-2 expression drives P-glycoprotein up-regulation. Together, these results provide the first in vivo proof-of-principle that specific COX-2 inhibition may be used as a new therapeutic strategy to prevent seizure-induced P-glycoprotein up-regulation at the blood-brain barrier for improving pharmacotherapy of drug-resistant epilepsy. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Zibell, Guido; Unkrueer, Bernadette; Pekcec, Anton; Potschka, Heidrun] Univ Munich, Inst Pharmacol Toxicol & Pharm, D-80539 Munich, Germany. [Hartz, Anika M. S.] Univ Minnesota, Sch Med, Dept Biochem & Mol Biol, Duluth, MN 55812 USA. [Bauer, Bjoern] Univ Minnesota, Coll Pharm, Dept Pharmaceut Sci, Duluth, MN 55812 USA. [Bauer, Bjoern] Natl Inst Environm Hlth Sci, Pharmacol Lab, NIH, Res Triangle Pk, NC USA. RP Potschka, H (reprint author), Univ Munich, Inst Pharmacol Toxicol & Pharm, Koeniginstr 16, D-80539 Munich, Germany. EM potschka@pharmtox.vetmed.uni-muenchen.de OI Potschka, Heidrun/0000-0003-1506-0252; Gualtieri, Fabio/0000-0002-4972-0039 FU German Research Foundation [681/4-1]; University of Minnesota GIA [20919]; NIH; National Institute of Environmental Health Sciences FX We thank Sylvia Notenboom and Christina Fuest for their excellent technical assistance. This research was supported by the grant DFG PO 681/4-1 (to HP) from the German Research Foundation, by a University of Minnesota GIA grant #20919 (to BB) and by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 31 TC 49 Z9 54 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD APR PY 2009 VL 56 IS 5 BP 849 EP 855 DI 10.1016/j.neuropharm.2009.01.009 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 441MY UT WOS:000265774500002 PM 19371577 ER PT J AU Woicik, PA Moeller, SJ Alia-Klein, N Maloney, T Lukasik, TM Yeliosof, O Wang, GJ Volkow, ND Goldstein, RZ AF Woicik, Patricia A. Moeller, Scott J. Alia-Klein, Nelly Maloney, Thomas Lukasik, Tanya M. Yeliosof, Olga Wang, Gene-Jack Volkow, Nora D. Goldstein, Rita Z. TI The Neuropsychology of Cocaine Addiction: Recent Cocaine Use Masks Impairment SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE cocaine addiction; neuropsychological function; alcohol; dysphoria; cigarette smoking; urine status ID ANTERIOR CINGULATE CORTEX; PREFRONTAL CORTEX; ATTENTIONAL NETWORKS; DECISION-MAKING; NEUROCOGNITIVE DEFICITS; DEPENDENT OUTPATIENTS; CLINICAL-IMPLICATIONS; FACIAL EXPRESSIONS; ALCOHOL DEPENDENCE; CRACK-COCAINE AB Individuals with current cocaine use disorders (CUD) form a heterogeneous group, making sensitive neuropsychological (NP) comparisons with healthy individuals difficult. The current study examined the effects on NP functioning of four factors that commonly vary among CUD: urine status for cocaine (positive vs negative on study day), cigarette smoking, alcohol consumption, and dysphoria. Sixty-four cocaine abusers were matched to healthy comparison subjects on gender and race; the groups also did not differ in measures of general intellectual functioning. All subjects were administered an extensive NP battery measuring attention, executive function, memory, facial and emotion recognition, and motor function. Compared with healthy control subjects, CUD exhibited performance deficits on tasks of attention, executive function, and verbal memory (within one standard deviation of controls). Although CUD with positive urine status, who had higher frequency and more recent cocaine use, reported greater symptoms of dysphoria, these cognitive deficits were most pronounced in the CUD with negative urine status. Cigarette smoking, frequency of alcohol consumption, and dysphoria did not alter these results. The current findings replicate a previously reported statistically significant, but relatively mild NP impairment in CUD as compared with matched healthy control individuals and further suggest that frequent/recent cocaine may mask underlying cognitive (but not mood) disturbances. These results call for development of pharmacological agents targeted to enhance cognition, without negatively impacting mood in individuals addicted to cocaine. C1 [Woicik, Patricia A.; Alia-Klein, Nelly; Maloney, Thomas; Lukasik, Tanya M.; Yeliosof, Olga; Wang, Gene-Jack; Goldstein, Rita Z.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Moeller, Scott J.] Univ Michigan, Dept Psychol, Ann Arbor, MI USA. [Volkow, Nora D.] NIDA, Bethesda, MD 20892 USA. RP Woicik, PA (reprint author), Brookhaven Natl Lab, Dept Med, POB 5000, Upton, NY 11973 USA. EM pwoicik@bnl.gov; rgoldstein@bnl.gov RI Reis, Aline/G-9573-2012; Moeller, Scott/L-5549-2016 OI Moeller, Scott/0000-0002-4449-0844 FU National Institute on Drug Abuse [RZG: 1K23 DA15517-01, DA6278, DAO6891]; NARSAD [79/1025459]; National Institute on Alcohol Abuse and Alcoholism [AA/ODO9481]; US Department of Energy [DE-ACO2-98CH10886]; General Clinical Research Center [5-MO1-RR-10710] FX This study was supported by grants from the National Institute on Drug Abuse (RZG: 1K23 DA15517-01, DA6278, DAO6891); NARSAD Young Investigator Award and Stony Brook/Brookhaven National Laboratory seed grant (RZG: 79/1025459); National Institute on Alcohol Abuse and Alcoholism (NDV: AA/ODO9481); Laboratory Directed Research and Development from US Department of Energy (OBER; DE-ACO2-98CH10886); and General Clinical Research Center (5-MO1-RR-10710). NR 95 TC 86 Z9 87 U1 2 U2 28 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2009 VL 34 IS 5 BP 1112 EP 1122 DI 10.1038/npp.2008.60 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 418VX UT WOS:000264178600004 PM 18496524 ER PT J AU Enoch, MA Hodgkinson, CA Yuan, QP Albaugh, B Virkkunen, M Goldman, D AF Enoch, Mary-Anne Hodgkinson, Colin A. Yuan, Qiaoping Albaugh, Bernard Virkkunen, Matti Goldman, David TI GABRG1 and GABRA2 as Independent Predictors for Alcoholism in Two Populations SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE linkage disequilibrium; GABA(A) receptor; ancestral haplotypes; alcohol use disorders; anxiety; American Indians ID SUBUNIT MESSENGER-RNAS; GABA(A) RECEPTORS; LINKAGE DISEQUILIBRIUM; GENOTYPE DATA; RAT-BRAIN; ADULT-RAT; DEPENDENCE; ASSOCIATION; GENE; HAPLOTYPE AB The chromosome 4 cluster of GABA(A) receptor genes is predominantly expressed in the brain reward circuitry and this chromosomal region has been implicated in linkage scans for alcoholism. Variation in one chromosome 4 gene, GABRA2, has been robustly associated with alcohol use disorders (AUD) although no functional locus has been identified. As HapMap data reveal moderate long-distance linkage disequilibrium across GABRA2 and the adjacent gene, GABRG1, it is possible that the functional locus is in GABRG1. We genotyped 24 SNPs across GABRG1 and GABRA2 in two population isolates: 547 Finnish Caucasian men (266 alcoholics) and 311 community-derived Plains Indian men and women (181 alcoholics). In both the Plains Indians and the Caucasians: (1) the GABRG1 haplotype block(s) did not extend to GABRA2; (2) GABRG1 haplotypes and SNPs were significantly associated with AUD; (3) there was no association between GABRA2 haplotypes and AUD; (4) there were several common (>= 0.05) haplotypes that spanned GABRG1 and GABRA2 (341 kb), three of which were present in both populations: one of these ancestral haplotypes was associated with AUD, the other two were more common in non-alcoholics; this association was determined by GABRG1; (5) in the Finns, three less common (<0.05) extended haplotypes showed an association with AUD that was determined by GABRA2. Our results suggest that there are likely to be independent, complex contributions from both GABRG1 and GABRA2 to alcoholism vulnerability. C1 [Enoch, Mary-Anne; Hodgkinson, Colin A.; Yuan, Qiaoping; Goldman, David] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Albaugh, Bernard] Ctr Human Behav Studies, Weatherford, OK USA. [Virkkunen, Matti] Univ Helsinki, Dept Psychiat, SF-00180 Helsinki, Finland. RP Enoch, MA (reprint author), NIAAA, Neurogenet Lab, NIH, 5625 Fishers Lane,Suite 3S32,MSC 9412, Bethesda, MD 20892 USA. EM maenoch@dicbr.niaaa.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institute on Alcohol Abuse and Alcoholism, NIH; Office of Research on Minority Health FX This research was supported by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH, and in part by the Office of Research on Minority Health. NR 37 TC 54 Z9 54 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD APR PY 2009 VL 34 IS 5 BP 1245 EP 1254 DI 10.1038/npp.2008.171 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 418VX UT WOS:000264178600016 PM 18818659 ER PT J AU Cannon, DM Klaver, JM Peck, SA Rallis-Voak, D Erickson, K Drevets, WC AF Cannon, Dara M. Klaver, Jacqueline M. Peck, Summer A. Rallis-Voak, Denise Erickson, Kristine Drevets, Wayne C. TI Dopamine Type-1 Receptor Binding in Major Depressive Disorder Assessed Using Positron Emission Tomography and [C-11]NNC-112 SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE caudate; striatum; anhedonia; G-protein-coupled receptor ID AGE-RELATED-CHANGES; D-1 RECEPTOR; HUMAN-BRAIN; PREFRONTAL CORTEX; D1 RECEPTORS; STRIATAL DOPAMINE-D-2; MOOD-DISORDERS; SEROTONIN TRANSPORTER; GREATER AVAILABILITY; PARKINSONS-DISEASE AB The dopamine type-1 receptor has been implicated in major depressive disorder (MDD) by clinical and preclinical evidence from neuroimaging, post mortem, and behavioral studies. To date, however, selective in vivo assessment of D-1 receptors has been limited to the striatum in MDD samples manifesting anger attacks. We employed the PET radioligand, [C-11] NNC-112, to selectively assess D-1 receptor binding in extrastriatal and striatal regions in a more generalized sample of MDD subjects. The [C-11] NNC-112 nondisplaceable binding potential (BPND) was assessed using PET in 18 unmedicated, currently depressed subjects with MDD and 19 healthy controls, and compared between groups using MRI-based region-of-interest analysis. The mean v receptor BPND was reduced (14%) in the left middle caudate of the MDD group relative to control group (p<0.05). Among the MDD subjects D-1 receptor BPND in this region correlated negatively with illness duration (r = -0.53; p = 0.02), and the left-to-right BPND ratio correlated inversely with anhedonia ratings (r = -0.65, p = 0.0040). The D-1 receptor BPND was strongly lateralized in striatal regions (p<0.002 for main effects of hemisphere in accumbens area, putamen, and caudate). In post hoc analyses, a group-by-hemisphere-by-gender interaction was detected in the dorsal putamen, which was accounted for by a loss of the normal asymmetry in depressed women (F = 7.33, p = 0.01). These data extended a previous finding of decreased striatal D-1 receptor binding in an MDD sample manifesting anger attacks to a sample selected more generally according to MDD criteria. Our data also more specifically localized this abnormality in MDD to the left middle caudate, which is the target of afferent neural projections from the orbitofrontal and anterior cingulate cortices where neuropathological changes have been reported in MDD. Finally, D-1 receptor binding was asymmetrical across hemispheres in healthy humans, compatible with evidence that dopaminergic function in the striatum is lateralized during reward processing, voluntary movement, and self-stimulation behavior. C1 [Cannon, Dara M.] Natl Univ Ireland Univ Coll Galway, Inst Clin Sci, Dept Psychiat, Galway, Co Galway, Ireland. [Cannon, Dara M.; Klaver, Jacqueline M.; Peck, Summer A.; Rallis-Voak, Denise; Erickson, Kristine; Drevets, Wayne C.] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Cannon, DM (reprint author), Natl Univ Ireland Univ Coll Galway, Inst Clin Sci, Dept Psychiat, Room 201,Comerford Bldg, Galway, Co Galway, Ireland. EM dara.cannon@nuigalway.ie RI Cannon, Dara/C-1323-2009 OI Cannon, Dara/0000-0001-7378-3411 FU IH/NIMH; National Alliance for Research on Schizophrenia and Depression FX We acknowledge Victor Pike, Robert Innis, and Masahiro Fujita for providing the radioligand, Peter Herscovitch, MD and the Clinical Center PET Department for Technical Assistance, Michele Drevets, RN and Joan Williams, RN, for evaluation and recruitment of the research subjects, the staff of the NIH Clinical Center, Allison Nugent, Stephen Fromm, Summer Peck, Suzanne Wood, Kelly Anastasi, and Laurentina Cizza for assistance in data management, and Dave Luckenbaugh, PhD for advice regarding the statistical analysis of the PET data. This study was supported by the intramural research program of the NIH/NIMH and a National Alliance for Research on Schizophrenia and Depression Young Investigator Award. NR 98 TC 43 Z9 45 U1 1 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 APR PY 2009 VL 34 IS 5 BP 1277 EP 1287 DI 10.1038/npp.2008.194 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 418VX UT WOS:000264178600019 PM 18946469 ER PT J AU Scattoni, ML Crawley, J Ricceri, L AF Scattoni, Maria Luisa Crawley, Jacqueline Ricceri, Laura TI Ultrasonic vocalizations: A tool for behavioural phenotyping of mouse models of neurodevelopmental disorders SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Ultrasonic vocalizations; Maternal potentiation; Animal models of neurodevelopmental disorders ID MEDIATED SEPARATION RESPONSE; MATERNAL-BEHAVIOR; RATTUS-NORVEGICUS; INFANT RATS; KNOCKOUT MICE; FEMALE MICE; RECEPTOR FUNCTION; BASAL FOREBRAIN; SOCIAL DEFICITS; RETT-SYNDROME AB In neonatal mice ultrasonic vocalizations have been studied both as an early communicative behaviour of the pup-mother dyad and as a sign of an aversive affective state. Adult mice of both sexes produce complex ultrasonic vocalization patterns in different experimental/social contexts. Vocalizations are becoming an increasingly valuable assay for behavioural phenotyping throughout the mouse life-span and alterations of the ultrasound patterns have been reported in several mouse models of neurodevelopmental disorders. Here we also show that the modulation of vocalizations by maternal cues (maternal potentiation paradigm) - originally identified and investigated in rats - can be measured in C57BL/6 mouse pups with appropriate modifications of the rat protocol and can likely be applied to mouse behavioural phenotyping. In addition we suggest that a detailed qualitative evaluation of neonatal calls together with analysis of adult mouse vocalization patterns in both sexes in social settings, may lead to a greater understanding of the communication value of vocalizations in mice. Importantly, both neonatal and adult USV altered patterns can be determined during the behavioural phenotyping of mouse models of human neurodevelopmental and neuropsychiatric disorders, starting from those in which deficits in communication are a primary symptom. (C) 2008 Elsevier Ltd All rights reserved. C1 [Scattoni, Maria Luisa; Ricceri, Laura] Ist Super Sanita, Dept Cell Biol & Neurosci, Sect Neurotoxicol & Neuroendocrinol, I-00161 Rome, Italy. [Scattoni, Maria Luisa; Crawley, Jacqueline] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. RP Ricceri, L (reprint author), Ist Super Sanita, Dept Cell Biol & Neurosci, Sect Neurotoxicol & Neuroendocrinol, Viale Regina Elena 299, I-00161 Rome, Italy. EM laura.ricceri@iss.it OI Ricceri, Laura/0000-0001-9850-2284 FU ISS-NIH; National Institute of Mental Health [Z01-MH-02179] FX This research was supported by ISS-NIH OF14 "Neurobehavioural phenotyping of genetically modified mouse models of mental retardation" (LR), by the National Institute of Mental Health Intramural Research program (JNC), and in part by the NIMH Intramural Research Program (Z01-MH-02179). NR 86 TC 142 Z9 143 U1 1 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD APR PY 2009 VL 33 IS 4 BP 508 EP 515 DI 10.1016/j.neubiorev.2008.08.003 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 431ST UT WOS:000265084700003 PM 18771687 ER PT J AU Cirulli, F Francia, N Berry, A Aloe, L Alleva, E Suomi, SJ AF Cirulli, Francesca Francia, Nadia Berry, Alessandra Aloe, Luigi Alleva, Enrico Suomi, Stephen J. TI Early life stress as a risk factor for mental health: Role of neurotrophins from rodents to non-human primates SO NEUROSCIENCE AND BIOBEHAVIORAL REVIEWS LA English DT Review DE Maternal deprivation; Stress; Brain development; Nerve growth factor; Brain-derived neurotrophic factor; Vulnerability; Depression; Anxiety ID NERVE GROWTH-FACTOR; PITUITARY-ADRENAL AXIS; EARLY ADVERSE EXPERIENCES; EARLY MATERNAL SEPARATION; FAMILY-BASED ASSOCIATION; FACTOR GENE-EXPRESSION; TOTAL SOCIAL ISOLATION; DEVELOPING RAT-BRAIN; INDIVIDUAL-DIFFERENCES; BDNF LEVELS AB Early adverse events can enhance stress responsiveness and lead to greater susceptibility for psychopathology at adulthood. The epigenetic factors involved in transducing specific features of the rearing environment into stable changes in brain and behavioural plasticity have only begun to be elucidated. Neurotrophic factors, such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), are affected by stress and play a major role in brain development and in the trophism of specific neuronal networks involved in cognitive function and in mood disorders. In addition to the central nervous system, these effectors are produced by peripheral tissues, thus being in a position to integrate the response to external challenges. In this paper we will review data, obtained from animal models, indicating that early maternal deprivation stress can affect neurotrophin levels. Maladaptive or repeated activation of NGF and BDNF, early during postnatal life, may influence stress sensitivity at adulthood and increase vulnerability for stress-related psychopathology. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Cirulli, Francesca; Francia, Nadia; Berry, Alessandra; Alleva, Enrico] Ist Super Sanita, Dept Cell Biol & Neurosci, Sect Behav Neurosci, I-00161 Rome, Italy. [Aloe, Luigi] CNR, Inst Neurobiol & Mol Med, Rome, Italy. [Suomi, Stephen J.] NICHHD, Comparat Ethol Lab, Poolesville, MD USA. RP Cirulli, F (reprint author), Ist Super Sanita, Dept Cell Biol & Neurosci, Sect Behav Neurosci, Viale Regina Elena 299, I-00161 Rome, Italy. EM francesca.cirulli@iss.it RI Cirulli, Francesca/B-1581-2013; Alleva, Enrico/B-1630-2013; OI Berry, Alessandra/0000-0001-6562-9043; cirulli, francesca/0000-0001-9440-1873 FU ISS-NIH [0F14]; Italian Ministry of Health; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX Supported by the ISS-NIH Collaborative Project (0F14) to F.C. and E.A. and by the Italian Ministry of Health, Ricerca Finalizzata ex art. 12-2006. This research was also supported by funds from the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The authors thank A. Ruggiero, S. Miletta, F. Capone and L.T. Bonsignore for technical assistance, F. Chiarotti for statistical advice. NR 160 TC 103 Z9 110 U1 2 U2 36 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0149-7634 EI 1873-7528 J9 NEUROSCI BIOBEHAV R JI Neurosci. Biobehav. Rev. PD APR PY 2009 VL 33 IS 4 SI SI BP 573 EP 585 DI 10.1016/j.neubiorev.2008.09.001 PG 13 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 431ST UT WOS:000265084700009 PM 18817811 ER PT J AU Cadet, JL Krasnova, IN Ladenheim, B Cai, NS Mccoy, MT Atianjoh, FE AF Cadet, Jean Lud Krasnova, Irina N. Ladenheim, Bruce Cai, Ning-Sheng McCoy, Michael T. Atianjoh, Fidelis E. TI Methamphetamine Preconditioning: Differential Protective Effects on Monoaminergic Systems in the Rat Brain SO NEUROTOXICITY RESEARCH LA English DT Article DE Methamphetamine; Toxicity; Preconditioning; Hormesis; Dopamine; Serotonin; Striatum ID NERVE-TERMINAL DEGENERATION; INDUCED NEUROTOXICITY; NEURONAL APOPTOSIS; ISCHEMIC TOLERANCE; CEREBRAL-ISCHEMIA; TRANSGENIC MICE; DOPAMINE; MECHANISMS; ABUSE; PRETREATMENT AB Pretreatment with methamphetamine (METH) can attenuate toxicity due to acute METH challenges. The majority of previous reports have focused mainly on the effects of the drug on the striatal dopaminergic system. In the present study, we used a regimen that involves gradual increases in METH administration to rats in order to mimic progressively larger doses of the drug used by some human METH addicts. We found that this METH preconditioning was associated with complete protection against dopamine depletion caused by a METH challenge (5 mg/kg x 6 injections given 1 h apart) in the striatum and cortex. In contrast, there was no preconditioning-mediated protection against METH-induced serotonin depletion in the striatum and hippocampus, with some protection being observed in the cortex. There was also no protection against METH-induced norepinephrine (NE) depletion in the hippocampus. These results indicate that, in contrast to the present dogmas, there might be differences in the mechanisms involved in METH toxicity on monoaminergic systems in the rodent brain. Thus, chronic injections of METH might activate programs that protect against dopamine toxicity without influencing drug-induced pathological changes in serotoninergic systems. Further studies will need to evaluate the cellular and molecular bases for these differential responses. C1 [Cadet, Jean Lud; Krasnova, Irina N.; Ladenheim, Bruce; Cai, Ning-Sheng; McCoy, Michael T.; Atianjoh, Fidelis E.] NIDA, Mol Neuropsychiat Branch, NIH, DHHS, Baltimore, MD 21224 USA. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Branch, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov FU National Institute on Drug Abuse, NIH/DHHS FX This research was supported in part by the Intramural Research Program of the National Institute on Drug Abuse, NIH/DHHS. The authors thank the staff of the NIDA/IRP animal facility for the excellent care provided to the animals used in our studies. NR 48 TC 24 Z9 24 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD APR PY 2009 VL 15 IS 3 BP 252 EP 259 DI 10.1007/s12640-009-9026-0 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 418YB UT WOS:000264184900007 PM 19384598 ER PT J AU Patient, R Hourioux, C Vaudin, P Pages, JC Roingeard, P AF Patient, Romuald Hourioux, Christophe Vaudin, Pascal Pages, Jean-Christophe Roingeard, Philippe TI Chimeric hepatitis B and C viruses envelope proteins can form subviral particles: implications for the design of new vaccine strategies SO NEW BIOTECHNOLOGY LA English DT Article ID SURFACE-ANTIGEN PARTICLES; ENDOPLASMIC-RETICULUM; GLYCOPROTEIN COMPLEX; SECRETION; MORPHOGENESIS; MEMBRANE; EPITOPES; DOMAINS; TYPE-1; CELLS AB The hepatitis B virus (HBV) envelope protein (S) self-assembles into subviral particles used as commercial vaccines against hepatitis B. These particles are excellent carriers for foreign epitopes, which can be inserted into the external hydrophilic loop or at the N- or C-terminal end of the HBV S protein. We show here that the N-terminal transmembrane domain (TMD) of HBV S can be replaced by the TMDs of the hepatitis C virus (HCV) envelope proteins El and E2, to generate fusion proteins containing the entire HCV El or E2 sequence that are efficiently coassembled with the HBV S into particles. This demonstrates the remarkable tolerance of the HBV S protein to sequence substitutions conserving its subviral particle assembly properties. These findings may have implications for the design of new vaccine strategies based on the use of HBV subviral particles as carriers for various transmembrane proteins and produced using the same industrial procedures that are established for the HBV vaccine. C1 Univ Tours, INSERM, U966, F-37041 Tours, France. CHRU Tours, Tours, France. RP Patient, R (reprint author), NIDDK, NIH, Liver Dis Branch, Bldg 10,Room 9B06, Bethesda, MD 20892 USA. EM roingeard@med.univ-tours.fr RI Vaudin, Pascal/J-1870-2014 NR 34 TC 18 Z9 18 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1871-6784 J9 NEW BIOTECHNOL JI New Biotech. PD APR PY 2009 VL 25 IS 4 BP 226 EP 234 DI 10.1016/j.nbt.2009.01.001 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 455VU UT WOS:000266796400016 PM 19356608 ER PT J AU Reid, AE Hooker, J Shumay, E Logan, J Shea, C Kim, SW Collins, S Xu, YW Volkow, N Fowler, JS AF Reid, Alicia E. Hooker, Jacob Shumay, Elena Logan, Jean Shea, Colleen Kim, Sung Won Collins, Shanika Xu, Youwen Volkow, Nora Fowler, Joanna S. TI Evaluation of 6-([(18)F]fluoroacetamido)-1-hexanoicanilide for PET imaging of histone deacetylase in the baboon brain SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE PET; Histone deacetylase; Pharmacokinetics; [(18)F]FAHA ID ANTICANCER AGENTS; HDAC INHIBITORS; HUMAN-DISEASE; RAT-BRAIN; CANCER; THERAPY; TRACERS; ACETATE; BINDING; SYSTEM AB Introduction: Historic deacetylases (HDACs) are enzymes involved in epigenetic modifications that shift the balance toward chromatin condensation and silencing of gene expression. Here, we evaluate the utility of 6-([(18)F]fluoroaectamido)-1-hexanoicanilide ([(18)F]FAHA) for positron emission tomography imaging of HDAC activity in the baboon brain. For this purpose, we assessed its in vivo biodistribution, sensitivity to HDAC inhibition, metabolic stability and the distribution of the putative metabolite [(18)F]fluoroacetate ([(18)F]FAC). Methods: [(18)F]FAHA and its metabolite [(18)F]FAC were prepared, and their in vivo biodistribution and pharmacokinetics were determined in baboons. [(18)F]FAHA metabolism and its sensitivity to HDAC inhibition using suberanilohydroxamic acid (SAHA) were assessed in arterial plasma and by in vitro incubation studies. The chemical form of F- 18 in rodent brain was assessed by ex vivo studies. Distribution volumes for [(18)F]FAHA in the brain were derived. Results: [(18)F]FAHA was rapidly metabolized to [(18)F]FAC, and both labeled compounds entered the brain. [(18)F]FAHA exhibited regional differences in brain uptake and kinetics. In contrast, [(18)F]FAC showed little variation in regional brain uptake and kinetics. A kinetic analysis that takes into account the uptake of peripherally produced [(18)F]FAC indicated that SAHA inhibited binding of [(18)F]FAHA in the baboon brain dose-dependently. In vitro studies demonstrated SAHA-sensitive metabolism of [(18)F]FAHA to [(18)F]FAC within the cell and diffusion of [(18)F]FAC out of the cell. All radioactivity in brain homogenate from rodents was [(18)F]FAC at 7 min postinjection of [(18)F]FAHA. Conclusion: The rapid metabolism of [(18)F]FAHA to [(18)F]FAC in the periphery complicates the quantitative analysis of HDAC in the brain. However, dose-dependent blocking studies with SAHA and kinetic modeling indicated that a specific interaction of [(18)F]FAHA in the brain was observed. Validating the nature of this interaction as HDAC specific will require additional studies. Published by Elsevier Inc. C1 [Reid, Alicia E.; Volkow, Nora] NIAAA, Bethesda, MD 20892 USA. [Reid, Alicia E.; Hooker, Jacob; Shumay, Elena; Logan, Jean; Shea, Colleen; Kim, Sung Won; Xu, Youwen; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Collins, Shanika] Hlth & Technol Medgar Evers Coll, Sch Sci, Brooklyn, NY 11225 USA. [Volkow, Nora] NIDA, Bethesda, MD 20892 USA. RP Reid, AE (reprint author), NIAAA, Bethesda, MD 20892 USA. EM areid@bnl.gov OI Hooker, Jacob/0000-0002-9394-7708 FU U.S. Department of Energy's Office of Biological and Environmental Research; National Institutes of Health-National Institute on Alcohol Abuse and Alcoholism Intramural Research Program FX This work was supported by the U.S. Department of Energy's Office of Biological and Environmental Research and by the National Institutes of Health-National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. Special thanks to Kwesi Amoa and Frank Ogero, of Medgar Evers College for help in chemical synthesis and Michael Schueller, David Alexoff, Lisa Muench, Pauline Carter, Payton King and Donald Warrier of the PET Imaging Group at Brookhaven National Laboratory for technical support. NR 36 TC 21 Z9 21 U1 3 U2 14 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD APR PY 2009 VL 36 IS 3 BP 247 EP 258 DI 10.1016/j.nucmedbio.2008.12.005 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 432JT UT WOS:000265130000003 PM 19324270 ER PT J AU Kim, SW Biegon, A Katsamanis, ZE Ehrlich, CW Hooker, JM Shea, C Muench, L Xu, Y King, P Carter, P Alexoff, DL Fowler, JS AF Kim, Sung Won Biegon, Anat Katsamanis, Zachary E. Ehrlich, Carolin W. Hooker, Jacob M. Shea, Colleen Muench, Lisa Xu, Youwen King, Payton Carter, Pauline Alexoff, David L. Fowler, Joanna S. TI Reinvestigation of the synthesis and evaluation of [N-methyl-(11)C]vorozole, a radiotracer targeting cytochrome P450 aromatase SO NUCLEAR MEDICINE AND BIOLOGY LA English DT Article DE [N-methyl-(11)C]vorozole; Positron emission tomography; Breast cancer; Steroid abuse; Estrogen ID ANABOLIC-ANDROGENIC STEROIDS; IN-VITRO EVALUATION; BRAIN AROMATASE; INHIBITORS; BINDING; ENZYME; VIVO; CONVERSION; R-76713; TISSUE AB Introduction: We reinvestigated the synthesis of [N-inethyl-(11)C]vorozole, a radiotracer for aromatase, and discovered the presence of an N-methyl isomer which was not removed in the original purification method. Herein we report the preparation and positron emission tomography (PET) studies of pure [N-methyl-(11)C]vorozole. Methods: Norvorozole was alkylated with [(11)C]methyl iodide as previously described and also with unlabeled methyl iodide. A high-performance liquid chromatography (HPLC) method was developed to separate the regioisomers. Nuclear magnetic resonance (NMR) spectroscopy ((13)C and 2D-nuclear Overhauser effect spectroscopy NMR) was used to identify and assign structures to the N-methylated products. Pure [N-methyl-(11)C]vorozole and the contaminating isomer were compared by PET imaging in the baboon. Results: Methylation of norvorozole resulted in a mixture of isomers (1:1:1 ratio) based on new HPLC analysis using a pentafluorophenylpropyl bonded silica column, in which vorozole coeluted one of its isomers under the original HPLC conditions. Baseline separation of the three labeled isomers was achieved. The N-3 isomer was the contaminant of vorozole, thus correcting the original assignment of isomers. PET studies of pure [N-methyl-(11)C]vorozole with and without the contaminating N-3 isomer revealed that only [N-methyl-(11)C]vorozole binds to aromatase. (N-methyl-(11)C]Vorozole accumulated in all brain regions with highest accumulation in the aromatase-rich amygdala and preoptic area. Accumulation was blocked with vorozole and letrozole consistent with reports of some level of aromatase in many brain regions. Conclusions: The discovery of a contaminating labeled isomer and the development of a method for isolating pure [N-methyl-(11)C]vorozole combine to provide a new scientific tool for PET Studies of the biology of aromatase and for drug research and development. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kim, Sung Won; Biegon, Anat; Katsamanis, Zachary E.; Hooker, Jacob M.; Shea, Colleen; Xu, Youwen; King, Payton; Carter, Pauline; Alexoff, David L.; Fowler, Joanna S.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Ehrlich, Carolin W.] Johannes Gutenberg Univ Mainz, Inst Organ Chem, D-6500 Mainz, Germany. [Muench, Lisa] NIAAA, Bethesda, MD USA. [Fowler, Joanna S.] Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. [Fowler, Joanna S.] SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA. RP Kim, SW (reprint author), Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. EM swkim@bnl.gov OI Hooker, Jacob/0000-0002-9394-7708 FU Brookhaven National Laboratory, US Department of Energy [DE-AC02-98CH10886]; Office of Biological and Environmental Research; National Institutes of Health [K05 DA 020001]; Deutscher Akademischer Austausch Dienst, Bonn, Germany FX This work was carried out at Brookhaven National Laboratory under contract DE-AC02-98CH10886 with the US Department of Energy and supported by its Office of Biological and Environmental Research and also by the National Institutes of Health (K05 DA 020001) and, in part, by Deutscher Akademischer Austausch Dienst, Bonn, Germany, for a student fellowship for Carolin Ehrlich. We also thank Johnson & Johnson Pharmaceutical Research and Development for a postdoctoral fellowship to Sung Won Kim. We thank Michael Schueller and David Schlyer for cyclotron operations and Donald Warner for PET operations. We are also grateful to Jean Logan for advice and discussions and to Dr. Nick Carruthers for his help in obtaining samples of vorozole and norvorozole. NR 28 TC 20 Z9 20 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0969-8051 J9 NUCL MED BIOL JI Nucl. Med. Biol. PD APR PY 2009 VL 36 IS 3 BP 323 EP 334 DI 10.1016/j.nucmedbio.2008.12.013 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 432JT UT WOS:000265130000011 PM 19324278 ER PT J AU Post, K Kankia, B Gopalakrishnan, S Yang, V Cramer, E Saladores, P Gorelick, RJ Guo, JH Musier-Forsyth, K Levin, JG AF Post, Klara Kankia, Besik Gopalakrishnan, Swathi Yang, Victoria Cramer, Elizabeth Saladores, Pilar Gorelick, Robert J. Guo, Jianhui Musier-Forsyth, Karin Levin, Judith G. TI Fidelity of plus-strand priming requires the nucleic acid chaperone activity of HIV-1 nucleocapsid protein SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSCRIPTASE RNASE-H; DEPENDENT DNA POLYMERASE; TYPE-1 POLYPURINE TRACT; ZINC-FINGER STRUCTURES; PRIMER BINDING-SITE; REVERSE-TRANSCRIPTASE; IN-VITRO; STRUCTURAL DETERMINANTS; DESTABILIZING ACTIVITY AB During minus-strand DNA synthesis, RNase H degrades viral RNA sequences, generating potential plus-strand DNA primers. However, selection of the 3 polypurine tract (PPT) as the exclusive primer is required for formation of viral DNA with the correct 5-end and for subsequent integration. Here we show a new function for the nucleic acid chaperone activity of HIV-1 nucleocapsid protein (NC) in reverse transcription: blocking mispriming by non-PPT RNAs. Three representative 20-nt RNAs from the PPT region were tested for primer extension. Each primer had activity in the absence of NC, but less than the PPT. NC reduced priming by these RNAs to essentially base-line level, whereas PPT priming was unaffected. RNase H cleavage and zinc coordination by NC were required for maximal inhibition of mispriming. Biophysical properties, including thermal stability, helical structure and reverse transcriptase (RT) binding affinity, showed significant differences between PPT and non-PPT duplexes and the trends were generally correlated with the biochemical data. Binding studies in reactions with both NC and RT ruled out a competition binding model to explain NCs observed effects on mispriming efficiency. Taken together, these results demonstrate that NC chaperone activity has a major role in ensuring the fidelity of plus-strand priming. C1 [Post, Klara; Gopalakrishnan, Swathi; Yang, Victoria; Cramer, Elizabeth; Saladores, Pilar; Guo, Jianhui; Levin, Judith G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Mol Genet Lab, Bethesda, MD 20892 USA. [Kankia, Besik; Musier-Forsyth, Karin] Ohio State Univ, Dept Chem, Columbus, OH 43210 USA. [Kankia, Besik; Musier-Forsyth, Karin] Ohio State Univ, Dept Biochem, Columbus, OH 43210 USA. [Gorelick, Robert J.] SAIC Frederick Inc, NCI, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Guo, Jianhui] Shanghai Allist Pharmaceut, Shanghai 201203, Peoples R China. RP Levin, JG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Mol Genet Lab, Bethesda, MD 20892 USA. EM levinju@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH [GM065056, N01-CO-12400]; National Cancer Institute FX This research was supported in part by the Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (to J.G.L.) and NIH grant GM065056 (to K. M. F.) and was also funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 (to R.J.G.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government. Funding for open access charge: Intramural Research Program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 90 TC 17 Z9 18 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2009 VL 37 IS 6 BP 1755 EP 1766 DI 10.1093/nar/gkn1045 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431XF UT WOS:000265097400011 PM 19158189 ER PT J AU Castillo-Acosta, VM Ruiz-Perez, LM Yang, W Gonzalez-Pacanowska, D Vidal, AE AF Castillo-Acosta, Victor M. Ruiz-Perez, Luis M. Yang, Wei Gonzalez-Pacanowska, Dolores Vidal, Antonio E. TI Identification of a residue critical for the excision of 3'-blocking ends in apurinic/apyrimidinic endonucleases of the Xth family SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN APURINIC ENDONUCLEASE; COLI EXONUCLEASE-III; SINGLE-STRAND BREAKS; HUMAN CELL-EXTRACTS; DNA-REPAIR ENZYMES; ESCHERICHIA-COLI; ABASIC SITE; LEISHMANIA-MAJOR; AP ENDONUCLEASE; ACTIVE-SITE AB DNA single-strand breaks containing 3'-blocking groups are generated from attack of the sugar backbone by reactive oxygen species or after base excision by DNA glycosylase/apurinic/apyrimidinic (AP) lyases. In human cells, APE1 excises sugar fragments that block the 3'-ends thus facilitating DNA repair synthesis. In Leishmania major, the causal agent of leishmaniasis, the APE1 homolog is the class II AP endonuclease LMAP. Expression of LMAP but not of APE1 reverts the hypersensitivity of a xth nfo repair-deficient Escherichia coli strain to the oxidative compound hydrogen peroxide (H(2)O(2)). To identify the residues specifically involved in the repair of oxidative DNA damage, we generated random mutations in the ape1 gene and selected those variants that conferred protection against H(2)O(2). Among the resistant clones, we isolated a mutant in the nuclease domain of APE1 (D70A) with an increased capacity to remove 3'-blocking ends in vitro. D70 of APE1 aligns with A138 of LMAP and mutation of the latter to aspartate significantly reduces its 3'-phosphodiesterase activity. Kinetic analysis shows a novel role of residue D70 in the excision rate of 3'-blocking ends. The functional and structural differences between the parasite and human enzymes probably reflect a divergent molecular evolution of their DNA repair responses to oxidative damage. C1 [Castillo-Acosta, Victor M.; Ruiz-Perez, Luis M.; Gonzalez-Pacanowska, Dolores; Vidal, Antonio E.] CSIC, Inst Parasitol & Biomed Lopez Neyra, Granada 18100, Spain. [Yang, Wei] NIDDK, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Vidal, AE (reprint author), CSIC, Inst Parasitol & Biomed Lopez Neyra, Avda Conocimiento S-N, Granada 18100, Spain. EM avidal@ipb.csic.es RI Yang, Wei/D-4926-2011; OI Yang, Wei/0000-0002-3591-2195; Vidal, Antonio/0000-0001-9491-8901 FU Plan Nacional de Investigacion [SAF2005-02287]; Programa de Ayudas de Retorno de Doctores; Programa Ramon y Cajal; Ministerio de Ciencia e Innovacion (Spain). FX Plan Nacional de Investigacion (SAF2005-02287); Programa de Ayudas de Retorno de Doctores (Junta de Andalucia to A.E.V.); Programa Ramon y Cajal (Ministerio de Educacion y Ciencia to A.E.V.). Funding for open access charge: Plan Nacional de Investigacion (SAF2008-03953), Ministerio de Ciencia e Innovacion (Spain). NR 68 TC 14 Z9 14 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2009 VL 37 IS 6 BP 1829 EP 1842 DI 10.1093/nar/gkp021 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431XF UT WOS:000265097400018 PM 19181704 ER PT J AU Prasad, R Longley, MJ Sharief, FS Hou, EW Copeland, WC Wilson, SH AF Prasad, Rajendra Longley, Matthew J. Sharief, Farida S. Hou, Esther W. Copeland, William C. Wilson, Samuel H. TI Human DNA polymerase theta possesses 5-dRP lyase activity and functions in single-nucleotide base excision repair in vitro SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DEOXYRIBOSE PHOSPHATE LYASE; SENSITIVITY PROTEIN MUS308; SOMATIC HYPERMUTATION; IG GENES; INSERTION FIDELITY; BETA; POLQ; SITE; DEOXYNUCLEOTIDES; IDENTIFICATION AB DNA polymerase (Pol ) is a low-fidelity DNA polymerase that belongs to the family A polymerases and has been proposed to play a role in somatic hypermutation. Pol has the ability to conduct translesion DNA synthesis opposite an AP site or thymine glycol, and it was recently proposed to be involved in base excision repair (BER) of DNA damage. Here, we show that Pol has intrinsic 5-deoxyribose phosphate (5-dRP) lyase activity that is involved in single-nucleotide base excision DNA repair (SN-BER). Full-length human Pol is a 300-kDa polypeptide, but we show here that the 98-kDa C-terminal region of Pol possesses both DNA polymerase activity and dRP lyase activity and is sufficient to carry out base excision repair in vitro. The 5-dRP lyase activity is independent of the polymerase activity, in that a polymerase inactive mutant retained full 5-dRP lyase activity. Domain mapping of the 98-kDa enzyme by limited proteolysis and NaBH(4) cross-linking with a BER intermediate revealed that the dRP lyase active site resides in a 24-kDa domain of Pol . These results are consistent with a role of Pol in BER. C1 [Prasad, Rajendra; Hou, Esther W.; Wilson, Samuel H.] NIEHS, NIH, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Longley, Matthew J.; Sharief, Farida S.; Copeland, William C.] NIEHS, NIH, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, NIH, Struct Biol Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences; [Z01-ES050159-12]; [Z01-ES065078] FX Research Project Numbers Z01-ES050159-12 (to S.H.W.) and Z01-ES065078 ( to W.C.C.), in the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. Funding for open access charge: the Intramural Research Program, National Institutes of Health, National Institute of Environmental Health Sciences. NR 33 TC 42 Z9 43 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2009 VL 37 IS 6 BP 1868 EP 1877 DI 10.1093/nar/gkp035 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 431XF UT WOS:000265097400021 PM 19188258 ER PT J AU Stuart, GR Copeland, WC Strand, MK AF Stuart, Gregory R. Copeland, William C. Strand, Micheline K. TI Construction and application of a protein and genetic interaction network (yeast interactome) SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TRANSCRIPTIONAL REGULATORY NETWORKS; DNA-POLYMERASE-GAMMA; SACCHAROMYCES-CEREVISIAE; MITOCHONDRIAL-DNA; CELL CYCLE; GLUCOSE; EXPRESSION; PATHWAYS; PROVIDE; CAT8 AB Cytoscape is a bioinformatic data analysis and visualization platform that is well-suited to the analysis of gene expression data. To facilitate the analysis of yeast microarray data using Cytoscape, we constructed an interaction network (interactome) using the curated interaction data available from the Saccharomyces Genome Database (www. yeastgenome.org) and the database of yeast transcription factors at YEASTRACT (www.yeastract.com). These data were formatted and imported into Cytoscape using semi-automated methods, including Linux-based scripts, that simplified the process while minimizing the introduction of processing errors. The methods described for the construction of this yeast interactome are generally applicable to the construction of any interactome. Using Cytoscape, we illustrate the use of this interactome through the analysis of expression data from a recent yeast diauxic shift experiment. We also report and briefly describe the complex associations among transcription factors that result in the regulation of thousands of genes through coordinated changes in expression of dozens of transcription factors. These cells are thus able to sensitively regulate cellular metabolism in response to changes in genetic or environmental conditions through relatively small changes in the expression of large numbers of genes, affecting the entire yeast metabolome. C1 [Stuart, Gregory R.; Copeland, William C.; Strand, Micheline K.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Strand, Micheline K.] USA, Res Off, Div Life Sci, Res Triangle Pk, NC 27709 USA. RP Copeland, WC (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM copelan1@niehs.nih.gov FU National Institutes of Health; National Institute of Environmental Health Sciences [Z01-ES065078]; US Army Research Office [W991NF-04-D0001, DAAG55-98-D-0002]; National Research Council Research Associateship Award; Intramural Research Program FX National Institutes of Health, National Institute of Environmental Health Sciences (Z01-ES065078 to W. C. C.); US Army Research Office (W991NF-04-D0001 and DAAG55-98-D-0002 to G. R. S.); National Research Council Research Associateship Award. Funding for open access charge: Intramural Research Program, National Institutes of Health, National Institute of Environmental Health Sciences. NR 28 TC 6 Z9 6 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD APR PY 2009 VL 37 IS 7 AR e54 DI 10.1093/nar/gkp140 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 441AM UT WOS:000265741600037 PM 19273534 ER PT J AU Lieb, W Manning, AK Florez, JC Dupuis, J Cupples, LA McAteer, JB Vasan, RS Hoffmann, U O'Donnell, CJ Meigs, JB Fox, CS AF Lieb, Wolfgang Manning, Alisa K. Florez, Jose C. Dupuis, Josee Cupples, L. Adrienne McAteer, Jarred B. Vasan, Ramachandran S. Hoffmann, Udo O'Donnell, Christopher J. Meigs, James B. Fox, Caroline S. TI Variants in the CNR1 and the FAAH Genes and Adiposity Traits in the Community SO OBESITY LA English DT Article ID BODY-MASS INDEX; CANNABINOID-1 RECEPTOR BLOCKER; GENOMEWIDE LINKAGE ANALYSIS; METABOLIC RISK-FACTORS; FOOD-INTAKE; OVERWEIGHT PATIENTS; ENERGY-BALANCE; HEART-DISEASE; OBESITY; RIMONABANT AB Pharmacologic blockade of the endocannabinoid receptor 1 leads to weight loss and an improved metabolic risk profile in overweight and obese individuals. We hypothesize that common genetic variants in the CNR1 (encoding endocannabinoid receptor 1) and FAAH genes (encoding fatty acid amide hydrolase, a key enzyme hydrolyzing endocannabinoids) are associated with adiposity traits. We genotyped 18 single-nucleotide polymorphisms (SNPs) in the CNR1 gene and 9 SNPs in the FAAH gene in 2,415 Framingham Offspring Study participants (mean age 61 +/- 10 years; 52.6% women; mean BMI 28.2 +/- 5.4 kg/m(2); 30.3% obese) and studied them for association with cross-sectional and longitudinal measures of adiposity (BMI, waist circumference, change over time in BMI and waist circumference, visceral and subcutaneous adipose tissue) using linear mixed-effect models. The selected SNPs captured 85% (r(2) = 0.8) of the common variation (minor allele frequency >5%) at the CNR1 locus and 96% (r(2) = 0.8) of the common variation at the FAAH locus (defined as the genomic segment containing the gene + 20 kb upstream and + 10 kb downstream). After correction for multiple testing, none of the SNPs in the CNR1 gene or in the FAAH gene displayed statistical evidence for association with BMI, waist circumference, and visceral adipose tissue or subcutaneous adipose tissue (all P > 0.18). Despite comprehensive SNP mapping across the genes and their regulatory regions in a large unselected sample, we failed to find evidence for an association of common variants in the CNR1 and FAAH genes with measures of adiposity in our community-based sample. C1 [Lieb, Wolfgang; Vasan, Ramachandran S.; O'Donnell, Christopher J.; Fox, Caroline S.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Manning, Alisa K.; Dupuis, Josee; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Florez, Jose C.; McAteer, Jarred B.] Massachusetts Gen Hosp, Diabet Unit, Dept Med, Boston, MA 02114 USA. [Florez, Jose C.; McAteer, Jarred B.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Florez, Jose C.; McAteer, Jarred B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Florez, Jose C.; McAteer, Jarred B.] Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Div Endocrinol, Sch Med, Boston, MA 02115 USA. RP Fox, CS (reprint author), Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. EM foxca@nhlbi.nih.gov RI Lieb, Wolfgang/C-1990-2012; OI Cupples, L. Adrienne/0000-0003-0273-7965; Ramachandran, Vasan/0000-0001-7357-5970; Dupuis, Josee/0000-0003-2871-3603 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Diabetes Association Career Development Award; sanofi-aventis; NIH NCRR [1S10RR163736-01A1]; NIDDK [K24 DK080140]; NIH [K23 DK65978-04]; [2K24HL04334] FX This study was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), an American Diabetes Association Career Development Award (J.B.M.), a research grant from sanofi-aventis (J.B.M.), and the Boston University Linux Cluster for Genetic Analysis (LinGA) funded by the NIH NCRR Shared Instrumentation grant (1S10RR163736-01A1). J.B.M. is also supported by NIDDK K24 DK080140. R. S. V. is supported by 2K24HL04334. J.C.F. is supported by NIH Research Career Award K23 DK65978-04 NR 37 TC 19 Z9 19 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD APR PY 2009 VL 17 IS 4 BP 755 EP 760 DI 10.1038/oby.2008.608 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 425TA UT WOS:000264658800028 PM 19165169 ER PT J AU Gluck, ME Venti, CA Lindsay, RS Knowler, WC Salbe, AD Krakoff, J AF Gluck, Marci E. Venti, Colleen A. Lindsay, Robert S. Knowler, William C. Salbe, Arline D. Krakoff, Jonathan TI Maternal Influence, Not Diabetic Intrauterine Environment, Predicts Children's Energy Intake SO OBESITY LA English DT Article ID PIMA INDIAN WOMEN; FOOD-INTAKE; PHYSICAL-ACTIVITY; BIRTH-WEIGHT; OBESITY; EXPENDITURE; RATS AB Offspring of women with diabetes during pregnancy are at increased risk of accelerated weight gain and diabetes, effects partly mediated by the in utero environment. Whether differences in energy intake can explain this increased risk is unknown. We compared diet composition, eating patterns, and physiological responses to a mixed meal in 63 nondiabetic children whose mothers developed diabetes either before (offspring of diabetic mothers, ODMs, n = 31, age 9.2 +/- 1.7 years, mean +/- s.d.) or after (offspring of prediabetic mothers, OPDMs, n = 32, 9.6 +/- 1.3 years) the pregnancy. After consuming a standardized diet for 3 days, participants ate ad libitum from a computer- operated vending machine stocked with foods they had rated favorably on a food preferences questionnaire. Mothers and children always ate together. A subset of 35 children underwent a meal test with blood draws to measure insulin and glucose. Children's energy intake was associated with age, sex, and percent body fat, and strongly with mother's energy intake (r = 0.57, P < 0.0001). After adjustment for these variables, there were no differences between ODM and OPDM in energy intake or diet composition. The insulin area under the curve (AUC) following the meal test was significantly correlated with total energy intake but not after adjustment for the above covariates. Differences in energy intake were not observed between ODM and OPDM. Mother's energy intake was a significant predictor of children's energy intake. These findings indicate that in this subset of children in a controlled in- patient setting, maternal influence may outweigh intrauterine effects on energy intake. C1 [Gluck, Marci E.; Venti, Colleen A.; Krakoff, Jonathan] NIDDKD, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ USA. [Lindsay, Robert S.] Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow, Lanark, Scotland. [Lindsay, Robert S.; Knowler, William C.] NIDDKD, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. [Salbe, Arline D.] Kronos Longev Res Inst, Phoenix, AZ USA. RP Gluck, ME (reprint author), NIDDKD, Obes & Diabet Clin Res Sect, NIH, Phoenix, AZ USA. EM gmarci@mail.nih.gov FU Intramural NIH HHS [Z01 DK069091-01] NR 17 TC 5 Z9 5 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD APR PY 2009 VL 17 IS 4 BP 772 EP 777 DI 10.1038/oby.2008.620 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 425TA UT WOS:000264658800031 PM 19148117 ER PT J AU Spong, CY AF Spong, Catherine Y. TI Preterm Birth An Enigma and a Priority SO OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Spong, CY (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. EM spongc@dir49.nichd.nih.gov NR 1 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2009 VL 113 IS 4 BP 770 EP 771 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 424PG UT WOS:000264578000001 PM 19305317 ER PT J AU Partridge, E Kreimer, AR Greenlee, RT Williams, C Xu, JL Church, TR Kessel, B Johnson, CC Weissfeld, JL Isaacs, C Andriole, GL Ogden, S Ragard, LR Buys, SS AF Partridge, Edward Kreimer, Aimee R. Greenlee, Robert T. Williams, Craig Xu, Jian-Lun Church, Timothy R. Kessel, Bruce Johnson, Christine C. Weissfeld, Joel L. Isaacs, Claudine Andriole, Gerald L. Ogden, Sheryl Ragard, Lawrence R. Buys, Saundra S. CA PLCO Project Team TI Results From Four Rounds of Ovarian Cancer Screening in a Randomized Trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID RISK AB OBJECTIVE: To test whether annual screening with transvaginal ultrasonography and CA 125 reduces ovarian cancer mortality. METHODS: Data from the first four annual screens, denoted T0-T3, are reported. A CA 125 value at or above 35 units/mL or an abnormality on transvaginal ultrasonography was considered a positive screen. Diagnostic follow-up of positive screens was performed at the discretion of participants' physicians. Diagnostic procedures and cancers were tracked and verified through medical records. RESULTS: Among 34,261 screening arm women without prior oophorectomy, compliance with screening ranged from 83.1% (T0) to 77.6% (T3). Screen positivity rates declined slightly with transvaginal ultrasonography, from 4.6 at T0 to 2.9-3.4 at T1-T3; CA 125 positivity rates (range 1.4-1.8%) showed no time trend. Eighty-nine invasive ovarian or peritoneal cancers were diagnosed; 60 were screen detected. The positive predictive value (PPV) and cancer yield per 10,000 women screened on the combination of tests were similar across screening rounds (range 1.0-1.3% for PPV and 4.7-6.2 for yield); however, the biopsy (surgery) rate among screen positives decreased from 34% at T0 to 15-20% at T1-T3. The overall ratio of surgeries to screen-detected cancers was 19.5:1. Seventy-two percent of screen-detected cases were late stage (III/IV). CONCLUSION: Through four screening rounds, the ratio of surgeries to screen-detected cancers was high, and most cases were late stage. However, the effect of screening on mortality is as yet unknown. C1 Univ Alabama, Sch Med, Birmingham, AL USA. NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. Marshfield Med Res & Educ Fdn, Marshfield, WI USA. Informat Management Serv Inc, Rockville, MD USA. Univ Minnesota, Minneapolis, MN USA. Pacific Hlth Res Inst, Honolulu, HI USA. Henry Ford Hlth Syst, Detroit, MI USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Washington, DC USA. Washington Univ, Sch Med, St Louis, MO USA. Univ Colorado, Ctr Canc, Denver, CO 80262 USA. Westat Corp, Rockville, MD USA. Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. RP Partridge, E (reprint author), 7802 6th Ave S,NP 2555, Birmingham, AL 35294 USA. EM pakers@uabmc.edu RI Kreimer, Aimee/H-1687-2015; OI Kessel, Bruce/0000-0001-9979-2068 FU Vivus (Mountain View, CA); Wyeth (Madison, NJ); Proctor & Gamble (Cincinnati, OH) FX Dr. Kessel has received research funding from Vivus (Mountain View, CA), Wyeth (Madison, NJ), and Proctor & Gamble (Cincinnati, OH). He has been a consultant to Novartis (Bavel, Switzerland), Merck (West Point, PA), and Eli-Lilly & Q. (Indianapolis, IN). He has also served on the speakers bureau for Bayer (Leverkusen, Germany) and Merck. The other authors did not report any potential conflicts of interest. NR 12 TC 121 Z9 126 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2009 VL 113 IS 4 BP 775 EP 782 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 424PG UT WOS:000264578000003 PM 19305319 ER PT J AU Ashton, DM Lawrence, HC Adams, NL Fleischman, AR AF Ashton, Diane M. Lawrence, Hal C., III Adams, Nelson L., III Fleischman, Alan R. TI Surgeon General's Conference on the Prevention of Preterm Birth SO OBSTETRICS AND GYNECOLOGY LA English DT Article AB To address the serious and seemingly intractable problem of preterm birth, the Surgeon General's Conference on the Prevention of Preterm Birth convened many of the country's experts from the public and private sectors of research, public health, and health care delivery to discuss preventive strategies. The purpose of the conference was to increase awareness of preterm birth in the United States, review key findings and reports issued by experts in the field, and establish an agenda for activities in both the public and private sectors to mitigate the problem. The six work groups created focused on biomedical research, epidemiological research, psychosocial and behavioral factors in preterm birth, professional education and training, outreach and communication, and quality of care and health services. Several crosscutting issues between the work groups were identified, and the conference concluded with the request to the Surgeon General to make the prevention of preterm birth a national public health priority. Reaching this goal through the implementation of the conference recommendations will require new resources to create broad-based research capacity, a vigorous national vital records system, multidisciplinary intervention programs, careful study of factors contributing to racial and ethnic disparities, reinvigorated health professional and consumer education programs, and access to high-quality preconception and perinatal healthcare for all Americans. Clinicians must be adequately informed to initiate activities to prevent this serious problem. Recommendations from this conference will inform Congress and create a national agenda to address the identification of the causes, risk factors, prevention, and treatment of preterm birth. C1 [Ashton, Diane M.] March Dimes, Natl Off, White Plains, NY 10605 USA. Amer Coll Obstetricians & Gynecologists, Washington, DC 20024 USA. Jackson N Med Ctr, Dept Obstet & Gynecol, N Miami Beach, FL USA. Natl Med Assoc, Washington, DC USA. Board Trustees Access Hlth Solut, Sunrise, FL USA. SUNY Downstate, Hlth Sci Ctr Brooklyn, Brooklyn, NY USA. NICHHD, Advisory Comm Natl Childrens Study, NIH, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. RP Ashton, DM (reprint author), March Dimes, Natl Off, 1275 Mamaroneck Ave, White Plains, NY 10605 USA. EM dashton@marchofdimes.com NR 2 TC 27 Z9 29 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD APR PY 2009 VL 113 IS 4 BP 925 EP 930 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 424PG UT WOS:000264578000024 PM 19305340 ER PT J AU Vikram, B Coleman, CN Deye, JA AF Vikram, Bhadrasain Coleman, C. Norman Deye, James A. TI Current Status and Future Potential of Advanced Technologies in Radiation Oncology Part 2. State of the Science by Anatomic Site Clinical Trials and Radiation Oncology Technologies SO ONCOLOGY-NEW YORK LA English DT Article AB In December 2006, the Radiation Research Program of the Division of Cancer Treatment and Diagnosis of the National Cancer Institute hosted a workshop intended to address current issues related to advanced radiation therapy technologies, with an eye toward (1) defining the specific toxicities that have limited the success of "conventional" radiation therapy, (2) examining the evidence from phase III studies for the improvements attributed to the advanced technologies in the treatment of several cancers commonly treated with radiation therapy, and (3) determining the opportunities and priorities for further technologic development and clinical trials. The new technologies offer substantial theoretical advantage in radiation dose distributions that, if realized in clinical practice, may help many cancer patients live longer and/or better. The precision of the advanced technologies may allow us to reduce the volume of normal tissue irradiated in the vicinity of the clinical target volume. Part 1 of this two-part article, which appeared in the March issue of ONCOLOGY, provided a general overview of the workshop discussion, focusing on the challenges posed by the new technologies and resources available or in development for meeting those challenges. This month, part 2 will outline the state of the science for each disease site. C1 [Vikram, Bhadrasain] NCI, Clin Radiat Oncol Branch, Radiat Res Program, Div Canc Treatment & Diag, Rockville, MD 20852 USA. RP Vikram, B (reprint author), NCI, Clin Radiat Oncol Branch, Radiat Res Program, Div Canc Treatment & Diag, 6130 Execut Blvd, Rockville, MD 20852 USA. EM vikramb@mail.nih.gov NR 32 TC 9 Z9 10 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD APR PY 2009 VL 23 IS 4 BP 380 EP 385 PG 6 WC Oncology SC Oncology GA V18PN UT WOS:000208016800011 PM 19476269 ER PT J AU Domingo, DL Trujillo, MI Council, SE Merideth, MA Gordon, LB Wu, T Introne, WJ Gahl, WA Hart, TC AF Domingo, D. L. Trujillo, M. I. Council, S. E. Merideth, M. A. Gordon, L. B. Wu, T. Introne, W. J. Gahl, W. A. Hart, T. C. TI Hutchinson-Gilford progeria syndrome: oral and craniofacial phenotypes SO ORAL DISEASES LA English DT Article DE progeria; craniofacial; dentition; oral; phenotype AB Hutchinson-Gilford progeria syndrome (HGPS) is a rare early-onset accelerated senescence syndrome. In HGPS, a recently identified de novo dominant mutation of the lamin A gene (LMNA) produces abnormal lamin A, resulting in compromised nuclear membrane integrity. Clinical features include sclerotic skin, cardiovascular and bone abnormalities, and marked growth retardation. Craniofacial features include 'bird-like' facies, alopecia, craniofacial disproportion, and dental crowding. Our prospective study describes dental, oral soft tissue, and craniofacial bone features in HGPS. Fifteen patients with confirmed p.G608G LMNA mutation (1-17 years, seven males, eight females) received comprehensive oral evaluations. Anomalies of oral soft tissue, gnathic bones, and dentition were identified. Radiographic findings included hypodontia (n = 7), dysmorphic teeth (n = 5), steep mandibular angles (n = 11), and thin basal bone (n = 11). Soft tissue findings included ogival palatal arch (n = 8), median sagittal palatal fissure (n = 7), and ankyloglossia (n = 7). Calculated dental ages (9 months to 11 years 2 months) were significantly lower than chronological ages (1 year 6 months to 17 years 8 months) (P = 0.002). Eleven children manifested a shorter mandibular body, anterior/posterior cranial base and ramus, but a larger gonial angle, compared to age/gender/race norms. Novel oral-craniofacial phenotypes and quantification of previously reported features are presented. Our findings expand the HGPS phenotype and provide additional insight into the complex pathogenesis of HGPS. C1 [Domingo, D. L.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Merideth, M. A.; Introne, W. J.; Gahl, W. A.] NHGRI, Bethesda, MD 20892 USA. [Merideth, M. A.] NIH, Intramural Off Rare Dis, Bethesda, MD USA. [Gordon, L. B.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. RP Domingo, DL (reprint author), Natl Inst Dent & Craniofacial Res, NIH, 10 Ctr Dr,Bldg 10 Room 1N-117 MSC 1191, Bethesda, MD 20892 USA. EM ddomingo@mail.nih.gov FU NIDCR; NHGRI; NIH FX This work was supported by the intramural programs of NIDCR and NHGRI, NIH. We thank the children with progeria, their families, and The Progeria Research Foundation Diagnostics Program (Peabody, MA) for their participation in this study. NR 29 TC 10 Z9 10 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD APR PY 2009 VL 15 IS 3 BP 187 EP 195 DI 10.1111/j.1601-0825.2009.01521.x PG 9 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 421GJ UT WOS:000264347100002 PM 19236595 ER PT J AU Bassim, CW Wright, JT Guadagnini, JP Muralidharan, R Sloan, J Domingo, DL Venditti, CP Hart, TC AF Bassim, C. W. Wright, J. T. Guadagnini, J. P. Muralidharan, R. Sloan, J. Domingo, D. L. Venditti, C. P. Hart, T. C. TI Enamel defects and salivary methylmalonate in methylmalonic acidemia SO ORAL DISEASES LA English DT Article DE enamel; methylmalonic acidemia; enamel hypoplasia; enamel microstructure; salivary biomarker ID CHRONIC-RENAL-FAILURE; AMELOGENESIS IMPERFECTA; PROPIONIC ACIDEMIA; STABLE-ISOTOPE; IDENTIFICATION; MANAGEMENT; ACIDURIA; TRANSPLANTATION; HOMOCYSTINURIA; HETEROGENEITY AB To characterize enamel defects in patients with methylmalonic acidemia (MMA) and cobalamin (cbl) metabolic disorders and to examine salivary methylmalonate levels in MMA. Teeth from patients (n = 32) were evaluated for enamel defects and compared with age- and gender-matched controls (n = 55). Complementation class (mut, cblA, cblB and cblC) and serum methylmalonate levels were examined. Primary teeth from two patients were examined by light and scanning electron microscopy and salivary methylmalonate levels from two patients were analyzed. Enamel defects were significantly more prevalent per tooth in the affected group than the control group, across complementation types (P < 0.0001). The mut MMA subgroup had a significantly higher prevalence per individual of severe enamel defects than controls (P = 0.021), and those with enamel defects exhibited higher serum methylmalonate levels than those without (P = 0.017). Salivary methylmalonate levels were extremely elevated and were significantly higher than controls (P = 0.002). Primary teeth were free of enamel defects except for two cblC patients who exhibited severe enamel hypoplasia. One primary tooth from a cblC patient manifested markedly altered crystal microstructure. Enamel anomalies represent a phenotypic manifestation of MMA and cbl metabolic disorders. These findings suggest an association between enamel developmental pathology and disordered metabolism. C1 [Venditti, C. P.] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Bassim, C. W.; Guadagnini, J. P.; Muralidharan, R.; Domingo, D. L.; Hart, T. C.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Wright, J. T.] Univ N Carolina, Sch Dent, Dept Pediat Dent, Chapel Hill, NC USA. RP Venditti, CP (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. EM venditti@mail.nih.gov FU NHGRI; NIDCR/IRP; NIH; DHHS FX This study was supported through the Divisions of Intramural Research of the NHGRI and NIDCR/IRP, NIH, DHHS. NR 53 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD APR PY 2009 VL 15 IS 3 BP 196 EP 205 DI 10.1111/j.1601-0825.2008.01509.x PG 10 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 421GJ UT WOS:000264347100003 PM 19143946 ER PT J AU Czerninski, R Krichevsky, S Ashhab, Y Gazit, D Patel, V Ben-Yehuda, D AF Czerninski, R. Krichevsky, S. Ashhab, Y. Gazit, D. Patel, V. Ben-Yehuda, D. TI Promoter hypermethylation of mismatch repair genes, hMLH1 and hMSH2 in oral squamous cell carcinoma SO ORAL DISEASES LA English DT Article DE oral cancer; hypermethylation; hMLH1; hMSH2; multiple malignancies ID NECK-CANCER; MICROSATELLITE INSTABILITY; DNA HYPERMETHYLATION; MULTIPLE GENES; FIELD CANCERIZATION; HEAD; METHYLATION; INACTIVATION; EPIGENETICS; EXPRESSION AB Major risk factors of oral squamous cell carcinoma (OSCC) are environmental and can lead to DNA mutagenesis. Mismatch repair (MMR) system functions to repair small DNA lesions, which can be targeted for promoter hypermethylation. We therefore wanted to test whether hypermethylation of MMR genes (hMLH1, hMSH2) could contribute to oral carcinogenesis by correlating the information to patient clinical data. Genomic DNA was extracted from 28 OSCC and six normal oral epithelium samples. The methylation status of the two MMR genes was assessed using Methylation Specific PCR after DNA modification with sodium bisulfite. Serial sections of the same tissues were immunostained with antibodies against hMLH1 and hMSH2 protein. Promoter hypermethylation was observed in 14/28 OSCC cases. Remarkably, 100% of patients with multiple oral malignancies showed hypermethylation in hMLH1 or hMSH2 compared with 31.5% of single tumor patients. In 10 cancer cases, expression of the hMLH1 and hMSH2 genes by immunostaining showed reduced or absence of expression of one of the genes, although some did not reflect the methylation status. Hypermethylation of hMLH1 and hMSH2 might play a role in oral carcinogenesis and may be correlated with a tendency to develop multiple oral malignancies. C1 [Czerninski, R.] Hebrew Univ Jerusalem, Hadassah Sch Dent Med, Dept Oral Med, IL-91120 Jerusalem, Israel. [Krichevsky, S.; Ashhab, Y.; Ben-Yehuda, D.] Hebrew Univ Jerusalem, Hadassah Med Ctr, Dept Hematol, IL-91120 Jerusalem, Israel. [Gazit, D.] Hebrew Univ Jerusalem, Hadassah Med Ctr, Skeletal Biotechnol Lab, IL-91120 Jerusalem, Israel. [Patel, V.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Czerninski, R (reprint author), Hebrew Univ Jerusalem, Hadassah Sch Dent Med, Dept Oral Med, POB 12272, IL-91120 Jerusalem, Israel. EM rakefetc@hadassah.org.il FU Dr Izador I. Cabakoff Research Endowment Fund FX The research was partially supported by the Dr Izador I. Cabakoff Research Endowment Fund. NR 40 TC 29 Z9 31 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1354-523X J9 ORAL DIS JI Oral Dis. PD APR PY 2009 VL 15 IS 3 BP 206 EP 213 DI 10.1111/j.1601-0825.2008.01510.x PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 421GJ UT WOS:000264347100004 PM 19207881 ER PT J AU Molinolo, AA Amornphimoltham, P Squarize, CH Castilho, RM Patel, V Gutkind, JS AF Molinolo, Alfredo A. Amornphimoltham, Panomwat Squarize, Cristiane H. Castilho, Rogerio M. Patel, Vyomesh Gutkind, J. Silvio TI Dysregulated molecular networks in head and neck carcinogenesis SO ORAL ONCOLOGY LA English DT Review DE Oral cancer; Signal transduction; Targeted therapies; Oncogenes; Tumor suppressor genes; mTOR ID SQUAMOUS-CELL CARCINOMA; GROWTH-FACTOR RECEPTOR; NF-KAPPA-B; LASER-CAPTURE MICRODISSECTION; CANCER STEM-CELLS; TANDEM MASS-SPECTROMETRY; LYMPH-NODE METASTASIS; CONSTITUTIVE ACTIVATION; GENE-EXPRESSION; ORAL-CANCER AB Multiple genetic and epigenetic events, including the aberrant expression and function of molecules regulating cell signaling, growth, survival, motility, angiogenesis, and cell cycle control, underlie the progressive acquisition of a malignant phenotype in squamous carcinomas of the head and neck (HNSCC). In this regard, there has been a recent explosion in our understanding on how extracellular components, cell surface molecules, and a myriad of intracellular proteins and second messenger systems interact with each other, and are organized in pathways and networks to control cellular and tissue functions and cell fate decisions. This emerging ability to understand the basic mechanism controlling inter-and intra-cellular communication has provided an unprecedented opportunity to understand how their dysregulation contributes to the growth and dissemination of human cancers. Here, we will discuss the emerging information on how the use of modern technologies, including gene array and proteomic studies, combined with the molecular dissection of aberrant signaling networks, including the EGFR, ras, NF kappa B, Stat, Wnt/beta-catenin, TGF-beta, and PI3K-AKT-mTOR signaling pathways, can help elucidate the molecular mechanisms underlying HNSCC progression. Ultimately, we can envision that this knowledge may provide tremendous opportunities for the diagnosis of premalignant squamous lesions, and for the development of novel molecular-targeted strategies for the prevention and treatment of HNSCC. Published by Elsevier Ltd. C1 [Molinolo, Alfredo A.; Amornphimoltham, Panomwat; Squarize, Cristiane H.; Castilho, Rogerio M.; Patel, Vyomesh; Gutkind, J. Silvio] Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Craniofacial & Dent Res, Oral & Pharyngeal Canc Branch, NIH, Bldg 30,Room 211,30 Convent Dr, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Castilho, Rogerio/E-4987-2010; Gutkind, J. Silvio/A-1053-2009 FU US National Institutes of Health (NIH); National Institute of Dental and Craniofacial Research (NIDCR) FX We truly regret that we could not cite the seminal work of many of our colleagues owing to space limitations. The authors are supported by funding from the Intramural Research Program of the US National Institutes of Health (NIH) and National Institute of Dental and Craniofacial Research (NIDCR). NR 149 TC 160 Z9 161 U1 1 U2 24 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1368-8375 J9 ORAL ONCOL JI Oral Oncol. PD APR-MAY PY 2009 VL 45 IS 4-5 BP 324 EP 334 DI 10.1016/j.oraloncology.2008.07.011 PG 11 WC Oncology; Dentistry, Oral Surgery & Medicine SC Oncology; Dentistry, Oral Surgery & Medicine GA 440EJ UT WOS:000265682700005 PM 18805044 ER PT J AU Wang, XM Hamza, M Wu, TX Dionne, RA AF Wang, Xiao-Min Hamza, May Wu, Tian-Xia Dionne, Raymond A. TI Upregulation of IL-6, IL-8 and CCL2 gene expression after acute inflammation: Correlation to clinical pain SO PAIN LA English DT Article DE Gene expression; Acute inflammatory pain; Cytokines; Chemokines; NSAIDs ID TUMOR-NECROSIS-FACTOR; MONOCYTE CHEMOATTRACTANT PROTEIN-1; NERVE GROWTH-FACTOR; PROSTAGLANDIN E-2; SOLUBLE RECEPTOR; FACTOR-ALPHA; CYCLOOXYGENASE-2 INHIBITORS; ANTIINFLAMMATORY STEROIDS; NEUTROPHIL INFILTRATION; DIFFERENTIAL REGULATION AB Tissue injury initiates a cascade of inflammatory mediators and hyperalgesic Substances including prostaglandins, cytokines and chemokines. Using microarray and qRT-PCR gene expression analyses, the present Study evaluated changes in gene expression of a cascade of cytokines following acute inflammation and the correlation between the changes in the gene expression level and pain intensity in the oral surgery model Of tissue injury and acute pain. Tissue injury resulted in a significant Upregulation in the gene expression of interleukin-6 (IL-6; 63.3-fold), IL-8 (8.1-fold), chemokine (C-C motif) ligand 2 (CCL2: 8.9-fold), chemokine (C-X-C motif ligand CXCL1; 30.5-fold), chemokine (C-X-C motif) ligand 2 (CXCL2; 26-fold) and annexin A1 (ANXA1; 12-fold). The upregulation of IL-6 gene expression was significantly correlated to the upregulation of IL-8, CCL2, CXCL1 and CXCL2 gene expression. Interestingly, the tissue injury-induced upregulation of IL-6, IL-8 and CCL2 gene expression, was positively correlated to pain intensity at 3 h post-surgery, the onset of acute inflammatory pain. However, ketorolac treatment did not have a significant effect on the gene expression of IL-6, IL-8, CCL2, CXCL2 and ANXA1 at the same time point Of acute inflammation. These results demonstrate that the upregulation of IL-6, IL-8 and CCL2 gene expression contributes to the development of acute inflammation and inflammatory pain. The lack of effect of ketorolac on the expression of these gene products may be related to the ceiling analgesic effects of non-steroidal anti-inflammatory drugs. Published by Elsevier B.V. on behalf of International Association for the Study of Pain. C1 [Wang, Xiao-Min; Hamza, May; Dionne, Raymond A.] NINR, NIH, CRC, Bethesda, MD 20892 USA. [Wu, Tian-Xia] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Hamza, May] Ain Shams Univ, Dept Pharmacol, Fac Med, Cairo, Egypt. RP Dionne, RA (reprint author), NINR, NIH, CRC, Bldg 10,Room 2-1339, Bethesda, MD 20892 USA. EM dionner@mail.nih.gov RI Hamza, May/A-5053-2010 OI Hamza, May/0000-0002-7637-3060 FU Division of Intramural Research NINR; NIDCR/NIH FX This work was supported by Division of Intramural Research NINR and NIDCR/NIH NR 76 TC 46 Z9 49 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD APR PY 2009 VL 142 IS 3 BP 275 EP 283 DI 10.1016/j.pain.2009.02.001 PG 9 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 430CY UT WOS:000264967600017 PM 19233564 ER PT J AU Hernandez, LV Bhutani, MS Eisner, M Guda, NM Lu, N Geenen, JE Catalano, MF AF Hernandez, Lyndon V. Bhutani, Manoop S. Eisner, Milton Guda, Nalini M. Lu, Na Geenen, Joseph E. Catalano, Marc F. TI Non-Surgical Tissue Biopsy Among Patients With Advanced Pancreatic Cancer Effect on Survival SO PANCREAS LA English DT Article DE endoscopic ultrasound; endoscopic retrograde cholangiopancreatography; pancreatic cancer; survival; biopsy ID EUS-GUIDED FNA; NEEDLE ASPIRATION BIOPSY; CARCINOMA; FREQUENCY; TRACT AB Objective: The aim was to determine the survival of patients with advanced, unresectable pancreatic cancer in relation to whether they underwent nonsurgical biopsy of their primary tumor. Methods: A total of 1481 patients with distant stage pancreatic cancer diagnosed between 1992 and 2001 who underwent radiation treatment but not cancer-directed surgery were analyzed. The design is a retrospective cohort study from the Surveillance, Epidemiology, and End Results program of the US National Cancer Institute. Survival curves were created using Kaplan-Meier method and compared via log-rank test. Results: Of 1481 patients (median age, 66 years) included in our analysis, 1406 (95%) underwent nonsurgical biopsy (95%) and 75 (5%) did not. There was no statistically significant difference in overall median survival according to receipt of nonsurgical biopsy (Kaplan-Meier curve, log-rank test = 0.09). A subgroup analysis of patients younger than 65 years who did not undergo biopsy revealed a hazard ratio of 1.76 (95% confidence interval, 1.14-2.72); that is, there was a 76% higher hazard for death among younger patients who did not undergo biopsy compared with those who did (P = 0.011). Conclusion: Nonsurgical biopsy did not seem to negatively impact survival among patients with advanced pancreatic cancer. C1 [Hernandez, Lyndon V.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bhutani, Manoop S.] Univ Texas Galveston, Dept Gastroenterol, Galveston, TX 77555 USA. [Eisner, Milton; Guda, Nalini M.] NCI, Canc Stat Branch, Bethesda, MD 20892 USA. [Geenen, Joseph E.; Catalano, Marc F.] St Lukes Hosp, Dept Gastroenterol, Milwaukee, WI USA. [Lu, Na] Med Coll Wisconsin, Dept Biostat, Milwaukee, WI 53226 USA. RP Hernandez, LV (reprint author), 3805A Spring St,Suite 212, Racine, WI 53405 USA. EM lhernan@mcw.edu NR 18 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0885-3177 J9 PANCREAS JI Pancreas PD APR PY 2009 VL 38 IS 3 BP 289 EP 292 DI 10.1097/MPA.0b013e318192eb9b PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 427EU UT WOS:000264763400008 PM 19136909 ER PT J AU Staretz-Chacham, O Lang, TC LaMarca, ME Krasnewich, D Sidransky, E AF Staretz-Chacham, Orna Lang, Tess C. LaMarca, Mary E. Krasnewich, Donna Sidransky, Ellen TI Lysosomal Storage Disorders in the Newborn SO PEDIATRICS LA English DT Review DE lysosomal storage disorders; neonatal; hydrops; enzyme deficiency ID I-CELL-DISEASE; NONIMMUNE HYDROPS-FETALIS; BETA-GLUCURONIDASE DEFICIENCY; MULTIPLE SULFATASE DEFICIENCY; EARLY-INFANTILE GALACTOSIALIDOSIS; MUCOPOLYSACCHARIDOSIS TYPE-VII; CONGENITAL ADRENAL-HYPERPLASIA; ALPHA-GLUCOSIDASE ACTIVITY; TANDEM MASS-SPECTROMETRY; LETHAL GAUCHER-DISEASE AB Lysosomal storage disorders are rare inborn errors of metabolism, with a combined incidence of 1 in 1500 to 7000 live births. These relatively rare disorders are seldom considered when evaluating a sick newborn. A significant number of the >50 different lysosomal storage disorders, however, do manifest in the neonatal period and should be part of the differential diagnosis of several perinatal phenotypes. We review the earliest clinical features, diagnostic tests, and treatment options for lysosomal storage disorders that can present in the newborn. Although many of the lysosomal storage disorders are characterized by a range in phenotypes, the focus of this review is on the specific symptoms and clinical findings that present in the perinatal period, including neurologic, respiratory, endocrine, and cardiovascular manifestations, dysmorphic features, hepatosplenomegaly, skin or ocular involvement, and hydrops fetalis/congenital ascites. A greater awareness of these features may help to reduce misdiagnosis and promote the early detection of lysosomal storage disorders. Implementing therapy at the earliest stage possible is crucial for several of the lysosomal storage disorders; hence, an early appreciation of these disorders by physicians who treat newborns is essential. Pediatrics 2009; 123: 1191-1207 C1 [Lang, Tess C.; LaMarca, Mary E.; Sidransky, Ellen] NHGRI, NIH, Sect Mol Neurogenet, Med Genet Branch, Bethesda, MD 20892 USA. [Staretz-Chacham, Orna; Krasnewich, Donna] NHGRI, NIH, Off Clin Director, Bethesda, MD 20892 USA. RP Sidransky, E (reprint author), NHGRI, NIH, Sect Mol Neurogenet, Med Genet Branch, Bldg 35,Room 1A213,35 Convent Dr,MSC 3-08, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU National Institutes of Health and National Human Genome Research Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health and National Human Genome Research Institute. NR 170 TC 61 Z9 65 U1 0 U2 5 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 APR PY 2009 VL 123 IS 4 BP 1191 EP 1207 DI 10.1542/peds.2008-0635 PG 17 WC Pediatrics SC Pediatrics GA 425UO UT WOS:000264663100016 PM 19336380 ER PT J AU van Noord, C Aarnoudse, AJLHJ Eijgelsheim, M Sturkenboom, MCJM Sabine, MJM Hofman, A Kors, JA Newton-Cheh, C Witteman, JCM Stricker, BHC AF van Noord, Charlotte Aarnoudse, Albert-Jan L. H. J. Eijgelsheim, Mark Sturkenboom, Miriam C. J. M. Straus, Sabine M. J. M. Hofman, Albert Kors, Jan A. Newton-Cheh, Christopher Witteman, Jacqueline C. M. Stricker, Bruno H. Ch. TI Calcium channel blockers, NOS1AP, and heart-rate-corrected QT prolongation SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE calcium channel blockers; NOS1AP variant; QTc prolongation ID NITRIC-OXIDE SYNTHASE; TORSADE-DE-POINTES; LEFT-VENTRICULAR HYPERTROPHY; MYOCARDIAL-INFARCTION; CARDIAC REPOLARIZATION; GENETIC-VARIANTS; DRUG DEVELOPMENT; INTERVAL; ROTTERDAM; DURATION AB Objectives To study whether NOS1AP single nucleotide polymorphisms (SNPS), rs10494.366 T>G and rs10918594 C>G, modify the heart-rate-corrected QT (QTc) prolonging effect of calcium channel blockers. Background Common variation in the NOS1AP gene has been associated with QT interval variation in several large population samples. NOS1 is presumed to influence intracellular calcium. Methods The prospective population-based Rotterdam Study includes 16 603 ECGs from 7565 participants (>= 55 years), after exclusion of patients with left ventricular hypertrophy, left and right bundle branch block, as well as carriers of pacemakers. The endpoint was the length of the QTc interval in calcium channel blocker users and non-users with the minor alleles compared with the major alleles (wild type). We used a repeated-measurement analysis, adjusted for all known confounders. Results Use of verapamil was associated with a significant QTc interval prolongation [6.0 ms 95% confidence interval (CI) 1.7; 10-2] compared with non-users. Furthermore, users of verapamil with the rs 10494366 GG genotype showed significantly more QTc prolongation than users with the TT genotype [25.4 ms (95% Cl: 5.9-44.9)] (P value for multiplicative interaction 0.0038). Users of isradipine with the GG genotype showed more QTc prolongation than users with the TT genotype [19.8 ms (95% CI: 1.9-37.7)]; however, SNP rs10494366 did not modify the effect on QTc interval on a multiplicative scale (P=0.3563). SNP rs10918594 showed similar results. Conclusion In conclusion, we showed that the minor alleles of both NOS1AP SNPs significantly potentiate the QTc prolonging effect of verapamil. Pharmacogenetics and Genomics 19:260-266 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [van Noord, Charlotte; Aarnoudse, Albert-Jan L. H. J.; Eijgelsheim, Mark; Sturkenboom, Miriam C. J. M.; Straus, Sabine M. J. M.; Hofman, Albert; Witteman, Jacqueline C. M.; Stricker, Bruno H. Ch.] Erasmus MC, Dept Epidemiol, NL-3015 GE Rotterdam, Netherlands. [Stricker, Bruno H. Ch.] Erasmus MC, Dept Internal Med, NL-3015 GE Rotterdam, Netherlands. [Sturkenboom, Miriam C. J. M.; Kors, Jan A.] Erasmus MC, Dept Med Informat, NL-3015 GE Rotterdam, Netherlands. [van Noord, Charlotte; Straus, Sabine M. J. M.] Dutch Med Evaluat Board, The Hague, Netherlands. [Aarnoudse, Albert-Jan L. H. J.; Stricker, Bruno H. Ch.] Inspectorate Hlth Care, The Hague, Netherlands. [Newton-Cheh, Christopher] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Newton-Cheh, Christopher] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Newton-Cheh, Christopher] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. RP Stricker, BHC (reprint author), Erasmus MC, Dept Epidemiol, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. EM b.stricker@erasmusmc.nl FU Pfizer; MerckJohnsonJohnson; Amgen; Roche; GSK; Boehringer; Yamanouchi and Altana FX Conflicts of interest: As employee of Erasmus Medical Center, M.C.J.M.S. has been involved as project leader and in analyses contracted by various pharmaceutical companies and received unconditional research grants from Pfizer, Merck, Johnson&Johnson, Amgen, Roche, GSK, Boehringer, Yamanouchi and Altana, none of which are related to the subject of this-study. M.C.J.M.S. has been consultant to Pfizer, Servier, Celgene, Novartis and Lundbeck on issues not related to this paper. All other authors have no conflicts of interest. NR 49 TC 16 Z9 16 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD APR PY 2009 VL 19 IS 4 BP 260 EP 266 DI 10.1097/FPC.0b013e328324e556 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 429TV UT WOS:000264943900002 PM 19247217 ER PT J AU Uhl, G Drgon, T Johnson, C Rose, JE AF Uhl, G. R. Drgon, T. Johnson, C. Rose, J. E. TI Nicotine abstinence genotyping: assessing the impact on smoking cessation clinical trials SO PHARMACOGENOMICS JOURNAL LA English DT Article DE clinical trial power; pharmacogenomics; pharmacogenetics; nicotine dependence; pharmacotherapies; addiction ID MOLECULAR-GENETICS; COST-EFFECTIVENESS; TWINS; DEPENDENCE; QUIT; INTERRELATIONSHIP; ASSOCIATION; PATCH AB Twin studies document substantial heritability for successful abstinence from smoking. A genome-wide association study has identified markers whose allele frequencies differ with nominal P<0.005 in nicotine-dependent clinical trial participants who were successful vs unsuccessful in abstaining from smoking; many of these results are also supported by data from two additional samples. More study is required to precisely determine the variance in quitting success that can be accounted for by the single-nucleotide polymorphisms that are currently identified and to precisely classify individuals who may display varying degrees of genetic vs environmental effects into quitters or nonquitters. However, the data at hand do allow us to model the effects of genotypic stratification in smoking cessation trials. We identify relationships between the costs of identifying and genotyping prospective trial participants vs the costs of performing the clinical trials. We quantitate the increasing savings that result from genetically stratified designs as recruiting/genotyping costs go down and trial costs increase. This model helps to define the circumstances in which genetically stratified designs may enhance power and reduce costs for smoking cessation clinical trials. C1 [Uhl, G. R.; Drgon, T.; Johnson, C.] NIDA, NIH IRP, Mol Neurobiol Branch, Baltimore, MD 21224 USA. [Rose, J. E.] Duke Univ, Dept Psychiat & Behav Sci, Ctr Nicotine & Smoking Cessat Res, Durham, NC USA. RP Uhl, G (reprint author), NIDA, NIH IRP, Mol Neurobiol Branch, Suite 3510,333 Cassell Dr,Box 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov FU NIH IRP (NIDA); DHSS FX We acknowledge the support given by the NIH IRP (NIDA), DHSS, unrestricted support for studies of adult smoking cessation to the Duke Center for Nicotine and Smoking Cessation Research from Philip Morris USA Inc. and advice on the article and statistical approaches from Dr Greg Samsa. NR 16 TC 12 Z9 12 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD APR PY 2009 VL 9 IS 2 BP 111 EP 115 DI 10.1038/tpj.2008.10 PG 5 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA 422HR UT WOS:000264418800005 PM 18781146 ER PT J AU Bonow, RH Aid, S Zhang, Y Becker, KG Bosetti, F AF Bonow, R. H. Aid, S. Zhang, Y. Becker, K. G. Bosetti, F. TI The brain expression of genes involved in inflammatory response, the ribosome, and learning and memory is altered by centrally injected lipopolysaccharide in mice SO PHARMACOGENOMICS JOURNAL LA English DT Article DE LPS; neuroinflammation; microarray; Arc; Egr1; cerebral cortex; hippocampus ID LONG-TERM POTENTIATION; NEURONAL OXIDATIVE DAMAGE; RAT DENTATE GYRUS; SYNAPTIC PLASTICITY; ALZHEIMERS-DISEASE; NITRIC-OXIDE; IN-VIVO; HIPPOCAMPAL NEUROGENESIS; SYSTEMIC INFLAMMATION; TRANSCRIPTION FACTORS AB Neuroinflammation plays a role in the progression of several neurodegenerative disorders. We used a lipopolysaccharide (LPS) model of neuroinflammation to characterize the gene expression changes underlying the inflammatory and behavioral effects of neuroinflammation. A single intracerebroventricular injection of LPS (5 mu g) was administered into the lateral ventricle of mice and, 24 h later, we examined gene expression in the cerebral cortex and hippocampus using microarray technology. Gene Ontology (GO) terms for inflammation and the ribosome were significantly enriched by LPS, whereas GO terms associated with learning and memory had decreased expression. We detected 224 changed transcripts in the cerebral cortex and 170 in the hippocampus. Expression of Egr1 (also known as Zif268) and Arc, two genes associated with learning and memory, was significantly lower in the cortex, but not in the hippocampus, of LPS-treated animals. Overall, altered expression of these genes may underlie some of the inflammatory and behavioral effects of neuroinflammation. C1 [Bonow, R. H.; Aid, S.; Bosetti, F.] NIA, NIH, Mol Neurosci Unit, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. [Zhang, Y.; Becker, K. G.] NIA, NIH, Gene Express & Genom Unit, Baltimore, MD USA. RP Bosetti, F (reprint author), NIA, NIH, Mol Neurosci Unit, Brain Physiol & Metab Sect, 9 Mem Dr, Bethesda, MD 20892 USA. EM frances@mail.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU Intramural Research Program of the National Institutes of Health; National Institute on Aging FX We thank Dr Christopher Toscano and Dr Sang-Ho Choi for helpful discussion and Dr Marcel Van Der Brug for statistical help. This work was entirely supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 59 TC 34 Z9 36 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD APR PY 2009 VL 9 IS 2 BP 116 EP 126 DI 10.1038/tpj.2008.15 PG 11 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA 422HR UT WOS:000264418800006 PM 18957951 ER PT J AU Soto, PL Katz, JL AF Soto, Paul L. Katz, Jonathan L. TI Fluoxetine does not alter the ability of dopamine D-1- and D-2-like agonists to substitute for cocaine in squirrel monkeys SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE Cocaine; Serotonin; Dopamine receptor subtypes; Fluoxetine; Quinpirole; (-)-NPA; SKF 82958; Drug discrimination; Squirrel monkey ID DISCRIMINATIVE STIMULUS PROPERTIES; REUPTAKE INHIBITORS ENHANCE; PHARMACOLOGICAL CHARACTERIZATION; SELECTIVE SEROTONIN; LOCOMOTOR-ACTIVITY; RECEPTOR AGONISTS; MONOAMINE UPTAKE; MODULATION; SUBTYPES; RAT AB Fluoxetine has been shown to enhance several behavioral effects of cocaine, including its discriminative-stimulus effects. An interaction between increased serotonergic and dopaminergic actions produced by blockade of serotonin and dopamine reuptake, is one possible mechanism for the enhancement. The present study investigated the effects or fluoxetine on the cocaine-like discriminative-stimulus effects of the D-2-like agonists quinpirole and (-)-NPA, and the D-1-like agonist SKF 82958 in squirrel monkeys trained to discriminate cocaine. The direct dopaminergic agonists, injected 5 min before testing. produced maximal levels of cocaine-appropriate responding of 50% (0.3 mg/kg. SKF 82958), 67% (0.003 mg/kg, (-)-NPA), and 77% (0.1 mg/kg, quinpirole) with ED50 values of 0.43, 0.003. and 0.06 mg/kg, respectively. Fluoxetine at doses up to 10 mg/kg (also 5 min before testing) did not alter the effectiveness or the potency of any of the dopamine agonists in substituting for cocaine. The present failure of fluoxetine to alter the cocaine-like discriminative effects of the dopamine agonists is consistent with the notion that the mechanism underlying the enhancement of the effects of cocaine by fluoxetine is not simply an interaction between enhanced serotonergic and dopaminergic activation as it is not obtained with direct-acting dopamine receptor agonists. (C) Published by Elsevier Inc. C1 [Soto, Paul L.; Katz, Jonathan L.] NIDA, DHHS, NIH, IRP,Med Discovery Res Branch,Psychobiol Sect,BRC, Baltimore, MD 21224 USA. RP Soto, PL (reprint author), NIDA, DHHS, NIH, IRP,Med Discovery Res Branch,Psychobiol Sect,BRC, Room 06A707,251 Bayview Blvd,Suite 200, Baltimore, MD 21224 USA. EM sotop@mail.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 FU Department of Health and Human Services; National Institutes of Health; National Institute on Drug Abuse FX These studies were supported by the Intramural Research Program of the Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse. We thank Gianluigi Tanda for discussions on the findings and Eric Adams for technical assistance and data collection. NR 24 TC 1 Z9 1 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD APR PY 2009 VL 92 IS 2 BP 219 EP 223 DI 10.1016/j.pbb.2008.11.013 PG 5 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 419YJ UT WOS:000264255300004 PM 19101584 ER PT J AU Dean, DS Horgan, RR Naji, A Podgornik, R AF Dean, David S. Horgan, R. R. Naji, Ali Podgornik, R. TI Thermal Casimir effect between random layered dielectrics SO PHYSICAL REVIEW A LA English DT Article DE Casimir effect; dielectric function; dielectric materials; inhomogeneous media; random media ID DER-WAALS INTERACTIONS; FORCES AB We study the thermal Casimir effect between two thick slabs composed of plane-parallel layers of random dielectric materials interacting across an intervening homogeneous dielectric. It is found that the effective interaction at long distances is self-averaging and is given by a description in terms of effective dielectric functions. The behavior at short distances becomes random (sample dependent) and is dominated by the local values of the dielectric function proximal to each other across the dielectrically homogeneous slab. C1 [Dean, David S.; Horgan, R. R.; Naji, Ali; Podgornik, R.] Univ Calif Santa Barbara, Kavli Inst Theoret Phys, Santa Barbara, CA 93106 USA. [Dean, David S.] Univ Toulouse 3, Phys Theor Lab, IRSAMC, F-31062 Toulouse 4, France. [Horgan, R. R.] Univ Cambridge, DAMTP, CMS, Cambridge CB3 0WA, England. [Naji, Ali] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. [Naji, Ali] Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA. [Podgornik, R.] Univ Ljubljana, Dept Phys, Fac Math & Phys, SI-1000 Ljubljana, Slovenia. [Podgornik, R.] Jozef Stefan Inst, Dept Theoret Phys, SI-1000 Ljubljana, Slovenia. [Podgornik, R.] NIH, Lab Phys & Struct Biol, Bethesda, MD 20892 USA. RP Dean, DS (reprint author), Univ Calif Santa Barbara, Kavli Inst Theoret Phys, Santa Barbara, CA 93106 USA. RI Naji, Ali/F-6352-2010; Podgornik, Rudolf/C-6209-2008; Dean, David/N-6601-2013 OI Naji, Ali/0000-0003-3436-1499; Podgornik, Rudolf/0000-0002-3855-4637; FU National Science Foundation [PHY05-51164]; Institut Universtaire de France; Agency for Research and Development of Slovenia [P1-0055C, Z1-7171, L2-7080]; Intramural Research Program of the NIH, National Institute of Child Health and Human Development FX This research was supported in part by the National Science Foundation under Grant No. PHY05-51164. D. S. D. acknowledges support from the Institut Universtaire de France. R. P. would like to acknowledge the financial support by the Agency for Research and Development of Slovenia, Grants No. P1-0055C, No. Z1-7171, and No. L2-7080. This study was supported in part by the Intramural Research Program of the NIH, National Institute of Child Health and Human Development. NR 15 TC 14 Z9 14 U1 3 U2 8 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1050-2947 J9 PHYS REV A JI Phys. Rev. A PD APR PY 2009 VL 79 IS 4 AR 040101 DI 10.1103/PhysRevA.79.040101 PG 4 WC Optics; Physics, Atomic, Molecular & Chemical SC Optics; Physics GA 443YO UT WOS:000265946900001 ER PT J AU Obolensky, OI Doerr, TP Ray, R Yu, YK AF Obolensky, O. I. Doerr, T. P. Ray, R. Yu, Yi-Kuo TI Rigorous treatment of electrostatics for spatially varying dielectrics based on energy minimization SO PHYSICAL REVIEW E LA English DT Article DE biochemistry; dielectric materials; electrostatics; minimisation ID VARIATIONAL APPROACH; MODELS; WATER; SIMULATIONS; SOLVATION; DYNAMICS; SOLVENT; POLARIZATION; PROTEINS AB An energy minimization formulation of electrostatics that allows computation of the electrostatic energy and forces to any desired accuracy in a system with arbitrary dielectric properties is presented. An integral equation for the scalar charge density is derived from an energy functional of the polarization vector field. This energy functional represents the true energy of the system even in nonequilibrium states. Arbitrary accuracy is achieved by solving the integral equation for the charge density via a series expansion in terms of the equation's kernel, which depends only on the geometry of the dielectrics. The streamlined formalism operates with volume charge distributions only, not resorting to introducing surface charges by hand. Therefore, it can be applied to any spatial variation of the dielectric susceptibility, which is of particular importance in applications to biomolecular systems. The simplicity of application of the formalism to real problems is shown with analytical and numerical examples. C1 [Obolensky, O. I.; Doerr, T. P.; Ray, R.; Yu, Yi-Kuo] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Obolensky, O. I.] AF Ioffe Inst, St Petersburg, Russia. RP Yu, YK (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov RI Obolensky, Oleg/A-5839-2008; OI Obolensky, Oleg/0000-0003-3315-1828; Ray, Rajarshi/0000-0001-8633-7808 FU Intramural NIH HHS [Z99 LM999999] NR 28 TC 3 Z9 3 U1 1 U2 3 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 APR PY 2009 VL 79 IS 4 AR 041907 DI 10.1103/PhysRevE.79.041907 PG 15 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 443WK UT WOS:000265941300101 PM 19518256 ER PT J AU Shumway-Cook, A Ciol, MA Hoffman, J Dudgeon, BJ Yorkston, K Chan, L AF Shumway-Cook, Anne Ciol, Marcia A. Hoffman, Jeanne Dudgeon, Brian J. Yorkston, Kathryn Chan, Leighton TI Falls in the Medicare Population: Incidence, Associated Factors, and Impact on Health Care SO PHYSICAL THERAPY LA English DT Article ID DWELLING OLDER PERSONS; RISK; PREVENTION; MANAGEMENT; PHYSICIANS; PEOPLE; ADULTS; TRIAL AB Background and Purpose. Falls are a major health problem in the elderly community; however, questions regarding incidence, risk factors, and provider response to falls exist. The purpose of this study was to examine the incidence of falls, associated factors, health care costs, and provider response to falls among Medicare beneficiaries. Participants. The participants were 12,669 respondents to the Medicare Current Beneficiaries Survey (MCBS). Methods. Categories of number of falls (none, one, recurrent) and injury type (medically injurious versus not medically injurious) were created from the falls supplement to the MCBS. Means and proportions for the entire Medicare population were estimated using sampling weights. The association between sociodemographic variables and fall status was modeled using ordinal or binary logistic regression. Aggregate health costs by fall category were estimated from claims data. Results. Population estimates of falls reported in 2002 ranged from 3.7 million (single fall) to 3.1 million (recurrent falls), with an estimated 2.2 million people having a medically injurious fall. Recurrent falls were more likely with increased age, being female, being nonwhite, reporting fair or poor health, and increased number of limitations in personal activities of daily living and instrumental activities of daily living and comorbidities. Although estimates of the actual costs of falls could not be determined, "fallers" consistently had larger utilization costs than "nonfallers" for the year 2002. Fewer than half (48%) of the beneficiaries reported talking to a health care provider following a fall, and 60% of those beneficiaries reported receiving fall prevention information. Discussion and Conclusions. Falls are common and may be associated with significant health care costs. Most importantly, health care providers may be missing many opportunities to provide fall prevention information to older people. C1 [Shumway-Cook, Anne; Ciol, Marcia A.; Hoffman, Jeanne; Dudgeon, Brian J.; Yorkston, Kathryn] Univ Washington, Dept Rehabil Med, Seattle, WA 98195 USA. [Chan, Leighton] NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. RP Shumway-Cook, A (reprint author), Univ Washington, Dept Rehabil Med, Box 356490, Seattle, WA 98195 USA. EM ashumway@u.washington.edu FU Centers for Disease Control and Prevention through an Extramural Project Grant with the Association of Academic Medical Centers [MM-0625-04/04] FX This study was supported with funding from Centers for Disease Control and Prevention (MM-0625-04/04) through an Extramural Project Grant with the Association of Academic Medical Centers. Additional resources were provided by the Centers for Medicare and Medicaid Services. NR 22 TC 87 Z9 88 U1 3 U2 20 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD APR PY 2009 VL 89 IS 4 BP 324 EP 332 DI 10.2522/ptj.20070107 PG 9 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 426WH UT WOS:000264738500002 PM 19228831 ER PT J AU Coelho, SG Zhou, Y Bushar, HF Miller, SA Zmudzka, BZ Hearing, VJ Beer, JZ AF Coelho, Sergio G. Zhou, Yanchun Bushar, Harry F. Miller, Sharon A. Zmudzka, Barbara Z. Hearing, Vincent J. Beer, Janusz Z. TI Long-lasting pigmentation of human skin, a new look at an overlooked response to UV SO PIGMENT CELL & MELANOMA RESEARCH LA English DT Letter DE long-lasting pigmentation; melanogenesis; ultraviolet radiation ID MECHANISMS; EXPOSURE C1 [Coelho, Sergio G.; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Zhou, Yanchun; Bushar, Harry F.; Miller, Sharon A.; Zmudzka, Barbara Z.; Beer, Janusz Z.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. RP Coelho, SG (reprint author), NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM coelhos@mail.nih.gov FU Intramural NIH HHS [Z01 BC010784-01, Z99 CA999999] NR 14 TC 9 Z9 9 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1755-1471 J9 PIGM CELL MELANOMA R JI Pigment Cell Melanoma Res. PD APR PY 2009 VL 22 IS 2 BP 238 EP 241 DI 10.1111/j.1755-148X.2009.00550.x PG 4 WC Oncology; Cell Biology; Dermatology SC Oncology; Cell Biology; Dermatology GA 417NY UT WOS:000264084200016 PM 19226313 ER PT J AU Breban, R Drake, JM Stallknecht, DE Rohani, P AF Breban, Romulus Drake, John M. Stallknecht, David E. Rohani, Pejman TI The Role of Environmental Transmission in Recurrent Avian Influenza Epidemics SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID WILD AQUATIC BIRDS; A VIRUSES; COMMUNITY SIZE; SPATIAL HETEROGENEITY; MENINGITIS EPIDEMICS; BORNE TRANSMISSION; CHOLERA OUTBREAKS; PERSISTENCE; DYNAMICS; MEASLES AB Avian influenza virus (AIV) persists in North American wild waterfowl, exhibiting major outbreaks every 2-4 years. Attempts to explain the patterns of periodicity and persistence using simple direct transmission models are unsuccessful. Motivated by empirical evidence, we examine the contribution of an overlooked AIV transmission mode: environmental transmission. It is known that infectious birds shed large concentrations of virions in the environment, where virions may persist for a long time. We thus propose that, in addition to direct fecal/oral transmission, birds may become infected by ingesting virions that have long persisted in the environment. We design a new host-pathogen model that combines within-season transmission dynamics, between-season migration and reproduction, and environmental variation. Analysis of the model yields three major results. First, environmental transmission provides a persistence mechanism within small communities where epidemics cannot be sustained by direct transmission only (i.e., communities smaller than the critical community size). Second, environmental transmission offers a parsimonious explanation of the 2-4 year periodicity of avian influenza epidemics. Third, very low levels of environmental transmission (i.e., few cases per year) are sufficient for avian influenza to persist in populations where it would otherwise vanish. C1 [Breban, Romulus; Drake, John M.; Rohani, Pejman] Univ Georgia, Odum Sch Ecol, Athens, GA 30602 USA. [Stallknecht, David E.] Univ Georgia, SE Cooperat Wildlife Dis Study, Athens, GA 30602 USA. [Rohani, Pejman] Univ Georgia, Ctr Trop & Emerging Global Dis, Athens, GA 30602 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Breban, R (reprint author), Inst Pasteur, Unite Epidemiol Malad Emergentes, Paris, France. EM breban@gmail.com RI Drake, John/D-6622-2012; OI Drake, John/0000-0003-4646-1235 FU Centers for Disease Control and Prevention [5U19Cl000401]; National Science Foundation [EF-0723601]; James S. McDonnell Foundation FX RB, DES, and PR were supported by a grant from the Centers for Disease Control and Prevention (5U19Cl000401). JMD was supported by the National Science Foundation (EF-0723601) and the James S. McDonnell Foundation. The authors declare that they do not have any financial interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 58 TC 99 Z9 102 U1 3 U2 31 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD APR PY 2009 VL 5 IS 4 AR e1000346 DI 10.1371/journal.pcbi.1000346 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 447TH UT WOS:000266214200012 PM 19360126 ER PT J AU Behra, M Bradsher, J Sougrat, R Gallardo, V Allende, ML Burgess, SM AF Behra, Martine Bradsher, John Sougrat, Rachid Gallardo, Viviana Allende, Miguel L. Burgess, Shawn M. TI Phoenix Is Required for Mechanosensory Hair Cell Regeneration in the Zebrafish Lateral Line SO PLOS GENETICS LA English DT Article ID AVIAN INNER-EAR; ACOUSTIC TRAUMA; DANIO-RERIO; TECTORIAL MEMBRANE; LASER-ABLATION; CHICK COCHLEA; SENSE-ORGANS; IN-VIVO; SYSTEM; NEUROMASTS AB In humans, the absence or irreversible loss of hair cells, the sensory mechanoreceptors in the cochlea, accounts for a large majority of acquired and congenital hearing disorders. In the auditory and vestibular neuroepithelia of the inner ear, hair cells are accompanied by another cell type called supporting cells. This second cell population has been described as having stem cell-like properties, allowing efficient hair cell replacement during embryonic and larval/fetal development of all vertebrates. However, mammals lose their regenerative capacity in most inner ear neuroepithelia in postnatal life. Remarkably, reptiles, birds, amphibians, and fish are different in that they can regenerate hair cells throughout their lifespan. The lateral line in amphibians and in fish is an additional sensory organ, which is used to detect water movements and is comprised of neuroepithelial patches, called neuromasts. These are similar in ultra-structure to the inner ear's neuroepithelia and they share the expression of various molecular markers. We examined the regeneration process in hair cells of the lateral line of zebrafish larvae carrying a retroviral integration in a previously uncharacterized gene, phoenix (pho). Phoenix mutant larvae develop normally and display a morphologically intact lateral line. However, after ablation of hair cells with copper or neomycin, their regeneration in pho mutants is severely impaired. We show that proliferation in the supporting cells is strongly decreased after damage to hair cells and correlates with the reduction of newly formed hair cells in the regenerating phoenix mutant neuromasts. The retroviral integration linked to the phenotype is in a novel gene with no known homologs showing high expression in neuromast supporting cells. Whereas its role during early development of the lateral line remains to be addressed, in later larval stages phoenix defines a new class of proteins implicated in hair cell regeneration. C1 [Behra, Martine; Burgess, Shawn M.] NHGRI, NIH, Bethesda, MD 20892 USA. [Gallardo, Viviana; Allende, Miguel L.] Univ Chile, Fac Ciencias, Ctr Genom Cell, Santiago, Chile. [Bradsher, John] NCI, Bethesda, MD 20892 USA. [Sougrat, Rachid] NICHHD, Bethesda, MD 20892 USA. RP Behra, M (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM burgess@mail.nih.gov RI Allende, Miguel/C-5167-2008; OI Allende, Miguel/0000-0002-2783-2152; Sougrat, Rachid/0000-0001-6476-1886; Burgess, Shawn/0000-0003-1147-0596 FU National Human Genome Research Institute; National Institutes of Health; FONDECYT [1070867]; ICM [P06-037F]; CONICYT Fellowship; Vicerrectoria de Asuntos Academicos; Departamento de Postgrado y Postitulo; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (SB). MLA was supported by FONDECYT (1070867) and ICM (P06-037F). VG received a CONICYT Fellowship and a travel grant from the Vicerrectoria de Asuntos Academicos, Departamento de Postgrado y Postitulo. Part of this work was supported by the Intramural Program of Eunice Kennedy Shriver National Institute of Child Health and Human Development. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 34 Z9 37 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD APR PY 2009 VL 5 IS 4 AR e1000455 DI 10.1371/journal.pgen.1000455 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 449HA UT WOS:000266320200015 PM 19381250 ER PT J AU Cai, T Hirai, H Fukushige, T Yu, P Zhang, GF Notkins, AL Krause, M AF Cai, Tao Hirai, Hiroki Fukushige, Tetsunari Yu, Ping Zhang, Guofeng Notkins, Abner L. Krause, Michael TI Loss of the Transcriptional Repressor PAG-3/Gfi-1 Results in Enhanced Neurosecretion that is Dependent on the Dense-Core Vesicle Membrane Protein IDA-1/IA-2 SO PLOS GENETICS LA English DT Article ID CELL LUNG-CARCINOMA; NEMATODE CAENORHABDITIS-ELEGANS; GROWTH-FACTOR INDEPENDENCE-1; ZINC-FINGER PROTEIN; C-ELEGANS; TYROSINE-PHOSPHATASE; TRANSMEMBRANE PROTEIN; SYNAPTIC-TRANSMISSION; INSULIN-SECRETION; GENE FAMILY AB It is generally accepted that neuroendocrine cells regulate dense core vesicle (DCV) biogenesis and cargo packaging in response to secretory demands, although the molecular mechanisms of this process are poorly understood. One factor that has previously been implicated in DCV regulation is IA-2, a catalytically inactive protein phosphatase present in DCV membranes. Our ability to directly visualize a functional, GFP-tagged version of an IA-2 homolog in live Caenorhabditis elegans animals has allowed us to capitalize on the genetics of the system to screen for mutations that disrupt DCV regulation. We found that loss of activity in the transcription factor PAG-3/Gfi-1, which functions as a repressor in many systems, results in a dramatic up-regulation of IDA-1/IA-2 and other DCV proteins. The up-regulation of DCV components was accompanied by an increase in presynaptic DCV numbers and resulted in phenotypes consistent with increased neuroendocrine secretion. Double mutant combinations revealed that these PAG-3 mutant phenotypes were dependent on wild type IDA-1 function. Our results support a model in which IDA-1/IA-2 is a critical element in DCV regulation and reveal a novel genetic link to PAG-3-mediated transcriptional regulation. To our knowledge, this is the first mutation identified that results in increased neurosecretion, a phenotype that has clinical implications for DCV-mediated secretory disorders. C1 [Cai, Tao; Hirai, Hiroki; Notkins, Abner L.] Natl Inst Dent & Craniofacial Res NIDCR, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. [Fukushige, Tetsunari; Krause, Michael] NIDDK, Sect Dev Biol, Mol Biol Lab, NIH, Bethesda, MD USA. [Yu, Ping] Natl Canc Inst NCI Frederick, Prot Nucle Acid Interact Sect, Struct Biophys Lab, Frederick, MD USA. [Zhang, Guofeng] Natl Inst Biomed Imaging & Bioengn NIBIB, Lab Bioengn & Phys Sci, NIH, Bethesda, MD USA. RP Cai, T (reprint author), Natl Inst Dent & Craniofacial Res NIDCR, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. EM tcai@mail.nih.gov; mwkrause@helix.nih.gov OI Krause, Michael/0000-0001-6127-3940 FU NIH; NIDDK; National Institutes of Health Center for Research Resources FX This research was supported by the Intramural Research Program of the NIH, including the Institutes of NIDDK, NCI Frederick, NIBIB, and NIDCR. Some strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the National Institutes of Health Center for Research Resources. NR 85 TC 6 Z9 16 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD APR PY 2009 VL 5 IS 4 AR e1000447 DI 10.1371/journal.pgen.1000447 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 449HA UT WOS:000266320200007 PM 19343207 ER PT J AU Hsu, SN Yonekura, S Ting, CY Robertson, HM Iwai, Y Uemura, T Lee, CH Chiba, A AF Hsu, Shu-Ning Yonekura, Shinichi Ting, Chun-Yuan Robertson, Hugh M. Iwai, Youichi Uemura, Tadashi Lee, Chi-Hon Chiba, Akira TI Conserved Alternative Splicing and Expression Patterns of Arthropod N-Cadherin SO PLOS GENETICS LA English DT Article ID PRE-MESSENGER-RNA; AXON GUIDANCE; HUMAN GENOME; DN-CADHERIN; DROSOPHILA; DIVERSITY; SELECTION; RECEPTOR; PROTEIN; DOMAIN AB Metazoan development requires complex mechanisms to generate cells with diverse function. Alternative splicing of pre-mRNA not only expands proteomic diversity but also provides a means to regulate tissue-specific molecular expression. The N-Cadherin gene in Drosophila contains three pairs of mutually-exclusive alternatively-spliced exons (MEs). However, no significant differences among the resulting protein isoforms have been successfully demonstrated in vivo. Furthermore, while the N-Cadherin gene products exhibit a complex spatiotemporal expression pattern within embryos, its underlying mechanisms and significance remain unknown. Here, we present results that suggest a critical role for alternative splicing in producing a crucial and reproducible complexity in the expression pattern of arthropod N-Cadherin. We demonstrate that the arthropod N-Cadherin gene has maintained the three sets of MEs for over 400 million years using in silico and in vivo approaches. Expression of isoforms derived from these MEs receives precise spatiotemporal control critical during development. Both Drosophila and Tribolium use ME-13a and ME-13b in "neural'' and "mesodermal'' splice variants, respectively. As proteins, either ME-13a- or ME-13b-containing isoform can cell-autonomously rescue the embryonic lethality caused by genetic loss of N-Cadherin. Ectopic muscle expression of either isoform beyond the time it normally ceases leads to paralysis and lethality. Together, our results offer an example of well-conserved alternative splicing increasing cellular diversity in metazoans. C1 [Chiba, Akira] Univ Miami, Dept Biol, Coral Gables, FL 33124 USA. [Iwai, Youichi] RIKEN Brain Sci Inst, Saitama, Japan. [Iwai, Youichi; Uemura, Tadashi] Kyoto Univ, Grad Sch Biostudies, Kyoto, Japan. [Robertson, Hugh M.] Univ Illinois, Dept Entomol, Urbana, IL 61801 USA. [Yonekura, Shinichi; Ting, Chun-Yuan; Lee, Chi-Hon] NICHHD, Unit Neuronal Connect, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Hsu, Shu-Ning; Robertson, Hugh M.; Chiba, Akira] Univ Illinois, Neurosci Program, Urbana, IL 61801 USA. RP Hsu, SN (reprint author), Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92717 USA. EM shuningh@uci.edu RI Lee, Chi-Hon/G-9190-2012; Ting, chun-yuan/F-6448-2013; OI UEMURA, Tadashi/0000-0001-7204-3606 FU NIH/NINDS; NIH/NIMH; NIH, National Institute of Child Health and Human Development [HD008748-03]; NIH/NIAID; MEXT of Japan [17024025] FX S-NH was supported in part by University of Illinois Critical Research Initiatives. This study was supported by grants from NIH/NINDS and NIH/NIMH (AC), intramural research program of the NIH, National Institute of Child Health and Human Development (grant HD008748-03) (C-HL), NIH/NIAID (HMR), and the programs Grants-in-Aid for Scientific Research on Priority Areas-Molecular Brain Science (17024025) of the MEXT of Japan (TU). The funding agencies were not involved in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and nor were they involved in the preparation of the manuscript. NR 48 TC 8 Z9 8 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD APR PY 2009 VL 5 IS 4 AR e1000441 DI 10.1371/journal.pgen.1000441 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 449HA UT WOS:000266320200001 PM 19343204 ER PT J AU Harsha, HC Kandasamy, K Ranganathan, P Rani, S Ramabadran, S Gollapudi, S Balakrishnan, L Dwivedi, SB Telikicherla, D Selvan, LDN Goel, R Mathivanan, S Marimuthu, A Kashyap, M Vizza, RF Mayer, RJ DeCaprio, JA Srivastava, S Hanash, SM Hruban, RH Pandey, A AF Harsha, H. C. Kandasamy, Kumaran Ranganathan, Prathibha Rani, Sandhya Ramabadran, Subhashri Gollapudi, Sashikanth Balakrishnan, Lavanya Dwivedi, Sutopa B. Telikicherla, Deepthi Selvan, Lakshmi Dhevi N. Goel, Renu Mathivanan, Suresh Marimuthu, Arivusudar Kashyap, Manoj Vizza, Robert F. Mayer, Robert J. DeCaprio, James A. Srivastava, Sudhir Hanash, Samir M. Hruban, Ralph H. Pandey, Akhilesh TI A Compendium of Potential Biomarkers of Pancreatic Cancer SO PLOS MEDICINE LA English DT Editorial Material ID STEM-CELL ANTIGEN; GENE-EXPRESSION; INTRAEPITHELIAL NEOPLASIA; ADENOCARCINOMA; DATABASE; PROFILES; PROTEINS; MARKERS C1 [Harsha, H. C.; Kandasamy, Kumaran; Ranganathan, Prathibha; Rani, Sandhya; Ramabadran, Subhashri; Gollapudi, Sashikanth; Balakrishnan, Lavanya; Dwivedi, Sutopa B.; Telikicherla, Deepthi; Selvan, Lakshmi Dhevi N.; Goel, Renu; Mathivanan, Suresh; Marimuthu, Arivusudar; Kashyap, Manoj; Pandey, Akhilesh] Int Technol Pk, Inst Bioinformat, Bangalore, Karnataka, India. [Harsha, H. C.; Marimuthu, Arivusudar] Manipal Univ, Manipal, Karnataka, India. [Harsha, H. C.; Kandasamy, Kumaran; Mathivanan, Suresh; Marimuthu, Arivusudar; Kashyap, Manoj; Pandey, Akhilesh] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Harsha, H. C.; Kandasamy, Kumaran; Mathivanan, Suresh; Marimuthu, Arivusudar; Kashyap, Manoj; Pandey, Akhilesh] Johns Hopkins Univ, Dept Biol Chem, Baltimore, MD USA. [Vizza, Robert F.] Lustgarten Fdn Pancreat Canc Res, Bethpage, NY USA. [Mayer, Robert J.; DeCaprio, James A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Srivastava, Sudhir] NCI, Canc Biomarkers Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Hanash, Samir M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Hruban, Ralph H.; Pandey, Akhilesh] Johns Hopkins Med Inst, Dept Pathol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA. [Hruban, Ralph H.; Pandey, Akhilesh] Johns Hopkins Med Inst, Dept Oncol, Sol Goldman Pancreat Canc Res Ctr, Baltimore, MD 21205 USA. RP Harsha, HC (reprint author), Int Technol Pk, Inst Bioinformat, Bangalore, Karnataka, India. EM pandey@jhmi.edu RI Kandasamy, Kumaran/C-8981-2009; Pandey, Akhilesh/B-4127-2009; Mathivanan, Suresh/D-2045-2009; OI Pandey, Akhilesh/0000-0001-9943-6127; Mathivanan, Suresh/0000-0002-7290-5795; Kashyap, Manoj K./0000-0003-3314-3318 NR 20 TC 129 Z9 131 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD APR PY 2009 VL 6 IS 4 AR e1000046 DI 10.1371/journal.pmed.1000046 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 447TN UT WOS:000266214800002 PM 19360088 ER PT J AU Khurana, S Suguitan, AL Rivera, Y Simmons, CP Lanzavecchia, A Sallusto, F Manischewitz, J King, LR Subbarao, K Golding, H AF Khurana, Surender Suguitan, Amorsolo L., Jr. Rivera, Yonaira Simmons, Cameron P. Lanzavecchia, Antonio Sallusto, Federica Manischewitz, Jody King, Lisa R. Subbarao, Kanta Golding, Hana TI Antigenic Fingerprinting of H5N1 Avian Influenza Using Convalescent Sera and Monoclonal Antibodies Reveals Potential Vaccine and Diagnostic Targets SO PLOS MEDICINE LA English DT Article ID A-VIRUS; NEUTRALIZING ANTIBODY; DIFFERENTIAL-DIAGNOSIS; HEMAGGLUTININ MOLECULE; GENERATED ANTIBODIES; HIV-INFECTIONS; M2 PROTEIN; MICE; SITES; IDENTIFICATION AB Background: Transmission of highly pathogenic avian H5N1 viruses from poultry to humans have raised fears of an impending influenza pandemic. Concerted efforts are underway to prepare effective vaccines and therapies including polyclonal or monoclonal antibodies against H5N1. Current efforts are hampered by the paucity of information on protective immune responses against avian influenza. Characterizing the B cell responses in convalescent individuals could help in the design of future vaccines and therapeutics. Methods and Findings: To address this need, we generated whole-genome-fragment phage display libraries (GFPDL) expressing fragments of 15-350 amino acids covering all the proteins of A/Vietnam/1203/2004 (H5N1). These GFPDL were used to analyze neutralizing human monoclonal antibodies and sera of five individuals who had recovered from H5N1 infection. This approach led to the mapping of two broadly neutralizing human monoclonal antibodies with conformation-dependent epitopes. In H5N1 convalescent sera, we have identified several potentially protective H5N1-specific human antibody epitopes in H5 HA[(-10)-223], neuraminidase catalytic site, and M2 ectodomain. In addition, for the first time to our knowledge in humans, we identified strong reactivity against PB1-F2, a putative virulence factor, following H5N1 infection. Importantly, novel epitopes were identified, which were recognized by H5N1-convalescent sera but did not react with sera from control individuals (H5N1 naive, H1N1 or H3N2 seropositive). Conclusion: This is the first study, to our knowledge, describing the complete antibody repertoire following H5N1 infection. Collectively, these data will contribute to rational vaccine design and new H5N1-specific serodiagnostic surveillance tools. C1 [Khurana, Surender; Rivera, Yonaira; Manischewitz, Jody; King, Lisa R.; Golding, Hana] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD USA. [Suguitan, Amorsolo L., Jr.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Simmons, Cameron P.] Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Lanzavecchia, Antonio; Sallusto, Federica] Biomed Res Inst, Bellinzona, Switzerland. RP Khurana, S (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD USA. EM hana.golding@fda.hhs.gov OI Simmons, Cameron P./0000-0002-9039-7392 FU OPHEMC/HHS (2007); BARDA/HHS (2008); CBER (FDA); NIAID (NIH) FX This study was partly supported by funds from OPHEMC/HHS (2007) and BARDA/HHS (2008). This research was supported by the Intramural Research Program of CBER (FDA) and NIAID (NIH). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 95 Z9 96 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1549-1676 J9 PLOS MED JI PLos Med. PD APR PY 2009 VL 6 IS 4 AR e1000049 DI 10.1371/journal.pmed.1000049 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 447TN UT WOS:000266214800004 PM 19381279 ER PT J AU Babu, S Bhat, SQ Kumar, NP Lipira, AB Kumar, S Karthik, C Kumaraswami, V Nutman, TB AF Babu, Subash Bhat, Sajid Q. Kumar, N. Pavan Lipira, Angelo B. Kumar, Sanath Karthik, C. Kumaraswami, V. Nutman, Thomas B. TI Filarial Lymphedema Is Characterized by Antigen-Specific Th1 and Th17 Proinflammatory Responses and a Lack of Regulatory T Cells SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID ENDOSYMBIOTIC WOLBACHIA-BACTERIA; BANCROFTIAN FILARIASIS; LYMPHATIC FILARIASIS; BRUGIA-MALAYI; WUCHERERIA-BANCROFTI; IMMUNE-RESPONSES; DENDRITIC CELLS; INFLAMMATION; EXPRESSION; INFECTION AB Background: Lymphatic filariasis can be associated with development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Methods and Findings: To elucidate the role of CD4(+) T cell subsets in the development of lymphatic pathology, we examined specific sets of cytokines in individuals with filarial lymphedema in response to parasite antigen (BmA) and compared them with responses from asymptomatic infected individuals. We also examined expression patterns of Toll-like receptors (TLR1-10) and Nod-like receptors (Nod1, Nod2, and NALP3) in response to BmA. BmA induced significantly higher production of Th1-type cytokines-IFN-gamma and TNF-alpha-in patients with lymphedema compared with asymptomatic individuals. Notably, expression of the Th17 family of cytokines-IL-17A, IL-17F, IL-21, and IL-23-was also significantly upregulated by BmA stimulation in lymphedema patients. In contrast, expression of Foxp3, GITR, TGF beta, and CTLA-4, known to be expressed by regulatory T cells, was significantly impaired in patients with lymphedema. BmA also induced significantly higher expression of TLR2, 4, 7, and 9 as well Nod1 and 2 mRNA in patients with lymphedema compared with asymptomatic controls. Conclusion: Our findings implicate increased Th1/Th17 responses and decreased regulatory T cells as well as regulation of Toll- and Nod-like receptors in pathogenesis of filarial lymphedema. C1 [Babu, Subash; Bhat, Sajid Q.; Kumar, N. Pavan; Lipira, Angelo B.; Kumar, Sanath; Karthik, C.; Kumaraswami, V.] Natl Inst Hlth Int Ctr Excellence Res, Chennai, Tamil Nadu, India. [Babu, Subash] NCI, SAIC Frederick, Frederick, MD 21701 USA. [Kumaraswami, V.] TB Res Ctr, Chennai, Tamil Nadu, India. [Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Babu, S (reprint author), Natl Inst Hlth Int Ctr Excellence Res, Chennai, Tamil Nadu, India. EM sbabu@mail.nih.gov OI Janaka, Sanath Kumar/0000-0003-2341-1526 FU Intramural NIH HHS NR 42 TC 47 Z9 51 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD APR PY 2009 VL 3 IS 4 AR e420 DI 10.1371/journal.pntd.0000420 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 438DV UT WOS:000265537000014 PM 19381284 ER PT J AU Bennuru, S Semnani, R Meng, Z Ribeiro, JMC Veenstra, TD Nutman, TB AF Bennuru, Sasisekhar Semnani, Roshanak Meng, Zhaojing Ribeiro, Jose M. C. Veenstra, Timothy D. Nutman, Thomas B. TI Brugia malayi Excreted/Secreted Proteins at the Host/Parasite Interface: Stage- and Gender-Specific Proteomic Profiling SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID EXCRETORY-SECRETORY PRODUCTS; FILARIAL NEMATODE PARASITES; MIGRATION INHIBITORY FACTOR; CUZN SUPEROXIDE DISMUTASES; ONCHOCERCA-VOLVULUS; ASCARIS-SUUM; IN-VITRO; CAENORHABDITIS-ELEGANS; BANCROFTIAN FILARIASIS; PROTECTIVE IMMUNITY AB Relatively little is known about the filarial proteins that interact with the human host. Although the filarial genome has recently been completed, protein profiles have been limited to only a few recombinants or purified proteins of interest. Here, we describe a large-scale proteomic analysis using microcapillary reverse-phase liquid chromatography-tandem-mass spectrometry to identify the excretory-secretory (ES) products of the L3, L3 to L4 molting ES, adult male, adult female, and microfilarial stages of the filarial parasite Brugia malayi. The analysis of the ES products from adult male, adult female, microfilariae (Mf), L3, and molting L3 larvae identified 852 proteins. Annotation suggests that the functional and component distribution was very similar across each of the stages studied; however, the Mf contributed a higher proportion to the total number of identified proteins than the other stages. Of the 852 proteins identified in the ES, only 229 had previous confirmatory expressed sequence tags (ESTs) in the available databases. Moreover, this analysis was able to confirm the presence of 274 "hypothetical'' proteins inferred from gene prediction algorithms applied to the B. malayi (Bm) genome. Not surprisingly, the majority (160/274) of these "hypothetical'' proteins were predicted to be secreted by Signal IP and/or SecretomeP 2.0 analysis. Of major interest is the abundance of previously characterized immunomodulatory proteins such as ES-62 (leucyl aminopeptidase), MIF-1, SERPIN, glutathione peroxidase, and galectin in the ES of microfilariae (and Mf-containing adult females) compared to the adult males. In addition, searching the ES protein spectra against the Wolbachia database resulted in the identification of 90 Wolbachia-specific proteins, most of which were metabolic enzymes that have not been shown to be immunogenic. This proteomic analysis extends our knowledge of the ES and provides insight into the host-parasite interaction. C1 [Bennuru, Sasisekhar; Semnani, Roshanak; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Meng, Zhaojing; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, SAIC Frederick, Frederick, MD 21701 USA. [Ribeiro, Jose M. C.] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Bennuru, S (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov OI Ribeiro, Jose/0000-0002-9107-0818 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; National Institutes of Health [N01-CO-12400] FX This project was funded primarily by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, and in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 86 TC 114 Z9 115 U1 1 U2 11 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD APR PY 2009 VL 3 IS 4 AR e410 DI 10.1371/journal.pntd.0000410 PG 12 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 438DV UT WOS:000265537000007 PM 19352421 ER PT J AU Cardosa, J Ooi, MH Tio, PH Perera, D Holmes, EC Bibi, K Manap, ZA AF Cardosa, Jane Ooi, Mong How Tio, Phaik Hooi Perera, David Holmes, Edward C. Bibi, Khatijar Manap, Zahara Abdul TI Dengue Virus Serotype 2 from a Sylvatic Lineage Isolated from a Patient with Dengue Hemorrhagic Fever SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID NEUTRALIZATION; ARBOVIRUSES; MONKEYS AB Dengue viruses circulate in both human and sylvatic cycles. Although dengue viruses (DENV) infecting humans can cause major epidemics and severe disease, relatively little is known about the epidemiology and etiology of sylvatic dengue viruses. A 20-year old male developed dengue hemorrhagic fever (DHF) with thrombocytopenia (12,000/ul) and a raised hematocrit (29.5% above baseline) in January 2008 in Malaysia. Dengue virus serotype 2 was isolated from his blood on day 4 of fever. A phylogenetic analysis of the complete genome sequence revealed that this virus was a member of a sylvatic lineage of DENV-2 and most closely related to a virus isolated from a sentinel monkey in Malaysia in 1970. This is the first identification of a sylvatic DENV circulating in Asia since 1975. C1 [Cardosa, Jane; Ooi, Mong How; Tio, Phaik Hooi; Perera, David] Univ Malaysia Sarawak, Inst Hlth & Community Med, Kota Samarahan, Sarawak, Malaysia. [Ooi, Mong How] Sibu Hosp, Sibu, Sarawak, Malaysia. [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bibi, Khatijar; Manap, Zahara Abdul] Univ Malaysia Sarawak, Univ Clin, Kota Samarahan, Sarawak, Malaysia. RP Cardosa, J (reprint author), Univ Malaysia Sarawak, Inst Hlth & Community Med, Kota Samarahan, Sarawak, Malaysia. EM jane.cardosa@gmail.com OI Holmes, Edward/0000-0001-9596-3552 FU Institute of Health and Community Medicine, Universiti Malaysia Sarawak FX This work was performed during the course of routine fever surveillance and was funded through the operational budget of the Institute of Health and Community Medicine, Universiti Malaysia Sarawak. The authors had no grant funding nor sponsors for the work described here. NR 16 TC 39 Z9 39 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD APR PY 2009 VL 3 IS 4 AR e423 DI 10.1371/journal.pntd.0000423 PG 5 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 438DV UT WOS:000265537000017 PM 19399166 ER PT J AU Quaia, C Ying, HS Nichols, AM Optican, LM AF Quaia, Christian Ying, Howard S. Nichols, Altah M. Optican, Lance M. TI The Viscoelastic Properties of Passive Eye Muscle in Primates. I: Static Forces and Step Responses SO PLOS ONE LA English DT Article ID GENERATING LINE SPECTRA; SUPERIOR OBLIQUE PALSY; SKELETAL-MUSCLE; EXTRAOCULAR-MUSCLES; RESTING TENSION; RAT MUSCLE; FIBERS; MECHANICS; MODEL; FROG AB The viscoelastic properties of passive eye muscles are prime determinants of the deficits observed following eye muscle paralysis, the root cause of several types of strabismus. Our limited knowledge about such properties is hindering the ability of eye plant models to assist in formulating a patient's diagnosis and prognosis. To investigate these properties we conducted an extensive in vivo study of the mechanics of passive eye muscles in deeply anesthetized and paralyzed monkeys. We describe here the static length-tension relationship and the transient forces elicited by small step-like elongations. We found that the static force increases nonlinearly with length, as previously shown. As expected, an elongation step induces a fast rise in force, followed by a prolonged decay. The time course of the decay is however considerably more complex than previously thought, indicating the presence of several relaxation processes, with time constants ranging from 1 ms to at least 40 s. The mechanical properties of passive eye muscles are thus similar to those of many other biological passive tissues. Eye plant models, which for lack of data had to rely on (erroneous) assumptions, will have to be updated to incorporate these properties. C1 [Quaia, Christian; Nichols, Altah M.; Optican, Lance M.] NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. [Ying, Howard S.] Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. RP Quaia, C (reprint author), NEI, Sensorimotor Res Lab, Bldg 10, Bethesda, MD 20892 USA. EM quaiac@nei.nih.gov FU National Eye Institute; NIH [EY19347, EY15025]; Knights' Templar Eye Foundation [Young Investigator Award]; Research to Prevent Blindness FX This work was supported by the intramural research program of the National Eye Institute (CQ, AMN, LMO), by NIH grants NIH EY19347 and NIH EY15025 (HSY), the Knights' Templar Eye Foundation Young Investigator Award (HSY), and Research to Prevent Blindness Core Grant (HSY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 22 Z9 24 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD APR 1 PY 2009 VL 4 IS 4 AR e4850 DI 10.1371/journal.pone.0004850 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437PY UT WOS:000265500600002 PM 19337381 ER PT J AU Jern, P Russell, RA Pathak, VK Coffin, JM AF Jern, Patric Russell, Rebecca A. Pathak, Vinay K. Coffin, John M. TI Likely Role of APOBEC3G-Mediated G-to-A Mutations in HIV-1 Evolution and Drug Resistance SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE; CYTIDINE DEAMINASE; APOBEC PROTEINS; DNA; HYPERMUTATION; RETROVIRUS; VIF; IDENTIFICATION; RESTRICTION AB The role of APOBEC3 (A3) protein family members in inhibiting retrovirus infection and mobile element retrotransposition is well established. However, the evolutionary effects these restriction factors may have had on active retroviruses such as HIV-1 are less well understood. An HIV-1 variant that has been highly G-to-A mutated is unlikely to be transmitted due to accumulation of deleterious mutations. However, G-to-A mutated hA3G target sequences within which the mutations are the least deleterious are more likely to survive selection pressure. Thus, among hA3G targets in HIV-1, the ratio of nonsynonymous to synonymous changes will increase with virus generations, leaving a footprint of past activity. To study such footprints in HIV-1 evolution, we developed an in silico model based on calculated hA3G target probabilities derived from G-to-A mutation sequence contexts in the literature. We simulated G-to-A changes iteratively in independent sequential HIV-1 infections until a stop codon was introduced into any gene. In addition to our simulation results, we observed higher ratios of nonsynonymous to synonymous mutation at hA3G targets in extant HIV-1 genomes than in their putative ancestral genomes, compared to random controls, implying that moderate levels of A3G-mediated G-to-A mutation have been a factor in HIV-1 evolution. Results from in vitro passaging experiments of HIV-1 modified to be highly susceptible to hA3G mutagenesis verified our simulation accuracy. We also used our simulation to examine the possible role of A3G-induced mutations in the origin of drug resistance. We found that hA3G activity could have been responsible for only a small increase in mutations at known drug resistance sites and propose that concerns for increased resistance to other antiviral drugs should not prevent Vif from being considered a suitable target for development of new drugs. C1 [Jern, Patric; Coffin, John M.] Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. [Russell, Rebecca A.; Pathak, Vinay K.] NCI, HIV Drug Resistance Program, Frederick, MD 21701 USA. RP Jern, P (reprint author), Tufts Univ, Sch Med, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. EM john.coffin@tufts.edu OI Jern, Patric/0000-0003-3393-5825 FU National Cancer Institute [R37 CA 089441]; Wenner-Gren foundation (Sweden); Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX This work was supported by grant R37 CA 089441 from the National Cancer Institute to JMC. PJ was supported by a fellowship from the Wenner-Gren foundation (Sweden). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. JMC was a Research Professor of the American Cancer Society, with support from the George Kirby Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 68 Z9 69 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD APR PY 2009 VL 5 IS 4 AR e1000367 DI 10.1371/journal.ppat.1000367 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 447UC UT WOS:000266216300011 PM 19343218 ER PT J AU Kuwata, T Nishimura, Y Whitted, S Ourmanov, I Brown, CR Dang, Q Buckler-White, A Iyengar, R Brenchley, JM Hirsch, VM AF Kuwata, Takeo Nishimura, Yoshiaki Whitted, Sonya Ourmanov, Ilnour Brown, Charles R. Dang, Que Buckler-White, Alicia Iyengar, Ranjini Brenchley, Jason M. Hirsch, Vanessa M. TI Association of Progressive CD4(+) T Cell Decline in SIV Infection with the Induction of Autoreactive Antibodies SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; FUSION INHIBITOR T-20; HIV-1 INFECTION; GASTROINTESTINAL-TRACT; IMMUNE ACTIVATION; IN-VIVO; LYMPHOCYTE DEPLETION; AIDS PATHOGENESIS; NONHUMAN-PRIMATES; VIRAL REPLICATION AB The progressive decline of CD4(+) T cells is a hallmark of disease progression in human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) infection. Whereas the acute phase of the infection is dominated by virus-mediated depletion of memory CD4(+) T cells, chronic infection is often associated with a progressive decline of total CD4(+) T cells, including the naive subset. The mechanism of this second phase of CD4(+) T cell loss is unclear and may include immune activation-induced cell death, immune-mediated destruction, and regenerative or homeostatic failure. We studied patterns of CD4(+) T cell subset depletion in blood and tissues in a group of 20 rhesus macaques inoculated with derivatives of the pathogenic SIVsmE543-3 or SIVmac239. Phenotypic analysis of CD4(+) T cells demonstrated two patterns of CD4(+) T cell depletion, primarily affecting either naive or memory CD4(+) T cells. Progressive decline of total CD4(+) T cells was observed only in macaques with naive CD4(+) T cell depletion (ND), though the depletion of memory CD4(+) T cells was profound in macaques with memory CD4(+) T cell depletion (MD). ND macaques exhibited lower viral load and higher SIV-specific antibody responses and greater B cell activation than MD macaques. Depletion of naive CD4(+) T cells was associated with plasma antibodies autoreactive with CD4(+) T cells, increasing numbers of IgG-coated CD4(+) T cells, and increased incidence of autoreactive antibodies to platelets (GPIIIa), dsDNA, and phospholipid (aPL). Consistent with a biological role of these antibodies, these latter antibodies were accompanied by clinical features associated with autoimmune disorders, thrombocytopenia, and catastrophic thrombotic events. More importantly for AIDS pathogenesis, the level of autoreactive antibodies significantly correlated with the extent of naive CD4(+) T cell depletion. These results suggest an important role of autoreactive antibodies in the CD4(+) T cell decline observed during progression to AIDS. C1 [Kuwata, Takeo] Kumamoto Univ, Prior Org Innovat & Excellence, Kumamoto, Japan. [Kuwata, Takeo; Nishimura, Yoshiaki; Whitted, Sonya; Ourmanov, Ilnour; Brown, Charles R.; Dang, Que; Buckler-White, Alicia; Iyengar, Ranjini; Brenchley, Jason M.; Hirsch, Vanessa M.] NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Kuwata, T (reprint author), Kumamoto Univ, Prior Org Innovat & Excellence, Kumamoto, Japan. EM vhirsch@nih.gov RI Kuwata, Takeo/F-5809-2013 FU Intramural Program of the NIAID; NIH; Ministry of Education, Culture, Sport, Science, and Technology, Japan FX This work was supported by the Intramural Program of the NIAID, NIH, and in part by the Special Coordination Funds for Promoting Science and Technology from the Ministry of Education, Culture, Sport, Science, and Technology, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 69 TC 21 Z9 22 U1 1 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7374 J9 PLOS PATHOG JI PLoS Pathog. PD APR PY 2009 VL 5 IS 4 AR e1000372 DI 10.1371/journal.ppat.1000372 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 447UC UT WOS:000266216300016 PM 19360097 ER PT J AU Pesce, JT Ramalingam, TR Wilson, MS Mentink-Kane, MM Thompson, RW Cheever, AW Urban, JF Wynn, TA AF Pesce, John T. Ramalingam, Thirumalai R. Wilson, Mark S. Mentink-Kane, Margaret M. Thompson, Robert W. Cheever, Allen W. Urban, Joseph F., Jr. Wynn, Thomas A. TI Retnla (Relm alpha/Fizz1) Suppresses Helminth-Induced Th2-Type Immunity SO PLOS PATHOGENS LA English DT Article ID RESISTIN-LIKE-MOLECULE; GENE-EXPRESSION PROFILES; INDUCED LUNG FIBROSIS; NEMATODE PARASITES; ALTERNATIVE ACTIVATION; PULMONARY INFLAMMATION; MACROPHAGE ACTIVATION; ALVEOLAR MACROPHAGES; LIVER FIBROSIS; INFECTION AB Retnla (Resistin-like molecule alpha/FIZZ1) is induced during Th2 cytokine immune responses. However, the role of Retnla in Th2-type immunity is unknown. Here, using Retnla(-/-) mice and three distinct helminth models, we show that Retnla functions as a negative regulator of Th2 responses. Pulmonary granuloma formation induced by the eggs of the helminth parasite Schistosoma mansoni is dependent on IL-4 and IL-13 and associated with marked increases in Retnla expression. We found that both primary and secondary pulmonary granuloma formation were exacerbated in the absence of Retlna. The number of granuloma-associated eosinophils and serum IgE titers were also enhanced. Moreover, when chronically infected with S. mansoni cercariae, Retnla(-/-) mice displayed significant increases in granulomatous inflammation in the liver and the development of fibrosis and progression to hepatosplenic disease was markedly augmented. Finally, Retnla(-/-) mice infected with the gastrointestinal (GI) parasite Nippostrongylus brasiliensis had intensified lung pathology to migrating larvae, reduced fecundity, and accelerated expulsion of adult worms from the intestine, suggesting Th2 immunity was enhanced. When their immune responses were compared, helminth infected Retnla(-/-) mice developed stronger Th2 responses, which could be reversed by exogenous rRelm alpha treatment. Studies with several cytokine knockout mice showed that expression of Retnla was dependent on IL-4 and IL-13 and inhibited by IFN-gamma, while tissue localization and cell isolation experiments indicated that eosinophils and epithelial cells were the primary producers of Retnla in the liver and lung, respectively. Thus, the Th2-inducible gene Retnla suppresses resistance to GI nematode infection, pulmonary granulomatous inflammation, and fibrosis by negatively regulating Th2-dependent responses. C1 [Pesce, John T.; Ramalingam, Thirumalai R.; Wilson, Mark S.; Mentink-Kane, Margaret M.; Thompson, Robert W.; Wynn, Thomas A.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Cheever, Allen W.] Biomed Res Inst, Rockville, MD 20852 USA. [Urban, Joseph F., Jr.] ARS, Diet Gen & Immunol Lab, Beltsville Human Nutr Res Ctr, USDA, Beltsville, MD USA. RP Pesce, JT (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU NIH/NIAID; ARS [1235-52000-053] FX This research was supported by the Intramural Research Program of the NIH/NIAID (http://www3.niaid.nih.gov/) and ARS Project 1235-52000-053 (JFU). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 114 Z9 116 U1 2 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD APR PY 2009 VL 5 IS 4 AR e1000393 DI 10.1371/journal.ppat.1000393 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 447UC UT WOS:000266216300036 PM 19381262 ER PT J AU Pesce, JT Ramalingam, TR Mentink-Kane, MM Wilson, MS El Kasmi, KC Smith, AM Thompson, RW Cheever, AW Murray, PJ Wynn, TA AF Pesce, John T. Ramalingam, Thirumalai R. Mentink-Kane, Margaret M. Wilson, Mark S. El Kasmi, Karim C. Smith, Amber M. Thompson, Robert W. Cheever, Allen W. Murray, Peter J. Wynn, Thomas A. TI Arginase-1-Expressing Macrophages Suppress Th2 Cytokine-Driven Inflammation and Fibrosis SO PLOS PATHOGENS LA English DT Article ID ALTERNATIVELY ACTIVATED MACROPHAGES; NITRIC-OXIDE SYNTHASE; L-ARGININE METABOLISM; ARGINASE-I EXPRESSION; CD4(+) T-CELLS; GRANULOMATOUS PATHOLOGY; MURINE SCHISTOSOMIASIS; LIVER FIBROSIS; IL-13; MICE AB Macrophage-specific expression of Arginase-1 is commonly believed to promote inflammation, fibrosis, and wound healing by enhancing L-proline, polyamine, and Th2 cytokine production. Here, however, we show that macrophage-specific Arg1 functions as an inhibitor of inflammation and fibrosis following infection with the Th2-inducing pathogen Schistosoma mansoni. Although susceptibility to infection was not affected by the conditional deletion of Arg1 in macrophages, Arg1(-/flox); LysMcre mice died at an accelerated rate. The mortality was not due to acute Th1/NOS2-mediated hepatotoxicity or endotoxemia. Instead, granulomatous inflammation, liver fibrosis, and portal hypertension increased in infected Arg1(-/flox); LysMcre mice. Similar findings were obtained with Arg1(flox/flox);Tie2cre mice, which delete Arg1 in all macrophage populations. Production of Th2 cytokines increased in the infected Arg1(-/flox); LysMcre mice, and unlike alternatively activated wild-type macrophages, Arg1(-/flox); LysMcre macrophages failed to inhibit T cell proliferation in vitro, providing an underlying mechanism for the exacerbated Th2 pathology. The suppressive activity of Arg1-expressing macrophages was independent of IL-10 and TGF-beta 1. However, when exogenous L-arginine was provided, T cell proliferation was restored, suggesting that Arg1-expressing macrophages deplete arginine, which is required to sustain CD4(+) T cell responses. These data identify Arg1 as the essential suppressive mediator of alternatively activated macrophages (AAM) and demonstrate that Arg1-expressing macrophages function as suppressors rather than inducers of Th2-dependent inflammation and fibrosis. C1 [Pesce, John T.; Ramalingam, Thirumalai R.; Mentink-Kane, Margaret M.; Wilson, Mark S.; Thompson, Robert W.; Wynn, Thomas A.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [El Kasmi, Karim C.; Smith, Amber M.; Murray, Peter J.] St Jude Childrens Hosp, Dept Infect Dis, Memphis, TN 38105 USA. [El Kasmi, Karim C.; Smith, Amber M.; Murray, Peter J.] St Jude Childrens Hosp, Dept Immunol, Memphis, TN 38105 USA. [Cheever, Allen W.] Biomed Res Inst, Rockville, MD 20852 USA. RP Pesce, JT (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM peter.murray@stjude.org; twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU Intramural Research Program of the NIH; NIAID; NIH [AI062921]; Sandler Program for Asthma Research; NIH CORE [P30 CA21765]; American Lebanese Syrian Associated Charities FX This research was supported by the Intramural Research Program of the NIH, NIAID and NIH grant AI062921 (PJM), Sandler Program for Asthma Research (PJM), NIH CORE grant P30 CA21765, and the American Lebanese Syrian Associated Charities. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 318 Z9 325 U1 3 U2 29 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD APR PY 2009 VL 5 IS 4 AR e1000371 DI 10.1371/journal.ppat.1000371 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 447UC UT WOS:000266216300015 PM 19360123 ER PT J AU Rao, SS Styles, D Kong, W Andrews, C Gorres, JP Nabel, GJ AF Rao, S. S. Styles, D. Kong, W. Andrews, C. Gorres, J. P. Nabel, G. J. TI A gene-based avian influenza vaccine in poultry SO POULTRY SCIENCE LA English DT Article; Proceedings Paper CT 97th Annual Meeting of the Poultry-Science-Association CY JUL 20-23, 2008 CL Niagara Falls, CANADA SP Poultry Sci Assoc DE poultry; influenza; vaccine; gene based; deoxyribonucleic acid ID REVERSE GENETICS; A VIRUS; PROTECTS CHICKENS; NEWCASTLE-DISEASE; VECTORED VACCINE; DNA VACCINATION; DENDRITIC CELLS; H5N1; CHALLENGE; IMMUNITY AB Highly pathogenic avian influenza A ( HPAI) viruses, specifically H5N1 strains, cause widespread morbidity and mortality in domestic and wild bird populations, and recent outbreaks have resulted in severe economic losses. Although still largely confined to birds, more than 300 human cases resulting in deaths have been reported to the World Health Organization. These sporadic human cases result from direct transmission from infected birds; however, a sustained outbreak of HPAI H5N1 increases the potential for the emergence of a human pandemic strain. One approach to the containment of HPAI H5N1 is the development of vaccines for use in poultry. Currently, the majority of avian influenza vaccines for poultry are traditional whole-virus vaccines produced in eggs. Although highly efficacious, these vaccines are hindered by long production times, inflexibility in quickly altering antigenic composition, and limited breadth of protection. Newer vaccines with more efficient manufacturing processes, enhanced efficacy, and cross-protection against multiple strains would improve preparedness. Reverse genetics technology has provided one such method, and emerging gene-based vaccines offer another approach that reduces dependence on egg-based production and human exposure to pathogenic viruses. Gene-based vaccines also provide rapid manufacturing, enhanced precision and versatility, and the capacity to protect against a broad range of viral subtypes. Vectors for these vaccines include replication-defective viruses, bacterial vectors, and DNA. Here we review the features of gene-based vaccination that may facilitate the control of HPAI H5N1 in poultry, and highlight the development of a hemagglutinin-based multivalent DNA vaccine that confers protection in mice and chickens. C1 [Rao, S. S.; Kong, W.; Andrews, C.; Gorres, J. P.; Nabel, G. J.] NIAID, Vaccine Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. [Styles, D.] Anim & Plant Hlth Inspect Serv, Anim Care Program, USDA, Riverdale, MD 20737 USA. RP Rao, SS (reprint author), NIAID, Vaccine Res Ctr, Natl Inst Hlth, 40 Convent Dr, Bethesda, MD 20892 USA. EM srao1@mail.nih.gov NR 58 TC 8 Z9 9 U1 0 U2 3 PU POULTRY SCIENCE ASSOC INC PI SAVOY PA 1111 N DUNLAP AVE, SAVOY, IL 61874-9604 USA SN 0032-5791 J9 POULTRY SCI JI Poult. Sci. PD APR 1 PY 2009 VL 88 IS 4 BP 860 EP 866 DI 10.3382/ps.2008-00360 PG 7 WC Agriculture, Dairy & Animal Science SC Agriculture GA 421SJ UT WOS:000264378300027 PM 19276436 ER PT J AU Masison, DC Kirkland, PA Sharma, D AF Masison, Daniel C. Kirkland, P. Aaron Sharma, Deepak TI Influence of Hsp70s and their regulators on yeast prion propagation SO PRION LA English DT Review DE Hsp70; Hsp40; chaperone; prion; yeast ID BETA-SHEET STRUCTURE; NUCLEOTIDE EXCHANGE FACTORS; SACCHAROMYCES-CEREVISIAE; PSI+ PRION; MOLECULAR CHAPERONES; IN-VITRO; CYTOSOLIC HSP70; ANTAGONISTIC INTERACTIONS; PROTEIN AGGREGATION; HSP104 CHAPERONE AB Propagation of yeast prions requires normal abundance and activity of many protein chaperones. Central among them is Hsp70, a ubiquitous and essential chaperone involved in many diverse cellular processes that helps promote proper protein folding and acts as a critical component of several chaperone machines. Hsp70 is regulated by a large cohort of co-chaperones, whose effects on prions are likely mediated through Hsp70. Hsp104 is another chaperone, absent from mammalian cells, that resolubilizes proteins from aggregates. This activity, which minimally requires Hsp70 and its co-chaperone Hsp40, is essential for yeast prion replication. Although much is known about how yeast prions can be affected by altering protein chaperones, mechanistic explanations for these effects are uncertain. We discuss the variety of effects Hsp70 and its regulators have on different prions and how the effects might be due to the many ways chaperones interact with each other and with amyloid. C1 [Masison, Daniel C.] NIDDK, LBG, NIDDKD, NIH, Bethesda, MD 20892 USA. RP Masison, DC (reprint author), NIDDK, LBG, NIDDKD, NIH, Bldg 8,Room 225,8 Ctr Dr, Bethesda, MD 20892 USA. EM masisond@helix.nih.gov FU National Institutes of Health; National Institute of Diabetes, Digestive and Kidney diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes, Digestive and Kidney diseases. NR 102 TC 25 Z9 26 U1 0 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1933-6896 J9 PRION JI Prion PD APR-JUN PY 2009 VL 3 IS 2 BP 65 EP 73 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 467EJ UT WOS:000267720300003 PM 19556854 ER PT J AU Green, AG Hawley, GC AF Green, Angela G. Hawley, Gary C. TI Early Career Psychologists: Understanding, Engaging, and Mentoring Tomorrow's Leaders SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article DE early career psychologist; ECP; mentoring; mentor; mentee ID PERSPECTIVES; PROGRAMS; GAP AB This article on mentoring describes demographic characteristics and challenges faced by early career psychologists (ECPs) and how mentoring can significantly shape the development of ECPs' professional and personal identity. ECPs have a significant impact on how psychology will evolve and be recognized in the marketplace. Mentors have the opportunity to significantly shape the development of this early career professional and thus assure the dynamic future of psychology. The characteristics of a mentor, the mentoring process of an ECP, diversity issues, and strategies for effective mentoring are discussed. C1 [Green, Angela G.] Natl Inst Mental Hlth, Centennial Mental Hlth Ctr, Elizabeth, CO 80107 USA. RP Green, AG (reprint author), Natl Inst Mental Hlth, Centennial Mental Hlth Ctr, 650 E Walnut,Unit C,POB 533, Elizabeth, CO 80107 USA. EM AngelaG@CentennialMHC.org NR 43 TC 16 Z9 16 U1 1 U2 2 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7028 J9 PROF PSYCHOL-RES PR JI Prof. Psychol.-Res. Pract. PD APR PY 2009 VL 40 IS 2 BP 206 EP 212 DI 10.1037/a0012504 PG 7 WC Psychology, Multidisciplinary SC Psychology GA 433ZV UT WOS:000265245900017 ER PT J AU John, K Ragavan, N Pratt, MM Singh, PB Al-Buheissi, S Matanhelia, SS Phillips, DH Poirier, MC Martin, FL AF John, Kaarthik Ragavan, Narasimhan Pratt, M. Margaret Singh, Paras B. Al-Buheissi, Salah Matanhelia, Shyam S. Phillips, David H. Poirier, Miriam C. Martin, Francis L. TI Quantification of Phase I/II Metabolizing Enzyme Gene Expression and Polycyclic Aromatic Hydrocarbon-DNA Adduct Levels in Human Prostate SO PROSTATE LA English DT Article DE automated cellular imaging system; immunohistochemistry; peripheral zone; radical retropubic prostatectomy; RT-PCR; transition zone ID HETEROCYCLIC AMINES; CANCER-MORTALITY; N-ACETYLTRANSFERASE; CYTOCHROMES P450; UNITED-STATES; COOKED FOOD; CELL-LINES; CARCINOGENS; IMMUNOHISTOCHEMISTRY; ADENOCARCINOMA AB BACKGROUND. Studies of migrant populations suggest that dietary and/or environmental factors play a crucial role in the etiology of prostatic adenocarcinoma (CaP). The human prostate consists of the peripheral zone (PZ), transition zone (TZ), and central zone (CZ); CaP occurs most often in the PZ. METHODS. To investigate the notion that an underlying differential expression of phase I/II genes, and/or the presence of polycyclic aromatic hydrocarbon (PAH)-DNA adducts might explain the elevated PZ susceptibility, we examined prostate tissues (matched tissue sets consisting of PZ and TZ) from men undergoing radical retropubic prostatectomy for CaP (n = 26) or cystoprostatectomy (n = 1). Quantitative gene expression analysis was employed for cytochrome P450 (CYP) isoforms CYP1A1, CYP1B1, and CYP1A2, as well as N-acetyltransferase I and 2 (NAT1 and NAT2) and catechol-O-methyl transferase (COMT). RESULTS. CYP1B1, NAT1, and COMT were expressed in all tissue sets; levels of CYP1B1 and NAT1 were consistently higher in the PZ compared to TZ Immunohistochemistry confirmed the presence of CYP1B1 (nuclear-associated and primarily in basal epithelial cells) and NAT1. Normal tissue from 23 of these aforementioned 27 matched tissue sets was analyzed for PAH-DNA adduct levels using antiserum elicited against DNA modified with r7,t8-dihydroxy-t9,10-oxy-7,8,9,10-tetrahydro-benzo[a]pyrene (BPDE). PAH-DNA adduct levels were highest in glandular epithelial cells, but a comparison of PZ and TZ showed no significant differences. CONCLUSION. Although expression of activating and/or detoxifying enzymes maybe higher in the PZ, PAH-DNA adduct levels appear to be similar in both zones. Therefore, factors other than PAH-DNA adducts may be responsible for promotion of tumor formation in the human prostate. Prostate 69: 505-519, 2009. (c) 2009 Wiley-Liss, Inc. C1 [Ragavan, Narasimhan; Singh, Paras B.; Matanhelia, Shyam S.; Martin, Francis L.] Univ Lancaster, Lancaster Environm Ctr, Lancaster LA1 4YQ, England. [John, Kaarthik; Pratt, M. Margaret; Poirier, Miriam C.] NCI, Carcinogen DNA Interact Sect, LCBG, Ctr Canc Res,NIH, Bethesda, MD USA. [Al-Buheissi, Salah; Phillips, David H.] Inst Canc Res, Sutton, Surrey, England. RP Martin, FL (reprint author), Univ Lancaster, Lancaster Environm Ctr, Lancaster LA1 4YQ, England. EM f.martin@lancaster.ac.uk OI Phillips, David/0000-0001-8509-3485; L Martin, Francis/0000-0001-8562-4944 FU Rosemere Cancer Foundation; Cancer Research UK; US National Institutes of Health; National Cancer Institute; Center for Cancer Research FX This work was funded by: the Rosemere Cancer Foundation (Ragavan, N., Singh, P.B., and Martin, F.L.); Cancer Research UK (Phillips, D.H.); and the intramural program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research (Poirier, M.C., John, K., and Pratt, M.M.). NR 61 TC 30 Z9 30 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0270-4137 J9 PROSTATE JI Prostate PD APR 1 PY 2009 VL 69 IS 5 BP 505 EP 519 DI 10.1002/pros.20898 PG 15 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 426GI UT WOS:000264695600006 PM 19143007 ER PT J AU Chakrabarti, S Panchenko, AR AF Chakrabarti, Saikat Panchenko, Anna R. TI Coevolution in defining the functional specificity SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE coevolution; correlated mutation; covariation; functional diversification; specificity determinants; subfamily specificity; mutual information; protein evolution ID MULTIPLE SEQUENCE ALIGNMENTS; INFORMATION-THEORETIC ANALYSIS; LACTOSE REPRESSOR PROTEIN; CORRELATED MUTATIONS; ALLOSTERIC COMMUNICATION; COEVOLVING POSITIONS; CONTACT PREDICTION; MUTUAL INFORMATION; RESIDUE CONTACTS; DETERMINANTS AB Covariation between sites can arise due to a common evolutionary history. At the same time, structure and function of proteins play significant role in evolvability of different sites that are not directly connected with the common ancestry. The nature of forces which cause residues to coevolve is still not thoroughly understood, it is especially not clear how coevolutionary processes are related to functional diversification within protein families. We analyzed both functional and structural factors that might cause covariation of specificity determinants an showed that they more often participate in coevolutionary relationships with each other and other sites compared with functional sites and those sites that are not under strong functional constraints. We also found that protein sites with higher number of coevolutionary connections with other sites have a tendency to evolve slower. Our results indicate that in some cases coevolutionary connections exist between specificity sites that are locate far away in space but are under similar functional constraints. Such correlated changes and compensations can be realized through the stepwise coevolutionary processes which in turn can shed light on the mechanisms of functional diversification. C1 [Chakrabarti, Saikat; Panchenko, Anna R.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Chakrabarti, S (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM chakraba@ncbi.nlm.nih.gov; panch@ncbi.nlm.nih.gov FU National Library of Medicine at National Institutes of Health/DHHS FX Grant sponsor: Intramural Research Program of the National Library of Medicine at National Institutes of Health/DHHS NR 64 TC 33 Z9 33 U1 0 U2 9 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 APR PY 2009 VL 75 IS 1 BP 231 EP 240 DI 10.1002/prot.22239 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 410AG UT WOS:000263546600019 PM 18831050 ER PT J AU Carbonell, P Nussinov, R del Sol, A AF Carbonell, Pablo Nussinov, Ruth del Sol, Antonio TI Energetic determinants of protein binding specificity: Insights into protein interaction networks SO PROTEOMICS LA English DT Article DE Affinity; Protein hubs; Protein networks; Protein-protein interactions; Specificity ID MODULAR ARCHITECTURE; SACCHAROMYCES-CEREVISIAE; CYTOCHROME-B; SITES; RECEPTOR; YEAST; INTERFACE; UBIQUITIN; DOMAINS; REGIONS AB One of the challenges of the postgenomic era is to provide a more realistic representation of cellular processes by combining a systems biology description of functional networks with information on their interacting components. Here we carried out a systematic large-scale computational study on a structural protein-protein interaction network dataset in order to dissect thermodynamic characteristics of binding determining the interplay between protein affinity and specificity. As expected, interactions involving specific binding sites display higher affinities than those of promiscuous binding sites. Next, in order to investigate a possible role of modular distribution of hot spots in binding specificity, we divided binding sites into modules previously shown to be energetically independent. In general, hot spots that interact with different partners are located in different modules. We further observed that common hot spots tend to interact with partners exhibiting common binding motifs, whereas different hot spots tend to interact with partners with different motifs. Thus, energetic properties of binding sites provide insights into the way proteins modulate interactions with different partners. Knowledge of those factors playing a role in protein specificity is important for understanding how proteins acquire additional partners during evolution. It should also be useful in drug design. C1 [Carbonell, Pablo; del Sol, Antonio] Fujirebio Inc, Bioinformat Res Unit, Div Res & Dev, Hachioji, Tokyo 1920031, Japan. [Nussinov, Ruth] SAIC Frederick Inc, Basic Res Program, Ctr Canc Res Nanobiol Program, NCI Frederick, Frederick, MD USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP del Sol, A (reprint author), Fujirebio Inc, Bioinformat Res Unit, Div Res & Dev, Komiya Cho, Hachioji, Tokyo 1920031, Japan. EM ao-mesa@fujirebio.co.jp RI Carbonell, Pablo/A-3572-2011 OI Carbonell, Pablo/0000-0002-0993-5625 FU National Cancer Institute; National Institutes of Health [N01-CO-12400]; Center for Cancer Research FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 56 TC 25 Z9 25 U1 1 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1615-9853 J9 PROTEOMICS JI Proteomics PD APR PY 2009 VL 9 IS 7 BP 1744 EP 1753 DI 10.1002/pmic.200800425 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 435JA UT WOS:000265339000001 PM 19253304 ER PT J AU Zhou, XB Wang, HH Wang, J Wang, Y Hoehn, G Azok, J Brennan, ML Hazen, SL Li, K Chang, SF Wong, STC AF Zhou, Xiaobo Wang, Honghui Wang, Jun Wang, Yuan Hoehn, Gerard Azok, Joseph Brennan, Marie-Luise Hazen, Stanley L. Li, King Chang, Shih-Fu Wong, Stephen T. C. TI Identification of biomarkers for risk stratification of cardiovascular events using genetic algorithm with recursive local floating search SO PROTEOMICS LA English DT Article DE Biomarker panel; Genetic algorithm; Major adverse cardiac events (MACE); Mass spectrometry; Recursive local floating search ID PARTIAL LEAST-SQUARES; FEATURE-SELECTION; MUTUAL INFORMATION; CLASSIFICATION; REGRESSION; REDUNDANCY; RELEVANCE AB Conventional biomarker discovery focuses mostly on the identification of single markers and thus often has limited success in disease diagnosis and prognosis. This study proposes a method to identify an optimized protein biomarker panel based on MS studies for predicting the risk of major adverse cardiac events (MACE) in patients. Since the simplicity and concision requirement for the development of immunoassays can only tolerate the complexity of the prediction model with a very few selected discriminative biomarkers, established optimization methods, such as conventional genetic algorithm (CA), thus fails in the high-dimensional space. in this paper, we present a novel variant of CA that embeds the recursive local floating enhancement technique to discover a panel of protein biomarkers with far better prognostic value for prediction of MACE than existing methods, including the one approved recently by FDA (Food and Drug Administration). The new pragmatic method applies the constraints of MACE relevance and biomarker redundancy to shrink the local searching space in order to avoid heavy computation penalty resulted from the local floating optimization. The proposed method is compared with standard CA and other variable selection approaches based on the MACE prediction experiments. Two powerful classification techniques, partial least squares logistic regression (PLS-LR) and support vector machine classifier (SVMC), are deployed as the MACE predictors owing to their ability in dealing with small scale and binary response data. New preprocessing algorithms, such as low-level signal processing, duplicated spectra elimination, and outliner patient's samples removal, are also included in the proposed method. The experimental results show that an optimized panel of seven selected biomarkers can provide more than 77.1% MACE prediction accuracy using SVMC. The experimental results empirically demonstrate that the new CA algorithm with local floating enhancement (GA-LFE) can achieve the better MACE prediction performance comparing with the existing techniques. The method has been applied to SELDI/MALDI MS datasets to discover an optimized panel of protein biomarkers to distinguish disease from control. C1 [Zhou, Xiaobo; Wang, Jun; Wang, Yuan; Wong, Stephen T. C.] Methodist Hosp, Res Inst, Ctr Biotechnol & Informat, Houston, TX 77030 USA. [Zhou, Xiaobo; Wang, Jun; Wang, Yuan; Wong, Stephen T. C.] Cornell Univ, Houston, TX USA. [Zhou, Xiaobo; Li, King; Wong, Stephen T. C.] Methodist Hosp, Weill Cornell Coll Med, Dept Radiol, Houston, TX 77030 USA. [Wang, Honghui; Hoehn, Gerard; Azok, Joseph] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Wang, Jun; Chang, Shih-Fu] Columbia Univ, Dept Elect Engn, New York, NY 10027 USA. [Brennan, Marie-Luise; Hazen, Stanley L.] CCF, Ctr Cardiovasc Diagnost & Prevent, Cleveland, OH USA. RP Zhou, XB (reprint author), Methodist Hosp, Res Inst, Ctr Biotechnol & Informat, 6535 Fannin, Houston, TX 77030 USA. EM xzhou@tmhs.org FU HCNR Center for Bioinformatics Research; Harvard Medical School (STCW); NIH Clinical Center; Methodist Hospital Research Institute FX This research is partially funded by the HCNR Center for Bioinformatics Research Grant, Harvard Medical School (STCW), NIH Clinical Center (KL), and The Methodist Hospital Research Institute Scholarship Award (XZ). NR 17 TC 2 Z9 2 U1 0 U2 5 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 APR PY 2009 VL 9 IS 8 BP 2286 EP 2294 DI 10.1002/pmic.200700867 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 441UJ UT WOS:000265795700021 PM 19337989 ER PT J AU Dahdouh, F Anthoni, H Tapia-Paez, I Peyrard-Janvid, M Schulte-Korne, G Warnke, A Remschmidt, H Ziegler, A Kere, J Muller-Myhsok, B Nothen, MM Schumacher, J Zucchelli, M AF Dahdouh, Faten Anthoni, Heidi Tapia-Paez, Isabel Peyrard-Janvid, Myriam Schulte-Koerne, Gerd Warnke, Andreas Remschmidt, Helmut Ziegler, Andreas Kere, Juha Mueller-Myhsok, Bertram Noethen, Markus M. Schumacher, Johannes Zucchelli, Marco TI Further evidence for DYX1C1 as a susceptibility factor for dyslexia SO PSYCHIATRIC GENETICS LA English DT Article DE behavioral genetics; candidate gene; developmental genes; identification of disease genes ID DEVELOPMENTAL DYSLEXIA; READING-DISABILITY; CANDIDATE GENE; ASSOCIATION; SUPPORT; MEMORY; COHORT; EKN1 AB Objective Dyslexia-susceptibility-1-candidate-1 (DYX1C1) was the first gene associated with dyslexia. Since the original report of 2003, eight replication attempts have been published reporting discordant results. As the dyslexia community still considers the role of DYX1C1 unsettled, we explored the contribution of this gene in a sample of 366 trios of German descent. Methods To the common four markers used in previous studies, we added two new single nucleotide polymorphisms found by resequencing both the putative regulatory and coding region of the gene in randomly selected cases and controls. As linkage disequilibrium blocks of the region were not easy to define, we approached the association problem by running a transmission disequilibrium test over sliding windows of dimension 1 to 6 on consecutive markers. The significance of this test was calculated generating the empirical distribution of the global P value by simulating the data. As our study sample had a large female proband content, we also stratified our analysis by sex. Results We found statistically significant association with global corrected P value of 0.036. The three-marker haplotype G/G/G spanning rs3743205/rs3743204/rs600753 was most associated with a P value of 0.006 and odds ratio 3.7 (95% confidence interval: 1.4-9.6) in female probands. A detailed haplotype-phenotype analysis revealed that the dyslexia subphenotype short-term memory contributed mainly to the observed findings. This is in accordance with a recent short-term memory DYX1C1 association in an independent sample of dyslexia. Conclusion As significant association was proved in our sample, we could also conclude that denser maps, sex information, and well-defined subphenotypes are crucial to correctly determine the contribution of DYX1C1 to dyslexia. Psychiatr Genet 19:59-63 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Anthoni, Heidi; Tapia-Paez, Isabel; Peyrard-Janvid, Myriam; Kere, Juha; Zucchelli, Marco] Karolinska Inst, Dept Biosci & Nutr, S-14157 Huddinge, Sweden. [Dahdouh, Faten; Schumacher, Johannes] Univ Bonn, Inst Human Genet, Life & Brain Ctr, D-5300 Bonn, Germany. [Noethen, Markus M.] Univ Bonn, Dept Genom, Life & Brain Ctr, D-5300 Bonn, Germany. [Schulte-Koerne, Gerd] Univ Munich, Dept Child & Adolescent Psychiat, D-80539 Munich, Germany. [Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-80804 Munich, Germany. [Warnke, Andreas] Univ Wurzburg, Dept Child & Adolescent Psychiat & Psychotherapy, Wurzburg, Germany. [Remschmidt, Helmut] Univ Marburg, Dept Child & Adolescent Psychiat & Psychotherapy, Marburg, Germany. [Ziegler, Andreas] Med Univ Lubeck, Inst Med Biometry & Stat, D-23538 Lubeck, Germany. [Kere, Juha] Univ Helsinki, Dept Med Genet, Helsinki, Finland. [Kere, Juha] Karolinska Inst, Dept Clin Res Ctr, S-14157 Huddinge, Sweden. [Schumacher, Johannes] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. RP Kere, J (reprint author), Karolinska Inst, Dept Biosci & Nutr, S-14157 Huddinge, Sweden. EM Juha.Kere@biosci.ki.se RI Kere, Juha/A-9179-2008; Peng, Bo/A-6920-2009; Tapia-Paez, Isabel/N-1210-2013; Schumacher, Johannes/F-4970-2015; OI Kere, Juha/0000-0003-1974-0271; Peng, Bo/0000-0001-8225-2284; Schumacher, Johannes/0000-0001-9217-6457; Ziegler, Andreas/0000-0002-8386-5397; Nothen, Markus/0000-0002-8770-2464 FU Deutsche Forschungsgemeinschaft (DFG); Alfried Krupp von Bohlen und Halbach-Stiftung; NIH/DFG Research Career Transition Awards; Swedish Brain Foundation; Centennial Foundation of Helsingin Sanomat; Bioinformatics and Expression Analysis Core Facility at Karolinska Institutet; Swedish Research Council; Academy of Finland; Sigrid Juselius Foundation; Paivikki and Sakari Sohlberg Foundation FX The authors are grateful to all investigated individuals for their cooperation in this study. This study was supported by the Deutsche Forschungsgemeinschaft (DFG). M.M.N. received support for this study from the Alfried Krupp von Bohlen und Halbach-Stiftung; J.S. is a research fellow of the NIH/DFG Research Career Transition Awards Program; M.P.J. is a recipient of a research position from Swedish Research Council; I.T.P is supported by a grant from Swedish Brain Foundation; H.A. is supported by the Centennial Foundation of Helsingin Sanomat; M.Z. is partly supported by the Bioinformatics and Expression Analysis Core Facility at Karolinska Institutet; and J.K. is supported by grants from Swedish Research Council, Academy of Finland, Sigrid Juselius Foundation, and Paivikki and Sakari Sohlberg Foundation. NR 25 TC 33 Z9 35 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD APR PY 2009 VL 19 IS 2 BP 59 EP 63 DI 10.1097/YPG.0b013e32832080e1 PG 5 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 426GC UT WOS:000264695000001 PM 19240663 ER PT J AU Georgi, A Schumacher, J Leon, CA Wolf, AV Klein, K Bosshenz, KV Schirmbeck, F Strohmaier, J Propping, P Schulze, TG Rietschel, M Nothen, MM Cichon, S Abou Jamra, R AF Georgi, Alexander Schumacher, Johannes Leon, Chady Abboud Wolf, Angela Villela Klein, Katrin Boesshenz, Katja V. Schirmbeck, Frederike Strohmaier, Jana Propping, Peter Schulze, Thomas G. Rietschel, Marcella Noethen, Markus M. Cichon, Sven Abou Jamra, Rami TI No association between genetic variants at the DGCR2 gene and schizophrenia in a German sample SO PSYCHIATRIC GENETICS LA English DT Letter C1 [Schumacher, Johannes; Leon, Chady Abboud; Wolf, Angela Villela; Klein, Katrin; Propping, Peter; Abou Jamra, Rami] Univ Bonn, Inst Human Genet, Life & Brain Ctr, D-53111 Bonn, Germany. [Georgi, Alexander; Boesshenz, Katja V.; Schirmbeck, Frederike; Strohmaier, Jana; Schulze, Thomas G.; Rietschel, Marcella] Univ Bonn, Cent Inst Mental Hlth, Life & Brain Ctr, D-53111 Bonn, Germany. [Noethen, Markus M.; Cichon, Sven] Univ Bonn, Dept Genom, Life & Brain Ctr, D-53111 Bonn, Germany. [Schumacher, Johannes] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. RP Abou Jamra, R (reprint author), Univ Bonn, Inst Human Genet, Life & Brain Ctr, Wilhelmstr 31, D-53111 Bonn, Germany. EM rami.aboujamra@uni-bonn.de RI Schulze, Thomas/H-2157-2013; Cichon, Sven/H-8803-2013; Cichon, Sven/B-9618-2014; Abou Jamra, Rami/I-4805-2015; Schirmbeck, Frederike/G-8187-2016; Schumacher, Johannes/F-4970-2015; OI Nothen, Markus/0000-0002-8770-2464; Cichon, Sven/0000-0002-9475-086X; Cichon, Sven/0000-0002-9475-086X; Abou Jamra, Rami/0000-0002-1542-1399; Schumacher, Johannes/0000-0001-9217-6457; Georgi, Alexander/0000-0002-1499-8524; Schirmbeck, Frederike/0000-0003-1700-0958 NR 2 TC 2 Z9 2 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD APR PY 2009 VL 19 IS 2 BP 104 EP 104 DI 10.1097/YPG.0b013e328311874a PG 1 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 426GC UT WOS:000264695000008 PM 19668116 ER PT J AU Hennessy, KD Chambers, DA AF Hennessy, Kevin D. Chambers, David A. TI Delivery of Excellent Mental Health Care and Acceleration of Research: Federal Activities Since the President's Commission Report SO PSYCHIATRIC SERVICES LA English DT Article AB The report of the President's New Freedom Commission set forth six goals and related recommendations to enable adults with serious mental illness and children with serious emotional disturbance to participate fully in their communities. This article focuses on goal 5-"Excellent mental health care is delivered and research is accelerated"-and its four related recommendations. The authors describe federal government activities undertaken since the report was released. To accelerate research, the National Institute of Mental Health (NIMH) has launched initiatives to find ways to interrupt the progress of schizophrenia and to identify interventions for combat veterans with mental health problems. To advance evidence-based practices, the Substance Abuse and Mental Health Services Administration (SAMHSA) has expanded and transformed its National Registry of Evidence-Based Programs and Practices and NIMH has launched a major research initiative to build the knowledge base for dissemination and implementation. To improve and expand the workforce, SAMHSA has published an action plan for workforce development and NIMH has established grants to develop curricula to integrate training in evidence-based practices into clinical training programs. To develop knowledge in understudied areas, NIMH has funded studies to reduce and eliminate disparities and SAMHSA has supported efforts to improve delivery of trauma-informed services, such as the National Child Traumatic Stress Network. Continued advancement in goal 5 areas calls for commitment to working across agency and organizational boundaries to ensure more rapid and widespread dissemination and implementation of research and policies and for further development of ways to promote the participation of all stakeholders. (Psychiatric Services 60: 433-438, 2009) C1 [Hennessy, Kevin D.] Subst Abuse & Mental Hlth Serv Adm, Off Policy Planning & Budget, Rockville, MD 20857 USA. [Chambers, David A.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Hennessy, KD (reprint author), Subst Abuse & Mental Hlth Serv Adm, Off Policy Planning & Budget, 1 Choke Cherry Rd,Room 8-1017, Rockville, MD 20857 USA. EM kevin.hennessy@samhsa.hhs.gov NR 21 TC 3 Z9 3 U1 1 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD APR PY 2009 VL 60 IS 4 BP 433 EP 438 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 427QJ UT WOS:000264793500005 PM 19339316 ER PT J AU Blair, RJR Mitchell, DGV AF Blair, R. J. R. Mitchell, D. G. V. TI Psychopathy, attention and emotion SO PSYCHOLOGICAL MEDICINE LA English DT Review DE Antisocial behaviour; biased competition model; callous-unemotional traits; emotional attention; psychopathy ID POSTTRAUMATIC-STRESS-DISORDER; ORBITOFRONTAL CORTEX DYSFUNCTION; NEUROPSYCHOLOGICAL TEST FINDINGS; ABNORMAL SELECTIVE ATTENTION; CALLOUS-UNEMOTIONAL TRAITS; ROSTRAL ANTERIOR CINGULATE; VISUAL-ATTENTION; CRIMINAL PSYCHOPATHS; PASSIVE-AVOIDANCE; NONPSYCHOPATHIC OFFENDERS AB Psychopathy is a developmental disorder marked by emotional hypo-responsiveness and an increased risk for antisocial behavior. Influential attention-based accounts of psychopathy have long been made; however, these accounts have made relatively little reference to general models of attention in healthy individuals. This review has three aims: (1) to summarize Current cognitive neuroscience data on differing attentional systems; (2) to examine the functional integrity of these attentional systems in individuals with psychopathy; and (3) to consider the implications of these data for attention and emotion dysfunction accounts of psychopathy. C1 [Blair, R. J. R.] NIMH, Mood & Anxiety Program, NIH, Bethesda, MD 20892 USA. [Mitchell, D. G. V.] Univ Western Ontario, Dept Psychiat, Schulich Sch Med & Dent, London, ON N6A 3K7, Canada. [Mitchell, D. G. V.] Univ Western Ontario, Dept Anat & Cell Biol, Schluich Sch Med & Dent, London, ON N6A 3K7, Canada. RP Blair, RJR (reprint author), NIMH, Mood & Anxiety Program, NIH, 15K N Dr, Bethesda, MD 20892 USA. EM blairj@intra.nimh.nih.gov FU NIH:NIMH; Natural Sciences and Engineering Research Council of Canada; Ontario Mental Health Foundation FX R.J.R.B. was supported by the Intramural Research Program of the NIH:NIMH. D. G. V. M. was supported by funding from the Natural Sciences and Engineering Research Council of Canada, and the Ontario Mental Health Foundation New Investigator Fellowship. NR 126 TC 58 Z9 58 U1 6 U2 39 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0033-2917 J9 PSYCHOL MED JI Psychol. Med. PD APR PY 2009 VL 39 IS 4 BP 543 EP 555 DI 10.1017/S0033291708003991 PG 13 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 426EO UT WOS:000264691000002 PM 18700991 ER PT J AU Koffarnus, MN Greedy, B Husbands, SM Grundt, P Newman, AH Woods, JH AF Koffarnus, Mikhail N. Greedy, Benjamin Husbands, Stephen M. Grundt, Peter Newman, Amy Hauck Woods, James H. TI The discriminative stimulus effects of dopamine D2-and D3-preferring agonists in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Drug discrimination; Either/or discrimination; D2; D3; Dopamine; Pramipexole; Sumanirole; Rat ID D-3 RECEPTOR AGONISTS; DRUG DISCRIMINATION; ANTAGONISTS; COCAINE; D3; ENHANCEMENT; AMPHETAMINE; 7-OH-DPAT; VEHICLE; LIGANDS AB Previous research has found the stimulus effects of dopamine D2- and D3-preferring agonists difficult to distinguish in drug discrimination studies. Antagonism studies suggest that the stimulus effects of both types of agonists may be mediated primarily through D2 receptors. The current study was designed to further assess the receptors mediating the stimulus effects of these agonists and to attempt to train rats to discriminate directly between D2- and D3-preferring dopamine agonists. Four groups of eight rats were trained to discriminate either 0.1 mg/kg of the D3-preferring agonist pramipexole from saline, 1.0 mg/kg of the D2-preferring agonist sumanirole from saline, 0.1 mg/kg pramipexole from either saline or 1.0 mg/kg sumanirole, or 1.0 mg/kg sumanirole from either saline or 0.1 mg/kg pramipexole. Three of eight rats in the 0.1 mg/kg pramipexole vs. 1.0 mg/kg sumanirole or saline failed to meet the training criteria, and the discrimination in this group was tenuous. The D2-preferring antagonist L-741,626 at 1.0 mg/kg was more effective at shifting to the right the pramipexole dose-response curve in pramipexole-trained rats, while 32 mg/kg of the selective D3 antagonist PG01037 had little effect. Quinpirole and 7-OH-DPAT fully or partially substituted for both pramipexole and sumanirole in each group tested, while cocaine did not substitute in any group. Antagonist data along with the pattern of training and substitution data suggested that D2 receptor activation is primarily responsible for the stimulus effects of both sumanirole and pramipexole with D3 receptor activation playing little or no role. C1 [Koffarnus, Mikhail N.; Woods, James H.] Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. [Woods, James H.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Greedy, Benjamin; Husbands, Stephen M.] Univ Bath, Dept Pharm & Pharmacol, Bath BA2 7AY, Avon, England. [Grundt, Peter] Univ Minnesota Duluth, Dept Chem & Biochem, Duluth, MN 55812 USA. [Newman, Amy Hauck] NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Koffarnus, MN (reprint author), Univ Michigan, Dept Psychol, 1301 MSRB 3,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM mickyk@umich.edu RI Husbands, Stephen/D-5926-2011; OI Husbands, Stephen/0000-0002-9928-6322 FU USPHS/NIDA [R01 DA020669, T32 DA007267] FX The authors would like to thank Gail Winger and Emily Jutkiewicz for advice and guidance throughout the experiment and with manuscript preparation. The authors also thank Alexa Cohen, Simon Cohen, Antwan Hall, Eugene Kligman, Elizabeth Kossak, Jennifer Montgomery, Nathaniel Reichwage, and Emily West for technical assistance. This research was supported by USPHS/NIDA grants R01 DA020669 and T32 DA007267. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute on Drug Abuse or the National Institutes of Health. NR 26 TC 10 Z9 10 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2009 VL 203 IS 2 BP 317 EP 327 DI 10.1007/s00213-008-1323-4 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 418FU UT WOS:000264134900013 PM 18807248 ER PT J AU Justinova, Z Ferre, S Barnes, C Wertheim, CE Pappas, LA Goldberg, SR Le Foll, B AF Justinova, Zuzana Ferre, Sergi Barnes, Chanel Wertheim, Carrie E. Pappas, Lara A. Goldberg, Steven R. Le Foll, Bernard TI Effects of chronic caffeine exposure on adenosinergic modulation of the discriminative-stimulus effects of nicotine, methamphetamine, and cocaine in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Adenosine A(1) receptor; Adenosine A(2A) receptor; Caffeine; Cocaine; Drug discrimination; Methamphetamine; Nicotine; Rats ID A(2A) RECEPTORS; AMPHETAMINE; INVOLVEMENT; POTENTIATION; MECHANISM; A(1) AB Adenosine receptors are involved in cocaine and methamphetamine discrimination and exposure to caffeine can affect behavioral effects of nicotine in rats. Here we investigated the relative involvement of adenosine A(1) and A(2A) receptors in nicotine, cocaine, and methamphetamine discrimination, before and/or during chronic caffeine exposure. The nonselective adenosine receptor antagonist caffeine, the A(1)-receptor antagonist cyclopentyltheophylline (CPT), and the A(2A)-receptor antagonist MSX-3 were evaluated in rats trained to discriminate 0.4 mg/kg nicotine from saline under a fixed-ratio schedule of food delivery. Effects of adenosine receptor antagonists were then compared in rats discriminating nicotine, methamphetamine, or cocaine from saline during chronic caffeine exposure in their drinking water. Caffeine, CPT, and MSX-3 partially generalized to nicotine and shifted nicotine dose-response curves leftwards. During chronic caffeine exposure, however, all three ligands failed to generalize to nicotine and failed to shift nicotine dose-response curves. In previous experiments, CPT and MSX-3 partially generalized to methamphetamine and cocaine and shifted dose-response curves leftwards. In the present experiments, CPT neither generalized nor shifted dose-response curves for methamphetamine or cocaine during chronic caffeine exposure. However, MSX-3 partially generalized to both psychostimulants and shifted their dose-response curves leftwards. Caffeine partially generalized to cocaine, but not methamphetamine, and shifted both dose-response curves leftwards. Both adenosine A(1) and A(2A) receptors are capable of modulating the discriminative-stimulus effects of nicotine. Chronic caffeine exposure produces complete tolerance to both A(1)- and A(2A)-mediated effects in nicotine-trained rats. In contrast, chronic caffeine exposure produces tolerance to adenosine A(1)-mediated, but not A(2A)-mediated, effects in methamphetamine- and cocaine-trained rats. C1 [Justinova, Zuzana; Ferre, Sergi; Barnes, Chanel; Wertheim, Carrie E.; Pappas, Lara A.; Goldberg, Steven R.; Le Foll, Bernard] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,DHHS,Biomed Res Ctr, Baltimore, MD 21224 USA. [Justinova, Zuzana] Univ Maryland, Sch Med, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. [Le Foll, Bernard] Univ Toronto, Translat Addict Res Lab, Ctr Addict & Mental Hlth, Toronto, ON, Canada. RP Justinova, Z (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,DHHS,Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM zjustino@intra.nida.nih.gov RI Justinova, Zuzana/A-9109-2011; Ferre, Sergi/K-6115-2014; Le Foll, Bernard/K-2952-2014 OI Justinova, Zuzana/0000-0001-5793-7484; Ferre, Sergi/0000-0002-1747-1779; Le Foll, Bernard/0000-0002-6406-4973 FU Intramural NIH HHS [Z01 DA000003-22, Z99 DA999999]; NIDA NIH HHS [N01 DA059909] NR 27 TC 14 Z9 14 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 APR PY 2009 VL 203 IS 2 BP 355 EP 367 DI 10.1007/s00213-008-1270-0 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 418FU UT WOS:000264134900016 PM 18688601 ER PT J AU Kohut, SJ Roma, PG Davis, CM Zernig, G Saria, A Dominguez, JM Rice, KC Riley, AL AF Kohut, Stephen J. Roma, Peter G. Davis, Catherine M. Zernig, Gerald Saria, Alois Dominguez, Juan M. Rice, Kenner C. Riley, Anthony L. TI The impact of early environmental rearing condition on the discriminative stimulus effects and Fos expression induced by cocaine in adult male and female rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Maternal separation; Discriminative-stimulus effects; Drug discrimination learning; Cocaine; Dopamine generalization; Time course; Immediate-early gene c-Fos ID NEONATAL MATERNAL SEPARATION; ADVERSE CHILDHOOD EXPERIENCES; INDUCED LOCOMOTOR-ACTIVITY; RECEPTOR MUTANT MICE; NUCLEUS-ACCUMBENS; DRUG-ABUSE; HOUSEHOLD DYSFUNCTION; BEHAVIORAL-RESPONSES; ETHANOL INTAKE; MESSENGER-RNA AB A number of environmental manipulations, including maternal separation (MS), have been shown to alter behavioral responses to drugs of abuse. This study assessed if MS affected the stimulus and Fos-inducing effects of cocaine. In experiment 1, male and female Sprague-Dawley rats were exposed to brief maternal separations (BMS), long maternal separations (LMS), or animal facility rearing (AFR) and then trained as adults to discriminate cocaine (10 mg/kg, intraperitoneally) from saline. Following training, generalization tests to novel doses of cocaine and other dopaminergic compounds were performed. Assessments of variations in training dose pretreatment times were also made. In experiment 2, male and female rats exposed to MS conditions were administered cocaine or saline for 14 days, and Fos expression in the mesolimbic system was measured. In males, BMS retarded the acquisition of the cocaine discrimination. Generalization to novel doses of cocaine did not differ among rearing conditions, but the training dose cue lasted longer in LMS. Distinct generalization and ED(50) profiles were found between male rearing conditions for all dopamine compounds. While BMS females had higher cocaine ED(50) estimates, no other differences were found in females. LMS males and females, as well as AFR females, had significant increases in Fos expression after cocaine in a region-specific manner. No differences were found with other rearing groups. Early environmental variables altered the stimulus effects (in a sex-dependent manner) as well as the neuronal responsiveness to cocaine, which may be mediated by the dopamine system. C1 [Kohut, Stephen J.; Roma, Peter G.; Davis, Catherine M.; Riley, Anthony L.] American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. [Dominguez, Juan M.] American Univ, Dept Psychol, Behav Neurosci Lab, Washington, DC 20016 USA. [Zernig, Gerald; Saria, Alois] Med Univ, Dept Psychiat, Expt Psychiat Unit, Innsbruck, Austria. [Rice, Kenner C.] NIAAA, Drug Design & Synth Sect, Chem Biol Res Branch, NIDA, Rockville, MD 20852 USA. RP Kohut, SJ (reprint author), American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. EM steve.kohut@gmail.com OI Davis-Takacs, Catherine/0000-0002-2591-6352 FU Intramural NIH HHS [Z01 DA000520-01] NR 58 TC 9 Z9 9 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2009 VL 203 IS 2 BP 383 EP 397 DI 10.1007/s00213-008-1368-4 PG 15 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 418FU UT WOS:000264134900018 PM 18953528 ER PT J AU Davis, CM Stevenson, GW Canadas, F Ullrich, T Rice, KC Riley, AL AF Davis, Catherine M. Stevenson, Glenn W. Canadas, Fernando Ullrich, Thomas Rice, Kenner C. Riley, Anthony L. TI Discriminative stimulus properties of naloxone in Long-Evans rats: assessment with the conditioned taste aversion baseline of drug discrimination learning SO PSYCHOPHARMACOLOGY LA English DT Article DE Naloxone; CTA; Drug discrimination; Opiate-naive; Rat; Naltrexone; Naltrindole; MR2266; Naltrexone methobromide ID MORPHINE-DEPENDENT RATS; TREATED RHESUS-MONKEYS; OPIATE ANTAGONISTS; ADMINISTERED MORPHINE; NARCOTIC-ANTAGONISTS; RECEPTORS MEDIATE; OPIOID RECEPTORS; PLACE AVERSION; NALTREXONE; KAPPA AB The characterization of the discriminative stimulus properties of naloxone has focused primarily on its actions at the mu opioid receptor, although naloxone also displays an affinity for delta and kappa receptor subtypes. The present study extends this characterization of the naloxone cue by investigating if relatively specific antagonists for the mu (naltrexone: 0.10-0.56 mg/kg), delta (naltrindole: 1-18 mg/kg), and kappa (MR2266: 1.8-10 mg/kg) opioid receptor subtypes will substitute for naloxone in animals trained to discriminate naloxone from its vehicle. The temporal nature of the naloxone cue was examined by varying pretreatment time points (15, 30, 45, 60 min). Finally, various doses of naltrexone methobromide (1-18 mg/kg) were assessed to determine peripheral mediation of the cue. Female Long-Evans rats (N = 30) received an injection of naloxone (1 mg/kg; i.p.) 15 min prior to a pairing of saccharin (20-min access) and the emetic LiCl (1.8 mEq; i.p.; n = 16, group NL) or vehicle (n = 14, group NW); on other days, they were injected with saline prior to saccharin alone. Substitution tests with compounds with various receptor affinities and selective CNS and PNS actions were then assessed. Only naloxone and naltrexone produced dose-dependent decreases in saccharin consumption. Naloxone administered at 15 and 30 min before saccharin produced decreases in consumption similar to that displayed on training days. Naltrexone methobromide substituted only at the highest dose tested (18 mg/kg). Naloxone's stimulus effects appear to be mediated centrally via activity at the mu opioid receptor. C1 [Davis, Catherine M.; Canadas, Fernando; Riley, Anthony L.] American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. [Stevenson, Glenn W.] Univ New England, Biddeford, ME 04005 USA. [Ullrich, Thomas; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Rockville, MD 20852 USA. [Ullrich, Thomas; Rice, Kenner C.] NIAAA, Rockville, MD 20852 USA. RP Davis, CM (reprint author), American Univ, Dept Psychol, Psychopharmacol Lab, 4400 Massachusetts Ave NW, Washington, DC 20016 USA. EM cd2994a@american.edu OI Davis-Takacs, Catherine/0000-0002-2591-6352 FU Intramural NIH HHS [Z01 DA000520-01] NR 47 TC 8 Z9 9 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2009 VL 203 IS 2 BP 421 EP 429 DI 10.1007/s00213-008-1233-5 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 418FU UT WOS:000264134900021 PM 18594795 ER PT J AU Panlilio, LV Mazzola, C Medalie, J Hahn, B Justinova, Z Drago, F Cadet, JL Yasar, S Goldberg, SR AF Panlilio, Leigh V. Mazzola, Carmen Medalie, Julie Hahn, Britta Justinova, Zuzana Drago, Filippo Cadet, Jean Lud Yasar, Sevil Goldberg, Steven R. TI Anandamide-induced behavioral disruption through a vanilloid-dependent mechanism in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE Endocannabinoid; 5-Choice serial reaction-time task (5-CSRRT); Open-field activity; Transient receptor potential vanilloid 1 receptor (TRPV1); Peroxisome proliferator-activated receptor (PPAR); Anxiety; Feeding ID ENDOGENOUS CANNABINOID ANANDAMIDE; REACTION-TIME-TASK; IMPULSIVE BEHAVIOR; PREFRONTAL CORTEX; IN-VIVO; RECEPTORS; INVOLVEMENT; LIPOXYGENASES; PHARMACOLOGY; ANTAGONISTS AB Endocannabinoids are involved in a variety of behavioral and physiological processes that are just beginning to be understood. In the five-choice serial reaction-time task, exogenous cannabinoids have been found to alter attention, but endocannabinoids such as anandamide have not been studied. We used this task to evaluate the effects of anandamide in rats. Since anandamide is a ligand for not only cannabinoid receptors but also transient receptor potential vanilloid 1 (TRPV1) receptors, and as recently suggested, peroxisome proliferator-activated nuclear receptor-alpha (PPAR alpha), we also determined whether anandamide's effects in this task were mediated by each of these receptors. Whenever one of five holes was illuminated for 2 s, a food pellet was delivered if a response occurred in that hole during the light or within 2 s after the light. Anandamide increased omission errors and decreased responding during inter-trial intervals. These effects were blocked by the TRPV1 antagonist capsazepine, but not by the cannabinoid-receptor antagonist rimonabant or the PPAR alpha antagonist MK886. Testing with open-field activity and food-consumption procedures in the same rats suggested that the disruption of operant responding observed in the attention task was not due to motor depression, anxiety, decreased appetite, or an inability to find and consume food pellets. The vanilloid-dependent behavioral disruption induced by anandamide was specific to the operant attention task. These effects of anandamide resemble effects of systemically administered dopamine antagonists and might reflect changes in vanilloid-mediated dopamine transmission. C1 [Panlilio, Leigh V.; Mazzola, Carmen; Medalie, Julie; Justinova, Zuzana; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. [Mazzola, Carmen; Drago, Filippo] Univ Catania, Dept Expt & Clin Pharmacol, Sch Med, Catania, Italy. [Hahn, Britta; Justinova, Zuzana] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Dept Psychiat, Baltimore, MD 21201 USA. [Cadet, Jean Lud; Yasar, Sevil] NIDA, Mol Neuropsychiat Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Yasar, Sevil] Johns Hopkins Sch Med, Div Geriatr Med & Gerontol, Dept Med, Baltimore, MD 21224 USA. RP Goldberg, SR (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,DHHS, 05A711,251 Bayview Blvd, Baltimore, MD 21224 USA. EM sgoldber@mail.nih.gov RI Justinova, Zuzana/A-9109-2011; Hahn, Britta/G-4593-2012; OI Justinova, Zuzana/0000-0001-5793-7484; Drago, Filippo/0000-0003-2887-5223 FU NIH, National Institute on Drug Abuse FX This research was supported by the Intramural Research Program of the NIH, National Institute on Drug Abuse. We thank John E. Warner and Chanel Barnes for technical assistance. NR 36 TC 17 Z9 17 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 APR PY 2009 VL 203 IS 3 BP 529 EP 538 DI 10.1007/s00213-008-1399-x PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 420CO UT WOS:000264266200007 PM 19015836 ER PT J AU Zhao, LY Zhang, XL Shi, J Epstein, D Lu, L AF Zhao, Li-Yan Zhang, Xiao-Li Shi, Jie Epstein, David H. Lu, Lin TI Psychosocial stress after reactivation of drug-related memory impairs later recall in abstinent heroin addicts SO PSYCHOPHARMACOLOGY LA English DT Article DE Stress; Glucocorticoids; Heroin-related memory; Reconsolidation ID GLUCOCORTICOID-INDUCED IMPAIRMENT; CONDITIONED PLACE PREFERENCE; LONG-TERM-MEMORY; BASOLATERAL AMYGDALA; DECLARATIVE MEMORY; COCAINE-SEEKING; SPATIAL MEMORY; FEAR MEMORIES; DISRUPTING RECONSOLIDATION; INCENTIVE-SENSITIZATION AB Stress and stress hormone are known to play important roles in modulating different stages of memory including reconsolidation. In a previous study, we found that treatment with stress or corticosterone after a single memory reactivation disrupted reconsolidation of a drug-related memory in rats. Here we presumed that stress after memory reactivation can effectively inhibit drug-related memory by disrupting its reconsolidation in abstinent heroin addicts. In the present study, 21 abstinent heroin addicts learned a word list (containing ten neutral, ten heroin-related negative, and ten heroin-related positive words) on day 1; retrieval of a word list (learned 24 h earlier) was made on day 2; and immediately after retrieval, they were exposed to either a standardized psychosocial laboratory stressor (Trier Social Stress Test) or a control condition in a crossover manner. On day 3, free recall of the word list and other psychological and physical responses were assessed. The stressor induced a significant increase in salivary free cortisol and a decrease in mood. Memory recall was significantly impaired after the stress condition. Follow-up analysis revealed that heroin-related negative and positive words (i.e., heroin-related words) were affected, whereas no effect was observed for neutral words. No changes were detected for cued recall, working memory, or attention. Stress after drug-related memory retrieval significantly decreased its subsequent recall, likely through impaired drug-related memory reconsolidation process. Reconsolidation blockade may thus provide a potential therapeutic strategy for the prevention of relapse in drug addiction. C1 [Zhao, Li-Yan; Zhang, Xiao-Li; Shi, Jie; Lu, Lin] Peking Univ, Natl Inst Drug Dependence, Beijing 100083, Peoples R China. [Epstein, David H.] Natl Inst Drug Abuse, Intramural Res Program, Natl Inst Hlth, Baltimore, MD 21224 USA. RP Lu, L (reprint author), Peking Univ, Natl Inst Drug Dependence, 38 Xueyuan Rd, Beijing 100083, Peoples R China. EM linlu@bjmu.edu.cn FU National Basic Research Program of China [2007CB512302, 2009CB522004]; National High Technology Research and Development Program of China [2006AA02Z4D1]; Natural Science Foundation of China [30570576, 30670713] FX The authors wish to thank the National Basic Research Program of China (973 Program, 2007CB512302 and 2009CB522004), the National High Technology Research and Development Program of China (863 Program, 2006AA02Z4D1), and the Natural Science Foundation of China (nos. 30570576 and 30670713). NR 88 TC 33 Z9 36 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2009 VL 203 IS 3 BP 599 EP 608 DI 10.1007/s00213-008-1406-2 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 420CO UT WOS:000264266200014 PM 19020867 ER PT J AU Carney, RM Freedland, KE Steinmeyer, B Blumenthal, JA de Jonge, P Davidson, KW Czajkowski, SM Jaffe, AS AF Carney, Robert M. Freedland, Kenneth E. Steinmeyer, Brian Blumenthal, James A. de Jonge, Peter Davidson, Karina W. Czajkowski, Susan M. Jaffe, Allan S. TI History of Depression and Survival After Acute Myocardial Infarction SO PSYCHOSOMATIC MEDICINE LA English DT Article DE depression; depression history; acute myocardial infarction; mortality ID CORONARY-ARTERY-DISEASE; HEART-RATE-VARIABILITY; MAJOR DEPRESSION; CARDIOVASCULAR EVENTS; TREATING DEPRESSION; ENHANCING RECOVERY; MEDICAL MORBIDITY; PATIENTS ENRICHD; MORTALITY; ANTIDEPRESSANT AB Objective: To compare survival in post-myocardial (MI) participants from the Enhancing Recovery In Coronary Heart Disease (ENRICHD) clinical trial with a first episode of major depression (MD) and those with recurrent MID, which is a risk factor for mortality after acute MI. Recent reports suggest that the level of risk may depend on whether the comorbid MD is a first or a recurrent episode. Methods: Survival was compared over a median of 29 months in 370 patients with an initial episode of MD, 550 with recurrent MD, and 408 who were free of depression. Results: After adjusting for an all-cause mortality risk score, initial Beck Depression Inventory score, and the use of selective serotonin reuptake inhibitor antidepressants, patients with a first episode of MD had poorer survival (18.4% all-cause mortality) than those with recurrent MD (11.8%) (hazard ratio (HR)=1.4; 95% Confidence Interval (CI)=1.0-2.0; p=.05). Both first depression (HR=3.1; 95% CI=1.6-6.1; p=.001) and recurrent MD (HR=2.2; 95% CI=1.1-4.4; p=.03) had significantly poorer survival than did the nondepressed patients (3.4%). A secondary analysis of deaths classified as probably due to a cardiovascular cause resulted in similar HRs, but the difference between depression groups was not significant. Conclusions: Both initial and recurrent episodes of MD predict shorter survival after acute MI, but initial MD episodes are more strongly predictive than recurrent episodes. Exploratory analyses suggest that this cannot be explained by more severe heart disease at index, poorer response to depression treatment, or a higher risk of cerebrovascular disease in patients with initial MD episodes. C1 [Carney, Robert M.; Freedland, Kenneth E.; Steinmeyer, Brian] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Blumenthal, James A.] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. [de Jonge, Peter] Univ Groningen, Dept Psychiat, Groningen, Netherlands. Tilburg Univ, Tilburg, Netherlands. [Davidson, Karina W.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Czajkowski, Susan M.] NHLBI, Bethesda, MD 20892 USA. [Jaffe, Allan S.] Mayo Clin, Dept Med, Rochester, MN USA. RP Carney, RM (reprint author), Behav Med Ctr, 4320 Forest Pk Ave,Suite 301, St Louis, MO 63108 USA. EM carneyr@bmc.wustl.edu RI de Jonge, peter/L-6395-2013 OI de Jonge, peter/0000-0002-0866-6929 FU National Heart, Lung, and Blood Institute [2 RO-1HL58946]; National Institutes of Health, Bethesda, Maryland; Lewis and Jean Sachs Charitable Lead Trust FX Supported, in part, by Grant 2 RO-1HL58946 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, and from the Lewis and Jean Sachs Charitable Lead Trust. NR 32 TC 43 Z9 46 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD APR PY 2009 VL 71 IS 3 BP 253 EP 259 DI 10.1097/PSY.0b013e31819b69e3 PG 7 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 434NQ UT WOS:000265281800001 PM 19251868 ER PT J AU Little, MP Wakeford, R Tawn, EJ Bouffler, SD de Gonzalez, AB AF Little, Mark P. Wakeford, Richard Tawn, E. Janet Bouffler, Simon D. de Gonzalez, Amy Berrington TI Risks Associated with Low Doses and Low Dose Rates of Ionizing Radiation: Why Linearity May Be (Almost) the Best We Can Do SO RADIOLOGY LA English DT Article ID ATOMIC-BOMB SURVIVORS; ACUTE MYELOCYTIC-LEUKEMIA; CHROMOSOME-ABERRATION ANALYSIS; CANADIAN FLUOROSCOPY COHORT; INDUCED GENOMIC INSTABILITY; BREAST-CANCER INCIDENCE; X-RAY TREATMENT; IN-VIVO; CHILDHOOD-CANCER; MICROSATELLITE INSTABILITY C1 [Little, Mark P.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, Fac Med, London W2 1PG, England. [Wakeford, Richard] Univ Manchester, Dalton Nucl Inst, Manchester, Lancs, England. [Bouffler, Simon D.] Ctr Radiat Chem & Radiat Hazards, Radiat Protect Div, Hlth Protect Agcy, Didcot, Oxon, England. [de Gonzalez, Amy Berrington] NCI, Div Canc Epidemiol & Genet, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Little, MP (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, Fac Med, St Marys Campus,Norfolk Pl, London W2 1PG, England. EM mark.little@imperial.ac.uk OI Wakeford, Richard/0000-0002-2934-0987; Little, Mark/0000-0003-0980-7567 NR 85 TC 144 Z9 150 U1 0 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 APR PY 2009 VL 251 IS 1 BP 6 EP 12 DI 10.1148/radiol.2511081686 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 439QV UT WOS:000265643000003 PM 19332841 ER PT J AU Tubiana, M Feinendegen, LE Yang, CC Kaminski, JM AF Tubiana, Maurice Feinendegen, Ludwig E. Yang, Chichuan Kaminski, Joseph M. TI The Linear No-Threshold Relationship Is Inconsistent with Radiation Biologic and Experimental Data SO RADIOLOGY LA English DT Review ID ATOMIC-BOMB SURVIVORS; DOUBLE-STRAND BREAKS; DIAGNOSTIC X-RAYS; INDUCED GENOMIC INSTABILITY; TRANSFORMATION IN-VITRO; DOSE HYPER-RADIOSENSITIVITY; NORMAL HUMAN FIBROBLASTS; DNA-DAMAGE CHECKPOINTS; IONIZING-RADIATION; CANCER INCIDENCE AB T he carcinogenic risk induced by low doses of ionizing radiation is controversial. It cannot be assessed with epidemiologic methods alone because at low doses the data are imprecise and often conflicting. Since the 1970s, the radiation protection community has estimated the risk of low doses by means of extrapolation from the risk assessed at high doses, generally by using the linear no-threshold (LNT) model. The LNT relationship implies proportionality between dose and cancer risk. This approach is based on one set of data and two hypotheses: (a) The relationship between dose and DNA damage in vivo seems linear from 1 mGy to 100 Gy with use of H2AX foci as a marker for DNA double-strand breaks (DSBs)-however, this marker is not specific (1); (b) each DSB is hypothesized to have the same probability of inducing cell transformation, irrespective of the quantity of DSBs present simultaneously in the cell; and (c) each transformed cell is hypothesized to have the same probability of developing into an invasive cancer, irrespective of the dose delivered to the tissue. The advances during the past 2 decades in radiation biology, the understanding of carcinogenesis, and the discovery of defenses against carcinogenesis challenge the LNT model, which appears obsolete (2-6). Life developed in a bath of ionizing radiation and solar ultraviolet radiation and created aerobic organisms requiring (a) defenses against the metabolically induced reactive oxygen species, (b) DNA repair, and (c) elimination of damaged cells. Several sets of data show the efficacy of these defenses to be much higher at low than at high doses and for fractionated or protracted irradiation than for acute irradiation. The LNT model was introduced as a concept to facilitate radiation protection (7). But the use of this model led to the claim that even the smallest dose (one electron traversing a cell) may initiate carcinogenesis-for instance, from diagnostic x-ray sources (8,9). This claim is highly hypothetical and has resulted in medical, economic, and other societal harm. The French Academies report (10) concluded that the LNT model and its use for assessing the risks associated with low doses are not based on scientific evidence. In contrast, the Biological Effects of Ionizing Radiation (BEIR) VII report (11) and that of the International Commission on Radiological Protection (ICRP) (12) recommended the use of the LNT model. We wish to update this debate by using recent radiation biologic and epidemiologic data. C1 [Kaminski, Joseph M.] NIH, Bethesda, MD 20892 USA. [Tubiana, Maurice] Ctr Antoine Beclere, Dept Med, Paris, France. [Feinendegen, Ludwig E.] Univ Dusseldorf, Dept Nucl Med, Lindau, Germany. [Yang, Chichuan] Amer Radiol Serv, Bethesda, MD USA. RP Kaminski, JM (reprint author), NIH, 6610 Rockledge Dr,Room 4018, Bethesda, MD 20892 USA. EM joseph.kaminski@fda.hhs.gov FU National Institutes of Health FX J.M.K. is an employee of the National Institutes of Health. NR 169 TC 213 Z9 226 U1 6 U2 34 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 APR PY 2009 VL 251 IS 1 BP 13 EP 22 DI 10.1148/radiol.2511080671 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 439QV UT WOS:000265643000016 PM 19332842 ER PT J AU Gavrielides, MA Kinnard, LM Myers, KJ Petrick, N AF Gavrielides, Marios A. Kinnard, Lisa M. Myers, Kyle J. Petrick, Nicholas TI Noncalcified Lung Nodules: Volumetric Assessment with Thoracic CT SO RADIOLOGY LA English DT Article ID SMALL PULMONARY NODULES; IMAGE DATABASE CONSORTIUM; COMPUTED-TOMOGRAPHY IMAGES; MULTIDETECTOR ROW CT; MULTISLICE CT; INTRAOBSERVER VARIABILITY; AUTOMATIC SEGMENTATION; PRELIMINARY EXPERIENCE; TREATMENT RESPONSE; AIDED DETECTION AB Lung nodule volumetry is used for nodule diagnosis, as well as for monitoring tumor response to therapy. Volume measurement precision and accuracy depend on a number of factors, including image-acquisition and reconstruction parameters, nodule characteristics, and the performance of algorithms for nodule segmentation and volume estimation. The purpose of this article is to provide a review of published studies relevant to the computed tomographic (CT) volumetric analysis of lung nodules. A number of underexamined areas of research regarding volumetric accuracy are identified, including the measurement of non-solid nodules, the effects of pitch and section overlap, and the effect of respiratory motion. The need for public databases of phantom scans, as well as of clinical data, is discussed. The review points to the need for continued research to examine volumetric accuracy as a function of a multitude of interrelated variables involved in the assessment of lung nodules. Understanding and quantifying the sources of volumetric measurement error in the assessment of lung nodules with CT would be a first step toward the development of methods to minimize that error through system improvements and to correctly account for any remaining error. (c) RSNA, 2009 C1 [Gavrielides, Marios A.; Kinnard, Lisa M.; Myers, Kyle J.; Petrick, Nicholas] US FDA, Natl Inst Biomed Imaging & Bioengn,Ctr Devices &, Ctr Devices & Radiol Hlth,Off Sci & Engn Labs, Joint Lab Assessment Med Imaging Syst,Div Imaging, Silver Spring, MD 20993 USA. RP Gavrielides, MA (reprint author), US FDA, Natl Inst Biomed Imaging & Bioengn,Ctr Devices &, Ctr Devices & Radiol Hlth,Off Sci & Engn Labs, Joint Lab Assessment Med Imaging Syst,Div Imaging, 10903 New Hampshire Ave,Bldg 62,Room 3139, Silver Spring, MD 20993 USA. EM marios.gavrielides@fda.hhs.gov FU Cancer Imaging Program of the National Cancer Institute; Intramural Program of the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health FX This research was supported by the Cancer Imaging Program of the National Cancer Institute and the Intramural Program of the National Institute of Biomedical Imaging and Bioengineering of the National Institutes of Health. NR 62 TC 103 Z9 104 U1 1 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 APR PY 2009 VL 251 IS 1 BP 26 EP 37 DI 10.1148/radiol.2511071897 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 439QV UT WOS:000265643000005 PM 19332844 ER PT J AU Dromi, SA Walsh, MP Herby, S Traughber, B Xie, JW Sharma, KV Sekhar, KP Luk, A Liewehr, DJ Dreher, MR Fry, TJ Wood, BJ AF Dromi, Sergio A. Walsh, Meghaan P. Herby, Sarah Traughber, Bryan Xie, Jianwu Sharma, Karun V. Sekhar, Kiran P. Luk, Alfred Liewehr, David J. Dreher, Matthew R. Fry, Terry J. Wood, Bradford J. TI Radiofrequency Ablation Induces Antigen-presenting Cell Infiltration and Amplification of Weak Tumor-induced Immunity SO RADIOLOGY LA English DT Article ID INTENSITY FOCUSED ULTRASOUND; SECONDARY LIVER-TUMORS; ANTITUMOR IMMUNITY; HEPATOCELLULAR-CARCINOMA; DENDRITIC CELLS; COMBINATION; METASTASES; THERAPY AB Purpose: To evaluate the influence of subtotal radiofrequency (RF) ablation on a tumor-specific immune response in a murine tumor model and to explore the role of intratumoral dendritic cells (ITDCs) in mediating this effect. Materials and Methods: Animal work was performed according to an approved protocol and in compliance with the National Cancer Institute Animal Care and Use Committee guidelines and regulations. A murine urothelial carcinoma (MB49) model expressing the male minor histocompatibility (HY) antigen was inoculated subcutaneously in female mice. Fourteen days later, splenic T cells were analyzed with enzyme-linked immunosorbent spot for HY immune response (n = 57). In subsequent experiments, mice were randomized into control (n = 7), RF ablation, ITDC (n = 9), and RF ablation + ITDC (n = 9) groups and monitored for tumor growth. Eleven days after treatment, tumors were harvested for histologic and immunohistochemical analysis. Animals demonstrating complete tumor regression were rechallenged in the contralateral flank. Results: Animals treated with subtotal RF ablation showed significant increases in tumor-specific class I and II responses to HY antigens and tumor regression. RF ablation, ITDC, and combined groups demonstrated similar levels of antigen-presenting cell infiltration; all groups demonstrated greater levels of infiltration compared with untreated controls. ITDC injection also resulted in tumor regression. However, combination therapy did not enhance tumor regression when compared with either treatment alone. Rechallenged mice in RF ablation, ITDC, and combination groups demonstrated significant tumor growth inhibition compared with controls. Conclusion: Subtotal RF ablation treatment results in enhanced systemic antitumor T-cell immune responses and tumor regression that is associated with increased dendritic cell infiltration. ITDC injection mimics the RF ablation effect but does not increase immune responses when injected immediately after RF ablation. (c) RSNA, 2009 C1 [Dromi, Sergio A.; Traughber, Bryan; Xie, Jianwu; Sharma, Karun V.; Sekhar, Kiran P.; Luk, Alfred; Dreher, Matthew R.; Wood, Bradford J.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Walsh, Meghaan P.; Herby, Sarah; Fry, Terry J.] NCI, Pediat Oncol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Liewehr, David J.] NCI, Biostat & Data Management Sect, Natl Inst Hlth, Bethesda, MD 20892 USA. [Fry, Terry J.] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Div Blood & Marrow Transplantat, Washington, DC 20010 USA. RP Wood, BJ (reprint author), NIH, Dept Diagnost Radiol, Ctr Clin, 9000 Rockville Pike Bldg 10,CC,Room 2N236, Bethesda, MD 20892 USA. EM bwood@nih.gov FU Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research [Z01-CL040011] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research [grant no. Z01-CL040011]. NR 29 TC 45 Z9 52 U1 0 U2 5 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 APR PY 2009 VL 251 IS 1 BP 58 EP 66 DI 10.1148/radiol.2511072175 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 439QV UT WOS:000265643000008 PM 19251937 ER PT J AU Delclos, KB Weis, CC Bucci, TJ Olson, G Mellick, P Sadovova, N Latendresse, JR Thorn, B Newbold, RR AF Delclos, K. Barry Weis, Constance C. Bucci, Thomas J. Olson, Greg Mellick, Paul Sadovova, Natalya Latendresse, John R. Thorn, Brett Newbold, Retha R. TI Overlapping but distinct effects of genistein and ethinyl estradiol (EE2) in female Sprague-Dawley rats in multigenerational reproductive and chronic toxicity studies SO REPRODUCTIVE TOXICOLOGY LA English DT Review DE Genistein; Ethinyl estradiol; Rat; Multigenerational; Reproductive toxicity; Estrous cycle; Puberty acceleration; Reproductive senescence; Soy-free diet ID ESTROGEN-RECEPTOR-BETA; SUPPRESSES MAMMARY-CANCER; PHYTOESTROGEN GENISTEIN; NEONATAL EXPOSURE; SOY ISOFLAVONE; BREAST-CANCER; GENE-EXPRESSION; IN-UTERO; DIETARY GENISTEIN; PRENATAL EXPOSURE AB Genistein and ethinyl estradiol (EE2) were examined in multigenerational reproductive and chronic toxicity studies that had different treatment intervals among generations. Sprague-Dawley rats received genistein (0, 5, 100, or 500 ppm) or EE2 (0, 2, 10, or 50 ppb) in a low phytoestrogen diet. Nonneoplastic effects in females are summarized here. Genistein at 500 ppm and EE2 at 50 ppb produced similar effects in continuously exposed rats, including decreased body weights, accelerated vaginal opening, and altered estrous cycles in young animals. At the high dose, anogenital distance was subtly affected by both compounds, and a reduction in litter size was evident in genistein-treated animals. Genistein at 500 ppm induced an early onset of aberrant cycles relative to controls in the chronic studies. EE2 significantly increased the incidence of uterine lesions (atypical focal hyperplasia and squamous metaplasia). These compound-specific effects appeared to be enhanced in the offspring of prior exposed generations. Published by Elsevier Inc. C1 [Delclos, K. Barry] Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. [Bucci, Thomas J.; Olson, Greg; Mellick, Paul; Sadovova, Natalya; Latendresse, John R.] Toxicol Pathol Associates, Jefferson, AR 72079 USA. [Newbold, Retha R.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Delclos, KB (reprint author), Natl Ctr Toxicol Res, Div Biochem Toxicol, HFT 110,3900 NCTR Rd, Jefferson, AR 72079 USA. EM barry.delclos@fda.hhs.gov FU U.S. Food and Drug Administration [IAG 224-07-007]; National Institute for Environmental Health Sciences FX This work was supported by Interagency Agreement IAG 224-07-007 between the U.S. Food and Drug Administration and the National Institute for Environmental Health Sciences. The extensive and expert technical assistance of the NCTR support staff in providing diet preparation, chemical analysis, animal care, computer support, necropsy, and tissue processing services for these studies is gratefully acknowledged. The views presented in this article do not necessarily reflect those of the U.S. Food and Drug Administration. NR 133 TC 36 Z9 39 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD APR PY 2009 VL 27 IS 2 BP 117 EP 132 DI 10.1016/j.reprotox.2008.12.005 PG 16 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 429BA UT WOS:000264894600004 PM 19159674 ER PT J AU Thompson, HJ Voss, JG AF Thompson, Hilaire J. Voss, Joachim G. TI Health- and Disease-Related Biomarkers in Aging Research SO RESEARCH IN GERONTOLOGICAL NURSING LA English DT Review AB This article focuses on a synthesis of knowledge about healthy aging research in human beings and then synthesized nurse-led research in gerontology and geriatrics that use biomarkers. Healthy aging research has attracted considerable attention in the biomedical and basic sciences within the context of four major areas: (a) genetic variations as an expression of successful or unsuccessful aging; (b) caloric restriction as an intervention to slow the progression of aging; (c) immunological aging; (d) neurobiology of the aging brain. A systematic review of the literature was performed to identify nurse-led geriatric-related biomarker research. Nurse researchers who have chosen to integrate biomarkers as part of their research studies have been working in six focal areas, which are reviewed: health promotion within risk populations, cancer, vascular disease, Alzheimer's disease, caregiving, and complementary therapies. The article provides a discussion of contributions to date, identifying existing gaps and future research opportunities. C1 [Thompson, Hilaire J.] Univ Washington, Biobehav Nursing & Hlth Syst, John A Hartford Fdn, NIH, Seattle, WA 98195 USA. [Voss, Joachim G.] Univ Washington, Biobehav Nursing & Hlth Syst, Robert Wood Johnson Nurse Fac, Seattle, WA 98195 USA. RP Thompson, HJ (reprint author), Univ Washington, Biobehav Nursing & Hlth Syst, John A Hartford Fdn, NIH, Seattle, WA 98195 USA. EM hilairet@u.washington.edu FU The John A. Hartford Foundation [06-202]; NIH Roadmap for Medical Research [KL2RR025015]; Robert Wood Johnson Faculty; National Institute for Nursing Research [5K22NR008672-02] FX This research was supported, in part, by a Claire M. Fagin Building Academic Geriatric Nursing Capacity Fellowship from The John A. Hartford Foundation (06-202; H.J.T.) and the NIH Roadmap for Medical Research (KL2RR025015; H.J.T.); the Robert Wood Johnson Faculty Scholars Program (J.G.V); and the National Institute for Nursing Research (5K22NR008672-02; J.G.V). NR 100 TC 8 Z9 8 U1 1 U2 3 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 1940-4921 J9 RES GERONTOL NURS JI Res. Gerontol. Nurs. PD APR PY 2009 VL 2 IS 2 SI SI BP 137 EP 148 PG 12 WC Nursing SC Nursing GA V20LH UT WOS:000208141000008 PM 20077975 ER PT J AU Taubenberger, JK Morens, DM AF Taubenberger, J. K. Morens, D. M. TI Pandemic influenza - including a risk assessment of H5N1 SO REVUE SCIENTIFIQUE ET TECHNIQUE-OFFICE INTERNATIONAL DES EPIZOOTIES LA English DT Article DE Epidemiology; History; Influenza A virus; Pandemic ID A H1N1 VIRUSES; AVIAN INFLUENZA; CONTINUING EVOLUTION; EPIDEMIOLOGY; H3N2; TRANSMISSION; CHINA; ASIA; FLU; 20TH-CENTURY AB Influenza pandemics and epidemics have apparently occurred since at least the Middle Ages. When pandemics appear, 50% or more of an affected population can be infected in a single year, and the number of deaths caused by influenza can dramatically exceed what is normally expected. Since 1500, there appear to have been 13 or more influenza pandemics. In the past 120 years there were undoubted pandemics in 1889, 1918, 1957, 1968, and 1977. Although most experts believe we will face another influenza pandemic, it is impossible to predict when it will appear, where it will originate, or how severe it will be. Nor is there agreement about the subtype of influenza virus most likely to cause the next pandemic. The continuing spread of H5N1 highly pathogenic avian influenza viruses has heightened interest in pandemic prediction. Despite uncertainties in the historical record of the pre-virology era, study of previous pandemics may help guide future pandemic planning and lead to a better understanding of the complex ecobiology underlying the formation of pandemic strains of influenza A viruses. C1 [Taubenberger, J. K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Morens, D. M.] NIAID, Off Director, NIH, Bethesda, MD 20892 USA. RP Taubenberger, JK (reprint author), NIAID, Infect Dis Lab, NIH, 33 North Dr, Bethesda, MD 20892 USA. EM taubenbergerj@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000995-01] NR 81 TC 72 Z9 72 U1 3 U2 31 PU OFFICE INT EPIZOOTIES PI PARIS PA 12 RUE DE PRONY, 75017 PARIS, FRANCE SN 0253-1933 J9 REV SCI TECH OIE JI Rev. Sci. Tech. Off. Int. Epizoot. PD APR PY 2009 VL 28 IS 1 BP 187 EP 202 PG 16 WC Veterinary Sciences SC Veterinary Sciences GA 462VV UT WOS:000267386500013 PM 19618626 ER PT J AU Kavlock, RJ Austin, CP Tice, RR AF Kavlock, Robert J. Austin, Christopher P. Tice, Raymond R. TI Toxicity Testing in the 21st Century: Implications for Human Health Risk Assessment SO RISK ANALYSIS LA English DT Editorial Material C1 [Kavlock, Robert J.] US EPA, Off Res & Dev, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA. [Austin, Christopher P.] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Tice, Raymond R.] Natl Inst Environm Hlth Sci, Biomol Screening Branch, Natl Toxicol Program, Res Triangle Pk, NC USA. RP Kavlock, RJ (reprint author), US EPA, Off Res & Dev, Natl Ctr Computat Toxicol, Res Triangle Pk, NC 27711 USA. EM Kavlock.Robert@epamail.epa.gov FU Intramural NIH HHS [ZIA HG200319-06] NR 2 TC 87 Z9 88 U1 0 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0272-4332 J9 RISK ANAL JI Risk Anal. PD APR PY 2009 VL 29 IS 4 BP 485 EP 487 DI 10.1111/j.1539-6924.2008.01168.x PG 3 WC Public, Environmental & Occupational Health; Mathematics, Interdisciplinary Applications; Social Sciences, Mathematical Methods SC Public, Environmental & Occupational Health; Mathematics; Mathematical Methods In Social Sciences GA 421GM UT WOS:000264347400006 PM 19076321 ER PT J AU Wang, X Wang, HK McCoy, JP Banerjee, NS Rader, JS Broker, TR Meyers, C Chow, LT Zheng, ZM AF Wang, Xiaohong Wang, Hsu-Kun McCoy, J. Philip Banerjee, Nilam S. Rader, Janet S. Broker, Thomas R. Meyers, Craig Chow, Louise T. Zheng, Zhi-Ming TI Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6 SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE miR-34a; p53; human papillomavirus; E6; oncoprotein ID HUMAN-PAPILLOMAVIRUS TYPE-16; SARCOMA-ASSOCIATED HERPESVIRUS; CARCINOMA CELL-LINES; CERVICAL-CANCER; DIFFERENTIATED KERATINOCYTES; GENE-EXPRESSION; MESSENGER-RNAS; E7 ONCOPROTEIN; RAFT CULTURES; GROWTH ARREST AB MicroRNAs (miRNA) play pivotal roles in controlling cell proliferation and differentiation. Aberrant miRNA expression in human is becoming recognized as a new molecular mechanism of carcinogenesis. However, the causes for alterations in miRNA expression remain largely unknown. Infection with oncogenic human papillomavirus types 16 (HPV16) and 18 (HPV18) can lead to cervical and other ano-genital cancers. Here, we have demonstrated that cervical cancer tissues and cervical cancer-derived cell lines containing oncogenic HPVs display reduced expression of tumor-suppressive miR-34a. The reduction of miR34a expression in organotypic tissues derived from HPV-containing primary human keratinocytes correlates with the early productive phase and is attributed to the expression of viral E6, which destabilizes the tumor suppressor p53, a known miR-34a transactivator. Knockdown of viral E6 expression in HPV16(+) and HPV18(+) cervical cancer cell lines by siRNAs leads to an increased expression of p53 and miR-34a and accumulation of miR-34a in G(0)/G(1) phase cells. Ectopic expression of miR-34a in HPV18 + HeLa cells and HPV(-) HCT116 cells results in a substantial induction of cell growth retardation and a moderate cell apoptosis. Together, this is the first time a viral oncoprotein has been shown to regulate cellular miRNA expression. Our data have provided new insights into mechanisms by which high-risk HPVs contribute to the development of cervical cancer. C1 [Wang, Xiaohong; Zheng, Zhi-Ming] NCI, HIV & AIDS Maignancy Branch, Canc Res Ctr, Ctr Canc Res, Bethesda, MD 20892 USA. [Wang, Hsu-Kun; Banerjee, Nilam S.; Broker, Thomas R.; Chow, Louise T.] Univ Alabama, Dept Biochem & Mol Genet, Birmingham, AL 35294 USA. [McCoy, J. Philip] NHLBI, NIH, Bethesda, MD 20892 USA. [Rader, Janet S.] Washington Univ, Sch Med, Dept Gynecol, St Louis, MO 63110 USA. [Meyers, Craig] Penn State Univ, Coll Med, Dept Microbiol & Immunol, Hershey, PA 17033 USA. RP Zheng, ZM (reprint author), NCI, HIV & AIDS Maignancy Branch, Canc Res Ctr, Ctr Canc Res, Room 6N106,10 Ctr Dr, Bethesda, MD 20892 USA. EM zhengt@exchange.nih.gov FU National Institutes of Health; National Cancer Institute; Center for Cancer Research; National Heart, Lung, and Blood Institute; U. S. National Institutes of Health [CA095713, AI057988, CA083679] FX We thank John Brady at the National Cancer Institute for the p53 expression vector. This work was supported by the Intramural Research Program of the National Institutes of Health, the National Cancer Institute, and the Center for Cancer Research and National Heart, Lung, and Blood Institute. This work also was supported partially by grants from the U. S. National Institutes of Health: Grant Nos. CA095713 (to J. S. R.), AI057988 (to C. M.), and CA083679 (to L. T. C.). NR 58 TC 120 Z9 132 U1 1 U2 17 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 APR PY 2009 VL 15 IS 4 BP 637 EP 647 DI 10.1261/rna.1442309 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 420HP UT WOS:000264280100012 PM 19258450 ER PT J AU Stepchenkova, EI Kozmin, SG Alenin, VV Pavlov, YI AF Stepchenkova, E. I. Kozmin, S. G. Alenin, V. V. Pavlov, Yu. I. TI Genetic control of metabolism of mutagenic purine base analogs 6-hydroxylaminopurine and 2-amino-6-hydroxylaminopurine in yeast Saccharomyces cerevisiae SO RUSSIAN JOURNAL OF GENETICS LA English DT Article ID MOLYBDENUM COFACTOR BIOSYNTHESIS; ESCHERICHIA-COLI; PROTEIN; DNA; 6-N-HYDROXYLAMINOPURINE; MUTANTS; INOSINE; DAMAGE AB We studied the effect of inactivation of genes, which control biosynthesis of inosine monophosphate (IMP) de novo and purine salvage and interconversion pathways, on sensitivity of yeast Saccharomyces cerevisiae to the mutagenic and toxic action of 6-hydroxylaminopurine (HAP) and 2-amino-6-hydroxylaminopurine (AHA). It was shown that the manifestation of HAP and AHA mutagenic properties depends on the action of enzyme adenine phosphoribosyltransferase encoded in yeast by APT1 gene. A blockade of any step of IMP biosynthesis, with the exception of the block mediated by inactivation of genes ADE16 and ADE17 leading to the accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), was shown to enhance yeast cell sensitivity to the HAP mutagenic effect; however, it does not affect the sensitivity to AHA. A block of conversion of IMP into adenosine monophosphate (AMP) causes hypersensitivity of yeast cells to the mutagenic action of HAP and to the toxic effect of HAP, AHA, and hypoxanthine. It is possible that this enhancement of sensitivity to HAP and AHA is due to changes in the pool of purines. We conclude that genes ADE12, ADE13, AAH1, and HAM1 controlling processes of purine salvage and interconversion in yeast, make the greatest contribution to the protection against the toxic and mutagenic action of the examined analogs. Possible mechanisms of HAP detoxication in bacteria, yeast, and humans are discussed. C1 [Stepchenkova, E. I.; Kozmin, S. G.; Alenin, V. V.] St Petersburg State Univ, Dept Genet & Select, St Petersburg 199034, Russia. [Stepchenkova, E. I.] St Petersburg State Univ, Vavilov Inst Gen Genet, St Petersburg Branch, St Petersburg 199034, Russia. [Kozmin, S. G.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. [Pavlov, Yu. I.] 985880 Univ Nebraska, Med Ctr, Eppley Inst Res Canc, Omaha, NE 68198 USA. RP Stepchenkova, EI (reprint author), St Petersburg State Univ, Dept Genet & Select, St Petersburg 199034, Russia. EM stepchenkova@gmail.com RI Kozmin, Stanislav/J-6849-2012; Stepchenkova, Elena/F-9931-2014 OI Kozmin, Stanislav/0000-0002-4128-4447; Stepchenkova, Elena/0000-0002-5854-8701 FU BRHE; CRDF3; Ministry of Education of the Russian Federation FX This study was supported by BRHE, presented by CRDF, and the Ministry of Education of the Russian Federation. NR 28 TC 2 Z9 2 U1 0 U2 7 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 1022-7954 J9 RUSS J GENET+ JI Russ. J. Genet. PD APR PY 2009 VL 45 IS 4 BP 409 EP 414 DI 10.1134/S1022795409040048 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 437UG UT WOS:000265511800004 ER PT J AU Makhnovskii, YA Zitserman, VY Berezhkovskii, AM AF Makhnovskii, Yu. A. Zitserman, V. Yu. Berezhkovskii, A. M. TI Diffusion in quasi-one-dimensional structures with a periodic sharp narrowing of the cross section SO RUSSIAN JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID ENTROPY BARRIER; TRANSPORT; KINETICS AB The problem of diffusion of particles in a tube with periodically positioned partitions with circular orifices at the center of each was considered. Using an approach based on the methods and results of the theory of diffusion-controlled reactions and the idea of homogenization of the permeability of partitions, we derived a formula for the effective diffusion coefficient for the steady-state regime of the process. The accuracy and applicability domain of the formula were determined by comparing its predictions with computer simulation results. C1 [Makhnovskii, Yu. A.] Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Moscow 117912, Russia. [Zitserman, V. Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. [Berezhkovskii, A. M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Makhnovskii, YA (reprint author), Russian Acad Sci, AV Topchiev Petrochem Synth Inst, Leninskii Pr 29, Moscow 117912, Russia. EM yuam@ips.ac.ru RI Makhnovskii, Yurii/B-1223-2014 OI Makhnovskii, Yurii/0000-0002-1517-536X FU Russian Foundation for Basic Research [06-03-32373] FX This work was supported by the Russian Foundation for Basic Research, project no. 06-03-32373. NR 36 TC 7 Z9 7 U1 0 U2 3 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 1990-7931 EI 1990-7923 J9 RUSS J PHYS CHEM B+ JI Russ. J. Phys. Chem. B PD APR PY 2009 VL 3 IS 2 BP 313 EP 319 DI 10.1134/S1990793109020225 PG 7 WC Physics, Atomic, Molecular & Chemical SC Physics GA 445LD UT WOS:000266051400022 ER PT J AU Stephens, SH Logel, J Barton, A Franks, A Schultz, J Short, M Dickenson, J James, B Fingerlin, TE Wagner, B Hodgkinson, C Graw, S Ross, RG Freedman, R Leonard, S AF Stephens, Sarah H. Logel, Judith Barton, Amanda Franks, Alexis Schultz, Jessica Short, Margaret Dickenson, Jane James, Benjamin Fingerlin, Tasha E. Wagner, Brandie Hodgkinson, Colin Graw, Sharon Ross, Randal G. Freedman, Robert Leonard, Sherry TI Association of the 5 '-upstream regulatory region of the alpha 7 nicotinic acetylcholine receptor subunit gene (CHRNA7) with schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Nicotinic receptor; Schizophrenia; Polymorphism; Association; Sensory Processing; Alpha 7 nicotinic receptor; Regulatory region; Promoter ID SAMPLE-SIZE REQUIREMENTS; CIGARETTE-SMOKING; LINKAGE ANALYSIS; TRANSMISSION DISEQUILIBRIUM; CHROMOSOME-15 LOCUS; PARTIAL DUPLICATION; PARKINSONS-DISEASE; POSTMORTEM BRAIN; SELF-MEDICATION; MENTAL-ILLNESS AB Background: The alpha 7 neuronal nicotinic acetylcholine receptor subunit gene (CHRNA7) is localized in a chromosomal region (15q14) linked to schizophrenia in multiple independent studies. CHRNA7 was selected as the best candidate gene in the region for a well-documented endophenotype of schizophrenia, the P50 sensory processing deficit, by genetic linkage and biochemical studies. Methods: Subjects included Caucasian-Non Hispanic and African-American case-control subjects collected in Denver, and schizophrenic subjects from families in the NIMH Genetics Initiative on Schizophrenia. Thirty-five single nucleotide polymorphisms (SNPs) in the 5'-upstream regulatory region of CHRNA7 were genotyped for association with schizophrenia, and for smoking in schizophrenia. Results: The rs3087454 SNP, located at position - 1831 bp in the upstream regulatory region of CHRNA7, was significantly associated with schizophrenia in the case-control samples after multiple-testing correction (P=0.0009, African American; P=0.013, Caucasian-Non Hispanic); the association was supported in family members. There was nominal association of this SNP with smoking in schizophrenia. Conclusions: The data support association of regulatory region polymorphisms in the CHRNA7 gene with schizophrenia. Published by Elsevier B.V. C1 [Stephens, Sarah H.; Logel, Judith; Barton, Amanda; Franks, Alexis; Schultz, Jessica; Short, Margaret; Dickenson, Jane; James, Benjamin; Graw, Sharon; Ross, Randal G.; Freedman, Robert; Leonard, Sherry] Univ Colorado Denver, Dept Psychiat, Aurora, CO 80045 USA. [Fingerlin, Tasha E.; Wagner, Brandie] Univ Colorado Denver, Dept Prevent Med & Biometr, Aurora, CO 80045 USA. [Freedman, Robert; Leonard, Sherry] Vet Affairs Med Res Ctr, Denver, CO 80045 USA. [Hodgkinson, Colin] NIAAA, NIH, Rockville, MD 20852 USA. RP Leonard, S (reprint author), Univ Colorado Denver, Dept Psychiat, Mailstop 8344,POB 6511, Aurora, CO 80045 USA. EM Sherry.Leonard@UCHSC.edu RI Hodgkinson, Colin/F-9899-2010; OI Wagner, brandie/0000-0002-2745-0103 FU NIDA NIH HHS [DA09457, R01 DA009457-11, R01 DA009457]; NIMH NIH HHS [MH081177, P50 MH044212, P50 MH044212-100006, P50 MH068582, R01 MH081177-02, MH068582, R01 MH081177] NR 75 TC 60 Z9 63 U1 3 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD APR PY 2009 VL 109 IS 1-3 BP 102 EP 112 DI 10.1016/j.schres.2008.12.017 PG 11 WC Psychiatry SC Psychiatry GA 437VZ UT WOS:000265516300016 PM 19181484 ER PT J AU Coppes, RP van der Goot, A Lombaert, IMA AF Coppes, Rob P. van der Goot, Annemieke Lombaert, Isabelle M. A. TI Stem Cell Therapy to Reduce Radiation-Induced Normal Tissue Damage SO SEMINARS IN RADIATION ONCOLOGY LA English DT Review ID MARROW-DERIVED CELLS; FUNCTIONAL MAMMARY-GLAND; LABEL-RETAINING CELLS; HUMAN SOMATIC-CELLS; BONE-MARROW; PROGENITOR CELLS; SALIVARY-GLANDS; ADULT MICE; INTERFOLLICULAR EPIDERMIS; MYOCARDIAL-INFARCTION AB Normal tissue damage after radiotherapy is still a major problem in cancer treatment. Stem cell therapy may provide a means to reduce radiation-induced side effects and improve the quality of life of patients. This review discusses the current status in stem cell research with respect to their potential to reduce radiation toxicity. A number of different types of stem cells are being investigated for their potential to treat a variety of disorders. Their current status, localization, characterization, isolation, and potential in stem cell-based therapies are addressed. Although clinical adult stem cell research is still at an early stage, preclinical experiments show the potential these therapies may have. Based on the major advances made in this field, stem cell-based therapy has great potential to allow prevention or treatment of normal tissue damage after radiotherapy. Semin Radiat Oncol 19:112-121 (C) 2009 Elsevier Inc. All rights reserved. C1 [Coppes, Rob P.] Univ Groningen, Dept Cell Biol, Sect Radiat & Stress Cell Biol, NL-9700 AD Groningen, Netherlands. [Lombaert, Isabelle M. A.] Univ Groningen, Sect Stem Cells Biol, NL-9700 AD Groningen, Netherlands. [Coppes, Rob P.] Univ Groningen, Univ Med Ctr Groningen, Dept Radiat Oncol, NL-9700 AD Groningen, Netherlands. [Lombaert, Isabelle M. A.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. RP Coppes, RP (reprint author), Univ Groningen, Dept Cell Biol, Sect Radiat & Stress Cell Biol, Ant Deusinglaan 1,Postbus 196, NL-9700 AD Groningen, Netherlands. EM r.p.coppes@med.umcg.nl RI Coppes, Robert P/B-4089-2008 OI Coppes, Robert P/0000-0001-5503-1064 NR 118 TC 27 Z9 28 U1 1 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1053-4296 J9 SEMIN RADIAT ONCOL JI Semin. Radiat. Oncol. PD APR PY 2009 VL 19 IS 2 BP 112 EP 121 DI 10.1016/j.semradonc.2008.11.005 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 420SZ UT WOS:000264310800007 PM 19249649 ER PT J AU El Khouli, RH Louie, A AF El Khouli, Riham H. Louie, Adeline TI Case of the Season: A Giant Fibroadenoma in the Guise of a Phyllodes Tumor; Characterization Role of MRI SO SEMINARS IN ROENTGENOLOGY LA English DT Article ID BREAST-TUMORS; LESIONS; CANCER C1 [El Khouli, Riham H.] NIH, Ctr Clin, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. RP El Khouli, RH (reprint author), NIH, Ctr Clin, Dept Radiol & Imaging Sci, Bethesda, MD 20892 USA. EM elkhoulir@cc.nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 9 TC 1 Z9 2 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-198X J9 SEMIN ROENTGENOL JI Semin. Roentgenology PD APR PY 2009 VL 44 IS 2 BP 64 EP 66 DI 10.1053/j.ro.2008.12.003 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 416FB UT WOS:000263989900002 PM 19233082 ER PT J AU Turkbey, EB Dombroski, DA AF Turkbey, Evrim Bengi Dombroski, David A. TI Cardiac Magnetic Resonance Imaging: Techniques and Clinical Applications SO SEMINARS IN ROENTGENOLOGY LA English DT Review ID CORONARY-ARTERY-DISEASE; ACUTE MYOCARDIAL-INFARCTION; STATE-FREE-PRECESSION; BYPASS GRAFT PATENCY; POSITRON-EMISSION-TOMOGRAPHY; RIGHT-VENTRICULAR CARDIOMYOPATHY; SENSITIVE INVERSION-RECOVERY; AMERICAN-HEART-ASSOCIATION; REGIONAL SYSTOLIC FUNCTION; GADOLINIUM-ENHANCED MRI C1 [Turkbey, Evrim Bengi] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Dombroski, David A.] Johns Hopkins Univ, Sch Med, Div MR1, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. RP Dombroski, DA (reprint author), Johns Hopkins Univ Hosp, MR1 Room 110 Nelson Basement,600 N Wolfe St, Baltimore, MD 21287 USA. EM ddombro@jhmt.edu NR 147 TC 1 Z9 1 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-198X J9 SEMIN ROENTGENOL JI Semin. Roentgenology PD APR PY 2009 VL 44 IS 2 BP 67 EP 83 DI 10.1053/j.ro.2008.12.001 PG 17 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 416FB UT WOS:000263989900003 PM 19233083 ER PT J AU Kannan, M Saxena, R Adiguzel, C Fareed, J AF Kannan, Meganathan Saxena, Renu Adiguzel, Cafer Fareed, Jawed TI An Update on the Prevalence and Characterization of H-PF4 Antibodies in Asian-Indian Patients SO SEMINARS IN THROMBOSIS AND HEMOSTASIS LA English DT Article DE Heparin-PF4 antibody; diagnosis; Indian; heparin contaminant ID HEPARIN-INDUCED THROMBOCYTOPENIA; ADVERSE CLINICAL EVENTS; LABORATORY DIAGNOSIS; RISK-FACTORS; PREVENTION; INHIBITORS; THERAPY AB Heparin is the second most widely used anticoagulant/antithrombotic agent besides warfarin and is commonly used for various purposes such as treatment and surgical indications. A significant adverse effect of heparin treatment can occur when heparin binds platelet factor 4 (H-PF4) to form a complex that results in formation of H-PF4 antibodies, which in turn leads to platelet/endothelial cell activation followed by heparin-induced thrombocytopenia (HIT). Based on the heparin-induced platelet aggregation and enzyme-linked immunosorbent assay tests, the H-PF4 antibody (HIT antibody) was diagnosed in 6% of Indian patients undergoing cardiovascular surgery who received unfractionated heparin, but the frequency of occurrence rose to 15% when the patients were tested with the (14)C-serotonin release assay. This highlights some methodological variations in the diagnosis of HIT antibodies. It was also found that all the HIT-positive patients were either homozygous or heterozygous for the Fc gamma RIIa polymorphism, which also highlights the role of this polymorphism in the occurrence of HIT. Very recent studies show that increases in HIT antibody production may also be due to heparin contaminants. Although these antibodies do not result in thrombocytopenia, contaminants in heparin may be capable of triggering a differential immunogenic response in comparison with contaminant-free heparin. Here we discuss the methodological differences in diagnosing HIT, the potential impact of contaminants in heparin, as well as future considerations. C1 [Kannan, Meganathan] US FDA, Div Hematol, NIH, Bethesda, MD 20014 USA. [Adiguzel, Cafer] Marmara Univ, Sch Med, Dept Hematol, Istanbul, Turkey. [Fareed, Jawed] Loyola Univ, Med Ctr, Dept Pharmacol, Chicago, IL 60611 USA. RP Fareed, J (reprint author), Loyola Univ, Med Ctr, Dept Pathol, Hemostasis & Thrombosis Res Program, 2160 S 1st Ave, Maywood, IL 60153 USA. EM jfareed@lumc.edu NR 34 TC 4 Z9 4 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0094-6176 J9 SEMIN THROMB HEMOST JI Semin. Thromb. Hemost. PD APR PY 2009 VL 35 IS 3 BP 337 EP 343 DI 10.1055/s-0029-1222612 PG 7 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 450DZ UT WOS:000266382500011 PM 19452409 ER PT J AU Kawamoto, S Solomon, SB Bluemke, DA Fishman, EK AF Kawamoto, Satomi Solomon, Stephen B. Bluemke, David A. Fishman, Elliot K. TI Computed Tomography and Magnetic Resonance Imaging Appearance of Renal Neoplasms After Radiofrequency Ablation and Cryoablation SO SEMINARS IN ULTRASOUND CT AND MRI LA English DT Article ID RADIO-FREQUENCY ABLATION; CELL CARCINOMA; THERMAL ABLATION; FOLLOW-UP; LAPAROSCOPIC CRYOABLATION; PERCUTANEOUS CRYOABLATION; CLINICAL-EXPERIENCE; TUMOR ABLATION; CT; THERAPY C1 [Kawamoto, Satomi; Fishman, Elliot K.] Johns Hopkins Univ Hosp, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Solomon, Stephen B.] Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. [Bluemke, David A.] Natl Inst Hlth, New York, NY USA. RP Kawamoto, S (reprint author), Johns Hopkins Univ Hosp, Dept Radiol, JHOC 3235A,601 N Caroline St, Baltimore, MD 21287 USA. EM skawamoI@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS [ZIA CL090019-01, ZIA EB000072-01] NR 49 TC 15 Z9 17 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0887-2171 J9 SEMIN ULTRASOUND CT JI Semin. Ultrasound CT MRI PD APR PY 2009 VL 30 IS 2 BP 67 EP 77 DI 10.1053/j.sult.2008.12.005 PG 11 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 421OE UT WOS:000264367400003 PM 19358438 ER PT J AU Gungor, D Bornstein, MH AF Guengoer, Derya Bornstein, Marc H. TI Gender, Development, Values, Adaptation, and Discrimination in Acculturating Adolescents: The Case of Turk Heritage Youth Born and Living in Belgium SO SEX ROLES LA English DT Article DE Immigrants; Adolescents; Gender; Acculturation; Adaptation; Perceived discrimination ID INTERGENERATIONAL TRANSMISSION; PSYCHOLOGICAL ADJUSTMENT; IMMIGRANT FAMILIES; ACHIEVEMENT VALUES; COLLECTIVISM; IDENTITY; NETHERLANDS; TRANSITIONS; WOMEN; DUTCH AB This study addressed gender differences and similarities in acculturation, values, adaptation, and perceived discrimination among middle (14-17 years) and late (18-20 years) adolescents. Girls perceived less discrimination and showed better adaptation than did boys. All adolescents valued openness to change and self-transcendence similarly, but older adolescents attached greater importance to their heritage culture and conservatism. Overall, a larger gender gap in acculturation experiences emerged in late adolescence. The findings are discussed with reference to acculturative and developmental processes in a multicultural context. C1 [Guengoer, Derya; Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, Natl Inst Hlth, Bethesda, MD 20892 USA. [Guengoer, Derya] Univ Utrecht, Utrecht, Netherlands. RP Gungor, D (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, Natl Inst Hlth, 6705 Rockledge Dr,Suite 8030, Bethesda, MD 20892 USA. EM D.Gungor1@uu.nl NR 78 TC 8 Z9 8 U1 4 U2 20 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0360-0025 J9 SEX ROLES JI Sex Roles PD APR PY 2009 VL 60 IS 7-8 BP 537 EP 548 DI 10.1007/s11199-008-9531-2 PG 12 WC Psychology, Developmental; Psychology, Social; Women's Studies SC Psychology; Women's Studies GA 428IH UT WOS:000264840700008 ER PT J AU Suntoke, TR Hardick, A Tobian, AAR Mpoza, B Laeyendecker, O Serwadda, D Opendi, P Gaydos, CA Gray, RH Wawer, MJ Quinn, TC Reynolds, SJ AF Suntoke, T. R. Hardick, A. Tobian, A. A. R. Mpoza, B. Laeyendecker, O. Serwadda, D. Opendi, P. Gaydos, C. A. Gray, R. H. Wawer, M. J. Quinn, T. C. Reynolds, S. J. TI Evaluation of multiplex real-time PCR for detection of Haemophilus ducreyi, Treponema pallidum, herpes simplex virus type 1 and 2 in the diagnosis of genital ulcer disease in the Rakai District, Uganda SO SEXUALLY TRANSMITTED INFECTIONS LA English DT Article ID SEXUALLY-TRANSMITTED-DISEASES; LINKED IMMUNOSORBENT ASSAYS; POLYMERASE-CHAIN-REACTION; GLYCOPROTEIN-G; INFECTION; ANTIBODIES; ETIOLOGY; PERFORMANCE; PREVALENCE; COMMUNITY AB Objective: To develop a real-time PCR assay that reliably and accurately detects the predominant sexually transmitted aetiological agents of genital ulcer disease (GUD) (Haemophilus ducreyi, Treponema pallidum and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2)) and to assess the use of real-time PCR diagnostic testing in a rural African field site. Methods: Two multiplex real-time PCR reactions were used to detect H ducreyi/and HSV-1/HSV-2 in ulcer swabs from 100 people with symptomatic genital ulcers in rural Rakai, Uganda. Results were compared with syphilis, HSV-1 and HSV-2 serology. Results: Of 100 GUD samples analysed from 43 HIV positive and 57 HIV negative individuals, 71% were positive for one or more sexually transmitted infection (STI) pathogens by real-time PCR (61% for HSV-2, 5% for T pallidum, 3% for HSV-1, 1% for H ducreyi and 1% for dual H ducreyi/HSV-2). The frequency of HSV in genital ulcers was 56% (32/57) in HIV negative individuals and 77% (33/43) in HIV positive individuals (p = 0.037). Assay reproducibility was evaluated by repeat PCR testing in the USA with 96% agreement (kappa = 0.85). Conclusions: STI pathogens were detected in the majority of GUD swab samples from symptomatic patients in Rakai, Uganda, by real-time PCR. HSV-2 was the predominant cause of genital ulcers. Real-time PCR technology can provide sensitive, rapid and reproducible evaluation of GUD aetiology in a resource-limited setting. C1 [Hardick, A.; Tobian, A. A. R.; Laeyendecker, O.; Gaydos, C. A.; Quinn, T. C.; Reynolds, S. J.] Johns Hopkins Med Inst, Div Infect Dis, Baltimore, MD 21205 USA. [Suntoke, T. R.; Laeyendecker, O.; Quinn, T. C.; Reynolds, S. J.] NIAID, NIH, Bethesda, MD 20892 USA. [Serwadda, D.] Makerere Univ, Inst Publ Hlth, Kampala, Uganda. [Mpoza, B.; Opendi, P.] Rakai Hlth Sci Program, Rakai, Uganda. [Gray, R. H.; Wawer, M. J.] Johns Hopkins Med Inst, Dept Populat & Family Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Quinn, TC (reprint author), Johns Hopkins Med Inst, Div Infect Dis, 855 N Wolfe St,Room 531, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; Gaydos, Charlotte/E-9937-2010; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This research was supported by The Division of Intramural Research, The National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 29 TC 40 Z9 42 U1 1 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1368-4973 J9 SEX TRANSM INFECT JI Sex. Transm. Infect. PD APR PY 2009 VL 85 IS 2 BP 97 EP 101 DI 10.1136/sti.2008.034207 PG 5 WC Infectious Diseases SC Infectious Diseases GA 427EJ UT WOS:000264762300005 PM 19066198 ER PT J AU Yao, L Gai, N AF Yao, Lawrence Gai, Neville TI Median nerve cross-sectional area and MRI diffusion characteristics: normative values at the carpal tunnel SO SKELETAL RADIOLOGY LA English DT Article DE Magnetic resonance imaging; Diffusion tensor imaging; Median nerve; Carpal tunnel syndrome; Fractional anisotropy ID DIAGNOSIS; SONOGRAPHY AB Enlargement of the median nerve is an objective potential imaging sign of carpal tunnel syndrome. Diffusion tensor MRI (DTI) may provide additional structural information that may prove useful in characterizing median neuropathy. This study further examines normal values for median nerve cross-sectional area (CSA), apparent diffusion coefficient (ADC), and fractional anisotropy (FA). Twenty-three wrists in 17 healthy volunteers underwent MRI of the wrist at 3 T. In 13 subjects, DTI was performed at a B value of 600 mm(2)/s. Median nerve CSA, ADC, and FA were analyzed at standardized anatomic levels. Mean (SD) median nerve CSA within the proximal carpal tunnel was 10.0 (3.4) mm(2). The mean (SD) FA of the median nerve was 0.71 (0.06) and 0.70 (0.13) proximal to and within the carpal tunnel, respectively. There was a significant difference between nerve CSA and ADC, but not FA, at the distal forearm and proximal carpal tunnel. Nerve CSA, ADC, and FA did not differ between men and women or between dominant and non-dominant wrists. Nerve CSA at the proximal carpal tunnel was positively correlated with subject age and body mass index. Our results suggest a 90% upper confidence limit for normal median nerve CSA of 14.4 mm(2) at the proximal carpal tunnel, higher than normal limits reported by many ultrasound studies. We observed a difference between the CSA and ADC, but not the FA, of the median nerve at the distal forearm and proximal carpal tunnel levels. C1 [Yao, Lawrence; Gai, Neville] Clin Ctr, Bethesda, MD 20892 USA. RP Yao, L (reprint author), Clin Ctr, 10 Ctr Dr, Bethesda, MD 20892 USA. EM lyao@cc.nih.gov NR 20 TC 39 Z9 42 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-2348 J9 SKELETAL RADIOL JI Skeletal Radiol. PD APR PY 2009 VL 38 IS 4 BP 355 EP 361 DI 10.1007/s00256-008-0626-1 PG 7 WC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging SC Orthopedics; Radiology, Nuclear Medicine & Medical Imaging GA 409ZV UT WOS:000263545200007 PM 19132371 ER PT J AU Kim, HJ Yu, BB Feuer, EJ AF Kim, Hyune-Ju Yu, Binbing Feuer, Eric J. TI SELECTING THE NUMBER OF CHANGE-POINTS IN SEGMENTED LINE REGRESSION SO STATISTICA SINICA LA English DT Article DE Change-points; model selection; permutation test; segmented line regression ID VARIABLE SELECTION; CANCER RATES; MODEL; TESTS AB Segmented line regression has been used in many applications, and the problem of estimating the number of change-points in segmented line regression has been discussed in Kim et al. (2000). This paper studies asymptotic properties of the number of change-points selected by the permutation procedure of Kim et al. (2000). This procedure is based on a sequential application of likelihood ratio type tests, and controls the over-fitting probability by its design. In this paper we show that, under some conditions, the number of change-points selected by the permutation procedure is consistent. Via simulations, the permutation procedure is compared with such information-based criterior as the Bayesian Information Criterion (BIC), the Akaike Information Criterion (AIC), and Generalized Cross Validation (GCV). C1 [Kim, Hyune-Ju] Syracuse Univ, Dept Math, Syracuse, NY 13244 USA. [Yu, Binbing] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Feuer, Eric J.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Kim, HJ (reprint author), Syracuse Univ, Dept Math, Syracuse, NY 13244 USA. EM hjkim@syr.edu; yubi@mail.nih.gov; feuerr@mail.nih.gov FU NIH [263-MQ-413149] FX Kim's research was partially supported by NIH Contract 263-MQ-413149. The authors thank the associate editor and the referees for many valuable comments and suggestions. NR 22 TC 20 Z9 20 U1 0 U2 5 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 EI 1996-8507 J9 STAT SINICA JI Stat. Sin. PD APR PY 2009 VL 19 IS 2 BP 597 EP 609 PG 13 WC Statistics & Probability SC Mathematics GA 437EK UT WOS:000265469000010 PM 19738935 ER PT J AU Petrea, RE Beiser, AS Seshadri, S Kelly-Hayes, M Kase, CS Wolf, PA AF Petrea, Rodica E. Beiser, Alexa S. Seshadri, Sudha Kelly-Hayes, Margaret Kase, Carlos S. Wolf, Philip A. TI Gender Differences in Stroke Incidence and Poststroke Disability in the Framingham Heart Study SO STROKE LA English DT Article DE gender; stroke; incidence; disability outcome ID SEX-DIFFERENCES; LIFETIME RISK; CASE-FATALITY; CARDIOVASCULAR-DISEASE; ALZHEIMERS-DISEASE; ISCHEMIC-STROKE; SELF-REPORT; MORTALITY; OUTCOMES; WOMEN AB Background and Purpose-Stroke is emerging as a major public health problem for women, as it is for men. Controversy persists regarding gender differences in stroke incidence, severity, and poststroke disability. Methods-Participants in the Framingham Original (n=5119; 2829 women) and Offspring (n=4957, 2565 women) cohorts who were 45 years and stroke-free were followed to first incident stroke. Gender-specific outcome measures were adjusted for the Framingham Stroke Risk Profile components. Results-We observed 1136 incident strokes (638 in women) over 56 years of follow-up. Women were significantly (P<0.001) older (75.1 versus 71.1 years for men) at their first-ever stroke, had a higher stroke incidence above 85 years of age, lower at all other ages, and a higher lifetime risk of stroke at all ages. There was no significant difference in stroke subtype, stroke severity, and case fatality rates between genders. Women were significantly (P<0.01) more disabled before stroke and in the acute phase of stroke in dressing (59% versus 37%), grooming (57% versus 34%), and transfer from bed to chair (59% versus 35%). At 3 to 6 months poststroke women were more disabled, more likely to be single, and 3.5 times more likely to be institutionalized (P<0.01). Conclusions-These results from the Framingham Heart Study (FHS) support the existence of gender-differences in stroke incidence, lifetime risk (LTR) of stroke, age at first stroke, poststroke disability, and institutionalization rates. Prestroke disability and sociodemographic factors may contribute to the high rate of institutionalization and poorer outcome observed in women. (Stroke. 2009;40:1032-1037.) C1 [Petrea, Rodica E.; Beiser, Alexa S.; Seshadri, Sudha; Kelly-Hayes, Margaret; Kase, Carlos S.; Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Beiser, Alexa S.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Beiser, Alexa S.; Seshadri, Sudha; Kelly-Hayes, Margaret; Kase, Carlos S.; Wolf, Philip A.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. RP Wolf, PA (reprint author), Boston Univ, Sch Med, Dept Neurol, 72 E Concord St,B-610, Boston, MA 02118 USA. EM pawolf@bu.edu OI Seshadri, Sudha/0000-0001-6135-2622; Beiser, Alexa/0000-0001-8551-7778 FU National Institute of Health/National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; National Institute of Neurological Disorders and Stroke [5R01-NS 17950] FX This work was supported in part by the National Institute of Health/National Heart, Lung, and Blood Institute's Framingham Heart Study (NIH/NHLBI Contract #N01-HC-25195) and a grant from the National Institute of Neurological Disorders and Stroke (5R01-NS 17950). NR 44 TC 184 Z9 192 U1 3 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2009 VL 40 IS 4 BP 1032 EP 1037 DI 10.1161/STROKEAHA.108.542894 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 426LJ UT WOS:000264709500003 PM 19211484 ER PT J AU Lisabeth, LD Beiser, AS Brown, DL Murabito, JM Kelly-Hayes, M Wolf, PA AF Lisabeth, Lynda D. Beiser, Alexa S. Brown, Devin L. Murabito, Joanne M. Kelly-Hayes, Margaret Wolf, Philip A. TI Age at Natural Menopause and Risk of Ischemic Stroke The Framingham Heart Study SO STROKE LA English DT Article DE stroke; cerebrovascular disease; women; menopause; bone mineral density ID BONE-MINERAL DENSITY; RANDOMIZED CONTROLLED-TRIAL; ESTROGEN PLUS PROGESTIN; ENDOGENOUS SEX-HORMONES; POSTMENOPAUSAL WOMEN; CARDIOVASCULAR-DISEASE; NATION SWAN; HEALTH; COHORT; TRANSITION AB Background and Purpose-Women have increased lifetime stroke risk and more disabling strokes compared with men. Insights into the association between menopause and stroke could lead to new prevention strategies for women. The objective of this study was to examine the association of age at natural menopause with ischemic stroke risk in the Framingham Heart Study. Methods-Participants, included women who survived stroke-free until age 60, experienced natural menopause, did not use estrogen before menopause, and who had complete data (n=1430). Participants were followed until first ischemic stroke, death, or end of follow-up (2006). Age at natural menopause was self-reported. Cox proportional hazards models were used to examine the association between age at natural menopause (<42, 42 to 54, >= 55) and ischemic stroke risk adjusted for age, systolic blood pressure, atrial fibrillation, diabetes, current smoking, cardiovascular disease and estrogen use. Results-There were 234 ischemic strokes identified. Average age at menopause was 49 years (SD=4). Women with menopause at ages 42 to 54 (hazard ratio=0.50; 95% CI: 0.29 to 0.89) and at ages >= 55 (hazard ratio=0.31; 95% CI: 0.13 to 0.76) had lower stroke risk compared with those with menopause <42 years adjusted for covariates. Women with menopause before age 42 had twice the stroke risk compared to all other women (hazard ratio=2.03; 95% CI: 1.16 to 3.56). Conclusion-In this prospective study, age at natural menopause before age 42 was associated with increased ischemic stroke risk. Future stroke studies with measures of endogenous hormones are needed to inform the underlying mechanisms so that novel prevention strategies for midlife women can be considered. (Stroke. 2009;40:1044-1049.) C1 [Lisabeth, Lynda D.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Lisabeth, Lynda D.; Brown, Devin L.] Univ Michigan, Sch Med, Stroke Program, Ann Arbor, MI 48109 USA. [Beiser, Alexa S.; Kelly-Hayes, Margaret; Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Beiser, Alexa S.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Beiser, Alexa S.; Murabito, Joanne M.; Kelly-Hayes, Margaret; Wolf, Philip A.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Bethesda, MD USA. RP Lisabeth, LD (reprint author), 109 S Observ St,Room 4641, Ann Arbor, MI 48109 USA. EM llisabet@umich.edu OI Murabito, Joanne/0000-0002-0192-7516; Brown, Devin/0000-0002-9815-3421; Beiser, Alexa/0000-0001-8551-7778 FU National Institute for Neurological Disorders and Stroke [K23 NS050161, 5R01-NS 17950]; Framingham Heart Study's National Heart, Lung and Blood Institute's [N01-HC-25195]; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute on Aging [R01 AR/AG 41398] FX Dr Lisabeth is funded by National Institute for Neurological Disorders and Stroke K23 NS050161. This work was supported by the Framingham Heart Study's National Heart, Lung and Blood Institute's contract (N01-HC-25195) and grants from the National Institute of Neurological Disorders and Stroke (5R01-NS 17950) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Institute on Aging (R01 AR/AG 41398). NR 42 TC 89 Z9 93 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2009 VL 40 IS 4 BP 1044 EP 1049 DI 10.1161/STROKEAHA.108.542993 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 426LJ UT WOS:000264709500005 PM 19233935 ER PT J AU Dichgans, M Bevan, S Cole, JW Plourde, A Matarin, M Ross-Adams, H Meitinger, T Wichmann, E Mitchel, BD Furie, K Rich, SS MacLeod, MJ Meschia, J Rosand, J Kittner, SJ Markus, HS Muller-Myhsok, B Gschwendtner, A AF Dichgans, Martin Bevan, Steve Cole, John W. Plourde, Anna Matarin, Mar Ross-Adams, Helen Meitinger, Thomas Wichmann, Erich Mitchel, Braxton D. Furie, Karen Rich, Stephen S. MacLeod, Mary J. Meschia, James Rosand, Jonathan Kittner, Steve J. Markus, Hugh S. Muller-Myhsok, Betram Gschwendtner, Andreas CA Int Stroke Genetics Consortium TI Sequence Variants on Chromosome 9p21 Confer Risk of Large Vessel Stroke. SO STROKE LA English DT Meeting Abstract CT American-Association-International-Stroke Conference 2009 CY FEB 17-20, 2009 CL San Diego, CA SP Amer Assoc Int Stroke C1 [Dichgans, Martin; Gschwendtner, Andreas] Univ Munich, Dept Neurol, Klinikum Grosshadern, Munich, Germany. [Bevan, Steve; Markus, Hugh S.] Univ London, Cntr Clin Neurosci, London, England. [Cole, John W.; Kittner, Steve J.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. [Plourde, Anna; Furie, Karen; Rosand, Jonathan] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Matarin, Mar] NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Ross-Adams, Helen] Univ Aberdeen, Dept Med & Therapeut, Aberdeen, Scotland. [Meitinger, Thomas] Inst Human Genet, Helmholtz Zentrum Munchen, Munich, Germany. [Wichmann, Erich] Inst Epidemiol, Helmholtz Zentrum Munchen, Munich, Germany. [Mitchel, Braxton D.] Univ Maryland, Dept Neurol, Sch Med, Baltimore, MD 21201 USA. [Rich, Stephen S.] Univ Virginia, Cntr Publ Hlth Genom, Charlottesville, VA USA. [MacLeod, Mary J.] Univ Aberdeen, Dept Med & Therapeut, Aberdeen, Scotland. [Meschia, James] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. [Muller-Myhsok, Betram] Max Planck Inst Psychiat, D-80804 Munich, Germany. RI Muller-Myhsok, Bertram/A-3289-2013; Matarin, Mar/F-1771-2016 OI Matarin, Mar/0000-0002-4717-5735 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 0039-2499 J9 STROKE JI Stroke PD APR PY 2009 VL 40 IS 4 BP E109 EP E109 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 426LJ UT WOS:000264709500110 ER PT J AU Howard, G Kleindorfer, D Moy, CS Safford, MM Unverzagt, FW Howard, VJ AF Howard, George Kleindorfer, Dawn Moy, Claudia S. Safford, Monika M. Unverzagt, Fredrick W. Howard, Virginia J. CA REGARDS Investigators TI Stroke Symptoms Without Stroke Or Tia Diagnosis Are Associated With Higher Mortality SO STROKE LA English DT Meeting Abstract CT American-Association-International-Stroke Conference 2009 CY FEB 17-20, 2009 CL San Diego, CA SP Amer Assoc Int Stroke C1 [Howard, George; Safford, Monika M.; Howard, Virginia J.] Univ Alabama, Birmingham, AL USA. [Kleindorfer, Dawn] Univ Cincinnati, Cincinnati, OH USA. [Moy, Claudia S.] NINDS, NIH, Bethesda, MD 20892 USA. [Unverzagt, Fredrick W.] Indiana Univ, Indianalopis, IN 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 0039-2499 J9 STROKE JI Stroke PD APR PY 2009 VL 40 IS 4 BP E187 EP E187 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 426LJ UT WOS:000264709500424 ER PT J AU Hsia, AW Lee, KY Latour, LL Warach, S Merino, JG Kidwell, CS AF Hsia, Amie W. Lee, Kyung-Yul Latour, Lawrence L. Warach, Steven Merino, Jose G. Kidwell, Chelsea S. CA NIH Nat Hist Investigators TI Early Recanalization by Magnetic Resonance Imaging Identifies Patients with Large Vessel Occlusion Likely to Respond to Standard Intravenous Tissue Plasminogen Activator SO STROKE LA English DT Meeting Abstract CT American-Association-International-Stroke Conference 2009 CY FEB 17-20, 2009 CL San Diego, CA SP Amer Assoc Int Stroke C1 [Hsia, Amie W.] Washington Hosp Ctr Stroke Cntr, Washington, DC USA. [Lee, Kyung-Yul] Yonsei Univ, Dept Neurol, Seoul 120749, South Korea. [Latour, Lawrence L.; Warach, Steven; Merino, Jose G.] NINDS, NIH, Bethesda, MD 20892 USA. [Kidwell, Chelsea S.] Georgetown Univ, Dept Neurol, Washington, DC 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 0039-2499 J9 STROKE JI Stroke PD APR PY 2009 VL 40 IS 4 BP E159 EP E160 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 426LJ UT WOS:000264709500308 ER PT J AU Jia, J Lee, CR Bradbury, JA DeGraff, LM Zeldin, DC Alkayed, NJ AF Jia, Jia Lee, Craig R. Bradbury, J. Alyce DeGraff, Laura M. Zeldin, Darryl C. Alkayed, Nabil J. TI P450 Epoxygenase Overexpression in Vascular Endothelium Alters Blood Flow and Infarct Size after Middle Cerebral Artery Occlusion in a Sex- and Isoform-Specific Manner SO STROKE LA English DT Meeting Abstract CT American-Association-International-Stroke Conference 2009 CY FEB 17-20, 2009 CL San Diego, CA SP Amer Assoc Int Stroke C1 [Jia, Jia; Alkayed, Nabil J.] Oregon Hlth & Sci Univ, Dept Anesthesiol & Peri Operat Med, Portland, OR 97201 USA. [Lee, Craig R.; Bradbury, J. Alyce; DeGraff, Laura M.; Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Div Intramural Rsch, Res Triangle Pk, NC 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 0039-2499 J9 STROKE JI Stroke PD APR PY 2009 VL 40 IS 4 BP E150 EP E150 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 426LJ UT WOS:000264709500270 ER PT J AU Martin, AR Henning, EC Spatz, M Warach, S AF Martin, Ashleigh R. Henning, Erica C. Spatz, Maria Warach, Steven TI MRI Characteristics of Cerebrovascular Events in Aged Stroke-Prone Rats SO STROKE LA English DT Meeting Abstract CT American-Association-International-Stroke Conference 2009 CY FEB 17-20, 2009 CL San Diego, CA SP Amer Assoc Int Stroke C1 [Martin, Ashleigh R.; Henning, Erica C.; Spatz, Maria; Warach, Steven] NINDS, 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 0039-2499 J9 STROKE JI Stroke PD APR PY 2009 VL 40 IS 4 BP E218 EP E218 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 426LJ UT WOS:000264709500548 ER PT J AU Silva, GS Lima, F Camargo, EC Singhal, AB Greer, DM Ay, H Halpern, EF Smith, WS Lev, MH Koroshetz, W Furie, KL AF Silva, Gisele S. Lima, Fabricio Camargo, Erica C. Singhal, Aneesh B. Greer, David M. Ay, Hakan Halpern, Elkan F. Smith, Wade S. Lev, Michael H. Koroshetz, Walter Furie, Karen L. TI Starting IV t-PA Infusions for Acute Ischemic Stroke at Community Hospitals prior to Transfer to a Regional Stroke Center is Feasible and Safe SO STROKE LA English DT Meeting Abstract CT American-Association-International-Stroke Conference 2009 CY FEB 17-20, 2009 CL San Diego, CA SP Amer Assoc Int Stroke C1 [Silva, Gisele S.; Lima, Fabricio; Camargo, Erica C.; Singhal, Aneesh B.; Greer, David M.; Ay, Hakan; Halpern, Elkan F.; Lev, Michael H.; Furie, Karen L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Smith, Wade S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Koroshetz, Walter] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2009 VL 40 IS 4 BP E162 EP E162 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 426LJ UT WOS:000264709500315 ER PT J AU Schoch, CL Sung, GH Lopez-Giraldez, F Townsend, JP Miadlikowska, J Hofstetter, V Robbertse, B Matheny, PB Kauff, F Wang, Z Gueidan, C Andrie, RM Trippe, K Ciufetti, LM Wynns, A Fraker, E Hodkinson, BP Bonito, G Groenewald, JZ Arzanlou, M de Hoog, GS Crous, PW Hewitt, D Pfister, DH Peterson, K Gryzenhout, M Wingfield, MJ Aptroot, A Suh, SO Blackwell, M Hillis, DM Griffith, GW Castlebury, LA Rossman, AY Lumbsch, HT Lucking, R Budel, B Rauhut, A Diederich, P Ertz, D Geiser, DM Hosaka, K Inderbitzin, P Kohlmeyer, J Volkmann-Kohlmeyer, B Mostert, L O'Donnell, K Sipman, H Rogers, JD Shoemaker, RA Sugiyama, J Summerbell, RC Untereiner, W Johnston, PR Stenroos, S Zuccaro, A Dyer, PS Crittenden, PD Cole, MS Hansen, K Trappe, JM Yahr, R Lutzoni, F Spatafora, JW AF Schoch, Conrad L. Sung, Gi-Ho Lopez-Giraldez, Francesc Townsend, Jeffrey P. Miadlikowska, Jolanta Hofstetter, Valerie Robbertse, Barbara Matheny, P. Brandon Kauff, Frank Wang, Zheng Gueidan, Cecile Andrie, Rachael M. Trippe, Kristin Ciufetti, Linda M. Wynns, Anja Fraker, Emily Hodkinson, Brendan P. Bonito, Gregory Groenewald, Johannes Z. Arzanlou, Mahdi de Hoog, G. Sybren Crous, Pedro W. Hewitt, David Pfister, Donald H. Peterson, Kristin Gryzenhout, Marieka Wingfield, Michael J. Aptroot, Andre Suh, Sung-Oui Blackwell, Meredith Hillis, David M. Griffith, Gareth W. Castlebury, Lisa A. Rossman, Amy Y. Lumbsch, H. Thorsten Luecking, Robert Buedel, Burkhard Rauhut, Alexandra Diederich, Paul Ertz, Damien Geiser, David M. Hosaka, Kentaro Inderbitzin, Patrik Kohlmeyer, Jan Volkmann-Kohlmeyer, Brigitte Mostert, Lizel O'Donnell, Kerry Sipman, Harrie Rogers, Jack D. Shoemaker, Robert A. Sugiyama, Junta Summerbell, Richard C. Untereiner, Wendy Johnston, Peter R. Stenroos, Soili Zuccaro, Alga Dyer, Paul S. Crittenden, Peter D. Cole, Mariette S. Hansen, Karen Trappe, James M. Yahr, Rebecca Lutzoni, Francois Spatafora, Joseph W. TI The Ascomycota Tree of Life: A Phylum-wide Phylogeny Clarifies the Origin and Evolution of Fundamental Reproductive and Ecological Traits SO SYSTEMATIC BIOLOGY LA English DT Article DE Ancestral character reconstruction; Fungi; large data sets; lichenization; phylogeny ID RNA-POLYMERASE-II; MULTIPLE SEQUENCE ALIGNMENT; FUNGAL LINEAGES; CLEISTOTHECIAL FUNGI; CLASSIFICATION; SUBUNIT; PEZIZOMYCOTINA; DIVERGENCE; MORPHOLOGY; EUKARYOTES AB We present a 6-gene, 420-species maximum-likelihood phylogeny of Ascomycota, the largest phylum of Fungi. This analysis is the most taxonomically complete to date with species sampled from all 15 currently circumscribed classes. A number of superclass-level nodes that have previously evaded resolution and were unnamed in classifications of the Fungi are resolved for the first time. Based on the 6-gene phylogeny we conducted a phylogenetic informativeness analysis of all 6 genes and a series of ancestral character state reconstructions that focused on morphology of sporocarps, ascus dehiscence, and evolution of nutritional modes and ecologies. A gene-by-gene assessment of phylogenetic informativeness yielded higher levels of informativeness for protein genes (RPB1, RPB2, and TEF1) as compared with the ribosomal genes, which have been the standard bearer in fungal systematics. Our reconstruction of sporocarp characters is consistent with 2 origins for multicellular sexual reproductive structures in Ascomycota, once in the common ancestor of Pezizomycotina and once in the common ancestor of Neolectomycetes. This first report of dual origins of ascomycete sporocarps highlights the complicated nature of assessing homology of morphological traits across Fungi. Furthermore, ancestral reconstruction supports an open sporocarp with an exposed hymenium (apothecium) as the primitive morphology for Pezizomycotina with multiple derivations of the partially (perithecia) or completely enclosed (cleistothecia) sporocarps. Ascus dehiscence is most informative at the class level within Pezizomycotina with most superclass nodes reconstructed equivocally. Character-state reconstructions support a terrestrial, saprobic ecology as ancestral. In contrast to previous studies, these analyses support multiple origins of lichenization events with the loss of lichenization as less frequent and limited to terminal, closely related species. C1 [Schoch, Conrad L.; Sung, Gi-Ho; Robbertse, Barbara; Andrie, Rachael M.; Trippe, Kristin; Ciufetti, Linda M.; Spatafora, Joseph W.] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. [Lopez-Giraldez, Francesc; Townsend, Jeffrey P.; Wang, Zheng] Yale Univ, Dept Ecol & Evolutionary Biol, New Haven, CT 06520 USA. [Miadlikowska, Jolanta; Fraker, Emily; Hodkinson, Brendan P.; Bonito, Gregory; Lutzoni, Francois] Duke Univ, Dept Biol, Durham, NC 27708 USA. [Hofstetter, Valerie] Swiss Fed Res Stn Plant Prod Changins RAC, CH-1260 Nyon 1, Switzerland. [Matheny, P. Brandon] Clark Univ, Dept Biol, Worcester, MA 01610 USA. [Matheny, P. Brandon] Univ Tennessee, Dept Ecol & Evolutionary Biol, Knoxville, TN 37996 USA. [Kauff, Frank] TU Kaiserslautern, FB Biol, D-67653 Kaiserslautern, Germany. [Gueidan, Cecile; Groenewald, Johannes Z.; Arzanlou, Mahdi; de Hoog, G. Sybren; Crous, Pedro W.] Fungal Biodivers Ctr, Cent Bur Schimmelcultures, NL-3508 AD Utrecht, Netherlands. [Wynns, Anja] Univ Copenhagen, Inst Ecol, Dept Zool, DK-1871 Copenhagen, Denmark. [Hewitt, David; Pfister, Donald H.; Peterson, Kristin] Harvard Univ, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. [Gryzenhout, Marieka; Wingfield, Michael J.] Univ Pretoria, Forestry & Agr Biotechnol Inst, ZA-0002 Pretoria, South Africa. [Aptroot, Andre] Adviesbur Bryol & Lichenol, NL-3762 XK Soest, Netherlands. [Suh, Sung-Oui] Mycol Program, Manassas, VA 20110 USA. [Blackwell, Meredith] Louisiana State Univ, Dept Biol Sci, Baton Rouge, LA 70803 USA. [Hillis, David M.] Univ Texas Austin, Sect Integrat Biol, Austin, TX 78712 USA. [Griffith, Gareth W.] Aberystwyth Univ, Inst Biol Environm & Rural Sci, Aberystwyth SY23 3DD, Ceredigion, Wales. [Castlebury, Lisa A.; Rossman, Amy Y.] ARS, USDA, Systemat Mycol & Microbiol Lab, Beltsville, MD 20705 USA. [Lumbsch, H. Thorsten; Luecking, Robert] Field Museum Nat Hist, Dept Bot, Chicago, IL 60605 USA. [Buedel, Burkhard; Rauhut, Alexandra] Abt Pflanzenokol & Systemat, Fachbereich Biol, D-67653 Kaiserslautern, Germany. [Diederich, Paul] Musee Natl Hist Nat, L-2160 Luxembourg, Luxembourg. [Ertz, Damien] Natl Bot Garden Belgium, Dept Cryptogamy BT, B-1860 Meise, Belgium. [Geiser, David M.] Penn State Univ, Dept Plant Pathol, University Pk, PA 16802 USA. [Hosaka, Kentaro] Natl Museum Nat & Sci, Dept Bot, Tsukuba, Ibaraki 3050005, Japan. [Inderbitzin, Patrik] Univ Calif, Kearney Agr Ctr, Parlier, CA 93648 USA. [Kohlmeyer, Jan; Volkmann-Kohlmeyer, Brigitte] Univ N Carolina, Inst Marine Sci, Morehead City, NC 28557 USA. [Mostert, Lizel] Univ Stellenbosch, Dept Plant Pathol, ZA-7602 Matieland, South Africa. [O'Donnell, Kerry] ARS, Microbial Genom Res Unit, Natl Ctr Agr Utilizat Res, USDA, Peoria, IL 61604 USA. [Sipman, Harrie] Free Univ Berlin, Bot Garten & Bot Museum Berlin Dahlem, D-14195 Berlin, Germany. [Rogers, Jack D.] Washington State Univ, Dept Plant Pathol, Pullman, WA 99164 USA. [Shoemaker, Robert A.] Agr & Agri Food Canada, Biodivers Mycol & Bot, Ottawa, ON K1A 0C6, Canada. [Sugiyama, Junta] TechnoSuruga Lab Co Ltd, Tokyo Off, Chiyoda Ku, Tokyo 1010052, Japan. [Untereiner, Wendy] Brandon Univ, Dept Biol, Brandon, MB R7A 6A9, Canada. [Johnston, Peter R.] Herbarium PDD, Auckland 92170, New Zealand. [Stenroos, Soili] Univ Helsinki, Bot Museum, Finnish Museum Nat Hist, FI-00014 Helsinki, Finland. [Zuccaro, Alga] Univ Giessen, Inst Phytopathol & Appl Zool, D-35392 Giessen, Germany. [Dyer, Paul S.; Crittenden, Peter D.] Univ Nottingham, Sch Biol, Nottingham NG7 2RD, England. [Hansen, Karen] Swedish Museum Nat Hist, Dept Cryptogam Bot, SE-10405 Stockholm, Sweden. [Trappe, James M.] Oregon State Univ, Dept Forest Sci, Corvallis, OR 97331 USA. [Yahr, Rebecca] Royal Bot Gardens, Edinburgh EH3 5LR, Midlothian, Scotland. [Arzanlou, Mahdi] Univ Tabriz, Dept Plant Protect, Fac Agr, Tabriz, Iran. RP Schoch, CL (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, 45 Ctr Dr, Bethesda, MD 20892 USA. EM schoch2@mail.nih.gov RI Zuccaro, Alga/Q-2450-2015; Hillis, David/B-4278-2008; Wang, Zheng/A-2318-2011; griffith, gareth/A-1970-2009; Zuccaro, Alga/A-9290-2014; Gueidan, Cecile/C-8803-2014; Geiser, David/J-9950-2013; Lopez-Giraldez, Francesc/A-5251-2011; Gryzenhout, Marieka/C-5165-2008; Groenewald, Johannes/F-4667-2011; Wynns, Anja/E-5434-2012; Crous, Pedro/H-1489-2012; Schoch, Conrad/J-4825-2012; Lumbsch, Thorsten/K-3573-2012 OI Zuccaro, Alga/0000-0002-8026-0114; Amtoft Wynns, Anja/0000-0002-6013-9456; Wang, Zheng/0000-0002-8849-8549; Lopez-Giraldez, Francesc/0000-0001-7476-9822; Crous, Pedro/0000-0001-9085-8825; Lumbsch, Thorsten/0000-0003-1512-835X NR 75 TC 250 Z9 256 U1 11 U2 122 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1063-5157 J9 SYST BIOL JI Syst. Biol. PD APR PY 2009 VL 58 IS 2 BP 224 EP 239 DI 10.1093/sysbio/syp020 PG 16 WC Evolutionary Biology SC Evolutionary Biology GA 475CC UT WOS:000268332400005 PM 20525580 ER PT J AU Kelly, RJ Billemont, B Rixe, O AF Kelly, Ronan J. Billemont, Bertrand Rixe, Olivier TI Renal toxicity of targeted therapies SO TARGETED ONCOLOGY LA English DT Review DE Targeted therapies; Renal toxicity; Sunitinib; Bevacizumab; Sorafenib ID ENDOTHELIAL GROWTH-FACTOR; CELL LUNG-CANCER; METASTATIC COLORECTAL-CANCER; VASCULAR-PERMEABILITY FACTOR; RANDOMIZED PHASE-III; ADVANCED HEPATOCELLULAR-CARCINOMA; IMATINIB MESYLATE TREATMENT; FACTOR MONOCLONAL-ANTIBODY; TYROSINE KINASE INHIBITOR; CHRONIC MYELOID-LEUKEMIA AB The use of molecular targeted therapies for the treatment of cancer has increased over the last decade. The benefits of these compounds in terms of efficacy are often relatively modest and counter balanced by the occurrence of significant toxicities. Many of these newer agents used in clinical practice lack specificity and selectivity and have a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined and numerous class-specific toxicities have been described. The kidney is an organ where most of these targeted pathways are expressed. Preclinical data and human renal biopsies have generated an understanding of the mechanisms involved in how targeted agents can cause renal toxicity. This review article discusses the observed nephrotoxicity with this burgeoning class of therapeutics and reviews both the biological reasons for its occurrence and possible ways to prevent significant renal damage. C1 [Kelly, Ronan J.; Rixe, Olivier] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Billemont, Bertrand] Cochin Hosp, CERIA, Paris, France. RP Rixe, O (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM rixeo@mail.nih.gov NR 99 TC 23 Z9 23 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1776-2596 EI 1776-260X J9 TARGET ONCOL JI Target. Oncol. PD APR PY 2009 VL 4 IS 2 BP 121 EP 133 DI 10.1007/s11523-009-0109-x PG 13 WC Oncology SC Oncology GA 451RL UT WOS:000266487500008 PM 19421832 ER PT J AU Figueiredo, C Mbulaiteye, S Ndugwa, CM Schulz, T Eiz-Vesper, B AF Figueiredo, C. Mbulaiteye, S. Ndugwa, C. M. Schulz, T. Eiz-Vesper, B. TI Assessment of the amino acid substitution in HLA-B*5719 for allorecognition SO TISSUE ANTIGENS LA English DT Editorial Material DE allorecognition; human leukocyte antigen; transplantation ID RECOGNITION AB The novel allele human leukocyte antigen (HLA)-B*5719 differs from HLA-B*5701 by a synonymous nucleotide exchange at position 539 in exon 3 (C -> T), replacing Leucine by Arginine at amino acid position 156 in the alpha 2 domain. C1 [Figueiredo, C.; Eiz-Vesper, B.] Hannover Med Sch, Inst Transfus Med, D-30625 Hannover, Germany. [Mbulaiteye, S.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD USA. [Ndugwa, C. M.] Makerere Univ, Med Sch & Mulago Hosp, Kampala, Uganda. [Schulz, T.] Hannover Med Sch, Inst Virol, D-30625 Hannover, Germany. RP Eiz-Vesper, B (reprint author), Hannover Med Sch, Inst Transfus Med, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM eiz-vesper.britta@mh-hannover.de FU Intramural NIH HHS [Z01 CP010150-08] NR 5 TC 3 Z9 3 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD APR PY 2009 VL 73 IS 4 BP 376 EP 378 DI 10.1111/j.1399-0039.2009.01227.x PG 3 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 418ZF UT WOS:000264188200016 PM 19317752 ER PT J AU Zhu, SH Wang, JB Hartman, A Zhuang, Y Gamst, A Gibson, JT Gilljam, H Galanti, MR AF Zhu, S-H Wang, J. B. Hartman, A. Zhuang, Y. Gamst, A. Gibson, J. T. Gilljam, H. Galanti, M. R. TI Quitting cigarettes completely or switching to smokeless tobacco: do US data replicate the Swedish results? SO TOBACCO CONTROL LA English DT Article ID HARM REDUCTION; NORTHERN SWEDEN; SMOKING; PREVALENCE; PRODUCTS; SMOKERS; TRENDS; SNUFF AB Background: Swedish male smokers are more likely than female smokers to switch to smokeless tobacco (snus) and males' smoking cessation rate is higher than that of females. These results have fuelled international debate over promoting smokeless tobacco for harm reduction. This study examines whether similar results emerge in the United States, one of few other western countries where smokeless tobacco has long been widely available. Methods: US data source: national sample in Tobacco Use Supplement to Current Population Survey, 2002, with 1-year follow-up in 2003. Analyses included adult self-respondents in this longitudinal sample (n = 15 056). Population-weighted rates of quitting smoking and switching to smokeless tobacco were computed for the 1-year period. Results: Among US men, few current smokers switched to smokeless tobacco (0.3% in 12 months). Few former smokers turned to smokeless tobacco (1.7%). Switching between cigarettes and smokeless tobacco, infrequent among current tobacco users (< 4%), was more often from smokeless to smoking. Men quit smokeless tobacco at three times the rate of quitting cigarettes (38.8% vs 11.6%, p < 0.001). Overall, US men have no advantage over women in quitting smoking (11.7% vs 12.4%, p = 0.65), even though men are far likelier to use smokeless tobacco. Conclusion: The Swedish results are not replicated in the United States. Both male and female US smokers appear to have higher quit rates for smoking than have their Swedish counterparts, despite greater use of smokeless tobacco in Sweden. Promoting smokeless tobacco for harm reduction in countries with ongoing tobacco control programmes may not result in any positive population effect on smoking cessation. C1 [Zhu, S-H] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Gibson, J. T.] Informat Management Serv Inc, Rockville, MD USA. [Hartman, A.] NCI, Rockville, MD USA. [Gilljam, H.; Galanti, M. R.] Karolinska Inst, Stockholm, Sweden. RP Zhu, SH (reprint author), Univ Calif San Diego, Dept Family & Prevent Med, 9500 Gilman Dr 0905, La Jolla, CA 92093 USA. EM szhu@ucsd.edu FU National Cancer Institute (NCI) [5 P30 CA 23100-22S4] FX This work was supported in part by a supplemental grant to the University of California, San Diego Cancer Center from the National Cancer Institute (NCI): grant 5 P30 CA 23100-22S4 ( to S-HZ). Findings and conclusions are those of the authors and do not reflect the views of the NCI. NR 41 TC 49 Z9 50 U1 1 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PD APR PY 2009 VL 18 IS 2 BP 82 EP 87 DI 10.1136/tc.2008.028209 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 423TN UT WOS:000264518700014 PM 19168476 ER PT J AU Cullen, JM Brown, DL Kissling, GE Foley, JF Rizzo, J Marion, PL Parron, VI French, JE AF Cullen, John M. Brown, Danielle L. Kissling, Grace E. Foley, Julie F. Rizzo, Jennifer Marion, Patricia L. Parron, Vandy I. French, John E. TI Aflatoxin B1 and/or Hepatitis B Virus Induced Tumor Spectrum in a Genetically Engineered Hepatitis B Virus Expression and Trp53 Haploinsufficient Mouse Model System for Hepatocarcinogenesis SO TOXICOLOGIC PATHOLOGY LA English DT Article DE aflatoxin B(1); hepatitis B virus; hepatocellular carcinoma; p53; transgenic; Trp53; tumorigenesis; FVB/N strain ID HEPATOCELLULAR-CARCINOMA; P53-DEFICIENT MICE; TRANSGENIC MICE; LIVER-CANCER; P53 GENE; CARCINOGENICITY; PATHOGENESIS; MUTATIONS; INFECTION; DEVELOP AB The authors investigated the spectrum of tumors and Trp53 mutations in genetically engineered models using the FVB/N mouse that expressed the hepatitis B virus genome and/or carried a Trp53 null and wildtype allele and/or were exposed to aflatoxin B1. Liver tumor incidence was increased when all three risk factors were present. Without aflatoxin B1 exposure, neither Trp53 haploinsufficiency nor HBV expression affected liver tumor development. Liver tumor prevalence increased with aflatoxin B1 exposure (p < .001), as thirteen of fourteen mice with liver tumors were initiated with aflatoxin B1. Liver tumors were more frequent in males (12/190) than females (2/170). Seventy-three mice developed sarcomas. Trp53 haploinsufficiency was associated with increased sarcoma incidence in males and females (p < .001). In Trp53 haploinsufficient mice, the HBV transgene increased the risk of sarcoma in males and females (p < .001). Lymphoma was significantly increased in Trp53 haploinsufficient FVB/N mice. There was no loss of heterozygosity at the wildtype Trp53 locus in twenty-five sarcomas or four hepatocellular tumors examined. No mutations were identified in the mRNA (exons 2-11) of Trp53 in six liver neoplasms or twenty-four sarcomas. In this model system, HBV expression affected only hepatocellular neoplasia in association with both aflatoxin B1 initiation and p53 haploinsufficiency. C1 [Cullen, John M.; Brown, Danielle L.; Rizzo, Jennifer] N Carolina State Univ, Coll Vet Med, Raleigh, NC 27606 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Foley, Julie F.] NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. [Marion, Patricia L.] Stanford Univ, Palo Alto, CA 94305 USA. [Marion, Patricia L.] HepadnaVirus Testing Inc, Mountain View, CA 94043 USA. [Parron, Vandy I.; French, John E.] NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. RP Cullen, JM (reprint author), N Carolina State Univ, Coll Vet Med, 4700 Hillsborough St, Raleigh, NC 27606 USA. EM john_cullen@ncsu.edu FU National Institutes of Health, National Institute of Environmental Health Sciences FX This research was supported in part by the Division of Intramural Research of the National Institutes of Health, National Institute of Environmental Health Sciences, and funds from the State of North Carolina. NR 35 TC 2 Z9 3 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD APR PY 2009 VL 37 IS 3 BP 333 EP 342 DI 10.1177/0192623309333137 PG 10 WC Pathology; Toxicology SC Pathology; Toxicology GA 463XU UT WOS:000267468200007 PM 19258306 ER PT J AU Howroyd, P Allison, N Foley, JF Hardisty, J AF Howroyd, Paul Allison, Neil Foley, Julie F. Hardisty, Jerry TI Apparent Alveolar Bronchiolar Tumors Arising in the Mediastinum of F344 Rats SO TOXICOLOGIC PATHOLOGY LA English DT Article DE rat; carcinogenicity; lung; mediastinum; alveolar bronchiolar carcinoma; mesothelioma; immunohistochemistry ID EPITHELIOID MESOTHELIOMA; MALIGNANT MESOTHELIOMA; SQUAMOUS METAPLASIA; LUNG; EXPRESSION; PROTEIN; ADENOCARCINOMA; DIAGNOSIS; WT1 AB Rare tumors were observed in chronic studies in F-344 rats that were purely or largely free in the mediastinal cavity, yet had the histological architecture of alveolar bronchiolar tumors. They had originally been diagnosed as either pulmonary alveolar bronchiolar tumors, mediastinal mesotheliomas, or thymomas. The authors described these tumors, estimated the fraction of thoracic tumors that they represented, and carried out a preliminary immunohistochemical investigation of whether they were of pulmonary or mesothelial origin. Sections of 715 thoracic tumors originally diagnosed as alveolar bronchiolar tumors, mesotheliomas, or thymomas from control or treated F-344 rats in NTP two-year studies were reviewed. Thirty (4%) were found to be purely or largely mediastinal, yet to have an alveolar bronchiolar histological pattern. A subset of these tumors and some typical intrapulmonary alveolar bronchiolar carcinomas and pleural mesotheliomas were immunostained for Clara cell secretory protein (CCSP), beta-tubulin IV, and Wilm's tumor 1 susceptibility gene products (WT1). The tumors with the histological architecture of alveolar bronchiolar tumors immunostained positive for CCSP and negative for WT1, implying they might have been of alveolar bronchiolar origin, despite their predominantly mediastinal location, although more certain identification would require the use of a larger panel of antibodies. C1 [Allison, Neil] Expt Pathol Labs Inc, Natl Toxicol Program Arch, Res Triangle Pk, NC 27709 USA. [Howroyd, Paul] MDS Pharma Serv, Les Oncins, France. [Foley, Julie F.] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. RP Allison, N (reprint author), Expt Pathol Labs Inc, Natl Toxicol Program Arch, POB 13566, Res Triangle Pk, NC 27709 USA. EM nallison@epl-inc.com FU NIH, National Institute of Environmental Sciences FX This research was supported ( in part) by the Intramural Research Program of NIH, National Institute of Environmental Sciences. NR 27 TC 1 Z9 3 U1 1 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD APR PY 2009 VL 37 IS 3 BP 351 EP 358 DI 10.1177/0192623309332988 PG 8 WC Pathology; Toxicology SC Pathology; Toxicology GA 463XU UT WOS:000267468200010 PM 19380845 ER PT J AU Reed, W Noga, SJ Gee, AP Rooney, CM Wagner, JE McCullough, J McKenna, DH Whiteside, TL Donnenberg, AD Baker, AK Lindblad, RW Wagner, EL Mondoro, TH AF Reed, William Noga, Stephen J. Gee, Adrian P. Rooney, Cliona M. Wagner, John E. McCullough, Jeffrey McKenna, David H. Whiteside, Theresa L. Donnenberg, Albert D. Baker, Acacia K. Lindblad, Robert W. Wagner, Elizabeth L. Mondoro, Traci Heath TI Production Assistance for Cellular Therapies (PACT): four-year experience from the United States National Heart, Lung, and Blood Institute (NHLBI) contract research program in cell and tissue therapies SO TRANSFUSION LA English DT Review ID NATURAL-KILLER-CELLS; T-LYMPHOCYTES; IMMUNOTHERAPY; EXPANSION; DISEASE; BIOLOGY; CANCER; LINES AB In 2002, the US National Heart, Lung, and Blood Institute (NHLBI) conducted a workshop to determine needs of the cell therapy community. A consensus emerged that improved access to cGMP facilities, regulatory assistance, and training would foster the advancement of cellular therapy. A 2003 NHLBI request for proposals resulted in four contracts being awarded to three cell-manufacturing facilities (Baylor College of Medicine, University of Minnesota, and University of Pittsburgh) and one administrative center (The EMMES Corporation). As a result, Production Assistance for Cellular Therapies (PACT) was formed. As of October 1, 2008, PACT has received 65 preliminary applications of which 45 have been approved for product manufacture. A variety of cell therapies are represented including T-regulatory cells, natural killer cells, adipose-derived stem cells, cardiac progenitor cells for cardiac disease, hematopoietic progenitor cells (HPCs) for central nervous system applications, cytotoxic T lymphocytes, and dendritic cells. A total of 169 products have been administered under 12 applications and 2 reagents were manufactured and delivered. Fourteen peer-reviewed publications and 15 abstracts have resulted from the PACT project to date. A cell therapy textbook is nearly complete. PACT technical projects have addressed assay development, rapid endotoxin testing, shipping of cell products, and CD34+ HPC isolation from low-volume marrow. Educational Web seminars and onsite training through workshops have been conducted. PACT is an active and successful cell therapy manufacturing resource in the United States, addressing research and training while forging relationships among academia, industry, and participating institutions. C1 [Reed, William] Blood Syst Res Inst, San Francisco, CA 94118 USA. Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. Johns Hopkins Univ, Sinai Hosp, Baltimore, MD USA. Baylor Coll Med, Houston, TX 77030 USA. Univ Minnesota, Minneapolis, MN USA. Univ Pittsburgh, Pittsburgh, PA USA. EMMES Corp, Rockville, MD USA. NHLBI, Bethesda, MD 20892 USA. RP Reed, W (reprint author), Blood Syst Res Inst, 270 Masonic Ave, San Francisco, CA 94118 USA. EM william.reed@.ucsf.edu FU PACT FX All authors have signed a conflict of interest form and hereby attest that they have no conflict of interests to disclose regarding the publication of this article. The authors express their appreciation to David Styers and Deborah Wood of EMMES for providing data tables and figures and their assistance and dedication in bringing this article to fruition. The following individuals are being acknowledged for their valued contribution of and participation in PACT group initiatives: Baylor College of Medicine-April Durett, Helen Heslop, MD, Helen Huls, Deborah Lyon, and Pamela Watson; University of Minnesota-Sheryl Adams, Mary Clay, Diane Kadidlo, Jeff Miller, MD, Therese Schierman, and Darin Sumstad; and University of Pittsburgh-Deborah Griffin, Joseph Kiss, MD, Eileen Koch, Linda Moore, Jennifer Sprague, and Joanna Stanson. NR 19 TC 18 Z9 18 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0041-1132 J9 TRANSFUSION JI Transfusion PD APR PY 2009 VL 49 IS 4 BP 786 EP 796 DI 10.1111/j.1537-2995.2008.02027.x PG 11 WC Hematology SC Hematology GA 421TA UT WOS:000264380000028 PM 19170985 ER PT J AU Mulkidjanian, AY Galperin, MY Koonin, EV AF Mulkidjanian, Armen Y. Galperin, Michael Y. Koonin, Eugene V. TI Co-evolution of primordial membranes and membrane proteins SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID UNIVERSAL COMMON ANCESTOR; ATP SYNTHASE; ESCHERICHIA-COLI; VACUOLAR ATPASES; F-TYPE; ILYOBACTER-TARTARICUS; F1F0-ATP SYNTHASE; LIPID-BILAYERS; CENTRAL STALK; NA+-ATPASE AB Studies of the past several decades have provided major insights into the structural organization of biological membranes and mechanisms of many membrane molecular machines. However, the origin(s) of the membrane(s) and membrane proteins remains enigmatic. We discuss different concepts of the origin and early evolution of membranes with a focus on the evolution of the (im)permeability to charged molecules such as proteins, nucleic acids and small ions. Reconstruction of the evolution of F-type and A/V-type membrane ATPases (ATP synthases), which are either proton- or sodium-dependent, might help us to understand not only the origin of membrane bioenergetics but also of membranes themselves. We argue that evolution of biological membranes occurred as a process of co-evolution of lipid bilayers, membrane proteins and membrane bioenergetics. C1 [Mulkidjanian, Armen Y.] Univ Osnabruck, Sch Phys, D-49069 Osnabruck, Germany. [Mulkidjanian, Armen Y.] Moscow MV Lomonosov State Univ, AN Belozersky Inst Physicochem Biol, Moscow 119991, Russia. [Galperin, Michael Y.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Mulkidjanian, AY (reprint author), Univ Osnabruck, Sch Phys, D-49069 Osnabruck, Germany. EM amulkid@uos.de; koonin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013; Mulkidjanian, Armen/J-8086-2013 OI Galperin, Michael/0000-0002-2265-5572; Mulkidjanian, Armen/0000-0001-5844-3064 FU Deutsche Forschungsgemeinschaft; Volkswagen Foundation; National Library of Medicine at the National Institutes of Health FX Valuable discussions with A.A. Baykov. AN. Bogachev, D.A. Cherepanov, P.A. Dibrov, P. Dirnroth, A.V. Finkelstein, T. Haines, W. Junge, T. Krulwich, T. Meier, K.S. Makarova, D. Pogoryelov, V.P. Skulachev, H.-J. Steinhoff. J.E. Walker and Y.I. Wolfare greatly appreciated. We thank M. Kozlova for the hell) with Figure 1. This study was supported by grants to A.Y.M. from the Deutsche Forschungsgemeinschaft (www.dfg.de/en) and the Volkswagen Foundation (www.volkswagenstiftung.de) and by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health (M.Y.G., E.V.K.; www.nih.gov). NR 98 TC 70 Z9 76 U1 0 U2 22 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD APR PY 2009 VL 34 IS 4 BP 206 EP 215 DI 10.1016/j.tibs.2009.01.005 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 441GP UT WOS:000265757600008 PM 19303305 ER PT J AU Strait, JB Uda, M Lakatta, EG Najjar, SS AF Strait, James B. Uda, Manuela Lakatta, Edward G. Najjar, Samer S. TI Using New Tools to Define the Genetic Underpinnings of Risky Traits Associated With Coronary Artery Disease: The SardiNIA Study SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Review ID GENOME-WIDE ASSOCIATION; DENSITY-LIPOPROTEIN CHOLESTEROL; LINKAGE DISEQUILIBRIUM; CARDIOVASCULAR-DISEASE; FAMILIAL HYPERCHOLESTEROLEMIA; ADULT OBESITY; HEART-DISEASE; URIC-ACID; FTO GENE; STIFFNESS AB Genomewide association studies are increasingly being applied to search for novel genes that might underlie cardiovascular diseases. In this article, we briefly review the principles that underlie modern genetic analyses and provide several illustrations from the SardiNIA study of genomewide association studies for cardiovascular risk factor traits. (Trends Cardiovasc Med 2009;19:69-75) (C) 2009, Elsevier Inc. C1 [Strait, James B.; Lakatta, Edward G.; Najjar, Samer S.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Strait, James B.] NIA, Genet Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Uda, Manuela] Cittadella Univ Monseratto, CNR, INN, I-09042 Cagliari, Italy. RP Najjar, SS (reprint author), Harbor Hosp, NIA ASTRA Unit, 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM najjarsa@mail.nih.gov FU National Institute on Aging [NO1-AG-1-2109]; Intramural Research Program of the National Institute on Aging; National Institutes of Health, Baltimore, MD FX The SardiNIA ("ProgeNIA") team was supported by contract NO1-AG-1-2109 from the National Institute on Aging.; This research was supported (in part) by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Baltimore, MD. NR 42 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD APR PY 2009 VL 19 IS 3 BP 69 EP 75 AR PII S1050-1738(09)00067-X PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 489OW UT WOS:000269430900001 PM 19679263 ER PT J AU Jochim, RC Teixeira, C AF Jochim, Ryan C. Teixeira, Clarissa TI Leishmania commandeers the host inflammatory response through neutrophils SO TRENDS IN PARASITOLOGY LA English DT Article ID T-CELL-ACTIVATION; SAND FLIES; CUTANEOUS LEISHMANIASIS; INTRACELLULAR SURVIVAL; LYMPH-NODES; PROMASTIGOTES; GRANULOCYTES; MACROPHAGES; MICROBES; DONOVANI AB Neutrophils are the first cells to migrate to the site of tissue damage. Recent work has addressed Leishmania survival and entry into macrophages through the infection of neutrophils that are recruited as a normal response to sandfly bites. New findings indicate that Leishmania is able to escape from neutrophils and 'silently' enter macrophages, a modification of the 'Trojan horse' model. Neutrophil depletion impaired disease progression, indicating an important role for neutrophils in leishmaniasis. C1 [Jochim, Ryan C.; Teixeira, Clarissa] NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Jochim, RC (reprint author), NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM rjochim@niaid.nih.gov RI Jochim, Ryan/C-6756-2013 FU Intramural NIH HHS NR 24 TC 10 Z9 11 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 J9 TRENDS PARASITOL JI Trends Parasitol. PD APR PY 2009 VL 25 IS 4 BP 145 EP 147 DI 10.1016/j.pt.2009.01.001 PG 3 WC Parasitology SC Parasitology GA 432LS UT WOS:000265135900001 PM 19269250 ER PT J AU Malkesman, O Pine, DS Tragon, T Austin, DR Henter, ID Chen, G Manji, HK AF Malkesman, Oz Pine, Daniel S. Tragon, Tyson Austin, Daniel R. Henter, Ioline D. Chen, Guang Manji, Husseini K. TI Animal models of suicide-trait-related behaviors SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID AGGRESSIVE-BEHAVIOR; ADOLESCENT SUICIDE; ANTIDEPRESSANT TREATMENT; IMPULSIVE BEHAVIOR; D-AMPHETAMINE; YOUNG-ADULTS; DEPRESSION; MICE; IDEATION; RAT AB Although antidepressants are moderately effective in treating major depressive disorder (MDD), concerns have arisen that selective serotonin-reuptake inhibitors (SSRIs) are associated with suicidal thinking and behavior, especially in children, adolescents and young adults. Almost no experimental research in model systems has considered the mechanisms by which SSRIs might be associated with this potential side effect in some susceptible individuals. Suicide is a complex behavior and impossible to fully reproduce in an animal model. However, by investigating traits that show strong cross-species parallels in addition to associations with suicide in humans, animal models might elucidate the mechanisms by which SSRIs are associated with suicidal thinking and behavior. Traits linked with suicide in humans that can be successfully modeled in rodents include aggression, impulsivity, irritability and hopelessness/helplessness. Modeling these relevant traits in animals can help to clarify the impact of SSRIs on these traits, suggesting avenues for reducing suicide risk in this vulnerable population. C1 [Malkesman, Oz; Tragon, Tyson; Austin, Daniel R.; Chen, Guang; Manji, Husseini K.] NIMH, Mol Pathophysiol Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Pine, Daniel S.] NIMH, Sect Dev & Affect Neurosci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Malkesman, Oz; Pine, Daniel S.; Tragon, Tyson; Austin, Daniel R.; Henter, Ioline D.; Chen, Guang; Manji, Husseini K.] NIMH, Mood & Anxiety Disorders Res Program, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. EM manji@nih.gov RI Chen, Guang/A-2570-2017 FU Intramural Research Program (IRP) at the National Institute of Mental Health (NIMH-NIH) FX This work was supported by the Intramural Research Program (IRP) at the National Institute of Mental Health (NIMH-NIH; www.nimh.nih.gov). NR 78 TC 22 Z9 22 U1 5 U2 18 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD APR PY 2009 VL 30 IS 4 BP 165 EP 173 DI 10.1016/j.tips.2009.01.004 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 435GE UT WOS:000265331100001 PM 19269045 ER PT J AU Choi, SH Aid, S Bosetti, F AF Choi, Sang-Ho Aid, Saba Bosetti, Francesca TI The distinct roles of cyclooxygenase-1 and -2 in neuroinflammation: implications for translational research SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; TRAUMATIC BRAIN-INJURY; AMYOTROPHIC-LATERAL-SCLEROSIS; ALZHEIMERS-DISEASE; PARKINSON-DISEASE; PROSTAGLANDIN E-2; MICROGLIAL ACTIVATION; INFLAMMATORY PROCESSES; PHOSPHOLIPASE A(2); CEREBRAL-ISCHEMIA AB Cyclooxygenases (COX-1 and COX-2) are key enzymes in the conversion of arachidonic acid to prostaglandins and other lipid mediators. Because it can be induced by inflammatory stimuli, COX-2 has been classically considered as the most appropriate target for anti-inflammatory drugs. However, recent data indicate that COX-2 can mediate neuroprotection and that COX-1 is a major player in the neuroinflammatory process. We discuss the specific contributions of COX-1 and COX-2 in various neurodegenerative diseases and in models of neuroinflammation. We suggest that, owing to its predominant localization in microglia, COX-1 might be the major player in neuroinflammation, whereas COX-2, which is localized in neurons, might have a major role in models in which the neurons are directly challenged. Overall, the benefit of using COX-2 inhibitors should be carefully evaluated and COX-1 preferential inhibitors should be further investigated as a potential therapeutic approach in neurodegenerative diseases with an inflammatory component. C1 [Choi, Sang-Ho; Aid, Saba; Bosetti, Francesca] NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Bosetti, F (reprint author), NIA, Mol Neurosci Unit, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. EM frances@mail.nih.gov FU Intramural NIH HHS [ZIA AG000425-04] NR 75 TC 142 Z9 150 U1 4 U2 20 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD APR PY 2009 VL 30 IS 4 BP 174 EP 181 DI 10.1016/j.tips.2009.01.002 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 435GE UT WOS:000265331100002 PM 19269697 ER PT J AU Sen, HN Caruso, R Arat, YO Nussenblatt, RB AF Sen, H. Nida Caruso, Raphael Arat, Yonca Ozkan Nussenblatt, Robert B. TI Indocyanine Green Angiography and Scanning Laser Ophthalmoscope Microperimetry in Punctate Inner Choroidopathy SO TURKIYE KLINIKLERI TIP BILIMLERI DERGISI LA English DT Article DE Indocyanine green; choroid; uveitis, posterior ID MULTIFOCAL CHOROIDITIS AB Our purpose is to describe indocyanine green angiography (ICG) and scanning laser ophthalmoscopy (SLO) findings in a patient with punctuate inner choroidopathy (PIC). The clinical record of a patient with PIC evaluated at the National Eye Institute (NEI) using fluorescein angiography (FA), ICG and SLO was reviewed. ICG showed hypofluorescent spots in early and late phases that corresponded to areas of leakage in FA. These hypofluorescent spots disappeared following immunosuppressive treatment. SLO mapped the location of scotomas that correlated to FA and ICG. ICG and SLO can be useful adjuncts to FA and clinical exam in assessing disease activity and guiding immunosuppressive therapy in patients with PIC. C1 [Sen, H. Nida; Caruso, Raphael; Nussenblatt, Robert B.] NEI, NIH, Bethesda, MD 20892 USA. [Arat, Yonca Ozkan] Univ Wisconsin, Dept Ophthalmol, Madison, WI 53706 USA. RP Arat, YO (reprint author), 301 S Yellowstone Dr 400, Madison, WI 53705 USA. EM yoncaozkan@hotmail.com NR 12 TC 0 Z9 0 U1 0 U2 0 PU ORTADOGU AD PRES & PUBL CO PI ANKARA PA TALATPASA BULVARI 102-1, HAMAMONU, ANKARA, 06230, TURKEY SN 1300-0292 J9 TURK KLIN TIP BILIM JI Turk. Klin. Tip Bilim. Derg. PD APR PY 2009 VL 29 IS 2 BP 536 EP 539 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 444YI UT WOS:000266016400036 ER PT J AU Lee, W Balasubramaniam, M Deter, RL Hassan, SS Gotsch, F Kusanovic, JP Goncalves, LF Romero, R AF Lee, W. Balasubramaniam, M. Deter, R. L. Hassan, S. S. Gotsch, F. Kusanovic, J. P. Goncalves, L. F. Romero, R. TI Fractional limb volume - a soft tissue parameter of fetal body composition: validation, technical considerations and normal ranges during pregnancy SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE fetal growth; fractional arm volume; fractional thigh volume; soft tissue ID INDIVIDUALIZED GROWTH ASSESSMENT; HEAD CIRCUMFERENCE RATIOS; TO-CHEEK DIAMETER; 3-DIMENSIONAL ULTRASOUND; MIDARM CIRCUMFERENCE; THIGH VOLUME; BIRTH-WEIGHT; ANTHROPOMETRIC ASSESSMENT; NUTRITIONAL-STATUS; NEWBORN-INFANTS AB Objectives The main goals were to provide normal reference ranges for fractional limb volume as a new index of generalized fetal nutritional status, to evaluate the reproducibility of fractional fetal limb volume measurement during the second and third trimesters of pregnancy, and to demonstrate technical considerations for this technique. Methods This was a prospective, cross-sectional study of gravid women during mid to late pregnancy. Fractional limb volumes were based on either 50%, of humeral or femoral diaphysis length. Each partial volume was subdivided into five equidistant slices that were centered along the mid-arm or mid-thigh. Slices were traced manually to obtain fractional arm (AVol) or fractional thigh (TVol) volume. Reproducibility studies were performed, using Bland-Altman plots, to assess blinded interobserver and intraobserver measurement bias and agreement. Selected images were chosen to demonstrate technical factors for the acquisition mid analysis of these parameters. Reference charts were established to describe normal ranges for A Vol and TVol. Results Three hundred mid eighty-seven subjects were scanned to include 380 AVol (range, 1.1-68.3 mL) and 378 TVol (range 2.0-163.2 mL) measurements between 18.0 and 42.1 weeks' menstrual age. No gender differences were found in these soft tissue measurements (A Vol, P = 0.90; TVol, P = 0.91; Mann-Whitney test). Intraobserver mean bias +/- SD mid 95% limits of agreement (LOA) for fractional limb volumes were: 2.2 +/- 4.2% (95%, LOA, -6.0 to 10.5%) for A Vol and 2.0 +/- 4.2%, (95%, LOA, -6.3 to 10.3%,) for TVol. Interobserver bias and agreement were -1.9 +/- 4.9%, (95%, LOA, -11.6 to 7.8%) for AVol and -2.0 +/- 5.4% (9.5% LOA, -12.5 to 8.6%,) for TVol. Technical factors were related to image optimization, transducer pressure, fetal movement, soft tissue compression and amniotic fluid volume. Conclusions Fractional limb volume assessment may improve the detection and monitoring of malnourished fetuses because this soft tissue parameter can be obtained quickly and reproducibly during mid to late pregnancy. Careful attention should be placed on technical factors that can potentially affect optimal acquisition and analysis of these volume measurements. Copyright (C) 2009 ISUOG. Published by John Wiley & Sons, Ltd. C1 [Lee, W.] William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48073 USA. [Balasubramaniam, M.] William Beaumont Hosp, Res Inst, Div Biostat, Royal Oak, MI 48073 USA. [Deter, R. L.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Lee, W.; Hassan, S. S.; Gotsch, F.; Kusanovic, J. P.; Goncalves, L. F.; Romero, R.] Eunice Kennedy Shriver Natl Inst Child & Human De, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Lee, W.; Hassan, S. S.; Gotsch, F.; Kusanovic, J. P.; Goncalves, L. F.; Romero, R.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. RP Lee, W (reprint author), William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, 3601 W 13 Mile Rd, Royal Oak, MI 48073 USA. EM wlee@beaumont.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX The authors wish to acknowledge the technical assistance of Melissa Powell, RDMS, and Beverley McNie, BS, COO. This research was supported partially, by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 45 TC 34 Z9 36 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD APR PY 2009 VL 33 IS 4 BP 427 EP 440 DI 10.1002/uog.6319 PG 14 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 451YA UT WOS:000266505600010 PM 19253340 ER PT J AU Lee, W Balasubramaniam, M Deter, RL Hassan, SS Gotsch, F Kusanovic, JP Goncalves, LF Romero, R AF Lee, W. Balasubramaniam, M. Deter, R. L. Hassan, S. S. Gotsch, F. Kusanovic, J. P. Goncalves, L. F. Romero, R. TI Fetal growth parameters and birth weight: their relationship to neonatal body composition SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Article DE 3D ultrasonography; air displacement plethysmography; fetal growth; fractional thigh volume; infant body composition; soft tissue ID SUBCUTANEOUS TISSUE THICKNESS; AIR-DISPLACEMENT PLETHYSMOGRAPHY; TO-CHEEK DIAMETER; MENSTRUAL AGE; RESTRICTED FETUSES; SOFT-TISSUE; LIMB VOLUME; LEAN MASS; INFANTS; CIRCUMFERENCE AB Objectives The main goal was to investigate the relationship between prenatal sonographic parameters and birth weight in predicting neonatal body composition. Methods Standard fetal biometry and soft tissue parameters were assessed prospectively in third-trimester pregnancies using three-dimensional ultrasonography. Growth parameters included biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), mid-thigh circumference and femoral diaphysis length (FDL). Soft tissue parameters included fractional arm volume (AVol) and fractional thigh volume (TVol) that were derived from 50% of the humeral or femoral diaphysis lengths, respectively. Percentage of neonatal body fat (%BF) was determined within 48h of delivery using a pediatric air displacement plethysmography system based on principles of whole-body densitometry. Correlation and stepwise multiple linear regression analyses were performed with potential prenatal predictors and %BF as the outcome variable. Results Eight-seven neonates were studied with a mean +/- SD %BF of 10.6 +/- 4.6%. TVol had the greatest correlation with newborn %BF of all single-parameter models. This parameter alone explained 46.1% of the variability in %BF and the best stepwise multiple linear regression model was: %BF = 0.129 (TVol) - 1.03933 (P < 0.001). Birth weight similarly explained 44.7% of the variation in %BF. AC and estimated fetal weight (EFW) accounted for only 24.8% and 30.4% of the variance in %BF, respectively. Skeletal growth parameters, such as FDL, (14.2%), HC (7.9%) and BPD (4.0%), contributed the least towards explaining the variance in %BF. Conclusions During the late third trimester of pregnancy %BF is most highly correlated with TVol. Similar to actual birth weight, this soft tissue parameter accounts for a significant improvement in explaining the variation in neonatal %BF compared with fetal AC or EFW alone. Copyright (C) 2009 ISUOG, Published by John Wiley & Sons, Ltd. C1 [Lee, W.] William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, Royal Oak, MI 48073 USA. [Balasubramaniam, M.] William Beaumont Hosp, Res Inst, Div Biostat, Royal Oak, MI 48073 USA. [Deter, R. L.] Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Lee, W.; Hassan, S. S.; Gotsch, F.; Kusanovic, J. P.; Goncalves, L. F.; Romero, R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. [Lee, W.; Hassan, S. S.; Gotsch, F.; Kusanovic, J. P.; Goncalves, L. F.; Romero, R.] Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. RP Lee, W (reprint author), William Beaumont Hosp, Dept Obstet & Gynecol, Div Fetal Imaging, 3601 W 13 Mile Rd, Royal Oak, MI 48073 USA. EM wlee@beaumont.edu FU Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services FX The authors Wish to acknowledge the technical assistance of Melissa Powell, RDMS, and Beverley McNie, BS, CCRP. This research was supported partially by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 53 TC 37 Z9 40 U1 0 U2 6 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD APR PY 2009 VL 33 IS 4 BP 441 EP 446 DI 10.1002/uog.6317 PG 6 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 451YA UT WOS:000266505600011 PM 19253324 ER PT J AU Nivitchanyong, T Tsai, YC Betenbaugh, MJ Oyler, GA AF Nivitchanyong, Toey Tsai, Yien Che Betenbaugh, Michael J. Oyler, George A. TI An improved in vitro and in vivo Sindbis virus expression system through host and virus engineering SO VIRUS RESEARCH LA English DT Article DE Sindbis virus; Bcl-2; Mammalian cells; Recombinant protein expression; ER stress; Parkin; Apoptosis ID UNFOLDED PROTEIN RESPONSE; SEMLIKI-FOREST-VIRUS; ENDOPLASMIC-RETICULUM STRESS; MAMMALIAN-CELL CULTURES; AMINO-ACID CHANGE; GENE-EXPRESSION; ALPHAVIRUS VECTORS; E2 GLYCOPROTEIN; BHK CELLS; PERSISTENT INFECTION AB The Sindbis viral expression system enables the rapid production of high levels of recombinant protein in mammalian cells; however, this expression is typically limited to transient production due to the cytotoxicity of the virus. Limiting the lethality inherent in the Sindbis virus vector in order to enable long term, sustained expression of recombinant proteins may be possible. In this study, modifications to virus and host have been combined in order to reduce the cytopathic effects. Non-cytopathic replication competent viruses of two Sindbis viral strains, TE and 633, were developed using a non-structural protein (nsP) P726S point mutation in order to obtain persistent heterologous gene expression in infected Baby Hamster Kidney (BHK) cells and Chinese Hamster Ovary (CHO) cells. Cells infected with the P726S variant viruses were able to recover after infection, while cells infected with normal virus died within 3 days. The P726S mutation did not reduce the susceptibility of 5- and 14-day-old mice to 633 and TE viruses in vivo. in addition, animal survival with the P726S variant viruses was increased and GFP expression was sustained for at least 14 days while the 633 and TE infection resulted in short-term GFP expression or an earlier mortality. Modifications to the host BHK and CHO cells themselves were subsequently undertaken by including the anti-apoptotic gene Bcl-2 and a deletion mutant of Bcl-2 (Bcl-2 Delta) as another method for limiting the cytopathic effects of the Sindbis virus. The inclusion of anti-apoptotic genes permitted higher production of heterologous GFP protein following Sindbis virus infection, and the combination of the TE-P726S virus and the CHO-Bcl-2 Delta cell line showed the greatest improvement in cell survival. Sindbis virus infection also induced ER stress in mammalian cells as detected by increased PERK phosphorylation and ATF4 translation. Overexpression of Parkin, an E3 ubiquitin ligase that can protect cells against agents that induce ER stress, suppressed Sindbis virus-induced cell death in both BHK cells and in vivo studies in mice. Such findings show that viral and host modifications can improve cell survival and production of heterologous proteins, change viral behavior in vitro and in vivo, and assist in the development of new expression or gene delivery vehicles. (C) 2009 Elsevier B.V. All rights reserved. C1 [Nivitchanyong, Toey; Betenbaugh, Michael J.; Oyler, George A.] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. [Tsai, Yien Che] NCI, Lab Prot Dynam & Signaling, NIH, Frederick, MD 21701 USA. [Oyler, George A.] Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. RP Nivitchanyong, T (reprint author), Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. EM Tarangsri.niv@biotec.or.th OI Tsai, Yien Che/0000-0001-9624-1092 FU NINDS NIH HHS [R21 NS043658-02] NR 61 TC 8 Z9 8 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD APR PY 2009 VL 141 IS 1 BP 1 EP 12 DI 10.1016/j.virusres.2008.12.019 PG 12 WC Virology SC Virology GA 430MJ UT WOS:000264992900001 PM 19200810 ER PT J AU Rosenfeld, JA Wang, ZB Schones, DE Zhao, K DeSalle, R Zhang, MQ AF Rosenfeld, Jeffrey A. Wang, Zhibin Schones, Dustin E. Zhao, Keji DeSalle, Rob Zhang, Michael Q. TI Determination of enriched histone modifications in non-genic portions of the human genome SO BMC GENOMICS LA English DT Article ID H3 LYSINE-9 METHYLATION; FALSE DISCOVERY RATES; EMBRYONIC STEM-CELLS; MAMMALIAN CHROMATIN; CENTROMERIC CHROMATIN; DNA METHYLATION; CODING REGIONS; HETEROCHROMATIN; PATTERNS; DISTINCT AB Background: Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) has recently been used to identify the modification patterns for the methylation and acetylation of many different histone tails in genes and enhancers. Results: We have extended the analysis of histone modifications to gene deserts, pericentromeres and subtelomeres. Using data from human CD4(+) T cells, we have found that each of these non-genic regions has a particular profile of histone modifications that distinguish it from the other noncoding regions. Different methylation states of H4K20, H3K9 and H3K27 were found to be enriched in each region relative to the other regions. These findings indicate that non-genic regions of the genome are variable with respect to histone modification patterns, rather than being monolithic. We furthermore used consensus sequences for unassembled centromeres and telomeres to identify the significant histone modifications in these regions. Finally, we compared the modification patterns in non-genic regions to those at silent genes and genes with higher levels of expression. For all tested methylations with the exception of H3K27me3, the enrichment level of each modification state for silent genes is between that of non-genic regions and expressed genes. For H3K27me3, the highest levels are found in silent genes. Conclusion: In addition to the histone modification pattern difference between euchromatin and heterochromatin regions, as is illustrated by the enrichment of H3K9me2/3 in non-genic regions while H3K9me1 is enriched at active genes; the chromatin modifications within non-genic (heterochromatin-like) regions (e. g. subtelomeres, pericentromeres and gene deserts) are also quite different. C1 [Rosenfeld, Jeffrey A.; Zhang, Michael Q.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Rosenfeld, Jeffrey A.] NYU, Dept Biol, New York, NY 10003 USA. [Rosenfeld, Jeffrey A.; DeSalle, Rob] Amer Museum Nat Hist, New York, NY 10024 USA. [Wang, Zhibin; Schones, Dustin E.; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Zhang, MQ (reprint author), Cold Spring Harbor Lab, POB 100, Cold Spring Harbor, NY 11724 USA. EM rosenfel@cshl.edu; wangz3@mail.nih.gov; schonesde@nhlbi.nih.gov; zhaok@mail.nih.gov; desalle@amnh.org; mzhang@cshl.edu FU NIH [HG10696] FX We thank Dan Tranchina, Andrew Smith, Zhenyu Xuan, Xiaoyue Zhao, and Rob Martienssen for helpful discussions. We would also like to thank Steve Small, Ken Birnbaum, Christopher Vakoc, and Matt Vaughn who read and commented on the manuscript. We would also like to thank Todd Heywood of the Cold Spring Harbor High Performance Computing Center who provided assistance in making sure that adequate computational facilities were available for this study. This work was partially supported by NIH grant HG10696 to M. Q. Z. and by the Intramural Research Program of the NIH National Heart, Lung, and Blood Institute (ZW, DES, KZ). J. A. R is supported by an NIH training grant to New York University and is further supported by a McCracken Fellowship. We would also like to thank the three anonymous reviewers for their helpful comments. NR 58 TC 100 Z9 102 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAR 31 PY 2009 VL 10 AR 143 DI 10.1186/1471-2164-10-143 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 441TN UT WOS:000265793500002 PM 19335899 ER PT J AU Fox, CS Gona, P Hoffmann, U Porter, SA Salton, CJ Massaro, JM Levy, D Larson, MG D'Agostino, RB O'Donnell, CJ Manning, WJ AF Fox, Caroline S. Gona, Philimon Hoffmann, Udo Porter, Stacy A. Salton, Carol J. Massaro, Joseph M. Levy, Daniel Larson, Martin G. D'Agostino, Ralph B., Sr. O'Donnell, Christopher J. Manning, Warren J. TI Pericardial Fat, Intrathoracic Fat, and Measures of Left Ventricular Structure and Function The Framingham Heart Study SO CIRCULATION LA English DT Article DE epidemiology; magnetic resonance imaging; obesity; pericardium; risk factors ID EPICARDIAL ADIPOSE-TISSUE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; COMPUTED-TOMOGRAPHY; OBESE SUBJECTS; WEIGHT-LOSS; MASS; ECHOCARDIOGRAPHY; MORPHOLOGY; THICKNESS AB Background-Pericardial fat has been implicated in the pathogenesis of obesity-related cardiovascular disease. Whether the associations of pericardial fat and measures of cardiac structure and function are independent of the systemic effects of obesity and visceral adiposity has not been fully explored. Methods and Results-Participants from the Framingham Heart Study (n = 997; 54.4% women) underwent chest and abdominal computed tomography and cardiovascular magnetic resonance imaging between 2002 and 2005. Pericardial fat, intrathoracic fat, and visceral adipose tissue quantified from multidetector computed tomography, along with body mass index and waist circumference, were examined in relation to cardiovascular magnetic resonance measures of left ventricular (LV) mass, LV end-diastolic volume, and left atrial dimension. In women, pericardial fat (r = 0.20 to 0.35, P < 0.001), intrathoracic fat (r = 0.25 to 0.37, P < 0.001), visceral adipose tissue (r = 0.24 to 0.45, P < 0.001), body mass index (r = 0.36 to 0.53, P < 0.001), and waist circumference (r = 0.30 to 0.48, P < 0.001) were directly correlated with LV mass, LV end-diastolic volume, and left atrial dimension. In men, pericardial fat (r = 0.19 to 0.37, P < 0.001), intrathoracic fat (r = 0.17 to 0.31, P < 0.001), visceral adipose tissue (r = 0.19 to 0.36, P < 0.001), body mass index (r = 0.32 to 0.44, P < 0.001), and waist circumference (r = 0.34 to 0.44, P < 0.001) were directly correlated with LV mass and left atrial dimension, but LV end-diastolic volume was not consistently associated with adiposity measures. Associations persisted after multivariable adjustment but not after additional adjustment for body weight and visceral adipose tissue, except for pericardial fat and left atrial dimension in men. Conclusions-Pericardial fat is correlated with cardiovascular magnetic resonance measures, but the association is not independent of or stronger than other ectopic fat stores or proxy measures of visceral adiposity. An important exception is left atrial dimension in men. These results suggest that the systemic effects of obesity on cardiac structure and function may outweigh the local pathogenic effects of pericardial fat. (Circulation. 2009; 119: 1586-1591.) C1 [Fox, Caroline S.; Gona, Philimon; Massaro, Joseph M.; Larson, Martin G.; D'Agostino, Ralph B., Sr.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Med, Div Endocrinol Diabet & Metab, Boston, MA 02115 USA. [Fox, Caroline S.; Porter, Stacy A.] Harvard Univ, Sch Med, Boston, MA USA. [Gona, Philimon; Massaro, Joseph M.; Larson, Martin G.; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Hoffmann, Udo] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol, Boston, MA USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med, Boston, MA USA. [Salton, Carol J.; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Div Cardiol, Boston, MA 02215 USA. [Manning, Warren J.] Beth Israel Deaconess Med Ctr, Dept Radiol, Boston, MA 02215 USA. RP Fox, CS (reprint author), 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812; Larson, Martin/0000-0002-9631-1254 FU National Heart, Lung and Blood Institute [N01-HC-25195, R01-HL70279] FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (N01-HC-25195 and R01-HL70279). NR 27 TC 99 Z9 101 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 31 PY 2009 VL 119 IS 12 BP 1586 EP 1591 DI 10.1161/CIRCULATIONAHA.108.828970 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 426LI UT WOS:000264709400005 PM 19289634 ER PT J AU Koh, KK Quon, MJ AF Koh, Kwang Kon Quon, Michael J. TI Letter by Koh and Quon Regarding Article, "Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia" SO CIRCULATION LA English DT Letter ID INSIGHTS; CANCER; RISK C1 [Koh, Kwang Kon] Gachon Univ, Gil Med Ctr, Div Cardiol, Inchon, South Korea. [Quon, Michael J.] NIH, Clin Invest Lab, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Koh, KK (reprint author), Gachon Univ, Gil Med Ctr, Div Cardiol, Inchon, South Korea. OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 NR 5 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 31 PY 2009 VL 119 IS 12 BP E376 EP E376 DI 10.1161/CIRCULATIONAHA.108.827584 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 426LI UT WOS:000264709400019 PM 19332476 ER PT J AU Ashwood, P Schauer, J Pessah, IN de Water, JV AF Ashwood, Paul Schauer, Joseph Pessah, Isaac N. de Water, Judy Van TI Preliminary evidence of the in vitro effects of BDE-47 on innate immune responses in children with autism spectrum disorders SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE ASD; Autism; LPS; Monocyte; Innate immunity; BDE-47 ID POLYBROMINATED DIPHENYL ETHERS; DISEASE VIRUS-INFECTION; CENTRAL-NERVOUS-SYSTEM; BROMINATED FLAME RETARDANTS; FETAL-BRAIN-DEVELOPMENT; SWEDISH HUMAN-MILK; 2,2',4,4',5-PENTABROMODIPHENYL ETHER; CYTOKINE PRODUCTION; NEONATAL EXPOSURE; DENDRITIC CELLS AB Autism spectrum disorders (ASD) are complex neurodevelopmental disorders that manifest in childhood. Immune dysregulation and autoimmune reactivity may contribute to the etiology of ASD and are likely the result of both genetic and environmental susceptibilities. A common environmental contaminant, 2,2',4,4'-tetrabrominated biphenyl (BDE-47), was tested for differential effects on the immune response of peripheral blood mononuclear cells (PBMC) isolated from children with ASD (n=19) and age-matched typically developing controls (TD, n=18). PBMC were exposed in vitro to either 100 nM or 500 nM BDE-47, before challenge with bacterial lipopolysaccharide (LPS), an innate immune activator, with resultant cytokine production measured using the Luminex (TM) multiplex platform. The cytokine responses of LIPS stimulated PBMC from ASD and TD subjects diverged in the presence of 100 nM BDE. For example, cells cultured from the TD group demonstrated significantly decreased levels of the cytokines IL-12p40, GM-CSF, IL-6, TNF alpha, and the chemokines MIP-1 alpha and MIP-1 beta following LPS stimulation of PBMC pretreated with 100 nM BDE-47 compared with samples treated with vehicle control (p<0.05). In contrast, cells cultured from subjects with ASD demonstrated an increased IL-1 beta response to LPS (p=0.033) when pretreated with 100 nM BDE-47 compared with vehicle control. Preincubation with 500 nM BDE-47 significantly increased the stimulated release of the inflammatory chemokine IL-8 (p<0.04) in cells cultured from subjects with ASD but not in cells from TD controls. These data suggest that in vitro exposure of PBMC to BDE-47 affects cell cytokine production in a pediatric population. Moreover, PBMC from the ASD subjects were differentially affected when compared with the TD controls suggesting a biological basis for altered sensitivity to BDE-47 in the ASD population. (C) 2009 Elsevier B.V. All rights reserved. C1 [Schauer, Joseph; de Water, Judy Van] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Pessah, Isaac N.] Univ Calif Davis, Dept Vet Mol Biosci, Davis, CA 95616 USA. [Ashwood, Paul; Schauer, Joseph; Pessah, Isaac N.; de Water, Judy Van] Univ Calif Davis, MIND Inst, Davis, CA 95616 USA. [Ashwood, Paul; Schauer, Joseph; Pessah, Isaac N.; de Water, Judy Van] Univ Calif Davis, NIEHS Ctr Childrens Environm Hlth, Davis, CA 95616 USA. RP de Water, JV (reprint author), Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, 451 E Hlth Sci Dr, Davis, CA 95616 USA. EM javandewater@ucdavis.edu FU National Institute of Environmental Health Sciences [P01ES011269, R01ES015359]; Environmental Protection Agency [R833292, R829388] FX This research was supported by Award Number P01ES011269 and R01ES015359 from the National Institute of Environmental Health Sciences and Award Numbers R833292 and R829388 from the Environmental Protection Agency. The content is solely the responsibility of the investigators and does not necessarily represent the official views of the National Institute of Environmental Health Sciences, the National Institutes of Health or the Environmental Protection Agency. In addition, funding was received from Cure Autism Now, Autism Speaks, The Peter Emch Foundation and a generous gift from the Johnson Family. We would like to thank the staff of both the UC Davis M.I.N.D Institute and the CHARGE study for their technical support. The commitment of the families who took part in these studies, at both the M.I.N.D Institute and as part of the CHARGE study, is also gratefully acknowledged. NR 57 TC 22 Z9 25 U1 3 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 EI 1872-8421 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD MAR 31 PY 2009 VL 208 IS 1-2 BP 130 EP 135 DI 10.1016/j.jneuroim.2008.12.012 PG 6 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 435QJ UT WOS:000265358100017 PM 19211157 ER PT J AU Franco, R Panayiotidis, MI AF Franco, Rodrigo Panayiotidis, Mihalis I. TI Environmental toxicity, oxidative stress, human disease and the "black box" of their synergism: How much have we revealed? SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Editorial Material C1 [Franco, Rodrigo] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Panayiotidis, Mihalis I.] Univ Nevada, Sch Community Hlth Sci, Reno, NV 89557 USA. RP Panayiotidis, MI (reprint author), Democritus Univ Thrace, Dept Med, Biochem Lab, Univ Campus, Alexandroupolis 68100, Greece. EM mpanagiotidis@unr.edu OI Panagiotidis, Mihalis/0000-0002-1130-5972 NR 0 TC 17 Z9 17 U1 0 U2 4 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 MAR 31 PY 2009 VL 674 IS 1-2 BP 1 EP 2 DI 10.1016/j.mrgentox.2009.01.005 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 432KX UT WOS:000265133000001 PM 19386238 ER PT J AU Franco, R Sanchez-Olea, R Reyes-Reyes, EM Panayiotidis, MI AF Franco, Rodrigo Sanchez-Olea, Roberto Reyes-Reyes, Elsa M. Panayiotidis, Mihalis I. TI Environmental toxicity, oxidative stress and apoptosis: Menage a Trois SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Review DE Cell death; Environmental stress; Environmental toxicants; Environmental agents; ROS; Free radicals; Oxidative stress; Glutathione; Metals; Pesticides; Ionizing radiation; Ultraviolet radiation; Particulate matter; Asbestos; Cigarette smoke; DNA damage; Endoplasmic reticulum stress; SAPK; MAPK; p53; Dioxins ID TRIOXIDE-INDUCED APOPTOSIS; RADIATION-INDUCED APOPTOSIS; CADMIUM-INDUCED APOPTOSIS; ACTIVATED PROTEIN-KINASE; CELL-CYCLE ARREST; POLYCYCLIC AROMATIC-HYDROCARBONS; ACUTE PROMYELOCYTIC LEUKEMIA; ENDOPLASMIC-RETICULUM STRESS; FACTOR-KAPPA-B; ARSENIC INDUCES APOPTOSIS AB Apoptosis is an evolutionary conserved homeostatic process involved in distinct physiological processes including organ and tissue morphogenesis, development and senescence. its deregulation is also known to participate in the etiology of several human diseases including cancer, neurodegenerative and autoimmune disorders. Environmental stressors (cytotoxic agents, pollutants or toxicants) are well known to induce apoptotic cell death and to contribute to a variety of pathological conditions. Oxidative stress seems to be the central element in the regulation of the apoptotic pathways triggered by environmental stressors. In this work, we review the established mechanisms by which oxidative stress and environmental stressors regulate the apoptotic machinery with the aim to underscore the relevance of apoptosis as a component in environmental toxicity and human disease progression. Published by Elsevier B.V. C1 [Franco, Rodrigo] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Sanchez-Olea, Roberto] Autonomous Univ San Luis Potosi, Inst Phys, Dept Biophys, San Luis Potosi 78290, Mexico. [Reyes-Reyes, Elsa M.] Univ Louisville, Dept Biochem, Louisville, KY 40202 USA. [Panayiotidis, Mihalis I.] Univ Nevada, Sch Publ Hlth, Reno, NV 89557 USA. RP Franco, R (reprint author), NIEHS, Lab Signal Transduct, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM franco2@mail.nih.gov RI Franco, Rodrigo/D-9470-2013; OI Franco, Rodrigo/0000-0003-3241-8615; Panagiotidis, Mihalis/0000-0002-1130-5972 FU NIH, NIEHS; FOMIX [FMSLP 2008-C01-86772]; School of Public Health of the University of Nevada FX This work was supported by the Intramural Research Program of the NIH, NIEHS (Franco R.); FOMIX project number FMSLP 2008-C01-86772 (Sanchez-Olea R); funds provided by the School of Public Health of the University of Nevada at Reno (Panagiotidis MI). Due to space limitations we would like to apologize in advance to all our colleagues whose research was not cited in this review but whose work has certainly advanced our understanding of this complex field of research. NR 419 TC 203 Z9 219 U1 8 U2 68 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 MAR 31 PY 2009 VL 674 IS 1-2 BP 3 EP 22 DI 10.1016/j.mrgentox.2008.11.012 PG 20 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 432KX UT WOS:000265133000002 PM 19114126 ER PT J AU Nowsheen, S Wukovich, RL Aziz, K Kalogerinis, PT Richardson, CC Panayiotidis, MI Bonner, WM Sedelnikova, OA Georgakilas, AG AF Nowsheen, Somaira Wukovich, Rebecca L. Aziz, Khaled Kalogerinis, Peter T. Richardson, Christopher C. Panayiotidis, Milialis I. Bonner, William M. Sedelnikova, Olga A. Georgakilas, Alexandros G. TI Accumulation of oxidatively induced clustered DNA lesions in human tumor tissues SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE Oxidative stress; Clustered DNA damage; Human tumors; Cancer biomarkers ID BASE EXCISION-REPAIR; ENDONUCLEASE-III HNTH1; BREAST-CANCER CELLS; IONIZING-RADIATION; DAMAGE CLUSTERS; STRAND BREAKS; COLON-CANCER; MECHANISMS; SKIN; 8-OXO-7,8-DIHYDROGUANINE AB Increased levels of oxidatively induced DNA damage have been reported in various cases of human pathogenesis like age-related and chronic diseases. Advances in experimental carcinogenesis associate high oxidative stress with genome instability and oncogenic transformation. Cancer biomarkers are helpful for early tumor diagnostics, prediction Of tumor development, and analysis of individual tumors' response to therapy as well as recurrence. The repair resistant oxidatively induced clustered DNA lesions (OCDLs) could serve as a common indicator of oxidative stress in human malignant cells or tissues. To test this hypothesis, we assessed the levels of endogenous OCDLs in several human tumor and adjacent normal tissues from patients with liver. ovary, kidney, breast and colon cancer. These tumor tissues have already been shown to accumulate higher endogenous levels of gamma-H2AX foci. For the detection of clustered DNA lesions we used the human repair enzymes APE1, OGG1 and NTH1 as well as the Escherichia coli homologue Endonuclease III. In the majority of cases we detected higher levels of OCDLs in tumor vs. normal tissues but not always with a statistically significant difference and not with uniform tissue dependence. These data suggest for the first time the importance of endogenous non-DSB clusters in human cancer and their potential Use as cancer biomarkers. (C) 2008 Elsevier B.V. All rights reserved. C1 [Nowsheen, Somaira; Wukovich, Rebecca L.; Aziz, Khaled; Kalogerinis, Peter T.; Richardson, Christopher C.; Georgakilas, Alexandros G.] E Carolina Univ, Dept Biol, Thomas Harriot Coll Arts & Sci, Greenville, NC 27858 USA. [Panayiotidis, Milialis I.] Univ Nevada, Sch Publ Hlth, Reno, NV 89557 USA. [Bonner, William M.; Sedelnikova, Olga A.] NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Georgakilas, AG (reprint author), E Carolina Univ, Dept Biol, Thomas Harriot Coll Arts & Sci, Howell Sci Complex, Greenville, NC 27858 USA. EM georgakilasa@ecu.edu OI Panagiotidis, Mihalis/0000-0002-1130-5972 FU Biology Department of East Carolina University; National Cancer Institute, NIH; University of Nevada at Reno FX This work was supported by funds provided to Dr. Georgakilas by the Biology Department of East Carolina University, a Research/Creative Activity Grant and a College Research Award to A. Georgakilas (East Carolina University), and partly by the Intramural Research Program of the National Cancer Institute, NIH. Dr. Panayiotidis was supported by funds provided by the University of Nevada at Reno. NR 49 TC 45 Z9 47 U1 0 U2 1 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 MAR 31 PY 2009 VL 674 IS 1-2 SI SI BP 131 EP 136 DI 10.1016/j.mrgentox.2008.09.010 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 432KX UT WOS:000265133000016 PM 18948225 ER PT J AU Lee, KY Latour, LL Luby, M Hsia, AW Merino, JG Warach, S AF Lee, K. Y. Latour, L. L. Luby, M. Hsia, A. W. Merino, J. G. Warach, S. TI Distal hyperintense vessels on FLAIR An MRI marker for collateral circulation in acute stroke? SO NEUROLOGY LA English DT Article ID ACUTE ISCHEMIC-STROKE; CEREBRAL-ARTERY OCCLUSION; INTRAARTERIAL THROMBOLYSIS; PROGNOSTIC VALUE; MCA SIGN; ANGIOGRAPHY; INFARCTION; SEQUENCES; TRIAL; FLOW AB Background: Hyperintense vessels (HV) on fluid-attenuated inversion recovery imaging are frequently observed in acute ischemic stroke patients. However, the exact mechanism and clinical implications of this sign have not yet been clearly defined. The features of HV and its relevance to other imaging factors are presented here. Methods: Prominence and location of HV were documented in 52 consecutive patients with middle cerebral artery (MCA) territory infarction, before treatment with IV recombinant tissue plasminogen activator. Pretreatment ischemic lesion volume, perfusion lesion volume, and vessel occlusion were determined in addition to recanalization status and ischemic lesion volume on follow-up imaging. NIH Stroke Scale (NIHSS) was used as a measure of clinical severity. Results: HV distal to arterial occlusion was observed in 73% of patients; more frequent in proximal than distal MCA occlusion patients. Among the 38 patients with proximal MCA occlusion, initial perfusion lesion volume was comparable among patients with different grade distal HV. However, patients with more prominent distal HV had smaller initial, 24-hour, and subacute ischemic lesion volumes and lower initial NIHSS scores. Conclusions: The presence of distal hyperintense vessels before thrombolytic treatment is associated with large diffusion-perfusion mismatch and smaller subacute ischemic lesion volumes in patients with proximal middle cerebral artery occlusion. Neurology (R) 2009;72:1134-1139 C1 [Lee, K. Y.; Latour, L. L.; Luby, M.; Merino, J. G.; Warach, S.] NINDS, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD 20892 USA. [Hsia, A. W.] Washington Hosp Ctr, Stroke Ctr, Washington, DC 20010 USA. [Lee, K. Y.] Yonsei Univ, Coll Med, Dept Neurol, Seoul, South Korea. RP Warach, S (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, NIH, 10 Ctr Dr,Room B1D733, Bethesda, MD 20892 USA. EM warachs@ninds.nih.gov OI Lee, Kyung-Yul/0000-0001-5585-7739; Merino, Jose/0000-0002-6676-0008 FU Intramural NIH HHS [Z99 NS999999] NR 22 TC 73 Z9 91 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 31 PY 2009 VL 72 IS 13 BP 1134 EP 1139 DI 10.1212/01.wnl.0000345360.80382.69 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 426LE UT WOS:000264709000006 PM 19211928 ER PT J AU Segarane, B Li, A Paudel, R Scholz, S Neumann, J Lees, A Revesz, T Hardy, J Mathias, CJ Wood, NW Holton, J Houlden, H AF Segarane, B. Li, A. Paudel, R. Scholz, S. Neumann, J. Lees, A. Revesz, T. Hardy, J. Mathias, C. J. Wood, N. W. Holton, J. Houlden, H. TI GLUCOCEREBROSIDASE MUTATIONS IN 108 NEUROPATHOLOGICALLY CONFIRMED CASES OF MULTIPLE SYSTEM ATROPHY SO NEUROLOGY LA English DT Editorial Material ID ALPHA-SYNUCLEIN; RISK-FACTOR; DISEASE C1 [Segarane, B.; Li, A.; Paudel, R.; Scholz, S.; Neumann, J.; Lees, A.; Revesz, T.; Hardy, J.; Wood, N. W.; Holton, J.; Houlden, H.] UCL, Dept Mol Neurosci, Inst Neurol, London WC1N 3BG, England. [Segarane, B.; Li, A.; Paudel, R.; Scholz, S.; Neumann, J.; Lees, A.; Revesz, T.; Hardy, J.; Wood, N. W.; Holton, J.; Houlden, H.] UCL, Reta Lila Weston Labs, Inst Neurol, London WC1N 3BG, England. [Scholz, S.] Natl Inst Aging & Hlth, Mol Genet Sect, Neurogenet Lab, Bethesda, MD USA. [Mathias, C. J.] Univ London Imperial Coll Sci Technol & Med, St Marys Hosp, Neurovasc Med Unit, Fac Med, London, England. RP Houlden, H (reprint author), UCL, Dept Mol Neurosci, Inst Neurol, Queen Sq, London WC1N 3BG, England. EM h.houlden@ion.ucl.ac.uk RI Houlden, Henry/C-1532-2008; Hardy, John/C-2451-2009; Revesz, Tamas/A-8732-2010; Holton, Janice/F-6831-2011; Lees, Andrew/A-6605-2009; Wood, Nicholas/C-2505-2009 OI Houlden, Henry/0000-0002-2866-7777; Scholz, Sonja/0000-0002-6623-0429; Revesz, Tamas/0000-0003-2501-0259; Holton, Janice/0000-0002-3882-5249; Wood, Nicholas/0000-0002-9500-3348 FU Medical Research Council [G0701075, G108/638]; Parkinson's UK [G-0907] NR 7 TC 35 Z9 36 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 31 PY 2009 VL 72 IS 13 BP 1185 EP 1186 DI 10.1212/01.wnl.0000345356.40399.eb PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 426LE UT WOS:000264709000015 PM 19332698 ER PT J AU Ho, LN Jothi, R Ronan, JL Cui, KR Zhao, KJ Crabtree, GR AF Ho, Lena Jothi, Raja Ronan, Jehnna L. Cui, Kairong Zhao, Keji Crabtree, Gerald R. TI An embryonic stem cell chromatin remodeling complex, esBAF, is an essential component of the core pluripotency transcriptional network SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE BAF complexes; Brg; SWI/SNF ATP-dependent chromatin remodeling ID SELF-RENEWAL; ES CELLS; DEVELOPMENTAL REGULATORS; MOUSE; NANOG; DIFFERENTIATION; EXPRESSION; CIRCUITRY; POLYCOMB; OCT4 AB Distinctive SWI/SNF-like ATP-dependent chromatin remodeling es-BAF complexes are indispensable for the maintenance and pluripotency of mouse embryonic stem (ES) cells [Ho L, et al. (2009) Proc Natl Acad Sci USA 10.1073/pnas.0812889106). To understand the mechanism underlying the roles of these complexes in ES cells, we performed high-resolution genome-wide mapping of the core ATPase subunit, Brg, using ChIP-Seq technology. We find that esBAF, as represented by Brg, binds to genes encoding components of the core ES transcriptional circuitry, including Polycomb group proteins. esBAF colocalizes extensively with transcription factors Oct4, Sox2 and Nanog genome-wide, and shows distinct functional interactions with Oct4 and SoxZ at its target genes. Surprisingly, no significant colocalization of esBAF with PRC2 complexes, represented by Suz12, is observed. Lastly, esBAF colocalizes with Stat3 and Smad1 genome-wide, consistent with a direct and critical role in LIF and BMP signaling for maintaining self-renewal. Taken together, our studies indicate that esBAF is an essential component of the core pluripotency transcriptional network, and might also be a critical component of the LIF and BMP signaling pathways essential for maintenance of self-renewal and pluripotency. C1 [Crabtree, Gerald R.] Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. [Crabtree, Gerald R.] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA. [Crabtree, Gerald R.] Stanford Univ, Dept Dev Biol, Stanford, CA 94305 USA. [Ho, Lena] Stanford Univ, Program Immunol, Stanford, CA 94305 USA. [Ronan, Jehnna L.] Stanford Univ, Program Canc Biol, Stanford, CA 94305 USA. [Jothi, Raja; Cui, Kairong; Zhao, Keji] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Crabtree, GR (reprint author), Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. EM crabtree@cmgm.stanford.edu RI Jothi, Raja/G-3780-2015 FU Howard Hughes Medical Institute; NIH [NS046789, Hd155391, A1060037]; JDRF; Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health; Agency of Science, Technology and Research of Singapore FX We are grateful to Jiang Wu, Andrew Yoo, and Elena Gallo for critical comments on the manuscript. This work was supported by the Howard Hughes Medical Institute, NIH grants NS046789, Hd155391 and A1060037 and the JDRF (G.R.C.) and the Intramural Research Program of the National Heart, Lung, and Blood Institute, National Institutes of Health (R.J., K.C., and K.Z). L.H. was funded by the Agency of Science, Technology and Research of Singapore. NR 35 TC 209 Z9 210 U1 1 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 31 PY 2009 VL 106 IS 13 BP 5187 EP 5191 DI 10.1073/pnas.0812888106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 427PG UT WOS:000264790600043 PM 19279218 ER PT J AU Schwander, M Xiong, W Tokita, J Lelli, A Elledge, HM Kazmierczak, P Sczaniecka, A Kolatkar, A Wiltshire, T Kuhn, P Holt, JR Kachar, B Tarantino, L Muller, U AF Schwander, Martin Xiong, Wei Tokita, Joshua Lelli, Andrea Elledge, Heather M. Kazmierczak, Piotr Sczaniecka, Anna Kolatkar, Anand Wiltshire, Tim Kuhn, Peter Holt, Jeffrey R. Kachar, Bechara Tarantino, Lisa Mueller, Ulrich TI A mouse model for nonsyndromic deafness (DFNB12) links hearing loss to defects in tip links of mechanosensory hair cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cadherin 23; Cdh23; Usher syndrome; progressive hearing loss ID SYNDROME TYPE 1D; USHER-SYNDROME TYPE-1; CDH23 MUTATIONS; WALTZER MICE; GENE-MUTATIONS; CADHERIN GENE; MYOSIN VIIA; PROTOCADHERIN-15; MECHANOTRANSDUCTION; STEREOCILIA AB Deafness is the most common form of sensory impairment in humans and is frequently caused by single gene mutations. Interestingly, different mutations in a gene can cause syndromic and nonsyndromic forms of deafness, as well as progressive and age-related hearing loss. We provide here an explanation for the phenotypic variability associated with mutations in the cadherin 23 gene (CDH23). CDH23 null alleles cause deaf-blindness (Usher syndrome type 1D; USH1D), whereas missense mutations cause nonsyndromic deafness (DFNB12). In a forward genetic screen, we have identified salsa mice, which suffer from hearing loss due to a Cdh23 missense mutation modeling DFNB12. In contrast to waltzer mice, which carry a CDH23 null allele mimicking USH1D, hair cell development is unaffected in salsa mice. Instead, tip links, which are thought to gate mechanotransduction channels in hair cells, are progressively lost. Our findings suggest that DFNB12 belongs to a new class of disorder that is caused by defects in tip links. We propose that mutations in other genes that cause USH1 and nonsyndromic deafness may also have distinct effects on hair cell development and function. C1 [Schwander, Martin; Xiong, Wei; Elledge, Heather M.; Kazmierczak, Piotr; Sczaniecka, Anna; Kolatkar, Anand; Kuhn, Peter; Mueller, Ulrich] Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. [Schwander, Martin; Xiong, Wei; Elledge, Heather M.; Kazmierczak, Piotr; Sczaniecka, Anna; Mueller, Ulrich] Scripps Res Inst, Inst Childhood & Neglected Dis, La Jolla, CA 92037 USA. [Tokita, Joshua; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. [Lelli, Andrea; Holt, Jeffrey R.] Univ Virginia, Sch Med, Dept Neurosci, Charlottesville, VA 22908 USA. [Wiltshire, Tim; Tarantino, Lisa] Genom Inst Novartis Res Fdn, San Diego, CA 92121 USA. RP Muller, U (reprint author), Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. EM umueller@scripps.edu RI Wang, Shirong/G-1698-2011; Xiong, Wei/A-6170-2012 FU National Institutes of Health [DC005969, DC007704]; Skaggs Institute for Chemical Biology; Bruce Ford and Anne Smith Bundy Foundation FX We thank T. Ricci for advice with electrophysiology and K. Spencer for help with microscopy. This work was funded by National Institutes of Health Grants DC005969 and DC007704 (to U.M.), the Skaggs Institute for Chemical Biology (U.M.), and the Bruce Ford and Anne Smith Bundy Foundation (W.X.). NR 50 TC 44 Z9 48 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 MAR 31 PY 2009 VL 106 IS 13 BP 5252 EP 5257 DI 10.1073/pnas.0900691106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 427PG UT WOS:000264790600055 PM 19270079 ER PT J AU Grebe, KM Hickman, HD Irvine, KR Takeda, K Bennink, JR Yewdell, JW AF Grebe, Kristie M. Hickman, Heather D. Irvine, Kari R. Takeda, Kazuyo Bennink, Jack R. Yewdell, Jonathan W. TI Sympathetic nervous system control of anti-influenza CD8(+) T cell responses SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antigen presentation; vaccine; cross-priming; direct-priming; dendritic cell ID INFLUENZA-A VIRUS; CHEMICAL SYMPATHECTOMY; CYTOKINE PRODUCTION; IMMUNODOMINANCE HIERARCHIES; MURINE LYMPHOCYTES; IMMUNE-RESPONSES; BONE-MARROW; ANTIGEN; INFECTION; MICE AB Despite the longstanding appreciation of communication between the nervous and the immune systems, the nature and significance of these interactions to immunity remain enigmatic. Here, we show that 6-hydroxydopamine-mediated ablation of the mouse peripheral sympathetic nervous system increases primary CD8(+) T cell responses to viral and cellular antigens presented by direct priming or cross-priming. The sympathetic nervous system also suppresses antiviral CD4(+) T cell responses, but this is not required for suppressing CD8(+) T cell responses. Adoptive transfer experiments indicate that enhanced CD8(+) responses do not result from permanent alterations in CD8(+) T cell function in sympathectomized mice. Rather, additional findings suggest that the sympathetic nervous system tempers the capacity of antigen-presenting cells to activate naive CD8(+) T cells. We also show that antiviral CD8(+) T cell responses are enhanced by administration of a beta(2) (but not beta(1) or alpha) adrenergic antagonist. These findings demonstrate a critical role for the sympathetic nervous system in limiting CD8(+) T cell responses and indicate that CD8(+) T cell responses may be altered in patients using beta-blockers, one of the most widely prescribed classes of drugs. C1 [Grebe, Kristie M.; Hickman, Heather D.; Irvine, Kari R.; Takeda, Kazuyo; Bennink, Jack R.; Yewdell, Jonathan W.] NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services FX Deborah Tokarchick and Glennys Reynoso provided excellent technical assistance. We are grateful to David Topham (University of Rochester Medical Center, Rochester, NY) for his generous gift of WSN-OVA and Richard Webby (St Jude's Children Research Hospital, Memphis, TN) for the PR8-OVA. We would also like to thank Virginia Sanders for help in establishing the 6-OHDA model and Steve Cole for the SPG protocol. This work was generously supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services. NR 34 TC 34 Z9 34 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 MAR 31 PY 2009 VL 106 IS 13 BP 5300 EP 5305 DI 10.1073/pnas.0808851106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 427PG UT WOS:000264790600063 PM 19286971 ER PT J AU Mayer, DCG Cofie, J Jiang, LB Hartl, DL Tracy, E Kabat, J Mendoza, LH Miller, LH AF Mayer, D. C. Ghislaine Cofie, Joann Jiang, Lubin Hartl, Daniel L. Tracy, Erin Kabat, Juraj Mendoza, Laurence H. Miller, Louis H. TI Glycophorin B is the erythrocyte receptor of Plasmodium falciparum erythrocyte-binding ligand, EBL-1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Duffy-binding-like erythrocyte-binding protein; invasion; malaria; red blood cells ID PROTEIN; VIVAX; POLYMORPHISM; SPECIFICITY; MEROZOITES; INVASION; DOMAINS AB In the war against Plasmodium, humans have evolved to eliminate or modify proteins on the erythrocyte surface that serve as receptors for parasite invasion, such as the Duffy blood group, a receptor for Plasmodium vivax, and the Gerbich-negative modification of glycophorin C for Plasmodium falciparum. In turn, the parasite counters with expansion and diversification of ligand families. The high degree of polymorphism in glycophorin B found in malaria-endemic regions suggests that it also may be a receptor for Plasmodium, but, to date, none has been identified. We provide evidence from erythrocyte-binding that glycophorin B is a receptor for the P. falciparum protein EBL-1, a member of the Duffy-binding-like erythrocyte-binding protein (DBL-EBP) receptor family. The erythrocyte-binding domain, region 2 of EBL-1, expressed on CHO-K1 cells, bound glycophorin B(+) but not glycophorin B-null erythrocytes. In addition, glycophorin B(+) but not glycophorin B-null erythrocytes adsorbed native EBL-1 from the P. falciparum culture supernatants. Interestingly, the Efe pygmies of the Ituri forest in the Democratic Republic of the Congo have the highest gene frequency of glycophorin B-null in the world, raising the possibility that the DBL-EBP family may have expanded in response to the high frequency of glycophorin B-null in the population. C1 [Mayer, D. C. Ghislaine; Cofie, Joann; Tracy, Erin; Mendoza, Laurence H.; Miller, Louis H.] Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. [Jiang, Lubin] NIAID, Lab Malaria Vector Res, NIH, Rockville, MD 20852 USA. [Kabat, Juraj] NIAID, Biol Imaging Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA. [Hartl, Daniel L.] Harvard Univ, Dept Organism & Evolut Biol, Cambridge, MA 02138 USA. RP Mayer, DCG (reprint author), Virginia Commonwealth Univ, Dept Biol, 1000 W Cary St,Room 126, Richmond, VA 23284 USA. EM gmayer@vcu.edu; lmiller@niaid.nih.gov NR 21 TC 73 Z9 76 U1 3 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 31 PY 2009 VL 106 IS 13 BP 5348 EP 5352 DI 10.1073/pnas.0900878106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 427PG UT WOS:000264790600071 PM 19279206 ER PT J AU Guderian, S Schott, BH Richardson-Klavehn, A Duzel, E AF Guderian, Sebastian Schott, Bjoern H. Richardson-Klavehn, Alan Duezel, Emrah TI Medial temporal theta state before an event predicts episodic encoding success in humans SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hippocampus; magnetoencephalography; memory; oscillations; prestimulus ID LONG-TERM POTENTIATION; BRAIN ACTIVITY; RECOGNITION MEMORY; EXPLICIT MEMORY; LEARNING RATE; HIPPOCAMPAL; RETRIEVAL; RECOLLECTION; CORTEX; RHYTHM AB We report a human electrophysiological brain state that predicts successful memory for events before they occur. Using magnetoencephalographic recordings of brain activity during episodic memory encoding, we show that amplitudes of theta oscillations shortly preceding the onsets of words were higher for later-recalled than for later-forgotten words. Furthermore, single-trial analyses revealed that recall rate in all 24 participants tested increased as a function of increasing prestimulus theta amplitude. This positive correlation was independent of whether participants were preparing for semantic or phonemic stimulus processing, thus likely signifying a memory-related theta state rather than a preparatory task set. Source analysis located this theta state to the medial temporal lobe, a region known to be critical for encoding and recall. These findings provide insight into state-related aspects of memory formation in humans, and open a perspective for improving memory through theta-related brain states. C1 [Guderian, Sebastian; Schott, Bjoern H.; Richardson-Klavehn, Alan] Otto Von Guericke Univ, Ctr Adv Imaging, D-39120 Magdeburg, Germany. [Guderian, Sebastian; Schott, Bjoern H.; Richardson-Klavehn, Alan] Otto Von Guericke Univ, Dept Neurol, D-39120 Magdeburg, Germany. [Richardson-Klavehn, Alan] Otto Von Guericke Univ, Dept Stereotact Neurosurg, D-39120 Magdeburg, Germany. [Duezel, Emrah] Otto Von Guericke Univ, Inst Cognit Neurol & Dementia Res, D-39120 Magdeburg, Germany. [Schott, Bjoern H.] Leibniz Inst Neurobiol, D-39118 Magdeburg, Germany. [Schott, Bjoern H.] Charite Univ Med Berlin, Dept Psychiat, D-10117 Berlin, Germany. [Duezel, Emrah] UCL, Inst Cognit Neurosci, London WC1N 3AR, England. RP Guderian, S (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Room 1B80,49 Convent Dr,MSC 4415, Bethesda, MD 20892 USA. EM guderians@mail.nih.gov RI Duzel, Emrah/A-1794-2010; Schott, Bjorn/B-9369-2012; OI Schott, Bjorn/0000-0002-8237-4481 FU Deutsche Forschungsgemeinschaft; Bundesministerium fur Bildung und Forschung FX We thank Michael Scholz for assistance with data analysis, Maja Fremuth for assistance with data acquisition, and 3 anonymous reviewers for helpful comments on a previous version of the manuscript. This work was supported by grants from the Deutsche Forschungsgemeinschaft (Kognitive Kontrolle von Gedaechtnis TP1 and TP3) and Bundesministerium fur Bildung und Forschung (Center for Advanced Imaging). NR 38 TC 98 Z9 98 U1 1 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 31 PY 2009 VL 106 IS 13 BP 5365 EP 5370 DI 10.1073/pnas.0900289106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 427PG UT WOS:000264790600074 PM 19289818 ER PT J AU Leyk, S Binder, CR Nuckols, JR AF Leyk, Stefan Binder, Claudia R. Nuckols, John R. TI Spatial modeling of personalized exposure dynamics: the case of pesticide use in small-scale agricultural production landscapes of the developing world SO INTERNATIONAL JOURNAL OF HEALTH GEOGRAPHICS LA English DT Article ID GEOGRAPHIC INFORMATION-SYSTEMS; LAND-USE DATA; RESIDENTIAL EXPOSURE; DEVELOPING-COUNTRIES; CELLULAR-AUTOMATA; AIR-POLLUTION; HEALTH; RISK; EPIDEMIOLOGY; LOCATION AB Background: Pesticide poisoning is a global health issue with the largest impacts in the developing countries where residential and small-scale agricultural areas are often integrated and pesticides sprayed manually. To reduce health risks from pesticide exposure approaches for personalized exposure assessment (PEA) are needed. We present a conceptual framework to develop a spatial individual-based model (IBM) prototype for assessing potential exposure of farm-workers conducting small-scale agricultural production, which accounts for a considerable portion of global food crop production. Our approach accounts for dynamics in the contaminant distributions in the environment, as well as patterns of movement and activities performed on an individual level under different safety scenarios. We demonstrate a first prototype using data from a study area in a rural part of Colombia, South America. Results: Different safety scenarios of PEA were run by including weighting schemes for activities performed under different safety conditions. We examined the sensitivity of individual exposure estimates to varying patterns of pesticide application and varying individual patterns of movement. This resulted in a considerable variation in estimates of magnitude, frequency and duration of exposure over the model runs for each individual as well as between individuals. These findings indicate the influence of patterns of pesticide application, individual spatial patterns of movement as well as safety conditions on personalized exposure in the agricultural production landscape that is the focus of our research. Conclusion: This approach represents a conceptual framework for developing individual based models to carry out PEA in small-scale agricultural settings in the developing world based on individual patterns of movement, safety conditions, and dynamic contaminant distributions. The results of our analysis indicate our prototype model is sufficiently sensitive to differentiate and quantify the influence of individual patterns of movement and decision-based pesticide management activities on potential exposure. This approach represents a framework for further understanding the contribution of agricultural pesticide use to exposure in the small-scale agricultural production landscape of many developing countries, and could be useful to evaluate public health intervention strategies to reduce risks to farm-workers and their families. Further research is needed to fully develop an operational version of the model. C1 [Leyk, Stefan] Univ Colorado, Dept Geog, Boulder, CO 80309 USA. [Leyk, Stefan; Binder, Claudia R.] Univ Zurich, Dept Geog, CH-8057 Zurich, Switzerland. [Nuckols, John R.] Colorado State Univ, Dept Environm & Radiol Hlth Sci, Ft Collins, CO 80523 USA. [Nuckols, John R.] NIH, Div Int Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Leyk, S (reprint author), Univ Colorado, Dept Geog, 260 UCB, Boulder, CO 80309 USA. EM stefan.leyk@colorado.edu; claudia.binder@geo.uzh.ch; john.nuckols@colostate.edu RI Binder, Claudia/A-4382-2008 NR 60 TC 7 Z9 7 U1 3 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-072X J9 INT J HEALTH GEOGR JI Int. J. Health Geogr. PD MAR 30 PY 2009 VL 8 AR 17 DI 10.1186/1476-072X-8-17 PG 16 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 445IG UT WOS:000266043900001 PM 19331690 ER PT J AU House, SB Li, CY Yue, CM Gainer, H AF House, Shirley B. Li, Congyu Yue, Chunmei Gainer, Harold TI Effects of ciliary neurotrophic factor and leukemia inhibiting factor on oxytocin and vasopressin magnocellular neuron survival in rat and mouse hypothalamic organotypic cultures SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Hypothalamus; Neurotrophic; Organotypic; CNTF; LIF; Magnocellular neurons; Oxytocin; Vasopressin ID CEREBELLAR SLICE CULTURE; NUCLEUS IN-VITRO; SUPRACHIASMATIC NUCLEUS; SUPRAOPTIC NUCLEUS; GENE-EXPRESSION; PARAVENTRICULAR NUCLEUS; BRAIN-STEM; CELL-DEATH; NEUROHYPOPHYSEAL SYSTEM; HORSERADISH-PEROXIDASE AB Organotypic cultures of mouse and rat magnocellular neurons (MCNs) in the hypothalamo-neurohypophysial system (HNS) have served as important experimental models for the molecular and physiological study of this neuronal phenotype. However, it has been difficult to maintain significant numbers of the MCNs, particularly vasopressin MCNs, in these cultures for long periods. In this paper, we describe the use of the neurotrophic factors, leukemia inhibiting factor (LIF)and ciliary neurotrophic factor (CNTF) to rescue rat vasopressin (Avp)- and oxytocin (Oxt)-MCNs from axotomy-induced, programmed cell death in vitro. Quantitative data are presented for the efficacy of the LIF family of neurotrophic factors on the survival of MCNs in three nuclei, the paraventricular (PVN), supraoptic (SON), and accessory (ACC) nuclei in the mouse and rat hypothalamus. Published by Elsevier B.V. C1 [House, Shirley B.; Li, Congyu; Yue, Chunmei; Gainer, Harold] NINDS, Mol Neurosci Sect, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), NINDS, Mol Neurosci Sect, Neurochem Lab, NIH, Bldg 49,Room 5A78, Bethesda, MD 20892 USA. EM gainerh@ninds.nih.gov FU NIH; NINDS FX This research was supported by the intramural research program of the NIH, NINDS. NR 65 TC 4 Z9 4 U1 0 U2 1 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 MAR 30 PY 2009 VL 178 IS 1 BP 128 EP 133 DI 10.1016/j.jneumeth.2008.12.004 PG 6 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 416NO UT WOS:000264013000018 PM 19118574 ER PT J AU Granville, CA Memmott, RM Balogh, A Mariotti, J Kawabata, S Han, W LoPiccolo, J Foley, J Liewehr, DJ Steinberg, SM Fowler, DH Hollander, MC Dennis, PA AF Granville, Courtney A. Memmott, Regan M. Balogh, Andria Mariotti, Jacopo Kawabata, Shigeru Han, Wei LoPiccolo, Jaclyn Foley, Jason Liewehr, David J. Steinberg, Seth M. Fowler, Daniel H. Hollander, M. Christine Dennis, Phillip A. TI A Central Role for Foxp3+Regulatory T Cells in K-Ras-Driven Lung Tumorigenesis SO PLOS ONE LA English DT Article AB Background: K-Ras mutations are characteristic of human lung adenocarcinomas and occur almost exclusively in smokers. In preclinical models, K-Ras mutations are necessary for tobacco carcinogen-driven lung tumorigenesis and are sufficient to cause lung adenocarcinomas in transgenic mice. Because these mutations confer resistance to commonly used cytotoxic chemotherapies and targeted agents, effective therapies that target K-Ras are needed. Inhibitors of mTOR such as rapamycin can prevent K-Ras-driven lung tumorigenesis and alter the proportion of cytotoxic and Foxp3+ regulatory T cells, suggesting that lung-associated T cells might be important for tumorigenesis. Methods: Lung tumorigenesis was studied in three murine models that depend on mutant K-Ras; a tobacco carcinogen-driven model, a syngeneic inoculation model, and a transgenic model. Splenic and lung-associated T cells were studied using flow cytometry and immunohistochemistry. Foxp3+ cells were depleted using rapamycin, an antibody, or genetic ablation. Results: Exposure of A/J mice to a tobacco carcinogen tripled lung-associated Foxp3+ cells prior to tumor development. At clinically relevant concentrations, rapamycin prevented this induction and reduced lung tumors by 90%. In A/J mice inoculated with lung adenocarcinoma cells resistant to rapamycin, antibody-mediated depletion of Foxp3+ cells reduced lung tumorigenesis by 80%. Likewise, mutant K-Ras transgenic mice lacking Foxp3+ cells developed 75% fewer lung tumors than littermates with Foxp3+ cells. Conclusions: Foxp3+ regulatory T cells are required for K-Ras-mediated lung tumorigenesis in mice. These studies support clinical testing of rapamycin or other agents that target Treg in K-Ras driven human lung cancer. C1 [Granville, Courtney A.; Memmott, Regan M.; Balogh, Andria; Kawabata, Shigeru; Han, Wei; LoPiccolo, Jaclyn; Hollander, M. Christine; Dennis, Phillip A.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Mariotti, Jacopo; Foley, Jason; Fowler, Daniel H.] NCI, Ctr Canc Res, Expt Transplant & Immunol Branch, Bethesda, MD USA. [Liewehr, David J.; Steinberg, Seth M.] NCI, Ctr Canc Res, Biostat & Data Management Sect, Bethesda, MD USA. RP Granville, CA (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM pdennis@nih.gov FU Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute FX This research was supported by the Intramural Research Program of the NIH, Center for Cancer Research, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 25 Z9 30 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 30 PY 2009 VL 4 IS 3 AR e5061 DI 10.1371/journal.pone.0005061 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437PP UT WOS:000265499700006 PM 19330036 ER PT J AU Paoloni, MC Tandle, A Mazcko, C Hanna, E Kachala, S LeBlanc, A Newman, S Vail, D Henry, C Thamm, D Sorenmo, K Hajitou, A Pasqualini, R Arap, W Khanna, C Libutti, SK AF Paoloni, Melissa C. Tandle, Anita Mazcko, Christina Hanna, Engy Kachala, Stefan LeBlanc, Amy Newman, Shelley Vail, David Henry, Carolyn Thamm, Douglas Sorenmo, Karin Hajitou, Amin Pasqualini, Renata Arap, Wadih Khanna, Chand Libutti, Steven K. TI Launching a Novel Preclinical Infrastructure: Comparative Oncology Trials Consortium Directed Therapeutic Targeting of TNF alpha to Cancer Vasculature SO PLOS ONE LA English DT Article AB Background: Under the direction and sponsorship of the National Cancer Institute, we report on the first pre-clinical trial of the Comparative Oncology Trials Consortium (COTC). The COTC is a novel infrastructure to integrate cancers that naturally develop in pet dogs into the development path of new human drugs. Trials are designed to address questions challenging in conventional preclinical models and early phase human trials. Large animal spontaneous cancer models can be a valuable addition to successful studies of cancer biology and novel therapeutic drug, imaging and device development. Methodology/Principal Findings: Through this established infrastructure, the first trial of the COTC (COTC001) evaluated a targeted AAV-phage vector delivering tumor necrosis factor (RGD-A-TNF) to alpha V integrins on tumor endothelium. Trial progress and data was reviewed contemporaneously using a web-enabled electronic reporting system developed for the consortium. Dose-escalation in cohorts of 3 dogs (n = 24) determined an optimal safe dose (5x10(12) transducing units intravenous) of RGD-A-TNF. This demonstrated selective targeting of tumor-associated vasculature and sparing of normal tissues assessed via serial biopsy of both tumor and normal tissue. Repetitive dosing in a cohort of 14 dogs, at the defined optimal dose, was well tolerated and led to objective tumor regression in two dogs (14%), stable disease in six (43%), and disease progression in six (43%) via Response Evaluation Criteria in Solid Tumors (RECIST). Conclusions/Significance: The first study of the COTC has demonstrated the utility and efficiency of the established infrastructure to inform the development of new cancer drugs within large animal naturally occurring cancer models. The preclinical evaluation of RGD-A-TNF within this network provided valuable and necessary data to complete the design of first-in-man studies. C1 [Paoloni, Melissa C.; Mazcko, Christina; Khanna, Chand] NCI, Comparat Oncol Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Tandle, Anita; Hanna, Engy; Kachala, Stefan; Libutti, Steven K.] NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [LeBlanc, Amy; Newman, Shelley] Univ Tennessee, Knoxville, TN 37996 USA. [Vail, David] Univ Wisconsin, Madison, WI 53706 USA. [Henry, Carolyn] Univ Missouri, Columbia, MO 65211 USA. [Thamm, Douglas] Colorado State Univ, Ft Collins, CO 80523 USA. [Sorenmo, Karin] Univ Penn, Philadelphia, PA 19104 USA. [Hajitou, Amin] Imperial Coll London, Wright Flemming Inst, Dept Gene Therapy, London, England. [Hajitou, Amin] Imperial Coll London, Wright Flemming Inst, Div Med, London, England. [Pasqualini, Renata; Arap, Wadih] Univ Texas MD Anderson Canc Ctr, David H Koch Ctr, Houston, TX USA. RP Paoloni, MC (reprint author), NCI, Comparat Oncol Program, Ctr Canc Res, Bethesda, MD 20892 USA. EM khannac@mail.nih.gov RI Thamm, Douglas/I-5976-2013; OI Thamm, Douglas/0000-0002-8914-7767; Newman, Shelley/0000-0002-3471-4816 FU Center for Cancer Research, National Cancer Institute, NIH FX We would like to thank the Center for Cancer Research, National Cancer Institute, NIH for their support of this work. This research was made possible in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 54 Z9 54 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 30 PY 2009 VL 4 IS 3 AR e4972 DI 10.1371/journal.pone.0004972 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437PP UT WOS:000265499700001 PM 19330034 ER PT J AU Bodaghi, S Jia, R Zheng, ZM AF Bodaghi, Sohrab Jia, Rong Zheng, Zhi-Ming TI Human papillomavirus type 16 E2 and E6 are RNA-binding proteins and inhibit in vitro splicing of pre-mRNAs with suboptimal splice sites SO VIROLOGY LA English DT Article DE Human papillomavirus type 16; RNA splicing; RNA-protein interaction; SR proteins; Protein-protein interaction; Viral proteins ID HPV ONCOPROTEIN E6; DNA-BINDING; TRANSCRIPTIONAL ACTIVATION; GENE-EXPRESSION; E1-BOOLEAN-AND-E4 PROTEIN; TRANSACTIVATION DOMAIN; NUCLEAR-LOCALIZATION; SR PROTEINS; E7; RECOGNITION AB Human papillomavirus type 16 (HPV16) genome expresses six regulatory proteins (E1, E2, E4, E5, E6, and E7) which regulate viral DNA replication, gene expression, and cell function. We expressed HPV16 E2, E4, E6, and E7 from bacteria as GST fusion proteins and examined their possible functions in RNA splicing. Both HPV16 E2, a viral transactivator protein. and E6, a viral oncoprotein, inhibited splicing of pre-mRNAs containing an intron with suboptimal splice sites, whereas HPV5 E2 did not. The N-terminal half and the hinge region of HPV16 E2 as well as the N-terminal and central portions of HPV16 E6 are responsible for the suppression. HPV16 E2 interacts with pre-mRNAs through its C-terminal DNA-binding domain. HPV16 E6 binds pre-mRNAs via nuclear localization signal (NLS3) in its C-terminal half. Low-risk HPV6 E6, a cytoplasmic protein, does not bind RNA. Notably, both HPV16 E2 and E6 selectively bind to the intron region of pre-mRNAs and interact with a subset of cellular SR proteins. Together, these findings suggest that HPV16 E2 and E6 are RNA binding proteins and might play roles in posttranscriptional regulation during virus infection. Published by Elsevier Inc. C1 [Bodaghi, Sohrab; Jia, Rong; Zheng, Zhi-Ming] NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Zheng, ZM (reprint author), NCI, HIV & AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM zhengt@exchange.nih.gov FU NIH; National Cancer Institute [8340201]; Center for Cancer Research FX This study was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. We greatly acknowledge Drs. E.-M. de Villiers and H. zur Hausen for providing HPV 16 plasmid and Dr. W.Y. Tarn for HPV5 E2 expression vector. We thank Alison McBride for inducible HPV16 E2 cell line and Ian Morgan for monoclonal anti-E2 antibody and HPV16 E2 stable U2OS cells for our in vivo attempts. We also thank Drs. Douglas Lowy, Carl Baker, and Alison McBride for critical reading of the manuscript. S. B. was supported by an NCI intramural grant 8340201 (to Z.M.Z). NR 55 TC 23 Z9 23 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 30 PY 2009 VL 386 IS 1 BP 32 EP 43 DI 10.1016/j.virol.2008.12.037 PG 12 WC Virology SC Virology GA 429CP UT WOS:000264898700006 PM 19187948 ER PT J AU Wang, KN Mahalingam, G Imai, Y Pesnicak, L Margolis, TT Straus, SE Cohen, JI AF Wang, Kening Mahalingam, Gowtham Imai, Yumi Pesnicak, Lesley Margolis, Todd T. Straus, Stephen E. Cohen, Jeffrey I. TI Cell type specific accumulation of the major latency-associated transcript (LAT) of herpes simplex virus type 2 in LAT transgenic mice SO VIROLOGY LA English DT Article DE Herpes simplex virus 2; Tissue specific gene expression; Latency-associated transcript; Transgenic mouse; In situ hybridization; Neuron ID GENITAL HERPES; IN-SITU; SPONTANEOUS REACTIVATION; TRIGEMINAL GANGLIA; SENSORY NEURONS; NERVOUS-SYSTEM; INFECTED MICE; GUINEA-PIGS; EXPRESSION; PROMOTER AB We performed in situ hybridization to determine the cell type specific accumulation of the intron of the latency-associated transcript (LAT) in tissues in HSV-2 LAT transgenic mice in which LAT expression is driven by its native promoter. We identified LAT in multiple cell types in most tissues analyzed from HSV-2 LAT transgenic mice. While weak to moderate signals were seen in brain and spinal cord neurons, epithelial cells, and muscle cells, the strongest signals were detected in neurons from dorsal root and trigeminal ganglia. About 70-86% of neurons in these ganglia were LAT-positive with varying signal intensities, while cells surrounding the neurons were LAT-negative. The frequency of A5 or KH10-positive neurons was similar in LAT-positive and total neurons. These data indicate that HSV-2 LAT promoter activity is not restricted to neurons and that LAT accumulation in ganglionic neurons is likely regulated by cell-specific factors. Published by Elsevier Inc. C1 [Wang, Kening; Mahalingam, Gowtham; Pesnicak, Lesley; Straus, Stephen E.; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Imai, Yumi; Margolis, Todd T.] Univ Calif San Francisco, Francis I Proctor Fdn, San Francisco, CA 94143 USA. [Imai, Yumi; Margolis, Todd T.] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA 94143 USA. RP Wang, KN (reprint author), NIAID, Med Virol Sect, Lab Clin Infect Dis, 10 Ctr Dr,Room 11N234, Bethesda, MD 20892 USA. EM kwang@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX We thank Drs. Jerrold M. Ward, David Kleiner, and Stefania Pittaluga, for their help in determining cell types in which LAT signals were detected. This study was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases. NR 29 TC 4 Z9 4 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 30 PY 2009 VL 386 IS 1 BP 79 EP 87 DI 10.1016/j.virol.2008.12.035 PG 9 WC Virology SC Virology GA 429CP UT WOS:000264898700011 PM 19200567 ER PT J AU Klinman, DM Klaschik, S Sato, T Tross, D AF Klinman, Dennis M. Klaschik, Sven Sato, Takashi Tross, Debbie TI CpG oligonucleotides as adjuvants for vaccines targeting infectious diseases SO ADVANCED DRUG DELIVERY REVIEWS LA English DT Review DE CpG; Adjuvant; Vaccine; Immunogenicity; Antibody; IFNg; Protection ID HEPATITIS-B-VACCINE; PLASMACYTOID DENDRITIC CELLS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; INDUCE AUTOIMMUNE-DISEASE; BACTERIAL-DNA; IMMUNOSTIMULATORY DNA; IMMUNE-RESPONSES; SURFACE-ANTIGEN; T-CELLS; CONTAINING OLIGODEOXYNUCLEOTIDES AB Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs act as immune adjuvants, accelerating and boosting antigen-specific immune responses. CpG motifs promote the induction of Th1 and pro-inflammatory cytokines and support the maturation/activation of professional antigen presenting cells (particularly plasmacytoid dendritic cells). These effects are optimized by maintaining close physical contact between the CpG ODN and the immunogen. Co-administering CpG ODN with a variety of vaccines has improved the resultant humoral and/or cellular immune responses, culminating in enhanced protective immunity in rodent and primate challenge models. Ongoing clinical studies indicate that CpG ODN are safe and well-tolerated when administered as adjuvants to humans, and that they can support increased vaccine-specific immune responses. Published by Elsevier B.V. C1 [Klinman, Dennis M.; Klaschik, Sven; Sato, Takashi; Tross, Debbie] NCI, Expt Immunol Lab, Frederick, MD 21702 USA. RP Klinman, DM (reprint author), NCI, Expt Immunol Lab, Bldg 567 Rm 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov NR 80 TC 86 Z9 89 U1 4 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-409X J9 ADV DRUG DELIVER REV JI Adv. Drug Deliv. Rev. PD MAR 28 PY 2009 VL 61 IS 3 BP 248 EP 255 DI 10.1016/j.addr.2008.12.012 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 429DR UT WOS:000264901500008 PM 19272313 ER PT J AU O'Brien, EP Morrison, G Brooks, BR Thirumalai, D AF O'Brien, Edward P. Morrison, Greg Brooks, Bernard R. Thirumalai, D. TI How accurate are polymer models in the analysis of Forster resonance energy transfer experiments on proteins? SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE biochemistry; Gaussian distribution; molecular biophysics; molecular collisions; polymers; proteins ID SINGLE-MOLECULE FRET; INTRAMOLECULAR DISTANCES; DENATURING CONDITIONS; FLUORESCENCE; SPECTROSCOPY; TRANSITION; DYNAMICS; KINETICS; COLLAPSE; BARSTAR AB Single molecule Forster resonance energy transfer (FRET) experiments are used to infer the properties of the denatured state ensemble (DSE) of proteins. From the measured average FRET efficiency, < E >, the distance distribution P(R) is inferred by assuming that the DSE can be described as a polymer. The single parameter in the appropriate polymer model (Gaussian chain, wormlike chain, or self-avoiding walk) for P(R) is determined by equating the calculated and measured < E >. In order to assess the accuracy of this "standard procedure," we consider the generalized Rouse model (GRM), whose properties [< E > and P(R)] can be analytically computed, and the Molecular Transfer Model for protein L for which accurate simulations can be carried out as a function of guanadinium hydrochloride (GdmCl) concentration. Using the precisely computed < E > for the GRM and protein L, we infer P(R) using the standard procedure. We find that the mean end-to-end distance can be accurately inferred (less than 10% relative error) using < E > and polymer models for P(R). However, the value extracted for the radius of gyration (R-g) and the persistence length (l(p)) are less accurate. For protein L, the errors in the inferred properties increase as the GdmCl concentration increases for all polymer models. The relative error in the inferred R-g and l(p), with respect to the exact values, can be as large as 25% at the highest GdmCl concentration. We propose a self-consistency test, requiring measurements of < E > by attaching dyes to different residues in the protein, to assess the validity of describing DSE using the Gaussian model. Application of the self-consistency test to the GRM shows that even for this simple model, which exhibits an order -> disorder transition, the Gaussian P(R) is inadequate. Analysis of experimental data of FRET efficiencies with dyes at several locations for the cold shock protein, and simulations results for protein L, for which accurate FRET efficiencies between various locations were computed, shows that at high GdmCl concentrations there are significant deviations in the DSE P(R) from the Gaussian model. C1 [O'Brien, Edward P.; Morrison, Greg; Thirumalai, D.] Univ Maryland, Biophys Program, College Pk, MD 20742 USA. [O'Brien, Edward P.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Morrison, Greg] Harvard Univ, Sch Engn & Appl Sci, Cambridge, MA 02138 USA. [Thirumalai, D.] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Thirumalai, D.] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. RP Thirumalai, D (reprint author), Univ Maryland, Biophys Program, College Pk, MD 20742 USA. EM thirum@umd.edu RI O'Brien, Edward/C-3587-2015 FU NSF [05-14056]; NIH; National Heart Lung and Blood Institute FX We thank Sam Cho, Govardan Reddy, and David Pincus for their comments on the manuscript. E. O. thanks Guy Ziv for many useful discussions on experimental aspects of FRET measurements and analysis. This work was supported in part by grants from the NSF (No. 05-14056) to D. T., a NIH GPP Biophysics Fellowship to E. O., by the Intramural Research Program of the NIH, National Heart Lung and Blood Institute. NR 31 TC 29 Z9 29 U1 2 U2 19 PU AMER INST PHYSICS PI MELVILLE PA 1305 WALT WHITMAN RD, STE 300, MELVILLE, NY 11747-4501 USA SN 0021-9606 EI 1089-7690 J9 J CHEM PHYS JI J. Chem. Phys. PD MAR 28 PY 2009 VL 130 IS 12 AR 124903 DI 10.1063/1.3082151 PG 10 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 427JI UT WOS:000264775200087 PM 19334885 ER PT J AU Benkstein, KD Raman, B Lahr, DL Bonevich, JE Semancik, S AF Benkstein, K. D. Raman, B. Lahr, D. L. Bonevich, J. E. Semancik, S. TI Inducing analytical orthogonality in tungsten oxide-based microsensors using materials structure and dynamic temperature control SO SENSORS AND ACTUATORS B-CHEMICAL LA English DT Article DE Chemiresistor; Microhotplate; Nanowire; Nanoparticle ID CHEMICAL SENSORS; GAS SENSORS; NANOSTRUCTURED MATERIALS; MICROHOTPLATE PLATFORMS; SNO2 NANOWIRE; THIN-FILMS; METAL; FABRICATION; NANOFIBERS; MORPHOLOGY AB The influence of material Structure and dimension on the chemical sensing performance was investigated as a function of sensor operating temperature. Polycrystalline tungsten oxides (WO(3)) were prepared both as nanowires of different diameters (d approximate to 100 nm, 175 non; l = 4-5 mu m) using a template-directed electrodeposition process, and as a continuous film through thermal decomposition of peroxytungstate solution. The WO(3) materials were integrated with microscale conductometric platforms featuring millisecond dynamic temperature control up to 500,C. The nanowires and film were assessed for efficacy as transducers in gas-phase chemical sensors using these platforms, both in a fixed-temperature operating mode and in a dynamic pulsed-temperature operating mode. Statistical analysis of the tungsten oxide chemiresistor responses to analytes at varied operating temperatures revealed that orthogonal information can be obtained from stoichiometrically similar materials; the differences were exaggerated by probing the sensor responses with different dynamic temperature programs. We conclude that nanowire sensors yield non-redundant analytical information with respect to their complementary film-based sensor. These results demonstrate that as sensors move to nanoscale Structures, unique interactions will differentiate the materials and the devices' performance from their microscale counterparts. Published by Elsevier B.V. C1 [Benkstein, K. D.; Raman, B.; Lahr, D. L.; Semancik, S.] NIST, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. [Raman, B.] NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. [Bonevich, J. E.] NIST, Mat Sci & Engn Lab, Gaithersburg, MD 20899 USA. RP Benkstein, KD (reprint author), NIST, Chem Sci & Technol Lab, 100 Bur Dr, Gaithersburg, MD 20899 USA. EM kurt.benkstein@nist.gov OI Lahr, David/0000-0001-6283-0286 FU NIH-NIST; NIST; National Research Council FX We acknowledge the technical assistance of C. B. Montgomery in preparing the microhotplate sensor platforms. We also thank Professor T. E. Mallouk, R. M. Hernandez and Y. Cao, and Professor K. J. Stevenson for useful discussions on nanowire and WO3 electrodeposition. BR was supported by a NIH-NIST joint Postdoctoral Associateship Award and DILL was supported by a NIST Postdoctoral Associateship Award, both administered through the National Research Council. NR 36 TC 11 Z9 11 U1 3 U2 8 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0925-4005 J9 SENSOR ACTUAT B-CHEM JI Sens. Actuator B-Chem. PD MAR 28 PY 2009 VL 137 IS 1 BP 48 EP 55 DI 10.1016/j.snb.2008.10.029 PG 8 WC Chemistry, Analytical; Electrochemistry; Instruments & Instrumentation SC Chemistry; Electrochemistry; Instruments & Instrumentation GA 420ZA UT WOS:000264326500009 ER PT J AU Aldrovandi, GM Lindsey, JC Jacobson, DL Zadzilka, A Sheeran, E Moye, J Borum, P Meyer, WA Hardin, DS Mulligan, K AF Aldrovandi, Grace M. Lindsey, Jane C. Jacobson, Denise L. Zadzilka, Amanda Sheeran, Elizabeth Moye, Jack Borum, Peggy Meyer, William A., III Hardin, Dana S. Mulligan, Kathleen CA Pediat AIDS Clinical Trials Grp TI Morphologic and metabolic abnormalities in vertically HIV-infected children and youth SO AIDS LA English DT Article DE antiretroviral therapy; children and youth; metabolic abnormalities; morphological abnormalities; protease inhibitors ID CARDIOVASCULAR RISK-FACTORS; BETA-CELL FUNCTION; FAT DISTRIBUTION; ANTIRETROVIRAL THERAPY; PROTEASE INHIBITORS; INSULIN-RESISTANCE; HIV-1-INFECTED CHILDREN; LIPODYSTROPHY SYNDROME; UNITED-STATES; ADOLESCENTS AB Objective: To compare the distribution of lipid and glucose abnormalities and altered fat distribution among vertically HIV-infected patients and controls. Design: Cross-sectional multicenter study on HIV-infected (HIV-positive) patients, 7-24 years of age, stratified by Tanner stage and protease inhibitor use (protease inhibitor, n = 161 and non-protease inhibitor, n = 79) and seronegative controls (HIV-negative, n = 146). Methods: Measurements included fasting lipids, glucose, insulin, 2-h oral glucose tolerance test, dual-energy X-ray absorptiometry, anthropometry, and antiretroviral therapy and medical histories. Multiple linear regression models were used to compare distributions between HIV-positive and HIV-negative groups. Results: Both HIV-positive groups had long exposures to antiretroviral therapy. Protease inhibitor and nonprotease inhibitor groups had similar Current CD4 cell count and HIV-1 RNA, but the protease inhibitor group had lower nadir CD4 cell count, higher peak HIV-1 RNA, and more advanced Centers for Disease Control disease stage. In adjusted analyses, both HIV-positive groups had significantly lower mean Z scores for height, weight, BMI, and total and limb fat than the HIV-negative group. Mean triglycerides were significantly higher and high-density lipoprotein cholesterol lower in both HIV-positive groups relative to the HIV-negative group. The protease inhibitor group also had significantly higher mean total, low-density lipoprotein, and non-high density lipoprotein cholesterol. Mean fasting insulin was higher in both HIV-positive groups, and 2-h glucose and insulin were higher in the protease inhibitor group. Ritonavir was associated with increasing dyslipidemia and altered glucose metabolism. Conclusion: In a large group of vertically HIV-infected children and Youth With extensive antiretroviral therapy exposure, height, weight, and total and limb fat were lower than in controls. There was a high prevalence of lipid abnormalities among those on protease inhibitors and evidence of developing insulin resistance, factors that may accelerate lifetime risk for cardiovascular disease. (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Aldrovandi, Grace M.] Univ So Calif, Saban Res Inst, Childrens Hosp Los Angeles, Los Angeles, CA 90089 USA. [Lindsey, Jane C.; Jacobson, Denise L.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Zadzilka, Amanda; Sheeran, Elizabeth] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Moye, Jack] NICHD, NIH, Bethesda, MD USA. [Borum, Peggy] Univ Florida, Gainesville, FL USA. [Meyer, William A., III] Quest Diagnost Inc, Baltimore, MD USA. [Hardin, Dana S.] Ohio State Univ, Columbus, OH 43210 USA. [Hardin, Dana S.] Nationwide Childrens Res Inst, Columbus, OH USA. [Mulligan, Kathleen] Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Aldrovandi, GM (reprint author), Univ So Calif, Saban Res Inst, Childrens Hosp Los Angeles, 4650 Sunset Blvd MS 51, Los Angeles, CA 90089 USA. EM galdrovandi@chla.usc.edu OI moye, john/0000-0001-9976-8586 FU Pediatric AIDS Clinical Trials Group of the National Institute of Allergy and Infectious Diseases; Pediatric/Perinatal HIV Clinical Trials Network of the Eunice Kennedy Shiver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA; UCSF PCRC [RR-001271]; National Institute of Allergy and Infectious Diseases [U01 AI068632, 5 U01 AI41110]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; [U01 AI41089]; [RO1 HD 40777] FX Author contributions: G.M.A. and K.M. designed the study and the analyses, with input from other authors. J.C.L. and D.L.J. had primary responsibility for data analysis. A.Z., D.S.H. and WA.M. III contributed to the collection and analysis of clinical and laboratory data. G.M.A. wrote the first draft of the paper, but all authors contributed to writing the paper and approved the final version of the paper. NR 70 TC 52 Z9 54 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 27 PY 2009 VL 23 IS 6 BP 661 EP 672 DI 10.1097/QAD.0b013e3283269dfb PG 12 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 429VT UT WOS:000264948900003 PM 19279441 ER PT J AU Reynolds, SJ Nakigozi, G Newell, K Ndyanabo, A Galiwongo, R Roaz, I Quinn, TC Gray, R Wawer, M Serwadda, D AF Reynolds, Steven J. Nakigozi, Gertrude Newell, Kevin Ndyanabo, Anthony Galiwongo, Ronald Roaz, Iga Quinn, Thomas C. Gray, Ron Wawer, Maria Serwadda, David TI Failure of immunologic criteria to appropriately identify antiretroviral treatment failure in Uganda SO AIDS LA English DT Article DE antiretroviral therapy; HIV/AIDS; immunologic monitoring ID THERAPY; RESPONSES; ADULTS AB Objective: Most antiretroviral treatment program in resource-limited settings use immunologic or clinical monitoring to measure response to therapy and to decide when to change to a second-line regimen. Our objective was to evaluate immunologic failure criteria against gold standard virologic monitoring. Design: Observational cohort. Methods: Participants enrolled in an antiretroviral treatment program in rural Uganda who had at least 6 months of follow-up were included in this analysis. Immunologic monitoring was performed by CD4 cell counts every 3 months during the first year, and every 6 months thereafter. HIV-1 viral loads were performed every 6 months. Results: A total of 1133 participants enrolled in the Rakai Health Sciences Program antiretroviral treatment program between June 2004 and September 2007 were followed for Lip to 44.4 months (median follow-up 20.2 months; IQR 12.4-29.5 months). WHO immunologic failure criteria were reached by 125 (11.0%) participants. A virologic failure endpoint defined as HIV-1 viral load more than 400 copies/ml on two measurements was reached by 112 participants (9.9%). Only 26 participants (2.3%) experienced both an immunologic and virologic failure endpoint (2 viral load > 400 copies/ml) during follow-up. Conclusion: immunologic failure criteria performed poorly in our setting and would have resulted in a substantial proportion of participants with suppressed HIV-1 viral load being switched unnecessarily. These criteria also lacked sensitivity to identify participants failing virologically. Periodic viral load measurements may be a better marker for treatment failure in our setting. (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Reynolds, Steven J.; Quinn, Thomas C.] NIAID, Bethesda, MD 20892 USA. [Reynolds, Steven J.; Quinn, Thomas C.] Johns Hopkins Sch Med, Baltimore, MD USA. [Nakigozi, Gertrude; Ndyanabo, Anthony; Galiwongo, Ronald; Roaz, Iga] Rakai Hlth Sci Program, Kalisizo, Uganda. [Newell, Kevin] NCI, SAIC Frederick Inc, SAIC Frederick Directorate, Frederick, MD 21701 USA. [Gray, Ron; Wawer, Maria] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Serwadda, David] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. RP Reynolds, SJ (reprint author), 2190 Kampala Pl, Washington, DC 20521 USA. EM sjr@jhmi.edu FU United States President's Emergency Plan for AIDS Relief (PEPFAR); National Cancer Institute, National Institutes of Health [N01-CO-12400]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 8 TC 105 Z9 108 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAR 27 PY 2009 VL 23 IS 6 BP 697 EP 700 DI 10.1097/QAD.0b013e3283262a78 PG 4 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 429VT UT WOS:000264948900007 PM 19209067 ER PT J AU Ichihara, S Yamada, Y Gonzalez, FJ Nakajima, T Murohara, T Ichihara, G AF Ichihara, Sahoko Yamada, Yoshiji Gonzalez, Frank J. Nakajima, Tamie Murohara, Toyoaki Ichihara, Gaku TI Inhibition of ischemia-induced angiogenesis by benzo[a]pyrene in a manner dependent on the aryl hydrocarbon receptor SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Angiogenesis; Hpoxia; Smoking; Benzo[a]pyrene; Peripheral vascular disease; Metallothionein; Interleukin-6 ID ENDOTHELIAL GROWTH-FACTOR; HEALTHY-YOUNG ADULTS; AH RECEPTOR; MICE LACKING; DNA-BINDING; IN-VIVO; SMOKING; DISEASE; INTERLEUKIN-6; ACTIVATION AB We have investigated the effect of benzo[a]pyrene (B[a]P). a carcinogen of tobacco smoke and an agonist for the aryl hydrocarbon receptor (AHR), on hypoxia-induced angiogenesis. Ischemia was induced by femoral artery ligation in wild-type and ASR-null mice, and the animals were subjected to oral administration of B[a]P (125 mg/kg) once a week. Exposure to B[a]P up-regulated the expression of metallothionein in the ischemic hindlimb and markedly inhibited ischemia-induced angiogenesis in wild-type mice. The amounts of interleukin-6 and of vascular endothelial growth factor (VEGF) mRNA in the ischemic hindlimb of wild-type mice were reduced by exposure to B[a]P. These various effects of B[a]P were markedly attenuated in ASR-null mice. Our observations suggest that the loss of the inhibitory effect of B[a]P on ischemia-induced angiogenesis apparent in ASR-null mice may be attributable to maintenance of interleukin-6 expression and consequent promotion of angiogenesis through up-regulation of VEGF expression. (C) 2009 Elsevier Inc. All rights reserved. C1 [Ichihara, Sahoko; Yamada, Yoshiji] Mie Univ, Dept Human Funct Genom, Life Sci Res Ctr, Tsu, Mie 5148507, Japan. [Murohara, Toyoaki] Nagoya Univ, Sch Med, Dept Cardiol, Nagoya, Aichi 4648601, Japan. [Gonzalez, Frank J.] Natl Canc Inst, Lab Metab, NIH, Bethesda, MD USA. RP Ichihara, S (reprint author), Mie Univ, Dept Human Funct Genom, Life Sci Res Ctr, 1577 Kurimamachiya Cho, Tsu, Mie 5148507, Japan. EM saho@gene.mie-u.ac.jp RI Murohara, Toyoaki/M-4958-2014 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan [18590553] FX This study was supported in part by grants (to S.I.) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (No. 18590553). NR 29 TC 14 Z9 14 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 27 PY 2009 VL 381 IS 1 BP 44 EP 49 DI 10.1016/j.bbrc.2009.01.187 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 423RK UT WOS:000264513200009 PM 19351592 ER PT J AU Yi, CL Liu, YW Xiong, KM Stewart, RR Peoples, RW Tian, XA Zhou, L Ai, YX Li, ZW Wang, QW Li, CY AF Yi, Chu-Li Liu, Yu-Wei Xiong, Ke-Ming Stewart, Randall R. Peoples, Robert W. Tian, Xiang Zhou, Li Ai, Yong-Xun Li, Zhi-Wang Wang, Qin-Weng Li, Chao-Ying TI Conserved extracellular cysteines differentially regulate the inhibitory effect of ethanol in rat P2X(4) receptors SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE P2X; P2X(4) receptor; Cysteine; Disulfide bond; Mutation; Ethanol; Competitive inhibition; Noncompetitive inhibition ID XENOPUS OOCYTES; CELL-SURFACE; ATP; PURINOCEPTOR; MECHANISM AB Relatively little information is available about the molecular mechanism of ethanol inhibition of P2X receptors. Here, we investigated the possibility that 10 conserved cysteine residues in the extracellular loop of the rat P2X(4) receptor may regulate ethanol inhibition of the receptor using a series of individual cysteine to alanine point mutations. Each of the mutated receptors generated robust inward current in response to ATP and the mutations produced less than a sixfold change in the ATP EC50 value. For the C116A, C126A, C149A, and C165A mutants. 100 mM ethanol did not significantly affect the current activated by an EC40 concentration of ATP. By contrast, for the C261A and C270A mutants, ethanol inhibited ATP-activated current in a competitive manner similar to that for the wild-type receptor. Interestingly, for the C132A, C159A. C217A, and C227A mutants, ethanol inhibited ATP-activated current, but decreased the maximal response to ATP by 70-75% without significantly changing the EC50 value of ATP, thus exhibiting a noncompetitive-type inhibition. The results suggest that cysteines and disulfide bonds between cysteines are differentially involved in the inhibition of the rat P2X(4) receptor by ethanol. (C) 2009 Elsevier Inc. All rights reserved. C1 [Wang, Qin-Weng] Ningbo Univ, Res Ctr Behav Sci, Sch Med, Ningbo 315211, Zhejiang, Peoples R China. [Yi, Chu-Li; Liu, Yu-Wei; Tian, Xiang; Zhou, Li; Ai, Yong-Xun; Li, Zhi-Wang; Li, Chao-Ying] Jianghan Univ, Wuhan Inst Neurosc & Drug Res, Wuhan 430056, Peoples R China. [Xiong, Ke-Ming; Stewart, Randall R.] NIAAA, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Peoples, Robert W.] Marquette Univ, Dept Biomed Sci, Milwaukee, WI 53201 USA. RP Li, CY (reprint author), Ningbo Univ, Res Ctr Behav Sci, Sch Med, Ningbo 315211, Zhejiang, Peoples R China. EM Chuli_yi@hotmail.com; liu-yuwei@163.com; wangqinwen@nbu.edu.cn; licwhindr@gmail.com RI Liu, Yuwei/H-6985-2013 NR 15 TC 14 Z9 17 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 MAR 27 PY 2009 VL 381 IS 1 BP 102 EP 106 DI 10.1016/j.bbrc.2009.02.018 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 423RK UT WOS:000264513200020 PM 19351603 ER PT J AU Yoon, S Hinnebusch, AG AF Yoon, Sungpil Hinnebusch, Alan G. TI Mcm1p binding sites in ARG1 positively regulate Gcn4p binding and SWI/SNF recruitment SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Gcn4p; Mcm1p; ARG1; SWI/SNF; snf2p ID RNA-POLYMERASE-II; SACCHAROMYCES-CEREVISIAE; TRANSCRIPTIONAL ACTIVATION; GENE-EXPRESSION; COMPLEX; YEAST; REPRESSION; INDUCTION; SEQUENCE; ARGININE AB Transcription of the arginine biosynthetic gene ARG1 is activated by Gcn4p, a transcription factor induced by starvation for any amino acid. Previously, we showed that Gcn4p binding stimulates the recruitment of Mcm1p and co-activator SWI/SNF to ARG1 in cells via Gcn4p induction through amino acid starvation. Here, we report that Gcn4p binding is reduced by point mutations of the Mcm1p binding site and increased by overexpression of Mcm1p. This result suggests that Mcm1p plays a positive role in recruiting activator Gcn4p to ARG1, similar to the previously described cooperative interaction of Mcm1p with sequence-specific transcription factors at their promoters. In addition, the mutational analysis of Mcm1p binding sites showed that recruitment of the co-activator SWI/SNF correlated more closely with binding of Mcm1p than of Gcn4p at ARG1. Consistent with this, SWI/SNF co-immunoprecipitated with Mcm1p, but not with Gcn4p. These results support that Mcm1p increases the SWI/SNF recruitment at ARGI, a Gcn4p target promoter. The interaction between Mcm1p and SWI/SNF was abolished in a snf2 deletion strain containing an intact SWI/SNF sub-complex, suggesting that Mcm1p targets the catalytic subunit, which has ATPase activity, during SWI/SNF recruitment. We propose that Mcm1p contributes to active transcription at the ARGI promoter by increasing the binding of the activator Gcn4p and by recruiting the co-activator complex SWI/SNF at ARG1 under Gcn4p-induced conditions. (C) 2009 Elsevier Inc. All rights reserved. C1 [Yoon, Sungpil] Natl Canc Ctr, Res Inst, Goyang Si 411764, Gyeonggi Do, South Korea. [Hinnebusch, Alan G.] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Yoon, S (reprint author), Natl Canc Ctr, Res Inst, 809 Madu 1 Dong, Goyang Si 411764, Gyeonggi Do, South Korea. EM yoons@ncc.re.kr FU Intramural NIH HHS [Z99 HD999999, Z01 HD001004-24] NR 17 TC 3 Z9 3 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 27 PY 2009 VL 381 IS 1 BP 123 EP 128 DI 10.1016/j.bbrc.2009.02.045 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 423RK UT WOS:000264513200024 PM 19233144 ER PT J AU Sack, MN AF Sack, Michael N. TI Innate Short-Circuiting of Mitochondrial Metabolism in Cardiac Hypertrophy Identification of Novel Consequences of Enhanced Anaplerosis SO CIRCULATION RESEARCH LA English DT Editorial Material DE malic enzyme; anaplerosis; cardiac hypertrophy; triacylglycerol ID FATTY-ACID; RAT HEARTS; INSULIN-RESISTANCE; ENERGY-METABOLISM; SKELETAL-MUSCLE; OXIDATION; CARDIOMYOPATHY; DYSFUNCTION; EXPRESSION; GROWTH C1 [Sack, Michael N.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Sack, MN (reprint author), Bldg 10-CRC,Room 5-3150,10 Ctr Dr,MSC 1454, Bethesda, MD 20892 USA. EM sackm@nhlbi.nih.gov FU Intramural NIH HHS [ZIA HL005102-07] NR 24 TC 4 Z9 4 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 MAR 27 PY 2009 VL 104 IS 6 BP 717 EP 719 DI 10.1161/CIRCRESAHA.109.195495 PG 3 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 424KM UT WOS:000264565600005 PM 19325159 ER PT J AU Chen, Q Zhang, H Li, QM An, Y Herkenham, M Lai, WM Popovich, P Agarwal, S Quan, N AF Chen, Qun Zhang, Hao Li, Qiming An, Ying Herkenham, Miles Lai, Wenmin Popovich, Phillip Agarwal, Sudha Quan, Ning TI Three Promoters Regulate Tissue- and Cell Type-specific Expression of Murine Interleukin-1 Receptor Type I SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MESSENGER-RNA EXPRESSION; IL-1 RECEPTOR; MOUSE-BRAIN; INFLAMMATION; INDUCTION; GENE; LIPOPOLYSACCHARIDE; GLUCOCORTICOIDS; POLYMORPHISMS; TRANSCRIPTION AB The type 1 interleukin-1 receptor (IL-1R1) mediates diverse functions of interleukin-1 (IL-1) in the nervous, immune, and neuroendocrine systems. It has been suggested previously that the versatile functions of IL-1 may in part be conferred by the multiple promoters of IL-1R1 that have been identified for the human IL-1R1 gene. Promoters for murine IL-1R1 (mIL-1R1) gene have not been studied in detail. We performed 5'-rapid amplification of cDNA ends to determine the transcription start sites (TSS) in mIL-1R1, using mRNAs derived from 24 different tissues. The results revealed three putative TSSs of mIL-1R1. Three full-length cDNAs containing these distinct TSSs were recovered in screens of cloned cDNA libraries. Translation of these cDNAs produced IL-1R1 proteins that were verified by Western blot analysis. IL-1 stimulation of the individual IL-1R1 proteins resulted in the activation of NF-kappa B. Promoter-reporter assay for genomic DNA sequences immediately upstream of the three TSSs validated that the sequences possess promoter activity in a cell type-specific manner. These promoters are termed P1, P2, and P3 of the mIL-1R1, in 5' to 3' order. Quantitative PCR analysis of P1-, P2-, and P3-specific mIL-1R1 mRNAs showed that there is tissue-specific distribution of these mRNAs in vivo, and there are distinct patterns of P1, P2, and P3 mRNA expression in different cell lines. In the brain, P3 mRNA is expressed preferentially in the dentate gyrus. Further, glucocorticoids differentially regulate these promoters in a cell type-specific manner. Together, these results suggest that the different IL-1R1 promoters contribute to the discrete and diverse actions of IL-1. C1 [Quan, Ning] Ohio State Univ, Dept Oral Biol, Columbus, OH 43210 USA. [Herkenham, Miles] NIMH, Funct Neuroanat Sect, Bethesda, MD 20892 USA. [Lai, Wenmin; Popovich, Phillip] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. RP Quan, N (reprint author), 4179 Postle Hall,305 W 12th Ave, Columbus, OH 43210 USA. EM quan.14@osu.edu RI Popovich, Phillip/C-9187-2009; OI Popovich, Phillip/0000-0003-1329-7395; Herkenham, Miles/0000-0003-2228-4238 FU National Institutes of Health [R01 AI076926]; Intramural Research Program of the National Institute of Mental Health FX This work was supported, in whole or in part, by National Institutes of Health Grant R01 AI076926 (to N.Q.). This work was also supported by the Intramural Research Program of the National Institute of Mental Health. NR 31 TC 1 Z9 1 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 MAR 27 PY 2009 VL 284 IS 13 BP 8694 EP 8704 DI 10.1074/jbc.M808261200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 421ZW UT WOS:000264397800054 ER PT J AU Zhang, G Chen, S Goldoni, S Calder, BW Simpson, HC Owens, RT McQuillan, DJ Young, MF Iozzo, RV Birk, DE AF Zhang, Guiyun Chen, Shoujun Goldoni, Silvia Calder, Bennett W. Simpson, Holly C. Owens, Rick T. McQuillan, David J. Young, Marian F. Iozzo, Renato V. Birk, David E. TI Genetic Evidence for the Coordinated Regulation of Collagen Fibrillogenesis in the Cornea by Decorin and Biglycan SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID KERATAN SULFATE PROTEOGLYCAN; LEUCINE-RICH PROTEOGLYCANS; DEFICIENT MICE; FIBRIL SEGMENTS; LUMICAN-DEFICIENT; IN-SITU; EXTRACELLULAR COMPARTMENTS; TARGETED DISRUPTION; SKIN FRAGILITY; LATERAL GROWTH AB Decorin and biglycan are class I small leucine-rich proteoglycans (SLRPs) involved in regulation of collagen fibril and matrix assembly. We hypothesize that tissue-specific matrix assembly, such as in the cornea, requires a coordinate regulation involving multiple SLRPs. To this end, we investigated the expression of decorin and biglycan in the cornea of mice deficient in either SLRP gene and in double-mutant mice. Decorin and biglycan exhibited overlapping spatial expression patterns throughout the corneal stroma with differential temporal expression. Whereas decorin was expressed at relatively high levels in all developmental stages, biglycan expression was high early, decreased during development, and was present at very low levels in the mature cornea. Ultrastructural analyses demonstrated comparable fibril structure in the decorin-and biglycan-null corneas compared with wild-type controls. We found a compensatory up-regulation of biglycan gene expression in the decorin-deficient mice, but not the reverse. Notably, the corneas of compound decorin/biglycan-null mice showed severe disruption in fibril structure and organization, especially affecting the posterior corneal regions, corroborating the idea that biglycan compensates for the loss of decorin. Fibrillogenesis assays using recombinant decorin and biglycan confirmed a functional compensation, with both having similar effects at high SLRP/collagen ratios. However, at low ratios decorin was a more efficient regulator. The use of proteoglycan or protein core yielded comparable results. These findings provide firm genetic evidence for an interaction of decorin and biglycan during corneal development and further suggest that decorin has a primary role in regulating fibril assembly, a function that can be fine-tuned by biglycan during early development. C1 [Iozzo, Renato V.] Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. [Owens, Rick T.; McQuillan, David J.] LifeCell Corp, Branchburg, NJ 08876 USA. [Young, Marian F.] NIDCR, NIH, Bethesda, MD 20892 USA. [Chen, Shoujun; Birk, David E.] Univ S Florida, Dept Pathol & Cell Biol, Coll Med, Tampa, FL 33612 USA. RP Birk, DE (reprint author), 12901 Bruce B Downs Blvd,MDC11, Tampa, FL 33612 USA. EM dbirk@health.usf.edu RI Birk, David/I-4072-2012; OI Birk, David/0000-0002-4865-9088; Iozzo, Renato/0000-0002-5908-5112 FU National Institutes of Health NEI [EY005129]; Intramural Research Program, NIDCR FX This work was supported, in whole or in part, by National Institutes of Health NEI Grant EY005129 (to D.E.B.) and support from the Intramural Research Program, NIDCR (to M.F.Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 48 TC 91 Z9 93 U1 2 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 27 PY 2009 VL 284 IS 13 BP 8888 EP 8897 DI 10.1074/jbc.M806590200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 421ZW UT WOS:000264397800071 PM 19136671 ER PT J AU Bartolini, M Greig, NH Yu, QS Andrisano, V AF Bartolini, Manuela Greig, Nigel H. Yu, Qian-sheng Andrisano, Vincenza TI Immobilized butyrylcholinesterase in the characterization of new inhibitors that could ease Alzheimer's disease SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 3rd Summer School on Monolith Technology for Biochromatography, Bioconversion and Solid-Phase Synthesis CY MAY 30-JUN 04, 2008 CL Portoroz, SLOVENIA DE Human butyrylcholinesterase; Covalent immobilization; Monolithic disks; Pseudo-irreversible inhibitors; Kinetic constants; On-line studies; Phenserine; Cymserine ID PERFORMANCE LIQUID-CHROMATOGRAPHY; ENZYME REACTOR; HUMAN ACETYLCHOLINESTERASE; SELECTIVE INHIBITORS; PHENSERINE; ANALOGS; DERIVATIVES; PHYSOSTIGMINE; MECHANISM; SUPPORT AB Focus of this work was the development and characterization of a new immobilized enzyme reactor (IMER) containing human recombinant butyrylcholinesterase (rBChE) for the on-line kinetic characterization of specific, pseudo-irreversible and brain-targeted BChE inhibitors as potential drug candidates for Alzheimer's disease (AD). Specifically, a rBChE-IMER containing 0.99 U of covalently bound target enzyme was purposely developed and inserted into a HPLC system connected to a UV-vis detector. Selected reversible cholinesterase inhibitors, (-)-phenserine and (-)-cymserine analogues, were then kinetically characterized by rBChE-IMER, and by classical in solution assays and their carbamoylation and decarbamoylation constants were determined. The results support the elucidation of the potency, inhibition duration, mode of action and specific structure/activity relations of these agents and allow cross-validation of the two assay techniques. (C) 2008 Elsevier B.V. All rights reserved. C1 [Bartolini, Manuela; Andrisano, Vincenza] Univ Bologna, Dept Pharmaceut Sci, I-40126 Bologna, Italy. [Greig, Nigel H.; Yu, Qian-sheng] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Andrisano, V (reprint author), Univ Bologna, Dept Pharmaceut Sci, Via Belmeloro 6, I-40126 Bologna, Italy. EM vincenza.andrisano@unibo.it OI ANDRISANO, VINCENZA/0000-0003-4396-1904; Bartolini, Manuela/0000-0002-2890-3856 FU Intramural NIH HHS [Z01 AG000311-08] NR 42 TC 21 Z9 21 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD MAR 27 PY 2009 VL 1216 IS 13 BP 2730 EP 2738 DI 10.1016/j.chroma.2008.09.100 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 423NX UT WOS:000264504100020 PM 18950780 ER PT J AU Qiu, HF Hu, CH Hinnebusch, AG AF Qiu, Hongfang Hu, Cuihua Hinnebusch, Alan G. TI Phosphorylation of the Pol II CTD by KIN28 Enhances BUR1/BUR2 Recruitment and Ser2 CTD Phosphorylation Near Promoters SO MOLECULAR CELL LA English DT Article ID RNA-POLYMERASE-II; CARBOXYL-TERMINAL DOMAIN; CYCLIN-DEPENDENT KINASE; HISTONE METHYLATION; TRANSCRIPTIONAL ELONGATION; PAF1 COMPLEX; SACCHAROMYCES-CEREVISIAE; H2B UBIQUITYLATION; PROCESSING FACTORS; CAPPING ENZYME AB Cyclin-dependent kinase BUR1/BUR2 appears to be the yeast ortholog of P-TEFb, which phosphorylates Ser2 of the RNA Pol II CTD, but the importance of BUR1/BUR2 in CTD phosphorylation is unclear. We show that BUR1/BUR2 is cotranscriptionally recruited to the 5' end of ARG1 in a manner stimulated by interaction of the BUR1 C terminus with CTD repeats phosphorylated on Ser5 by KIN28. Impairing BUR1/BUR2 function, or removing the CTD-interaction domain in BUR1, reduces Ser2 phosphorylation in bulk Pol II and eliminates the residual Ser2P in cells lacking the major Ser2 CTD kinase, CTK1. Impairing BUR1/BUR2 or CTK1 evokes a similar reduction of Ser2P in Pol II phosphorylated on Ser5 and in elongating Pol II near the ARG1 promoter. By contrast, CTK1 is responsible for the bulk of Ser2P in total Pol II and at promoter-distal sites. In addition to phosphorylating Ser2 near promoters, BUR1/BUR2 also stimulates Ser2P formation by CTK1 during transcription elongation. C1 [Qiu, Hongfang; Hu, Cuihua; Hinnebusch, Alan G.] NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov FU National Institute of Child Health and Human Development (NICHD); National Institutes of Health (NIH) FX We thank Stephen Buratowski for BUR1 plasmids and Chhabi Govind, Dan Ginsburg, Stephen Buratowski, and Greg Prelich for critical reading of the manuscript. This research was supported by the Intramural Research Program of the National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH). NR 44 TC 94 Z9 94 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAR 27 PY 2009 VL 33 IS 6 BP 752 EP 762 DI 10.1016/j.molcel.2009.02.018 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 426NC UT WOS:000264714000012 PM 19328068 ER PT J AU Hashimoto, K Amano, T Kasakura, A Uhl, GR Sora, I Sakai, N Kuzumaki, N Suzuki, T Narita, M AF Hashimoto, Keisuke Amano, Taku Kasakura, Akiko Uhl, George R. Sora, Ichiro Sakai, Norio Kuzumaki, Naoko Suzuki, Tsutomu Narita, Minoru TI mu-Opioid receptor-independent fashion of the suppression of sodium currents by mu-opioid analgesics in thalamic neurons SO NEUROSCIENCE LETTERS LA English DT Article DE Morphine; Fentanyl; Oxycodone; Lidocaine; Voltage-gated sodium channels ID LOCAL-ANESTHETICS; MYELINATED NERVE; LIDOCAINE BLOCK; PHOSPHOLIPASE-C; SPINAL-CORD; CHANNELS; MORPHINE; MICE; RAT; INHIBITION AB Most reports in the literature have shown that the effects of opioid analgesics are primarily mediated by mu-opioid receptor (MOR), whereas other potential targets of opioid analgesics have not been thoroughly characterized. In this study, we found that extracellular application of morphine, fentanyl or oxycodone,which are all considered to be MOR agonists, at relatively high concentrations, but not endogenous mu-opioid peptides, produced a concentration-dependent suppression of sodium currents in cultured thalamic neurons. These effects of opioids were not affected by either a MOR antagonist naloxone or a deletion of MOR gene. Among these opioids, fentanyl strongly suppressed sodium currents to the same degree as lidocaine, and both morphine and oxycodone slightly but significantly reduced sodium currents when they were present extracellularly. In contrast, the intracellular application of morphine, but not oxycodone, fentanyl or lidocaine, reduced sodium currents. These results suggest that morphine, fentanyl and oxycodone each produce the MOR-independent suppression of sodium currents by distinct mechanisms in thalamic neurons. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Hashimoto, Keisuke; Amano, Taku; Kasakura, Akiko; Kuzumaki, Naoko; Suzuki, Tsutomu; Narita, Minoru] Hoshi Univ, Dept Toxicol, Sch Pharm & Pharmaceut Sci, Shinagawa Ku, Tokyo 1428501, Japan. [Amano, Taku; Sakai, Norio] Hiroshima Univ, Dept Mol & Pharmacol Neurosci, Div Integrated Med Sci, Grad Sch Biomed Sci,Minami Ku, Hiroshima 7348551, Japan. [Uhl, George R.] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Sora, Ichiro] Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, Sendai, Miyagi 9808574, Japan. RP Suzuki, T (reprint author), Hoshi Univ, Dept Toxicol, Sch Pharm & Pharmaceut Sci, Shinagawa Ku, 2-4-41 Ebara, Tokyo 1428501, Japan. EM suzuki@hoshi.ac.jp; narita@hoshi.ac.jp RI Kuzumaki, Naoko/L-1287-2013 FU Intramural NIH HHS [Z01 DA000492-03, Z01 DA000165-13, Z01 DA000401-10, Z01 DA000406-10] NR 17 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 27 PY 2009 VL 453 IS 1 BP 62 EP 67 DI 10.1016/j.neulet.2009.01.066 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 426HM UT WOS:000264698600015 PM 19429017 ER PT J AU Li, QS Skinner, PJ Ha, SJ Duan, LJ Mattila, TL Hage, A White, C Barber, DL O'Mara, L Southern, PJ Reilly, CS Carlis, JV Miller, CJ Ahmed, R Haase, AT AF Li, Qingsheng Skinner, Pamela J. Ha, Sang-Jun Duan, Lijie Mattila, Teresa L. Hage, Aaron White, Cara Barber, Daniel L. O'Mara, Leigh Southern, Peter J. Reilly, Cavan S. Carlis, John V. Miller, Christopher J. Ahmed, Rafi Haase, Ashley T. TI Visualizing Antigen-Specific and Infected Cells in Situ Predicts Outcomes in Early Viral Infection SO SCIENCE LA English DT Article ID LYMPHOCYTIC CHORIOMENINGITIS VIRUS; SIMIAN IMMUNODEFICIENCY VIRUS; CD8(+) T-CELLS; SIV INFECTION; PERSISTENCE; TRANSMISSION; GLYCOPROTEIN; REPLICATION; RESPONSES; EPITOPES AB In the early stages of viral infection, outcomes depend on a race between expansion of infection and the immune response generated to contain it. We combined in situ tetramer staining with in situ hybridization to visualize, map, and quantify relationships between immune effector cells and their targets in tissues. In simian immunodeficiency virus infections in macaques and lymphocytic choriomeningitis virus infections in mice, the magnitude and timing of the establishment of an excess of effector cells versus targets were found to correlate with the extent of control and the infection outcome (i.e., control and clearance versus partial or poor control and persistent infection). This method highlights the importance of the location, timing, and magnitude of the immune response needed for a vaccine to be effective against agents of persistent infection, such as HIV-1. C1 [Li, Qingsheng; Duan, Lijie; Southern, Peter J.; Haase, Ashley T.] Univ Minnesota, Sch Med, Dept Microbiol, Minneapolis, MN 55455 USA. [Skinner, Pamela J.; Mattila, Teresa L.; Hage, Aaron; White, Cara] Univ Minnesota, Dept Vet & Biomed Sci, St Paul, MN 55108 USA. [Ha, Sang-Jun; O'Mara, Leigh; Ahmed, Rafi] Emory Univ, Sch Med, Emory Vaccine Ctr, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. [Barber, Daniel L.] NIAID, Immunobiol Sect, Bethesda, MD 20892 USA. [Reilly, Cavan S.] Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. [Carlis, John V.] Univ Minnesota, Inst Technol, Dept Comp Sci & Engn, Minneapolis, MN 55455 USA. [Miller, Christopher J.] Univ Calif Davis, Calif Natl Primate Res Ctr, Ctr Comparat Med, Davis, CA 95616 USA. RP Haase, AT (reprint author), Univ Minnesota, Sch Med, Dept Microbiol, Minneapolis, MN 55455 USA. EM haase001@umn.edu OI Skinner, Pamela/0000-0003-3388-1687; Ha, Sang-Jun/0000-0002-1192-6031 FU NIH [AI48484, AI20048, AI066314]; National Center for Research Resources [RR00169] FX We thank the Immunology Core Laboratory and Primate Services Unit of the California National Primate Research Center (CNPRC); D. Lu, T. Rourke, R. Dizon, and B. Vang for technical assistance; J. Sedgewick for assistance in setting up the confocal microscope to capture images of silver grains; D. Masopust for helpful discussion; and C. O'Neill and T. Leonard for help in preparing the manuscript and figures. Supported in part by NIH research grants AI48484 (A.T.H.), AI20048 (R.A.), and AI066314 (C.J.M.); National Center for Research Resources grant RR00169 (CNPRC, University of California, Davis); and a gift from the James B. Pendleton Charitable Trust (C.J.M.). NR 18 TC 125 Z9 127 U1 0 U2 8 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 MAR 27 PY 2009 VL 323 IS 5922 BP 1726 EP 1729 DI 10.1126/science.1168676 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 424IG UT WOS:000264559800039 PM 19325114 ER PT J AU Starr, TK Allaei, R Silverstein, KAT Staggs, RA Sarver, AL Bergemann, TL Gupta, M O'Sullivan, MG Matise, I Dupuy, AJ Collier, LS Powers, S Oberg, AL Asmann, YW Thibodeau, SN Tessarollo, L Copeland, NG Jenkins, NA Cormier, RT Largaespada, DA AF Starr, Timothy K. Allaei, Raha Silverstein, Kevin A. T. Staggs, Rodney A. Sarver, Aaron L. Bergemann, Tracy L. Gupta, Mihir O'Sullivan, M. Gerard Matise, Ilze Dupuy, Adam J. Collier, Lara S. Powers, Scott Oberg, Ann L. Asmann, Yan W. Thibodeau, Stephen N. Tessarollo, Lino Copeland, Neal G. Jenkins, Nancy A. Cormier, Robert T. Largaespada, David A. TI A Transposon-Based Genetic Screen in Mice Identifies Genes Altered in Colorectal Cancer SO SCIENCE LA English DT Article ID TUMOR-SUPPRESSOR; EXPRESSION; CELLS; METHYLATION; INSTABILITY; MUTAGENESIS; EPITHELIUM; MOUSE AB Human colorectal cancers (CRCs) display a large number of genetic and epigenetic alterations, some of which are causally involved in tumorigenesis (drivers) and others that have little functional impact (passengers). To help distinguish between these two classes of alterations, we used a transposon-based genetic screen in mice to identify candidate genes for CRC. Mice harboring mutagenic Sleeping Beauty (SB) transposons were crossed with mice expressing SB transposase in gastrointestinal tract epithelium. Most of the offspring developed intestinal lesions, including intraepithelial neoplasia, adenomas, and adenocarcinomas. Analysis of over 16,000 transposon insertions identified 77 candidate CRC genes, 60 of which are mutated and/or dysregulated in human CRC and thus are most likely to drive tumorigenesis. These genes include APC, PTEN, and SMAD4. The screen also identified 17 candidate genes that had not previously been implicated in CRC, including POLI, PTPRK, and RSPO2. C1 [Starr, Timothy K.; Allaei, Raha; Largaespada, David A.] Univ Minnesota, Dept Genet Cell Biol & Dev, Ctr Genome Engn, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Silverstein, Kevin A. T.; Staggs, Rodney A.; Sarver, Aaron L.] Univ Minnesota, Dept Biostat & Informat, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Bergemann, Tracy L.] Univ Minnesota, Sch Publ Hlth, Dept Biostat, Minneapolis, MN 55455 USA. [Gupta, Mihir] Harvard Univ, Dept Phys & Chem Biol, Cambridge, MA 02138 USA. [O'Sullivan, M. Gerard; Matise, Ilze] Univ Minnesota, Coll Vet Med, St Paul, MN 55108 USA. [Dupuy, Adam J.] Univ Iowa, Dept Anat & Cell Biol, Iowa City, IA 52242 USA. [Collier, Lara S.] Univ Wisconsin, Sch Pharm, Madison, WI 53705 USA. [Powers, Scott] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Oberg, Ann L.; Asmann, Yan W.; Thibodeau, Stephen N.] Mayo Clin, Coll Med, Rochester, MN 55905 USA. [Tessarollo, Lino] NCI, Neural Dev Grp, Mouse Canc Genet Program, Ctr Canc Res, Frederick, MD 21702 USA. [Copeland, Neal G.; Jenkins, Nancy A.] Inst Mol & Cell Biol, Singapore 138673, Singapore. [Cormier, Robert T.] Univ Minnesota, Sch Med, Duluth, MN 55812 USA. RP Starr, TK (reprint author), Univ Minnesota, Dept Genet Cell Biol & Dev, Ctr Genome Engn, Masonic Canc Ctr, Minneapolis, MN 55455 USA. EM star0044@umn.edu; larga002@umn.edu RI ASTAR, IMCB/E-2320-2012; Largaespada, David/C-9832-2014; OI Bergemann, Tracy/0000-0003-3902-2605; Starr, Timothy/0000-0002-6308-3451 FU American Cancer Society fellowship [PF-06-282-01-MGO]; NIH [R01CA113636-01A1]; NCI [K01CA122183-03]; Biomedical Research Council of A*STAR, Singapore; NCI Intramural Research Program of NIH; University of Minnesota Academic Health Center FX Insertion data are deposited in the Retrovirus Tagged Cancer Gene Database (RTCGD). We thank S. Singh for help with GSFlex 454 sequencing; K. Akagi for maintaining the RTCGD; A. Weber-Main and K. Stone for editing assistance; the Masonic Cancer Center shared resources including Biostatistics and Bioinformatics, Comparative Pathology, and the Mouse Genetics Laboratory; and the Minnesota Supercomputing Institute for providing computational resources. Research was funded by the American Cancer Society fellowship PF-06-282-01-MGO (to T.K.S.), NIH grant R01CA113636-01A1 (to D.A.L.), NCI grant K01CA122183-03 (to L.S.C.), the Biomedical Research Council of A*STAR (Agency for Science, Technology and Research) Singapore (N.A.J. and N.G.C.), and the NCI Intramural Research Program of NIH (L.T.). A University of Minnesota Academic Health Center Faculty Development Grant provided additional funding to D.A.L. and R.T.C. D.A.L. is a cofounder of, and has an equity interest in, Discovery Genomics, Inc., a biotechnology company that is pursuing SB technology for human gene therapy. The University of Minnesota has filed a patent related to the work described in this paper. NR 25 TC 201 Z9 206 U1 0 U2 11 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAR 27 PY 2009 VL 323 IS 5922 BP 1747 EP 1750 DI 10.1126/science.1163040 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 424IG UT WOS:000264559800045 PM 19251594 ER PT J AU Nabel, EG AF Nabel, Elizabeth G. TI Notes from the Director, National Heart, Lung, and Blood Institute: transitions SO BLOOD LA English DT Article AB During this time of transition in the federal government and the National Institutes of Health, I write to assure the Blood community of the National Heart, Lung, and Blood Institute's (NHLBI) commitment to new and established investigators as outlined in the NHLBI Strategic Plan. This perspective discusses the NHLBI budget for the fiscal year 2009 and new policies for funding early stage investigators and revised grant applications. (Blood. 2009; 113:2875-2877) C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, NIH, 31 Ctr Dr,5A48, Bethesda, MD 20892 USA. EM NHLBIIOD@mail.nih.gov NR 8 TC 0 Z9 0 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 MAR 26 PY 2009 VL 113 IS 13 BP 2875 EP 2877 DI 10.1182/blood-2008-12-194100 PG 3 WC Hematology SC Hematology GA 424HY UT WOS:000264559000004 PM 19324910 ER PT J AU Ringden, O Pavletic, SZ Anasetti, C Barrett, AJ Wang, T Wang, D Antin, JH Di Bartolomeo, P Bolwell, BJ Bredeson, C Cairo, MS Gale, RP Gupta, V Hahn, T Hale, GA Halter, J Jagasia, M Litzow, MR Locatelli, F Marks, DI McCarthy, PL Cowan, MJ Petersdorf, EW Russell, JA Schiller, GJ Schouten, H Spellman, S Verdonck, LF Wingard, JR Horowitz, MM Arora, M AF Ringden, Olle Pavletic, Steven Z. Anasetti, Claudio Barrett, A. John Wang, Tao Wang, Dan Antin, Joseph H. Di Bartolomeo, Paolo Bolwell, Brian J. Bredeson, Christopher Cairo, Mitchell S. Gale, Robert P. Gupta, Vikas Hahn, Theresa Hale, Gregory A. Halter, Jorg Jagasia, Madan Litzow, Mark R. Locatelli, Franco Marks, David I. McCarthy, Philip L. Cowan, Morton J. Petersdorf, Effie W. Russell, James A. Schiller, Gary J. Schouten, Harry Spellman, Stephen Verdonck, Leo F. Wingard, John R. Horowitz, Mary M. Arora, Mukta TI The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; MINOR HISTOCOMPATIBILITY ANTIGENS; CHRONIC MYELOGENOUS LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; HOST-DISEASE; CYCLOSPORINE-A; INCREASED RISK; DOSE CYCLOSPORINE; MYELOID-LEUKEMIA; RELAPSE AB Do some patients benefit from an unrelated donor (URD) transplant because of a stronger graft-versus-leukemia (GVL) effect? We analyzed 4099 patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) undergoing a myeloablative allogeneic hematopoietic cell transplantation (HCT) from an URD (8/8 human leukocyte antigen [HLA]matched, n = 941) or HLA-identical sibling donor (n = 3158) between 1995 and 2004 reported to the CIBMTR. In the Cox regression model, acute and chronic GVHD were added as time-dependent variables. In multivariate analysis, URD transplant recipients had a higher risk for transplantation-related mortality (TRM; relative risk [RR], 2.76; P < .001) and relapse (RR, 1.50; P < .002) in patients with AML, but not ALL or CML. Chronic GVHD was associated with a lower relapse risk in all diagnoses. Leukemia-free survival (LFS) was decreased in patients with AML without acute GVHD receiving a URD transplant (RR, 2.02; P < .001) but was comparable to those receiving HLA-identical sibling transplants in patients with ALL and CML. In patients without GVHD, multivariate analysis showed similar risk of relapse but decreased LFS for URD transplants for all 3 diagnoses. In conclusion, risk of relapse was the same (ALL, CML) or worse (AML) in URD transplant recipients compared with HLA-identical sibling transplant recipients, suggesting a similar GVL effect. (Blood. 2009; 113: 3110-3118) C1 [Ringden, Olle] Karolinska Univ, Huddinge Hosp, Karolinska Inst, Div Clin Immunol,Ctr Allogene Stem & Cell Transpl, SE-14186 Stockholm, Sweden. [Pavletic, Steven Z.; Barrett, A. John] NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Anasetti, Claudio] H Lee Moffitt Canc Ctr & Res Inst, BMT Program, Tampa, FL USA. [Wang, Tao; Wang, Dan; Bredeson, Christopher; Spellman, Stephen; Horowitz, Mary M.] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Antin, Joseph H.] Brigham & Womens Hosp, Dana Farber Canc Inst, Boston, MA 02115 USA. [Di Bartolomeo, Paolo] Osped Civile, Dept Haematol, Pescara, Italy. [Bolwell, Brian J.] Cleveland Clin Fdn, Cleveland, OH USA. [Cairo, Mitchell S.] Columbia Univ, Med Ctr, New York, NY USA. [Gale, Robert P.] Ctr Adv Studies Leukemia, Los Angeles, CA USA. [Gupta, Vikas] Princess Margaret Hosp, BMT Program, Toronto, ON M4X 1K9, Canada. [Hahn, Theresa; McCarthy, Philip L.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Hale, Gregory A.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Halter, Jorg] Univ Basel Hosp, CH-4031 Basel, Switzerland. [Jagasia, Madan] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Litzow, Mark R.] Mayo Clin, Rochester, MN USA. [Locatelli, Franco] Policlin San Matteo, IRCCS, I-27100 Pavia, Italy. [Marks, David I.] United Bristol Healthcare Trust, Adult BMT Unit, Bristol, Avon, England. [Cowan, Morton J.] Univ Calif San Francisco, Childrens Hosp, BMT Div, San Francisco, CA 94143 USA. [Petersdorf, Effie W.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Russell, James A.] Tom Baker Canc Clin, Dept Med, Calgary, AB, Canada. [Schiller, Gary J.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA 90024 USA. [Schouten, Harry] Univ Hosp Maastricht, Maastricht, Netherlands. [Verdonck, Leo F.] Univ Utrecht Hosp, Utrecht, Netherlands. [Wingard, John R.] Univ Florida, Coll Med, Hlth Sci Ctr, Gainesville, FL USA. [Arora, Mukta] Univ Minnesota, Minneapolis, MN USA. RP Ringden, O (reprint author), Karolinska Univ, Huddinge Hosp, Karolinska Inst, Div Clin Immunol,Ctr Allogene Stem & Cell Transpl, F79, SE-14186 Stockholm, Sweden. EM Olle.Ringden@ki.se RI Halter, Joerg/C-9487-2012 FU NCI NIH HHS [R01 CA100019, U24 CA076518, U24-CA76518] NR 38 TC 96 Z9 98 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 26 PY 2009 VL 113 IS 13 BP 3110 EP 3118 DI 10.1182/blood-2008-07-163212 PG 9 WC Hematology SC Hematology GA 424HY UT WOS:000264559000031 PM 19059878 ER PT J AU Viard, M Garg, H Blumenthal, R Raviv, Y AF Viard, Mathias Garg, Himanshu Blumenthal, Robert Raviv, Yossef TI Photo-activation of the hydrophobic probe iodonaphthylazide in cells alters membrane protein function leading to cell death SO BMC CELL BIOLOGY LA English DT Article ID GLYCOPROTEIN-MEDIATED FUSION; HIV-1 ENVELOPE GLYCOPROTEIN; CHEMOKINE RECEPTOR CXCR4; MULTIDRUG-RESISTANCE; BIOLOGICAL-MEMBRANES; INFLUENZA HEMAGGLUTININ; STRUCTURAL INTEGRITY; MOLECULAR-BASIS; LIPID BILAYER; TUMOR-CELLS AB Background: Photo-activation of the hydrophobic membrane probe 1, 5 iodonaphthylazide (INA) by irradiation with UV light (310-380 nm) results in the covalent modification of transmembrane anchors of membrane proteins. This unique selectivity of INA towards the transmembrane anchor has been exploited to specifically label proteins inserted in membranes. Previously, we have demonstrated that photo-activation of INA in enveloped viruses resulted in the inhibition of viral membrane protein-induced membrane fusion and viral entry into cells. In this study we show that photo-activation of INA in various cell lines, including those over-expressing the multi-drug resistance transporters MRP1 or Pgp, leads to cell death. We analyzed mechanisms of cell killing by INA-UV treatment. The effects of INA-UV treatment on signaling via various cell surface receptors, on the activity of the multi-drug resistance transporter MRP1 and on membrane protein lateral mobility were also investigated. Results: INA treatment of various cell lines followed by irradiation with UV light (310-380 nm) resulted in loss of cell viability in a dose dependent manner. The mechanism of cell death appeared to be apoptosis as indicated by phosphatidylserine exposure, mitochondrial depolarization and DNA fragmentation. Inhibition by pan-caspase inhibitors and cleavage of caspase specific substrates indicated that at low concentrations of INA apoptosis was caspase dependent. The INA-UV treatment showed similar cell killing efficacy in cells over-expressing MRP1 function as control cells. Efflux of an MRP1 substrate was blocked by INA-UV treatment of the MRP1-overexpressing cells. Although INA-UV treatment resulted in inhibition of calcium mobilization triggered by chemokine receptor signaling, Akt phosphorylation triggered by IGF1 receptor signaling was enhanced. Furthermore, fluorescence recovery after photobleaching experiments indicated that INA-UV treatment resulted in reduced lateral mobility of a seven transmembrane G protein-coupled receptor. Conclusion: INA is a photo-activable agent that induces apoptosis in various cancer cell lines. It reacts with membrane proteins to alter the normal physiological function resulting in apoptosis. This activity of INA maybe exploited for use as an anti-cancer agent. C1 [Viard, Mathias; Garg, Himanshu; Blumenthal, Robert; Raviv, Yossef] NCI, Nanobiol Program, Ctr Canc Res, Frederick, MD 21701 USA. [Viard, Mathias; Raviv, Yossef] NCI, Basic Res Program, SAIC Frederick Inc, NIH, Frederick, MD 21701 USA. RP Blumenthal, R (reprint author), NCI, Nanobiol Program, Ctr Canc Res, Frederick, MD 21701 USA. EM viardm@mail.ncifcrf.gov; hgarg75@gmail.com; blumenthalr@mail.nih.gov; yraviv@ncifcrf.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; National Institutes of Health [NO1-CO-12400] FX We thank members of the Blumenthal Lab for their help with the studies and insightful comments. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the United States Government. NR 56 TC 1 Z9 1 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2121 J9 BMC CELL BIOL JI BMC Cell Biol. PD MAR 26 PY 2009 VL 10 AR 21 DI 10.1186/1471-2121-10-21 PG 14 WC Cell Biology SC Cell Biology GA 440HS UT WOS:000265692000001 PM 19323821 ER PT J AU Islami, F Pourshams, A Nasrollahzadeh, D Kamangar, F Fahimi, S Shakeri, R Abedi-Ardekani, B Merat, S Vahedi, H Semnani, S Abnet, CC Brennan, P Moller, H Saidi, F Dawsey, SM Malekzadeh, R Boffetta, P AF Islami, Farhad Pourshams, Akram Nasrollahzadeh, Dariush Kamangar, Farin Fahimi, Saman Shakeri, Ramin Abedi-Ardekani, Behnoush Merat, Shahin Vahedi, Homayoon Semnani, Shahryar Abnet, Christian C. Brennan, Paul Moller, Henrik Saidi, Farrokh Dawsey, Sanford M. Malekzadeh, Reza Boffetta, Paolo TI Tea drinking habits and oesophageal cancer in a high risk area in northern Iran: population based case-control study SO BRITISH MEDICAL JOURNAL LA English DT Article ID SQUAMOUS-CELL CARCINOMA; POLYCYCLIC AROMATIC-HYDROCARBONS; NORTHEASTERN IRAN; GOLESTAN COHORT; TP53 MUTATIONS; MATE DRINKING; P53 MUTATIONS; RATS; CHEMOPREVENTION; TUMORIGENESIS AB Objective To investigate the association between tea drinking habits in Golestan province, northern Iran, and risk of oesophageal squamous cell carcinoma. Design Population based case-control study. In addition, patterns of tea drinking and temperature at which tea was drunk were measured among healthy participants in a cohort study. Setting Golestan province, northern Iran, an area with a high incidence of oesophageal squamous cell carcinoma. Participants 300 histologically proved cases of oesophageal squamous cell carcinoma and 571 matched neighbourhood controls in the case-control study and 48 582 participants in the cohort study. Main outcome measure Odds ratio of oesophageal squamous cell carcinoma associated with drinking hot tea. Results Nearly all (98%) of the cohort participants drank black tea regularly, with a mean volume consumed of over one litre a day. 39.0% of participants drank their tea at temperatures less than 60 degrees C, 38.9% at 60-64 degrees C, and 22.0% at 65 degrees C or higher. A moderate agreement was found between reported tea drinking temperature and actual temperature measurements (weighted K 0.49). The results of the case-control study showed that compared with drinking lukewarm or warm tea, drinking hot tea (odds ratio 2.07, 95% confidence interval 1.28 to 3.35) or very hot tea (8.16, 3.93 to 16.9) was associated with an increased risk of oesophageal cancer. Likewise, compared with drinking tea four or more minutes after being poured, drinking tea 2-3 minutes after pouring (2.49, 1.62 to 3.83) or less than two minutes after pouring (5.41, 2.63 to 11.1) was associated with a significantly increased risk. A strong agreement was found between responses to the questions on temperature at which tea was drunk and interval from tea being poured to being drunk (weighted K 0.68). Conclusion Drinking hot tea, a habit common in Golestan province, was strongly associated with a higher risk of oesophageal cancer. C1 [Islami, Farhad; Pourshams, Akram; Nasrollahzadeh, Dariush; Fahimi, Saman; Shakeri, Ramin; Abedi-Ardekani, Behnoush; Merat, Shahin; Vahedi, Homayoon; Saidi, Farrokh; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran 14117, Iran. [Islami, Farhad; Brennan, Paul; Boffetta, Paolo] Int Agcy Res Canc, F-69372 Lyon, France. [Islami, Farhad; Moller, Henrik] Kings Coll London, Thames Canc Registry, London, England. [Nasrollahzadeh, Dariush] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Kamangar, Farin; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fahimi, Saman] Univ Cambridge, Inst Publ Hlth, Dept Publ Hlth & Primary Care, Cambridge CB2 1TN, England. [Semnani, Shahryar] Gorgan Univ Med Sci, Golestan Res Ctr Gastroenterol & Hepatol, Gorgan, Iran. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran 14117, Iran. EM malek@ams.ac.ir; boffetta@iarc.fr RI Abnet, Christian/C-4111-2015; Semnani, Shahryar/N-2270-2016; Abedi-Ardekani, Behnoush/O-7829-2016; OI Abnet, Christian/0000-0002-3008-7843; Semnani, Shahryar/0000-0002-8768-6142; Abedi-Ardekani, Behnoush/0000-0002-0980-0587; , Ramin/0000-0003-0487-3629; Moller, Henrik/0000-0001-8200-5929; Malekzadeh, Reza/0000-0003-1043-3814 FU Intramural NIH HHS NR 48 TC 102 Z9 105 U1 2 U2 24 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD MAR 26 PY 2009 VL 338 AR b929 DI 10.1136/bmj.b929 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 425LR UT WOS:000264639700004 PM 19325180 ER PT J AU Choi, WJ Kim, SE Stephen, AG Weidlich, I Giubellino, A Liu, F Worthy, KM Bindu, L Fivash, MJ Nicklaus, MC Bottaro, DP Fisher, RJ Burke, TR AF Choi, Won Jun Kim, Sung-Eun Stephen, Andrew G. Weidlich, Iwona Giubellino, Alessio Liu, Fa Worthy, Karen M. Bindu, Lakshman Fivash, Matthew J. Nicklaus, Marc C. Bottaro, Donald P. Fisher, Robert J. Burke, Terrence R., Jr. TI Identification of Shc Src Homology 2 Domain-Binding Peptoid-Peptide Hybrids SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RING-CLOSING METATHESIS; SIGNAL-TRANSDUCTION; ADAPTER PROTEIN; GRB2; RECEPTOR; RECOGNITION AB A fluorescence anisotropy (FA) competition-based Shc Src homology 2 (SH2) domain-binding was established using the high affinity fluorescein isothiocyanate (FITC) containing peptide, FITC-NH-(CH(2))(4)-CO-pY-Q-G-L-S-amide (8; K(d) = 0.35 mu M). Examination of a series of open-chain bis-alkenylamide containing peptides, prepared as ring-closing metathesis precursors, showed that the highest affinities were obtained by replacement of the original Gly residue with N(alpha)-substituted Gly (NSG) "peptoid" residues. This provided peptoid-peptide hybrids of the form "Ac-pY-Q-[NSG]-L-amide." Depending on the NSG substituent, certain of these hybrids exhibited up to 40-fold higher Shc SH2 domain-binding affinity than the parent Gly-containing peptide (IC(50) = 248 mu M) (for example, for N-homoallyl analogue 50, IC(50) = 6 mu M). To our knowledge, this work represents the first successful example of the application of peptoid-peptide hybrids in the design of SH2 domain-binding antagonists. These results could provide a foundation for further structural optimization of She SH2 domain-binding peptide mimetics. C1 [Choi, Won Jun; Kim, Sung-Eun; Weidlich, Iwona; Liu, Fa; Nicklaus, Marc C.; Burke, Terrence R., Jr.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Stephen, Andrew G.; Worthy, Karen M.; Bindu, Lakshman; Fisher, Robert J.] SAIC Frederick, Prot Chem Lab, Adv Technol Program, Frederick, MD 21702 USA. [Giubellino, Alessio; Bottaro, Donald P.] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fivash, Matthew J.] NCI, Data Management Serv Inc, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Fisher, Robert/B-1431-2009; Bottaro, Donald/F-8550-2010; liu, feng/J-4669-2013; Nicklaus, Marc/N-4183-2014; Burke, Terrence/N-2601-2014; OI Bottaro, Donald/0000-0002-5057-5334; Nicklaus, Marc/0000-0002-4775-7030; Giubellino, Alessio/0000-0002-5352-0662 FU NIH [N01-CO-12400] FX Appreciation is expressed to Dr. Oleg Chertov for purification of Shc SH2 domain protein. The work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, NCI-Frederick, and the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400. NR 30 TC 5 Z9 5 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 26 PY 2009 VL 52 IS 6 BP 1612 EP 1618 DI 10.1021/jm800789h PG 7 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 421VD UT WOS:000264385500017 PM 19226165 ER PT J AU Cohen, JA Podgornik, R Hansen, PL Parsegian, VA AF Cohen, J. A. Podgornik, R. Hansen, P. L. Parsegian, V. A. TI A Phenomenological One-Parameter Equation of State for Osmotic Pressures of PEG and Other Neutral Flexible Polymers in Good Solvents SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID STERICALLY STABILIZED LIPOSOMES; EXPONENTS; STRESS; WATER AB We present a phenomenological one-parameter scaling equation of state that accurately represents osmotic pressures of neutral flexible polymers in good solvents from the dilute through the semidilute regime. The equation comprises a sum of scaled van't Hoff and des Cloizeaux terms including a fitted parameter alpha, the "crossover index", which encapsulates all chemical specificity and determines the relevant prefactors. Strikingly different values of alpha are found for the two very different systems poly(ethyleneglycol)/water (PEG) and poly(alpha-methylstyrene)/toluene (PAMS). alpha-dependent rescaling collapses both data sets to a simple one-parameter scaling function. The fact that the anomalous system PEG/water and the canonical system PAMS/toluene can both be described by the same equation of state attests to the robustness of the polymer-scaling concepts introduced by de Gennes. C1 [Cohen, J. A.; Podgornik, R.; Hansen, P. L.; Parsegian, V. A.] NICHD, Lab Phys & Struct Biol, PPB, NIH, Bethesda, MD 20892 USA. [Cohen, J. A.] Univ Pacific, AA Dugoni Sch Dent, Dept Physiol, San Francisco, CA 94115 USA. [Podgornik, R.] Univ Ljubljana, Dept Phys, Fac Math & Phys, SI-1000 Ljubljana, Slovenia. [Podgornik, R.] Jozef Stefan Inst, Dept Theoret Phys, SI-1000 Ljubljana, Slovenia. [Hansen, P. L.] Univ So Denmark, Ctr Biomembrane Phys, DK-5230 Odense, Denmark. RP Cohen, JA (reprint author), NICHD, Lab Phys & Struct Biol, PPB, NIH, Bethesda, MD 20892 USA. EM jcohen@pacific.edu RI Podgornik, Rudolf/C-6209-2008 OI Podgornik, Rudolf/0000-0002-3855-4637 FU NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank M. Rubinstein, R. Colby, A. Berezhkovskii, and S. Bezrukov. This study was supported by the Intramural Research Program of NIH, Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 37 TC 32 Z9 32 U1 4 U2 28 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAR 26 PY 2009 VL 113 IS 12 BP 3709 EP 3714 DI 10.1021/jp806893a PG 6 WC Chemistry, Physical SC Chemistry GA 421HB UT WOS:000264348900015 PM 19265418 ER PT J AU Resnik, DB AF Resnik, David B. TI Review: necessary for protection even in minimal-risk research SO NATURE LA English DT Letter C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [ZIA ES102646-02] NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 26 PY 2009 VL 458 IS 7237 BP 404 EP 404 DI 10.1038/458404c PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 423YJ UT WOS:000264532400017 PM 19325605 ER PT J AU Ishii, M Egen, JG Klauschen, F Meier-Schellersheim, M Saeki, Y Vacher, J Proia, RL Germain, RN AF Ishii, Masaru Egen, Jackson G. Klauschen, Frederick Meier-Schellersheim, Martin Saeki, Yukihiko Vacher, Jean Proia, Richard L. Germain, Ronald N. TI Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis SO NATURE LA English DT Article ID PROTEIN-COUPLED RECEPTOR; SPHINGOSINE 1-PHOSPHATE; CELL-MIGRATION; VASCULAR MATURATION; LYMPHOID ORGANS; TRANSGENIC MICE; T-CELLS; MARROW; EXPRESSION; COLLAGEN AB Osteoclasts are the only somatic cells with bone-resorbing capacity and, as such, they have a critical role not only in normal bone homeostasis (called 'bone remodelling') but also in the pathogenesis of bone destructive disorders such as rheumatoid arthritis and osteoporosis(1). A major focus of research in the field has been on gene regulation by osteoclastogenic cytokines such as receptor activator of NF-kappa B-ligand (RANKL, also known as TNFSF11) and TNF-alpha, both of which have been well documented to contribute to osteoclast terminal differentiation(2,3). A crucial process that has been less well studied is the trafficking of osteoclast precursors to and from the bone surface, where they undergo cell fusion to form the fully differentiated multinucleated cells that mediate bone resorption. Here we report that sphingosine-1-phosphate (S1P), a lipid mediator enriched in blood(4,5), induces chemotaxis and regulates the migration of osteoclast precursors not only in culture but also in vivo, contributing to the dynamic control of bone mineral homeostasis. Cells with the properties of osteoclast precursors express functional S1P(1) receptors and exhibit positive chemotaxis along an S1P gradient in vitro. Intravital two-photon imaging of bone tissues showed that a potent S1P(1) agonist, SEW2871, stimulated motility of osteoclast precursor-containing monocytoid populations in vivo. Osteoclast/monocyte (CD11b, also known as ITGAM) lineage-specific conditional S1P(1) knockout mice showed osteoporotic changes due to increased osteoclast attachment to the bone surface. Furthermore, treatment with the S1P(1) agonist FTY720 relieved ovariectomy-induced osteoporosis in mice by reducing the number of mature osteoclasts attached to the bone surface. Together, these data provide evidence that S1P controls the migratory behaviour of osteoclast precursors, dynamically regulating bone mineral homeostasis, and identifies a critical control point in osteoclastogenesis that may have potential as a therapeutic target. C1 [Ishii, Masaru; Egen, Jackson G.; Germain, Ronald N.] NIDDK, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Klauschen, Frederick; Meier-Schellersheim, Martin; Germain, Ronald N.] NIDDK, Program Syst Immunol & Infect Dis Modeling, NIAID, NIH, Bethesda, MD 20892 USA. [Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Ishii, Masaru] Osaka Univ, WPI Immunol Frontier Res Ctr, Lab Biol Imaging, Suita, Osaka 5650871, Japan. [Ishii, Masaru; Saeki, Yukihiko] Natl Osaka Minami Med Ctr, Dept Clin Res, Osaka 5868521, Japan. [Vacher, Jean] Clin Res Inst Montreal, Montreal, PQ H2W 1R7, Canada. RP Germain, RN (reprint author), NIDDK, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM rgermain@niaid.nih.gov RI Ishii, Masaru/D-2361-2009; Proia, Richard/A-7908-2012; Klauschen, Frederick/C-5637-2015; OI Egen, Jackson/0000-0003-2053-0837 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases; NIH; US Department of Health and Human Services; International Human Frontier Science Program FX We thank U. H. von Andrian and I. B. Mazo for their help with the technique of intravital skull bone imaging. We also thank Y. Takuwa and N. Sugimoto for discussions, and P. M. Murphy and S. Venkatesan for their help in imaging in vitro chemotaxis using the EZ-Taxiscan. This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH, US Department of Health and Human Services, and by a fellowship grant to M. I. from the International Human Frontier Science Program. NR 29 TC 215 Z9 224 U1 5 U2 36 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 26 PY 2009 VL 458 IS 7237 BP 524 EP U8 DI 10.1038/nature07713 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 423YJ UT WOS:000264532400048 PM 19204730 ER PT J AU Pan, BX Dong, YL Ito, W Yanagawa, Y Shigemoto, R Morozov, A AF Pan, Bing-Xing Dong, Yulin Ito, Wataru Yanagawa, Yuchio Shigemoto, Ryuichi Morozov, Alexei TI Selective Gating of Glutamatergic Inputs to Excitatory Neurons of Amygdala by Presynaptic GABAb Receptor SO NEURON LA English DT Article ID LONG-TERM POTENTIATION; LATERAL AMYGDALA; TRANSMITTER RELEASE; GABAERGIC NEURONS; HETEROSYNAPTIC DEPRESSION; IMMUNOREACTIVE NEURONS; SYNAPTIC-TRANSMISSION; BASOLATERAL AMYGDALA; NERVE-TERMINALS; RAT HIPPOCAMPUS AB GABAb receptor (GABAbR)-mediated suppression of glutamate release is critical for limiting glutamatergic transmission across the central nervous system (CNS). Here we show that, upon tetanic stimulation of afferents to lateral amygdala, presynaptic GABAbR-mediated inhibition only occurs in glutamatergic inputs to principle neurons (PNs), not to inter-neurons (INs), despite the presence of GABAbR in terminals to both types of neurons. The selectivity is caused by differential local GABA accumulation; it requires GABA reuptake and parallels distinct spatial distributions of presynaptic GABAbR in terminals to PNs and INs. Moreover, GABAbR-mediated suppression of theta-burst-induced long-term potentiation (LTP) occurs only in the inputs to PNs, not to INs. Thus, target-cell-specific control of glutamate release by presynaptic GABAbR orchestrates the inhibitory dominance inside amygdala and might contribute to prevention of nonadaptive defensive behaviors. C1 [Pan, Bing-Xing; Ito, Wataru; Morozov, Alexei] NIMH, Unit Behav Genet, Mol Pathophysiol Lab, NIH, Bethesda, MD 20892 USA. [Dong, Yulin; Shigemoto, Ryuichi] Natl Inst Physiol Sci, Div Cerebral Struct, Okazaki, Aichi 4448787, Japan. [Yanagawa, Yuchio] Gunma Univ, Grad Sch Med, Dept Genet & Behav Neurosci, Maebashi, Gumma 3718511, Japan. RP Pan, BX (reprint author), NIMH, Unit Behav Genet, Mol Pathophysiol Lab, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM panb@mail.nih.gov; morozova@mail.nih.gov RI PAN, BINGXING/C-7870-2011 FU NIMH Intramural Research Program; SORST; Japan Science and Technology Agency; MEXT, Japan FX This research was supported by NIMH Intramural Research Program, grant from SORST, Japan Science and Technology Agency, and Grant-in-Aids for Scientific Research from the MEXT, Japan. We thank Chris McBain and Vadim Bolshakov for comments on the manuscript. NR 53 TC 43 Z9 44 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 26 PY 2009 VL 61 IS 6 BP 917 EP 929 DI 10.1016/j.neuron.2009.01.029 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 426XJ UT WOS:000264741400012 PM 19324000 ER PT J AU Tobian, AAR Serwadda, D Quinn, TC Kigozi, G Gravitt, PE Laeyendecker, O Charvat, B Ssempijja, V Riedesel, M Oliver, AE Nowak, RG Moulton, LH Chen, MZ Reynolds, SJ Wawer, MJ Gray, RH AF Tobian, Aaron A. R. Serwadda, David Quinn, Thomas C. Kigozi, Godfrey Gravitt, Patti E. Laeyendecker, Oliver Charvat, Blake Ssempijja, Victor Riedesel, Melissa Oliver, Amy E. Nowak, Rebecca G. Moulton, Lawrence H. Chen, Michael Z. Reynolds, Steven J. Wawer, Maria J. Gray, Ronald H. TI Male Circumcision for the Prevention of HSV-2 and HPV Infections and Syphilis SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SIMPLEX-VIRUS TYPE-2; SEXUALLY-TRANSMITTED INFECTIONS; HUMAN-PAPILLOMAVIRUS INFECTION; RANDOMIZED CONTROLLED-TRIAL; HIV-INFECTION; GENITAL HERPES; CERVICAL-CANCER; YOUNG MEN; PREVALENCE; UGANDA AB Background Male circumcision significantly reduced the incidence of human immunodeficiency virus (HIV) infection among men in three clinical trials. We assessed the efficacy of male circumcision for the prevention of herpes simplex virus type 2 (HSV-2) and human papillomavirus (HPV) infections and syphilis in HIV-negative adolescent boys and men. Methods We enrolled 5534 HIV-negative, uncircumcised male subjects between the ages of 15 and 49 years in two trials of male circumcision for the prevention of HIV and other sexually transmitted infections. Of these subjects, 3393 (61.3%) were HSV-2-seronegative at enrollment. Of the seronegative subjects, 1684 had been randomly assigned to undergo immediate circumcision (intervention group) and 1709 to undergo circumcision after 24 months (control group). At baseline and at 6, 12, and 24 months, we tested subjects for HSV-2 and HIV infection and syphilis, along with performing physical examinations and conducting interviews. In addition, we evaluated a subgroup of subjects for HPV infection at baseline and at 24 months. Results At 24 months, the cumulative probability of HSV-2 seroconversion was 7.8% in the intervention group and 10.3% in the control group (adjusted hazard ratio in the intervention group, 0.72; 95% confidence interval [CI], 0.56 to 0.92; P = 0.008). The prevalence of high-risk HPV genotypes was 18.0% in the intervention group and 27.9% in the control group (adjusted risk ratio, 0.65; 95% CI, 0.46 to 0.90; P = 0.009). However, no significant difference between the two study groups was observed in the incidence of syphilis (adjusted hazard ratio, 1.10; 95% CI, 0.75 to 1.65; P = 0.44). Conclusions In addition to decreasing the incidence of HIV infection, male circumcision significantly reduced the incidence of HSV-2 infection and the prevalence of HPV infection, findings that underscore the potential public health benefits of the procedure. (ClinicalTrials.gov numbers, NCT00425984 and NCT00124878.) C1 [Tobian, Aaron A. R.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Quinn, Thomas C.; Laeyendecker, Oliver; Oliver, Amy E.; Reynolds, Steven J.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Gravitt, Patti E.; Nowak, Rebecca G.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol & Mol Microbiol & Immunol, Baltimore, MD USA. [Charvat, Blake; Chen, Michael Z.; Wawer, Maria J.; Gray, Ronald H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Populat Family & Reprod Hlth, Baltimore, MD USA. [Moulton, Lawrence H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth & Biostat, Baltimore, MD USA. [Serwadda, David] Makerere Univ, Inst Publ Hlth, Kampala, Uganda. [Kigozi, Godfrey; Ssempijja, Victor] Rakai Hlth Sci Program, Entebbe, Uganda. [Quinn, Thomas C.; Laeyendecker, Oliver; Riedesel, Melissa; Reynolds, Steven J.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Quinn, TC (reprint author), Rangos Bldg,Rm 530,855 N Wolfe St, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760; Moulton, Lawrence/0000-0001-7041-7387 FU National Institutes of Health [U01-AI-51171]; Bill and Melinda Gates Foundation [22006.02]; Fogarty International Center [5D43TW001508, D43TW00015]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases FX Supported by grants from the National Institutes of Health (U01-AI-51171), the Bill and Melinda Gates Foundation (22006.02), and the Fogarty International Center (5D43TW001508 and D43TW00015) and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 41 TC 239 Z9 260 U1 1 U2 16 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 26 PY 2009 VL 360 IS 13 BP 1298 EP 1309 DI 10.1056/NEJMoa0802556 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 423VP UT WOS:000264524100005 PM 19321868 ER PT J AU Andriole, GL Grubb, RL Buys, SS Chia, D Church, TR Fouad, MN Gelmann, EP Kvale, PA Reding, DJ Weissfeld, JL Yokochi, LA Crawford, ED O'Brien, B Clapp, JD Rathmell, JM Riley, TL Hayes, RB Kramer, BS Izmirlian, G Miller, AB Pinsky, PF Prorok, PC Gohagan, JK Berg, CD AF Andriole, Gerald L. Grubb, Robert L., III Buys, Saundra S. Chia, David Church, Timothy R. Fouad, Mona N. Gelmann, Edward P. Kvale, Paul A. Reding, Douglas J. Weissfeld, Joel L. Yokochi, Lance A. Crawford, E. David O'Brien, Barbara Clapp, Jonathan D. Rathmell, Joshua M. Riley, Thomas L. Hayes, Richard B. Kramer, Barnett S. Izmirlian, Grant Miller, Anthony B. Pinsky, Paul F. Prorok, Philip C. Gohagan, John K. Berg, Christine D. CA PLCO Project Team TI Mortality Results from a Randomized Prostate-Cancer Screening Trial SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID QUALITY-OF-LIFE; RADICAL PROSTATECTOMY; ANDROGEN DEPRIVATION; RADIATION-THERAPY; RISK-FACTORS; OUTCOMES; COMPLICATIONS; BIOPSIES; LUNG AB Background The effect of screening with prostate-specific-antigen (PSA) testing and digital rectal examination on the rate of death from prostate cancer is unknown. This is the first report from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial on prostate-cancer mortality. Methods From 1993 through 2001, we randomly assigned 76,693 men at 10 U. S. study centers to receive either annual screening (38,343 subjects) or usual care as the control (38,350 subjects). Men in the screening group were offered annual PSA testing for 6 years and digital rectal examination for 4 years. The subjects and health care providers received the results and decided on the type of follow-up evaluation. Usual care sometimes included screening, as some organizations have recommended. The numbers of all cancers and deaths and causes of death were ascertained. Results In the screening group, rates of compliance were 85% for PSA testing and 86% for digital rectal examination. Rates of screening in the control group increased from 40% in the first year to 52% in the sixth year for PSA testing and ranged from 41 to 46% for digital rectal examination. After 7 years of follow-up, the incidence of prostate cancer per 10,000 person-years was 116 (2820 cancers) in the screening group and 95 (2322 cancers) in the control group (rate ratio, 1.22; 95% confidence interval [CI], 1.16 to 1.29). The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the control group (rate ratio, 1.13; 95% CI, 0.75 to 1.70). The data at 10 years were 67% complete and consistent with these overall findings. Conclusions After 7 to 10 years of follow-up, the rate of death from prostate cancer was very low and did not differ significantly between the two study groups. (ClinicalTrials.gov number, NCT00002540.) C1 [Berg, Christine D.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Andriole, Gerald L.; Grubb, Robert L., III] Washington Univ, Sch Med, St Louis, MO USA. [Buys, Saundra S.] Huntsman Canc Inst, Salt Lake City, UT USA. [Chia, David] Univ Calif Los Angeles, Immunogenet Ctr, Los Angeles, CA USA. [Church, Timothy R.] Univ Minnesota, Minneapolis, MN USA. [Fouad, Mona N.] Univ Alabama, Med Sch Birmingham, Birmingham, AL USA. [Gelmann, Edward P.] Georgetown Univ, Lombardi Canc Ctr, Washington, DC USA. [Kvale, Paul A.] Henry Ford Hlth Syst, Detroit, MI USA. [Reding, Douglas J.] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. [Weissfeld, Joel L.] Univ Pittsburgh, Med Ctr Canc Pavil, Pittsburgh, PA USA. [Yokochi, Lance A.] Pacific Hlth Res Inst, Honolulu, HI USA. [Crawford, E. David] Univ Colorado, Anschutz Canc Pavil, Denver, CO 80202 USA. [O'Brien, Barbara] WESTAT Corp, Rockville, MD 20850 USA. [Clapp, Jonathan D.; Rathmell, Joshua M.; Riley, Thomas L.] Informat Management Serv Inc, Rockville, MD USA. [Kramer, Barnett S.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. [Miller, Anthony B.] Univ Toronto, Dalla Lana Sch Publ Hlth, Toronto, ON, Canada. RP Berg, CD (reprint author), NCI, Canc Prevent Div, NIH, 6130 Execut Blvd,Rm 3112, Bethesda, MD 20892 USA. EM bergc@mail.nih.gov RI Schliep, Karen/A-2803-2012; OI Church, Timothy R./0000-0003-3292-5035 FU National Cancer Institute FX Supported by contracts from the National Cancer Institute. NR 33 TC 1511 Z9 1562 U1 8 U2 86 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 26 PY 2009 VL 360 IS 13 BP 1310 EP 1319 DI 10.1056/NEJMoa0810696 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 423VP UT WOS:000264524100006 PM 19297565 ER PT J AU Perera, PY Derrick, SC Kolibab, K Momoi, F Yamamoto, M Morris, SL Waldmann, TA Perera, LR AF Perera, Pin-Yu Derrick, Steven C. Kolibab, Kristopher Momoi, Fumiki Yamamoto, Masafumi Morris, Sheldon L. Waldmann, Thomas A. Perera, Liyanage R. TI A multi-valent vaccinia virus-based tuberculosis vaccine molecularly adjuvanted with interleukin-15 induces robust immune responses in mice SO VACCINE LA English DT Article DE Tuberculosis; Vaccines; IL-15 ID CD8(+) T-CELLS; MYCOBACTERIUM-TUBERCULOSIS; INTERFERON-GAMMA; ANTIGEN 85A; IL-15; INFECTION; BCG; DIFFERENTIATION; IMMUNIZATION; PROTECTION AB Tuberculosis caused by Mycobacterium tuberculosis is responsible for nearly two million deaths every year globally. A single licensed vaccine derived from Mycobacterium bovis, bacille Calmette-Guerin (BCG) administered perinatally as a prophylactic vaccine has been in use for over 80 years and confers substantial protection against childhood tuberculous meningitis and miliary tuberculosis. However, the BCG Vaccine is Virtually ineffective against the adult pulmonary form of tuberculosis that is pivotal in the transmission Of tuberculosis that has infected almost 33% of the global population. Thus, an effective vaccine to both prevent tuberculosis and reduce its transmission is urgently needed. We have generated a multi-valent, vectored vaccine candidate utilizing the modified virus Ankara (MVA) strain of vaccinia virus to tandemly express five antigens, ESAT6, Ag85A, Ag85B, HSP65 and Mtb39A of M. tuberculosis that have been reported to be protective individually in certain animal models together with an immunostimulatory cytokine interleukin-15 (MVA/IL-15/5Mtb). Although, immunological correlates of protection against tuberculosis in humans remain to be established, we demonstrate that our vaccine induced comparable CD4(+) T cell and greater CD8(+) T cell and antibody responses against M. tuberculosis in vaccinated mice in a direct comparison with the BCG vaccine and conferred protection against an aerogenic challenge of M. tuberculosis, thus warranting its further preclinical development. Published by Elsevier Ltd. C1 [Waldmann, Thomas A.; Perera, Liyanage R.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Perera, Pin-Yu] Vet Affairs Med Ctr, Washington, DC 20422 USA. [Derrick, Steven C.; Kolibab, Kristopher; Morris, Sheldon L.] US FDA, Lab Mycobacterial Dis & Cellular Immunol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Momoi, Fumiki; Yamamoto, Masafumi] Nihon Univ, Sch Dent Matsudo, Dept Microbiol & Immunol, Chiba 2718587, Japan. RP Perera, LR (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10,Room 4B40, Bethesda, MD 20892 USA. EM pereral@mail.nih.gov FU National Cancer Institute; NIH; Trans-NIH/FDA Intramural Biodefense Program FX This work was in part supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, NIH and by a 3-year competitive research funding award to L.P.P. from the Trans-NIH/FDA Intramural Biodefense Program. NR 28 TC 16 Z9 19 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAR 26 PY 2009 VL 27 IS 15 BP 2121 EP 2127 DI 10.1016/j.vaccine.2009.01.132 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 426AW UT WOS:000264680800007 PM 19356615 ER PT J AU Shirota, H Petrenko, L Hattori, T Klinman, DM AF Shirota, Hidekazu Petrenko, Lev Hattori, Toshio Klinman, Dennis M. TI Contribution of IRF-3 mediated IFN beta production to DNA vaccine dependent cellular immune responses SO VACCINE LA English DT Article DE DNA vaccine; IRF-3; Type 1 IFNs ID PLASMID DNA; GENE-EXPRESSION; CPG MOTIFS; T-CELLS; INNATE; MICE; ACTIVATION; PROTEIN; IMMUNOGENICITY; RECOGNITION AB The mechanism(s) by which DNA vaccines activate Ag-specific cellular immune responses is incompletely understood. Current findings indicate that IRF-3 plays an important role in this process. The IRF-3 dependent signaling pathway is triggered by the presence of intracytoplasmic DNA, and culminates in the production of type 1 IFNs. DNA vaccination of IRF-3 KO mice elicits a strong Ag-specific humoral response, yet CD4 and CD8 T cell responses (including the production of Th1, Th2 and Th17 cytokines) are severely impaired. Although expression of the immunogenic protein encoded by the DNA vaccine was similar in IRF-3 KO vs wild type mice, antigen presentation was severely impaired in the KO animals. This defect was remedied by the co-delivery of an IFN beta encoding plasmid. These findings suggest that the IRF-3/IFN beta pathways are key to the induction of cellular immunity following DNA vaccination. Published by Elsevier Ltd. C1 [Shirota, Hidekazu; Petrenko, Lev; Klinman, Dennis M.] NCI, Expt Immunol Lab, Frederick, MD 21702 USA. [Shirota, Hidekazu; Hattori, Toshio] Tohoku Univ, Sch Med, Dept Resp & Infect Dis, Sendai, Miyagi 980, Japan. RP Klinman, DM (reprint author), NCI, Expt Immunol Lab, Bldg 567,Room 205, Frederick, MD 21702 USA. EM klinmand@mail.nih.gov FU National Cancer Institute [261200800001 E] FX The authors thank Dr. Tadatsugu Taniguchi for kindly providing IRF-3 KO mice. This project was supported by funding from the intramural research program of the National Cancer Institute and contract #261200800001 E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsment by the U.S. Government NR 28 TC 8 Z9 8 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAR 26 PY 2009 VL 27 IS 15 BP 2144 EP 2149 DI 10.1016/j.vaccine.2009.01.134 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 426AW UT WOS:000264680800010 PM 19356618 ER PT J AU Ptak, K Yamanishi, T Aungst, J Milescu, LS Zhang, R Richerson, GB Smith, JC AF Ptak, Krzysztof Yamanishi, Tadashi Aungst, Jason Milescu, Lorin S. Zhang, Ruli Richerson, George B. Smith, Jeffrey C. TI Raphe Neurons Stimulate Respiratory Circuit Activity by Multiple Mechanisms via Endogenously Released Serotonin and Substance P SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PRE-BOTZINGER COMPLEX; CHRONIC INTERMITTENT HYPOXIA; PERSISTENT SODIUM CURRENT; BRAIN-STEM SLICES; RAT IN-VITRO; RHYTHM GENERATION; PACEMAKER NEURONS; RECEPTOR SUBTYPES; AWAKE RATS; MOTONEURONS AB Brainstem serotonin (5-HT) neurons modulate activity of many neural circuits in the mammalian brain, but in many cases endogenous mechanisms have not been resolved. Here, we analyzed actions of raphe 5-HT neurons on respiratory network activity including at the level of the pre-Botzinger complex (pre-BotC) in neonatal rat medullary slices in vitro, and in the more intact nervous system of juvenile rats in arterially perfused brainstem-spinal cord preparations in situ. At basal levels of activity, excitation of the respiratory network via simultaneous release of 5-HT and substance P (SP), acting at 5-HT(2A/2C), 5-HT(4), and/or neurokinin-1 receptors, was required to maintain inspiratory motor output in both the neonatal and juvenile systems. The midline raphe obscurus contained spontaneously active 5-HT neurons, some of which projected to the pre-BotC and hypoglossal motoneurons, colocalized 5-HT and SP, and received reciprocal excitatory connections from the pre-BotC. Experimentally augmenting raphe obscurus activity increased motor output by simultaneously exciting pre-BotC and motor neurons. Biophysical analyses in vitro demonstrated that 5-HT and SP modulated background cation conductances in pre-BotC and motor neurons, including a nonselective cation leak current that contributed to the resting potential, which explains the neuronal depolarization that augmented motor output. Furthermore, we found that 5-HT, but not SP, can transform the electrophysiological phenotype of some pre-BotC neurons to intrinsic bursters, providing 5-HT with an additional role in promoting rhythm generation. We conclude that raphe 5-HT neurons excite key circuit components required for generation of respiratory motor output. C1 [Ptak, Krzysztof; Yamanishi, Tadashi; Aungst, Jason; Milescu, Lorin S.; Zhang, Ruli; Smith, Jeffrey C.] NINDS, Cellular & Syst Neurobiol Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Richerson, George B.] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06520 USA. [Richerson, George B.] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA. [Richerson, George B.] Vet Adm Med Ctr, Dept Neurol, West Haven, CT 06516 USA. RP Smith, JC (reprint author), NINDS, Cellular & Syst Neurobiol Sect, Porter Neurosci Res Ctr, NIH, Bldg 35,Room 3C-917,35 Convent Dr, Bethesda, MD 20892 USA. EM jsmith@helix.nih.gov FU National Institutes of Health-National Institute of Neurological Disorders and Stroke; National Institutes of Health [P01HD36379]; Veterans Affairs Medical Center and Bumpus Foundation FX This research was supported by the Intramural Research Program of the National Institutes of Health-National Institute of Neurological Disorders and Stroke and in part by Grant P01HD36379 from the National Institutes of Health, and by grants from the Veterans Affairs Medical Center and Bumpus Foundation. NR 60 TC 123 Z9 124 U1 0 U2 7 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 MAR 25 PY 2009 VL 29 IS 12 BP 3720 EP 3737 DI 10.1523/JNEUROSCI.5271-08.2009 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 424DE UT WOS:000264544900007 PM 19321769 ER PT J AU Yang, HL Chen, WQ Cao, X Worschech, A Du, LF Fang, WY Xu, YY Stroncek, DF Li, X Wang, E Marincola, FM AF Yang, Hui-ling Chen, Wei-qiong Cao, Xuan Worschech, Andrea Du, Li-fen Fang, Wei-yi Xu, Yang-yan Stroncek, David F. Li, Xin Wang, Ena Marincola, Francesco M. TI Caveolin-1 enhances resveratrol-mediated cytotoxicity and transport in a hepatocellular carcinoma model SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID CELL-PROLIFERATION; ENDOTHELIAL-CELLS; INDUCED APOPTOSIS; EXPRESSION; MECHANISM; CANCER; BETA; PHOSPHORYLATION; ADENOCARCINOMA; RESISTANCE AB Background: Resveratrol (RES), an estrogen analog, is considered as a potential cancer chemo-preventive agent. However, it remains unclear how RES is transported into cells. In this study, we observed that Caveolin-1(CAV1) expression can increase the cytotoxic and pro-apoptotic activity of RES in a dose- and time-dependent manner both in vitro and in vivo in a Hepatocellular Carcinoma animal model. Methods: High performance liquid chromatography (HPLC) demonstrated that RES intra-cellular concentration is increased about 2-fold in cells stably expressing CAV1 or CAVM1 (a scaffolding domain (81-101AA)-defective CAV1 mutant) compared to the untransduced human Hepatoblastoma cell line (HepG2) or after transduction with the green fluorescent protein (GFP) control vector. The increased intra-cellular transport of RES was abolished in cells stably expressing CAVM2 (a cholesterol shuttle domain (143-156AA)-defective CAV1 mutant) or CAVRNAi. In order to further characterize CAV1-dependent RES transport, we synthesized RES-dansyl chloride derivatives as fluorescent probes to visualize the transport process, which demonstrated a distribution consistent with that of CAV1 in HepG2 cells. Results: In addition, RES endocytosis was not mediated by estrogen receptor (ER) alpha and beta, as suggested by lack of competitive inhibition by estrogen or Tamoxifen. Pathway analysis showed that RES can up-regulate the expression of endogenous CAV1; this activates further the MAPK pathway and caspase-3 expression. Discussion: This study provides novel insights about the role played by CAV1 in modulating cellular sensitivity to RES through enhancement of its internalization and trafficking. C1 [Worschech, Andrea; Wang, Ena; Marincola, Francesco M.] Natl Inst Hlth, CHI, Bethesda, MD 20892 USA. [Worschech, Andrea; Wang, Ena; Marincola, Francesco M.] Natl Inst Hlth, IDIS, Dept Transfus Med, Bethesda, MD 20892 USA. [Yang, Hui-ling; Chen, Wei-qiong] Univ S China, Affiliated Hosp 1, Inst Clin Med, Hengyang 421001, Peoples R China. [Yang, Hui-ling; Chen, Wei-qiong; Cao, Xuan; Du, Li-fen; Xu, Yang-yan] Univ S China, Inst Pharmacol, Hengyang 421001, Peoples R China. [Yang, Hui-ling; Chen, Wei-qiong; Cao, Xuan; Du, Li-fen; Xu, Yang-yan] Univ S China, Inst Pharm, Hengyang 421001, Peoples R China. [Fang, Wei-yi; Li, Xin] So Med Univ, Canc Res Inst, Guangzhou 510515, Guangdong, Peoples R China. [Worschech, Andrea] Genelux Corp, San Diego Sci Ctr, San Diego, CA USA. [Worschech, Andrea] Univ Wurzburg, Inst Biochem, D-8700 Wurzburg, Germany. [Stroncek, David F.] Natl Inst Hlth, Cellular Proc Sect, Dept Transfus Med, Bethesda, MD USA. RP Yang, HL (reprint author), Univ S China, Affiliated Hosp 1, Inst Clin Med, Hengyang 421001, Peoples R China. EM yanghuiling3018@sina.com; sunnychen823@163.com; inter315@sina.com; worschecha@mail.nih.gov; du-lifen@163.com; fangweiyi1975@yahoo.com.cn; xuhengyuy999@yahoo.com.cn; DStroncek@cc.nih.gov; xinli268@gmail.com; EWang@cc.nih.gov; FMarincola@cc.nih.gov RI Worschech, Andrea/I-3919-2012 OI Worschech, Andrea/0000-0002-4303-8653 FU National Natural Science Foundation of China [30400265, 30671047]; Ministry of Education Science and Technology Key Project [207078]; Youth Foundation of Hunan Province Education Department [06B079]; Hunan Provincial Natural Science Foundation of China [08JJ3016] FX This work was supported by grants from the National Natural Science Foundation of China (No. 30400265 and 30671047), Ministry of Education Science and Technology Key Project (No. 207078), the Youth Foundation of Hunan Province Education Department (No. 06B079) and Hunan Provincial Natural Science Foundation of China (08JJ3016). NR 34 TC 25 Z9 25 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAR 25 PY 2009 VL 7 AR 22 DI 10.1186/1479-5876-7-22 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 447BA UT WOS:000266165400001 PM 19321006 ER PT J AU Arnold, JT AF Arnold, Julia T. TI DHEA metabolism in prostate: For better or worse? SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE DHEA; TGF beta 1; Androgen receptor; Estrogen receptor; Stromal; Epithelial prostate; PSA; Testosterone; Coculture; Red clover isoflavones ID ESTROGEN-RECEPTOR-BETA; CANCER-CELL-LINES; BREAST-CANCER; REACTIVE STROMA; DEHYDROEPIANDROSTERONE; ANDROGEN; PROGRESSION; CARCINOGENESIS; HYPERPLASIA; MECHANISMS AB Dehydroepiandrosterone (DHEA) is commonly used in the USA as a nutritional supplement for antiaging, metabolic support or other uses. Investigations into understanding the effects of DHEA on human prostate cancer progression have posed more questions than answers and highlight the importance of communications between stromal and epithelial tuoitiuot elements within the prostate that contribute to the regulation of DHEA metabolism. Intracrine metabolism of DHEA to androgens (A) and/or estrogens (E) may occur in one cell compartment (stromal) which may release paracrine hormones or growth/inhibitory factors to the epithelial cells. Alternatively no metabolism of DHEA may occur, resulting in no harmful consequences of high levels of DHEA in prostate tissues. We herein review the tissue components involved and interactions with the prohormone, DHEA and/or resulting metabolites, including dihydrotestosterone (DHT) or 17 beta-estradiol (E-2) in an in vitro model of endocrine-immune-paracrine interactions within the prostate. This work raises questions and hypotheses concerning the role of DHEA in prostate in normal tissues, vs. preneoplastic tissues. Published by Elsevier Ireland Ltd. C1 NIH, NCCAM, LCI Endocrine Sect, Bethesda, MD 20892 USA. RP Arnold, JT (reprint author), NIH, NCCAM, LCI Endocrine Sect, Bldg 10-2B47 MSC 1547,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jarnold@mail.nih.gov FU Intramural Research Program, National Center for Complementary and Alternative Medicine; National Institutes of Health, Bethesda FX This work was supported by the Intramural Research Program, National Center for Complementary and Alternative Medicine, National Institutes of Health, Bethesda, MD. NR 67 TC 15 Z9 15 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAR 25 PY 2009 VL 301 IS 1-2 SI SI BP 83 EP 88 DI 10.1016/j.mce.2008.10.019 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 423DH UT WOS:000264476100013 PM 19013497 ER PT J AU Watters, JL Satia, JA AF Watters, Joanne L. Satia, Jessie A. TI Psychosocial correlates of dietary fat intake in African-American adults: a cross-sectional study SO NUTRITION & METABOLISM LA English DT Article ID VEGETABLE CONSUMPTION; BEHAVIORAL-APPROACH; HEALTHFUL DIETS; FRUIT; OBESITY; FIBER; PREDICTORS; VALIDITY AB Background: Current dietary guidelines recommend that dietary fat should comprise 20-35% percent of total energy intake, with less than 10% of energy from saturated fat. However, many Americans exceed these goals and data suggest that African Americans tend to consume a higher percentage of energy from dietary fat than Whites. Because diets low in dietary fat, particularly saturated fat, are associated with lower risk for many chronic illnesses, it is important to identify strategies to reduce high fat intakes. This study examined associations of psychosocial factors with dietary fat intake in African American adults 18 to 70 years. Methods: Data are self-reported from a cross-sectional survey of African Americans (n = 658) using an 11-page questionnaire, collected from June to October 2003. Associations of psychosocial (predisposing, reinforcing, and enabling) factors based on the PRECEDE framework, dietary fat-related behaviors, and participant characteristics (e. g., age, sex, education, BMI) with total and saturated fat consumption are described using linear regression and analysis of variance. Results: The mean age of participants was 43.9 years, 57% were female, 37% were college graduates, and 76% were overweight/obese. Respondents with lower fat intakes were female, older, had high education and very good/excellent perceived health. Among the psychosocial factors, the strongest (inverse) associations with fat intake were with two predisposing factors: belief in the importance of a low-fat diet (both genders) and high self-efficacy (women only). Fat intake was also significantly lower among participants who could count on those close for encouragement to eat healthy foods (a reinforcing factor) and among men who needed more information about preparing healthy foods (an enabling factor). Conclusion: Dietary interventions to decrease fat intake in African American adults may benefit from incorporating predisposing factors, such as personal beliefs and self-efficacy, in their design and implementation. C1 [Watters, Joanne L.] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, NIH, Bethesda, MD 20852 USA. [Watters, Joanne L.; Satia, Jessie A.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [Satia, Jessie A.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Satia, Jessie A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Satia, Jessie A.] Univ N Carolina, Ctr Gastrointestinal Biol & Dis, Div Digest Dis & Nutr, Chapel Hill, NC 27599 USA. RP Watters, JL (reprint author), NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, NIH, Bethesda, MD 20852 USA. EM jwatters@email.unc.edu; jsatia@unc.edu FU National Institutes of Health [K22 CA96556, R01 CA74846, P30 CA16086]; National Cancer Institute Training Grant [T32 CA72319]; UNC Program on Ethnicity, Culture, and Outcomes FX This work was supported in part by grants from the National Institutes of Health (K22 CA96556, R01 CA74846, P30 CA16086), the National Cancer Institute Training Grant T32 CA72319, and the UNC Program on Ethnicity, Culture, and Outcomes. We would also like to thank Dr. Joseph Galanko for his assistance with statistical methods and data analysis. NR 41 TC 4 Z9 4 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1743-7075 J9 NUTR METAB JI Nutr. Metab. PD MAR 25 PY 2009 VL 6 AR 15 DI 10.1186/1475-2891-8-15 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 434EB UT WOS:000265256900001 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Discarding Logic 2008 Ancel Keys Memorial Lecture SO CIRCULATION LA English DT Article; Proceedings Paper CT 81st Annual Scientific Session of the American-Heart-Association CY NOV 08-12, 2008 CL New Orleans, LA SP Amer Heart Assoc DE prevention; history; trials ID RANDOMIZED CONTROLLED-TRIAL; ANTIHYPERTENSIVE DRUG-TREATMENT; ISOLATED SYSTOLIC HYPERTENSION; CORONARY-HEART-DISEASE; FECAL OCCULT-BLOOD; CARDIOVASCULAR-DISEASE; COLORECTAL-CANCER; SCREENING-TESTS; BREAST-CANCER; OLDER PERSONS C1 [Lauer, Michael S.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), 6701 Rockledge Dr,Room 10122, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 44 TC 12 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 EI 1524-4539 J9 CIRCULATION JI Circulation PD MAR 24 PY 2009 VL 119 IS 11 BP 1533 EP 1537 DI 10.1161/CIRCULATIONAHA.108.842765 PG 5 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 422XK UT WOS:000264460800011 PM 19307485 ER PT J AU McDermott, MM Guralnik, JM Tian, L Liu, K Ferrucci, L Liao, YH Sharma, L Criqui, MH AF McDermott, Mary M. Guralnik, Jack M. Tian, Lu Liu, Kiang Ferrucci, Luigi Liao, Yihua Sharma, Leena Criqui, Michael H. TI Associations of Borderline and Low Normal Ankle-Brachial Index Values With Functional Decline at 5-Year Follow-Up SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE ankle-brachial index; physical functioning; peripheral arterial disease; intermittent claudication ID PERIPHERAL ARTERIAL-DISEASE; LOWER-EXTREMITY FUNCTION; PHYSICAL-ACTIVITY; 6-MINUTE WALK; LEG SYMPTOMS; PREVALENCE; ATHEROSCLEROSIS; CLASSIFICATION; OSTEOARTHRITIS; DISABILITY AB Objectives We studied associations of borderline and low normal ankle-brachial index (ABI) values with functional decline over a 5-year follow-up. Background The associations of borderline and low normal ABI with functional decline are unknown. Methods The 666 participants included 412 with peripheral arterial disease (PAD). Participants were categorized as follows: severe PAD (ABI <0.50), moderate PAD (ABI 0.50 to 0.69), mild PAD (ABI 0.70 to 0.89), borderline ABI (0.90 to 0.99), low normal ABI (1.00 to 1.09), and normal ABI (ABI 1.10 to 1.30). Outcomes were assessed annually for 5 years. Mobility loss was defined as loss of the ability to walk one-quarter mile or walk up and down 1 flight of stairs without assistance among participants without baseline mobility impairment. Becoming unable to walk for 6 min continuously was defined as stopping during the 6-min walk at follow-up among those who walked for 6 min continuously at baseline. Results were adjusted for age, sex, race, comorbidities, and other confounders. Results Hazard ratios (HRs) for mobility loss according to ABI category were as follows: severe PAD, HR: 4.16 (95% confidence interval [CI]: 1.58 to 10.92); moderate PAD, HR: 3.82 (95% CI: 1.66 to 8.81); mild PAD, HR: 3.22 (95% CI: 1.43 to 7.21); borderline ABI, HR: 3.07 (95% CI: 1.21 to 7.84); and low normal ABI, HR: 2.61 (95% CI: 1.08 to 6.32; p trend = 0.0018). Similar associations were observed for becoming unable to walk for 6 min continuously (p trend < 0.0001). Conclusions At 5-year follow-up, persons with borderline ABI values have a higher incidence of mobility loss and becoming unable to walk for 6 min continuously compared with persons who have a normal baseline ABI. A low normal ABI is associated with an increased incidence of mobility loss compared with persons who have a normal ABI. (J Am Coll Cardiol 2009;53:1056-62) (C) 2009 by the American College of Cardiology Foundation C1 [McDermott, Mary M.; Sharma, Leena] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [McDermott, Mary M.; Tian, Lu; Liu, Kiang; Liao, Yihua] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, NIH, Baltimore, MD 21224 USA. [Ferrucci, Luigi] NIA, Lab Clin Epidemiol, NIH, Baltimore, MD 21224 USA. [Criqui, Michael H.] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. RP McDermott, MM (reprint author), 750 N Lake Shore Dr,10th Floor, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU NCRR NIH HHS [M01 RR000048, M01 RR000048-430366, M01 RR000048-45S16166, RR 00048]; NHLBI NIH HHS [R01 HL 071223, R01 HL 076298, R01 HL 58099, R01 HL 64739, R01 HL058099, R01 HL058099-02, R01 HL058099-03, R01 HL058099-04, R01 HL064739, R01 HL064739-01A1, R01 HL064739-02, R01 HL064739-04, R01 HL071223, R01 HL071223-01, R01 HL071223-02, R01 HL071223-03, R01 HL071223-04, R01 HL076298, R01 HL076298-01A1, R01 HL076298-02, R01 HL076298-03, R01 HL076298-04] NR 25 TC 77 Z9 79 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 MAR 24 PY 2009 VL 53 IS 12 BP 1056 EP 1062 DI 10.1016/j.jacc.2008.09.063 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 420VI UT WOS:000264316900007 PM 19298919 ER PT J AU Nabel, EG Lauer, MS AF Nabel, Elizabeth G. Lauer, Michael S. TI The Cardiovascular Programs of the National Heart, Lung, and Blood Institute: From Vision to Action to Impact SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material C1 [Nabel, Elizabeth G.] NHLBI, Off Director, NIH, Bethesda, MD 20892 USA. [Lauer, Michael S.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, Off Director, NIH, Bldg 5A-48,31 Ctr Dr, Bethesda, MD 20892 USA. EM NHLBIIOD@mail.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 FU Intramural NIH HHS [Z99 HL999999] NR 0 TC 4 Z9 4 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 MAR 24 PY 2009 VL 53 IS 12 BP 1082 EP 1083 DI 10.1016/j.jacc.2009.01.010 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 420VI UT WOS:000264316900012 PM 19298924 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Comparative Effectiveness Research: The View From the NHLBI SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Editorial Material DE comparative effectiveness; government; funding; policy; outcomes; NIH ID ACUTE MYOCARDIAL-INFARCTION; COST-EFFECTIVENESS; OUTCOMES; INFORMATION; MANAGEMENT; TRIAL C1 NHLBI, Div Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Div Prevent & Populat Sci, NIH, 6701 Rockledge Dr,Room 10122, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 FU Intramural NIH HHS [Z99 HL999999] NR 19 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 EI 1558-3597 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 24 PY 2009 VL 53 IS 12 BP 1084 EP 1086 DI 10.1016/j.jacc.2008.11.047 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 420VI UT WOS:000264316900013 PM 19298925 ER PT J AU Dong, LM Brennan, P Karami, S Hung, RJ Menashe, I Berndt, SI Yeager, M Chanock, S Zaridze, D Matveev, V Janout, V Kollarova, H Bencko, V Schwartz, K Davis, F Navratilova, M Szeszenia-Dabrowska, N Mates, D Colt, JS Holcatova, I Boffetta, P Rothman, N Chow, WH Rosenberg, PS Moore, LE AF Dong, Linda M. Brennan, Paul Karami, Sara Hung, Rayjean J. Menashe, Idan Berndt, Sonja I. Yeager, Meredith Chanock, Stephen Zaridze, David Matveev, Vsevolod Janout, Vladimir Kollarova, Hellena Bencko, Vladimir Schwartz, Kendra Davis, Faith Navratilova, Marie Szeszenia-Dabrowska, Neonila Mates, Dana Colt, Joanne S. Holcatova, Ivana Boffetta, Paolo Rothman, Nathaniel Chow, Wong-Ho Rosenberg, Philip S. Moore, Lee E. TI An Analysis of Growth, Differentiation and Apoptosis Genes with Risk of Renal Cancer SO PLOS ONE LA English DT Article AB We conducted a case-control study of renal cancer (987 cases and 1298 controls) in Central and Eastern Europe and analyzed genomic DNA for 319 tagging single-nucleotide polymorphisms (SNPs) in 21 genes involved in cellular growth, differentiation and apoptosis using an Illumina Oligo Pool All (OPA). A haplotype-based method (sliding window analysis of consecutive SNPs) was used to identify chromosome regions of interest that remained significant at a false discovery rate of 10%. Subsequently, risk estimates were generated for regions with a high level of signal and individual SNPs by unconditional logistic regression adjusting for age, gender and study center. Three regions containing genes associated with renal cancer were identified: caspase 1/5/ 4/12(CASP 1/5/ 4/12), epidermal growth factor receptor (EGFR), and insulin-like growth factor binding protein-3 (IGFBP3). We observed that individuals with CASP1/5/4/12 haplotype (spanning area upstream of CASP1 through exon 2 of CASP5) GGGCTCAGT were at higher risk of renal cancer compared to individuals with the most common haplotype (OR: 1.40, 95% CI: 1.10-1.78, p-value = 0.007). Analysis of EGFR revealed three strong signals within intron 1, particularly a region centered around rs759158 with a global p = 0.006 (GGG: OR: 1.26, 95% CI: 1.04-1.53 and ATG: OR: 1.55, 95% CI: 1.14-2.11). A region in IGFBP3 was also associated with increased risk (global p = 0.04). In addition, the number of statistically significant (p-value, 0.05) SNP associations observed within these three genes was higher than would be expected by chance on a gene level. To our knowledge, this is the first study to evaluate these genes in relation to renal cancer and there is need to replicate and extend our findings. The specific regions associated with risk may have particular relevance for gene function and/or carcinogenesis. In conclusion, our evaluation has identified common genetic variants in CASP1, CASP5, EGFR, and IGFBP3 that could be associated with renal cancer risk. C1 [Dong, Linda M.; Karami, Sara; Menashe, Idan; Berndt, Sonja I.; Colt, Joanne S.; Rothman, Nathaniel; Chow, Wong-Ho; Rosenberg, Philip S.; Moore, Lee E.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Brennan, Paul] Intl Agcy Res Canc, Lyon, France. [Hung, Rayjean J.; Boffetta, Paolo] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON, Canada. [Yeager, Meredith; Chanock, Stephen] NCI, Core Genotyping Facil, Gaithersburg, MD USA. [Zaridze, David; Matveev, Vsevolod] Inst Carcinogenesis, Moscow, Russia. [Janout, Vladimir; Kollarova, Hellena] Palacky Univ, Olomouc, Czech Republic. [Bencko, Vladimir; Holcatova, Ivana] Inst Hyg & Epidemiol, Prague, Czech Republic. [Schwartz, Kendra] Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Schwartz, Kendra] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Davis, Faith] Univ Illinois, Dept Biostat & Epidemiol, Chicago, IL 60680 USA. [Navratilova, Marie] Masaryk Memorial Canc Inst, Brno, Czech Republic. [Szeszenia-Dabrowska, Neonila] Inst Occupat Med, Lodz, Poland. [Mates, Dana] Inst Publ Hlth, Bucharest, Romania. RP Dong, LM (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM donglm@mail.nih.gov RI Liao, Linda/B-3960-2011; Hung, Rayjean/A-7439-2013; Zaridze, David/K-5605-2013; Janout, Vladimir/M-5133-2014; Szeszenia-Dabrowska, Neonila/F-7190-2010; OI mates, dana/0000-0002-6219-9807 FU Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX This work was supported in part by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 16 Z9 18 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 24 PY 2009 VL 4 IS 3 AR e4895 DI 10.1371/journal.pone.0004895 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437PI UT WOS:000265499000004 PM 19603096 ER PT J AU Gomez, GA Veldman, MB Zhao, Y Burgess, S Lin, S AF Gomez, Gustavo A. Veldman, Matthew B. Zhao, Yan Burgess, Shawn Lin, Shuo TI Discovery and Characterization of Novel Vascular and Hematopoietic Genes Downstream of Etsrp in Zebrafish SO PLOS ONE LA English DT Article AB The transcription factor Etsrp is required for vasculogenesis and primitive myelopoiesis in zebrafish. When ectopically expressed, etsrp is sufficient to induce the expression of many vascular and myeloid genes in zebrafish. The mammalian homolog of etsrp, ER71/Etv2, is also essential for vascular and hematopoietic development. To identify genes downstream of etsrp, gain-of-function experiments were performed for etsrp in zebrafish embryos followed by transcription profile analysis by microarray. Subsequent in vivo expression studies resulted in the identification of fourteen genes with blood and/or vascular expression, six of these being completely novel. Regulation of these genes by etsrp was confirmed by ectopic induction in etsrp overexpressing embryos and decreased expression in etsrp deficient embryos. Additional functional analysis of two newly discovered genes, hapln1b and sh3gl3, demonstrates their importance in embryonic vascular development. The results described here identify a group of genes downstream of etsrp likely to be critical for vascular and/or myeloid development. C1 [Gomez, Gustavo A.; Veldman, Matthew B.; Zhao, Yan; Lin, Shuo] Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90024 USA. [Burgess, Shawn] Natl Human Genome Res Inst, NIH, Genome Technol Branch, Bethesda, MD USA. RP Gomez, GA (reprint author), Univ Calif Los Angeles, Dept Mol Cell & Dev Biol, Los Angeles, CA 90024 USA. EM shuolin@ucla.edu OI Burgess, Shawn/0000-0003-1147-0596 FU HIN FX HIN. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 66 TC 28 Z9 28 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 24 PY 2009 VL 4 IS 3 AR e4994 DI 10.1371/journal.pone.0004994 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437PI UT WOS:000265499000011 PM 19308258 ER PT J AU Liu, ZH Meray, RK Grammatopoulos, TN Fredenburg, RA Cookson, MR Liu, YC Logan, T Lansbury, PT AF Liu, Zhihua Meray, Robin K. Grammatopoulos, Tom N. Fredenburg, Ross A. Cookson, Mark R. Liu, Yichin Logan, Todd Lansbury, Peter T., Jr. TI Membrane-associated farnesylated UCH-L1 promotes alpha-synuclein neurotoxicity and is a therapeutic target for Parkinson's disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE farnesylation; synuclein ID TERMINAL HYDROLASE L1; CHAPERONE-MEDIATED AUTOPHAGY; UBIQUITIN-PROTEASOME SYSTEM; S18Y POLYMORPHISM; TRANSFECTED CELLS; MUTATION ANALYSIS; NEURONAL CELLS; SHSY-5Y CELLS; LUNG-CANCER; IN-VIVO AB Ubiquitin C-terminal hydrolase-L1 (UCH-L1) is linked to Parkinson's disease (PD) and memory and is selectively expressed in neurons at high levels. Its expression pattern suggests a function distinct from that of its widely expressed homolog UCH-L3. We report here that, in contrast to UCH-L3, UCH-L1 exists in a membrane-associated form (UCH-L1(M)) in addition to the commonly studied soluble form. C-terminal farnesylation promotes the association of UCH-L1 with cellular membranes, including the endoplasmic reticulum. The amount of UCH-L1(M) in transfected cells is shown to correlate with the intracellular level of alpha-synuclein, a protein whose accumulation is associated with neurotoxicity and the development of PD. Reduction of UCH-L1(M) in cell culture models of alpha-synuclein toxicity by treatment with a farnesyltransferase inhibitor (FTI-277) reduces alpha-synuclein levels and increases cell viability. Proteasome function is not affected by UCH-L1(M), suggesting that it may negatively regulate the lysosomal degradation of alpha-synuclein. Therefore, inhibition of UCH-L1 farnesylation may be a therapeutic strategy for slowing the progression of PD and related synucleinopathies. C1 [Liu, Zhihua; Meray, Robin K.; Liu, Yichin; Lansbury, Peter T., Jr.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, Cambridge, MA 02139 USA. [Liu, Zhihua; Meray, Robin K.; Liu, Yichin; Lansbury, Peter T., Jr.] Harvard Univ, Sch Med, Dept Neurol, Cambridge, MA 02139 USA. [Liu, Zhihua; Meray, Robin K.; Grammatopoulos, Tom N.; Fredenburg, Ross A.; Logan, Todd; Lansbury, Peter T., Jr.] Link Med Corp, Cambridge, MA 02142 USA. [Cookson, Mark R.] NIH, Neurogenet Lab, Bethesda, MD 20892 USA. RP Lansbury, PT (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Ctr Neurol Dis, 65 Landsdowne St, Cambridge, MA 02139 USA. EM peter@linkmedicine.com OI Grammatopoulos, Tom/0000-0001-7175-051X FU National Institutes of Health (NIH); National Institute of Neurological Disorders and Stroke; Intramural Research Program of the NIH, National Institute on Aging [1 Z01 AG000953] FX We thank James Warsaw and Edward Rudman for their support, financial and otherwise, during the course of this work; and Craig Justman, Valerie Cullen, Berkley Lynch, and Mark Duggan for their input and critical reading of the manuscript. Finally, we acknowledge the helpful suggestions of Daniel Finley, Michael Wolfe, and Hidde Ploegh, all from Harvard Medical School. This work was supported, in part, by a Morris K. Udall Parkinson's Disease Research Center of Excellence Grant from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke, and by the Intramural Research Program of the NIH, National Institute on Aging, project number 1 Z01 AG000953. Y.L. was an NIH postdoctoral fellow during the execution of this research. NR 64 TC 68 Z9 70 U1 1 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 24 PY 2009 VL 106 IS 12 BP 4635 EP 4640 DI 10.1073/pnas.0806474106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 423VA UT WOS:000264522600014 PM 19261853 ER PT J AU Pazgiera, M Liu, M Zou, GZ Yuan, WR Li, CQ Li, C Li, J Monbo, J Zella, D Tarasov, SG Lu, W AF Pazgiera, Marzena Liu, Min Zou, Guozhang Yuan, Weirong Li, Changqing Li, Chong Li, Jing Monbo, Juahdi Zella, Davide Tarasov, Sergey G. Lu, Wuyuan TI Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SUPPRESSOR TRANSACTIVATION DOMAIN; PROTEIN-PROTEIN INTERACTIONS; IN-VIVO; CHEMICAL LIGATION; TERMINAL DOMAIN; BINDING; ACTIVATION; DEGRADATION; RESTORATION; CELLS AB The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53-a cellular process initiated by MDM2 and/or MDMX binding to the N-terminal transactivation domain of p53. MDM2 and MDMX in many tumors confer p53 inactivation and tumor survival, and are important molecular targets for anticancer therapy. We screened a duodecimal peptide phage library against site-specifically biotinylated p53-binding domains of human MDM2 and MDMX chemically synthesized via native chemical ligation, and identified several peptide inhibitors of the p53-MDM2/MDMX interactions. The most potent inhibitor (TSFAEYWNLLSP), termed PMI, bound to MDM2 and MDMX at low nanomolar affinities-approximately 2 orders of magnitude stronger than the wild-type p53 peptide of the same length (ETFSDLWKLLPE). We solved the crystal structures of synthetic MDM2 and MDMX, both in complex with PMI, at 1.6 angstrom resolution. Comparative structural analysis identified an extensive, tightened intramolecular H-bonding network in bound PMI that contributed to its conformational stability, thus enhanced binding to the 2 oncogenic proteins. Importantly, the C-terminal residue Pro of PMI induced formation of a hydrophobic cleft in MDMX previously unseen in the structures of p53-bound MDM2 or MDMX. Our findings deciphered the structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX, shedding new light on structure-based rational design of different classes of p53 activators for potential therapeutic use. C1 [Pazgiera, Marzena; Liu, Min; Zou, Guozhang; Yuan, Weirong; Li, Changqing; Li, Chong; Li, Jing; Monbo, Juahdi; Zella, Davide; Lu, Wuyuan] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Liu, Min] Xi An Jiao Tong Univ, Sch Med, Affiliated Hosp 1, Xian 710061, Shaanxi Prov, Peoples R China. [Tarasov, Sergey G.] NCI, Struct Biophys Lab, Frederick, MD 21702 USA. RP Lu, W (reprint author), Univ Maryland, Sch Med, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. EM wlu@ihv.umaryland.edu RI Lu, Wuyuan/B-2268-2010; LIU, MIN/B-3497-2010; Li, Chong/H-2515-2011 FU American Cancer Society Research Scholar Grant [CDD112858]; National Institutes of Health Grants [AI056264, AI061482]; Intramural Research Program of the National Institutes of Health FX This work was supported by American Cancer Society Research Scholar Grant CDD112858, National Institutes of Health Grants AI056264 and AI061482 (to W. L.), and the Intramural Research Program of the National Institutes of Health (S. G. T.). NR 51 TC 150 Z9 160 U1 5 U2 53 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 MAR 24 PY 2009 VL 106 IS 12 BP 4665 EP 4670 DI 10.1073/pnas.0900947106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 423VA UT WOS:000264522600019 PM 19255450 ER PT J AU Belkina, NV Liu, Y Hao, JJ Karasuyama, H Shawa, S AF Belkina, Natalya V. Liu, Yin Hao, Jian-Jiang Karasuyama, Hajime Shawa, Stephen TI LOK is a major ERM kinase in resting lymphocytes and regulates cytoskeletal rearrangement through ERM phosphorylation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ezrin; kinase specificity; knockout; migration; moesin ID PROTEIN-KINASE; EZRIN/RADIXIN/MOESIN ERM; UROKINASE RECEPTOR; T-LYMPHOCYTES; MOESIN; RHO; MICROVILLI; CELLS; POLARIZATION; SPECIFICITY AB ERM (ezrin-radixin-moesin) proteins mediate linkage of actin cytoskeleton to plasma membrane in many cells. ERM activity is regulated in part by phosphorylation at a C-terminal threonine, but the identity of ERM kinases is unknown in lymphocytes and incompletely defined in other mammalian cells. Our studies show that lymphocyte-oriented kinase (LOK) is an ERM kinase in vitro and in vivo. Mass spectrometric analysis indicates LOK is abundant at the lymphocyte plasma membrane and immunofluorescence studies show LOK enrichment at the plasma membrane near ERM. In vitro peptide specificity analyses characterize LOK as a basophilic kinase whose optimal substrate sequence resembles the ERM site, including unusual preference for tyrosine at P-2. LOK's activity on moesin peptide and protein was comparable to reported ERM kinases ROCK and PKC but unlike them LOK displayed preferential specificity for moesin compared to traditional basophilic kinase substrates. Two genetic approaches demonstrate a role for LOK in ERM phosphorylation: cell transfection with LOK kinase domain augments ERM phosphorylation and lymphocytes from LOK knockout mice have >50% reduction in ERM phosphorylation. The findings on localization and specificity argue that LOK is a direct ERM kinase. The knockout mice have normal hematopoietic cell development but notably lymphocyte migration and polarization in response to chemokine are enhanced. These functional alterations fit the current understanding of the role of ERM phosphorylation in regulating cortical reorganization. Thus, these studies identify a new ERM kinase of importance in lymphocytes and confirm the role of ERM phosphorylation in regulating cell shape and motility. C1 [Belkina, Natalya V.; Liu, Yin; Hao, Jian-Jiang; Shawa, Stephen] NCI, Expt Immunol Branch, Natl Canc Inst, Bethesda, MD 20892 USA. [Karasuyama, Hajime] Tokyo Med & Dent Univ, Grad Sch, Bunkyo Ku, Tokyo 1138519, Japan. RP Shawa, S (reprint author), NCI, Expt Immunol Branch, Natl Canc Inst, Bethesda, MD 20892 USA. EM sshaw@nih.gov RI Karasuyama, Hajime/A-7966-2011 FU National Institutes of Health; Center for Cancer Research; National Cancer Institute FX We thank A. Avery, T. Chavakis, G. Crabtree, J. Delon, D. Esposito, W. Gillette, J. Hartley, C. Khanna, M. Kruhlak, K. Nagashima, R. Nijhara, L. Ren, B. Turk, and G. Zhu for sharing of reagents, technical assistance and/ or helpful discussion. This research was supported by the Intramural Research Program of the National Institutes of Health, and Center for Cancer Research, National Cancer Institute. NR 31 TC 73 Z9 77 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 24 PY 2009 VL 106 IS 12 BP 4707 EP 4712 DI 10.1073/pnas.0805963106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 423VA UT WOS:000264522600026 PM 19255442 ER PT J AU Arur, S Ohmachi, M Nayak, S Hayes, M Miranda, A Hay, A Golden, A Schedl, T AF Arur, Swathi Ohmachi, Mitsue Nayak, Sudhir Hayes, Matthew Miranda, Alejandro Hay, Amanda Golden, Andy Schedl, Tim TI Multiple ERK substrates execute single biological processes in Caenorhabditis elegans germ-line development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE functional genomics; signaling; MPK-1; RNAi screen ID RIBOSOMAL S6 KINASE; MAP KINASE; C-ELEGANS; PROTEIN-KINASE; DOCKING SITE; IN-VIVO; ACTIVATION; IDENTIFICATION; DOMAIN; RAS AB RAS-extracellular signal regulated kinase (ERK) signaling governs multiple aspects of cell fate specification, cellular transitions, and growth by regulating downstream substrates through phosphorylation. Understanding how perturbations to the ERK signaling pathway lead to developmental disorders and cancer hinges critically on identification of the substrates. Yet, only a limited number of substrates have been identified that function in vivo to execute ERK-regulated processes. The Caenorhabditis elegans germ line utilizes the well-conserved RAS-ERK signaling pathway in multiple different contexts. Here, we present an integrated functional genomic approach that identified 30 ERK substrates, each of which functions to regulate one or more of seven distinct biological processes during C. elegans germ-line development. Our results provide evidence for three themes that underlie the robustness and specificity of biological outcomes controlled by ERK signaling in C. elegans that are likely relevant to ERK signaling in other organisms: (i) multiple diverse ERK substrates function to control each individual biological process; (ii) different combinations of substrates function to control distinct biological processes; and (iii) regulatory feedback loops between ERK and its substrates help reinforce or attenuate ERK activation. Substrates identified here have conserved orthologs in humans, suggesting that insights from these studies will contribute to our understanding of human diseases involving deregulated ERK activity. C1 [Arur, Swathi; Ohmachi, Mitsue; Nayak, Sudhir; Hayes, Matthew; Miranda, Alejandro; Hay, Amanda; Schedl, Tim] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Golden, Andy] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Schedl, T (reprint author), Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. EM ts@genetics.wustl.edu FU Siteman Cancer Center; National Science Foundation [0416502]; National Institutes of Health [GM63310]; National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health FX We thank Drs. K. Kornfeld, M. Sundaram, J. Skeath, A. Kalia, D. Hansen, M. Dorsett, S. Dutcher, and M. Johnston for insightful comments on the manuscript. We are grateful to our colleagues for reagents, Dr. Andrey Shaw (14-3-3-GST) and Dr. Phyllis Hanson (p97) (Washington University School of Medicine, St. Louis). M. H. and A. H. were supported by the Howard Hughes Medical Institute Undergraduate Education Research Program, and A. M. was supported by the Siteman Cancer Center summer student program. Work in the T. S. laboratory was supported by National Science Foundation Grant 0416502 and National Institutes of Health Grant GM63310. A. G. was supported by the Intramural Research Program at the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health. NR 29 TC 50 Z9 83 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 24 PY 2009 VL 106 IS 12 BP 4776 EP 4781 DI 10.1073/pnas.0812285106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 423VA UT WOS:000264522600038 PM 19264959 ER PT J AU Kapogiannis, D Barbey, AK Su, M Zamboni, G Krueger, F Grafman, J AF Kapogiannis, Dimitrios Barbey, Aron K. Su, Michael Zamboni, Giovanna Krueger, Frank Grafman, Jordan TI Cognitive and neural foundations of religious belief SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID AUTISM SPECTRUM DISORDERS; PERSPECTIVE-TAKING; MENTAL-IMAGERY; FMRI; RESPONSES; EXPLICIT; EMOTION; CORTEX; COMPREHENSION; CONSEQUENCES AB We propose an integrative cognitive neuroscience framework for understanding the cognitive and neural foundations of religious belief. Our analysis reveals 3 psychological dimensions of religious belief (God's perceived level of involvement, God's perceived emotion, and doctrinal/experiential religious knowledge), which functional MRI localizes within networks processing Theory of Mind regarding intent and emotion, abstract semantics, and imagery. Our results are unique in demonstrating that specific components of religious belief are mediated by well-known brain networks, and support contemporary psychological theories that ground religious belief within evolutionary adaptive cognitive functions. C1 [Kapogiannis, Dimitrios; Barbey, Aron K.; Su, Michael; Zamboni, Giovanna; Krueger, Frank; Grafman, Jordan] NINDS, NIH, Bethesda, MD 20892 USA. [Kapogiannis, Dimitrios] NIA, NIH, Baltimore, MD 21225 USA. [Barbey, Aron K.] Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. RP Grafman, J (reprint author), NINDS, NIH, MSC 1440,10 Ctr Dr, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov RI Barbey, Aron/L-7312-2015; Zamboni, Giovanna/F-3583-2017; OI Barbey, Aron/0000-0002-6092-0912; Zamboni, Giovanna/0000-0002-6133-3373; Grafman, Jordan H./0000-0001-8645-4457 FU National Institutes of Health; National Institute of Neurological Disorders and Stroke FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 54 TC 81 Z9 84 U1 4 U2 43 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 MAR 24 PY 2009 VL 106 IS 12 BP 4876 EP 4881 DI 10.1073/pnas.0811717106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 423VA UT WOS:000264522600055 PM 19273839 ER PT J AU Tao, JF Hu, KP Chang, Q Wu, H Sherman, NE Martinowich, K Klose, RJ Schanen, C Jaenisch, R Wang, WD Sun, YE AF Tao, Jifang Hu, Keping Chang, Qiang Wu, Hao Sherman, Nicholas E. Martinowich, Keri Klose, Robert J. Schanen, Carolyn Jaenisch, Rudolf Wang, Weidong Sun, Yi Eve TI Phosphorylation of MeCP2 at Serine 80 regulates its chromatin association and neurological function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE MeCP2 phosphorylation; neuronal activity; Rett syndrome ID CPG-BINDING PROTEIN-2; RETT-SYNDROME; MOUSE MODEL; GENE-EXPRESSION; METHYL-CPG; SYNAPTIC PLASTICITY; DNA METHYLATION; KINASE-IV; MATURATION; MEMORY AB Mutations of MECP2 (Methyl-CpG Binding Protein 2) cause Rett syndrome. As a chromatin-associated multifunctional protein, how MeCP2 integrates external signals and regulates neuronal function remain unclear. Although neuronal activity-induced phosphorylation of MeCP2 at serine 421 (S421) has been reported, the full spectrum of MeCP2 phosphorylation together with the in vivo function of such modifications are yet to be revealed. Here, we report the identification of several MeCP2 phosphorylation sites in normal and epileptic brains from multiple species. We demonstrate that serine 80 (S80) phosphorylation of MeCP2 is critical as its mutation into alanine (S80A) in transgenic knock-in mice leads to locomotor deficits. S80A mutation attenuates MeCP2 chromatin association at several gene promoters in resting neurons and leads to transcription changes of a small number of genes. Calcium influx in neurons causes dephosphorylation at S80, potentially contributing to its dissociation from the chromatin. We postulate that phosphorylation of MeCP2 modulates its dynamic function in neurons transiting between resting and active states within neural circuits that underlie behaviors. C1 [Chang, Qiang; Jaenisch, Rudolf] MIT, Whitehead Inst Biomed Res, Cambridge, MA 02139 USA. [Chang, Qiang; Jaenisch, Rudolf] MIT, Dept Biol, Cambridge, MA 02139 USA. [Tao, Jifang; Wu, Hao; Martinowich, Keri; Sun, Yi Eve] Univ Calif Los Angeles, Dept Mol & Med Pharmacol & Psychiat & Behav Sci, Los Angeles, CA 90095 USA. [Hu, Keping; Wang, Weidong] NIA, Baltimore, MD 21224 USA. [Sherman, Nicholas E.] Univ Virginia, Dept Microbiol, WM Keck Biomed Mass Spectrometry Lab, Charlottesville, VA 22908 USA. [Klose, Robert J.] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England. [Hu, Keping; Schanen, Carolyn] Alfred I DuPont Hosp Children, Nemours Biomed Res, Wilmington, DE 19803 USA. RP Jaenisch, R (reprint author), MIT, Whitehead Inst Biomed Res, Cambridge, MA 02139 USA. EM jaenisch@wi.mit.edu; wangw@grc.nia.nih.gov; ysun@mednet.ucla.edu RI Wu, Hao/G-4145-2013; Martinowich, Keri/F-9841-2012; OI Wu, Hao/0000-0002-1256-6891; Martinowich, Keri/0000-0002-5237-0789 FU National Institutes of Health [R56MH082068]; National Institute on Aging [Z01 AG000668-06]; Rett Syndrome Research Foundation; International Rett Syndrome Foundation FX We thank Dr. Adrian Bird for his comments on the manuscript, members of Sun Lab for helpful discussion, and Wenyu Zhu for technical assistance. This work was supported by National Institutes of Health Grant R56MH082068 (to Y.E.S.), Intramural Research Program of the National Institute on Aging Grant Z01 AG000668-06 (to W. W.), and grants from Rett Syndrome Research Foundation and International Rett Syndrome Foundation (to W.W., Y.E.S., Q.C. and R.J.). NR 36 TC 114 Z9 119 U1 4 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 MAR 24 PY 2009 VL 106 IS 12 BP 4882 EP 4887 DI 10.1073/pnas.0811648106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 423VA UT WOS:000264522600056 PM 19225110 ER PT J AU Sinha, R Cross, AJ Graubard, BI Leitzmann, MF Schatzkin, A AF Sinha, Rashmi Cross, Amanda J. Graubard, Barry I. Leitzmann, Michael F. Schatzkin, Arthur TI Meat Intake and Mortality A Prospective Study of Over Half a Million People SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID HETEROCYCLIC AMINE CONTENT; ISCHEMIC-HEART-DISEASE; HEALTH-AMERICAN-ASSOCIATION; RETIRED-PERSONS DIET; COLORECTAL-CANCER; IRON INTAKE; NATIONAL-INSTITUTES; VARYING DEGREES; NONMEAT EATERS; BREAST-CANCER AB Background: High intakes of red or processed meat may increase the risk of mortality. Our objective was to determine the relations of red, white, and processed meat intakes to risk for total and cause-specific mortality. Methods: The study population included the National Institutes of Health-AARP (formerly known as the American Association of Retired Persons) Diet and Health Study cohort of half a million people aged 50 to 71 years at baseline. Meat intake was estimated from a food frequency questionnaire administered at baseline. Cox proportional hazards regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) within quintiles of meat intake. The covariates included in the models were age, education, marital status, family history of cancer (yes/no) (cancer mortality only), race, body mass index, 31-level smoking history, physical activity, energy intake, alcohol intake, vitamin supplement use, fruit consumption, vegetable consumption, and menopausal hormone therapy among women. Main outcome measures included total mortality and deaths due to cancer, cardiovascular disease, injuries and sudden deaths, and all other causes. Results: There were 47 976 male deaths and 23 276 female deaths during 10 years of follow-up. Men and women in the highest vs lowest quintile of red (HR, 1.31 [95% CI, 1.27-1.35], and HR, 1.36 [95% CI, 1.30-1.43], respectively) and processed meat (HR, 1.16 [95% CI, 1.12-1.20], and HR, 1.25 [95% CI, 1.20-1.31], respectively) intakes had elevated risks for overall mortality. Regarding cause-specific mortality, men and women had elevated risks for cancer mortality for red (HR, 1.22 [95% CI, 1.16-1.29], and HR, 1.20 [95% CI, 1.12-1.30], respectively) and processed meat (HR, 1.12 [95% CI, 1.061.19], and HR, 1.11 [95% CI 1.04-1.19], respectively) intakes. Furthermore, cardiovascular disease risk was elevated for men and women in the highest quintile of red (HR, 1.27 [95% CI, 1.20-1.35], and HR, 1.50 [95% CI, 1.37-1.65], respectively) and processed meat (HR, 1.09 [95% CI, 1.03-1.15], and HR, 1.38 [95% CI, 1.26-1.51], respectively) intakes. When comparing the highest with the lowest quintile of white meat intake, there was an inverse association for total mortality and cancer mortality, as well as all other deaths for both men and women. Conclusion: Red and processed meat intakes were associated with modest increases in total mortality, cancer mortality, and cardiovascular disease mortality. C1 [Sinha, Rashmi; Cross, Amanda J.; Leitzmann, Michael F.; Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Graubard, Barry I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Sinha, R (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd, Rockville, MD 20852 USA. EM sinhar@nih.gov RI Sinha, Rashmi/G-7446-2015 OI Sinha, Rashmi/0000-0002-2466-7462 FU Intramural Research Program of the NIH, National Cancer Institute (NCI) FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute (NCI). NR 36 TC 182 Z9 188 U1 4 U2 47 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 23 PY 2009 VL 169 IS 6 BP 562 EP 571 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 423HO UT WOS:000264487600004 PM 19307518 ER PT J AU Baker, SG Soto, AM Sonnenschein, C Cappuccio, A Potter, JD Kramer, BS AF Baker, Stuart G. Soto, Ana M. Sonnenschein, Carlos Cappuccio, Antonio Potter, John D. Kramer, Barnett S. TI Plausibility of stromal initiation of epithelial cancers without a mutation in the epithelium: a computer simulation of morphostats SO BMC CANCER LA English DT Article ID MAMMARY-GLAND; MORPHOGEN GRADIENT; CELL-ADHESION; HUMAN BREAST; IN-VIVO; CARCINOGENESIS; INSTABILITY; EXPRESSION; PHENOTYPE; FIBROBLASTS AB Background: There is experimental evidence from animal models favoring the notion that the disruption of interactions between stroma and epithelium plays an important role in the initiation of carcinogenesis. These disrupted interactions are hypothesized to be mediated by molecules, termed morphostats, which diffuse through the tissue to determine cell phenotype and maintain tissue architecture. Methods: We developed a computer simulation based on simple properties of cell renewal and morphostats. Results: Under the computer simulation, the disruption of the morphostat gradient in the stroma generated epithelial precursors of cancer without any mutation in the epithelium. Conclusion: The model is consistent with the possibility that the accumulation of genetic and epigenetic changes found in tumors could arise after the formation of a founder population of aberrant cells, defined as cells that are created by low or insufficient morphostat levels and that no longer respond to morphostat concentrations. Because the model is biologically plausible, we hope that these results will stimulate further experiments. C1 [Baker, Stuart G.] NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Soto, Ana M.; Sonnenschein, Carlos] Tufts Univ, Sch Med, Dept Anat & Cell Biol, Boston, MA 02111 USA. [Cappuccio, Antonio] Inst Curie, Bioinformat & Computat Syst Biol Canc, Paris, France. [Potter, John D.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Kramer, Barnett S.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. EM sb16i@nih.gov; ana.soto@tufts.edu; carlos.sonnenschein@tufts.edu; cappuccio@iac.cnr.it; jpotter@fhcrc.org; kramerb@od.nih.gov OI Potter, John/0000-0001-5439-1500 NR 48 TC 18 Z9 18 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAR 23 PY 2009 VL 9 AR 89 DI 10.1186/1471-2407-9-89 PG 11 WC Oncology SC Oncology GA 429IV UT WOS:000264915000001 PM 19309499 ER PT J AU Ren, JQ Jin, P Wang, E Marincola, FM Stroncek, DF AF Ren, Jiaqiang Jin, Ping Wang, Ena Marincola, Francesco M. Stroncek, David F. TI MicroRNA and gene expression patterns in the differentiation of human embryonic stem cells SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID MESSENGER-RNA EXPRESSION; CENTRAL-NERVOUS-SYSTEM; CAENORHABDITIS-ELEGANS; ANIMAL DEVELOPMENT; MIR-200 FAMILY; CANCER-CELLS; MESENCHYMAL TRANSITION; MIR-17-92 CLUSTER; REPRESSORS ZEB1; BREAST-CANCER AB Background: The unique features of human embryonic stem (hES) cells make them the best candidate resource for both cell replacement therapy and development research. However, the molecular mechanisms responsible for the simultaneous maintenance of their self-renewal properties and undifferentiated state remain unclear. Non-coding microRNAs (miRNA) which regulate mRNA cleavage and inhibit encoded protein translation exhibit temporal or tissue-specific expression patterns and they play an important role in development timing. Results: In this study, we analyzed miRNA and gene expression profiles among samples from 3 hES cell lines (H9, 16 and BG01v), differentiated embryoid bodies (EB) derived from H9 cells at different time points, and 5 adult cell types including Human Microvascular Endothelial Cells (HMVEC), Human Umbilical Vein Endothelial Cells (HUVEC), Umbilical Artery Smooth Muscle Cells (UASMC), Normal Human Astrocytes (NHA), and Lung Fibroblasts (LFB). This analysis rendered 104 miRNAs and 776 genes differentially expressed among the three cell types. Selected differentially expressed miRNAs and genes were further validated and confirmed by quantitative real-time-PCR (qRT-PCR). Especially, members of the miR-302 cluster on chromosome 4 and miR-520 cluster on chromosome 19 were highly expressed in undifferentiated hES cells. MiRNAs in these two clusters displayed similar expression levels. The members of these two clusters share a consensus 7-mer seed sequence and their targeted genes had overlapping functions. Among the targeted genes, genes with chromatin structure modification function are enriched suggesting a role in the maintenance of chromatin structure. We also found that the expression level of members of the two clusters, miR-520b and miR-302c, were negatively correlated with their targeted genes based on gene expression analysis Conclusion: We identified the expression patterns of miRNAs and gene transcripts in the undifferentiation of human embryonic stem cells; among the miRNAs that are highly expressed in undifferentiated embryonic stem cells, the miR-520 cluster may be closely involved in hES cell function and its relevance to chromatin structure warrants further study. C1 [Ren, Jiaqiang; Jin, Ping; Wang, Ena; Marincola, Francesco M.; Stroncek, David F.] Natl Inst Hlth, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), Natl Inst Hlth, Dept Transfus Med, Ctr Clin, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM renj@mail.nih.gov; PJin@mail.cc.nih.gov; EWang@cc.nih.gov; francesco_marincola@nih.gov; DStroncek@cc.nih.gov FU DTM; CC; NIH, Bethesda, Maryland FX The work was supported by the DTM, CC, NIH, Bethesda, Maryland. NR 88 TC 110 Z9 120 U1 2 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAR 23 PY 2009 VL 7 AR 20 DI 10.1186/1479-5876-7-20 PG 17 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 447AZ UT WOS:000266165300001 PM 19309508 ER PT J AU Smith, IM Glazer, CA Mithani, SK Ochs, MF Sun, W Bhan, S Vostrov, A Abdullaev, Z Lobanenkov, V Gray, A Liu, C Chang, SS Ostrow, KL Westra, WH Begum, S Dhara, M Califano, J AF Smith, Ian M. Glazer, Chad A. Mithani, Suhail K. Ochs, Michael F. Sun, Wenyue Bhan, Sheetal Vostrov, Alexander Abdullaev, Ziedulla Lobanenkov, Victor Gray, Andrew Liu, Chunyan Chang, Steven S. Ostrow, Kimberly L. Westra, William H. Begum, Shahnaz Dhara, Mousumi Califano, Joseph TI Coordinated Activation of Candidate Proto-Oncogenes and Cancer Testes Antigens via Promoter Demethylation in Head and Neck Cancer and Lung Cancer SO PLOS ONE LA English DT Article AB Background: Epigenetic alterations have been implicated in the pathogenesis of solid tumors, however, proto-oncogenes activated by promoter demethylation have been sporadically reported. We used an integrative method to analyze expression in primary head and neck squamous cell carcinoma (HNSCC) and pharmacologically demethylated cell lines to identify aberrantly demethylated and expressed candidate proto-oncogenes and cancer testes antigens in HNSCC. Methodology/Principal Findings: We noted coordinated promoter demethylation and simultaneous transcriptional upregulation of proto-oncogene candidates with promoter homology, and phylogenetic footprinting of these promoters demonstrated potential recognition sites for the transcription factor BORIS. Aberrant BORIS expression correlated with upregulation of candidate proto-oncogenes in multiple human malignancies including primary non-small cell lung cancers and HNSCC, induced coordinated proto-oncogene specific promoter demethylation and expression in non-tumorigenic cells, and transformed NIH3T3 cells. Conclusions/Significance: Coordinated, epigenetic unmasking of multiple genes with growth promoting activity occurs in aerodigestive cancers, and BORIS is implicated in the coordinated promoter demethylation and reactivation of epigenetically silenced genes in human cancers. C1 [Smith, Ian M.; Glazer, Chad A.; Sun, Wenyue; Bhan, Sheetal; Gray, Andrew; Liu, Chunyan; Chang, Steven S.; Ostrow, Kimberly L.; Dhara, Mousumi; Califano, Joseph] Johns Hopkins Med Inst, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. [Mithani, Suhail K.] Johns Hopkins Med Inst, Dept Surg, Div Plastic & Reconstruct Surg, Baltimore, MD 21205 USA. [Ochs, Michael F.] Johns Hopkins Med Inst, Dept Oncol, Div Oncol Biostat, Baltimore, MD 21205 USA. [Westra, William H.; Begum, Shahnaz] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. [Vostrov, Alexander; Abdullaev, Ziedulla; Lobanenkov, Victor] Inst Allergy & Infect Dis, NIH, Rockville, MD USA. [Califano, Joseph] Greater Baltimore Med Ctr, Milton J Dance Head & Neck Ctr, Baltimore, MD USA. RP Califano, J (reprint author), Johns Hopkins Med Inst, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21205 USA. EM jcalifa@jhmi.edu OI Lobanenkov, Victor/0000-0001-6665-3635 FU NIH [T32 grant]; Flight Attendant Medical Research Institute [Clinical Innovator Award]; National Cancer Institute SPORE [5P50CA096784-05] FX NIH T32 grant, Clinical Innovator Award from the Flight Attendant Medical Research Institute, and the National Cancer Institute SPORE (5P50CA096784-05). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 63 Z9 64 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 23 PY 2009 VL 4 IS 3 AR e4961 DI 10.1371/journal.pone.0004961 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437PG UT WOS:000265498800010 PM 19305507 ER PT J AU Klutz, AM Gao, ZG Lloyd, J Shainberg, A Jacobson, K AF Klutz, Athena M. Gao, Zhan-Guo Lloyd, John Shainberg, Asher Jacobson, Kenneth TI Modulation of the selectivity of nucleoside functionalized congeners as A1 and A3 adenosine receptor agonists by attachment to poly(amidoamine) (PAMAM) dendrimer carriers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Klutz, Athena M.; Gao, Zhan-Guo; Lloyd, John; Jacobson, Kenneth] NIDDK, NIH, Bethesda, MD 20892 USA. [Shainberg, Asher] Bar Ilan Univ, Fac Life Sci, IL-52100 Ramat Gan, Israel. EM klutza@mail.nih.gov; ZhanguoG@intra.niddk.nih.gov; kajacobs@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 MAR 22 PY 2009 VL 237 MA 107-BIOL BP 473 EP 473 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857800427 ER PT J AU Basudhar, D Ridnour, LA Miranda, KM Wink, DA AF Basudhar, Debashree Ridnour, Lisa A. Miranda, Katrina M. Wink, David A. TI JS-K: Pathways of anticancer action SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Basudhar, Debashree; Ridnour, Lisa A.; Wink, David A.] NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. [Miranda, Katrina M.] Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. RI Miranda, Katrina/B-7823-2009 NR 2 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 MAR 22 PY 2009 VL 237 MA 102-BIOL BP 577 EP 577 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857800531 ER PT J AU Li, Q Anver, MR Butcher, DO Gildersleeve, JC AF Li, Qian Anver, Miriam R. Butcher, Donna O. Gildersleeve, Jeffrey C. TI Resolving conflicting data on expression of the Tn antigen and implications for clinical trials with cancer vaccines SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Li, Qian; Gildersleeve, Jeffrey C.] NCI, Med Chem Lab, Frederick, MD 21702 USA. [Anver, Miriam R.; Butcher, Donna O.] SAIC Frederick Inc, NCI, Frederick, MD 21702 USA. EM qianli@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 MAR 22 PY 2009 VL 237 MA 57-CARB BP 701 EP 701 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857800627 ER PT J AU Kaczmarek, P Keay, SK Koch, KR Zhang, CO Guo, L Michejda, CJ Shahjee, H Barchi, JJ AF Kaczmarek, Piotr Keay, Susan K. Koch, Kristopher R. Zhang, Chen-Ou Guo, Li Michejda, Christopher J. Shahjee, Hanief Barchi, Joseph J., Jr. TI SAR study for the carbohydrate segment of the antiproliferative factor from interstitial cystitis patients SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Michejda, Christopher J.] NCI, Struct Biophys Lab, Mol Aspects Drug Design Sect, Frederick, MD 21702 USA. [Keay, Susan K.; Koch, Kristopher R.; Zhang, Chen-Ou; Guo, Li; Shahjee, Hanief] Univ Maryland, Sch Med, Baltimore VA Med Ctr, Baltimore, MD 21201 USA. [Barchi, Joseph J., Jr.] NCI, Med Chem Lab, Frederick, MD 21702 USA. EM pkaczmarek@ncifcrf.gov; skeay@medicine.umaryland.edu; michejda@ncifcrf.gov; barchi@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 MAR 22 PY 2009 VL 237 MA 42-CARB BP 744 EP 744 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857800669 ER PT J AU Barchi, JJ Sundgren, A Brinas, RP Rittenhouse-Olson, K Heimburg, J Houghton, A Sahoo, P Morey, S AF Barchi, Joseph J., Jr. Sundgren, Andreas Brinas, Raymond P. Rittenhouse-Olson, Kate Heimburg, Jamie Houghton, Amy Sahoo, Padmini Morey, Suasn TI Sugar/peptide nanoconstructions as antitumor therapeutics and vaccine platforms SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Barchi, Joseph J., Jr.; Sundgren, Andreas; Brinas, Raymond P.] NCI, Med Chem Lab, Frederick, MD 21702 USA. [Rittenhouse-Olson, Kate; Heimburg, Jamie; Houghton, Amy; Sahoo, Padmini; Morey, Suasn] SUNY Buffalo, Dept Clin Lab Sci, Sch Hlth Related Profess, Buffalo, NY 14214 USA. EM barchi@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 MAR 22 PY 2009 VL 237 MA 41-CARB BP 747 EP 747 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857800672 ER PT J AU Best, RB Hummer, G AF Best, Robert B. Hummer, Gerhard TI PHYS 197-Are current molecular dynamics force fields too helical? SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Best, Robert B.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. [Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM rbb24@cam.ac.uk; Gerhard.Hummer@nih.gov RI Hummer, Gerhard/A-2546-2013; Best, Robert/H-7588-2016 OI Hummer, Gerhard/0000-0001-7768-746X; Best, Robert/0000-0002-7893-3543 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 MAR 22 PY 2009 VL 237 MA 197-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857808302 ER PT J AU Bolton, E AF Bolton, Evan TI Use and utility of InChI in PubChem SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Bolton, Evan] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM bolton@ncbi.nlm.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 MAR 22 PY 2009 VL 237 MA 14-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857802629 ER PT J AU Chen, JY Bai, LC Zaneta, NC Zhang, J Gomez, C Han, Y Krzysztof, K Sheng, J Roller, P Wang, SM AF Chen, Jianyong Bai, Longchuan Zaneta, Nikolovska-Coleska Zhang, Jian Gomez, Cindy Han, Yi Krzysztof, Krajewski Sheng, Jiang Roller, Peter Wang, Shaomeng TI Design, synthesis, biochemical and biological evaluations of novel and potent small-molecule inhibitors of STAT3 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Chen, Jianyong; Bai, Longchuan; Zaneta, Nikolovska-Coleska; Zhang, Jian; Gomez, Cindy; Han, Yi; Wang, Shaomeng] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Krzysztof, Krajewski; Sheng, Jiang; Roller, Peter] NIH, Med Chem Lab, Frederick, MD 21702 USA. EM jiachen@umich.edu 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 MAR 22 PY 2009 VL 237 MA 276-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857804602 ER PT J AU Cisneros, GA Perera, L Garcia-Diaz, M Bebenek, K Kunkel, T Pedersen, LG AF Cisneros, G. Andres Perera, Lalith Garcia-Diaz, Miguel Bebenek, Katarzyna Kunkel, Thomas Pedersen, Lee G. TI Quantum mechanical/molecular mechanical studies of the reaction mechanism of human DNA polymerase lambda with Mg2+ and Mn2+ SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Cisneros, G. Andres; Perera, Lalith; Garcia-Diaz, Miguel; Bebenek, Katarzyna; Kunkel, Thomas] Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Garcia-Diaz, Miguel; Bebenek, Katarzyna; Kunkel, Thomas] Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. [Pedersen, Lee G.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. EM cisnero1@niehs.nih.gov RI Pedersen, Lee/E-3405-2013 OI Pedersen, Lee/0000-0003-1262-9861 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 MAR 22 PY 2009 VL 237 MA 93-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857803492 ER PT J AU Englund, EA Appella, DH AF Englund, Ethan A. Appella, Daniel H. TI ORGN 13-Development of gamma-substituted PNA as versatile scaffolds for multivalent display SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Englund, Ethan A.; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, DHHS, NIH, Bethesda, MD 20892 USA. EM englunde@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 MAR 22 PY 2009 VL 237 MA 13-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857806387 ER PT J AU Hajjo, R Grulke, C Golbraikh, A Roth, BR Tropsha, A AF Hajjo, Rima Grulke, Christopher Golbraikh, Alexander Roth, Bryan R. Tropsha, Alexander TI QSAR models of 5-HT2B receptor ligands and their application to predicting compounds that could cause valvulopathy SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Hajjo, Rima; Grulke, Christopher; Golbraikh, Alexander; Tropsha, Alexander] Univ N Carolina, Sch Pharm, Lab Mol Modeling, Chapel Hill, NC 27599 USA. [Roth, Bryan R.] Univ N Carolina, Sch Med, Dept Pharmacol, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC 27599 USA. [Roth, Bryan R.] Univ N Carolina, Sch Med, Dept Pharmacol, Dept Biochem, Chapel Hill, NC 27599 USA. EM hajjo@email.unc.edu; grulke@unc.edu; golbraik@email.unc.edu; bryan_roth@med.unc.edu; alex_tropsha@unc.edu RI Tropsha, Alexander/G-6245-2014 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 MAR 22 PY 2009 VL 237 MA 115-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857804470 ER PT J AU Han, HJ Romero, R Kannan, RM AF Han, Hye Jung Romero, Roberto Kannan, Rangaramanujam M. TI Dendrimer based diagnostic nanodevices for improved detection of inflammatory markers in the amniotic fluid SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Han, Hye Jung; Kannan, Rangaramanujam M.] Wayne State Univ, Mott Ctr, Detroit, MI 48201 USA. [Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Detroit, MI USA. EM hhan@med.wayne.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 MAR 22 PY 2009 VL 237 MA 368-PMSE PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857807380 ER PT J AU Horkay, F Basser, PJ AF Horkay, Ferenc Basser, Peter J. TI DNA gels: pH mediated structural changes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Horkay, Ferenc; Basser, Peter J.] NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov; pjbasser@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 MAR 22 PY 2009 VL 237 MA 340-PMSE PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857807241 ER PT J AU Horkay, F Lin, DC Horkayne-Szakaly, I Silva, C Dimitriadis, EK Basser, PJ AF Horkay, Ferenc Lin, David C. Horkayne-Szakaly, Iren Silva, Candida Dimitriadis, Emilios K. Basser, Peter J. TI Cartilage biopolymers: Self-assembly and load-bearing properties SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Horkay, Ferenc; Lin, David C.; Horkayne-Szakaly, Iren; Silva, Candida; Basser, Peter J.] NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] NIBIB, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov; lindavid@mail.nih.gov; horkayi@mail.nih.gov; dimitria@helix.nih.gov; pjbasser@helix.nih.gov RI Basser, Peter/H-5477-2011 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 MAR 22 PY 2009 VL 237 MA 59-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857804604 ER PT J AU Iyer, MR Dersch, CM Rothman, RB Deschamps, JR Jacobson, AE Rice, KC AF Iyer, Malliga R. Dersch, Christina M. Rothman, Richard B. Deschamps, Jeffrey R. Jacobson, Arthur E. Rice, Kenner C. TI Probes for narcotic receptor mediated phenomena: Binding studies on racemic cis benzofuro[2,3-c]pyridin-8-ols SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Iyer, Malliga R.; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, NIH, DFIHS, Rockville, MD 20852 USA. [Dersch, Christina M.; Rothman, Richard B.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Rockville, MD 20852 USA. [Dersch, Christina M.; Rothman, Richard B.] NIDA IRP, Clin Psychopharmacol Sect, NIH, DHHS, Baltimore, MD 21224 USA. [Deschamps, Jeffrey R.] USN, Res Lab, Washington, DC 20375 USA. EM iyerma@mail.nih.gov; aej@helix.nih.gov; kr21f@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 MAR 22 PY 2009 VL 237 MA 261-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857804650 ER PT J AU Jiao, GS Cregar-Hernandez, L Moayeri, M McKasson, L Millis, SZ Leppla, SH Johnson, AT AF Jiao, Guan-Sheng Cregar-Hernandez, Lynne Moayeri, Mahtab McKasson, Linda Millis, Sherri Z. Leppla, Stephen H. Johnson, Alan T. TI Discovery of alpha-arylamino hydroxamic acids as novel anthrax lethal factor inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Jiao, Guan-Sheng; McKasson, Linda; Johnson, Alan T.] PanThera Biopharma LLC, Dept Chem, Aiea, HI 96701 USA. [Cregar-Hernandez, Lynne; Millis, Sherri Z.] PanThera Biopharma LLC, Dept Biosci, Aiea, HI 96701 USA. [Moayeri, Mahtab; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, NIH, Bethesda, MD 20892 USA. EM gjiao@pantherabio.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 MAR 22 PY 2009 VL 237 MA 238-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857804613 ER PT J AU Kalish, H Phillips, TM AF Kalish, Heather Phillips, Terry M. TI Microchip analysis of neuronal secretions by immunoaffinity capillary electrophoresis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Kalish, Heather; Phillips, Terry M.] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, Bethesda, MD 20892 USA. EM KalishH@mail.nih.gov; PhillipT@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 MAR 22 PY 2009 VL 237 MA 26-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857804500 ER PT J AU Liao, CZ Nicklaus, MC AF Liao, Chenzhong Nicklaus, Marc C. TI Theoretical study of HIV-1 integrase inhibitors' tautomerism and their chelating complexes with two magnesium ions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Liao, Chenzhong; Nicklaus, Marc C.] NCI, Med Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. EM czliao@helix.nih.gov; mn1@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 MAR 22 PY 2009 VL 237 MA 118-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857804661 ER PT J AU Lucas, HR Jackson, MS Lee, JC AF Lucas, Heather R. Jackson, Mark S. Lee, Jennifer C. TI Copper binding properties of membrane-bound alpha-synuclein SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Lucas, Heather R.; Jackson, Mark S.; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. EM hlucas4@jhu.edu; jacksonms@mail.nih.gov; leej4@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 MAR 22 PY 2009 VL 237 MA 691-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857805294 ER PT J AU Micklitsch, CM Appella, DH AF Micklitsch, Christopher M. Appella, Daniel H. TI ORGN 262-Improvement of PNA-based DNA detection via cross-linked PNA oligomers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Micklitsch, Christopher M.; Appella, Daniel H.] NIDDK, Lab Biorgan Chem, DHHS, NIH, Bethesda, MD 20892 USA. EM micklitschc@niddk.nih.gov 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 MAR 22 PY 2009 VL 237 MA 262-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857806484 ER PT J AU Monda, JK Potter, WT Hall, MD Brimacombe, KR Gottesman, MM AF Monda, Julie K. Potter, William T. Hall, Matthew D. Brimacombe, Kyle R. Gottesman, Michael M. TI Analysis of metal content in multidrug resistant cancer cells by ICP-MS SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Monda, Julie K.; Potter, William T.] Univ Tulsa, Dept Chem & Biochem, Tulsa, OK 74104 USA. [Hall, Matthew D.; Brimacombe, Kyle R.; Gottesman, Michael M.] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. EM julie-monda@utulsa.edu; william-potter@utulsa.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 MAR 22 PY 2009 VL 237 MA 286-CHED PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857801228 ER PT J AU Pegg, AE Guida, WC Vankayala, SL Pauly, GT Loktionova, N Fang, QM AF Pegg, Anthony E. Guida, Wayne C. Vankayala, Sai Lakshmana Pauly, Gary T. Loktionova, Natalia Fang, Qingming TI Computational correlation studies toward inactivation of O6-alkylguanine-DNA alkyltransferase by O6-benzylguanine analogs SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Pegg, Anthony E.] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershley, PA 17033 USA. [Guida, Wayne C.] H Lee Moffitt Canc Ctr & Res Inst, Drug Discovery Program, Tampa, FL 33612 USA. [Vankayala, Sai Lakshmana] Univ S Florida, Dept Chem, Tampa, FL 33620 USA. [Pauly, Gary T.] NCI, Dept Comparat Carcinogenesis, Frederick, MD 21702 USA. [Loktionova, Natalia] Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Hershey, PA 17033 USA. [Fang, Qingming] Penn State Univ, Dept Cellular & Mol Physiol, Milton S Hershey Med Ctr, Hershey, PA 17033 USA. EM wguida@cas.usf.edu; svankaya@mail.usf.edu 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 MAR 22 PY 2009 VL 237 MA 120-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857804741 ER PT J AU Piquemal, JP Cisneros, GA Darden, TA Gresh, N AF Piquemal, Jean-Philip Cisneros, G. Andres Darden, Thomas A. Gresh, Nohad TI PHYS 447-Progress toward a multiscale SIBFA/GEM/QM integrated polarizable scheme using Hermite Gaussian densities SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Piquemal, Jean-Philip] Univ Paris 06, Lab Chim Theor, CNRS, UMR 7616, F-75252 Paris 05, France. [Cisneros, G. Andres; Darden, Thomas A.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Gresh, Nohad] CNRS, IFR Biomed, Lab Pharmacochim Mol, FRE 2718, F-75006 Paris, France. EM jpp@lct.jussieu.fr; cisnerol@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 MAR 22 PY 2009 VL 237 MA 447-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857808024 ER PT J AU Remsberg, J Lou, H Tarasov, SG Adams, KM Barchi, JJ Gustafson, K Dean, M Tarasova, NI AF Remsberg, Jarrett Lou, Hong Tarasov, Sergey G. Adams, Kristie M. Barchi, Joseph J., Jr. Gustafson, Kirk Dean, Michael Tarasova, Nadya I. TI Inhibiting smoothened from inside: Rationally designed nanomolar inhibitors of the Hedgehog pathway SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Remsberg, Jarrett; Gustafson, Kirk; Tarasova, Nadya I.] NCI, Mol Targets Dev Program, Frederick, MD 21702 USA. [Lou, Hong; Dean, Michael] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Tarasov, Sergey G.] NCI Frederick, Struct Biophys Lab, Frederick, MD 21702 USA. [Adams, Kristie M.; Barchi, Joseph J., Jr.] NCI, Med Chem Lab, Frederick, MD 21702 USA. EM remsberg@mit.edu; louh@ncifcrf.gov; tarasovs@ncifcrf.gov; adamskm@mail.nih.gov; barchi@helix.nih.gov; gustafson@ncifcrf.gov; dean@ncifcrf.gov; tarasova@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 MAR 22 PY 2009 VL 237 MA 179-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857804683 ER PT J AU Salmon, DJ Andrei, D Miranda, KM Keefer, LK AF Salmon, Debra J. Andrei, Daniela Miranda, Katrina M. Keefer, Larry K. TI Comparison of HNO detection methods for quantitative results SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Salmon, Debra J.; Miranda, Katrina M.] Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. [Andrei, Daniela; Keefer, Larry K.] Natl Canc Inst, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. EM keefer@ncifcrf.gov 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 MAR 22 PY 2009 VL 237 MA 459-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857805590 ER PT J AU Simeon, F Wendahl, M Pike, VW AF Simeon, Fabrice Wendahl, Matthew Pike, Victor W. TI ORGN 504-Halogenation of 1,3-thiazole derivatives with copper halides SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Simeon, Fabrice; Wendahl, Matthew; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM simeonf@intra.nimh.nih.gov; wendahlm@mail.nih.gov; pikev@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 MAR 22 PY 2009 VL 237 MA 504-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857806313 ER PT J AU Sitzmann, M Filippov, IV Nicklaus, MC AF Sitzmann, Markus Filippov, Igor V. Nicklaus, Marc C. TI InChI/InChIKey vs. NCI/CADD Identifiers: A comparison SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Sitzmann, Markus] NCI, Med Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. [Filippov, Igor V.] SAIC Frederick Inc, Med Chem Lab, NCI Frederick, Frederick, MD 21702 USA. EM sitzmann@helix.nih.gov; igorf@helix.nih.gov; mnl@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 MAR 22 PY 2009 VL 237 MA 17-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857802682 ER PT J AU Vu, VV Emerson, JP Martinho, M Kim, YS Munck, E Park, MH Que, L AF Vu, Van V. Emerson, Joseph P. Martinho, Marlene Kim, Yeon Sook Munck, Eckard Park, Myung Hee Que, Lawrence, Jr. TI Reduced diiron site in human deoxyhypusine hydroxylase can bind dioxygen to form a stable diferric peroxo cluster SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Vu, Van V.; Emerson, Joseph P.; Que, Lawrence, Jr.] Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. [Martinho, Marlene; Munck, Eckard] Carnegie Mellon Univ, Dept Chem, Pittsburgh, PA 15213 USA. [Kim, Yeon Sook; Park, Myung Hee] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. EM vuxxx047@umn.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 MAR 22 PY 2009 VL 237 MA 610-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857805314 ER PT J AU Weidlich, IE Dexheimer, T Pommier, Y Marchand, C Nicklaus, MC AF Weidlich, Iwona E. Dexheimer, Thomas Pommier, Yves Marchand, Christophe Nicklaus, Marc C. TI Screening tools and results for inhibitors of human tyrosyl DNA phosphodiesterase (Tdp1) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Weidlich, Iwona E.; Nicklaus, Marc C.] NCI, Med Chem Lab, Ctr Canc Res, NIH,DFIHS, Frederick, MD 21702 USA. [Dexheimer, Thomas; Pommier, Yves; Marchand, Christophe] NCI, Mol Pharmacol Lab, CCR, NIH, Bethesda, MD 20892 USA. EM iweidlic@helix.nih.gov; pommier@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 MAR 22 PY 2009 VL 237 MA 211-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857803508 ER PT J AU Zohorsky, SM Mitra, I Munk, R Takahashi, H Morris, C Longo, D Ghosh, P AF Zohorsky, Sean M. Mitra, Indrani Munk, Rachel Takahashi, Hidenori Morris, Christa Longo, Dan Ghosh, Paritosh TI Effect of different oxygen concentration on cell growth and proliferation SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Zohorsky, Sean M.] Univ Dallas, Dept Chem, Irving, TX 75062 USA. [Mitra, Indrani; Munk, Rachel; Takahashi, Hidenori; Morris, Christa; Longo, Dan; Ghosh, Paritosh] NIA, Biomed Res Ctr, Baltimore, MD 21224 USA. EM szohorsky@hotmail.com; ghoshp@grc.nia.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 MAR 22 PY 2009 VL 237 MA 326-CHED PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V16GJ UT WOS:000207857801430 ER PT J AU Jo, J Choi, MY Koh, DS AF Jo, Junghyo Choi, Moo Young Koh, Duk-Su TI Beneficial effects of intercellular interactions between pancreatic islet cells in blood glucose regulation SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Glucose homeostasis; Islets of Langerhans; Feedback; Diabetes ID STIMULATED INSULIN-SECRETION; BETA-CELLS; ALPHA-CELLS; ENDOCRINE PANCREAS; GLUCAGON-SECRETION; DELTA-CELLS; CONFOCAL MICROSCOPY; INTACT ISLETS; LANGERHANS; RELEASE AB Glucose homeostasis is controlled by the islets of Langerhans which are equipped with a-cells increasing the blood glucose level, beta-cells decreasing it, and delta-cells the precise role of which still needs identifying. Although intercellular communications between these endocrine cells have recently been observed, their roles in glucose homeostasis have not been clearly understood. In this study, we construct a mathematical model for an islet consisting of two-state alpha-, beta-, and delta-cells, and analyze effects of known chemical interactions between them with emphasis on the combined effects of those interactions. In particular, such features as paracrine signals of neighboring cells and cell-to-cell variations in response to external glucose concentrations as well as glucose dynamics, depending on insulin and glucagon hormone, are considered explicitly. Our model predicts three possible benefits of the cell-to-cell interactions: First, the asymmetric interaction between alpha- and beta-cells contributes to the dynamic stability while the perturbed glucose level recovers to the normal level. Second, the inhibitory interactions of delta-cells for glucagon and insulin secretion prevent the wasteful co-secretion of them at the normal glucose level. Finally, the glucose dose-responses of insulin secretion is modified to become more pronounced at high glucose levels due to the inhibition by delta-cells. It is thus concluded that the intercellular communications in islets of Langerhans should contribute to the effective control of glucose homeostasis. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Choi, Moo Young] Seoul Natl Univ, Dept Phys & Astron, Seoul 151747, South Korea. [Choi, Moo Young] Seoul Natl Univ, Ctr Theoret Phys, Seoul 151747, South Korea. [Jo, Junghyo] NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Koh, Duk-Su] Univ Washington, Dept Physiol & Biophys, Seattle, WA 98195 USA. RP Choi, MY (reprint author), Seoul Natl Univ, Dept Phys & Astron, Seoul 151747, South Korea. EM mychoi@snu.ac.kr RI Jo, Junghyo/D-4889-2011; OI Choi, MooYoung/0000-0001-8070-7716 FU KOSEF/MOST; KOSEF-CNRS FX We thank D. Gardner-Hofatt and W. Heuett for useful comments on the manuscript. M.Y.C. thanks Asia Pacific Center for Theoretical Physics, where part of this work was performed, for hospitality. This work was supported in part by the KOSEF/MOST grant through National Core Research Center for Systems Bio-Dynamics and by the KOSEF-CNRS Cooperative Program. NR 46 TC 10 Z9 12 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD MAR 21 PY 2009 VL 257 IS 2 BP 312 EP 319 DI 10.1016/j.jtbi.2008.12.005 PG 8 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 419ZP UT WOS:000264258500012 PM 19135066 ER PT J AU Margulies, DH AF Margulies, David H. TI Home Schooling of NK Cells SO IMMUNITY LA English DT Editorial Material ID NATURAL-KILLER-CELLS; MHC CLASS-I; INHIBITORY RECEPTORS; SELF-TOLERANCE; MOLECULES; ASSOCIATION AB In this issue of Immunity, Chalifour et al. (2009) show that for natural killer (NK) cells to achieve their full effector potential, NK inhibitory receptors must developmentally interact with MHC-I ligands expressed in cis. C1 NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Margulies, DH (reprint author), NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. EM dhm@nih.gov RI Margulies, David/H-7089-2013; OI Margulies, David/0000-0001-8530-7375 NR 10 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAR 20 PY 2009 VL 30 IS 3 BP 313 EP 315 DI 10.1016/j.immuni.2009.02.002 PG 3 WC Immunology SC Immunology GA 422CU UT WOS:000264405500001 PM 19303382 ER PT J AU Durum, SK Mazzucchelli, RI AF Durum, Scott K. Mazzucchelli, Renata I. TI Live from the Liver: Hepatocyte IL-7 SO IMMUNITY LA English DT Editorial Material ID INTERLEUKIN-7; EXPRESSION; CELLS AB Interleukin 7 (IL-7), which is required for T cell survival, was previously found in lymphoid tissues. In this issue of Immunity, Sawa et al. (2009) have identified the liver as a new source of IL-7. C1 [Durum, Scott K.] NCI, Lab Immunoregulat Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Mazzucchelli, Renata I.] San Raffaele Telethon Inst Gene Therapy, Lab Gene Therapy & Primary Immunodeficiency, I-20132 Milan, Italy. RP Durum, SK (reprint author), NCI, Lab Immunoregulat Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM durums@mail.nih.gov NR 8 TC 3 Z9 3 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAR 20 PY 2009 VL 30 IS 3 BP 320 EP 321 DI 10.1016/j.immuni.2009.03.001 PG 2 WC Immunology SC Immunology GA 422CU UT WOS:000264405500004 PM 19303385 ER PT J AU Belkaid, Y Tarbell, KV AF Belkaid, Yasmine Tarbell, Kristin V. TI Arming Treg Cells at the Inflammatory Site SO IMMUNITY LA English DT Editorial Material ID REGULATORY T-CELLS; MICE AB In this issue of Immunity, Zhang et al. (2009) propose that Treg cells, in order to efficiently control alloimmune response, need to be educated first in the target tissue before entering the draining lymph node. C1 [Belkaid, Yasmine] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Tarbell, Kristin V.] NIDDK, Immune Tolerance Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM ybelkaid@niaid.nih.gov OI Tarbell, Kristin/0000-0003-3738-379X NR 10 TC 15 Z9 15 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAR 20 PY 2009 VL 30 IS 3 BP 322 EP 323 DI 10.1016/j.immuni.2009.03.004 PG 2 WC Immunology SC Immunology GA 422CU UT WOS:000264405500005 PM 19303386 ER PT J AU Sinha, RK Park, C Hwang, IY Davis, MD Kehrl, JH AF Sinha, Rajesh K. Park, Chung Hwang, Il-Young Davis, Michael D. Kehrl, John H. TI B Lymphocytes Exit Lymph Nodes through Cortical Lymphatic Sinusoids by a Mechanism Independent of Sphingosine-1-Phosphate-Mediated Chemotaxis SO IMMUNITY LA English DT Article ID SPHINGOSINE 1-PHOSPHATE RECEPTORS; IMMUNOSUPPRESSANT FTY720; THYMOCYTE EMIGRATION; ENDOTHELIAL-CELLS; T-CELLS; IN-VIVO; MIGRATION; EGRESS; INHIBITION; MOTILITY AB Sphingosine-1-phosphate (S1P) helps mediate lymphocyte egress from lymph nodes, yet many mechanistic questions remain. Here, we show the presence of B lymphocyte egress sites located in the lymph node cortex close to lymph node follicles. B cells exited lymph nodes by squeezing through apparent portals in the lymphatic endothelium of these sinusoids. Treatment with the S1P receptor agonist FTY720 emptied the cortical sinusoids of lymphocytes, blocked lymphatic endothelial penetration, and displaced B lymphocytes into the T cell zone. Slpr3(-/-) B cells, which lack chemoattractant responses to S1P, transited lymph nodes normally, whereas Gnai2(-/-) B cells, which have impaired responses to chemokines and S1P, transited more rapidly than did wild-type cells. This study identifies a major site of B lymphocyte lymph node egress, shows that FTY720 treatment blocks passage through the cortical lymphatic endothelium, and argues against a functional role for S1P chemotaxis in B lymphocyte egress. C1 [Sinha, Rajesh K.; Park, Chung; Hwang, Il-Young; Davis, Michael D.; Kehrl, John H.] NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Kehrl, JH (reprint author), NIAID, B Cell Mol Immunol Sect, Immunoregulat Lab, Bethesda, MD 20892 USA. EM jkehrl@niaid.nih.gov OI Kehrl, John/0000-0002-6526-159X FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX The authors would like thank M. Rust for her editorial assistance; A.S. Fauci for his continued support, and 0. Schwartz, M. Czapiga, and J. a at o t e Research Technology Branch of the National Institutes of Allergy and Infectious Diseases for their help in the acquisition and analysis of the TP-LSM data. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 41 TC 57 Z9 57 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD MAR 20 PY 2009 VL 30 IS 3 BP 434 EP 446 DI 10.1016/j.immuni.2008.12.018 PG 13 WC Immunology SC Immunology GA 422CU UT WOS:000264405500015 PM 19230723 ER PT J AU Kumari, D Usdin, K AF Kumari, Daman Usdin, Karen TI Chromatin Remodeling in the Noncoding Repeat Expansion Diseases SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID FRAGILE-X-SYNDROME; HISTONE DEACETYLASE INHIBITORS; FRIEDREICHS-ATAXIA; MYOTONIC-DYSTROPHY; TRINUCLEOTIDE REPEAT; EPIGENETIC CHANGES; TRIPLET REPEATS; FRATAXIN GENE; CTG REPEATS; FMR-1 GENE AB Friedreich ataxia, myotonic dystrophy type 1 and 3 forms of intellectual disability, fragile X syndrome, FRAXE mental retardation, and FRA12A mental retardation are repeat expansion diseases caused by expansion of CTG.CAG, GAA.TTC, or CGG.CCG repeat tracts. These repeats are transcribed but not translated. They are located in different parts of different genes and cause symptoms that range from ataxia and hypertrophic cardiomyopathy to muscle wasting, male infertility, and mental retardation, yet recent reports suggest that, despite these differences, the repeats may share a common property, namely the ability to initiate repeat-mediated epigenetic changes that result in heterochromatin formation. C1 [Kumari, Daman; Usdin, Karen] NIDDK, Sect Gene Struct & Dis, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. RP Usdin, K (reprint author), NIDDK, Sect Gene Struct & Dis, Mol & Cellular Biol Lab, NIH, Bethesda, MD 20892 USA. EM ku@helix.nih.gov NR 44 TC 36 Z9 36 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 MAR 20 PY 2009 VL 284 IS 12 BP 7413 EP 7417 DI 10.1074/jbc.R800026200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419CB UT WOS:000264195600003 PM 18957431 ER PT J AU Sommers, JA Rawtani, N Gupta, R Bugreev, DV Mazin, AV Cantor, SB Brosh, RM AF Sommers, Joshua A. Rawtani, Nina Gupta, Rigu Bugreev, Dmitry V. Mazin, Alexander V. Cantor, Sharon B. Brosh, Robert M. TI FANCJ Uses Its Motor ATPase to Destabilize Protein-DNA Complexes, Unwind Triplexes, and Inhibit RAD51 Strand Exchange SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HOMOLOGOUS RECOMBINATION; BREAST-CANCER; NUCLEOPROTEIN FILAMENTS; SUBSTRATE-SPECIFICITY; GENOMIC STABILITY; SYNDROME HELICASE; REPLICATION-FORK; BINDING PROTEIN; RECQ HELICASES; IN-VIVO AB Mutations in the FANCJ helicase predispose individuals to breast cancer and are genetically linked to the Fanconi anemia (FA) complementation group J.FA is a chromosomal instability disorder characterized by multiple congenital anomalies, progressive bone marrow failure, and high cancer risk. FANCJ has been proposed to function downstream of FANCD2 monoubi-quitination, a critical event in the FA pathway. Evidence supports a role for FANCJ in a homologous recombination pathway of double strand break repair. In an effort to understand the molecular functions of FANCJ, we have investigated the ability of purified FANCJ recombinant protein to use its motor ATPase function for activities in addition to unwinding of conventional duplex DNA substrates. These efforts have led to the discovery that FANCJ ATP hydrolysis can be used to destabilize protein-DNA complexes and unwind triple helix alternate DNA structures. These novel catalytic functions of FANCJ may be important for its role in cellular DNA repair, recombination, or resolving DNA structural obstacles to replication. Consistent with this, we show that FANCJ can inhibit RAD51 strand exchange, an activity that is likely to be important for its role in controlling DNA repair through homologous recombination. C1 [Sommers, Joshua A.; Rawtani, Nina; Gupta, Rigu; Brosh, Robert M.] NIA, Lab Mol Gerontol, NIH, Natl Inst Hlth Biomed Res Ctr, Baltimore, MD 21224 USA. [Bugreev, Dmitry V.; Mazin, Alexander V.] Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19102 USA. [Bugreev, Dmitry V.] Russian Acad Sci, Inst Chem Biol & Fundamental Med, Siberian Branch, Novosibirsk 630090, Russia. [Cantor, Sharon B.] Univ Massachusetts, Sch Med, Womens Canc Program, UMass Mem Canc Ctr,Dept Canc Biol, Worcester, MA 01605 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Natl Inst Hlth Biomed Res Ctr, 251 Bayview Dr,Suite 100,Rm 06B125, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU National Institutes of Health Intramural Research Program; NIA; National Institutes of Health [CA100839, MH084119]; Fanconi Anemia Research Fund; Leukemia and Lymphoma Society Scholar Award [1054-09] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program; NIA, National Institutes of Health; and National Institutes of Health Grants CA100839 and MH084119. This work was also supported by the Fanconi Anemia Research Fund (to R.M.B.) and by Leukemia and Lymphoma Society Scholar Award 1054-09 (to A.V.M.). NR 49 TC 55 Z9 56 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 MAR 20 PY 2009 VL 284 IS 12 BP 7505 EP 7517 DI 10.1074/jbc.M809019200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419CB UT WOS:000264195600014 PM 19150983 ER PT J AU Ishii, H Du, H Zhang, Z Henderson, A Sen, R Pazin, MJ AF Ishii, Haruhiko Du, Hansen Zhang, Zhaoqing Henderson, Angus Sen, Ranjan Pazin, Michael J. TI Mi2 beta Shows Chromatin Enzyme Specificity by Erasing a DNase I-hypersensitive Site Established by ACF SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAVY-CHAIN GENE; TRANSCRIPTIONAL ACTIVATION; REMODELING COMPLEX; NUCLEOSOMAL DNA; HISTONE DEACETYLASE; FUNCTIONAL DIFFERENCES; REGULATORY PROTEINS; BINDING PROTEINS; B-CELLS; ENHANCER AB ATP-dependent chromatin-remodeling enzymes are linked to changes in gene expression; however, it is not clear how the multiple remodeling enzymes found in eukaryotes differ in function and work together. In this report, we demonstrate that the ATP-dependent remodeling enzymes ACF and Mi2 beta can direct consecutive, opposing chromatin-remodeling events, when recruited to chromatin by different transcription factors. In a cell-free system based on the immunoglobulin heavy chain gene enhancer, we show that TFE3 induces a DNase I-hypersensitive site in an ATP-dependent reaction that requires ACF following transcription factor binding to chromatin. In a second step, PU.1 directs Mi2 beta to erase an established DNase I-hypersensitive site, in an ATP-dependent reaction subsequent to PU.1 binding to chromatin, whereas ACF will not support erasure. Erasure occurred without displacing the transcription factor that initiated the site. Other tested enzymes were unable to erase the DNase I-hypersensitive site. Establishing and erasing the DNase I-hypersensitive site required transcriptional activation domains from TFE3 and PU.1, respectively. Together, these results provide important new mechanistic insight into the combinatorial control of chromatin structure. C1 [Du, Hansen; Sen, Ranjan; Pazin, Michael J.] NIA, Lab Cellular & Mol Biol, NIH, Baltimore, MD 21224 USA. [Ishii, Haruhiko] Brandeis Univ, Grad Program Biophys & Struct Biol, Waltham, MA 02454 USA. [Zhang, Zhaoqing; Pazin, Michael J.] Massachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USA. [Henderson, Angus] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. RP Pazin, MJ (reprint author), NIA, Lab Cellular & Mol Biol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM pazinm@mail.nih.gov FU Intramural NIH HHS [ZIA AG000524-05]; NIGMS NIH HHS [GM38925, GM61011] NR 79 TC 3 Z9 3 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 MAR 20 PY 2009 VL 284 IS 12 BP 7533 EP 7541 DI 10.1074/jbc.M807617200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419CB UT WOS:000264195600016 PM 19158090 ER PT J AU Bailey, MJ Coon, SL Carter, DA Humphries, A Kim, JS Shi, Q Gaildrat, P Morin, F Ganguly, S Hogenesch, JB Weller, JL Rath, MF Moller, M Baler, R Sugden, D Rangel, ZG Munson, PJ Klein, DC AF Bailey, Michael J. Coon, Steven L. Carter, David A. Humphries, Ann Kim, Jong-So Shi, Qiong Gaildrat, Pascaline Morin, Fabrice Ganguly, Surajit Hogenesch, John B. Weller, Joan L. Rath, Martin F. Moller, Morten Baler, Ruben Sugden, David Rangel, Zoila G. Munson, Peter J. Klein, David C. TI Night/Day Changes in Pineal Expression of > 600 Genes CENTRAL ROLE OF ADRENERGIC/cAMP SIGNALING SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID ARYLALKYLAMINE-N-ACETYLTRANSFERASE; PHOTORECEPTOR CONSERVED ELEMENTS; O-METHYLTRANSFERASE ACTIVITY; PHOSPHOLIPASE-C ACTIVITY; OTX2 HOMEOBOX GENE; PROTEIN-KINASE-C; RAT PINEAL; MELATONIN SYNTHESIS; THYROID-HORMONE; MESSENGER-RNA AB The pineal gland plays an essential role in vertebrate chronobiology by converting time into a hormonal signal, melatonin, which is always elevated at night. Here we have analyzed the rodent pineal transcriptome using Affymetrix GeneChip (R) technology to obtain a more complete description of pineal cell biology. The effort revealed that 604 genes (1,268 probe sets) with Entrez Gene identifiers are differentially expressed greater than 2-fold between midnight and mid-day (false discovery rate <0.20). Expression is greater at night in similar to 70%. These findings were supported by the results of radiochemical in situ hybridization histology and quantitative real time-PCR studies. We also found that the regulatory mechanism controlling the night/day changes in the expression of most genes involves norepinephrine-cyclic AMP signaling. Comparison of the pineal gene expression profile with that in other tissues identified 334 genes (496 probe sets) that are expressed greater than 8-fold higher in the pineal gland relative to other tissues. Of these genes, 17% are expressed at similar levels in the retina, consistent with a common evolutionary origin of these tissues. Functional categorization of the highly expressed and/or night/day differentially expressed genes identified clusters that are markers of specialized functions, including the immune/inflammation response, melatonin synthesis, photodetection, thyroid hormone signaling, and diverse aspects of cellular signaling and cell biology. These studies produce a paradigm shift in our understanding of the 24-h dynamics of the pineal gland from one focused on melatonin synthesis to one including many cellular processes. C1 [Bailey, Michael J.; Coon, Steven L.; Kim, Jong-So; Shi, Qiong; Gaildrat, Pascaline; Morin, Fabrice; Ganguly, Surajit; Weller, Joan L.; Klein, David C.] NICHD, Sect Neuroendocrinol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Carter, David A.; Humphries, Ann] Cardiff Univ, Sch Biosci, Cardiff CF10 3AX, S Glam, Wales. [Hogenesch, John B.] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA. [Rath, Martin F.; Moller, Morten] Univ Copenhagen, Fac Hlth Sci, Dept Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark. [Baler, Ruben] NIMH, Unit Temporal Gene Express, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. [Sugden, David] Kings Coll London, Sch Biomed & Hlth Sci, Div Reprod & Endocrinol, London SE1 1UL, England. [Rangel, Zoila G.; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), 49 Convent Dr,Bldg 49,Rm 6A82, Bethesda, MD 20892 USA. EM kleind@mail.nih.gov RI Carter, David/A-4479-2010; OI Carter, David/0000-0002-8419-3975; Rath, Martin/0000-0002-4047-6324 FU Intramural NIH HHS; NIMH NIH HHS [P50 MH074924]; NINDS NIH HHS [R01 NS054794]; Wellcome Trust NR 124 TC 72 Z9 80 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 MAR 20 PY 2009 VL 284 IS 12 BP 7606 EP 7622 DI 10.1074/jbc.M808394200 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419CB UT WOS:000264195600023 PM 19103603 ER PT J AU Raj, DK Mu, JB Jiang, HY Kabat, J Singh, S Sullivan, M Fay, MP McCutchan, TF Su, XZ AF Raj, Dipak Kumar Mu, Jianbing Jiang, Hongying Kabat, Juraj Singh, Subash Sullivan, Margery Fay, Michael P. McCutchan, Thomas F. Su, Xin-zhuan TI Disruption of a Plasmodium falciparum Multidrug Resistance-associated Protein (PfMRP) Alters Its Fitness and Transport of Antimalarial Drugs and Glutathione SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BINDING CASSETTE TRANSPORTERS; CHLOROQUINE RESISTANCE; MALARIA PARASITES; ABC TRANSPORTERS; QUININE RESISTANCE; DIGESTIVE VACUOLE; P-GLYCOPROTEIN; PFMDR1 GENE; SENSITIVITY; MEFLOQUINE AB ATP-binding cassette transporters play an important role in drug resistance and nutrient transport. In the human malaria parasite Plasmodium falciparum, a homolog of the human p-glycoprotein (PfPgh-1) was shown to be involved in resistance to several drugs. More recently, many transporters were associated with higher IC(50) levels in responses to chloroquine (CQ) and quinine (QN) in field isolates. Subsequent studies, however, could not confirm the associations, although inaccuracy in drug tests in the later studies could contribute to the lack of associations. Here we disrupted a gene encoding a putative multidrug resistance-associated protein (PfMRP) that was previously shown to be associated with P. falciparum responses to CQ and QN. Parasites with disrupted PfMRP (W2/MRP Delta) could not grow to a parasitemia higher than 5% under normal culture conditions, possibly because of lower efficiency in removing toxic metabolites. The W2/MRP Delta parasite also accumulated more radioactive glutathione, CQ, and QN and became more sensitive to multiple antimalarial drugs, including CQ, QN, artemisinin, piperaquine, and primaquine. PfMRP was localized on the parasite surface membrane, within membrane-bound vesicles, and along the straight side of the D-shaped stage II gametocytes. The results suggest that PfMRP plays a role in the efflux of glutathione, CQ, and QN and contributes to parasite responses to multiple antimalarial drugs, possibly by pumping drugs outside the parasite. C1 [Raj, Dipak Kumar; Mu, Jianbing; Jiang, Hongying; Singh, Subash; Sullivan, Margery; McCutchan, Thomas F.; Su, Xin-zhuan] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Kabat, Juraj] NIAID, Res Technol Branch, NIH, Rockville, MD 20852 USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Rockville, MD 20852 USA. RP Su, XZ (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Rm 3E-24B, Rockville, MD 20852 USA. EM xsu@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625; Su, Xinzhuan/0000-0003-3246-3248 FU Division of Intramural Research FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of the Division of Intramural Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 61 TC 79 Z9 80 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 MAR 20 PY 2009 VL 284 IS 12 BP 7687 EP 7696 DI 10.1074/jbc.M806944200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419CB UT WOS:000264195600031 PM 19117944 ER PT J AU Lizunov, VA Lisinski, I Stenkula, K Zimmerberg, J Cushman, SW AF Lizunov, Vladimir A. Lisinski, Ivonne Stenkula, Karin Zimmerberg, Joshua Cushman, Samuel W. TI Insulin Regulates Fusion of GLUT4 Vesicles Independent of Exo70-mediated Tethering SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RAT ADIPOSE-CELLS; GLUCOSE-TRANSPORTER GLUT4; PLASMA-MEMBRANE; SIGNALING PATHWAY; TRANSLOCATION; TRAFFICKING; EXOCYST; ADIPOCYTES; INTERACTS; COMPLEX AB Insulin regulates cellular glucose uptake by changing the amount of glucose transporter-4 (GLUT4) in the plasma membrane through stimulation of GLUT4 exocytosis. However, how the particular trafficking, tethering, and fusion steps are regulated by insulin is still debated. In a 3T3-L1 adipocyte cell line, the Exocyst complex and its Exo70 subunit were shown to critically affect GLUT4 exocytosis. Here we investigated the effects of Exo70 on tethering and fusion of GLUT4 vesicles in primary isolated rat adipose cells. We found that Exo70 wild type was sequestered away from the plasma membrane in non-stimulated cells, and its overexpression had no effect on GLUT4 trafficking. The addition of insulin increased the amount of Exo70 in the vicinity of the plasma membrane and stimulated the tethering and fusion of GLUT4 vesicles, but the rates of fusion and GLUT4 exposure were not affected by overexpression of Exo70. Surprisingly, the Exo70-N mutant induced insulin-independent tethering of GLUT4 vesicles, which, however, did not lead to fusion and exposure of GLUT4 at the plasma membrane. Upon insulin stimulation, the stationary pretethered GLUT4 vesicles in Exo70-N mutant cells underwent fusion without relocation. Taken together, our data suggest that fusion of GLUT4 vesicles is the rate-limiting step regulated by insulin downstream of Exo70-mediated tethering. C1 [Lizunov, Vladimir A.; Zimmerberg, Joshua] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Cellular & Mol Biophys, Program Phys Biol, Bethesda, MD 20892 USA. [Lisinski, Ivonne; Stenkula, Karin; Cushman, Samuel W.] NIDDK, Expt Diabet Metab & Nutr Sect, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Cellular & Mol Biophys, Program Phys Biol, Bethesda, MD 20892 USA. EM joshz@mail.nih.gov RI Lizunov, Vladimir/B-5468-2009 FU National Institutes of Health FX This work was supported, in whole or in part, by an National Institutes of Health grant through the Intramural Research Programs of the NICHD and NIDDK. The costs of publication of this article were defrayed in part by the payment of page charges. NR 28 TC 18 Z9 18 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 MAR 20 PY 2009 VL 284 IS 12 BP 7914 EP 7919 DI 10.1074/jbc.M806460200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419CB UT WOS:000264195600053 PM 19155211 ER PT J AU Wilkinson, TA Januszyk, K Phillips, ML Tekeste, SS Zhang, M Miller, JT Le Grice, SFJ Clubb, RT Chow, SA AF Wilkinson, Thomas A. Januszyk, Kurt Phillips, Martin L. Tekeste, Shewit S. Zhang, Min Miller, Jennifer T. Le Grice, Stuart F. J. Clubb, Robert T. Chow, Samson A. TI Identifying and Characterizing a Functional HIV-1 Reverse Transcriptase-binding Site on Integrase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROVIRAL DNA FORMATION; VIRAL NUCLEIC-ACIDS; DOUBLE-STRANDED DNA; PREINTEGRATION COMPLEXES; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURE; IN-VITRO; NONDIVIDING CELLS; GENETIC-ANALYSIS AB Integrase (IN) from human immunodeficiency virus, type 1 (HIV-1) exerts pleiotropic effects in the viral replication cycle. Besides integration, IN mutations can impact nuclear import, viral maturation, and reverse transcription. IN and reverse transcriptase (RT) interact in vitro, and the IN C-terminal domain (CTD) is both necessary and sufficient for binding RT. We used nuclear magnetic resonance spectroscopy to identify a putative RT-binding surface on the IN CTD, and surface plasmon resonance to obtain kinetic parameters and the binding affinity for the IN-RT interaction. An IN K258A substitution that disrupts reverse transcription in infected cells is located at the putative RT-binding surface, and we found that this substitution substantially weakens IN CTD-RT interactions. We also identified two additional IN amino acid substitutions located at the putative RT-binding surface (W243E and V250E) that significantly impair viral replication in tissue culture. These results strengthen the notion that IN-RT interactions are biologically relevant during HIV-1 replication and also provide insights into this interaction at the molecular level. C1 [Wilkinson, Thomas A.; Tekeste, Shewit S.; Zhang, Min; Chow, Samson A.] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. [Januszyk, Kurt; Phillips, Martin L.; Clubb, Robert T.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA. [Miller, Jennifer T.; Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. RP Chow, SA (reprint author), Univ Calif Los Angeles, Dept Mol & Med Pharmacol, CHS 23-133,10833 Le Conte Ave, Los Angeles, CA 90095 USA. EM schow@mednet.ucla.edu RI zhang, min/C-6300-2011 FU National Institutes of Health [CA68859, AI077386]; UCLA AIDS Institute; UCLA Center for AIDS Researc [AI28697]; State of California Universitywide AIDS Research Program [CC95 LA 137, 05-LA-021]; Intramural Research Program of the Center for Cancer Research; NCI; National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Grants CA68859 and AI077386 (to S. A. C.). This work was also supported by the UCLA AIDS Institute, UCLA Center for AIDS Research (AI28697 to T. A. W.), State of California Universitywide AIDS Research Program Grants CC95 LA 137 (to T. A. W.) and 05-LA-021 (to S. A. C.), and by the Intramural Research Program of the Center for Cancer Research, NCI, National Institutes of Health (to S. F. J. L.). NR 65 TC 40 Z9 45 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 MAR 20 PY 2009 VL 284 IS 12 BP 7931 EP 7939 DI 10.1074/jbc.M806241200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419CB UT WOS:000264195600055 PM 19150986 ER PT J AU Green, JA Berrier, AL Pankov, R Yamada, KM AF Green, J. Angelo Berrier, Allison L. Pankov, Roumen Yamada, Kenneth M. TI beta(1) Integrin Cytoplasmic Domain Residues Selectively Modulate Fibronectin Matrix Assembly and Cell Spreading through Talin and Akt-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MONOCLONAL-ANTIBODIES; FOCAL ADHESIONS; BETA-1 SUBUNIT; ACTIVATION; BINDING; BETA-1-INTEGRIN; PHOSPHORYLATION; FIBRILLOGENESIS; IDENTIFICATION; LAMININ-10/11 AB The integrin beta(1) cytoplasmic domain (tail) serves as a scaffold for numerous intracellular proteins. The mechanisms by which the tail coordinates these proteins to facilitate extracellular matrix assembly and cell spreading are not clear. This study demonstrates that the beta(1) cytoplasmic domain can regulate cell spreading on fibronectin and fibronectin matrix assembly through Akt- and talin-dependent mechanisms, respectively. To identify these mechanisms, we characterized GD25 cells expressing the beta(1) integrin cytoplasmic domain mutants W775A and R760A. Although cell spreading appears normal in R760A mutant-integrin cells compared with wild type, it is inhibited in W775A mutant cells. In contrast, both mutant cell lines show defective fibronectin matrix assembly. Inhibition of cell spreading, but not matrix assembly, in the W775A mutant cells is due to a specific defect in Akt-1 activation. In addition, we find that both W775A and R760A mutant integrins have reduced surface expression of the 9EG7 epitope that correlates with reduced recruitment of talin to beta(1) integrin cytoplasmic complexes. Down-regulation of talin with small interfering RNA or expression of green fluorescent protein-talin head domain inhibits matrix assembly in beta(1) wild-type cells, mimicking the defect seen with the W775A and R760A mutant cells. These results demonstrate distinct mechanisms by which integrins regulate cell spreading and matrix assembly through the beta(1) integrin cytoplasmic tail. C1 [Green, J. Angelo; Berrier, Allison L.; Pankov, Roumen; Yamada, Kenneth M.] NIDCR, NIH, Lab Cell & Dev Biol, Bethesda, MD 20892 USA. [Berrier, Allison L.] Louisiana State Univ, Hlth Sci Ctr, Sch Dent, Dept Oral & Craniofacial Biol, New Orleans, LA 70119 USA. [Pankov, Roumen] Sofia Univ St Kliment Ohridski, Fac Biol, Dept Cytol Histol & Embryol, Sofia 1164, Bulgaria. RP Green, JA (reprint author), NIDCR, NIH, Lab Cell & Dev Biol, Bethesda, MD 20892 USA. EM angelo.green@nih.gov; kenneth.yamada@nih.gov RI Pankov, Roumen/B-3284-2014 OI Pankov, Roumen/0000-0002-3157-3659 FU NIDCR; National Institutes of Health; National Center on Minority Health and Health Disparities FX This work was supported by the Intramural Research Program of the NIDCR, National Institutes of Health, and the National Center on Minority Health and Health Disparities. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 45 TC 21 Z9 22 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 MAR 20 PY 2009 VL 284 IS 12 BP 8148 EP 8159 DI 10.1074/jbc.M805934200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 419CB UT WOS:000264195600077 PM 19144637 ER PT J AU Bookman, MA Brady, MF McGuire, WP Harper, PG Alberts, DS Friedlander, M Colombo, N Fowler, JM Argenta, PA De Geest, K Mutch, DG Burger, RA Swart, AM Trimble, EL Accario-Winslow, C Roth, LM AF Bookman, Michael A. Brady, Mark F. McGuire, William P. Harper, Peter G. Alberts, David S. Friedlander, Michael Colombo, Nicoletta Fowler, Jeffrey M. Argenta, Peter A. De Geest, Koen Mutch, David G. Burger, Robert A. Swart, Ann Marie Trimble, Edward L. Accario-Winslow, Chrisann Roth, Lawrence M. TI Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer: A Phase III Trial of the Gynecologic Cancer InterGroup SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 02-06, 2006 CL Atlanta, GA SP Amer Soc Clin Oncol ID PEGYLATED LIPOSOMAL DOXORUBICIN; PRIMARY PERITONEAL CANCER; LONG-TERM SURVIVAL; ONCOLOGY-GROUP; EPITHELIAL OVARIAN; 1ST-LINE TREATMENT; PLUS CARBOPLATIN; RANDOMIZED-TRIAL; CLINICAL-TRIALS; PACLITAXEL AB Purpose To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel. Patients and Methods Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons. Results Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup. Conclusion Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC. C1 [Bookman, Michael A.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Stat & Data Ctr, Gynecol Oncol Grp, Buffalo, NY USA. Franklin Sq Hosp, Baltimore, MD USA. Guys Hosp, London SE1 9RT, England. Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. Australia New Zealand Gynaecol Oncol Grp, Camperdown, NSW, Australia. European Inst Canc Res, Milan, Italy. Ohio State Univ, Columbus, OH 43210 USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. Univ Iowa Hosp & Clin, Iowa City, IA 52242 USA. Washington Univ, Sch Med, St Louis, MO USA. Univ Calif Irvine, Irvine Med Ctr, Orange, CA 92668 USA. UCL, London, England. MRC, Clin Trials Unit, London, England. NCI, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Indianapolis, IN USA. RP Bookman, MA (reprint author), Fox Chase Canc Ctr, 333 Cottman Ave,W41, Philadelphia, PA 19111 USA. EM michael.bookman@fccc.edu RI friedlander, michael/G-3490-2013 OI friedlander, michael/0000-0002-6488-0604 FU Medical Research Council [, MC_U122861379]; NCI NIH HHS [CA 27469, CA 37517, U10 CA027469, U10 CA037517] NR 33 TC 283 Z9 298 U1 2 U2 17 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2009 VL 27 IS 9 BP 1419 EP 1425 DI 10.1200/JCO.2008.19.1684 PG 7 WC Oncology SC Oncology GA 447MA UT WOS:000266194000014 PM 19224846 ER PT J AU Altekruse, SF McGlynn, KA Reichman, ME AF Altekruse, Sean F. McGlynn, Katherine A. Reichman, Marsha E. TI Hepatocellular Carcinoma Incidence, Mortality, and Survival Trends in the United States From 1975 to 2005 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID HEPATITIS-C INFECTION; VIRAL-HEPATITIS; CANCER; POPULATION; RISK; EPIDEMIOLOGY; ASSOCIATION; PREVALENCE; AMERICANS; OUTCOMES AB Purpose Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Incidence rates are increasing in the United States. Monitoring incidence, survival, and mortality rates within at-risk populations can facilitate control efforts. Methods Age-adjusted incidence trends for HCC were examined in the Surveillance, Epidemiology, and End Results (SEER) registries from 1975 to 2005. Age-specific rates were examined for birth cohorts born between 1900 and 1959. Age-adjusted incidence and cause-specific survival rates from 1992 to 2005 were examined in the SEER 13 registries by race/ethnicity, stage, and treatment. United States liver cancer mortality rates were also examined. Results Age-adjusted HCC incidence rates tripled between 1975 and 2005. Incidence rates increased in each 10-year birth cohort from 1900 through the 1950s. Asians/Pacific Islanders had higher incidence and mortality rates than other racial/ethnic groups, but experienced a significant decrease in mortality rates over time. From 2000 to 2005, marked increases in incidence rates occurred among Hispanic, black, and white middle-aged men. Between 1992 and 2004, 2- to 4-year HCC survival rates doubled, as more patients were diagnosed with localized and regional HCC and prognosis improved, particularly for patients with reported treatment. Recent 1-year survival rates remained, however, less than 50%. Conclusion HCC incidence and mortality rates continue to increase, particularly among middle-aged black, Hispanic, and white men. Screening of at-risk groups and treatment of localized-stage tumors may contribute to increasing HCC survival rates in the United States. More progress is needed. C1 NCI, Div Canc Control & Populat Sci, Rockville, MD USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Altekruse, SF (reprint author), NCI, Canc Stat Branch, Div Canc Control & Populat Sci, 6116 Execut Blvd Suite 504, Bethesda, MD 20892 USA. EM altekrusesf@mail.nih.gov FU Division of Cancer Control and Population Sciences, Surveillance Research Program; National Cancer Institute; National Institutes of Health FX Supported by the Division of Cancer Control and Population Sciences, Surveillance Research Program, National Cancer Institute, National Institutes of Health. NR 45 TC 756 Z9 777 U1 5 U2 29 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2009 VL 27 IS 9 BP 1485 EP 1491 DI 10.1200/JCO.2008.20.7753 PG 7 WC Oncology SC Oncology GA 447MA UT WOS:000266194000025 PM 19224838 ER PT J AU Kramer, BS Hagerty, KL Justman, S Somerfield, MR Albertsen, PC Blot, WJ Carter, HB Costantino, JP Epstein, JI Godley, PA Harris, RP Wilt, TJ Wittes, J Zon, R Schellhammer, P AF Kramer, Barnett S. Hagerty, Karen L. Justman, Stewart Somerfield, Mark R. Albertsen, Peter C. Blot, William J. Carter, H. Ballentine Costantino, Joseph P. Epstein, Jonathan I. Godley, Paul A. Harris, Russell P. Wilt, Timothy J. Wittes, Janet Zon, Robin Schellhammer, Paul TI Use of 5-alpha-Reductase Inhibitors for Prostate Cancer Chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID URINARY-TRACT SYMPTOMS; RANDOMIZED CONTROLLED-TRIAL; SURGICAL ADJUVANT BREAST; BOWEL PROJECT P-1; PREVENTION TRIAL; COMBINATION THERAPY; FINASTERIDE THERAPY; MODELING APPROACH; HYPERPLASIA; MEN AB Purpose To develop an evidence-based guideline on the use of 5-alpha-reductase inhibitors (5-ARIs) for prostate cancer chemoprevention. Methods The American Society of Clinical Oncology (ASCO) Health Services Committee (HSC), ASCO Cancer Prevention Committee, and the American Urological Association Practice Guidelines Committee jointly convened a Panel of experts, who used the results from a systematic review of the literature to develop evidence-based recommendations on the use of 5-ARIs for prostate cancer chemoprevention. Results The systematic review completed for this guideline identified 15 randomized clinical trials that met the inclusion criteria, nine of which reported prostate cancer period prevalence. Conclusion Asymptomatic men with a prostate-specific antigen (PSA) <= 3.0 ng/mL who are regularly screened with PSA or are anticipating undergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of both the benefits of 5-ARIs for 7 years for the prevention of prostate cancer and the potential risks (including the possibility of high-grade prostate cancer). Men who are taking 5-ARIs for benign conditions such as lower urinary tract [obstructive] symptoms (LUTS) may benefit from a similar discussion, understanding that the improvement of LUTS relief should be weighed with the potential risks of high-grade prostate cancer from 5-ARIs (although the majority of the Panel members judged the latter risk to be unlikely). A reduction of approximately 50% in PSA by 12 months is expected in men taking a 5-ARI; however, because these changes in PSA may vary across men, and within individual men over time, the Panel cannot recommend a specific cut point to trigger a biopsy for men taking a 5-ARI. No specific cut point or change in PSA has been prospectively validated in men taking a 5-ARI. C1 [Kramer, Barnett S.] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. NIH, Bethesda, MD 20892 USA. Univ Montana Liberal Studies, Missoula, MT USA. Univ Connecticut, Ctr Hlth, Farmington, CT USA. Int Epidemiol Inst, Rockville, MD USA. Johns Hopkins Univ, Baltimore, MD USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Univ N Carolina, Chapel Hill, NC USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. Michiana Hematol Oncol, Granger, IN USA. Stat Collaborat, Washington, DC USA. Eastern Virginia Med Sch, Norfolk, VA 23501 USA. RP Kramer, BS (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org NR 55 TC 52 Z9 56 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2009 VL 27 IS 9 BP 1502 EP 1516 DI 10.1200/JCO.2008.16.9599 PG 15 WC Oncology SC Oncology GA 447MA UT WOS:000266194000027 PM 19252137 ER PT J AU Hansen, DF Zhou, Z Fen, HQ Jenkins, LMM Bai, YW Kay, LE AF Hansen, D. Flemming Zhou, Zheng Fen, Haniqiao Jenkins, Lisa M. Miller Bai, Yawen Kay, Lewis E. TI Binding Kinetics of Histone Chaperone Chz1 and Variant Histone H2A.Z-H2B by Relaxation Dispersion NMR Spectroscopy SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE NMR spectroscopy; histone chaperone; relaxation dispersion; binding kinetics; histone variant ID CHARACTERIZING CHEMICAL-EXCHANGE; PROTEIN ASSOCIATION RATES; NUCLEOSOME CORE PARTICLE; TIME-SCALE; ANGSTROM RESOLUTION; SEQUENCE; COMPLEX; STATES; H2A; LANDSCAPE AB The genome of eukaryotic cells is packed into a compact structure called chromatin that consists of DNA as well as histone and non-histone proteins. Histone chaperones associate with histone proteins and play important roles in the assembly of chromatin structure and transport of histones in the cell. The recently discovered histone chaperone Chz1 associates with the variant histone H2A.Z of budding yeast and plays a critical role in the exchange of the canonical histone pair H2A-H2B for the variant H2A.Z-H2B. Here, we Present an NMR approach that provides accurate estimates for the rates of association and dissociation of Chz1 and H2A.Z-H2B. The methodology exploits the fact that in a 1:1 mixture of Chz1 and H2A.Z-H2B, the small amounts of unbound proteins that are invisible in spectra produce tine broadening of signals from the complex that can be quantified in terms of the thermodynamics and kinetics of the exchange process. The dissociation rate constant measured, 22 +/- 2 s(-1), provides an upper bound for the rate of transfer of H2A.Z-H2B to the chromatin remodeling complex, and the faster-than-diffusion association rate, 10(8) +/- 10(7) M(-1) s(-1), establishes the importance of attractive electrostatic interactions that form the chaperone-histone complex. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Hansen, D. Flemming; Kay, Lewis E.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Hansen, D. Flemming; Kay, Lewis E.] Univ Toronto, Dept Biochem, Toronto, ON M5S 1A8, Canada. [Hansen, D. Flemming; Kay, Lewis E.] Univ Toronto, Dept Chem, Toronto, ON M5S 1A8, Canada. [Zhou, Zheng; Fen, Haniqiao; Bai, Yawen] NCI, Biochem & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Jenkins, Lisa M. Miller] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kay, LE (reprint author), Univ Toronto, Dept Mol Genet, 1 Kings Coll Circle, Toronto, ON M5S 1A8, Canada. EM kay@pound.med.utoronto.ca FU Canadian Institutes of Health Research; National Cancer Institute, NIH; CIHR FX This work was supported by a grant from the Canadian Institutes of Health Research (L.E.K.) and by the intramural program of The National Cancer Institute, NIH (Y.B.). D.F.H. acknowledges support in the form of a post-doctoral fellowship from the CIHR. L.E.K. holds a Canada Research Chair in Biochemistry. NR 38 TC 12 Z9 12 U1 0 U2 5 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 MAR 20 PY 2009 VL 387 IS 1 BP 1 EP 9 DI 10.1016/j.jmb.2009.01.009 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 425AS UT WOS:000264610000001 PM 19385041 ER PT J AU Revilla-Lopez, G Torras, J Jimenez, AI Cativiela, C Nussinov, R Aleman, C AF Revilla-Lopez, Guillem Torras, Juan Jimenez, Ana I. Cativiela, Carlos Nussinov, Ruth Aleman, Carlos TI Side-Chain to Backbone Interactions Dictate the Conformational Preferences of a Cyclopentane Arginine Analogue SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ALPHA-AMINO-ACIDS; X-RAY-DIFFRACTION; TRANS-CYCLOHEXANE ANALOGS; C-ALPHA,ALPHA-DIALKYLATED GLYCINES; STRUCTURAL VERSATILITY; 1-AMINOCYCLOPENTANE-1-CARBOXYLIC ACID; LINEAR OLIGOPEPTIDES; 1-AMINOCYCLOHEXANE-1-CARBOXYLIC ACID; MODEL PEPTIDES; 1-AMINOCYCLOBUTANE-1-CARBOXYLIC ACID AB The intrinsic conformational preferences of the nonproteinogenic amino acids constructed by incorporating the arginine side chain in the beta position of 1-aminocyclopentane-l-carboxylic acid (either in a cis or a trans orientation relative to the amino group) have been investigated by using computational methods. These compounds may be considered as constrained analogues of arginine (denoted as c(5)Arg) in which the orientation of the side chain is fixed by the cyclopentane moiety. Specifically, the N-acetyl-N'-methylamide derivatives of cis- and trans-c(5)Arg have been examined in the gas phase and in solution by using B3LYP/6-311+G(d,p) calculations and Molecular Dynamics simulations. Results indicate that the conformational space available to these compounds is highly restricted, their conformational preferences being dictated by the ability of the guanidinium group in the side chain to establish hydrogen bond interactions with the backbone, A comparison with the behavior previously described for the analogous phenylalanine derivatives is presented. C1 [Revilla-Lopez, Guillem; Aleman, Carlos] Univ Politecn Cataluna, ETS Engn Ind Barcelona, Dept Engn Quim, E-08028 Barcelona, Spain. [Torras, Juan] Univ Politecn Cataluna, Dept Engn Quim, EUETH, Igualada 08700, Spain. [Jimenez, Ana I.; Cativiela, Carlos] Univ Zaragoza, CSIC, Dept Quim Organ, Inst Ciencia Mat Aragon, E-50009 Zaragoza, Spain. [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sch Med, Dept Human Genet Sackler, IL-69978 Tel Aviv, Israel. RP Aleman, C (reprint author), Univ Politecn Cataluna, ETS Engn Ind Barcelona, Dept Engn Quim, Diagonal 647, E-08028 Barcelona, Spain. EM carlos.aleman@upc.edu RI Revilla-Lopez, Guillem/G-8552-2011; Torras, Juan/F-5622-2015 OI Torras, Juan/0000-0001-8737-7609 FU Ministerio de Educacion y Ciencia-FEDER [CTQ2007-62245]; National Cancer Institute; National Institutes of Health [N01-CO-12400]; NIH; Center for Cancer Research FX Gratitude is expressed to the Centre de Supercomputacio de Catalunya (CESCA). Financial support from the Ministerio de Educacion y Ciencia-FEDER (project CTQ2007-62245) and Gobierno de Aragon (research group E40) is gratefully acknowledged. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract no. N01-CO-12400. The content of this publication does not necessarily reflect the view of the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 72 TC 8 Z9 8 U1 0 U2 2 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 MAR 20 PY 2009 VL 74 IS 6 BP 2403 EP 2412 DI 10.1021/jo802704h PG 10 WC Chemistry, Organic SC Chemistry GA 417XI UT WOS:000264111400018 PM 19236034 ER PT J AU Simeon, FG Wendahl, MT Pike, VW AF Simeon, Fabrice G. Wendahl, Matthew T. Pike, Victor W. TI Efficient and Regioselective Halogenations of 2-Amino-1,3-thiazoles with Copper Salts SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID GLUTAMATE SUBTYPE-5 RECEPTORS; POSITRON-EMISSION-TOMOGRAPHY; ARYL HALIDES; RADIOLIGAND; ARYLAMINES; ANALOGS; POTENT; BRAIN AB Monohalo and dihalo 1,3-thiazole derivatives can be efficiently and selectively prepared under mild conditions from 2-amino-1,3-thiazoles. Halogenations proceed easily in the presence of copper(I) or copper(II) chlorides, bromides, or iodides directly in solution or with supported copper halides. C1 [Simeon, Fabrice G.; Wendahl, Matthew T.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. RP Simeon, FG (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Room B3C346A,10 Ctr Dr, Bethesda, MD 20892 USA. EM simeonf@intra.nimh.nih.gov FU Intramural Research Program of the National Institutes of Health (NIMH) FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIMH). NR 21 TC 9 Z9 9 U1 0 U2 3 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 MAR 20 PY 2009 VL 74 IS 6 BP 2578 EP 2580 DI 10.1021/jo802799c PG 3 WC Chemistry, Organic SC Chemistry GA 417XI UT WOS:000264111400045 PM 19231816 ER PT J AU Layne, SP Monto, AS Taubenberger, JK AF Layne, Scott P. Monto, Arnold S. Taubenberger, Jeffery K. TI Pandemic Influenza: An Inconvenient Mutation SO SCIENCE LA English DT Letter C1 [Layne, Scott P.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. [Layne, Scott P.] Univ Calif Los Angeles, Sch Publ Hlth, Ctr Rapid Influenza Surveillance & Res, Los Angeles, CA 90095 USA. [Monto, Arnold S.] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Taubenberger, Jeffery K.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Layne, SP (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. EM scott.layne@ucla.edu FU Intramural NIH HHS [ZIA AI000986-03] NR 4 TC 52 Z9 55 U1 1 U2 6 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 MAR 20 PY 2009 VL 323 IS 5921 BP 1560 EP 1561 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 421EN UT WOS:000264342300012 PM 19299601 ER PT J AU McPherron, AC Huynh, TV Lee, SJ AF McPherron, Alexandra C. Huynh, Thanh V. Lee, Se-Jin TI Redundancy of myostatin and growth/differentiation factor 11 function SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article ID BONE-MORPHOGENETIC PROTEIN; SKELETAL-MUSCLE MASS; BETA SUPERFAMILY; NEGATIVE REGULATOR; SIGNALING PATHWAY; AXIAL SKELETON; GROWTH; FOLLISTATIN; ACTIVIN; GDF11 AB Background: Myostatin (Mstn) and growth/differentiation factor 11 (Gdf11) are highly related transforming growth factor beta (TGF beta) family members that play important roles in regulating embryonic development and adult tissue homeostasis. Despite their high degree of sequence identity, targeted mutations in these genes result in non- overlapping phenotypes affecting distinct biological processes. Loss of Mstn in mice causes a doubling of skeletal muscle mass while loss of Gdf11 in mice causes dramatic anterior homeotic transformations of the axial skeleton, kidney agenesis, and an increase in progenitor cell number in several tissues. In order to investigate the possible functional redundancy of myostatin and Gdf11, we analyzed the effect of eliminating the functions of both of these signaling molecules. Results: We show that Mstn(-/-) Gdf11(-/-) mice have more extensive homeotic transformations of the axial skeleton than Gdf11(-/-) mice in addition to skeletal defects not seen in single mutants such as extra forelimbs. We also show that deletion of Gdf11 specifically in skeletal muscle in either Mstn(+/+) or Mstn(-/-) mice does not affect muscle size, fiber number, or fiber type. Conclusion: These results provide evidence that myostatin and Gdf11 have redundant functions in regulating skeletal patterning in mice but most likely not in regulating muscle size. C1 [McPherron, Alexandra C.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Huynh, Thanh V.; Lee, Se-Jin] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. RP McPherron, AC (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mcpherrona@niddk.nih.gov; thuynh@jhmi.edu; sjlee@jhmi.edu OI McPherron, Alexandra/0000-0002-5875-9154 FU National Institutes of Health [R01HD35887, U54AR052646]; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health, USA FX We thank N. Brockoff and J. Portas for assistance in maintenance of mouse lines, B. Sauer for the Cre vector, S. Pearson-White for the MDAF2 vector, and the Johns Hopkins Transgenic Core Facility for carrying out the pronuclear and blastocyst injections. This work was supported by grants from the National Institutes of Health (R01HD35887 and U54AR052646, to S- J. L.) and the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, USA (A. C. M.). NR 41 TC 59 Z9 67 U1 1 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD MAR 19 PY 2009 VL 9 AR 24 DI 10.1186/1471-213X-9-24 PG 9 WC Developmental Biology SC Developmental Biology GA 429OD UT WOS:000264929100001 PM 19298661 ER PT J AU Bonville, CA Percopo, CM Dyer, KD Gao, JL Prussin, C Foster, B Rosenberg, HF Domachowske, JB AF Bonville, Cynthia A. Percopo, Caroline M. Dyer, Kimberly D. Gao, Jiliang Prussin, Calman Foster, Barbara Rosenberg, Helene F. Domachowske, Joseph B. TI Interferon-gamma coordinates CCL3-mediated neutrophil recruitment in vivo SO BMC IMMUNOLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; ACUTE LUNG INJURY; A H5N1 VIRUS; PNEUMOVIRUS INFECTION; PNEUMONIA VIRUS; DISTRESS-SYNDROME; HOST-DEFENSE; CYTOKINE RESPONSES; INFLUENZA-VIRUSES; IFN-GAMMA AB Background: We have shown previously that acute infection with the respiratory pathogen, pneumonia virus of mice (PVM), results in local production of the proinflammatory chemokine, CCL3, and that neutrophil recruitment in response to PVM infection is reduced dramatically in CCL3 -/- mice. Results: In this work, we demonstrate that CCL3-mediated neutrophil recruitment is coordinated by interferon-gamma (IFN gamma). Neutrophil recruitment in response to PVM infection was diminished five-fold in IFN gamma receptor gene-deleted mice, although neutrophils from IFN gamma R -/- mice expressed transcripts for the CCL3 receptor, CCR1 and responded functionally to CCL3 ex vivo. Similarly, in the absence of PVM infection, CCL3 overexpression alone could not elicit neutrophil recruitment in the absence of IFN gamma. Interestingly, although supplemental IFN gamma restored neutrophil recruitment and resulted in a sustained weight loss among CCL3-overexpressing IFN gamma -/- mice, CCL3-mediated neutrophil recruitment alone did not result in the pulmonary edema or respiratory failure characteristic of severe viral infection, suggesting that CCL3 and IFN-gamma together are sufficient to promote neutrophil recruitment but not pathologic activation. Conclusion: Our findings reveal a heretofore unrecognized hierarchical interaction between the IFN gamma and CCL3, which demonstrate that IFN gamma is crucial for CCL3-mediated neutrophil recruitment in vivo. C1 [Percopo, Caroline M.; Dyer, Kimberly D.; Prussin, Calman; Foster, Barbara; Rosenberg, Helene F.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Bonville, Cynthia A.; Domachowske, Joseph B.] SUNY Upstate Med Univ, Syracuse, NY 13210 USA. [Gao, Jiliang] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Foster, Barbara] Proteus Technol, Annapolis Jct, MD 20701 USA. RP Rosenberg, HF (reprint author), NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. EM bonvillc@upstate.edu; percopoc@niaid.nih.gov; kdyer@niaid.nih.gov; jgao@niaid.nih.gov; cprussin@niaid.nih.gov; bfoster@cablespeed.com; hrosenberg@niaid.nih.gov; domachoj@upstate.edu OI Prussin, Calman/0000-0002-3917-3326 FU Children's Miracle Network of NY; NIAID DIR FX The authors thank Ms. Leslie Pesnicak for assistance with the intraperitoneal inoculations. Grant support provided by Children's Miracle Network of NY to JBD and NIAID DIR funding to HFR. NR 57 TC 24 Z9 24 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD MAR 19 PY 2009 VL 10 AR 14 DI 10.1186/1471-2172-10-14 PG 13 WC Immunology SC Immunology GA 430KT UT WOS:000264988700001 PM 19298652 ER PT J AU Guo, TQ Jou, W Chanturiya, T Portas, J Gavrilova, O McPherron, AC AF Guo, Tingqing Jou, William Chanturiya, Tatyana Portas, Jennifer Gavrilova, Oksana McPherron, Alexandra C. TI Myostatin Inhibition in Muscle, but Not Adipose Tissue, Decreases Fat Mass and Improves Insulin Sensitivity SO PLOS ONE LA English DT Article AB Myostatin (Mstn) is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn(-/-) mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn(-/-) mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn(-/-) mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn(-/-) mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn(-/-) mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn(-/-) mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes. C1 [Guo, Tingqing; Portas, Jennifer; McPherron, Alexandra C.] NIDDK, Genet Dev & Dis Branch, Natl Inst Hlth, Bethesda, MD USA. [Jou, William; Chanturiya, Tatyana; Gavrilova, Oksana] NIDDK, Mouse Metabol Core Lab, Natl Inst Hlth, Bethesda, MD USA. RP Guo, TQ (reprint author), NIDDK, Genet Dev & Dis Branch, Natl Inst Hlth, Bethesda, MD USA. EM mcpherrona@niddk.nih.gov OI McPherron, Alexandra/0000-0002-5875-9154 FU Intramural Research Program of the NIH, NIDDK FX This research is supported by the Intramural Research Program of the NIH, NIDDK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 144 Z9 149 U1 1 U2 21 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 19 PY 2009 VL 4 IS 3 AR e4937 DI 10.1371/journal.pone.0004937 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437OL UT WOS:000265496700010 PM 19295913 ER PT J AU Tahirov, TH Makarova, KS Rogozin, IB Pavlov, YI Koonin, EV AF Tahirov, Tahir H. Makarova, Kira S. Rogozin, Igor B. Pavlov, Youri I. Koonin, Eugene V. TI Evolution of DNA polymerases: an inactivated polymerase-exonuclease module in Pol epsilon and a chimeric origin of eukaryotic polymerases from two classes of archaeal ancestors SO BIOLOGY DIRECT LA English DT Article ID ZINC-FINGER DOMAIN; SACCHAROMYCES-CEREVISIAE; REPLICATION FORK; STRUCTURE PREDICTION; URACIL RECOGNITION; CATALYTIC DOMAINS; STRANDED-DNA; FAMILY; PROTEINS; SUBUNIT AB Background: Evolution of DNA polymerases, the key enzymes of DNA replication and repair, is central to any reconstruction of the history of cellular life. However, the details of the evolutionary relationships between DNA polymerases of archaea and eukaryotes remain unresolved. Results: We performed a comparative analysis of archaeal, eukaryotic, and bacterial B-family DNA polymerases, which are the main replicative polymerases in archaea and eukaryotes, combined with an analysis of domain architectures. Surprisingly, we found that eukaryotic Polymerase epsilon consists of two tandem exonuclease-polymerase modules, the active N-terminal module and a C-terminal module in which both enzymatic domains are inactivated. The two modules are only distantly related to each other, an observation that suggests the possibility that Pol epsilon evolved as a result of insertion and subsequent inactivation of a distinct polymerase, possibly, of bacterial descent, upstream of the C-terminal Zn-fingers, rather than by tandem duplication. The presence of an inactivated exonuclease-polymerase module in Pol epsilon parallels a similar inactivation of both enzymatic domains in a distinct family of archaeal B-family polymerases. The results of phylogenetic analysis indicate that eukaryotic B-family polymerases, most likely, originate from two distantly related archaeal B-family polymerases, one form giving rise to Pol epsilon, and the other one to the common ancestor of Pol alpha, Pol delta, and Pol zeta. The C-terminal Zn-fingers that are present in all eukaryotic B-family polymerases, unexpectedly, are homologous to the Zn-finger of archaeal D-family DNA polymerases that are otherwise unrelated to the B family. The Zn-finger of Pole shows a markedly greater similarity to the counterpart in archaeal PolD than the Zn-fingers of other eukaryotic B-family polymerases. Conclusion: Evolution of eukaryotic DNA polymerases seems to have involved previously unnoticed complex events. We hypothesize that the archaeal ancestor of eukaryotes encoded three DNA polymerases, namely, two distinct B-family polymerases and a D-family polymerase all of which contributed to the evolution of the eukaryotic replication machinery. The Zn-finger might have been acquired from PolD by the B-family form that gave rise to Pol epsilon prior to or in the course of eukaryogenesis, and subsequently, was captured by the ancestor of the other B-family eukaryotic polymerases. The inactivated polymerase-exonuclease module of Pol epsilon might have evolved by fusion with a distinct polymerase, rather than by duplication of the active module of Pol epsilon, and is likely to play an important role in the assembly of eukaryotic replication and repair complexes. Reviewers: This article was reviewed by Patrick Forterre, Arcady Mushegian, and Chris Ponting. For the full reviews, please go to the Reviewers' Reports section. C1 [Tahirov, Tahir H.; Pavlov, Youri I.] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. [Makarova, Kira S.; Rogozin, Igor B.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Tahirov, TH (reprint author), Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. EM ttahirov@unmc.edu; makarova@ncbi.nlm.nih.gov; Rogozin@ncbi.nlm.nih.gov; ypavlov@unmc.edu; koonin@ncbi.nlm.nih.gov FU DHHS; NCI [R01 CA129925-01A2]; Eppley Institute Pilot; NE DHHS 2008 [LB506]; NIGMS [1R01GM082923-01A2] FX KSM, IBR, and EVK are supported by intramural funds of the DHHS (NIH, National Library of Medicine). YIP was supported in part by NCI grant R01 CA129925-01A2, an Eppley Institute Pilot grant and NE DHHS 2008 grant LB506. THT is supported by the Eppley Institute Pilot grant and in part by NIGMS grant 1R01GM082923-01A2. NR 67 TC 51 Z9 53 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD MAR 18 PY 2009 VL 4 AR 11 DI 10.1186/1745-6150-4-11 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 438DI UT WOS:000265535700001 PM 19296856 ER PT J AU Teng, SL Madej, T Panchenko, A Alexov, E AF Teng, Shaolei Madej, Thomas Panchenko, Anna Alexov, Emil TI Modeling Effects of Human Single Nucleotide Polymorphisms on Protein-Protein Interactions SO BIOPHYSICAL JOURNAL LA English DT Article ID ONLINE MENDELIAN INHERITANCE; PHOTOSYNTHETIC REACTION CENTERS; BINDING FREE-ENERGY; HUMAN GENES; MAN OMIM; T-TEST; CONFORMATIONAL FLEXIBILITY; ELECTROSTATIC INTERACTIONS; FUNCTIONAL-ANALYSIS; CATHEPSIN-D AB A large set of three-dimensional structures of 264 protein-protein complexes with known nonsynonymous single nucleotide polymorphisms (nsSNPs) at the interface was built using homology-based methods. The nsSNPs were mapped on the proteins' structures and their effect on the binding energy was investigated with CHARMM force field and continuum electrostatic calculations. Two sets of nsSNPs were studied: disease annotated Online Mendelian Inheritance in Man (OMIM) and nonannotated (non-OMIM). It was demonstrated that OMIM nsSNPs tend to destabilize the electrostatic component of the binding energy, in contrast with the effect of non-OMIM nsSNPs. In addition, it was shown that the change of the binding energy upon amino acid substitutions is not related to the conservation of the net charge, hydrophobicity, or hydrogen bond network at the interface. The results indicate that, generally, the effect of nsSNPs on protein-protein interactions cannot be predicted from amino acids' physico-chemical properties alone, since in many cases a substitution of a particular residue with another amino acid having completely different polarity or hydrophobicity had little effect on the binding energy. Analysis of sequence conservation showed that nsSNP at highly conserved positions resulted in a large variance of the binding energy changes. In contrast, amino acid substitutions corresponding to nsSNPs at nonconserved positions, on average, were not found to have a large effect on binding affinity. pKa calculations were performed and showed that amino acid substitutions could change the wild-type proton uptake/release and thus resulting in different pH-dependence of the binding energy. C1 [Teng, Shaolei; Alexov, Emil] Clemson Univ, Dept Phys, Clemson, SC 29634 USA. [Teng, Shaolei] Clemson Univ, Dept Biochem & Genet, Clemson, SC USA. [Madej, Thomas; Panchenko, Anna] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Computat Biol Branch, Bethesda, MD 20894 USA. RP Alexov, E (reprint author), Clemson Univ, Dept Phys, Clemson, SC 29634 USA. EM ealexov@clemson.edu FU Intramural NIH HHS NR 65 TC 54 Z9 55 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAR 18 PY 2009 VL 96 IS 6 BP 2178 EP 2188 DI 10.1016/j.bpj.2008.12.3904 PG 11 WC Biophysics SC Biophysics GA 450BT UT WOS:000266376700014 PM 19289044 ER PT J AU Volkow, ND Fowler, JS Logan, J Alexoff, D Zhu, W Telang, F Wang, GJ Jayne, M Hooker, JM Wong, C Hubbard, B Carter, P Warner, D King, P Shea, C Xu, YW Muench, L Apelskog-Torres, K AF Volkow, Nora D. Fowler, Joanna S. Logan, Jean Alexoff, David Zhu, Wei Telang, Frank Wang, Gene-Jack Jayne, Millard Hooker, Jacob M. Wong, Christopher Hubbard, Barbara Carter, Pauline Warner, Donald King, Payton Shea, Colleen Xu, Youwen Muench, Lisa Apelskog-Torres, Karen TI Effects of Modafinil on Dopamine and Dopamine Transporters in the Male Human Brain Clinical Implications SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID INDUCED WAKEFULNESS; DOUBLE-BLIND; ORAL METHYLPHENIDATE; C-11 RACLOPRIDE; BLOOD-FLOW; BINDING; DRUG; PET; AMPHETAMINE; INCREASES AB Context Modafinil, a wake-promoting drug used to treat narcolepsy, is increasingly being used as a cognitive enhancer. Although initially launched as distinct from stimulants that increase extracellular dopamine by targeting dopamine transporters, recent preclinical studies suggest otherwise. Objective To measure the acute effects of modafinil at doses used therapeutically (200 mg and 400 mg given orally) on extracellular dopamine and on dopamine transporters in the male human brain. Design, Setting, and Participants Positron emission tomography with [(11)C] raclopride (D(2)/D(3) radioligand sensitive to changes in endogenous dopamine) and [(11)C] cocaine (dopamine transporter radioligand) was used to measure the effects of modafinil on extracellular dopamine and on dopamine transporters in 10 healthy male participants. The study took place over an 8-month period (2007-2008) at Brookhaven National Laboratory. Main Outcome Measures Primary outcomes were changes in dopamine D(2)/D(3) receptor and dopamine transporter availability (measured by changes in binding potential) after modafinil when compared with after placebo. Results Modafinil decreased mean (SD) [(11)C] raclopride binding potential in caudate (6.1% [6.5%]; 95% confidence interval [CI], 1.5% to 10.8%; P = .02), putamen (6.7% [4.9%]; 95% CI, 3.2% to 10.3%; P = .002), and nucleus accumbens (19.4% [20%]; 95% CI, 5% to 35%; P = .02), reflecting increases in extracellular dopamine. Modafinil also decreased [(11)C] cocaine binding potential in caudate (53.8% [13.8%]; 95% CI, 43.9% to 63.6%; P < .001), putamen (47.2% [11.4%]; 95% CI, 39.1% to 55.4%; P < .001), and nucleus accumbens (39.3% [10%]; 95% CI, 30% to 49%; P = .001), reflecting occupancy of dopamine transporters. Conclusions In this pilot study, modafinil blocked dopamine transporters and increased dopamine in the human brain ( including the nucleus accumbens). Because drugs that increase dopamine in the nucleus accumbens have the potential for abuse, and considering the increasing use of modafinil, these results highlight the need for heightened awareness for potential abuse of and dependence on modafinil in vulnerable populations. C1 [Volkow, Nora D.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. [Volkow, Nora D.; Telang, Frank; Jayne, Millard; Muench, Lisa] NIAAA, Bethesda, MD USA. [Fowler, Joanna S.; Logan, Jean; Alexoff, David; Wang, Gene-Jack; Hooker, Jacob M.; Wong, Christopher; Hubbard, Barbara; Carter, Pauline; Warner, Donald; King, Payton; Shea, Colleen; Xu, Youwen; Apelskog-Torres, Karen] Brookhaven Natl Lab, Upton, NY 11973 USA. [Fowler, Joanna S.; Wang, Gene-Jack] Mt Sinai Sch Med, New York, NY USA. [Fowler, Joanna S.] SUNY Stony Brook, Dept Chem, Stony Brook, NY USA. [Zhu, Wei] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY USA. RP Volkow, ND (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,Room 5274,MSC 9581, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov OI Hooker, Jacob/0000-0002-9394-7708 FU Brookhaven National Laboratory [DE-AC02-98CH10886]; Office of Biological and Environmental Research; National Institutes of Health [K05DA020001]; National Institute on Alcohol Abuse; Alcoholism Intramural research program [F32EB997320]; National Institute of Biomedical Imaging and Bioengineering; General Research Clinical Centers [MO1RR10710] FX This research was carried out at Brookhaven National Laboratory under contract DE-AC02-98CH10886 with the US Department of Energy with infrastructure support from its Office of Biological and Environmental Research. Support was also provided by grant K05DA020001 (J.S.F.) from the National Institutes of Health, the National Institute on Alcohol Abuse and Alcoholism Intramural research program, grant F32EB997320 (J.M.H.) from the National Institute of Biomedical Imaging and Bioengineering, and grant MO1RR10710 from the General Research Clinical Centers. A Goldhaber distinguished fellowship provided support for Dr Hooker. NR 38 TC 248 Z9 249 U1 8 U2 25 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 18 PY 2009 VL 301 IS 11 BP 1148 EP 1154 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 419UC UT WOS:000264244200020 PM 19293415 ER PT J AU Peabody, NC Pohl, JB Diao, F Vreede, AP Sandstrom, DJ Wang, H Zelensky, PK White, BH AF Peabody, Nathan C. Pohl, Jascha B. Diao, Fengqiu Vreede, Andrew P. Sandstrom, David J. Wang, Howard Zelensky, Paul K. White, Benjamin H. TI Characterization of the Decision Network for Wing Expansion in Drosophila Using Targeted Expression of the TRPM8 Channel SO JOURNAL OF NEUROSCIENCE LA English DT Article ID INSECT ECDYSIS; MANDUCA-SEXTA; NEUROENDOCRINE CONTROL; CUTICLE EXTENSIBILITY; BEHAVIORAL SEQUENCE; NEURONAL NETWORK; ECLOSION HORMONE; ACTIVATION; BURSICON; RECEPTOR AB After emergence, adult flies and other insects select a suitable perch and expand their wings. Wing expansion is governed by the hormone bursicon and can be delayed under adverse environmental conditions. How environmental factors delay bursicon release and alter perch selection and expansion behaviors has not been investigated in detail. Here we provide evidence that in Drosophila the motor programs underlying perch selection and wing expansion have different environmental dependencies. Using physical manipulations, we demonstrate that the decision to perch is based primarily on environmental valuations and is incrementally delayed under conditions of increasing perturbation and confinement. In contrast, the all-or-nonemotorpatterns underlying wing expansion are relatively invariant in length regardless of environmental conditions. Using a novel technique for targeted activation of neurons, we show that the highly stereotyped wing expansion motor patterns can be initiated by stimulation of N(CCAP), a small network of central neurons that regulates the release of bursicon. Activation of this network using the cold-sensitive rat TRPM8 channel is sufficient to trigger all essential behavioral and somatic processes required for wing expansion. The delay of wing expansion under adverse circumstances thus couples an environmentally sensitive decision network to a command-like network that initiates a fixed action pattern. Because NCCAP mediates environmentally insensitive ecdysis-related behaviors in Drosophila development before adult emergence, the study of wing expansion promises insights not only into how networks mediate behavioral choices, but also into how decision networks develop. C1 [Peabody, Nathan C.; Pohl, Jascha B.; Diao, Fengqiu; Vreede, Andrew P.; Sandstrom, David J.; Wang, Howard; Zelensky, Paul K.; White, Benjamin H.] NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP White, BH (reprint author), NIMH, Mol Biol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM benjaminwhite@mail.nih.gov FU National Institute of Mental Health FX This work was supported by the Intramural Research Program of the National Institute of Mental Health. We thank David Julius for providing the TRPM8 cDNA and John Ewer, Paul Taghert, and the Bloomington stock center for fly stocks. We appreciate early help with behavioral assays from Hailyn Nielsen and William Lemon. Special thanks to Grace Gray for editorial assistance and to Howard Nash for insightful comments and persistent insistence on clarity of thought. NR 53 TC 41 Z9 41 U1 1 U2 6 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 MAR 18 PY 2009 VL 29 IS 11 BP 3343 EP 3353 DI 10.1523/JNEUROSCI.4241-08.2009 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 421EL UT WOS:000264342100003 PM 19295141 ER PT J AU Vogeli, B Yao, LS AF Voegeli, Beat Yao, Lishan TI Correlated Dynamics between Protein HN and HC Bonds Observed by NMR Cross Relaxation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID RESIDUAL DIPOLAR COUPLINGS; CHEMICAL-SHIFT ANISOTROPY; MODEL-FREE APPROACH; DIHEDRAL ANGLE PSI; MAGNETIC-RESONANCE RELAXATION; MULTIPLE-QUANTUM NMR; MOLECULAR-DYNAMICS; SPIN RELAXATION; BACKBONE DYNAMICS; SCALAR COUPLINGS AB Although collective dynamics of atom groups steer many biologically relevant processes in biomacromolecules, most atomic resolution motional studies focus on isolated bonds. In this study, a new method is introduced to assess correlated dynamics between bond vectors by cross relaxation nuclear magnetic resonance (NMR). Dipole-dipole cross correlated relaxation rates between intra- and inter-residual H(N)-N and H(alpha)-C(alpha) in the 56 residue protein GB3 are measured with high accuracy. It is demonstrated that the assumption of anisotropic molecular tumbling is necessary to evaluate rates accurately and predictions from the static structure using effective bond lengths of 1.041 and 1.117 angstrom for H(N)-N and H(alpha)-C(alpha) are within 3% of both experimental intra- and inter-residual rates. Deviations are matched to models of different degrees of motional correlation. These models are based on previously determined orientations and motional amplitudes from residual dipolar couplings with high accuracy and precision. Clear evidence of correlated motion in the loops comprising residues 10-14, 20-22, and 47-50 and anticorrelated motion in the a helix comprising 23-38 is presented. Somewhat weaker correlation is observed in the beta strands 2-4, which have previously been shown to exhibit slow correlated motional modes. C1 [Voegeli, Beat] ETH Honggerberg, Swiss Fed Inst Technol, Phys Chem Lab, CH-8093 Zurich, Switzerland. [Yao, Lishan] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Vogeli, B (reprint author), ETH Honggerberg, Swiss Fed Inst Technol, Phys Chem Lab, CH-8093 Zurich, Switzerland. EM beat.voegeli@phys.chem.ethz.ch RI Yao, Lishan /C-6961-2009; yao, lishan/H-3662-2012 OI yao, lishan/0000-0003-1797-922X FU NIDDK, NIH; Office of the Director, NIH FX We thank Dr. Ad Bax for valuable discussion. This work was supported by the Intramural Research Program of the NIDDK, NIH, and by the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. NR 64 TC 21 Z9 21 U1 2 U2 7 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 MAR 18 PY 2009 VL 131 IS 10 BP 3668 EP 3678 DI 10.1021/ja808616v PG 11 WC Chemistry, Multidisciplinary SC Chemistry GA 427QA UT WOS:000264792600059 PM 19235934 ER PT J AU Draisma, G Etzioni, R Tsodikov, A Mariotto, A Wever, E Gulati, R Feuer, E de Koning, H AF Draisma, Gerrit Etzioni, Ruth Tsodikov, Alex Mariotto, Angela Wever, Elisabeth Gulati, Roman Feuer, Eric de Koning, Harry TI Lead Time and Overdiagnosis in Prostate-Specific Antigen Screening: Importance of Methods and Context SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CANCER INCIDENCE TRENDS; POPULATION-MODEL; WHITE MEN; PSA; MORTALITY; TRIAL; OVERDETECTION; DIAGNOSIS; DISEASE; LUNG AB Background The time by which prostate-specific antigen (PSA) screening advances prostate cancer diagnosis, called the lead time, has been reported by several studies, but results have varied widely, with mean lead times ranging from 3 to 12 years. A quantity that is closely linked with the lead time is the overdiagnosis frequency, which is the fraction of screen-detected cancers that would not have been diagnosed in the absence of screening. Reported overdiagnosis estimates have also been variable, ranging from 25% to greater than 80% of screen-detected cancers. Methods We used three independently developed mathematical models of prostate cancer progression and detection that were calibrated to incidence data from the Surveillance, Epidemiology, and End Results program to estimate lead times and the fraction of overdiagnosed cancers due to PSA screening among US men aged 54-80 years in 1985-2000. Lead times were estimated by use of three definitions. We also compared US and earlier estimates from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) that were calculated by use of a microsimulation screening analysis (MISCAN) model. Results The models yielded similar estimates for each definition of lead time, but estimates differed across definitions. Among screen-detected cancers that would have been diagnosed in the patients' lifetimes, the estimated mean lead time ranged from 5.4 to 6.9 years across models, and overdiagnosis ranged from 23% to 42% of all screen-detected cancers. The original MISCAN model fitted to ERSPC Rotterdam data predicted a mean lead time of 7.9 years and an overdiagnosis estimate of 66%; in the model that was calibrated to the US data, these were 6.9 years and 42%, respectively. Conclusion The precise definition and the population used to estimate lead time and overdiagnosis can be important drivers of study results and should be clearly specified. C1 [Draisma, Gerrit; Wever, Elisabeth; de Koning, Harry] Univ Med Ctr, Erasmus MC, Dept Publ Hlth, NL-3000 CA Rotterdam, Netherlands. [Etzioni, Ruth; Gulati, Roman] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Tsodikov, Alex] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Mariotto, Angela; Feuer, Eric] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Draisma, G (reprint author), Univ Med Ctr, Erasmus MC, Dept Publ Hlth, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM g.draisma@erasmusmc.nl FU Cancer Intervention and Surveillance Modeling Network, through a National Cancer Institute [U01-CA88160] FX Cancer Intervention and Surveillance Modeling Network, through a National Cancer Institute cooperative agreement mechanism (U01-CA88160 to Erasmus MC [H.K]). NR 40 TC 339 Z9 353 U1 2 U2 17 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 MAR 18 PY 2009 VL 101 IS 6 BP 374 EP 383 DI 10.1093/jnci/djp001 PG 10 WC Oncology SC Oncology GA 421YB UT WOS:000264393100006 PM 19276453 ER PT J AU Wolpin, BM Chan, AT Hartge, P Chanock, SJ Kraft, P Hunter, DJ Giovannucci, EL Fuchs, CS AF Wolpin, Brian M. Chan, Andrew T. Hartge, Patricia Chanock, Stephen J. Kraft, Peter Hunter, David J. Giovannucci, Edward L. Fuchs, Charles S. TI ABO Blood Group and the Risk of Pancreatic Cancer SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GROUP-RELATED ANTIGENS; PHYSICAL-ACTIVITY QUESTIONNAIRE; HELICOBACTER-PYLORI INFECTION; DUCTAL ADENOCARCINOMA; EXPRESSION; DISEASE; REPRODUCIBILITY; MALIGNANCY; CARCINOMA; GENETICS AB Background Other than several rare, highly penetrant familial syndromes, genetic risk factors for sporadic pancreatic cancer are largely unknown. ABO blood type is an inherited characteristic that in previous small studies has been associated with the risk of gastrointestinal malignancies. Methods We separately examined the relationship between ABO blood type and the risk of incident pancreatic cancer in two large, independent, prospective cohort studies (the Nurses' Health Study and Health Professionals Follow-up Study) that collected blood group data on 107 503 US health professionals. Hazard ratios for pancreatic cancer by ABO blood type were calculated using Cox proportional hazards models with adjustment for other known risk factors, including age, tobacco use, body mass index, physical activity, and history of diabetes mellitus. All statistical tests were two-sided. Results During 927 995 person-years of follow-up, 316 participants developed pancreatic cancer. ABO blood type was associated with the risk of developing pancreatic cancer (P=.004; log-rank test). Compared with participants with blood group O, those with blood groups A, AB, or B were more likely to develop pancreatic cancer (adjusted hazard ratios for incident pancreatic cancer were 1.32 [95% confidence interval {CI} = 1.02 to 1.72], 1.51 [95% CI = 1.02 to 2.23], and 1.72 [95% CI = 1.25 to 2.38], respectively). The association between blood type and pancreatic cancer risk was nearly identical in the two cohorts (P(interaction)=.97). Overall, 17% of the pancreatic cancer cases were attributable to inheriting a non-O blood group (blood group A, B, or AB). The age-adjusted incidence rates for pancreatic cancer per 100 000 person-years were 27 (95% CI = 23 to 33) for participants with blood type O, 36 (95% CI = 26 to 50) for those with blood type A, 41 (95% CI = 31 to 56) for those with blood type AB, and 46 (95% CI = 32 to 68) for those with blood type B. Conclusions In two large, independent populations, ABO blood type was statistically significantly associated with the risk of pancreatic cancer. Further studies are necessary to define the mechanisms by which ABO blood type or closely linked genetic variants may influence pancreatic cancer risk. C1 [Wolpin, Brian M.; Fuchs, Charles S.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chan, Andrew T.; Giovannucci, Edward L.; Fuchs, Charles S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. [Wolpin, Brian M.; Hunter, David J.; Fuchs, Charles S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. [Chan, Andrew T.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Gastrointestinal Unit, Boston, MA 02115 USA. [Hartge, Patricia; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Hunter, David J.; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Kraft, Peter; Hunter, David J.; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. RP Wolpin, BM (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St, Boston, MA 02115 USA. EM bwolpin@partners.org FU National Cancer Institute; National Institutes of Health [P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908, T32 CA09001]; Lustgarten Foundation for Pancreatic Cancer Research FX National Cancer Institute, National Institutes of Health (P01 CA87969, P01 CA55075, P50 CA127003, R01 CA124908, T32 CA09001); Lustgarten Foundation for Pancreatic Cancer Research. NR 50 TC 142 Z9 150 U1 1 U2 13 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 MAR 18 PY 2009 VL 101 IS 6 BP 424 EP 431 DI 10.1093/jnci/djp020 PG 8 WC Oncology SC Oncology GA 421YB UT WOS:000264393100010 PM 19276450 ER PT J AU Gavara, N Chadwick, RS AF Gavara, Nuria Chadwick, Richard S. TI Collagen-Based Mechanical Anisotropy of the Tectorial Membrane: Implications for Inter-Row Coupling of Outer Hair Cell Bundles SO PLOS ONE LA English DT Article AB Background: The tectorial membrane (TM) in the mammalian cochlea displays anisotropy, where mechanical or structural properties differ along varying directions. The anisotropy arises from the presence of collagen fibrils organized in fibers of,1 mm diameter that run radially across the TM. Mechanical coupling between the TM and the sensory epithelia is required for normal hearing. However, the lack of a suitable technique to measure mechanical anisotropy at the microscale level has hindered understanding of the TM's precise role. Methodology/Principal Findings: Here we report values of the three elastic moduli that characterize the anisotropic mechanical properties of the TM. Our novel technique combined Atomic Force Microscopy (AFM), modeling, and optical tracking of microspheres to determine the elastic moduli. We found that the TM's large mechanical anisotropy results in a marked transmission of deformations along the direction that maximizes sensory cell excitation, whereas in the perpendicular direction the transmission is greatly reduced. Conclusions/Significance: Computational results, based on our values of elastic moduli, suggest that the TM facilitates the directional cooperativity of sensory cells in the cochlea, and that mechanical properties of the TM are tuned to guarantee that the magnitude of sound-induced tip-link stretching remains similar along the length of the cochlea. Furthermore, we anticipate our assay to be a starting point for other studies of biological tissues that require directional functionality. C1 [Gavara, Nuria; Chadwick, Richard S.] Natl Inst Deafness & Other Commun Disorders, Auditory Mech Sect, NIH, Bethesda, MD USA. RP Gavara, N (reprint author), Natl Inst Deafness & Other Commun Disorders, Auditory Mech Sect, NIH, Bethesda, MD USA. EM chadwick@helix.nih.gov FU NIDCD Intramural Program [Z01-DC000033-10] FX The NIDCD Intramural Program Project Z01-DC000033-10 supported this research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 20 Z9 20 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 18 PY 2009 VL 4 IS 3 AR e4877 DI 10.1371/journal.pone.0004877 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437OK UT WOS:000265496600006 PM 19293929 ER PT J AU Lacey, JV Kreimer, AR Buys, SS Marcus, PM Chang, SC Leitzmann, MF Hoover, RN Prorok, PC Berg, CD Hartge, P AF Lacey, James V., Jr. Kreimer, Aimee R. Buys, Saundra S. Marcus, Pamela M. Chang, Shih-Chen Leitzmann, Michael F. Hoover, Robert N. Prorok, Philip C. Berg, Christine D. Hartge, Patricia CA Prostate Lung Colorectal Ovarian P TI Breast cancer epidemiology according to recognized breast cancer risk factors in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial Cohort SO BMC CANCER LA English DT Article ID HORMONE-REPLACEMENT THERAPY; COLLABORATIVE REANALYSIS; INDIVIDUAL DATA; WOMEN; AGE; MENOPAUSE; GENOME; GENES; BIRTH; ASSOCIATION AB Background: Multidisciplinary attempts to understand the etiology of breast cancer are expanding to increasingly include new potential markers of disease risk. Those efforts may have maximal scientific and practical influence if new findings are placed in context of the well-understood lifestyle and reproductive risk factors or existing risk prediction models for breast cancer. We therefore evaluated known risk factors for breast cancer in a cancer screening trial that does not have breast cancer as a study endpoint but is large enough to provide numerous analytic opportunities for breast cancer. Methods: We evaluated risk factors for breast cancer (N = 2085) among 70,575 women who were randomized in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Using Poisson regression, we calculated adjusted relative risks [RRs, with 95% confidence intervals (CIs)] for lifestyle and reproductive factors during an average of 5 years of follow-up from date of randomization. Results: As expected, increasing age, nulliparity, positive family history of breast cancer, and use of menopausal hormone therapy were positively associated with breast cancer. Later age at menarche (16 years or older vs. < 12: RR = 0.81, 95% CI, 0.65-1.02) or menopause (55 years or older vs. < 45: RR = 1.29, 95% CI, 1.03-1.62) were less strongly associated with breast cancer than was expected. There were weak positive associations between taller height and heavier weight, and only severe obesity [ body mass index (BMI; kg/m(2)) 35 or more vs. 18.5-24.9: RR = 1.21, 95% CI, 1.02-1.43] was statistically significantly associated with breast cancer. Conclusion: The ongoing PLCO trial offers continued opportunities for new breast cancer investigations, but these analyses suggest that the associations between breast cancer and age at menarche, age at menopause, and obesity might be changing as the underlying demographics of these factors change. C1 [Lacey, James V., Jr.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Kreimer, Aimee R.; Berg, Christine D.] NIH, Early Detect Res Grp, Canc Prevent Div, Rockville, MD USA. [Kreimer, Aimee R.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Buys, Saundra S.] Univ Utah, Dept Internal Med, Huntsman Canc Inst, Hlth Sci Ctr, Salt Lake City, UT 84112 USA. [Marcus, Pamela M.; Prorok, Philip C.] NCI, Biometry Res Grp, Canc Prevent Div, NIH, Rockville, MD USA. [Chang, Shih-Chen] AstraZeneca, Global Epidemiol Dept, Wilmington, DE USA. [Chang, Shih-Chen; Leitzmann, Michael F.] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Leitzmann, Michael F.] Univ Regensburg, Inst Epidemiol & Prevent Med, Regensburg, Germany. [Hoover, Robert N.; Hartge, Patricia] NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Lacey, JV (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. EM jimlacey@nih.gov; kreimera@mail.nih.gov; saundra.buys@hci.utah.edu; marcusp@mail.nih.gov; Shih-Chen.Chang@astrazeneca.com; michael.leitzmann@klinik.uni-regensburg.de; hooverr@mail.nih.gov; prorokp@mail.nih.gov; bergc@mail.nih.gov; hartgep@mail.nih.gov RI Kreimer, Aimee/H-1687-2015 FU National Cancer Institute intramural and extramural funds; National Cancer Institute FX The authors thank Drs. Richard Hayes and John K. Gohagan of the National Cancer Institute, the Screening Center investigators and staff of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, and Mr. Thomas L. Riley and Craig Williams and staff of IMS, Inc., Silver Spring, MD. This work was supported by National Cancer Institute intramural and extramural funds and by individual contracts from the National Cancer Institute to each of the 10 screening centers and to the coordinating center. NR 41 TC 43 Z9 43 U1 1 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAR 17 PY 2009 VL 9 AR 84 DI 10.1186/1471-2407-9-84 PG 8 WC Oncology SC Oncology GA 439EA UT WOS:000265609200001 PM 19292893 ER PT J AU Diaz, R Nguewa, PA Diaz-Gonzalez, JA Hamel, E Gonzalez-Moreno, O Catena, R Serrano, D Redrado, M Sherris, D Calvo, A AF Diaz, R. Nguewa, P. A. Diaz-Gonzalez, J. A. Hamel, E. Gonzalez-Moreno, O. Catena, R. Serrano, D. Redrado, M. Sherris, D. Calvo, A. TI The novel Akt inhibitor Palomid 529 (P529) enhances the effect of radiotherapy in prostate cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE prostate cancer; radioresistance; Akt/PKB activation; VEGF; Id-1; Palomid 529 ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY; TUMOR ANGIOGENESIS; RADIATION; CELLS; ACTIVATION; EXPRESSION; PATHWAY; ID-1; 2-METHOXYESTRADIOL AB Radiotherapy (RT) is a common treatment for localised prostate cancer, but can cause important side effects. The therapeutic efficacy of RT can be enhanced by pharmacological compounds that target specific pathways involved in cell survival. This would elicit a similar therapeutic response using lower doses of RT and, in turn, reducing side effects. This study describes the antitumour activity of the novel Akt inhibitor 8-(1-Hydroxy-ethyl)-2-methoxy-3-(4-methoxy-benzyloxy)-benzo[c]chromen-6-one (Palomid 529 or P529) as well as its ability to decrease radiation-activated phospho-Akt (p-Akt) signalling in a prostate cancer model. P529 showed a potent antiproliferative activity in the NCI-60 cell lines panel, with growth inhibitory 50 (G150) <35 mu M. In addition, P529 significantly enhanced the antiproliferative effect of radiation in prostate cancer cells (PC-3). Analysis of signalling pathways targeted by P529 exhibited a decrease in p-Akt, VEGF, MMP-2, MMP-9, and Id-1 levels after radiation treatment. Moreover, the Bcl-2/Bax ratio was also reduced. Treatment of PC-3 tumour-bearing mice with 20 mg kg(-1) P529 or 6Gy radiation dose decreased tumour size by 42.9 and 53%, respectively. Combination of both treatments resulted in 77.4% tumour shrinkage. Decreased tumour growth was due to reduced proliferation and increased apoptosis (as assessed by PCNA and caspase-3 immunostaining). Our results show the antitumour efficacy of P529 alone, and as a radiosensitiser, and suggest that this compound could be used in the future to treat human prostate cancer. C1 [Diaz, R.; Nguewa, P. A.; Gonzalez-Moreno, O.; Catena, R.; Serrano, D.; Redrado, M.; Calvo, A.] Univ Navarra, Div Oncol, Ctr Appl Med Res CIMA, Pamplona 31008, Spain. [Diaz-Gonzalez, J. A.] Univ Navarra, Dept Oncol, Clin Univ, Pamplona 31008, Spain. [Hamel, E.] NCI, Div Canc Treatment & Diag, Toxicol & Pharmacol Branch, NIH, Frederick, MD 21702 USA. [Sherris, D.] Paloma Pharmaceut, Jamaica, NY USA. RP Calvo, A (reprint author), Univ Navarra, Div Oncol, Ctr Appl Med Res CIMA, Avda Pio 12 55, Pamplona 31008, Spain. EM acalvo@unav.es OI Serrano, Diego/0000-0002-3729-9195 NR 28 TC 28 Z9 30 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAR 17 PY 2009 VL 100 IS 6 BP 932 EP 940 DI 10.1038/sj.bjc.6604938 PG 9 WC Oncology SC Oncology GA 420RH UT WOS:000264306400012 PM 19240717 ER PT J AU Malekzadeh, R Nasrollahzadeh, D Kamangar, F AF Malekzadeh, R. Nasrollahzadeh, D. Kamangar, F. TI Hookah, opium, and tobacco smoking in relation to ESCC Reply SO BRITISH JOURNAL OF CANCER LA English DT Letter ID HIGH-RISK; IRAN C1 [Malekzadeh, R.] Univ Tehran Med Sci, Digest Dis Res Ctr, Shariati Hosp, Tehran 14117, Iran. [Nasrollahzadeh, D.] Karolinska Inst, Stockholm, Sweden. [Kamangar, F.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Digest Dis Res Ctr, Shariati Hosp, Kargar St, Tehran 14117, Iran. EM malek@ams.ac.ir OI Malekzadeh, Reza/0000-0003-1043-3814 NR 2 TC 0 Z9 0 U1 0 U2 1 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 MAR 17 PY 2009 VL 100 IS 6 BP 1016 EP 1016 DI 10.1038/sj.bjc.6604959 PG 1 WC Oncology SC Oncology GA 420RH UT WOS:000264306400025 ER PT J AU Nabel, EG AF Nabel, Elizabeth G. TI National Heart, Lung, and Blood Institute Transitions SO CIRCULATION LA English DT Article DE National Heart, Lung, and Blood Institute; National Institutes of Health; public policy C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, NIH, 31 Ctr Dr,5A48, Bethesda, MD 20892 USA. EM nabele@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 5 TC 1 Z9 1 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 MAR 17 PY 2009 VL 119 IS 10 BP 1453 EP 1455 DI 10.1161/CIRCULATIONAHA.108.841551 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700014 PM 19289650 ER PT J AU Allison, MA Granston, T Aboyans, V McDermott, M Kamineni, A Ni, HY Criqui, MH AF Allison, Matthew A. Granston, Tanya Aboyans, Victor McDermott, Mary Kamineni, Aruna Ni, Hanyu Criqui, Michael H. TI The Relevance of Different Methods of Calculating the Ankle-Brachial Index: The Multi-Ethnic Study of Atherosclerosis SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Allison, Matthew A.; Criqui, Michael H.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Granston, Tanya; Kamineni, Aruna] Univ Washington, Seattle, WA 98195 USA. [Aboyans, Victor] Dupuytren Univ Hosp, Limoges, France. [McDermott, Mary] Northwestern Univ, Chicago, IL 60611 USA. [Ni, Hanyu] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E281 EP E282 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700067 ER PT J AU Anthony, JA Rosamond, W Thom, T Massing, M Golden, SH Heiss, G AF Anthony, Joseph A. Rosamond, Wayne Thom, Thomas Massing, Mark Golden, Sherita H. Heiss, Gerardo TI Calibration of Heart Failure as the Cause of Death: The Atherosclerosis Risk in Communities (ARIC) Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Anthony, Joseph A.; Rosamond, Wayne; Massing, Mark; Heiss, Gerardo] Univ N Carolina, Chapel Hill, NC USA. [Thom, Thomas] NHLBI, NIH, Bethesda, MD 20892 USA. [Golden, Sherita H.] Johns Hopkins Univ, Sch Med, Baltimore, 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 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E353 EP E353 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700396 ER PT J AU Bazzano, LA Gu, DF Chen, J Huang, JF Rao, DC Jaquish, CE Hixson, JE Chen, CS Chen, JC Duan, XF Rice, T Kelly, T Hamm, L Whelton, PK He, J AF Bazzano, Lydia A. Gu, Dongfeng Chen, Jing Huang, Jianfeng Rao, D. C. Jaquish, Cashell E. Hixson, James E. Chen, Chung-Shiuan Chen, Jichun Duan, Xiufang Rice, Treva Kelly, Tanika Hamm, Lee Whelton, Paul K. He, Jiang CA GenSalt Collaborative Rsch Grp TI Effect of Dietary Sodium and Potassium Intervention on Blood Lipids SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Bazzano, Lydia A.; Chen, Jing; Chen, Chung-Shiuan; Kelly, Tanika; Hamm, Lee; He, Jiang] Tulane Univ, Sch Publ Hlth, New Orleans, LA 70118 USA. [Gu, Dongfeng; Chen, Jichun; Duan, Xiufang] Chinese Acad Med Sci, Beijing 100037, Peoples R China. [Rao, D. C.; Rice, Treva] Washington Univ, Sch Med, St Louis, MO USA. [Jaquish, Cashell E.] NHLBI, Bethesda, MD 20892 USA. [Hixson, James E.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Whelton, Paul K.] Loyola Univ, Hlth Sci Ctr, Chicago, IL 60611 USA. RI Rice, Treva/D-1385-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E321 EP E322 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700252 ER PT J AU Chichlowska, KL Rose, KM Calhoun, D Lee, ET Best, LG Fabsitz, RR Cole, S MacCluer, JW North, KE AF Chichlowska, Kristal L. Rose, Kathryn M. Calhoun, Darren Lee, Elisa T. Best, Lyle G. Fabsitz, Richard R. Cole, Shelley MacCluer, Jean W. North, Kari E. TI Socioeconomic Status and the Metabolic Syndrome: The Strong Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [MacCluer, Jean W.; North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC USA. [Calhoun, Darren] MedStar Rsch Inst, Phoenix, AZ USA. [Lee, Elisa T.] Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Rsch, Oklahoma City, OK USA. [Best, Lyle G.] Missouri Breaks Ind Rsch Inc, Timber Lake, SD USA. [Fabsitz, Richard R.] NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. [Cole, Shelley] SW Fdn Biomed Res, San Antonio, TX 78284 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E300 EP E300 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700152 ER PT J AU Chuang, ML Gona, P Salton, CJ Yeon, SB Blease, SJ Kissinger, KV Levy, D O'Donnell, CJ Manning, WJ AF Chuang, Michael L. Gona, Philimon Salton, Carol J. Yeon, Susan B. Blease, Susan J. Kissinger, Kraig V. Levy, Daniel O'Donnell, Christopher J. Manning, Warren J. TI Comparison of Volumetric and Geometric Methods for Determination of Left Ventricular Mass and Prediction of Cardiovascular Morbidity and Mortality in a Healthy Cohort SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Chuang, Michael L.; Salton, Carol J.; Yeon, Susan B.; Kissinger, Kraig V.; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Gona, Philimon; Blease, Susan J.; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E339 EP E340 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700334 ER PT J AU Cole, SA Voruganti, VS Roman, MJ Bella, JN Okin, PM Haack, K Laston, S Gorling, HH Almasy, L Rutherford, S Proffitt, JM Best, LG Fabsitz, RR Lee, ET Howard, BV Comuzzie, AG MacCluer, JW Devereux, RB AF Cole, Shelley A. Voruganti, V. S. Roman, Mary J. Bella, Jonathan N. Okin, Peter M. Haack, Karin Laston, Sandra Goerling, Harald H. Almasy, Laura Rutherford, Sue Proffitt, J. M. Best, Lyle G. Fabsitz, Richard R. Lee, Elisa T. Howard, Barbara V. Comuzzie, Anthony G. MacCluer, Jean W. Devereux, Richard B. TI A Chromosome 22 Genetic Locus for Presence of Carotid Artery Plaque in the Strong Heart Family Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Cole, Shelley A.; Voruganti, V. S.; Haack, Karin; Laston, Sandra; Goerling, Harald H.; Almasy, Laura; Rutherford, Sue; Proffitt, J. M.; Comuzzie, Anthony G.; MacCluer, Jean W.] SW Fdn Biomed Res, San Antonio, TX 78284 USA. [Roman, Mary J.; Bella, Jonathan N.; Okin, Peter M.; Devereux, Richard B.] Cornell Univ, New York Presbyterian Hosp Weill Med Coll, New York, NY 10021 USA. [Fabsitz, Richard R.] NHLBI, Epidemiol & Biometry Program, Bethesda, MD 20892 USA. [Best, Lyle G.] Missouri Breaks Ind Rsch Inc, Timber Lake, SD USA. [Lee, Elisa T.] Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Cntr Amer Indian Hlth Rsch, Oklahoma City, OK USA. [Howard, Barbara V.] MedStar Rsch Inst, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E329 EP E329 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700287 ER PT J AU Cornelis, M Qi, L Zhang, CL Kraft, P Manson, J Cai, TX Hunter, DJ Hu, FB AF Cornelis, Marilyn Qi, Lu Zhang, Cuilin Kraft, Peter Manson, JoAnn Cai, Tianxi Hunter, David J. Hu, Frank B. TI Joint Effects of Common Genetic Variants on the Risk of Type 2 Diabetes in US Men and Women SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Cornelis, Marilyn; Kraft, Peter; Manson, JoAnn; Cai, Tianxi; Hunter, David J.; Hu, Frank B.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Zhang, Cuilin] NICHHD, Rockville, 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 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E276 EP E277 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700043 ER PT J AU Dehghan, A Bis, JC Dupuis, J Barbalic, M Baumert, J Smith, AV Witteman, JC Harris, T Rotter, JI Nambi, V Koenig, WF Benjamin, EJ AF Dehghan, Abbas Bis, Joshua C. Dupuis, Josee Barbalic, Maja Baumert, Jens Smith, Albert V. Witteman, Jacqueline C. Harris, Tamara Rotter, Jerome I. Nambi, Vijay Koenig, Wolfgang Benjamin, Emilia J. TI Meta-analysis of Genome-wide Association Study in 26,967 Subjects of 6 Population-Based Studies Identifies 6 Loci for C-Reactive Protein Serum Levels: The Charge Consortium SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Dehghan, Abbas; Witteman, Jacqueline C.] Erasmus Med Cntr, Rotterdam, Netherlands. [Bis, Joshua C.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Dupuis, Josee; Benjamin, Emilia J.] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Barbalic, Maja] Univ Texas Houston Hlth Sci Cntr, Ctr Human Genet, Houston, TX USA. [Baumert, Jens] Helmholtz Cntr Munich, Inst Epidemiol, Munich, Germany. [Smith, Albert V.] Iceland Heart Assoc, Kopavogur, Iceland. [Harris, Tamara] NIA, Bethesda, MD 20892 USA. [Rotter, Jerome I.] Med Genet Rsch Inst, Los Angeles, CA USA. [Nambi, Vijay] Baylor Coll Med, Houston, TX 77030 USA. [Koenig, Wolfgang] Univ Ulm, Med Ctr, Ulm, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E325 EP E325 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700267 ER PT J AU Gorodeski, EZ Shishehbor, MH Ishwaran, H Bild, DE Blackstone, EH Lauer, MS AF Gorodeski, Eiran Z. Shishehbor, Mehdi H. Ishwaran, Hemant Bild, Diane E. Blackstone, Eugene H. Lauer, Michael S. TI Random Forest Analysis to Assess Predictors of Coronary Artery Calcium: The Multi-Ethnic Study of Atherosclerosis SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Gorodeski, Eiran Z.; Shishehbor, Mehdi H.; Ishwaran, Hemant; Blackstone, Eugene H.] Cleveland Clin, Cleveland, OH 44106 USA. [Bild, Diane E.; Lauer, Michael S.] NHLBI, Bethesda, MD 20892 USA. RI Gorodeski, Eiran/D-5384-2009; Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E350 EP E350 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700382 ER PT J AU He, J Gu, DF Kelly, TN Hixson, JE Rao, DC Jaquish, CE Chen, J Gu, CC Huang, JF Shimmin, LC Liu, DP Liu, DP Whelton, PK AF He, Jiang Gu, Dongfeng Kelly, Tanika N. Hixson, James E. Rao, D. C. Jaquish, Cashell E. Chen, Jing Gu, C. C. Huang, Jianfeng Shimmin, Lawrence C. Liu, Depei Liu, Depei Whelton, Paul K. TI Genetic Variants in the Aldosterone System and Blood Pressure Responses to Potassium Intake SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [He, Jiang; Kelly, Tanika N.; Chen, Jing] Tulane Univ, New Orleans, LA 70118 USA. [Gu, Dongfeng; Huang, Jianfeng] Fuwai Hosp, Beijing, Peoples R China. [Hixson, James E.; Shimmin, Lawrence C.] Univ Texas Houston, Houston, TX USA. [Rao, D. C.; Gu, C. C.; Liu, Depei] Washington Univ, St Louis, MO USA. [Jaquish, Cashell E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Liu, Depei] Peking Union Med Coll, Beijing 100021, Peoples R China. [Whelton, Paul K.] Loyola Univ, Chicago, IL 60611 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E324 EP E324 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700266 ER PT J AU He, K Liu, K Morris, SJ Daviglus, ML Colangelo, L Jacobs, DR Loria, CM AF He, Ka Liu, Kiang Morris, Steven J. Daviglus, Martha L. Colangelo, Laura Jacobs, David R., Jr. Loria, Catherine M. TI Longitudinal Association of Toenail Selenium Levels with Incidence of Type 2 Diabetes: 18-Year Follow-up of the CARDIA Trace Element Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [He, Ka] Univ N Carolina, Chapel Hill, NC USA. [Liu, Kiang; Daviglus, Martha L.; Colangelo, Laura] Northwestern Univ, Chicago, IL 60611 USA. [Morris, Steven J.] Univ Missouri, Columbia Rsch Reactor Ctr, Columbia, MO USA. [Jacobs, David R., Jr.] Univ Minnesota, Minneapolis, MN USA. [Loria, Catherine M.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 2 Z9 3 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E300 EP E300 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700151 ER PT J AU Howard, BV Comuzzie, A Devereux, RB Ebbesson, SO Fabsitz, RR Howard, WJ Laston, S MacCluer, JW Silverman, A Wang, H Weissman, NJ Wenger, CR AF Howard, Barbara V. Comuzzie, Anthony Devereux, Richard B. Ebbesson, Sven O. Fabsitz, Richard R. Howard, Wm James Laston, Sandra MacCluer, Jean W. Silverman, Angela Wang, Hong Weissman, Neil J. Wenger, Charlotte R. TI CVD and Its Relation to Risk Factors in Alaska Eskimos: The GOCADAN Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Howard, Barbara V.; Silverman, Angela; Wang, Hong; Weissman, Neil J.] Medstar Rsch Inst, Hyattsville, MD USA. [Comuzzie, Anthony; Laston, Sandra; MacCluer, Jean W.; Wenger, Charlotte R.] SW Fdn Biomed Res, San Antonio, TX 78284 USA. [Devereux, Richard B.] Cornell Univ, Weill Med Coll, New York, NY 10021 USA. [Ebbesson, Sven O.] Norton Sound Hlth Corp, Nome, AK USA. [Fabsitz, Richard R.] NHLBI, Bethesda, MD 20892 USA. [Howard, Wm James] Washington Hosp Ctr, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E365 EP E365 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700450 ER PT J AU Kabagambe, E Nyirenda, C Potter, D Zulu, I Stringer, JS Bosire, C Saag, MS Ye, JT Chi, BH Arnett, DK Heimburger, DC AF Kabagambe, Edmond Nyirenda, Christopher Potter, Dara Zulu, Isaac Stringer, Jeffrey S. Bosire, Claire Saag, Michael S. Ye, Jiatao Chi, Benjamin H. Arnett, Donna K. Heimburger, Douglas C. TI Cardiovascular Risk Factors in HIV Patients Before and After Antiretroviral Therapy in Zambia SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Kabagambe, Edmond; Ye, Jiatao; Arnett, Donna K.] Univ Alabama, Sch Publ Hlth, Birmingham, AL 35294 USA. [Nyirenda, Christopher; Zulu, Isaac] Univ Teaching Hosp, Lusaka, Zambia. [Potter, Dara; Stringer, Jeffrey S.; Chi, Benjamin H.] Cntr Infect Dis Rsch Zambia, Lusaka, Zambia. [Bosire, Claire] NCI, Risk Factor Monitoring & Methods Branch, NIH, Bethesda, MD 20892 USA. [Saag, Michael S.; Heimburger, Douglas C.] Univ Alabama, Sch Med, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E299 EP E299 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700146 ER PT J AU Kelly, TN Chen, J Chen, JC Hixson, JE Rao, DC Liu, DP Jaquish, CE Rice, T Gu, C Whelton, PK Gu, DF He, J AF Kelly, Tanika N. Chen, Jing Chen, Ji-Chun Hixson, James E. Rao, D. C. Liu, Depei Jaquish, Cashell E. Rice, Treva Gu, Charles Whelton, Paul K. Gu, Dongfeng He, Jiang TI The Association Between Novel Genetic Variants in the ADD1 and GNB3 Genes and Salt Sensitivity of Blood Pressure SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Kelly, Tanika N.; Chen, Jing] Tulane Univ, New Orleans, LA 70118 USA. [Chen, Ji-Chun; Liu, Depei; Gu, Dongfeng] Chinese Acad Med Sci, Cardiovasc Inst & Fuwai Hosp, Beijing 100037, Peoples R China. [Chen, Ji-Chun; Liu, Depei; Gu, Dongfeng] Peking Union Med Coll, Beijing 100021, Peoples R China. [Hixson, James E.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Rao, D. C.; Gu, Charles] Washington Univ, St Louis, MO USA. [Jaquish, Cashell E.] NHLBI, Bethesda, MD 20892 USA. [Whelton, Paul K.] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. RI Rice, Treva/D-1385-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E330 EP E330 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700291 ER PT J AU Kelly, TN Gu, DF Hixson, JE Chen, J Liu, DP Chen, JC Rao, DC Mu, JJ Ma, JX Jaquish, CE Whelton, PK He, J AF Kelly, Tanika N. Gu, Dongfeng Hixson, James E. Chen, Jing Liu, Depei Chen, Ji-Chun Rao, D. C. Mu, Jianjun Ma, Jixiang Jaquish, Cashell E. Whelton, Paul K. He, Jiang TI Genetic Variants in the Renin-Angiotensin System and Salt Sensitivity of Blood Pressure SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Kelly, Tanika N.; Chen, Jing; He, Jiang] Tulane Univ, New Orleans, LA 70118 USA. [Gu, Dongfeng; Liu, Depei; Chen, Ji-Chun] Chinese Acad Med Sci, Cardiovasc Inst & Fuwai Hosp, Beijing 100037, Peoples R China. [Gu, Dongfeng; Liu, Depei; Chen, Ji-Chun] Peking Union Med Coll, Beijing 100021, Peoples R China. [Hixson, James E.] Univ Texas Houston, Houston, TX USA. [Rao, D. C.] Washington Univ, St Louis, MO USA. [Mu, Jianjun] Xi An Jiao Tong Univ, Xian, Shanxi, Peoples R China. [Ma, Jixiang] Shandong Cntr Dis Control & Prevent, Jinan, Shandong, Peoples R China. [Jaquish, Cashell E.] NHLBI, Bethesda, MD 20892 USA. [Whelton, Paul K.] Loyola Univ Hlth Syst & Med Cntr, Maywood, IL USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E330 EP E330 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700290 ER PT J AU Kim, LJ Nalls, M Eiriksdottir, G Sigurdsson, S Launer, LJ Koster, A Jonsdottir, B Garcia, M Gudnason, V Harris, TB AF Kim, Lauren J. Nalls, Michael Eiriksdottir, Gudny Sigurdsson, Sigurdur Launer, Lenore J. Koster, Annemarie Jonsdottir, Birna Garcia, Melissa Gudnason, Vilmundur Harris, Tamara B. TI Overweight and Obesity Modify the Association of Visceral and Liver Fat with the Metabolic Syndrome in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Kim, Lauren J.; Nalls, Michael; Launer, Lenore J.; Koster, Annemarie; Garcia, Melissa; Harris, Tamara B.] NIA, Bethesda, MD 20892 USA. [Eiriksdottir, Gudny; Sigurdsson, Sigurdur; Jonsdottir, Birna; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. RI Gudnason, Vilmundur/K-6885-2015 OI Gudnason, Vilmundur/0000-0001-5696-0084 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E303 EP E303 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700164 ER PT J AU Kottgen, A Glazer, NL Dehghan, A Hwang, SJ Katz, R Li, M Yang, Q Kao, WHL Coresh, J Shlipak, MG Witteman, J Fox, CS AF Kottgen, Anna Glazer, Nicole L. Dehghan, Abbas Hwang, Shih-Jen Katz, Ronit Li, Man Yang, Qiong Kao, Wen Hong Linda Coresh, Josef Shlipak, Michael G. Witteman, Jacqueline Fox, Caroline S. TI Genome-Wide Association Study of Chronic Kidney Disease and Related Traits in 19,877 Participants in 4 Population-Based Studies Identifies Common Genetic Variants Conferring Disease Risk SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Kottgen, Anna; Li, Man; Kao, Wen Hong Linda; Coresh, Josef] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Glazer, Nicole L.; Katz, Ronit] Univ Washington, Seattle, WA 98195 USA. [Dehghan, Abbas; Witteman, Jacqueline] Erasmus MC, Rotterdam, Netherlands. [Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Yang, Qiong] Boston Univ, Boston, MA 02215 USA. [Shlipak, Michael G.] San Francisco VA Med Ctr, San Francisco, CA USA. RI Yang, Qiong/G-5438-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E283 EP E283 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700072 ER PT J AU Li, RL Anderson, ND Nalls, M Scherer, M Thomas, F Ziv, E Newman, A Satterfield, S AF Li, Rongling Anderson, Nancy D. Nalls, Michael Scherer, Matthew Thomas, Fridtjof Ziv, Elad Newman, Anne Satterfield, Suzanne TI Interaction Between SNPs Identified from Genome-wide Admixture Mapping and Candidate Genes for Risk of Lower Extremity Arterial Disease in the Health, Aging and Body Composition Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Li, Rongling; Anderson, Nancy D.; Thomas, Fridtjof; Satterfield, Suzanne] Univ Tennessee, Memphis, TN USA. [Nalls, Michael; Scherer, Matthew] NIA, Bethesda, MD 20892 USA. [Ziv, Elad] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Newman, Anne] Univ Pittsburgh, Pittsburgh, PA USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E326 EP E326 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700273 ER PT J AU Mei, H Gu, DF Rice, T Hixson, JE Chen, J Jaquish, CE Zhao, Q Chen, CS Chen, JC Gu, CC Kelly, TN He, J AF Mei, Hao Gu, Dongfeng Rice, Treva Hixson, James E. Chen, Jing Jaquish, Cashell E. Zhao, Qi Chen, Chung-Shiuan Chen, Jichun Gu, C. Charles Kelly, Tanika N. He, Jiang TI Heritability of Blood Pressure Response to Cold Pressor Test in a Chinese Population SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Mei, Hao; Chen, Jing; Zhao, Qi; Chen, Chung-Shiuan] Tulane Univ, New Orleans, LA 70118 USA. [Gu, Dongfeng; Chen, Jichun] Chinese Acad Med Sci, Beijing 100037, Peoples R China. [Rice, Treva; Gu, C. Charles] Washington Univ, St Louis, MO USA. [Hixson, James E.] Univ Texas Houston, Houston, TX USA. [Jaquish, Cashell E.] Natl Inst Hlth, Bethesda, MD USA. RI Rice, Treva/D-1385-2009 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E329 EP E329 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700286 ER PT J AU Mills, KT Anthony, JA Chambless, LE Coresh, J Folsom, AR Heiss, G Mosley, TH Ni, HY Rosamond, WD Wagenknecht, L Wood, JL AF Mills, Katherine T. Anthony, Joseph A. Chambless, Lloyd E. Coresh, Josef Folsom, Aaron R. Heiss, Gerardo Mosley, Thomas H., Jr. Ni, Hanyu Rosamond, Wayne D. Wagenknecht, Lynne Wood, Joy L. TI Prediction of Heart Failure Hospitalization from Self-Reported Signs and Symptoms: The Atherosclerosis Risk in Communities (ARIC) Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Mills, Katherine T.; Anthony, Joseph A.; Chambless, Lloyd E.; Heiss, Gerardo; Rosamond, Wayne D.; Wood, Joy L.] Univ N Carolina, Chapel Hill, NC USA. [Coresh, Josef] Johns Hopkins Univ, Baltimore, MD USA. [Folsom, Aaron R.] Univ Minnesota, Minneapolis, MN USA. [Mosley, Thomas H., Jr.] Univ Mississippi, Med Cntr, Jackson, MS 39216 USA. [Ni, Hanyu] NHLBI, Bethesda, MD 20892 USA. [Wagenknecht, Lynne] Wake Forest Sch Med, Winston Salem, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E359 EP E360 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700426 ER PT J AU Newton-Cheh, C Eijgelsheim, M Rice, K de Bakker, PI Yin, XY Estrada, K Bis, J Rivadeneira, F Noseworthy, PA Sotoodehnia, N Smith, NL Rotter, JI Kors, JA Witteman, JC Hofman, A Heckbert, SR O'Donnell, CJ Uitterlinden, AG Psaty, BM Lumley, T Larson, MG Stricker, BH AF Newton-Cheh, Christopher Eijgelsheim, Mark Rice, Kenneth de Bakker, Paul I. Yin, Xiaoyan Estrada, Karol Bis, Joshua Rivadeneira, Fernando Noseworthy, Peter A. Sotoodehnia, Nona Smith, Nicholas L. Rotter, Jerome I. Kors, Jan A. Witteman, Jacqueline C. Hofman, Albert Heckbert, Susan R. O'Donnell, Christopher J. Uitterlinden, Andre G. Psaty, Bruce M. Lumley, Thomas Larson, Martin G. Stricker, Bruno H. TI Common Variants at 10 Loci Influence Myocardial Repolarization: The QTGEN Consortium SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Newton-Cheh, Christopher; Noseworthy, Peter A.] Massachusetts Gen Hosp, Ctr Human Genet Rsch, Cardiovasc Rsch Ctr, Boston, MA 02114 USA. [Newton-Cheh, Christopher; de Bakker, Paul I.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Boston, MA USA. [Eijgelsheim, Mark; Estrada, Karol; Rivadeneira, Fernando; Kors, Jan A.; Witteman, Jacqueline C.; Hofman, Albert; Uitterlinden, Andre G.; Stricker, Bruno H.] Erasmus MC, Rotterdam, Netherlands. [Smith, Nicholas L.] Univ Washington, Sch Med, Cardiovasc Hlth Rsch Unit, Seattle Epidemiol Rsch Cntr, Seattle, WA 98195 USA. [de Bakker, Paul I.] Harvard Univ, Sch Med, Partners HealthCare Cntr Genet & Genom, Brigham & Womens Hosp, Cambridge, MA 02138 USA. [Yin, Xiaoyan; Larson, Martin G.] Boston Univ, Framingham, MA USA. [Yin, Xiaoyan; Larson, Martin G.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Heckbert, Susan R.] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Cambridge, MA USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Cambridge, MA USA. [Uitterlinden, Andre G.] Univ Washington, Grp Hlth, Ctr Hlth Sci, Seattle, WA USA. [Stricker, Bruno H.] Inspectorate Hlth Care, Rotterdam, Netherlands. RI Rice, Kenneth/A-4150-2013; de Bakker, Paul/B-8730-2009; Rivadeneira, Fernando/O-5385-2015 OI Rice, Kenneth/0000-0001-5779-4495; de Bakker, Paul/0000-0001-7735-7858; Rivadeneira, Fernando/0000-0001-9435-9441 NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E277 EP E277 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700044 ER PT J AU Pearson, T Harlan, W Wagener, D Haines, J Kwok, R Hendershot, T Ramos, E Hamilton, C AF Pearson, Thomas Harlan, William Wagener, Diane Haines, Jonathan Kwok, Richard Hendershot, Tabitha Ramos, Erin Hamilton, Carol TI Consensus Measures for Genome-wide Association Studies of Cardiovascular Outcomes SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Pearson, Thomas] Univ Rochester, Rochester, NY USA. [Harlan, William] Natl Lib Med, Chevy Chase, MD USA. [Wagener, Diane; Hendershot, Tabitha; Hamilton, Carol] RTI Int, Rsch Triangle Pk, NC USA. [Haines, Jonathan] Vanderbilt Univ, Nashville, TN USA. [Ramos, Erin] NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E327 EP E327 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700276 ER PT J AU Polak, JF Person, SD Wei, GS Jacobs, DR Harrington, A Godreau, A Sidney, S O'Leary, DH AF Polak, Joseph F. Person, Sharina D. Wei, Gina S. Jacobs, David R., Jr. Harrington, Anita Godreau, Ayleen Sidney, Stephen O'Leary, Daniel H. TI Segment-Specific Associations of Carotid IMT with Cardiovascular Risk Factors: The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Polak, Joseph F.] Tufts Univ, Sch Med, Tufts Med Ctr, Boston, MA 02111 USA. [Person, Sharina D.] Univ Alabama, Birmingham, AL USA. [Wei, Gina S.] NHLBI, Bethesda, MD 20892 USA. [Jacobs, David R., Jr.] Univ Minnesota, St Paul, MN 55108 USA. [Jacobs, David R., Jr.] Univ Oslo, Oslo, Norway. [Godreau, Ayleen] Univ Wisconsin, Madison, WI USA. [Sidney, Stephen] Kaiser Permanente, Oakland, CA USA. [O'Leary, Daniel H.] Tufts Univ, Sch Med, Carney Hosp, Dorchester, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E337 EP E337 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700320 ER PT J AU Preis, SR Massaro, JM Hoffmann, U D'Agostino, RB Robins, SJ Meigs, JB Vasan, RS O'Donnell, CJ Fox, CS AF Preis, Sarah R. Massaro, Joseph M. Hoffmann, Udo D'Agostino, Ralph B. Robins, Sander J. Meigs, James B. Vasan, Ramachandran S. O'Donnell, Christopher J. Fox, Caroline S. TI Neck Circumference as a Novel Measure of Cardiometabolic Risk: The Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Preis, Sarah R.; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI Framingham Heart Study, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Hoffmann, Udo; Meigs, James B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Robins, Sander J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E302 EP E302 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700160 ER PT J AU Preis, SR Massaro, JM Robins, SJ Hoffmann, U Meigs, JB Vasan, RS Sutherland, P D'Agostino, RB O'Donnell, CJ Fox, CS AF Preis, Sarah R. Massaro, Joseph M. Robins, Sander J. Hoffmann, Udo Meigs, James B. Vasan, Ramachandran S. Sutherland, Patrice D'Agostino, Ralph B., Sr. O'Donnell, Christopher J. Fox, Caroline S. TI Visceral and Subcutaneous Adipose Tissue and Insulin Resistance in the Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Preis, Sarah R.; Sutherland, Patrice; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI Framingham Heart Study, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Boston, MA USA. [Robins, Sander J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Hoffmann, Udo; Meigs, James B.] Massachusetts Gen Hosp, Boston, MA 02114 USA. NR 0 TC 9 Z9 11 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E296 EP E296 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700131 ER PT J AU Spangler, EL Watson, NL Venkitachalam, L Sutton-Tyrrell, K Simonsick, EM Najjar, SS Brach, JS Mackey, RH Bauer, DC Rodondi, N Johnson, KC Newman, AB AF Spangler, Emily L. Watson, Nora L. Venkitachalam, Lakshmi Sutton-Tyrrell, Kim Simonsick, Eleanor M. Najjar, Samer S. Brach, Jennifer S. Mackey, Rachel H. Bauer, Douglas C. Rodondi, Nicolas Johnson, Karen C. Newman, Anne B. CA Hlth ABC Study TI Arterial Stiffness and Walking Endurance in Community-Dwelling Older Adults SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Spangler, Emily L.; Watson, Nora L.; Venkitachalam, Lakshmi; Sutton-Tyrrell, Kim; Brach, Jennifer S.; Mackey, Rachel H.; Newman, Anne B.] Univ Pittsburgh, Pittsburgh, PA USA. [Simonsick, Eleanor M.; Najjar, Samer S.] NIA, NIH, Baltimore, MD 21224 USA. [Bauer, Douglas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Rodondi, Nicolas] Univ Lausanne, Lausanne, Switzerland. [Johnson, Karen C.] Univ Tennessee, Memphis, TN USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E318 EP E318 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700235 ER PT J AU Strasak, AM Pfeiffer, RM Brant, LJ Borena, W Concin, H Diem, G Ruttmann, E Pfeiffer, KP Ulmer, H AF Strasak, Alexander M. Pfeiffer, Ruth M. Brant, Larry J. Borena, Wegene Concin, Hans Diem, Guenter Ruttmann, Elfriede Pfeiffer, Karl P. Ulmer, Hanno TI Association of Total Serum Cholesterol and Cancer Incidence in a Cohort of 172,210 Men and Women: A Prospective 19-Year Follow-up Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Strasak, Alexander M.; Borena, Wegene; Ruttmann, Elfriede; Pfeiffer, Karl P.; Ulmer, Hanno] Innsbruck Med Univ, Innsbruck, Austria. [Pfeiffer, Ruth M.] NCI, Bethesda, MD 20892 USA. [Brant, Larry J.] NIA, Gerontol Rsch Ctr, Baltimore, MD 21224 USA. [Concin, Hans; Diem, Guenter] Agcy Prevent & Social Med, Bregenz, Austria. RI Ruttmann, Elfriede/D-6501-2011; Pfeiffer, Ruth /F-4748-2011; vhmpp, aks/F-9756-2012; Ulmer, Hanno/C-3488-2011 OI Ulmer, Hanno/0000-0001-5911-1002 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E332 EP E332 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700299 ER PT J AU Ulmer, H Brant, LJ Kelleher, CC Borena, W Strasak, A Concin, H Diem, G Ruttmann, E AF Ulmer, Hanno Brant, Larry J. Kelleher, Cecily C. Borena, Wegene Strasak, Alexander Concin, Hans Diem, Guenter Ruttmann, Elfriede TI Gamma-Glutamyltransferase: A New Biomarker for Heart Failure Mortality? SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Ulmer, Hanno; Borena, Wegene; Strasak, Alexander; Ruttmann, Elfriede] Innsbruck Med Univ, Innsbruck, Austria. [Brant, Larry J.] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Kelleher, Cecily C.] Univ Coll Dublin, Sch Publ Hlth & Populat Sci, Dublin 2, Ireland. [Concin, Hans; Diem, Guenter] Agcy Social & Prevent Med, Bregenz, Austria. RI Ruttmann, Elfriede/D-6501-2011; vhmpp, aks/F-9756-2012; Ulmer, Hanno/C-3488-2011 OI Ulmer, Hanno/0000-0001-5911-1002 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E314 EP E314 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700216 ER PT J AU Watson, NL Sutton-Tyrrell, K Mackey, RH Brach, JS Najjar, SS Venkitachalam, L Bauer, DC Rodondi, N Johnson, KC Simonsick, EM Newman, AB AF Watson, Nora L. Sutton-Tyrrell, Kim Mackey, Rachel H. Brach, Jennifer S. Najjar, Samer S. Venkitachalam, Lakshmi Bauer, Douglas C. Rodondi, Nicolas Johnson, Karen C. Simonsick, Eleanor M. Newman, Anne B. CA Hlth ABC Study TI Subclinical Cardiovascular Disease and Gait Speed in Well-Functioning Older Adults SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Watson, Nora L.; Sutton-Tyrrell, Kim; Mackey, Rachel H.; Brach, Jennifer S.; Venkitachalam, Lakshmi; Newman, Anne B.] Univ Pittsburgh, Pittsburgh, PA USA. [Najjar, Samer S.; Simonsick, Eleanor M.] NIA, NIH, Baltimore, MD 21224 USA. [Bauer, Douglas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Rodondi, Nicolas] Univ Lausanne, Lausanne, Switzerland. [Johnson, Karen C.] Univ Tennessee, Memphis, TN USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E318 EP E318 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700236 ER PT J AU Yazdanyar, A Inzitari, M Boudreau, R Arnold, A Patel, KV Newman, AB AF Yazdanyar, Ali Inzitari, Marco Boudreau, Robert Arnold, Alice Patel, Kushang V. Newman, Anne B. TI Factors Associated with Physical Functional Performance in an Elderly Cohort with High Subclinical Cardiovascular Burden: The Cardiovascular Health Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Yazdanyar, Ali; Inzitari, Marco; Boudreau, Robert; Newman, Anne B.] Univ Pittsburgh, Pittsburgh, PA USA. [Arnold, Alice] Univ Washington, Seattle, WA 98195 USA. [Patel, Kushang V.] NIA, Bethesda, MD 20892 USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E318 EP E318 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700237 ER PT J AU Zhao, Q Gu, DF Hixson, JE Rao, DC Jaquish, CE Chen, J Huang, JF Kelly, TN Gu, CC Whelton, PK He, J AF Zhao, Qi Gu, Dongfeng Hixson, James E. Rao, Dabeeru C. Jaquish, Cashell E. Chen, Jing Huang, Jianfeng Kelly, Tanika N. Gu, C. Charles Whelton, Paul K. He, Jiang TI Association Between Genetic Variants of the ACE2 and Apelin-APJ System and Blood Pressure Responses to a Dietary Potassium Supplement: The GenSalt Study SO CIRCULATION LA English DT Meeting Abstract CT Joint Nutrition, Physical Activity and Metabolism Conference/49th Cardiovascular Disease Epidemiology and Prevention of the American-Heart-Association CY MAR 10-14, 2009 CL Palm Harbor, FL SP Amer Heart Assoc C1 [Zhao, Qi; Kelly, Tanika N.; He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, New Orleans, LA USA. [Gu, Dongfeng; Huang, Jianfeng] Chinese Acad Med Sci, Cardiovasc Inst & Fuwai Hosp, Beijing 100037, Peoples R China. [Gu, Dongfeng; Huang, Jianfeng] Chinese Natl Cntr Cardiovasc Dis Control & Rsch, Beijing, Peoples R China. [Gu, Dongfeng; Huang, Jianfeng] Peking Union Med Coll, Beijing 100021, Peoples R China. [Hixson, James E.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Rao, Dabeeru C.; Gu, C. Charles] Washington Univ, Sch Med, St Louis, MO USA. [Jaquish, Cashell E.] NHLBI, Bethesda, MD 20892 USA. [Chen, Jing] Tulane Univ, Sch Med, New Orleans, LA 70112 USA. [Whelton, Paul K.] Loyola Univ, Med Ctr, Maywood, IL 60153 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 17 PY 2009 VL 119 IS 10 BP E329 EP E329 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 419TX UT WOS:000264243700288 ER PT J AU Nishimura, T Kubosaki, A Ito, Y Notkins, AL AF Nishimura, T. Kubosaki, A. Ito, Y. Notkins, A. L. TI DISTURBANCES IN THE SECRETION OF NEUROTRANSMITTERS IN IA-2/IA-2 beta NULL MICE: CHANGES IN BEHAVIOR, LEARNING AND LIFESPAN SO NEUROSCIENCE LA English DT Article DE IA-2; IA-2 beta; secretory vesicles; behavior ID PROTEIN-TYROSINE-PHOSPHATASE; DEPENDENT DIABETES-MELLITUS; GAMMA-AMINOBUTYRIC ACID; INSULIN-SECRETION; TRANSMEMBRANE PROTEIN; TARGETED DISRUPTION; MOLECULAR-CLONING; TRANSGENIC MICE; RECEPTOR-TYPE; RAT-BRAIN AB Islet-associated protein 2 (IA-2) and IA-2 beta are major autoantigens in type 1 diabetes and transmembrane proteins in dense core secretory vesicles (DCV) of neuroendocrine cells. The deletion of these genes results in a decrease in insulin secretion. The present study was initiated to test the hypothesis that this deletion not only affects the secretion of insulin, but has a more global effect on neuroendocrine secretion that leads to disturbances in behavior and learning. Measurement of neurotransmitters showed that norepinephrine, dopamine and 5-HT were significantly decreased in the brain of double knockout (DKO) mice (P<0.05 to <0.001). In tests evaluating anxiety-like behavior and conditioned-learning, the DKO mice showed a highly significant increase in anxiety-like behavior (P<0.01 to <0.001) and impairment of conditioned learning (P<0.01) as compared to WT mice. The DKO mice also displayed an increase in spontaneous and induced seizures (P<0.01) and age-related death. Contrary to the generally held view that IA-2 and IA-2 beta are expressed exclusively in DCV, subcellular fractionation studies revealed that IA-2 beta, but not IA-2, co-purifies with fractions rich in synaptic vesicles (SV), and that the secretion of dopamine, GABA and glutamate from the synaptosomes of the DKO mice was significantly decreased as was the number of SV (P<0.01). Taken together, these findings show that IA-2 beta is present in both DCV and SV, and that the deletion of IA-2/IA-2 beta has a global effect on the secretion of neurotransmitters. The impairment of secretion leads to behavioral and learning disturbances, seizures and reduced lifespan. Published by Elsevier Ltd on behalf of IBRO. C1 [Nishimura, T.; Kubosaki, A.; Notkins, A. L.] Natl Inst Dent & Craniofacial Res, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Ito, Y.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Notkins, AL (reprint author), Natl Inst Dent & Craniofacial Res, Expt Med Sect, Oral Infect & Immun Branch, NIH, Bldg 30,Room 106,30 Convent Dr,MSC4322, Bethesda, MD 20892 USA. EM anotkins@mail.nih.gov FU National Institute of Dental and Craniofacial Research, National Institutes of Health; Japan Society for the Promotion of Science Fellowship FX This work was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health and in part by a Japan Society for the Promotion of Science Fellowship (T. N.). The authors thank Dr. Shinichiro Nakamura for his histology studies. NR 39 TC 22 Z9 25 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD MAR 17 PY 2009 VL 159 IS 2 BP 427 EP 437 DI 10.1016/j.neuroscience.2009.01.022 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 418QC UT WOS:000264162300001 PM 19361477 ER PT J AU Cattoli, G Monne, I Fusaro, A Joannis, TM Lombin, LH Aly, MM Arafa, AS Sturm-Ramirez, KM Couacy-Hymann, E Awuni, JA Batawui, KB Awoume, KA Aplogan, GL Sow, A Ngangnou, AC Hamza, IMEN Gamatie, D Dauphin, G Domenech, JM Capua, I AF Cattoli, Giovanni Monne, Isabella Fusaro, Alice Joannis, Tony M. Lombin, Lami H. Aly, Mona M. Arafa, Abdel S. Sturm-Ramirez, Katharine M. Couacy-Hymann, Emmanuel Awuni, Joseph A. Batawui, Komla B. Awoume, Kodzo A. Aplogan, Gilbert L. Sow, Adama Ngangnou, Andre C. Hamza, Iman M. El Nasri Gamatie, Djibo Dauphin, Gwenaelle Domenech, Joseph M. Capua, Ilaria TI Highly Pathogenic Avian Influenza Virus Subtype H5N1 in Africa: A Comprehensive Phylogenetic Analysis and Molecular Characterization of Isolates SO PLOS ONE LA English DT Article AB Highly pathogenic avian influenza virus A/H5N1 was first officially reported in Africa in early 2006. Since the first outbreak in Nigeria, this virus spread rapidly to other African countries. From its emergence to early 2008, 11 African countries experienced A/H5N1 outbreaks in poultry and human cases were also reported in three of these countries. At present, little is known of the epidemiology and molecular evolution of A/H5N1 viruses in Africa. We have generated 494 full gene sequences from 67 African isolates and applied molecular analysis tools to a total of 1,152 A/H5N1 sequences obtained from viruses isolated in Africa, Europe and the Middle East between 2006 and early 2008. Detailed phylogenetic analyses of the 8 gene viral segments confirmed that 3 distinct sublineages were introduced, which have persisted and spread across the continent over this 2-year period. Additionally, our molecular epidemiological studies highlighted the association between genetic clustering and area of origin in a majority of cases. Molecular signatures unique to strains isolated in selected areas also gave us a clearer picture of the spread of A/H5N1 viruses across the continent. Mutations described as typical of human influenza viruses in the genes coding for internal proteins or associated with host adaptation and increased resistance to antiviral drugs have also been detected in the genes coding for transmembrane proteins. These findings raise concern for the possible human health risk presented by viruses with these genetic properties and highlight the need for increased efforts to monitor the evolution of A/H5N1 viruses across the African continent. They further stress how imperative it is to implement sustainable control strategies to improve animal and public health at a global level. C1 [Cattoli, Giovanni; Monne, Isabella; Fusaro, Alice; Capua, Ilaria] Ist Zooprofilatt Sperle Venezie, OIE FAO Reference Lab Avian Influenza & Newcastle, Legnaro, PD, Italy. [Joannis, Tony M.; Lombin, Lami H.] Natl Vet Res Inst, Vom, Nigeria. [Aly, Mona M.; Arafa, Abdel S.] Natl Lab Qual Control Poultry Product, Cairo, Egypt. [Sturm-Ramirez, Katharine M.] Fogarty Int Ctr, NIH, Bethesda, MD USA. [Couacy-Hymann, Emmanuel] Lab Cent Pathol Anim, Bingerville, Cote Ivoire. [Awuni, Joseph A.] Accra Vet Lab, Accra, Ghana. [Batawui, Komla B.; Awoume, Kodzo A.] Lab Cent Vet, Lome, Togo. [Aplogan, Gilbert L.] Lab Diagnost Vet Serosurveillance, Parakou, Benin. [Sow, Adama] Lab Natl Elevage, Ouagadougou, Burkina Faso. [Ngangnou, Andre C.] Lab Natl Vet, Garoua, Cameroon. [Hamza, Iman M. El Nasri] Cent Vet Res Lab, Khartoum, Sudan. [Gamatie, Djibo] Direct Lab Vet, Niamey, Niger. [Dauphin, Gwenaelle; Domenech, Joseph M.] Food & Agr Org UN, AGAH Div, Rome, Italy. RP Cattoli, G (reprint author), Ist Zooprofilatt Sperle Venezie, OIE FAO Reference Lab Avian Influenza & Newcastle, Legnaro, PD, Italy. EM gcattoli@izsvenezie.it OI Fusaro, Alice/0000-0002-8213-5472 FU Food and Agricultural Organization of the United Nations (UN-FAO); EU-projects EPIZONE; FLUTRAIN FX The Food and Agricultural Organization of the United Nations (UN-FAO) financially supported part of this project and facilitated samples collection and submission. The EU-projects EPIZONE (Network of excellence for epizootic disease diagnosis and control) and FLUTRAIN (Training and technology transfer of avian influenza diagnostics and disease management skills) also contributed to the realization of this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 62 Z9 63 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 17 PY 2009 VL 4 IS 3 AR e4842 DI 10.1371/journal.pone.0004842 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437OJ UT WOS:000265496500002 PM 19290041 ER PT J AU Santhanam, AN Bindewald, E Rajasekhar, VK Larsson, O Sonenberg, N Colburn, NH Shapiro, BA AF Santhanam, Arti N. Bindewald, Eckart Rajasekhar, Vinagolu K. Larsson, Ola Sonenberg, Nahum Colburn, Nancy H. Shapiro, Bruce A. TI Role of 3 ' UTRs in the Translation of mRNAs Regulated by Oncogenic eIF4E-A Computational Inference SO PLOS ONE LA English DT Article AB Eukaryotic cap-dependent mRNA translation is mediated by the initiation factor eIF4E, which binds mRNAs and stimulates efficient translation initiation. eIF4E is often overexpressed in human cancers. To elucidate the molecular signature of eIF4E target mRNAs, we analyzed sequence and structural properties of two independently derived polyribosome recruited mRNA datasets. These datasets originate from studies of mRNAs that are actively being translated in response to cells overexpressing eIF4E or cells with an activated oncogenic AKT: eIF4E signaling pathway, respectively. Comparison of eIF4E target mRNAs to mRNAs insensitive to eIF4E-regulation has revealed surprising features in mRNA secondary structure, length and microRNA-binding properties. Fold-changes (the relative change in recruitment of an mRNA to actively translating polyribosomal complexes in response to eIF4E overexpression or AKT upregulation) are positively correlated with mRNA G+C content and negatively correlated with total and 3'UTR length of the mRNAs. A machine learning approach for predicting the fold change was created. Interesting tendencies of secondary structure stability are found near the start codon and at the beginning of the 3'UTR region. Highly upregulated mRNAs show negative selection (site avoidance) for binding sites of several microRNAs. These results are consistent with the emerging model of regulation of mRNA translation through a dynamic balance between translation initiation at the 5'UTR and microRNA binding at the 3'UTR. C1 [Santhanam, Arti N.] NCI, Gene Regulat Sect, Lab Canc Prevent, Frederick, MD 21701 USA. [Bindewald, Eckart; Colburn, Nancy H.] NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. [Rajasekhar, Vinagolu K.] Memorial Sloan Kettering Canc Ctr, Dev Biol Program, New York, NY USA. [Larsson, Ola; Sonenberg, Nahum] McGill Univ, Dept Biochem, Montreal, PQ H3A 2T5, Canada. [Larsson, Ola; Sonenberg, Nahum] McGill Univ, McGill Canc Ctr, Montreal, PQ H3A 2T5, Canada. [Shapiro, Bruce A.] NCI, Ctr Canc Res, Nanobiol Program, Frederick, MD USA. RP Santhanam, AN (reprint author), NCI, Gene Regulat Sect, Lab Canc Prevent, Frederick, MD 21701 USA. EM bshapiro@ncifcrf.gov RI Larsson, Ola/F-8151-2013; OI Larsson, Ola/0000-0003-1412-1308 FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported [in part] by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 47 TC 10 Z9 10 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 17 PY 2009 VL 4 IS 3 AR e4868 DI 10.1371/journal.pone.0004868 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437OJ UT WOS:000265496500005 PM 19290046 ER PT J AU Yang, Y Baboolal, TG Siththanandan, V Chen, M Walker, ML Knight, PJ Peckham, M Sellers, JR AF Yang, Yi Baboolal, Thomas G. Siththanandan, Verl Chen, Michael Walker, Matthew L. Knight, Peter J. Peckham, Michelle Sellers, James R. TI A FERM domain autoregulates Drosophila myosin 7a activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE regulation; electron microscopy; ATPase activity ID SMOOTH-MUSCLE MYOSIN; DUTY RATIO MOTOR; TAIL DOMAIN; KINETIC MECHANISM; SENSORY EPITHELIA; IONIC-STRENGTH; NEGATIVE STAIN; VIIA; ACTIN; CONFORMATION AB Full-length Drosophila myosin 7a ( myosin 7a-FL) has a complex tail containing a short predicted coiled coil followed by a MyTH4-FERM domain, an SH3 domain, and a C-terminal MyTH4-FERM domain. Myosin 7a-FL expressed in Sf9 cells is monomeric despite the predicted coiled coil. We showed previously that Subfragment-1 (S1) from this myosin has MgATPase of V(max) approximate to 1s(-1) and K(ATPase) approximate to 1 mu M actin. We find that myosin 7a-FL has Vmax similar to S1 but K(ATPase) approximate to 30 mu M. Thus, at low actin concentrations ( 5 mu M), the MgATPase of S1 is fully activated, whereas that of myosin 7a-FL is low, suggesting that the tail regulates activity. Electron microscopy of myosin 7a-FL with ATP shows the tail is tightly bent back against the motor domain. Myosin 7a-FL extends at either high ionic strength or without ATP, revealing the motor domain, lever, and tail. A series of C-terminal truncations show that deletion of 99 aa ( the MyTH7 subdomain of the C-terminal FERM domain) is sufficient to abolish bending, and the K(ATPase) is then similar to S1. This region is highly conserved in myosin 7a. We found that a double mutation in it, R2140A-K2143A, abolishes bending and reduces K(ATPase) to S1 levels. In addition, the expressed C-terminal FERM domain binds actin with K(d) approximate to 30 mu M regardless of ATP, similar to the K(ATPase) value for myosin 7a-FL. We propose that at low cellular actin concentrations, myosin 7a-FL is bent and inactive, but at high actin concentrations, it is unfolded and active because the C-terminal FERM domain binds to actin. C1 [Yang, Yi; Siththanandan, Verl; Chen, Michael; Sellers, James R.] NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. [Baboolal, Thomas G.; Knight, Peter J.; Peckham, Michelle] Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. [Baboolal, Thomas G.; Knight, Peter J.; Peckham, Michelle] Univ Leeds, Inst Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England. [Walker, Matthew L.] MLW Consulting, Launceston PL15 9BB, Cornwall, England. RP Sellers, JR (reprint author), NHLBI, Lab Mol Physiol, NIH, Bldg 50,Room 3523,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sellersj@nhlbi.nih.gov RI Baboolal, Thomas/L-4590-2013; Peckham, Michelle/J-4991-2015 OI Baboolal, Thomas/0000-0003-4444-0318; Peckham, Michelle/0000-0002-3754-2028 FU National Heart, Lung, and Blood Institute; Biotechnology and Biological Sciences Research Council FX We thank Erica Perez for help in engineering some of the clones used in this study and Fang Zhang for excellent technical assistance. We are grateful for financial support from the National Heart, Lung, and Blood Institute intramural program and project funding and an Underwood Fellowship from the Biotechnology and Biological Sciences Research Council. NR 42 TC 48 Z9 49 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 17 PY 2009 VL 106 IS 11 BP 4189 EP 4194 DI 10.1073/pnas.0808682106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 420HD UT WOS:000264278800027 PM 19255446 ER PT J AU Hatziioannou, T Ambrose, Z Chung, NPY Piatak, M Yuan, F Trubey, CM Coalter, V Kiser, R Schneider, D Smedley, J Pung, R Gathuka, M Estes, JD Veazey, RS KewalRamani, VN Lifson, JD Bieniasz, PD AF Hatziioannou, Theodora Ambrose, Zandrea Chung, Nancy P. Y. Piatak, Michael, Jr. Yuan, Fang Trubey, Charles M. Coalter, Vicky Kiser, Rebecca Schneider, Doug Smedley, Jeremy Pung, Rhonda Gathuka, Mercy Estes, Jacob D. Veazey, Ronald S. KewalRamani, Vineet N. Lifson, Jeffrey D. Bieniasz, Paul D. TI A macaque model of HIV-1 infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE AIDS; PrEP; SIV; stHIV-1 ID IMMUNODEFICIENCY-VIRUS TYPE-1; MACACA-NEMESTRINA; RESTRICTION FACTOR; RHESUS MACAQUES; ENZYME APOBEC3G; CYCLOPHILIN-A; ANIMAL-MODEL; VIF PROTEIN; AIDS; RESISTANCE AB The lack of a primate model that utilizes HIV-1 as the challenge virus is an impediment to AIDS research; existing models generally employ simian viruses that are divergent from HIV-1, reducing their usefulness in preclinical investigations. Based on an understanding of species-specific variation in primate TRIM5 and APOBEC3 antiretroviral genes, we constructed simian-tropic (st) HIV-1 strains that differ from HIV-1 only in the vif gene. We demonstrate that such minimally modified stHIV-1 strains are capable of high levels of replication in vitro in pig-tailed macaque (Macaca nemestrina) lymphocytes. Importantly, infection of pig-tailed macaques with stHIV-1 results in acute viremia, approaching the levels observed in HIV-1-infected humans, and an ensuing persistent infection for several months. stHIV-1 replication was controlled thereafter, at least in part, by CD8+ T cells. We demonstrate the potential utility of this HIV-1-based animal model in a chemoprophylaxis experiment, by showing that a commonly used HIV-1 therapeutic regimen can provide apparently sterilizing protection from infection following a rigorous high-dose stHIV-1 challenge. C1 [Hatziioannou, Theodora; Bieniasz, Paul D.] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY 10021 USA. [Bieniasz, Paul D.] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10021 USA. [Bieniasz, Paul D.] Rockefeller Univ, Lab Retrovirol, New York, NY 10021 USA. [Ambrose, Zandrea; Chung, Nancy P. Y.; KewalRamani, Vineet N.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Piatak, Michael, Jr.; Yuan, Fang; Trubey, Charles M.; Coalter, Vicky; Kiser, Rebecca; Schneider, Doug; Estes, Jacob D.; Lifson, Jeffrey D.] NCI, AIDS & Canc Virus Program, Frederick, MD 21702 USA. [Smedley, Jeremy; Pung, Rhonda; Gathuka, Mercy] NCI, Lab Anim Sci Program, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. [Veazey, Ronald S.] Tulane Univ, Sch Med, Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. RP Hatziioannou, T (reprint author), Rockefeller Univ, Aaron Diamond AIDS Res Ctr, 1230 York Ave, New York, NY 10021 USA. EM thatziio@adarc.org; vineet@ncifcrf.gov; lifson@ncifcrf.gov; pbienias@adarc.org OI Smedley, Jeremy/0000-0003-3369-4662 FU NIH [R01AI078788, R01AI64003]; American Foundation for AIDS Research [106404-33-RFMC, 107149-44-RGRL]; National Cancer Institute, NIH [N01-CO-12400, HHSN266200400088C]; Intramural Center for Cancer Research FX We thank Zerina Kratovac, Cesar Virgen, Bernice Kaack, Lara Doyle, Linda Green, Kelsi Rasmussen, Janell LeBlanc, and Adam Wiles for assistance, Sunil Ahuja for the pR1-D plasmid, Norbert Bischofberger and Gilead Sciences for providing TDF and FTC, and Ronald Desrosiers and Joseph Sodroski for the SIVMAC239 and SHIVKB9 clones, which were obtained through the National Institutes of Health (NIH) AIDS Research and Reference Reagent program, Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH, as were the overlapping 15-mer SIVMAC239 and HIV-1 peptides. The cM-T807 antibody was provided by the NIH Nonhuman Primate Reagent Resource (R24 RR016001, N01 AI040101). This work was supported by Grants from the NIH, R01AI078788 (to T. H.) and R01AI64003 (to P. D. B.), American Foundation for AIDS Research (amFAR) 106404-33-RFMC and 107149-44-RGRL (to Z. A.), and with federal funds from the National Cancer Institute, NIH, under contracts N01-CO-12400 and HHSN266200400088C (to J. D. L.) and through the Intramural Center for Cancer Research, which supports the HIV Drug Resistance Program (V. N. K.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. NR 47 TC 83 Z9 92 U1 6 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 17 PY 2009 VL 106 IS 11 BP 4425 EP 4429 DI 10.1073/pnas.0812587106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 420HD UT WOS:000264278800067 PM 19255423 ER PT J AU Omsland, A Cockrell, DC Howe, D Fischer, ER Virtaneva, K Sturdevant, DE Porcella, SF Heinzen, RA AF Omsland, Anders Cockrell, Diane C. Howe, Dale Fischer, Elizabeth R. Virtaneva, Kimmo Sturdevant, Daniel E. Porcella, Stephen F. Heinzen, Robert A. TI Host cell-free growth of the Q fever bacterium Coxiella burnetii SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE axenic growth; metabolism; microaerophile; obligate intracellular pathogen ID LEGIONELLA-PNEUMOPHILA; CHOLESTEROL-METABOLISM; GENOME SEQUENCE; CYTOCHROME BD; GUINEA-PIGS; INFECTION; OXYGEN; REQUIREMENTS; MACROPHAGES; VIRULENCE AB The inability to propagate obligate intracellular pathogens under axenic (host cell-free) culture conditions imposes severe experimental constraints that have negatively impacted progress in understanding pathogen virulence and disease mechanisms. Coxiella burnetii, the causative agent of human Q (Query) fever, is an obligate intracellular bacterial pathogen that replicates exclusively in an acidified, lysosome-like vacuole. To define conditions that support C. burnetii growth, we systematically evaluated the organism's metabolic requirements using expression microarrays, genomic reconstruction, and metabolite typing. This led to development of a complex nutrient medium that supported substantial growth (approximately 3 log(10)) of C. burnetii in a 2.5% oxygen environment. Importantly, axenically grown C. burnetii were highly infectious for Vero cells and exhibited developmental forms characteristic of in vivo grown organisms. Axenic cultivation of C. burnetii will facilitate studies of the organism's pathogenesis and genetics and aid development of Q fever preventatives such as an effective subunit vaccine. Furthermore, the systematic approach used here may be broadly applicable to development of axenic media that support growth of other medically important obligate intracellular pathogens. C1 [Omsland, Anders; Cockrell, Diane C.; Howe, Dale; Heinzen, Robert A.] NIAID, NIH, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Hamilton, MT 59840 USA. [Fischer, Elizabeth R.] NIAID, NIH, Electron Microscopy Unit, Hamilton, MT 59840 USA. [Virtaneva, Kimmo; Sturdevant, Daniel E.; Porcella, Stephen F.] NIAID, NIH, Genom Unit, Res Technol Sect,Res Technol Branch,Rocky Mt Labs, Hamilton, MT 59840 USA. RP Heinzen, RA (reprint author), NIAID, NIH, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, Hamilton, MT 59840 USA. EM rheinzen@niaid.nih.gov FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX We thank Ted Hackstadt, Harlan Caldwell, Shelly Robertson, and Frank Gherardini for critical review of this manuscript; Gary Hettrick for graphic illustrations; and Kent Barbian for initial help with the OmniLog detection system. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 37 TC 156 Z9 161 U1 0 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 17 PY 2009 VL 106 IS 11 BP 4430 EP 4434 DI 10.1073/pnas.0812074106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 420HD UT WOS:000264278800068 PM 19246385 ER PT J AU Liao, SY Lerman, MI Stanbridge, EJ AF Liao, Shu-Yuan Lerman, Michael I. Stanbridge, Eric J. TI Expression of transmembrane carbonic anhydrases, CAIX and CAXII, in human development SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article ID DIAGNOSTIC BIOMARKER; CELL CARCINOMA; STEM-CELLS; HUMAN GUT; MN/CA IX; HYPOXIA; IDENTIFICATION; PROTEIN; MARKER; XII AB Background: Transmembrane CAIX and CAXII are members of the alpha carbonic anhydrase (CA) family. They play a crucial role in differentiation, proliferation, and pH regulation. Expression of CAIX and CAXII proteins in tumor tissues is primarily induced by hypoxia and this is particularly true for CAIX, which is regulated by the transcription factor, hypoxia inducible factor-1 (HIF-1). Their distributions in normal adult human tissues are restricted to highly specialized cells that are not always hypoxic. The human fetus exists in a relatively hypoxic environment. We examined expression of CAIX, CAXII and HIF-1 alpha in the developing human fetus and postnatal tissues to determine whether expression of CAIX and CAXII is exclusively regulated by HIF-1. Results: The co-localization of CAIX and HIF-1 alpha was limited to certain cell types in embryonic and early fetal tissues. Those cells comprised the primitive mesenchyma or involved chondrogenesis and skin development. Transient CAIX expression was limited to immature tissues of mesodermal origin and the skin and ependymal cells. The only tissues that persistently expressed CAIX protein were coelomic epithelium (mesothelium) and its remnants, the epithelium of the stomach and biliary tree, glands and crypt cells of duodenum and small intestine, and the cells located at those sites previously identified as harboring adult stem cells in, for example, the skin and large intestine. In many instances co-localization of CAIX and HIF-1 alpha was not evident. CAXII expression is restricted to cells involved in secretion and water absorption such as parietal cells of the stomach, acinar cells of the salivary glands and pancreas, epithelium of the large intestine, and renal tubules. Co-localization of CAXII with CAIX or HIF-1 alpha was not observed. Conclusion: The study has showed that: 1) HIF-1 alpha and CAIX expression co-localized in many, but not all, of the embryonic and early fetal tissues; 2) There is no evidence of co-localization of CAIX and CAXII; 3) CAIX and CAXII expression is closely related to cell origin and secretory activity involving proton transport, respectively. The intriguing finding of rare CAIX-expressing cells in those sites corresponding to stem cell niches requires further investigation. C1 [Liao, Shu-Yuan] St Joseph Hosp, Dept Pathol, Orange, CA USA. [Liao, Shu-Yuan] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 94697 USA. [Lerman, Michael I.] NCI, Ctr Canc Res, Frederick, MD 21702 USA. [Stanbridge, Eric J.] Univ Calif Irvine, Sch Med, Dept Microbiol & Mol Genet, Irvine, CA 94697 USA. RP Liao, SY (reprint author), St Joseph Hosp, Dept Pathol, Orange, CA USA. EM syliao@uci.edu; lermanmi@gmail.com; ejstanbr@uci.edu FU Institutional Funds (EJS); NIH [NO1-CO-56000] FX This research was supported by Institutional Funds (EJS) and by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research and by Contract No. NO1-CO-56000 to Basic Research Program, SAIC-Frederick, Inc (MIL). The content of the publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 38 TC 27 Z9 28 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD MAR 16 PY 2009 VL 9 AR 22 DI 10.1186/1471-213X-9-22 PG 16 WC Developmental Biology SC Developmental Biology GA 440JC UT WOS:000265695600002 PM 19291313 ER PT J AU Linterman, MA Rigby, RJ Wong, RK Yu, D Brink, R Cannons, JL Schwartzberg, PL Cook, MC Walters, GD Vinuesa, CG AF Linterman, Michelle A. Rigby, Robert J. Wong, Raphael. K. Yu, Di Brink, Robert Cannons, Jennifer L. Schwartzberg, Pamela L. Cook, Matthew C. Walters, Giles D. Vinuesa, Carola G. TI Follicular helper T cells are required for systemic autoimmunity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID GERMINAL-CENTER FORMATION; AUTOREACTIVE B-CELLS; LUPUS-ERYTHEMATOSUS; HUMORAL IMMUNITY; ANTIBODY-RESPONSES; SOMATIC MUTATION; DISEASE; MICE; EXPRESSION; CENTERS AB Production of high-affinity pathogenic autoantibodies appears to be central to the pathogenesis of lupus. Because normal high-affinity antibodies arise from germinal centers (GCs), aberrant selection of GC B cells, caused by either failure of negative selection or enhanced positive selection by follicular helper T (T(FH)) cells, is a plausible explanation for these autoantibodies. Mice homozygous for the san allele of Roquin, which encodes a RING-type ubiquitin ligase, develop GCs in the absence of foreign antigen, excessive T(FH) cell numbers, and features of lupus. We postulated a positive selection defect in GCs to account for autoantibodies. We first demonstrate that autoimmunity in Roquin(san/san) (sanroque) mice is GC dependent: deletion of one allele of Bcl6 specifically reduces the number of GC cells, ameliorating pathology. We show that Roquin(san) acts autonomously to cause accumulation of T(FH) cells. Introduction of a null allele of the signaling lymphocyte activation molecule family adaptor Sap into the sanroque background resulted in a substantial and selective reduction in sanroque T(FH) cells, and abrogated formation of GCs, autoantibody formation, and renal pathology. In contrast, adoptive transfer of sanroque T(FH) cells led to spontaneous GC formation. These findings identify T(FH) dysfunction within GCs and aberrant positive selection as a pathway to systemic autoimmunity. C1 [Linterman, Michelle A.; Rigby, Robert J.; Wong, Raphael. K.; Yu, Di; Vinuesa, Carola G.] Australian Natl Univ, John Curtin Sch Med Res, Div Immunol & Genet, Canberra, ACT 2601, Australia. [Brink, Robert] Garvan Inst Med Res, Sydney, NSW 2010, Australia. [Cannons, Jennifer L.; Schwartzberg, Pamela L.] NHGRI, NIH, Bethesda, MD 20892 USA. [Cook, Matthew C.] Canberra Hosp, Dept Immunol, Canberra, ACT 2605, Australia. [Walters, Giles D.] Canberra Hosp, Dept Renal Med, Canberra, ACT 2605, Australia. [Walters, Giles D.] Australian Natl Univ, Sch Med, Canberra, ACT 2605, Australia. RP Vinuesa, CG (reprint author), Australian Natl Univ, John Curtin Sch Med Res, Div Immunol & Genet, Canberra, ACT 2601, Australia. EM carola.vinuesa@anu.edu.au RI Yu, Di/C-2163-2009; Brink, Robert/B-7910-2010; Vinuesa, Carola/B-1108-2010; OI Yu, Di/0000-0003-1721-8922; Brink, Robert/0000-0002-9586-3655; Vinuesa, Carola/0000-0001-9799-0298; Rigby, Robert/0000-0003-3853-1707; Linterman, Michelle/0000-0001-6047-1996 FU Viertel Senior Medical Research Fellowship; National Health and Medical Research Council [316956, 427620] FX This work was funded by a Viertel Senior Medical Research Fellowship and National Health and Medical Research Council grants 316956 and 427620 to C. G. Vinuesa. NR 64 TC 288 Z9 307 U1 3 U2 22 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 MAR 16 PY 2009 VL 206 IS 3 BP 561 EP 576 DI 10.1084/jem.20081886 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 444VT UT WOS:000266009200008 PM 19221396 ER PT J AU Pechhold, K Koczwara, K Zhu, XL Harrison, VS Walker, G Lee, J Harlan, DM AF Pechhold, Klaus Koczwara, Kerstin Zhu, Xiaolong Harrison, Victor S. Walker, Greg Lee, Janet Harlan, David M. TI Blood Glucose Levels Regulate Pancreatic beta-Cell Proliferation during Experimentally-Induced and Spontaneous Autoimmune Diabetes in Mice SO PLOS ONE LA English DT Article AB Background: Type 1 diabetes mellitus is caused by immune-mediated destruction of pancreatic beta-cells leading to insulin deficiency, impaired intermediary metabolism, and elevated blood glucose concentrations. While at autoimmune diabetes onset a limited number of beta-cells persist, the cells' regenerative potential and its regulation have remained largely unexplored. Using two mouse autoimmune diabetes models, this study examined the proliferation of pancreatic islet beta-cells and other endocrine and non-endocrine subsets, and the factors regulating that proliferation. Methodology and Principal Findings: We adapted multi-parameter flow cytometry techniques (including DNA-content measurements and 5'-bromo-2'-deoxyuridine [BrdU] incorporation) to study pancreatic islet single cell suspensions. These studies demonstrate that beta-cell proliferation rapidly increases at diabetes onset, and that this proliferation is closely correlated with the diabetic animals' elevated blood glucose levels. For instance, we show that when normoglycemia is restored by exogenous insulin or islet transplantation, the beta-cell proliferation rate returns towards low levels found in control animals, yet surges when hyperglycemia recurs. In contrast, other-than-beta endocrine islet cells did not exhibit the same glucose-dependent proliferative responses. Rather, disease-associated alterations of BrdU-incorporation rates of delta-ells (minor decrease), and non-endocrine islet cells (slight increase) were not affected by blood glucose levels, or were inversely related to glycemia control after diabetes onset (alpha-cells). Conclusion: We conclude that murine beta-cells' ability to proliferate in response to metabolic need (i. e. rising blood glucose concentrations) is remarkably well preserved during severe, chronic beta-cell autoimmunity. These data suggest that timely control of the destructive immune response after disease manifestation could allow spontaneous regeneration of sufficient beta-cell mass to restore normal glucose homeostasis. C1 [Pechhold, Klaus; Koczwara, Kerstin; Zhu, Xiaolong; Harrison, Victor S.; Walker, Greg; Lee, Janet; Harlan, David M.] NIDDK, NIH, Diabetes Branch, Bethesda, MD USA. RP Pechhold, K (reprint author), NIDDK, NIH, Diabetes Branch, Bethesda, MD USA. EM KlausP@intra.NIDDK.NIH.gov FU Intramural Research Program of the NIH, NIDDK FX This research was supported by the Intramural Research Program of the NIH, NIDDK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 62 TC 23 Z9 23 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 16 PY 2009 VL 4 IS 3 AR e4827 DI 10.1371/journal.pone.0004827 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437OI UT WOS:000265496400003 PM 19287497 ER PT J AU Jacobs, ET Ahnen, DJ Ashbeck, EL Baron, JA Greenberg, ER Lance, P Lieberman, DA McKeown-Eyssen, G Schatzkin, A Thompson, PA Martinez, ME AF Jacobs, Elizabeth T. Ahnen, Dennis J. Ashbeck, Erin L. Baron, John A. Greenberg, E. Robert Lance, Peter Lieberman, David A. McKeown-Eyssen, Gail Schatzkin, Arthur Thompson, Patricia A. Martinez, Maria Elena TI Association Between Body Mass Index and Colorectal Neoplasia at Follow-Up Colonoscopy: A Pooling Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adenoma; body mass index; colorectal neoplasms; meta-analysis as topic; neoplasms; second primary; recurrence ID COLON-CANCER RISK; WOMEN UNITED-STATES; PHYSICAL-ACTIVITY; WAIST CIRCUMFERENCE; ADENOMA RECURRENCE; METABOLIC SYNDROME; RECTAL-CANCER; WEIGHT-GAIN; OBESITY; MEN AB A direct relation between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses by sex, family history, colorectal subsite, or features of metachronous lesions. Data from 8,213 participants in 7 prospective studies of metachronous colorectal adenomas were pooled to assess whether the association between BMI and metachronous neoplasia varied by these factors. A statistically significant direct association between BMI and the odds of nonadvanced adenomas (P(trend) < 0.001) was observed, while the relation for advanced adenomas was of marginal significance (P(trend) < 0.07). In sex-stratified analyses, obesity was statistically significantly associated with the odds of any metachronous lesion among men (odds ratio = 1.36, 95% confidence interval: 1.17, 1.58) but not among women (odds ratio = 1.10, 95% confidence interval: 0.89, 1.37). The associations with BMI appeared to be limited to proximal neoplasia, with statistically significant results for BMI and proximal (P(trend) < 0.001), but not distal (P(trend) < 0.85), neoplasia. Exploratory analyses indicated that BMI was significantly related to most histologic characteristics of metachronous adenomas among men but not among women. Our results provide further support for the association between BMI and metachronous colorectal adenomas, particularly among men, thereby indicating that body size may affect colorectal carcinogenesis at comparatively early stages. C1 [Jacobs, Elizabeth T.] Univ Arizona, Arizona Canc Ctr, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ 85724 USA. [Ahnen, Dennis J.] Denver VA Med Ctr, Denver, CO USA. [Ahnen, Dennis J.] Univ Colorado, Denver, CO 80202 USA. [Baron, John A.; Greenberg, E. Robert] Dartmouth Med Sch, Sect Biostat & Epidemiol, Lebanon, NH USA. [Greenberg, E. Robert] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Lance, Peter] Univ Arizona, Coll Med, Tucson, AZ 85724 USA. [Lieberman, David A.] Oregon Hlth & Sci Univ, Div Gastroenterol & Hepatol, Portland, OR 97201 USA. [Lieberman, David A.] Portland VA Med Ctr, Portland, OR USA. [McKeown-Eyssen, Gail] Univ Toronto, Dalla Lana Sch Publ Heath, Toronto, ON, Canada. [McKeown-Eyssen, Gail] Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada. [Schatzkin, Arthur] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Thompson, Patricia A.] Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. RP Jacobs, ET (reprint author), Univ Arizona, Arizona Canc Ctr, Mel & Enid Zuckerman Coll Publ Hlth, POB 245024, Tucson, AZ 85724 USA. EM jacobse@u.arizona.edu RI Lance, Peter/I-2196-2014 OI Lance, Peter/0000-0003-2944-1881 FU National Cancer Institute [CA-41108, CA-23074, CA95060, CA37287, CA23108, CA 59005, CA 26852]; K07 Career Development Award [CA106269]; Cooperative Studies Program; Department of Veterans Affairs FX This work was supported by the National Cancer Institute ( grants CA-41108, CA-23074, CA95060, CA37287, CA37287, CA23108, CA 59005, and CA 26852). Dr. Jacobs is supported by a K07 Career Development Award ( grant CA106269) from the National Cancer Institute. Funding for the Veterans Affairs Study was supported by the Cooperative Studies Program, Department of Veterans Affairs. Conflict of interest: none declared. NR 52 TC 40 Z9 42 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 15 PY 2009 VL 169 IS 6 BP 657 EP 666 DI 10.1093/aje/kwn401 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 413ZT UT WOS:000263834400002 PM 19147743 ER PT J AU O'Reilly, EJ Chen, HL Gardener, H Gao, X Schwarzschild, MA Ascherio, A AF O'Reilly, Eilis J. Chen, Honglei Gardener, Hannah Gao, Xiang Schwarzschild, Michael A. Ascherio, Alberto TI Smoking and Parkinson's Disease: Using Parental Smoking as a Proxy to Explore Causality SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE causality; Parkinson disease; smoking; tobacco smoke pollution ID CIGARETTE-SMOKING; TOBACCO USE; RISK; METAANALYSIS; CONSUMPTION; HEALTH; WOMEN; TWINS AB In epidemiologic studies and in studies of discordant twins, cigarette smoking has been consistently associated with a lower risk of Parkinson's disease, but whether this association is causal remains controversial. Alternatively, an infectious or toxic exposure in childhood or early adulthood could affect both the reward mechanisms that determine smoking behavior and the future risk of Parkinson's disease. If so, parental smoking, commonly established before the birth of the first child, would be unlikely to be related to Parkinson's disease risk. The authors assessed the association between Parkinson's disease and parental smoking during childhood in the Nurses' Health Study and the Health Professionals Follow-up Study conducted in the United States. During 26 years and 18 years of follow-up, respectively, 455 newly diagnosed Parkinson's disease cases were documented among those who provided information on parental smoking. The age-adjusted, pooled relative rate of Parkinson's disease was 0.73 (95% confidence interval: 0.53, 1.00; P-trend = 0.04) comparing participants who reported that both parents smoked with those who reported that neither did. Adjustment for caffeine and alcohol intake did not materially change the results. If the inverse association between smoking and Parkinson's disease were due to confounding by an environmental factor or were the result of reverse causation, it is unlikely that parental smoking would predict Parkinson's disease. C1 [O'Reilly, Eilis J.; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [O'Reilly, Eilis J.; Gao, Xiang; Ascherio, Alberto] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02215 USA. [Chen, Honglei] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Gardener, Hannah] Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. [Schwarzschild, Michael A.] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. [Ascherio, Alberto] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Ascherio, Alberto] Harvard Univ, Sch Med, Boston, MA USA. RP O'Reilly, EJ (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02215 USA. EM eoreilly@hsph.harvard.edu OI Chen, Honglei/0000-0003-3446-7779 FU National Institutes of Health/National Institute of Neurological Diseases and Stroke grant; National Institute of Environmental Health Sciences FX The study was supported by a National Institutes of Health/National Institute of Neurological Diseases and Stroke grant ( to A. A.) to study Parkinson's disease in the Health Professionals Follow-up Study and Nurses' Health Study cohorts and by the intramural program of the National Institutes of Health, the National Institute of Environmental Health Sciences ( to H. C.). NR 18 TC 22 Z9 24 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 MAR 15 PY 2009 VL 169 IS 6 BP 678 EP 682 DI 10.1093/aje/kwn388 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 413ZT UT WOS:000263834400004 PM 19131566 ER PT J AU Prentice, RL Chlebowski, RT Stefanick, ML Rossouw, JE Anderson, GL AF Prentice, Ross L. Chlebowski, Rowan T. Stefanick, Marcia L. Rossouw, Jacques E. Anderson, Garnet L. TI RE: "SHOULD META-ANALYSES OF INTEVENTIONS INCLUDE OBSERVATIONAL STUDIES IN ADDITION TO RANDOMIZED CONTROLLED TRIALS? A CRITICAL EXAMINATION OF UNDERLYING PRINCIPLES" REPLY SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID BREAST-CANCER C1 [Prentice, Ross L.; Anderson, Garnet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Chlebowski, Rowan T.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA. [Stefanick, Marcia L.] Stanford Univ, Sch Med, Stanford Prevent Res Ctr, Stanford, CA 94305 USA. [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20824 USA. RP Prentice, RL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. EM rprentic@fhcrc.org NR 3 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 15 PY 2009 VL 169 IS 6 BP 785 EP 786 DI 10.1093/aje/kwn423 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 413ZT UT WOS:000263834400019 ER PT J AU Aletaha, D Funovits, J Ward, MM Smolen, JS Kvien, TK AF Aletaha, D. Funovits, J. Ward, M. M. Smolen, J. S. Kvien, T. K. TI Perception of Improvement in Patients With Rheumatoid Arthritis Varies With Disease Activity Levels at Baseline SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID EULAR/ACR COLLABORATIVE RECOMMENDATIONS; ACUTE-PHASE REACTANTS; CLINICAL-TRIALS; OUTCOME MEASURES; ACTIVITY SCORE; SYMPTOM STATE; INDEXES; VALIDATION; VARIABLES; THERAPY AB Objective. To analyze the minimum clinically important improvement (MCII) of disease activity measures in rheumatoid arthritis (RA) using patient-derived anchors, and to assess whether criteria for improvement differ with baseline disease activity. Methods. We used data from a Norwegian observational database comprising 1,050 patients (73% women, 65% rheumatoid factor-positive, mean duration of RA 7.7 years). At 3 months after initiation of therapy, patients indicated whether their condition had improved, had considerably improved, was unchanged, had worsened, or had considerably worsened. We used receiver operating characteristic curve analysis to determine the MCII for the Disease Activity Score based on the assessment of 28 joints (DAS28), the Simplified Disease Activity Index (SDAI), and the Clinical Disease Activity Index (CDAI), and analyzed the effects of different levels of baseline disease activity on the MCII. Results. On average, patients started with high disease activity and improved significantly during treatment (American College of Rheumatology 20%, 50%, and 70% improvement criteria responses were 37%, 17%, and 5%, respectively). The overall mean (95% confidence interval [95% CI]) thresholds for MCII after 3 months for the DAS28, SDAI, and CDAI were 1.20 (95% CI 1.18-1.22), 10.95 (95% CI 10.69-11.20), and 10.76 (95% CI 10.49-11.04), respectively, and the mean (95% CI) thresholds for major responses were 1.82 (95% Cl 1.80-1.83), 15.82 (95% Cl 15.65-16.00), and 15.00 (95% CI 14.82-15.18), respectively. With increasing disease activity, much higher changes in disease activity were needed to achieve MCII according to patient judgment. Conclusion. The perception of improvement of disease activity of patients with RA is considerably different depending on the disease activity level at which they start. C1 [Aletaha, D.] Med Univ Vienna, Dept Internal Med 3, Vienna, Austria. [Ward, M. M.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Smolen, J. S.] Hietzing Hosp, Vienna, Austria. [Kvien, T. K.] Diakonhiemet Hosp, Oslo, Norway. RP Aletaha, D (reprint author), Med Univ Vienna, Dept Internal Med 3, Vienna, Austria. EM daniel.aletaha@meduniwien.ac.at FU Intramural NIH HHS [ZIA AR041153-05] NR 29 TC 26 Z9 27 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD MAR 15 PY 2009 VL 61 IS 3 BP 313 EP 320 DI 10.1002/art.24282 PG 8 WC Rheumatology SC Rheumatology GA 419JH UT WOS:000264215100005 PM 19248136 ER PT J AU Newman, D Cragg, G AF Newman, David Cragg, Gordon TI Natural Products in Medicinal Chemistry Preface SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Editorial Material C1 [Newman, David; Cragg, Gordon] NCI, Nat Prod Branch, Bethesda, MD 20892 USA. RP Newman, D (reprint author), NCI, Nat Prod Branch, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CA999999] NR 0 TC 2 Z9 3 U1 1 U2 9 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 MAR 15 PY 2009 VL 17 IS 6 BP 2120 EP 2120 DI 10.1016/j.bmc.2009.03.010 PG 1 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 419RJ UT WOS:000264236700001 PM 19298944 ER PT J AU Jeffery, DD Tzeng, JP Keefe, FJ Porter, LS Hahn, EA Flynn, KE Reeve, BB Weinfurt, KP AF Jeffery, Diana D. Tzeng, Janice P. Keefe, Francis J. Porter, Laura S. Hahn, Elizabeth A. Flynn, Kathryn E. Reeve, Bryce B. Weinfurt, Kevin P. TI Initial Report of the Cancer Patient-Reported Outcomes Measurement Information System (PROMIS) Sexual Function Committee Review of Sexual Function Measures and Domains Used in Oncology SO CANCER LA English DT Review DE neoplasms; psychometrics; quality of life; sexual function ID QUALITY-OF-LIFE; LOCALIZED PROSTATE-CANCER; VULVAR INTRAEPITHELIAL NEOPLASIA; EXTERNAL-BEAM RADIOTHERAPY; ERECTILE FUNCTION IIEF; BREAST-CANCER; PSYCHOSOCIAL ADJUSTMENT; INTERNATIONAL INDEX; RADICAL PROSTATECTOMY; RECTAL-CANCER AB For this report, the authors described the initial activities of the Cancer Patient-Reported Outcomes Measurement Information System (PROMIS)-Sexual Function domain group, which is part of the National Institutes of Health Roadmap Initiative to develop brief questionnaires or individually tailored assessments of quality-of-life domains. Presented are a literature review of sexual function measures used in cancer populations and descriptions of the domains found in those measures. By using a consensus-driven approach, an electronic bibliographic search was conducted for articles that were published from 1991 to 2007, and 486 articles were identified for in-depth review. In total, 257 articles reported the administration of a psychometrically evaluated sexual function measure to individuals who were diagnosed with cancer. Apart from the University of California-Los Angeles Prostate Cancer Index, the International Index of Erectile Function, and the Female Sexual Function Index, the 31 identified measures have not been tested widely in cancer populations. Most measures were multidimensional and included domains related to the sexual response cycle and to general sexual satisfaction. The current review supports the need for a flexible, psychometrically robust measure of sexual function for use in oncology settings and strongly justifies the development of the PROMIS-Sexual Function instrument. When the PROMIS-Sexual Function instrument is available publicly, cancer clinicians and researchers will have another measure with which to assess patient-reported sexual function outcomes in addition to the few legacy measures that were identified through this review. Cancer 2009;115:1142-53. (C) 2009 American Cancer Society. C1 [Jeffery, Diana D.] NCI, Div Canc Control & Populat Sci, Off Canc Survivorship, Bethesda, MD 20892 USA. [Tzeng, Janice P.; Flynn, Kathryn E.; Weinfurt, Kevin P.] Duke Univ, Duke Clin Res Inst, Ctr Clin & Genet Econ, Durham, NC USA. [Keefe, Francis J.; Porter, Laura S.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. [Hahn, Elizabeth A.] NorthShore Univ HealthSyst, Res Inst, Evanston, IL USA. [Hahn, Elizabeth A.] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Reeve, Bryce B.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Outcomes Res Branch, Bethesda, MD 20892 USA. RP Jeffery, DD (reprint author), NCI, Div Canc Control & Populat Sci, Off Canc Survivorship, 6116 Execut Blvd,Suite 404, Bethesda, MD 20892 USA. EM jefferyd@mail.nih.gov RI Flynn, Kathryn/M-5346-2013 OI Flynn, Kathryn/0000-0002-4427-3583 FU National Institutes of Health [U-5-U01-AR052186] FX Supported by grant U-5-U01-AR052186 from the National Institutes of Health. NR 68 TC 28 Z9 28 U1 2 U2 13 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD MAR 15 PY 2009 VL 115 IS 6 BP 1142 EP 1153 DI 10.1002/cncr.24134 PG 12 WC Oncology SC Oncology GA 418KY UT WOS:000264148300005 PM 19195044 ER PT J AU Gillette, JM Nielsen-Preiss, SM AF Gillette, Jennifer M. Nielsen-Preiss, Sheila M. TI Cancer stem cells Seeds of growth in osteosarcoma SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE osteosarcoma; cancer stem cell; oct; nanog; sarcospheres; OS99-1; self-renewal ID SOLID TUMORS C1 [Nielsen-Preiss, Sheila M.] Montana State Univ, Dept Cell Biol & Neurosci, Bozeman, MT 59717 USA. [Gillette, Jennifer M.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Nielsen-Preiss, SM (reprint author), Montana State Univ, Dept Cell Biol & Neurosci, 413 Leon Johnson Hall,POB 173148, Bozeman, MT 59717 USA. EM sheila.nielsenpreiss@montana.edu NR 13 TC 4 Z9 4 U1 1 U2 2 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAR 15 PY 2009 VL 8 IS 6 BP 553 EP 554 DI 10.4161/cbt.8.6.8142 PG 2 WC Oncology SC Oncology GA 435WR UT WOS:000265374500012 PM 19411864 ER PT J AU Greenwald, P Dunn, BK AF Greenwald, Peter Dunn, Barbara K. TI Landmarks in the History of Cancer Epidemiology SO CANCER RESEARCH LA English DT Review ID GENOME-WIDE ASSOCIATION; POSTMENOPAUSAL HORMONE-THERAPY; COMMUNITY INTERVENTION TRIAL; RANDOMIZED CONTROLLED TRIAL; SMOKING CESSATION COMMIT; ESTROGEN PLUS PROGESTIN; EPSTEIN-BARR-VIRUS; BREAST-CANCER; LUNG-CANCER; PROSTATE-CANCER AB The application of epidemiology to cancer prevention is relatively new, although observations of the potential causes of cancer have been reported for more than 2,000 years. Cancer was generally considered incurable until the late 19th century. Only with a refined understanding of the nature of cancer and strategies for cancer treatment could a systematic approach to cancer prevention emerge. The 20th century saw the elucidation of clues to cancer causation from observed associations with population exposures to tobacco, diet, environmental chemicals, and other exogenous factors. With repeated confirmation of such associations, researchers entertained for the first time the possibility that cancer, like many of the infectious diseases of the time, might be prevented. By the mid-20th century, with antibiotics successfully addressing the majority of infectious diseases and high blood pressure treatment beginning to affect the prevalence of heart disease in a favorable direction, the focus of much of epidemiology shifted to cancer. The early emphasis was on exploring, in greater depth, the environmental, dietary, hormonal, and other exogenous exposures for their potential associations with increased cancer risk. The first major breakthrough in identifying a modifiable cancer risk factor was the documentation of an association between tobacco smoking and lung cancer. During the past four decades, epidemiologic studies have generated population data identifying risk factors for cancers at almost every body site, with many cancers having multiple risk factors. The development of technologies to identify biological molecules has facilitated the incorporation of these molecular manifestations of biological variation into epidemiologic studies, as markers of exposure as well as putative surrogate markers of cancer outcome. This technological trend has, during the past two decades, culminated in emphasis on the identification of genetic variants and their products as correlates of cancer risk, in turn, creating opportunities to incorporate the discipline of molecular/genetic epidemiology into the study of cancer prevention. Epidemiology will undoubtedly continue contributing to cancer prevention by using traditional epidemiologic study designs to address broad candidate areas of interest, with molecular/genetic epidemiology investigations honing in on promising areas to identify specific factors that can be modified with the goal of reducing risk. [Cancer Res 2009;69(6):2151-62] C1 [Greenwald, Peter; Dunn, Barbara K.] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. RP Greenwald, P (reprint author), NCI, Canc Prevent Div, NIH, 6130 Execut Blvd,Suite 2040, Bethesda, MD 20892 USA. EM greenwald@nih.gov NR 111 TC 18 Z9 19 U1 1 U2 11 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 MAR 15 PY 2009 VL 69 IS 6 BP 2151 EP 2162 DI 10.1158/0008-5472.CAN-09-0416 PG 12 WC Oncology SC Oncology GA 424BU UT WOS:000264541300001 PM 19276341 ER PT J AU Schildkraut, JM Goode, EL Clyde, MA Iversen, ES Moorman, PG Berchuck, A Marks, JR Lissowska, J Brinton, L Peplonska, B Cunningham, JM Vierkant, RA Rider, DN Chenevix-Trench, G Webb, PM Beesley, J Chen, XQ Phelan, C Sutphen, R Sellers, TA Pearce, L Wu, AH Van den Berg, D Conti, D Elund, CK Anderson, R Goodman, MT Lurie, G Carney, ME Thompson, PJ Gayther, SA Ramus, SJ Jacobs, I Kjaer, SK Hogdall, E Blaakaer, J Hogdall, C Easton, DF Song, HL Pharoah, PDP Whittemore, AS McGuire, V Quaye, L Anton-Culver, H Ziogas, A Terry, KL Cramer, DW Hankinson, SE Tworoger, SS Calingaert, B Chanock, S Sherman, M Garcia-Closas, M AF Schildkraut, Joellen M. Goode, Ellen L. Clyde, Merlise A. Iversen, Edwin S. Moorman, Patricia G. Berchuck, Andrew Marks, Jeffrey R. Lissowska, Jolanta Brinton, Louise Peplonska, Beata Cunningham, Julie M. Vierkant, Robert A. Rider, David N. Chenevix-Trench, Georgia Webb, Penelope M. Beesley, Jonathan Chen, Xiaoqing Phelan, Catherine Sutphen, Rebecca Sellers, Thomas A. Pearce, Leigh Wu, Anna H. Van den Berg, David Conti, David Elund, Christopher K. Anderson, Rebecca Goodman, Marc T. Lurie, Galina Carney, Michael E. Thompson, Pamela J. Gayther, Simon A. Ramus, Susan J. Jacobs, Ian Kjaer, Susanne Krueger Hogdall, Estrid Blaakaer, Jan Hogdall, Claus Easton, Douglas F. Song, Honglin Pharoah, Paul D. P. Whittemore, Alice S. McGuire, Valerie Quaye, Lydia Anton-Culver, Hoda Ziogas, Argyrios Terry, Kathryn L. Cramer, Daniel W. Hankinson, Susan E. Tworoger, Shelley S. Calingaert, Brian Chanock, Stephen Sherman, Mark Garcia-Closas, Montserrat CA Australian Canc Study Australian Ovarian Canc Study Grp TI Single Nucleotide Polymorphisms in the TP53 Region and Susceptibility to Invasive Epithelial Ovarian Cancer SO CANCER RESEARCH LA English DT Article ID P53 CODON-72 POLYMORPHISM; BREAST-CANCER; PROGNOSTIC-SIGNIFICANCE; DANISH MALOVA; RISK; MUTATIONS; VARIANTS; TUMORS; GENE; OVEREXPRESSION AB The p53 protein is critical for multiple cellular functions including cell growth and DNA repair. We assessed whether polymorphisms in the region encoding TP53 were associated with risk of invasive ovarian cancer. The study population includes a total of 5,206 invasive ovarian cancer cases (2,829 of which were serous) and 8,790 controls from 13 case-control or nested case-control studies participating in the Ovarian Cancer Association Consortium (OCAC). Three of the studies performed independent discovery investigations involving genotyping of up to 23 single nucleotide polymorphisms (SNP) in the TP53 region. Significant findings from this discovery phase were followed up for replication in the other OCAC studies. Mixed effects logistic regression was used to generate posterior median per allele odds ratios (OR), 95% probability intervals (PI), and Bayes factors (1313) for genotype associations. Five SNPs showed significant associations with risk in one or more of the discovery investigations and were followed up by OCAC. Mixed effects analysis confirmed associations with serous invasive cancers for two correlated (r(2) = 0.62) SNPs: rs2287498 (median per allele OR, 1.30; 95% PI, 1.07-1.57) and rs12951053 (median per allele OR, 1.19; 95% PI, 1.01-1.38). Analyses of other histologic subtypes suggested similar associations with endometrioid but not with mucinous or clear cell cancers. This large study provides statistical evidence for a small increase in risk of ovarian cancer associated with common variants in the TP53 region. [Cancer Res 2009;69(6):2349-57] C1 [Schildkraut, Joellen M.; Iversen, Edwin S.; Moorman, Patricia G.; Berchuck, Andrew; Marks, Jeffrey R.; Calingaert, Brian] Duke Univ, Ctr Comprehens Canc, Med Ctr, Durham, NC 27706 USA. [Schildkraut, Joellen M.; Moorman, Patricia G.] Duke Univ, Dept Community & Family Med, Med Ctr, Durham, NC 27706 USA. [Berchuck, Andrew] Duke Univ, Dept Obstet & Gynecol, Med Ctr, Durham, NC 27706 USA. [Marks, Jeffrey R.] Duke Univ, Dept Surg, Med Ctr, Durham, NC 27706 USA. [Clyde, Merlise A.; Iversen, Edwin S.] Duke Univ, Dept Stat Sci, Durham, NC USA. [Goode, Ellen L.; Cunningham, Julie M.; Vierkant, Robert A.; Rider, David N.] Mayo Clin, Coll Med, Rochester, MN USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Chanock, Stephen] NCI, Core Genotyping Fac, Div Canc Epidemiol & Genet, Rockville, MD USA. [Peplonska, Beata] Nofer Inst Occupat Med, Dept Occupat & Environm Epidemiol, Lodz, Poland. [Chenevix-Trench, Georgia; Webb, Penelope M.; Beesley, Jonathan; Chen, Xiaoqing; Australian Canc Study] Royal Brisbane Hosp, Queensland Inst Med Res, Post Off, Australia Australian Canc Studv, Brisbane, Qld, Australia. [Australian Ovarian Canc Study Grp] Peter MacCallum Ctr, Melbourne, Vic, Australia. [Phelan, Catherine; Sutphen, Rebecca; Sellers, Thomas A.] H Lee Moffift Canc Ctr, Tampa, FL USA. [Pearce, Leigh; Wu, Anna H.; Conti, David] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Rider, David N.] Univ So Calif, Dept Urol, Norris Comprehens Canc Ctr, Los Angeles, CA 90089 USA. [Goodman, Marc T.; Lurie, Galina; Thompson, Pamela J.] Univ Hawaii, Program Epidemiol, Canc Res Ctr Hawaii, Honolulu, HI 96822 USA. [Gayther, Simon A.; Ramus, Susan J.; Jacobs, Ian; Quaye, Lydia] UCL, Gynaecolg Canc Res Ctr, EGA, Inst Women Hlth, London, England. [Kjaer, Susanne Krueger; Hogdall, Estrid] Danish Canc Soc, Dept Virus Hormones & Canc, Copenhagen, Denmark. [Hogdall, Claus] Univ Copenhagen, Gynaecol Clin, Juliane Marie Ctr, Copenhagen, Denmark. [Blaakaer, Jan; Easton, Douglas F.] Aarhus Univ Hosp, Dept Gynecol & Obstet, DK-8000 Aarhus, Denmark. [Song, Honglin; Pharoah, Paul D. P.] Univ Cambridge, Canc Res UK Dept Oncol, Strangeways Res Lab, Cambridge, England. [Whittemore, Alice S.; McGuire, Valerie; Anton-Culver, Hoda; Ziogas, Argyrios] Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. [Terry, Kathryn L.] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Ramus, Susan J.; Tworoger, Shelley S.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Schildkraut, Joellen M.; Goode, Ellen L.; Iversen, Edwin S.; Moorman, Patricia G.; Berchuck, Andrew; Cunningham, Julie M.; Chenevix-Trench, Georgia; Webb, Penelope M.; Phelan, Catherine; Sutphen, Rebecca; Sellers, Thomas A.; Pearce, Leigh; Wu, Anna H.; Goodman, Marc T.; Lurie, Galina; Carney, Michael E.; Gayther, Simon A.; Ramus, Susan J.; Kjaer, Susanne Krueger] Ovarian Canc Assoc Consortium, Durham, NC USA. RP Schildkraut, JM (reprint author), 2424 Erwin Rd,Ste 602,DUMC 2949, Durham, NC 27710 USA. EM schil001@me.duke.edu RI Susan, Ramus/C-1607-2008; Peplonska, Beata/F-6004-2010; Webb, Penelope/D-5736-2013; Jacobs, Ian/F-1743-2013; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Bowtell, David/H-1007-2016; OI Tworoger, Shelley/0000-0002-6986-7046; Webb, Penelope/0000-0003-0733-5930; Jacobs, Ian/0000-0002-8112-4624; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Bowtell, David/0000-0001-9089-7525; Vierkant, Robert/0000-0001-6242-5221; Kjaer, Susanne/0000-0002-8347-1398; Ramus, Susan/0000-0003-0005-7798; Lissowska, Jolanta/0000-0003-2695-5799 FU Ovarian Cancer Research Fund; USPHS [CA58598, CA122443, CA76016, NCA76016, CA14089, CA17054, CA61132, CA63464, N01-PC-67010, HL090559, R03-CA113148]; National Cancer Institute, NIH; Department of Health and Human Services (Hawaii) [N01-CN-55424, N01-67001]; NIH; Department of Health and Human Services (Hawaii); Roswell Park Alliance; National Cancer Institute [CA71966]; Family Registry for Ovarian Cancer [CA16056]; National Cancer Institute, NIH, Bethesda, MD (POCS); California Cancer Research Program [00-01389V-20170, 2110200]; Department of Defense [DAMD17-02-1-0666]; California Department of Health Services [050-E8709, R01 CA 58598, N01 PC 35137, CA54419, CA105009, CA49449, CA087969]; U.S. Army Medical Research and Materiel Command [DAMD17-01-1-0729]; Cancer Council Tasmania and Cancer Foundation of Western Australia (Australian Ovarian Cancer Study); National Health and Medical Research Council of Australia [199600]; National Health and Medical Research Council; Cancer Research UK; CRUK Senior Clinical Research Fellow FX Grant support: Genotyping for the replication of findings was supported by a grant from the Ovarian Cancer Research Fund provided by the family and friends of Kathryn Sladek Smith. Additional support was provided by USPHS grant CA58598 and contracts N01-CN-55424 and N01-67001 from the National Cancer Institute, NIH; Department of Health and Human Services (Hawaii); the Roswell Park Alliance and the National Cancer Institute CA71966 and Core Grant CA16056 (Family Registry for Ovarian Cancer), Intramural Funds from the National Cancer Institute, NIH, Bethesda, MD (POCS); the California Cancer Research Program grants 00-01389V-20170 and 2110200; USPHS grants CA122443 (MAYO), CA76016 (NCOCS), NCA76016, CA14089, CA17054, CA61132, CA63464, N01-PC-67010, HL090559 and R03-CA113148; Department of Defense grant DAMD17-02-1-0666, and California Department of Health Services subcontract 050-E8709 as part of its statewide cancer reporting program (USC), R01 CA 58598 and N01 PC 35137 (Hawaii), CA54419, CA105009(-NECC,) CA49449, and CA087969(NHS). H. Song was funded by a grant from WellBeing. The Australian Ovarian Cancer Study Management Group (D. Bowtell, G. Chenevix-Trench. A. deFazio, D. Gertig, A. Green, P. Webb) thanks the contribution of all the clinical and scientific collaborators. Australian Ovarian Cancer Study and the Australian Cancer Study Management Group (A. Green, P. Parsons, N. Hayward, P. Webb, D. Whiteman) also thank all of the project staff, collaborating institutions, and study participants. Financial support was provided by U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, the Cancer Council Tasmania and Cancer Foundation of Western Australia (Australian Ovarian Cancer Study); The National Health and Medical Research Council of Australia (199600; Australian Cancer Study); G. Chenevix-Trench and P. Webb are supported by the National Health and Medical Research Council. SEARCH is funded through a program grant from Cancer Research UK. Dr. Paul Pharoah is a CRUK Senior Clinical Research Fellow. NR 41 TC 44 Z9 45 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2009 VL 69 IS 6 BP 2349 EP 2357 DI 10.1158/0008-5472.CAN-08-2902 PG 9 WC Oncology SC Oncology GA 424BU UT WOS:000264541300027 PM 19276375 ER PT J AU Kortylewski, M Kujawski, M Herrmann, A Yang, CM Wang, L Liu, Y Salcedo, R Yu, H AF Kortylewski, Marcin Kujawski, Maciej Herrmann, Andreas Yang, Chunmei Wang, Lin Liu, Yong Salcedo, Rosalba Yu, Hua TI Toll-like Receptor 9 Activation of Signal Transducer and Activator of Transcription 3 Constrains Its Agonist-Based Immunotherapy SO CANCER RESEARCH LA English DT Article ID HYPER-IGE SYNDROME; DENDRITIC CELLS; ANTITUMOR IMMUNITY; STAT3; CANCER; GENERATION; MICE; DIFFERENTIATION; SUPPRESSION; CROSSTALK AB Although toll-like receptor (TLR) agonists, such as CpG, are used as immunotherapeutic agents in clinical trials for cancer and infectious diseases, their effects are limited and the underlying mechanism(s) that restrains CpG efficacy remains obscure. Here, we show that signal transducer and activator of transcription 3 (Stat3) plays a key role in down-modulating immunostimulatory effects of CpG. In the absence of interleukin-6 (IL-6) and IL-10 induction, CpG directly activates Stat3 within minutes through TLR9. Ablating Stat3 in hematopoietic cells results in rapid activation of innate immunity by CpG, with enhanced production of IFN-gamma, tumor necrosis factor-alpha, IL-12, and activation of macrophages, neutrophils, and natural killer cells marked with Stat1 activation. Innate immune responses induced by CpG in mice with a Stat3-ablated hematopoietic system cause potent antitumor effects, leading to eradication of large (>1 cm) B16 melanoma tumors within 72 It. Moreover, ablating Stat3 in myeloid cells increases CpG-induced dendritic cell maturation, T-cell activation, generation of tumor antigen-specific T cells, and long-lasting antitumor immunity. A critical role of Stat3 in mediating immunosuppression by certain cytokines and growth factors in the tumor microenvironment has been recently documented. By demonstrating direct and rapid activation of Stat3 by TLR agonists, we identify a second level of Stat3-mediated immunosuppression. Our results further suggest that targeting Stat3 can drastically improve CpG-based immunotherapeutic approaches. [Cancer Res 2009;69(6):2497-505] C1 [Kortylewski, Marcin; Kujawski, Maciej; Herrmann, Andreas; Yang, Chunmei; Wang, Lin; Liu, Yong; Yu, Hua] Beckman Res Inst City Hope, Div Canc Immunotherapeut & Tumor Immunol, Duarte, CA USA. [Salcedo, Rosalba] Sci Applicat Int Corp, Canc Inflammat Program, Natl Canc Inst, Frederick, MD USA. RP Yu, H (reprint author), 1500 E Duarte Rd, Duarte, CA 91010 USA. EM mkortylewski@coh.org; hyu@coh.org RI Liu, Yong/A-2031-2013 FU Harry Lloyd Charitable Trust; Keck Foundation; NIH [R01CA122976]; Board of Governors at City of Hope FX Grant support: This work is funded by grants from Harry Lloyd Charitable Trust, Keck Foundation, NIH R01CA122976, and by the Board of Governors at City of Hope. NR 33 TC 53 Z9 56 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2009 VL 69 IS 6 BP 2497 EP 2505 DI 10.1158/0008-5472.CAN-08-3031 PG 9 WC Oncology SC Oncology GA 424BU UT WOS:000264541300044 PM 19258507 ER PT J AU Sebastian, T Johnson, PF AF Sebastian, Thomas Johnson, Peter F. TI Ras(V12)-Mediated Down-regulation of CCAAT/Enhancer Binding Protein beta in Immortalized Fibroblasts Requires Loss of p19(Arf) and Facilitates Bypass of Oncogene-Induced Senescence SO CANCER RESEARCH LA English DT Article ID CELL-CYCLE ARREST; C/EBP-BETA; TRANSCRIPTION FACTORS; MEDIATED APOPTOSIS; TUMOR SUPPRESSION; EPITHELIAL-CELLS; RAS; EXPRESSION; TRANSFORMATION; GENE AB The transcription factor CCAAT/enhancer binding protein beta (C/EBP beta) is involved in cellular responses to oncogenic and physiologic Ras signals. C/EBP beta is required for premature senescence of primary mouse fibroblasts induced by expression of H-Ras(V12), demonstrating its role in oncogene-induced senescence. Here, we have investigated the mechanisms by which Ras inhibits proliferation of normal cells but transforms immortalized cells. We show that oncogenic Ras down-regulates C/EBP beta expression in NIH 3T3 cells, which are immortalized by a deletion of the CDKN2A locus and, therefore, lack the p16(Ink4a) and p19(Arf) tumor suppressors. Ras(V12)-induced silencing of C/EBP beta occurred at the mRNA level and involved both the Raf-mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase-ERK and phosphatidylinositol 3-kinase signaling pathways. Oncogenic Ras decreased C/EBP beta expression in Ink4a/Arf(-/-) mouse embryo fibroblasts (MEF) but increased C/EBP beta levels in wild-type MEFs. C/EBP beta down-regulation in NIH 3T3 cells was reversed by expression of p19(Arf), but not of p53 or p16(Ink4a), highlighting a critical role for p19(Arf) in sustaining C/EBP 3 levels. Ectopic expression of p34 C/EBP beta (LAP) inhibited Ras(V12)-mediated transformation of NIH 3T3 cells, suppressed their tumorigenicity in nude mice, and reactivated expression of the proapoptotic Fas receptor, which is also down-regulated by Ras. Our findings indicate that Cebpb gene silencing eliminates a growth inhibitory transcription factor that would otherwise restrain oncogenesis. We propose that C/EBP beta is part of a p53-independent, p19(Arf)-mediated network that enforces Ras-induced cell cycle arrest and tumor suppression in primary fibroblasts. [Cancer lies 2009;69(6):2588-98] C1 [Sebastian, Thomas; Johnson, Peter F.] NCI Frederick, Basic Res Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Johnson, PF (reprint author), NCI Frederick, Basic Res Lab, Ctr Canc Res, Bldg 539,Room 122, Frederick, MD 21702 USA. EM johnsopf@ncifcrf.gov RI Johnson, Peter/A-1940-2012 OI Johnson, Peter/0000-0002-4145-4725 FU NIH; National Cancer Institute; Center for Cancer Research FX Grant support: Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. NR 50 TC 23 Z9 23 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2009 VL 69 IS 6 BP 2588 EP 2598 DI 10.1158/0008-5472.CAN-08-2312 PG 11 WC Oncology SC Oncology GA 424BU UT WOS:000264541300054 PM 19276382 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI Towards a postmodern synthesis of evolutionary biology SO CELL CYCLE LA English DT Editorial Material DE Darwin's anniversary; Darwinism; modern synthesis; genome evolution; systems biology; horizontal gene transfer; Tree of Life ID SEQUENCE EVOLUTION; COMPLEXITY; ORIGINS 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.nlm.nih.gov FU Intramural NIH HHS [Z01 LM000073-12] NR 23 TC 8 Z9 9 U1 1 U2 10 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 15 PY 2009 VL 8 IS 6 BP 799 EP 800 DI 10.4161/cc.8.6.8187 PG 2 WC Cell Biology SC Cell Biology GA 426KG UT WOS:000264706600004 PM 19242109 ER PT J AU Adjei, AA Christian, M Ivy, P AF Adjei, Alex A. Christian, Michaele Ivy, Percy TI Novel Designs and End Points for Phase II Clinical Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; COLORECTAL-CANCER; SOLID TUMORS; SORAFENIB; KINASE; AGENTS AB The large number of negative phase III trials in oncology over the last several years has renewed interest in refining phase II oncology clinical trials to maximize the chances of success in phase III testing. More efficient phase II study designs will improve our ability to identify promising agents for testing while accurately identifying nonefficacious agents. Recognizing that new paradigms of phase II trial designs need to be developed, the Clinical Trial Design Task Force of the National Cancer Institute (NCI) Investigational Drug Steering Committee has tackled the question of improving efficiency of phase II clinical trials. In this issue of CCR Focus, four of the major topics discussed are presented. First, the task force recommended that alternate phase II end points should be studied. Second, depending on the characteristics of the specific trial and study population, historical controls or a randomized design may be more appropriate. Third, rational incorporation of biomarkers into phase II trials should be encouraged. Last, novel imaging modalities will be critical in evaluating the clinical benefit of new cytostatic agents. C1 [Adjei, Alex A.] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Christian, Michaele; Ivy, Percy] NCI, Bethesda, MD 20892 USA. RP Adjei, AA (reprint author), Roswell Pk Canc Inst, Dept Med, Elm & Carlton St, Buffalo, NY 14263 USA. EM Alex.Adjei@RoswellPark.org NR 36 TC 36 Z9 37 U1 1 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 MAR 15 PY 2009 VL 15 IS 6 BP 1866 EP 1872 DI 10.1158/1078-0432.CCR-08-2035 PG 7 WC Oncology SC Oncology GA 423QO UT WOS:000264511000006 PM 19276272 ER PT J AU Dhani, N Tu, DS Sargent, DJ Seymour, L Moore, MJ AF Dhani, Neesha Tu, Dongsheng Sargent, Daniel J. Seymour, Lesley Moore, Malcolm J. TI Alternate Endpoints for Screening Phase II Studies SO CLINICAL CANCER RESEARCH LA English DT Article ID CELL LUNG-CANCER; METASTATIC COLORECTAL-CANCER; CLINICAL-TRIALS GROUP; ADVANCED HEPATOCELLULAR-CARCINOMA; PROGRESSION-FREE SURVIVAL; ADVANCED OVARIAN-CANCER; TARGETED AGENTS; TUMOR RESPONSE; 1ST-LINE CHEMOTHERAPY; ANTICANCER AGENTS AB Phase II trials are screening trials that seek to identify agents with sufficient activity to continue development and those for which further evaluation should be halted. Although definitive phase III trials use progression-free or overall survival to confirm clinical benefit, earlier endpoints are preferable for phase II trials. Traditionally, tumor shrinkage of a predetermined degree (response) has been used as a surrogate of eventual survival benefit based on the observation that high response rates (RR), and particularly complete responses, in the phase II setting resulted in survival benefit in subsequent phase III trials. Recently, some molecularly targeted agents have shown survival and clinical benefit despite very modest RRs in early clinical trials. These observations provide a major conundrum, with concerns of inappropriate termination of development for active agents with low RRs being balanced by concerns of inactive agents being taken to late-phase development with resultant increases in the failure rate of phase III trials. Numerous alternate or complementary endpoints have been explored, incorporating multinomial endpoints (including progression and response), progression-free survival, biomarkers, and, more recently, evaluation of tumor size as a continuous variable. In this review, we discuss the current status of phase II endpoints and present retrospective analyses of two international gastrointestinal cancer studies showing the potential utility of one novel approach. Alternate endpoints, although promising, require additional evaluation and prospective validation before their use as a primary endpoint for phase II trials. C1 [Tu, Dongsheng; Seymour, Lesley] Queens Univ, NCI, Canada Clin Trials Grp, Kingston, ON, Canada. [Dhani, Neesha; Moore, Malcolm J.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Sargent, Daniel J.] Mayo Clin, Rochester, MN USA. RP Seymour, L (reprint author), Queens Univ, NCI, Canada Clin Trials Grp, 10 Stuart St, Kingston, ON, Canada. EM Lseymour@ctg.queensu.ca OI Sargent, Daniel/0000-0002-2684-4741 FU Canadian Cancer Society FX Canadian Cancer Society. NR 56 TC 55 Z9 57 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 MAR 15 PY 2009 VL 15 IS 6 BP 1873 EP 1882 DI 10.1158/1078-0432.CCR-08-2034 PG 10 WC Oncology SC Oncology GA 423QO UT WOS:000264511000007 PM 19276273 ER PT J AU Rubinstein, L Crowley, J Ivy, P Leblanc, M Sargent, D AF Rubinstein, Larry Crowley, John Ivy, Percy Leblanc, Michael Sargent, Dan TI Randomized Phase II Designs SO CLINICAL CANCER RESEARCH LA English DT Article ID PROGRESSION-FREE SURVIVAL; CLINICAL-TRIAL DESIGNS; END-POINTS; DISCONTINUATION DESIGN; COLORECTAL-CANCER; TUMOR RESPONSE; AGENTS; METAANALYSIS; ONCOLOGY; MELANOMA AB As the use of molecularly targeted agents, which are anticipated to increase overall survival (OS)and progression-free survival (PFS) but not necessarily tumor response, has increased in oncology, there has been a corresponding increase in the recommendation and use of randomized phase II designs. Such designs reduce the potential for bias, existent in comparisons with historical controls, but also substantially increase the sample size requirements. We review the principal statistical designs for historically controlled and randomized phase II trials, along with their advantages, disadvantages, and statistical design considerations. We review the arguments for and against the use of randomization in phase II studies, the situations in which the use of historical controls is preferred, and the situations in which the use of randomized designs is preferred. We review methods used to calculate predicted OS or PFS values from historical controls, adjusted so as to be appropriate for an experimental sample with particular prognostic characteristics. We show how adjustment of the type I and type II error bounds for randomized studies can facilitate the detection of appropriate target increases in median PFS or OS with sample sizes appropriate for phase II studies. Although there continue to be differences among investigators concerning the use of randomization versus historical controls in phase II trials, there is agreement that each approach will continue to be appropriate, and the optimal approach will depend upon the circumstances of the individual trial. C1 [Rubinstein, Larry] NCI, NIH, Biometr Res Branch, Bethesda, MD 20892 USA. [Crowley, John; Leblanc, Michael] Fred Hutchinson Canc Res Ctr, Canc Res & Biostat, Seattle, WA 98104 USA. [Sargent, Dan] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. RP Rubinstein, L (reprint author), NCI, NIH, Biometr Res Branch, 6130 Execut Blvd,Room 8130,MSC 7434, Bethesda, MD 20892 USA. EM rubinsteinl@ctep.nci.nih.gov OI Sargent, Daniel/0000-0002-2684-4741 FU NCI NIH HHS [U10 CA038926-23, U10 CA038926] NR 39 TC 59 Z9 60 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 MAR 15 PY 2009 VL 15 IS 6 BP 1883 EP 1890 DI 10.1158/1078-0432.CCR-08-2031 PG 8 WC Oncology SC Oncology GA 423QO UT WOS:000264511000008 PM 19276275 ER PT J AU Shankar, LK den Abbeele, A Yap, J Benjamin, R Scheutze, S FitzGerald, TJ AF Shankar, Lalitha K. den Abbeele, AnnickVan Yap, Jeff Benjamin, Robert Scheutze, Scott FitzGerald, T. J. TI Considerations for the Use of Imaging Tools for Phase II Treatment Trials in Oncology SO CLINICAL CANCER RESEARCH LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; GASTROINTESTINAL STROMAL TUMORS; IMATINIB MESYLATE; NEOADJUVANT CHEMOTHERAPY; PET; CANCER; THERAPY; RECOMMENDATIONS; EFFICACY; SARCOMAS AB In the context of assessing tumor response, imaging tools have the potential to play a vital role in phase II and III treatment trials. If the imaging test is able to predict potential phase III success in a reliable fashion, it would be a useful tool in phase II trial design as it may provide for a more rapid and timely response assessment. The benefits and challenges of using anatomic imaging measures as well as the promising molecular imaging measures, primarily fluorodeoxyglucose-positron emission tomography, are discussed here. The general issues related to successful implementation of advanced imaging in the context of phase II treatment trials are discussed. C1 [Shankar, Lalitha K.] NCI, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [den Abbeele, AnnickVan; Yap, Jeff] Dana Farber Canc Inst, Boston, MA 02115 USA. [Benjamin, Robert] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Scheutze, Scott] Univ Michigan Hlth Syst, Ann Arbor, MI USA. [FitzGerald, T. J.] Qual Assurance Review Ctr, Providence, RI USA. RP Shankar, LK (reprint author), NCI, Div Canc Treatment & Diag, 6130 Execut Blvd,Room 6056, Bethesda, MD 20892 USA. EM shankarl@mail.nih.gov FU NCI NIH HHS [U10 CA029511-30, U10 CA029511] NR 31 TC 38 Z9 38 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 MAR 15 PY 2009 VL 15 IS 6 BP 1891 EP 1897 DI 10.1158/1078-0432.CCR-08-2030 PG 7 WC Oncology SC Oncology GA 423QO UT WOS:000264511000009 PM 19276276 ER PT J AU McShane, LM Hunsberger, S Adjei, AA AF McShane, Lisa M. Hunsberger, Sally Adjei, Alex A. TI Effective Incorporation of Biomarkers into Phase II Trials SO CLINICAL CANCER RESEARCH LA English DT Article ID METASTATIC BREAST-CANCER; SURROGATE END-POINTS; CLINICAL-TRIALS; OVARIAN-CANCER; MONOCLONAL-ANTIBODY; TARGETED THERAPIES; PROSTATE-CANCER; WORKING GROUP; DESIGN; RECOMMENDATIONS AB The incorporation of biomarkers into the drug development process will improve understanding of how new therapeutics work and allow for more accurate identification of patients who will benefit from those therapies. Strategically planned biomarker evaluations in phase II studies may allow for the design of more efficient phase III trials and better screening of therapeutics for entry into phase III development, hopefully leading to increased chances of positive phase III trial results. Some examples of roles that a biomarker can play in a phase II trial include predictor of response or resistance to specific therapies, patient enrichment, correlative endpoint, or surrogate endpoint. Considerations for using biomarkers most effectively in these roles are discussed in the context of several examples. The substantial technical, logistic, and ethical challenges that can be faced when trying to incorporate biomarkers into phase II trials are also addressed. A rational and coordinated approach to the inclusion of biomarker studies throughout the drug development process will be the key to attaining the goal of personalized medicine. C1 [McShane, Lisa M.; Hunsberger, Sally] NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Adjei, Alex A.] Roswell Pk Canc Inst, Katherine Anne Gioia Chair Canc Med, Buffalo, NY 14263 USA. RP McShane, LM (reprint author), NCI, Biometr Res Branch, Div Canc Treatment & Diag, Room 8126,Execut Plaza N,MSC 7434,6130 Execut Blv, Bethesda, MD 20892 USA. EM lm5h@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 37 TC 47 Z9 48 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2009 VL 15 IS 6 BP 1898 EP 1905 DI 10.1158/1078-0432.CCR-08-2033 PG 8 WC Oncology SC Oncology GA 423QO UT WOS:000264511000010 PM 19276274 ER PT J AU Almanzar, G Olkhanud, PB Bodogai, M DellAgnola, C Baatar, D Hewitt, SM Ghimenton, C Tummala, MK Weeraratna, AT Hoek, KS Kouprina, N Larionov, V Biragyn, A AF Almanzar, Giovanni Olkhanud, Purevdorj B. Bodogai, Monica DellAgnola, Chiara Baatar, Dolgor Hewitt, Stephen M. Ghimenton, Claudio Tummala, Mohan K. Weeraratna, Ashani T. Hoek, Keith Sean Kouprina, Natalay Larionov, Vladimir Biragyn, Arya TI Sperm-Derived SPANX-B Is a Clinically Relevant Tumor Antigen That Is Expressed in Human Tumors and Readily Recognized by Human CD4(+) and CD8(+) T Cells SO CLINICAL CANCER RESEARCH LA English DT Article ID IMMATURE LAMININ RECEPTOR; HEMATOLOGIC MALIGNANCIES; GENOMIC ORGANIZATION; GENE-EXPRESSION; FAMILY; LOCALIZATION; RESPONSES; PROTEIN; LINES AB Purpose: The sperm-derived SPANX family proteins can be found expressed in human tumors. Here, we aimed to perform a comprehensive study to evaluate immunotherapeutic relevance of one of its members, SPANX-B. We wanted to test its expression pattern in human tumors and to evaluate CD4(+) and CD8(+) T-cell responses in healthy humans after in vitro immunizations. Experimental Design: Expression of SPANX-B in human malignancies, including a multitumor tissue array of 145 primary tumors, was assessed using reverse transcription-PCR, Western blotting, and immunohistochemical analysis. T-cell immunogenicity and immunodominant epitopes of SPANX-B were studied using in vitro immunizations of healthy human donor-derived leukocytes. Results: SPANX-B was abundantly expressed in melanoma and carcinomas of lung, ovary, colon, and breast. In melanoma, tissue array data indicated that it was expressed in advanced and metastatic disease. Unlike most tumor-associated antigens, SPANX-B was an immunogenic antigen that was recognized by circulating T-cell precursors in healthy humans. Importantly, these T cells were readily expanded to generate SPANX-B-specific helper CD4(+) and cytolytic CD8(+) T cells that recognized unique immunodominant epitopes: at least one HLA-DR-restricted Pep-9 epitope (SPANX-B12-23) and two H LA-A2-restricted Pep-2 and Pep-4 epitopes (SPANX-B23-31 and SPANX-B57-65, respectively). CD8(+) T cells were fully functional to recognize and lyse HLA-A2-expressing tumors, including primary human melanomas. Conclusions: SPANX-B is an immunogenic sperm-derived antigen that is expressed in several human tumors. SPANX-B is also efficiently recognized by the human T-cell immune arm, indicating its significant value for the development of protective and therapeutic cancer vaccines. C1 [Biragyn, Arya] NIA, Gerontol Res Ctr, NIH, Immunol Lab, Baltimore, MD 21224 USA. [Tummala, Mohan K.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Kouprina, Natalay; Larionov, Vladimir] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [DellAgnola, Chiara] Univ Verona, Div Clin Oncol, Dept Clin & Expt Med, I-37100 Verona, Italy. [Ghimenton, Claudio] Civile Maggiore Hosp, Dept Pathol, Verona, Italy. [Hoek, Keith Sean] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland. RP Biragyn, A (reprint author), NIA, Gerontol Res Ctr, NIH, Immunol Lab, 5600 Nathan Shock Dr,Box 21, Baltimore, MD 21224 USA. EM biragyna@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU Intramural NIH HHS [Z01 AG000770-04] NR 21 TC 5 Z9 5 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 MAR 15 PY 2009 VL 15 IS 6 BP 1954 EP 1963 DI 10.1158/1078-0432.CCR-08-1290 PG 10 WC Oncology SC Oncology GA 423QO UT WOS:000264511000017 PM 19276289 ER PT J AU Bass, SE Sienkiewicz, P MacDonald, CJ Cheng, RYS Sparatore, A Del Soldato, P Roberts, DD Moody, TW Wink, DA Yeh, GC AF Bass, Sara E. Sienkiewicz, Pawel MacDonald, Christopher J. Cheng, Robert Y. S. Sparatore, Anna Del Soldato, Piero Roberts, David D. Moody, Terry W. Wink, David A. Yeh, Grace Chao TI Novel Dithiolethione-Modified Nonsteroidal Anti-Inflammatory Drugs in Human Hepatoma HepG2 and Colon LS180 Cells SO CLINICAL CANCER RESEARCH LA English DT Article ID ARYL-HYDROCARBON RECEPTOR; HYDROGEN-SULFIDE; OXIDATIVE STRESS; AH-RECEPTOR; TRANSCRIPTIONAL ACTIVATION; GASTROINTESTINAL SAFETY; IN-VITRO; RAT; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; SULINDAC AB Purpose: Nonsteroidal anti-inflammatory drugs (NSAID) are promising chemopreventive agents against colon and other cancers. However, the molecular basis mediated by NSAIDs for chemoprevention has not been fully elucidated. Environmental carcinogens induce DNA mutation and cellular transformation; therefore, we examined the effect of NSAIDs on carcinogenesis mediated by the aryl hydrocarbon receptor signaling pathway. In this study, we investigated the activities of a new class of NSAIDs containing dithiolethione moieties (S-NSAID) on both arms of carcinogenesis. Experimental Design: We investigated the effects of the S-NSAIDs, S-diclofenac and S-sulindac, on carcinogen activation and detoxification mechanisms in human hepatoma HepG2 and human colonic adenocarcinoma LS180 cells. Results: We found that S-diclofenac and S-sulindac inhibited the activity and expression of the carcinogen activating enzymes, cytochromes P-450 (CYP) CYP1A1, CYP1B1, and CYP1A2. Inhibition was mediated by transcriptional regulation of the aryl hydrocarbon receptor (AhR) pathway. The S-NSAIDs down-regulated carcinogen-induced expression of CYP1A1 heterogeneous nuclear RNA, a measure of transcription rate. Both compounds blocked carcinogen-activated AhR from binding to the xenobiotic responsive element as shown by chromatin immunoprecipitation. S-diclofenac and S-sulindac inhibited carcinogen-induced CYP enzyme activity through direct inhibition as well as through decreased transcriptional activation of the AhR. S-sulindac induced expression of several carcinogen detoxification enzymes of the glutathione cycle including glutathione S-transferase A2, glutamate cysteine ligase catalytic subunit, glutamate cysteine ligase modifier subunit, and glutathione reductase. Conclusions: These results indicate that S-diclofenac and S-sulindac may serve as effective chemoprevention agents by favorably balancing the equation of carcinogen activation and detoxification mechanisms. C1 [Sienkiewicz, Pawel; MacDonald, Christopher J.; Cheng, Robert Y. S.; Yeh, Grace Chao] NCI, Lab Metab, Frederick, MD 21701 USA. [Sparatore, Anna] Univ Milan, Ist Chim Farmaceut, I-20122 Milan, Italy. [Del Soldato, Piero] Sulfidris, Milan, Italy. [Wink, David A.] NCI, Ctr Canc Res, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. [Roberts, David D.] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Moody, Terry W.] NCI, Off Director, NIH, Bethesda, MD 20892 USA. RP Yeh, GC (reprint author), NCI, Ctr Canc Res, Bldg 31,Room 3A11,31 Ctr Dr, Bethesda, MD 20892 USA. EM yeh@ncifcrf.gov RI Roberts, David/A-9699-2008; Sparatore, Anna/J-8634-2015; OI Roberts, David/0000-0002-2481-2981; Sparatore, Anna/0000-0003-2135-2649; Cheng, Robert/0000-0003-0287-6439 FU Intramural NIH HHS; NCI NIH HHS [HHSN261200800001E, N01-CO-12400, N01CO12400]; PHS HHS [HHSN261200800001E] NR 48 TC 21 Z9 24 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 MAR 15 PY 2009 VL 15 IS 6 BP 1964 EP 1972 DI 10.1158/1078-0432.CCR-08-1870 PG 9 WC Oncology SC Oncology GA 423QO UT WOS:000264511000018 PM 19276279 ER PT J AU Bertagnolli, MM Warren, RS Niedzwiecki, D Mueller, E Compton, CC Redston, M Hall, M Hahn, HP Jewell, SD Mayer, RJ Goldberg, RM Saltz, LB Loda, M AF Bertagnolli, Monica M. Warren, Robert S. Niedzwiecki, Donna Mueller, Elke Compton, Carolyn C. Redston, Mark Hall, Margaret Hahn, Hejin P. Jewell, Scott D. Mayer, Robert J. Goldberg, Richard M. Saltz, Leonard B. Loda, Massimo TI p27(Kip1) in Stage III Colon Cancer: Implications for Outcome following Adjuvant Chemotherapy in Cancer and Leukemia Group B Protocol 89803 SO CLINICAL CANCER RESEARCH LA English DT Article ID DEPENDENT KINASE INHIBITOR; UBIQUITIN LIGASE SUBUNIT; COLORECTAL-CANCER; MICROSATELLITE INSTABILITY; ALTERED EXPRESSION; MOLECULAR ANALYSIS; PROGNOSTIC ROLE; P27 EXPRESSION; CARCINOMA; ADENOCARCINOMA AB Background: In retrospective studies, loss of p27(Kip1) (p27), a cyclin-dependent kinase inhibitor, has been associated with poor prognosis following colorectal cancer treatment. In a prospective study, we validated this relationship in patients enrolled on a trial of adjuvant chemotherapy for stage III colon cancer. Methods: Cancer and Leukemia Group B protocol 89803 randomized 1,264 stage III colon cancer patients to receive weekly bolus 5-fluorouracil/leucovorin or weekly bolus irinotecan, 5-fluorouracil, and leucovorin (IFL). The primary endpoint was overall survival (OS); disease-free survival was a secondary endpoint. Expression of p27 and DNA mismatch repair proteins were determined by immunohistochemistry in primary tumor and normal tissue from paraffin blocks. Data were analyzed using log-rank test. Results: Of 601 tumors analyzed, 207 (34.4%) showed p27 loss, 377 (62.8%) retained p27, and 17 (2.8%) were indeterminate. Patients with p27-negative tumors showed reduced OS [5-year CS 66%: 95% confidence interval (95% CI), 0.59-0.72 versus 75%: 95% CI, 0.70-0.79; log-rank P = 0.021]. This relationship was not influenced by treatment arm. Combination of p27 status with mismatch repair status, however, identified a small subset of patients that may benefit from IFL (n = 36; 5-year disease-free survival 81%: 95% CI, 0.64-0.98 versus 47% 95% CI, 0.21-0.72; log-rank P = 0.042; 5-year OS 81%: 95% CI, 0.64-0.98 versus 60%: 95% CI, 0.35-0.85; log-rank P = 0.128). Conclusions: Loss of p27 is associated with reduced survival in stage III colon cancer but by itself does not indicate a significant difference in outcome between patients treated IFL or 5-fluorouracil/leucovorin. C1 [Bertagnolli, Monica M.; Mueller, Elke; Redston, Mark; Hahn, Hejin P.; Loda, Massimo] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bertagnolli, Monica M.; Mayer, Robert J.; Loda, Massimo] Dana Farber Canc Inst, Boston, MA 02115 USA. [Warren, Robert S.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Niedzwiecki, Donna; Hall, Margaret] Duke Univ, Med Ctr, Canc & Leukemia Grp B Stat Ctr, Durham, NC USA. [Compton, Carolyn C.] NCI, Bethesda, MD USA. [Jewell, Scott D.] Ohio State Univ, Columbus, OH 43210 USA. [Goldberg, Richard M.] Univ N Carolina, Chapel Hill, NC USA. [Saltz, Leonard B.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Bertagnolli, MM (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. EM Mbertagnolli@partners.org RI Goldberg , Richard/M-1311-2013; OI Saltz, Leonard/0000-0001-8353-4670 FU USPHS [CA31946]; National Cancer Institute, NIH, Department of Health and Human Services; CALGB Statistical Center [CA33601] FX The research for CALGB protocol 89803 was supported, in part, by USPHS grant CA31946 from the National Cancer Institute, NIH, Department of Health and Human Services, to the CALGB (Richard L. Schilsky, M.D., Chairman) and to the CALGB Statistical Center (Stephen George, Ph. D., CA33601). NR 28 TC 13 Z9 13 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 MAR 15 PY 2009 VL 15 IS 6 BP 2116 EP 2122 DI 10.1158/1078-0432.CCR-08-2674 PG 7 WC Oncology SC Oncology GA 423QO UT WOS:000264511000035 PM 19276255 ER PT J AU Davis, JL Huang, L Kovacs, JA Masur, H Murray, P Havlir, DV Worodria, WO Charlebois, ED Srikantiah, P Cattamanchi, A Huber, C Shea, YR Chow, Y Fischer, SH AF Davis, J. Lucian Huang, Laurence Kovacs, Joseph A. Masur, Henry Murray, Patrick Havlir, Diane V. Worodria, William O. Charlebois, Edwin D. Srikantiah, Padmini Cattamanchi, Adithya Huber, Charles Shea, Yvonne R. Chow, Yuenwah Fischer, Steven H. TI Polymerase Chain Reaction of secA1 on Sputum or Oral Wash Samples for the Diagnosis of Pulmonary Tuberculosis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID ACID-AMPLIFICATION TESTS; SMEAR MICROSCOPY; MYCOBACTERIUM-TUBERCULOSIS; META-REGRESSION; METAANALYSIS; SPECIMENS; ACCURACY; PCR; TB AB Background. Nucleic acid amplification tests are sensitive and specific for identifying Mycobacterium tuberculosis in sputum smear-positive populations, but they are less sensitive in sputum smear-negative populations. Few studies have assessed their performance among patients infected with HIV, and no studies have assessed their performance with oral wash specimens, which may be easier to obtain than sputum samples. Methods. We performed a prospective study involving 127 adults from 2 populations who were undergoing evaluation for respiratory complaints at Mulago Hospital in Kampala, Uganda. We obtained and tested sputum samples for Mycobacterium tuberculosis, and we simultaneously obtained oral wash specimens to test for M. tuberculosis DNA by polymerase chain reaction (PCR) amplification of a novel locus, the secA1 gene. A positive mycobacterial culture of sputum was used to define cases of tuberculosis; we calculated the sensitivity and specificity of the PCR assay with sputum or oral wash specimens in reference to the standard of sputum culture results. Results. Tuberculosis (75 [59%] of 127 patients) and HIV infection (58 [46%] of 126 patients) were both common in the study population. PCR of sputum samples was highly sensitive (sensitivity, 99%; 95% confidence interval, 93%-100%) and specific (specificity, 88%; 95% confidence interval, 77%-96%) for detection of pulmonary tuberculosis and performed well among HIV-infected patients and among patients with negative sputum smear results. PCR of oral wash specimens was less sensitive (sensitivity, 73%; 95% confidence interval, 62%-83%) but also detected a substantial proportion of tuberculosis cases. Conclusions. PCR targeting the secA1 gene was highly sensitive and specific for identifying M. tuberculosis in sputum samples, independent of smear or HIV infection status. Oral washes showed promise as an easily obtained respiratory specimen for tuberculosis diagnosis. PCR of sputum for detection of the secA1 gene could be a rapid, effective diagnostic tool for tuberculosis referral centers. C1 [Davis, J. Lucian; Huang, Laurence; Havlir, Diane V.; Charlebois, Edwin D.; Srikantiah, Padmini; Cattamanchi, Adithya] San Francisco Gen Hosp, Dept Med, San Francisco, CA 94110 USA. [Davis, J. Lucian; Huang, Laurence; Havlir, Diane V.; Charlebois, Edwin D.; Srikantiah, Padmini; Cattamanchi, Adithya] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Davis, J. Lucian; Cattamanchi, Adithya] Francis J Curry Natl TB Ctr, San Francisco, CA USA. [Kovacs, Joseph A.; Masur, Henry] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. [Murray, Patrick; Huber, Charles; Shea, Yvonne R.; Chow, Yuenwah; Fischer, Steven H.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Davis, J. Lucian; Huang, Laurence; Havlir, Diane V.; Worodria, William O.; Charlebois, Edwin D.; Srikantiah, Padmini; Cattamanchi, Adithya] Univ Calif San Francisco Res Collaborat, Makerere Univ, San Francisco, CA USA. [Worodria, William O.] Mulago Hosp, Dept Med, Kampala, Uganda. RP Davis, JL (reprint author), San Francisco Gen Hosp, Dept Med, 1001 Potrero Ave,Rm 5K1, San Francisco, CA 94110 USA. EM Lucian.Davis@ucsf.edu OI Davis, J. Lucian/0000-0002-8629-9992 FU NIH [1K23AI080147-01, P30AI027763-15]; National Heart Lung and Blood Institute [5T32HL007185-30, 1F32HL088990-01, K24HL087713]; National Institute of Mental Health [R01MH075637A]; National Center for Research Resources [KL2RR024130]; National Institute of Allergy and Infectious Diseases FX The NIH supported this work through the National Institute of Allergy and Infectious Diseases (1K23AI080147-01 P30AI027763-15 to J.L.D.), the National Heart Lung and Blood Institute (5T32HL007185-30 and 1F32HL088990-01 to J.L.D., and K24HL087713 to L. H.), the National Institute of Mental Health (R01MH075637A to E. D. C.), the National Center for Research Resources (KL2RR024130), an NIH Bench-to-Bedside Grant (to J.A.K. and L. H.), and the Intramural Research Program of the NIH Clinical Center and the National Institute of Allergy and Infectious Diseases. NR 25 TC 9 Z9 10 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 15 PY 2009 VL 48 IS 6 BP 725 EP 732 DI 10.1086/597038 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 415QI UT WOS:000263949000006 PM 19207077 ER PT J AU Li, ZH Zhang, H Zheng, G Gastwirth, JL Gail, MH AF Li, Zhaohai Zhang, Hong Zheng, Gang Gastwirth, Joseph L. Gail, Mitchell H. TI Excess false positive rate caused by population stratification and disease rate heterogeneity in case-control association studies SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article ID GENOME-WIDE ASSOCIATION; TRANSMISSION/DISEQUILIBRIUM TEST; LINKAGE DISEQUILIBRIUM; GENETIC ASSOCIATION; DIABETES-MELLITUS; POWER; TRANSMISSION; TESTS; EFFICIENCY; GENOTYPES AB Case-control association studies using unrelated cases and controls may suffer from potential confounding due to population stratification. Bias and variance distortion caused by population stratification in the commonly used allele-based tests can considerably inflate the Type I error rate. It is shown that the bias vanishes in the absence of disease rate heterogeneity. If only population stratification exists, a proper estimate of the variance of the allele-based test statistic is developed. Using this estimated variance yields a valid Type I error However, when the frequencies of the allele under study and the disease rates differ among the subpopulations, it is difficult to correct for this bias. Explicit expressions for the excess false positive rate (EFPR) of the test due to bias and variance distortion are derived. It turns out that the bias created when both population stratification and disease rate heterogeneity are present usually has a greater effect on the EFPR than variance distortion. Comprehensive simulation studies strongly support these results. (C) 2008 Elsevier B.V. All rights reserved. C1 [Li, Zhaohai; Zhang, Hong; Gastwirth, Joseph L.] George Washington Univ, Dept Stat, Washington, DC 20052 USA. [Li, Zhaohai; Gastwirth, Joseph L.; Gail, Mitchell H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Zhang, Hong] Univ Sci & Technol China, Dept Stat & Finance, Hefei, Peoples R China. RP Li, ZH (reprint author), George Washington Univ, Dept Stat, 2140 Penn Ave NW, Washington, DC 20052 USA. EM zli@gwu.edu NR 49 TC 4 Z9 4 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD MAR 15 PY 2009 VL 53 IS 5 BP 1767 EP 1781 DI 10.1016/j.csda.2008.02.021 PG 15 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 427AH UT WOS:000264751000023 ER PT J AU Sung, HJ Ji, F Levy, DL Matthysse, S Mendell, NR AF Sung, Heejong Ji, Fei Levy, Deborah L. Matthysse, Steven Mendell, Nancy Role TI The power of linkage analysis of a disease-related endophenotype using asymmetrically ascertained sib pairs SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article ID THOUGHT-DISORDER INDEX; GENETIC-LINKAGE; SCHIZOPHRENIA; RELATIVES; COMMUNICATION; PEDIGREES; DIAGNOSIS; DEFICIT; TRAIT; ASSOCIATION AB A linkage study ora qualitative disease endophenotype in a sample of sib pairs, consisting of one disease affected proband and one sibling is considered. The linkage statistic compares marker allele sharing with the proband in siblings with an abnormal endophenotype to siblings with the normal endophenotype. Expressions are derived for the distribution of this linkage statistic, in terms of the recombination fraction and (1) the genetic parameter values (allele frequency and endophenotype and disease penetrance) and (2) the abnormal endophenotype rates in the population and in classes of relatives of disease affected probands. It is then shown that when either the disease or the abnormal endophenotype has additive penetrance, the expressions simplify to a monotonic function of the difference between abnormal endophenotype rates in siblings and in the population. Thought disorder is considered as a putative schizophrenia endophenotype. Forty sets of genetic parameter values that correspond to the known prevalence values for thought disorder in schizophrenic patients, siblings of schizophrenics and the general population are evaluated. For these genetic parameter values, numerical results show that the test statistic has >70% power (alpha = 0.0001) in general with a sample of 200 or more proband-sibling pairs to detect linkage between a marker (theta = 0.01) and a locus pleiotropic for schizophrenia and thought disorder. Published by Elsevier B.V. C1 [Sung, Heejong; Mendell, Nancy Role] SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. [Sung, Heejong] NHGRI, Genometr Sect, IDRB, NIH, Baltimore, MD USA. [Ji, Fei] Rockefeller Univ, Lab Stat Genet, New York, NY 10021 USA. [Levy, Deborah L.; Matthysse, Steven] McLean Hosp, Psychol Res Lab, Belmont, MA 02178 USA. RP Mendell, NR (reprint author), SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. EM heejongsung@gmail.com; nmendell@notes.cc.sunysb.edu FU NHGRI NIH HHS [Z01 HG000200]; NIMH NIH HHS [R01 MH071523-03, R01 MH071523] NR 47 TC 5 Z9 5 U1 3 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD MAR 15 PY 2009 VL 53 IS 5 BP 1829 EP 1842 DI 10.1016/j.csda.2008.08.030 PG 14 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 427AH UT WOS:000264751000028 PM 20160849 ER PT J AU Chi, YH Cheng, LI Myers, T Ward, JM Williams, E Su, Q Faucette, L Wang, JY Jeang, KT AF Chi, Ya-Hui Cheng, Lily I. Myers, Tim Ward, Jerrold M. Williams, Elizabeth Su, Qin Faucette, Larry Wang, Jing-Ya Jeang, Kuan-Teh TI Requirement for Sun1 in the expression of meiotic reproductive genes and piRNA SO DEVELOPMENT LA English DT Article DE Sun1; Sad1; Unc84; Nuclear envelope; Gametogenesis; piRNA; Mouse ID DROSOPHILA-MELANOGASTER GENOME; DOUBLE-STRAND BREAKS; NUCLEAR-ENVELOPE; MUSCULAR-DYSTROPHY; CAENORHABDITIS-ELEGANS; PIWI PROTEINS; GERM-CELLS; LAMIN-A; MOUSE; CHROMOSOMES AB The inner nuclear envelope (NE) proteins interact with the nuclear lamina and participate in the architectural compartmentalization of chromosomes. The association of NE proteins with DNA contributes to the spatial rearrangement of chromosomes and their gene expression. Sun1 is an inner nuclear membrane (INM) protein that locates to telomeres and anchors chromosome movement in the prophase of meiosis. Here, we have created Sun1(-/-) mice and have found that these mice are born and grow normally but are reproductively infertile. Detailed molecular analyses showed that Sun1(-/-) P14 testes are repressed for the expression of reproductive genes and have no detectable piRNA. These findings raise a heretofore unrecognized role of Sun1 in the selective gene expression of coding and non-coding RNAs needed for gametogenesis. C1 [Chi, Ya-Hui; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Chi, Ya-Hui; Wang, Jing-Ya] Natl Hlth Res Inst, Inst Cellular & Syst Med, Zhunan 35053, Taiwan. [Cheng, Lily I.; Ward, Jerrold M.; Williams, Elizabeth; Faucette, Larry] NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, Div Intramural Res,NIH, Bethesda, MD 20892 USA. [Myers, Tim; Su, Qin] NIH, Microarray Res Facil, Genom Technol Sect, Inst Allergy & Infect Dis, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kj7e@nih.gov RI Chi, Ya-Hui/B-1080-2010; Jeang, Kuan-Teh/A-2424-2008 FU NIAID/NIH intramural funds; Intramural AIDS Targeted Anti-viral Program (IATAP); NIAID; National Health Research Institutes, Taiwan FX We thank members of the Jeang laboratory for critical readings of this manuscript. This work was supported by in part NIAID/NIH intramural funds, the Intramural AIDS Targeted Anti-viral Program (IATAP), an NIAID contract to SoBran, and by intramural grants to Y.-H.C. from the National Health Research Institutes, Taiwan. Deposited in PMC for release after 12 months. NR 59 TC 40 Z9 42 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAR 15 PY 2009 VL 136 IS 6 BP 965 EP 973 DI 10.1242/dev.029868 PG 9 WC Developmental Biology SC Developmental Biology GA 410DW UT WOS:000263558100010 PM 19211677 ER PT J AU McGhee, JD Fukushige, T Krause, MW Minnema, SE Goszczynski, B Gaudet, J Kohara, Y Bossinger, O Zhao, Y Khattra, J Hirst, M Jones, SJM Marra, MA Ruzanov, P Warner, A Zapf, R Moerman, DG Kalb, JM AF McGhee, James D. Fukushige, Tetsunari Krause, Michael W. Minnema, Stephanie E. Goszczynski, Barbara Gaudet, Jeb Kohara, Yuji Bossinger, Olaf Zhao, Yongjun Khattra, Jaswinder Hirst, Martin Jones, Steven J. M. Marra, Marco A. Ruzanov, Peter Warner, Adam Zapf, Richard Moerman, Donald G. Kalb, John M. TI ELT-2 is the predominant transcription factor controlling differentiation and function of the C. elegans intestine, from embryo to adult SO DEVELOPMENTAL BIOLOGY LA English DT Article DE C. elegans; Intestine; Endoderm; Transcription; Transcriptional control; Gene expression; GATA factor; ELT-2; Development; Differentiation ID NEMATODE CAENORHABDITIS-ELEGANS; CELL-SPECIFIC EXPRESSION; INNATE IMMUNE-SYSTEM; CIS-REGULATORY ARCHITECTURE; OXIDATIVE STRESS-RESPONSE; GENE-EXPRESSION; GATA-FACTOR; LIFE-SPAN; COMPUTATIONAL ANALYSIS; RECEPTOR NHR-49 AB Starting with SAGE-libraries prepared from C elegans FAC-sorted embryonic intestine cells (8E-16E cell stage), from total embryos and from purified oocytes, and taking advantage of the NextDB in situ hybridization data base, we define sets of genes highly expressed from the zygotic genome, and expressed either exclusively or preferentially in the embryonic intestine or in the intestine of newly hatched larvae: we had previously defined a similarly expressed set of genes from the adult intestine. We show that an extended TGATAA-like sequence is essentially the only candidate for a cis-acting regulatory motif common to intestine genes expressed at all stages. This sequence is a strong ELT-2 binding site and matches the sequence of GATA-like sites found to be important for the expression of every intestinal gene so far analyzed experimentally. We show that the majority of these three sets of highly expressed intestinal-specific/intestinal-enriched genes respond strongly to ectopic expression of ELT-2 within the embryo. By flow-sorting elt-2(null) larvae from elt-2(+) larvae and then preparing Solexa/Illumina-SAGE libraries, we show that the majority of these genes also respond strongly to loss-of-function of ELT-2. To test the consequences of loss of other transcription factors identified in the embryonic intestine, we develop a strain of worms that is RNAi-sensitive only in the intestine: however, we are unable (with one possible exception) to identify any other transcription factor whose intestinal loss-of-function causes a phenotype of comparable severity to the phenotype caused by loss of ELT-2. Overall, our results support a model in which ELT-2 is the predominant transcription factor in the post-specification C elegans intestine and participates directly in the transcriptional regulation of the majority (>80%) of intestinal genes. We present evidence that ELT-2 plays a central role in most aspects of C elegans intestinal physiology: establishing the structure of the enterocyte, regulating enzymes and transporters involved in digestion and nutrition, responding to environmental toxins and pathogenic infections, and regulating the downstream intestinal components of the daf-2/daf-16 pathway influencing aging and longevity. (C) 2008 Elsevier Inc. All rights reserved. C1 [McGhee, James D.; Minnema, Stephanie E.; Goszczynski, Barbara; Gaudet, Jeb; Kalb, John M.] Univ Calgary, Dept Biochem & Mol Biol, Dept Med Genet, Genes & Dev Res Grp, Calgary, AB T2N 4N1, Canada. [Fukushige, Tetsunari; Krause, Michael W.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Kohara, Yuji] Natl Inst Genet, Genome Biol Lab, Mishima, Shizuoka 4118560, Japan. [Bossinger, Olaf] Univ Dusseldorf, Inst Genet, D-40225 Dusseldorf, Germany. [Zhao, Yongjun; Khattra, Jaswinder; Hirst, Martin; Jones, Steven J. M.; Marra, Marco A.] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. [Ruzanov, Peter] Univ British Columbia, Michael Smith Labs, Vancouver, BC V6T 1Z4, Canada. [Warner, Adam; Zapf, Richard; Moerman, Donald G.] Univ British Columbia, Dept Zool, Vancouver, BC V6T 1Z4, Canada. RP McGhee, JD (reprint author), Univ Calgary, Dept Biochem & Mol Biol, Dept Med Genet, Genes & Dev Res Grp, Calgary, AB T2N 4N1, Canada. EM jmcghee@ucalgary.ca RI Hirst, Martin/C-3619-2009; Tang, Macy/B-9798-2014; Jones, Steven/C-3621-2009; Marra, Marco/B-5987-2008; Hirst, Martin/B-7684-2016; OI Krause, Michael/0000-0001-6127-3940; McGhee, James/0000-0001-7266-7275 FU Canadian Institutes of Health Research; Genome Canada; Genome British Columbia; NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX The authors would like to thank M. Sleumer, M. Bilenky and G. Robertson, (Genome Sciences Centre, Vancouver) for programs and for helpful advice on the computational analysis of promoters, Z. Bhao (University of Washington, Seattle) for providing a list of C. elegans transcription factors, and D. Hansen (University of Calgary) for critical reading of the manuscript. This work was supported by an operating grant from the Canadian Institutes of Health Research (to J.D.M.) and from Genome Canada and Genome British Columbia (to D.G.M., M.A.M. and S.J.J.). This research was also supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. M.A.M. and S.J.J are scholars of the Michael Smith Research Foundation for Health Research. M.A.M. is a Terry Fox Young Investigator. J.D.M. is a Medical Scientist of the Alberta Heritage Foundation for Medical Research and a Canada Research Chair in Developmental Biology. This work is dedicated to the late Dr. M.G. Persico. NR 93 TC 69 Z9 71 U1 5 U2 19 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAR 15 PY 2009 VL 327 IS 2 BP 551 EP 565 DI 10.1016/j.ydbio.2008.11.034 PG 15 WC Developmental Biology SC Developmental Biology GA 417FA UT WOS:000264060700027 PM 19111532 ER PT J AU Shabalina, SA Zaykin, DV Gris, P Ogurtsov, AY Gauthier, J Shibata, K Tchivileva, IE Belfer, I Mishra, B Kiselycznyk, C Wallace, MR Staud, R Spiridonov, NA Max, MB Goldman, D Fillingim, RB Maixner, W Diatchenko, L AF Shabalina, Svetlana A. Zaykin, Dmitri V. Gris, Pavel Ogurtsov, Aleksey Y. Gauthier, Josee Shibata, Kyoko Tchivileva, Inna E. Belfer, Inna Mishra, Bikashkumar Kiselycznyk, Carly Wallace, Margaret R. Staud, Roland Spiridonov, Nikolay A. Max, Mitchell B. Goldman, David Fillingim, Roger B. Maixner, William Diatchenko, Luda TI Expansion of the human mu-opioid receptor gene architecture: novel functional variants SO HUMAN MOLECULAR GENETICS LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISM; MORPHINE-INDUCED ANALGESIA; EXPERIMENTAL PAIN; INTERGENIC REGIONS; OPIATE RECEPTOR; MESSENGER-RNAS; MOUSE GENOMES; MICE LACKING; OPRM GENE; ASSOCIATION AB The mu-opioid receptor (OPRM1) is the principal receptor target for both endogenous and exogenous opioid analgesics. There are substantial individual differences in human responses to painful stimuli and to opiate drugs that are attributed to genetic variations in OPRM1. In searching for new functional variants, we employed comparative genome analysis and obtained evidence for the existence of an expanded human OPRM1 gene locus with new promoters, alternative exons and regulatory elements. Examination of polymorphisms within the human OPRM1 gene locus identified strong association between single nucleotide polymorphism (SNP) rs563649 and individual variations in pain perception. SNP rs563649 is located within a structurally conserved internal ribosome entry site (IRES) in the 5'-UTR of a novel exon 13-containing OPRM1 isoforms (MOR-1K) and affects both mRNA levels and translation efficiency of these variants. Furthermore, rs563649 exhibits very strong linkage disequilibrium throughout the entire OPRM1 gene locus and thus affects the functional contribution of the corresponding haplotype that includes other functional OPRM1 SNPs. Our results provide evidence for an essential role for MOR-1K isoforms in nociceptive signaling and suggest that genetic variations in alternative OPRM1 isoforms may contribute to individual differences in opiate responses. C1 [Shabalina, Svetlana A.; Ogurtsov, Aleksey Y.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Zaykin, Dmitri V.; Shibata, Kyoko] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Gris, Pavel; Gauthier, Josee; Tchivileva, Inna E.; Maixner, William; Diatchenko, Luda] Univ N Carolina, Ctr Neurosensory Disorders, Sch Dent, Chapel Hill, NC 27599 USA. [Belfer, Inna; Mishra, Bikashkumar; Kiselycznyk, Carly; Max, Mitchell B.] NIH, Dept Hlth & Human Serv, Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. [Belfer, Inna; Mishra, Bikashkumar; Kiselycznyk, Carly; Goldman, David] NIAAA, Neurogenet Lab, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. [Belfer, Inna; Max, Mitchell B.] Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Wallace, Margaret R.] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL 32608 USA. [Staud, Roland; Fillingim, Roger B.] Univ Florida, Coll Dent Community Dent & Behav Sci, Gainesville, FL 32608 USA. [Spiridonov, Nikolay A.] US FDA, Div Therapeut Prot, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Shabalina, SA (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM shabalin@ncbi.nlm.nih.gov; lbdiatch@email.unc.edu RI Goldman, David/F-9772-2010; Shabalina, Svetlana/N-8939-2013; Spiridonov, Nikolay/B-6287-2014 OI Goldman, David/0000-0002-1724-5405; Shabalina, Svetlana/0000-0003-2272-7473; FU NIDCR; NINDS [RO1-DE16558, UO1-DE017018, NS41670, PO1 NS045685]; RO1-DE16558, UO1-DE017018, NS41670 and PO1 NS045685, and the Intramural Research Programs of NIEHS; NCBI/NLM; NIDRC; National Institutes of Health; National Library of Medicine FX This work was supported in part by NIDCR and NINDS grants RO1-DE16558, UO1-DE017018, NS41670 and PO1 NS045685, and the Intramural Research Programs of NIEHS, NCBI/NLM and NIDRC. Funding to pay the Open Access Charge was provided by Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 77 TC 89 Z9 94 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 15 PY 2009 VL 18 IS 6 BP 1037 EP 1051 DI 10.1093/hmg/ddn439 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 413XT UT WOS:000263828100005 PM 19103668 ER PT J AU Asai-Coakwell, M French, CR Ye, M Garcha, K Bigot, K Perera, AG Staehling-Hampton, K Mema, SC Chanda, B Mushegian, A Bamforth, S Doschak, MR Li, G Dobbs, MB Giampietro, PF Brooks, BP Vijayalakshmi, P Sauve, Y Abitbol, M Sundaresan, P van Heyningen, V Pourquie, O Underhill, TM Waskiewicz, AJ Lehmann, OJ AF Asai-Coakwell, Mika French, Curtis R. Ye, Ming Garcha, Kamal Bigot, Karin Perera, Anoja G. Staehling-Hampton, Karen Mema, Silvina C. Chanda, Bhaskar Mushegian, Arcady Bamforth, Steven Doschak, Michael R. Li, Guang Dobbs, Matthew B. Giampietro, Philip F. Brooks, Brian P. Vijayalakshmi, Perumalsamy Sauve, Yves Abitbol, Marc Sundaresan, Periasamy van Heyningen, Veronica Pourquie, Olivier Underhill, T. Michael Waskiewicz, Andrew J. Lehmann, Ordan J. TI Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes SO HUMAN MOLECULAR GENETICS LA English DT Article ID BONE MORPHOGENETIC PROTEIN; KLIPPEL-FEIL-SYNDROME; BRACHYDACTYLY TYPE A2; GROWTH-FACTOR-BETA; PREMATURE OVARIAN FAILURE; BARDET-BIEDL-SYNDROME; BMP15 GENE; ACROMESOMELIC CHONDRODYSPLASIA; DEVELOPMENTAL ANOMALIES; GERMLINE MUTATIONS AB Proteins of the bone morphogenetic protein (BMP) family are known to have a role in ocular and skeletal development; however, because of their widespread expression and functional redundancy, less progress has been made identifying the roles of individual BMPs in human disease. We identified seven heterozygous mutations in growth differentiation factor 6 (GDF6), a member of the BMP family, in patients with both ocular and vertebral anomalies, characterized their effects with a SOX9-reporter assay and western analysis, and demonstrated comparable phenotypes in model organisms with reduced Gdf6 function. We observed a spectrum of ocular and skeletal anomalies in morphant zebrafish, the latter encompassing defective tail formation and altered expression of somite markers noggin1 and noggin2. Gdf6(+/-) mice exhibited variable ocular phenotypes compatible with phenotypes observed in patients and zebrafish. Key differences evident between patients and animal models included pleiotropic effects, variable expressivity and incomplete penetrance. These data establish the important role of this determinant in ocular and vertebral development, demonstrate the complex genetic inheritance of these phenotypes, and further understanding of BMP function and its contributions to human disease. C1 [Asai-Coakwell, Mika; Ye, Ming; Mema, Silvina C.; Chanda, Bhaskar; Sauve, Yves; Lehmann, Ordan J.] Univ Alberta, Dept Ophthalmol, Edmonton, AB T6G 2H7, Canada. [French, Curtis R.; Waskiewicz, Andrew J.] Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada. [Garcha, Kamal; Underhill, T. Michael] Univ British Columbia, Dept Cell & Dev Biol, Vancouver, BC V6T 1Z3, Canada. [Bigot, Karin; Abitbol, Marc] CERTO EA 2502 Minist Rech, Fac Med, F-75015 Paris, France. [Perera, Anoja G.; Staehling-Hampton, Karen; Mushegian, Arcady; Pourquie, Olivier] Stowers Inst Med Res, Kansas City, MO 64110 USA. [Bamforth, Steven] Univ Alberta, Dept Med Genet, Edmonton, AB T6G 2H7, Canada. [Doschak, Michael R.; Li, Guang] Univ Alberta, Dept Pharm & Pharmaceut Sci, Edmonton, AB T6G 2H7, Canada. [Dobbs, Matthew B.] Washington Univ, Dept Orthoped Surg, St Louis, MO 63130 USA. [Giampietro, Philip F.] Marshfield Clin Fdn Med Res & Educ, Dept Med Genet Serv, Marshfield, WI 54449 USA. [Brooks, Brian P.] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Vijayalakshmi, Perumalsamy] Aravind Eye Hosp, Dept Paediat Ophthalmol & Strabismus, Madurai, Tamil Nadu, India. [Sundaresan, Periasamy] Aravind Med Res Fdn, Dept Genet, Madurai, Tamil Nadu, India. [van Heyningen, Veronica] MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. RP Lehmann, OJ (reprint author), Univ Alberta, Dept Ophthalmol, Edmonton, AB T6G 2H7, Canada. EM olehmann@ualberta.ca RI Li, Guang/C-9539-2011; van Heyningen, Veronica/B-8039-2008; Waskiewicz, Andrew/A-3769-2014; OI Li, Guang/0000-0002-7648-0464; van Heyningen, Veronica/0000-0003-0359-0141; Doschak, Michael/0000-0002-0293-6596; Pourquie, Olivier/0000-0001-5189-1227; Mema, Silvina/0000-0001-5895-9159; Mushegian, Arcady/0000-0002-6809-9225 FU Canadian Institutes of Health Research; Alberta Heritage Foundation; National Scientific Engineering Council; Alberta Ingenuity Fund FX The Canadian Institutes of Health Research (to O.J.L. and T. M. U.), Alberta Heritage Foundation for Medical Research and Canadian Foundation for Innovation (to O. J.L.), National Scientific Engineering Council (to C. R. F. and A.J.W.) and Alberta Ingenuity Fund (to A.J.W.). A. J. W. and O. J. L. are recipients of Canada Research Chairs. NR 95 TC 48 Z9 49 U1 1 U2 5 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 MAR 15 PY 2009 VL 18 IS 6 BP 1110 EP 1121 DI 10.1093/hmg/ddp008 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 413XT UT WOS:000263828100012 PM 19129173 ER PT J AU Dunning, AM Healey, CS Baynes, C Maia, AT Scollen, S Vega, A Rodriguez, R Barbosa-Morais, NL Ponder, BAJ Low, YL Bingham, S Haiman, CA Le Marchand, L Broeks, A Schmidt, MK Hopper, J Southey, M Beckmann, MW Fasching, PA Peto, J Johnson, N Bojesen, SE Nordestgaard, B Milne, RL Benitez, J Hamann, U Ko, Y Schmutzler, RK Burwinkel, B Schurmann, P Dork, T Heikkinen, T Nevanlinna, H Lindblom, A Margolin, S Mannermaa, A Kosma, VM Chen, XQ Spurdle, A Change-Claude, J Flesch-Janys, D Couch, FJ Olson, JE Severi, G Baglietto, L Brresen-Dale, AL Kristensen, V Hunter, DJ Hankinson, SE Devilee, P Vreeswijk, M Lissowska, J Brinton, L Liu, JJ Hall, P Kang, D Yoo, KY Shen, CY Yu, JC Anton-Culver, H Ziogoas, A Sigurdson, A Struewing, J Easton, DF Garcia-Closas, M Humphreys, MK Morrison, J Pharoah, PDP Pooley, KA Chenevix-Trench, G AF Dunning, Alison M. Healey, Catherine S. Baynes, Caroline Maia, Ana-Teresa Scollen, Serena Vega, Ana Rodriguez, Raquel Barbosa-Morais, Nuno L. Ponder, Bruce A. J. Low, Yen-Ling Bingham, Sheila Haiman, Christopher A. Le Marchand, Loic Broeks, Annegien Schmidt, Marjanka K. Hopper, John Southey, Melissa Beckmann, Matthias W. Fasching, Peter A. Peto, Julian Johnson, Nichola Bojesen, Stig E. Nordestgaard, Borge Milne, Roger L. Benitez, Javier Hamann, Ute Ko, Yon Schmutzler, Rita K. Burwinkel, Barbara Schuermann, Peter Doerk, Thilo Heikkinen, Tuomas Nevanlinna, Heli Lindblom, Annika Margolin, Sara Mannermaa, Arto Kosma, Veli-Matti Chen, Xiaoqing Spurdle, Amanda Change-Claude, Jenny Flesch-Janys, Dieter Couch, Fergus J. Olson, Janet E. Severi, Gianluca Baglietto, Laura Brresen-Dale, Anne-Lise Kristensen, Vessela Hunter, David J. Hankinson, Susan E. Devilee, Peter Vreeswijk, Maaike Lissowska, Jolanta Brinton, Louise Liu, Jianjun Hall, Per Kang, Daehee Yoo, Keun-Young Shen, Chen-Yang Yu, Jyh-Cherng Anton-Culver, Hoda Ziogoas, Argyrios Sigurdson, Alice Struewing, Jeff Easton, Douglas F. Garcia-Closas, Montserrat Humphreys, Manjeet K. Morrison, Jonathan Pharoah, Paul D. P. Pooley, Karen A. Chenevix-Trench, Georgia CA SEARCH EPIC MEC ABCS ABCFS BBCC BBCS CGPS CNIO-BCS GENICA GC-HBOC HABCS HEBCS KARBAC KBCS kConFab AOCS Management Grp MARIE MCBCS MCCS NBCS NHS ORIGO PBCS SASBAC SEBCS TWBCS UCIBCS USRTS BCAC TI Association of ESR1 gene tagging SNPs with breast cancer risk SO HUMAN MOLECULAR GENETICS LA English DT Article ID ESTROGEN-RECEPTOR GENE; ALPHA GENE; POLYMORPHISMS; HAPLOTYPES; DISEASE; ONSET AB We have conducted a three-stage, comprehensive single nucleotide polymorphism (SNP)-tagging association study of ESR1 gene variants (SNPs) in more than 55 000 breast cancer cases and controls from studies within the Breast Cancer Association Consortium (BCAC). No large risks or highly significant associations were revealed. SNP rs3020314, tagging a region of ESR1 intron 4, is associated with an increase in breast cancer susceptibility with a dominant mode of action in European populations. Carriers of the c-allele have an odds ratio (OR) of 1.05 [95% Confidence Intervals (CI) 1.02-1.09] relative to t-allele homozygotes, P = 0.004. There is significant heterogeneity between studies, P = 0.002. The increased risk appears largely confined to oestrogen receptor-positive tumour risk. The region tagged by SNP rs3020314 contains sequence that is more highly conserved across mammalian species than the rest of intron 4, and it may subtly alter the ratio of two mRNA splice forms. C1 [Dunning, Alison M.; Healey, Catherine S.; Baynes, Caroline; Scollen, Serena; Vega, Ana; Rodriguez, Raquel; Pharoah, Paul D. P.] Univ Cambridge, Dept Oncol, Cambridge, England. [Easton, Douglas F.; Humphreys, Manjeet K.; Morrison, Jonathan; Pharoah, Paul D. P.; Pooley, Karen A.; USRTS] Univ Cambridge, Dept Publ Hlth, Cambridge, England. [Maia, Ana-Teresa; Barbosa-Morais, Nuno L.; Ponder, Bruce A. J.] CR UK Cambridge Res Inst, Li Ka Shing Ctr, London WC2A 3PX, England. [Low, Yen-Ling; Bingham, Sheila; SEARCH; EPIC] MRC Ctr Nutr Epidemiol, Cambridge, England. [Haiman, Christopher A.] Univ So Calif, Dept Prevent Med, Alhambra, CA 91803 USA. [Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Honolulu, HI 96822 USA. [Broeks, Annegien; Schmidt, Marjanka K.] Netherlands Canc Inst, Div Expt Therapy, NL-1066 CX Amsterdam, Netherlands. [Broeks, Annegien; Schmidt, Marjanka K.; MEC; ABCS] Netherlands Canc Inst, Div Epidemiol, NL-1066 CX Amsterdam, Netherlands. [Hopper, John] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne, Vic, Australia. [Southey, Melissa] Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia. [Beckmann, Matthias W.; ABCFS] Univ Hosp Erlangen, Univ Breast Ctr Franken, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, Dept Hematol & Oncol, Los Angeles, CA USA. [Peto, Julian] London Sch Hyg & Trop Med, CR UK Epidemiol & Genet Grp, London WC1E 7HT, England. [Peto, Julian; BBCC] Inst Canc Res, CR UK Epidemiol & Genet Grp, Sutton, Surrey, England. [Johnson, Nichola] Inst Canc Res, Breakthrough Breast Canc Res Ctr, London SW3 6JB, England. [Bojesen, Stig E.; Nordestgaard, Borge; BBCS; CGPS] Copenhagen Univ Hosp, Dept Clin Biochem, Copenhagen, Denmark. [Milne, Roger L.; Benitez, Javier] CNIO, Human Canc Genet Programme, Madrid, Spain. [Milne, Roger L.; Benitez, Javier; CNIO-BCS] CEGEN, Madrid, Spain. [Ko, Yon] Evangel Kliniken Bonn gGmbH, Dept Internal Med, Bonn, Germany. [Schmutzler, Rita K.; GENICA] Univ Cologne, Dept Obstet & Gynaecol, Cologne, Germany. [Burwinkel, Barbara] DKFZ, Grp Mol Epidemiol, Heidelberg, Germany. [Schuermann, Peter; Doerk, Thilo] Hannover Med Sch, Clin Obstet & Gynaecol, Hannover, Germany. [Schuermann, Peter; Doerk, Thilo; GC-HBOC; HABCS] Hannover Med Sch, Clin Radiat Oncol, Hannover, Germany. [Heikkinen, Tuomas; Nevanlinna, Heli; HEBCS] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00014 Helsinki, Finland. [Lindblom, Annika; Margolin, Sara] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Lindblom, Annika; Margolin, Sara] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Lindblom, Annika; Margolin, Sara; KARBAC] Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden. [Mannermaa, Arto; Kosma, Veli-Matti] Univ Kuopio, Inst Clin Med Pathol & Forens Med, FIN-70211 Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; KBCS] Kuopio Univ Hosp, Dept Pathol, SF-70210 Kuopio, Finland. [Chen, Xiaoqing; Spurdle, Amanda; Chenevix-Trench, Georgia] Univ Queensland, Royal Brisbane Hosp, Queensland Inst Med Res, Herston, Qld, Australia. [Chenevix-Trench, Georgia; kConFab; AOCS Management Grp] Peter MacCallum Canc Ctr, Melbourne, Vic 3002, Australia. [Change-Claude, Jenny] DFKZ Heidelberg, Div Canc Epidemiol, Heidelberg, Germany. [Flesch-Janys, Dieter] Univ Clin Hamburg Eppendorf, Inst Med Biometr & Epidemiol, Hamburg, Germany. [Couch, Fergus J.; Olson, Janet E.; MARIE; MCBCS] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Severi, Gianluca; Baglietto, Laura; Hall, Per; MCCS] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Vic 3053, Australia. [Brresen-Dale, Anne-Lise; Kristensen, Vessela] Rikshosp Radiumhosp, Dept Genet, Med Ctr, Oslo, Norway. [Brresen-Dale, Anne-Lise; Kristensen, Vessela; NBCS] Univ Oslo, Fac Med, Oslo, Norway. [Hunter, David J.; Hankinson, Susan E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hunter, David J.; Hankinson, Susan E.; NHS] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Devilee, Peter; Vreeswijk, Maaike] Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands. [Devilee, Peter; Vreeswijk, Maaike; ORIGO] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Brinton, Louise; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Liu, Jianjun; PBCS] Genome Inst Singapore, Singapore, Singapore. [Kang, Daehee; Yoo, Keun-Young; SASBAC; SEBCS] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Shen, Chen-Yang; Yu, Jyh-Cherng] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. [Shen, Chen-Yang; Yu, Jyh-Cherng; TWBCS] Tri Serv Gen Hosp, Deparment Surg, Taipei, Taiwan. [Anton-Culver, Hoda; Ziogoas, Argyrios; UCIBCS] Univ Calif Irvine, Deparment Epidemiol, Sch Med, Irvine, CA 92697 USA. [Sigurdson, Alice] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Struewing, Jeff] NHGRI, Bethesda, MD 20892 USA. RP Dunning, AM (reprint author), Strangeways Res Lab, Worts Causeway, Cambridge CB1 8RN, England. EM alisond@srl.cam.ac.uk RI Struewing, Jeffery/C-3221-2008; Yoo, Keun-Young/J-5548-2012; Barbosa-Morais, Nuno/I-2743-2013; Garcia-Closas, Montserrat /F-3871-2015; Spurdle, Amanda/A-4978-2011; Brinton, Louise/G-7486-2015; Maia, Ana-Teresa/F-4404-2012; Shen, CY/F-6271-2010; Struewing, Jeffery/I-7502-2013; Dork, Thilo/J-8620-2012; Bowtell, David/H-1007-2016; Kang, Dae Hee/E-8631-2012; OI Barbosa-Morais, Nuno/0000-0002-1215-0538; Garcia-Closas, Montserrat /0000-0003-1033-2650; Spurdle, Amanda/0000-0003-1337-7897; Brinton, Louise/0000-0003-3853-8562; Maia, Ana-Teresa/0000-0002-0454-9207; Struewing, Jeffery/0000-0002-4848-3334; Bowtell, David/0000-0001-9089-7525; Lissowska, Jolanta/0000-0003-2695-5799; Dunning, Alison Margaret/0000-0001-6651-7166; Nevanlinna, Heli/0000-0002-0916-2976 FU Cancer Research-UKgrants [C490/A11021, C20/A3084, C1287/A7497] FX This work has been predominantly funded by Cancer Research-UKgrants: C490/A11021 and C20/A3084 for SEARCH, C1287/A7497 for BCAC. NR 14 TC 58 Z9 58 U1 0 U2 10 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 MAR 15 PY 2009 VL 18 IS 6 BP 1131 EP 1139 DI 10.1093/hmg/ddn429 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 413XT UT WOS:000263828100014 PM 19126777 ER PT J AU Chung, TKH Cheung, TH Huen, NY Wong, KWY Lo, KWK Yim, SF Siu, NSS Wong, YM Tsang, PT Pang, MW Yu, MY To, KF Mok, SC Wang, VW Li, C Cheung, AYK Doran, G Birrer, MJ Smith, DI Wong, YF AF Chung, Tony K. H. Cheung, Tak-Hong Huen, Ngar-Yee Wong, Katherine W. Y. Lo, Keith W. K. Yim, So-Fan Siu, Nelson S. S. Wong, Yin-Mei Tsang, Po-Ting Pang, Man-Wah Yu, Mei-Yun To, Ka-Fei Mok, Samuel C. Wang, Vivian W. Li, Chen Cheung, Albert Y. K. Doran, Graeme Birrer, Michael J. Smith, David I. Wong, Yick-Fu TI Dysregulated microRNAs and their predicted targets associated with endometrioid endometrial adenocarcinoma in Hong Kong women SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE microRNA; endometrial; adenocarcinoma ID CHRONIC LYMPHOCYTIC-LEUKEMIA; EXPRESSION PROFILES; GENE-EXPRESSION; MIR-200 FAMILY; LUNG CANCERS; DIFFERENTIATION; APOPTOSIS; CELLS; IDENTIFICATION; NEUROBLASTOMA AB The objective of this study, a parallel study to global gene expression profiling, was to identify dysregulated microRNAs (miRNAs) associated with endometrioid endometrial adenocarcinoma (EEC), examine their correlation with clinico-pathological characteristics and identify predicted target genes of the dysregulated miRNAs. Using real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR), profiling of miRNA expression was performed in 30 EECs and 22 normal counterparts in which genome-wide gene expression had been previously profiled and reported. Clustering analysis identified 30 miRNAs which were significantly dysregulated in EEC. The expression of a sub-group of miRNAs was significantly correlated with clinico-pathological characteristics including stage, myometrial invasion, recurrence and lymph node involvement. By searching for predicted miRNA targets that were linked to the dysregulated genes previously identified, 68 genes were predicted as candidate targets of these 30 dysregulated miRNAs. miR-205 was significantly overexpressed in EECs compared with normal controls. After transfection of a miR-205 inhibitor, the expression of miR-205 in endometrial cancer cell line RL95-2 cells decreased whereas its predicted target gene, JPH4, showed increased protein expression. JPH4 seems to be a real miR-205 target in vitro and in vivo, and a candidate tumor suppressor gene in EEC. Based on this study in EEC, miRNAs predicted to be involved in tumorigenesis and tumor progression have been identified and placed in the context of the transcriptome of EEC. This work provides a framework on which further research into novel diagnosis and treatment of EEC can be focused. (c) 2008 Wiley-Liss, Inc. C1 [Chung, Tony K. H.; Cheung, Tak-Hong; Huen, Ngar-Yee; Wong, Katherine W. Y.; Lo, Keith W. K.; Yim, So-Fan; Siu, Nelson S. S.; Wong, Yin-Mei; Tsang, Po-Ting; Pang, Man-Wah; Wong, Yick-Fu] Chinese Univ Hong Kong, Prince Wales Hosp, Dept Obstet & Gynaecol, Shatin, Hong Kong, Peoples R China. [Yu, Mei-Yun; To, Ka-Fei] Prince Wales Hosp, Dept Anat & Cellular Pathol, Shatin, Hong Kong, Peoples R China. [Mok, Samuel C.; Wang, Vivian W.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet Gynecol & Reprod Med, Boston, MA 02115 USA. [Li, Chen] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Cheung, Albert Y. K.] Chinese Univ Hong Kong, Sch Publ Hlth, Ctr Biostat & Epidemiol, Shatin, Hong Kong, Peoples R China. [Doran, Graeme] MIT, Ctr Canc Res, Dept Biol, Cambridge, MA 02139 USA. [Birrer, Michael J.] NCI, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. [Smith, David I.] Mayo Clin, Sch Med, Dept Lab Med & Pathol, Rochester, MN USA. RP Wong, YF (reprint author), Chinese Univ Hong Kong, Prince Wales Hosp, Dept Obstet & Gynaecol, Shatin, Hong Kong, Peoples R China. EM yickfuwong@cuhk.edu.hk FU Hong Kong Special Administration Region [CUHK463807/07M] FX Grant sponsor: Research Grant Council of the Hong Kong Special Administration Region: Grant number: CUHK463807/07M. NR 35 TC 81 Z9 91 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 15 PY 2009 VL 124 IS 6 BP 1358 EP 1365 DI 10.1002/ijc.24071 PG 8 WC Oncology SC Oncology GA 409XR UT WOS:000263539600015 PM 19065659 ER PT J AU Kioi, M Shimamura, T Nakashima, H Hirota, M Tohnai, I Husain, SR Puri, RK AF Kioi, Mitomu Shimamura, Takeshi Nakashima, Hideyuki Hirota, Makoto Tohnai, Iwai Husain, Syed R. Puri, Raj K. TI IL-13 cytotoxin has potent antitumor activity and synergizes with paclitaxel in a mouse model of oral squamous cell carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE interleukin-13 receptor; squamous cell carcinoma; oral cancer; synergistic effect; gene transfer; retrovirus; paclitaxel; orthotopic animal model ID RECEPTOR ALPHA-2 CHAIN; INTERLEUKIN-13 RECEPTOR; PSEUDOMONAS EXOTOXIN; NECK-CANCER; INDUCTION CHEMOTHERAPY; OVARIAN-CANCER; BREAST-CANCER; HEAD; CISPLATIN; SUBUNIT AB Interleukin-13 receptor-targeted cytotoxin (IL13-PE38) is highly cytotoxic to certain types of human cancers expressing abundant levels of IL-13R alpha 2 chain. Although IL13-PE38 is being tested in a Phase III clinical trial in brain tumors, the activity of IL13-PE38 alone or when combined with taxane, a chemotherapeutic drug for oral squamous cell carcinoma (OSCC), has not been investigated. Here, we show that approximately 40% of OSCCs (n = 150) in a tissue array are strongly positive for IL-13R alpha 2, whereas normal oral mucosa (n = 10) expresses very low or undetectable levels evaluated by immunohistochemistry. IL13-PE38 was highly cytotoxic to OSCC cell lines, but not cytotoxic to normal oral fibroblasts. IL13-PE38 mediated a synergistic antitumor effect with paclitaxel in OSC-19 in vitro and in vivo in the orthotopic OSCC tongue tumor model. Real-time tumor growth was monitored by optical imaging using a Xenogen-IVIS imaging system. Treated animals showed significant (p < 0.05) improvement in survival, which correlated with in vivo imaging of tumor response without evidence of visible toxicity. Gene transfer of IL-13Ra2 in oral cancer cells increased sensitivity of OSCC cell line to IL13-PE38 in vitro. Retro-virus-mediated gene-transfer of IL-13R alpha 2 in HSC-3 into tongue tumors in vivo dramatically enhanced the antitumor activity of IL13-PE38, providing complete elimination of established tumors and prolonging survival of these animals. These results indicate that IL13-PE38 in combination with paclitaxel acting via different mechanisms may be a potential treatment option for IL-13R alpha 2 expressing OSCC or for the treatment of nom-IL-13R alpha 2 expressing OSCC combined with gene transfer of IL-13R alpha 2. Published 2008 Wiley-Liss, Inc. C1 [Kioi, Mitomu; Shimamura, Takeshi; Nakashima, Hideyuki; Husain, Syed R.; Puri, Raj K.] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Hirota, Makoto; Tohnai, Iwai] Yokohama City Univ, Sch Med, Dept Oral & Maxillofacial Surg, Kanazawa Ku, Yokohama, Kanagawa 232, Japan. RP Puri, RK (reprint author), US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, NIH Bldg 29B,Room 2NN20,29 Lincoln Dr, Bethesda, MD 20892 USA. EM raj.puri@fda.hhs.gov OI Kioi, Mitomu/0000-0002-7981-3340 NR 34 TC 13 Z9 13 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 MAR 15 PY 2009 VL 124 IS 6 BP 1440 EP 1448 DI 10.1002/ijc.24067 PG 9 WC Oncology SC Oncology GA 409XR UT WOS:000263539600027 PM 19065664 ER PT J AU Chi, YH Ward, JM Cheng, LI Yasunaga, J Jeang, KT AF Chi, Ya-Hui Ward, Jerrold M. Cheng, Lily I. Yasunaga, Junichiro Jeang, Kuan-Teh TI Spindle assembly checkpoint and p53 deficiencies cooperate for tumorigenesis in mice SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE Mad1; Mad2; p53; spindle assembly checkpoint; tumorigenesis ID CELL-CYCLE CONTROL; MITOTIC CHECKPOINT; CHROMOSOME INSTABILITY; SACCHAROMYCES-CEREVISIAE; CANCER PREDISPOSITION; PROTEIN MAD2; ANEUPLOIDY; MUTATION; BUB3; HETEROZYGOSITY AB The spindle assembly checkpoint (SAC) guards against chromosomal missegregation during mitosis. To investigate the role of SAC in tumor development, mice heterozygously knocked out for the mitotic arrest deficient (Mad) genes Mad1 and/or Mad2 were mated with p53(+/-) mice. Increased tumor frequencies were reproducibly observed in Mad2(+/-)p53(+/-) (88.2%) and Mad1(+/-) Mad2(+/-) p53(+/-) (95.0%) mice compared with p53(+/-) (66.7%) mice. Moreover, 53% of Mad2(+/-) p53(+/-) mice developed lymphomas compared with 11% of p53(+/-) mice. By examining chromosome content, increased loss in diploidy was seen in cells from Mad2(+/-) p53(+/-) versus p53(+/-) mice, correlating loss of SAC function, in a P53(+/-) context, with increased aneuploidy and tumorigenesis. The findings here provide evidence for a cooperative role of Mad1/Mad2 and p53 genes in preventing tumor development. (C) 2008 Wiley-Liss, Inc. C1 [Chi, Ya-Hui; Yasunaga, Junichiro; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Ward, Jerrold M.; Cheng, Lily I.] NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), Bldg 4,Room 306,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kj7e@nih.gov RI Chi, Ya-Hui/B-1080-2010; Jeang, Kuan-Teh/A-2424-2008; OI Yasunaga, Jun-ichirou/0000-0002-7939-2080 FU NIAID/NIH Intramural Funds; MAID; SoBran, Inc FX This work was supported by intramural NIAID funds and a contract to SoBran, Inc. NR 45 TC 25 Z9 26 U1 2 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 15 PY 2009 VL 124 IS 6 BP 1483 EP 1489 DI 10.1002/ijc.24094 PG 7 WC Oncology SC Oncology GA 409XR UT WOS:000263539600033 PM 19065665 ER PT J AU Wasserman, TH Coleman, CN AF Wasserman, Todd H. Coleman, C. Norman TI MENTORS, MENSCHES, AND MODELS SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Editorial Material C1 [Coleman, C. Norman] NCI, Radiat Res Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Wasserman, Todd H.] Washington Univ, Med Ctr, Dept Radiat Oncol, St Louis, MO USA. RP Coleman, CN (reprint author), NCI, Radiat Res Program, Div Canc Treatment & Diag, EPN Rm 6014,6130 Execut Blvd, Bethesda, MD 20892 USA. EM ccoleman@mail.nih.gov NR 6 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 15 PY 2009 VL 73 IS 4 BP 974 EP 975 DI 10.1016/j.ijrobp.2008.10.078 PG 2 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 419ZE UT WOS:000264257400003 PM 19251083 ER PT J AU Yang, JH Ritchey, M Yoshida, Y Bush, CA Cisar, JO AF Yang, Jinghua Ritchey, Mary Yoshida, Yasuo Bush, C. Allen Cisar, John O. TI Comparative Structural and Molecular Characterization of Ribitol-5-Phosphate-Containing Streptococcus oralis Coaggregation Receptor Polysaccharides SO JOURNAL OF BACTERIOLOGY LA English DT Article ID ACTINOMYCES-VISCOSUS T14V; CAPSULAR BIOSYNTHETIC LOCI; CELL-WALL POLYSACCHARIDES; GENETIC-TRANSFORMATION; GORDONII; GLYCOSYLTRANSFERASES; RECOGNITION; COMPETENCE; MOTIFS AB The antigenically related coaggregation receptor polysaccharides (RPS) of Streptococcus oralis strains C104 and SK144 mediate recognition of these bacteria by other members of the dental plaque biofilm community. In the present study, the structure of strain SK144 RPS was established by high resolution NMR spectroscopy as [6Galf beta 1-6GalNAc beta 1-3Gal alpha 1-2ribitol-5-PO(4)(-)-6Galf beta 1-3Gal beta 1](n), thereby indicating that this polysaccharide and the previously characterized RPS of strain C104 are identical, except for the linkage between Gal and ribitol-5-phosphate, which is alpha 1-2 in strain SK144 versus alpha 1-1 in strain C104. Studies to define the molecular basis of RPS structure revealed comparable genes for six putative transferases and a polymerase in the rps loci of these streptococci. Cell surface RPS production was abolished by disrupting the gene for the first transferase of strain C104 with a nonpolar erm cassette. It was restored in the resulting mutant by plasmid-based expression of either wcjG, the corresponding gene of S. pneumoniae for serotype 10A capsular polysaccharide (CPS) biosynthesis or wbaP for the transferase of Salmonella enterica that initiates O-polysaccharide biosynthesis. Thus, WcjG, like WbaP, appears to initiate polysaccharide biosynthesis by transferring galactose-1-phosphate to a lipid carrier. In further studies, the structure of strain C104 RPS was converted to that of strain SK144 by replacing the gene (wefM) for the fourth transferase in the rps locus of strain C104 with the corresponding gene (wcrC) of strain SK144 or Streptococcus pneumoniae serotype 10A. These findings identify genetic markers for the different ribitol-5-phosphate-containing types of RPS present in S. oralis and establish a close relationship between these polysaccharides and serogroup 10 CPSs of S. pneumoniae. C1 [Yang, Jinghua; Cisar, John O.] NIDCR, NIH, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. [Ritchey, Mary; Bush, C. Allen] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21228 USA. [Yoshida, Yasuo] Iwate Med Univ, Dept Pharmacol, Sch Dent, Morioka, Iwate 0208505, Japan. RP Cisar, JO (reprint author), NIDCR, NIH, Oral Infect & Immun Branch, Bldg 30,Room 3A-301,30 Convent Dr, Bethesda, MD 20892 USA. EM john.cisar@nih.gov FU NIH; NIDCR FX This work was supported in part by the Intramural Research Program of the NIH, NIDCR. NR 37 TC 20 Z9 20 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD MAR 15 PY 2009 VL 191 IS 6 BP 1891 EP 1900 DI 10.1128/JB.01532-08 PG 10 WC Microbiology SC Microbiology GA 413VB UT WOS:000263819500017 PM 19151140 ER PT J AU Charni, S Aguilo, JI Garaude, J de Bettignies, G Jacquet, C Hipskind, RA Singer, D Anel, A Villalba, M AF Charni, Seyma Ignacio Aguilo, Juan Garaude, Johan de Bettignies, Geolfroy Jacquet, Chantal Hipskind, Robert A. Singer, Dinah Anel, Alberto Villalba, Martin TI ERK5 Knockdown Generates Mouse Leukemia Cells with Low MHC Class I Levels That Activate NK Cells and Block Tumorigenesis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; NF-KAPPA-B; T-CELLS; TARGET-CELLS; EXPRESSION; VIVO; IMMUNITY; LIGANDS; NKG2D; FAS AB Tumor cell-based vaccines are currently used in clinical trails, but they are in general poorly immunogenic because they are composed of cell extracts or apoptotic cells. Live tumor cells should be much better Ags provided that they are properly processed by the host immune system. We show herein that stable expression of a small hairpin RNA for ERK5 (shERK5) decreases ERK5 levels in human and mouse leukemic cells and leads to their elimination by NK cells in vivo. The shERK5 cells show downregulation of MHC class I expression at the plasma membrane. Accordingly, ectopic activation of the ERK5 pathway induces MHC class I gene expression. Coinjection of shERK5-expressing cells into the peritoneum diminishes survival of engrafted wild-type tumor cells. Moreover, s.c. injection of shERK5-expressing cells strongly diminishes tumor development by wild-type cells. Our results show that shERK5 expression in leukemia cells effectively attenuates their tumor activity and allows their use as a tumor cell-based vaccine. The Journal of Immunology, 2009, 182: 3398-3405. C1 [Charni, Seyma; Garaude, Johan; de Bettignies, Geolfroy; Jacquet, Chantal; Hipskind, Robert A.; Villalba, Martin] Univ Montpellier 1&2, CNRS, Inst Mol Genet Montpellier, UMR 5535, F-34293 Montpellier 5, France. [Ignacio Aguilo, Juan; Anel, Alberto] Univ Zaragoza, Dept Bioquim & Biol Mol & Celular, Zaragoza, Spain. [Singer, Dinah] NCI, Expt Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Villalba, M (reprint author), Univ Montpellier 1&2, CNRS, Inst Mol Genet Montpellier, UMR 5535, 1919 Route Mende, F-34293 Montpellier 5, France. EM martin.villalba@igmm.cnrs.fr RI AGUILO, NACHO/K-2750-2014 OI AGUILO, NACHO/0000-0001-7897-9173 FU Institut National do Caricer/Canceropole; La Ligue Nationale Contre le Cancer; Comite de la Lozere; Association pour la Recherche sur le Cancer; Spanish Ministerio de Educacion [SAF2007-65144]; Ministerio de Educacion y Ciencia/Fondo Social Europeo [SAF2004-03058]; National Institutes of Health National Cancer Institute; Center for Cancer Research FX This work was supported by the Institut National do Caricer/Canceropole Grand Sud-Ouest (to M.V.), La Ligue Nationale Contre le Cancer: Comite de la Lozere (to M.V.), the Association pour la Recherche sur le Cancer (to R.A.H.), the Spanish Ministerio de Educacion Grant SAF2007-65144 (to A.A.), as well its by fellowships from La Ligue Nationale Contre le Cancer: Comite Nationale (to J.G.), the Region Languedoc-Rousillon (to S.C.), and a Formacion de Personal Investigador fellowship associated with Grant SAF2004-03058 from the the Ministerio de Educacion y Ciencia/Fondo Social Europeo (to J.I.A.). Ibis research was also supported in part by the Intramural Research Program of the National Institutes of Health National Cancer Institute, Center for Cancer Research. NR 39 TC 17 Z9 17 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 MAR 15 PY 2009 VL 182 IS 6 BP 3398 EP 3405 DI 10.4049/jimmunol.0803006 PG 8 WC Immunology SC Immunology GA 417NX UT WOS:000264084100009 PM 19265117 ER PT J AU Claudio, E Saret, S Wang, HS Siebenlist, U AF Claudio, Estefania Saret, Sun Wang, Hongshan Siebenlist, Ulrich TI Cell-Autonomous Role for NF-kappa B in Immature Bone Marrow B Cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NUCLEAR-FACTOR; LYMPHOCYTE DEVELOPMENT; SIGNALING PATHWAY; SELF-TOLERANCE; IKK-ALPHA; ACTIVATION; RECEPTOR; BAFF; IMMUNITY; DIFFERENTIATION AB The NF-kappa B transcription factors have many essential functions in B cells, such as during differentiation and proliferation of Ag-challenged mature B cells, but also during final maturation of developing B cells in the spleen. Among the various specific functions NF-kappa B factors carry out in these biologic contexts, their ability to assure the survival of mature and maturing B cells in the periphery stands out. Less clear is what if any roles NF-kappa B factors play during earlier stages of B cell development in the bone marrow. Using mice deficient in both NF-kappa B1 and NF-kappa B2, which are thus partially compromised in both the classical and alternative activation pathways, we demonstrate a B cell-autonomous contribution of NF-kappa B to the survival of immature B cells in the bone marrow. NF-kappa B1 and NF-kappa B2 also play a role during the earlier transition from proB to late preB cells; however, in this context these factors do not act in a B cell-autonomous fashion. Although NF-kappa B1 and NF-kappa B2 are not absolutely required for survival and progression of immature B cells in the bone marrow, they nevertheless make a significant contribution that marks the beginning of the profound cell-autonomous control these factors exert during all subsequent stages of B cell development. Therefore, the lifelong dependency of B cells on NF-kappa B-mediated survival functions is set in motion at the time of first expression of a full BCR. The Journal of Immunology, 2009, 182: 3406-3413. C1 [Claudio, Estefania; Saret, Sun; Wang, Hongshan; Siebenlist, Ulrich] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Siebenlist, U (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 11B15A, Bethesda, MD 20892 USA. EM USiebenlist@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases FX This work was supported by funds front the intramural program of the National Institute of Allergy and Infectious Diseases. NR 44 TC 9 Z9 10 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 MAR 15 PY 2009 VL 182 IS 6 BP 3406 EP 3413 DI 10.4049/jimmunol.0803360 PG 8 WC Immunology SC Immunology GA 417NX UT WOS:000264084100010 PM 19265118 ER PT J AU Omokaro, SO Desierto, MJ Eckhaus, MA Ellison, FM Chen, JC Young, NS AF Omokaro, Stephanie O. Desierto, Marie J. Eckhaus, Michael A. Ellison, Felicia M. Chen, Jichun Young, Neal S. TI Lymphocytes with Aberrant Expression of Fas or Fas Ligand Attenuate Immune Bone Marrow Failure in a Mouse Model SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACQUIRED APLASTIC-ANEMIA; NECROSIS-FACTOR-ALPHA; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; BLOOD MONONUCLEAR-CELLS; REGULATORY T-CELLS; MEDIATED APOPTOSIS; INTERFERON-GAMMA; HEMATOPOIETIC-CELLS; CD34(+) CELLS; IN-VITRO AB Bone marrow (BM) and lymphocyte samples from aplastic anemia patients show up-regulated Fas and Fas-ligand (FasL) expression, respectively, supporting a relationship between immune-mediated BM destruction and the Fas apoptotic pathway. Mice with spontaneous lymphoproliferation (lpr) and generalized lymphoproliferative disease (gld) mutations exhibit abnormal expression of Fas and FasL, serving as potential models to elucidate underlying mechanisms of BM failure. We examined cellular and functional characteristics of lpr and gld mutants on the C57BL/6 (B6) background. Lymph node (LN) cells from lpr and gld mice produced less apoptosis when coincubated with C.B10-H2(b)/LilMcd (C.B10) BM cells in vitro. This functional difference was confirmed by infusing lpr, gld, and B6 LN cells into sublethally irradiated CB10 mice. All donor LN cells showed significant T cell expansion and activation, but only B6 LN cells caused severe BM destruction. Mice infused with gld LN cells developed mild to moderate BM failure despite receiving FasL-deficient effectors, thus suggesting the existence of alternative pathways or incomplete penetrance of the mutation. Paradoxically, mice that received Fas-deficient lpr LN cells also had reduced BM failure, likely due to down-regulation of proapoptotic genes, an effect that can be overcome by higher doses of lpr LN cells. Our model demonstrates that abnormal Fas or FasL expression interferes with the development of pancytopenia and marrow hypoplasia, validating a major role for the Fas/FasL cytotoxic pathway in immune-mediated BM failure, although disruption of this pathway does not completely abolish marrow destruction. The Journal of Immunology, 2009, 182: 3414-3422. C1 [Omokaro, Stephanie O.; Desierto, Marie J.; Ellison, Felicia M.; Chen, Jichun; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Eckhaus, Michael A.] NIH, Div Vet Resources, Off Res Serv, Bethesda, MD 20892 USA. RP Omokaro, SO (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10 Clin Res Ctr Room 3E-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM omokaros@mail.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 54 TC 13 Z9 18 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAR 15 PY 2009 VL 182 IS 6 BP 3414 EP 3422 DI 10.4049/jimmunol.0801430 PG 9 WC Immunology SC Immunology GA 417NX UT WOS:000264084100011 PM 19265119 ER PT J AU Florese, RH Demberg, T Xiao, P Kuller, L Larsen, K Summers, LE Venzon, D Cafaro, A Ensoli, B Robert-Guroff, M AF Florese, Ruth H. Demberg, Thorsten Xiao, Peng Kuller, LaRene Larsen, Kay Summers, L. Ebonita Venzon, David Cafaro, Aurelio Ensoli, Barbara Robert-Guroff, Marjorie TI Contribution of Nonneutralizing Vaccine-Elicited Antibody Activities to Improved Protective Efficacy in Rhesus Macaques Immunized with Tat/Env Compared with Multigenic Vaccines SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DEPENDENT CELLULAR CYTOTOXICITY; HIV-1 TAT PROTEIN; DIFFERENT CLINICAL STAGES; MEDIATED CYTOTOXICITY; DISEASE PROGRESSION; T-CELLS; CYTO-TOXICITY; NEF PROTEIN; PASSIVE-IMMUNIZATION AB Previously, chronic-phase protection against SHIV(89.6P) challenge was significantly greater in macaques primed with replicating adenovirus type 5 host range mutant (Ad5hr) recombinants encoding HIVtat and env and boosted with Tat and Env protein compared with macaques primed with multigenic adenovirus recombinants (HIVtat, HIVenv, SIVgag, SIVnef) and boosted with Tat, Env, and Nef proteins. The greater protection was correlated with Tat- and Env-binding Abs. Because the macaques lacked SHIV(89.6P)-neutralizing activity prechallenge, we investigated whether Ab-dependent cellular cytotoxicity (ADCC) and Ab-dependent cell-mediated viral inhibition (ADCVI) might exert a protective effect. We clearly show that Tat can serve as an ADCC target, although the Tat-specific activity elicited did not correlate with better protection. However, Env-specific ADCC activity was consistently higher in the Tat/Env group, with sustained cell killing postchallenge exhibited at higher levels (P < 0.00001) for a longer duration (p = 0.0002) compared with the multigenic group. ADCVI was similarly higher in the Tat/Env group and significantly correlated with reduced acute-phase viremia at wk 2 and 4 postchallenge (p = 0.046 and 0.011, respectively). Viral-specific IgG and IgA Abs in mucosal secretions were elicited but did not influence the outcome of the i.v. SHIV(89.6P) challenge. The higher ADCC and ADCVI activities seen in the Tat/Env group provide a plausible mechanism responsible for the greater chronic-phase protection. Because Tat is known to enhance cell-mediated immunity to coadministered Ags, further studies should explore its impact on Ab induction so that it may be optimally incorporated into HIV vaccine regimens. The Journal of Immunology, 2009, 182: 3718-3727. C1 [Florese, Ruth H.; Demberg, Thorsten; Xiao, Peng; Summers, L. Ebonita; Robert-Guroff, Marjorie] NCI, NIH, Vaccine Branch, Bethesda, MD 20892 USA. [Venzon, David] NCI, NIH, Biostat & Data Management Sect, Bethesda, MD 20892 USA. [Kuller, LaRene; Larsen, Kay] Univ Washington, Washington Natl Primate Res Ctr, Seattle, WA 98195 USA. [Cafaro, Aurelio; Ensoli, Barbara] Natl AIDS Ctr, Ist Super Sanita, Rome, Italy. RP Robert-Guroff, M (reprint author), NCI, NIH, Vaccine Branch, 41 Medars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov RI Ensoli, Barbara/J-9169-2016; Cafaro, Aurelio/K-5314-2016 OI Ensoli, Barbara/0000-0002-0545-8737; FU National Institutes of Health; National Cancer Institute; National Institute of Allergy and Infectious Diseases [N01-AI-15431] FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute and by National Institutes of Health. National Institute of Allergy and Infectious Diseases Simian Vaccine Evaluation Contract N01-AI-15431 to the University of Washington. NR 71 TC 82 Z9 82 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 MAR 15 PY 2009 VL 182 IS 6 BP 3718 EP 3727 DI 10.4049/jimmunol.0803115 PG 10 WC Immunology SC Immunology GA 417NX UT WOS:000264084100042 PM 19265150 ER PT J AU Kim, MJ Romero, R Kim, CJ Tarca, AL Chhauy, S LaJeunesse, C Lee, DC Draghici, S Gotsch, F Kusanovic, JP Hassan, SS Kim, JS AF Kim, Mi Jeong Romero, Roberto Kim, Chong Jai Tarca, Adi L. Chhauy, Sovantha LaJeunesse, Christopher Lee, Deug-Chan Draghici, Sorin Gotsch, Francesca Kusanovic, Juan Pedro Hassan, Sonia S. Kim, Jung-Sun TI Villitis of Unknown Etiology Is Associated with a Distinct Pattern of Chemokine Up-Regulation in the Feto-Maternal and Placental Compartments: Implications for Conjoint Maternal Allograft Rejection and Maternal Anti-Fetal Graft-versus-Host Disease SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BONE-MARROW-TRANSPLANTATION; IN-SITU HYBRIDIZATION; GENE-EXPRESSION; ENDOTHELIAL-CELLS; T-CELLS; INFLAMMATION; PATHWAY; LEVEL; SERUM; CXCR3 AB The co-presence of histoincompatible fetal and maternal cells is a characteristic of human placental inflammation. Villitis of unknown etiology (VUE), a destructive inflammatory lesion of villous placenta, is characterized by participation of Hofbauer cells (placental macrophages) and maternal T cells. In contrast to acute chorioamnionitis of infection-related origin, the fundamental immunopathology of VUE is unknown. This study was performed to investigate the placental transcriptome of VUE and to determine whether VUE is associated with systemic maternal and/or fetal inflammatory response(s). Comparison of the. transcriptome between term placentas without and with VUE revealed differential expression of 206 genes associated with pathways related to immune response. The mRNA expression of a subset of chemokines and their receptors (CXCL9, CXCL10, CXCL11, CXCL13, CCL4, CCL5, CXCR3, CCR5) was higher in VUE placentas than in normal placentas (p < 0.05). Analysis of blood cell mRNA showed a higher expression of CXCL9 and CXCL13 in the mother, and CXCL11 and CXCL13 in the fetus of VUE cases (p < 0.05). The median concentrations of CXCL9, CXCL10, and CXCL11 in maternal and fetal plasma were higher in VUE (P < 0.05). Comparison of preterm cases without and with acute chorioamnionitis revealed elevated CXCL9, CXCL10, CXCL11, and CXCL13 concentrations in fetal plasma (p < 0.05), but not in maternal plasma with chorioamnionitis. We report for the first time the placental transcriptome of VUE. A systemic derangement of CXC chemokines in maternal and fetal circulation distinguishes VUE from acute chorioamnionitis. We propose that VUE be a unique state combining maternal allograft rejection and maternal antifetal graft-vs-host disease mechanisms. The Journal of Immunology, 2009, 182: 3919-3927. C1 [Kim, Mi Jeong; Romero, Roberto; Kim, Chong Jai; Tarca, Adi L.; Chhauy, Sovantha; LaJeunesse, Christopher; Lee, Deug-Chan; Gotsch, Francesca; Kusanovic, Juan Pedro; Hassan, Sonia S.; Kim, Jung-Sun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Romero, Roberto; Tarca, Adi L.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Tarca, Adi L.; Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Detroit, MI 48201 USA. [Kim, Chong Jai; Kim, Jung-Sun] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Kusanovic, Juan Pedro; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Kim, JS (reprint author), Wayne State Univ, Perinatol Res Branch, NICHHD, NIH,Dept Hlth & Human Serv,Hutzel Womens Hosp, 3990 John R,4th Floor, Detroit, MI 48201 USA. EM jkim@med.wayne.edu RI Draghici, Sorin/B-3074-2013 OI Draghici, Sorin/0000-0002-0786-8377 FU Perinatology Research Branch; Division of Intramural Research; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institutes of Health; Department of Health and Human Services FX This work was supported by the Perinatology Research Branch, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services. NR 54 TC 70 Z9 73 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 MAR 15 PY 2009 VL 182 IS 6 BP 3919 EP 3927 PG 9 WC Immunology SC Immunology GA 417NX UT WOS:000264084100063 PM 19265171 ER PT J AU Wilkin, TJ McKinnon, JE DiRienzo, AG Mollan, K Fletcher, CV Margolis, DM Bastow, B Thal, G Woodward, W Godfrey, C Wiegand, A Maldarelli, F Palmer, S Coffin, JM Mellors, JW Swindells, S AF Wilkin, Timothy J. McKinnon, John E. DiRienzo, A. Gregory Mollan, Katie Fletcher, Courtney V. Margolis, David M. Bastow, Barbara Thal, Gary Woodward, William Godfrey, Catherine Wiegand, Ann Maldarelli, Frank Palmer, Sarah Coffin, John M. Mellors, John W. Swindells, Susan TI Regimen Simplification to Atazanavir-Ritonavir Alone as Maintenance Antiretroviral Therapy: Final 48-Week Clinical and Virologic Outcomes SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID LOPINAVIR-RITONAVIR; INITIAL TREATMENT; HIV-1 INFECTION; MONOTHERAPY; TRIAL; LOPINAVIR/RITONAVIR; SUPPRESSION; EFFICACY; VIREMIA; SAFETY AB Background. Simplified maintenance therapy with ritonavir-boosted atazanavir ATV/RTV) alone is attractive because of nucleoside reverse-transcriptase inhibitor NRTI)-sparing benefits, low pill burden, once-daily dosage, and safety. Methods. Subjects with virologic suppression after >= 48 weeks of initial antiretroviral therapy with 2 NRTIs and a protease inhibitor PI) were enrolled. Subjects switched to ATV/RTV at entry and discontinued NRTIs after 6 weeks. The primary end point was time to virologic failure confirmed HIV-1 RNA level >= 200 copies/mL). Drug resistance at virologic failure was evaluated by standard genotyping and single-genome sequencing SGS). Residual viremia 1.1-49 copies/mL) was measured by single-copy assay. Results. Thirty-four subjects simplified to ATV/RTV alone, of whom 30 88%) did not experience virologic failure by 48 weeks after simplification. Residual viremia did not change significantly after NRTI discontinuation among those without virologic failure but did increase 4-12 weeks before confirmed virologic failure. No major PI-resistance mutations were identified at virologic failure by standard genotyping or SGS. Conclusions. In this pilot study, simplified maintenance therapy with ATV/RTV alone maintained viral suppression in most subjects through 48 weeks. PI resistance was not detected among subjects experiencing virologic failure. Larger, randomized trials are warranted to further define the efficacy and safety of this strategy. Trial registration. Clinical Trials. gov identifier: NCT00084019. C1 [Wilkin, Timothy J.] Weill Cornell Med Coll, Div Int Med & Infect Dis, New York, NY USA. [DiRienzo, A. Gregory] SUNY Albany, Rensselaer, NY USA. [McKinnon, John E.; Mellors, John W.] Univ Pittsburgh, Pittsburgh, PA USA. [Woodward, William] Abbott Labs, Sinking Spring, PA USA. [Mollan, Katie] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Coffin, John M.] Tufts Univ, Boston, MA 02111 USA. [Fletcher, Courtney V.; Swindells, Susan] Univ Nebraska, Med Ctr, Omaha, NE USA. [Margolis, David M.] Univ N Carolina, Chapel Hill, NC USA. [Bastow, Barbara] Social & Sci Syst Inc, Silver Spring, MD USA. [Godfrey, Catherine] NIAID, Div AIDS, NIH, Rockville, MD USA. [Wiegand, Ann; Maldarelli, Frank; Palmer, Sarah] NCI, HIV Drug Resistance Program, Frederick, MD USA. [Thal, Gary] Bristol Myers Squibb Co, Princeton, NJ USA. RP Wilkin, TJ (reprint author), 119 W 24th St,Ground Floor, New York, NY 10011 USA. EM tiw2001@med.cornell.edu OI Margolis, David/0000-0001-5714-0002 FU NCATS NIH HHS [KL2 TR000146]; NCRR NIH HHS [K12 RR024154, KL2 RR024154, KL2 RR024154-03, M01 RR000046, M01 RR000046-48, M01 RR000047, M01 RR000047-460702, M01 RR000047-476126, M01 RR000051, RR00046, RR00051, RR024154, RR024996, UL1 RR024979, UL1 RR024996, UL1 RR024996-01]; NIAID NIH HHS [T32 AI007333, AI069415, AI27661, AI34853, AI46376, AI46383, AI50410, AI68634, AI68636, AI69419, AI69423, AI69450, AI69484, AI69513, AI69556, K23 AI055038, K23 AI055038-05, K23 AI55038, P30 AI050410, P30 AI050410-11, T32 AI007333-19, U01 AI027661, U01 AI027661-14, U01 AI034853, U01 AI034853-12, U01 AI046376, U01 AI046376-04, U01 AI046383, U01 AI046383-05, U01 AI068634, U01 AI068634-01, U01 AI068636, U01 AI068636-01, U01 AI068636-03, U01 AI069415, U01 AI069415-03, U01 AI069419, U01 AI069419-03, U01 AI069423, U01 AI069423-03, U01 AI069450, U01 AI069450-03, U01 AI069484, U01 AI069484-03, U01 AI069513, U01 AI069513-03, U01 AI069556, U01 AI069556-03, UM1 AI068634, UM1 AI068636, UM1 AI069419, UM1 AI069423, UM1 AI069450, UM1 AI069484, UM1 AI069513, UM1 AI069556] NR 21 TC 39 Z9 41 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2009 VL 199 IS 6 BP 866 EP 871 DI 10.1086/597119 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 411UU UT WOS:000263677900014 PM 19191590 ER PT J AU Morens, DM Taubenberger, JK Fauci, AS AF Morens, David M. Taubenberger, Jeffery K. Fauci, Anthony S. TI Commentary on Fatalities in the 1918-1919 Influenza Pandemic Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter C1 [Morens, David M.; Taubenberger, Jeffery K.; Fauci, Anthony S.] NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), NIAID, NIH, Bldg 31,Room 7A-10,31 Ctr Dr,MSC 2520, Bethesda, MD 20892 USA. EM dmorens@niaid.nih.gov NR 3 TC 1 Z9 1 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2009 VL 199 IS 6 BP 913 EP 914 DI 10.1086/597047 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 411UU UT WOS:000263677900021 ER PT J AU Li, RJ Keil, A Principe, JC AF Li, Ruijiang Keil, Andreas Principe, Jose C. TI Single-trial P300 estimation with a spatiotemporal filtering method SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Event-related potentials; Single-trial analysis; P300; Spatiotemporal filtering ID INDEPENDENT COMPONENT ANALYSIS; HUMAN BRAIN; EEG; POTENTIALS; ATTENTION; AMPLITUDE AB A spatiotemporal filtering method for single-trial ERP component estimation is presented. Instead of modeling the entire ERP waveform, the method focuses on the ERP component local descriptors (amplitude and latency) thru the spatial diversity of multichannel recordings and thus it is tailored to extract signals in negative signal to noise ratio conditions. The model allows for both amplitude and latency variability in the ERP component under investigation. We applied the method to the estimation of the P300 component in an oddball target detection task and found that negative correlations exist between response time and single-trial P300 amplitude. (C) 2008 Elsevier B.V. All rights reserved. C1 [Li, Ruijiang; Principe, Jose C.] Univ Florida, Computat Neuroengn Lab, Gainesville, FL 32611 USA. [Keil, Andreas] Univ Florida, Dept Psychol, Gainesville, FL 32611 USA. [Keil, Andreas] Univ Florida, NIMH Ctr Study Emot &Attent, Gainesville, FL 32611 USA. RP Li, RJ (reprint author), Univ Florida, Computat Neuroengn Lab, POB 116130, Gainesville, FL 32611 USA. EM ruijiang@cnel.ufl.edu; akeil@ufl.edu; principe@cnel.ufl.edu RI Keil, Andreas/F-9427-2011 OI Keil, Andreas/0000-0002-4064-1924 FU NIMH [P50 MH072850-01]; University of Florida FX This work was partially supported by NIMH grant P50 MH072850-01 and Graduate Alumni Fellowship from the University of Florida. NR 29 TC 14 Z9 14 U1 1 U2 5 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 MAR 15 PY 2009 VL 177 IS 2 BP 488 EP 496 DI 10.1016/j.jneumeth.2008.10.035 PG 9 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 407VV UT WOS:000263393300029 PM 19041343 ER PT J AU Good, CH Lupica, CR AF Good, Cameron H. Lupica, Carl R. TI Properties of distinct ventral tegmental area synapses activated via pedunculopontine or ventral tegmental area stimulation in vitro SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID MIDBRAIN DOPAMINE NEURONS; NICOTINIC ACETYLCHOLINE-RECEPTORS; LONG-TERM POTENTIATION; RAT NUCLEUS-ACCUMBENS; BRAIN REWARD AREAS; CHOLINERGIC NEURONS; GABAERGIC NEURONS; SUBSTANTIA-NIGRA; GLUTAMATE RECEPTORS; SYNAPTIC MECHANISMS AB Anatomical studies indicate that synaptic inputs from many cortical and subcortical structures converge on neurons of the ventral tegmental area (VTA). Although in vitro electrophysiological studies have examined synaptic inputs to dopamine (DA) and non-DA neurons in the VTA, they have largely relied upon local electrical stimulation to activate these synapses. This provides little information regarding the distinct properties of synapses originating from different brain areas. Using whole-cell recordings in parasagittal rat brain slices that preserved subcortical axons from the pedunculopontine nucleus (PPN) to the VTA, we compared these synapses with those activated by intra-VTA stimulation. PPN-evoked currents demonstrated longer latencies than intra-VTA-evoked currents, and both VTA and PPN responses were mediated by GABA(A) and AMPA receptors. However, unlike VTA-evoked currents, PPN currents were exclusively mediated by glutamate in 25-40% of the VTA neurons. Consistent with a cholinergic projection from the PPN to the VTA, nicotinic acetylcholine receptors (nAChR) were activated by endogenous acetylcholine released during PPN, but not VTA, stimulation. This was seen as a reduction of PPN-evoked, and not VTA-evoked, synaptic currents by the alpha 7-nAChR antagonist methyllycaconitine (MLA) and the agonist nicotine. The beta 2-nAChR subunit antagonist dihydro-beta-erythroidine had no effect on VTA- or PPN-evoked synaptic currents. The effects of MLA on PPN-evoked currents were unchanged by the GABA(A) receptor blocker picrotoxin, indicating that alpha 7-nAChRs presynaptically modulated glutamate and not GABA release. These differences in physiological and pharmacological properties demonstrate that ascending PPN and presumed descending inputs to VTA utilize distinct mechanisms to differentially modulate neuronal activity and encode cortical and subcortical information. C1 [Good, Cameron H.; Lupica, Carl R.] NIDA, NIH, Electrophysiol Res Sect, Cellular Neurobiol Branch,Intramural Res Program, Baltimore, MD 21224 USA. RP Lupica, CR (reprint author), NIDA, NIH, Electrophysiol Res Sect, Cellular Neurobiol Branch,Intramural Res Program, 333 Cassell Dr, Baltimore, MD 21224 USA. EM clupica@intra.nida.nih.gov FU The U. S. Department of Health and Human Services; National Institutes of Health; National Institute on Drug Abuse Intramural Research Program FX This work was supported by The U. S. Department of Health and Human Services, the National Institutes of Health, and the National Institute on Drug Abuse Intramural Research Program. We would like to thank Dr Cristina Backman and YaJun Zhang for performing DAT immunohistochemistry and biocytin reconstruction of VTA neurons. NR 74 TC 23 Z9 23 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2009 VL 587 IS 6 BP 1233 EP 1247 DI 10.1113/jphysiol.2008.164194 PG 15 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 418ZH UT WOS:000264188400010 PM 19188251 ER PT J AU Evans, LH Alamgir, ASM Owens, N Weber, N Virtaneva, K Barbian, K Babar, A Malik, F Rosenke, K AF Evans, Leonard H. Alamgir, A. S. M. Owens, Nick Weber, Nick Virtaneva, Kimmo Barbian, Kent Babar, Amenah Malik, Frank Rosenke, Kyle TI Mobilization of Endogenous Retroviruses in Mice after Infection with an Exogenous Retrovirus SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; FOCUS-FORMING VIRUSES; LONG TERMINAL REPEATS; RECOMBINANT VIRUSES; NFS/N MICE; SEQUENCES; DIFFERENTIATION; PROVIRUSES; EXPRESSION; IDENTIFICATION AB Mammalian genomes harbor a large number of retroviral elements acquired as germ line insertions during evolution. Although many of the endogenous retroviruses are defective, several contain one or more intact viral genes that are expressed under certain physiological or pathological conditions. This is true of the endogenous polytropic retroviruses that generate recombinant polytropic murine leukemia viruses (MuLVs). In these recombinants the env gene sequences of exogenous ecotropic MuLVs are replaced with env gene sequences from an endogenous polytropic retrovirus. Although replication-competent endogenous polytropic retroviruses have not been observed, the recombinant polytropic viruses are capable of replicating in numerous species. Recombination occurs during reverse transcription of a virion RNA heterodimer comprised of an RNA transcript from an endogenous polytropic virus and an RNA transcript from an exogenous ecotropic MuLV RNA. It is possible that homodimers corresponding to two full-length endogenous RNA genomes are also packaged. Thus, infection by an exogenous virus may result not only in recombination with endogenous sequences, but also in the mobilization of complete endogenous retrovirus genomes via pseudotyping within exogenous retroviral virions. We report that the infection of mice with an ecotropic virus results in pseudotyping of intact endogenous viruses that have not undergone recombination. The endogenous retroviruses infect and are integrated into target cell genomes and subsequently replicate and spread as pseudotyped viruses. The mobilization of endogenous retroviruses upon infection with an exogenous retrovirus may represent a major interaction of exogenous retroviruses with endogenous retroviruses and may have profound effects on the pathogenicity of retroviral infections. C1 [Evans, Leonard H.; Alamgir, A. S. M.; Owens, Nick; Weber, Nick; Virtaneva, Kimmo; Malik, Frank; Rosenke, Kyle] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. [Barbian, Kent; Babar, Amenah] NIAID, Res Technol Branch, RML Res Technol Sect, Genom Unit,Rocky Mt Labs, Hamilton, MT 59840 USA. RP Evans, LH (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. EM levans@niaid.nih.gov FU NIAID; NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. NR 38 TC 17 Z9 18 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR 15 PY 2009 VL 83 IS 6 BP 2429 EP 2435 DI 10.1128/JVI.01926-08 PG 7 WC Virology SC Virology GA 411LG UT WOS:000263650500003 PM 19116259 ER PT J AU Satheshkumar, PS Anton, LC Sanz, P Moss, B AF Satheshkumar, P. S. Anton, Luis C. Sanz, Patrick Moss, Bernard TI Inhibition of the Ubiquitin-Proteasome System Prevents Vaccinia Virus DNA Replication and Expression of Intermediate and Late Genes SO JOURNAL OF VIROLOGY LA English DT Article ID PROTEIN-SYNTHESIS; RNA SYNTHESIS; POXVIRUS DNA; VIRAL-DNA; CELLS; ENTRY; LIGASE; MICE; DESTRUCTION; MECHANISMS AB The ubiquitin-proteasome system has a central role in the degradation of intracellular proteins and regulates a variety of functions. Viruses belonging to several different families utilize or modulate the system for their advantage. Here we showed that the proteasome inhibitors MG132 and epoxomicin blocked a postentry step in vaccinia virus (VACV) replication. When proteasome inhibitors were added after virus attachment, early gene expression was prolonged and the expression of intermediate and late genes was almost undetectable. By varying the time of the removal and addition of MG132, the adverse effect of the proteasome inhibitors was narrowly focused on events occurring 2 to 4 h after infection, the time of the onset of viral DNA synthesis. Further analyses confirmed that genome replication was inhibited by both MG132 and epoxomicin, which would account for the effect on intermediate and late gene expression. The virus-induced replication of a transfected plasmid was also inhibited, indicating that the block was not at the step of viral DNA uncoating. UBEI-41, an inhibitor of the ubiquitin-activating enzyme E1, also prevented late gene expression, supporting the role of the ubiquitin-proteasome system in VACV replication. Neither the overexpression of ubiquitin nor the addition of an autophagy inhibitor was able to counter the inhibitory effects of MG132. Further studies of the role of the ubiquitin-proteasome system for VACV replication may provide new insights into virus-host interactions and suggest potential antipoxviral drugs. C1 [Satheshkumar, P. S.; Anton, Luis C.; Sanz, Patrick; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 33 North Dr,MSC 3210, Bethesda, MD 20892 USA. EM bmoss@nih.gov RI Anton, Luis/C-4740-2013 OI Anton, Luis/0000-0001-9665-011X FU National Institute of Allergy and Infectious Diseases; National Institutes of Health FX The work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 56 TC 54 Z9 56 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR 15 PY 2009 VL 83 IS 6 BP 2469 EP 2479 DI 10.1128/JVI.01986-08 PG 11 WC Virology SC Virology GA 411LG UT WOS:000263650500007 PM 19129442 ER PT J AU Chaudhuri, R Mattera, R Lindwasser, OW Robinson, MS Bonifacino, JS AF Chaudhuri, Rittik Mattera, Rafael Lindwasser, O. Wolf Robinson, Margaret S. Bonifacino, Juan S. TI A Basic Patch on alpha-Adaptin Is Required for Binding of Human Immunodeficiency Virus Type 1 Nef and Cooperative Assembly of a CD4-Nef-AP-2 Complex SO JOURNAL OF VIROLOGY LA English DT Article ID CD4 DOWN-REGULATION; CELL-SURFACE CD4; GOLGI NETWORK LOCALIZATION; TRANSFERRIN RECEPTOR INTERNALIZATION; CLATHRIN-MEDIATED ENDOCYTOSIS; HIV-1 NEF; CYTOPLASMIC DOMAIN; STRUCTURAL EXPLANATION; DILEUCINE MOTIF; INTRACELLULAR TRAFFICKING AB A critical function of the human immunodeficiency virus type 1 Nef protein is the downregulation of CD4 from the surfaces of infected cells. Nef is believed to act by linking the cytosolic tail of CD4 to the endocytic machinery, thereby increasing the rate of CD4 internalization. In support of this model, weak binary interactions between CD4, Nef, and the endocytic adaptor complex, AP-2, have been reported. In particular, dileucine and diacidic motifs in the C-terminal flexible loop of Nef have been shown to mediate binding to a combination of the alpha and sigma 2 subunits of AP-2. Here, we report the identification of a potential binding site for the Nef diacidic motif on alpha-adaptin. This site comprises two basic residues, lysine-297 and arginine-340, on the alpha-adaptin trunk domain. The mutation of these residues specifically inhibits the ability of Nef to bind AP-2 and downregulate CD4. We also present evidence that the diacidic motif on Nef and the basic patch on alpha-adaptin are both required for the cooperative assembly of a CD4-Nef-AP-2 complex. This cooperativity explains how Nef is able to efficiently downregulate CD4 despite weak binary interactions between components of the tripartite complex. C1 [Chaudhuri, Rittik; Mattera, Rafael; Lindwasser, O. Wolf; Bonifacino, Juan S.] Kennedy Shriver NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Chaudhuri, Rittik; Robinson, Margaret S.] Univ Cambridge, Addenbrookes Hosp, Cambridge Inst Med Res, Cambridge CB2 0XY, England. RP Bonifacino, JS (reprint author), Kennedy Shriver NICHHD, Cell Biol & Metab Program, NIH, 18T,Room 101, Bethesda, MD 20892 USA. EM juan@helix.nih.gov FU NICHD; NIH Intramural AIDS Targeted Antiviral Program (IATAP); Wellcome Trust; NIH-Cambridge and Gates-Cambridge graduate scholarships FX This work was supported by the intramural program of NICHD, the NIH Intramural AIDS Targeted Antiviral Program (IATAP), and the Wellcome Trust. R. C. was supported by the NIH-Cambridge and Gates-Cambridge graduate scholarships. NR 81 TC 33 Z9 35 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR 15 PY 2009 VL 83 IS 6 BP 2518 EP 2530 DI 10.1128/JVI.02227-08 PG 13 WC Virology SC Virology GA 411LG UT WOS:000263650500012 PM 19129443 ER PT J AU Jang, MK Kwon, D McBride, AA AF Jang, Moon Kyoo Kwon, Deukwoo McBride, Alison A. TI Papillomavirus E2 Proteins and the Host Brd4 Protein Associate with Transcriptionally Active Cellular Chromatin SO JOURNAL OF VIROLOGY LA English DT Article ID BROMODOMAIN PROTEIN; CELLS; CHROMOSOMES; TRANSACTIVATOR; ACTIVATION; CARCINOMA; PLASMIDS; BINDING; SITES AB The interaction of papillomavirus E2 proteins with cellular Brd4 protein is important for transcriptional regulation of viral genes and partitioning of viral genomes. Bovine papillomavirus type 1 (BPV-1) E2 binds cellular chromatin in complex with Brd4 in both mitotic and interphase cells. To identify specific sites of E2 interaction on cellular chromatin, a genome-wide chromatin immunoprecipitation-on-chip analysis was carried out using human promoter sequences. Both E2 and Brd4 were found bound to most transcriptionally active promoters in C33A cells. These promoters were also bound by RNA polymerase II and were modified by histone H3 acetylation and K4 trimethylation, all indicators of active transcription. E2 binding strongly correlated with Brd4 and RNA polymerase II occupancy and H3K4me3 modification at all human promoters, indicating that E2 bound to active promoters. E2 binding did not correlate with the presence of consensus E2 binding sites in the promoters. Furthermore, the mRNA levels of E2-bound cellular genes were not significantly changed by E2 expression. Thus, the papillomavirus E2 proteins bind to transcriptionally active cellular genes but do not change their activity. We propose that this may be a way for the virus to ensure that the viral genome is retained in transcriptionally active regions of the nucleus to escape silencing. Therefore, E2-mediated tethering of viral genomes to host chromatin has multiple roles: to partition the viral genome to daughter cells, to ensure that the genomes are retained in the nucleus, and to make certain that the genomes are retained in functionally active nuclear domains. C1 [McBride, Alison A.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. [Kwon, Deukwoo] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4,Room 137,4 Ctr Dr MSC 0445, Bethesda, MD 20892 USA. EM amcbride@nih.gov OI McBride, Alison/0000-0001-5607-5157 FU National Institute of Allergy and Infectious Diseases; NIH FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, NIH. NR 24 TC 27 Z9 28 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR 15 PY 2009 VL 83 IS 6 BP 2592 EP 2600 DI 10.1128/JVI.02275-08 PG 9 WC Virology SC Virology GA 411LG UT WOS:000263650500019 PM 19129460 ER PT J AU Chatterjee, AG Leem, YE Kelly, FD Levin, HL AF Chatterjee, Atreyi Ghatak Leem, Young Eun Kelly, Felice D. Levin, Henry L. TI The Chromodomain of Tf1 Integrase Promotes Binding to cDNA and Mediates Target Site Selection SO JOURNAL OF VIROLOGY LA English DT Article ID TERMINAL REPEAT-RETROTRANSPOSON; POL-II PROMOTERS; REVERSE-TRANSCRIPTASE; FISSION YEAST; SCHIZOSACCHAROMYCES-POMBE; HIV-1 INTEGRATION; PROTEIN; VIRUS; SEQUENCE; DOMAIN AB The long terminal repeat (LTR) retrotransposon Tf1 of Schizosaccharomyces pombe integrates specifically into the promoters of pol II-transcribed genes. Its integrase (IN) contains a C-terminal chromodomain related to the chromodomains that bind to the N-terminal tail of histone H3. Although we have been unable to detect an interaction between histone tails and the chromodomain of Tf1 IN, it is possible that the chromodomain plays a role in directing IN to its target sites. To test this idea, we generated transposons with single amino acid substitutions in highly conserved residues of the chromodomain and created a chromodomain-deleted mutant. The mutations, V1290A, Y1292A, W1305A, and CHD Delta, substantially reduced transposition activity in vivo. Blotting assays showed that there was little or no reduction in the levels of IN or cDNA. By measuring the homologous recombination between cDNA and the plasmid copy of Tf1, we found that two of the mutations did not reduce the import of cDNA into the nucleus, while another caused a 33% reduction. Chromatin immunoprecipitation assays revealed that CHD Delta caused an approximately threefold reduction in the binding of IN to the downstream LTR of the cDNA. These data indicate that the chromodomain contributed directly to integration. We therefore tested whether the chromodomain contributed to selecting insertion sites. Results of a target plasmid assay showed that the deletion of the chromodomain resulted in a drastic reduction in the preference for pol II promoters. Collectively, these data indicate that the chromodomain promotes binding of cDNA and plays a key role in efficient targeting. C1 [Chatterjee, Atreyi Ghatak; Leem, Young Eun; Kelly, Felice D.; Levin, Henry L.] NIH, Sect Eukaryot Transposable Elements, Lab Gene Regulat & Dev, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. RP Levin, HL (reprint author), NIH, Sect Eukaryot Transposable Elements, Lab Gene Regulat & Dev, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bldg 10, Bethesda, MD 20892 USA. EM henry_levin@nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by the Intramural Research Program of the NIH from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 47 TC 16 Z9 16 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR 15 PY 2009 VL 83 IS 6 BP 2675 EP 2685 DI 10.1128/JVI.01588-08 PG 11 WC Virology SC Virology GA 411LG UT WOS:000263650500027 PM 19109383 ER PT J AU Yeh, WW Jaru-Ampornpan, P Nevidomskyte, D Asmal, M Rao, SS Buzby, AP Montefiori, DC Korber, BT Letvin, NL AF Yeh, Wendy W. Jaru-Ampornpan, Pimkwan Nevidomskyte, Daiva Asmal, Mohammed Rao, Srinivas S. Buzby, Adam P. Montefiori, David C. Korber, Bette T. Letvin, Norman L. TI Partial Protection of Simian Immunodeficiency Virus (SIV)-Infected Rhesus Monkeys against Superinfection with a Heterologous SIV Isolate SO JOURNAL OF VIROLOGY LA English DT Article ID INJECTION-DRUG USERS; TYPE-1 SUPERINFECTION; HIV-1 SUPERINFECTION; PRIMARY INFECTION; CYNOMOLGUS MONKEYS; RAPID PROGRESSION; ATTENUATED VIRUS; LONG-TERM; IMMUNE-RESPONSES; DUAL INFECTION AB Although there is increasing evidence that individuals already infected with human immunodeficiency virus type 1 (HIV-1) can be infected with a heterologous strain of the virus, the extent of protection against superinfection conferred by the first infection and the biologic consequences of superinfection are not well understood. We explored these questions in the simian immunodeficiency virus (SIV)/rhesus monkey model of HIV-1/AIDS. We infected cohorts of rhesus monkeys with either SIVmac251 or SIVsmE660 and then exposed animals to the reciprocal virus through intrarectal inoculations. Employing a quantitative real-time PCR assay, we determined the replication kinetics of the two strains of virus for 20 weeks. We found that primary infection with a replication-competent virus did not protect against acquisition of infection by a heterologous virus but did confer relative control of the superinfecting virus. In animals that became superinfected, there was a reduction in peak replication and rapid control of the second virus. The relative susceptibility to superinfection was not correlated with CD4(+) T-cell count, CD4(+) memory T-cell subsets, cytokine production by virus-specific CD8(+) or CD4(+) cells, or neutralizing antibodies at the time of exposure to the second virus. Although there were transient increases in viral loads of the primary virus and a modest decline in CD4(+) T-cell counts after superinfection, there was no evidence of disease acceleration. These findings indicate that an immunodeficiency virus infection confers partial protection against a second immunodeficiency virus infection, but this protection may be mediated by mechanisms other than classical adaptive immune responses. C1 [Letvin, Norman L.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02115 USA. [Rao, Srinivas S.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Korber, Bette T.] Los Alamos Natl Lab, Los Alamos, NM 87545 USA. [Korber, Bette T.] Santa Fe Inst, Santa Fe, NM USA. RP Letvin, NL (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, CLS 1043,3 Blackfan Circle, Boston, MA 02115 USA. EM nletvin@bidmc.harvard.edu OI Korber, Bette/0000-0002-2026-5757 FU NIH NIAID PHS [K08-AI069995, AI-067854]; Center for HIV/AIDS Vaccine Immunology FX We thank Vanessa Hirsch for providing virus stock SIVsmE660. This work was supported by NIH NIAID PHS grants K08-AI069995 (W.W.Y.) and AI-067854 (W.W.Y. and N.L.L.) and the Center for HIV/AIDS Vaccine Immunology. NR 67 TC 28 Z9 28 U1 4 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR 15 PY 2009 VL 83 IS 6 BP 2686 EP 2696 DI 10.1128/JVI.02237-08 PG 11 WC Virology SC Virology GA 411LG UT WOS:000263650500028 PM 19129440 ER PT J AU Kearney, M Maldarelli, F Shao, W Margolick, JB Daar, ES Mellors, JW Rao, V Coffin, JM Palmer, S AF Kearney, M. Maldarelli, F. Shao, W. Margolick, J. B. Daar, E. S. Mellors, J. W. Rao, V. Coffin, J. M. Palmer, S. TI Human Immunodeficiency Virus Type 1 Population Genetics and Adaptation in Newly Infected Individuals SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; CTL ESCAPE; DRUG-RESISTANCE; IN-VIVO; HIV POLYMORPHISMS; IMMUNE-RESPONSES; TRANSMISSION; EVOLUTION; DIVERSITY; MUTATIONS AB Studies on human immunodeficiency virus type 1 (HIV-1) diversity are critical for understanding viral pathogenesis and the emergence of immune escape variants and for design of vaccine strategies. To investigate HIV-1 population genetics, we used single-genome sequencing to obtain pro-pol and env sequences from longitudinal samples (n = 93) from 14 acutely or recently infected patients. The first available sample after infection for 12/14 patients revealed HIV-1 populations with low genetic diversity, consistent with transmission or outgrowth of a single variant. In contrast, two patients showed high diversity and coexistence of distinct virus populations in samples collected days after a nonreactive enzyme-linked immunosorbent assay or indeterminate Western blot, consistent with transmission or outgrowth of multiple variants. Comparison of PR and RT sequences from the first sample for all patients with the consensus subgroup B sequence revealed that nearly all nonsynonymous differences were confined to identified cytotoxic T-lymphocyte (CTL) epitopes. For HLA-typed patients, mutations compared to the consensus in transmitted variants were found in epitopes that would not be recognized by the patient's major histocompatibility complex type. Reversion of transmitted mutations was rarely seen over the study interval (up to 5 years). These data indicate that acute subtype B HIV-1 infection usually results from transmission or outgrowth of single viral variants carrying mutations in CTL epitopes that were selected prior to transmission either in the donor or in a previous donor and that reversion of these mutations can be very slow. These results have important implications for vaccine strategies because they imply that some HLA alleles could be compromised in newly acquired HIV infections. C1 [Kearney, M.] NCI, HIV Drug Resistance Program, NIH, Ft Detrick, MD 21702 USA. [Kearney, M.; Rao, V.] Catholic Univ Amer, Dept Biol, Washington, DC 20064 USA. [Shao, W.] SAIC, Adv Biomed Comp Ctr, Frederick, MD USA. [Margolick, J. B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Daar, E. S.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Mellors, J. W.] Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. [Coffin, J. M.] Tufts Univ, Dept Mol Biol & Microbiol, Boston, MA 02111 USA. RP Kearney, M (reprint author), NCI, HIV Drug Resistance Program, NIH, 1050 Boyles St,Bldg 535,Room 109, Ft Detrick, MD 21702 USA. EM kearneym@ncifcrf.gov FU NIH; NCI; National Institute for Allergy and Infectious Diseases [AI 41532]; SAIC [25XS119]; George Kirby Foundation; [AI043638]; [M01-RR004425]; [CH05-SD-607-005] FX We thank Linda Apuzzo of Johns Hopkins Bloomberg School of Public Health for aid in obtaining clinical specimens and sample information, Christopher Kearney for aid in sample preparation, and Valerie Boltz and Ann Wiegand of NCI-Frederick for many helpful conversations. We are especially indebted to our patient volunteers, without whom this study would not have been possible. NR 39 TC 88 Z9 90 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR 15 PY 2009 VL 83 IS 6 BP 2715 EP 2727 DI 10.1128/JVI.01960-08 PG 13 WC Virology SC Virology GA 411LG UT WOS:000263650500031 PM 19116249 ER PT J AU Jagannathan, P Osborne, CM Royce, C Manion, MM Tilton, JC Li, L Fischer, S Hallahan, CW Metcalf, JA McLaughlin, M Pipeling, M McDyer, JF Manley, TJ Meier, JL Altman, JD Hertel, L Davey, RT Connors, M Migueles, SA AF Jagannathan, Prasanna Osborne, Christine M. Royce, Cassandra Manion, Maura M. Tilton, John C. Li, Li Fischer, Steven Hallahan, Claire W. Metcalf, Julia A. McLaughlin, Mary Pipeling, Matthew McDyer, John F. Manley, Thomas J. Meier, Jeffery L. Altman, John D. Hertel, Laura Davey, Richard T., Jr. Connors, Mark Migueles, Stephen A. TI Comparisons of CD8(+) T Cells Specific for Human Immunodeficiency Virus, Hepatitis C Virus, and Cytomegalovirus Reveal Differences in Frequency, Immunodominance, Phenotype, and Interleukin-2 Responsiveness SO JOURNAL OF VIROLOGY LA English DT Article ID LONG-TERM NONPROGRESSORS; CELLULAR IMMUNE-RESPONSES; HIV TYPE-1 INFECTION; DENDRITIC CELLS; IN-VIVO; EFFICIENT PRESENTATION; ANTIGEN PRESENTATION; LYMPHOCYTE EPITOPES; EFFECTOR FUNCTION; PERIPHERAL-BLOOD AB To better understand the components of an effective immune response to human immunodeficiency virus (HIV), the CD8(+) T-cell responses to HIV, hepatitis C virus (HCV), and cytomegalovirus (CMV) were compared with regard to frequency, immunodominance, phenotype, and interleukin-2 (IL-2) responsiveness. Responses were examined in rare patients exhibiting durable immune-mediated control over HIV, termed long-term nonprogressors (LTNP) or elite controllers, and patients with progressive HIV infection (progressors). The magnitude of the virus-specific CD8(+) T-cell response targeting HIV, CMV, and HCV was not significantly different between LTNP and progressors, even though their capacity to proliferate to HIV antigens was preserved only in LTNP. In contrast to HIV-specific CD8(+) T-cell responses of LTNP, HLA B5701-restricted responses within CMV pp65 were rare and did not dominate the total CMV-specific response. Virus-specific CD8(+) T cells were predominantly CD27(+) 45RO(+) for HIV and CD27(-)45RA(+) for CMV; however, these phenotypes were highly variable and heavily influenced by the degree of viremia. Although IL-2 induced significant expansions of CMV-specific CD8(+) T cells in LTNP and progressors by increasing both the numbers of cells entering the proliferating pool and the number of divisions, the proliferative capacity of a significant proportion of HIV-specific CD8(+) T cells was not restored with exogenous IL-2. These results suggest that immunodominance by HLA B5701-restricted cells is specific to HIV infection in LTNP and is not a feature of responses to other chronic viral infections. They also suggest that poor responsiveness to IL-2 is a property of HIV-specific CD8(+) T cells of progressors that is not shared with responses to other viruses over which immunologic control is maintained. C1 [Jagannathan, Prasanna; Osborne, Christine M.; Royce, Cassandra; Manion, Maura M.; Tilton, John C.; Metcalf, Julia A.; McLaughlin, Mary; Davey, Richard T., Jr.; Connors, Mark; Migueles, Stephen A.] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Li, Li; Fischer, Steven] NIH, Dept Lab Med, Bethesda, MD 20892 USA. [Hallahan, Claire W.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Pipeling, Matthew; McDyer, John F.] Johns Hopkins Univ, Dept Pulm & Crit Care Med, Baltimore, MD USA. [Manley, Thomas J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Meier, Jeffery L.] Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. [Altman, John D.] Emory Univ, Emory Vaccine Ctr Yerkes, Atlanta, GA 30322 USA. [Hertel, Laura] Univ Western Ontario, Dept Microbiol & Immunol, London, ON, Canada. RP Connors, M (reprint author), NIAID, LIR, NIH, Bldg 10,Rm 11B-09,10 Ctr Dr,MSC 1876, Bethesda, MD 20892 USA. EM mconnors@niaid.nih.gov FU Intramural Research Program of the NIH; National Institute of Allergy and Infectious Diseases FX This research was supported (in part) by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 75 TC 35 Z9 35 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR 15 PY 2009 VL 83 IS 6 BP 2728 EP 2742 DI 10.1128/JVI.02128-08 PG 15 WC Virology SC Virology GA 411LG UT WOS:000263650500032 PM 19129459 ER PT J AU Garriz, A Qiu, HF Dey, M Seo, EJ Dever, TE Hinnebusch, AG AF Garriz, Andres Qiu, Hongfang Dey, Madhusudan Seo, Eun-Joo Dever, Thomas E. Hinnebusch, Alan G. TI A Network of Hydrophobic Residues Impeding Helix alpha C Rotation Maintains Latency of Kinase Gcn2, Which Phosphorylates the alpha Subunit of Translation Initiation Factor 2 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; TRANSFER-RNA-BINDING; UNCHARGED TRANSFER-RNA; PROTEIN-KINASE; STRUCTURAL BASIS; AMINO-ACID; SUBSTRATE RECOGNITION; STRESS CONDITIONS; MAMMALIAN-CELLS; ACTIVATION AB Kinase Gcn2 is activated by amino acid starvation and downregulates translation initiation by phosphorylating the alpha subunit of translation initiation factor 2 (eIF2 alpha). The Gcn2 kinase domain (KD) is inert and must be activated by tRNA binding to the adjacent regulatory domain. Previous work indicated that Saccharomyces cerevisiae Gcn2 latency results from inflexibility of the hinge connecting the N and C lobes and a partially obstructed ATP-binding site in the KD. Here, we provide strong evidence that a network of hydrophobic interactions centered on Leu-856 also promotes latency by constraining helix alpha C rotation in the KD in a manner relieved during amino acid starvation by tRNA binding and autophosphorylation of Thr-882 in the activation loop. Thus, we show that mutationally disrupting the hydrophobic network in various ways constitutively activates eIF2 alpha phosphorylation in vivo and bypasses the requirement for a key tRNA binding motif (m2) and Thr-882 in Gcn2. In particular, replacing Leu-856 with any nonhydrophobic residue activates Gcn2, while substitutions with various hydrophobic residues maintain kinase latency. We further provide strong evidence that parallel, back-to-back dimerization of the KD is a step on the Gcn2 activation pathway promoted by tRNA binding and autophosphorylation. Remarkably, mutations that disrupt the L856 hydrophobic network or enhance hinge flexibility eliminate the need for the conserved salt bridge at the parallel dimer interface, implying that KD dimerization facilitates the reorientation of alpha C and remodeling of the active site for enhanced ATP binding and catalysis. We propose that hinge remodeling, parallel dimerization, and reorientation of alpha C are mutually reinforcing conformational transitions stimulated by tRNA binding and secured by the ensuing autophosphorylation of T882 for stable kinase activation. C1 [Garriz, Andres; Qiu, Hongfang; Dey, Madhusudan; Seo, Eun-Joo; Dever, Thomas E.; Hinnebusch, Alan G.] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bldg 6A,Room B1A 13, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov OI Dever, Thomas/0000-0001-7120-9678 FU Intramural Research Program of the NIH FX This work was supported by the Intramural Research Program of the NIH. NR 43 TC 15 Z9 15 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR 15 PY 2009 VL 29 IS 6 BP 1592 EP 1607 DI 10.1128/MCB.01446-08 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 412JB UT WOS:000263720000019 PM 19114556 ER PT J AU Goetz, CG Stebbins, GT Wolff, D DeLeeuw, W Bronte-Stewart, H Elble, R Hallet, M Nutt, J Ramig, L Sanger, T Wu, AD Kraus, PH Blasucci, LM Shamim, EA Sethi, KD Spielman, J Kubota, K Grove, AS Dishman, E Taylor, CB AF Goetz, Christopher G. Stebbins, Glenn T. Wolff, David DeLeeuw, William Bronte-Stewart, Helen Elble, Rodger Hallet, Mark Nutt, John Ramig, Lorraine Sanger, Terence Wu, Allan D. Kraus, Peter H. Blasucci, Lucia M. Shamim, Ejaz A. Sethi, Kapil D. Spielman, Jennifer Kubota, Ken Grove, Andrew S. Dishman, Eric Taylor, C. Barr TI Testing Objective Measures of Motor Impairment in Early Parkinson's Disease: Feasibility Study of an At-Home Testing Device SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; tremor; bradykinesia; computer-based technology; accelerometer ID CLINICAL-TRIALS; BARRIERS; MOVEMENT AB We tested the feasibility of a computer based at home testing device (AHTD) in early-stage, unmedicated Parkinson's disease (PD) patients over 6 months. We measured compliance, technical reliability, and patient satisfaction to weekly assessments of tremor, small and large muscle bradykinesia. , speech, reaction/movement times, and complex motor control, relative to the UPDRS motor score. The AHTD is a 6.5 '' x 10 '' computerized assessment battery. Data are stored on a USB memory stick and sent by internet to a central data repository as encrypted data packets. Although not designed or powered to measure change. the study collected data to observe patterns relative to UPDRS motor scores. Fifty-two PD patients enrolled, and 50 completed the 6 month trial, 48 remaining without Medication. Patients complied with 90.6% of weekly 30-minute assessments. and 98.5% of data packets were successfully transmitfed and decrypted. On a 100-point scale, patient satisfaction with the program at study, end was 87.2 (range: 80-100). UPDRS motor scores significantly worsened over 6 months, and trends for worsening over time occurred for alternating finger taps (P = 0.08). tremor (P = 0.06) and speech (P = 0.11). Change in tremor was a significant predictor of change in UPDRS (P = 0.047) and was detected in the first month of the study. This new computer-based technology offers a feasible format for assessing PD-related impairment from home. The high patient compliance and satisfaction suggest the feasibility of its incorporation into larger clinical trials. especially when travel is difficult and early changes or frequent data collection are considered important to document. (C) 2008 Movement Disorder Society C1 [Goetz, Christopher G.; Stebbins, Glenn T.; Blasucci, Lucia M.] Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. [Wolff, David; Kubota, Ken; Taylor, C. Barr] Kinet Fdn, Los Altos, CA USA. [DeLeeuw, William; Grove, Andrew S.; Dishman, Eric] Intel Corp, Santa Clara, CA USA. [Bronte-Stewart, Helen; Sanger, Terence] Stanford Univ, Stanford Comprehens Movement Disorder Ctr, Palo Alto, CA 94304 USA. [Elble, Rodger] So Illinois Univ, Sch Med, Dept Neurol, Springfield, IL USA. [Hallet, Mark; Shamim, Ejaz A.] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Nutt, John] Oregon Hlth & Sci Univ, Dept Neurol, Portland, OR USA. [Ramig, Lorraine] Univ Colorado, Boulder, CO 80309 USA. [Ramig, Lorraine; Spielman, Jennifer] Natl Ctr Voice & Speech, Denver, CO USA. [Wu, Allan D.] Univ Calif Los Angeles, Dept Neurol, Los Angeles, CA 90024 USA. [Kraus, Peter H.] Ruhr Univ Bochum, Dept Neurol, Bochum, Germany. [Shamim, Ejaz A.] Georgetown Univ Hosp, Dept Neurol, Washington, DC 20007 USA. [Sethi, Kapil D.] Med Coll Georgia, Augusta, GA 30912 USA. RP Goetz, CG (reprint author), 1725 W Harrison St,Suite 755, Chicago, IL 60612 USA. EM cgoetz@rush.edu FU Kinetics Foundation; Intel INc. FX This work supported by a grant from the Kinetics Foundation, Intel INc., provided technical support. We thank the assistance of Cambridge Neurotechnology Ltd for adaptations of their actigraph to the AHTD. NR 13 TC 55 Z9 55 U1 0 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAR 15 PY 2009 VL 24 IS 4 BP 551 EP 556 DI 10.1002/mds.22379 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 430QO UT WOS:000265003800010 PM 19086085 ER PT J AU Defazio, G Matarin, M Peckham, EL Martino, D Valente, EM Singleton, A Crawley, A Aniello, MS Brancati, F Abbruzzese, G Girlanda, P Livrea, P Hallett, M Berardelli, A AF Defazio, Giovanni Matarin, Mar Peckham, Elizabeth L. Martino, Davide Valente, Enza M. Singleton, Andrew Crawley, Anthony Aniello, Maria Stella Brancati, Francesco Abbruzzese, Giovanni Girlanda, Paolo Livrea, Paolo Hallett, Mark Berardelli, Alfredo TI The TOR1A Polymorphism rs1182 and the Risk of Spread in Primary Blepharospasm SO MOVEMENT DISORDERS LA English DT Article DE TOR1A; single-nucelotide polymorphisms; blepharospasm; primary adult-onset; dystonia; spread ID IDIOPATHIC DYSTONIA; DIAGNOSTIC-CRITERIA; ASSOCIATION; HAPLOTYPE; DYT1 AB We studied the influence of the rs1182 polymorphism of the TOR1A gene on the risk of dystonia spread in two representative cohorts of patients presenting with primary blepharospasm (BSP), one from Italy and the other front the United States of America. The relationship between rs1182 polymorphism and spread was estimated by Kaplan-Meier survival curves and Cox proportional hazard regression models adjusted by age and sex, age of BSP onset. In both series, patients carrying the T allele (G/T or T/T) in the rs1182 polymorphism were more likely to have dystonia spread as compared with the homozygous carriers of the common G allele. The comparable findings obtained in two independent cohorts support it genetic contribution to BSP spread. (C) 2009 Movement Disorder Society C1 [Defazio, Giovanni; Martino, Davide; Aniello, Maria Stella; Livrea, Paolo] Univ Bari, Dept Neurol & Psychiat Sci, I-70124 Bari, Italy. [Matarin, Mar; Singleton, Andrew] NIA, Mol Genet Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Peckham, Elizabeth L.; Crawley, Anthony; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Valente, Enza M.; Brancati, Francesco] IRCCS CSS Mendel Inst, Neurogenet Unit, Rome, Italy. [Abbruzzese, Giovanni] Univ Genoa, Dept Neurosci Ophthalmol & Genet, I-16126 Genoa, Italy. [Girlanda, Paolo] Univ Messina, Dept Neurosci Psychiat & Anesthesiol, I-98100 Messina, Italy. [Berardelli, Alfredo] Univ Roma La Sapienza, Dept Neurol Sci, Rome, Italy. [Berardelli, Alfredo] Univ Roma La Sapienza, NEUROMED Inst, Rome, Italy. RP Defazio, G (reprint author), Univ Bari, Dept Neurol & Psychiat Sci, Policlin Piazza Ciulio Cesare 1, I-70124 Bari, Italy. EM gdefazio@neurol.uniba.it RI Singleton, Andrew/C-3010-2009; Matarin, Mar/F-1771-2016; OI Matarin, Mar/0000-0002-4717-5735; Livrea, Paolo/0000-0001-7410-3860; GIRLANDA, Paolo/0000-0002-7152-2290 FU Comitato Promotore Telethon, Italy [GGP05165]; Benign Essential Belpharospasm Research Foundation, Beaumont, TX, USA; National Institute on Aging and National Institute of Neurological Disorders and Stoke, National Institutes of Health; Department of Health and Human Service, Bethesda, MD, USA [Z01 AG000957-05] FX This work was funded by the Comitato Promotore Telethon, Italy (Grant No. GGP05165); the Benign Essential Belpharospasm Research Foundation, Beaumont, TX, USA; and the Intramural Research Programs of the National Institute on Aging and National Institute of Neurological Disorders and Stoke, National Institutes of Health; Department of Health and Human Service (project number Z01 AG000957-05), Bethesda, MD, USA. NR 16 TC 11 Z9 12 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAR 15 PY 2009 VL 24 IS 4 BP 613 EP 616 DI 10.1002/mds.22471 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 430QO UT WOS:000265003800020 PM 19202559 ER PT J AU Liu, AM Xie, SL Sun, H Gonzalez, FJ Wei, XX Dai, RK AF Liu, Aiming Xie, Shuilin Sun, He Gonzalez, Frank J. Wei, Xiaoxiong Dai, Renke TI Myotoxicity of gemfibrozil in Cynomolgus monkey model and its relationship to pharmacokinetic properties SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Gemfibrozil; Myotoxicity; Cynomolgus monkey; Animal model; Pharmacokinetics ID ACTIVATED-RECEPTOR-ALPHA; COA REDUCTASE INHIBITORS; RAT SKELETAL-MUSCLE; PEROXISOME PROLIFERATION; MITOCHONDRIAL-FUNCTION; CERIVASTATIN; METABOLISM; MYOPATHY; INDUCE; STATIN AB Fibrate drugs are PPAR alpha agonists prescribed for the treatment of dyslipidemia. Severe myotoxicity has been reportedly associated with their use albeit at a low frequency, especially for gemfibrozil. Few studies have investigated the mechanism of fibrate-induced myotoxicity in vivo. Considering the apparent species-related differences in PPAR alpha agonist-induced hepatotoxicity, We Studied the myotoxicity of gemfibrozil in a Cynomolgus monkey model and explored the relationship between myotoxicity and pharmacokinetics. Six Cynomolgus monkeys were dosed with gemfibrozil twice daily at 600 mg/kg/day for the first two periods (P1 and P2, 8 days and 9 days respectively) and 300 mg/kg/day for the third period (P3, 14 clays). Creatine kinase and myoglobin were measured, together with hepatotoxicity and nephrotoxicity markers. Behavioral responses were recorded for indication of toxicity. Pharmacokinetics was carried out following the 16th dosage of P1 and 17th dosage of P2 when myotoxicity was identified. Multivariable data analysis was employed to explore the relationship between pharmacokinetic parameters and myotoxicity markers. Consequently, myotoxicity occurred in monkey #2 (M2) and M6 in P1, M3 and M4 in P2, M3 and M6 in P3. Data analysis showed T80-150 (sustained time above the given concentration) contributed for myotoxicity discriminance and correlated with myotoxicity risk. This Study revealed Cynomolgus monkey may be a good animal model for myotoxicity evaluation with sensitivity, reproducibility and similarities to humans. More interestingly, they exhibited a much higher incidence of myotoxicity than that of humans. Sustained high drug concentration plays an important role for the occurrence of myotoxicity. This may suggest an influence of drug transport and metabolism on myotoxicity. (C) 2008 Elsevier Inc. All rights reserved. C1 [Liu, Aiming; Xie, Shuilin; Dai, Renke] Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou 510663, Guangdong, Peoples R China. [Sun, He] Tianjin Univ, Sch Pharmaceut Sci & Technol, Tianjin 300072, Peoples R China. [Gonzalez, Frank J.] NCI, NIH, Bethesda, MD 20892 USA. [Gonzalez, Frank J.] Medpace Inc, Cincinnati, OH 45212 USA. RP Dai, RK (reprint author), Chinese Acad Sci, Guangzhou Inst Biomed & Hlth, Guangzhou 510663, Guangdong, Peoples R China. EM dai_renke@gibh.ac.cn FU National High-tech Research and Development Program [2006AA02Z339]; Guangzhou Science and Technology Bureau [2006Z1-E4031, 2006P067]; Guangzhou Development District [2006Ss-P067] FX This work was supported by the National High-tech Research and Development Program [grant number 2006AA02Z339]; Guangzhou Science and Technology Bureau [grant number 2006Z1-E4031, 2006P067]; and Guangzhou Development District [grant number 2006Ss-P067]. NR 28 TC 9 Z9 10 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 15 PY 2009 VL 235 IS 3 BP 287 EP 295 DI 10.1016/j.taap.2008.12.015 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 419GQ UT WOS:000264207900003 PM 19150455 ER PT J AU Yen, CH Hung, JH Ueng, YF Liu, SP Chen, SY Liu, HH Chou, TY Tsai, TF Darbha, R Hsieh, LL Chen, YMA AF Yen, Chia-Hung Hung, Jung-Hsien Ueng, Yune-Fang Liu, Shih-Ping Chen, Shih-Yin Liu, Hsiao-Han Chou, Teh-Ying Tsai, Ting-Fen Darbha, Ramalakshmi Hsieh, Ling-Ling Chen, Yi-Ming Arthur TI Glycine N-methyltransferase affects the metabolism of aflatoxin B-1 and blocks its carcinogenic effect SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE AFB(1) metabolism; Detoxification; DNA adducts; Hepatocelluar carcinoma; Transgenic mouse model ID HYDROCARBON-BINDING RECEPTOR; TUMOR SUSCEPTIBILITY GENE; HEPATOCELLULAR-CARCINOMA; TRANSGENIC MICE; LIVER-CANCER; RAT-LIVER; FORMED INVIVO; P53 GENE; EXPRESSION; PROTEIN AB Previously, we reported that glycine N-methyltransferase (GNMT) knockout mice develop chronic hepatitis and hepatocellular carcinoma (HCC) spontaneously. For this study we used a phosphoenolpyruvate carboxykinase promoter to establish a GNMT transgenic (TG) mouse model. Animals were intraperitoneally inoculated with aflatoxin B-1 (AFB(1)) and monitored for 11 months, during which neither male nor female GNMT-TG mice developed HCC. In contrast, 4 of 6 (67%) male wild-type mice developed HCC. Immunofluorescent antibody test showed that GNMT was translocated into nuclei after AFB(1) treatment. Competitive enzyme immunoassays indicated that after AFB(1) treatment, the AFB(1)-DNA adducts formed in stable clones expressing GNMT reduced 51.4% compared to the vector control clones. Experiments using recombinant adenoviruses carrying GNMT cDNA (Ad-GNMT) further demonstrated that the GNMT-related inhibition of AFB(1)-DNA adducts formation is dose-dependent. HPLC analysis of the metabolites of AFB(1) in the cultural supernatants of cells exposed to AFB(1) showed that the AFM(1) level in the GNMT group was significantly higher than the control group, indicating the presence of GNMT can enhance the detoxification pathway of AFB(1). Cytotoxicity assay showed that the GNMT group had higher survival rate than the control group after they were treated with AFB(1). Automated docking experiments showed that AFB(1) binds to the S-adenosylmethionine binding domain of GNMT. Affinity sensor assay demonstrated that the dissociation constant for GNMT-AFB(1) interaction is 44.9 mu M. Therefore, GNMT is a tumor suppressor for HCC and it exerts protective effects in hepatocytes via direct interaction with AFB(1), resulting in reduced AFB(1)-DNA adducts formation and cell death. (C) 2008 Elsevier Inc. All rights reserved. C1 [Chen, Yi-Ming Arthur] Natl Yang Ming Univ, Inst Microbiol & Immunol, Sch Med, Taipei 112, Taiwan. [Yen, Chia-Hung] Natl Yang Ming Univ, Sch Med, Inst Publ Hlth, Div Mol Med, Taipei 112, Taiwan. [Yen, Chia-Hung; Hung, Jung-Hsien; Liu, Shih-Ping; Chen, Shih-Yin; Liu, Hsiao-Han; Chen, Yi-Ming Arthur] Natl Yang Ming Univ, AIDS Prevent & Res Ctr, Taipei 112, Taiwan. [Ueng, Yune-Fang] Natl Res Inst Chinese Med, Taipei, Taiwan. [Liu, Shih-Ping] China Med Univ & Hosp, Ctr Neuropsychiat, Taichung, Taiwan. [Chou, Teh-Ying] Taipei Vet Gen Hosp, Dept Pathol & Lab Med, Taipei, Taiwan. [Tsai, Ting-Fen] Natl Yang Ming Univ, Fac Life Sci, Taipei 112, Taiwan. [Tsai, Ting-Fen] Natl Yang Ming Univ, Inst Genome, Taipei 112, Taiwan. [Darbha, Ramalakshmi] NCI, Biol Struct Sect, Macromol Crystallog Lab, Frederick, MD 21701 USA. [Hsieh, Ling-Ling] Chang Gung Univ, Dept Publ Hlth, Tao Yuan, Taiwan. RP Chen, YMA (reprint author), Natl Yang Ming Univ, Inst Microbiol & Immunol, Sch Med, Taipei 112, Taiwan. EM arthur@ym.edu.tw RI Liu, Hsiao-Han/G-7169-2016; OI Liu, Hsiao-Han/0000-0001-6604-248X FU National Science Council of Taiwan [NSC96-3112-B-010-003, NSC96-2628-B-010-031-MY3]; Taiwan's Ministry of Education; Genomic Research Center of the National Yang-Ming University. FX We thank Dr. Xinhua Ji for permission to Use facilities at the Macromolecular Crystallography Laboratory, National Cancer Institute in Frederick, MD; Dr. Michael Hsiao for the retrovirus-carrying GNMT: and colleagues at the Division of Preventive Medicine of the Institute of Public Health at National Yang Ming University for their feedback and technical support. We also thank technical services provided by the Imaging Core Facility of Nanotechnology of the UST-YMU for their assistance with confocal microscopy. This study was Supported in part by two grants from the National Science Council of Taiwan (NSC96-3112-B-010-003 and NSC96-2628-B-010-031-MY3) and a grant from the Taiwan's Ministry of Education "Aim for the Top University Plan" program via the Genomic Research Center of the National Yang-Ming University. NR 40 TC 22 Z9 24 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 15 PY 2009 VL 235 IS 3 BP 296 EP 304 DI 10.1016/j.taap.2008.12.013 PG 9 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 419GQ UT WOS:000264207900004 PM 19146867 ER PT J AU Kononchik, JR Nelson, S Hernandez, R Brown, DI AF Kononchik, Joseph R., Jr. Nelson, Steevenson Hernandez, Raquel Brown, Dennis I. TI Helical virus particles formed from morphological subunits of a membrane containing icosahedral virus SO VIROLOGY LA English DT Article DE Sindbis virus; Virus assembly; Protein interactions; Morphological variants; Helix symmetry; Icosahedral symmetry ID PAPILLOMA-POLYOMA TYPE; SINDBIS VIRUS; ELECTRON-MICROSCOPY; CELL-SURFACE; GLYCOPROTEIN; MATURATION; BACTERIOPHAGE-T4; FIBROBLASTS; MICROVILLI; MUTATIONS AB The classic publication by Caspar and Mug in 1962 [Physical principles in the construction of regular viruses. Cold Spring Harbor Symp. Quant. Biol. 27:1-24.] has formed the basis of much research on virus assembly. Caspar and Klug predicted that a single virus morphological unit could form a two dimensional lattice composed of 6-fold arrays (primitive plane), a family of icosahedra of increasing triangulation numbers (T) and helical arrays of varying length. We have shown that icosahedral viruses of varying T numbers can be produced using Sindbis virus [Ferreira, D. F. et al. 2003. Morphological variants of Sindbis virus produced by a mutation in the capsid protein. Virology 307:54-66]. Other studies have shown that Sindbis glycoproteins can also form a 2-dimensional lattice confirming Caspar and Klug's prediction of the primitive plane as a biologically relevant Structure [VonBonsdorff, C. H., and S. C, Harrison. 1978. Sindbis virus glycoproteins form a regular icosahedral surface lattice. J. Virol. 28:578]. In this study we have used mutations in the glycoproteins of membrane containing Sindbis virus to create helical-virus-like particles from the morphological subunits of a virus of icosahedral geometry. The resulting virus particles were examined for subunit organization and were determined to be constructed of only 6-fold rotational arrays of the virus glycoproteins. A model of the tubular virus particles created from the 6-fold rotational arrays of Sindbis Virus confirmed the observed structure. These experiments show that a common morphological unit (the Sindbis E1-E2 heterodimer) can produce three different morphological entities of varying dimensions in a membrane-containing virus system. (c) 2008 Elsevier Inc. All rights reserved. C1 [Kononchik, Joseph R., Jr.; Hernandez, Raquel; Brown, Dennis I.] N Carolina State Univ, Dept Mol & Struct Biochem, Raleigh, NC 27695 USA. [Nelson, Steevenson] NIAID, NIH, Viral Dis Lab, Bethesda, MD 20892 USA. RP Brown, DI (reprint author), N Carolina State Univ, Dept Mol & Struct Biochem, Campus Box 7622, Raleigh, NC 27695 USA. EM dennis_brown@ncsu.edu RI Kononchik, Joseph/A-3221-2013 FU The Foundation for Research (Carson City, NV); North Carolina Agricultural Research Service FX The authors wish to thank Angel Paredes (University of Texas Health Sciences Center) for the Sindbis cryo reconstruction used to produce Fig. 6 and Valerie Knowlton (North Carolina State University) for imaging the scanning electron micrographs. This Research was supported by The Foundation for Research (Carson City, NV) and the North Carolina Agricultural Research Service. NR 30 TC 2 Z9 2 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 MAR 15 PY 2009 VL 385 IS 2 BP 285 EP 293 DI 10.1016/j.virol.2008.12.015 PG 9 WC Virology SC Virology GA 419XE UT WOS:000264252200001 PM 19144371 ER PT J AU Ozarslan, E Shemesh, N Basser, PJ AF Ozarslan, Evren Shemesh, Noam Basser, Peter J. TI A general framework to quantify the effect of restricted diffusion on the NMR signal with applications to double pulsed field gradient NMR experiments SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE algebra; diffusion; magnetic resonance imaging; mathematical operators; NMR spectroscopy; spin echo (NMR) ID SPIN-ECHO ANALYSIS; STRUCTURAL INFORMATION; WAVE-FORMS; TIME; GEOMETRIES; PORES; DECAY; WATER AB Based on a description introduced by Robertson, Grebenkov recently introduced a powerful formalism to represent the diffusion-attenuated NMR signal for simple pore geometries such as slabs, cylinders, and spheres analytically. In this work, we extend this multiple correlation function formalism by allowing for possible variations in the direction of the magnetic field gradient waveform. This extension is necessary, for example, to incorporate the effects of imaging gradients in diffusion-weighted NMR imaging scans and in characterizing anisotropy at different length scales via double pulsed field gradient (PFG) experiments. In cylindrical and spherical pores, respectively, two- and three-dimensional vector operators are employed whose form is deduced from Grebenkov's results via elementary operator algebra for the case of cylinders and the Wigner-Eckart theorem for the case of spheres. The theory was validated by comparison with known findings and with experimental double-PFG data obtained from water-filled microcapillaries. C1 [Ozarslan, Evren; Basser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. [Shemesh, Noam] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Chem, IL-69978 Tel Aviv, Israel. RP Ozarslan, E (reprint author), NICHD, Sect Tissue Biophys & Biomimet, NIH, 13 South Drive, Bethesda, MD 20892 USA. EM evren@helix.nih.gov RI Ozarslan, Evren/B-4858-2013; Basser, Peter/H-5477-2011; OI Ozarslan, Evren/0000-0003-0859-1311; Shemesh, Noam/0000-0001-6681-5876 FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH) FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH). NR 32 TC 55 Z9 55 U1 2 U2 16 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAR 14 PY 2009 VL 130 IS 10 AR 104702 DI 10.1063/1.3082078 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 420IF UT WOS:000264281800028 PM 19292544 ER PT J AU Li, XR Chen, HQ Bahamontes-Rosa, N Kun, JFJ Traore, B Crompton, PD Chishti, AH AF Li, Xuerong Chen, Huiqing Bahamontes-Rosa, Noemi Kun, Jurgen F. J. Traore, Boubacar Crompton, Peter D. Chishti, Athar H. TI Plasmodium falciparum signal peptide peptidase is a promising drug target against blood stage malaria SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Malaria; Plasmodium falciparum; Signal peptide peptidase; Intramembrane aspartyl protease; Erythrocyte; Band 3; Presenilins ID ERYTHROCYTE INVASION; INTRAMEMBRANE PROTEOLYSIS; ASPARTIC PROTEASE; PARASITES; PROTEINS AB The resistance of malaria parasites to current anti-malarial drugs is an issue of major concern globally. Recently we identified a Plasmodium falciparum cell membrane aspartyl protease, which binds to erythrocyte band 3, and is involved in merozoite invasion. Here we report the complete primary structure of P. falciparum signal peptide peptidase (PfSPP), and demonstrate that it is essential for parasite invasion and growth in human erythrocytes. Gene silencing suggests that PfSPP may be essential for parasite survival in human erythrocytes. Remarkably. mammalian signal peptide peptidase inhibitors (Z-LL)(2)-ketone and L-685,458 effectively inhibited malaria parasite invasion as well as growth in human erythrocytes. In contrast, DAPT, an inhibitor of a related gamma-secretase/presenilin-1, was ineffective. Thus, SPIR inhibitors specific for PfSPP may function as potent anti-malarial drugs against the blood stage malaria. (C) 2009 Elsevier Inc. All rights reserved. C1 [Li, Xuerong; Chen, Huiqing; Chishti, Athar H.] Univ Illinois, Coll Med, Dept Pharmacol, UIC Canc Ctr, Chicago, IL 60612 USA. [Bahamontes-Rosa, Noemi; Kun, Jurgen F. J.] Univ Tubingen, Dept Parasitol, D-72074 Tubingen, Germany. [Traore, Boubacar] Univ Bamako, Fac Med Pharm & Dent, Dept Epidemiol Parasit Dis, Malaria Res & Training Ctr, Bamako, Mali. [Crompton, Peter D.] NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. RP Chishti, AH (reprint author), Univ Illinois, Coll Med, Dept Pharmacol, UIC Canc Ctr, 909 S Wolcott Ave,MC-704 Room 5100, Chicago, IL 60612 USA. EM chishti@uic.edu RI Kun, Jurgen/C-1280-2010; Crompton, Peter/N-1130-2016 FU NIH [HL 60961] FX This work was supported by the NIH Grant HL 60961 (AC). We are grateful to Dr. Sam Sisodia for sharing SPP inhibitors with us and Dr. Alan Cowman for providing the gene targeting vector. We gratefully acknowledge the gift of WR-99210 drug from Dr. Guy Schiellser ofjacobus Pharmaceutical Company, Newjersey. We are also grateful to Dr. Louis H. Miller for helping us to obtain plasma samples from the malaria patients. Critical cornments and discussions with Drs. Ronald Dubreuil and John Quigley considerably improved this manuscript. We also thank Ms. Alex Chavez for help with the prediction and drawing of the PfSSP topology structure. Finally, we thank Dr. Anwar Khan, Farnaz Bakhshi, and Deanna Rybak for careful reading and editing of the manuscript. NR 17 TC 22 Z9 23 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 13 PY 2009 VL 380 IS 3 BP 454 EP 459 DI 10.1016/j.bbrc.2009.01.083 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 419LZ UT WOS:000264222400005 PM 19174148 ER PT J AU Anaganti, S Hansen, JK Ha, D Hahn, Y Chertov, O Pastan, I Bera, TK AF Anaganti, Suresh Hansen, Johanna K. Ha, Duc Hahn, Yoonsoo Chertov, Oleg Pastan, Ira Bera, Tapan K. TI Non-AUG translational initiation of a short CAPC transcript generating protein isoform SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE LRRC26; Prostate cancer; Breast cancer; Alternate transcript; Non-AUG initiation ID MAMMALIAN-CELLS; HIGH EXPRESSION; CODONS AB CAPC (also known as LRRC26) is a new gene with restricted expression in normal tissues, and with expression in many cancers and cancer cell lines. We have identified and characterized a short-transcript of CAPC(S-CAPC). The nucleotide sequence analysis of CAPC mRNA showed that the transcription for S-CAPC starts at position +610 on the L-CAPC transcript. Interestingly, no translation initiation codon 'AUG' is present in this transcript. To determine if a non-AUG start site is utilized, the S-CAPC sequence was cloned into an expression vector With C-terminal myc and histidine tags, and transfected into 293T cells. Western blot and MALDI-TOF MS analysis on purified S-CAPC gave two distinct peaks at approximately 7.5 kDa. N-terminal amino acid sequencing of the purified 7.5 kDa protein product indicated that translation starts at the codon for cysteine on the S-CAPC transcript generating a 7.5 kDa CAPC Protein products translated from a non-AUG initiation site. Published by Elsevier Inc C1 [Anaganti, Suresh; Hansen, Johanna K.; Ha, Duc; Hahn, Yoonsoo; Pastan, Ira; Bera, Tapan K.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Chertov, Oleg] SAIC Frederick Inc, NCI, Adv Technol Program, Prot Chem Lab, Frederick, MD 21702 USA. RP Bera, TK (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5110, Bethesda, MD 20892 USA. EM tkbera@helix.nih.gov FU NIH [NO1-CO-12400]; NCI; CCR FX We thank Susan Garfield and Poonarn Mannan for technical Support; and NIH Fellows Editorial Board for valuable comments. NR 8 TC 2 Z9 3 U1 1 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 13 PY 2009 VL 380 IS 3 BP 508 EP 513 DI 10.1016/j.bbrc.2009.01.089 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 419LZ UT WOS:000264222400015 PM 19250639 ER PT J AU Stybayeva, G Zhu, H Ramanculov, E Dandekar, S George, M Revzin, A AF Stybayeva, Gulnaz Zhu, He Ramanculov, Erlan Dandekar, Satya George, Michael Revzin, Alexander TI Micropatterned co-cultures of T-lymphocytes and epithelial cells as a model of mucosal immune system SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Antibody microarrays; Micropatterned co-cultures; Mucosal immune system; T-lymphocytes; Epithelial cells; HIV enteropathy ID IMMUNODEFICIENCY-VIRUS-INFECTION; GENE-EXPRESSION; BLOOD; PHOTOLITHOGRAPHY; REGENERATION; REPAIR; TISSUE AB Gut-associated lymphoid tissue is a major target and reservoir of human immunodeficiency virus (HIV)infected T-cells. Our studies seek to recapitulate, in vitro, interactions between HIV-infected T-lymphocytes and intestinal epithelial cells in order to investigate the mechanisms underlying the disruption of normal epithelial cell and barrier function. Here, we describe a novel approach for creating co-cultures of healthy or HIV-infected T-lymphocytes (Jurkat) and human intestinal epithelial (HT-29) cells where both cell types are positioned on the same surface in a price spatial configuration (micropattern). This co-culture method simplified observation/monitoring of the two cell types and was particularly suited for laser microdissection-based retrieval of the desired cells for downstream gene expressions Studies. DNA microarray analysis of epithelial cells retrieved from co-cultures with HIV-1-infected vs. uninfected Jurkat cells revealed that epithelial cells from HIV-infected co-cultures exhibited gene expression patterns consistent with disruption of epithelial barrier formation. Overall, the micropatterned co-culture system described here is envisioned as a valuable new tool for delineating how HIV and other infections contribute to dysfunction of mucosal epithelium. (C) 2009 Elsevier Inc. All rights reserved. C1 [Dandekar, Satya; George, Michael] Univ Calif Davis, Sch Med, Dept Med Microbiol & Immunol, Davis, CA 95616 USA. [Stybayeva, Gulnaz; Zhu, He; Revzin, Alexander] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. [Stybayeva, Gulnaz; Ramanculov, Erlan] Natl Ctr Biotechnol Republ Kazakhstan, Astana 010000, Kazakhstan. RP George, M (reprint author), Univ Calif Davis, Sch Med, Dept Med Microbiol & Immunol, 451 E Hlth Sci Dr, Davis, CA 95616 USA. EM mdgeorge@ucdavis.edu; arevzin@ucdavis.edu FU NIH [R21 DE01 8097, R01 Al 43274] FX We thank Prof. Louie's tab for the use of confocal microscope. Laser microdissection and RT-PCR experiments were carried out LUCY Whittier Molecular and Diagnostic Core Facility. GS was supported through a grant frorn the National Center for Biotechnology, Republic of Kazakhstan. Financial support for this work was provided in part by the California Research Center for the Biology of HIV in Minorities, California HIVIAIDS Research Program #CH05D-606. Financial support was also provided through NIH grants (R21 DE01 8097 awarded to MDG and R01 Al 43274 awarded to SD). NR 20 TC 7 Z9 7 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 13 PY 2009 VL 380 IS 3 BP 575 EP 580 DI 10.1016/j.bbrc.2009.01.164 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 419LZ UT WOS:000264222400027 PM 19285003 ER PT J AU Zhuang, J Li, F Liu, X Liu, ZP Lin, JX Ge, YH Kaminski, JM Summers, JB Wang, ZC Ge, J Yu, KM AF Zhuang, Jing Li, Fan Liu, Xuan Liu, Zhiping Lin, Jianxian Ge, Yihong Kaminski, Joseph M. Summers, James Bradley Wang, Zhichong Ge, Jian Yu, Keming TI Lithium chloride protects retinal neurocytes from nutrient deprivation by promoting DNA non-homologous end-joining SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Lithium chloride; Retinal neuron; Neuroprotection; NHEJ; Ligase IV ID COCKAYNE-SYNDROME PATIENTS; XRCC4-DNA LIGASE-IV; BINDING-PROTEIN; GANGLION-CELLS; RAT-BRAIN; REPAIR; NEURONS; GENE; REGENERATION; ELEMENT AB Lithium chloride is a therapeutic agent for treatment of bipolar affective disorders. Increasing number's of Studies have indicated that lithium has neuroprotective effects. However, the molecular mechanisms underlying the actions of lithium have not been fully elucidated. This study aimed to investigate whether lithium chloride produces neuroprotective function by improving DNA repair pathway in retinal neurocyte. In vitro, the primary Cultured retinal neurocytes (85.7% are MAP-2 positive cells) were treated with lithium chloride, then cultured with serum-free media to simulate the nutrient deprived state resulting from ischemic insult. The neurite Outgrowth of the cultured cells increased significantly in a dose-dependent manner when exposed to different levels of lithium chloride. Genomic DNA electrophoresis demonstrated greater DNA integrity of retinal neurocytes when treated with lithium chloride as compared to the control. Moreover, mRNA and protein levels of Ligase IV (involved in DNA non-homologous end-joining (NHEJ) pathway) in retinal neurocytes increased with lithium chloride. The end joining activity assay was performed to determine the role of lithium on NHEJ in the presence of extract from retinal neurocytes. The rejoining levels in retinal neurocytes treated with lithium were significantly increased as compared to the control. Furthermore, XRCC4, the Ligase IV partner, and the transcriptional factor, CREB and CTCF, were up-regulated in retinal cells after treating with 1.0 mM lithium chloride. Therefore, our data suggest that lithium chloride protects the retinal neural cells from nutrient deprivation in vitro, which may be similar to the mechanism of cell death in glaucoma. The improvement in DNA repair pathway involving in Ligase IV might have an important role in lithium neuroprotection. This study provides new insights into the neural protective mechanisms of lithium chloride. (C) 2009 Elsevier Inc. All rights reserved. C1 [Zhuang, Jing; Li, Fan; Liu, Xuan; Liu, Zhiping; Lin, Jianxian; Wang, Zhichong; Ge, Jian; Yu, Keming] Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China. [Ge, Yihong] So Med Univ, Dept Stomatol, Guangzhou, Guangdong, Peoples R China. [Kaminski, Joseph M.] Univ S Alabama, NIAID, Div Allergy Immunol & Transplantat, Mobile, AL 36688 USA. [Summers, James Bradley] Univ S Alabama, Dept Radiol, Mobile, AL 36617 USA. RP Ge, J (reprint author), Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, 54 S Xianlie Rd, Guangzhou 510060, Guangdong, Peoples R China. EM gejian@mail.sysu.edu.cn; yukeming@mail.sysu.edu.cn FU Ministry of Science and Technology of China; National High Technology Research and Development of China; Guangdong Province and the Ministry of Education of PR China [2007CB512207, 2006AA02A133, 3 7001573, 20070558283] FX This research was supported by the grants from the Ministry of Science and Technology of China, National High Technology Research and Development of China, Guangdong Province and the Ministry of Education of PR China) (2007CB512207; 2006AA02A133; 3 7001573; 20070558283). NR 36 TC 9 Z9 9 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 13 PY 2009 VL 380 IS 3 BP 650 EP 654 DI 10.1016/j.bbrc.2009.01.162 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 419LZ UT WOS:000264222400040 PM 19285016 ER PT J AU Swift, MR Weinstein, BM AF Swift, Matthew R. Weinstein, Brant M. TI Arterial-Venous Specification During Development SO CIRCULATION RESEARCH LA English DT Review DE arterial-venous specification; Hh; VEGF; Notch; COUP-TFII ID ENDOTHELIAL-GROWTH-FACTOR; RECEPTOR TYROSINE KINASE; EMBRYONIC VASCULAR DEVELOPMENT; PROTEIN-COUPLED RECEPTOR; MURINE YOLK-SAC; SONIC-HEDGEHOG; EPH RECEPTORS; CARDIOVASCULAR DEVELOPMENT; BRANCHING MORPHOGENESIS; NOTCH PATHWAY AB The major arteries and veins of the vertebrate circulatory system are formed early in embryonic development, before the onset of circulation, following de novo aggregation of "angioblast" progenitors in a process called vasculogenesis. Initial embryonic determination of artery or vein identity is regulated by variety of genetic factors that work in concert to specify endothelial cell fate, giving rise to 2 distinct components of the circulatory loop possessing unique structural characteristics. Work in multiple in vivo animal model systems has led to a detailed examination of the interacting partners that determine arterial and venous specification. We discuss the hierarchical arrangement of many signaling molecules, including Hedgehog (Hh), vascular endothelial growth factor (VEGF), Notch, and chicken ovalbumin upstream-transcription factor II (COUP-TFII) that promote or inhibit divergent pathways of endothelial cell fate. Elucidation of the functional role of these genetic determinants of blood vessel specification together with the epigenetic factors involved in subsequent modification of arterial-venous identity will allow for potential new therapeutic targets for vascular disorders. (Circ Res. 2009; 104: 576-588.) C1 [Swift, Matthew R.; Weinstein, Brant M.] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHD, Mol Genet Lab, NIH, Bldg 6B,Room 309,6 Ctr Dr, Bethesda, MD 20892 USA. EM flyingfish@nih.gov FU National Institute of Child Health and Human Development (NIH); Leducq Foundation FX This work was supported by the intramural program of the National Institute of Child Health and Human Development (NIH) and by the Leducq Foundation. NR 144 TC 181 Z9 191 U1 4 U2 24 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 MAR 13 PY 2009 VL 104 IS 5 BP 576 EP 588 DI 10.1161/CIRCRESAHA.108.188805 PG 13 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 418CX UT WOS:000264125900006 PM 19286613 ER PT J AU Nezu, A Parvin, MN Turner, RJ AF Nezu, Akihiro Parvin, Most. Nahid Turner, R. James TI A Conserved Hydrophobic Tetrad near the C Terminus of the Secretory Na(+)-K(+)-2Cl(-) Cotransporter (NKCC1) Is Required for Its Correct Intracellular Processing SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEPHROGENIC DIABETES-INSIPIDUS; ENDOPLASMIC-RETICULUM; CHLORIDE COTRANSPORTERS; FUNCTIONAL EXPRESSION; CARBOXYL-TERMINUS; QUALITY-CONTROL; RECEPTOR; PROTEIN; TRANSPORT; DOMAIN AB Little is known about the intracellular folding and trafficking of integral membrane proteins. Here we identify a hydrophobic amino acid tetrad (ILLV) close to the C terminus of the secretory Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) that is important for the proper intracellular processing of this protein. This tetrad appears in a C-terminal sequence pattern that is conserved across species in a number of members of the NKCC1 gene family (slc12) of electroneutral salt transporters. We studied the effects of various mutations of these amino acids on NKCC1 transiently transfected into HEK-293 cells. Our results show that mutation of two of these residues to alanine leads to a>50% reduction in expression and complex glycosylation levels and that multiple mutations to alanine have cumulative effects. By contrast, scrambling of these amino acids, or mutation of other nearby conserved C-terminal residues, has little effect on these parameters. Mutation of ILLV to AAA reduces complex glycosylation of NKCC1 by similar to 90% and results in a protein that does not form stable dimers and is retained in the endoplasmic reticulum in a highly aggregated state. Our results are consistent with the hypothesis that mutation of the hydrophobic tetrad ILLV to AAAA leads to the ab initio misfolding and concomitant aggregation of this NKCC1 mutant, resulting in its retention in the endoplasmic reticulum. C1 [Nezu, Akihiro; Parvin, Most. Nahid; Turner, R. James] Natl Inst Hlth, Membrane Biol Sect, Mol Physiol & Therapeut Branch, NIDCR,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Turner, RJ (reprint author), Natl Inst Hlth, Membrane Biol Sect, Mol Physiol & Therapeut Branch, NIDCR,Dept Hlth & Human Serv, Bldg 10,Rm 1A01,10 Ctr Dr,MSC 1190, Bethesda, MD 20892 USA. EM rjturner@nih.gov FU Intramural NIH HHS NR 33 TC 13 Z9 13 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 MAR 13 PY 2009 VL 284 IS 11 BP 6869 EP 6876 DI 10.1074/jbc.M804302200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 415FF UT WOS:000263919000034 PM 19129177 ER PT J AU Rausch, JW Chelico, L Goodman, MF Le Grice, SFJ AF Rausch, Jason W. Chelico, Linda Goodman, Myron F. Le Grice, Stuart F. J. TI Dissecting APOBEC3G Substrate Specificity by Nucleoside Analog Interference SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HIV REVERSE-TRANSCRIPTASE; DNA DEAMINASE DOMAIN; SINGLE-STRANDED-DNA; CYTIDINE DEAMINASE; VIF PROTEIN; CRYSTAL-STRUCTURE; FUNCTIONAL IMPLICATIONS; RETROVIRAL INFECTION; ANTIVIRAL ACTIVITY; VIRUS INFECTIVITY AB The apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminase genes encode a set of enzymes including APOBEC1(A1), APOBEC2(A2), APOBEC4 (A4), and APOBEC3A-H (A3A-H). Although each possesses one or more zinc binding motifs conserved among enzymes catalyzing C -> U conversion, the functions and substrate specificities of these gene products vary considerably. For example, although two closely related enzymes, A3F and A3G, both restrict HIV-1 infection in strains deficient in virus infectivity factor (vif), A3F selectively deaminates cytosine within 5'-TTCA-3' motifs in single stranded DNA, whereas A3G targets 5'-CCCA-3' sequences. In the present study we have used nucleoside analog interference mapping to probe A3G-DNA interactions throughout the enzyme-substrate complex as well as to determine which DNA structural features determine substrate specificity. Our results indicate that multiple components of nucleosides within the consensus sequence are important for substrate recognition by A3G (with base moieties being most critical), whereas deamination interference by analog substitution outside this region is minimal. Furthermore, exocyclic groups in pyrimidines 1-2 nucleotides 5' of the target cytosine were shown to dictate substrate recognition by A3G, with chemical composition at ring positions 3 and 4 found to be more important than at ring position 5. Taken together, these results provide insights into how the enzyme selects A3G hotspot motifs for deamination as well as which approaches might be best suited for forming a stable, catalytically competent crosslinked A3G-DNA complex for future structural studies. C1 [Chelico, Linda; Goodman, Myron F.] Univ So Calif, Dept Biol Sci, Mol & Computat Sect, Los Angeles, CA 90089 USA. [Rausch, Jason W.; Le Grice, Stuart F. J.] NCI Frederick, Retroviral Replicat Lab, HIV Drug Resistance Program, Natl Inst Hlth, Ft Detrick, MD 21702 USA. RP Le Grice, SFJ (reprint author), 1050 Boyles St, Frederick, MD 21702 USA. EM slegrice@ncifcrf.gov FU National Institutes of Health staff FX This work was authored, in whole or in part, by National Institutes of Health staff. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 49 TC 29 Z9 31 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 MAR 13 PY 2009 VL 284 IS 11 BP 7047 EP 7058 DI 10.1074/jbc.M807258200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 415FF UT WOS:000263919000053 PM 19136562 ER PT J AU Palmer, SM Playford, MP Craig, SW Schaller, MD Campbell, SL AF Palmer, Sean M. Playford, Martin P. Craig, Susan W. Schaller, Michael D. Campbell, Sharon L. TI Lipid Binding to the Tail Domain of Vinculin SPECIFICITY AND THE ROLE OF THE N AND C TERMINI SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; INTRAMOLECULAR ASSOCIATION; ACTIN-FILAMENTS; HYPERTROPHIC CARDIOMYOPATHY; DILATED CARDIOMYOPATHY; ACIDIC PHOSPHOLIPIDS; MISSENSE MUTATION; CRYSTAL-STRUCTURE; CELL-MIGRATION; TALIN-BINDING AB Vinculin is a highly conserved and abundant cytoskeletal protein involved in linking the actin cytoskeleton to the cell membrane at sites of cellular adhesion. At these sites of adhesion, vinculin plays a role in physiological processes such as cell motility, migration, development, and wound healing. Loss of normal vinculin function has been associated with cancer phenotypes, cardiovascular disease, and lethal errors in embryogenesis. The tail domain of vinculin (Vt) binds to acidic phospholipids and has been proposed to play a role in vinculin activation and focal adhesion turnover. To better characterize Vt-lipid specificity, we conducted a series of lipid co-sedimentation experiments and find that Vt shows specific association with phosphatidylinositol 4,5-bisphosphate (PIP(2)), compared with phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidylserine (PS), or phosphatidylinositol (PI) in the context of mixed lipid vesicles. The C terminus of Vt has been proposed to be important for PIP(2) association, as various mutations and deletions within the C-terminal reduce PIP(2) association. Lipid co-sedimentation and NMR analyses indicate that removal of the hydrophobic hairpin does not alter Vt structure or PIP(2) association. However, more extensive deletions within the C-terminal introduce Vt structural perturbations and reduce PIP(2) binding. Intriguingly, a significant increase in PIP(2) binding was observed for multiple Vt variants that perturb interactions between the N-terminal strap and helix bundle, suggesting that a rearrangement of this N-terminal strap may be required for PIP(2) binding. C1 [Palmer, Sean M.; Campbell, Sharon L.] Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. [Playford, Martin P.; Schaller, Michael D.] Univ N Carolina, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. [Schaller, Michael D.; Campbell, Sharon L.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Playford, Martin P.] NHLBI, NIH, Bethesda, MD 20892 USA. [Craig, Susan W.] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21205 USA. RP Campbell, SL (reprint author), Univ N Carolina, Dept Biochem & Biophys, CB 7260, Chapel Hill, NC 27599 USA. EM sharon_campbell@med.unc.edu FU NIGMS NIH HHS [R01 GM080568, R01 GM080568-01A1] NR 61 TC 36 Z9 36 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 MAR 13 PY 2009 VL 284 IS 11 BP 7223 EP 7231 DI 10.1074/jbc.M807842200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 415FF UT WOS:000263919000069 PM 19110481 ER PT J AU Gong, ZH Cho, YW Kim, JE Ge, K Chen, JJ AF Gong, Zihua Cho, Young-Wook Kim, Ja-Eun Ge, Kai Chen, Junjie TI Accumulation of Pax2 Transactivation Domain Interaction Protein (PTIP) at Sites of DNA Breaks via RNF8-dependent Pathway Is Required for Cell Survival after DNA Damage SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LYSINE-4 METHYLTRANSFERASE COMPLEX; BRCT-DOMAIN; BINDING; MDC1; PHOSPHORYLATION; CHECKPOINTS; STABILITY; REPAIR; P53 AB Genomic stability in eukaryotic cells is maintained by the coordination of multiple cellular events including cell cycle checkpoint, DNA repair, transcription, and apoptosis after DNA damage. Pax2 transactivation domain interaction protein (PTIP), a protein that contains six BRCT domains, has been implicated in DNA damage response. In this study we showed that recruitment of PTIP to damaged chromatin depends on DNA damage signaling proteins gamma H2AX center dot MDC1 center dot RNF8, which in turn facilitates sustained localization of PA1 (PTIP-associated protein 1) to sites of DNA break. Similar to PTIP, depletion of PA1 increases cellular sensitivity to ionizing radiation. Furthermore, we demonstrated that the N-terminal PA1 binding domain and the C-terminal focus-localization domain of PTIP are critical for PTIP function in DNA damage repair. Interestingly, although PTIP and PA1 associate with MLL (mixed lineage leukemia) complexes and participate in transcriptional regulation, this function of PTIP center dot PA1 in DNA damage response is likely to be independent of the MLL complexes. Taken together, we propose that a subset of PTIP center dot PA1 complex is recruited to DNA damage sites via the RNF8-dependent pathway and is required for cell survival in response to DNA damage. C1 [Gong, Zihua; Kim, Ja-Eun; Chen, Junjie] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. [Cho, Young-Wook; Ge, Kai] NIDDK, Nucl Receptor Biol Sect, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. [Kim, Ja-Eun] Kyung Hee Univ, Sch Med, Dept Pharmacol, Seoul 130701, South Korea. RP Chen, JJ (reprint author), Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. EM Junjie.chen@yale.edu RI Cho, Young-Wook /F-8269-2011; OI Ge, Kai/0000-0002-7442-5138 FU National Institutes of Health [CA089239, CA092312, CA100109] FX This work was supported, in whole or in part, by National Institutes of Health Grants CA089239, CA092312, and CA100109 (to J. C.). NR 26 TC 39 Z9 42 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 MAR 13 PY 2009 VL 284 IS 11 BP 7284 EP 7293 DI 10.1074/jbc.M809158200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 415FF UT WOS:000263919000075 PM 19124460 ER PT J AU Effantin, G Rosenzweig, R Glickman, MH Steven, AC AF Effantin, Gregory Rosenzweig, Rina Glickman, Michael H. Steven, Alasdair C. TI Electron Microscopic Evidence in Support of alpha-Solenoid Models of Proteasomal Subunits Rpn1 and Rpn2 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE negative staining electron microscopy; image classification; circular dichroism; alpha-solenoids ID PROTEIN SECONDARY STRUCTURE; CIRCULAR-DICHROISM SPECTRA; 26S PROTEASOME; REGULATORY PARTICLE; CRYOELECTRON MICROSCOPY; S-PROTEASOME; COMPLEX; BINDS; YEAST; VISUALIZATION AB Rpn1 (109 kDa) and Rpn2 (1.04 kDa) are components of the 19S regulatory complex of the proteasome. The central portions of both proteins are predicted to have toroidal alpha-solenoid folds composed of 9-11 proteasome/cyclosome repeats, each similar to 40 residues long and containing two alpha-helices and turns [A. V. Kajava, J. Biol. Chem. 277, 49791-49798, 2002]. To evaluate this prediction, we examined the full-length yeast proteins and truncated versions thereof consisting only of the repeat-containing regions by gel filtration, CD spectroscopy, and negative-staining electron microscopy (EM). All four proteins are monomeric in solution and highly alpha-helical, particularly the truncated ones. The EM data were analyzed by image classification and averaging techniques. The preponderant projections, in each case, show near-annular molecules 6-7 nm in diameter. Comparison of the full-length with the truncated proteins showed molecules similar in size and shape, indicating that their terminal regions are flexible and thus smeared to invisibility in the averaged images. We tested the toroidal model further by calculating resolution-limited projections and comparing them with the EM images. The results support the alpha-solenoid model, except that they indicate that the repeats are organized not as symmetrical circular toroids but in less regular horseshoe-like structures. Published by Elsevier Ltd. C1 [Effantin, Gregory; Steven, Alasdair C.] NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. [Rosenzweig, Rina; Glickman, Michael H.] Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. EM Alasdair_Steven@nih.gov FU NIAMS; Israel Science Foundation; USA-Israel Binational Science Foundation FX We thank Dr. A. V. Kajava for providing PDB coordinates for his models. This work was supported by the Intramural Research Program of NIAMS and by grants from the Israel Science Foundation and the USA-Israel Binational Science Foundation to M.H.G. NR 48 TC 29 Z9 29 U1 1 U2 1 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 MAR 13 PY 2009 VL 386 IS 5 BP 1204 EP 1211 DI 10.1016/j.jmb.2009.01.039 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 421UJ UT WOS:000264383500002 PM 19361443 ER PT J AU Lo, YC Lin, SC Rospigliosi, CC Conze, DB Wu, CJ Ashwell, JD Eliezer, D Wu, H AF Lo, Yu-Chih Lin, Su-Chang Rospigliosi, Carla C. Conze, Dietrich B. Wu, Chuan-Jin Ashwell, Jonathan D. Eliezer, David Wu, Hao TI Structural Basis for Recognition of Diubiquitins by NEMO SO MOLECULAR CELL LA English DT Article ID KAPPA-B ACTIVATION; POLYUBIQUITIN CHAINS; BINDING; UBIQUITINATION; MUTATION; PATHWAY; DOMAIN AB NEMO is the regulatory subunit of the I kappa B kinase (IKK) in NF-kappa B activation, and its CC2-LZ region interacts with Lys63 (K63)-linked polyubiquitin to recruit IKK to receptor signaling complexes. In vitro, CC2-LZ also interacts with tandem diubiquitin. Here we report the crystal structure of CC2-LZ with two dimeric coiled coils representing CC2 and LZ, respectively. Surprisingly, mutagenesis and nuclear magnetic resonance experiments reveal that the binding sites for diubiquitins at LZ are composites of both chains and that each ubiquitin in diubiquitins interacts with symmetrical NEMO asymmetrically. For tandem diubiquitin, the first ubiquitin uses the conserved hydrophobic patch and the C-terminal tail, while the second ubiquitin uses an adjacent surface patch. For K63-linked diubiquitin, the proximal ubiquitin uses its conserved hydrophobic patch, while the distal ubiquitin mostly employs the C-terminal arm including the K63 linkage residue. These studies uncover the energetics and geometry for mutual recognition of NEMO and diubiquitins. C1 [Lo, Yu-Chih; Lin, Su-Chang; Rospigliosi, Carla C.; Eliezer, David; Wu, Hao] Weill Cornell Med Coll, Dept Biochem, New York, NY 10021 USA. [Conze, Dietrich B.; Wu, Chuan-Jin; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wu, H (reprint author), Weill Cornell Med Coll, Dept Biochem, New York, NY 10021 USA. EM haowu@med.cornell.edu OI Lin, Su-Chang/0000-0003-0687-3139 FU NIA NIH HHS [R01 AG025440, R01 AG019391-09, R01 AG025440-04, R37 AG019391, R01 AG019391] NR 21 TC 143 Z9 146 U1 2 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAR 13 PY 2009 VL 33 IS 5 BP 602 EP 615 DI 10.1016/j.molcel.2009.01.012 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 419RT UT WOS:000264237800007 PM 19185524 ER PT J AU Carlson, DE Le, WW Chiu, WC Hoffman, GE AF Carlson, Drew E. Le, WeiWei Chiu, William C. Hoffman, Gloria E. TI Messenger RNA for neuropeptide Y in the arcuate nucleus increases in parallel with plasma adrenocorticotropin during sepsis in the rat SO NEUROSCIENCE LETTERS LA English DT Article DE Adrenocorticotropin; Arcuate nucleus; Cecal ligation and puncture; In situ hybridization; Neuropeptide Y; Sepsis ID CORTICOTROPIN-RELEASING HORMONE; GENE-EXPRESSION; FOOD-INTAKE; CECAL LIGATION; ENERGY-BALANCE; CORTICOSTERONE; HYPOTHALAMUS; ANOREXIA; PUNCTURE; RECEPTOR AB Loss of appetite occurs in the cecal ligation and puncture (CLP) model of sepsis in conjunction with the activation of central neural stress pathways. Neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus is upregulated by several stressors and is stimulatory to feeding. To examine the response of NPY messenger RNA in the arcuate nucleus to sepsis,we used biotinylated RNA probes and a quantitative non-isotopic in situ hybridization approach in cryo-preserved sections from rats made septic by CLP. The mRNA in arcuate neurons was upregulated from the first day after CLP. By the afternoon of the third day through the morning of the fourth day, the average grey level of NPY mRNA clusters was 30% greater after CLP than after sham surgery (P < 0.05), and the integrated optical density based on both the grey level and the amount of area with detectable mRNA was 60% greater after CLP than after sham surgery (P < 0.03). Both the average grey level and area with detectable staining were positively correlated to plasma ACTH (r = 0.953 and 0.917, respectively, n = 10 and P < 0.01 in each case). Thus sepsis increases the expression of the mRNA for NPY in the arcuate nucleus in proportion to the magnitude of the stress response. However, the suppression of feeding behavior in the CLP model suggests that sepsis activates additional mechanisms that negate the orexigenic contribution of the neuronal increase in NPY mRNA. Published by Elsevier Ireland Ltd. C1 [Carlson, Drew E.; Chiu, William C.] Univ Maryland, Dept Surg, Sch Med, Baltimore, MD 21201 USA. [Carlson, Drew E.] Univ Maryland, Dept Physiol, Sch Med, Baltimore, MD 21201 USA. [Le, WeiWei; Hoffman, Gloria E.] Univ Maryland, Dept Anat & Neurobiol, Sch Med, Baltimore, MD 21201 USA. RP Carlson, DE (reprint author), NHLBI, Div Cardiovasc Dis, 6701 Rockledge Dr,Room 8142, Bethesda, MD 20892 USA. EM carlsonde@mail.nih.gov FU National Institutes of Health [GM-063050, NS-28730] FX This work was supported in part by National Institutes of Health Grants GM-063050 and NS-28730. NR 33 TC 6 Z9 6 U1 1 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 13 PY 2009 VL 452 IS 2 BP 146 EP 150 DI 10.1016/j.neulet.2009.01.046 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 422ZM UT WOS:000264466200013 PM 19383429 ER PT J AU Klinman, DM Tross, D AF Klinman, Dennis M. Tross, Debra TI A single-dose combination therapy that both prevents and treats anthrax infection SO VACCINE LA English DT Article DE Anthrax; CpG ODN; Vaccine; Dalbavancin; Protection ID CPG OLIGONUCLEOTIDES IMPROVE; BACILLUS-ANTHRACIS; BACTERIAL-DNA; INHALATIONAL ANTHRAX; PROTECTIVE ANTIGEN; INTERFERON-GAMMA; RHESUS MACAQUES; DENDRITIC CELLS; ADVERSE EVENTS; VACCINE AB Exposure to anthrax leaves susceptible hosts at prolonged risk of infection since spores can persist in vivo for months before germinating to cause life-threatening disease. Anthrax vaccine adsorbed (AVA, the licensed US vaccine) induces immunity too slowly to protect Susceptible individuals post-exposure. Antibiotics prevent the proliferation of vegetative bacilli but do not block latent spores from germinating. Thus, anthrax-exposed individuals must remain on antibiotic therapy for months to eliminate the threat posed by delayed spore germination. Unfortunately, long-term antibiotic treatment is poorly tolerated and frequently discontinued. This work explores whether administering a single dose of a long-acting antibiotic (Dalbavancin) combined with a rapidly immunogenic vaccine/adjuvant combination can provide seamless protection from anthrax with minimal patient compliance. Results show that significant protection is achieved by delivering a single dose of this therapeutic combination any time before through 3 days after anthrax exposure. Published by Elsevier Ltd. C1 [Klinman, Dennis M.; Tross, Debra] NCI Frederick, Canc & Inflammat Program, Ft Detrick, MD 21702 USA. RP Klinman, DM (reprint author), NCI Frederick, Canc & Inflammat Program, Bldg 567,Rm 205, Ft Detrick, MD 21702 USA. EM klinmand@mail.nth.gov NR 52 TC 8 Z9 9 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAR 13 PY 2009 VL 27 IS 12 BP 1811 EP 1815 DI 10.1016/j.vaccine.2009.01.094 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 426AU UT WOS:000264680600004 PM 19402202 ER PT J AU Goldstein, DS Holmes, C Imrich, R AF Goldstein, David S. Holmes, Courtney Imrich, Richard TI Clinical laboratory evaluation of autoimmune autonomic ganglionopathy: Preliminary observations SO AUTONOMIC NEUROSCIENCE-BASIC & CLINICAL LA English DT Article DE Autonomic failure; Dysautonomia; Sympathetic nervous system; Norepinephrine; Fluorodopamine ID CARDIAC SYMPATHETIC DENERVATION; ORTHOSTATIC HYPOTENSION; PARKINSON-DISEASE; PLASMA-LEVELS; CATECHOLS; FAILURE; NOREPINEPHRINE; HUMANS AB Several forms of chronic autonomic failure manifest as neurogenic orthostatic hypotension, including autoimmune autonomic ganglionopathy (AAG) and pure autonomic failure (PAF). AAG and PAIF are thought to differ in pathogenesis, AAG reflecting decreased ganglionic neurotransmission due to circulating antibodies to the neuronal nicotinic receptor and PAF being a Lewy body disease with prominent loss of sympathetic noradrenergic nerves. AAG therefore would be expected to differ from PAIF in terms of clinical laboratory findings indicating postganglionic noradrenergic denervation. Both diseases are rare. Here we report preliminary observations about clinical physiologic neuropharmacologic, neurochemical, and neuroimaging data that seem to fit with the hypothesized pathogenetic difference between AAG and PAR Patients with either condition have evidence of baroreflex-sympathoneural and baroreflex-cardiovagal failure. Both disorders feature low plasma levels of catecholamines during supine rest, but plasma levels of the other endogenous catechols, dihydroxyphenylalanine (DOPA), dihydroxyphenylacetic acid (DOPAC) and dihydroxyphenylglycol (DHPG), seem to be lower in PAF than in AAG, probably reflecting decreased norepinephrine synthesis and turnover in PAF, due to diffuse sympathetic noradrenergic denervation. PAF entails cardiac sympathetic denervation, whereas cardiac sympathetic neuroimaging by thoracic 6-[(18)F]fluorodopamine scanning indicates intact myocardial sympathetic innervation in AAG. (C) 2008 Published by Elsevier B.V. C1 [Goldstein, David S.; Holmes, Courtney; Imrich, Richard] NINDS, Clin Neurocardiol Sect, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 17 TC 8 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1566-0702 J9 AUTON NEUROSCI-BASIC JI Auton. Neurosci-Basic Clin. PD MAR 12 PY 2009 VL 146 IS 1-2 BP 18 EP 21 DI 10.1016/j.autneu.2008.12.004 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 424OV UT WOS:000264576900005 PM 19155193 ER PT J AU Eddahri, F Denanglaire, S Bureau, F Spolski, R Leonard, WJ Leo, O Andris, F AF Eddahri, Fouad Denanglaire, Sebastien Bureau, Fabrice Spolski, Rosanne Leonard, Warren J. Leo, Oberdan Andris, Fabienne TI Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities SO BLOOD LA English DT Article ID CXC CHEMOKINE RECEPTOR-5; IMMUNE-RESPONSES; IN-VIVO; TRANSCRIPTION FACTOR; IMMUNOGLOBULIN PRODUCTION; AUTOCRINE REGULATION; LINEAGE COMMITMENT; DENDRITIC CELLS; IL-21 RECEPTOR; EFFECTOR-CELLS AB The conditions leading to the activation/differentiation of T-helper (Th) cells dedicated for B-cell antibody production are still poorly characterized. We now demonstrate that interleukin-6 (IL-6) promotes the differentiation of naive T lymphocytes into helper cells able to promote B-cell activation and antibody secretion. IL-6 driven acquisition of B-cell help capacity requires expression of the signal transducer and activator of transcription 3 (STAT3), but not STAT4 or STAT6 transcription factors, suggesting that the ability to provide help to B cells is not restricted to a well-defined Th1 or Th2 effector population. T cell-specific STAT3-deficient mice displayed reduced humoral responses in vivo that could not be related to an altered expansion of CXCR5-expressing helper T cells. IL-6 was shown to promote IL-21 secretion, a cytokine that was similarly found to promote the differentiation of naive T cells into potent B-cell helper cells. Collectively, these data indicate that the ability to provide B-cell help is regulated by IL-6/IL-21 through STAT3 activation, independently of Th1, Th2, Th17, or follicular helper T cell (T(FH)) differentiation. (Blood. 2009;113:2426-2433) C1 [Eddahri, Fouad; Denanglaire, Sebastien; Leo, Oberdan; Andris, Fabienne] Univ Libre Bruxelles, Physiol Anim Lab, Brussels, Belgium. [Bureau, Fabrice] Univ Liege, Lab Cellular & Mol Physiol, Grp Interdisciplinaire Genom Appl Res, Liege, Belgium. [Spolski, Rosanne; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Andris, F (reprint author), Univ Libre Bruxelles IBMM, Physiol Anim Lab, 12 Rue Prof Jeener & Brachet, B-6041 Gosselies, Belgium. EM fandris@ulb.ac.be FU Belgian Program in Interuniversity Poles of Attraction; Fonds Jean Brachet (Gosselies, Belgium); GSK Biologicals (Rixensart, Belgium); Division of Intramural Research, National Heart, Lung, and Blood Institute (R.S., W.J.L.).; Fonds National de la Recherche Scientifique (Bruxelles, Belgium); DGTRE-Region Wallonne (Namur, Belgium) FX This work was supported by the Belgian Program in Interuniversity Poles of Attraction Initiated by the Belgian State, Prime Minister's Office, Science Policy Programming, by a Research Concerted Action of the Communaute francaise de Belgique (Namur, Belgium) grant from the Fonds Jean Brachet (Gosselies, Belgium), and a collaborative research agreement fee from GSK Biologicals (Rixensart, Belgium), and support from the Division of Intramural Research, National Heart, Lung, and Blood Institute (R.S., W.J.L.). F. A. is a Research Associate at the National Fund for Scientific Research, Fonds National de la Recherche Scientifique (Bruxelles, Belgium). F. E. is supported by a First Post Doc fellow from the DGTRE-Region Wallonne (Namur, Belgium). NR 44 TC 90 Z9 94 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 MAR 12 PY 2009 VL 113 IS 11 BP 2426 EP 2433 DI 10.1182/blood-2008-04-154682 PG 8 WC Hematology SC Hematology GA 417XA UT WOS:000264110600010 PM 19020307 ER PT J AU Yamaza, T Miura, Y Akiyama, K Bi, YM Sonoyama, W Gronthos, S Chen, WJ Le, A Shi, ST AF Yamaza, Takayoshi Miura, Yasuo Akiyama, Kentaro Bi, Yanming Sonoyama, Wataru Gronthos, Stan Chen, WanJun Le, Anh Shi, Songtao TI Mesenchymal stem cell-mediated ectopic hematopoiesis alleviates aging-related phenotype in immunocompromised mice SO BLOOD LA English DT Article ID GROWTH-FACTOR-I; MARROW STROMAL FIBROBLASTS; HUMAN BONE-MARROW; LIFE-SPAN; CIRCULATING CONCENTRATIONS; CANCER RISK; OSTEOGENESIS; DISEASE; ERYTHROPOIETIN; INSIGHTS AB Subcutaneous transplants of bone marrow mesenchymal stem cells (BMMSCs) are capable of generating ectopic bone and organizing functional hematopoietic marrow elements in animal models. Here we report that immunocompromised mice received subcutaneous BMMSC transplants using hydroxyapatite tricalcium phosphate as a carrier suppressed age-related degeneration in multiple organs and benefited an increase in life span extension compared with control littermates. The newly organized ectopic bone/marrow system restores active hematopoiesis via the erythropoietin receptor/signal transducer and activator of transcription 5 (Stat5) pathway. Furthermore, the BMMSC recipient mice showed elevated level of Klotho and suppression of insulin-like growth factor I signaling, which may be the mechanism contributing to the alleviation of aging-like phenotypes and prolongation of life in the treated mice. This work reveals that erythropoietin receptor/Stat5 pathway contributes to BMMSC-organized ectopic hematopoiesis, which may offer a treatment paradigm of reversing age-related degeneration of multiple organs in adult immunocompromised mice. (Blood.2009;113:2595-2604) C1 [Yamaza, Takayoshi; Akiyama, Kentaro; Sonoyama, Wataru; Le, Anh; Shi, Songtao] Univ So Calif, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. [Miura, Yasuo] Kyoto Univ, Grad Sch Med, Kyoto, Japan. [Bi, Yanming; Chen, WanJun] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. [Gronthos, Stan] Inst Med & Vet Sci, Mesenchymal Stem Cell Grp, Div Haematol, Adelaide, SA 5000, Australia. RP Shi, ST (reprint author), Univ So Calif, Ctr Craniofacial Mol Biol, Hlth Sci Campus,2250 Alcazar St,CSA103, Los Angeles, CA 90033 USA. EM songtaos@usc.edu FU National Institute of Dental and Craniofacial Research [R01DE017449, R21 DE017632]; National Institutes of Health; Department of Health and Human Services; California Institute for Regenerative Medicine [RN1-00572]; National Institute of Dental and Craniofacial Research FX This work was supported by the National Institute of Dental and Craniofacial Research (grants R01DE017449 and R21 DE017632), National Institutes of Health, Department of Health and Human Services (S.S.), the California Institute for Regenerative Medicine (grant RN1-00572; S.S., A.L.), and in part by the Intramural Research Program of the National Institute of Dental and Craniofacial Research, National Institutes of Health. NR 38 TC 29 Z9 30 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 MAR 12 PY 2009 VL 113 IS 11 BP 2595 EP 2604 DI 10.1182/blood-2008-10-182246 PG 10 WC Hematology SC Hematology GA 417XA UT WOS:000264110600028 PM 19074727 ER PT J AU Kim, P Zhang, L Manjunatha, UH Singh, R Patel, S Jiricek, J Keller, TH Boshoff, HI Barry, CE Dowd, CS AF Kim, Pilho Zhang, Liano Manjunatha, Ujjini H. Singh, Ramandeep Patel, Sejal Jiricek, Jan Keller, Thomas H. Boshoff, Helena I. Barry, Clifton E., III Dowd, Cynthia S. TI Structure-Activity Relationships of Antitubercular Nitroimidazoles. 1. Structural Features Associated with Aerobic and Anaerobic Activities of 4-and 5-Nitroimidazoles SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; IN-VITRO; AGENTS; NITROFURANYLAMIDES; PROSPECTS; PA-824; SERIES AB The 4-nitroimidazole PA-824 is active against aerobic and anaerobic Mycobacterium tuberculosis (Mtb) while 5-nitroimidazoles like metronidazole are active against only anaerobic Mtb. We have synthesized analogues of both 4- and 5-nitroimidazoles and explored their antitubercular activities. The nitro group is required for both activities in all compounds. The key determinants of aerobic activity in the 4-nitroimidazoles include the bicyclic oxazine, the lipophilic tail, and the 2-position oxygen. For the 5-nitroimidazoles. neither the corresponding bicyclic analogue not-addition of a lipophilic tail conveyed aerobic activity. Incorporation of a 2-position oxygen atom into a rigid 5-nitroimidazooxazine provided the first 5-nitroimidazole with aerobic activity. Across both series, anaerobic and aerobic activities were not correlated and Mtb mutants lacking the deazaflavin-dependent nitroreductase (Ddn) retained anaerobic sensitivity to some Compounds. Aerobic activity appears to be correlated with efficiency as a substrate for Ddn, suggesting a means of structure-based optimization of improved nitroimidazoles. C1 [Kim, Pilho; Zhang, Liano; Manjunatha, Ujjini H.; Singh, Ramandeep; Boshoff, Helena I.; Barry, Clifton E., III; Dowd, Cynthia S.] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Patel, Sejal; Jiricek, Jan; Keller, Thomas H.] Novartis Inst Trop Dis, Singapore 138670, Singapore. RP Dowd, CS (reprint author), George Washington Univ, Dept Chem, Washington, DC 20052 USA. EM cdowd@gwu.edu RI Barry, III, Clifton/H-3839-2012; OI Keller, Thomas/0000-0002-7553-6235 FU National Institute of Allergy and Infectious Diseases, NIH; Bill and Melinda Gates Foundation; Wellcome Trust FX This work was funded (in part) by the intramural research program of National Institute of Allergy and Infectious Diseases, NIH, and (in part) by a grant from the Bill and Melinda Gates Foundation and the Wellcome Trust through the Grand Challenges in Global Health Initiative. We thank Dr. Lacy Daniels (Texas A&M University Health Science Center) for F420 and Michael Goodwin (TRS, MAID, NIH), John Lloyd (NIDDK, NIH), and Wesley White (NIDDK. NIH) with assistance in obtaining analytical data. NR 29 TC 55 Z9 58 U1 1 U2 13 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 MAR 12 PY 2009 VL 52 IS 5 BP 1317 EP 1328 DI 10.1021/jm801246z PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 415ZJ UT WOS:000263974700013 PM 19209889 ER PT J AU Kim, P Kang, S Boshoff, HI Jiricek, J Collins, M Singh, R Manjunatha, UH Niyomrattanakit, P Zhang, L Goodwin, M Dick, T Keller, TH Dowd, CS Barry, CE AF Kim, Pilho Kang, Sunhee Boshoff, Helena I. Jiricek, Jan Collins, Margaret Singh, Ramandeep Manjunatha, Ujjini H. Niyomrattanakit, Pornwaratt Zhang, Liang Goodwin, Michael Dick, Thomas Keller, Thomas H. Dowd, Cynthia S. Barry, Clifton E., III TI Structure-Activity Relationships of Antitubercular Nitroimidazoles. 2. Determinants of Aerobic Activity and Quantitative Structure-Activity Relationships SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID MYCOBACTERIUM-TUBERCULOSIS; DERIVATIVES; PA-824; INTERMEDIATE; ACTIVATION; INHIBITORS; BEARING AB The (S)-2-nitro-6-substituted 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazines have been extensively explored for their potential use as new antituberculars based on their excellent bactericidal properties on aerobic whole cells of Mycobacterium tuberculosis. An oxygen atom at the 2-position of the imidazole ring is required for aerobic activity. Here, we show that substitution of this oxygen by either nitrogen or sulfur yielded equipotent analogues. Acylating the amino series, oxidizing the thioether, or replacing the ether oxygen with carbon significantly reduced the potency of the compounds. Replacement of the benzylic oxygen at the 6-position by nitrogen slightly improved potency and facilitated exploration of the SAR in the more soluble 6-amino series. Significant improvements in potency were realized by extending, the linker region between the 6-(S) position and the terminal hydrophobic aromatic substituent. A simple four-feature QSAR model was derived to rationalize MIC results in this series of bicyclic nitroimidazoles. C1 [Kim, Pilho; Kang, Sunhee; Boshoff, Helena I.; Collins, Margaret; Singh, Ramandeep; Manjunatha, Ujjini H.; Zhang, Liang; Goodwin, Michael; Dowd, Cynthia S.; Barry, Clifton E., III] NIAID, TB Res Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Jiricek, Jan; Manjunatha, Ujjini H.; Niyomrattanakit, Pornwaratt; Dick, Thomas] Novartis Inst Trop Dis, Singapore 138670, Singapore. RP Dowd, CS (reprint author), George Washington Univ, Dept Chem, Washington, DC 20052 USA. EM cdowd@gwu.edu; cbarry@mail.nih.gov RI Barry, III, Clifton/H-3839-2012; OI Keller, Thomas/0000-0002-7553-6235 FU National Institute of Allergy and Infectious Diseases, NIH; Bill and Melinda Gates Foundation; Wellcome Trust; Korea Foundation for International Cooperation of Science and Technology (KICOS); Korean Ministry of Education, Science and Technology (MEST) [K20501000001] FX This work was funded (in part) by the intramural research program of National Institute of Allergy and Infectious Diseases, NIH, and (in part) by a grant from the Bill and Melinda Gates Foundation and the Wellcome Trust through the Grand Challenges in Global Health Initiative. This work was also supported (in part) by the Korea Foundation for International Cooperation of Science and Technology (KICOS) through a grant provided by the Korean Ministry of Education, Science and Technology (MEST) (No. K20501000001). We thank Melvin Au and Elaine Chai (NITD) for protein purification. NR 33 TC 56 Z9 58 U1 3 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 12 PY 2009 VL 52 IS 5 BP 1329 EP 1344 DI 10.1021/jm801374t PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 415ZJ UT WOS:000263974700014 PM 19209893 ER PT J AU Auld, DS Zhang, YQ Southall, NT Rai, G Landsman, M MacLure, J Langevin, D Thomas, CJ Austin, CP Inglese, J AF Auld, Douglas S. Zhang, Ya-Qin Southall, Noel T. Rai, Ganesha Landsman, Marc MacLure, Jennifer Langevin, Daniel Thomas, Craig J. Austin, Christopher P. Inglese, James TI A Basis for Reduced Chemical Library Inhibition of Firefly Luciferase Obtained from Directed Evolution SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID THROUGHPUT SCREENING ASSAYS; PROTEIN-KINASE; BIOLUMINESCENT ASSAYS; IDENTIFICATION; TRANSCREENER(TM); FLUORESCENCE; ACTIVATION; DISCOVERY; DRUGABILITY; MECHANISM AB We measured the "druggability" of the ATP-dependent luciferase derived from the firefly Photuris pennsylvanica that was optimized using directed evolution (Ultra-Glo, Promega). Quantitative high-throughput screening (qHTS) was used to determine IC(50)S of 198899 samples against a formulation of Ultra-Glo luciferase (Kinase-Glo). We found that only 0.1 % of the Kinase-Glo inhibitors showed an IC(50) < 10 mu M compared to 0.9% found from a previous qHTS against the firefly luciferase from Photinus pyralis (lucPpy). Further, the maximum affinity identified in the lucPpy qHTS was 50 nM, while for Kinase-Glo this value increased to 600 nM. Compounds with interactions stretching outside the luciferin binding pocket were largely lost with Ultra-Glo luciferase. Therefore, Ultra-Glo luciferase will show less compound interference when used as an ATP sensor compared to lucPpy. This study demonstrates the power of large-scale quantitative analysis of structure-activity relationships (> 100K compounds) in addressing important questions such as a target's druggability. C1 [Auld, Douglas S.; Zhang, Ya-Qin; Southall, Noel T.; Rai, Ganesha; Landsman, Marc; MacLure, Jennifer; Langevin, Daniel; Thomas, Craig J.; Austin, Christopher P.; Inglese, James] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Auld, DS (reprint author), NIH, Chem Genom Ctr, Bldg 10, Bethesda, MD 20892 USA. EM dauld@mail.nih.gov RI Southall, Noel/H-8991-2012 OI Southall, Noel/0000-0003-4500-880X FU NIH Roadmap for Medical Research; National Human Genome Research Institute FX This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. We thank Adam Yasgar, Paul Shinn for compound management support, Jererny Smith for analytical chemistry support, and Carleen Klumpp and Sam Michael for assistance with the Kalypsys robotic system. NR 46 TC 42 Z9 43 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 12 PY 2009 VL 52 IS 5 BP 1450 EP 1458 DI 10.1021/jm8014525 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 415ZJ UT WOS:000263974700024 PM 19215089 ER PT J AU Wollert, T Wunder, C Lippincott-Schwartz, J Hurley, JH AF Wollert, Thomas Wunder, Christian Lippincott-Schwartz, Jennifer Hurley, James H. TI Membrane scission by the ESCRT-III complex SO NATURE LA English DT Article ID MULTIVESICULAR ENDOSOMES; STRUCTURAL BASIS; CELL-DIVISION; PROTEINS; VPS4; RECOGNITION; BIOGENESIS; MACHINERY; HIV-1; ALIX AB The endosomal sorting complex required for transport (ESCRT) system is essential for multivesicular body biogenesis, in which cargo sorting is coupled to the invagination and scission of intralumenal vesicles. The ESCRTs are also needed for budding of enveloped viruses including human immunodeficiency virus 1, and for membrane abscission in cytokinesis. In Saccharomyces cerevisiae, ESCRT-III consists of Vps20, Snf7, Vps24 and Vps2 (also known as Did4), which assemble in that order and require the ATPase Vps4 for their disassembly. In this study, the ESCRT-III-dependent budding and scission of intralumenal vesicles into giant unilamellar vesicles was reconstituted and visualized by fluorescence microscopy. Here we show that three subunits of ESCRT-III, Vps20, Snf7 and Vps24, are sufficient to detach intralumenal vesicles. Vps2, the ESCRT-III subunit responsible for recruiting Vps4, and the ATPase activity of Vps4 were required for ESCRT-III recycling and supported additional rounds of budding. The minimum set of ESCRT-III and Vps4 proteins capable of multiple cycles of vesicle detachment corresponds to the ancient set of ESCRT proteins conserved from archaea to animals. C1 [Wollert, Thomas; Hurley, James H.] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. [Wunder, Christian; Lippincott-Schwartz, Jennifer] NICHHD, Cell Biol & Metab Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov OI Wollert, Thomas/0000-0001-9732-4789; Wunder, Christian/0000-0001-9091-0080 FU Intramural NIH HHS [Z01 DK036123-01] NR 38 TC 290 Z9 294 U1 5 U2 34 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 12 PY 2009 VL 458 IS 7235 BP 172 EP U2 DI 10.1038/nature07836 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 417EQ UT WOS:000264059700036 PM 19234443 ER PT J AU Jhou, TC Fields, HL Baxter, MG Saper, CB Holland, PC AF Jhou, Thomas C. Fields, Howard L. Baxter, Mark G. Saper, Clifford B. Holland, Peter C. TI The Rostromedial Tegmental Nucleus (RMTg), a GABAergic Afferent to Midbrain Dopamine Neurons, Encodes Aversive Stimuli and Inhibits Motor Responses SO NEURON LA English DT Article ID MEDIAN RAPHE NUCLEUS; LATERAL HABENULA; BASOLATERAL AMYGDALA; STRIA TERMINALIS; SUBSTANTIA-NIGRA; BED NUCLEUS; TEMPORARY INACTIVATION; ORBITOFRONTAL CORTEX; MESOLIMBIC DOPAMINE; MEDULLA-OBLONGATA AB Separate studies have implicated the lateral habenula (LHb) or amygdala-related regions in processing aversive stimuli, but their relationships to each other and to appetitive motivational systems are poorly understood. We show that neurons in the recently identified GABAergic rostromedial tegmental nucleus (RMTg), which receive a major LHb input, project heavily to midbrain dopamine neurons, and show phasic activations and/or Fos induction after aversive stimuli (footshocks, shock-predictive cues, food deprivation, or reward omission) and inhibitions after rewards or reward-predictive stimuli. RMTg lesions markedly reduce passive fear behaviors (freezing, open-arm avoidance) dependent on the extended amygdala, periaqueductal gray, or septum, all regions that project directly to the RMTg. In contrast, RMTg lesions spare or enhance active fear responses (treading, escape) in these same paradigms. These findings suggest that aversive inputs from widespread brain regions and stimulus modalities converge onto the RMTg, which opposes reward and motor-activating functions of midbrain dopamine neurons. C1 [Jhou, Thomas C.] NIDA, Behav Neurosci Branch, Baltimore, MD 21224 USA. [Fields, Howard L.] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Emeryville, CA 94608 USA. [Baxter, Mark G.] Univ Oxford, Dept Expt Psychol, Oxford OX1 3UD, England. [Saper, Clifford B.] Harvard Univ, Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Holland, Peter C.] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA. RP Jhou, TC (reprint author), NIDA, Behav Neurosci Branch, Baltimore, MD 21224 USA. EM tomjhou@gmail.com FU NIH [HL60292, MH53667, MH60179]; Merck; Cephalon; Sepracor; Allen Brain Institute FX We are grateful for comments on the manuscript draft from Daniel S. Zahm. We also acknowledge excellent technical assistance from Quan Ha, Minh Ha, and Weidong Hu. This research was supported by NIH grants HL60292 (to C.B.S.), MH53667 (to P.C.H.), and MH60179 (to Michela Gallagher), and also by the State of California Research Program for Alcoholism and Addiction and by the Intramural Research Program of the NIH, NIDA. C.B.S. has received consulting fees and grant support from Merck, Cephalon, Sepracor, and the Allen Brain Institute. These compensations are each under $10,000. C.B.S. also receives a stipend as editor-in-chief of the Joumal of Comparative Neurology and President-Elect of the Sleep Research Society, which exceed $10,000. These have not influenced the results or interpretation of the current work. NR 78 TC 234 Z9 241 U1 3 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD MAR 12 PY 2009 VL 61 IS 5 BP 786 EP 800 DI 10.1016/j.neuron.2009.02.001 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 421NZ UT WOS:000264366900017 PM 19285474 ER PT J AU Parashar, UD Glass, RI AF Parashar, Umesh D. Glass, Roger I. TI Global Health: Rotavirus Vaccines - Early Success, Remaining Questions. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID UNITED-STATES; VACCINATION; EFFICACY; SAFETY C1 [Parashar, Umesh D.] Ctr Dis Control & Prevent, Div Viral Dis, Viral Gastroenteritis Epidemiol Team, Atlanta, GA USA. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Parashar, UD (reprint author), Ctr Dis Control & Prevent, Div Viral Dis, Viral Gastroenteritis Epidemiol Team, Atlanta, GA USA. NR 5 TC 51 Z9 52 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 12 PY 2009 VL 360 IS 11 BP 1063 EP 1065 DI 10.1056/NEJMp0810154 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 417BW UT WOS:000264051000003 PM 19279338 ER PT J AU Di Bisceglie, AM Wright, E Dienstag, JL AF Di Bisceglie, Adrian M. Wright, Elizabeth Dienstag, Jules L. CA HALT-C Trial Investigators TI Prolonged Therapy for Hepatitis C with Low-Dose Peginterferon Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID BRIEF COMMUNICATION; REGRESSION; CIRRHOSIS C1 [Di Bisceglie, Adrian M.] St Louis Univ, Sch Med, St Louis, MO 63104 USA. [Wright, Elizabeth] NIDDKD, Bethesda, MD 20892 USA. [Dienstag, Jules L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Di Bisceglie, AM (reprint author), St Louis Univ, Sch Med, St Louis, MO 63104 USA. EM dibiscam@slu.edu NR 7 TC 1 Z9 1 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 12 PY 2009 VL 360 IS 11 BP 1152 EP 1153 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 417BW UT WOS:000264051000025 ER PT J AU Gearhart, PJ Lindahl, T Neuberger, MS AF Gearhart, Patricia J. Lindahl, Tomas Neuberger, Michael S. TI DNA deamination in immunity, virology and cancer SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Editorial Material C1 [Neuberger, Michael S.] MRC, Mol Biol Lab, Cambridge CB2 0QH, England. [Gearhart, Patricia J.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Lindahl, Tomas] Canc Res UK London Res Inst, Clare Hall Labs, S Mimms EN6 3LD, Herts, England. RP Neuberger, MS (reprint author), MRC, Mol Biol Lab, Hills Rd, Cambridge CB2 0QH, England. EM msn@mrc-lmb.cam.ac.uk NR 2 TC 0 Z9 0 U1 0 U2 4 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAR 12 PY 2009 VL 364 IS 1517 BP 561 EP 562 DI 10.1098/rstb.2008.0236 PG 2 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 400VR UT WOS:000262898000001 PM 19008190 ER PT J AU Saribasak, H Rajagopal, D Maul, RW Gearhart, PJ AF Saribasak, Huseyin Rajagopal, Deepa Maul, Robert W. Gearhart, Patricia J. TI Hijacked DNA repair proteins and unchained DNA polymerases SO PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE immunoglobulin genes; somatic hypermutation; class switch recombination; MSH2-MSH6; DNA polymerase eta; Cockayne syndrome B ID CLASS-SWITCH RECOMBINATION; IMMUNOGLOBULIN GENE HYPERMUTATION; SOMATIC HYPERMUTATION; MISMATCH REPAIR; MICE DEFICIENT; ANTIBODY DIVERSIFICATION; B-CELLS; EXCISION-REPAIR; VARIABLE GENES; CUTTING EDGE AB Somatic hypermutation of immunoglobulin (Ig) genes occurs at a frequency that is a million times greater than the mutation in other genes. Mutations occur in variable genes to increase antibody affinity, and in switch regions before constant genes to cause switching from IgM to IgG. Hypermutation is initiated in activated B cells when the activation-induced deaminase protein deaminates cytosine in DNA to uracil. Uracils can be processed by either a mutagenic pathway to produce mutations or a non-mutagenic pathway to remove mutations. In the mutagenic pathway, we first studied the role of mismatch repair proteins, MSH2, MSH3, MSH6, PMS2 and MLH1, since they would recognize mismatches. The MSH2-MSH6 heterodimer is involved in hypermutation by binding to U: G and other mismatches generated during repair synthesis, but the other proteins are not necessary. Second, we analysed the role of low-fidelity DNA polymerases eta, iota and theta in synthesizing mutations, and conclude that polymerase h is the dominant participant by generating mutations at A: T base pairs. In the non-mutagenic pathway, we examined the role of the Cockayne syndrome B protein that interacts with other repair proteins. Mice deficient in this protein had normal hypermutation and class switch recombination, showing that it is not involved. C1 [Saribasak, Huseyin; Rajagopal, Deepa; Maul, Robert W.; Gearhart, Patricia J.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Gearhart, PJ (reprint author), NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. EM gearhartp@grc.nia.nih.gov RI Saribasak, Huseyin/C-9331-2012 OI Maul, Robert/0000-0002-6958-8514; Saribasak, Huseyin/0000-0003-0055-062X FU Intramural Research Program of the NIH, National Institute on Aging FX We acknowledge the past contributions by members of the laboratory over the years. Vilhelm Bohr provided the CSBdeficient mice. Thanks to Joe Jiricny for comments on the manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 41 TC 17 Z9 17 U1 0 U2 2 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8436 J9 PHILOS T R SOC B JI Philos. Trans. R. Soc. B-Biol. Sci. PD MAR 12 PY 2009 VL 364 IS 1517 BP 605 EP 611 DI 10.1098/rstb.2008.0188 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 400VR UT WOS:000262898000007 PM 19008198 ER PT J AU Sousa, AD Andrade, LR Salles, FT Pillai, AM Buttermore, ED Bhat, MA Kachar, B AF Sousa, Aurea D. Andrade, Leonardo R. Salles, Felipe T. Pillai, Anilkumar M. Buttermore, Elizabeth D. Bhat, Manzoor A. Kachar, Bechara TI The Septate Junction Protein Caspr Is Required for Structural Support and Retention of KCNQ4 at Calyceal Synapses of Vestibular Hair Cells SO JOURNAL OF NEUROSCIENCE LA English DT Article ID MYELINATED AXONS; ADHESION MOLECULES; FREEZE-FRACTURE; ION CHANNELS; GUINEA-PIG; INNER-EAR; SYSTEM; ORGANIZATION; AFFERENTS; RANVIER AB The afferent innervation contacting the type I hair cells of the vestibular sensory epithelia form distinct calyceal synapses. The apposed presynaptic and postsynaptic membranes at this large area of synaptic contact are kept at a remarkably regular distance. Here, we show by freeze-fracture electron microscopy that a patterned alignment of proteins at the calyceal membrane resembles a type of intercellular junction that is rare in vertebrates, the septate junction (SJ). We found that a core molecular component of SJs, Caspr, colocalizes with the K(+) channel KCNQ4 at the postsynaptic membranes of these calyceal synapses. Immunolabeling and ultrastructural analyses of Caspr knock-out mice reveal that, in the absence of Caspr, the separation between the membranes of the hair cells and the afferent neurons is conspicuously irregular and often increased by an order of magnitude. In these mutants, KCNQ4 fails to cluster at the postsynaptic membrane and appears diffused along the entire calyceal membrane. Our results indicate that a septate-like junction provides structural support to calyceal synaptic contact with the vestibular hair cell and that Caspr is required for the recruitment or retention of KCNQ4 at these synapses. C1 [Sousa, Aurea D.; Andrade, Leonardo R.; Salles, Felipe T.; Kachar, Bechara] Natl Inst Deafness & Other Commun Disorders, NIH, Lab Cell Struct & Dynam, Bethesda, MD 20892 USA. [Andrade, Leonardo R.] Univ Fed Rio de Janeiro, Ctr Hlth Sci, Inst Biomed Sci, BR-21941590 Rio De Janeiro, Brazil. [Pillai, Anilkumar M.; Buttermore, Elizabeth D.; Bhat, Manzoor A.] Univ N Carolina, Sch Med, Ctr Neurosci,Neurodev Disorders Res Ctr, Dept Cell & Mol Physiol,Curriculum Neurobiol, Chapel Hill, NC 27599 USA. RP Kachar, B (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Lab Cell Struct & Dynam, Bldg 50,Room 4249,50 S Dr, Bethesda, MD 20892 USA. EM kacharb@nidcd.nih.gov RI Andrade, Leonardo/C-9554-2011; Salles, Felipe/H-7544-2013; OI Andrade, Leonardo/0000-0002-0004-5677; Sousa, Aurea/0000-0002-9153-7414 FU National Institute on Deafness and Other Communication Disorders; Division of Intramural Research; National Institutes of Health [GM063074] FX This work was supported by National Institute on Deafness and Other Communication Disorders, Division of Intramural Research, National Institutes of Health (NIH; B. K.), and NIH Grant GM063074 (M. A. B.). We thank Cole Graydon and Drs. Mark Schneider, Stephan Brenowitz, and Ronald Petralia for helpful discussions, and Uri Manor for assistance on statistical analysis of measurements. NR 26 TC 15 Z9 15 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 MAR 11 PY 2009 VL 29 IS 10 BP 3103 EP 3108 DI 10.1523/JNEUROSCI.4868-08.2009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 417RD UT WOS:000264093200012 PM 19279247 ER PT J AU Park, JS Voitenko, N Petralia, RS Guan, XW Xu, JT Steinberg, JP Takamiya, K Sotnik, A Kopach, O Huganir, RL Tao, YX AF Park, Jang-Su Voitenko, Nana Petralia, Ronald S. Guan, Xiaowei Xu, Ji-Tian Steinberg, Jordan P. Takamiya, Kogo Sotnik, Andrij Kopach, Olga Huganir, Richard L. Tao, Yuan-Xiang TI Persistent Inflammation Induces GluR2 Internalization via NMDA Receptor-Triggered PKC Activation in Dorsal Horn Neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM DEPRESSION; COMPLETE FREUNDS-ADJUVANT; KINASE-C-ALPHA; CA2+-PERMEABLE AMPA RECEPTORS; LAMINAE-I-III; SPINAL-CORD; SYNAPTIC PLASTICITY; GLUTAMATE-RECEPTOR; PROTEIN-KINASE; PDZ DOMAIN AB Spinal cord GluR2-lacking AMPA receptors (AMPARs) contribute to nociceptive hypersensitivity in persistent pain, but the molecular mechanisms underlying this event are not completely understood. We report that complete Freund's adjuvant (CFA)-induced peripheral inflammation induces synaptic GluR2 internalization in dorsal horn neurons during the maintenance of CFA-evoked nociceptive hypersensitivity. This internalization is initiated by GluR2 phosphorylation at Ser(880) and subsequent disruption of GluR2 binding to its synaptic anchoring protein (GRIP), resulting in a switch of GluR2-containing AMPARs to GluR2-lacking AMPARs and an increase of AMPAR Ca(2+) permeability at the synapses in dorsal horn neurons. Spinal cord NMDA receptor-mediated triggering of protein kinase C (PKC) activation is required for the induction and maintenance of CFA-induced dorsal horn GluR2 internalization. Moreover, preventing CFA-induced spinal GluR2 internalization through targeted mutation of the GluR2 PKC phosphorylation site impairs CFA- evoked nociceptive hypersensitivity during the maintenance period. These results suggest that dorsal horn GluR2 internalization might participate in the maintenance of NMDA receptor/PKC-dependent nociceptive hypersensitivity in persistent inflammatory pain. C1 [Park, Jang-Su; Guan, Xiaowei; Xu, Ji-Tian; Tao, Yuan-Xiang] Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, Baltimore, MD 21205 USA. [Voitenko, Nana; Sotnik, Andrij; Kopach, Olga] AA Bogomolets Physiol Inst, Dept Gen Physiol Nervous Syst, UA-01024 Kiev, Ukraine. [Petralia, Ronald S.] Natl Inst Deafness & Other Commun Disorders, NIH, Neurochem Lab, Bethesda, MD 20892 USA. [Steinberg, Jordan P.; Takamiya, Kogo; Huganir, Richard L.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21287 USA. [Takamiya, Kogo] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21287 USA. [Huganir, Richard L.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21287 USA. RP Tao, YX (reprint author), Johns Hopkins Univ, Sch Med, Dept Anesthesiol & Crit Care Med, 367 Ross,720 Rutland Ave, Baltimore, MD 21205 USA. EM ytao1@jhmi.edu OI Voitenko, Nana/0000-0002-2450-3134; Kopach, Olga/0000-0002-3921-3674 FU National Institutes of Health (NIH) [NS058886, NS057343]; Johns Hopkins University Blaustein Pain Research Fund; Juvenile Diabetes Research Foundation [1-2004-30]; INTAS [8061]; National Institute on Deafness and Other Communication Disorders; NIH [NS036715]; Howard Hughes Medical Institute FX This work was supported by National Institutes of Health (NIH) Grants NS058886 and NS057343 and the Johns Hopkins University Blaustein Pain Research Fund (Y.-X.T.), Juvenile Diabetes Research Foundation Grant 1-2004-30 and INTAS Grant 8061 (N. V.), the Intramural Research Program of National Institute on Deafness and Other Communication Disorders (R. S. P.), and NIH Grant NS036715 and the Howard Hughes Medical Institute (R. L. H.). We thank R. Dubner, K. Ren, S. N. Raja, Y. Guan, and P. Belan for their consultation, D. Isaev and J. Galik for their electrophysiological technical support, Y. X. Wang for her help with the immunogold labeling, and C. F. Levine for her editorial assistance. NR 61 TC 82 Z9 89 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 11 PY 2009 VL 29 IS 10 BP 3206 EP 3219 DI 10.1523/JNEUROSCI.4514-08.2009 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 417RD UT WOS:000264093200023 PM 19279258 ER PT J AU Machado, ES Afonso, AO Nissley, DV Lemey, P Cunha, SM Oliveira, RH Soares, MA AF Machado, Elizabeth S. Afonso, Adriana O. Nissley, Dwight V. Lemey, Philippe Cunha, Silvia M. Oliveira, Ricardo H. Soares, Marcelo A. TI Emergency of Primary NNRTI Resistance Mutations without Antiretroviral Selective Pressure in a HAART-Treated Child SO PLOS ONE LA English DT Article AB Objective: The use of antiretrovirals (ARV) during pregnancy has drastically reduced the rate of the human immunodeficiency virus perinatal transmission (MTCT). As a consequence of widespread ARV use, transmission of drug resistant strains from mothers to their babies is increasing. Ultra-sensitive PCR techniques have permitted the quantification of minority viral populations, but little is known about the transmission of drug-resistant HIV-1 minority population in the setting of MTCT. Methodology/Principal Findings: We describe the case of a female child born to an HIV-infected mother, which had not taken any ARV during the pregnancy. The child's first genotype demonstrated a minor non-nucleoside reverse transcriptase inhibitor (K101E), and during her treatment with reverse transcriptase and protease inhibitors full resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) emerged (G190A). Phenotypic/genotypic analysis of variant quasispecies through yeast TyHRT assay was conducted to characterize minority resistant viral strains circulating in both mother and child. Maximum likelihood and Bayesian MCMC phylogenetic analyses were performed with samples from the pair to assess genetic relatedness among minor viral strains. The analysis showed that the child received a minor NNRTI resistant variant, containing the mutation K101E that was present in less than 1% of the mother's quasispecies. Phylogenetic analyses have suggested common ancestry between the mother's virus strain carrying K101E with the viral sequences from the child. Conclusion: This is the first documentation of MTCT of a minority resistant strain of HIV-1. The transmission of minor resistant variants carries the threat of emergence of multi-drug primary mutations without identified specific selective pressures. C1 [Machado, Elizabeth S.] Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Rio De Janeiro, Brazil. [Machado, Elizabeth S.; Afonso, Adriana O.; Soares, Marcelo A.] Univ Fed Rio de Janeiro, Dept Genet, Rio De Janeiro, Brazil. [Nissley, Dwight V.] NCI, NIH, Gene Regulat & Chromosome Biol Lab, Frederick, MD USA. [Nissley, Dwight V.] NCI, SAIC Frederick Inc, NIH, Basic Sci Program, Frederick, MD USA. [Lemey, Philippe] Univ Oxford, Dept Zool, Oxford OX1 2JD, England. [Cunha, Silvia M.; Oliveira, Ricardo H.] Univ Fed Rio de Janeiro, Inst Puericult Pediat Martagao Gesteira, Rio De Janeiro, Brazil. [Soares, Marcelo A.] Inst Nacl Canc, Div Genet, Rio De Janeiro, Brazil. RP Machado, ES (reprint author), Univ Fed Rio de Janeiro, Hosp Univ Clementino Fraga Filho, Rio De Janeiro, Brazil. EM masoares@biologia.ufrj.br RI Inca, Inct/K-2204-2013 FU National Institutes of Health [R01 HD37780-01]; Brazilian Ministry of Health; Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This study has been funded by grants of the National Institutes of Health R01 HD37780-01 (U.S.A.), by the Brazilian Ministry of Health and by Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) - Research Grant to ESM. This project has been also partly funded with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 20 TC 4 Z9 4 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 11 PY 2009 VL 4 IS 3 AR e4806 DI 10.1371/journal.pone.0004806 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437OF UT WOS:000265496100023 PM 19277127 ER PT J AU Mai, PL Chatterjee, N Hartge, P Tucker, M Brody, L Struewing, JP Wacholder, S AF Mai, Phuong L. Chatterjee, Nilanjan Hartge, Patricia Tucker, Margaret Brody, Lawrence Struewing, Jeffery P. Wacholder, Sholom TI Potential Excess Mortality in BRCA1/2 Mutation Carriers beyond Breast, Ovarian, Prostate, and Pancreatic Cancers, and Melanoma SO PLOS ONE LA English DT Article AB Background: Although the increase in risk of developing breast, ovarian, and prostate cancer in BRCA1 and BRCA2 mutation carriers has been studied extensively, its impact on mortality is not well quantified. Further, possible effect of BRCA mutations on non-cancer mortality risk has not been examined. Methodology/Principal Findings: Using mortality data from the relatives of 5,287 genotyped participants, of whom 120 carried a BRCA Ashkenazi Jewish founder mutation, in a community-based study of the Ashkenazi Jewish population in the Washington D. C area, we examined the association between the three Ashkenazi BRCA founder mutations and risk of overall and non-cancer mortality. To examine risks beyond the established effects of these mutations, we analyzed the data excluding both deaths and follow-up times after reported diagnosis of melanoma and cancer of the breast, ovary, prostate, and pancreas. Using an extension of the kin-cohort method that accounts for informative censoring, we estimated that, in the absence of breast, ovarian, and pancreatic cancers, and melanoma, female carriers had a life expectancy that was 6.8 years lower (95% CI: 1.2-10.5) than non-carriers. In male mutation carriers, the reduction in life expectancy, in the absence of prostate and pancreatic cancers and melanoma, was 3.7 (95% CI: -0.4, 6.8) years. When deaths and follow-up times after any cancer diagnosis were excluded, the difference in life expectancy was 5.7 years for women (95% CI: -0.1, 10.4) and 3.7 years for men (95% CI: -0.4, 6.9). An overall test of association for men and women together showed a statistically significant association between BRCA1/2 mutations and increased non-cancer mortality (p=0.024). Conclusions/Significance: These findings suggest that there may be unknown effects of BRCA1/2 mutations on nonneoplastic diseases that cause death at older ages. C1 [Mai, Phuong L.] NCI, Clin Genet Branch, Rockville, MD USA. [Chatterjee, Nilanjan; Wacholder, Sholom] NCI, Biostat Branch, Rockville, MD USA. [Hartge, Patricia] NCI, Off Director Biostat & Epidemiol Program, Rockville, MD USA. [Tucker, Margaret] NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Rockville, MD USA. [Brody, Lawrence; Struewing, Jeffery P.] Natl Human Genome Res Inst, Rockville, MD USA. RP Mai, PL (reprint author), NCI, Clin Genet Branch, Rockville, MD USA. EM maip@mail.nih.gov RI Tucker, Margaret/B-4297-2015; Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 31 TC 25 Z9 26 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 11 PY 2009 VL 4 IS 3 AR e4812 DI 10.1371/journal.pone.0004812 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437OF UT WOS:000265496100029 PM 19277124 ER PT J AU Tu, C Tropea, JE Austin, BP Court, DL Waugh, DS Ji, XH AF Tu, Chao Tropea, Joseph E. Austin, Brian P. Court, Donald L. Waugh, David S. Ji, Xinhua TI Structural Basis for Binding of RNA and Cofactor by a KsgA Methyltransferase SO STRUCTURE LA English DT Article ID MITOCHONDRIAL TRANSCRIPTION FACTOR; AMINO-ACID-RESIDUES; 2 ADJACENT N6,N6-DIMETHYLADENOSINES; N6-ADENINE DNA METHYLTRANSFERASE; 30S RIBOSOMAL-SUBUNIT; ESCHERICHIA-COLI; S-ADENOSYLMETHIONINE; CRYSTAL-STRUCTURE; 3' END; ADENINE METHYLTRANSFERASES AB Among methyltransferases, KsgA and the reaction it catalyzes are conserved throughout evolution. However, the specifics of substrate recognition by the enzyme remain unknown. Here we report structures of Aquifex aeolicus KsgA, in its ligand-free form, in complex with RNA, and in complex with both RNA and S-adenosylhomocysteine (SAH, reaction product of cofactor S-adenosylmethionine, revealing critical structural information on KsgA-RNA and KsgA-SAH interactions. Moreover, the structures show how conformational changes that occur upon RNA binding create the cofactor-binding site. There are nine conserved functional motifs (motifs I-VIII and X) in KsgA. Prior to RNA binding, motifs I and VIII are flexible, each exhibiting two distinct conformations. Upon RNA binding, the two motifs become stabilized in one of these conformations, which is compatible with the binding of SAH. Motif X, which is also stabilized upon RNA binding, is directly involved in the binding of SAH. C1 [Tu, Chao; Tropea, Joseph E.; Austin, Brian P.; Court, Donald L.; Waugh, David S.; Ji, Xinhua] NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Ji, XH (reprint author), NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM jix@ncifcrf.gov RI Tu, Chao/D-3637-2009; Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU Center for Cancer Research; National Cancer Institute; NIH FX X-ray diffraction data were collected at the 22-ID and 22-BM beamlines of SER-CAT, Advanced Photon Source, Argonne National Laboratory. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 55 TC 14 Z9 15 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAR 11 PY 2009 VL 17 IS 3 BP 374 EP 385 DI 10.1016/j.str.2009.01.010 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 421AR UT WOS:000264330800011 PM 19278652 ER PT J AU Ren, XF Kloer, DP Kim, YC Ghirlando, R Saidi, LF Hummer, G Hurley, JH AF Ren, Xuefeng Kloer, Daniel P. Kim, Young C. Ghirlando, Rodolfo Saidi, Layla F. Hummer, Gerhard Hurley, James H. TI Hybrid Structural Model of the Complete Human ESCRT-0 Complex SO STRUCTURE LA English DT Article ID UBIQUITIN-BINDING DOMAINS; RECEPTOR DOWN-REGULATION; EARLY ENDOSOMES; ANALYTICAL ULTRACENTRIFUGATION; MULTIVESICULAR BODIES; HRS; PROTEINS; STAM; MACHINERY; LOCALIZATION AB The human Hrs and STAM proteins comprise the ESCRT-0 complex, which sorts ubiquitinated cell surface receptors to lysosomes for degradation. Here we report a model for the complete ESCRT-0 complex based on the crystal structure of the Hrs-STAM core complex, previously solved domain structures, hydrodynamic measurements, and Monte Carlo simulations. ESCRT-0 expressed in insect cells has a hydrodynamic radius of R(H) = 7.9 nm and is a 1:1 heterodimer. The 2.3 angstrom crystal structure of the ESCRT-0 core complex reveals two domain-swapped GAT domains and an antiparallel two-stranded coiled-coil, similar to yeast ESCRT-0. ESCRT-0 typifies a class of biomolecular assemblies that combine structured and unstructured elements, and have dynamic and open conformations to ensure versatility in target recognition. Coarse-grained Monte Carlo simulations constrained by experimental R(H) values for ESCRT-0 reveal a dynamic ensemble of conformations well suited for diverse functions. C1 [Ren, Xuefeng; Kloer, Daniel P.; Ghirlando, Rodolfo; Saidi, Layla F.; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kim, Young C.; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDK, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov RI Ghirlando, Rodolfo/A-8880-2009; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU U.S. DOE, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]; NIH; NIDDK; IATAP FX We thank C. Biertumpfel for assistance with light scattering measurements and the staff of SER-CAT for user support at the APS. Use of the APS was supported by the U.S. DOE, Basic Energy Sciences, Office of Science, under Contract No.W-31-109-Eng-38. This research was supported by NIH intramural support, NIDDK (J.H.H. and G.H.) and IATAP (J.H.H.). D.P.K. is supported by the DFG-NIH program. The NIH Biowulf cluster was used for simulations. NR 53 TC 40 Z9 43 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD MAR 11 PY 2009 VL 17 IS 3 BP 406 EP 416 DI 10.1016/j.str.2009.01.012 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 421AR UT WOS:000264330800014 PM 19278655 ER PT J AU Weihofen, A Thomas, KJ Ostaszewski, BL Cookson, MR Selkoe, DJ AF Weihofen, Andreas Thomas, Kelly Jean Ostaszewski, Beth L. Cookson, Mark R. Selkoe, Dennis J. TI Pink1 Forms a Multiprotein Complex with Miro and Milton, Linking Pink1 Function to Mitochondrial Trafficking SO BIOCHEMISTRY LA English DT Article ID COIL DOMAIN PROTEINS; KINESIN HEAVY-CHAIN; PARKINSONS-DISEASE; AXONAL-TRANSPORT; OXIDATIVE STRESS; DYSFUNCTION; MORPHOLOGY; MUTATIONS; DROSOPHILA-PINK1; SYNAPSES AB Recessive mutations in Pink1 lead to a selective degeneration of dopaminergic neurons in the substantia nigra that is characteristic of Parkinson disease. Pink1 is a kinase that is targeted in part to mitochondria, and loss of Pink1 function can alter mitochondrial morphology and dynamics, thus supporting a link between mitochondrial dysfunction and Parkinson disease etiology. Here, we report the unbiased identification and confirmation of a mitochondrial multiprotein complex that contains Pink1, the atypical GTPase Miro, and the adaptor protein Milton. Our screen also identified an interaction between Pink1 and Mitofilin. Based on previously established functions for Miro and Milton in the trafficking of mitochondria along microtubules, we postulate here a role for Pink1 in mitochondrial trafficking. Using subcellular fractionation, we show that the overexpression of Miro and Milton, both of which are known to reside at the outer mitochondrial membrane, increases the mitochondrial Pink I pool, suggesting a function of Pink1 at the outer membrane. Further, we document that Pink1 expressed without a mitochondrial targeting sequence can still be targeted to a mitochondria-enriched subcellular fraction via Miro and Milton. The latter finding is important for the interpretation of a previously reported protective effect of Pink] expressed without a mitochondrial targeting sequence. Finally, we find that Miro and Milton expression suppresses altered mitochondrial morphology induced by loss of Pink1 function in cell culture. Our findings suggest that Pink1 functions in the trafficking of mitochondria in cells. C1 [Weihofen, Andreas; Ostaszewski, Beth L.; Selkoe, Dennis J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Weihofen, Andreas; Ostaszewski, Beth L.; Selkoe, Dennis J.] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [Thomas, Kelly Jean; Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20893 USA. RP Selkoe, DJ (reprint author), Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. EM dselkoe@rics.bwh.harvard.edu RI Weihofen, Andreas/A-1566-2011 FU Intramural NIH HHS; NIA NIH HHS [Z01 AG000953]; NINDS NIH HHS [NS038375, NS051318, P50 NS038375, P50 NS038375-07, R01 NS051318, R01 NS051318-04] NR 27 TC 142 Z9 147 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 10 PY 2009 VL 48 IS 9 BP 2045 EP 2052 DI 10.1021/bi8019178 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 414WO UT WOS:000263896100021 PM 19152501 ER PT J AU Parikh, NI Gona, P Larson, MG Fox, CS Benjamin, EJ Murabito, JM O'Donnell, CJ Vasan, RS Levy, D AF Parikh, Nisha I. Gona, Philimon Larson, Martin G. Fox, Caroline S. Benjamin, Emelia J. Murabito, Joanne M. O'Donnell, Christopher J. Vasan, Ramachandran S. Levy, Daniel TI Long-Term Trends in Myocardial Infarction Incidence and Case Fatality in the National Heart, Lung, and Blood Institute's Framingham Heart Study SO CIRCULATION LA English DT Article DE biomarkers; electrocardiography; epidemiology; myocardial infarction ID HOSPITAL CARDIAC-ARREST; 4 US COMMUNITIES; DISEASE MORTALITY; TEMPORAL TRENDS; CORONARY-DISEASE; UNITED-STATES; MEDICAL-CARE; RISK-FACTORS; EVENT RATES; DECLINE AB Background-Whereas the prevalence of coronary heart disease risk factors has declined over the past decades in the United States, acute myocardial infarction (AMI) rates have been steady. We hypothesized that this paradox is due partly to the advent of increasingly sensitive biomarkers for AMI diagnosis. Methods and Results-In Framingham Heart Study participants over 4 decades, we compared the incidence and survival rates of initial AMI diagnosis by ECG (AMI-ECG) regardless of biomarkers with those based exclusively on infarction biomarkers (AMI-marker). We used Poisson regression to calculate annual incidence rates of first AMI over 4 decades (1960 to 1969, 1970 to 1979, 1980 to 1989, and 1990 to 1999) and compared rates of AMI-ECG with rates of AMI-marker. Cox proportional-hazards analysis was used to compare AMI case fatality over 4 decades. In 9824 persons (54% women; follow-up, 212 539 person-years; age, 40 to 89 years), 941 AMIs occurred, including 639 AMI-ECG and 302 AMI-marker events. From 1960 to 1999, rates of AMI-ECG declined by approximate to 50% and rates of AMI-marker increased approximate to 2-fold. Crude 30-day, 1-year, and 5-year case fatality rates in 1960 to 1969 and 1990 to 1999 were 0.20 and 0.14, 0.24 and 0.21, and 0.45 and 0.41, respectively. Age-and sex-adjusted 30-day, 1-year, and 5-year AMI case fatality declined by 60% in 1960 to 1999 (P for trend <0.001), with parallel declines noted after AMI-ECG and AMI-marker. Conclusions-Over the past 40 years, rates of AMI-ECG have declined by 50%, whereas rates of AMI-marker have doubled. Our findings offer an explanation for the apparently steady national AMI rates in the face of improvements in primary prevention. (Circulation. 2009; 119: 1203-1210.) C1 [Parikh, Nisha I.; Gona, Philimon; Larson, Martin G.; Fox, Caroline S.; Benjamin, Emelia J.; Murabito, Joanne M.; O'Donnell, Christopher J.; Vasan, Ramachandran S.; Levy, Daniel] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Parikh, Nisha I.] Beth Israel Deaconess Med Ctr, Div Cardiovasc, Boston, MA 02215 USA. [Benjamin, Emelia J.; Murabito, Joanne M.; Vasan, Ramachandran S.; Levy, Daniel] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Benjamin, Emelia J.; Murabito, Joanne M.; Vasan, Ramachandran S.; Levy, Daniel] Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Fox, Caroline S.; O'Donnell, Christopher J.; Levy, Daniel] NHLBI, Ctr Populat Studies, NIH, Bethesda, MD 20892 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM levyd@nih.gov OI Larson, Martin/0000-0002-9631-1254; Murabito, Joanne/0000-0002-0192-7516; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Institutes of Health/National Heart, Lung, and Blood Institute [N01-HC-25195] FX This work was supported by National Institutes of Health/National Heart, Lung, and Blood Institute contract N01-HC-25195. NR 39 TC 93 Z9 97 U1 0 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 MAR 10 PY 2009 VL 119 IS 9 BP 1203 EP 1210 DI 10.1161/CIRCULATIONAHA.108.825364 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 416KK UT WOS:000264004800006 PM 19237656 ER PT J AU Chakir, K Daya, SK Aiba, T Tunin, RS Dimaano, VL Abraham, TP Jacques, K Lai, EW Pacak, K Zhu, WZ Xiao, RP Tomaselli, GF Kass, DA AF Chakir, Khalid Daya, Samantapudi K. Aiba, Takeshi Tunin, Richard S. Dimaano, Veronica L. Abraham, Theodore P. Jacques, Kathryn Lai, Edwin W. Pacak, Karel Zhu, Wei-Zhong Xiao, Rui-ping Tomaselli, Gordon F. Kass, David A. TI Mechanisms of Enhanced beta-Adrenergic Reserve From Cardiac Resynchronization Therapy SO CIRCULATION LA English DT Article DE adenylate cyclase; heart failure; myocytes; pacing; receptors, adrenergic, beta; RGS proteins ID BIVENTRICULAR PACING IMPROVES; MYOCARDIAL GENE-EXPRESSION; FORCE-FREQUENCY RELATION; HEART-FAILURE PATIENTS; DILATED CARDIOMYOPATHY; CONDUCTION DELAY; UP-REGULATION; G-PROTEINS; RGS PROTEINS; MYOCYTES AB Background-Cardiac resynchronization therapy (CRT) is the first clinical heart failure treatment that improves chamber systolic function in both the short-term and long-term yet also reduces mortality. The mechanical impact of CRT is immediate and well documented, yet its long-term influences on myocyte function and adrenergic modulation that may contribute to its sustained benefits are largely unknown. Methods and Results-We used a canine model of dyssynchronous heart failure (DHF; left bundle ablation, atrial tachypacing for 6 weeks) and CRT (DHF for 3 weeks, biventricular tachypacing for subsequent 3 weeks), contrasting both to nonfailing controls. CRT restored contractile synchrony and improved systolic function compared with DHF. Myocyte sarcomere shortening and calcium transients were markedly depressed at rest and after isoproterenol stimulation in DHF (both anterior and lateral walls), and CRT substantially improved both. In addition, beta(1) and beta(2) stimulation was enhanced, coupled to increased beta(1) receptor abundance but no change in binding affinity. CRT also augmented adenylate cyclase activity over DHF. Inhibitory G-protein (G alpha(i)) suppression of beta-adrenergic stimulation was greater in DHF and reversed by CRT. G alpha(i) expression itself was unaltered; however, expression of negative regulators of G alpha(i) signaling (particularly RGS3) rose uniquely with CRT over DHF and controls. CRT blunted elevated myocardial catecholamines in DHF, restoring levels toward control. Conclusions-CRT improves rest and beta-adrenergic-stimulated myocyte function and calcium handling, upregulating beta(1) receptors and adenylate cyclase activity and suppressing G(i)-coupled signaling associated with novel RGS upregulation. The result is greater rest and sympathetic reserve despite reduced myocardial neurostimulation as components underlying its net benefit. (Circulation. 2009; 119: 1231-1240.) C1 [Kass, David A.] Johns Hopkins Univ, Sch Med, Dept Med, Johns Hopkins Med Inst,Div Cardiol, Baltimore, MD 21205 USA. [Lai, Edwin W.; Pacak, Karel] NICHHD, Reprod Biol & Med Branch, Sect Med Neuroendocrinol, Bethesda, MD 20892 USA. [Zhu, Wei-Zhong; Xiao, Rui-ping] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Kass, DA (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Johns Hopkins Med Inst,Div Cardiol, 720 Rutland Ave,Ross Bldg 835, Baltimore, MD 21205 USA. EM dkass@jhmi.edu OI Schunke, Kathryn/0000-0002-0815-8457 FU National Heart, Lung, and Blood Institute [PO1-HL077180, RO1: HL-089297]; Peter Belfer Laboratory and Abraham and Virginia Weiss Professorship; Intramural Research Program of the National Institutes of Health, National Institute on Aging FX This work was supported by National Heart, Lung, and Blood Institute grants PO1-HL077180 (Drs Kass and Tomaselli) and RO1: HL-089297, the Peter Belfer Laboratory and Abraham and Virginia Weiss Professorship (Dr Kass), and the Intramural Research Program of the National Institutes of Health, National Institute on Aging (Dr Xiao). NR 48 TC 66 Z9 67 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 10 PY 2009 VL 119 IS 9 BP 1231 EP U22 DI 10.1161/CIRCULATIONAHA.108.774752 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 416KK UT WOS:000264004800009 PM 19237665 ER PT J AU Canals, S Beyerlein, M Merkle, H Logothetis, NK AF Canals, Santiago Beyerlein, Michael Merkle, Hellmut Logothetis, Nikos K. TI Functional MRI Evidence for LTP-Induced Neural Network Reorganization SO CURRENT BIOLOGY LA English DT Article ID LONG-TERM POTENTIATION; SYNAPTIC-TRANSMISSION; PERFORANT PATH; RAT HIPPOCAMPUS; PYRAMIDAL CELLS; NMDA RECEPTORS; IN-VIVO; MEMORY; FMRI; STIMULATION AB The hippocampal formation is a region of the forebrain that is important for memory and spatial navigation [1, 2]. On the basis of a vast amount of literature, the hippocampus is linked with long-term potentiation (LTP), the increased synaptic strength following repeated stimulation of the hippocampal neurons [3, 4]. LTP is considered to be the experimental demonstration of Hebb's postulate on synaptic strength and learning [5], and it is the dominant model of an experience-dependent modification of brain circuits. Yet, despite the importance of this phenomenon for brain physiology and behavior, little is known about how experimentally measured regional synaptic modifications alter the activity of global, widespread networks. Here, we use simultaneous fMRI, microstimulation, and electrophysiology [6-8] to unveil global changes in brain activity due to local hippocampal plasticity. Our findings offer the first evidence of an LTP-induced network reorganization that includes increased interhemispheric communication and recruitment of limbic and neocortical circuits after changes in synaptic strength within the hippocampus. C1 [Canals, Santiago; Beyerlein, Michael; Logothetis, Nikos K.] Max Planck Inst Biol Cybernet, D-72076 Tubingen, Germany. [Logothetis, Nikos K.] Univ Manchester, Manchester M13 9PL, Lancs, England. [Merkle, Hellmut] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Canals, S (reprint author), Inst Neurociencias CSIC UMH, Campus San Juan, Alacant 03550, Spain. EM scanals@iib.uam.es RI yu, yan/C-2322-2012; Canals, Santiago/N-5838-2014 OI Canals, Santiago/0000-0003-2175-8139 FU Human Frontier Science Program; Max Planck Society; NIH (National Institute Neurological Disorders and Stroke), Bethesda, Maryland FX The authors acknowledge Yusuke Murayama for his help with data analysis and A. Oeltermann and M. Augath for technical support. This work was funded by a Long Term Fellowship from the Human Frontier Science Program, the Max Planck Society, and in part (H.M.) by the Intramural Research Program of the NIH (National Institute Neurological Disorders and Stroke), Bethesda, Maryland. NR 29 TC 45 Z9 45 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD MAR 10 PY 2009 VL 19 IS 5 BP 398 EP 403 DI 10.1016/j.cub.2009.01.037 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 418TE UT WOS:000264171100028 PM 19230667 ER PT J AU Kraus, WE Ellis, SJ Fleg, JL Keteyian, SJ Pina, IL Bensimhon, DR Leifer, ES Kittzman, DW O'Connor, CM Whellan, DJ AF Kraus, William E. Ellis, Stephen J. Fleg, Jerry L. Keteyian, Steven J. Pina, Ileana L. Bensimhon, Daniel R. Leifer, Eric S. Kittzman, Dalane W. O'Connor, Christopher M. Whellan, David J. CA HF ACTION Investigators TI A Multivariable Model From HF-ACTION Predicting Peak VO2 in a Heart Failure Population SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 58th Annual Scientific Session of the American-College-of-Cardiology CY MAR 28-31, 2009 CL Orlando, FL SP Amer Coll Cardiol C1 Duke Univ, Durham, NC USA. NHLBI, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 10 PY 2009 VL 53 IS 10 BP A301 EP A301 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 414LD UT WOS:000263864201248 ER PT J AU Rogers, IS Massaro, JM Truong, QA Mahabadi, AA Fox, CS Isselbacher, EM Hoffmann, U O'Donnell, CJ AF Rogers, Ian S. Massaro, Joseph M. Truong, Quynh A. Mahabadi, Amir A. Fox, Caroline S. Isselbacher, Eric M. Hoffmann, Udo O'Donnell, Christopher J. TI Determinants of Thoracic and Abdominal Aortic Diameter by Computed Tomography in the Framingham Heart Study: The Influence of Gender, Age, and Body Surface Area SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 58th Annual Scientific Session of the American-College-of-Cardiology CY MAR 28-31, 2009 CL Orlando, FL SP Amer Coll Cardiol C1 Massachusetts Gen Hosp, Boston, MA 02114 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 10 PY 2009 VL 53 IS 10 BP A456 EP A456 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 414LD UT WOS:000263864201893 ER PT J AU Velagaleti, RS Massaro, J Vasan, RS Robins, SJ Kannel, WB Levy, D AF Velagaleti, Raghava S. Massaro, Joseph Vasan, Ramachandran S. Robins, Sander J. Kannel, William B. Levy, Daniel TI Dyslipidemia and Heart Failure Risk: The Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 58th Annual Scientific Session of the American-College-of-Cardiology CY MAR 28-31, 2009 CL Orlando, FL SP Amer Coll Cardiol C1 Framingham Heart Dis Epidemiol Study, Framingham, MA USA. NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 10 PY 2009 VL 53 IS 10 BP A460 EP A460 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 414LD UT WOS:000263864201908 ER PT J AU Esteve-Puig, R Canals, F Colome, N Merlino, G Recio, JA AF Esteve-Puig, Rosaura Canals, Francesc Colome, Nuria Merlino, Glenn Angel Recio, Juan TI Uncoupling of the LKB1-AMPK alpha Energy Sensor Pathway by Growth Factors and Oncogenic BRAF(V600E) SO PLOS ONE LA English DT Article AB Background: Understanding the biochemical mechanisms contributing to melanoma development and progression is critical for therapeutical intervention. LKB1 is a multi-task Ser/Thr kinase that phosphorylates AMPK controlling cell growth and apoptosis under metabolic stress conditions. Additionally, LKB1(Ser428) becomes phosphorylated in a RAS-Erk1/2-p90(RSK) pathway dependent manner. However, the connection between the RAS pathway and LKB1 is mostly unknown. Methodology/Principal Findings: Using the UV induced HGF transgenic mouse melanoma model to investigate the interplay among HGF signaling, RAS pathway and PI3K pathway in melanoma, we identified LKB1 as a protein directly modified by HGF induced signaling. A variety of molecular techniques and tissue culture revealed that LKB1(Ser428) (Ser431 in the mouse) is constitutively phosphorylated in BRAF(V600E) mutant melanoma cell lines and spontaneous mouse tumors with high RAS pathway activity. Interestingly, BRAF(V600E) mutant melanoma cells showed a very limited response to metabolic stress mediated by the LKB1-AMPK-mTOR pathway. Here we show for the first time that RAS pathway activation including BRAF(V600E) mutation promotes the uncoupling of AMPK from LKB1 by a mechanism that appears to be independent of LKB1(Ser428) phosphorylation. Notably, the inhibition of the RAS pathway in BRAF(V600E) mutant melanoma cells recovered the complex formation and rescued the LKB1-AMPK alpha metabolic stress-induced response, increasing apoptosis in cooperation with the pro-apoptotic proteins Bad and Bim, and the down-regulation of Mcl-1. Conclusions/Significance: These data demonstrate that growth factor treatment and in particular oncogenic BRAF(V600E) induces the uncoupling of LKB1-AMPK alpha complexes providing at the same time a possible mechanism in cell proliferation that engages cell growth and cell division in response to mitogenic stimuli and resistance to low energy conditions in tumor cells. Importantly, this mechanism reveals a new level for therapeutical intervention particularly relevant in tumors harboring a deregulated RAS-Erk1/2 pathway. C1 [Esteve-Puig, Rosaura; Angel Recio, Juan] Vall Hebron Hosp, Vall Hebron Res Inst VHIO, Med Oncol Res Program, Anim Models & Canc Lab, Barcelona, Spain. [Canals, Francesc; Colome, Nuria] Vall Hebron Hosp, Vall Hebron Res Inst VHIO, Med Oncol Res Program, Proteom Lab, Barcelona, Spain. [Merlino, Glenn] NCI, NHI, Lab Canc Biol & Genet, Bethesda, MD USA. RP Esteve-Puig, R (reprint author), Vall Hebron Hosp, Vall Hebron Res Inst VHIO, Med Oncol Res Program, Anim Models & Canc Lab, Barcelona, Spain. EM jarecio@ir.vhebron.net OI Esteve-Puig, Rosaura/0000-0003-0547-1752 FU Instituto Carlos III; Fondo de Investigaciones Sanitarias [PI050227, PI080653]; Marie Curie [MIRG-CT-2005-029135]; Fundacion Mutua Madrilena (FMM); Fundacion Genoma Espana; Fundacio Institut de Recerca Vall d'Hebron [REP fellowship] FX This work was supported by: Instituto Carlos III, Fondo de Investigaciones Sanitarias projects PI050227, PI080653, Marie Curie Reintegration Grant MIRG-CT-2005-029135 and Fundacion Mutua Madrilena (FMM). The Proteomics Laboratory at IR-HUVH is a member of the National Spanish Institute for Proteomics (PROTEORED), supported by Fundacion Genoma Espana. REP fellowship was sponsored by Fundacio Institut de Recerca Vall d'Hebron. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 68 Z9 69 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 10 PY 2009 VL 4 IS 3 AR e4771 DI 10.1371/journal.pone.0004771 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437OE UT WOS:000265496000011 PM 19274086 ER PT J AU Lipsitch, M Viboud, CC AF Lipsitch, Marc Viboud, Cecile TI Influenza seasonality: Lifting the fog SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID TRANSMISSION; VIRUS; TEMPERATURE C1 [Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02130 USA. [Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02130 USA. [Viboud, Cecile] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Lipsitch, M (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02130 USA. EM mlipsitc@hsph.harvard.edu RI Chiang, Vincent, Ming-Hsien/D-4312-2016; OI Chiang, Vincent, Ming-Hsien/0000-0002-2029-7863; Lipsitch, Marc/0000-0003-1504-9213 FU NIGMS NIH HHS [5U01GM076497, U01 GM076497] NR 20 TC 74 Z9 80 U1 0 U2 8 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 10 PY 2009 VL 106 IS 10 BP 3645 EP 3646 DI 10.1073/pnas.0900933106 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 416WT UT WOS:000264036900002 PM 19276125 ER PT J AU Li, W Tu, D Li, LY Wollert, T Ghirlando, R Brunger, AT Ye, YH AF Li, Wei Tu, Daqi Li, Lianyun Wollert, Thomas Ghirlando, Rodolfo Brunger, Axel T. Ye, Yihong TI Mechanistic insights into active site-associated polyubiquitination by the ubiquitin-conjugating enzyme Ube2g2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE crystallography; endoplasmic reticulum-associated protein degradation; gp78; polyubiquitin chain ID ENDOPLASMIC-RETICULUM; QUALITY-CONTROL; CHAIN FORMATION; RING FINGER; IN-VIVO; COMPLEX; DEGRADATION; DOMAIN; PROTEASOME; PROTEINS AB Lys-48-linked polyubiquitination regulates a variety of cellular processes by targeting ubiquitinated proteins to the proteasome for degradation. Although polyubiquitination had been presumed to occur by transferring ubiquitin molecules, one at a time, from an E2 active site to a substrate, we recently showed that the endoplasmic reticulum-associated RING finger ubiquitin ligase gp78 can mediate the preassembly of Lys-48-linked polyubiquitin chains on the catalytic cysteine of its cognate E2 Ube2g2 and subsequent transfer to a substrate. Active site-linked polyubiquitin chains are detected in cells on Ube2g2 and its yeast homolog Ubc7p, but how these chains are assembled is unclear. Here, we show that gp78 forms an oligomer via 2 oligomerization sites, one of which is a hydrophobic segment located in the gp78 cytosolic domain. We further demonstrate that a gp78 oligomer can simultaneously associate with multiple Ube2g2 molecules. This interaction is mediated by a novel Ube2g2 surface distinct from the predicted RING binding site. Our data suggest that a large gp78-Ube2g2 heterooligomer brings multiple Ube2g2 molecules into close proximity, allowing ubiquitin moieties to be transferred between neighboring Ube2g2s to form active site-linked polyubiquitin chains. C1 [Tu, Daqi; Brunger, Axel T.] Stanford Univ, Howard Hughes Med Inst, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. [Tu, Daqi; Brunger, Axel T.] Stanford Univ, Howard Hughes Med Inst, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. [Tu, Daqi; Brunger, Axel T.] Stanford Univ, Howard Hughes Med Inst, Dept Biol Struct, Stanford, CA 94305 USA. [Tu, Daqi; Brunger, Axel T.] Stanford Univ, Howard Hughes Med Inst, Dept Photon Sci, Stanford, CA 94305 USA. [Li, Wei; Li, Lianyun; Wollert, Thomas; Ghirlando, Rodolfo; Ye, Yihong] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Brunger, AT (reprint author), Stanford Univ, Howard Hughes Med Inst, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. EM brunger@stanford.edu; yihongy@mail.nih.gov RI Ghirlando, Rodolfo/A-8880-2009; OI Brunger, Axel/0000-0001-5121-2036; Wollert, Thomas/0000-0001-9732-4789 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX We thank N.Soetandyo (National Institute of Diabetes and Digestive and Kidney Diseases) for technical assistance and M. Krause and M. Gellert (National Institute of Diabetes and Digestive and Kidney Diseases) for critical reading of the manuscript. This work was supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 36 TC 64 Z9 64 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 10 PY 2009 VL 106 IS 10 BP 3722 EP 3727 DI 10.1073/pnas.0808564106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 416WT UT WOS:000264036900017 PM 19223579 ER PT J AU Calvo, E Mans, BJ Ribeiro, JMC Andersen, JF AF Calvo, Eric Mans, Ben J. Ribeiro, Jose M. C. Andersen, John F. TI Multifunctionality and mechanism of ligand binding in a mosquito antiinflammatory protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE biogenic amine; bloodfeeding; leukotriene; odorant-binding protein; saliva ID ANOPHELES-GAMBIAE; SALIVARY-GLANDS; EICOSANOID MEDIATORS; FEMALE MOSQUITO; AEDES-AEGYPTI; MAST-CELLS; FAMILY; MODEL; EVOLUTION; SIALOME AB The mosquito D7 salivary proteins are encoded by a multigene family related to the arthropod odorant-binding protein (OBP) superfamily. Forms having either one or two OBP domains are found in mosquito saliva. Four single-domain and one two-domain D7 proteins from Anopheles gambiae and Aedes aegypti (AeD7), respectively, were shown to bind biogenic amines with high affinity and with a stoichiometry of one ligand per protein molecule. Sequence comparisons indicated that only the C-terminal domain of AeD7 is homologous to the single-domain proteins from A. gambiae, suggesting that the N-terminal domain may bind a different class of ligands. Here, we describe the 3D structure of AeD7 and examine the ligand-binding characteristics of the N- and C-terminal domains. Isothermal titration calorimetry and ligand complex crystal structures show that the N- terminal domain binds cysteinyl leukotrienes (cysLTs) with high affinities (50-60 nM) whereas the C-terminal domain binds biogenic amines. The lipid chain of the cysLT binds in a hydrophobic pocket of the N- terminal domain, whereas binding of norepinephrine leads to an ordering of the C-terminal portion of the C-terminal domain into an alpha-helix that, along with rotations of Arg-176 and Glu-268 side chains, acts to bury the bound ligand. C1 [Calvo, Eric; Mans, Ben J.; Ribeiro, Jose M. C.; Andersen, John F.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Andersen, JF (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Room 2E32B,Twinbrook 3 Bldg,12735 Twinbrook Pkway, Rockville, MD 20852 USA. EM jandersen@niaid.nih.gov OI Mans, Ben/0000-0002-0177-0029; Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU National Institute of Allergy and Infectious Diseases; National Institutes of Health; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38] FX We thank Drs. D. Garboczi, A. Gittis, and K. Singh for discussions and assistance with data collection. We also thank the staffs of the Structural Biology Center Collaborative Access Team and the Southeast Regional Collaborative Access Team, Advanced Photon Source, Argonne National Laboratory for assistance with X-ray data collection. This work was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. Use of the Advanced Photon Source beamlines was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract W-31-109-Eng-38. NR 36 TC 46 Z9 48 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 10 PY 2009 VL 106 IS 10 BP 3728 EP 3733 DI 10.1073/pnas.0813190106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 416WT UT WOS:000264036900018 PM 19234127 ER PT J AU El-Chemaly, S Malide, D Zudaire, E Ikeda, Y Weinberg, BA Pacheco-Rodriguez, G Rosas, IO Aparicio, M Ren, P MacDonald, SD Wu, HP Nathan, SD Cuttitta, F Mccoy, JP Gochuico, BR Moss, J AF El-Chemaly, Souheil Malide, Daniela Zudaire, Enrique Ikeda, Yoshihiko Weinberg, Benjamin A. Pacheco-Rodriguez, Gustavo Rosas, Ivan O. Aparicio, Marta Ren, Ping MacDonald, Sandra D. Wu, Hai-Ping Nathan, Steven D. Cuttitta, Frank McCoy, J. Philip Gochuico, Bernadette R. Moss, Joel TI Abnormal lymphangiogenesis in idiopathic pulmonary fibrosis with insights into cellular and molecular mechanisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE endothelial cell; hyaluronan; idiopathic pulmonary fibrosis; lymphangiogenesis; macrophage ID GROWTH-FACTOR-C; LYMPHATIC VESSELS; LUNG INJURY; ALVEOLAR MACROPHAGES; MEDIATED MOTILITY; IN-VIVO; HYALURONAN; CELLS; INFLAMMATION; ANGIOGENESIS AB Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, debilitating respiratory disease whose pathogenesis is poorly understood. In IPF, the lung parenchyma undergoes extensive remodeling. We hypothesized that lymphangiogenesis is part of lung remodeling and sought to characterize pathways leading to lymphangiogenesis in IPF. We found that the diameter of lymphatic vessels in alveolar spaces in IPF lung tissue correlated with disease severity, suggesting that the alveolar microenvironment plays a role in the lymphangiogenic process. In bronchoalveolar lavage fluid (BALF) from subjects with IPF, we found short-fragment hyaluronic acid, which induced migration and proliferation of lymphatic endothelial cells (LECs), processes required for lymphatic vessel formation. To determine the origin of LECs in IPF, we isolated macrophages from the alveolar spaces; CD11b(+) macrophages from subjects with IPF, but not those from healthy volunteers, formed lymphatic-like vessels in vitro. Our findings demonstrate that in the alveolar microenvironment of IPF, soluble factors such as short-fragment hyaluronic acid and cells such as CD11b(+) macrophages contribute to lymphangiogenesis. These results improve our understanding of lymphangiogenesis and tissue remodeling in IPF and perhaps other fibrotic diseases as well. C1 [El-Chemaly, Souheil; Ikeda, Yoshihiko; Pacheco-Rodriguez, Gustavo; Rosas, Ivan O.; Ren, Ping; MacDonald, Sandra D.; Wu, Hai-Ping; Moss, Joel] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Malide, Daniela; Weinberg, Benjamin A.] NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. [McCoy, J. Philip] NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. [Zudaire, Enrique; Aparicio, Marta; Cuttitta, Frank] Natl Canc Inst, Angiogenesis Core Facil, NIH, Gaithersburg, MD 20877 USA. [Nathan, Steven D.] Inova Fairfax Hosp, Adv Lung Dis & Transplant Program, Inova Heart & Vasc Inst, Falls Church, VA 22042 USA. [Gochuico, Bernadette R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov RI Cuttitta, Frank/B-4758-2016 FU Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI); National Human Genome Research Institute; National Cancer Institute; Oak Ridge Institute for Science and Education FX This study was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute (NHLBI), the National Human Genome Research Institute, and the National Cancer Institute. Partial support was provided by a Senior Fellowship from the Oak Ridge Institute for Science and Education (to Y. I.). We are indebted to Dr. Martha Vaughan for her valuable input and manuscript review. We also thank Drs. M. E. Monzon, S. M. Casalino-Matsuda, and R. M. Forteza (University of Miami Airway Biology Laboratory) and Dr. Zu-Xi Yu (NHLBI Pathology Core Facility) for constructive suggestions and recommendations. This research would not have been possible without the commitment of the patients of the Translational Medicine Branch and the staff of the National Institutes of Health Clinical Research Center. NR 43 TC 51 Z9 53 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 MAR 10 PY 2009 VL 106 IS 10 BP 3958 EP 3963 DI 10.1073/pnas.0813368106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 416WT UT WOS:000264036900057 PM 19237567 ER PT J AU Su, TP Hayashi, T Vaupel, DB AF Su, Tsung-Ping Hayashi, Teruo Vaupel, D. Bruce TI When the Endogenous Hallucinogenic Trace Amine N,N-Dimethyltryptamine Meets the Sigma-1 Receptor SO SCIENCE SIGNALING LA English DT Article ID LYSERGIC-ACID DIETHYLAMIDE; NMDA ANTAGONIST MODEL; HEALTHY-VOLUNTEERS; DOSE-RESPONSE; BINDING; SCHIZOPHRENIA; AYAHUASCA; DMT; MODULATION; PSYCHOSIS AB N,N-dimethyltryptamine (DMT) is a hallucinogen found endogenously in human brain that is commonly recognized to target the 5-hydroxytryptamine 2A receptor or the trace amine-associated receptor to exert its psychedelic effect. DMT has been recently shown to bind sigma-1 receptors, which are ligand-regulated molecular chaperones whose function includes inhibiting various voltage-sensitive ion channels. Thus, it is possible that the psychedelic action of DMT might be mediated in part through sigma-1 receptors. Here, we present a hypothetical signaling scheme that might be triggered by the binding of DMT to sigma-1 receptors. C1 [Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, IRP,Dept Hlth & Human Serv, Cellular Neurobiol Res Branch,NIH, Baltimore, MD 21224 USA. [Vaupel, D. Bruce] NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Sect, IRP,Dept Hlth & Human Serv, Cellular Neurobiol Res Branch,NIH, Suite 3304,333 Cassell Dr, Baltimore, MD 21224 USA. EM TSU@intra.nida.nih.gov FU Intramural NIH HHS [ZIA DA000206-25] NR 44 TC 45 Z9 45 U1 3 U2 27 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1937-9145 J9 SCI SIGNAL JI Sci. Signal. PD MAR 10 PY 2009 VL 2 IS 61 AR pe12 DI 10.1126/scisignal.261pe12 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 567UV UT WOS:000275473000001 PM 19278957 ER PT J AU Zhu, BP Zhou, QF Shi, J Shung, KK Irisawa, S Takeuchi, S AF Zhu, B. P. Zhou, Q. F. Shi, J. Shung, K. K. Irisawa, S. Takeuchi, S. TI Self-separated hydrothermal lead zirconate titanate thick films for high frequency transducer applications SO APPLIED PHYSICS LETTERS LA English DT Article DE annealing; dielectric losses; dielectric polarisation; dielectric thin films; lead compounds; permittivity; piezoelectric materials; scanning electron microscopy; ultrasonic transducers ID ULTRASONIC TRANSDUCER; ELECTRICAL-PROPERTIES; DEPOSITION AB Using a simple rapid heating process, Pb(Zr(0.52)Ti(0.48))O(3) (PZT) thick films prepared by hydrothermal method were separated from a Ti substrate. Scanning electron microscopy (SEM) revealed that the self-separated films were crack-free. After solution infiltration and high temperature annealing, the PZT thick films were shown to possess good electric properties. At 1 kHz, the dielectric constant and the loss were 593 and 0.05, respectively. The remnant polarization was 30.0 mu C/cm(2) at room temperature. A high frequency single element ultrasound transducer fabricated with these films showed a bandwidth at -6 dB of 73% at a center frequency of 67 MHz. C1 [Zhu, B. P.; Zhou, Q. F.; Shung, K. K.] Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. [Zhu, B. P.; Zhou, Q. F.; Shung, K. K.] Univ So Calif, Transducer Resource Ctr, NIH, Los Angeles, CA 90089 USA. [Zhu, B. P.; Shi, J.] Wuhan Univ, Minist Educ, Dept Phys, Wuhan 430072, Peoples R China. [Zhu, B. P.; Shi, J.] Wuhan Univ, Minist Educ, Key Lab Acoust & Photon Mat & Devices, Wuhan 430072, Peoples R China. [Irisawa, S.; Takeuchi, S.] Toin Univ Yokohama, Grad Sch Engn, Med Engn Course, Yokohama, Kanagawa 2258501, Japan. RP Zhou, QF (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu FU NIH [P41EB2182]; Chinese Scholarship Council, China FX This research was supported by NIH Grant No. P41EB2182 and Chinese Scholarship Council, China. NR 15 TC 17 Z9 17 U1 0 U2 13 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0003-6951 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD MAR 9 PY 2009 VL 94 IS 10 AR 102901 DI 10.1063/1.3095504 PG 3 WC Physics, Applied SC Physics GA 420HO UT WOS:000264280000067 PM 19529788 ER PT J AU Hanchate, A Kronman, AC Young-Xu, Y Ash, AS Emanuel, E AF Hanchate, Amresh Kronman, Andrea C. Young-Xu, Yinong Ash, Arlene S. Emanuel, Ezekiel TI Racial and Ethnic Differences in End-of-Life Costs SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID MEDICARE MANAGED CARE; ACUTE MYOCARDIAL-INFARCTION; NURSING-HOME RESIDENTS; HOSPITAL UTILIZATION; AFRICAN-AMERICAN; UNITED-STATES; HEALTH-CARE; LAST YEAR; DISPARITIES; PREFERENCES AB Background: Racial and ethnic minorities generally receive fewer medical interventions than whites, but racial and ethnic patterns in Medicare expenditures and interventions may be quite different at life's end. Methods: Based on a random, stratified sample of Medicare decedents (N = 158780) in 2001, we used regression to relate differences in age, sex, cause of death, total morbidity burden, geography, life-sustaining interventions (eg, ventilators), and hospice to racial and ethnic differences in Medicare expenditures in the last 6 months of life. Results: In the final 6 months of life, costs for whites average $20166; blacks, $26704 ( 32% more); and Hispanics, $31702 (57% more). Similar differences exist within sexes, age groups, all causes of death, all sites of death, and within similar geographic areas. Differences in age, sex, cause of death, total morbidity burden, geography, socioeconomic status, and hospice use account for 53% and 63% of the higher costs for blacks and Hispanics, respectively. While whites use hospice most frequently (whites, 26%; blacks, 20%; and Hispanics, 23%), racial and ethnic differences in end-of-life expenditures are affected only minimally. However, fully 85% of the observed higher costs for nonwhites are accounted for after additionally modeling their greater end-of-life use of the intensive care unit and various intensive procedures (such as, gastrostomies, used by 10.5% of blacks, 9.1% of Hispanics, and 4.1% of whites). Conclusions: At life's end, black and Hispanic decedents have substantially higher costs than whites. More than half of these cost differences are related to geographic, sociodemographic, and morbidity differences. Strikingly greater use of life-sustaining interventions accounts for most of the rest. C1 [Emanuel, Ezekiel] NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Hanchate, Amresh; Kronman, Andrea C.; Ash, Arlene S.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Young-Xu, Yinong] Lown Cardiovasc Res Fdn, Brookline, MA USA. RP Emanuel, E (reprint author), NIH, Dept Clin Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM eemanuel@nih.gov FU National Institutes of Health FX This study was supported by contracts with the Department of Bioethics of the Clinical Center of the National Institutes of Health. NR 43 TC 93 Z9 93 U1 2 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 9 PY 2009 VL 169 IS 5 BP 493 EP 501 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 416EX UT WOS:000263989500011 PM 19273780 ER PT J AU Patel, KV Ferrucci, L Ershler, WB Longo, DL Guralnik, JM AF Patel, Kushang V. Ferrucci, Luigi Ershler, William B. Longo, Dan L. Guralnik, Jack M. TI Red Blood Cell Distribution Width and the Risk of Death in Middle-aged and Older Adults SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID SERUM CREATININE; ROC CURVE; DISEASE; MARKER; ANEMIA; COUNT AB Background: Red blood cell distribution width (RDW), a component of an electronic complete blood count, is a measure of heterogeneity in the size of circulating erythrocytes. In patients with symptomatic cardiovascular disease (CVD), RDW is associated with mortality. However, it has not been demonstrated that RDW is a predictor of mortality independent of nutritional deficiencies or in the general population. Methods: Red blood cell distribution width was measured in a national sample of 8175 community-dwelling adults 45 years or older who participated in the 19881994 National Health and Nutrition Examination Survey; mortality follow-up occurred through December 31, 2000. Deaths from all causes, CVD, cancer, and other causes were examined as a function of RDW. Results: Higher RDW values were strongly associated with an increased risk of death. Compared with the lowest quintile of RDW, the following were adjusted hazard ratios (HRs) for all-cause mortality (and 95% confidence intervals [CIs]): second quintile, HR, 1.1 (95% CI, 0.9-1.3); third quintile, HR, 1.2 (95% CI, 1.0-1.4); fourth quintile, HR, 1.4 ( 95% CI, 1.2-1.8); and fifth quintile, HR, 2.1 (95% CI, 1.7-2.6). For every 1% increment in RDW, all-cause mortality risk increased by 22% (HR, 1.22; 95% CI, 1.15-1.30; P <.001). Even when analyses were restricted to nonanemic participants or to those in the reference range of RDW (11%-15%) without iron, folate, or vitamin B(12) deficiency, RDW remained strongly associated with mortality. The prognostic effect of RDW was observed in both middle-aged and older adults for multiple causes of death. Conclusion: Red blood cell distribution width is a widely available test that is a strong predictor of mortality in the general population of adults 45 years or older. C1 [Patel, Kushang V.; Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20814 USA. [Ferrucci, Luigi; Ershler, William B.; Longo, Dan L.] NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Patel, KV (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Ste 3C309, Bethesda, MD 20814 USA. EM patelku@mail.nih.gov FU US National Institute on Aging; National Institutes of Health FX This study was supported by the Intramural Research Program of the US National Institute on Aging, National Institutes of Health. NR 22 TC 223 Z9 233 U1 2 U2 10 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 9 PY 2009 VL 169 IS 5 BP 515 EP 523 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 416EX UT WOS:000263989500014 PM 19273783 ER PT J AU Dean, DS Horgan, RR Naji, A Podgornik, R AF Dean, David S. Horgan, Ron R. Naji, Ali Podgornik, Rudolf TI One-dimensional counterion gas between charged surfaces: Exact results compared with weak- and strong-coupling analyses SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE statistical mechanics; surface charging ID DOUBLE-LAYER INTERACTIONS; MONTE-CARLO SIMULATIONS; POISSON-BOLTZMANN; ELECTROSTATIC INTERACTIONS; COULOMB-SYSTEMS; FIELD-THEORY; SOFT MATTER; FORCES; APPROXIMATION; ELECTROLYTES AB We evaluate exactly the statistical integral for an inhomogeneous one-dimensional (1D) counterion-only Coulomb gas between two charged boundaries and from this compute the effective interaction, or disjoining pressure, between the bounding surfaces. Our exact results are compared to the limiting cases of weak and strong couplings which are the same for 1D and three-dimensional (3D) systems. For systems with a large number of counterions it is found that the weak-coupling (mean-field) approximation for the disjoining pressure works perfectly and that fluctuations around the mean-field in 1D are much smaller than in 3D. In the case of few counterions it works less well and strong-coupling approximation performs much better as it takes into account properly the discreteness of the counterion charges. C1 [Dean, David S.] Univ Toulouse, Phys Theor Lab, IRSAMC, UPS, F-31062 Toulouse, France. [Dean, David S.; Horgan, Ron R.; Naji, Ali; Podgornik, Rudolf] Univ Calif Santa Barbara, Kavli Inst Theoret Phys, Santa Barbara, CA 93106 USA. [Horgan, Ron R.] Univ Cambridge, DAMTP, CMS, Cambridge CB3 0WA, England. [Naji, Ali] Univ Calif Santa Barbara, Dept Phys, Dept Chem & Biochem, Santa Barbara, CA 93106 USA. [Naji, Ali] Univ Calif Santa Barbara, Mat Res Lab, Santa Barbara, CA 93106 USA. [Podgornik, Rudolf] Univ Ljubljana, Dept Phys, Fac Math & Phys, SI-1000 Ljubljana, Slovenia. [Podgornik, Rudolf] Jozef Stefan Inst, Dept Theoret Phys, SI-1000 Ljubljana, Slovenia. [Podgornik, Rudolf] NIH, Lab Phys & Struct Biol, Bethesda, MD 20892 USA. RP Dean, DS (reprint author), Univ Toulouse, Phys Theor Lab, IRSAMC, UPS, F-31062 Toulouse, France. EM dean@irsamc.ups-tlse.fr RI Naji, Ali/F-6352-2010; Podgornik, Rudolf/C-6209-2008; Dean, David/N-6601-2013 OI Naji, Ali/0000-0003-3436-1499; Podgornik, Rudolf/0000-0002-3855-4637; FU National Science Foundation [PHY05-51164]; Institut Universtaire de France; Agency for Research and Development of Slovenia [P1-0055C, Z1-7171, L2-7080]; Intramural Research Program of the NIH; National Institute of Child Health and Human Development FX This research was supported in part by the National Science Foundation under Grant No. PHY05-51164 (while at the KITP program The theory and practice of fluctuation induced interactions, UCSB, 2008). D. S. D acknowledges support from the Institut Universtaire de France. R. P. would like to acknowledge the financial support by the Agency for Research and Development of Slovenia, Grant Nos. P1-0055C, Z1-7171, and L2-7080. This study was supported, in part, by the Intramural Research Program of the NIH, National Institute of Child Health and Human Development. NR 46 TC 19 Z9 19 U1 0 U2 3 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAR 7 PY 2009 VL 130 IS 9 AR 094504 DI 10.1063/1.3078492 PG 11 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 423VD UT WOS:000264522900017 PM 19275406 ER PT J AU Chen, J Gu, DF Huang, JF Rao, DC Jaquish, CE Hixson, JE Chen, CS Chen, JC Lu, FH Hu, DS Rice, T Kelly, TN Hamm, LL Whelton, PK He, J AF Chen, Jing Gu, Dongfeng Huang, Jianfeng Rao, Dabeeru C. Jaquish, Cashell E. Hixson, James E. Chen, Chung-Shiuan Chen, Jichun Lu, Fanghong Hu, Dongsheng Rice, Treva Kelly, Tanika N. Hamm, L. Lee Whelton, Paul K. He, Jiang CA GenSalt Collaborative Res Grp TI Metabolic syndrome and salt sensitivity of blood pressure in non-diabetic people in China: a dietary intervention study SO LANCET LA English DT Article ID US ADULTS; HYPERTENSION; SODIUM; SYSTEM; PREVALENCE; PREVENTION; DISEASE; HUMANS; HEALTH; MEN AB Background Since insulin resistance is thought to be the underlying mechanism for metabolic syndrome, affected individuals might be sensitive to a dietary sodium intervention. We aimed to examine the association between metabolic syndrome and salt sensitivity of blood pressure. Methods 1906 Chinese participants without diabetes, aged 16 years or more, were selected to receive a low-sodium diet (51.3 mmol per day) for 7 days followed by a high-sodium diet (307.8 mmol per day) for an additional 7 days. Participants were excluded from the analysis if metabolic risk factor information was missing or if they did not complete their dietary interventions. Blood pressure was measured at baseline and on days 2, 5, 6, and 7 of each intervention. Metabolic syndrome was defined as the presence of three or more of. abdominal obesity, raised blood pressure, high triglyceride concentration, low HDL cholesterol, or high glucose. High salt sensitivity was defined as a decrease in mean arterial blood pressure of more than 5 mm Hg during low-sodium or an increase of more than 5 mm Hg during high-sodium intervention. This study is registered with ClinicalTrials.gov, number NCT00721721. Findings Of the 1881 participants with information regarding metabolic syndrome, 283 had metabolic syndrome. 1853 participants completed the low-sodium diet and 1845 completed the high-sodium diet. Multivariable-adjusted mean changes in blood pressure were significantly greater in participants with metabolic syndrome than in those without on both low-sodium and high-sodium diets (p<0.0001 for all comparisons). Additionally, risk of salt sensitivity rose with increasing numbers of risk factors for metabolic syndrome. Compared with those with no risk factors participants with four or five had a 3.54-fold increased odds (95% CI 2.05-6.11) of high salt-sensitivity during the low-sodium and a 3.13-fold increased odds (1.80-5.43) of high salt-sensitivity during the high-sodium intervention. Interpretation These results suggest that metabolic syndrome enhances blood pressure response to sodium intake. Reduction in sodium intake could be an especially important component in reducing blood pressure in patients with multiple risk factors for metabolic syndrome. Funding National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. C1 [Chen, Jing; Hamm, L. Lee; He, Jiang] Tulane Univ, Dept Med, Sch Med, New Orleans, LA 70118 USA. [Chen, Jing; Hamm, L. Lee; He, Jiang] Tulane Univ, Tulane Hypertens & Renal Ctr Excellence, Sch Med, New Orleans, LA 70118 USA. [Chen, Jing; Chen, Chung-Shiuan; Kelly, Tanika N.; He, Jiang] Tulane Univ, Dept Epidemiol, Sch Publ Hlth & Trop Med, New Orleans, LA 70118 USA. [Gu, Dongfeng; Huang, Jianfeng; Chen, Jichun] Chinese Acad Med Sci, Fuwai Hosp & Cardiovasc Inst, Beijing 100037, Peoples R China. [Gu, Dongfeng; Huang, Jianfeng; Chen, Jichun] Peking Union Med Coll, Beijing 100021, Peoples R China. [Chen, Jing; Huang, Jianfeng; Chen, Jichun] Chinese Natl Ctr Cardiovasc Dis Control & Res, Beijing, Peoples R China. [Rao, Dabeeru C.; Rice, Treva] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Jaquish, Cashell E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Hixson, James E.] Univ Texas, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA. [Lu, Fanghong] Shandong Acad Med Sci, Shandong, Peoples R China. [Hu, Dongsheng] Zhengzhou Univ, Sch Publ Hlth, Zhengzhou, Henan, Peoples R China. [Whelton, Paul K.] Loyola Univ Hlth Syst & Med Ctr, Maywood, IL USA. RP Chen, J (reprint author), Tulane Univ, Dept Med, Sch Med, 1430 Tulane Ave,SL45, New Orleans, LA 70118 USA. EM jchen@tulane.edu RI Rice, Treva/D-1385-2009 FU National Heart, Lung, and Blood Institute [U01HL072507]; National Institutes of Health, Bethesda, MD, USA FX GenSalt is supported by a cooperative agreement project grant (U01HL072507) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA. NR 30 TC 115 Z9 122 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD MAR 7 PY 2009 VL 373 IS 9666 BP 829 EP 835 DI 10.1016/S0140-6736(09)60144-6 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 416BT UT WOS:000263980900033 PM 19223069 ER PT J AU Hyder, AA Dawson, L Bachani, AM Lavery, JV AF Hyder, Adrian A. Dawson, Liza Bachani, Abdulgafoor M. Lavery, James V. TI Moving from research ethics review to research ethics systems in low-income and middle-income countries SO LANCET LA English DT Article ID HEALTH RESEARCH C1 [Hyder, Adrian A.; Bachani, Abdulgafoor M.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21205 USA. [Hyder, Adrian A.] Johns Hopkins Berman Inst Bioeth, Baltimore, MD USA. [Dawson, Liza] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Lavery, James V.] St Michaels Hosp, Ctr Res Inner City Hlth, Keenan Res Ctr, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Lavery, James V.] St Michaels Hosp, Ctr Global Hlth Res, Keenan Res Ctr, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Lavery, James V.] Univ Toronto, Dept Publ Hlth Sci, Toronto, ON, Canada. [Lavery, James V.] Univ Toronto, Joint Ctr Bioeth, Toronto, ON, Canada. RP Hyder, AA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Int Hlth, 615 N Wolfe St,Suite E-8132, Baltimore, MD 21205 USA. EM ahyder@jhsph.edu RI Lavery, James/E-5254-2012 NR 22 TC 26 Z9 27 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD MAR 7 PY 2009 VL 373 IS 9666 BP 862 EP 865 DI 10.1016/S0140-6736(09)60488-8 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 416BT UT WOS:000263980900037 PM 19269523 ER PT J AU Jothi, R Raghavachari, B AF Jothi, Raja Raghavachari, Balaji TI Degree-bounded minimum spanning trees SO DISCRETE APPLIED MATHEMATICS LA English DT Article DE Spanning trees; Minimum spanning trees; Approximation algorithm; Geometric optimization; Network design ID APPROXIMATION SCHEMES; TRAVELING SALESMAN; GEOMETRIC PROBLEMS; ALGORITHMS; WEIGHT; GRAPHS; MST AB Given n points in the Euclidean plane, the degree-A minimum spanning tree (MST) problem asks for a spanning tree of minimum weight in which the degree of each vertex is at most delta. The problem is NP-hard for 2 <= delta <= 3, while the NP-hardness of the problem is open for delta = 4. The problem is polynomial-time solvable when delta = 5. By presenting an improved approximation analysis for Chan's degree-4 MST algorithm [T. Chan, Euclidean bounded-degree spanning tree ratios, Discrete & Computational Geometry 32 (2004) 177-194], we show that, for any arbitrary collection of points in the Euclidean plane, there always exists a degree-4 spanning tree of weight at most (root 2 + 2)/3 < 1.1381 times the weight of an MST. Published by Elsevier B.V. C1 [Jothi, Raja] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Raghavachari, Balaji] Univ Texas Dallas, Dept Comp Sci, Richardson, TX 75080 USA. RP Jothi, R (reprint author), NHLBI, Lab Mol Immunol, NIH, 9000 Rockville Pike,Bldg 10,Room 7B20A, Bethesda, MD 20892 USA. EM jothi@mail.nih.gov; rbk@utdallas.edu RI Jothi, Raja/G-3780-2015 FU National Science Foundation [CCR-9820902] FX An extended abstract of this paper appeared in Proceedings Of the 16th Canadian Conference on Computational Geometry, 2004. Research supported in part by the National Science Foundation under grant CCR-9820902. NR 23 TC 11 Z9 11 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-218X J9 DISCRETE APPL MATH JI Discret Appl. Math. PD MAR 6 PY 2009 VL 157 IS 5 BP 960 EP 970 DI 10.1016/j.dam.2008.03.037 PG 11 WC Mathematics, Applied SC Mathematics GA 425OF UT WOS:000264646300009 ER PT J AU Koh, KK Quon, MJ AF Koh, Kwang Kon Quon, Michael J. TI Targeting converging therapeutic pathways to overcome hypertension SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Editorial Material DE Hypertension; Combination treatment; Atherosclerosis; Blood pressure ID CORONARY-ARTERY DISEASE; INTERVENTIONS; SIMVASTATIN C1 [Koh, Kwang Kon] Gachon Univ, Div Cardiol, Vasc Med & Atherosclerosis Unit, Gil Med Ctr, Inchon 405760, South Korea. [Quon, Michael J.] NCCAM, Diabet Unit, Clin Invest Lab, NIH, Bethesda, MD USA. RP Koh, KK (reprint author), Gachon Univ, Div Cardiol, Vasc Med & Atherosclerosis Unit, Gil Med Ctr, 1198 Kuwoldong, Inchon 405760, South Korea. EM kwangk@gilhospital.com OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 FU Intramural NIH HHS [Z01 AT000001-06] NR 11 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD MAR 6 PY 2009 VL 132 IS 3 BP 297 EP 299 DI 10.1016/j.ijcard.2008.11.150 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 414VB UT WOS:000263892200001 PM 19136168 ER PT J AU Martin, D Galisteo, R Gutkind, JS AF Martin, Daniel Galisteo, Rebeca Gutkind, J. Silvio TI CXCL8/IL8 Stimulates Vascular Endothelial Growth Factor (VEGF) Expression and the Autocrine Activation of VEGFR2 in Endothelial Cells by Activating NF kappa B through the CBM (Carma3/Bcl10/Malt1) Complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CANCER CELLS; ANGIOGENESIS; INTERLEUKIN-8; HYPOXIA; SECRETION; PERMEABILITY; HIF-1-ALPHA; PATHWAYS; GENE AB Vascular endothelial growth factor (VEGF) is a potent mitogen and permeability factor for endothelial cells that plays a central role in angiogenesis, vascular maintenance, inflammation, and cancer. VEGF also mediates the homeostatic adaptation to hypoxic conditions by promoting an increase in vascular density to compensate for decreased oxygenation. This process is triggered by an oxygen-sensitive transcription factor, hypoxia-inducible factor-1 (HIF1 alpha), which becomes active in hypoxic tissues, leading to the synthesis and secretion of VEGF. The role of HIF1 alpha in other processes that involve angiogenesis such as in inflammation is less clear. Of interest, endothelial cells not only respond to but also store and secrete VEGF, which is required for the maintenance of the integrity of the vascular system. How this intracellular pool of VEGF is regulated is still not understood. Here, we found that CXCL8/IL8, a potent proangiogenic and inflammatory chemokine, up-regulates VEGF mRNA and protein levels in endothelial cells by acting on its cognate receptor, CXCR2, and that this results in the autocrine activation of VEGFR2. Surprisingly, this process does not involve HIFI alpha but instead requires the activation of the transcription factor NF kappa B. Furthermore, we identified the components of the CBM complex, Carma3, Bcl10, and Malt1, as key mediators of the CXCL8/IL8-induced NF kappa B activation and VEGF up-regulation. Together, these findings support the existence of an NF kappa B-mediated pathway by which the proinflammatory chemokine CXCL8/IL8 controls the expression of VEGF in endothelial cells, thereby promoting the activation of VEGF receptors in an autocrine fashion. C1 [Martin, Daniel; Galisteo, Rebeca; Gutkind, J. Silvio] NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 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 FU National Institutes of Health Intramural AIDS Targeted Antiviral Program; NIDCR (National Institutes of Health) FX This work was supported, in whole or in part, by a National Institutes of Health Intramural AIDS Targeted Antiviral Program and by the a grant from the NIDCR (National Institutes of Health). NR 25 TC 157 Z9 162 U1 1 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 6 PY 2009 VL 284 IS 10 BP 6038 EP 6042 DI 10.1074/jbc.C800207200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 412RU UT WOS:000263742700004 PM 19112107 ER PT J AU Hakim, O John, S Ling, JQ Biddie, SC Hoffman, AR Hager, GL AF Hakim, Ofir John, Sam Ling, Jian Qun Biddie, Simon C. Hoffman, Andrew R. Hager, Gordon L. TI Glucocorticoid Receptor Activation of the Ciz1-Lcn2 Locus by Long Range Interactions SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BETA-GLOBIN GENE; CHROMOSOME CONFORMATION; NUCLEAR-ORGANIZATION; LIVING CELLS; CHROMATIN; TRANSCRIPTION; GENOME; EXPRESSION; SITES; MECHANISMS AB The cellular response to glucocorticoid receptor (GR) activation involves a highly orchestrated series of regulatory actions influenced at multiple levels by a variety of mechanisms including the action of transcription factors and chromatin modifiers. Because the majority of GR binding sites (glucocorticoid-responsive elements (GREs)) are distant from promoters, it is likely that interactions at a distance play an important role in GR action. To determine whether long range chromosomal associations play a role in transcription regulation by GR, we utilized a chromosome conformation capture-based technique (associated chromosome trap) to identify unknown, remote sequences that interact with the GR-induced Lipocalin2 (Lcn2) gene. Our screen revealed that the Lcn2 GRE interacts with the Ciz1 gene, nearly 30 kb upstream. Ciz1 was subsequently found to be a novel GR-responsive gene. The GRE proximal to the Lcn2 promoter apparently functions to regulate both the Lcn2 gene and the distal Ciz1 gene. Using quantitative chromosome conformation capture, we find that a loop structure is organized between these two genes. This structure is hormone-independent and present only in cell types where the genes are active. The strong correlation between gene expression and loop structure in different cell lines suggests that high order interactions play a role in determining tissue-specific gene regulation. C1 [Hakim, Ofir; John, Sam; Biddie, Simon C.; Hager, Gordon L.] NCI, LRBGE, NIH, Bethesda, MD 20892 USA. [Ling, Jian Qun; Hoffman, Andrew R.] Palo Alto Hlth Care Syst, Dept Vet Affairs, Palo Alto, CA 94304 USA. [Ling, Jian Qun; Hoffman, Andrew R.] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. RP Hager, GL (reprint author), NCI, LRBGE, NIH, Bldg 41,B602, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov RI Hakim, Ofir/A-6239-2012; OI Biddie, Simon/0000-0002-8253-0253 FU National Institutes of Health; NCI; Center for Cancer Research FX This work was supported, in whole or in part, by a National Institutes of Health grant from the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research. NR 35 TC 46 Z9 47 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 MAR 6 PY 2009 VL 284 IS 10 BP 6048 EP 6052 DI 10.1074/jbc.C800212200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 412RU UT WOS:000263742700006 PM 19124469 ER PT J AU Wu, WH Wu, CH Ladurner, A Mizuguchi, G Wei, D Xiao, H Luk, E Ranjan, A Wu, C AF Wu, Wei-Hua Wu, Chwen-Huey Ladurner, Andreas Mizuguchi, Gaku Wei, Debbie Xiao, Hua Luk, Ed Ranjan, Anand Wu, Carl TI N Terminus of Swr1 Binds to Histone H2AZ and Provides a Platform for Subunit Assembly in the Chromatin Remodeling Complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SACCHAROMYCES-CEREVISIAE GENOME; ACTIN-RELATED PROTEINS; VARIANT H2A.Z; HETEROCHROMATIN BOUNDARIES; H4 ACETYLATION; HSA DOMAIN; NUA4; HTZ1; NUCLEOSOME; EXCHANGE AB Variant histone H2AZ-containing nucleosomes are involved in the regulation of gene expression. In Saccharomyces cerevisiae, chromatin deposition of histone H2AZ is mediated by the fourteen-subunit SWR1 complex, which catalyzes ATP-dependent exchange of nucleosomal histone H2A for H2AZ. Previous work defined the role of seven SWR1 subunits (Swr1 ATPase, Swc2, Swc3, Arp6, Swc5, Yaf9, and Swc6) in maintaining complex integrity and H2AZ histone replacement activity. Here we examined the function of three additional SWR1 subunits, bromodomain containing Bdf1, actin-related protein Arp4 and Swc7, by analyzing affinity-purified mutant SWR1 complexes. We observed that depletion of Arp4 (arp4-td) substantially impaired the association of Bdf1, Yaf9, and Swc4. In contrast, loss of either Bdf1 or Swc7 had minimal effects on overall complex integrity. Furthermore, the basic H2AZ histone replacement activity of SWR1 in vitro required Arp4, but not Bdf1 or Swc7. Thus, three out of fourteen SWR1 subunits, Bdf1, Swc7, and previously noted Swc3, appear to have roles auxiliary to the basic histone replacement activity. The N-terminal region of the Swr1 ATPase subunit is necessary and sufficient to direct association of Bdf1 and Swc7, as well as Arp4, Act1, Yaf9 and Swc4. This same region contains an additional H2AZ-H2B specific binding site, distinct from the previously identified Swc2 subunit. These findings suggest that one SWR1 enzyme might be capable of binding two H2AZ-H2B dimers, and provide further insight on the hierarchy and interdependency of molecular interactions within the SWR1 complex. C1 [Wu, Wei-Hua; Wu, Chwen-Huey; Mizuguchi, Gaku; Wei, Debbie; Xiao, Hua; Luk, Ed; Ranjan, Anand; Wu, Carl] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Ladurner, Andreas] European Mol Biol Lab, Gene Express Unit, D-69117 Heidelberg, Germany. RP Wu, WH (reprint author), NCI, Biochem & Mol Biol Lab, NIH, Bldg 37,Rm 6066, Bethesda, MD 20892 USA. EM wuwe@mail.nih.gov; carlwu@helix.nih.gov OI Luk, Ed/0000-0002-6619-2258 FU NCI; National Institutes of Health FX This work was supported, in whole or in part, by the intramural research program of the NCI, National Institutes of Health. NR 53 TC 45 Z9 47 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 6 PY 2009 VL 284 IS 10 BP 6200 EP 6207 DI 10.1074/jbc.M808830200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 412RU UT WOS:000263742700023 PM 19088068 ER PT J AU Lee, IH Finkel, T AF Lee, In Hye Finkel, Toren TI Regulation of Autophagy by the p300 Acetyltransferase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID C-ELEGANS; LIFE-SPAN; RESTRICTION; EXTENSION; DISEASE; GENES; CELLS; MTOR; MICE AB Autophagy is a regulated process of intracellular catabolism required for normal cellular maintenance, as well as serving as an adaptive response under various stress conditions, including starvation. The molecular regulation of autophagy in mammalian cells remains incompletely understood. Here we demonstrate a role for protein acetylation in the execution and regulation of autophagy. In particular, we demonstrate that the p300 acetyltransferase can regulate the acetylation of various known components of the autophagy machinery. Knockdown of p300 reduces acetylation of Atg5, Atg7, Atg8, and Atg12, although overexpressed p300 increases the acetylation of these same proteins. Furthermore, p300 and Atg7 colocalize within cells, and the two proteins physically interact. The interaction between p300 and Atg7 is dependent on nutrient availability. Finally, we demonstrate that knockdown of p300 can stimulate autophagy, whereas overexpression of p300 inhibits starvation-induced autophagy. These results demonstrate a role for protein acetylation and particularly p300 in the regulation of autophagy under conditions of limited nutrient availability. C1 [Lee, In Hye; Finkel, Toren] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10,CRC 5-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU National Institutes of Health staff FX This work was authored, in whole or in part, by National Institutes of Health staff. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 17 TC 88 Z9 94 U1 5 U2 16 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 6 PY 2009 VL 284 IS 10 BP 6322 EP 6328 DI 10.1074/jbc.M807135200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 412RU UT WOS:000263742700035 PM 19124466 ER PT J AU Blackinton, J Lakshminarasimhan, M Thomas, KJ Ahmad, R Greggio, E Raza, AS Cookson, MR Wilson, MA AF Blackinton, Jeff Lakshminarasimhan, Mahadevan Thomas, Kelly J. Ahmad, Rili Greggio, Elisa Raza, Ashraf S. Cookson, Mark R. Wilson, Mark A. TI Formation of a Stabilized Cysteine Sulfinic Acid Is Critical for the Mitochondrial Function of the Parkinsonism Protein DJ-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RESOLUTION CRYSTAL-STRUCTURE; DISEASE GENE DJ-1; ALPHA-SYNUCLEIN; SACCHAROMYCES-CEREVISIAE; LOCALIZATION; SUPERFAMILY; MUTATIONS; OXIDATION; IDENTIFICATION; EVOLUTIONARY AB The formation of cysteine-sulfinic acid has recently become appreciated as a modification that links protein function to cellular oxidative status. Human DJ-1, a protein associated with inherited parkinsonism, readily forms cysteine-sulfinic acid at a conserved cysteine residue (Cys(106) in human DJ-1). Mutation of Cys(106) causes the protein to lose its normal protective function in cell culture and model organisms. However, it is unknown whether the loss of DJ-1 protective function in these mutants is due to the absence of Cys(106) oxidation or the absence of the cysteine residue itself. To address this question, we designed a series of substitutions at a proximal glutamic acid residue (Glu(18)) in human DJ-1 that alter the oxidative propensity of Cys(106) through changes in hydrogen bonding. We show that two mutations, E18N and E18Q, allow Cys(106) to be oxidized to Cys(106)-sulfinic acid under mild conditions. In contrast, the E18D mutation stabilizes a cysteine-sulfenic acid that is readily reduced to the thiol in solution and in vivo. We show that E18N and E18Q can both partially substitute for wild-type DJ-1 using mitochondrial fission and cell viability assays. In contrast, the oxidatively impaired E18D mutant behaves as an inactive C106A mutant and fails to protect cells. We therefore conclude that formation of Cys(106)-sulfinic acid is a key modification that regulates the protective function of DJ-1. C1 [Blackinton, Jeff; Thomas, Kelly J.; Ahmad, Rili; Greggio, Elisa; Cookson, Mark R.] NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, Bethesda, MD 20982 USA. [Lakshminarasimhan, Mahadevan; Raza, Ashraf S.; Wilson, Mark A.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Lakshminarasimhan, Mahadevan; Raza, Ashraf S.; Wilson, Mark A.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, Rm 1A116,MSC 3707,35 Convent Dr, Bethesda, MD 20982 USA. EM cookson@mail.nih.gov; mwilson13@unl.edu RI Greggio, Elisa/H-6119-2013 OI Greggio, Elisa/0000-0002-8172-3598 FU National Institutes of Health [P20RR17675]; National Institutes of Health, NIA [Z01-AG000953]; American Parkinson's Disease Association FX This work was supported, in whole or in part, by National Institutes of Health Grant P20RR17675 (to M. A. W.) and by the Intramural Research Program of the National Institutes of Health, NIA, Project Z01-AG000953 (to M. R. C.). This work was also supported in part by the American Parkinson's Disease Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 40 TC 122 Z9 125 U1 2 U2 11 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 6 PY 2009 VL 284 IS 10 BP 6476 EP 6485 DI 10.1074/jbc.M806599200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 412RU UT WOS:000263742700050 PM 19124468 ER PT J AU Issaq, HJ Chan, KC Blonder, J Ye, XY Veenstra, TD AF Issaq, Haleem J. Chan, King C. Blonder, Josip Ye, Xiaoying Veenstra, Timothy D. TI Separation, detection and quantitation of peptides by liquid chromatography and capillary electrochromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Review DE HPLC-MS; Mass spectrometry; Peptide quantitation; Peptide fractionation and separation; Proteomics; Capillary electrochromatography ID INDUCED FLUORESCENCE DETECTION; LASER-INDUCED FLUORESCENCE; EVAPORATIVE LIGHT-SCATTERING; IONIZATION-MASS-SPECTROMETRY; HYDROPHILIC-INTERACTION CHROMATOGRAPHY; CHARGED AEROSOL DETECTION; POROUS GRAPHITIC CARBON; LC-MS SEPARATION; STATIONARY-PHASE; AMINO-ACIDS AB This review discusses different liquid chromatographic and capillary electrochromatographic approaches to the separation and quantitation of peptides using silica-based and polymeric-based columns with emphasis on liquid chromatography. Mass spectrometry detection and quantitation of peptides using labeled and label-free procedures, will also be discussed, as well as the effect of amino acids' properties on the solubility of peptides, an important parameter that influences the selection of the mobile phase. A discussion of different column packing materials, reversed-phase, cyclodextrins, macrocyclic antibiotics, porous graphitic carbon, mixed-phases, and normal-phase will be included, as well as a short discussion of multi-dimensional approaches for the separation of complex peptide mixtures. (C) 2008 Elsevier B.V. All rights reserved. C1 [Issaq, Haleem J.; Chan, King C.; Blonder, Josip; Ye, Xiaoying; Veenstra, Timothy D.] NCI Frederick, SAIC Frederick Inc, Lab Prote & Analyt Technol, Adv Technol Program, Frederick, MD 21702 USA. RP Issaq, HJ (reprint author), NCI Frederick, SAIC Frederick Inc, Lab Prote & Analyt Technol, Adv Technol Program, POB B, Frederick, MD 21702 USA. EM issaqh@ncifcrf.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. NR 124 TC 31 Z9 34 U1 0 U2 32 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD MAR 6 PY 2009 VL 1216 IS 10 BP 1825 EP 1837 DI 10.1016/j.chroma.2008.12.052 PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 416SK UT WOS:000264025600019 PM 19131068 ER PT J AU Wrona, IE Lowe, JT Turbyville, TJ Johnson, TR Beignet, J Beutler, JA Panek, JS AF Wrona, Iwona E. Lowe, Jason T. Turbyville, Thomas J. Johnson, Tanya R. Beignet, Julien Beutler, John A. Panek, James S. TI Synthesis of a 35-Member Stereoisomer Library of Bistramide A: Evaluation of Effects on actin State, Cell Cycle and Tumor Cell Growth SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Review ID RING-OPENING REACTIONS; CATALYTIC ASYMMETRIC EPOXIDATION; LISSOCLINUM-BISTRATUM SLUITER; FUNCTIONAL-GROUPS PROXIMATE; SECONDARY ALLYLIC ALCOHOLS; FLUOROUS MIXTURE SYNTHESIS; SKELETAL-MUSCLE FIBERS; DDQ-SUBSTRATE ADDUCTS; SILYL ENOL ETHERS; STEREOSELECTIVE-SYNTHESIS AB Synthesis and preliminary biological evaluation of a 35-member library of bistramide A stereoisomers are reported. All eight stereoisomers of the C1-C13 tetrahydropyran fragment of the molecule were prepared utilizing crotylsilane reagents 9 and 10 in our [4+2]-annulation methodology. In addition, the four isomers of the C14-C18 gamma-amino acid unit were accessed via a Lewis acid mediated crotylation reaction with use of both enantiomers of organosilane 11. The spiroketal subunit of bistramide A was modified at the C39-alcohol to give another point of stereochemical diversification. The fragments were coupled by using a standard peptide coupling protocol to provide 35 stereoisomers of the natural product. These stereochemical analogues were screened for their effects on cellular actin and cytotoxicity against cancer cell lines (UO-31 renal and SF-295 CNS). The results of these assays identified one analogue, 1.21, with enhanced potency relative to the natural product, bistramide A. C1 [Wrona, Iwona E.; Lowe, Jason T.; Beignet, Julien; Panek, James S.] Boston Univ, Dept Chem, Boston, MA 02215 USA. [Wrona, Iwona E.; Lowe, Jason T.; Beignet, Julien; Panek, James S.] Boston Univ, Ctr Chem Methodol & Lib Dev CMLD BU, Boston, MA 02215 USA. [Turbyville, Thomas J.; Johnson, Tanya R.; Beutler, John A.] NCI, Mol Targets Dev Program, Frederick, MD 21702 USA. RP Panek, JS (reprint author), Boston Univ, Dept Chem, 590 Commonwealth Ave, Boston, MA 02215 USA. EM panek@bu.edu RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU NIH [CA56304, N01-CO-12400]; Amgen; Johnson Johnson; Merck Co.; Novartis; Pfizer; GSK; Novartis Graduate Fellowship; ACS; Merck Co. Graduate Fellowship; Intramural Research Program of the National Cancer Institute; Center for Cancer Research; National Cancer Institute FX Financial support for this research was obtained from NIH CA56304. J.S.P. is grateful to Amgen, Johnson & Johnson, Merck Co., Novartis, Pfizer, and GSK for financial support. I.E.W. acknowledges a Novartis Graduate Fellowship. J.T.L. acknowledges an ACS Graduate Fellowship (sponsored by Bristol-Myers Squibb) and Merck Co. Graduate Fellowship, Supported by the Intramural Research Program of the National Cancer Institute, NIH, Center for Cancer Research. Flow cytometry and cell cycle analysis were done by Kathleen Noer, Roberta Matthai, and Samantha Bauchiero of the CCR-Frederick Flow Cytometry Core, SAIC-Frederick, Inc. We thank the Developmental Therapeutics Program, NCI, for 60-cell testing. This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. NR 123 TC 35 Z9 35 U1 0 U2 16 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 MAR 6 PY 2009 VL 74 IS 5 BP 1897 EP 1916 DI 10.1021/jo802269q PG 20 WC Chemistry, Organic SC Chemistry GA 415GG UT WOS:000263921700011 PM 19191575 ER PT J AU Blackinton, J Kumaran, R van der Brug, MP Ahmad, R Olson, L Galter, D Lees, A Bandopadhyay, R Cookson, MR AF Blackinton, Jeff Kumaran, Ravindran van der Brug, Marcel P. Ahmad, Rili Olson, Lars Galter, Dagmar Lees, Andrew Bandopadhyay, Rina Cookson, Mark R. TI Post-transcriptional regulation of mRNA associated with DJ-1 in sporadic Parkinson disease SO NEUROSCIENCE LETTERS LA English DT Article DE Sporadic Parkinson's disease; Recessive parkinsonism; Translational regulation; Oxidative stress ID OXIDATIVE DAMAGE; PROTEIN DJ-1 AB Mutations in DJ-1 lead to a monogenic form of early onset recessive parkinsonism. DJ-1 can respond to oxidative stress, which has been proposed to be involved in the pathogenesis of sporadic Parkinson disease (PD). We have recently reported that DJ-1 interacts with mRNA in an oxidation-dependent manner. Here, we confirm interaction of DJ-1 and RNA in human brain using immunoprecipitation followed by quantitative real time PCR. We confirmed previous reports that DJ-1 is more oxidized in cortex from cases of sporadic PD compared to controls. In the same samples, protein and RNA expression was measured for four DJ-1 target genes GPx4, MAPK8IP1, ND2 and ND5. While no alterations in mRNA expression were observed, an increase in protein expression was observed in PD cases for GPx4 and MAPK8IP1. In the same patients, we saw decreased mRNA and protein levels of two mitochondrial targets, ND2 and ND5. These results suggest that these proteins undergo regulation at the post-transcriptional level that may involve translational regulation by DJ-1. (C) Published by Elsevier Ireland Ltd. C1 [Blackinton, Jeff; van der Brug, Marcel P.; Ahmad, Rili; Cookson, Mark R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Blackinton, Jeff; Olson, Lars; Galter, Dagmar] Karolinska Inst, Dept Neurosci, S-17177 Stockholm, Sweden. [Kumaran, Ravindran; Lees, Andrew; Bandopadhyay, Rina] UCL, Inst Neurol, Reta Lila Weston Inst Neurol Studies, London WC1N 1PJ, England. RP Cookson, MR (reprint author), NIA, Neurogenet Lab, NIH, 35 Convent Dr,Bldg 35 Room 1A1015, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov RI Bandopadhyay, Rina /C-7926-2009; Galter, Dagmar/C-4826-2011; Lees, Andrew/A-6605-2009 OI Galter, Dagmar/0000-0001-6485-6244; FU Intramural Research Program of the NIH; National Institute on Aging FX This research was supported in part by the Intramural Research Program of the NIH. National Institute on Aging. RB acknowledges funding from PE) Society UK and PD SPRING UK. We would like to thank Karin Pernold, Karin Lundstromer and Eva Lindqvist for technical assistance. NR 10 TC 32 Z9 34 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 6 PY 2009 VL 452 IS 1 BP 8 EP 11 DI 10.1016/j.neulet.2008.12.053 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 417QT UT WOS:000264092100003 PM 19146923 ER PT J AU Anderson, TM vonHoldt, BM Candille, SI Musiani, M Greco, C Stahler, DR Smith, DW Padhukasahasram, B Randi, E Leonard, JA Bustamante, CD Ostrander, EA Tang, H Wayne, RK Barsh, GS AF Anderson, Tovi M. vonHoldt, Bridgett M. Candille, Sophie I. Musiani, Marco Greco, Claudia Stahler, Daniel R. Smith, Douglas W. Padhukasahasram, Badri Randi, Ettore Leonard, Jennifer A. Bustamante, Carlos D. Ostrander, Elaine A. Tang, Hua Wayne, Robert K. Barsh, Gregory S. TI Molecular and Evolutionary History of Melanism in North American Gray Wolves SO SCIENCE LA English DT Article ID DOMESTIC DOGS; COAT COLOR; MICROSATELLITE LOCI; HAPLOTYPE STRUCTURE; GENETIC-BASIS; DIFFERENTIATION; INTROGRESSION; PATTERNS; SEQUENCE; GENOME AB Morphological diversity within closely related species is an essential aspect of evolution and adaptation. Mutations in the Melanocortin 1 receptor (Mc1r) gene contribute to pigmentary diversity in natural populations of fish, birds, and many mammals. However, melanism in the gray wolf, Canis lupus, is caused by a different melanocortin pathway component, the K locus, that encodes a beta-defensin protein that acts as an alternative ligand for Mc1r. We show that the melanistic K locus mutation in North American wolves derives from past hybridization with domestic dogs, has risen to high frequency in forested habitats, and exhibits a molecular signature of positive selection. The same mutation also causes melanism in the coyote, Canis latrans, and in Italian gray wolves, and hence our results demonstrate how traits selected in domesticated species can influence the morphological diversity of their wild relatives. C1 [Anderson, Tovi M.; Candille, Sophie I.; Tang, Hua; Barsh, Gregory S.] Stanford Univ, Dept Genet, Stanford, CA 94305 USA. [Anderson, Tovi M.; Candille, Sophie I.; Tang, Hua; Barsh, Gregory S.] Stanford Univ, Dept Pediat, Stanford, CA 94305 USA. [vonHoldt, Bridgett M.; Stahler, Daniel R.; Wayne, Robert K.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 91302 USA. [Musiani, Marco] Univ Calgary, Fac Environm Design, Calgary, AB T2N 1N4, Canada. [Greco, Claudia; Randi, Ettore] Ist Nazl Fauna Selvat, I-40064 Ozzano Dell Emilia, BO, Italy. [Stahler, Daniel R.; Smith, Douglas W.] Natl Pk Serv, Yellowstone Ctr Resources, Yellowstone Natl Pk, WY 82190 USA. [Padhukasahasram, Badri; Bustamante, Carlos D.] Cornell Univ, Dept Biol Stat & Computat Biol, Ithaca, NY 14853 USA. [Leonard, Jennifer A.] Uppsala Univ, Dept Evolutionary Biol, S-75236 Uppsala, Sweden. [Ostrander, Elaine A.] NHGRI, Bethesda, MD 20892 USA. RP Barsh, GS (reprint author), Stanford Univ, Dept Genet, Stanford, CA 94305 USA. EM gbarsh@stanford.edu RI Leonard, Jennifer/A-7894-2010; OI Leonard, Jennifer/0000-0003-0291-7819; Greco, Claudia/0000-0002-8678-0890 FU NIH; NSF; Swedish Research Council FX Supported by grants from NIH (G.S.B.), NSF (R.K.W., D.R.S., and D.W.S.), and the Swedish Research Council (J. A.L.). We are grateful to H. Chen and S. Schmutz for advice, to H. Manuel for technical assistance, and to members of the U.S. Department of Agriculture Wildlife Services and private citizens for assistance with sample collection. Sequences generated in this study are deposited in GenBank under accession numbers FJ609634 to FJ609641. NR 29 TC 172 Z9 181 U1 18 U2 151 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 MAR 6 PY 2009 VL 323 IS 5919 BP 1339 EP 1343 DI 10.1126/science.1165448 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 414PC UT WOS:000263876700041 PM 19197024 ER PT J AU Le-Niculescu, H Patel, SD Bhat, M Kuczenski, R Faraone, SV Tsuang, MT McMahon, FJ Schork, NJ Nurnberger, JI Niculescu, AB AF Le-Niculescu, H. Patel, S. D. Bhat, M. Kuczenski, R. Faraone, S. V. Tsuang, M. T. McMahon, F. J. Schork, N. J. Nurnberger, J. I., Jr. Niculescu, A. B., III TI Convergent Functional Genomics of Genome-Wide Association Data for Bipolar Disorder: Comprehensive Identification of Candidate Genes, Pathways and Mechanisms SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Review DE gene expression; genetics; convergent functional genomics; genome-wide association; brain; blood; bipolar ID ONSET MAJOR DEPRESSION; SINGLE NUCLEOTIDE POLYMORPHISM; SEASONAL AFFECTIVE-DISORDER; POSTMORTEM FRONTAL-CORTEX; FAMILY-BASED ASSOCIATION; OPIOID-RECEPTOR GENE; SUSCEPTIBILITY LOCI; NATIONAL-INSTITUTE; PREFRONTAL CORTEX; MOOD DISORDERS AB Given the mounting convergent evidence implicating many more genes in complex disorders such as bipolar disorder than the small number identified unambiguously by the first-generation Genome-Wide Association studies (GWAS) to date, there is a strong need for improvements in methodology. One strategy is to include in the next generation GWAS larger numbers of subjects, and/or to pool independent studies into meta-analyses. We propose and provide proof of principle for the use of a complementary approach, convergent functional genomics (CFG), as a way of mining the existing GWAS datasets for signals that are there already, but did not reach significance using a genetics-only approach. With the CFG approach, the integration of genetics with genomics, of human and animal model data, and of multiple independent lines of evidence converging on the same genes offers a way of extracting signal from noise and prioritizing candidates. It) essence our analysis is the most comprehensive integration of genetics and functional genomics to date in the field of bipolar disorder, Yielding a series of novel (such as Klf12, Aldh1a1, A2bp1, Ak3l1, Rorb, Rora) and previously known (such as Bdnf, Arntl, Gsk3b, Disc1, Nrg1, Htr2a) candidate genes, blood biomarkers, as well as a comprehensive identification of pathways and mechanisms. These become prime targets for hypothesis driven follow-up studies, new drug development and personalized medicine approaches. (C) 2008 Wiley-Liss, Inc. C1 [Le-Niculescu, H.; Patel, S. D.; Bhat, M.; Niculescu, A. B., III] Indiana Univ, Sch Med, Dept Psychiat, Lab Neurophen, Indianapolis, IN 46202 USA. [Le-Niculescu, H.; Patel, S. D.; Niculescu, A. B., III] Indiana Univ, Sch Med, Dept Psychiat, INBRAIN, Indianapolis, IN 46202 USA. [Le-Niculescu, H.; Patel, S. D.; Bhat, M.; Nurnberger, J. I., Jr.; Niculescu, A. B., III] Indiana Univ, Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. [Kuczenski, R.; Tsuang, M. T.] UC San Diego, Dept Psychiat, La Jolla, CA USA. [Faraone, S. V.] SUNY Upstate Med Univ, Dept Psychiat, Syracuse, NY USA. [McMahon, F. J.] NIMH, Mood & Anxiety Disorders Branch, Bethesda, MD 20892 USA. [Schork, N. J.] Scripps Res Inst, La Jolla, CA 92037 USA. RP Niculescu, AB (reprint author), Indiana Univ, Sch Med, Dept Psychiat, Lab Neurophen, 791 Union Dr, Indianapolis, IN 46202 USA. EM anicules@iupui.edu RI Niculescu, Alexander/A-3328-2012; OI Nurnberger, John/0000-0002-7674-1767; McMahon, Francis/0000-0002-9469-305X; Faraone, Stephen/0000-0002-9217-3982 FU U.S. National Institute of Mental Health [1 R01 MH 071912]; NARSAD Mogens Schou Young Investigator award FX This work was supported by a grant (1 R01 MH 071912) from the U.S. National Institute of Mental Health to M.T.T. andA.B.N., and a NARSAD Mogens Schou Young Investigator award to ABN. We are grateful to Nick Craddock, Mick O'Donovan, Mike Owen and Pamela Sklar for sharing of data and very helpful discussions. We would also like to thank Griffin Fitzgerald, Bhavana Pandya and Jesse Townes for their help with database construction and bioinformatic analyses. Supplementary information for this paper is available from the journal website. Additional information is available at www.neurophenomics.info. NR 183 TC 106 Z9 109 U1 7 U2 15 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD MAR 5 PY 2009 VL 150B IS 2 BP 155 EP 181 DI 10.1002/ajmg.b.30887 PG 27 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 416CT UT WOS:000263983500001 PM 19025758 ER PT J AU Johnson, C Drgon, T McMahon, FJ Uhl, GR AF Johnson, Catherine Drgon, Tomas McMahon, Francis J. Uhl, George R. TI Convergent Genome Wide Association Results for Bipolar Disorder and Substance Dependence SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE complex genetics; addiction; depressive disorder; single nucleotide polymorphism ID ADDICTION MOLECULAR-GENETICS; NICOTINE DEPENDENCE; VULNERABILITY LOCI; GENES; VALIDATION; ALCOHOLISM; MOOD; SNPS; RDC AB Twin studies document substantial heritability for substance dependence and bipolar disorder [Shih et a]. (2004); Uhl et al. (2008a)]. Individuals with bipolar disorder display substance use disorders at rates that are much higher than those in the general population [Krishnan (2005)]. We Would thus predict: 1) substantial overlap between different genome wide association (GWA) studies of bipolar disorder 2) significant overlap between results from bipolar disorder and substance dependence. Recent GWA studies [Baum et al. (2007); Sklar et al. (2008); Uhl et al. (2008a); Wellcome Trust Consortium (2007)] allow us to test these ideas, although 1) these datasets display difficult features that include use of differing sets of SNPs, likely polyenic,9 genetics, likely differences in linkage disequilibrium between samples, heterogeneity both between and within loci and 2) several, though not all, reports have failed to identify any allele of any single nucleotide polymorphism (SNP) ("same SNP same allele") that is reproducibly associated with bipolar disorder with "genome wide" significance. We now report analyses that identify clustered, P< 0.05 SNPs within genes that overlap between the bipolar samples (Monte Carlo P < 0.00001). Overlapping data from at least three of these studies identify 69 genes. 23 of these genes also contain overlapping clusters of nominally-positive SNPs for substance dependence. Variants in these "addiction/bipolar" genes are candidates to influence the brain in ways that manifest as enhanced vulnerabilites to both substance dependence and bipolar disorder. (C) 2009 Wiley-Liss, Inc. C1 [Johnson, Catherine; Drgon, Tomas; Uhl, George R.] NIDA, Mol Neurobiol Branch, IRP, NIH, Baltimore, MD USA. [McMahon, Francis J.] Mood & Anxiety Disorders Program, Unit Genet Basis Mood & Anxiety Disorders, Bethesda, MD USA. RP Uhl, GR (reprint author), POB 5180, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov OI McMahon, Francis/0000-0002-9469-305X FU NIH; NIDA; NIMH, DHSS; Wellcome Trust [076113] FX This research was supported financially by the NIH Intramural Research Programs of NIDA and NIMH, DHSS. We are very grateful for access to bipolar and control data generated by the Wellcome Trust Case-Control Consortium and by Dr. Pamela Sklar and colleagues. A full list of the WTCC investigators who contributed to the generation of the WTCCC data is available from www.wtccc.org.uk. Funding for this project was provided by the Wellcome Trust under award 076113. For Studies of substance dependence, we are also grateful I.-Or dedicated help with clinical characterization of subjects from Judith Hess, Dan Lipstein, Fely Carillo and other Johns Hopkins-Bayview support staff. NR 25 TC 29 Z9 29 U1 3 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD MAR 5 PY 2009 VL 150B IS 2 BP 182 EP 190 DI 10.1002/ajmg.b.30900 PG 9 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 416CT UT WOS:000263983500002 PM 19127564 ER PT J AU Evans, J Xu, K Heron, J Enoch, MA Araya, R Lewis, G Timpson, N Davies, S Nutt, D Goldman, D AF Evans, Jonathan Xu, Ke Heron, Jon Enoch, Mary-Anne Araya, Ricardo Lewis, Glyn Timpson, Nic Davies, Simon Nutt, David Goldman, David TI Emotional Symptoms in Children: The Effect of Maternal Depression, Life Events, and COMT Genotype SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE anxiety; depression; genotype; depression postpartum; catechol-O-methyltransferase; stress psychological; longitudinal studies ID CATECHOL-O-METHYLTRANSFERASE; POSTNATAL DEPRESSION; DIFFICULTIES QUESTIONNAIRE; ADOLESCENT DEPRESSION; PREFRONTAL CORTEX; MAJOR DEPRESSION; GENETIC ETIOLOGY; STRESSFUL LIFE; MESSENGER-RNA; HUMAN BRAIN AB Early adversity, predicts anxiety and depression but variation in response to adversity is not understood. We investigated whether association between earl), adversity and emotional symptoms in young children differs according to variation of the COMT gene. The main outcome measure was the emotionality subscale of the Strengths and Difficulties Questionnaire (SDQ) completed by mothers for 8,431 children aged 6-7 years old in the Avon Longitudinal Study of Parents and Children. Adversity measures included exposure to maternal postpartum depressive symptoms and adverse life events for children. DNA from the children was genotyped for five COMT polymorphisms including the COMT Val 158Met locus. Maternal depression increased the odds of high emotionality in the children, (OR 1.99, 95% CI 1.73-2.29, P < 0.001) as did life events score, (OR 1.21 for each s.d. increase in life event score, 95% CI 1.15-1.27, P < 0.001). There was no main effect of Val 158Met genotype on emotional symptoms (OR for effect of each cop), of the methionine allele was 1.04, 95% CI 0.97-1.10, P = 0.284). The relationship between adversity and emotional symptoms did not vary by genotype (G x E for maternal depression chi(2) = 3.17, P = 0.205; G x E for life events chi(2) = 1.69, P = 0.430). There was no main effect of COMT haplotype, nor was there an interaction with adversity. Early adversity predicts emotional symptoms in children aged 6-7 years. Although some studies indicate a role for COMT in emotionality, anxiety, and depression in adults, no direct effect or interaction of COMT genotype was observed in this large sample of young children. (C) 2008 Wiley-Liss, Inc. C1 [Evans, Jonathan; Araya, Ricardo; Lewis, Glyn; Davies, Simon; Nutt, David] Univ Bristol, Acad Unit Psychiat, Bristol, Avon, England. [Xu, Ke; Enoch, Mary-Anne; Goldman, David] Natl Inst Alcoholism & Alcoholism, Neurogenet Lab, NIH, Rockville, MD USA. [Heron, Jon] Univ Bristol, Dept Social Med, ALSPAC, Bristol, Avon, England. RP Evans, J (reprint author), Cotham House, Bristol BS6 6JL, Avon, England. EM j.evans@bristol.ac.uk RI Goldman, David/F-9772-2010; Heron, Jon/D-5884-2011; Fox, Laura /C-6249-2016; Lewis, Glyn/E-9944-2012 OI Goldman, David/0000-0002-1724-5405; Heron, Jon/0000-0001-6199-5644; Evans, Jonathan/0000-0003-3171-640X; nutt, david/0000-0002-1286-1401; Timpson, Nicholas/0000-0002-7141-9189; Davies, Simon/0000-0003-0095-5993; Lewis, Glyn/0000-0001-5205-8245 FU Medical Research Council; Wellcome Trust; University of Bristol; National Institute on Alcohol Abuse and Alcoholism, NIH; National Institutes of Health and the National Institute on Alcoholism and Alcohol Abuse FX Core Support for the Avon Longitudinal Study of Parents and Children (ALSPAC) is provided by the Medical Research Council, the Wellcome Trust, and the University of Bristol. This research was supported in part by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH. Dr. Goldman receives intramural funding through the National Institutes of Health and the National Institute on Alcoholism and Alcohol Abuse. The authors thank the families who took part in this study, the midwives for their help with recruitment, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists, and nurses. The authors also thank Professor George Davey-Smith and Professor Jean Golding for comments on an earlier draft of this article. NR 56 TC 13 Z9 13 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD MAR 5 PY 2009 VL 150B IS 2 BP 209 EP 218 DI 10.1002/ajmg.b.30789 PG 10 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 416CT UT WOS:000263983500005 PM 18535998 ER PT J AU Jirmanova, L Sarma, DN Jankovic, D Mittelstadt, PR Ashwell, JD AF Jirmanova, Ludmila Sarma, Dandapantula N. Jankovic, Dragana Mittelstadt, Paul R. Ashwell, Jonathan D. TI Genetic disruption of p38 alpha Tyr323 phosphorylation prevents T-cell receptor-mediated p38 alpha activation and impairs interferon-gamma production SO BLOOD LA English DT Article ID P38 MAP KINASE; NF-KAPPA-B; PROTEIN-KINASE; TOXOPLASMA-GONDII; ACTIVE MUTANTS; EXPRESSION; PATHWAY; STRESS; BETA; DIFFERENTIATION AB T cells possess a p38 activation alternative pathway in which stimulation via the antigen receptor (T-cell receptor [TCR]) induces phosphorylation of p38 alpha and beta on Tyr323. To assess the contribution of this pathway to normal T-cell function, we generated p38 alpha knockin mice in which Tyr323 was replaced with Phe (p38 alpha(Y323F)). TCR-mediated stimulation failed to activate p38 alpha(Y323F) as measured by phosphorylation of the Thr-Glu-Tyr activation motif and p38 alpha catalytic activity. Cell-cycle entry was delayed in TCR-stimulated p38 alpha(Y323F) T cells, which also produced less interferon (IFN)-gamma than wild-type T cells in response to TCR-mediated but not TCR-independent stimuli. p38 alpha(Y323F) mice immunized with T-helper 1 (Th1)-inducing antigens generated normal Th1 effector cells, but these cells produced less IFN-gamma than wild-type cells when stimulated through the TCR. Thus, the Tyr323-dependent pathway and not the classic mitogen-activated protein (MAP) kinase cascade is the physiologic means of p38 alpha activation through the TCR and is necessary for normal Th1 function but not Th1 generation. (Blood. 2009; 113: 2229-2237) C1 [Jirmanova, Ludmila; Sarma, Dandapantula N.; Mittelstadt, Paul R.; Ashwell, Jonathan D.] NCI, NIH, Lab Immune Cell Biol, Bethesda, MD 20892 USA. [Jankovic, Dragana] NIAID, NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, NIH, Lab Immune Cell Biol, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU Intramural Research Program of the Center for Cancer Research; National Cancer Institute; NIH FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH. NR 50 TC 26 Z9 27 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 MAR 5 PY 2009 VL 113 IS 10 BP 2229 EP 2237 DI 10.1182/blood-2008-04-153304 PG 9 WC Hematology SC Hematology GA 415EZ UT WOS:000263918400015 PM 19011223 ER PT J AU Melenhorst, JJ Scheinberg, P Chattopadhyay, PK Gostick, E Ladell, K Roederer, M Hensel, NF Douek, DC Barrett, AJ Price, DA AF Melenhorst, J. Joseph Scheinberg, Phillip Chattopadhyay, Pratip K. Gostick, Emma Ladell, Kristin Roederer, Mario Hensel, Nancy F. Douek, Daniel C. Barrett, A. John Price, David A. TI High avidity myeloid leukemia-associated antigen-specific CD8(+) T cells preferentially reside in the bone marrow SO BLOOD LA English DT Article ID BREAST-CANCER PATIENTS; CHRONIC MYELOGENOUS LEUKEMIA; CLASS-I TETRAMERS; SELECTIVE ACCUMULATION; MEMORY; LYMPHOCYTES; CORECEPTOR; IMMUNOTHERAPY; ELIMINATION; POPULATIONS AB The activity of allogeneic CD8(+) T cells specific for leukemia-associated antigens (LAAs) is thought to mediate, at least in part, the curative effects of hematopoietic stem cell transplantation (HSCT) in myeloid malignancies. However, the identity and nature of clinically relevant LAA-specific CD8(+) T-cell populations have proven difficult to define. Here, we used a combination of coreceptor-mutated peptide-major histocompatibility complex class I (pMHCI) tetramers and polychromatic flow cytometry to examine the avidity profiles, phenotypic characteristics, and anatomical distribution of HLA A*0201-restricted CD8(+) T-cell populations specific for LAAs that are over-expressed in myeloid leukemias. Remarkably, LAA-specific CD8(+) T-cell populations, regardless of fine specificity, were confined almost exclusively to the bone marrow; in contrast, CD8(+) T-cell populations specific for the HLA A*0201-restricted cytomegalovirus (CMV) pp65(495-503) epitope were phenotypically distinct and evenly distributed between bone marrow and peripheral blood. Furthermore, bone marrow-resident LAA-specific CD8(+) T cells frequently engaged cognate antigen with high avidity; notably, this was the case in all tested bone marrow samples derived from patients who achieved clinical remission after HSCT. These data suggest that concomitant examination of bone marrow specimens in patients with myeloid leukemias might yield more definitive information in the search for immunologic prognosticators of clinical outcome. (Blood. 2009; 113: 2238-2244) C1 [Melenhorst, J. Joseph; Scheinberg, Phillip; Hensel, Nancy F.; Barrett, A. John] NHLBI, NIH, Hematol Branch, Bethesda, MD 20892 USA. [Scheinberg, Phillip; Douek, Daniel C.; Price, David A.] NIAID, NIH, Vaccine Res Ctr, Human Immunol Sect, Bethesda, MD 20892 USA. [Chattopadhyay, Pratip K.; Roederer, Mario] NIAID, NIH, Vaccine Res Ctr, Immunotechnol Sect, Bethesda, MD 20892 USA. [Gostick, Emma; Ladell, Kristin; Price, David A.] Cardiff Univ, Sch Med, Dept Med Biochem & Immunol, Cardiff CF14 4XN, S Glam, Wales. RP Melenhorst, JJ (reprint author), NHLBI, NIH, Hematol Branch, Bldg 10, Bethesda, MD 20892 USA. EM melenhoj@nhibi.nih.gov; priced6@cardiff.ac.uk RI Chattopadhyay, Pratip/B-9227-2008; Scheinberg, Phillip/H-5251-2012; Ladell, Kristin/K-2475-2013; Price, David/C-7876-2013; Ladell, Kristin/C-8301-2013; OI Price, David/0000-0001-9416-2737; Ladell, Kristin/0000-0002-9856-2938; Scheinberg, Phillip/0000-0002-9047-4538; Chattopadhyay, Pratip/0000-0002-5457-9666 FU NIH; Vaccine Research Center; National Institute of Allergy and Infectious Diseases; NHLBI FX This work was supported by the Intramural Research Program of the NIH, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, and the NHLBI. D.A.P. is a Medical Research Council (UK) Senior Clinical Fellow. NR 43 TC 49 Z9 49 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 MAR 5 PY 2009 VL 113 IS 10 BP 2238 EP 2244 DI 10.1182/blood-2008-04-151969 PG 7 WC Hematology SC Hematology GA 415EZ UT WOS:000263918400016 PM 18997173 ER PT J AU Rezvani, K Yong, ASM Tawab, A Jafarpour, B Eniafe, R Mielke, S Savani, BN Keyvanfar, K Li, YX Kurlander, R Barrett, AJ AF Rezvani, Katayoun Yong, Agnes S. M. Tawab, Abdul Jafarpour, Behnam Eniafe, Rhoda Mielke, Stephan Savani, Bipin N. Keyvanfar, Keyvan Li, Yixin Kurlander, Roger Barrett, A. John TI Ex vivo characterization of polyclonal memory CD8(+) T-cell responses to PRAME-specific peptides in patients with acute lymphoblastic leukemia and acute and chronic myeloid leukemia SO BLOOD LA English DT Article ID CHRONIC MYELOGENOUS LEUKEMIA; TUMOR-ASSOCIATED ANTIGENS; MINIMAL RESIDUAL DISEASE; GLUTAMIC-ACID DECARBOXYLASE; CYTOKINE FLOW-CYTOMETRY; HEPATITIS-C VIRUS; GENE-EXPRESSION; MULTIPLE-MYELOMA; DENDRITIC CELLS; WT1 PEPTIDE AB Preferentially expressed antigen of melanoma (PRAME) is aberrantly expressed in hematologic malignancies and may be a useful target for immunotherapy in leukemia. To determine whether PRAME is naturally immunogenic, we studied CD8(+) T-cell responses to 4 HLA-A*0201-restricted PRAME-derived epitopes (PRA100, PRA142, PRA300, PRA425) in HLA-A*0201-positive patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and healthy donors. CD8(+) T-cells recognizing PRAME peptides could be detected ex vivo in 4 of 10 ALL, 6 of 10 AML, 3 of 10 CML patients, and 3 of 10 donors by HLA-A2 tetramer analysis and flow cytometry for intracellular interferon-gamma. The frequency of PRAME-specific CD8(+) T cells was greater in patients with AML, CML, and ALL than healthy controls. All peptides were immunogenic in patients, while responses were only detected to PRA300 in donors. High PRAME expression in patient peripheral blood mononuclear cells was associated with responses to greater than or equal to 2 PRAME epitopes compared with low PRAME expression levels (4/7 vs 0/23, P = .001), suggesting a PRAME-driven T-cell response. PRAME-specific T cells were readily expanded in short-term cultures in donors and patients. These results provide evidence for spontaneous T cell reactivity against multiple epitopes of PRAME in ALL, AML, and CML. The potential for developing PRAME as a target for immunotherapy in leukemia deserves further exploration. (Blood. 2009; 113: 2245-2255) C1 [Rezvani, Katayoun] Univ London Imperial Coll Sci Technol & Med, Dept Hematol, London W12 0NN, England. [Rezvani, Katayoun; Yong, Agnes S. M.; Jafarpour, Behnam; Eniafe, Rhoda; Mielke, Stephan; Savani, Bipin N.; Keyvanfar, Keyvan; Barrett, A. John] NHLBI, Stem Cell Allotransplantat Sect, Hematol Branch, Bethesda, MD 20892 USA. [Tawab, Abdul; Li, Yixin; Kurlander, Roger] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Mielke, Stephan] Univ Wurzburg, Med Ctr, Dept Internal Med 2, Div Hematol & Oncol, Wurzburg, Germany. [Savani, Bipin N.] Vanderbilt Univ, Dept Med, Nashville, TN USA. RP Rezvani, K (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Hematol, Hammersmith Campus,4th Floor Commonwealth Bldg,Du, London W12 0NN, England. EM k.rezvani@imperial.ac.uk FU Kay Kendall Leukemia Fund [KKL 314] FX We thank Mrs Faith Williams for her technical assistance in the presentation of figures. K. R. acknowledges the support of the National Institute for Health Research (NIHR) Biomedical Research Center.; This work was supported in part by the Kay Kendall Leukemia Fund (grant no. KKL 314). NR 57 TC 64 Z9 71 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 MAR 5 PY 2009 VL 113 IS 10 BP 2245 EP 2255 DI 10.1182/blood-2008-03-144071 PG 11 WC Hematology SC Hematology GA 415EZ UT WOS:000263918400017 PM 18988867 ER PT J AU O'Shea, D O'Riain, C Gupta, M Waters, R Yang, Y Wrench, D Gribben, J Rosenwald, A Ott, G Rimsza, LM Holte, H Cazier, JB Johnson, NA Campo, E Chan, WC Gascoyne, RD Young, BD Staudt, LM Lister, TA Fitzgibbon, J AF O'Shea, Derville O'Riain, Ciaran Gupta, Manu Waters, Rachel Yang, Youwen Wrench, David Gribben, John Rosenwald, Andreas Ott, German Rimsza, Lisa M. Holte, Harald Cazier, Jean-Baptiste Johnson, Nathalie A. Campo, Elias Chan, Wing C. Gascoyne, Randy D. Young, Bryan D. Staudt, Louis M. Lister, T. Andrew Fitzgibbon, Jude TI Regions of acquired uniparental disomy at diagnosis of follicular lymphoma are associated with both overall survival and risk of transformation SO BLOOD LA English DT Article ID GENE-EXPRESSION; COPY NUMBER; REVEALS; EVOLUTION; CELLS; ARRAY AB Acquired homozygosity in the form of segmental acquired uniparental disomy (aUPD) has been described in follicular lymphoma (FL) and is usually due to mitotic recombination. SNP array analysis was performed with the use of the Affymetrix 10K 2.0 Gene-chip array on DNA from 185 diagnostic FL patients to assess the prognostic relevance of aUPD. Genetic abnormalities were detected in 118 (65%) of 182 patients. Number of abnormalities was predictive of outcome; more than 3 abnormalities was associated with inferior overall survival (OS; P < .03). Sites of recurrent aUPD were detected on 6p (n = 25), 16p (n = 22), 12q (n = 17), 1p36 (n = 14), 10q (n = 8), and 6q (n = 8). On multivariate analysis aUPD on 1p36 correlated with shorter OS (P = .05). aUPD on 16p was predictive of transformation (P = .03) and correlated with poorer progression-free survival (P = .02). aUPD is frequent at diagnosis of FL and affects probability of disease transformation and clinical outcome. (Blood. 2009; 113: 2298-2301) C1 [O'Shea, Derville; O'Riain, Ciaran; Gupta, Manu; Yang, Youwen; Wrench, David; Gribben, John; Cazier, Jean-Baptiste; Gascoyne, Randy D.; Young, Bryan D.; Lister, T. Andrew; Fitzgibbon, Jude] Barts & London Queen Marys Sch Med & Dent, Ctr Med Oncol, London EC1M 6BQ, England. [Waters, Rachel] Univ Oxford, Ctr Stat Med, Oxford, England. [Rosenwald, Andreas; Ott, German] Univ Wurzburg, Inst Pathol, D-8700 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, Stuttgart, Germany. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Rimsza, Lisa M.] Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. [Holte, Harald] Univ Oslo, Rikshosp, Norwegian Radium Hosp, Canc Clin,Dept Oncol, N-0027 Oslo, Norway. [Cazier, Jean-Baptiste] Canc Res UK, Bioinformat & Biostat, London, England. [Johnson, Nathalie A.] British Columbia Canc Agcy, Dept Pathol, Vancouver, BC V5Z 4E6, Canada. [Johnson, Nathalie A.] British Columbia Canc Agcy, Div Med Oncol, Vancouver, BC V5Z 4E6, Canada. [Campo, Elias] Univ Barcelona, IDIBAPS, Dept Pathol, Barcelona, Spain. [Campo, Elias] Univ Barcelona, IDIBAPS, Hosp Clin, Barcelona, Spain. [Chan, Wing C.] Univ Nebraska Med Ctr, Dept Pathol & Microbiol, Omaha, NE USA. [Staudt, Louis M.] NCI, NIH, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP O'Shea, D (reprint author), Barts & London Queen Marys Sch Med & Dent, Ctr Med Oncol, London EC1M 6BQ, England. EM derville.oshea@cancer.org.uk RI Cazier, Jean-Baptiste/F-2369-2010; OI Campo, elias/0000-0001-9850-9793 FU Cancer Research UK; Medical Research Council; National Institutes of Health [5UO1CA114778] FX This work was supported by grants from Cancer Research UK, the Medical Research Council, and the National Institutes of Health (SPEC grant 5UO1CA114778). D.O. is supported by a Medical Research Council Clinical Research Fellow grant. C.O. is a Cancer Research UK Barts-Cambridge Molecular Pathology Clinical Research Fellow. NR 24 TC 45 Z9 45 U1 2 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 MAR 5 PY 2009 VL 113 IS 10 BP 2298 EP 2301 DI 10.1182/blood-2008-08-174953 PG 4 WC Hematology SC Hematology GA 415EZ UT WOS:000263918400023 PM 19141865 ER PT J AU Toleno, DM Renaud, G Wolfsberg, TG Islam, M Wildman, DE Siegmund, KD Hacia, JG AF Toleno, Donna M. Renaud, Gabriel Wolfsberg, Tyra G. Islam, Munirul Wildman, Derek E. Siegmund, Kimberly D. Hacia, Joseph G. TI Development and evaluation of new mask protocols for gene expression profiling in humans and chimpanzees SO BMC BIOINFORMATICS LA English DT Article ID DENSITY OLIGONUCLEOTIDE ARRAYS; PROBE LEVEL DATA; HUMAN GENOME; DIFFERENT GENERATIONS; PHYLOGENETIC ANALYSIS; AFFYMETRIX ARRAYS; OPEN SOFTWARE; MICROARRAY; SEQUENCE; PATTERNS AB Background: Cross-species gene expression analyses using oligonucleotide microarrays designed to evaluate a single species can provide spurious results due to mismatches between the interrogated transcriptome and arrayed probes. Based on the most recent human and chimpanzee genome assemblies, we developed updated and accessible probe masking methods that allow human Affymetrix oligonucleotide microarrays to be used for robust genome-wide expression analyses in both species. In this process, only data from oligonucleotide probes predicted to have robust hybridization sensitivity and specificity for both transcriptomes are retained for analysis. Results: To characterize the utility of this resource, we applied our mask protocols to existing expression data from brains, livers, hearts, testes, and kidneys derived from both species and determined the effects probe numbers have on expression scores of specific transcripts. In all five tissues, probe sets with decreasing numbers of probes showed non-linear trends towards increased variation in expression scores. The relationships between expression variation and probe number in brain data closely matched those observed in simulated expression data sets subjected to random probe masking. However, there is evidence that additional factors affect the observed relationships between gene expression scores and probe number in tissues such as liver and kidney. In parallel, we observed that decreasing the number of probes within probe sets lead to linear increases in both gained and lost inferences of differential cross-species expression in all five tissues, which will affect the interpretation of expression data subject to masking. Conclusion: We introduce a readily implemented and updated resource for human and chimpanzee transcriptome analysis through a commonly used microarray platform. Based on empirical observations derived from the analysis of five distinct data sets, we provide novel guidelines for the interpretation of masked data that take the number of probes present in a given probe set into consideration. These guidelines are applicable to other customized applications that involve masking data from specific subsets of probes. C1 [Toleno, Donna M.; Hacia, Joseph G.] Univ So Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90089 USA. [Renaud, Gabriel; Wolfsberg, Tyra G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Islam, Munirul; Wildman, Derek E.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Siegmund, Kimberly D.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. RP Hacia, JG (reprint author), Univ So Calif, Dept Biochem & Mol Biol, Los Angeles, CA 90089 USA. EM dtoleno@gmail.com; renaudg@mail.nih.gov; tw62w@nih.gov; mislam@med.wayne.edu; dwildman@med.wayne.edu; kims@usc.edu; hacia@usc.edu FU National Institutes of Health [GM072447, DE012711-09S1]; National Human Genome Research Institute, National Institutes of Health; National Center for Research Resources, National Institutes of Health [C06 RR10600-01, CA62528-01, RR14514-01] FX We thank Yoav Gilad at the University of Chicago, James MacDonald and Monica Uddin at the University of Michigan for thoughtful advice and discussion. We thank Dr. Patricia Dranchak, Mallory Gerace, and Timothy Triche, Jr. at the University of Southern California for critical reading and thoughtful discussion. Computation for the work described in this paper was supported by the University of Southern California Center for High-Performance Computing and Communications http://www.usc.edu/ hpcc. This research was supported by grants from the National Institutes of Health (GM072447 and DE012711-09S1 to J.G.H.). In addition, this research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 (RR10600-01, CA62528-01, RR14514-01) from the National Center for Research Resources, National Institutes of Health. NR 60 TC 6 Z9 7 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAR 5 PY 2009 VL 10 AR 77 DI 10.1186/1471-2105-10-77 PG 12 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 427GE UT WOS:000264767000001 PM 19265541 ER PT J AU Gross, KL Lu, NZ Cidlowski, JA AF Gross, Katherine L. Lu, Nick Z. Cidlowski, John A. TI Molecular mechanisms regulating glucocorticoid sensitivity and resistance SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 13th Conference on the Adrenal Cortex CY JUN 11-14, 2008 CL Burlingame, CA DE Glucocorticoid receptor; Glucocorticoid resistance; Hematological malignancy; Alternative initiation of translation ID ACUTE LYMPHOBLASTIC-LEUKEMIA; RECEPTOR MESSENGER-RNA; ACUTE LYMPHOCYTIC-LEUKEMIA; GENITAL SKIN FIBROBLASTS; BODY-MASS INDEX; ANDROGEN RECEPTOR; DOWN-REGULATION; IN-VIVO; INDUCED APOPTOSIS; SQUIRREL-MONKEY AB Glucocorticoid receptor agonists are mainstays in the treatment of various malignancies of hematological origin. Glucocorticoids are included in therapeutic regimens for their ability to stimulate intracellular signal transduction cascades that culminate in alterations in the rate of transcription of genes involved in cell cycle progression and programmed cell death. Unfortunately, subpopulations of patients undergoing systemic glucocorticoid therapy for these diseases are or become insensitive to glucocorticoid-induced cell death, a phenomenon recognized as glucocorticoid resistance. Multiple factors contributing to glucocorticoid resistance have been identified. Here we summarize several of these mechanisms and describe the processes involved in generating a host of glucocorticoid receptor isoforms from one gene, The potential role of glucocorticoid receptor isoforms in determining cellular responsiveness to glucocorticoids is (C) emphasized. 2008 Published by Elsevier Ireland Ltd. C1 [Gross, Katherine L.; Lu, Nick Z.; Cidlowski, John A.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233,MD F3-07, Res Triangle Pk, NC 27709 USA. EM cidlows1@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999, Z01 ES090057-12]; NHLBI NIH HHS [R01 HL094558] NR 162 TC 107 Z9 109 U1 2 U2 11 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAR 5 PY 2009 VL 300 IS 1-2 BP 7 EP 16 DI 10.1016/j.mce.2008.10.001 PG 10 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 416WO UT WOS:000264036400003 PM 19000736 ER PT J AU Krug, AW Langbein, H Ziegler, CG Bornstein, SR Eisenhofer, G Ehrhart-Bornstein, M AF Krug, Alexander W. Langbein, Heike Ziegler, Christian G. Bornstein, Stefan R. Eisenhofer, Graeme Ehrhart-Bornstein, Monika TI Dehydroepiandrosterone-sulphate (DHEA-S) promotes neuroendocrine differentiation of chromaffin pheochromocytoma PC12 cells SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 13th Conference on the Adrenal Cortex CY JUN 11-14, 2008 CL Burlingame, CA DE Dehydroepiandrosterone-sulfate (DHEA-S); Nerve growth factor (NGF); Pheochromocytoma PC12 cells; Mitogen-activated protein kinases ERK1/2 ID NERVE GROWTH-FACTOR; NEURONAL DIFFERENTIATION; 21-HYDROXYLASE-DEFICIENT MICE; SYMPATHOADRENAL PROGENITORS; ADRENAL-GLAND; EXPRESSION; LINE; PROLIFERATION; SECRETION; PHENOTYPE AB The major source for dehydroepiandrosterone (DHEA) and its sulphate compound DHEA-S is the inner zone of the adrenal cortex, which is in direct contact to adrenomedullary chromaffin cells. Due to their close proximity, direct interactions of DHEA and DHEA-S with chromaffin cells during adrenal gland development and throughout the whole life span are hypothesized. A possible direct effect of DHEAS and the cellular and molecular mechanisms of DHEA-S action on chromaffin cells remain unresolved. Therefore, in this study, we aimed at clarifying DHEA-S effects and mechanisms of action on rat chromaffin PC12 cells. DHEA-S (10(-6) mol/l) inhibited nerve growth factor (NGF, 20ng/ml)-induced cell proliferation by 66% (n=4, p<0.001). In NGF-stimulated cells, neuronal differentiation was inhibited by DHEA-S, as demonstrated by a 22% reduction (n=3; p<0.05) of neuronal differentiation marker expression, synaptosome-associated protein of 25 kDa (SNAP-25), and a 59% (n = 6; p<0.001) decrease in neurite outgrowth. Moreover, DHEA-S stimulated expression of endocrine marker chromogranin A (CgA) by 31% (n=4; p<0.05 vs. control) and catecholamine release from NGF-treated PC12 cells by 229% (n=3-5: p<0.001), indicating a DHEA-S-induced shift towards neuroendocrine differentiation. On a molecular level, DHEA-S diminished NGF-induced ERK1/2 phosphorylation. Taken together, DHEA-S inhibited NGF-induced proliferation and neuronal differentiation and shifted cells towards a more endocrine phenotype. Interference of DHEA-S with NGF-stimulated ERK1/2 activation might be involved in this effect. Our study provides support for the notion that adrenocortical-derived DHEA-S impacts adrenomedullary chromaffin cells during development and differentiation. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Krug, Alexander W.; Langbein, Heike; Ziegler, Christian G.; Bornstein, Stefan R.; Eisenhofer, Graeme; Ehrhart-Bornstein, Monika] Univ Dresden, Carl Gustav Carus Univ Hosp, Med Clin 3, Dresden, Germany. RP Krug, AW (reprint author), NIA, NIH, Gerontol Res Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM krugaw@mail.nih.gov NR 50 TC 9 Z9 9 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAR 5 PY 2009 VL 300 IS 1-2 BP 126 EP 131 DI 10.1016/j.mce.2008.10.026 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 416WO UT WOS:000264036400021 PM 19022340 ER PT J AU Stratakis, CA AF Stratakis, Constantine A. TI New genes and/or molecular pathways associated with adrenal hyperplasias and related adrenocortical tumors SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 13th Conference on the Adrenal Cortex CY JUN 11-14, 2008 CL Burlingame, CA DE Phosphodiesterases; Multiple endocrine neoplasia; Carney triad; Carney-Stratakis syndrome; Fumarate hydratase ID GASTROINTESTINAL STROMAL TUMORS; CARNEY COMPLEX; PHOSPHODIESTERASE 11A; GERMLINE MUTATIONS; CUSHING-SYNDROME; CANDIDATE GENES; PRKAR1A GENE; EXPRESSION; DISEASE; PDE11A AB Over the course of the last 10 years, we have studied the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are developmental, hereditary and associated with adrenal hypoplasia or hyperplasia, multiple tumors and abnormalities in other endocrine glands. On the basis of this work, we propose an hypothesis on how adrenocortical tumors form and the importance of the cyclic AMP-dependent signaling pathway in this process. The regulatory subunit type 1-alpha(R1 alpha) of protein kinase A (PKA) (the PRKAR1A gene) is mutated in most patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD). Phosphodiesterase-11A (the PDE11A gene) and -8B (the PDE8B gene) mutations were found in patients with isolated adrenal hyperplasia and Cushing syndrome, as well in patients with PPNAD. PKA effects on tumor suppression and/or development and the cell cycle are becoming clear: PICA and/or CAMP act as a coordinator of growth and proliferation in the adrenal cortex. Mouse models in which the respective genes have been knocked out see m to support this notion. Genome-wide searches for other genes responsible for adrenal tumors and related diseases are ongoing; recent evidece of the involvement of the mitochondrial oxidation pathway in adrenocortical tumorigenesis is derived from our study of rare associations such as those of disorders predisposing to adrenomedullary and related tumors (Carney triad, the dyad of paragangliomas and gastric stromal sarcomas or Carney-Stratakis syndrome, hereditary leiomyomatosis and renal cancer syndrome) which appear to be associated with adrenocortical lesions. Published by Elsevier Ireland Ltd. C1 Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, PDEGEN, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, PDEGEN, NIH, Bldg 10,CRC,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural NIH HHS [Z01 HD000642-10]; NICHD NIH HHS [Z01 HD000642] NR 29 TC 30 Z9 32 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAR 5 PY 2009 VL 300 IS 1-2 BP 152 EP 157 DI 10.1016/j.mce.2008.11.010 PG 6 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 416WO UT WOS:000264036400025 PM 19063937 ER PT J AU Bidere, N Ngo, VN Lee, J Collins, C Zheng, LX Wan, FY Davis, RE Lenz, G Anderson, DE Arnoult, D Vazquez, A Sakai, K Zhang, J Meng, ZJ Veenstra, TD Staudt, LM Lenardo, MJ AF Bidere, Nicolas Ngo, Vu N. Lee, Jeansun Collins, Cailin Zheng, Lixin Wan, Fengyi Davis, R. Eric Lenz, Georg Anderson, D. Eric Arnoult, Damien Vazquez, Aime Sakai, Keiko Zhang, Jun Meng, Zhaojing Veenstra, Timothy D. Staudt, Louis M. Lenardo, Michael J. TI Casein kinase 1 alpha governs antigen-receptor-induced NF-kappa B activation and human lymphoma cell survival SO NATURE LA English DT Article ID T-CELL; CARMA1; REQUIREMENT; PHOSPHORYLATION; BETA; WNT; UBIQUITINATION; PROLIFERATION; ADDICTION; REGULATOR AB The transcription factor NF-kappa B is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types(1,2). Antigen receptor stimulation assembles an NF-kappa B activating platform containing the scaffold protein CARMA1 (also called CARD11), the adaptor BCL10 and the paracaspase MALT1 (the CBM complex), linked to the inhibitor of NF-kappa B kinase complex(3-12), but signal transduction is not fully understood(1). We conducted parallel screens involving a mass spectrometry analysis of CARMA1 binding partners and an RNA interference screen for growth inhibition of the CBM-dependent 'activated B-cell-like' (ABC) subtype of diffuse large B-cell lymphoma (DLBCL)(12). Here we report that both screens identified casein kinase 1 alpha (CK1 alpha) as a bifunctional regulator of NF-kappa B. CK1 alpha dynamically associates with the CBM complex on T-cell-receptor (TCR) engagement to participate in cytokine production and lymphocyte proliferation. However, CK1 alpha kinase activity has a contrasting role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1 alpha has thus a dual 'gating' function which first promotes and then terminates receptor-induced NF-kappa B. ABCDLBCL cells required CK1 alpha for constitutive NF-kappa B activity, indicating that CK1 alpha functions as a conditionally essential malignancy gene-a member of a new class of potential cancer therapeutic targets. C1 [Bidere, Nicolas; Lee, Jeansun; Zheng, Lixin; Wan, Fengyi; Sakai, Keiko; Zhang, Jun; Lenardo, Michael J.] NIAID, Mol Dev Sect, Immunol Lab, Bethesda, MD 20892 USA. [Ngo, Vu N.; Collins, Cailin; Davis, R. Eric; Lenz, Georg; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Anderson, D. Eric] NIDDK, Proteom & Mass Spectrometry Facil, NIH, Bethesda, MD 20892 USA. [Arnoult, Damien; Vazquez, Aime] Univ Paris Sud, Hop Paul Brousse, INSERM, U542, F-94800 Villejuif, France. [Meng, Zhaojing; Veenstra, Timothy D.] NCI, LPAT, Frederick, MD 21702 USA. RP Lenardo, MJ (reprint author), NIAID, Mol Dev Sect, Immunol Lab, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov; lenardo@nih.gov RI Lenz, Georg/I-6844-2012; sakai, Keiko/F-5807-2013; bidere, nicolas/K-8887-2015 OI bidere, nicolas/0000-0001-9177-0008 FU Intramural Research Program of the NIH; NIAID; NCI; NIDDK; Agence Nationale de la Recherche (ANR) FX This work was supported by the Intramural Research Program of the NIH, NIAID, NCI, NIDDK and by the Agence Nationale de la Recherche (ANR). We thank M.-T. Auffredou for technical assistance; X. Lin and J. Gavard for reagents; R. Germain, R. Schwartz, U. Siebenlist, P. Schwartzberg, J. Bosco de Oliveira, L. Yu, D. Baltimore, P. Sharp, H. Varmus and A. Snow for discussions and comments; and S. Porcella and the DNA sequencing core facility of the Rocky Mountain Laboratories, NIAID. NR 31 TC 74 Z9 88 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 5 PY 2009 VL 458 IS 7234 BP 92 EP U7 DI 10.1038/nature07613 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 414AJ UT WOS:000263836000039 PM 19118383 ER PT J AU Gladwin, MT Kato, GJ Vichinsky, E AF Gladwin, Mark T. Kato, Gregory J. Vichinsky, Elliott TI Pulmonary Complications of Sickle Cell Disease - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Gladwin, Mark T.] Univ Pittsburgh, Pittsburgh, PA 15213 USA. [Kato, Gregory J.] NIH, Bethesda, MD 20892 USA. [Vichinsky, Elliott] Childrens Hosp, Oakland, CA 94609 USA. [Vichinsky, Elliott] Res Ctr, Oakland, CA 94609 USA. RP Gladwin, MT (reprint author), Univ Pittsburgh, Pittsburgh, PA 15213 USA. EM gladwinmt@upmc.edu RI Vichinsky, Elliott/F-8541-2011; Kato, Gregory/I-7615-2014 OI Vichinsky, Elliott/0000-0002-0500-9579; Kato, Gregory/0000-0003-4465-3217 NR 2 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 5 PY 2009 VL 360 IS 10 BP 1044 EP 1045 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 413WX UT WOS:000263824500031 ER PT J AU Keffer, JL Plaza, A Bewley, CA AF Keffer, Jessica L. Plaza, Alberto Bewley, Carole A. TI Motualevic Acids A-F, Antimicrobial Acids from the Sponge Siliquariaspongia sp. SO ORGANIC LETTERS LA English DT Article ID DYSIDEA-FRAGILIS; XESTOSPONGIA SP; FATTY-ACIDS; MARINE; AZACYCLOPROPENE; DEPSIPEPTIDES; BIOSYNTHESIS; AZIRINOMYCIN; CHALLENGES; DRUGS AB Seven new antibacterials, motualevic acids A-F (1-6) and (4E)-(R)-antazirine (7), have been isolated from the marine sponge Siliquariaspongia sp. and their structures elucidated by spectroscopic methods. Motualevic acids A-D are the first glycyl conjugates of the omega-brominated lipid (E)-14,14-dibromotetradeca-2,13-dienoic acid, and motualevic acid F Is the first long-chain 2H-azirine 2-carboxylic acid to be found in nature. Carboxylic acid-containing compounds 1 and 6 inhibit the growth of Staphylococcus aureus and methicillin-resistant S. aureus at 1.2-10.9 mu g/mL. C1 [Keffer, Jessica L.; Plaza, Alberto; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov OI Keffer, Jessica/0000-0002-0302-3588 FU NIH Intramural Research Program (NIDDK); Intramural AIDS Targeted Antiviral Program, Office of the Director, NIH FX We thank the Coral Reef Research Foundation, David Newman (NCI), and the country of Fiji for sample acquisition, John R. Lloyd (NIDDK) for HRMS measurements, and Michelle Kelly and the National Cancer Institute for sponge taxonomy. This work was supported in part by the NIH Intramural Research Program (NIDDK) and the Intramural AIDS Targeted Antiviral Program, Office of the Director, NIH (C.A.B.). NR 22 TC 24 Z9 24 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD MAR 5 PY 2009 VL 11 IS 5 BP 1087 EP 1090 DI 10.1021/ol802890b PG 4 WC Chemistry, Organic SC Chemistry GA 413ER UT WOS:000263776200012 PM 19191563 ER PT J AU Ahn, B Lee, JW Jung, H Beck, G Bohr, VA AF Ahn, Byungchan Lee, Jae Wan Jung, Hana Beck, Gad Bohr, Vilhelm A. TI Mechanism of Werner DNA Helicase: POT1 and RPA Stimulates WRN to Unwind beyond Gaps in the Translocating Strand SO PLOS ONE LA English DT Article AB WRN belongs to the RecQ family of DNA helicases and it plays a role in recombination, replication, telomere maintenance and long-patch base excision repair. Here, we demonstrate that WRN efficiently unwinds DNA substrates containing a 1-nucleotide gap in the translocating DNA strand, but when the gap size is increased to 3-nucleotides unwinding activity significantly declines. In contrast, E. coli UvrD (3'-> 5' helicase), which recognizes nicks in DNA to initiate unwinding, does not unwind past a 1-nucleotide gap. This unique ability of WRN to bypass gaps supports its involvement in DNA replication and LP-BER where such gaps can be produced by glycosylases and the apurinic/apyrimidinic endonuclease 1 (APE1). Furthermore, we tested telomere repeat binding factor 2 (TRF2), both variants 1 and 2 of protector of telomeres 1 (POT1v1 and POT1v2) and RPA on telomeric DNA substrates containing much bigger gaps than 3-nucleotides in order to determine whether unwinding could be facilitated through WRN-protein interaction. Interestingly, POT1v1 and RPA are capable of stimulating WRN helicase on gapped DNA and 5'-overhang substrates, respectively. C1 [Ahn, Byungchan; Jung, Hana; Beck, Gad] Univ Ulsan, Dept Life Sci, Ulsan 680749, South Korea. [Lee, Jae Wan; Bohr, Vilhelm A.] NIA, NIH, Biomed Res Ctr, Lab Mol Gerontol, Baltimore, MD USA. RP Ahn, B (reprint author), Univ Ulsan, Dept Life Sci, Ulsan 680749, South Korea. EM bohrv@grc.nia.nih.gov FU Intramural Research Program of the National Institute of Health, National Institute on Aging; Korean Government (MOEHRD) [KRF-2008-521-C00211]; Basic Research Promotion Fund [KRF-2008-412-J00303] FX This research was supported by the Intramural Research Program of the National Institute of Health, National Institute on Aging (to V.A.B). This work was supported by the Brain Korea 21 Project in 2008 from KRF, a Korea Research Foundation Grant of the Korean Government (MOEHRD) (KRF-2008-521-C00211), and the Basic Research Promotion Fund (KRF-2008-412-J00303) (to B.A.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 6 Z9 6 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 5 PY 2009 VL 4 IS 3 AR e4673 DI 10.1371/journal.pone.0004673 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437MC UT WOS:000265490600006 PM 19262689 ER PT J AU Berger, K Lindh, R Wierup, N Zmuda-Trzebiatowska, E Lindqvist, A Manganiello, VC Degerman, E AF Berger, Karin Lindh, Rebecka Wierup, Nils Zmuda-Trzebiatowska, Emilia Lindqvist, Andreas Manganiello, Vincent C. Degerman, Eva TI Phosphodiesterase 3B Is Localized in Caveolae and Smooth ER in Mouse Hepatocytes and Is Important in the Regulation of Glucose and Lipid Metabolism SO PLOS ONE LA English DT Article AB Cyclic nucleotide phosphodiesterases (PDEs) are important regulators of signal transduction processes mediated by cAMP and cGMP. One PDE family member, PDE3B, plays an important role in the regulation of a variety of metabolic processes such as lipolysis and insulin secretion. In this study, the cellular localization and the role of PDE3B in the regulation of triglyceride, cholesterol and glucose metabolism in hepatocytes were investigated. PDE3B was identified in caveolae, specific regions in the plasma membrane, and smooth endoplasmic reticulum. In caveolin-1 knock out mice, which lack caveolae, the amount of PDE3B protein and activity were reduced indicating a role of caveolin-1/caveolae in the stabilization of enzyme protein. Hepatocytes from PDE3B knock out mice displayed increased glucose, triglyceride and cholesterol levels, which was associated with increased expression of gluconeogenic and lipogenic genes/enzymes including, phosphoenolpyruvate carboxykinase, peroxisome proliferator-activated receptor c, sterol regulatory element-binding protein 1c and hydroxyl-3-methylglutaryl coenzyme A reductase. In conclusion, hepatocyte PDE3B is localized in caveolae and smooth endoplasmic reticulum and plays important roles in the regulation of glucose, triglyceride and cholesterol metabolism. Dysregulation of PDE3B could have a role in the development of fatty liver, a condition highly relevant in the context of type 2 diabetes. C1 [Berger, Karin; Lindh, Rebecka; Zmuda-Trzebiatowska, Emilia; Degerman, Eva] Lund Univ, Dept Expt Med Sci, Lund, Sweden. [Wierup, Nils; Lindqvist, Andreas] Lund Univ, Dept Expt Med Sci, BMC B11, Lund, Sweden. [Zmuda-Trzebiatowska, Emilia; Manganiello, Vincent C.] NHLBI, NIH, Translat Med Branch, Bethesda, MD USA. RP Berger, K (reprint author), Lund Univ, Dept Expt Med Sci, BMC C11, Lund, Sweden. EM karin.berger@med.lu.se FU Swedish Research Council; Lund University Diabetes Center (LUDC); Swedish Diabetes Association; Novo Nordisk, Denmark; The Swedish Society of Medicine FX This work was supported by the Swedish Research Council Project 3362 to E.D; K.B. was supported by Lund University Diabetes Center (LUDC); Grants were obtained from the following foundations: Swedish Diabetes Association; Novo Nordisk, Denmark; The Swedish Society of Medicine, Dr. P. Hakansson, Albert Pahlsson, Fredrik och Ingrid Thuring, Wiberg, Lars Hierta, Ahlan, Tore Nilsson and Magn. Bergvall. The funding agencies did not take any part in the design and conduct of the study, in the collection, analysis, and interpretation of the data, or in the preparation, review, or approval of the manuscript. NR 37 TC 13 Z9 13 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 5 PY 2009 VL 4 IS 3 AR e4671 DI 10.1371/journal.pone.0004671 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437MC UT WOS:000265490600004 PM 19262749 ER PT J AU Fatakia, SN Costanzi, S Chow, CC AF Fatakia, Sarosh N. Costanzi, Stefano Chow, Carson C. TI Computing Highly Correlated Positions Using Mutual Information and Graph Theory for G Protein-Coupled Receptors SO PLOS ONE LA English DT Article ID SPECIFICITY-DETERMINING RESIDUES; 2ND EXTRACELLULAR LOOP; MULTIPLE SEQUENCE ALIGNMENTS; STIMULATING HORMONE-RECEPTOR; A(2A) ADENOSINE RECEPTOR; AMINO-ACID SUBSTITUTIONS; HUMAN CA2+ RECEPTOR; CRYSTAL-STRUCTURE; LIGAND RECOGNITION; BINDING-SITE AB G protein-coupled receptors (GPCRs) are a superfamily of seven transmembrane-spanning proteins involved in a wide array of physiological functions and are the most common targets of pharmaceuticals. This study aims to identify a cohort or clique of positions that share high mutual information. Using a multiple sequence alignment of the transmembrane (TM) domains, we calculated the mutual information between all inter-TM pairs of aligned positions and ranked the pairs by mutual information. A mutual information graph was constructed with vertices that corresponded to TM positions and edges between vertices were drawn if the mutual information exceeded a threshold of statistical significance. Positions with high degree (i.e. had significant mutual information with a large number of other positions) were found to line a well defined inter-TM ligand binding cavity for class A as well as class C GPCRs. Although the natural ligands of class C receptors bind to their extracellular N-terminal domains, the possibility of modulating their activity through ligands that bind to their helical bundle has been reported. Such positions were not found for class B GPCRs, in agreement with the observation that there are not known ligands that bind within their TM helical bundle. All identified key positions formed a clique within the MI graph of interest. For a subset of class A receptors we also considered the alignment of a portion of the second extracellular loop, and found that the two positions adjacent to the conserved Cys that bridges the loop with the TM3 qualified as key positions. Our algorithm may be useful for localizing topologically conserved regions in other protein families. C1 [Fatakia, Sarosh N.; Costanzi, Stefano; Chow, Carson C.] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Fatakia, SN (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM carsonc@mail.nih.gov RI Chow, Carson/A-7970-2009; Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332; Fatakia, Sarosh/0000-0003-0430-3191 FU NIDDK/NIH FX This work was supported by the Intramural program of NIDDK/NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 126 TC 16 Z9 16 U1 2 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 5 PY 2009 VL 4 IS 3 AR e4681 DI 10.1371/journal.pone.0004681 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 437MC UT WOS:000265490600012 PM 19262747 ER PT J AU Vijayan, R Plested, AJR Mayer, ML Biggin, PC AF Vijayan, Ranjit Plested, Andrew J. R. Mayer, Mark L. Biggin, Philip C. TI Selectivity and Cooperativity of Modulatory Ions in a Neurotransmitter Receptor SO BIOPHYSICAL JOURNAL LA English DT Article ID LIGAND-BINDING DOMAIN; MOLECULAR-DYNAMICS SIMULATIONS; IONOTROPIC GLUTAMATE-RECEPTOR; FREE-ENERGY CALCULATIONS; KAINATE RECEPTORS; SYNAPTIC-TRANSMISSION; POTASSIUM CHANNELS; AGONIST BINDING; FORCE-FIELD; SODIUM AB Ions play a modulatory role in many proteins. Kainate receptors, members of the ionotropic glutamate receptor family, require both monovalent anions and cations in the extracellular milieu for normal channel activity. Molecular dynamics simulations and extensive relative binding free energy calculations using thermodynamic integration were performed to elucidate the rank order of binding of monovalent cations, using x-ray crystal structures of the GluR5 kainate receptor dimers with bound cations from the alkali metal family. The simulations show good agreement with experiments and reveal that the underlying backbone structure of the binding site is one of the most rigid regions of the protein. A simplified model where the partial charge of coordinating oxygens was varied suggests that selectivity arises from the presence of two carboxylate groups. Furthermore, using a potential of mean force derived from umbrella sampling, we show that the presence of cations lower the energy barrier for anion approach and binding in the buried anion binding cavity. C1 [Vijayan, Ranjit; Biggin, Philip C.] Univ Oxford, Dept Biochem, Oxford OX1 3QU, England. [Vijayan, Ranjit] Univ Oxford, Life Sci Interface Doctoral Training Ctr, Oxford OX1 3QU, England. [Plested, Andrew J. R.; Mayer, Mark L.] NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Biggin, PC (reprint author), Univ Oxford, Dept Biochem, Parks Rd, Oxford OX1 3QU, England. EM philip.biggin@bioch.ox.ac.uk RI Mayer, Mark/H-5500-2013; OI Vijayan, Ranjit/0000-0002-3830-7409; Plested, Andrew/0000-0001-6062-0832 FU Intramural NIH HHS; Wellcome Trust NR 60 TC 12 Z9 13 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 EI 1542-0086 J9 BIOPHYS J JI Biophys. J. PD MAR 4 PY 2009 VL 96 IS 5 BP 1751 EP 1760 DI 10.1016/j.bpj.2008.11.039 PG 10 WC Biophysics SC Biophysics GA 450BR UT WOS:000266376500008 PM 19254535 ER PT J AU Itsko, M Rabinovitch, A Zaritsky, A AF Itsko, Mark Rabinovitch, Avinoam Zaritsky, Arieh TI Kinetics of Repeat Propagation in the Microgene Polymerization Reaction SO BIOPHYSICAL JOURNAL LA English DT Article ID TANDEM REPETITIVE DNA; ESCHERICHIA-COLI; THERMOCOCCUS-LITORALIS; HUMAN-DISEASE; CHAIN GROWTH; POLYMERASE; SEQUENCES; PROTEINS; ELONGATION; STABILITY AB Repetitive DNA is a periodic copolymer with the intrinsic property of exponential propagation to longer repeats. Microgene polymerization reaction (MPR) is a model system in which a short nonrepetitive homo-duplex DNA evolves to multiple repetitive products during heat-cool cycles. The mechanism underlying this process involves staggered annealing of complementary DNA strands of variable lengths and polymerase-mediated filling-in of the generated overhangs. MPR is considered here as a process sharing common features with two polymerization types, chain-growth and step-growth, and significant distinctions from both types were highlighted. The involved reaction stages were formulated and a kinetic model was derived and tested experimentally. The model can quantitatively explain MPR propagation and be used as a good approximation for this phenomenon. C1 [Itsko, Mark; Zaritsky, Arieh] Ben Gurion Univ Negev, Dept Life Sci, IL-84105 Beer Sheva, Israel. [Rabinovitch, Avinoam] Ben Gurion Univ Negev, Dept Phys, IL-84105 Beer Sheva, Israel. RP Itsko, M (reprint author), NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM itskom@niehs.nih.gov RI Zaritsky, Arieh/K-2578-2012 OI Zaritsky, Arieh/0000-0001-9333-6854 NR 31 TC 2 Z9 2 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAR 4 PY 2009 VL 96 IS 5 BP 1866 EP 1874 DI 10.1016/j.bpj.2008.10.061 PG 9 WC Biophysics SC Biophysics GA 450BR UT WOS:000266376500018 PM 19254545 ER PT J AU Fernandez, C Minton, AP AF Fernandez, Cristina Minton, Allen P. TI Static Light Scattering From Concentrated Protein Solutions II: Experimental Test of Theory for Protein Mixtures and Weakly Self-Associating Proteins SO BIOPHYSICAL JOURNAL LA English DT Article ID BOVINE SERUM-ALBUMIN; HARD PARTICLE MODEL; SEDIMENTATION EQUILIBRIUM; OSMOTIC-PRESSURE; QUANTITATIVE CHARACTERIZATION; PHYSIOLOGICAL CONSEQUENCES; CONCENTRATION FORMULATIONS; ALPHA-CHYMOTRYPSIN; PH; DEPENDENCE AB Using an experimental technique recently developed in this laboratory (Fernandez C. and A. P. Minton. 2008. Anal. Biochem. 381:254-257), the Rayleigh light scattering of solutions of bovine serum albumin, hen egg white ovalbumin, hen egg white ovomucoid, and binary mixtures of these three proteins was measured as a function of concentration at concentrations up to 125 g/L. The measured concentration dependence of scattering of both pure proteins and binary mixtures is accounted for nearly quantitatively by an effective hard particle model (Minton A. P. 2007. Biophys. J. 93:1321-1328) in which each protein species is represented by an equivalent hard sphere, the size of which is determined by the nature of repulsive interactions between like molecules under a given set of experimental conditions. The light scattering of solutions of chymotrypsin A was measured as a function of concentration at concentrations up to 70 g/L at pH 4.1, 5.4, and 7.2. At each pH, the measured concentration dependence is accounted for quantitatively by an effective hard particle model, according to which monomeric protein may self-associate to form an equilibrium dimer and, depending upon pH, an equilibrium pentamer or hexamer. C1 [Fernandez, Cristina; Minton, Allen P.] NIDDK, Lab Biochem & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDK, Lab Biochem & Genet, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM minton@helix.nih.gov RI Fernandez, Cristina/G-2269-2015; OI Fernandez, Cristina/0000-0003-3792-4015; Minton, Allen/0000-0001-8459-1247 FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. National Institutes of Health. NR 36 TC 32 Z9 32 U1 2 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAR 4 PY 2009 VL 96 IS 5 BP 1992 EP 1998 DI 10.1016/j.bpj.2008.11.054 PG 7 WC Biophysics SC Biophysics GA 450BR UT WOS:000266376500032 PM 19254559 ER PT J AU DeVito, LM Konigsberg, R Lykken, C Sauvage, M Young, WS Eichenbaum, H AF DeVito, Loren M. Konigsberg, Rachael Lykken, Christine Sauvage, Magdalena Young, W. Scott, III Eichenbaum, Howard TI Vasopressin 1b Receptor Knock-Out Impairs Memory for Temporal Order SO JOURNAL OF NEUROSCIENCE LA English DT Article ID TRANSITIVE INFERENCE; AGGRESSIVE-BEHAVIOR; HIPPOCAMPUS; MICE; CA2; SCHIZOPHRENIA; RECOGNITION; OBJECT; RAT; ORGANIZATION AB Mice lacking a functional vasopressin 1b receptor (Avpr1b) display decreased levels of aggression and social memory. Here, we used Avpr1b-knock-out (Avpr1b(-/-))mice to examine whether an abnormality of this receptor results in specific cognitive deficits in the domain of hippocampal function. Avpr1b(-/-) mice were deficient in sociability and in detecting social novelty, extending previous findings of impairment in social recognition in these mutants. Avpr1b(-/-) mice could recognize previously explored objects and remember where they were experienced, but they were impaired in remembering the temporal order of presentation of those objects. Consistent with this finding, Avpr1b(-/-) mice were also impaired on an object-odor paired associate task that involved a temporal discontiguity between the associated elements. Finally, Avpr1b(-/-) mice performed normally in learning a set of overlapping odor discriminations and could infer relationships among odors that were only indirectly associated (i.e., transitive inference), indicating intact relational memory. The Avpr1b is expressed at much higher levels than any other part of the brain in the pyramidal cells of hippocampal CA2 area, a subfield of the hippocampus that has physiological and genetic properties that distinguish it from subfields CA1 and CA3. The combined results suggest that the Avpr1b, perhaps in CA2, may play a highly specific role in social behavior and episodic memory. Because schizophrenia and bipolar disorder are associated with a unique pathology in CA2 and impairments in both social behavior and episodic memory, this animal model could provide insights into the etiology of these disorders. C1 [DeVito, Loren M.; Konigsberg, Rachael; Lykken, Christine; Sauvage, Magdalena; Eichenbaum, Howard] Boston Univ, Ctr Memory & Brain, Boston, MA 02215 USA. [Young, W. Scott, III] NIMH, Sect Neural Gene Express, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Eichenbaum, H (reprint author), Boston Univ, Ctr Memory & Brain, Boston, MA 02215 USA. EM hbe@bu.edu RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 FU Conte Center for Schizophrenia Research; National Institutes of Health; National Institute of Mental Health Intramural Research Program [Z01-MH-002498-20] FX This work was supported by grants from the Conte Center for Schizophrenia Research-National Institutes of Health and by National Institute of Mental Health Intramural Research Program Grant Z01-MH-002498-20 (W.S.Y.). Thanks to Katherine O'Brien for assistance with behavioral training, Will Sauls for skilled mouse husbandry and maintenance of the breeding colony, and Emily Shepard for genotyping. We also thank Dr. Norbert Fortin for comments on this manuscript. NR 29 TC 52 Z9 53 U1 0 U2 8 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 MAR 4 PY 2009 VL 29 IS 9 BP 2676 EP 2683 DI 10.1523/JNEUROSCI.5488-08.2009 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 414SS UT WOS:000263886100003 PM 19261862 ER PT J AU Dilks, DD Baker, CI Peli, E Kanwisher, N AF Dilks, Daniel D. Baker, Chris I. Peli, Eli Kanwisher, Nancy TI Reorganization of Visual Processing in Macular Degeneration Is Not Specific to the "Preferred Retinal Locus" SO JOURNAL OF NEUROSCIENCE LA English DT Article ID SURFACE-BASED ANALYSIS; CORTICAL REORGANIZATION; ADULT CAT; CORTEX; LESIONS; SCOTOMA; MONKEY; AREA; MAPS AB Recent work has shown that foveal cortex, deprived of its normal bottom-up input as a result of macular degeneration (MD), begins responding to stimuli presented to a peripheral retinal location. However, these studies have only presented stimuli to the "preferred retinal location," or PRL, a spared part of the peripheral retina used by individuals with MD for fixating, face recognition, reading, and other visual tasks. Thus, previous research has not yet answered a question critical for understanding the mechanisms underlying this reorganization: Does formerly foveal cortex respond only to stimuli presented at the PRL, or does it also respond to other peripheral locations of similar eccentricity? If foveal cortex responds to stimuli at PRL because it is the long-term habitual use of this region as a functional fovea that drives the formerly foveal cortex to respond to stimuli presented at the PRL (the "use-dependent reorganization" hypothesis), then foveal cortex will not respond to stimuli presented at other locations. Alternatively, it may be that foveal cortex responds to any peripheral retinal input, independent of whether input at that retinal location has been chronically attended for months or years (the "use-independent reorganization" hypothesis). Using fMRI, we found clear activation of formerly foveal cortex to stimuli presented at either the PRL or an isoeccentricnon- PRL location in two individuals with MD, supporting the use-independent reorganization hypothesis. This finding suggests that reorganization is driven by passive, not use-dependent mechanisms. C1 [Dilks, Daniel D.; Kanwisher, Nancy] MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. [Baker, Chris I.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Peli, Eli] Harvard Univ, Sch Med, Schepens Eye Res Inst, Boston, MA 02114 USA. RP Dilks, DD (reprint author), MIT, McGovern Inst Brain Res, 46-4141, Cambridge, MA 02139 USA. EM dilks@mit.edu OI Baker, Chris/0000-0001-6861-8964 FU National Institutes of Health [EY016559, EY005957]; Kirschstein National Research Service Award [EY017507]; National Institute of Mental Health Intramural Research Program FX work was supported by National Institutes of Health Grants EY016559 (N.K.)and EY005957 ( E. P.), by Kirschstein National Research Service Award EY017507 ( D. D. D.), by the National Institute of Mental Health Intramural Research Program ( C. I. B.), and by Dr. Joseph Byrne and Nancy Byrne. We express our sincere thanks to the participants with macular degeneration and to Bradley Berk and Jonas Kubilius for help with data collection and analyses. We also thank the Athinoula A. Martinos Imaging Center at the McGovern Institute for Brain Research, Massachusetts Institute of Technology. NR 22 TC 52 Z9 54 U1 1 U2 9 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 MAR 4 PY 2009 VL 29 IS 9 BP 2768 EP 2773 DI 10.1523/JNEUROSCI.5258-08.2009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 414SS UT WOS:000263886100013 PM 19261872 ER PT J AU Uo, T Veenstra, TD Morrison, RS AF Uo, Takuma Veenstra, Timothy D. Morrison, Richard S. TI Histone Deacetylase Inhibitors Prevent p53-Dependent and p53-Independent Bax-Mediated Neuronal Apoptosis through Two Distinct Mechanisms SO JOURNAL OF NEUROSCIENCE LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; TRANSGENIC MOUSE MODEL; CELL-DEATH; HUNTINGTONS-DISEASE; BCL-2 FAMILY; DEPENDENT APOPTOSIS; CORTICAL-NEURONS; GENE-EXPRESSION; DNA-DAMAGE; P53 AB Pharmacological manipulation of protein acetylation levels by histone deacetylase (HDAC) inhibitors represents a novel therapeutic strategy to treat neurodegeneration as well as cancer. However, the molecular mechanisms that determine how HDAC inhibition exerts a protective effect in neurons as opposed to a cytotoxic action in tumor cells has not been elucidated. We addressed this issue in cultured postnatal mouse cortical neurons whose p53-dependent and p53-independent intrinsic apoptotic programs require the proapoptotic multidomain protein, Bax. Despite promoting nuclear p53 accumulation, Class I/II HDAC inhibitors (HDACIs) protected neurons from p53-dependent cell death induced by camptothecin, etoposide, heterologous p53 expression or the MDM2 inhibitor, nutlin-3a. HDACIs suppressed p53-dependent PUMA expression, a critical signaling intermediate linking p53 to Bax activation, thus preventing postmitochondrial events including cleavage of caspase-9 and caspase-3. In human SH-SY5Y neuroblastoma cells, however, HDACIs were not able to prevent p53-dependent cell death. Moreover, HDACIs also prevented caspase- 3 cleavage in postnatal cortical neurons treated with staurosporine,3-nitropropionic acid and a Bcl-2 inhibitor, all of which require the presence of Bax but not p53 to promote apoptosis. Although these three toxic agents displayed a requirement for Bax, they did not promote PUMA induction. These results demonstrate that HDACIs block Bax-dependent cell death by two distinct mechanisms to prevent neuronal apoptosis, thus identifying for the first time a defined molecular target for their neuroprotective actions. C1 [Uo, Takuma; Morrison, Richard S.] Univ Washington, Sch Med, Dept Neurol Surg, Seattle, WA 98195 USA. [Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Sci Applicat Int Corp Frederick Inc, Frederick, MD 21702 USA. RP Morrison, RS (reprint author), Univ Washington, Sch Med, Dept Neurol Surg, Box 356470, Seattle, WA 98195 USA. EM yael@u.washington.edu FU National Institutes of Health [NS35533, NS056031] FX This work was supported by National Institutes of Health Grants NS35533 and NS056031 to R.S.M. We acknowledge Drs. Yoshito Kinoshita and Sean P. Murphy at the University of Washington for thoughtful discussions of the data, Matthew L. Batten for technical assistance, and Bonita Lee for genotyping. Microarray analysis was performed at the Microarray Facility at the Center for Ecogenetics and Environmental Health (University of Washington). NR 53 TC 42 Z9 44 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 4 PY 2009 VL 29 IS 9 BP 2824 EP 2832 DI 10.1523/JNEUROSCI.6186-08.2009 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 414SS UT WOS:000263886100019 PM 19261878 ER PT J AU Besser, L Chorin, E Sekler, I Silverman, WF Atkin, S Russell, JT Hershfinkel, M AF Besser, Limor Chorin, Ehud Sekler, Israel Silverman, William F. Atkin, Stan Russell, James T. Hershfinkel, Michal TI Synaptically Released Zinc Triggers Metabotropic Signaling via a Zinc-Sensing Receptor in the Hippocampus SO JOURNAL OF NEUROSCIENCE LA English DT Article ID LONG-TERM POTENTIATION; PROTEIN-KINASE-II; INDUCED NEURONAL APOPTOSIS; EXTRACELLULAR ZINC; PYRAMIDAL NEURONS; REGULATED KINASE; MOUSE-BRAIN; 12-LIPOXYGENASE ACTIVATION; NEUROBLASTOMA-CELLS; GABA(A) RECEPTORS AB Zn(2+) is coreleased with glutamate from mossy fiber terminals and can influence synaptic function. Here, we demonstrate that synaptically released Zn(2+) activates a selective postsynaptic Zn(2+)-sensing receptor (ZnR) in the CA3 region of the hippocampus. ZnR activation induced intracellular release of Ca(2+), as well as phosphorylation of extracellular-regulated kinase and Ca(2+)/calmodulin kinase II. Blockade of synaptic transmission by tetrodotoxin or CdCl inhibited the ZnR-mediated Ca(2+) rises. The responses mediated by ZnR were largely attenuated by the extracellular Zn(2+) chelator, CaEDTA, and in slices from mice lacking vesicular Zn(2+), suggesting that synaptically released Zn(2+) triggers the metabotropic activity. Knockdown of the expression of the orphan G-protein-coupled receptor 39 (GPR39) attenuated ZnR activity in a neuronal cell line. Importantly, we observed widespread GPR39 labeling in CA3 neurons, suggesting a role for this receptor in mediating ZnR signaling in the hippocampus. Our results describe a unique role for synaptic Zn(2+) acting as the physiological ligand of a metabotropic receptor and provide a novel pathway by which synaptic Zn(2+) can regulate neuronal function. C1 [Hershfinkel, Michal] Ben Gurion Univ Negev, Fac Hlth Sci, Dept Morphol, IL-84105 Beer Sheva, Israel. [Sekler, Israel] Ben Gurion Univ Negev, Dept Physiol, IL-84105 Beer Sheva, Israel. [Besser, Limor; Chorin, Ehud; Sekler, Israel; Silverman, William F.; Hershfinkel, Michal] Ben Gurion Univ Negev, Zlotowski Ctr, IL-84105 Beer Sheva, Israel. [Atkin, Stan; Russell, James T.] NICHHD, Sect Cell Biol & Signal Transduct, NIH, Bethesda, MD 20892 USA. RP Hershfinkel, M (reprint author), Ben Gurion Univ Negev, Fac Hlth Sci, Dept Morphol, POB 653, IL-84105 Beer Sheva, Israel. EM hmichal@bgu.ac.il RI HERSHFINKEL, Michal/F-1548-2012 FU United States-Israel Binational Science Foundation [2003201]; Israel Science Foundation [585/05]; Astellas Pharma Inc [YM-254890] FX This work was supported by United States-Israel Binational Science Foundation Grant 2003201 (M. H., J. T. R.), a Rich Foundation grant, and Israel Science Foundation Grant 585/05 (M. H.). We thank Dr. Richard Palmiter for the ZnT3 KO mice, Dr. Meredin Stoltenberg for advice on the ZnT3 KO experiments, and Drs. Elias Aizenman and Edi Barkai for valuable discussions and critical reading of this manuscript. We thank Astellas Pharma Inc. for generously providing the G alpha q inhibitor YM-254890. NR 82 TC 96 Z9 96 U1 1 U2 13 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 MAR 4 PY 2009 VL 29 IS 9 BP 2890 EP 2901 DI 10.1523/JNEUROSCI.5093-08.2009 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 414SS UT WOS:000263886100026 PM 19261885 ER PT J AU Lauer, MS Sorlie, P AF Lauer, Michael S. Sorlie, Paul TI Alcohol, Cardiovascular Disease, and Cancer: Treat With Caution SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CORONARY-HEART-DISEASE; MORTALITY; WINE; CONSUMPTION; WOMEN; RISK C1 [Lauer, Michael S.; Sorlie, Paul] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Div Prevent & Populat Sci, 6701 Rockledge Dr,Rm 10122, Bethesda, MD 20892 USA. EM lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 16 TC 9 Z9 10 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 MAR 4 PY 2009 VL 101 IS 5 BP 282 EP 283 DI 10.1093/jnci/djp006 PG 2 WC Oncology SC Oncology GA 415UU UT WOS:000263962000004 PM 19244170 ER PT J AU Mougel, M Houzet, L Darlix, JL AF Mougel, Marylene Houzet, Laurent Darlix, Jean-Luc TI When is it time for reverse transcription to start and go? SO RETROVIROLOGY LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-1 NUCLEOCAPSID PROTEIN; MURINE LEUKEMIA-VIRUS; ROUS-SARCOMA VIRUS; DEPENDENT DNA POLYMERASE; HUMAN-ENDOGENOUS-RETROVIRUS; ACID-CHAPERONE ACTIVITY; PRIMER TRANSFER-RNA; SYNTHESIS IN-VIVO; ZINC-FINGER AB Upon cell infection by a retrovirus, the viral DNA polymerase, called reverse transcriptase (RT), copies the genomic RNA to generate the proviral DNA flanked by two long terminal repeats (LTR). A discovery twenty years ago demonstrated that the structural viral nucleocapsid protein (NC) encoded by Gag is an essential cofactor of reverse transcription, chaperoning RT during viral DNA synthesis. However, it is only recently that NC was found to exert a control on the timing of reverse transcription, in a spatio-temporal manner. This brief review summarizes findings on the timing of reverse transcription in wild type HIV-1 and in nucleopcapsid (NC) mutants where virions contain a large amount of newly made viral DNA. This brief review also proposes some explanations of how NC may control late reverse transcription during Gag assembly in virus producer cells. C1 [Darlix, Jean-Luc] ENS, IFR128, U758, INSERM,Unite Virol Humaine,LabRetro, Lyon, France. [Mougel, Marylene] Univ Montpellier 1, Ctr Etudes Agents Pathogenes & Biotechnol Sante, CNRS, UMR 5236,CPBS, F-34965 Montpellier, France. [Houzet, Laurent] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Darlix, JL (reprint author), ENS, IFR128, U758, INSERM,Unite Virol Humaine,LabRetro, 46 Allee Italie, Lyon, France. EM marylene.mougel@univ-montp1.fr; houzet1@niaid.nih.gov; jldarlix@ens-lyon.fr RI Mougel, Marylene/K-7958-2013 OI Mougel, Marylene/0000-0002-0345-1427 FU ANRS; CNRS; INSERM; Sidaction (France); NIH (USA) FX The work is supported by ANRS, CNRS, INSERM and Sidaction (France), and by the NIH (USA). Thanks are due to C. Darlix, L. Didierlaurent, Z. Morichaud and D. Muriaux for their contribution to the new results on HIV-1 NC mutants, and to M. Rau (UK) for manuscript corrections. NR 100 TC 37 Z9 39 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD MAR 4 PY 2009 VL 6 AR 24 DI 10.1186/1742-4690-6-24 PG 9 WC Virology SC Virology GA 425YA UT WOS:000264672700001 PM 19261185 ER PT J AU Sanders, JM Bucher, JR Peckham, JC Kissling, GE Hejtmancik, MR Chhabra, RS AF Sanders, J. M. Bucher, J. R. Peckham, J. C. Kissling, G. E. Hejtmancik, M. R. Chhabra, R. S. TI Carcinogenesis studies of cresols in rats and mice SO TOXICOLOGY LA English DT Article DE Carcinogenicity; Cresols; m-Cresol; p-Cresol; Forestomach papilloma; Renal tubule adenoma ID PHENOLIC-COMPOUNDS; P-CRESOL; GAS-CHROMATOGRAPHY; F344 RATS; O-CRESOL; IDENTIFICATION; COMPONENTS; QUANTIFICATION; SPECTROMETRY; INTOXICATION AB Cresols, monomethyl derivatives of phenol, are high production chemicals with potential for human exposure. The three isomeric forms of cresol are used individually or in mixtures as disinfectants, preservatives, and solvents or as intermediates in the production of antioxidants, fragrances, herbicides, insecticides, dyes, and explosives Carcinogenesis studies were conducted in groups of 50 male F344/N rats and 50 female B6C3F1 mice exposed to a 60:40 mixture of m- and p-cresols (m-/p-cresol) in feed. Rats and mice were fed diets containing 0, 1500,5000, or 15,000 ppm and 0, 1000, 3000, or 10,000 ppm, respectively. Survival of each exposed group was similar to that of their respective control group. Mean body weight gains were depressed in rats exposed to 15,000 ppm and in mice exposed to 3000 ppm and higher. A decrease of 25% over that of controls for the final mean body weight in mice exposed to 10,000 ppm appeared to be associated with lack of palatability of the feed. A marginally increased incidence of renal tubule adenoma was observed in the 15,000-ppm-exposed rats. The increased incidence was not statistically significant, but did exceed the range of historical controls. No increased incidence of hyperplasia of the renal tubules was observed; however, a significantly increased incidence of hyperplasia of the transitional epithelium associated with an increased incidence of nephropathy was observed at the high exposure concentration. The only significantly increased incidence of a neoplastic lesion related to cresol exposure observed in these studies was that of squamous cell papilloma in the forestomach of 10,000-ppm-exposed mice. A definitive association with irritation at the site-of-contact could not be made because of limited evidence of injury to the gastric mucosa at the time of necropsy. However, given the minimal chemical-related neoplastic response in these studies, it was concluded that there was no clear evidence of carcinogenicity in male rats or female mice exposed to the cresol mixture. (c) Published by Elsevier Ireland Ltd. C1 [Sanders, J. M.; Bucher, J. R.; Peckham, J. C.; Kissling, G. E.; Chhabra, R. S.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Hejtmancik, M. R.] Battelle Mem Inst, Columbus, OH 43201 USA. RP Sanders, JM (reprint author), NIEHS, Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM sander1O@niehs.nih.gov FU Intramural Research Program of the NIH; National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The authors thank Drs. June Dunnick and Michelle Hooth of the NTP for their critical review of the manuscript. NR 58 TC 17 Z9 17 U1 1 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD MAR 4 PY 2009 VL 257 IS 1-2 BP 33 EP 39 DI 10.1016/j.tox.2008.12.005 PG 7 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 411MW UT WOS:000263654700005 PM 19114085 ER PT J AU DiNapoli, JM Ward, JM Cheng, L Yang, L Elankumaran, S Murphy, BR Sarnal, SK Collins, PL Bukreyev, A AF DiNapoli, Joshua M. Ward, Jerrold M. Cheng, Lily Yang, Lijuan Elankumaran, Subbiah Murphy, Brian R. Sarnal, Siba K. Collins, Peter L. Bukreyev, Alexander TI Delivery to the lower respiratory tract is required for effective immunization with Newcastle disease virus-vectored vaccines intended for humans SO VACCINE LA English DT Article DE Virus; Vaccine; Vector; Immunization; Route of immunization; Newcastle disease virus ID SYNCYTIAL VIRUS; INFLUENZA-VIRUS; FUSION PROTEIN; AFRICAN-GREEN; LIVE; PRIMATES; INFANTS; MONKEYS; INFECTION; VIRULENCE AB Newcastle disease virus (NDV), an avian virus, is being evaluated for the development of vectored human vaccines against emerging pathogens. Previous studies of NDV-vectored vaccines in a mouse model suggested their potency after delivery by injection or by the intranasal route. We compared the efficacy of various routes of delivery of NDV-vectored vaccines in a non-human primate model. While delivery of an NDV-vectored vaccine by the combined intranasal/intratracheal route elicited protective immune responses, delivery by the subcutaneous route or the intranasal route alone elicited limited or no protective immune responses, suggesting the necessity for vaccine delivery to the lower respiratory tract. Furthermore, direct comparison of a vaccine based on an NDV mesogenic strain (NDV-BC) with a similarly designed NDV vector based on a modified lentogenic strain carrying a polybasic F cleavage site (NDV-VF) suggested that the two NDV strains were similar in immunogenicity and were equally protective. Published by Elsevier Ltd. C1 [DiNapoli, Joshua M.; Ward, Jerrold M.; Cheng, Lily; Yang, Lijuan; Murphy, Brian R.; Collins, Peter L.; Bukreyev, Alexander] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Elankumaran, Subbiah; Sarnal, Siba K.] Univ Maryland, Dept Vet Med, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. RP Bukreyev, A (reprint author), NIAID, Infect Dis Lab, NIH, 50 South Dr,Room 6505, Bethesda, MD 20892 USA. EM abukreyev@nih.gov RI Subbiah, Elankumaran/E-9277-2010 OI Subbiah, Elankumaran/0000-0003-4135-9477 FU NIAID; NIH FX We thank Elizabeth M. Williams and Lawrence J. Faucette for support of the IHC studies, Brad Finneyfrock and Anthony Cook of Bioqual, Inc. for their assistance with primate studies, and Ernest Williams and Fatemeh Davoodi for assistance with HAI and ELISA assays. This project was funded as a part of the Intramural Research Program of NIAID, NIH. NR 25 TC 17 Z9 17 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 MAR 4 PY 2009 VL 27 IS 10 BP 1530 EP 1539 DI 10.1016/j.vaccine.2009.01.009 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 420BY UT WOS:000264264600009 PM 19168110 ER PT J AU Reed, ZH Kieny, MP Engers, H Friede, M Chang, S Longacre, S Malhotra, P Pan, W Long, C AF Reed, Zarifah Hussain Kieny, Marie Paule Engers, Howard Friede, Martin Chang, Sandra Longacre, Shirley Malhotra, Pawan Pan, Weiqing Long, Carole TI Comparison of immunogenicity of five MSP1-based malaria vaccine candidate antigens in rabbits SO VACCINE LA English DT Article DE Malaria vaccine; Merozoite surface protem-1 (MSP1); Growth inhibition assay (GIA); Comparison of immunogenicity ID MEROZOITE SURFACE PROTEIN-1; APICAL MEMBRANE ANTIGEN-1; PLASMODIUM-FALCIPARUM MALARIA; BLOOD-STAGE MALARIA; RANDOMIZED CONTROLLED-TRIAL; INHIBIT PARASITE GROWTH; PROTECTS AOTUS MONKEYS; C-TERMINAL FRAGMENT; PAPUA-NEW-GUINEA; B-CELL EPITOPES AB A number of laboratories around the world are producing Plasmodium falciparum erythrocyte-stage vaccine candidates in the pursuit of a vaccine against clinical malaria disease. These candidates are often based on the same parasite protein. Rigorous clinical development and testing Of Multiple candidates is limited by available resources, which underscores the need to conduct comparative studies of the different vaccine candidates. The purpose of this study was to compare five different candidate proteins all based on P. falciparum merozoite surface protein-1 (MSP1). After investigators submitted their candidates, basic protein profiles Were evaluated in a blinded fashion by an independent laboratory, and groups of rabbits were immunized with the proteins. Sera obtained from the rabbits were compared for antibody titers by ELISA and for functional activity by an in vitro parasite growth inhibition assay (GIA) activity, again in a blinded fashion. In selected cases the fine specificity of the antibodies was assessed. Significant differences in immunogenicity as well as the functional activity of antibodies induced by the various vaccine candidates were noted. Data from this Study can assist in making decisions for further clinical development of MSP1-based candidates, and this process sets a precedent for future comparisons of malaria vaccine candidates. (C) 2009 Published by Elsevier Ltd. C1 [Reed, Zarifah Hussain; Kieny, Marie Paule; Friede, Martin] WHO, Initiat Vaccines Res, CH-1211 Geneva, Switzerland. [Engers, Howard] WHO, Special Programme Res & Training Trop Dis TDR, CH-1211 Geneva, Switzerland. [Chang, Sandra] Univ Hawaii, Dept Trop Med & Med Microbiol & Pharmacol, John A Burns Sch Med, Honolulu, HI 96822 USA. [Longacre, Shirley] Inst Pasteur, Lab Vaccinol Parasitaire, Paris, France. [Malhotra, Pawan] Int Ctr Genet Engn & Biotechnol, New Delhi, India. [Pan, Weiqing] Second Mil Med Univ, Shanghai, Peoples R China. [Long, Carole] NIAID, Malaria Vaccine Dev Branch, NIH, Bethesda, MD 20892 USA. RP Reed, ZH (reprint author), WHO, Initiat Vaccines Res, CH-1211 Geneva, Switzerland. EM reedz@who.int FU Intramural NIH HHS NR 59 TC 21 Z9 21 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X EI 1873-2518 J9 VACCINE JI Vaccine PD MAR 4 PY 2009 VL 27 IS 10 BP 1651 EP 1660 DI 10.1016/j.vaccine.2008.10.093 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 420BY UT WOS:000264264600025 PM 19038302 ER PT J AU Song, M Balakrishnan, M Gorelick, RJ Bambara, RA AF Song, Min Balakrishnan, Mini Gorelick, Robert J. Bambara, Robert A. TI A Succession of Mechanisms Stimulate Efficient Reconstituted HIV-1 Minus Strand Strong Stop DNA Transfer SO BIOCHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PRIMER-BINDING-SITE; TYPE-1 NUCLEOCAPSID PROTEIN; ACID-CHAPERONE ACTIVITY; ZINC-FINGER STRUCTURES; REVERSE TRANSCRIPTION; IN-VITRO; RNASE-H; PROMOTES RECOMBINATION; MUTATIONAL ANALYSIS AB Donor-acceptor template systems in vitro were designed to test mechanisms of minus strand transfer of human immunodeficiency virus 1 (HIV-1). Donor RNA D199, extending from the 5' end of the HIV-1 genome to the primer binding site (PBS), promoted transfer to only 35% with an acceptor RNA representing the 3' terminal 97 nucleotides, whereas donor RNA D520, including an additional 321 nucleotides 3' of PBS, exhibited 75% transfer. Both donors transferred through an invasion-driven pathway, but transfer was stimulated by the folding structure resulting from the extra segment in D520. In this study, the significance of interaction between the tRNA(lys3) primer and U3 was examined. Measurements utilizing acceptors having or lacking the U3 region complementary with tRNA(lys3) indicated that a tRNA(lys3)-U3 interaction compensated for inefficient acceptor invasion observed with D199. Stimulation presumably occurred because binding to tRNA(lys3) increased the proximity of the acceptor to elongated cDNA, improving transfer to 78% efficiency with D199, and even higher to 85% with D520. The stimulation did not require natural viral sequences but could be achieved by substituting the original U3 sequence with an equal length sequence that binds a different region of tRNA. Comparison between acceptors sharing the natural region for tRNA(lys3)-U3 interaction but having or lacking the acceptor invasion site demonstrated that tRNA(lys3)-U3 interaction and acceptor invasion cooperate for maximal stimulation. Overall, observations suggest that both proximity and invasion mechanisms are applied successively by HIV-1 for efficient minus strand transfer. C1 [Bambara, Robert A.] Univ Rochester, Med Ctr, Dept Biochem & Biophys, Rochester, NY 14642 USA. [Balakrishnan, Mini] SAIC Frederick Inc, Natl Canc Inst Frederick, Canc Virus Program, Frederick, MD 21702 USA. RP Bambara, RA (reprint author), Univ Rochester, Med Ctr, Dept Biochem & Biophys, 601 Elmwood Ave,Box 712, Rochester, NY 14642 USA. EM robert-bambara@urmc.rochester.edu RI so, strawberry/F-6515-2012 FU National Institutes of Health [GM049573] FX This work was supported by National Institutes of Health Grant GM049573 (to R.A.B.). NR 69 TC 7 Z9 7 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 3 PY 2009 VL 48 IS 8 BP 1810 EP 1819 DI 10.1021/bi80219j PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 412BD UT WOS:000263697300016 PM 19192967 ER PT J AU Gadalla, SM Amr, S Langenberg, P Baumgarten, M Davidson, WF Schairer, C Engels, EA Pfeiffer, RM Goedert, JJ AF Gadalla, S. M. Amr, S. Langenberg, P. Baumgarten, M. Davidson, W. F. Schairer, C. Engels, E. A. Pfeiffer, R. M. Goedert, J. J. TI Breast cancer risk in elderly women with systemic autoimmune rheumatic diseases: a population-based case-control study SO BRITISH JOURNAL OF CANCER LA English DT Article DE rheumatic diseases; autoimmune diseases; breast cancer ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; PRIMARY SJOGRENS-SYNDROME; LUPUS-ERYTHEMATOSUS; COHORT; MALIGNANCY; CELLS; CYTOKINES; ARTHRITIS; TRAIL; EPIDEMIOLOGY AB Systemic autoimmune rheumatic diseases (SARDs) are chronic inflammatory and immuno-modulatory conditions that have been suggested to affect cancer risk. Using the Surveillance, Epidemiology and End Results-Medicare-linked database, women aged 67-99 years and diagnosed with incident breast cancer in 1993-2002 (n = 84 778) were compared with an equal number of age-matched cancer-free female controls. Diagnoses of SARDs, including rheumatoid arthritis (RA, n = 5238), systemic lupus erythematosus (SLE, n = 340), Sjogren's syndrome (n = 374), systemic sclerosis (n = 128), and dermatomyositis (n = 31), were determined from claim files for individuals from age 65 years to 1 year before selection. Associations of SARD diagnoses with breast cancer, overall and by oestrogen receptor (ER) expression, were assessed using odds ratio (OR) estimates from multivariable logistic regression models. The women diagnosed with RA were less likely to develop breast cancer (OR = 0.87, 95% confidence interval (CI) = 0.82-0.93). The risk reduction did not differ by tumour ER-status (OR = 0.83, 95% CI = 0.78-0.89 for ER-positive vs OR = 0.91, 95% CI = 0.81-1.04 for ER-negative, P for heterogeneity = 0.14). The breast cancer risk was not associated with any of the other SARDs, except for a risk reduction of ER-negative cases (OR = 0.49, 95% CI = 0.26-0.93) among women with SLE. These findings suggest that systemic inflammation may affect breast epithelial neoplasia. C1 [Gadalla, S. M.; Schairer, C.; Engels, E. A.; Pfeiffer, R. M.; Goedert, J. J.] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Gadalla, S. M.; Amr, S.; Langenberg, P.; Baumgarten, M.] Univ Maryland, Dept Epidemiol & Prevent Med, Sch Med, Baltimore, MD 21201 USA. [Davidson, W. F.] Univ Maryland, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA. RP Goedert, JJ (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM goedertj@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 FU Applied Research Programme; Division of Cancer Control and Population Sciences; Information Management Services Inc. (IMS); Cancer Prevention Fellowship Program; National Cancer Institute FX This research was supported by an intramural fellowship at the National Cancer Institute. We acknowledge the efforts of Dr Joan Warren, Applied Research Programme, Division of Cancer Control and Population Sciences, NCI, in facilitating our access and understanding of the different components of the SEER-Medicare database, and Ms Winnie Ricker and Ms Ruth Parsons, Information Management Services Inc. (IMS), in managing the project dataset. Dr Gadalla is currently supported by the Cancer Prevention Fellowship Program, National Cancer Institute. NR 36 TC 23 Z9 25 U1 0 U2 1 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 MAR 3 PY 2009 VL 100 IS 5 BP 817 EP 821 DI 10.1038/sj.bjc.6604906 PG 5 WC Oncology SC Oncology GA 415AE UT WOS:000263905900023 PM 19190628 ER PT J AU Anderson, LA Pfeiffer, RM Landgren, O Gadalla, S Berndt, SI Engels, EA AF Anderson, L. A. Pfeiffer, R. M. Landgren, O. Gadalla, S. Berndt, S. I. Engels, E. A. TI Risks of myeloid malignancies in patients with autoimmune conditions SO BRITISH JOURNAL OF CANCER LA English DT Article DE autoimmune conditions; myeloid leukaemia; myelodysplastic syndrome; chronic myeloproliferative diseases ID INFLAMMATORY-BOWEL-DISEASE; POPULATION-BASED COHORT; MYELODYSPLASTIC SYNDROME; HEMATOPOIETIC MALIGNANCIES; HEMATOLOGICAL MALIGNANCIES; POLYMYALGIA-RHEUMATICA; ADULT LEUKEMIA; AZATHIOPRINE TREATMENT; HEMOLYTIC-ANEMIA; CANCER AB Autoimmune conditions are associated with an elevated risk of lymphoproliferative malignancies, but few studies have investigated the risk of myeloid malignancies. From the US Surveillance Epidemiology and End Results (SEER)-Medicare database, 13 486 myeloid malignancy patients (aged 67+ years) and 160 086 population-based controls were selected. Logistic regression models adjusted for gender, age, race, calendar year and number of physician claims were used to estimate odds ratios (ORs) for myeloid malignancies in relation to autoimmune conditions. Multiple comparisons were controlled for using the Bonferroni correction (P < 0.0005). Autoimmune conditions, overall, were associated with an increased risk of acute myeloid leukaemia (AML) (OR 1.29) and myelodysplastic syndrome (MDS, OR 1.50). Specifically, AML was associated with rheumatoid arthritis (OR 1.28), systemic lupus erythematosus (OR 1.92), polymyalgia rheumatica (OR 1.73), autoimmune haemolytic anaemia (OR 3.74), systemic vasculitis (OR 6.23), ulcerative colitis (OR 1.72) and pernicious anaemia (OR 1.57). Myelodysplastic syndrome was associated with rheumatoid arthritis (OR 1.52) and pernicious anaemia (OR 2.38). Overall, autoimmune conditions were not associated with chronic myeloid leukaemia (OR 1.09) or chronic myeloproliferative disorders (OR 1.15). Medications used to treat autoimmune conditions, shared genetic predisposition and/or direct infiltration of bone marrow by autoimmune conditions, could explain these excess risks of myeloid malignancies. C1 [Anderson, L. A.] Queens Univ Belfast, Ctr Publ Hlth, Belfast BT12 6BJ, Antrim, North Ireland. [Pfeiffer, R. M.; Landgren, O.; Gadalla, S.; Berndt, S. I.; Engels, E. A.] Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Landgren, O.] Natl Canc Inst, Med Oncol Branch, Ctr Canc Res, Bethesda, MD USA. RP Anderson, LA (reprint author), Queens Univ Belfast, Canc Epidemiol & Prevent Res Grp, Ctr Clin & Populat Sci, Mulhouse Bldg,Grosvenor Rd, Belfast BT12 6BJ, Antrim, North Ireland. EM landerson@qub.ac.uk RI Pfeiffer, Ruth /F-4748-2011; OI Anderson, Lesley/0000-0002-1000-3649 FU Intramural NIH HHS NR 35 TC 79 Z9 80 U1 0 U2 1 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 MAR 3 PY 2009 VL 100 IS 5 BP 822 EP 828 DI 10.1038/sj.bjc.6604935 PG 7 WC Oncology SC Oncology GA 415AE UT WOS:000263905900024 PM 19259097 ER PT J AU Dhingra, R Pencina, MJ Schrader, P Wang, TJ Levy, D Pencina, K Siwik, DA Colucci, WS Benjamin, EJ Vasan, RS AF Dhingra, Ravi Pencina, Michael J. Schrader, Peter Wang, Thomas J. Levy, Daniel Pencina, Karol Siwik, Deborah A. Colucci, Wilson S. Benjamin, Emelia J. Vasan, Ramachandran S. TI Relations of Matrix Remodeling Biomarkers to Blood Pressure Progression and Incidence of Hypertension in the Community SO CIRCULATION LA English DT Article DE hypertension; collagen; epidemiology; metalloproteinases; risk factors ID CARBOXY-TERMINAL PROPEPTIDE; CARDIOVASCULAR RISK-FACTORS; LEFT-VENTRICULAR STRUCTURE; PROCOLLAGEN TYPE-I; TISSUE INHIBITOR; HEART-DISEASE; METALLOPROTEINASE-1 LEVELS; ANTIHYPERTENSIVE THERAPY; MYOCARDIAL FIBROSIS; MATRIX-METALLOPROTEINASE-9 AB Background Biomarkers of extracellular matrix remodeling are associated with prevalent hypertension in cross-sectional studies, but their relations to longitudinal changes in blood pressure (BP) and hypertension incidence are unknown. Methods and Results We evaluated 595 nonhypertensive Framingham Offspring Study participants (mean age 55 years; 360 women) without prior heart failure or myocardial infarction who underwent routine measurements of plasma tissue inhibitor of metalloproteinase-1 (TIMP-1), metalloproteinase-9 (MMP-9), and procollagen III N-terminal peptide. We related plasma TIMP-1, procollagen III N-terminal peptide, and MMP-9 to the incidence of hypertension and progression of BP by >= 1 category (defined on the basis of the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure). On follow-up (4 years), 81 participants (51 women) developed hypertension, and 198 (114 women) progressed to a higher BP category. In multivariable models, a 1-SD increment of log-TIMP-1 was associated with a 50% higher incidence of hypertension (95% CI 1.08 to 2.08) and a 21% (95% CI 1.00 to 1.47) higher risk of BP progression. Individuals in the top TIMP-1 tertile had a 2.15-fold increased risk of hypertension (95% CI 0.99 to 4.68) and 1.68-fold (95% CI 1.05 to 2.70) increased risk of BP progression relative to the lowest tertile. Individuals with detectable MMP-9 had a 1.97-fold higher risk of BP progression (95% CI 1.06 to 3.64) than those with undetectable levels. Plasma procollagen III N-terminal peptide was not associated with hypertension incidence or BP progression. Conclusions In the present community-based sample, higher TIMP-1 and MMP-9 concentrations were associated with BP progression on follow-up. Additional studies are warranted to confirm our findings. (Circulation. 2009; 119: 1101-1107.) C1 [Dhingra, Ravi; Pencina, Michael J.; Wang, Thomas J.; Levy, Daniel; Benjamin, Emelia J.; Vasan, Ramachandran S.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Dhingra, Ravi] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Aging, Boston, MA 02115 USA. [Dhingra, Ravi] Alice Peck Day Mem Hosp, Dept Med, Lebanon, NH USA. [Pencina, Michael J.; Schrader, Peter; Pencina, Karol] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Wang, Thomas J.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Siwik, Deborah A.; Colucci, Wilson S.] Boston Univ, Sch Med, Myocardial Biol Unit, Boston, MA 02118 USA. [Colucci, Wilson S.; Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Prevent Med & Epidemiol Sect, Boston, MA 02118 USA. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Siwik, Deborah/0000-0002-7166-327X; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute [RO1 HL67288, HL080124, 2K24HL04334, 1R01AG028321, RO1HL076784] FX This work was supported through National Heart, Lung, and Blood Institute contracts RO1 HL67288, HL080124, and 2K24HL04334 (Dr Vasan) and 1R01AG028321 and RO1HL076784 (Dr Benjamin). NR 44 TC 31 Z9 36 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 3 PY 2009 VL 119 IS 8 BP 1101 EP U62 DI 10.1161/CIRCULATIONAHA.108.821769 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 413DC UT WOS:000263772100007 PM 19221217 ER PT J AU Frankel, DS Vasan, RS D'Agostino, RB Benjamin, EJ Levy, D Wang, TJ Meigs, JB AF Frankel, David S. Vasan, Ramachandran S. D'Agostino, Ralph B., Sr. Benjamin, Emelia J. Levy, Daniel Wang, Thomas J. Meigs, James B. TI Resistin, Adiponectin, and Risk of Heart Failure The Framingham Offspring Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE heart failure; resistin; adiponectin; adipokines; epidemiology ID CORONARY-ARTERY-DISEASE; BODY-MASS INDEX; INSULIN-RESISTANCE; CARDIOVASCULAR EVENTS; MYOCARDIAL-INFARCTION; PLASMA ADIPONECTIN; OXIDATIVE STRESS; ADIPOSE-TISSUE; SERUM RESISTIN; OBESITY AB Objectives We tested the association of the adipokines resistin and adiponectin with incident heart failure. Background Abnormal concentrations of adipokines may partially explain the association between obesity and heart failure. Methods We related circulating adipokine concentrations to the incidence of heart failure in 2,739 participants in the Framingham Offspring Study. Results During 6 years of follow-up, 58 participants developed new-onset heart failure. In proportional hazards models ( adjusting for age, sex, blood pressure, antihypertensive treatment, diabetes, smoking, total/high-density lipoprotein cholesterol ratio, prevalent coronary heart disease, valvular heart disease, left ventricular hypertrophy, and estimated glomerular filtration rate) using the lowest third of the resistin distribution as the referent, the hazard ratios for heart failure in the middle and top thirds were 2.89 (95% confidence interval [CI]: 1.05 to 7.92) and 4.01 ( 95% CI: 1.52 to 10.57), respectively ( p = 0.004 for trend). Additional adjustment for body mass index, insulin resistance ( measured with the homeostasis model), C-reactive protein, and B-type natriuretic peptide did not substantively weaken this association ( multivariable hazard ratios [HRs]: 2.62 and 3.74, p = 0.007). In the maximally adjusted model, each SD increment in resistin (7.45 ng/ml) was associated with a 26% increase in heart failure risk ( 95% CI: 1% to 60%). Concentrations of adiponectin were not associated with heart failure ( multivariable HRs: 0.87 and 0.97, p = 0.9). Conclusions Increased circulating concentrations of resistin were associated with incident heart failure, even after accounting for prevalent coronary heart disease, obesity, and measures of insulin resistance and inflammation. The findings suggest a role for resistin in human disease and a novel pathway to heart failure. (J Am Coll Cardiol 2009; 53: 754-62) (C) 2009 by the American College of Cardiology Foundation C1 [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Dept Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Boston, MA USA. [Vasan, Ramachandran S.; D'Agostino, Ralph B., Sr.; Benjamin, Emelia J.; Levy, Daniel; Wang, Thomas J.; Meigs, James B.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. [Levy, Daniel] NHLBI, Bethesda, MD 20892 USA. [Wang, Thomas J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, Dept Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jmeigs@partners.org OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; American Diabetes Association; GlaxoSmithKline; Lilly; [2K24HL404334]; [RO1 HL076784]; [1R01 AG028321] FX Supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study ( contract no. N01-HC-25195), 2K24HL404334 (Dr. Vasan), RO1 HL076784 ( Dr. Benjamin), 1R01 AG028321 ( Dr. Benjamin), and an American Diabetes Association Career Development Award ( Dr. Meigs). Dr. D'Agostino has received honoraria from Sanofi-Aventis and serves on advisory boards for Pfizer and Bayer. Dr. Meigs currently has research grants from GlaxoSmithKline and serves on safety boards for GlaxoSmithKline and Lilly. The funding agencies had no influence over the content or conduct of the analysis or the decision to publish the findings. Dr. Frankel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. NR 47 TC 135 Z9 141 U1 0 U2 4 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 MAR 3 PY 2009 VL 53 IS 9 BP 754 EP 762 DI 10.1016/j.jacc.2008.07.073 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 411RH UT WOS:000263667200004 PM 19245965 ER PT J AU Shtengel, G Galbraith, JA Galbraith, CG Lippincott-Schwartz, J Gillette, JM Manley, S Sougrat, R Waterman, CM Kanchanawong, P Davidson, MW Fetter, RD Hess, HF AF Shtengel, Gleb Galbraith, James A. Galbraith, Catherine G. Lippincott-Schwartz, Jennifer Gillette, Jennifer M. Manley, Suliana Sougrat, Rachid Waterman, Clare M. Kanchanawong, Pakorn Davidson, Michael W. Fetter, Richard D. Hess, Harald F. TI Interferometric fluorescent super-resolution microscopy resolves 3D cellular ultrastructure SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE fluorescence microscopy; interferometry; PALM; photoactivated localization microscopy; single molecule imaging ID OPTICAL RECONSTRUCTION MICROSCOPY; 3-DIMENSIONAL SUPERRESOLUTION; LOCALIZATION MICROSCOPY; ELECTRON-MICROSCOPY; RESOLUTION; FIBROBLASTS; IMPROVEMENT; TOPOGRAPHY; SAMPLES AB Understanding molecular-scale architecture of cells requires determination of 3D locations of specific proteins with accuracy matching their nanometer-length scale. Existing electron and light microscopy techniques are limited either in molecular specificity or resolution. Here, we introduce interferometric photoactivated localization microscopy ( iPALM), the combination of photoactivated localization microscopy with single-photon, simultaneous multiphase interferometry that provides sub-20-nm 3D protein localization with optimal molecular specificity. We demonstrate measurement of the 25-nm microtubule diameter, resolve the dorsal and ventral plasma membranes, and visualize the arrangement of integrin receptors within endoplasmic reticulum and adhesion complexes, 3D protein organization previously resolved only by electron microscopy. iPALM thus closes the gap between electron tomography and light microscopy, enabling both molecular specification and resolution of cellular nanoarchitecture. C1 [Lippincott-Schwartz, Jennifer; Gillette, Jennifer M.; Manley, Suliana; Sougrat, Rachid] NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. [Waterman, Clare M.; Kanchanawong, Pakorn] NHLBI, Lab Cell & Tissue Morphodynam, NIH, Bethesda, MD 20892 USA. [Davidson, Michael W.] Florida State Univ, Natl High Magnet Field Lab, Tallahassee, FL 32310 USA. [Davidson, Michael W.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32310 USA. [Shtengel, Gleb; Fetter, Richard D.; Hess, Harald F.] Howard Hughes Med Inst, Ashburn, VA USA. [Galbraith, James A.] NINDS, NIH, Bethesda, MD 20892 USA. [Galbraith, Catherine G.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM jlippin@helix.nih.gov; hessh@janelia.hhmi.org RI Manley, Suliana/D-3818-2012; OI Manley, Suliana/0000-0002-4755-4778; Sougrat, Rachid/0000-0001-6476-1886; Waterman, Clare/0000-0001-6142-6775 FU Howard Hughes Medical Institute; National Institutes of Health intramural programs of the National Institute of Neurological Disorders and Stroke; National Institute of Dental and Craniofacial Research; National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute FX We thank J. Wiedenmann and U. Nienhaus (Ulm University, Ulm, Germany) for the gift of the EosFP, A. Miyawaki (RIKEN, Wako, Saitama, Japan) for the m-KikGRFP, Patrick Lee for mechanical design of the iPALM, Hari Shroff and Eric Betzig for help and discussions, Ann McEvoy and Derek Greenfield (University of California, Berkeley) for intriguing 3D samples, and Kevin McGowan and Helen White for help with samples. This work was supported by the Howard Hughes Medical Institute and the National Institutes of Health intramural programs of the National Institute of Neurological Disorders and Stroke, the National Institute of Dental and Craniofacial Research, the National Institute of Child Health and Human Development, and the National Heart, Lung, and Blood Institute. NR 35 TC 376 Z9 381 U1 13 U2 108 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 MAR 3 PY 2009 VL 106 IS 9 BP 3125 EP 3130 DI 10.1073/pnas.0813131106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 414DM UT WOS:000263844100029 PM 19202073 ER PT J AU Liao, YY Plummer, NW George, MD Abramowitz, J Zhu, MX Birnbaumer, L AF Liao, Yanhong Plummer, Nicholas W. George, Margaret D. Abramowitz, Joel Zhu, Michael Xi Birnbaumer, Lutz TI A role for Orai in TRPC-mediated Ca2+ entry suggests that a TRPC:Orai complex may mediate store and receptor operated Ca2+ entry SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE diacylglycerol; STIM1; store operated calcium entry; transient receptor potential ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS; PLASMA MEMBRANE JUNCTIONS; TRANSIENT RECEPTOR; CHANNEL FUNCTION; CALCIUM CURRENT; CATION CHANNEL; STIM1; ACTIVATION; CRAC; DEPLETION AB TRPC and Orai proteins have both been proposed to form Ca2+ selective, store-operated calcium entry (SOCE) channels that are activated by store-depletion with Ca2+ chelators or calcium pump inhibitors. In contrast, only TRPC proteins have been proposed to form nonselective receptor-operated calcium entry (ROCE) cation channels that are activated by Gq/Gi-PLC beta signaling, which is the physiological stimulus for store depletion. We reported previously that a dominant negative Orai1 mutant, R91W, inhibits Ca2+ entry through both SOCE and ROCE channels, implicating Orai participation in both channel complexes. However, the argument for Orai participating in ROCE independently of store depletion is tenuous because store depletion is an integral component of the ROCE response, which includes formation of IP3, a store-depleting agent. Here we show that the R91W mutant also blocks diacylglycerol (DAG)-activated Ca2+ entry into cells that stably, or transiently, express DAG-responsive TRPC proteins. This strongly suggests that Orai and TRPC proteins form complexes that participate in Ca2+ entry with or without activation of store depletion. To integrate these results with recent data linking SOCE with recruitment of Orai and TRPCs to lipid rafts by STIM, we develop the hypothesis that Orai: TRPC complexes recruited to lipid rafts mediate SOCE, whereas the same complexes mediate ROCE when they are outside of lipid rafts. It remains to be determined whether the molecules forming the permeation pathway are the same when Orai: TRPC complexes mediate ROCE or SOCE. C1 [Liao, Yanhong; Plummer, Nicholas W.; George, Margaret D.; Abramowitz, Joel; Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Neurobiol Lab, Div Intramural Res, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Zhu, Michael Xi] Ohio State Univ, Dept Neurosci & Biochem, Columbus, OH 43210 USA. [Zhu, Michael Xi] Ohio State Univ, Ctr Mol Neurobiol, Columbus, OH 43210 USA. RP Birnbaumer, L (reprint author), Natl Inst Environm Hlth Sci, Neurobiol Lab, Div Intramural Res, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM birnbau1@niehs.nih.gov RI Abramowitz, Joel/A-2620-2015; OI Plummer, Nicholas/0000-0003-2971-814X FU Intramural Research Program of the NIH [Z01-ES-101684] FX This work was supported by the Intramural Research Program of the NIH (Z01-ES-101684). NR 44 TC 107 Z9 111 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 3 PY 2009 VL 106 IS 9 BP 3202 EP 3206 DI 10.1073/pnas.0813346106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 414DM UT WOS:000263844100042 PM 19221033 ER PT J AU Zhang, Z Alpert, D Francis, R Chatterjee, B Yu, Q Tansey, T Sabol, SL Cui, C Bai, YL Koriabine, M Yoshinaga, Y Cheng, JF Chen, F Martin, J Schackwitz, W Gunn, TM Kramer, KL De Jong, PJ Pennacchio, LA Lo, CW AF Zhang, Zhen Alpert, Deanne Francis, Richard Chatterjee, Bishwanath Yu, Qing Tansey, Terry Sabol, Steven L. Cui, Cheng Bai, Yongli Koriabine, Maxim Yoshinaga, Yuko Cheng, Jan-Fang Chen, Feng Martin, Joel Schackwitz, Wendy Gunn, Teresa M. Kramer, Kenneth L. De Jong, Pieter J. Pennacchio, Len A. Lo, Cecilia W. TI Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cardiogenesis; left-right; nodal ID LEFT-RIGHT ASYMMETRY; LEFT-RIGHT AXIS; LATERAL PLATE; GENOME; MOUSE; MICE; NODE; ESTABLISHMENT; GENERATION; MOLECULES AB Forward genetic screens with ENU (N-ethyl-N-nitrosourea) mutagenesis can facilitate gene discovery, but mutation identification is often difficult. We present the first study in which an ENU-induced mutation was identified by massively parallel DNA sequencing. This mutation causes heterotaxy and complex congenital heart defects and was mapped to a 2.2-Mb interval on mouse chromosome 7. Massively parallel sequencing of the entire 2.2-Mb interval identified 2 single-base substitutions, one in an intergenic region and a second causing replacement of a highly conserved cysteine with arginine (C193R) in the gene Megf8. Megf8 is evolutionarily conserved from human to fruit fly, and is observed to be ubiquitously expressed. Morpholino knockdown of Megf8 in zebrafish embryos resulted in a high incidence of heterotaxy, indicating a conserved role in laterality specification. Megf8(C193R) mouse mutants show normal breaking of symmetry at the node, but Nodal signaling failed to be propagated to the left lateral plate mesoderm. Videomicroscopy showed nodal cilia motility, which is required for left-right patterning, is unaffected. Although this protein is predicted to have receptor function based on its amino acid sequence, surprisingly confocal imaging showed it is translocated into the nucleus, where it is colocalized with Gfi1b and Baf60C, two proteins involved in chromatin remodeling. Overall, through the recovery of an ENU-induced mutation, we uncovered Megf8 as an essential regulator of left-right patterning. C1 [Zhang, Zhen; Alpert, Deanne; Francis, Richard; Chatterjee, Bishwanath; Yu, Qing; Tansey, Terry; Sabol, Steven L.; Cui, Cheng; Kramer, Kenneth L.; Lo, Cecilia W.] NHLBI, Dev Biol Lab, Bethesda, MD 20892 USA. [Bai, Yongli; Koriabine, Maxim; Yoshinaga, Yuko; De Jong, Pieter J.] Childrens Hosp, Oakland Res Inst, BACPAC Resources Ctr, Oakland, CA 94609 USA. [Cheng, Jan-Fang; Chen, Feng; Martin, Joel; Schackwitz, Wendy; Pennacchio, Len A.] US Dept Energy Joint Genome Inst, Walnut Creek, CA 94598 USA. [Gunn, Teresa M.] Cornell Univ, Coll Vet Med, Dept Biomed Sci, Ithaca, NY 14853 USA. RP Lo, CW (reprint author), NHLBI, Dev Biol Lab, Bldg 10, Bethesda, MD 20892 USA. EM loc@nhlbi.nih.gov RI Francis, Richard/P-2524-2015; OI Francis, Deanne/0000-0002-4158-1521; Gunn, Teresa/0000-0003-2688-6420; Zhang, Zhen/0000-0002-9898-054X FU National Institutes of Health; Department of Energy [DE-AC02-05CH11231] FX We thank Blake Carrington for technical support, Drs. Stuart H. Orkin and Yuko Fujiwara (Dana Farber Cancer Institute, Boston, MA) for providing Gfi1b knockout embryos, and Drs. Michael Shen (Columbia University Medical Center, New York) and Brent McCright (Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, Bethesda, MD) for providing in situ hybridization probes. This work was supported by National Institutes of Health grants (to C. L, and P.J.D.J.), and Department of Energy Contract DE-AC02-05CH11231 (to L.A.P.). NR 32 TC 27 Z9 28 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 MAR 3 PY 2009 VL 106 IS 9 BP 3219 EP 3224 DI 10.1073/pnas.0813400106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 414DM UT WOS:000263844100045 PM 19218456 ER PT J AU Yan, Y Buckler-White, A Wollenberg, K Kozak, CA AF Yan, Yuhe Buckler-White, Alicia Wollenberg, Kurt Kozak, Christine A. TI Origin, antiviral function and evidence for positive selection of the gammaretrovirus restriction gene Fv1 in the genus Mus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Fv1 gammaretrovirus restriction gene; mouse endogenous retrovirus; Mus evolution ID MURINE LEUKEMIA-VIRUS; MAJOR HOMOLOGY REGION; MUTATIONAL ANALYSIS; MAXIMUM-LIKELIHOOD; CAPSID PROTEIN; MOUSE; DETERMINANTS; RETROVIRUS; RESISTANCE; CLONING AB The Fv1 virus resistance gene is a coopted endogenous retrovirus (ERV) sequence related to the gag gene of the MuERV-L ERV family. Three major Fv1 resistance alleles have been identified in laboratory mice, and they target virus capsid genes to produce characteristic patterns of resistance to mouse leukemia viruses (MLVs). We identified Fv1 in 3 of the 4 Mus subgenera; its absence from Coelomys and 1 of 3 species of Pyromys indicate Fv1 was acquired shortly after the origin of the Mus genus. We sequenced Fv1 genes from 21 mice representative of the major taxonomic groups of Mus. Two lines of evidence indicate that Fv1 has had antiviral function for 7 million years of evolution. First, 2 species of African pygmy mice (subgenus Nannomys) show an Fv1-like MLV resistance, and transduced cells expressing the Nannomys Fv1 gene reproduce this resistance pattern. Second, sequence comparisons suggest that Fv1 has been involved in genetic conflicts throughout Mus evolution. We found evidence for strong positive selection of Fv1 and identified 6 codons that show evidence of positive selection: 3 codons in the C-terminal region including 2 previously shown to contribute to Fv1 restriction in laboratory mice, and 3 codons in a 10-codon segment overlapping the major homology region of Fv1; this segment is known to be involved in capsid multimerization. This analysis suggests that Fv1 has had an antiviral role throughout Mus evolution predating exposure of mice to the MLVs restricted by laboratory mouse Fv1, and suggests a mechanism for Fv1 restriction. C1 [Yan, Yuhe; Buckler-White, Alicia; Kozak, Christine A.] NIAID, Mol Microbiol Lab, Office Cyber Infrastruct & Computat Biol, Bethesda, MD 20892 USA. [Wollenberg, Kurt] NIAID, Mol Microbiol Lab, Bioinformat & Computat Biosci Branch, Bethesda, MD 20892 USA. RP Kozak, CA (reprint author), NIAID, Mol Microbiol Lab, Office Cyber Infrastruct & Computat Biol, Bethesda, MD 20892 USA. EM ckozak@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infectious Diseases FX We thank Esther Shaffer and Qingping Liu for expert technical assistance. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 29 TC 32 Z9 33 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 3 PY 2009 VL 106 IS 9 BP 3259 EP 3263 DI 10.1073/pnas.0900181106 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 414DM UT WOS:000263844100052 PM 19221034 ER PT J AU Nagao, K Ginhoux, F Leitner, WW Motegi, S Bennett, CL Clausen, BE Merad, M Udey, MC AF Nagao, Keisuke Ginhoux, Florent Leitner, Wolfgang W. Motegi, Sei-Ichiro Bennett, Clare L. Clausen, Bjoern E. Merad, Miriam Udey, Mark C. TI Murine epidermal Langerhans cells and langerin-expressing dermal dendritic cells are unrelated and exhibit distinct functions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE EpCAM; gene gun; langerin; TGF-beta ID T-CELLS; IN-VIVO; CONTACT HYPERSENSITIVITY; STEADY-STATE; MHC-I; SKIN; ANTIGEN; ADHESION; IMMUNITY; POPULATION AB A new langerin(+) DC subset has recently been identified in murine dermis (langerin(+) dDC), but the lineage and functional relationships between these cells and langerin(+) epidermal Langerhans cells (LC) are incompletely characterized. Selective expression of the cell adhesion molecule EpCAM by LC allowed viable LC to be easily distinguished from langerin(+) dDC in skin and lymphoid tissue and ex vivo as well. Differential expression of EpCAM and langerin revealed the presence of at least 3 distinct skin DC subsets. We determined that LC and langerin(+) dDC exhibit different migratory capabilities in vitro and repopulate distinct anatomic compartments in skin at different rates after conditional depletion in vivo. Langerin(+) dDC, in contrast to LC, did not require TGF beta 1 for development. Carefully timed gene gun immunization studies designed to take advantage of the distinct repopulation kinetics of langerin(+) dDC and LC revealed that langerin(+) dDC were required for optimal production of beta-galactosidase-specific IgG2a/c and IgG2b in the acute phase. In contrast, immunization via LC-deficient skin resulted in persistent and strikingly reduced IgG1 and enhanced IgG2a Ab production. Our data support the concepts that LC and langerin(+) dDC represent distinct DC subsets that have specialized functions and that LC are important immunoregulatory cells. The presence of at least 3 functionally distinct skin DC subsets may have particular relevance for vaccines that are administered epicutaneously. C1 [Nagao, Keisuke; Leitner, Wolfgang W.; Motegi, Sei-Ichiro; Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ginhoux, Florent; Merad, Miriam] Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY 10029 USA. [Ginhoux, Florent; Merad, Miriam] Mt Sinai Sch Med, Dept Med, New York, NY 10029 USA. [Bennett, Clare L.; Clausen, Bjoern E.] Univ Amsterdam, Acad Med Ctr, Dept Cell Biol & Histol, NL-1105 AZ Amsterdam, Netherlands. RP Udey, MC (reprint author), NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM udeym@mail.nih.gov RI CLAUSEN, Bjorn/A-8229-2010; Leitner, Wolfgang/F-5741-2011; Nagao, Keisuke/J-5116-2013; bennett, clare/J-5249-2013 OI CLAUSEN, Bjorn/0000-0002-2484-7842; Leitner, Wolfgang/0000-0003-3125-5922; Nagao, Keisuke/0000-0002-7005-3138; bennett, clare/0000-0001-9146-2347 FU Intramural Program of the National Institutes of Health (NIH); National Cancer Institute; Center for Cancer Research; The Waksman Foundation of Japan Inc.; Landsteiner Foundation for Blood Transfusion Research (LSBR); Dutch Research Foundation (NWO); Leukemia and Lymphoma Society FX This work was supported, in part, by the Intramural Program of the National Institutes of Health (NIH), National Cancer Institute, Center for Cancer Research. K. N. was supported, in part, by a grant from The Waksman Foundation of Japan Inc. B.E.C. is a fellow of the Landsteiner Foundation for Blood Transfusion Research (LSBR) and the Dutch Research Foundation (NWO). F.G. was supported by the Leukemia and Lymphoma Society. The authors thank Drs. Ralph M. Steinman and Chae Gyu Park (Rockefeller University) for providing anti-langerin L31 mAb. NR 28 TC 130 Z9 131 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 3 PY 2009 VL 106 IS 9 BP 3312 EP 3317 DI 10.1073/pnas.0807126106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 414DM UT WOS:000263844100061 PM 19218433 ER PT J AU Diaz, JC Simakova, O Jacobson, KA Arispe, N Pollard, HB AF Diaz, Juan Carlos Simakova, Olga Jacobson, Kenneth A. Arispe, Nelson Pollard, Harvey B. TI Small molecule blockers of the Alzheimer A beta calcium channel potently protect neurons from A beta cytotoxicity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE brain; neurodegeneration; rational drug design; drug; toxicity ID ION CHANNELS; MEMORY LOSS; CHOLINESTERASE-INHIBITORS; ZN2+-SENSITIVE CHANNEL; BILAYER-MEMBRANES; TRANSGENIC MODEL; GAMMA-SECRETASE; PDAPP MOUSE; CONGO RED; DISEASE AB Alzheimer's disease (AD) is a common, chronic neurodegenerative disease that is thought to be caused by the neurotoxic effect of the Amyloid beta peptides (A beta). We have hypothesized that the intrinsic A beta calcium channel activity of the oligomeric A beta polymer may be responsible for the neurotoxic properties of A beta, and that A beta channel blockers may be candidate AD therapeutics. As a consequence of a rational search paradigm based on the model structure of the A beta channel, we have identified two compounds of interest: MRS2481 and an enatiomeric species, MRS2485. These are amphiphilic pyridinium salts that both potently block the A beta channel and protect neurons from A beta toxicity. Both block the A beta channel with similar potency (similar to 500 nM) and efficacy (100%). However, we find that inhibition by MRS2481 is easily reversible, whereas inhibition by MRS2485 is virtually irreversible. We suggest that both species deserve consideration as candidates for Alzheimer's disease drug discovery. C1 [Diaz, Juan Carlos; Simakova, Olga; Arispe, Nelson; Pollard, Harvey B.] Uniformed Serv Univ Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Pollard, HB (reprint author), Uniformed Serv Univ Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. EM hpollard@usuhs.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU The Alzheimer's Disease Foundation; Institute for Alzheimer's Drug Discovery Foundation; The Institute for the Study of Aging, Inc.; Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [Z01DK031127-01] FX The authors are grateful for support for this work from The Alzheimer's Disease Foundation (N.A.); the Institute for Alzheimer's Drug Discovery Foundation and The Institute for the Study of Aging, Inc. (H.B.P.); and Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health: Z01DK031127-01 (K.A.J.). NR 56 TC 56 Z9 56 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 3 PY 2009 VL 106 IS 9 BP 3348 EP 3353 DI 10.1073/pnas.0813355106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 414DM UT WOS:000263844100067 PM 19204293 ER PT J AU Carpenito, C Milone, MC Hassan, R Simonet, JC Lakhal, M Suhoski, MM Varela-Rohena, A Haines, KM Heitjan, DF Albelda, SM Carroll, RG Riley, JL Pastan, I June, CH AF Carpenito, Carmine Milone, Michael C. Hassan, Raffit Simonet, Jacqueline C. Lakhal, Mehdi Suhoski, Megan M. Varela-Rohena, Angel Haines, Kathleen M. Heitjan, Daniel F. Albelda, Steven M. Carroll, Richard G. Riley, James L. Pastan, Ira June, Carl H. TI Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE adoptive immunotherapy; chimeric receptor; mesothelin ID ANTI-MESOTHELIN IMMUNOTOXIN; ADOPTIVE IMMUNOTHERAPY; TELOMERE LENGTH; GENE-TRANSFER; PHASE-I; LYMPHOCYTE DEVELOPMENT; OVARIAN-CANCER; SUICIDE GENE; EXPRESSION; RECEPTOR AB Mesothelin is a cell-surface molecule over-expressed on a large fraction of carcinomas, and thus is an attractive target of immunotherapy. A molecularly targeted therapy for these cancers was created by engineering T cells to express a chimeric receptor with high affinity for human mesothelin. Lentiviral vectors were used to express a single-chain variable fragment that binds mesothelin and that is fused to signaling domains derived from T-cell receptor zeta, CD28, and CD137 (4-1BB). When stimulated by mesothelin, lentivirally transduced T cells were induced to proliferate, express the antiapoptotic gene Bcl-X(L), and secrete multiple cytokines, all features characteristic of central memory T cells. When transferred intratumorally or intravenously into NOD/scid/IL2r gamma(-/-) mice engrafted with large pre-established tumors, the engineered T cells reduced the tumor burden, and in some cases resulted in complete eradication of the tumors at low effector-to-target ratios. Incorporation of the CD137 signaling domain specifically reprogrammed cells for multifunctional cytokine secretion and enhanced persistence of T cells. These findings have important implications for adoptive immunotherapy of cancer, especially in the context of poorly immunogenic tumors. Genetically redirected T cells have promise of targeting T lymphocytes to tumor antigens, confer resistance to the tumor microenvironment, and providing immunosurveillance. C1 [Hassan, Raffit; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Carpenito, Carmine; Milone, Michael C.; Simonet, Jacqueline C.; Lakhal, Mehdi; Suhoski, Megan M.; Varela-Rohena, Angel; Haines, Kathleen M.; Albelda, Steven M.; Carroll, Richard G.; Riley, James L.; June, Carl H.] Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. [Milone, Michael C.; Carroll, Richard G.; Riley, James L.; June, Carl H.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Heitjan, Daniel F.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Albelda, Steven M.] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov; cjune@exchange.upenn.edu OI Riley, James/0000-0002-1057-576X FU National Institutes of Health [1R01CA120409, 5P50CA083638, 2P01CA066726]; Alliance for Cancer Gene Therapy; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX We thank Gwendolyn Binder, Chrystal Paulos, and Gwenn-aelDanet-Desnoyers for helpful discussions, Cynthia June for support, Elizabeth Jaffee for the generous gift of mesothelin vector, and Ronghua Liu and Anthony Secreto for expert technical assistance. We also thank the Center for AIDS Research Immunology Core for providing primary human T cells. This work was supported by National Institutes of Health Grants 1R01CA120409, 5P50CA083638, and 2P01CA066726, the Alliance for Cancer Gene Therapy (the Joan Miller and Linda Bernstein Gene Therapy for Ovarian Cancer Award), and in part of by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 43 TC 298 Z9 305 U1 2 U2 33 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 MAR 3 PY 2009 VL 106 IS 9 BP 3360 EP 3365 DI 10.1073/pnas.0813101106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 414DM UT WOS:000263844100069 PM 19211796 ER PT J AU Du, J Wang, Y Hunter, R Wei, YL Blumenthal, R Falke, C Khairova, R Zhou, RL Yuan, PX Machado-Vieira, R McEwen, BS Manji, HK AF Du, Jing Wang, Yun Hunter, Richard Wei, Yanling Blumenthal, Rayah Falke, Cynthia Khairova, Rushaniya Zhou, Rulun Yuan, Peixiong Machado-Vieira, Rodrigo McEwen, Bruce S. Manji, Husseini K. TI Dynamic regulation of mitochondrial function by glucocorticoids SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE allostasis; Bcl-2; mitochondria; mood disorders; glucocorticoid receptor ID OXIDATIVE-PHOSPHORYLATION; CELL MITOCHONDRIA; RAT HIPPOCAMPUS; IN-VITRO; RECEPTOR; ACTIVATION; APOPTOSIS; NEURONS; STRESS; CA2+ AB Glucocorticoids play an important biphasic role in modulating neural plasticity; low doses enhance neural plasticity and spatial memory behavior, whereas chronic, higher doses produce inhibition. We found that 3 independent measures of mitochondrial function-mitochondrial oxidation, membrane potential, and mitochondrial calcium holding capacity-were regulated by long-term corticosterone (CORT) treatment in an inverted "U''-shape. This regulation of mitochondrial function by CORT correlated with neuroprotection; that is, treatment with low doses of CORT had a neuroprotective effect, whereas treatment with high doses of CORT enhanced kainic acid (KA)-induced toxicity of cortical neurons. We then undertook experiments to elucidate the mechanisms underlying these biphasic effects and found that glucocorticoid receptors (GRs) formed a complex with the anti-apoptotic protein Bcl-2 in response to CORT treatment and translocated with Bcl-2 into mitochondria after acute treatment with low or high doses of CORT in primary cortical neurons. However, after 3 days of treatment, high, but not low, doses of CORT resulted in decreased GR and Bcl-2 levels in mitochondria. As with the in vitro studies, Bcl-2 levels in the mitochondria of the prefrontal cortex were significantly decreased, along with GR levels, after long-term treatment with high-dose CORT in vivo. These findings have the potential to contribute to a more complete understanding of the mechanisms by which glucocorticoids and chronic stress regulate cellular plasticity and resilience and to inform the future development of improved therapeutics. C1 [Hunter, Richard; McEwen, Bruce S.] Rockefeller Univ, Neuroendocrinol Lab, New York, NY 10065 USA. [Du, Jing; Wang, Yun; Wei, Yanling; Blumenthal, Rayah; Falke, Cynthia; Khairova, Rushaniya; Zhou, Rulun; Yuan, Peixiong; Machado-Vieira, Rodrigo; Manji, Husseini K.] NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Program, Natl Inst Hlth, Bethesda, MD 20892 USA. RP McEwen, BS (reprint author), Rockefeller Univ, Neuroendocrinol Lab, New York, NY 10065 USA. EM bruce.mcewen@mail.rockefeller.edu; manjih@mail.nih.gov RI Hunter, Richard/A-8043-2009; Du, Jing/A-9023-2012; MACHADO-VIEIRA, RODRIGO/D-8293-2012; OI MACHADO-VIEIRA, RODRIGO/0000-0002-4830-1190; Hunter, Richard/0000-0002-3130-0941 FU NIMH; NIH [MH41256] FX We thank Ioline Henter for outstanding editorial assistance. We acknowledge the support of the Intramural Research Program of the NIMH and the Stanley Medical Research Institute. B.S.M. acknowledges grant support from NIH MH41256. NR 33 TC 134 Z9 139 U1 3 U2 21 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 MAR 3 PY 2009 VL 106 IS 9 BP 3543 EP 3548 DI 10.1073/pnas.0812671106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 414DM UT WOS:000263844100100 PM 19202080 ER PT J AU Auld, DS Thorne, N Maguire, WF Inglese, J AF Auld, Douglas S. Thorne, Natasha Maguire, William F. Inglese, James TI Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE reporter gene assays; high-throughput screening; Ataluren ID AMINOGLYCOSIDE ANTIBIOTICS; INHIBITORY-ACTIVITY; FIREFLY LUCIFERASE; MESSENGER-RNA; PROTEIN; MUTATIONS; READTHROUGH; STABILITY; SYSTEM; IDENTIFICATION AB High-throughput screening (HTS) assays used in drug discovery frequently use reporter enzymes such as firefly luciferase (FLuc) as indicators of target activity. An important caveat to consider, however, is that compounds can directly affect the reporter, leading to nonspecific but highly reproducible assay signal modulation. In rare cases, this activity appears counterintuitive; for example, some FLuc inhibitors, acting through posttranslational Fluc reporter stabilization, appear to activate gene expression. Previous efforts to characterize molecules that influence luciferase activity identified a subset of 3,5-diaryl-oxadiazole-containing compounds as FLuc inhibitors. Here, we evaluate a number of compounds with this structural motif for activity against FLuc. One such compound is PTC124 {3-[5-(2-fluorophenyl)- 1,2,4-oxadiazol-3-yl]benzoic acid}, a molecule originally identified in a cell-based FLuc assay as having nonsense codon suppression activity [Welch EM, et al., Nature (2007) 447: 87-91]. We find that the potency of FLuc inhibition for the tested compounds strictly correlates with their activity in a FLuc reporter cell-based nonsense codon assay, with PTC124 emerging as the most potent FLuc inhibitor (IC(50) = 7 +/- 1 nM). However, these compounds, including PTC124, fail to show nonsense codon suppression activity when Renilla reniformis luciferase (RLuc) is used as a reporter and are inactive against the RLuc enzyme. This suggests that the initial discovery of PTC124 may have been biased by its direct effect on the FLuc reporter, implicating firefly luciferase as a molecular target of PTC124. Our results demonstrate the value of understanding potential interactions between reporter enzymes and chemical compounds and emphasize the importance of implementing the appropriate control assays before interpreting HTS results. C1 [Auld, Douglas S.; Thorne, Natasha; Maguire, William F.; Inglese, James] NIH, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. RP Inglese, J (reprint author), NIH, Chem Genom Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM jinglese@mail.nih.gov FU Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health FX We thank Paul Shinn for compound management support, Craig Thomas and William Leister for analytical chemistry support, and Noel Southall for data analysis. We thank Christopher Austin and Charles Venditti for critical reading of the manuscript. This work was supported by the Molecular Libraries Initiative of the National Institutes of Health Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 34 TC 98 Z9 99 U1 0 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 3 PY 2009 VL 106 IS 9 BP 3585 EP 3590 DI 10.1073/pnas.0813345106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 414DM UT WOS:000263844100107 PM 19208811 ER PT J AU Shinoda, K Wyatt, LS Irvine, KR Moss, B AF Shinoda, Kaori Wyatt, Linda S. Irvine, Kari R. Moss, Bernard TI Engineering the vaccinia virus L1 protein for increased neutralizing antibody response after DNA immunization SO VIROLOGY JOURNAL LA English DT Article ID 14-KILODALTON ENVELOPE PROTEIN; SURFACE HEPARAN-SULFATE; SMALLPOX VACCINATION; NONHUMAN-PRIMATES; MONOCLONAL-ANTIBODIES; POXVIRUS CHALLENGE; MEMBRANE-FUSION; A27L PROTEIN; MICE; CELL AB Background: The licensed smallpox vaccine, comprised of infectious vaccinia virus, has associated adverse effects, particularly for immunocompromised individuals. Therefore, safer DNA and protein vaccines are being investigated. The L1 protein, a component of the mature virion membrane that is conserved in all sequenced poxviruses, is required for vaccinia virus entry into host cells and is a target for neutralizing antibody. When expressed by vaccinia virus, the unglycosylated, myristoylated L1 protein attaches to the viral membrane via a C-terminal transmembrane anchor without traversing the secretory pathway. The purpose of the present study was to investigate modifications of the gene expressing the L1 protein that would increase immunogenicity in mice when delivered by a gene gun. Results: The L1 gene was codon modified for optimal expression in mammalian cells and potential N-glycosylation sites removed. Addition of a signal sequence to the N-terminus of L1 increased cell surface expression as shown by confocal microscopy and flow cytometry of transfected cells. Removal of the transmembrane domain led to secretion of L1 into the medium. Induction of binding and neutralizing antibodies in mice was enhanced by gene gun delivery of L1 containing the signal sequence with or without the transmembrane domain. Each L1 construct partially protected mice against weight loss caused by intranasal administration of vaccinia virus. Conclusion: Modifications of the vaccinia virus L1 gene including codon optimization and addition of a signal sequence with or without deletion of the transmembrane domain can enhance the neutralizing antibody response of a DNA vaccine. C1 [Shinoda, Kaori; Wyatt, Linda S.; Irvine, Kari R.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM shinodak@niaid.nih.gov; lwyatt@niaid.nih.gov; kari@kariirvine.com; bmoss@nih.gov FU Norman Cooper and Catherine Cotter; Vaccine Research Center, NIAID; NIH [VRC8400]; Gary Cohen and Roselyn Eisenberg, University of Pennsylvania; Wolfgang Leitner, Dermatology Branch/NCI/NIH; Division of Intramural Research, NIAID; NIH FX The excellent assistance of Norman Cooper and Catherine Cotter in preparation of cells and purification of VACV is appreciated. Gary Nabel, Vaccine Research Center, NIAID, NIH generously provided the plasmid VRC8400 and Gary Cohen and Roselyn Eisenberg, University of Pennsylvania provided antiserum to the L1 protein. We thank Wolfgang Leitner, Dermatology Branch/NCI/NIH for supplying the gold particles used in the gene gun experiments. This study was supported by the Division of Intramural Research, NIAID, NIH. NR 47 TC 8 Z9 9 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA CURRENT SCIENCE GROUP, MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD MAR 3 PY 2009 VL 6 AR 28 DI 10.1186/1743-422X-6-28 PG 8 WC Virology SC Virology GA 426PW UT WOS:000264721200001 PM 19257896 ER PT J AU Abe, M Hanakawa, T AF Abe, Mitsunari Hanakawa, Takashi TI Functional coupling underlying motor and cognitive functions of the dorsal premotor cortex SO BEHAVIOURAL BRAIN RESEARCH LA English DT Review DE Cognitive manipulation; Functional segregation; Functional connectivity; Attentional selection; Sequence generation; Cortico-cortical network; Top-down and bottom-up information processing ID DORSOLATERAL PREFRONTAL CORTEX; HUMAN WORKING-MEMORY; MACAQUE MONKEY; HUMAN BRAIN; FRONTAL-CORTEX; ATTENTIONAL SELECTION; MENTAL CALCULATION; BRODMANN AREA-6; RHESUS-MONKEY; ORGANIZATION AB This review article discusses mechanisms of how distinct behavioral operations are organized by different modules distributed in the frontal cortex. Cognitive manipulation often requires a flow of multiple elementary sub-operations processed in specialized brain regions. The dorsolateral prefrontal cortex (dIPFC) is likely responsible for attentional selection, which orients organisms' mental resources to behaviorally relevant information. The dorsal premotor cortex (PMd) is implicated to possess a functional gradient along the rostral-caudal axis, The rostral sector of the PMd (pre-PMd) is involved in various cognitive/premovement processes while its Caudal sector (PMd proper) primarily controls actual movement. Neurophysiology studies in monkeys have shown that the pre-PMd, when functionally coupled with the dIPFC, may transform independent working memory items into a single sequence (sequence generation). A neuroimaging study has shown that the pre-PMd is indeed involved in sequence generation under the influence of the dIPFC in humans. It has been also indicated that the dIPFC and the pre-PMd are functionally coupled when attentional selection and sequence generation are to be unified for serial information processing. Functional interplay through the prefrontal-premotor connections may mediate the integration of specific sub-operations for multi-step cognitive manipulation. Furthermore, evidence from a meta-analysis of the imaging literature is argued for an idea that the coupling pattern with other frontal cortical areas may characterize of the function of the pre-PMd and PMd proper in various motor and cognitive tasks. (C) 2008 Elsevier B.V. All rights reserved. C1 [Hanakawa, Takashi] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Cort Funct Disorders, Kodaira, Tokyo 1878502, Japan. [Abe, Mitsunari] Kyoto Univ, Grad Sch Med, Human Brain Res Ctr, Sakyo Ku, Kyoto 6068507, Japan. [Abe, Mitsunari] Natl Inst Neurol Disorders & Stroke, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. [Abe, Mitsunari] Natl Inst Neurol Disorders & Stroke, Stroke Neurorehabil Clin, NIH, Bethesda, MD 20892 USA. [Hanakawa, Takashi] Japan Sci & Technol Agcy, PRESTO, Kawaguchi, Saitama 3320012, Japan. RP Hanakawa, T (reprint author), Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Cort Funct Disorders, 4-1-1 Ogawahigashi, Kodaira, Tokyo 1878502, Japan. EM hanakawa@ncnp.go.jp RI Abe, Mitsunari/F-1373-2014 OI Abe, Mitsunari/0000-0002-3913-2292 FU Ministry of Education, Science, Sports, Culture, and Technology, Japan FX This work was in part supported by Grant-in-Aid for Scientific Research on Priority Areas (integrative Brain Research; Emergence of Adaptive Motor Function through Interaction among the Body, Brain and Environment) to T.H. from the Ministry of Education, Science, Sports, Culture, and Technology, Japan. NR 86 TC 45 Z9 45 U1 2 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 2 PY 2009 VL 198 IS 1 BP 13 EP 23 DI 10.1016/j.bbr.2008.10.046 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 410ZH UT WOS:000263616300002 PM 19061921 ER PT J AU Drain, PK Holmes, KK Skeff, KM Hall, TL Gardner, P AF Drain, Paul K. Holmes, King K. Skeff, Kelley M. Hall, Thomas L. Gardner, Pierce TI Global Health Training and International Clinical Rotations During Residency: Current Status, Needs, and Opportunities SO ACADEMIC MEDICINE LA English DT Article ID TRAVEL MEDICINE; EXPERIENCE; ELECTIVES; WORLD; IMMIGRANTS; PROGRAM; CARE AB Increasing international travel and migration have contributed to globalization of diseases. Physicians today must understand the global burden and epidemiology of diseases, the disparities and inequities in global health systems, and the importance of cross-cultural sensitivity. To meet these needs, resident physicians across all specialties have expressed growing interest in global health training and international clinical rotations. More residents are acquiring international experience, despite inadequate guidance and support from most accreditation organizations and residency programs. Surveys of global health training, including international clinical rotations, highlight the benefits of global health training as well as the need for a more coordinated approach. In particular, international rotations broaden a resident's medical knowledge, reinforce physical examination skills, and encourage practicing medicine among underserved and multicultural populations. As residents recognize these personal and professional benefits, a strong majority of them seek to gain international clinical experience. In conclusion, with feasible and appropriate administrative steps, all residents can receive global health training and be afforded the accreditation and programmatic support to participate in safe international rotations. The next steps should address accreditation for international rotations and allowance for training away from continuity clinics by residency accreditation bodies, and stipend and travel support for six or more weeks of call-free elective time from residency programs. C1 [Drain, Paul K.; Skeff, Kelley M.] Stanford Univ, Dept Med, Palo Alto, CA 94304 USA. [Holmes, King K.] Univ Washington, Dept Med, Seattle, WA USA. [Holmes, King K.] Univ Washington, Dept Global Hlth, Seattle, WA 98195 USA. [Hall, Thomas L.] Global Hlth Educ Consortium, San Francisco, CA USA. [Hall, Thomas L.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Gardner, Pierce] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Drain, PK (reprint author), Stanford Univ, Dept Med, 300 Pasteur Dr,S101, Stanford, CA 94305 USA. EM pkdrain@stanford.edu OI Drain, Paul/0000-0003-3300-3817 FU NIAID NIH HHS [K23 AI108293] NR 28 TC 120 Z9 120 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD MAR PY 2009 VL 84 IS 3 BP 320 EP 325 PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 466IP UT WOS:000267655100013 PM 19240438 ER PT J AU Mani, V Chikkaveeraiah, BV Patel, V Gutkind, JS Rusling, JF AF Mani, Vigneshwaran Chikkaveeraiah, Bhaskara V. Patel, Vyomesh Gutkind, J. Silvio Rusling, James F. TI Ultrasensitive Immunosensor for Cancer Biomarker Proteins Using Gold Nanoparticle Film Electrodes and Multienzyme-Particle Amplification SO ACS NANO LA English DT Article DE gold nanoparticles; immunosensor; cancer biomarkers; multilabel amplification ID PROSTATE-SPECIFIC ANTIGEN; ELECTROCHEMICAL DETECTION; CARBON NANOTUBES; AU NANOPARTICLES; SYSTEMS BIOLOGY; CELL CARCINOMA; PROTEOMICS; MONOLAYER; CATALYSIS; SIZE AB A densely packed gold nanoparticle platform combined with a multiple-enzyme labeled detection antibody-magnetic bead bioconjugate was used as the basis for an ultrasensitive electrochemical immunosensor to detect cancer biomarkers in serum. Sensitivity was greatly amplified by synthesizing magnetic bioconjugates particles containing 7500 horseradish peroxidase (HRP) labels along with detection antibodies (Ab(2)) attached to activated carboxyl groups on 1 mu m diameter magnetic beads. These sensors had sensitivity of 31.5 mu A mL ng(-1) and detection limit (DL) of 0.5 pg mL(-1) for prostate specific antigen (PSA) in 10 mu L of undiluted serum. This represents an ultralow mass DL of 5 fg. PSA, 8-fold better than a previously reported carbon nanotube (CNT) forest immunosensor featuring multiple labels on carbon nanotubes, and near or below the normal serum levels of most cancer biomarkers. Measurements of PSA in cell lysates and human serum of cancer patients gave excellent correlations with standard ELISA assays. These easily fabricated AuNP immunosensors show excellent promise for future fabrication of bioelectronic arrays. C1 [Mani, Vigneshwaran; Chikkaveeraiah, Bhaskara V.; Rusling, James F.] Univ Connecticut, Dept Chem, Storrs, CT 06268 USA. [Rusling, James F.] Univ Connecticut, Inst Mat Sci, Storrs, CT 06268 USA. [Rusling, James F.] Univ Connecticut, Ctr Hlth, Dept Cell Biol, Farmington, CT 06032 USA. [Patel, Vyomesh; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Rusling, JF (reprint author), Univ Connecticut, Dept Chem, 55 N Eagleville Rd, Storrs, CT 06268 USA. EM james.rusling@uconn.edu RI Gutkind, J. Silvio/A-1053-2009 FU NIEHS/NIH [ES013557]; National Institute of Dental and Craniofacial Research, NIH FX This research was supported by PHS grant ES013557 from NIEHS/NIH, and by the intramural programs of the National Institute of Dental and Craniofacial Research, NIH. We thank Joseph D. Gong for TEM analysis and Debra Rood and Lawrence K. Silbart for assistance with ELISA measurements. NR 64 TC 310 Z9 313 U1 33 U2 247 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1936-0851 J9 ACS NANO JI ACS Nano PD MAR PY 2009 VL 3 IS 3 BP 585 EP 594 DI 10.1021/nn800863w PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 423ZL UT WOS:000264535200015 PM 19216571 ER PT J AU Liden, Y Landgren, O Arner, S Sjolund, KF Johansson, E AF Liden, Y. Landgren, O. Arner, S. Sjolund, K. -F. Johansson, E. TI Procedure-related pain among adult patients with hematologic malignancies SO ACTA ANAESTHESIOLOGICA SCANDINAVICA LA English DT Article; Proceedings Paper CT 11th World Congress on Pain CY AUG 21-26, 2005 CL Sydney, AUSTRALIA SP Int Assoc Study Pain, US Canc Pain Relief Comm, Natl Canc Inst ID NEEDLE-ASPIRATION-CYTOLOGY; RANDOMIZED CLINICAL-TRIAL; POSTOPERATIVE PAIN; PEDIATRIC ONCOLOGY; CANCER; PREVALENCE; SATISFACTION; MANAGEMENT; ANXIETY; POPULATION AB Cancer patients undergo numerous invasive diagnostic procedures. However, there are only sparse data on the characteristics and determinants for procedure-related pain among adult cancer patients. In this prospective study, we evaluated the characteristics and determinants of procedure-related pain in 235 consecutive hematologic patients (M/F:126/109; median age 62 years, range 20-89 years) undergoing a bone marrow aspiration/biopsy (BMA) under local anesthesia. Questionnaires were used to assess patients before-, 10 min and 1-7 days post BMA. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). 165/235 (70%) patients reported pain during BMA; 92 (56%), 53 (32%) and 5 (3%) of these indicated moderate [visual analogue scale (VAS)>= 30 mm], severe (VAS > 54 mm) and worst possible pain (VAS=100 mm), respectively. On multivariate analyses, pre-existing pain (OR=2.60 95% CI 1.26-5.36), anxiety about the diagnostic outcome of BMA (OR=3.17 95% CI 1.54-6.52), anxiety about needle-insertion (OR=2.49 95% CI 1.22-5.10) and low employment status (sick-leave/unemployed) (OR=3.14 95% CI 1.31-7.55) were independently associated with an increased risk of pain during BMA. At follow-up 10 min after BMA, 40/235 (17%) patients reported pain. At 1, 3, 6 and 7 days post BMA, pain was present in 137 (64%), 90 (42%), 43 (20%) and 25 (12%) patients, respectively. We found that 3/4 of hematologic patients who underwent BMA reported procedural pain; one third of these patients indicated severe pain. Pre-existing pain, anxiety about the diagnostic outcome of BMA or needle-insertion, and low employment status were independent risk factors. C1 [Liden, Y.; Arner, S.; Sjolund, K. -F.] Karolinska Inst, Dept Physiol & Pharmacol, Sect Anesthesiol & Intens Care, Stockholm, Sweden. [Landgren, O.; Johansson, E.] Karolinska Univ Hosp & Inst, Dept Med, Div Hematol, Stockholm, Sweden. [Landgren, O.] NCI, NIH, Bethesda, MD 20892 USA. RP Liden, Y (reprint author), Karolinska Univ, Hosp Solna, Dept Anesthesia, Surg Serv & Intens Care,Multidisciplinary Pain Ct, SE-17176 Stockholm, Sweden. EM ylva.liden@karolinska.se NR 40 TC 19 Z9 19 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-5172 J9 ACTA ANAESTH SCAND JI Acta Anaesthesiol. Scand. PD MAR PY 2009 VL 53 IS 3 BP 354 EP 363 DI 10.1111/j.1399-6576.2008.01874.x PG 10 WC Anesthesiology SC Anesthesiology GA 407GM UT WOS:000263351600012 PM 19243321 ER PT J AU Li, YF Poole, S Rasulova, F McVeigh, AL Savarino, SJ Xia, D AF Li, Yong-Fu Poole, Steven Rasulova, Fatima McVeigh, Annette L. Savarino, Stephen J. Xia, Di TI Crystallization and preliminary X-ray diffraction analyses of several forms of the CfaB major subunit of enterotoxigenic Escherichia coli CFA/I fimbriae SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS LA English DT Article ID FACTOR ANTIGEN-I; COLONIZATION FACTOR; DIARRHEA; ADHESIN; ARCHITECTURE; BIOGENESIS; RESOLUTION; PILI AB Enterotoxigenic Escherichia coli (ETEC), a major global cause of diarrhea, initiates the pathogenic process via fimbriae-mediated attachment to the small intestinal epithelium. A common prototypic ETEC fimbria, colonization factor antigen I (CFA/I), consists of a tip-localized minor adhesive subunit CfaE and the stalk-forming major subunit CfaB, both of which are necessary for fimbrial assembly. To elucidate the structure of CFA/I at atomic resolution, three recombinant proteins were generated consisting of fusions of the minor and major subunits (CfaEB) and of two (CfaBB) and three (CfaBBB) repeats of the major subunit. Crystals of CfaEB diffracted X-rays to 2.1 angstrom resolution and displayed the symmetry of space group P2(1). CfaBB exhibited a crystal diffraction limit of 2.3 angstrom resolution and had the symmetry of space group P2(1)2(1)2. CfaBBB crystallized in the monoclinic space group C2 and diffracted X-rays to 2.3 angstrom resolution. These structures were determined using the molecular-replacement method. C1 [Li, Yong-Fu; Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Poole, Steven; Rasulova, Fatima; McVeigh, Annette L.; Savarino, Stephen J.] USN, Med Res Ctr, Enter Dis Dept, Infect Dis Directorate, Silver Spring, MD 20910 USA. [Savarino, Stephen J.] Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM dixia@helix.nih.gov FU NIH; Center for Cancer Research; Trans NIH/FDA Intramural Biodefense Program; US Army Military Infectious Diseases Research Program [A0307]; Henry M. Jackson Foundation FX The authors wish to thank the staff members of the SER-CAT beamline at APS, ANL for their assistance in data collection. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, by a grant from the Trans NIH/FDA Intramural Biodefense Program (to DX), by the US Army Military Infectious Diseases Research Program Work Unit Number A0307 (to SJS) and by the Henry M. Jackson Foundation for the Advancement of Military Medicine (SJS). The views expressed in this article are those of the authors and do not necessarily reflect the official position of the Department of the Navy, Department of Defense or the US government. NR 28 TC 4 Z9 4 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1744-3091 J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Cryst. Commun. PD MAR PY 2009 VL 65 BP 242 EP 247 DI 10.1107/S1744309109001584 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 413DN UT WOS:000263773200012 PM 19255474 ER PT J AU Varga, T Palkovits, M Usdin, TB Dobolyi, A AF Varga, T. Palkovits, M. Usdin, T. B. Dobolyi, A. TI Identification and characterization of the medial paralemniscal nucleus and its neuronal connections in rat SO ACTA PHYSIOLOGICA HUNGARICA LA English DT Meeting Abstract ID TUBEROINFUNDIBULAR PEPTIDE; 39 RESIDUES C1 [Varga, T.; Palkovits, M.; Dobolyi, A.] Hungarian Acad Sci, Dept Anat Histol & Embryol, Neuromorphol & Neuroendocrine Res Lab, Budapest, Hungary. [Varga, T.; Palkovits, M.; Dobolyi, A.] Semmelweis Univ, Budapest, Hungary. [Usdin, T. B.] NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. RI Palkovits, Miklos/F-2707-2013 NR 3 TC 0 Z9 0 U1 0 U2 0 PU AKADEMIAI KIADO RT PI BUDAPEST PA PRIELLE K U 19, PO BOX 245,, H-1117 BUDAPEST, HUNGARY SN 0231-424X J9 ACTA PHYSIOL HUNG JI Acta Physiol. Hung. PD MAR PY 2009 VL 96 IS 1 BP 144 EP 145 PG 2 WC Physiology SC Physiology GA 413LK UT WOS:000263794400101 ER PT J AU Strupinska, M Rostafinska-Suchar, G Stables, JP Paruszewski, R AF Strupinska, Marzanna Rostafinska-Suchar, Grazyna Stables, James. P. Paruszewski, Ryszard TI NEW DERIVATIVES OF BENZYLAMIDE WITH ANTICONVULSANT ACTIVITY SO ACTA POLONIAE PHARMACEUTICA LA English DT Article DE anticonvulsants; synthesis; activity; neurotoxicity ID SEIZURE; ACID AB Previously obtained picolinic acid benzylamide is I potent anticonvulsant with low neurotoxicity. In search for new effective anticonvulsants twelve new benzylamides (1-12) were synthesized and preliminary evaluated in the Anticonvulsant Screening Program (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Two of them appeared the most promising: 1-cyclopentenecarboxylic acid benzylamide (1-Cpc-BZA) (9) showed MES ED(50) = 85,36 mg/kg (PI = 2,49), scPTZ ED(50) = 1,37 mg/kg (PI = 1,37), 6Hz-EST ED(50) = 50,29 mg/kg and cyclopentanecarboxylic acid benzylamide (Cpc-BZA) (11) showed pilocarpine ED(50) = 154.75 mg/kg and pilocarpine ED(97) = 270.95 mg/kg. C1 [Strupinska, Marzanna; Rostafinska-Suchar, Grazyna; Paruszewski, Ryszard] Med Univ Warsaw, Dept Drug Chem, PL-02097 Warsaw, Poland. [Stables, James. P.] NINDS, Epilepsy Branch, Rockville, MD 20852 USA. RP Paruszewski, R (reprint author), Med Univ Warsaw, Dept Drug Chem, PL-02097 Warsaw, Poland. EM ryszard.paruszewski@neostrada.pl FU Medical University of Warsaw; National Institute of Neurological Disorders and Stroke (ADDP) FX This investigation was supported in part by the Medical University of Warsaw and National Institute of Neurological Disorders and Stroke (ADDP). NR 9 TC 6 Z9 6 U1 0 U2 1 PU POLSKIEGO TOWARZYSTWA FARMACEUTYCZNEGO PI WARSAW PA DLUGA 16, 00-238 WARSAW, POLAND SN 0001-6837 J9 ACTA POL PHARM JI ACTA POL. PHARM. PD MAR-APR PY 2009 VL 66 IS 2 BP 155 EP 159 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 484ZZ UT WOS:000269091200008 PM 19719049 ER PT J AU Heinz, AJ Wu, J Witkiewitz, K Epstein, DH Preston, KL AF Heinz, Adrienne J. Wu, Johnny Witkiewitz, Katie Epstein, David H. Preston, Kenzie L. TI Marriage and relationship closeness as predictors of cocaine and heroin use SO ADDICTIVE BEHAVIORS LA English DT Article DE Heroin; Cocaine; Social support; Marital status; Treatment ID BEHAVIORAL COUPLES THERAPY; SUBSTANCE-ABUSING PATIENTS; DRUG-ABUSE; USE DISORDERS; RELATIONSHIP ADJUSTMENT; POSTTREATMENT DRINKING; INTERPERSONAL FACTORS; SOCIAL RELATIONSHIPS; ALCOHOL; OUTCOMES AB Marriage has been cited as a protective factor against drug use, but the relationship between marriage and drug use has not been explored longitudinally during addiction treatment. The current Study assessed individual trajectories of substance use during treatment as a function of marital status and perceived closeness of the marital relationship. A parallel-process growth model was used to (I) estimate the rate of change in percentage of cocaine-positive and heroin-positive urine samples, and (2) examine the relationship between marital status and drug use trajectories over 35 weeks, during and after treatment. Percent days of use for both drugs were lowest for married participants across all time points. Among married participants. reporting a close relationship with one's partner predicted less cocaine and heroin use. These findings suggest that being married and having a close relationship with one's spouse are associated with better outcomes over time. The causal nature of the association is suggested by previous research that has demonstrated the effectiveness of couples therapy as an adjunct to methadone maintenance. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Heinz, Adrienne J.] Univ Illinois, Dept Psychol MC 285, Chicago, IL 60302 USA. [Wu, Johnny; Witkiewitz, Katie] Univ Washington, Seattle, WA 98195 USA. [Epstein, David H.; Preston, Kenzie L.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Heinz, AJ (reprint author), Univ Illinois, Dept Psychol MC 285, 3022A Behav Sci Bldg,1007 W Harrison St, Chicago, IL 60302 USA. EM aheinz3@uic.edu RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU NIH, National Institute on Drug Abuse FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Drug Abuse. NR 33 TC 25 Z9 26 U1 2 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD MAR PY 2009 VL 34 IS 3 BP 258 EP 263 DI 10.1016/j.addbeh.2008.10.020 PG 6 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 404DF UT WOS:000263130200004 PM 19008050 ER PT J AU Kulmala, J Viljanen, A Sipila, S Pajala, S Parssinen, O Kauppinen, M Koskenvuo, M Kaprio, J Rantanen, T AF Kulmala, Jenni Viljanen, Anne Sipila, Sarianna Pajala, Satu Parssinen, Olavi Kauppinen, Markku Koskenvuo, Markku Kaprio, Jaakko Rantanen, Taina TI Poor vision accompanied with other sensory impairments as a predictor of falls in older women SO AGE AND AGEING LA English DT Article DE falls; vision; co-impairment; older adults; ageing; elderly ID RANDOMIZED CONTROLLED-TRIAL; ELDERLY-WOMEN; RISK-FACTORS; VISUAL IMPAIRMENT; BALANCE; COMMUNITY; PEOPLE; HEALTH; PREVENTION; STABILITY AB Objectives: we studied visual acuity (VA) and co-existing hearing impairment and poor standing balance as predictors of falls. Design: prospective study with 1-year follow-up. Setting: research laboratory and residential environment. Participants: 428 women aged 63-76 years from the Finnish Twin Study on Aging. Measurements: participants were followed up for incidence of falls over 1 year. VA, hearing ability and standing balance were assessed at the baseline. The incidence rate ratios (IRR) for falls were computed using the negative binomial regression model. Results: during the follow-up, 47% of participants experienced a fall. After adjusting for age and interdependence of twin sisters, participants with vision impairment (VA of < 1.0) but no other sensory impairments had a higher, but non-significant, risk for falls compared to persons with normal vision (IRR 1.5, 95% CI 0.6-4.2). Co-existing vision impairment and impaired balance increased the risk (IRR 2.7, 95% CI 0.9-8.0), as also did co-existing vision and hearing impairment (IRR 4.2, 95% CI 1.5-11.3), compared to those with normal vision. Among persons with all three impairments, the IRR for falls increased to 29.4 (95% CI 5.8-148.3) compared to participants with good vision. Conclusion: the impact of vision impairment on fall risk was higher when accompanied with other sensory and balance impairments, probably because the presence of other impairments prevented the reception of compensatory information about body posture and environment being received from other sensory sources. When aiming to prevent falls and their consequences in older people, it is important to check whether poor vision is accompanied with other impairments. C1 [Kulmala, Jenni; Viljanen, Anne; Sipila, Sarianna; Kauppinen, Markku; Rantanen, Taina] Univ Jyvaskyla, Finnish Ctr Interdisciplinary Gerontol, Dept Hlth Sci, FIN-40014 Viveca, Finland. [Pajala, Satu] NIA, LEBD, NIH, Bethesda, MD 20892 USA. [Parssinen, Olavi] Cent Hosp Cent Finland, Dept Ophthalmol, Jyvaskyla, Finland. [Koskenvuo, Markku; Kaprio, Jaakko] Univ Helsinki, Dept Publ Hlth, Helsinki, Finland. [Kaprio, Jaakko] Natl Publ Hlth Inst, Dept Mental Hlth & Alcohol Res, Helsinki, Finland. RP Kulmala, J (reprint author), Univ Jyvaskyla, Finnish Ctr Interdisciplinary Gerontol, Dept Hlth Sci, POB 35, FIN-40014 Viveca, Finland. EM jenni.kulmala@sport.jyu.fi RI Kaprio, Jaakko/A-1820-2008; Kulmala, Jenni/F-5612-2014; Rantanen, Taina/O-6579-2016; OI Kulmala, Jenni/0000-0003-0194-5551; Kaprio, Jaakko/0000-0002-3716-2455; Rantanen, Taina/0000-0002-1604-1945; Viljanen, Anne/0000-0002-8428-3604; Sipila, Sarianna/0000-0001-5934-7728 FU University of Jyvaskyla; Juho Vainio Foundation; Academy of Finland; NIH, National Institute of Aging FX This study was financially supported by the University of Jyvaskyla and Juho Vainio Foundation grants. J.K. is supported by the Academy of Finland Centre of Excellence in Complex Disease Genetics. S.P. was supported by the Intramural Research Program of the NIH, National Institute of Aging. The mentioned organizations have played a role neither in the design, execution, analysis and interpretation of data, nor in the writing of the studies. NR 28 TC 43 Z9 44 U1 2 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0002-0729 J9 AGE AGEING JI Age Ageing PD MAR PY 2009 VL 38 IS 2 BP 162 EP 167 DI 10.1093/ageing/afn228 PG 6 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 410UD UT WOS:000263602900007 PM 19008307 ER PT J AU Martin, AG Trama, J Crighton, D Ryan, KM Fearnhead, HO AF Martin, Angel G. Trama, Jason Crighton, Diane Ryan, Kevin M. Fearnhead, Howard O. TI Activation of p73 and induction of Noxa by DNA damage requires NF-kappa B SO AGING-US LA English DT Article DE apoptosis; p73; NF-kappa B B; Noxa ID TUMOR-SUPPRESSOR FUNCTIONS; ALPHA-INDUCED APOPTOSIS; CELL-DEATH; ENDOTHELIAL-CELLS; C-ABL; INDUCIBLE CHEMORESISTANCE; P53-DEPENDENT APOPTOSIS; P53-RELATED PROTEIN; CEREBRAL-ISCHEMIA; CANCER-CELLS AB Although the transcription factor NF-kappa B is most clearly linked to the inhibition of extrinsic apoptotic signals suchas TNF alpha by upregulating known anti-apoptotic genes, NF-kappa B has also been proposed to be required for p53-induced apoptosis in transformed cells. However, the involvement of NF-kappa B in this process is poorly understood. Here we investigate this mechanism and show that in transformed MEFs lacking NF-kappa B (p65 null cells) genotoxin-induced cytochrome c release is compromised. To further address how NF-kappa B contributes to apoptosis, gene profiling by microarray analysis of MEFs was performed, revealing that NF-kappa B is required for expression of Noxa, a pro-apoptotic BH3-only proteinthat is induced by genotoxins and that triggers cytochrome c release. Moreover, we find that in the absence of NF-kappa B, genotoxin treatment cannot induce Noxa mRNA expression. Noxa expression had been shown to be regulated directly by genes of the p53 family, like p73 and p63, following genotoxin treatment. Here we show that p73 is activated after genotoxin treatment only in the presence of NF-kappa B and that p73 induces Noxa gene expression through the p53 element in the promoter. Together our data provides an explanation for how loss of NF-kappa B abrogates genotoxin-induced apoptosis. C1 [Martin, Angel G.; Trama, Jason; Fearnhead, Howard O.] NCI, Apoptosis Sect, Frederick, MD 21702 USA. [Crighton, Diane; Ryan, Kevin M.] Canc Res UK Beatson Labs, Tumour Cell Death Lab, Glasgow G61 1BD, Lanark, Scotland. RP Martin, AG (reprint author), Fdn Inbiomed, Paseo Mekeletegi 61, San Sebastian 20009, Spain. EM agmartin@inbiomed.org RI Fearnhead, Howard/D-4826-2012 NR 75 TC 20 Z9 21 U1 1 U2 5 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD MAR PY 2009 VL 1 IS 3 BP 335 EP 349 PG 15 WC Cell Biology SC Cell Biology GA 579UM UT WOS:000276401000008 PM 20195489 ER PT J AU Richards, C Tao, W Hamer, D AF Richards, Chris Tao, Wang Hamer, Dean TI Re: "Enhancement of HIV Infection by Cellulose Sulfate," by Tao et al. Reply SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Letter ID MICROBICIDES C1 [Richards, Chris; Tao, Wang; Hamer, Dean] Natl Canc Inst, Vaccine Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Tao, W (reprint author), Natl Canc Inst, Vaccine Branch, Natl Inst Hlth, Bldg 37,Room 6002, Bethesda, MD 20892 USA. EM wangtao@mail.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAR PY 2009 VL 25 IS 3 BP 375 EP 376 DI 10.1089/aid.2008.0313 PG 2 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 425KV UT WOS:000264636300019 ER PT J AU Oroszi, G Anton, RF O'Malley, S Swift, R Pettinati, H Couper, D Yuan, QP Goldman, D AF Oroszi, Gabor Anton, Raymond F. O'Malley, Stephanie Swift, Robert Pettinati, Helen Couper, David Yuan, Qiaoping Goldman, David TI OPRM1 Asn40Asp Predicts Response to Naltrexone Treatment: A Haplotype-Based Approach SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE OPRM1 Asn40Asp; Naltrexone; Treatment Response; Haplotype; Good Clinical Outcome; Haplotype by Medication Interaction ID MU-OPIOID-RECEPTOR; ALCOHOL DEPENDENCE; TRANSCRIPTIONAL REGULATION; SUBSTANCE DEPENDENCE; GENE OPRM1; A118G POLYMORPHISM; OPIATE RECEPTOR; CANDIDATE GENE; MESSENGER-RNA; ASSOCIATION AB Individualized pharmacotherapy requires identification of genetic variants predictive of treatment response. In OPRM1, Asn40Asp has been reported to be predictive of response to naltrexone treatment. Nevertheless, the in vitro function of the polymorphism remains elusive and over 300 OPRM1 sequence variants have been identified to date. Therefore we used a haplotype-based approach to capture information of other genetic variants that might predict treatment response to naltrexone in the COMBINE Study. 5' nuclease genotyping assays (TaqMan((R))) were applied for 10 SNPs. Five-locus haplotypes in 2 OPRM1 haplotype blocks were assigned to Caucasian participants. The relationship of the haplotypes to medication reflected by "good clinical outcome" was analyzed in 306 Caucasians treated without Combined Behavioral Intervention and with either naltrexone or placebo. A significant haplotype by medication interaction (p = 0.03) was found in OPRM1 block 1. Naltrexone-treated alcoholics with haplotype AGCCC, the single haplotype carrying the Asp40 allele had the highest percent of good clinical outcome. When interaction of genotypes at each of the 5 loci comprising block 1 with medication was examined, only the Asn40/Asp40 and Asp40/Asp40 genotypes were found to significantly interact with naltrexone treatment. No haplotype by medication interaction was documented in OPRM1 block 2. Our haplotype-based approach confirms that the single OPRM1 locus predictive of response to naltrexone treatment is Asn40Asp in exon 1. A substantial contribution of any other OPRM1 genetic variant to interindividual variations in response to naltrexone treatment (at least in terms of good clinical outcome) is not supported by our findings. C1 [Oroszi, Gabor; Anton, Raymond F.] Med Univ S Carolina, Ctr Drug & Alcohol Programs, Charleston, SC 29425 USA. [O'Malley, Stephanie] Yale Univ, Sch Med, Substance Abuse Treatment Unit, New Haven, CT USA. [Swift, Robert] Brown Univ, Roger Williams Med Ctr, Providence, RI 02912 USA. [Swift, Robert] Brown Univ, Providence VA Med Ctr, Providence, RI 02912 USA. [Pettinati, Helen] Univ Penn, Sch Med, Treatment Res Ctr, Philadelphia, PA 19104 USA. [Couper, David] Univ N Carolina, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Yuan, Qiaoping; Goldman, David] NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP Anton, RF (reprint author), Med Univ S Carolina, Ctr Drug & Alcohol Programs, 67 President St,POB 250861, Charleston, SC 29425 USA. EM antonr@musc.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) [U10AA11715, 11716, 11721, 11727, 11756, 11768, 11773, 11776, 11777, 11783, 11787, 11799] FX The authors wish to acknowledge the work of all of the COMBINE Study investigators and staff whose names are listed on the COMBINE Study website (http://www.cscc.unc.edu/combine). The authors also wish to acknowledge the work of James D. Hosking, who, prior to his untimely death, served as principal investigator of the COMBINE Study Coordinating Center (University of North Carolina). NR 53 TC 57 Z9 58 U1 1 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2009 VL 33 IS 3 BP 383 EP 393 DI 10.1111/j.1530-0277.2008.00846.x PG 11 WC Substance Abuse SC Substance Abuse GA 409PN UT WOS:000263518400001 PM 19053977 ER PT J AU Tikkanen, R Sjoberg, RL Ducci, F Goldman, D Holi, M Tiihonen, J Virkkunen, M AF Tikkanen, Roope Sjoberg, Rickard L. Ducci, Francesca Goldman, David Holi, Matti Tiihonen, Jari Virkkunen, Matti TI Effects of MAOA-Genotype, Alcohol Consumption, and Aging on Violent Behavior SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Psychiatric Genetics; Alcoholism; Antisocial Personality Disorder; Borderline Personality Disorder; Violent Behavior ID MONOAMINE-OXIDASE-A; ANTISOCIAL PERSONALITY-DISORDER; IMPULSIVE FIRE SETTERS; PROMOTER-REGION; GENE PROMOTER; FUNCTIONAL POLYMORPHISM; REGULATORY POLYMORPHISM; DISRUPTIVE BEHAVIOR; GLUCOSE-METABOLISM; SALIVARY CORTISOL AB Environmental factors appear to interact with a functional polymorphism (MAOA-LPR) in the promoter region of the monoamine oxidase A gene (MAOA) in determining some forms of antisocial behavior. However, how MAOA-LPR modulates the effects of other factors such as alcohol consumption related to antisocial behavior is not completely understood. This study examines the conjunct effect of MAOA-LPR, alcohol consumption, and aging on the risk for violent behavior. Recidivism in severe impulsive violent behavior was assessed after 7 to 15 years in a sample of 174 Finnish alcoholic offenders, the majority of whom exhibited antisocial or borderline personality disorder or both, and featured impulsive temperament traits. The risk for committing new acts of violence increased by 2.3% for each kilogram of increase in yearly mean alcohol consumption (p = 0.004) and decreased by 7.3% for every year among offenders carrying the high activity MAOA genotype. In contrast, alcohol consumption and aging failed to affect violent behavior in the low activity MAOA genotyped offenders. MAOA-LPR showed no main effect on the risk for recidivistic violence. Violent offenders carrying the high activity MAOA genotype differ in several ways from carriers with the low activity MAOA risk allele previously associated with antisocial behavior. Finnish high activity MAOA genotyped risk alcoholics exhibiting antisocial behavior, high alcohol consumption, and abnormal alcohol-related impulsive and uncontrolled violence might represent an etiologically distinct alcohol dependence subtype. C1 [Tikkanen, Roope; Holi, Matti; Virkkunen, Matti] Univ Helsinki, Dept Psychiat, Inst Clin Med, Helsinki, Finland. [Sjoberg, Rickard L.; Goldman, David] NIAAA, NIH, Neurogenet Lab, Rockville, MD 20852 USA. [Sjoberg, Rickard L.] Uppsala Univ, Clin Res Ctr, Vasteras, Sweden. [Sjoberg, Rickard L.] Umea Univ Hosp, Dept Neurosurg, S-90185 Umea, Sweden. [Ducci, Francesca] Kings Coll London, London WC2R 2LS, England. [Tiihonen, Jari] Univ Kuopio, Niuvanniemi Hosp, Dept Forens Psychiat & Clin Physiol, FIN-70211 Kuopio, Finland. RP Tikkanen, R (reprint author), Univ Helsinki, Dept Psychiat, POB 590, Helsinki 00029, Finland. EM roope.tikkanen@helsinki.fi RI Goldman, David/F-9772-2010; Sjoberg, Rickard/B-9337-2008; Tiihonen, Jari/G-3078-2012; Sjoberg, Rickard/M-4690-2014 OI Goldman, David/0000-0002-1724-5405; Tiihonen, Jari/0000-0002-0400-6798; FU Intramural NIH HHS [Z01 AA000306-02, Z99 OD999999] NR 75 TC 32 Z9 34 U1 0 U2 7 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2009 VL 33 IS 3 BP 428 EP 434 DI 10.1111/j.1530-0277.2008.00853.x PG 7 WC Substance Abuse SC Substance Abuse GA 409PN UT WOS:000263518400006 PM 19120058 ER PT J AU Bice, P Valdar, W Zhang, LL Liu, LX Lai, DB Grahame, N Flint, J Li, TK Lumeng, L Foroud, T AF Bice, Paula Valdar, William Zhang, Lili Liu, Lixiang Lai, Dongbing Grahame, Nicholas Flint, Jonathan Li, Ting-Kai Lumeng, Lawrence Foroud, Tatiana TI Genomewide SNP Screen to Detect Quantitative Trait Loci for Alcohol Preference in the High Alcohol Preferring and Low Alcohol Preferring Mice SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE Quantitative Trait Locus; Alcohol Consumption; Association ID CONGENIC STRAINS; IDENTIFICATION; CONFIRMATION; ASSOCIATION; DEPENDENCE; CHOLECYSTOKININ; SENSITIVITY; ACTIVATION; RECEPTORS; GENETICS AB The high and low alcohol preferring (HAP1 and LAP1) mouse lines were selectively bred for differences in alcohol intake. The HAP1 and LAP1 mice are essentially noninbred lines that originated from the outbred colony of HS/Ibg mice, a heterogeneous stock developed from intercrossing 8 inbred strains of mice. A total of 867 informative SNPs were genotyped in 989 HAP1 x LAP1 F2, 68 F1s, 14 parents (6 LAP1, 8 HAP1), as well as the 8 inbred strains of mice crossed to generate the HS/Ibg colony. Multipoint genome wide analyses were performed to simultaneously detect linked QTLs and also fine map these regions using the ancestral haplotypes. QTL analysis detected significant evidence of association on 4 chromosomes: 1, 3, 5, and 9. The region on chromosome 9 was previously found linked in a subset of these F2 animals using a whole genome microsatellite screen. We have detected strong evidence of association to multiple chromosomal regions in the mouse. Several of these regions include candidate genes previously associated with alcohol dependence in humans or other animal models. C1 [Bice, Paula; Zhang, Lili; Liu, Lixiang; Lai, Dongbing; Lumeng, Lawrence; Foroud, Tatiana] Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA. [Valdar, William; Flint, Jonathan] Wellcome Trust Ctr Human Genet, Oxford, England. [Grahame, Nicholas] Indiana Univ Purdue Univ, Dept Psychol, Indianapolis, IN 46205 USA. [Li, Ting-Kai] NIAAA, Bethesda, MD USA. RP Bice, P (reprint author), Indiana Univ, Sch Med, Dept Med, 975 W Walnut St,1B 411, Indianapolis, IN 46202 USA. EM pbice@iupui.edu OI Flint, Jonathan/0000-0002-9427-4429 FU National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health [R01 AA015933, N01-HG-65403]; APC [P60 AA007611-21]; European Union [LHSG-CT-2003-503265] FX This work was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health (Grant R01 AA015933) and APC of P60 AA007611-21. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number N01-HG-65403. William Valdar is funded by a grant from the European Union Framework 6 Programme, contract no: LHSG-CT-2003-503265. We also wish to give special thanks to Christina Best for developing and phenotyping the F2 mice that were used in the genome screen. This study was supported by NIH/NIAAA Grant R01 AA015933, N01-HG-65403, APC of P60 AA007611-21, and LHSG-CT-2003-503265. NR 41 TC 10 Z9 11 U1 2 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD MAR PY 2009 VL 33 IS 3 BP 531 EP 537 DI 10.1111/j.1530-0277.2008.00866.x PG 7 WC Substance Abuse SC Substance Abuse GA 409PN UT WOS:000263518400017 PM 19120064 ER PT J AU Everson, GT Shiffman, ML Hoefs, JC Morgan, TR Sterling, RK Wagner, DA Desanto, JL Curto, TM Wright, EC AF Everson, G. T. Shiffman, M. L. Hoefs, J. C. Morgan, T. R. Sterling, R. K. Wagner, D. A. Desanto, J. L. Curto, T. M. Wright, E. C. CA Halt C Trial Grp TI Quantitative tests of liver function measure hepatic improvement after sustained virological response: results from the HALT-C trial SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Article ID VIRUS-INFECTION; UNITED-STATES; ANTIVIRAL THERAPY; REDUCES HEPATOCARCINOGENESIS; ADVANCED FIBROSIS; PLUS RIBAVIRIN; INTERFERON; CIRRHOSIS; MONOETHYLGLYCINEXYLIDIDE; PEGINTERFERON-ALPHA-2A AB The impact of virologic response on hepatic function has not been previously defined. To determine the relationships of quantitative liver function tests (QLFTs) with virological responses to peginterferon (PEG) +/- ribavirin (RBV) in patients with chronic hepatitis C and to use serial QLFTs to define the spectrum of hepatic improvement after sustained virological response (SVR). Participants (n = 232) were enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial, had failed prior therapy, had bridging fibrosis or cirrhosis and were retreated with PEG/RBV. All 232 patients had baseline QLFTs; 24 patients with SVR and 68 nonresponders had serial QLFTs. Lidocaine, [24-(13)C]cholate, galactose and (99m)Tc-sulfur colloid were administered intravenously; [2,2,4,2-(2)H]cholate, [1-(13)C]methionine, caffeine and antipyrine were administered orally. Clearances (Cl), breath (13)CO(2), monoethylglycylxylidide (MEGX), perfused hepatic mass (PHM) and liver volume were measured. Rates of SVR were 18-26% in patients with good function by QLFTs, but <= 6% in patients with poor function. Hepatic metabolism, measured by caffeine k(elim) (P = 0.02), antipyrine k(elim) (P = 0.05) and antipyrine Cl (P = 0.02) and the portal circulation, measured by cholate Cl(oral) (P = 0.0002) and cholate shunt (P = 0.0003) and PHM (P = 0.03) improved after SVR. Hepatic dysfunction impairs the virological response to PEG/RBV. SVR improves hepatic metabolism, the portal circulation and PHM. C1 [Everson, G. T.] Univ Colorado, Sect Hepatol, Hlth Sci Ctr, Div Gastroenterol & Hepatol,Sch Med, Aurora, CO 80045 USA. [Shiffman, M. L.; Sterling, R. K.] Virginia Commonwealth Univ, Hepatol Sect, Med Ctr, Richmond, VA USA. [Hoefs, J. C.; Morgan, T. R.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Hoefs, J. C.; Morgan, T. R.] VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA. [Wagner, D. A.] Metab Solut Inc, Nashua, NH USA. [Curto, T. M.] New England Res Inst, Watertown, MA 02172 USA. [Wright, E. C.] NIDDK, Off Director, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD USA. RP Everson, GT (reprint author), Univ Colorado, Sect Hepatol, Hlth Sci Ctr, Div Gastroenterol & Hepatol,Sch Med, UCH AOP Room 7085,1635 N Ursula,B-154, Aurora, CO 80045 USA. EM greg.everson@uchsc.edu FU University of Colorado School of Medicine, Denver, CO: [N01-DK-9-2327, M01RR-00051]; University of California - Irvine, Irvine, CA [N01-DK-9-2320, M01RR-00827]; Virginia Commonwealth University Health System, Richmond, VA [N01-DK-9-2322, M01RR-00065]; New England Research Institutes, Watertown, MA [N01-DK-9-2328] FX Declaration of personal interests: The authors wish to acknowledge the contributions of our co-investigators, study coordinators and staff at each of the participating institutions as follows: University of Colorado School of Medicine, Denver, CO: (Contract N01-DK-9-2327, Grant M01RR-00051) Marcelo Kugelmas, MD, Carol McKinley, RN, Brenda Easley, RN, Shannon Lauriski, BS, Stephanie Shea, BA, Michelle Jaramillo. University of California - Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827) Muhammad Sheikh, MD, Norah Milne, MD, Choon Park, RN, William Rietkerk, Richard Kesler-West, M. Mazen Jamal, MD, MPH; Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, Grant M01RR-00065) Charlotte Hofmann, RN, Paula Smith, RN; New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328) Michael C. Doherty, MA, Kristin K Snow, ScD, Marina Mihova, MHA; National Institute of Diabetes and Digestive and Kidney Diseases, Division of Digestive Diseases and Nutrition, Bethesda, MD: James E. Everhart, MD, Jay H. Hoofnagle, MD, Leonard Seeff, MD. Data and Safety Monitoring Board Members: (Chair) Gary L. Davis, MD, Guadalupe Garcia-Tsao, MD, Michael Kutner, PhD, Stanley M. Lemon, MD, Robert P. Perillo, MD. Declaration of funding interests: This study was supported by the National Institute of Diabetes & Digestive & Kidney Diseases (contract numbers are listed below). Additional support was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, the National Center for Minority Health and Health Disparities and by General Clinical Research Center grants from the National Center for Research Resources, National Institutes of Health (grant numbers are listed below). Additional funding to conduct this study was supplied by Metabolic Solutions, Inc. and by Hoffmann-La Roche, Inc., through a Cooperative Research and Development Agreement with the National Institutes of Health. Financial relationships of the authors with Hoffmann-La Roche, Inc., are as follows: G. T. Everson, M. L. Shiffman, T. R. Morgan and R. K. Sterling are consultants, on the speaker's bureau and receive research support. J. C. Hoefs is on the speaker's bureau. Financial relationships of the authors with Metabolic Solutions are: G. T. Everson, M. L. Shiffman, R. K. Sterling and T. R. Morgan received research support and D. A. Wagner is employed, has equity and has intellectual property rights. G. T. Everson and UCHSC have filed US Patent Application No. 60/647,689, 'Methods for Diagnosis and Intervention of Hepatic Disorders', 26 January 2005 and International Application Number PCT/US2006/003132 as published under the Patent Cooperation Treaty, World Intellectual Property Organization, International Patent Classification A61K 49/00 (2006.01), International Publication Number WO 2006/081521 A2, 3 August 2006 (03.08.2006). The authors J. L. DeSanto, T. M. Curto and E. C. Wright had no financial relationships to disclose. Contract and grants supporting this study included: University of Colorado School of Medicine, Denver, CO: (Contract N01-DK-9-2327, Grant M01RR-00051), University of California - Irvine, Irvine, CA: (Contract N01-DK-9-2320, Grant M01RR-00827), Virginia Commonwealth University Health System, Richmond, VA: (Contract N01-DK-9-2322, Grant M01RR-00065), and New England Research Institutes, Watertown, MA: (Contract N01-DK-9-2328). NR 36 TC 13 Z9 13 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD MAR 1 PY 2009 VL 29 IS 5 BP 589 EP 601 DI 10.1111/j.1365-2036.2008.03908.x PG 13 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 401KO UT WOS:000262939800014 PM 19053983 ER PT J AU Loomba, R Kleiner, DE Hoofnagle, JH AF Loomba, R. Kleiner, D. E. Hoofnagle, J. H. TI Mechanism of action of metformin in nonalcoholic steatohepatitis: authors' reply SO ALIMENTARY PHARMACOLOGY & THERAPEUTICS LA English DT Letter C1 [Loomba, R.] Univ Calif San Diego, Div Gastroenterol, San Diego, CA 92103 USA. [Kleiner, D. E.] Natl Canc Inst, Pathol Lab, Bethesda, MD USA. [Hoofnagle, J. H.] NIDDK, Liver Dis Branch, NIH, Bethesda, MD USA. RP Loomba, R (reprint author), Univ Calif San Diego, Div Gastroenterol, San Diego, CA 92103 USA. EM roloomba@ucsd.edu OI Kleiner, David/0000-0003-3442-4453 NR 6 TC 0 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0269-2813 J9 ALIMENT PHARM THER JI Aliment. Pharmacol. Ther. PD MAR 1 PY 2009 VL 29 IS 5 BP 604 EP 604 DI 10.1111/j.1365-2036.2008.03916.x PG 1 WC Gastroenterology & Hepatology; Pharmacology & Pharmacy SC Gastroenterology & Hepatology; Pharmacology & Pharmacy GA 401KO UT WOS:000262939800016 ER PT J AU Petanceska, S Ryan, L Silverberg, N Buckholtz, N AF Petanceska, Suzana Ryan, Laurie Silverberg, Nina Buckholtz, Neil TI Commentary on "A roadmap for the prevention of dementia II. Leon Thal Symposium 2008." Alzheimer's disease translational research programs at the National Institute on Aging SO ALZHEIMERS & DEMENTIA LA English DT Article C1 [Petanceska, Suzana; Ryan, Laurie; Silverberg, Nina; Buckholtz, Neil] NIA, Div Neurosci, NIH, Bethesda, MD 20892 USA. RP Buckholtz, N (reprint author), NIA, Div Neurosci, NIH, Bethesda, MD 20892 USA. EM buckholn@nia.nih.gov NR 4 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1552-5260 J9 ALZHEIMERS DEMENT JI Alzheimers. Dement. PD MAR PY 2009 VL 5 IS 2 BP 130 EP 132 DI 10.1016/j.jalz.2009.01.014 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 420FT UT WOS:000264275100010 PM 19328442 ER PT J AU Bittner, V Johnson, BD Zineh, I Rogers, WJ Vido, D Marroquin, OC Bairey-Merz, CN Sopko, G AF Bittner, Vera Johnson, B. Delia Zineh, Issam Rogers, William J. Vido, Diane Marroquin, Oscar C. Bairey-Merz, C. Noel Sopko, George TI The triglyceride/high-density lipoprotein cholesterol ratio predicts all-cause mortality in women with suspected myocardial ischemia: A Report From the Women's Ischemia Syndrome Evaluation (WISE) SO AMERICAN HEART JOURNAL LA English DT Article ID CORONARY-HEART-DISEASE; HDL-CHOLESTEROL; CARDIOVASCULAR-DISEASE; ESTERIFICATION RATE; RISK; ASSOCIATION; PLASMA AB High triglycerides (TG) and low high-density lipoprotein cholesterol (HDL-C) are important cardiovascular risk factors in women. The. prognostic utility of the TG/HDL-C ratio, a marker for insulin resistance and small dense low-density lipoprotein particles, is unknown among high-risk women. Methods We studied 544 women without prior myocardial infarction or coronary revascularization, referred for clinically indicated coronary angiography and enrolled in the Women's Ischemia Syndrome Evaluation (WISE). Fasting lipid profiles and detailed demographic and clinical data were obtained at baseline. Multivariate Cox-proportional hazards models for all-cause mortality and cardiovascular events (death, myocardial infarction, heart failure, stroke) over a median follow-up of 6 years were constructed using log TG/HDL-C ratio as a predictor variable and accounting for traditional cardiovascular risk factors. Results Mean age was 57 I I years; 84% were white, 55% hypertensive, 20% diabetic, 50% current or prior smokers. Triglyceride/HDL-C ranged from 0.3 to 18.4 (median 2.2, first quartile 0.35 to <1.4, fourth quartile 3.66-18.4). Deaths (n = 33) and cardiovascular events (n = 83) increased across TG/HDL-C quartiles (both P < .05 for trend). Triglyceride/HDL-C was a strong independent predictor of mortality in models adjusted for age, race, smoking, hypertension, diabetes, and angiographic coronary disease severity (hazard ratio 1.95, 95% Cl 1.05-3.64, P = .04). For cardiovascular events, the multivariate hazard ratio was 1.54 (95% Cl 1.05-2.22, P = .03) when adjusted for demographic and clinical variables, but become nonsignificant when angiographic results were included. Conclusion Among women with suspected ischemia, the TG/HDL-C ratio is a powerful independent predictor of all-cause mortality and cardiovascular events. (Am Heart J 2009; 157:548-55.) C1 [Bittner, Vera] Univ Alabama, Div Cardiovasc Dis, Dept Med, Birmingham, AL 35294 USA. [Johnson, B. Delia] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Zineh, Issam; Sopko, George] Univ Florida, Dept Pharm Practice, Coll Pharm, Gainesville, FL USA. [Zineh, Issam; Sopko, George] Univ Florida, Ctr Pharmacogenom, Coll Pharm, Gainesville, FL USA. [Vido, Diane] Allegheny Gen Hosp, Div Cardiol, Dept Med, Pittsburgh, PA 15212 USA. [Marroquin, Oscar C.] Univ Pittsburgh, Cardiovasc Inst, Med Ctr, Pittsburgh, PA USA. [Bairey-Merz, C. Noel] Cedars Sinai Med Ctr, Dept Med, Div Cardiol, Cedars Sinai Res Inst, Los Angeles, CA 90048 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Bittner, V (reprint author), Univ Alabama, Div Cardiovasc Dis, Dept Med, 701 19th St S LHRB 310, Birmingham, AL 35294 USA. EM vbittner@uob.edu RI Marroquin, Oscar/F-2214-2015; OI Marroquin, Oscar/0000-0002-0909-0319; Bittner, Vera/0000-0001-9456-850X FU National Heart, Lung and Blood Institutes [N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164]; GCRC [MO1-RR00425]; National Center for Research Resources [U0164829, U01 HL649141, U01 HL649241]; Gustavus and Louis Pfeiffer Research Foundation (Denville, NJ); The Women's Guild of Cedars-Sinai Medical Center (Los Angeles, CA); The Ladies Hospital Aid Society of Western Pennsylvania (Pittsburgh, PA); The Edythe Brood Endowment for Women's Heart Research (Los Angeles, CA) FX Funding sources: This work was supported by contracts from the National Heart, Lung and Blood Institutes, nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164; grants U0164829, U01 HL649141, U01 HL649241, GCRC grant MO1-RR00425 from the National Center for Research Resources; and grants from the Gustavus and Louis Pfeiffer Research Foundation (Denville, NJ), The Women's Guild of Cedars-Sinai Medical Center (Los Angeles, CA), The Ladies Hospital Aid Society of Western Pennsylvania (Pittsburgh, PA), and The Edythe Brood Endowment for Women's Heart Research (Los Angeles, CA). NR 26 TC 67 Z9 72 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD MAR PY 2009 VL 157 IS 3 BP 548 EP 555 DI 10.1016/j.ahj.2008.11.014 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 419JD UT WOS:000264214700022 PM 19249427 ER PT J AU Yetley, EA Brule, D Cheney, MC Davis, CD Esslinger, KA Fischer, PWF Friedl, KE Greene-Finestone, LS Guenther, PM Klurfeld, DM L'Abbe, MR McMurry, KY Starke-Reed, PE Trumbo, PR AF Yetley, Elizabeth A. Brule, Danielle Cheney, Margaret C. Davis, Cindy D. Esslinger, Krista A. Fischer, Peter W. F. Friedl, Karl E. Greene-Finestone, Linda S. Guenther, Patricia M. Klurfeld, David M. L'Abbe, Mary R. McMurry, Kathryn Y. Starke-Reed, Pamela E. Trumbo, Paula R. TI Dietary Reference Intakes for vitamin D: justification for a review of the 1997 values SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID CURRENT DILEMMAS; RESEARCH NEEDS; HEALTH; CANCER AB Recent Institute of Medicine (IOM) reviews of the process for deriving Dietary Reference Intakes (DRIs) suggest that determining the need for a new nutrient review should be evaluated against criteria set a priori. After selecting the criterion of significant new and relevant research, a working group of US and Canadian government scientists used results from a systematic review and 2 conferences on vitamin D and health to evaluate whether significant new and relevant scientific evidence had become available since the 1997 IOM publication of the DRIs for vitamin D. This working group concluded that there appears to be new research meeting the criteria for 4 key DRI questions. The new research is of larger quantity and quality for the elderly than for other groups, but overall 1) adds to the bone-related and status evidence available to the 1997 DRI Committee for several of the life-stage groups, 2) identifies new outcomes with respect to risk of falls and performance measures in the elderly and potential adverse effects, and 3) provides additional information on dose-response relations between intakes and circulating 25-hydroxyvitamin D concentrations and between 25-hydroxyvitamin D concentrations and several health outcomes (ie, bone-related outcomes for all ages and risk of falls and performance measures in older adults). Members of the working group concluded that significant new and relevant research was available for reviewing the existing DRIs for vitamin D while leaving the decision of whether the new research will result in changes to the current DRIs to a future IOM-convened DRI committee. Am J Clin Nutr 2009; 89: 719-27. C1 [Yetley, Elizabeth A.] Off Dietary Supplements, NIH, Bethesda, MD 20892 USA. [Klurfeld, David M.] Agr Res Serv, USDA, Washington, DC USA. [Guenther, Patricia M.] USDA, Ctr Nutr Policy & Promot, Washington, DC 20250 USA. [Friedl, Karl E.] USA, Med Res & Mat Command, Ft Detrick, MD USA. [Fischer, Peter W. F.; L'Abbe, Mary R.] Hlth Canada, Bur Nutr Sci, Food Directorate, Ottawa, ON K1A 0L2, Canada. [Brule, Danielle; Cheney, Margaret C.; Esslinger, Krista A.] Hlth Canada, Off Nutr Policy & Promot, Ottawa, ON K1A 0L2, Canada. [Trumbo, Paula R.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD USA. [Starke-Reed, Pamela E.] NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. [Davis, Cindy D.] NCI, NIH, Bethesda, MD 20892 USA. [McMurry, Kathryn Y.] US Dept Hlth & Human Serv, Off Dis Prevent & Hlth Promot, Washington, DC USA. [Greene-Finestone, Linda S.] Publ Hlth Agcy Canada, Ottawa, ON, Canada. RP Yetley, EA (reprint author), Off Dietary Supplements, NIH, 6100 Executive Blvd,Room 3B01, Bethesda, MD 20892 USA. EM beth@yetley.com OI Friedl, Karl/0000-0002-3134-8427 NR 20 TC 36 Z9 39 U1 0 U2 1 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 MAR 1 PY 2009 VL 89 IS 3 BP 719 EP 727 DI 10.3945/ajcn.2008.26903 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 410IS UT WOS:000263571300001 PM 19176741 ER PT J AU Russell, R Chung, M Balk, EM Atkinson, S Giovannucci, EL Ip, S Lichtenstein, AH Mayne, ST Raman, G Ross, AC Trikalinos, TA West, KP Lau, J AF Russell, Robert Chung, Mei Balk, Ethan M. Atkinson, Stephanie Giovannucci, Edward L. Ip, Stanley Lichtenstein, Alice H. Mayne, Susan Taylor Raman, Gowri Ross, A. Catharine Trikalinos, Thomas A. West, Keith P., Jr. Lau, Joseph TI Opportunities and challenges in conducting systematic reviews to support the development of nutrient reference values: vitamin A as an example SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID QUALITY AB Nutrient reference values have significant public health and policy implications. Given the importance of defining reliable nutrient reference values, there is a need for an explicit, objective, and transparent process to set these values. The Tufts Medical Center Evidence-based Practice Center assembled a group of nutrition experts from academic institutions and federal government agencies, led participants in discussions, conducted exercises in formulating questions and evidence review criteria that would be amenable to systematic reviews of the scientific literature, performed a literature search on the questions to identify potentially relevant publications, and identified challenges and limitations of applying this method to support the development of nutrient reference values using vitamin A as an example. The workgroup concluded that the systematic review approach could be productively used to inform the development of reference values. Challenges identified in this exercise include prioritizing and defining research questions when the volume of literature is large, relying on intermediate (surrogate) outcomes when few or no studies directly linking nutrient intake with clinical outcomes are available, and determining reliable nutrient biomarkers. Ultimately, an objective, unbiased systematic review of a defined question could be useful, not only in helping to set nutrient reference values, but also for increasing the transparency of the decision making process. Am J Clin Nutr 2009; 89: 728-33. C1 [Lau, Joseph] Tufts Med Ctr, Evidence Based Practice Ctr, Inst Clin Res & Hlth Policy Studies, Boston, MA 02111 USA. [Russell, Robert; Lichtenstein, Alice H.] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Russell, Robert] Off Dietary Supplements, NIH, Bethesda, MD USA. [Chung, Mei; Balk, Ethan M.; Ip, Stanley; Lichtenstein, Alice H.; Raman, Gowri; Trikalinos, Thomas A.; Lau, Joseph] Tufts Med Ctr, Evidence Based Practice Ctr, Boston, MA USA. [Atkinson, Stephanie] McMaster Univ, Hamilton, ON, Canada. [Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Giovannucci, Edward L.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Mayne, Susan Taylor] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Ross, A. Catharine] Penn State Univ, University Pk, PA 16802 USA. [West, Keith P., Jr.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Lau, J (reprint author), Tufts Med Ctr, Evidence Based Practice Ctr, Inst Clin Res & Hlth Policy Studies, Box 63,800 Washington St, Boston, MA 02111 USA. EM jlau1@tuftsmedicalcenter.org FU PHS HHS [290-020-0022] NR 24 TC 13 Z9 13 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 MAR 1 PY 2009 VL 89 IS 3 BP 728 EP 733 DI 10.3945/ajcn.2008.27154 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 410IS UT WOS:000263571300002 PM 19176732 ER PT J AU Troiano, RP AF Troiano, Richard P. y TI Can there be a single best measure of reported physical activity? SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material ID COMPENDIUM C1 NCI, NIH, Methods Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Troiano, RP (reprint author), NCI, NIH, Methods Branch, Div Canc Control & Populat Sci, 6130 Executive Blvd,EPN 4005, Bethesda, MD 20892 USA. EM troianor@mail.nih.gov OI Troiano, Richard/0000-0002-6807-989X NR 7 TC 14 Z9 14 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 MAR 1 PY 2009 VL 89 IS 3 BP 736 EP 737 DI 10.3945/ajcn.2008.27461 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 410IS UT WOS:000263571300004 PM 19176725 ER PT J AU Tanofsky-Kraff, M McDuffie, JR Yanovski, SZ Kozlosky, M Schvey, NA Shomaker, LB Salaita, C Yanovski, JA AF Tanofsky-Kraff, Marian McDuffie, Jennifer R. Yanovski, Susan Z. Kozlosky, Merel Schvey, Natasha A. Shomaker, Lauren B. Salaita, Christine Yanovski, Jack A. TI Laboratory assessment of the food intake of children and adolescents with loss of control eating SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID OVERWEIGHT CHILDREN; DISORDER EXAMINATION; PUBERTAL CHANGES; ADULT OBESITY; ENERGY-INTAKE; HIGH-RISK; BODY-FAT; BINGE; WEIGHT; BEHAVIORS AB Background: Loss of control (LOC) eating in youth predicts excessive weight gain. However, few studies have measured the actual energy intake of children reporting LOC eating. Objective: The objective was to characterize the energy intake and macronutrient composition of "normal'' and "binge'' laboratory meals in nonoverweight and overweight boys and girls with LOC eating. Design: Children aged 8-17 y (n=177) consumed 2 lunchtime meals ad libitum from a multi-item food array after being instructed to either binge eat (binge meal) or to eat normally (normal meal). Prior LOC eating was determined with a semistructured clinical interview. Results: Participants consumed more energy at the binge meal than at the normal meal (P=0.001). Compared with youth with no LOC episodes (n=127), those reporting LOC (n=50) did not consume more energy at either meal. However, at both meals, youth with LOC consumed a greater percentage of calories from carbohydrates and a smaller percentage from protein than did those without LOC (P < 0.05). Children with LOC ate more snack and dessert-type foods and less meats and dairy (P, 0.05). LOC participants also reported greater increases in postmeal negative affect at both meals than did those without LOC (P <= 0.05). Secondary analyses restricted to overweight and obese girls found that those with LOC consumed more energy at the binge meal (P=0.025). Conclusions: When presented with an array of foods, youth with LOC consumed more high-calorie snack and dessert-type foods than did those without LOC. Further research is required to determine whether habitual consumption of such foods may promote overweight. This trial was registered at clinicaltrials.gov as NCT00320177. Am J Clin Nutr 2009; 89: 738-45. C1 [Tanofsky-Kraff, Marian; Schvey, Natasha A.; Shomaker, Lauren B.] USUHS, Dept Med & Clin Psychol, Bethesda, MD 20814 USA. [Tanofsky-Kraff, Marian; McDuffie, Jennifer R.; Yanovski, Susan Z.; Schvey, Natasha A.; Shomaker, Lauren B.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Growth & Obes, Program Dev Endocrinol & Genet, NIH,Dept Hlth Human Serv, Bethesda, MD USA. [Yanovski, Susan Z.] NIH, Div Digest Dis & Nutr, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Kozlosky, Merel; Salaita, Christine] NIH, Dept Nutr, Ctr Clin, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tanofsky-Kraff, M (reprint author), USUHS, Dept Med & Clin Psychol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM mtanofsky@usuhs.edu OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural NIH HHS NR 43 TC 59 Z9 59 U1 2 U2 10 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 MAR 1 PY 2009 VL 89 IS 3 BP 738 EP 745 DI 10.3945/ajcn.2008.26886 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 410IS UT WOS:000263571300005 PM 19144730 ER PT J AU Votruba, SB Kirchner, H Tschop, M Salbe, AD Krakoff, J AF Votruba, Susanne B. Kirchner, Henriette Tschoep, Matthias Salbe, Arline D. Krakoff, Jonathan TI Morning ghrelin concentrations are not affected by short-term overfeeding and do not predict ad libitum food intake in humans SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID DOUBLY LABELED WATER; ENERGY-EXPENDITURE; CIRCULATING GHRELIN; PHYSICAL-ACTIVITY; OBESITY; QUESTIONNAIRE; HOMEOSTASIS; VALIDITY; PEPTIDE; SYSTEM AB Background: Ghrelin has a short-term orexigenic effect but may also be a marker of food intake over time. We previously found an inverse association between ghrelin concentrations and food intake. Objectives: The objectives were to determine whether the fasting plasma ghrelin concentration is related to food intake and whether the previous day's intake predicts the suppression of ghrelin. Design: Sixty-nine nondiabetic adults (40 men) aged 33 +/- 9 y were studied as inpatients at a Clinical Research Center. After 6 d of consuming a maintenance diet, the subjects self-selected their food from our vending machine system for 3 d. Total plasma ghrelin concentrations were measured every morning during the vending machine period. Results: The fasting ghrelin concentration was negatively correlated with body mass index (r = -0.31, P = 0.016) and weight (r = -0.26, P = 0.044). Mean morning ghrelin concentrations remained constant (149 +/- 59, 152 +/- 60, 148 +/- 61, and 145 +/- 59 pg/mL on days 1, 2, 3, and 4, respectively) even though the subjects overate while using the vending machines (160 +/- 42% of weight-maintenance needs). No associations were found between daily ghrelin concentrations and subsequent food intake on any day (day 1: r = -0.04, P = 0.76; day 2: r = -0.01, P = 0.95; day 3: r = -0.11, P = 0.38). Suppression of total ghrelin concentrations was not associated with the previous day's intake or with subsequent food intake. Conclusion: Morning plasma ghrelin concentrations do not affect acute increases in food intake. This trial was registered at clinical-trials. gov as NCT00342732. Am J Clin Nutr 2009;89:801-6. C1 [Votruba, Susanne B.] NIDDK, Obes & Diabet Clin Res Sect, NIH, DHHS, Phoenix, AZ 85016 USA. [Kirchner, Henriette; Tschoep, Matthias] Univ Cincinnati, Obes Res Ctr, Genome Res Inst, Cincinnati, OH USA. [Salbe, Arline D.] Kronos Longev Res Inst, Phoenix, AZ USA. RP Votruba, SB (reprint author), NIDDK, Obes & Diabet Clin Res Sect, NIH, DHHS, 4212 N 16th St, Phoenix, AZ 85016 USA. EM votrubas@mail.nih.gov RI Kirchner, Henriette/D-6699-2011; Tschoep, Matthias/I-5443-2014; OI Tschoep, Matthias/0000-0002-4744-371X FU National Institutes of Health; NIDDK FX Supported by the Intramural Research Program of the National Institutes of Health, NIDDK. NR 34 TC 11 Z9 12 U1 0 U2 1 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 MAR 1 PY 2009 VL 89 IS 3 BP 801 EP 806 DI 10.3945/ajcn.2008.27011 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 410IS UT WOS:000263571300013 PM 19158212 ER PT J AU Thompson, OM Beresford, SAA Kirk, EA Vaughan, TL AF Thompson, Olivia M. Beresford, Shirley A. A. Kirk, Elizabeth A. Vaughan, Thomas L. TI Vegetable and fruit intakes and risk of Barrett's esophagus in men and women SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID NEOPLASTIC PROGRESSION; GEOGRAPHIC PROXIMITY; CONTROL SELECTION; DIETARY PATTERNS; CHILDHOOD-CANCER; SERUM SELENIUM; VITAMIN-C; ADENOCARCINOMA; DISEASE; POPULATION AB Background: Barrett's esophagus (BE) is a risk factor for esophageal adenocarcinoma. Modifiable risk factors for BE are largely unknown. Objective: The purpose of this study was to determine whether vegetable and fruit intakes are associated with BE risk. Design: In a case-control study based in western Washington State, we compared the vegetable and fruit intakes of 170 patients with newly diagnosed BE with those of 182 controls from the general population. Relations between vegetable and fruit intakes and BE were examined by using unconditional logistic regression to compute odds ratios (ORs) and corresponding 95% CIs. Results: Participants in the second (adjusted OR: 0.40; 95% CI: 0.23, 0.71) and third (adjusted OR: 0.33; 95% CI: 0.17, 0.63) tertiles of vegetable intake appeared to have a lower risk of BE (P for trend = 0.048) than did participants in the first tertiles of vegetable intake. Similarly, participants in the second (adjusted OR: 0.49; 95% CI: 0.28, 0.86) and third (adjusted OR: 0.39; 95% CI: 0.21, 0.75) tertiles of combined vegetable and fruit intakes had a lower risk of BE (P for trend = 0.047) than did participants in the first tertile of vegetable and fruit intakes. Similar results were obtained in subanalyses limited to patients with visible and with long-segment BE. Conclusions: The results support previous findings that increased intakes of vegetables and of vegetables and fruit are associated with a lower risk of BE in men and women. Prospective data that examine relations between diet and BE are needed. Am J Clin Nutr 2009; 89:890-6. C1 [Thompson, Olivia M.; Kirk, Elizabeth A.] Univ Washington, Nutr Sci Program, Seattle, WA 98195 USA. [Beresford, Shirley A. A.; Vaughan, Thomas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Kirk, Elizabeth A.] Univ Washington, Dept Pathobiol, Seattle, WA 98195 USA. [Thompson, Olivia M.; Beresford, Shirley A. A.; Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Thompson, OM (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,Room 4074A,MSC 7332, Bethesda, MD 20892 USA. EM thompsonom@mail.nih.gov FU National Cancer Institute [R01 CA72866, 2R25 CA092408-06, K05 CA124911] FX Supported by National Cancer Institute grants R01 CA72866, 2R25 CA092408-06, and K05 CA124911. NR 36 TC 23 Z9 23 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 MAR 1 PY 2009 VL 89 IS 3 BP 890 EP 896 DI 10.3945/ajcn.2008.26497 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 410IS UT WOS:000263571300024 PM 19144726 ER PT J AU Leitzmann, MF Koebnick, C Abnet, CC Freedman, ND Park, Y Hollenbeck, A Ballard-Barbash, R Schatzkin, A AF Leitzmann, Michael F. Koebnick, Corinna Abnet, Christian C. Freedman, Neal D. Park, Yikyung Hollenbeck, Albert Ballard-Barbash, Rachel Schatzkin, Arthur TI Prospective Study of Physical Activity and Lung Cancer by Histologic Type in Current, Former, and Never Smokers SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE lung neoplasms; motor activity; neoplasms by histologic type; prospective studies; smoking ID FORCED EXPIRATORY VOLUME; OXIDATIVE STRESS BIOMARKERS; CIGARETTE-SMOKING; IMMUNE FUNCTION; DNA-DAMAGE; FOLLOW-UP; RISK; COHORT; WOMEN; MEN AB Increased physical activity has been associated with decreased lung cancer risk. However, no previous investigation has examined physical activity in relation to lung cancer histologic types by smoking status. The authors investigated these relations in the National Institutes of Health-AARP Diet and Health Study among 501,148 men and women aged 50-71 years at baseline in 1995-1996. During follow-up to 2003, 6,745 lung carcinomas occurred (14.8% small cell, 40.3% adenocarcinoma, 19.7% squamous cell, 6.1% undifferentiated large cell, 7.2% non-small cell not otherwise specified, and 11.8% carcinoma not otherwise specified). Among former smokers, the multivariate relative risks of small cell, adenocarcinoma, squamous cell, and undifferentiated large cell carcinomas comparing the highest with the lowest activity level (>= 5 times/week vs. inactive) were 0.93 (95% confidence interval (CI): 0.67, 1.28), 0.79 (95% CI: 0.67, 0.94), 0.73 (95% CI: 0.57, 0.93), and 0.61 (95% CI: 0.38, 0.98), respectively. Among current smokers, corresponding values were 0.77 (95% CI: 0.58, 1.02), 0.76 (95% CI: 0.61, 0.95), 0.85 (95% CI: 0.65, 1.11), and 1.10 (95% CI: 0.69, 1.78). In contrast, physical activity was unrelated to lung carcinoma among never smokers (P(interaction) between physical activity and smoking for total lung carcinomas = 0.002). The inverse findings among former and current smokers in combination with the null results for physical activity among never smokers may point toward residual confounding by cigarette smoking as an explanation for the relations observed. C1 [Leitzmann, Michael F.; Koebnick, Corinna; Abnet, Christian C.; Freedman, Neal D.; Park, Yikyung; Schatzkin, Arthur] NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Koebnick, Corinna] Kaiser Permanente So Calif, Dept Res & Evaluat, Pasadena, CA USA. [Freedman, Neal D.] NCI, Canc Prevent Fellowship Program, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Hollenbeck, Albert] AARP, Washington, DC USA. [Ballard-Barbash, Rachel] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Leitzmann, MF (reprint author), Univ Regensburg, Dept Epidemiol & Prevent Med, Franz Josef Strauss Allee 11, D-93053 Regensburg, Germany. EM michael.leitzmann@klinik.uni-regensburg.de RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015; Koebnick, Corinna/P-4767-2016; OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098; Koebnick, Corinna/0000-0001-8274-0309; Park, Yikyung/0000-0002-6281-489X FU Intramural Research Program of the National Cancer Institute; National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 47 TC 32 Z9 33 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 1 PY 2009 VL 169 IS 5 BP 542 EP 553 DI 10.1093/aje/kwn371 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 407ZT UT WOS:000263403500003 PM 19126591 ER PT J AU Arnold, SE Evans, JD Krishnan, RR Reynolds, CF AF Arnold, Steven E. Evans, Jovier D. Krishnan, Ranga Rama Reynolds, Charles F., III TI Evolving NIMH Priorities: Advancing a Translational Neuroscience Emphasis Within Geriatric Psychiatry Research SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Arnold, Steven E.] Univ Penn, Philadelphia, PA 19104 USA. [Evans, Jovier D.] NIMH, Bethesda, MD 20892 USA. [Krishnan, Ranga Rama] Duke Univ, Med Ctr, Durham, NC USA. [Reynolds, Charles F., III] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. RI Arnold, Steven/J-7546-2012 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 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2009 VL 17 IS 3 SU 1 BP A24 EP A25 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V16YW UT WOS:000207905900024 ER PT J AU Fiocco, AJ Lindquist, K Vittinghoff, E Simonsick, EM Newman, A Satterfield, S Rosano, C Rubin, S Ayonayon, HN Harris, TB Yaffe, K AF Fiocco, Alexandra J. Lindquist, Karla Vittinghoff, Eric Simonsick, Eleanor M. Newman, Anne Satterfield, Suzanne Rosano, Caterina Rubin, Susan Ayonayon, Hilsa N. Harris, Tamara B. Yaffe, Kristine TI Comprehensive Predictors of Maintaining Cognitive Function in Older Adults: Health ABC Study SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Fiocco, Alexandra J.; Lindquist, Karla; Vittinghoff, Eric; Rubin, Susan; Ayonayon, Hilsa N.; Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Harris, Tamara B.] NIA, NIH, Baltimore, MD 21224 USA. [Newman, Anne; Rosano, Caterina] Univ Pittsburgh, Pittsburgh, PA USA. [Satterfield, Suzanne] Univ Tennessee, Memphis, TN USA. RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2009 VL 17 IS 3 SU 1 BP A116 EP A116 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V16YW UT WOS:000207905900162 ER PT J AU Schneider, LS Mack, W Dagerman, K Hsiao, JK Lebowitz, BD Lyketsos, CG Stroup, TS Sultzer, DL Tariot, PN Vigen, C Zheng, L AF Schneider, Lon S. Mack, Wendy Dagerman, Karen Hsiao, John K. Lebowitz, Barry D. Lyketsos, Constantine G. Stroup, T. Scott Sultzer, David L. Tariot, Pierre N. Vigen, Cheryl Zheng, Ling TI Second-generation Antipsychotics for Alzheimer's Disease Patients and Metabolic Abnormalities: The CATIE-AD Study SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Schneider, Lon S.; Mack, Wendy; Dagerman, Karen; Vigen, Cheryl; Zheng, Ling] Univ So Calif, Los Angeles, CA USA. [Hsiao, John K.] NIMH, Bethesda, MD 20892 USA. [Lebowitz, Barry D.] Univ Calif San Diego, San Diego, CA 92103 USA. [Lyketsos, Constantine G.] Johns Hopkins Bayview, Baltimode, MD USA. [Stroup, T. Scott] Univ N Carolina, Chapel Hill, NC USA. [Sultzer, David L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Tariot, Pierre N.] Banner Alzheimers Inst, Phoenix, AZ 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 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2009 VL 17 IS 3 SU 1 BP A75 EP A76 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V16YW UT WOS:000207905900091 ER PT J AU Schneider, LS Vigen, CL Mack, WJ Dagerman, KS Keefe, R Sano, M Sultzer, D Stroup, S Hsiao, J Lebowitz, B Lyketsos, CG Tariot, PN Zheng, L AF Schneider, Lon S. Vigen, Cheryl L. Mack, Wendy J. Dagerman, Karen S. Keefe, Richard Sano, Mary Sultzer, David Stroup, Scott Hsiao, John Lebowitz, Barry Lyketsos, Constantine G. Tariot, Pierre N. Zheng, Ling TI Cognitive Effects of Atypical Antipsychotics in Patients with Alzheimer's Disease: Outcomes from CATIE-AD SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Schneider, Lon S.; Vigen, Cheryl L.; Mack, Wendy J.; Dagerman, Karen S.; Zheng, Ling] Univ So Calif, Los Angeles, CA USA. [Keefe, Richard] Duke Univ, Durham, NC USA. [Sano, Mary] Mt Sinai Sch Med, Bronx, NY USA. [Sultzer, David] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Stroup, Scott] Univ N Carolina, Chapel Hill, NC USA. [Hsiao, John] NIMH, Bethesda, MD 20892 USA. [Lebowitz, Barry] Univ Calif San Diego, Sch Med, La Jolla, CA 92093 USA. [Lyketsos, Constantine G.] Johns Hopkins Sch Med, Baltimore, MD USA. [Tariot, Pierre N.] Banner Alzheimers Inst, Phoenix, AZ USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2009 VL 17 IS 3 SU 1 BP A76 EP A76 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V16YW UT WOS:000207905900092 ER PT J AU Schneider, LS Vigen, CL Mack, WJ Davis, SM Sultzer, DL Weintraub, D Lyketsos, CG Zheng, L Dagerman, KS Stroup, S Hsiao, JK Lebowitz, BD Tariot, PN AF Schneider, Lon S. Vigen, Cheryl L. Mack, Wendy J. Davis, Sonia M. Sultzer, David L. Weintraub, Daniel Lyketsos, Constantine G. Zheng, Ling Dagerman, Karen S. Stroup, Scott Hsiao, John K. Lebowitz, Barry D. Tariot, Pierre N. TI Effectiveness of Citalopram Compared to Atypical Antipsychotics in Alzheimer's Disease Patients Who Discontinued Their Initially Assigned Treatment: CATIE-AD Phase 2 Results SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Schneider, Lon S.; Vigen, Cheryl L.; Mack, Wendy J.; Zheng, Ling; Dagerman, Karen S.] Univ So Calif, Los Angeles, CA USA. [Davis, Sonia M.] Quintiles, Morrisville, NC USA. [Sultzer, David L.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. [Weintraub, Daniel] Univ Penn, Philadelphia, PA 19104 USA. [Lyketsos, Constantine G.] Johns Hopkins Sch Med, Baltimore, MD USA. [Stroup, Scott] Univ N Carolina, Chapel Hill, NC USA. [Hsiao, John K.] NIMH, Bethesda, MD 20892 USA. [Lebowitz, Barry D.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Tariot, Pierre N.] Banner Alzheimers Inst, Phoenix, AZ USA. NR 0 TC 2 Z9 2 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2009 VL 17 IS 3 SU 1 BP A77 EP A77 PG 1 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V16YW UT WOS:000207905900093 ER PT J AU Sultzer, DL Davis, SM Tariot, PN Dagerman, KS Lebowitz, BD Lyketsos, CG Rosenheck, RA Hsiao, JK Lieberman, JA Schneider, LS AF Sultzer, David L. Davis, Sonia M. Tariot, Pierre N. Dagerman, Karen S. Lebowitz, Barry D. Lyketsos, Constantine G. Rosenheck, Robert A. Hsiao, John K. Lieberman, Jeffrey A. Schneider, Lon S. TI Antipsychotic Medication Treatment Response in Alzheimer's Disease (CATIE-AD): Patient Symptoms, Function, and Life Quality, and Caregiver Well-being SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract C1 [Sultzer, David L.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Sultzer, David L.] Univ Calif Los Angeles, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90024 USA. [Davis, Sonia M.] Quintiles, Res Triangle Pk, NC USA. [Tariot, Pierre N.] Banner Alzheimers Inst, Phoenix, AZ USA. [Dagerman, Karen S.] USC, Dept Psychiat, Keck Sch Med, Los Angeles, CA USA. [Lebowitz, Barry D.] UCSD, Div Geriatr Psychiat, La Jolla, CA USA. [Lyketsos, Constantine G.] Johns Hopkins Bayview Med Ctr, Dept Psychiat, Baltimore, MD USA. [Rosenheck, Robert A.] Yale Univ, Sch Med, VA Connecticut Healthcare Syst, New Haven, CT USA. [Hsiao, John K.] NIMH, Bethesda, MD 20892 USA. [Lieberman, Jeffrey A.] Columbia Univ, New York, NY USA. [Schneider, Lon S.] USC, Dept Psychiat, Los Angeles, CA 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 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2009 VL 17 IS 3 SU 1 BP A74 EP A75 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA V16YW UT WOS:000207905900090 ER PT J AU Dunton, GF Lagloire, R Robertson, T AF Dunton, Genevieve F. Lagloire, Renee Robertson, Trina TI Using the RE-AIM Framework to Evaluate the Statewide Dissemination of a School-Based Physical Activity and Nutrition Curriculum: "Exercise Your Options" SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Article DE Exercise; Dietary Habits; Schools; Intervention; Information Dissemination; Prevention Research ID OBESITY; INTERVENTIONS; CHILDREN; YOUTH AB Purpose. Examine the reach,, efficacy, adoption, implementation, and maintenance of a physical activity and nutrition curriculum for middle-school students Design. Nonexperimental pilot evaluation of a statewide dissemination trial. Setting. California middle schools during the 2006 to 2007 school year. Subjects. Sixteen classes (N = 668 students and 16 teachers) sampled from the statewide pool who used the program. Intervention. An eight-lesson nutrition and Physical activity curriculum, "Exercise Your Options" (EYO), including a teacher guide, video clips, a student. activity booklet., and ancillary materials was made available to teachers. Measures. Program. records, classroom observations, teacher surveys, and student presurveys and postsurveys (assessing physical activity, sedentary behaviors, and dietary intake). Analysis. Descriptive statistics and multilevel random-coefficient modeling. Results. The EYO program reached 234,442 middle-school students in California. During the program, total physical activity increased (p < .001), whereas watching TV/DVDs and playing electronic games/computer use decreased (p < .05). Intake of dairy products increased (p < .05), whereas consumption of sugars/sweets decreased (p <. 00 1). Forty-two percent, of eligible middle-school classrooms ordered the program materials. Eighty-six percent of sampled teachers implemented all of the lessons. Over the past 5 years, 51% of all middle-school students in California, were exposed to the program. Conclusions. The EYO program showed its potential for moderate to high. public health impact among California middle-school students. (Am J Health Promot 2009;23[4]:229-232.) C1 [Robertson, Trina] Dairy Council Calif, Irvine, CA 92612 USA. [Dunton, Genevieve F.] NCI, Canc Prevent Fellowship Program, Hlth Promot Res Branch, Behav Res Program,NIH, Bethesda, MD 20892 USA. [Lagloire, Renee] Harder & Co Community Res, La Crescenta, CA USA. RP Robertson, T (reprint author), Dairy Council Calif, 2151 Michelson,Suite 235, Irvine, CA 92612 USA. EM trobertson@dairycouncilofca.org FU Intramural NIH HHS [NIH0012663005]; PHS HHS [NIH0012663005] NR 9 TC 16 Z9 17 U1 1 U2 18 PU AMER J HEALTH PROMOTION INC PI KEEGO HARBOR PA 1660 CASS LAKE RD, STE 104, KEEGO HARBOR, MI 48320 USA SN 0890-1171 J9 AM J HEALTH PROMOT JI Am. J. Health Promot. PD MAR-APR PY 2009 VL 23 IS 4 BP 229 EP 232 DI 10.4278/ajhp.071211129 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 419KG UT WOS:000264217700002 PM 19288843 ER PT J AU Lampl, M Kusanovic, JP Erez, O Espinoza, J Gotsch, F Goncalves, L Hassan, S Gomez, R Nien, JK Frongillo, EA Romero, R AF Lampl, Michelle Kusanovic, Juan Pedro Erez, Offer Espinoza, Jimmy Gotsch, Francesca Goncalves, Luis Hassan, Sonia Gomez, Ricardo Nien, Jyh Kae Frongillo, Edward A. Romero, Roberto TI Early Rapid Growth, Early Birth: Accelerated Fetal Growth and Spontaneous Late Preterm Birth SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Article ID INNER CELL MASS; GESTATIONAL-AGE; PARTURITION SYNDROME; TROPHECTODERM CELLS; PLACENTAL VOLUME; WEIGHT; DELIVERY; INFANTS; ONSET; TERM AB The past two decades in the United States have seen a 24% rise in spontaneous late preterm delivery (34-36 weeks) of unknown etiology. This study tested the hypothesis that fetal growth was identical prior to spontaneous preterm (n = 221, median gestational age at birth 35.6 weeks) and term (n = 3706) birth among pregnancies followed longitudinally in Santiago, Chile. The hypothesis was not supported: Preterm-delivered fetuses were significantly larger than their term-delivered peers by mid-second trimester in estimated fetal weight, head, limb, and abdominal dimensions, and they followed different growth trajectories. Piecewise regression assessed time-specific differences in growth rates at 4-week intervals from 16 weeks. Estimated fetal weight and abdominal circumference growth rates slowed at 20 weeks among the preterm-delivered, only to match and/or exceed their term-delivered peers at 24-28 weeks. After an abrupt growth rate decline at 28 weeks, fetuses delivered preterm did so at greater population-specific sex and age-adjusted birth weight percentiles than their peers from uncomplicated pregnancies (P < 0.01). Growth rates predicted birth timing: one standard score of estimated fetal weight increased the odds ratio for late preterm birth from 2.8 prior to 23 weeks, to 3.6 (95% confidence interval, 1.82-7.11, P < 0.05) between 23 and 27 weeks. After 27 weeks, increasing size was protective (OR: 0.56, 95% confidence interval, 0.38-0.82, P = 0.003). These data document, for the first time, a distinctive fetal growth pattern across gestation preceding spontaneous late preterm birth, identify the importance of mid-gestation for alterations in fetal growth, and add perspective on human fetal biological variability. Am. J. Hum. Biol. 21:141-150, 2009. (C) 2008 Wiley-Liss, Inc. C1 [Lampl, Michelle] Emory Univ, Dept Anthropol, Atlanta, GA 30322 USA. [Lampl, Michelle; Kusanovic, Juan Pedro; Erez, Offer; Espinoza, Jimmy; Gotsch, Francesca; Goncalves, Luis; Hassan, Sonia; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Lampl, Michelle; Kusanovic, Juan Pedro; Erez, Offer; Espinoza, Jimmy; Gotsch, Francesca; Goncalves, Luis; Hassan, Sonia; Romero, Roberto] Eunice Kennedy Shriver Natl Inst Child Hlth & Dev, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Lampl, Michelle] Emory Univ, Predict Hlth Inst, Ctr Hlth Discovery, Atlanta, GA USA. [Kusanovic, Juan Pedro; Erez, Offer; Hassan, Sonia] Wayne State Univ, Hutzel Womens Hosp, Dept Obstet & Gynecol, Detroit, MI USA. [Gomez, Ricardo; Nien, Jyh Kae] Pontificia Univ Catolica Chile, Sotero Rio Hosp, Ctr Perinatal Diag & Res CEDIP, Puente Alto, Chile. [Frongillo, Edward A.] Univ S Carolina, Dept Hlth Promot Educ & Behav, Columbia, SC USA. [Romero, Roberto] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. RP Lampl, M (reprint author), Emory Univ, Dept Anthropol, 1557 Dickey Dr, Atlanta, GA 30322 USA. EM mlampl@emory.edu RI Lampl, Michelle/B-1619-2013 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH; DHHS FX Contract grant sponsor: Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 65 TC 13 Z9 13 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD MAR-APR PY 2009 VL 21 IS 2 BP 141 EP 150 DI 10.1002/ajhb.20840 PG 10 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 409TJ UT WOS:000263528400001 PM 18988282 ER PT J AU Choh, AC Lee, M Nahhas, RW Blangero, J Towne, B Wilson, AF Siervogel, RM Cole, SA Czerwinski, SA AF Choh, A. C. Lee, M. Nahhas, R. W. Blangero, J. Towne, B. Wilson, A. F. Siervogel, R. M. Cole, S. A. Czerwinski, S. A. TI Gene-by-age interaction effects on grip strength: The Southwest Ohio Family Study SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Meeting Abstract C1 [Choh, A. C.; Lee, M.; Nahhas, R. W.; Towne, B.; Siervogel, R. M.; Czerwinski, S. A.] Wright State Univ, Boonshoft Sch Med, Dayton, OH 45435 USA. [Blangero, J.; Cole, S. A.] SW Fdn Biomed Res, San Antonio, TX USA. [Wilson, A. F.] Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD MAR-APR PY 2009 VL 21 IS 2 BP 249 EP 250 PG 2 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 409TJ UT WOS:000263528400036 ER PT J AU Wellems, TE AF Wellems, T. E. TI How the malarias have molded the human genome. SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Meeting Abstract C1 [Wellems, T. E.] NIAID, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD MAR-APR PY 2009 VL 21 IS 2 BP 273 EP 274 PG 2 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 409TJ UT WOS:000263528400110 ER PT J AU Narva, AS Briggs, M AF Narva, Andrew S. Briggs, Michael TI The National Kidney Disease Education Program: Improving Understanding, Detection, and Management of CKD SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article; Proceedings Paper CT Conference on Developing a Comprehensive Public Health Strategy for Prenventing the Development, Progression, and Complications of CKD CY MAR, 2007 CL Atlanta, GA SP Ctr Dis Prevent & Control DE Chronic kidney disease; estimated glomerular filtration rate; creatinine standardization; UACR; patient education; NKDEP; NIDDK; Chronic Care Model ID CONVERTING ENZYME-INHIBITORS; NONDIABETIC RENAL-DISEASE; PROGRESSION; METAANALYSIS; PREVALENCE AB The National Kidney Disease Education Program (NKDEP), an initiative of the National Institute of Diabetes and Digestive and Kidney Diseases, works to reduce the morbidity and mortality caused by chronic kidney disease (CKD) and its complications. Established in 2000, the NKDEP initially focused on increasing awareness in at-risk populations and helping the laboratory community recalibrate serum creatinine measurement methods and begin using a revised equation to estimate glomerular filtration rate, Expanding its focus in recent years, the NKDEP now works to improve provider practices by collaborating with health systems, community health centers, and professional associations to encourage testing and treatment of patients. Among its top priorities is to develop such resources as clinical encounter tools, patient education aids, and training programs that help primary care professionals better identify and care for patients with CKD. Other priorities include improving the coordination of federal responses to CKD and addressing the standardization of measurement and reporting of urine albumin. Improving CKD detection and management is an important challenge. To succeed, the NKDEP must work in close partnership with the renal community, public health agencies, professional associations, and voluntary organizations that serve at-risk and patient communities. C1 [Narva, Andrew S.] NIDDK, Natl Kidney Dis Educ Program, DKUH, NIH, Bethesda, MD 20892 USA. RP Narva, AS (reprint author), NIDDK, Natl Kidney Dis Educ Program, DKUH, NIH, 2 Democracy Plaza,Rm 645,6707 Democracy Blvd, Bethesda, MD 20892 USA. EM narvaa@niddk.nih.gov NR 19 TC 19 Z9 20 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2009 VL 53 IS 3 BP S115 EP S120 DI 10.1053/j.ajkd.2008.05.038 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 414DN UT WOS:000263844200014 PM 19231755 ER PT J AU Peay, HL Hooker, GW Kassem, L Biesecker, BB AF Peay, H. L. Hooker, G. W. Kassem, L. Biesecker, B. B. TI Family Risk and Related Education and Counseling Needs: Perceptions of Adults With Bipolar Disorder and Siblings of Adults With Bipolar Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE genetic counseling; psychiatric; bipolar disorder ID MENTAL-ILLNESS; GENOMIC ERA; ATTITUDES; SCHIZOPHRENIA AB Genetics and mental health professionals increasingly provide education and counseling related to risk for psychiatric illness, but there is insufficient evidence about patient perceptions and needs to guide such interventions. Affected individuals and relatives may perceive increased family risk and have interest in genetic education and counseling. Our objectives were to explore perceptions of family vulnerability, perceived control, and coping strategies related to familial risk and needs from genetic counseling. Our methods included conducting semi-structured interviews (n=48) with individuals with bipolar disorder (BPD) and unaffected siblings. Content analysis generated descriptive data that provide guidance for clinical interventions and themes to evaluate in future studies. The results showed that participants perceived increased personal and family risk, attributing BPD to genes and family environment. Causal attributions were often uncertain and at times inconsistent. Participants wished to modify psychiatric risk to relatives, but were uncertain how to do so; despite the uncertainty, most parents reported risk-modification efforts. Efforts to cope with family vulnerability included monitoring and cognitive distancing. Participants endorsed the usefulness of education and psychological support, but described more ambivalence about receiving risk assessment. Educational and supportive interventions around family risk for BPD should focus on perceptions of cause and vulnerability, reproductive decision-making, and early intervention and risk modification in young relatives. Psychological support is an important component. Providers should evaluate patient coping strategies, which could facilitate or hinder genetic counseling interventions, and should not assume interest in quantitative risk assessment. (C) Published 2009 Wiley-Liss, Inc. C1 [Peay, H. L.; Hooker, G. W.; Biesecker, B. B.] NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP Peay, HL (reprint author), NHGRI, Social & Behav Res Branch, 31 Ctr Dr Bldg,31 B1B36H, Bethesda, MD 20892 USA. EM hpeay@mail.nih.gov FU National Human Genome Research Institute (Intramural Research Program), National Institutes of Health FX Grant sponsor: National Human Genome Research Institute (Intramural Research Program), National Institutes of Health. NR 23 TC 16 Z9 16 U1 1 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR PY 2009 VL 149A IS 3 BP 364 EP 371 DI 10.1002/ajmg.a.32696 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 418IQ UT WOS:000264142300013 PM 19215049 ER PT J AU Murphy, SP Hanna, NN Fast, LD Shaw, SK Berg, G Padbury, JF Romero, R Sharma, S AF Murphy, Shaun P. Hanna, Nazeeh N. Fast, Loren D. Shaw, Sunil K. Berg, Goeran Padbury, James F. Romero, Roberto Sharma, Surendra TI Evidence for participation of uterine natural killer cells in the mechanisms responsible for spontaneous preterm labor and delivery SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE cytokines; inflammation; preterm birth; uterine natural killer cells ID LOW-BIRTH-WEIGHT; NK CELLS; HUMAN PARTURITION; MESSENGER-RNA; IN-VITRO; IL-10; LIPOPOLYSACCHARIDE; MICE; INFECTION; CYTOKINES AB OBJECTIVE: The purpose of this study was to determine in a mouse model whether uterine natural killer (uNK) cell cytotoxic activation induces infection/inflammation-associated preterm labor and delivery. STUDY DESIGN: Wild type or interleukin (IL)-10(-/-) mice were injected intraperitoneally with lipopolysaccharide on gestational day 14. Mice were either killed for collection of uteroplacental tissue, spleen, and serum or allowed to deliver. Uteroplacental tissue was used for histology and characterization of uNK cells. RESULTS: Low-dose lipopolysaccharide treatment triggered preterm labor and delivery in IL-10(-/-), but not wild type mice, in a manner independent of progesterone levels. Preterm labor and delivery in IL-10(-/-) mice was associated with an increased number and placental infiltration of cytotoxic uNK cells and placental cell death. Depletion of NK cells or tumor necrosis factor (TNF)-alpha neutralization in these mice restored term delivery. Furthermore, TNF-alpha neutralization prevented uNK cell infiltration and placental cell apoptosis. CONCLUSION: The uNK cell-TNF-alpha-IL-10 axis plays an important role in the genesis of infection/inflammation-induced pretermlabor/delivery. C1 [Murphy, Shaun P.; Shaw, Sunil K.; Padbury, James F.; Sharma, Surendra] Brown Univ, Rhode Isl Warren Alpert Med Sch, Women & Infants Hosp, Dept Pediat, Providence, RI 02905 USA. [Hanna, Nazeeh N.] Winthrop Univ Hosp, Div Neonatol, Mineola, NY 11501 USA. [Fast, Loren D.] Brown Univ, Warren Alpert Med Sch, Rhode Isl Hosp, Dept Med, Providence, RI 02905 USA. [Berg, Goeran] Linkoping Univ Hosp, Fac Hlth & Sci, Div Obstet & Gynecol, S-58185 Linkoping, Sweden. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. RP Murphy, SP (reprint author), Brown Univ, Rhode Isl Warren Alpert Med Sch, Women & Infants Hosp, Dept Pediat, 101 Dudley St, Providence, RI 02905 USA. EM ssharma@wihri.org; prbchiefstaff@med.wayne.edu FU National Institutes of Health (NIH); National Center for Research Resources [P20RR018728]; National Institutes of Environmental Health Sciences Superfund Basic Research Program Award [P42ES013660]; NICHD [N01-HD-2-3342]; Subcontract [WSU05056]; Intramural Research Program of the Eunice Kennedy Shriver NICHD, NIH; Department of Health and Human Services FX Supported in part by the Grants from National Institutes of Health (NIH) National Center for Research Resources (P20RR018728), National Institutes of Environmental Health Sciences Superfund Basic Research Program Award (P42ES013660), and a Subcontract WSU05056 under NICHD Contract #N01-HD-2-3342. This research was also supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver NICHD, NIH, Department of Health and Human Services. NR 49 TC 19 Z9 20 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 MAR PY 2009 VL 200 IS 3 AR 308.e1 DI 10.1016/j.ajog.2008.10.043 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 422BT UT WOS:000264402700034 PM 19114277 ER PT J AU Ciner, E Ibay, G Wojciechowski, R Dana, D Holmes, TN Bailey-Wilson, JE Stambolian, D AF Ciner, Elise Ibay, Grace Wojciechowski, Robert Dana, Debra Holmes, Taura N. Bailey-Wilson, Joan E. Stambolian, Dwight TI Genome-wide Scan of African-American and White Families for Linkage to Myopia SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID OCULAR REFRACTION; SUSCEPTIBILITY LOCUS; CHROMOSOME 22Q12; PREVALENCE; REGION; ERRORS; POPULATION; CHILDREN; PROGRAMS; CITY AB PURPOSE: To identify myopia susceptibility genes in fluencing common myopia in 94 African,American and 36 White families. DESIGN: A prospective study of families with myopia consisting of a minimum of two individuals affected with myopia. METHODS: Extended families consisting of at least two siblings affected with myopia were ascertained. A genome-wide linkage scan using 387 markers was conducted by the Center for Inherited Disease Research. Linkage analyses were conducted with parametric and nonparametric methods. Model-free linkage analysis was performed maximizing over penetrance and over dominance (that is, fitting a wide range of both dominant and recessive models). RESULTS:Under the model-free analysis, the maximum two point heterogeneity logarithm of the odds score (MALOD) was 2.87 at D6S1009 in the White cohort and the maximum multipoint MALOD was 2.42 at D12S373-D12S1042 in the same cohort. The nonparametric linkage (NPL) maximum multipoint at D6S1035 had a P value of .005. An overall multipoint NPL score was obtained by combining NPL scores from both populations. The highest combined NPL score was observed at D20S478 with a significant P value of .008. Suggestive evidence of linkage in the White cohort mapped to a previously mapped locus on chromosome 11 at D11S1981 (NPL = 2.14; P = .02). CONCLUSIONS: Suggestive evidence of linkage to myopia in both African Americans and Whites was seen on chromosome 20 and became more significant when the scores were combined for both groups. The locus on chromosome 11 independently confirms a report by Hammond and associates mapping a myopia quantitative trait locus to this region. (Am J Ophthalmol 2009;147:512-517. (C) 2009 by Elsevier Inc. All rights reserved.) C1 [Stambolian, Dwight] Univ Penn, Dept Ophthalmol, Stellar Chance Labs, Philadelphia, PA 19104 USA. [Ibay, Grace; Wojciechowski, Robert; Holmes, Taura N.; Bailey-Wilson, Joan E.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Ciner, Elise] Penn Coll Optometry, Philadelphia, PA 19141 USA. RP Stambolian, D (reprint author), Univ Penn, Dept Ophthalmol, Stellar Chance Labs, Rm 313,422 Curie Blvd, Philadelphia, PA 19104 USA. EM stamboli@mail.med.upenn.edu OI Wojciechowski, Robert/0000-0002-9593-4652; Bailey-Wilson, Joan/0000-0002-9153-2920 FU NATIONAL EYE INSTITUTE, NATIONAL INSTITUTES OF Health [EY12226]; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland FX The authors thank Chris Moy, University of Pennsylvania, Philadelphia, Pennsylvania, Laura Hall, Pennsylvania College of Optometry, Elkins Park, Pennsylvania, Lauren Reider, University Of Pennsylvania, Philadelphia, Pennsylvania, Lori Schreiber and Marcy Graboyes, Pennsylvania College of Optometry, Elkins Park, Pennsylvania for their assistance in recruiting subjects and analysis of data. NR 33 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD MAR PY 2009 VL 147 IS 3 BP 512 EP 517 DI 10.1016/j.ajo.2008.09.004 PG 6 WC Ophthalmology SC Ophthalmology GA 411ON UT WOS:000263659000025 PM 19026404 ER PT J AU Johnson, DT Harris, RA French, S Aponte, A Balaban, RS AF Johnson, D. Thor Harris, Robert A. French, Stephanie Aponte, Angel Balaban, Robert S. TI Proteomic changes associated with diabetes in the BB-DP rat SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE metabolism; acyl carnitine; citrate synthase; methionine; liver; heart; skeletal muscle; mass spectroscopy; two-dimensional gel electrophoresis ID GLUCOKINASE REGULATORY PROTEIN; MIGRATION INHIBITORY FACTOR; GAMMA-AMINOBUTYRIC-ACID; GENE-EXPRESSION; UREA SYNTHESIS; CARBOHYDRATE-METABOLISM; CITRATE SYNTHASE; OXIDATIVE STRESS; ANIMAL-MODELS; LIVER AB Johnson DT, Harris RA, French S, Aponte A, Balaban RS. Proteomic changes associated with diabetes in the BB-DP rat. Am J Physiol Endocrinol Metab 296: E422-E432, 2009. First published November 4, 2008; doi:10.1152/ajpendo.90352.2008.-These studies were structured with the aim of utilizing emerging technologies in two-dimensional (2D) gel electrophoresis and mass spectrometry to evaluate protein expression changes associated with type 1 diabetes. We reasoned that a broad examination of diabetic tissues at the protein level might open up novel avenues of investigation of the metabolic and signaling pathways that are adversely affected in type 1 diabetes. This study compared the protein expression of the liver, heart, and skeletal muscle of diabetes-prone rats and matched control rats by semiquantitative liquid chromatography-mass spectrometry and differential in-gel 2D gel electrophoresis. Differential expression of 341 proteins in liver, 43 in heart, and 9 (2D gel only) in skeletal muscle was detected. These data were assembled into the relevant metabolic pathways affected primarily in liver. Multiple covalent modifications were also apparent in 2D gel analysis. Several new hypotheses were generated by these data, including mechanisms of net cytosolic protein oxidation, formaldehyde generation by the methionine cycle, and inhibition of carbon substrate oxidation via reduction in citrate synthase and short-chain acyl-CoA dehydrogenase. C1 [Johnson, D. Thor; French, Stephanie; Aponte, Angel; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Johnson, D. Thor; Harris, Robert A.] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN USA. [Johnson, D. Thor] Howard Hughes Med Inst, Bethesda, MD 20817 USA. RP Johnson, DT (reprint author), NHLBI, Cardiac Energet Lab, NIH, 10 Ctr Dr,Rm B1D416, Bethesda, MD 20892 USA. EM johnsondt@nhlbi.nih.gov NR 71 TC 25 Z9 26 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAR PY 2009 VL 296 IS 3 BP E422 EP E432 DI 10.1152/ajpendo.90352.2008 PG 11 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 410DJ UT WOS:000263556700003 PM 18984854 ER PT J AU Bischoff, SC Mailer, R Pabst, O Weier, G Sedlik, W Li, ZS Chen, JJ Murphy, DL Gershon, MD AF Bischoff, Stephan C. Mailer, Reiner Pabst, Oliver Weier, Gisela Sedlik, Wanda Li, Zhishan Chen, Jason J. Murphy, Dennis L. Gershon, Michael D. TI Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE neutrophils; motility; inflammatory bowel disease; epithelial cells ID IRRITABLE-BOWEL-SYNDROME; DELAYED-TYPE HYPERSENSITIVITY; ENTERIC NERVOUS-SYSTEM; TNBS-INDUCED COLITIS; GUINEA-PIG ILEUM; DEFICIENT MICE; FUNCTIONAL POLYMORPHISM; ENTEROCHROMAFFIN CELL; ENTEROENDOCRINE CELLS; VASCULAR-PERMEABILITY AB Bischoff SC, Mailer R, Pabst O, Weier G, Sedlik W, Li Z, Chen JJ, Murphy DL, Gershon MD. Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice. Am J Physiol Gastrointest Liver Physiol 296: G685-G695, 2009. First published December 18, 2008; doi: 10.1152/ajpgi.90685 .2008.-Serotonin (5-HT) regulates peristaltic and secretory reflexes in the gut. The serotonin reuptake transporter (SERT; SLC6A4), which inactivates 5-HT, is expressed in the intestinal mucosa and the enteric nervous system. Stool water content is increased and colonic motility is irregular in mice with a targeted deletion of SERT. We tested the hypotheses that 5-HT plays a role in regulating intestinal inflammation and that the potentiation of serotonergic signaling that results from SERT deletion is proinflammatory. Rectal installation of 2,4,6-trinitrobenzene sulfonic acid (TNBS) was used to induce an immune-mediated colitis, which was compared in SERT knockout mice and littermate controls. Intestinal myeloperoxidase and histamine levels were significantly increased, whereas the survival rate and state of health were significantly decreased in TNBS-treated mice that lacked SERT. Deletion of SERT thus increases the severity of TNBS colitis. These data suggest that 5-HT and its SERT-mediated termination play roles in intestinal immune/inflammatory responses in mice. C1 [Bischoff, Stephan C.] Univ Hohenheim, Dept Nutr Med & Immunol, D-70593 Stuttgart, Germany. [Bischoff, Stephan C.; Mailer, Reiner; Weier, Gisela] Univ Med Sch Hannover, Dept Gastroenterol Hepatol & Endocrinol, Hannover, Germany. [Pabst, Oliver] Univ Med Sch Hannover, Dept Immunol, Hannover, Germany. [Bischoff, Stephan C.; Sedlik, Wanda; Li, Zhishan; Chen, Jason J.; Gershon, Michael D.] Columbia Univ, Dept Anat & Cell Biol, New York, NY USA. [Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Bischoff, SC (reprint author), Univ Hohenheim, Dept Nutr Med & Immunol, D-70593 Stuttgart, Germany. EM bischoff.stephan@uni-hohenheim.de RI Pabst, Oliver/H-5014-2016 OI Pabst, Oliver/0000-0002-5533-883X FU Deutsche Gesellschaft fur Verdauungsund Stoffwechselerkrankungen; Columbia University of New York FX This work was supported by the Deutsche Gesellschaft fur Verdauungsund Stoffwechselerkrankungen (DGVS, Werner-Creutzfeldt-Grant to S. C. Bischoff), and by the Columbia University of New York (Ludwig Schaefer Award to S. C. Bischoff). NR 62 TC 69 Z9 70 U1 2 U2 6 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 MAR PY 2009 VL 296 IS 3 BP G685 EP G695 DI 10.1152/ajpgi.90685.2008 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 414YJ UT WOS:000263900800027 PM 19095763 ER PT J AU Moon, JO Welch, TP Gonzalez, FJ Copple, BL AF Moon, Jeon-Ok Welch, Timothy P. Gonzalez, Frank J. Copple, Bryan L. TI Reduced liver fibrosis in hypoxia-inducible factor-1 alpha-deficient mice SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE cholestasis; bile duct ligation; platelet-derived growth factor; collagen; alpha-smooth muscle actin ID HEPATIC STELLATE CELLS; GROWTH-FACTOR; FACTOR-I; OBSTRUCTIVE-JAUNDICE; FACTOR 1-ALPHA; ENDOTHELIAL-CELLS; GENE; EXPRESSION; INDUCTION; ALPHA AB Moon J, Welch TP, Gonzalez FJ, Copple BL. Reduced liver fibrosis in hypoxia-inducible factor-1 alpha-deficient mice. Am J Physiol Gastrointest Liver Physiol 296: G582-G592, 2009. First published January 8, 2009; doi:10.1152/ajpgi.90368.2008.-Liver fibrosis is characterized by excessive deposition of extracellular matrix in the liver during chronic injury. During early stages of this disease, cells begin to synthesize and secrete profibrotic proteins that stimulate matrix production and inhibit matrix degradation. Although it is clear that these proteins are important for development of fibrosis, what remains unknown is the mechanism by which chronic liver injury stimulates their production. In the present study, the hypothesis was tested that hypoxia-inducible factor-1 alpha (HIF-1 alpha) is activated in the liver during chronic injury and regulates expression of profibrotic proteins. To investigate this hypothesis, mice were subjected to bile duct ligation (BDL), an animal model of liver fibrosis. HIF-1 alpha protein was increased in the livers of mice subjected to BDL by 3 days after surgery. To test the hypothesis that HIF-1 alpha is required for the development of fibrosis, control and HIF-1 alpha-deficient mice were subjected to BDL. Levels of type I collagen and alpha-smooth muscle actin mRNA and protein were increased in control mice by 14 days after BDL. These levels were significantly reduced in HIF-1 alpha-deficient mice. Next, the levels of several profibrotic mediators were measured to elucidate the mechanism by which HIF-1 alpha promotes liver fibrosis. Platelet-derived growth factor (PDGF)-A, PDGF-B, and plasminogen activator inhibitor-1 mRNA levels were increased to a greater extent in control mice subjected to BDL compared with HIF-1 alpha-deficient mice at 7 and 14 days after BDL. Results from these studies suggest that HIF-1 alpha is a critical regulator of profibrotic mediator production during the development of liver fibrosis. C1 [Moon, Jeon-Ok; Welch, Timothy P.; Copple, Bryan L.] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. [Moon, Jeon-Ok] Pusan Natl Univ, Dept Pharm, Pusan, South Korea. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Copple, BL (reprint author), Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, 4063 KLSIC,3901 Rainbow Blvd, Kansas City, KS 66160 USA. EM bcopple@kumc.edu FU National Institutes of Health [DK073566]; Center of Biomedical Research Excellence (COBRE) [P20 RR021940]; COBRE FX This study was supported by National Institutes of Health Grants DK073566 (B. L. Copple) and Center of Biomedical Research Excellence (COBRE) P20 RR021940 as well as the Molecular Biology Core and the Histology Core supported by the COBRE grant. NR 34 TC 80 Z9 89 U1 1 U2 9 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 MAR PY 2009 VL 296 IS 3 BP G582 EP G592 DI 10.1152/ajpgi.90368.2008 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 414YJ UT WOS:000263900800015 PM 19136383 ER PT J AU Maltsev, VA Lakatta, EG AF Maltsev, Victor A. Lakatta, Edward G. TI Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE calcium; sarcoplasmic reticulum; ion channels; numerical modeling; sinoatrial node cell ID RABBIT SINOATRIAL NODE; CARDIAC SARCOPLASMIC-RETICULUM; SPONTANEOUS BEATING RATE; CAT RIGHT ATRIUM; MATHEMATICAL-MODEL; DIASTOLIC DEPOLARIZATION; NORMAL AUTOMATICITY; RYANODINE RECEPTOR; DEPENDENT PHOSPHORYLATION; ELECTRICAL-ACTIVITY AB Maltsev VA, Lakatta EG. Synergism of coupled subsarcolemmal Ca2+ clocks and sarcolemmal voltage clocks confers robust and flexible pacemaker function in a novel pacemaker cell model. Am J Physiol Heart Circ Physiol 296: H594-H615, 2009. First published January 9, 2009; doi:10.1152/ajpheart.01118.2008.-Recent experimental studies have demonstrated that sinoatrial node cells (SANC) generate spontaneous, rhythmic, local subsarcolemmal Ca2+ releases (Ca2+ clock), which occur during late diastolic depolarization (DD) and interact with the classic sarcolemmal voltage oscillator (membrane clock) by activating Na+-Ca2+ exchanger current (I-NCX). This and other interactions between clocks, however, are not captured by existing essentially membrane-delimited cardiac pacemaker cell numerical models. Using wide-scale parametric analysis of classic formulations of membrane clock and Ca2+ cycling, we have constructed and initially explored a prototype rabbit SANC model featuring both clocks. Our coupled oscillator system exhibits greater robustness and flexibility than membrane clock operating alone. Rhythmic spontaneous Ca2+ releases of sarcoplasmic reticulum (SR)-based Ca2+ clock ignite rhythmic action potentials via late DD I-NCX over much broader ranges of membrane clock parameters [e. g., L-type Ca2+ current (I-CaL) and/or hyperpolarization-activated ("funny") current (I-f) conductances]. The system Ca2+ clock includes SR and sarcolemmal Ca2+ fluxes, which optimize cell Ca2+ balance to increase amplitudes of both SR Ca2+ release and late DD I-NCX as SR Ca2+ pumping rate increases, resulting in a broad pacemaker rate modulation (1.8-4.6 Hz). In contrast, the rate modulation range via membrane clock parameters is substantially smaller when Ca2+ clock is unchanged or lacking. When Ca2+ clock is disabled, the system parametric space for fail-safe SANC operation considerably shrinks: without rhythmic late DD I-NCX ignition signals membrane clock substantially slows, becomes dysrhythmic, or halts. In conclusion, the Ca2+ clock is a new critical dimension in SANC function. A synergism of the coupled function of Ca2+ and membrane clocks confers fail-safe SANC operation at greatly varying rates. C1 [Maltsev, Victor A.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@grc.nia.nih.gov FU National Institutes of Health, National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 74 TC 90 Z9 95 U1 0 U2 13 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 MAR PY 2009 VL 296 IS 3 BP H594 EP H615 DI 10.1152/ajpheart.01118.2008 PG 22 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 412SY UT WOS:000263745700009 PM 19136600 ER PT J AU Manso, AM Kang, SM Plotnikov, SV Thievessen, I Oh, J Beggs, HE Ross, RS AF Manso, Ana Maria Kang, Seok-Min Plotnikov, Sergey V. Thievessen, Ingo Oh, Jaewon Beggs, Hilary E. Ross, Robert S. TI Cardiac fibroblasts require focal adhesion kinase for normal proliferation and migration SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE extracellular matrix; cytoskeleton; fibroblast ID SMOOTH-MUSCLE-CELLS; GROWTH-FACTOR; REGULATES PROLIFERATION; ENDOGENOUS INHIBITOR; ENDOTHELIAL-CELLS; SIGNALING EVENTS; TYROSINE KINASE; MESSENGER-RNAS; ANGIOTENSIN-II; LEADING-EDGE AB Manso AM, Kang SM, Plotnikov SV, Thievessen I, Oh J, Beggs HE, Ross RS. Cardiac fibroblasts require focal adhesion kinase for normal proliferation and migration. Am J Physiol Heart Circ Physiol 296: H627-H638, 2009. First published January 9, 2009; doi:10.1152/ajpheart.00444.2008.-Migration and proliferation of cardiac fibroblasts (CFs) play an important role in the myocardial remodeling process. While many factors have been identified that regulate CF growth and migration, less is known about the signaling mechanisms involved in these processes. Here, we utilized Cre-LoxP technology to obtain focal adhesion kinase (FAK)-deficient adult mouse CFs and studied how FAK functioned in modulating cell adhesion, proliferation, and migration of these cells. Treatment of FAK(flox/flox) CFs with Ad/Cre virus caused over 70% reduction of FAK protein levels within a cell population. FAK-deficient CFs showed no changes in focal adhesions, cell morphology, or protein expression levels of vinculin, talin, or paxillin; proline-rich tyrosine kinase 2 (Pyk2) expression and activity were increased. Knockdown of FAK protein in CFs increased PDGF-BB-induced proliferation, while it reduced PDGF-BB-induced migration. Adhesion to fibronectin was not altered. To distinguish between the function of FAK and Pyk2, FAK function was inhibited via adenoviral-mediated overexpression of the natural FAK inhibitor FAK-related nonkinase (FRNK). Ad/FRNK had no effect on Pyk2 expression, inhibited the PDGF-BB-induced migration, but did not change the PDGF-BB-induced proliferation. FAK deficiency had only modest effects on increasing PDGF-BB activation of p38 and JNK MAPKs, with no alteration in the ERK response vs. control cells. These results demonstrate that FAK is required for the PDGF-BB-induced migratory response of adult mouse CFs and suggest that FAK could play an essential role in the wound-healing response that occurs in numerous cardiac pathologies. C1 [Ross, Robert S.] VA San Diego Healthcare Syst, Cardiol Sect, La Jolla, CA 92161 USA. [Manso, Ana Maria; Kang, Seok-Min; Ross, Robert S.] Univ Calif San Diego, Sch Med, Dept Med, La Jolla, CA 92093 USA. [Kang, Seok-Min; Oh, Jaewon] Yonsei Univ, Coll Med, Div Cardiol, Seoul, South Korea. [Plotnikov, Sergey V.; Thievessen, Ingo] NIH, Heart Lung & Blood Inst, Bethesda, MD 20892 USA. [Beggs, Hilary E.] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA 94143 USA. RP Ross, RS (reprint author), VA San Diego Healthcare Syst, Cardiol Sect, 111A,3350 Jolla Village Dr, La Jolla, CA 92161 USA. EM rross@ucsd.edu FU Veterans Administration; National Institutes of Health [RO1-HL-057872, PO1-HL-066941, RO1-HL-088390] FX This work was supported by grants from the Veterans Administration (VA Merit to R. S. Ross) and the National Institutes of Health (RO1-HL-057872, PO1-HL-066941, and RO1-HL-088390 to R. S. Ross). NR 65 TC 17 Z9 18 U1 0 U2 3 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 MAR PY 2009 VL 296 IS 3 BP H627 EP H638 DI 10.1152/ajpheart.00444.2008 PG 12 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 412SY UT WOS:000263745700011 PM 19136609 ER PT J AU Li, JD Burton, KJ Zhang, CK Hu, SB Zhou, QY AF Li, Jia-Da Burton, Katherine J. Zhang, Chengkang Hu, Shuang-Bao Zhou, Qun-Yong TI Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE prokineticin ID PINEAL MELATONIN SYNTHESIS; DEFICIENT BRATTLEBORO RAT; ARGININE-VASOPRESSIN; DIABETES-INSIPIDUS; DIURNAL RHYTHM; PHASE-SHIFTS; CLONING; CELLS; VOLES; BRAIN AB Li JD, Burton KJ, Zhang C, Hu SB, Zhou QY. Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei. Am J Physiol Regul Integr Comp Physiol 296: R824-R830, 2009. First published December 3, 2008; doi:10.1152/ajpregu.90463.2008.-The suprachiasmatic nuclei (SCN) serve as the principal circadian pacemakers that coordinate daily cycles of behavior and physiology for mammals. A network of transcriptional and translational feedback loops underlies the operating molecular mechanism for circadian oscillation within the SCN neurons. It remains unclear how timing information is transmitted from SCN neurons to eventually evoke circadian rhythms. Intercellular communication between the SCN and its target neurons is critical for the generation of coherent circadian rhythms. At the molecular level, neuropeptides encoded by clock-controlled genes have been indicated as important output mediators. Arginine vasopressin (AVP) is the product of one such clock-controlled gene. Previous studies have demonstrated a circadian rhythm of AVP levels in the cerebrospinal fluid and the SCN. The physiological effects of AVP are mediated by three types of AVP receptors, designated as V1a, V1b, and V2. In this study, we report that V1a mRNA levels displayed a circadian rhythm in the SCN, peaking during night hours. The circadian rhythmicity of locomotor activities was significantly reduced in V1a-deficient (V1a(-/-)) mice (50-75% reduction in the power of fast Fourier transformation). However, the light masking and light-induced phase shift effects are intact in V1a(-/-) mice. Whereas the expression of clock core genes was unaltered, the circadian amplitude of prokineticin 2 (PK2) mRNA oscillation was attenuated in the SCN of V1a(-/-) mice (similar to 50% reduction in the peak levels). In vitro experiments demonstrated that AVP, acting through V1a receptor, was able to enhance the transcriptional activity of the PK2 promoter. These studies thus indicate that AVP-V1a signaling plays an important role in the generation of overt circadian rhythms. C1 [Li, Jia-Da; Burton, Katherine J.; Zhang, Chengkang; Zhou, Qun-Yong] Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92697 USA. [Hu, Shuang-Bao] NIMH, Clin Neuroendocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Zhou, QY (reprint author), Univ Calif Irvine, Dept Pharmacol, Irvine, CA 92697 USA. EM qzhou@uci.edu FU National Institute of Mental Health [MH67753] FX This work was supported in part by National Institute of Mental Health Grant MH67753. NR 44 TC 46 Z9 49 U1 2 U2 11 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD MAR PY 2009 VL 296 IS 3 BP R824 EP R830 DI 10.1152/ajpregu.90463.2008 PG 7 WC Physiology SC Physiology GA 412ST UT WOS:000263745200040 PM 19052319 ER PT J AU Nayeem, MA Ponnoth, DS Boegehold, MA Zeldin, DC Falck, JR Mustafa, SJ AF Nayeem, Mohammed A. Ponnoth, Dovenia S. Boegehold, Matthew A. Zeldin, Darryl C. Falck, John R. Mustafa, S. Jamal TI High-salt diet enhances mouse aortic relaxation through adenosine A(2A) receptor via CYP epoxygenases SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE vasodilation; vasoconstriction ID SMOOTH-MUSCLE-CELLS; RAT PREGLOMERULAR MICROVESSELS; PROTEIN-KINASE-C; EPOXYEICOSATRIENOIC ACIDS; ARACHIDONIC-ACID; NITRIC-OXIDE; SENSITIVE HYPERTENSION; CYTOCHROME P4502C; ENDOTHELIAL-CELLS; EXPRESSION AB Nayeem MA, Ponnoth DS, Boegehold MA, Zeldin DC, Falck JR, Mustafa SJ. High-salt diet enhances mouse aortic relaxation through adenosine A(2A) receptor via CYP epoxygenases. Am J Physiol Regul Integr Comp Physiol 296: R567-R574, 2009. First published December 24, 2008; doi: 10.1152/ajpregu.90798.2008. -We hypothesize that A(2A) adenosine receptors (A(2A) AR) promote aortic relaxation in mice through cytochrome P450 ( CYP)-epoxygenases and help to avoid salt sensitivity. Aortas from male mice maintained on a high-salt (HS; 7% NaCl) or normal-salt (NS; 0.45% NaCl) diet for 4-5 wks were used. Concentration-response curves (10(-11)-10(-5) M) for 5'-N-ethylcarboxamidoadenosine ( NECA; a nonselective adenosine analog) and CGS 21680 ( A2A AR agonist) were obtained with different antagonists including ZM 241385 ( A2A AR antagonist; 10(-6) M), SCH 58261 (A(2A) AR antagonist; 10(-6) M), N-omega-nitro-L-arginine methyl ester (L-NAME; endothelial nitric oxide synthase inhibitor; 10(-4) M) and inhibitors including methylsulfonyl-propargyloxyphenylhexanamide (MS-PPOH; CYP epoxygenases inhibitor; 10(-5)M), 14,15-epoxyeicosa-5(z)-enoic acid ( 14,15-EEZE; EET antagonist; 10(-5)M), dibromo-dodecenyl-methylsulfimide ( DDMS; CYP4A inhibitor; 10(-5)M), and HET0016 (20-HETE inhibitor; 10(-5)M). At 10(-7) M of NECA, significant relaxation in HS (+ 22.58 +/- 3.12%) was observed compared with contraction in NS ( - 10.62 +/- 6.27%, P < 0.05). ZM 241385 changed the NECA response to contraction ( P < 0.05) in HS. At 10(-7) M of CGS 21680, significant relaxation in HS ( + 32.04 +/- 3.08%) was observed compared with NS ( + 10.45 +/- 1.34%, P < 0.05). SCH 58261, L-NAME, MS-PPOH, and 14,15-EEZE changed the CGS 21680-induced relaxation to contraction ( P < 0.05) in HS. Interestingly, DDMS and HET0016 changed CGS 21680 response to relaxation ( P < 0.05) in NS; however, there was no significant difference found between DDMS, HET0016-treated HS and NS vs. nontreated HS group ( P > 0.05). CYP2C29 protein was 55% and 74% upregulated in HS vs. NS ( P < 0.05) mice aorta and kidney, respectively. CYP4A protein was 30.30% and 35.70% upregulated in NS vs. HS ( P < 0.05) mice aorta and kidneys, respectively. A(1) AR was downregulated, whereas A(2A) AR was upregulated in HS compared with NS. These data suggest that HS may activate CYP2C29 via A2A AR, causing relaxation, whereas NS may contribute to the upregulation of CYP4A causing contraction. C1 [Nayeem, Mohammed A.; Ponnoth, Dovenia S.; Boegehold, Matthew A.; Mustafa, S. Jamal] W Virginia Univ, Ctr Interdisciplinary Res Cardiovasc Sci, Dept Physiol & Pharmacol, Morgantown, WV 26506 USA. [Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Falck, John R.] Univ Texas SW Med Ctr Dallas, Dept Biochem, Dallas, TX 75390 USA. RP Nayeem, MA (reprint author), W Virginia Univ, Ctr Interdisciplinary Res Cardiovasc Sci, Dept Physiol & Pharmacol, 3051 Robert C Byrd Hlth Sci Ctr N,1 Med Ctr Dr,P, Morgantown, WV 26506 USA. EM mnayeem@hsc.wvu.edu RI Nayeem, Mohammed/A-3949-2017; OI Nayeem, Mohammed/0000-0002-7827-4760; Falck, John/0000-0002-9219-7845 FU National Heart, Lung, and Blood Institute [HL-027339, HL-094447,]; American Heart Association [0755264B,]; National Institutes of Health [GM31278]; National Institute of Environmental Health Sciences [z01-ES-025034] FX This work was supported by National Heart, Lung, and Blood Institute Grants HL-027339 and HL-094447, American Heart Association Great Rivers Affiliate Grant-in-Aid 0755264B, National Institutes of Health Grant GM31278, and the Intramural Research Program of the National Institute of Environmental Health Sciences Grant z01-ES-025034. NR 53 TC 12 Z9 13 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD MAR PY 2009 VL 296 IS 3 BP R567 EP R574 DI 10.1152/ajpregu.90798.2008 PG 8 WC Physiology SC Physiology GA 412ST UT WOS:000263745200012 PM 19109366 ER PT J AU Hashimoto, S Yamada, K Kawata, T Mochizuki, T Schnermann, J Koike, T AF Hashimoto, Seiji Yamada, Kanji Kawata, Tetsuya Mochizuki, Toshio Schnermann, Jurgen Koike, Takao TI Abnormal autoregulation and tubuloglomerular feedback in prediabetic and diabetic OLETF rats SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE type 2 diabetes; hemodynamics; deep nephrons; corticotomy; micropuncture; Otsuka Long-Evans Tokushima Fatty ID RENAL PERFUSION-PRESSURE; BLOOD-FLOW; JUXTAMEDULLARY CORTEX; CAPILLARY-PRESSURE; GLOMERULAR VOLUME; MELLITUS; KIDNEY; HYPERTENSION; NEPHROPATHY; MODEL AB Hashimoto S, Yamada K, Kawata T, Mochizuki T, Schnermann J, Koike T. Abnormal autoregulation and tubuloglomerular feedback in prediabetic and diabetic OLETF rats. Am J Physiol Renal Physiol 296: F598-F604, 2009. First published December 23, 2008; doi:10.1152/ajprenal.00074.2008.-The mechanisms underlying the development and prevention of diabetic nephropathy are still not fully understood. In the present study in the Otsuka Long-Evans Tokushima Fatty (OLETF) model of type 2 diabetic rats, we investigated whether renal hemodynamic abnormalities exist and whether they precede the onset of diabetes. Using OLETF rats in both prediabetic and diabetic stages, we assessed autoregulatory responses of total renal blood flow (RBF) and of superficial (SBF) and deep renal cortical (DBF) blood flow to stepwise reductions of renal perfusion pressure (RPP) induced by a manual clamp on the abdominal aorta. During clamp-induced reductions of RPP by 10 or 20 mmHg, RBF fell significantly more in OLETF rats than in lean control [Long-Evans Tokushima Otsuka (LETO)] rats. Whereas SBF showed no significant changes in either OLETF rats or LETO rats during mild clamping, DBF decreased significantly more in OLETF rats than LETO rats. Reduced autoregulatory efficiency in OLETF rats was observed in both prediabetic and diabetic stages. Micropuncture studies showed that tubuloglomerular feedback (TGF) responses of stop flow pressure are reduced in prediabetic (-7.3 vs. -25.7%)as well as in diabetic OLETF rats compared with LETO control rats (-4.4 vs. -18.8%). Renal corticotomy was performed to measure glomerular capillary pressure (P(gc)) directly. P(gc) of deep cortical glomeruli was higher than superficial glomerular P(gc) in both strains of rats, but the difference was especially pronounced in OLETF rats (deep 78 +/- 2 vs. superficial 57 +/- 4 mmHg). This study demonstrates reduced autoregulatory adjustments and impaired TGF efficiency in prediabetic OLETF rats. Thus abnormal RBF regulation precedes the onset of diabetes and is especially pronounced in the deep cortical region. C1 [Hashimoto, Seiji] Hokkaido Univ, Grad Sch Med, Kita Ku, Sapporo, Hokkaido 0608638, Japan. [Schnermann, Jurgen] NIDDK, NIH, Bethesda, MD USA. RP Hashimoto, S (reprint author), Hokkaido Univ, Grad Sch Med, Kita Ku, North 15,West 7, Sapporo, Hokkaido 0608638, Japan. EM seijinih@med.hokudai.ac.jp FU Japan Society for the Promotion of Science [17590814] FX This work was supported by Grant No. 17590814 from the Japan Society for the Promotion of Science. NR 29 TC 12 Z9 12 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2009 VL 296 IS 3 BP F598 EP F604 DI 10.1152/ajprenal.00074.2008 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 410CB UT WOS:000263552400017 PM 19106213 ER PT J AU Moeller, HB MacAulay, N Knepper, MA Fenton, RA AF Moeller, Hanne B. MacAulay, Nanna Knepper, Mark A. Fenton, Robert A. TI Role of multiple phosphorylation sites in the COOH-terminal tail of aquaporin-2 for water transport: evidence against channel gating SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE water channel; vasopressin; NDI; kidney ID NEPHROGENIC DIABETES-INSIPIDUS; XENOPUS-LAEVIS OOCYTES; COLLECTING DUCT; APICAL MEMBRANE; ION CHANNELS; VASOPRESSIN; CELLS; LOCALIZATION; EXPRESSION; DOMINANT AB Moeller HB, MacAulay N, Knepper MA, Fenton RA. Role of multiple phosphorylation sites in the COOH-terminal tail of aquaporin- 2 for water transport: evidence against channel gating. Am J Physiol Renal Physiol 296: F649-F657, 2009. First published January 14, 2009; doi: 10.1152/ajprenal.90682.2008.-Arginine vasopressin (AVP)-regulated phosphorylation of the water channel aquaporin-2 (AQP2) at serine 256 (S256) is essential for its accumulation in the apical plasma membrane of collecting duct principal cells. In this study, we examined the role of additional AVP-regulated phosphorylation sites in the COOH-terminal tail of AQP2 on protein function. When expressed in Xenopus laevis oocytes, prevention of AQP2 phosphorylation at S256A (S256A-AQP2) reduced osmotic water permeability threefold compared with wild-type (WT) AQP2-injected oocytes. In contrast, prevention of AQP2 single phosphorylation at S261 (S261A), S264 (S264A), and S269 (S269A), or all three sites in combination had no significant effect on water permeability. Similarly, oocytes expressing S264D-AQP2 and S269D-AQP2, mimicking AQP2 phosphorylated at these residues, had similar water permeabilities to WT-AQP2-expressing oocytes. The use of high-resolution confocal laser-scanning microscopy, as well as biochemical analysis demonstrated that all AQP2 mutants, with the exception of S256A-AQP2, had equal abundance in the oocyte plasma membrane. Correlation of osmotic water permeability relative to plasma membrane abundance demonstrated that lack of phosphorylation at S256, S261, S264, or S269 had no effect on AQP2 unit water transport. Similarly, no effect on AQP2 unit water transport was observed for the 264D and 269D forms, indicating that phosphorylation of the COOH-terminal tail of AQP2 is not involved in gating of the channel. The use of phosphospecific antibodies demonstrated that AQP2 S256 phosphorylation is not dependent on any of the other phosphorylation sites, whereas S264 and S269 phosphorylation depend on prior phosphorylation of S256. In contrast, AQP2 S261 phosphorylation is independent of the phosphorylation status of S256. C1 [Moeller, Hanne B.; Fenton, Robert A.] Univ Aarhus, Inst Anat, Water & Salt Res Ctr, DK-8000 Aarhus, Denmark. [MacAulay, Nanna] Univ Copenhagen, Panum Inst, Inst Cellular & Mol Med, DK-2200 Copenhagen, Denmark. [Knepper, Mark A.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Fenton, RA (reprint author), Univ Aarhus, Inst Anat, Water & Salt Res Ctr, Bldg 1233, DK-8000 Aarhus, Denmark. EM rofe@ana.au.dk OI MacAulay, Nanna/0000-0002-7800-6600 FU Marie Curie Intra-European; Faculty of Health Sciences, University of Aarhus; Danish National Research Foundation (Danmarks Grundforskningsfond); EU 7th; Danish Medical Research Council; Lundbeck Foundation; E. Danielsen Foundation; National Heart, Lung, and Blood Institute [ZO1-HL-001285] FX R. A. Fenton is supported by a Marie Curie Intra-European Fellowship. H. B. Moeller is supported by the Faculty of Health Sciences, University of Aarhus. The Water and Salt Research Center at the University of Aarhus is established and supported by the Danish National Research Foundation (Danmarks Grundforskningsfond). Additional funding was provided by the EU 7th Framework (to R. A. Fenton), the Danish Medical Research Council (to R. A. Fenton and N. MacAulay), the Lundbeck Foundation (to N. MacAulay), the E. Danielsen Foundation (to N. MacAulay), and The Nordic Centre of Excellence Program (NCoE) in Molecular Medicine (to R. A. Fenton and N. MacAulay). Funding to M. A. Knepper was provided by the Intramural Budget of the National Heart, Lung, and Blood Institute (National Institutes of Health Project ZO1-HL-001285). NR 33 TC 44 Z9 46 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2009 VL 296 IS 3 BP F649 EP F657 DI 10.1152/ajprenal.90682.2008 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 410CB UT WOS:000263552400023 PM 19144687 ER PT J AU Pabla, N Murphy, RF Liu, KB Dong, Z AF Pabla, Navjotsingh Murphy, Robert F. Liu, Kebin Dong, Zheng TI The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE apoptosis; necrosis; acute kidney injury ID ORGANIC CATION TRANSPORTER; METHIONINE-RICH CLUSTERS; CELLULAR ACCUMULATION; P53 ACTIVATION; APOPTOSIS; EXPRESSION; ARCHITECTURE; MECHANISMS; RESISTANCE; TOXICITY AB Pabla N, Murphy RF, Liu K, Dong Z. The copper transporter Ctr1 contributes to cisplatin uptake by renal tubular cells during cisplatin nephrotoxicity. Am J Physiol Renal Physiol 296: F505-F511, 2009. First published January 14, 2009; doi:10.1152/ajprenal.90545.2008.-The usefulness and efficacy of cisplatin, a chemotherapeutic drug, are limited by its toxicity to normal tissues and organs, including the kidneys. The uptake of cisplatin in renal tubular cells is high, leading to cisplatin accumulation and tubular cell injury and death, culminating in acute renal failure. While extensive investigations have been focused on the signaling pathways of cisplatin nephrotoxicity, much less is known about the mechanism of cisplatin uptake by renal cells and tissues. In this regard, evidence has been shown for the involvement of organic cation transporters (OCT), specifically OCT2. The copper transporter Ctr1 is highly expressed in the renal tubular cells; however, its role in cisplatin nephrotoxicity is not known. In this study, we demonstrate that Ctr1 is mainly expressed in both proximal and distal tubular cells in mouse kidneys. We further show that Ctr1 is mainly localized on the basolateral side of these cells, a proposed site for cisplatin uptake. Importantly, downregulation of Ctr1 by small interfering RNA or copper pretreatment results in decreased cisplatin uptake. Consistently, downregulation of Ctr1 suppresses cisplatin toxicity, including cell death by both apoptosis and necrosis. Cimetidine, a pharmacological inhibitor of OCT2, can also partially attenuate cisplatin uptake. Notably, cimetidine can further reduce cisplatin uptake and cisplatin toxicity in Ctr1-downregulated cells. The results have demonstrated the first evidence for a role of Ctr1 in cisplatin uptake and nephrotoxicity. C1 [Pabla, Navjotsingh; Dong, Zheng] Med Coll Georgia, Dept Cellular Biol & Anat, Augusta, GA 30912 USA. [Liu, Kebin] Med Coll Georgia, Dept Biochem & Mol Biol, Augusta, GA 30912 USA. [Liu, Kebin] Charlie Norwood Vet Affairs Med Ctr, Augusta, GA USA. [Murphy, Robert F.] NCI, NIH, Bethesda, MD 20892 USA. RP Dong, Z (reprint author), Med Coll Georgia, Dept Cellular Biol & Anat, 1459 Laney Walker Blvd, Augusta, GA 30912 USA. EM zdong@mail.mcg.edu RI Pabla, Navjotsingh /H-3568-2011; OI Liu, Kebin/0000-0003-1965-7240 FU National Institutes of Health and the Department of Veterans Affairs FX The study was supported by grants from the National Institutes of Health and the Department of Veterans Affairs (VA). Z. Dong is a VA Research Career Scientist. NR 34 TC 76 Z9 81 U1 3 U2 10 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2009 VL 296 IS 3 BP F505 EP F511 DI 10.1152/ajprenal.90545.2008 PG 7 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 410CB UT WOS:000263552400007 PM 19144690 ER PT J AU Pan, H Shen, ZJ Mukhopadhyay, P Wang, H Pacher, P Qin, XB Gao, B AF Pan, Hao Shen, Zhoujun Mukhopadhyay, Partha Wang, Hua Pacher, Pal Qin, Xuebin Gao, Bin TI Anaphylatoxin C5a contributes to the pathogenesis of cisplatin-induced nephrotoxicity SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE cytokines; caspase; STAT3; NF-kappa B ID ISCHEMIA-REPERFUSION INJURY; ACUTE-RENAL-FAILURE; ISCHEMIA/REPERFUSION INJURY; COMPLEMENT-SYSTEM; CANCER-THERAPY; ACTIVATION; MICE; KIDNEY; LIVER; NEPHROPATHY AB Pan H, Shen Z, Mukhopadhyay P, Wang H, Pacher P, Qin X, Gao B. Anaphylatoxin C5a contributes to the pathogenesis of cisplatin-induced nephrotoxicity. Am J Physiol Renal Physiol 296: F496-F504, 2009. First published January 14, 2009; doi:10.1152/ajprenal.90443.2008.-Nephrotoxicity is a common complication of cisplatin chemotherapy that limits its clinical use; however, the mechanisms underlying cisplatin-mediated nephrotoxicity are not fully understood. In this study, we investigated the role of anaphylatoxin C5a in the pathogenesis of cisplatin-mediated nephrotoxicity. Our data show that cisplatin-induced renal injury is significantly reduced in C5- or C5aR-deficient mice. However, pretreatment with C5 or C5a restores sensitivity to cisplatin-induced nephrotoxicity in C5-deficient mice. In wild-type mice, administration of cisplatin triggers the increased renal expression of multiple cytokines and caspases. This induction is diminished in C5-deficient mice, which is restored by pretreatment with C5 or C5a proteins. Interestingly, renal injury induced by cisplatin is similar between wildtype and CD59ab double knockout mice, and the formation of membrane attack complexes (MACs) by cisplatin in the kidney is diminished in C5- deficient mice, but not in C5aR-deficient mice. In conclusion, our findings suggest that C5a plays an important role in the pathogenesis of cisplatin nephrotoxicity. Likely, C5a binds to C5aR, leading to induction of proinflammatory cytokines and inflammation. The formation of MACs does not appear to contribute to the nephrotoxicity of cisplatin based on our study results. C1 [Pan, Hao; Wang, Hua; Gao, Bin] NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Pan, Hao; Shen, Zhoujun] Zhejiang Univ, Coll Med, Affiliated Hosp 1, Dept Urol, Hangzhou, Zhejiang, Peoples R China. [Mukhopadhyay, Partha; Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Qin, Xuebin] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. RP Gao, B (reprint author), NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. EM bgao@mail.nih.gov RI MUKHOPADHYAY, PARTHA/G-3890-2010; Pacher, Pal/B-6378-2008; Ji, Haofeng/G-6206-2012 OI MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Pacher, Pal/0000-0001-7036-8108; FU National Institute on Alcohol Abuse and Alcoholism; National Institutes of Health FX This work was supported by the Intramural Program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. NR 36 TC 14 Z9 17 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2009 VL 296 IS 3 BP F496 EP F504 DI 10.1152/ajprenal.90443.2008 PG 9 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 410CB UT WOS:000263552400006 PM 19144695 ER PT J AU Blake, SM Murray, KD El-Khorazaty, MN Gantz, MG Kiely, M Best, D Joseph, JG El-Mohandes, AAE AF Blake, Susan M. Murray, Kennan D. El-Khorazaty, M. Nabil Gantz, Marie G. Kiely, Michele Best, Dana Joseph, Jill G. El-Mohandes, Ayman A. E. TI Environmental Tobacco Smoke Avoidance Among Pregnant African-American Nonsmokers SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID INTIMATE PARTNER VIOLENCE; MOOD REGULATION EXPECTANCIES; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; UNINTENDED PREGNANCY; DEPRESSIVE SYMPTOMS; ETHNIC-DIFFERENCES; SERUM COTININE; PRENATAL-CARE; BIRTH-WEIGHT AB Background: Environmental tobacco smoke (ETS) exposure during pregnancy contributes to adverse infant health outcomes. Limited previous research has focused on identifying correlates of ETS avoidance. This study sought to identify proximal and more distal correlates of ETS avoidance early in pregnancy among African-American women. Methods: From a sample of low-income, black women (n=1044) recruited in six urban, prenatal care clinics (July 2001-October 2003), cotinine-confirmed nonsmokers with partners, household/family members, or friends who smoked (n=450) were identified and divided into two groups: any past-7-day ETS exposure and cotinine-confirmed ETS avoidance. Bivariate and multivariate logistic regression analyses identified factors associated with ETS avoidance. Data were initially analyzed in 2004. Final models were reviewed and revised in 2007 and 2008. Results: Twenty-seven percent of pregnant nonsmokers were confirmed as ETS avoiders. In multivariate logistic regression analysis, the odds of ETS avoidance were increased among women who reported household smoking bans (OR=2.96; 95% CI=1.83, 4.77; p<0.0001), that the father wanted the baby (OR=2.70; CI=1.26, 5.76; p=0.01), and that no/few family members/friends smoked (OR=3.15; 95% CI=1.58, 6.29; p<0.001). The odds were decreased among women who had a current partner (OR=0.42; 95% CI=0.23, 0.76; p<0.01), reported any intimate partner violence during pregnancy (OR=0.43; 95% CI=0.19, 0.95; p<0.05), and reported little social support to prevent ETS exposure (OR=0.50; 95% CI=0.30, 0.85; p=0.01). Parity, emotional coping strategies, substance use during pregnancy, partner/household member smoking status, and self-confidence in avoiding ETS were significant in bivariate, but not multivariate analyses. Conclusions: Social contextual factors were the strongest determinants of ETS avoidance during pregnancy. Results highlight the importance of prenatal screening to identify pregnant nonsmokers at risk, encouraging household smoking bans, gaining support from significant others, and fully understanding the interpersonal context of a woman's pregnancy before providing behavioral counseling and advice to prevent ETS exposure. C1 [Blake, Susan M.; El-Mohandes, Ayman A. E.] George Washington Univ, Med Ctr, Sch Publ Hlth & Hlth Serv, Dept Prevent & Community Hlth, Washington, DC 20037 USA. [Best, Dana; Joseph, Jill G.] George Washington Univ, Sch Med & Hlth Sci, Childrens Natl Med Ctr, Ctr Clin & Community Res, Washington, DC 20037 USA. [Best, Dana; Joseph, Jill G.] George Washington Univ, Sch Med & Hlth Sci, Dept Pediat, Washington, DC 20037 USA. [Murray, Kennan D.; El-Khorazaty, M. Nabil; Gantz, Marie G.] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Kiely, Michele] Eunice Kennedy Shriver NICHHD, Div Epidemiol Stat & Prevent Res, Collaborat Studies Unit, Rockville, MD USA. RP Blake, SM (reprint author), George Washington Univ, Med Ctr, Sch Publ Hlth & Hlth Serv, Dept Prevent & Community Hlth, 2175 K St NW,Suite 700, Washington, DC 20037 USA. EM smblake@gwu.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Center on Minority Health and Health [3U18HD030445, 3U18HD030447, 5U18HD31206, 3U18HD03919, 5U18HD036104] FX This study was part of the NIH-DC Initiative, a congressionally mandated project to reduce infant morbidity/mortality in minority populations in the District of Columbia. Collaborating institutions included: Children's National Medical Center, The George Washington University Medical Center, Georgetown University Medical Center, Howard University Hospital, and RTI International. The research on which this article was based was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Center on Minority Health and Health Disparities under cooperative agreement grant #s 3U18HD030445, 3U18HD030447, 5U18HD31206, 3U18HD03919, and 5U18HD036104. NR 90 TC 12 Z9 14 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAR PY 2009 VL 36 IS 3 BP 225 EP 234 DI 10.1016/j.amepre.2008.10.012 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 409XE UT WOS:000263538300006 PM 19215848 ER PT J AU Chutuape, K Willard, N Kapogiannis, BG Ellen, JM AF Chutuape, Kate Willard, Nancy Kapogiannis, Bill G. Ellen, Jonathan M. TI CREATIVE AND TAILORED STRATEGIES NEEDED TO FOSTER RESEARCHER-COMMUNITY PARTNERSHIPS SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Letter C1 [Chutuape, Kate] Johns Hopkins Sch Med, Dept Pediat, Div Gen Pediat & Adolescent Med Johns, Baltimore, MD 21224 USA. [Kapogiannis, Bill G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Adolescent Med Trials Network HIV AIDS Intervent, NIH, Bethesda, MD USA. RP Ellen, JM (reprint author), Johns Hopkins Sch Med, Dept Pediat, Div Gen Pediat & Adolescent Med Johns, Ctr Tower,5200 Eastern Ave,Ste 4200, Baltimore, MD 21224 USA. EM jellen@jhmi.edu FU NICHD NIH HHS [U01 HD040533] NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2009 VL 99 IS 3 BP 390 EP 390 DI 10.2105/AJPH.2008.151993 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 413QU UT WOS:000263808400001 PM 19106415 ER EF